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DRUG-DRUG INTERACTION STUDIES OF 

CEFPIROME 

rHLS]S PRESENfED FOR UIL DECRET' 

OF 

DOCTOR OF PHILOSOPHY 

BY 

MUHAMMAD NAWAZ 

M.Sc. 

DEPARTMENT OF CTIEMISTRY 

FACL'I-TY OF SCIENCE 

UNIVERSITY OF KARACHI 

DECEMBER 2OO8

Del.rir..i otcl.oia.y 

Unbtrdly of rO*U 

To wbod lt Mry Comenr 

tr ir 6dfi.d thn $j! ttdir dd.d "Dntgtrug blddio! Sidi.s of C!&itttr", 

$bin d b BSA& Uni6ity of Kndi br M'rtimd N'wz frffh .[ lt 

llquiro.olrfo.l!.tMrdof|t.daE ofDodor.b of Ptilo.opty Ga-D) h ddidr. 

&"^"eZ 

PDfclror Dr M. Srad Aey!.

D.psrhet ofch€minry 

Uni!6ity of Kechi 

TlEchlimd Dii.: 18{2-2010 

Board ofAdvdced Sludi€s ard R.eeh 

Un'sBity of K,trhi 

Thrcugh: Des, F&ulty of Sd€re 

Subjecl: CorectioN / R.plusing sugg€st d by Ext r l Exmiftr 

Sir, 

wnn rcf@.c lo lhc lerd of BASR d.t d 17-02-2010 (Fil. BASR/965/SG.) &earding th€ 

!i!d voe report of Mr. Mulammad NasE". . 6didl(e for Ph.D in ch@ilrry. TlE 

Add.ldrF ha ben pep@d aDd past d in l[. cnd ofdh th6is. 

h is lhftfoe rqusl.d thal Ph.D d.ge nuy bG sword.d ro rh. andida&. 

//'./ 

'24-{ $a1t18 $nAJUDll{ tlllll 

*"mm;*tu1fl|j:ifts" 

l) BASR l.ucr tued l?-02-2010 

2) PlDroopyof vi€ loe dmirEton Eporr ot Mut 6mdNawe 

4q a..z- r-+_/4 a 

o9.o 

* r:,_,/ 

r4::l 

4/",-,"..4 ",- 

,'"fp'

fhe wt thjf;tlb.d tt tl$ dts.rt aloh w dmld ott 

b|* td.r.t qqntb{M.&w D,. M b.d 

l,o,'c &sdt Wrtpr, d .b D*1d'! 4 

CWer 6d Pr&s Dr' Mu stdbt (Co' 

&q.rne) &F4't,.r 9f t@ ch.'it''r' 

l'.',t'rtt tltd, n},'. otu\rb. tt&ttc,t l,sDl 

tu Fdfu ad.s&cvtls. ere

5.No. 

B 

c 

D 

E 

Annbs.tcrid s!6nw of ..livity 

Sllbilnt 

Doege and adnini3tnliot 

alliot n.h Conv.dlt Eltt* I.[iUa.E 

Enalapnl 

C.LilD cb.m.l Bl4k B 

Esori.l md Tnc E|ir.rlt 

2 

6 

9 

t0 

ll 

tl 

l5 

l5 

t6 

t7 

t7 

t1 

l1 

l8 

l8 

t9 

20 

2l 

2l 

2l 

t 22 

23 

21 

24 

25 

25 

26 

26 

27 

28 

23 

29

G H r....plo r anr.gor ists 

tr Hrre.ptor A!l.gori!t3 

I llypogfenic &.d. 

J Non-St rciil.l A.tiirtdnhoty Dru3t (NSAlDt 

Diclofenac s.diun 

K Pmton -Pumpltrhibito6 

L Sr'rimnIMC-CoA lt dr.rae lrhibitod 

M Obj€crivd of Pr6ert Work 

C Equitmcnt Md glasw4€ 

I Aseyofccfpiom€ 

ll crlibErion curycs oa inl€tuling dru8s 

I /" itrd .vailabilii4 ofcehiFm€ dd inl@ding .rrugF 

lv Im.@tior 3|!di6 of efpi@ with inkdting druC) 

lv,t IntcEctions b) Uv/vis specrophotomdry 

rVB Dcvclopmc o|IIPLC m€lhods tbt cefpnonc and intcdctingdruss 

v CefDirond drus iner4clion sludies by rcv.6c phas hiSrl 

pclromdncc liquid cbrcmarosrapny (RP_HPLC) 

Vl Syn$esis ofcefphoo. fld inletuting drugs 

vII stc.Lmlsludicsolconrplexcs 

iii PdonNMR srldi.s 

ll 

J2 

l3 

33 

tl 

34 

l4 

It 

t5 

l1 

!7 

t7 

J7 

t8 

l9 

40 

42 

43 

45 

43 

55 

55 

55 

55

vtll Anribet.rialsrudiB 

R6ule..d Dir.!6ior 

,, vrru inl.nciion.l!di6 of saDiren. wilh inl.Ecrirydn$ hy 

Uv/risibl. tp.clrot opy &d rcr.B.d r,h.!. htgl perfom.trce liqlid 

I 

I 

2 

l 

5 

B 

'7 

t2 

l1 

l5 

t7 

D 

lnleruclior ltIudl6 by Uv/vhiblc Spetropbotom€lrv 

CalibEtio. curvca of reference st ndnds of drues 

Non-$midal anGinUmnarorr- druss (NSAIDS) 

tr rilfu srril.bllitics ol..fpitu6., ACE-irhlDiloB' C.{bannd blocko6' 

H.re.pror rnt.Sonists, NSAIDT ind preton puDP irbiltilot 

x_on srcmidll li-inl malory drues (NSAlDt 

sibu|r.ndlr d.t ]Eiortior or .dDircd. ttd ilt.ndirs dtug3 

Inlenclion of c.fpiome *i$ ACE_ innibilo6 

Inleacrion of efpiome wilh Ca{hmnel bloclcs 

Intemction olcfpione wilh Hr-@eplor a agonisls 

lntenction of o.ipilone wnn NSAIDS 

I'rqrdu'un ul {elpitumc {'th proron-pmp inhibnor 

(in(ric a.ldis ofcefpimn..nd in..r.cting druB! bv UVAii 

l8 Ccfpionc e ith C[_ innibilo6 

19 Cefpircm. eith Caahml blGk€b 

20 Cehimme sirh Hr@cplor mtagonisE 

2l Cefpirone {ilh NSAIDS 

22 Ccfpnome silh ptolon punp inlibnor 

Il C.6ironc DruI Int.r.criotr Sludies by R.vcned Phtse gigh 

Pditrmtnc! Liquid chmmltosmphv (Rl'UPl'c) 

A D.v.lopDent rd vdldtrior oltNlvrlc.l n.(hods f'r sindtrn'o!! 

d.t.rnin.lion ol..folmn.tnh i edc.irgdruas 

Oprimizalion of the chionalosnphic @ndil$!s 

24 c.&innc wilh AcE-i.nibnob 

15 C€himmc$ilh Ca{h!.nel bldk€6 

26 Cetiribmcqnh H -rcep{ot alagoni$s 

27 Cerbiomc wilh I lrEeploi fflasonists 

55 

53 

58 

59 

59 

59 

6{) 

'12 

72 

12 

12 

1i 

7l 

73 

33 

90 

91 

128 

129 

t29 

ll0 

130 

1I 

134 

B6 

ll9 

I4l 

l4l

Ceipirome sith hypoglycenic agen6 

Celpirome wi$ non-st roidal dti-in0dnatory dtuCs 

C.fpircme {ilh pbion-pMp irhibiloB 

Dog htenction tlodb of.dpircDe 

Inte6crion of efpione widi AcElnhibitoB 

svnthcsi\.l cefDimnc $ilh ACE inhibiloB 

linergy mininiztion sludics 

I daorion oi ceftironc *ith dtioxideN 

Inrc@rion of cefpirom. with Ca chmcl bl@ke6 

Synthesis otcelpnonc with Ca{h.ml bl@k.6 

Enc4y minidiarion sludi* 

Int@crion ofccfDibne $ilh e*nlial and ldcc clcm.nls 

lntcaclion of cefpitone wirh H' _eeplor .nt,rgontsls 

Sy.rbcsn ofcclpionc wilh llr recepLor dtlgonisrs 

lrnerel nlnimizion srudies 

Int;;rion of ccfDiom. wirh Hr@eplor anrdgonisrs 

Synlh€sis ofcefpnomc with H.repbr dlagonhrs 

Endgy minimiarion studies 

l.r.Eclion of cefpnonc with htlo8lycmic A8c.ls 

SFrhds of cehibmc wilh htloglymic 4.nts 

LneEv n,n,mianion 3ludi6 

lde;rion olelpimmc wth non-nmidtl dri_'nllmmabry drugs 

Syrlhcsh olc€lpiNme wnh (NSAlDt 

Enersy rinimiztion studies 

lnreietion of cebnome with Pmbn'pMp inhjbilors 

Synrhesis ofcefpitoE. th pmlon-pdp inhibiloB 

Lncray dioimiztion srudRs 

tncmclion ofetpionc wirh $arins 

Sy.ih6is ofeapircne wirh shlins 

F:nerey minimiTrrion sludi* 

148 

l5l 

155 

157 

I5? 

151 

169 

l?0 

l7t 

t?8 

180 

t80 

18r 

189 

189 

190 

198 

r98 

201 

201 

209 

213 

218 

2t9 

t4 

225 

226 

231 

234 

215

Dil 

Gti 

Flu 

Sin 

RSD 

LOD 

LOQ 

RP-HPIC 

FI.IR 

NMR 

Lilr of Abbab{6 

Rclaliv. St ndtrd ddi.ricr 

LiDil ofQwdncdion 

Ultr.vioLt vkibL sP.ctrsrcopY 

Rcvdd Pbe High P.rfortuc. Uquid CthrotogFphv 

Fwid Thrrfd Inftutd SFlDscoPY 

Nsld M.gMt R.$nds SF.losPY

Ackno*l.dg.mentr 

I e.meslly thanks lo All.h Almighry. $e Supren. Althorily. th€ Mosl Benclol.nt and the 

Mos Merciful. who Sifred m€ vith prudence..onsoncy a.d coume€ ro ehiclc this 8@l 

Induhnably- | havc no er& io dpEs ny lElitudc 

for mv sup.F'i$i Pmlcsr Dr M 

Sae.d A6y.e for giving nc de oppoduity b wk udd hn qceprioMl suFfrision. His 

valuble ides, keen i eesi, conlinuous suppon 4d n.vcr failing eninusish thougho fiis 

rcsca(h work afililakd tuc to aeonplish the tlrscl Without his excellcnt guidecc fiis 

wolk sould havc bcen uch nore onplicatd. 

| *kh ro €xpcs ny rinc.d g'a nude b Poleser Dr' Najna Sulba whos. our$andins 

suidme worth ehil. susg*tio6 and ontinuos trppon made rnis efon pcsible l am 'l$ 

sinccEly ind€bred io Pofcsor Dr. BNbE Kn$ for gdding ald helPins ne in $is wotk 

I also €speciallt applccialilc of nry &iends Saima Sher Aahadur, Faia Queshi ahd Ann 

I laider lbr lh.t suppon and Gsislmce in dy sork 

I d cordially snr.ful lo all ny ftiends and @ll.ag@s (Agha Zeshm Mna. M llshih 

Zuh.n. Fehd Ahned Siddiqui, Hie ShchDa Utuj Hl,mr, Bcln snd S@da Nadir) 

Thcy Fill be Enemb€r.d for all lh€ hatpv moD.iL. good hens rrickv debales dd sinc€E 

I havc no words lo exprcss m, galitude lo nv t4e 

s. brctheB 4d sislcN (siblingtr rheir 

consrdt prayeB dd never ending suPpon helped me thoush alld€ diificult dmes dutihS the 

course. rhcn encouragemcnl wd like oxvg€n for n. in lhc tihes ofdester'lion 

FiDllt. bundle ot fi4k G due lo nt fmee Adba Andleb. {ho mc in mv lile &d 

Eninded ne $ar rh.rc aG oihq imFn dinss in $i3 sorld b6idd $icnce'

Abrtnct 

Cefpircn. is a aoDnh emerarion cephalosponn wilh broad sp*ltum of activnt aB.ins 

cm-posnivc ad Gm-ncedive hd.l€ria. ln $e pr*m mrl, inktulion studics ol 

cefpimne pnh ACE inlibitoB (captopdl, enahPiil ald lhinopdl), dtioxiddls (vitanins 

a. C. F, and sodim m€tldisulfite), hydded sdltl of.smtisl and rrce elehcnts 

(nasn*ium, calcim, cbronim, mesde*. fenic, cob.lt njct l, copp€t, nhc sd 

cadninm), Ca{hmcl blclcB (diltiffi, vdp6nil md mlodipin€), Hr Keptor 

mragonisls (cednzine. lcrcc.dn2iie &d fdofcn diE), Hrdepto' dtagoni$s 

(cinetidin., uiridi.e md fdotidine), hypoglyc.nic ag€n1s (gliquidone, netfomin &d 

pioshdzonc), non{leroidal ed-inflamtory dtu$ (NSAID' (dhlofemc sodilm, 

nurbipioa.n, mefwic &id ald meloxi6), prolon pump innibnors (omep@ol. and 

lmop@le) rnd shtins (don6Llin, simvsltlin .nd pE6talin) scrc cdied our in 

simulalcd g6rnc jlice (pH I ), bufes of pH 4, 7.4 dd 9 at l7 md 60"C usi.g (Jv/visiblc 

sponophotomerry dd ev.scd Phse hid petfodMce liquid €hbn.ro$aphy (RP_ 

HPLC]. 

B€foG in.nction strdi€s, .sy nedods of efpimne and in.@tin8 dNss *.r 

develoFd on Uv/visible rFclophotom€l€r and RP.HPLC, which P.6 optimizd dd tncn 

applied lo inle@tions. Ill csults ofinl€tacliohs showed thar availabilily oferpirome was 

incieased in mosr cases. However. efpnome availabilily deccascd in pi€scncc of 

{lioxid&b &d .Lmenrs csndal lo hu!fu body. 

In odd ro llnd on d. .at'ft ot binding b€t*6n elbibme ad int@tiry druss. kinctic 

sudi€s w.re cmied out a1l7 sd 60'C in sU inc@ling medims. In ordo lo suppon thc* 

,i nd in8s, cc fpirome con plexcs wcrc ay.lhesi zed wnh all interm tin g d rugs Md chaacteri4d 

by uv-vis, FTIR dd |H-NMR. 

R€$lls of rh.* studis Bcd.d lhc fomalion ol chege F&sGr @bplexs of ef bm 

rilh ifle@ring drDgi. En rgy dininianion $!di6 weE als dicd our lo del€mine $. 

bindin8 snc olcetpione dd inlenclingdrugs. 

ArribscEial &rivity ofcefpnone dd ce&iomc.dtug complex€s wG aho ceied out .nd 

evalu|.d a$insr C'm-posniv. (e,prrrad.6 M6, cttnbttui@ tol@,ii 

stuptl}.@s laecdis tu tuils :.€c6) ed Cm-mgd,tv€ orgeisns ailPht'//o 

preumani&. Kllbtietl. s?ecies shige a .lysaktr, s.herichio coli, P$udotlu8 oet ainos

Proteu nnzblb, Citub@ sp.cis ad SalMrello Whl. Cfrnne show.d etib.ct ri.l 

erivity asdinst all dr.s orgrnjsms. Anrib{.r.rial ..dvily of ceftiM.ing conpl.x6 

*@ al$ .v.l!.t.n .!d oulp&.d Mrb p@nt dirg, Ccfpire@drug @mda6 lhoe.d rc 

antibacknal e$vny og.iisr tlw orsoims.

E' z'- + d, 1 i.+ s' J vt 1,21. fp l,,r 4 7 /!a 1 c* pn rospo'in/,iac"rpi'ome 

y't'4 /vc?t)/i,". t'si"apll ,r captopr I, enalspil 4 AcE inhlbito6 J cehiromeec 

, t \ \p;. 2o. f 2. 

f" I { ) z,t,F 6 -P QI /',,. v E,',J,,,.. r.liL J, J \t t /,g \t - | 

.amlodjpine ,l diltiazem. veEpamil 4 ca-channel 6tocke3, ((.!r'rJra6o 

H2-reeplor. fexofenadine ,r citirizine, l€vooilirizine 4 Hr{6ceptor antagonisls 

gliquidone 4 hyPogly@mic agenb namotidi.e , cimetidine ranllrdine4 anlagonlsls 

dicloienac. 4 non-steroidal anliinnammatory {NSAlOs). pioglitazone/r metio.mh 

,i ohepra2ole 4,poton punp inhibno6 .m6loxicam /r nulbipoien, mefanamic acid 

.4 pA it L-p)$,(ptara.r.tin ,r atoryastatin, simvastalin 4 stalins ,r lansoprazole 

e;!,1,6'atfi $h uh*,,f.,,,,Jgate L,r\a,y'+-"ao.t 37,l r,;-/Ls,t 7 a 

rJg-!J4|i\1)LJn &v'!-t'itr"' cô',. e1 -a,toi,!-fcv\rv't- 

-{t/" Jp | 4 - FZ.t oennizîo.'! i - U'Vr.,J'c ! dt t J 6,i 4,1, 

") 

[c,! n,,9 v'1,'r n,c I ip r,v v & 4i t ]Jh'4'! cetpi, ona Ju 1", - Lc L - tv 

5/-j;,t ''\ov-,L -!,,' t)r/.'t cEtpir,rc -{JlJ'Lh t "!)c,!'z 4 -v"it+ dJt 

cetei@ne 4L./-.b t4+, 'vff,r-,{-,!,1 ,t,';-iot,'r*- '+,ao"'zt 'ut'- ,9{ 

"tut. Jg*Lnrtt .JgAft,t, ;u. tct,|!'!-it-t,!-t. r+ivL-!"'itrit, I 

; vLe!,| I F (ctt Lcehircne JLiz:t I'vc I et'tc.f tic)t -W +' / J4 r,fN' 

- e,J")/,.F.,! tu z',,!-v,'i r4,' c*orore i/ A,* L,.t i'! iviur!-'-c-t t7,4 " "', 

(staphytococc u s ri(t/.tv,t'ir t,! -'//,ts L -t,' iF'L,t""c'tp"oê 

't 

a Baoilus sp€c,6s tj au.ls,Corynebacldiun hohns.i Sheplocotus tadcalts 

lKl.bsietta pnernoniaa, KeOsiels sp€cies, Shigetta .tvs.nte'v t /'l 'l 

schetichie @1, Pseudon@as aetuginB, tuoteus nnabilb ct?obacliat sp€c6s 

'{ql JtL')' i1 (satn@ett a Whi

cetenone -try- fu $ r] t tt b, tJ',t' )i r ( J, tLb t tt -\, L ett "t i FZ c!,c'hne 

La,.iz ot L-t t/L-t tI /Lcaorone 4 JAJ'/#vLe| iz,L s' trt'/"'.+tfi- 

-J!t+lJ,trJ/-a

Litr ol Ptrbliotioa 

A6yoc M.S.. Sulana N. dd N8u M. (2006) A RP_HPLC m.lhod for the 6sav 

efpircnc md its applietio. in dru8-n kl im@ction studies PalGbn .,ouml 

Phmaceutical Scierc€s, 19(l) 3944. 

Sult .a N., Amyne M.S,. lni*nd B. &d N.rs M. (2008) a ne* RP_HPLC mcthod 

for fronitoring ol at€nolo| Application lo al.nolol helal ihttaclion sudies Joum.l ol 

Cncmiel Sciery ofPati!|..n.30( | ) | Il-l18. 

Amyne M.S.. Suliaft N. dd N.re M. (2008) Simultmcons quantiElion of cefpircme 

wirh ld@ririziG or 4liri2ire in ph'l111:@rical fomulatim d|r| hms plas bv 

RPIIPLC. Journat of melyticrl ch€mislrv, 63(09) 881_887 

Sulha N.. Arlyne M.S,. M. N.i! and Kid A.A. (2008) D'velopmdt !d validarion 

of a liquid chronatosmPhy neihod tor thc delemimtion ol cloPidog€l tion 

pbmaceunel doege fom. Indim Jound of Cn€mical Seicrt (!aepLd)' 

Abrtirct! Publhh.d.nd Pc.nled i! Irt mortoml.nd N.riond Cotrf€rtn'e 

A6yrc M.S , Sulwu N , Abid I ed Nrs- M. (2005) Simulhds det'miMlion of 

cefpion dd cclirizin in pham@ulictl aomulatiols dd huha' s'rum bv RP_ 

HPI.C. tsi Krshmn l.tcrMliontl S.i€nce Conlcr'nc'. Aad Kdhmn Univesilv Azd 

K6hdn. Palnran. S.Pl. 20_21, Plo. 

AByne M S.. Sulla@ N., N.eu M and Abitl t (2005) SinDlhos d'temimdon of 

cefpnone dd lev@ririzine in ph.ma@ti*l fomulatiom dd hUlM elu bv RP- 

HPLC los Inr.miosl svmposin on N dal Pod@t chcmnFv H E J Res4h 

In$nute of Chcnisty, K@hi. Pati$an .le. G9, p242 

Nr*.z M., Ar.yn€ M.S.. Suli.tu N md Abid I (2006) A Epid 6av melhod fot the 

sihuldoc tnalysis of efaalin &d Mrbic acid bv RP-HPLC 61h Imemadond & 

l6'i Nalionalchcnhiry conler.ice Qulitv of life atd Chehical scienccs Depandcnt 

of Chenisrry. Balsud{lin Z.l{miva Univditv. Mulbn Patish April 0G0S p 99 

Inikhd 8.. Sul€m N.. Aravne MS ed N$u M (2006) High performancc liquld 

chrcmabg6phic nerho

l0 

N.vs M,. AEyne M.S.. lrd Sdtana N. (2006) Multivdial. chmmlogaphic 

calibEtion for the qwlilaliv. d.tcmination of celpiome 4d ncfe.amic scid hl 

lnrcmatbnol Chemh$y ConfeBncc CC UniveAily. FaGalabdd, Pakis(an GC 

Unive6ity, Faelabd, P.kitu. Nov.l- 3. pl6. 

lflikle 8.. Sul|aM N., Arayne M. S. ed N.wtz M. (2007) Liquid chomatographic 

m.thod for the simll1aMu dctmim on of ar€rclol, muivanarin, spioletore. 

llib.ncl.nide and nlpoxen $dium in bulk dru8, phamacedcal lodllalions ffd 

hudM plsn.. 7th Inlemaional & l?u Naiionat Chcnhq Conf€Ence Exceuence 

Thmu$ INEtim". Dcp..m61of Ch.hist y, Conlt Uriv6nv' DeB kmail Kln. 

NWFP, Poli$an. Feb.26-28, p7l, 

NNz M.. A6yre M.S. dd Sultam N. (200?) High Frfom&@ chmnalog€lhic 

deremimdon of oulliple cephalosponns dd NSAIDt in Pbam@utiul fomularions 

and hms plsnai applic5rion lo dru8 inl.i4lion studies T$ lnhstioml & lTrh 

Naiioml Chmistry Conlde"Exell.le Through l@vatioi Depanmcni ol 

Chemtury, Conal Univqsity, Dcd knail Khd, NWFP' Pakisbn F€b 26-28, pl37_ 

lt3. 

Sulbna N., Ara)ie M S , Moom M K ed N.wd M (2007) Dev'lopm€nl of a liquid 

chromatogEphic-Uv nethod ior monilori.S leflmonidc in bulk dru8. tebl'G and In 

*@. 7th lntmtiontl & l?n Nroon l Ch.mistrv Conl€tnce Exeuerc ThtouSn 

tnnovadon" D€padmeni of chemislry, Gonal uni!€6ny, Dera lsfr6i1 (nd' NWIP 

Patisk . ttb. 26-28, Pl6l. 

N$u M., Ady.e M S.. Sullan. N dd Ann H' eOOT) Dehination ol leolimus 

fom bulk dng dd dosse fom bv Gvere phde hiSI perfoMc' liquid 

chmnalogaphy.I .mtioml Chcmisrv Confetue. DePanndt olch€nisq rinoE 

College for women Univ.sity, Lahorc, Pakhtan Nov. 2_3 p12 

Sul@ N,. Amyne M S &td N$u M. (200?) RP-HPLC mcthod for |he sinurrDdts 

debminalion of cefpiome wilh HMG CoA reducllsc inhibnotr fton bulk dru8s $d 

doege foms. I.t€matio.al Chemistrv Conference. Depanment ol Chenistrv Lanor€ 

College for wond Udv6nv. bnoe, Paldn& Nov' 2-3 p37' 

Sulha N,, Aayn. M.S, Kirs AA dd Ntr- M (2007) Sinull&eous 

dcl€mi@tio. of clopidoeEl atd dpinn b, RP-HPLC lom bulk naterial dd doeae

l) 

l3 

l5 

l1 

fomulations usine dultivdiate calibradon lechnique. I cmationdl Ch.misliy 

Co.fe€ie. D.partn nl of Chchisrry, hhoE Cotlcge for Wons Univc6itv, 

Lahorc. Pakistan. Nov 2-3. p46. 

SulroE N. Aray.e M.S. rnd Nrwt M. (200?) Inltudon studi.s of @rpione with 

AcE-inhibib6 dd ca{hmel bloctG by RP_HPLC Ts Annu.l cof,leEn€e of 

Sociely of Ph@oviSilmce, Jaipu,lndia. Nov23'25 Conference. India (Jomal of 

Pham@vigilue and Drus sfcty, vol. 5, p?l )- 

N.wu M., Arayn€ M.S,, Sullana N. ed A Haider (2007) Liquid chtonalogaphh 

ey aor simul|,.@Edelmimlionof n6idic acid dd srdoidr abm bulk dogs md 

huhm plasna, ?6 Ahnual Cont rence of Sociely of Phamacovigilance. Jtipur. lndia 

Nov,23-25 Confe@ce, lndia (Jouhrl oa Ph@acovigilN. and Drug efetv. vol5' 

P76) 

N.w.z M.' Amyn€ M.S fld Sull4a N (2008) LC method for simulkn€ou 

d.reminalion of H.e.ptor dbgo.ists with C.hiom. tun bulk dro8 &d doest 

lbrms 181h Narional Chenhlly Conference Chemi$rv for lh€ Developmcnl of lleallh' 

lndsrry& Envibme l$tioL of ch.mistrv Univ€uitv o' the Pujtb tjlErc' 

Pakn|a!. Fcb. 25-27. P l6? 

Aarm M.S.. Sult d N md N.rt M. (2008) ln€t!'rion dd bnelics nudies of 

cclpibn€ vi$ non.st roidal ecinndmbrv drugs lsri Nariod Cnenntry 

CorfeEnce Chenistry for $e D.veloPdcnl of H€al$, lndustry & [nvimnmenl 

lniturc ofCh.misEy, Univ6ilv oflhe Pujlb, Lalorc' P'litu F'h25-21'p167 

N.ru M, AEyre Ms, Sultam N. ed Amn H (2008) svith'sis dd 

Ch@cbianion of Am4bdift-Melal conpl.xs bv CHNS Analvsis ln'del aid 

,\Lonic absotprion Sperbscopt, 19 Ch.mistrv Confeence Quihis Cuba Dae l5_ 

N.ru M., Aray.e M.S md Sultana N. (200s) simulancous detemirario' of 

ccbion€ *ith proton'p@P inhibilois bt rcreM Phde nigh p€rIodsce Iiquid 

choMogdphy. llm l.kmatioml SFlosiun on N'tuBl Pmd@r Chdisr^' 

Kaachi. Palislan. Oct 29-No! 01, p140

INTRODUCTION

( .phtlos@riun oc4noniun, tlE 6Bl slre ol $e ephrlospon.s, w6 ielaled i. | 918 by 

oiu*pp€ Brolzu (1.21, an Imlili scienli$ fion $e fa ned lhe s€weroutlel offlhe sardinia 

co6r. Crudc fillanc lon culues offtis fmgus *!rc found ro i.hibn lhe - rtro grcs1h oa 

StaphlococcB aurers ^ d ra .ur€ Si4,rlrlococ.a/ inleqions &d typhoid lcver in hunan 

b€i.ss [2]. subscq@nt w* by Abdlm F, al al oxfod resultcd in thc i$lrtio! md 

chanderiation ofrh. active drug, in paniculd c.phalGporin c. Confidn tion ofitl 31ruc1@ 

sas lal€r obtained by X 6y cry$rlloeBphr [5]. 'DE cephalosporin C attr4ld $e aficnioh 

ol$e *ienlhts mainly b€cause ofns sibility lo penicillin*s. Th. Oxfod work€r prcdmed 

al led sir mlibiolics fton $is f@gus. out ofuhcih filc were stceidal (ePhalosporins Pr 

P, dd etir. asaid G@.positivc bekna orly [6, 71, lhe mainins aner exracrion of 

cephalosporins P foction lcve.l€d the pr€s.@ ol cePhalosporin N *hich sd a nalor 

h)drophilic conponent, only onrhundedrh s rctive agaiNi Cam-posnive o4disrs $ 

pcnicillin C. bf 2-6 rimcs acrive against Gram-ncgadve otgetms [8. 9]. h is probably $e 

subst2ncc respoNible aor broad-sperM etirny of lhc dlbiolic pEpmrion orisinau) 

d6clibed by Brotzu lr0, l1l. Cephalospo n N wb suseprible to desradadon by 

penicilliM dd @ foud ro bc Mmino-44rhoxybulyl penicilli[ id.niic,l lo 

Sym€matin B. which had bec. descdbed edliei, ir hc ban renemed peni.illin N. In $e 

process of sludyins ion €xchrs€ .hDndosrapht of tne prodEl ftom the did desBd.tion ol 

pcnicillin N, AbdnM md N€Mon 13. l2l disvdd ccphalosporin C a scond hydrophilic 

dibiotic thar had smiled the degndado. which s6 appareh y presnl onl, in ninu€ 

mob6 in tbe oriSinal femmbrio. mixnc. Wilh th. i$lalion ot rnc .critc nmles of 

cephalosporin C. ?-minocephalosporeic acid (7-ACA), dd wnn the addilion of side chains, 

n b€.m€ pcsible ro produ€ emisyntndic conpouds wilh dtibacrerial divny vcry nEh 

lrcarei than rhat oflhe pmnt substance L2l 

'rhe nost sidely ued sysren of clssilication of @phalospodns (lable I ) is by e{dalion sd 

h basd on rh€ seneal f€atNs of rheir udb&cnal adilny [r]241. Prcently 

ccphalosporins lntibiotics ar cldsilied as fist. second. thnd od founh generation. In 

gdcnl, poeresion lron fid b aounb gqemio. is asdiacd wirh 6 bruadeninB ol lhe

Glm-negdive mtib.claim slellu, en. r.d@don in .cdvi9 against Om-positive 

org.nisms and enn&ced resisl:.c€ ro p-lad2me' Individ@lly ccphalosporins ditrer in $en 

phamacokinericsFropenies, espeiallyplan. prclein bindinga.d balf-life, bur the sirucrudl 

bes lbt th.r difcenc€s m not obvioE U4,251. 

T.bl.l 

ct4titdiM o,.t popertk! oldp@Npotins 

C€ph,lo\p.rio (ncraron Pla$. tslachm.s Sp€chn 

porcin bindin3EGqncc of sdiviry 

lt5 

lt-22 

ll-50 

25 

10"51 

fhe systcmic chemical nodencl ure ofde ccphalosporin is slightly more conplex lhan 

p€nicillins- due lo lhe presnce of a double bond in the dihydothiuin€ rins &d b6a$ of 

wiarion in 6e suhtilucnl al I-posnion. The fBd ring sysr.m is dBignat d by cheni.al 

abstmcls I 5rbia-l-uabicyclo{42.0locr-2-ene, Accodingly, the saluated bicyclic ling 

system wi$ dc lactam dbonyl oxySd is 'm.d 6 aphd; hetue all €o'De(illly 

.vailabh c.phrrospori.s d€ 'med 6 l€phams io d.signal. rh. Fsirsio. of ih. double 

IO

ond Althousl sne c.phalosponns bave ben nd€d d dedlati!.s of ephdGpo@ic 

acids. rhis pmctie applies ohly ro dre derivalivB that hav. a l-mloxynethtl goup 1261. 

l h. w@d$€id\ J2?, 2El syn$6is ofcephal6F.ins C (fisre l) provi.Ls a cl6ic exmple 

ol naru.al pddrt stnlhesir, Pol*tior of $e nnogd- sllftr md c&boxylic did eoup 

( r ) ctsGi.e (l) pmlid.d rhc ctr|n iirm€dial. (lD. Iruodndion of lh. hydruin€ gbup to 

gile (lll) was iollowed by oxidation md convesion lo 1he ties.hydrexy ester (lv). 

|omario. ofrhe mesylat€. ihv€rsion ofrhc stc@h€mistry by displacede wnh dide dd 

rcducrion pmvided fte cn-mino ees (V), which gave the key p-ldclm inlem€diale (vl) oo 

.ycli,arion. rnc srereeh.mislry b.ing onfimed by X-my cryasLllosrathy. 

Ihis l.ch re{red wirh lnc dialdehyde (vll) in a Mich&l liLe nener ro }ield (vlU). 

TEatinent with rriflouodric acid remov.d with nitlosfl and sultur proEcring e@nps md 

result€d ih cycliztion lo lhe ceptalospori! prcwsr (lX), in which the mino sblp M then 

Nylated wnh the appNpriately protecred D-d.minoadipic acid sid€ chaih fornin8 (X) 

Rcdurion- rettbdon and equilibalion povidcd $€ ceph.losponn c est r (xl)- from shich 

tlE prorcclina srcups vcE r€nove

v". 

h)- 

FlSurc I 

t2

C.phalosponns (fielc I l) de cha.aoerized by abicyclic nns systn. in whichlhe F ladan 

is fusd ro a six-denb.€d ling beding al posiion I a sultu atom; oxacephalosDori.s (tigue 

Lla). D oxysen aton; and .abacephalosDorins (ligure l.lb), a cdbon alom [32]. nE ae 

th. *cond najor srcup of ilactan {tibiolics. di{f.r frcm Fnicillins bt having lh€ a4lidone 

rinS ln*d b a dih)ddhizine nns ralher thatr a thi@lidinc. Th€ oth.r difeEnce is tnc 

ciistcnce ol a amctio.al group at positio. I of thc ausd ring sy$en. which .llo*s nolecular 

vdriado.s to be inlroduc.d at the 7-NH1goup, as ih Fnicillis.4 

well a3 !o efect cheSes ih 

pmFrli€s by di!€sifying thc noiedes al position 3. As 6-APA be@c th. p@mot for lhe 

s)nftcsis of all rhc sdisldhetic FnicilliN. so dcs the coftsponding 7- 

aninftephalosporeic acid (?-ACA) (figurc Llc) *fles fic sllogous tunclion lo. 

.ephalospori$ t3ll. Cephalosporin C (figK Lld) @nuitr a side chain denr€d frcn D_d_ 

eminoadiDic eid, wbich is conddsd with a dihydothiaine plerm dn8 syslen (7. 

aninocephalospordic acid). Compomds co ainins 7 minocephalospormic acids ae 

clalivelt sbbl. ih dilutc eid sd hidly rcsislrnl to penicilli@. r.Sddlcss of the mtue of 

rtunsid€ chains dd $eiramnirf ftr thc flync. 

" ra'\--') 

' ,) r-r>tr 

"'.r-r-') 

.---l-"^' 

ll 

"-y-/Y>Q_- 

f

Ceph,losporin C cu b. hydolrz.d by &id !o ?-@incephalospotuic eid, which 

subs€qufldy h6 b.d modifi€d by th€ addition of diftE side chric to cste a whol€ 

Lnil]., ofccphrlosponn edbiorics. It app.s 0w nodificdioN ar posnion 7 ofl|)e Pleram 

rine de asociared wnh ahmation in mdbercn.l {tivity dd subsftlions al Fsnion 3 of 

rhe dihydrorhirinc rin-s d€ 6si5t€d wnh €hanses in the ne|abolism 6d rh€ 

phdmacokinetiupropcniesofthedrugs[2].li c.phalospodns. Cl dd C7 posnions de 

available lor chemical mdipulalion. V&iely of anin€ &ylatioo oelhods have be€n usd for 

the production of C7-acylanino derivalives by lhe us of rcyl chloridcs, mix.d ohydndes. 

rctn e eie6. dd carbodiinides [34] 

lo i'npo\c rchcnricalrcac n) of7' C,1. r'*nubililt in orsaDir $lturs rs incresd 

b) convesior of $e carb.rylic &id al C4 ol 7-ACA inlo an esrer such ds lcn-bulll 

dimelh)lsilyl. benzhydrtl, p'nnrobdzyl, or p-n.thoxtbenzyl. However,.sler derivatives of 

7-,4CA bcconr rcry sensirilc ro b6ic cobditions and lhe d' double bond isoncri?.s to thc 

uD*!DrcJ \ nnrnuf 3al Reacrn,ns,r (r:l nrainly iivolve displaccmcnr o1 3:0ccl.rc. to rire 

subnnutur sirh hdcrorroms. especially sulfu! !M nirogen [36]. r'herN ciinindion 

rbrlosrd bt cdrltric h!.lr.8cmtion []?1. or eid{aralyzcd Ederion bt uscofrrialktlsilees 

I{ds b I 'ndh) | ccphilosporins [r5l /b allediri!. o $e displaament of thc iracero\r_ aor 

rhe s)ndcsis of l:he'eroarom ceph.losporinr is thouh functionzation of a l-m€thr_l 

den\dti\. ol ! cotlhalosnorirs sulbxidc b) dlltli( bn nination 1o lhc l.hbnhnrcrhrl 

co'nl.und srilahlo lnr Jisflaccmenr Edcriois 1381, wl'idr co be coiv.rlcd nlo cnrhnnoJl 

conrFlrds $rch N c.iumxnne (fi8urc I le) (xhcr inrpoi4t inrcncdiats d. l- 

cxone$llcnc dciv.ives $a! by o?,nolysh of $e cxeyclic dolblc bond. povide a 

hdenaron anach.{ dnectl:i ar C3 6 in .efrclor ( fisure I | 0 [391. 

In addnion to a hoad sp€ctM of dtibacterial &tion, rso addilional pop.nics.dely, a 

FtenI md rapid acrion agoinst ba.rena in th€ gofih phase od a very low frequc.cy ofloxic 

and orher ad!€se red.ions in the hosr contribul.s lo $e nnequaled imponecc of p-laclan 

utibiolics in chenolh.rapyr The Fiquely ledDl &ibeldial rction ol thcs. ae.nb hd b.en 

arribuled td a el*rire inhibnio. of b&lenal ell w.ll synth€sis ItOl. Pcniciuins dd 

ftphalospoii.s rcyl.te a sp€cific bmtrial D{lei.e tusFplide [rl]. lhercby endedng n 

imtive for ns DL i. fomins peptide cbselinb ot rwo liEe peptidoglycd st-dds by 

llssp€flidation and los of D{rani@. g.ldtd stibioti€s also innibil b&lciial Daldine

c.rboxyFplidses Sludi.s in 4 colt Ev€aled fi. .xislence of 4 mey as *v.n dilleEnt 

funclional prcteins, €ach havi.sminpond role inlhecellsallbiosyntbsis[,12]. 

vdiou neinods @ cponcd in lhe lirqaon fo. tlF .$y of ephalosporic- Th.F imlude 

micobiolosic.l nciho& [4aE], TLc {r9, s0l, HPTLC [5r], wsFcrrcpholonedic ls!- 

56l.CC Is7l, rHNMR [5E,59] and HPLC 16{{31. 

Antibadditl tpectun of uririry 

Cephalosporines arc aclive a8ainsl a wide @ge of C@-positiv. ed Clm-negatile 

be|cria ituludine Fnicilline podwirS &opbtdoc., Out rct &rero.oc.t). whil€ neNer 

ccphaldporins al$ rhow ativi9 againsl Prerdo@6 spei6 [6a] How.vo ihey rc nuch 

norc rcsislflt !o inerivatioi by Fl&lalrw, 

p6niculaly thos prod@.d bt G@-posniv. 

bacrclia,lhan mpicillin, Atoons 0lac!.n dtibiolics. cephalosporins exhibil uniqu€ly potenr 

activiry asainsl nosr sp4i$ of&6s@l/d [6s]. 

ln ce of t"rero.o.ci live fold dost of ephrlosponG is rcquircd to iohibn lhe grcvlh 

whilc th€ edlny agaiNt Aclretichia.oli at Pro'.s ni bilis is found cquiwldt !o ttar of 

lnpi.illin. .Sa/zorerae dd Sn,serlue & ale scnive bul opptciabl. &tiviti6 ,eains 

mosr siains of &erri?/& 4e obsfled [66, 67], Strohs of b&tena as E t rcbrcr.r. indole- 

pos\tie Prcte8, Pseu.lomotus nd Ba.t.riades fuagilis l6El ffi rcsisrdt to ccphalospoijns. 

Mcchohn of b&rerial Esbtance 1o epndlospolins s pe.icillii is thai of €l.bontion of o Blalhe. 

alhough enc ephdospori$ sc iDdivd€d by p€niciUins type of F-lact:l)*. 

smc {€ not bur ac aftftred by ephrlospori@ type. Theeforc. thee nay be cGs- 

Eskldce bet@i p.nicillins dd ccphalorporins, but not ftesily so. ln addition !o 9l&hse 

Elaled eskrance, o$r rypes of Gsist n€ malogou lo me$icillih r€sishce 

scur [69, ?0]. 

Ihe mosl pElalent m.cbsism of resi$a!* to cephalosporin is dcstruclion of tbe 

ccph2losporins by the hydolysis of Flslrn rin8. May G@-pciliv. ed Clm-n€gariv. 

b&ldi. nicmryanisms Elce Eladvcly ldgc dours of placlama dd dFtroy 

cephalosporis d thc, diltu* lo (beii rarge6 on th. imer ndhimq s is tbe cde for lhc 

l5

Md, cephalospori.s h.ling diiTere.t phamacokinctic popenies d. widely di$ributed 

h.cause ol lhen broad spectrun of rclivity havins conbi.ed fature of mdy tenicillins 

l73l Usully- cephalosporins are €xceted unch.ng.d inlh€ sne: @y a. rctilely sicted 

br lhc rcnal tubule, a proc.s *nicb cd be blaked $ith pob.n*id 1741. S.nc 

ocphalospori.s d€ ab6o.b.d o6lly bu fiis dcp.nds on then Bntlrcc to d€sruclion by 

sastic acid [7s, ?6]. MGt of the cephalospori.s h!rc good Fnetralion ir tissres I??1. sone 

lhird seneration cephalosporins d the dNgs ofchoice lor menin8rth [?E]. 

fhee finl-eehmlion (c.ph.lexin, epl'ndine. dd efadroxil) &d lwo second-s€neddon 

(cdncbr and cefmxinc arctil) ephalGponns e rcid sbbl. &d aberbed after oal 

adnihishrioa otb.r ccph.losponns, i@luding all $ird-e€neElion conpounds m suilablc 

only lbr pdentnl adminhtaion. C€phlb$in, .ephopin., ed cefolaxime are 20 to l0 

pcrcenl mersbolired, ro des@tyl melaboliles wnich e exceled ioro th. urine. cefopduohe 

and ceftrido.e in unchang.d fom re exs€tcd in lo lhe bil€ [?91. 

t0 

Chemical $udies hov€ shown cephalsporins to b. efretive a bo$ lh€FFric Md 

prophylactic ag€ s 1801. Inf.clion ofthe upFr &d low€r r€s"idrory r.ci skir &d elared 

sff tks@, unnary lt@t, bones dd joiots d will 6s seplicemi6 dd €ndocdditis dd intra- 

abdominal and bile rrrt inl€crioN caued by suceptible G@-posirile e usually 

rcspnsire ro cephalosporif,s 1811. They m th. choicc of drugs in paricnts having p.nicillin 

allcrscnisitt. A fid scrcadon asmt is pr.t€rabL, *hd a CM-posnivc orsoism is 

inlolv.d while pamlal u*s of third-geredtion .g€nr is pEfered in sioc inf€lioN 6 for 

te initial ftahenr ol m€ninsilis h adulrs dd childrcn old€r thd Utc. monds tE2l. 

ll Adwrte rc.ctions 

Ihe mosl comFo. adlcre crctions re allersy.nd hypeGetrnivily lt9l. unich are identicdl 

1o lhos caus€d by |hc p.nicillim, dd this n.y b. rlaled 10 thc shoEd F-letan strucl@ of 

borh gFups of dribiotics [83]. lm€diale @rions sh d @pny|ub, bomncpasm sd 

uni@ia m obsd€di more comnonly @ulop,'ul& r6h develops $ually afto sveral 

lays ol rh€iapy. and rhis nay or hay not bc acconpanied by fevs and cosinophilia. ftsc are 

no ski.rstsihalcan eliably predict wheth€r. patient wiu ndil.$analleAic rcaction b lhe 

ccpn bsporim [81]. The cthalospon.s hov. ben idplicarsl 6 pot.nliallt nepholoxic

lgors. ahhouen th€y de nor nedly a toxi€ lo thr hdn.' 6 rhe minoelycGides or the 

plytolains [85], while diatrh@a ad i.tol.dce of alcohol h6 b.cn not€d wilh eme 

ccphdlosponns Serious bleedins Elaled lo bypoprothombi.enia, rhrohbocyropenis, a.d/o! 

plaleler dysfuclion has b.en reporn:d wnh svdd pldcun eibioiics [E5]. 

cefpircm€ (c2H4NroJsr, a fourlh-sens.rion c-J 

quarcmdy mnonium cephalosporii. which b.ds a 2. 3- 

cyclopenF.opFd'nium at rh€ C 3 posirion of lhe 

ccphcm nucleus Il belon8s b th€ pa€nl€ral 2{nim-5- 

fiiuolyl cephalospon$ l8?1. is *hne b pal. yellosish 

-+'\ 

cry3talline sknb powd€r [8E]. cont insC = 5l lcr./r, H = 4.28%,N=16l2% O:15.55v.ed 

S =12.55% ft is ftely soluble in Mler fld panially in nethmol. [89!90]. 

C.liiomc k chemicall! namcd 6l 

l.lt7-l[(2nnima-lhielylxhethoxyinino)dtyu.dino]-2carboxy-E-oro-5{hia-luabicyclo[4.2.0] 

ocl-2{n.l-yll nedyll-6,?-dihydrc5H-l-ptdndiniu nydmxid. imer elt 

lsel or I6R-t6d, 70(z)ll-l'tp-lle-dino-4rhi@lylxdethoxyinino)-aceryll @inol-2- 

c,iboxy-8-oxo-5rhia-l-@bicydo[4.2.0]@t-2+nc!yllnethyll-6,7{ihydo.5H'yclopenta 

lbl rJrindinium innersah lq,l. 

C.fpircne inj(lions ad stored below 25'!C dnd proleded f@m lighl. nE r€co.sliluled 

prcducrs m slable 6-8 houn ar rcom lenpcratuE or 72 hods il potccted isn lighl rd 

refrigemred ar 2-8r [91]. The slability for I w.et at 4lo 8'C dd for l0 dals al -20'C R6 

C.fpnon€ in vrious bufer eluions ,6 .llo*!d b stand at 40rc dd 3tabl. i. rhc Egion 

pH 4-7 dd slighuy uNtlbl. beyond lltar cgion [93]. c.hirene .nd ccrepine $lutio6 

deleloped m imFonant colot chdgc (frcn lighi yellow lo ddk ed) upon exposure whcn 

sroed a' 10pc or hishc 1941.

Thc ay. csis ofcefpiom. hs b.6 Epo'icd by uirg cil. or Gimc 6 n nins nat@rl [95] 

3 Netnitd ot.c1'dl 

"iir.,) 

r",-Yt 

It;A= 

-'"f. x 

'\ ltl 

d" 

t\J 

.O 

1'l 

(Jr-rr"r t1 /-T-r'"H. 

t-,*{J*, 

).,"5 

/-""-a"r \ / 

r*--.2":-.J-, 

t \--l ! 

c!bitotu 

c.fpione is bo.ldicid.l .r low .om..tnlion .intt e *tiecly brc.d tpdrrm or cm- 

n.gaile ed cm-positivc pithoees b*au. ft p.netates lhe c.U w.ll of bact da Bpidly 

aid binds b ln. lalgd .ruym6 (FnicilliFbilding pblei6) wiih his! liEniy. h is nor 

etirc .gliEt dc{€!E$.d nut nts DlodEilg hd lq€l of c.pt lospdi|@ dd thitd 

l8 

@:

Senelationcephalosporins 

and shows synergislic acitirt di@glycosides ag.insl ndy 

"irh 

UY spedmna,r .rd pH pot nliotEttr 

lrv sFclromet-t dd pH polfltionet_a w.E u*d for lhe det€min ion md diGr 

cn.mctcriztion of the dissociation cons&rls ol c.f.pime and c€&iom€, -l1l. aberbac€/pll 

profil€s at tRo malydcal wav€l€ngths md diif.Fnt conditio.s wee assessd sd fou.d to 

confom lo thoe ol diprolic acids. Th€ lilraion cury.s indi.ated a lripotic &id pofil€ wilh 

le ovcrlappi.g dis$cidion @nstsnrs [91. 

HEn pctomn.. IqtU .hro"t4tos.tphr 

fes nelhods m reponed for lh. agy ol ccfpione in hmm serum wnno( cheSing 

chonarognphic cohdiion. Ihe Nay consistcd to deaue cef.pin. dd cdptone by 

ultnnlt€ralion fouow.d b! HPI-C silh a Suoelcosil ABZ+ colmn dd UV deteclio. rt a 

ralcleh8lh of 261 nn ll was foud to be lincd and hs b€en validaled over $e concenlEtion 

range 200 to 050 !e/ml tor bo$ cef@ine dd eipirene. nom 200 Fl- selm dtation 

1981. A pevioGly poblGhcd IIPLC me$od for d.tcmin8 cefpircne in *tud *6 adaflcd 

for us with nilk dd ui.e. Chrcmatogms r.rc dconplished using a mi.rcboF HPLC 

stst€m. s Ev€sed.phdc Crs colum md a nobil. phase of 0.1% tfi.lhylnine in wler (pH 

5.1). Cefpnome dd the intchal sra..lard (bera-hydoxyprcpylthophyllinc) werc nonnoed 

usnrs lrv detecrion !r 240 nm md had Elenlion times of2.84 and 5,05 minuF Estectively. 

'l1e me6od ss lirear up b 500 ngll- for both n rixes ad had a linit or dctcction o{ 0.6 

ngtr. The int€day vdiarion (eldiv. sDn

qd line& to 500 pg of cefpircne per nL dd had a sciliviry of 0.6 ug/hl. Analrlical 

rccovery 6 >86% and the b€tween-day coefficient of vdiation wa

Coryncbet.riun Dqeres 1106. 961. Cm,n€slliv€: CiEobacter spp. hch.rithia .oli. 

Saltunrfu spp., shiseAa spp. Ktebsiello qD. (indokpsitie aan i,nok tuAaiw). 

En!*obackr wp. Hajhia altei Md &iratia spp 1107, loal- Prctew nircbili!, Prot.tt 

rulgarit, PnteL\ rcttgtii Moryarello doryanii, Ptovidencia spp., leînia aat tocolitica. 

Pasteurella nulta.i.la, Haenophil,s inllrenzuei Haehophilut ducteri, Moruella 

.atufthali Ncistrtu n?hihgitidts. Ne ksetia Eonofthoeae Md Aerhohas htdro?hila I l. 

Mosr straihs of $c followins sp4i€s show F.siriry b efuircme in ritro: Enteto.occut 

h.colis. Cl^ti.liun vP- (cdm-positivc), Pte!.tonow etucitusq Pseudnow sW., 

Acinetobackr spp. ud Bact{oidestastlir (Om-n Fdve) [96] 

The drug can bc adninisteed by intnv€nous or intmusuld injection, but h nor wll 

aberb€d at€r oral adminisuado.. Biodvailability iollowinc iordsculd injecrion ereeds 

90%, it pencrhics r.lie prcsrare sland, Mal rissE [109], lus, blisr€r fluid. eEbtrospiMl fluid. 

a!€rior chhb.! of the .on-inflmed hlll@ .y. [110] nd pdito@l nuid r.achins 

onceotnlions lhar R sinilf io lho* &hiev.d by orhcr larer aereFlion c.phdosporins 

pporidatclt 8el. ofan inuarcmns do* is climinarcd uchdged in Oe uirc, no acrire 

mebbolil€s oa c.fpirone haE bed idqtified. Th. elimimrion balf-life is appbxiharcly 2 

hoB, by gloncolar filtrolion. Th. dD. dudoe which drug cofteirarions cxced rhc 

minimum inhibihly conenlmtio. (MlC) r.rresnrs lhe nost clinically ituponant 

phamMdynamic parameFr aor o'lacrd asents Il | | I 

D6a C. and ad hi t isrhtian 

CefpiDne is for in'a!€noE N only. $c dosg.. adninisradon &d dundon of t@rnenr 

d€pends upotr lhc svdty of 6e i.fecdon. snsitivity of lh. padogcns, condilion of lne 

paric.t ed 4nal tunction. For uinary t &r, slin dd eft ris@ infato6, un dos may b€ 

inc€ased ro 2.09 in very syeE cNs C€fpnom. h €xceted pnmily by thc lidn€t. rhe 

dose musl, th€rclbrc, b€ educed in pariens with inpaired rc.al functio. ro codp€nstc for 

rhe slower exclction I961, 

Cefpnome is g.ncElly w€U roleiaa( hyrEEtuity @cliom such d allergic stin rcactions 

(e.8. 6h. prurnis. dd di@ia), dgio{.d.n.. bonchospdn, nalaie. possibly 

culminalinlin sh@k. mat rely @cur. Il may allsl 86lrcinr6tinal l@l and ndy caus 

2l

n6useu, loniting. abdomiml pain dd diadhoea Thc posibility oI pseudoiedbrdous colilis 

should be considered in patienls i. whom sever€. pcshtent dinhoea occu6 during tEqtmen( 

or in rhe initial welc lhereaf!€r. Acde rnsl failure nay occu in rre c$s, s snh olhs F- 

lacun amibiolics. neulropenia and moE rarcly, agdnul@tlosis my develop durins 

Fatn. wnh ceapircme. paniculdly il gi!c. ovcr lons pn6

Aspirin &d noN.Didal &i-inflanrD|ory dtugs (NSA|D9 such s ibupmfm (Advil, 

lvlotin) dd naprcxen (Ahve) cd E le AcE inhibiloB lss eli€cliv. in lowrins bl@d 

nresuF [l29! 1301. aCE inhibitos cd al$ inreracr wi$ lirhiu (Lilhobid, Eskahh) md 

allopliinol to nale sidc .ff*$ lion these dluss noe lilely or morc s!.re [3013t]. 

}1) c#;1,' 

.-#e 

Capbpnl, l-{3-deMp|o-2d-turhyl-l.xopo-ppylll-pbliF ls S), is ured lh.EFutic.lly 

s m mdhrFnasiv. ag.nt rling s a porot and sp€cific iihibiror of elgioretubconvertq 

eDyme. ln addition. il h wd i. th. nanageeehi .f haan iailG. followi.g 

fryocardial infracion and in diabedc nephropathy, Abou 60-75% oaa dos of capbpnl is 

aberbed fron th€ gatrc-inl.srinrl r@i od peat plana on€ntralion is &hi€ved in about 

an hour Abom l0vo ol lhe dde is boud ro plMa potein [89]- 

S.v.nl nelnods har b€.n cportcd for the q@titnivc deamination ofcaptopril in dNgc 

forhs ad biological fluids, includiog litration wilh pordsim iodate in eidi€ mcdium [133]. 

chemilumineeence [3,11. capillary .l.cmphoFsis [13s], eledocheni$ry U3cl39l, 

specrrcphotonelry I140-1431, cc-MS 044, l45l ed HPLC [46nsl]. 

tinabril naleaL is &nvarive of 2dino &id. Laldire dd L-preline and is d 

anlhtpdd.divc dd a vaedilator in co.Senive n .n failre, ued in asocialion wilh 

hydrochlomrhiuide in the treat menl of hype d.nsion Il52l. 

E.ahrril Dalet€ w6 dci.mioed in phrllMeutidl tablets sing fiBt.d.rivdile ulraviol.i 

n!€.lmthotomerry ll5ln 551 ud by biel p€rfome liqnid chrcrologdphy {l5G r54. 

2)

LisimFil (sll-lil{lsrboryJ-pnoybopyl}lly3yll-lDrclic dihyd6c. mlccll& 

fmuh: CnHnNrOr2H:O) is e o6lly -tiE mgior.Bin

ntylarcd hydmxyeiele (BHA), butylatd hydrcxy tol@nc (BHD, r.r.butylby.ltlquimE 

(IBHQ), popyl sellat (PG) and tocophmls. 

The mosr 'hooudrly investgakd die&ry componcnts in iruils dd v€setables etins 6 

anrioxidan$ arc fihre, polyphe.oh. flaloioift. conjugat€d isom€s of linolcic acid. D' 

linolcnc. cpigallocakchin, gallare, $ya prorein. isoilavmon€s, vitamiN A, B, C dd E, 

locopherols. calcium. selenium, chlorophyllin. aliphdin, sulphid.s, cal4hin. 

tehnydGudmin, sMinol, elut lhjone, uric acid, indol6. $leymles md pDtes 

inhibnou l|831. |1l* compounds nay lcl indcp€ndenlly or in @nbimion $ eric&cer or 

caiio-pbretive agsc by . vdiely of me.hmisms. 

Discnsed h€loN arc sme of lhe most inpona naMal a.tioridmb pEsent in fruns md 

veger.bles that have b*n shou to play a c@irl ol. ir prevedion of v&io$ dis.s* Il E,lj. 

viumin A is a lar$luble otioxiddt, which is.snial lor ero*th, ndnlen4c of vis@l 

auncrron, eprodlctaon dd diferc.iiation of cpidelial ris@. Cadenoids m *no*n ro 

qwnch oxidst sp€i€s srch 6 sinsl€t nol6uld ortgna lh. mdhaism *ms lo b. a 

physical quenching e&tio. thar does nor affcct cbemislly lhe slrucnE of lhe piSnenl 

Il85l. 

It has ban rcpoded lhd vihin A deficienl !.ts €xhibiled Iowetd serum te$osleronc, and 

supplcmcnIation ofrcrionic acid lo $is vit.nin A deficient 6ts Glored nomal rcstostione 

cohenudion [E6]. Oi th€ basis of .pideoiologic obenaioB and labodory sludi6. b.ta 

.25

carctn€ dd litanin A have anracred wid. iil.rcsl 6 ag4c lhar my pEw lug .tud 

lr37-r901. 

A$orbic &id (vitanin C) is ore ofthc nost powdll mdoxiddti [9]-195]. Ihe ability lo 

donale electrons in a wide tu8. of .Eyrotic and rcn

indusny. ThGE h!v. b.en ce cpotu ofo !.t tllcrgy io todiM bisulfiL in cEms $ch 4 

lnnov.c" ed kcbcon@lc s wll s lo@l aNsth.liG [206,207]. In.ddnion, uni@ia 

dd sgiedcm linilcd ro thc fe, i6r, uppd ttod. ed dtqnonia without athm. hN 

be. eporr.d !ftcr rhc ingcnio of lood 8d dnnk @nLinine sulfiFa [10E, 209]. 

E C.l.ioa C!.D!cl Blo.LB 

calcim chu.l bl@t6s @ . h.t6g.n o@ group of ds$ [210] cpccnling a lary, 

$tuo.ally dircB goup ot ch@ic.h lhat shd thc .bility !o idibn cdcim otry inlo 

muele ell.0uough *iion on tlr crlciM-s.ldtivc iotr chlmh l2ll,2l2l Cdcim 

ch@el blclcf e wi&ly wld for thc u.aim.d of i*hmic h.!n disle be.u* lh* 

drugs achi.vc cff*(vc @@nary varodilstion [2131. Th.y iftlls coon.rt blood no{ 

(CBF) by inhibnion of Ca" otry i.lo 3!@th hulclc elk [2lai. v8!l3 ddothcli.l 

aunclion is inpola 0or thc pa*dllion of otS!tu .gaiff( i$h.hic or hypdr.NiE slK 

l2l5l &d ind..d. nifcdipin. is Epon d b b. odiopret ctiv. .sdin nyeatdi.l i$h.mia 

ad cpeduion inju.y [216j. lnt tstingly, ardodiPirc irc|lss No PdEtion bt wu6sed 

cobnsy r'rcry .ldoincli.l eur vi.. bodyti.ind.pd|d4r m@hdkn [217] .nd nif.dipiE 

d6 @l hlw $6 &lion [2r8]. HosG, bar UE difr.|tc b.t\@, wrEf,Ed .rd 

i$hoic codiliod mt inllMe nifcdipiFidw.d codEry u$dilrrron &d b@r 

aDth.r dihrd.oprridift calcium ch.ml blo.lG {bcnfttipitu) ift|!6s NO prcdEtion in 

i$h.nic he.ns lrl4. nif.dipin. my hrrc th. po|citi.l !o it@e @dirc NO l*lt in 

ishcnichcatr3 ed if it do* mt itutle NO l*ls in slEs!.d@ren ry vcsls 

27

Dihi!&m lnd orhd sldm chmnel bl@kds e moE ell€ctile agaiGt alrial ihm 

lcnticuld dyrhyolnia, $is drus is al$ used ro ucar hyp.rleNioh dd esino [219, 220] It 

is uscd i! {idc lad€ty of othd cohdiliohs, in luding hypenophic cardionyopa$y. migtd., 

Rayndud's phcnomcnom. poslinf&l isue fl.s.N.lion sd adero$lercsis [22]-2231 

Porentially h@!do6 drug inl@tions havc b.en Eponcd when diltiem is co-adninisl.r.d 

s ith disorin, proprmolol, cyclosporine, rheophillim sd nidaalm [22+23{]. 

Diltidn hldGhbnde d (2s{isFqseryloxy-5-l2.(dinetbyldim) ethyll -2, ]-dil'ydc 

I (4 mcrh.\J -phcnyl)- 1 .5-bcmr hia-a n-4(51i)-onc nonohJdchloride n . 

hcn,olhiaTcpinc derivative uscd in lhe halncnt ofdsina pectons. syslemic htt ncnnon. 

x]ld n'rrvrntricrlar arhyrhnrias 1231,2321. I' is oDllr acilc agenl. ch&acrcti^d by high 

rirn+$" !llucr, higlr ph$r prolenr birdir-r dnd cronsilc !&rabohnr 1213,23,11 

Sevcbl ndhods bav€ b€e. Eporled for lh. det€rdimtion of diltiden by spe.tropholomclry 

[2]5, 2J6l md hisn perfomflce liquid chrehalogdphy [2]7-2:Ol. 

v€hpanil- b.n?@ceronikil€. (+)-(alph.) ll-ll2-(lJ{in doxtThmyl)€rhyll merhylminol 

pmplu-1. 4{ine$Dxy- (alpha){l-melhyleiiyl) nomhydrochlorid€ is a calcid ion innux 

innibilor, cffccrile in rhc llfu.nl of dgina, uhr{mia, denlial hyFnemion. enain 

cddiohyopadies and reently nodifying agcnr in lumo6 which expi$s P-elycoFolein [24], 

2lZl, vorupdnril has been delemi.ed in plasms &d other biolosical l'luids using sv.Dl 

qp.s of analylical l{bniqu€s such s 8s chrchalography-rus spectohetry [243]. nss 

fraemcnroghph! l24al- high-nre$uE liquid chrondtoghphy coupl.d lo fluorineric 

dcedion [2d5], ulta{ioler detection [246249] .nd liquid chrcnarognphy €oupled to hds 

mlc{ipinc or R,s2[(2minethory)ndnylj4-(2th1orephdyl)

ext nsiv.ly metaboliad i. ih. liv€.; mctabohes e n6dt adacd in urirc roseder with 

le$ lhd l0% ofa dose as unchmsed drus [2s5] 

Seleral mallrical n€thods aor Mlyris of dlodipin. in biologicar spl* have b.€n 

Fporled nEs include sp.ctrophorondic melbod [256-258], gs chbmatogBpiic ndbods 

involvins capiUary @lum ed el*trcn sptE det@lion [251261l. LC-@s &nden syslem 

[262, 26] | and liquid cbmm.togiapbic nerhods [26+2?0]. 

E.$nrirl rnd Tn.. El.nctrtt 

Lseniial clcmenls m those which de €$eni.t ro huoe body ed rrace et.mftts aG rhoe 

which @ prtrnl in hln@ body in tae doot. They all perfofr dift€r. nncioN in 

huma body. Esentid t6c. elencots @ EquirEd by nu in momts r&!i.g tom 50 

micrcgms to 18 nilligms Ftr day [271]. Thes includ. magncsi@, calcilh, chrcmim. 

mesee*. no., cobalt, nict.l, n@ and csdnium dd di*ussed b€tow: 

Magnesiun is i.lohed wilh ATP podrction via rh€ Kr€bs cycle, gtycolysh, dd€nyl cyele 

and orhu Eacrions involving rcne ioplts trsnsnision lr72l. I Esular* $e abs.rplio of 

calciun and is involved in th€ structuali egrity ofboncs, t@rh.nd conFacilny oflhc hean 

mNle lr may Eld [eritu riss dd de be u*tut in lne Edritr€nt of egiD dd 

my@ddrd infarction I27J-t?91. 

Cslciun is rhe n6t 6nnon min@l in lne hmd bo

liom rh Lric lo lhc lerous lom bcfod il on b!.b$rbcd. Ion deficiocy is ale s$ilkd 

with c.lia di*ac, Crchn's diw! nercdh.gia (h€svy m.nsfiDrion), fcm.lc infcniliry snd 

rcsLs L$ syndronc [288]. 

cobalr is used in rhe developnent of ertlhocyl.s ed henoglobin, is a compon€.r of vilmin 

B r and rcrs ht inhibitins rhc eryEes inlolvcd in oxidative melabolisn Buhing in lissne 

hlpoxia and an inclede in lhe seErioi ofc.rrhbpoictin [289]. It blocts the conv.Bion of 

pyrulatc ro ac.tyl cauyme A ed ofd-ketogluralalc to swcinre [290]. In lbe h€sn, @balt 

lom a @nplcx wiln lipoic &id ed incrfccs wiih .l€...boxytarjon l@dons in pyruvaE 

and lany &id tul.bolis. CarJionyopadry, @glitw non failm wirh poicddid .fiBions, 

rhyro'd olarecm. dd nemloeical abrDm.liti6 @ nmif6|ario.s ol @bal bxiciry rhat 

occwd in drinkeB of be{ ro which th€ ndal had been added 6 a $abilize! [2911. Hisn 

lcvcls of cobah ce produce polycytheDia I!921, lsge dout of coball chbnd€ d.prcses 

the poduclion of eryttuocytes. Iig€slion of s.lF may ped!.e ise& ed vomning by local 

iftiution [284, 293]. Coball EDTA cwntly b bcjng ucd io ir.a1 cydde poi$iiig [273]. 

Nictel h inrolv.d iD $e stnth€sis of iEulin and &rivares trfuy oth€r €nzyn€s, pl.ys d 

impona mle in naincme of stocnrc &d iirgrily. Ir is pEsr in ert4hct16, $n 

rissues. lircr. lidrt. bones ed in bair High levrls ofniclcl N foud in *holc g6in, cftals 

dd in veg.t.bl.s. Phrur€ co fom a st ble @npld qirh nick€l e n is posibl. thal phtlale 

may ddrce nickel absnrion [29a]. 

Copper faciliutes the activirt of seveial eizyncs [289] md provid€s a Dle i. rhe 

deleldpnrcnl and nrainten$ce oflhe c&diovMuld syslem, including hsn. .n.rica, o$er 

blood v.ssels. skclelal system. slrucn@ dd fundion of the n€nous syslcm, i.cluding lhe 

bnih JtEll, X tuy pmvide b.n til sgai*l polludon cxpcw {rd pot4l lgainn 

cdcinoB.n sis od tdor arcfi!, ils d.ficicrcy nat pla, a Dle in arher@lcdis lrd mrtic 

murrsns &d nrr infllcne fie d.velopmcir of enic eulsm [295]. 

Zinc stimulal€s fie activity of appoximarcly 100 @Feq wnich prenore biehcnical 

t&tio.s in bodt [2?2, 296], lt is a @mpon of al lea{ 80 .hzym6 including qibo.ic 

dhyd@. which is €ssenlial for cdiage of COI in bl@d od in lhe secrelion of hydrogen 

ions bt kidneys [289]. Zinc aupp.tu a heillhy imnDc ayslen {2971 dd is n*d.d for woud 

halinS, nainhining FGe oa l!n€, smell md n .d.d for DNA syn$sis, Zi.c llso slDpods 

mimal e6wd and developmenr duine ptegMcy. childhood dd adolcsftc [2981. 

30

Cadniuh is toorly abstued fom C I lr&l Md it ngy caus irihlior of the espiarory t@r 

$Ih scvc!...arly pneunodit,s. chest paih &d diziness. loxicny may progress lo include 

lirlai pulfronrry cdcma or residual enphyscma with p€ribonchial sd p€rilascular fibosh 

2991 A suficicm concmrdion (200 t8 ml. ) damaSes rhe ki.lney cell, esuhing in 

pexihal tubuld ibjury md prcteinuia. Cldniu prcdues imos in a nmber of orsds 

when adnini$er€d to labo'alory dirEls [300, 301]. 

rj ll,-rcccprorAnt.aotrFts 

llishminc. naru€l body con$nre , h a loe-nolccll& right min€ synrh.sizd by 

histidiie dccdboxtlN. e edyne $ar is expre$ed in ceus throuehoDr rh. body, i.cludins 

cenldl neBous systen neens, CdEiemucosa p&iehl celk. nd c€lls rnd bephih, 

Hhunine cxcns iG diverse biologic efT*|s rhrough four l}?€s of r€ep1o6 (Hr, H,, Hl and 

lL) 1t02"3091. als posesss anrimnwhanr acrivirr [310.31t]. Acriviry could be incr.ased 

narkcdlt *ithlheintroductionofaecond aomatic o! heteMyclic rins into the slrudue and 

lhousands of salogues w€re synh€siad &d .valuted. For mey yem, d. norc ac !c 

hishirc H I Eaplor &tagodsts bav€ ben rcpE$nt d by r ewral lom a @mpiising tto 

enatic srcups lintcd by a shon chain ofalD6 to ! t diory 

JD,i,,o sroup .s sho*n belo$ snich cncoore rh€ -r. | | 

rlltu*nts lcdruc! Arr is aryl or here@yl. lhich nay be ./- i i-*"' 

audber subsfturedi Aa is a s*ond ryl nng or d aryl nedyl ^' 

srour. Thc rwo aryl group Arr &d Al m.y b. bide€d lo 

tbm rictclic derivoliles. 

lhe mosl common eroup h dinedyl amino and prymlidino which do not have a clo$ 

.hcmicrl ruscmhhnce lo hisranine except fial thcy sharc the featuE ofan amDonium alkll 

chain. h is presune.l tiar tltey bind to the s. eionic silc ar lh€ leplor, s dcs histinine, 

but tn{ th. emaric ring binds 10 a ndby eesry E8im. Ho$wa, theE m no* my 

@npolnds whicl' dow hth polmy t.r do @t lit in rhis geftrar sintu [3r2, 3lal. 

I lr -etihi$min* &t as inv* agonins lh.t combine with md sabiliz the inactivc fom of 

$c ll,i.ccptor. shinins the eguilibrim rowd& rh. in.cive state [314, 3lS]. TbeF ag.nc 

have bccn clasified into six chenical groups: rhe daoldires. elhylenediamin.s, 

alkyldnines, pip€razincs, piperidines dd phenothidi.es,Cl6sificarion &cordinC to luncdon 

oi li*r-gcncration Hi-erihislamines, which is s€dad.g, d cohpded *irh seond-geneddon 

coopounds, which m rcl.Iively nomedatng, is iow mor conmoily scd F021. 

ll

H r-ntihisllmincs Educe the nmbd. sia ad dustion of whesls fld de{)@e iiching. Th.t 

e etlicaciols in r.licvine tud tdentihS eutc unigid [316-318]. aldougb th.r. is 

considerably lcss publish.d evidence in suppon oflhcn emc&y in thh di$rder as comp.rcd 

wilhchronic uniceia Illt-3221, in which thc se@nd-genelaion Hrathistahines cclnizine, 

deslodladine. l€xofenodine md loialadine hlve b.en well srudied. 

Ihd. .rc nunrb.r ol drug inr€relios Epod.d s lh. €fat of thc stiau8al drug 

lddonvrlc, "hich blels heparic fiGt-pGs biordslonurion of ebdtire and lcracnadirc 

leading !o ince*d cardiobncny ot rerf.n.din. in nd, on d!€ ECG efrEts oft rf€nadine 

dd eb.slin. io eimal nodel 132!3251. Among lnc sond-gmmtion mtihislaminc, 

a{eni4le Md rerfcnadine. bul nol loEt din.. @ cluF senou c€rdiorsculd adv.rc 

efect, includihS dcad, wnen takd in hiSh doles or @adminisr€r€d wilh k bcon@le, 

iinconuole. or nocolid€ etibioths I326i Acdle hydophilic iebbolit€s of the *cond- 

Seneradon 

andhist minic @npouds (eb6ti.e{debatine. loratadine"dcslorahdine, 

t€rfenadine- f.xofemdine ed at€mielc-tu@t nizoh) hav€ pobably redu.ed dsk for drug 

inka.rions ed cddie roicny [32?,3281. 

1l 

cetnizine o, [2-14-[(4{hloreph6yl) 

O-O-'1: 

O- 

phenylhdnyl].1-pip.@inyll erhoxyl @elic .cid is . 

lon8 &tins non-Fd.rins mtihisr.nin. wi$ $mc nat{.ll sLbilizin3 a.tiviry od tu qsd for 

lhc stfrptomic tlief or alersic ondirioE including rhinitis od chrcnic unicaia 189, 2!l I. 

As s bull halenal, ednzine *6 6syed sing acid b&€ titrariotr {l29l ad HPLC in hmd 

dasmr l3!G34ll and unne [3al]. ceirizin. in ph@eeutical romulatiotr wd .le 

dclcrnrincd by o$e! techniqEs such a ulrraviolct sp€cuophotonefy [342, 3461, 

sperofluorin.tfy [317], 

TLC ed HPTLC (348, 3.191 

J2

I erocelnizine, thc acrive R ehmtioner ofcefiizioe is seledve Hr hhlahine blocker lbal 

.onlains dlihislaminic prcpeni€s ad is ed to meag. ihtemtuent ed p.uisrent ailergic 

rhinnis. It is dinerionic dd rclativ.ly pold ed lhs dcs @l Fnetane blood bnin Eadily. 

It is efctivc in ElievinS nasal synptom, ih!troling Mel air floq. rducing loce}l€ 

intliarion trd dini.ishing cyoldn€ lw€l [350] withou pbdrcinS my d.l.ldious elf*r o. 

coSnni\€ md psychomdic tlncdons omparod with plrcebo ir heainy mal€ volutes 

l35ll. 

1 o or knowledge. rhee is no r€porled m.thod for the alalysis of levocetirizine. 

Fexofen dine (a),2-[4-l l -hydrcxy-.4-[4{hydoxydiph.nyln rhyl)pipe.idiio]bulyll phdyu 

2-neibtlFopanoic acid. is a non-FdaIine hj$.ninc Hr alagonisr. This drus is a P- 

Bltcoproreih subsht d.r ha bm ued 6 a ptub. druC ro as6s P-glycoprcrein &tiviry t 

uira becaue n is nor nctaboliad in hmms 1352, 3531. How€verj thh drug conraiff an 

aymoeric carbon in ns chedical slrnctue ed is.dEinisleEd clinically or is usd a a P- 

rltcop.oteir 

prcbc 6 a racedic mixtur€ of x- dd S{n4tiom€s. 

liuxolc.adine is the ative &id n€tabolik ol 

drribiidinic eilech of th€ pared smpound. 

ll Hrr.epro.ADtgo.isrs 

rcracnrdine and posr$s rhe b€nefici.l 

bur is devoid ol lhe MhylhnoSsic side 

Scvelal liquid chrchabgraphic [351361] spatDpholom€tdc [162] dd s!.cronuorimetric 

{J631 m€thods nave been rcpori€d for lhe detdimtion of f.xofenadine. 

llistanine Ilrjeccplor &tlgonisls m rcveEiblc @npclitiv€ bl@lcE of histamine al Hr 

l*pror md much slcctivc, cvch do .o1 afiel th. H jc€pror. Tnes arc pole innibiros of 

lll phlse ol eslric acid secetion, th€y do so by bihding lo Hr receploB on rhe prietal celh 

ol srohach dd de analogs of hislani.e, conrain bulky side chain in pl&€ of ethylmine 

noicr! Bfimamid. dd cinetidine N edly nemb.6 of this srcup. Cim.ridine contains the 

nn izol! .in* ol hii rin.. Nhich is Rphc.d br fua in milidinc or d lhitll€ in 

ldolidine dd nizridine. Ttis grcup is moft hydrophili.lhd Hr dlasonhE l3tll. 

l.eldhe dd orh.B 1165-3681 sMied polcnli.l drug interudo$ with H,J*eplor 

antagonisls, which are mostly dispositio.ally bed wilh th€ abstption, n€tabolhn or 

cx$crion oforh€r drugs. or olher drugs intene!€ *ith $eir dhposnion, Significet clinicrl 

ll

consequehces arc lhosc *ilh cinerdine becaus. ir inrerfcrcs silh hepstic crGhbne P 450 

[369]. Desnond sd othds [370,371] reponed drug inter&lion with Hrreceplor fltagonisl 

on th€n .bilny to innibn c}tchmne P-450. Th. bi@vailability of H.fceplor et aonist h 

in€omplete owins lirsl pas n€|abolifl sn r ingBrion [3?t,3?J]. Aldinu nasnsim 

h! dmxide cohrainins era.ids have shom ro tunh.r dc@e the bioavail.bility ofcinetidim 

l]?al- fdoddnr. Il75-!77l tnd tunidine I!?8.1791. 

,f,..n: 

I \// 

H,c\r,\N/^\v,s\v,-N 

*Y;xr"J.\i* 

*fo^"""\."" 

( ime dihe is N {yam'N'ncthyl'N '[2-[l(5-dcthylindel4-yl)ncthrl]rhiollcthyll 

gmidinc. CroHbN6S). @ aitu inidr&l nns, innibils h€patic c}tehrem. P450, us€d lo 

alleviate the sFptoms ofpcplic ulcd di*e..osive gat@$phaBeal Bflux disese ed 

hyp€rsecrebry conditions includihg ZollingeFElltuon syndrone md nultiple endocrine 

Cincidine is appmxinat€ly ?ielo qmled lnchdScd by th€ kidrcys dd bdcrgcs 

drcnsive tubula sEtion w.llt enal .lcame r€lks .ppoxioar€ly tolFfold gH&r Ihn 

c@tiniE clwac I!8!1. Cincidi* hs ben &i.mircd in phm&atiql pEFEtioG 

usinS potenrion€rdc 138!1. apillary elecuophorclic F84, 3851 md sp4ttuphobneuic [386, 

l8?l ncfiods. Scvcml high-perlbma.ce liquid chroMtographic nethods have dso been 

deleloped for cinctidine. eitbr alone or wnh olher &lihhlminic compounds, in 

phfficeu$cals lJ8&J901 or brologul m|cnals [39]-]941 

Rannidine n N {2tlttt(dimdhyimino)-2-fumyll ndhyu rbiol erhyll-N:ndhyl_2_nirrcr, 

l-c(henc diaminc or 2ll[t(die$ylahino)-fr€thyl-2-furanyl] nethtll thiol_elhylmino 2- 

m€thylamino-l-nnroerhcn€(C rHrNiOrS). hrs a fura. ring srslem.Il is used in tlt ld*hent 

34

ot ganric lnd dlodenal ulces and olher Elaled disordes by inhibiting lhe ssrclion of Sastric 

rid I89,2311. Amo.s rhe dalrrical t€chniques ued m conducbm.tic [395]. polsosralhv 

l3t6l. capillary clNbpnoresis I39?, 3981. sFctophotohetry [39] dd bigb_perlomtuc€ 

li{tuid chonaberaphy [,olHoal. 

Fmoidinc (csH,N'o$t, is Nlminosulfotyl)'lf[[2ldidinonerhylen4 minol4 

thiozolyll me$yll'$iol-pop6linid,mide, is histomim Hlaepror dtaeoni$. contai$ 

$ir.l rinS in ns {ruclue. ll is usd for lhe r@hc oldmdenol ule6, benign ga$nc uher 

md Zollingct / Ellison syndom€ [41]5, 89, 2311. h n in@nplctclv abetbed od 

bioavailabilily of oral do* is 40-54%, pos*sses no cddiov@ular efects at a dE ap.utic 

dos. whilc il mat exen cddio stinularory etions aft€r drus overdoes lhal miBh Potcoiale 

rne prodhtrhnic porcnial ol @-adnini$dd cediolonic agclls bv incrcGins $e 

inrEcelluht ca'' oncemEtion 11061. 

SFctmphotomehic [a07-4lll &d hig! p€{ornece liquid cbbmatoSraphic meihods hav€ 

ben d€$ribed for the d.t miMtion oI fmoidi!€ in Phdacculical 

biological fl uids [412-al6]. 

I E poAqcntc AE.iB 

lonulatiotu dd 

No.-insulin depcndc.l diabcles ndh$ 0IIDDM) is rhe nosl common tvpe of diab.l.sl 

paricnts can vdy consid.rably in their ability lo $cdre iNdin, which howder, is inadequtc 

ro orj(om€ insulin di$ance Mia&d vith this rt?€ of diabel6 lnsulin is mrdc nalmllv 

in fic tancr.&s: il cgulares fi. amount of sugar in the blod lf thc bodv des nol dale 

..ough irrsulin to mecr its n€sds, o! does not prcP€llt use th€ insllin il mok€s,lhis retults 'n 

the condnion call.d diabeB nelliN whichis a dieider ofglucose m.labolism [417] Th€le 

dc gcncric dd cnviromenlal @npomc th.t affect ihe dsk of d.veloPing either typ.l or 

rype ll diab.t6. TtT. ll diabctcs, muh mw dnno!\ ba tw difimt defels: i.sulin 

resisr,rce dd failw of b.!a €lls lo sqete ituulin adequi.lv [al?l 

sullonylurcas are Drea d€iivarives wnb s aryhullbnyl eronp in 

de I posirioo &d d aliphatic Itoup al posilion 3 (R), $lich 

conf6 lil,othilic pbp.rlies to lhe nol€ule. Mdximrl activitv 

'

Aryl goups ar R genedlly eiv. toxic @npounds which inllEnes the dut'lioo of dion of 

rhce conpounds l4l?, .llEl K' chamck nomdlly @ esFnlilc io $e crtopldhic 

ATP/ADP dlio and close {hen the latio incEes b4aus of e increGe in slucose 

ndabolhn [419]. sulfonyluea h clssified into fi6r (chlorpopmide. lolburmide fld 

toludide) ed sKond gen€ntion iglipizidc, glicl@d€, glibenclmid., glim€pinde md 

gliquidone) [4r& {19]. The binding epocity of wios sdfonylwa to th€ sutpopd 

sullonylurea rcplor clo*ly oRlale with rhci. ability lo slioulale iDsulin E!* p201. 

The lhiuolidinedione insulin ehsiliafs pioglir@ne od rosiglibenc hav. denon$Dted 

cdicacy in loweriry elevabd bl@d glucos lev.h in Type 2 diabel$ pali€nb [421]. 

nr\n',o 

Pioslir.zooc 

t) 

I's 

cHa 

/N\ _N_ _ Nft2 

'ltil NH NH 

Nunercu inlmtioN hsve b€.n relDfl.d wirh SliquidoE, bta.ly EpGatila .ithcr 

phlmr&otinetics inrera€lion (duc to displ@n ni ofrhe mtidiab.lics fbfr plama protin or 

altcration in ils nelabo|nn or excr€tion) or phmacological int ialion wilh dru8s havihg m 

indep€ndenl ef€cl on blood glucose lte followine dags nay enhance tne elfccts of 

gliquidone leading to loB iugd ldels in the bloo4 apiia mn-sLrcid.l d1i-i!fl.mtory 

dtu$ (NsalDS): sulphondide; @trimox@lei bctt'bl@16; ACE inl bnoni aElolic 

slcroids: lcstosteronci dlifuneal (ni@n@le)i rom-mire oxidGe innibiroa (MAOll). 

clonbnle, llle aollowing drugs nay reduce the eilect of gliquidonc dd $ nay 6is blood 

strgdr lcveh: diur€tics (loop tud thi&ide diuElicrl conicosleroidsr o.al conlr&epdve pilli 

chlorpro@ine. Gliquidooc my aid lne bl@d thimins €Fet of wrf&in dd othd 

t6

Cliquidon€ is l-ctcloh€xy!3- [tF [2{33-dihydo-7-nelhoxy-4, 4-din€6yll, 3nioxe2 

(lH)-i$quinolyl) .tyll phoyll sulfonyu wr (c,HjNrO6S), is troM ro inpmv. 

Clyc.miccontrol in NIDDM palnnis [89], by sinulaling lhe prcduclion md Eleae ofimulin 

Iiom rhc pancreas and aho promot.s lhe mov.mcnl ofsned from blood inlo $e t.quir.d ells 

[39] h has bolh susar r€d@ins dd ocphrcpot dive efsrs [42.11 ad $ishl. fot ombined 

Verious nelhods have been repon.d loi the determimtion aod qunlitrtion of gliquidone by 

sp.cmphoronclty 14261, aunosph.ric PBsrc ch.nic.r ionizdion liqdd chofrarosnphrc- 

nu$ rp€dnmer'ic [427] dd uPl-c [{28-431,]. 

M.taomin or (N.N-dimethylinidodi@boninidic{idid._hvdr@hbnde) is a bieMid' 

pr.edH for thc u.atrncnl of ItF u d'abet6 m.niN {:l3rl lt iicres sl@e l6ns?on 

a*oss $e cell hembran€ in stel.hl nu$l€ ll h slowlv md in@Eplelelv absotbcd ftom the 

gasroinrdtiml ta.t and is excercd uocnmged in uin€ havins pl.sma elininacd hdl iie ol 

.bour 2-6 bom aftcr o.tl dos l,Ll2, 43lj 

The rcDoned nelhods for det mining fteformin includc sFclrcphotonclrv ['134-136] 

HPLC [4tt-'t4s]. gs chbmtosnphv lr(7l. caPiuarv elecrcphoEsh [48] condulom'rrv 

11491 cid volomhctry Fsol. 

Pioslit@ne hydrcchlotide, pbenvli 

G)-51[[4_21ted,yl-2-pvidinvl).lhoxv] ft$vll_2 4' 

die{litli.e

d.rirari!6 (napoxen. nqbiFor€n ibtrpofo dd mcloxim) [459]. NSAIDS e ithbno' ol 

lhc COX enzrres thal allltzc the conle6ion of 'midonic aid lo veious eicosoid. 

includinS $ronborec and piostaglddins [460-4{il].Co.ve6ely. pros$cyclin (PC 12) 

synthcsk, wbich h lesely mediat€d by COX-2 etility in nacrovasculd cndolhelial cells, 

count Bc|s th6e ef.crs csulring in innibition of plat€ler aggreStlion. vledilalion and 

dripoliledrive efi*l3 [a6l I. 

( " ? 

r-Y-'l-> 

o'u- )r("*' 

NsAlDs e u*d fd thc Fli.a of nild lo modcd. Dain, ninor febrilc @ndnios ond for 

acut ud cltro.ic intlamn.lory dierd.6 such s o$e@nhids [a6al, .h.lmloid arthrnn. 

juv.nilc idiop.thic anhrnh dd..kylci.8 spondyliB. They e appli€d topi€lly for lhe Elief 

ol muscule ed rn€malic pai. ed som. se us.d in ophdulnic ptPddons lbr ocul4 

inflanoao.y disrders [465]. -Ite hid incide@ ol cddioveul& dd gdlroincstinal 

discase. coupl€d qi$ asc.clate

s*ral mclhods have been describ€d for lhe quandfication of diclofeoac in plana b!*d on 

difi€rcnr exrrulion pftcdB dd coupled lo OC-MS 146& 4691 or HPLC eirh.r with Uv 

l4?0-a75j. flsnftfic [a76) dd uv spe[sphotom.cy [ilt?, 4?8]. 

rludiprolen(C rH rCrFOrh 2(2-fiuoro 4-biph.nyl) pmpmoic acid, h a cnttl (NSAlDs)of 

dc 2'arylpopionic eid dss. Altnough i F6ess a chnal c.nuc, wilh th€ S-(+)' 

enmtiohd Dossins no$ of de t@fcid ed-infllmtory !.tivig, boln e@!o@E 

nay posscss malsdic a. vny dd all llurbiPof.n prcpmliom b dat e @keted 6 th. 

rlurblprclin hs si8lincel dti-innalmatory. dalgesic and eliptielh p.openis. Il is a 

hiSily pordt iinibitor of prc$aglandin stn$6ie dzyme, wnich is Miar.d wilh 

innmmarion, pain ed fevcr sd is uds study for lEatm.nl of efl tisrc lesions, 

adminbrcad s a tscuhcous path, h al$ usd in Eubpe 6 dti pl.tchl lheEpv [4801. 

I.lulbiprolcn has been detcmined by UV spectropho(om€trt [481]. elcdrcPhoEsh I'1821and 

hish pcrlomoce liquid chtoE.tography [483-488]. 

Mef.ndic acid (CjrHBNO, or N{ubsduled phenylelhmili. &id e NSAID halin8 

analScsic. anti-inilmm.tory Md etipyretic a.dons, is ued foi lhc reliefofmild to noderdle 

pain ft is ale indicakd lo. rhc lE trnenl of l.cunatoid dtltrilis [E9]. pidarv drsneiodhca 

[{39 | and pdodo.tnn I{90, 491| 

The oflcill nerhod lor lhe 6ey 6f tbe pm dru8 ed rnc calsulcs is tnrihetrv, uing $dim 

hrdrcxide as til.&t and ph.nol Ed d itdicatot l2!l1 A vdiely of mc$ods hav€ b€en $.d 

lor ihe deleminado. of the nurbiPtufen in dGage foms including UV sp€clrcphobnetv 

1,192.,1941 dd hish perfomdcc liquid chrchalogapby [195-'l9E] 

Meloxicd or 4-nydoxy-2-neihyl-N15-n.d!yl_2-lhielvl)_2H-1 2_b€@1hidih._3_ 

ca$oxanide I,lnioxidc (cnH,rNiorst is m oxhd d€dvativ€ I89' 2311 lr is indicared ror 

relieving synprons oi acut and chohic oscoanhritis, demaloid anhritis dd $e katm.nl 

ol pimar! dysmercrrhea .nd ale for rclief of b.cr pai. [a9]. A .mb.t of HPIC [so0_5081 

dd spccuopholomelic l50tl nerhods seE rcponcd for the dehimtion ofmeloxim 

f9

l( Preton.Punp InhibitoE 

Poron-Dunp innibiloF (PPl3) re substitut d be@imidml.s that inhibn s$lnc eid 

Krclion by covalently binding to rhe prolon punp (H'/K' ATP&). l-lE four agenls dilfcr in 

rhen mei.holism by eff*ts on 3pecilic h€palic .nzymes ed th6 in $en abihy lo inrc8cl 

wnh o$er fredicarions. PPIS e inpotut asents usd for endic^ .e Hellcoha.tq prloti, in 

rearinS p€ptic ulcer disea*, gatrcsph.ge.l Eflu di*de, Zolling.rElli$n syndome, 

upper gdtrcinrdtiml bledif,& and aor pEwnlne eid dpianion. Shorr em side efec of 

fie folr agenrs @ sinil{ {510. slll. All PPk arc netaboli4d lowdds so major 

nclabolites. 5-hldroxy-PPl and PPl-sulfone, rcactions catllyed by lhe polynorphic 

CYP2C19 ed the nosl.b6d&t CYP3A4, respecdvely [512]. 

PNron Dump inhibitoE (PPls) e t rs€t€d to th. gasic &id pmp, H', K(+|ad€iosi.e 

riphosphan* (ATP&). Con*q@r oEldt inhibirion ol H'. ( (+)-ATP& blcls thc 

final stcp of acid s{rcrion. ncnce lhe PPls on.prele, losp@ol. ed panlopMlc &e 

nore e8tcrile lhe hnhhine HrFceptor tulasonisls (HtRAt in cohrolling rcid seelion, 

lhe PPIS h€al the lesions ol gar@sphagdl r.nu disee, lcs*n synpioms moE 

clrcdircly and moG quickly de rhe HzRAs, lnd e €fr(tive and lastcr etinB fo. FPtic 

nlet ni*ze. Helicobrcte I pylo.t is c,elly ifrplicat.d ih lnc najority of p.plic ul6 ed in 

.rophic saldis Since PPls, but not HzRAs. de slhersislic wnh ddbiotics in d.dicalih8 /t 

Arori, dci us is approp atc in aU acidaelated diwes since allpaticnts wno de r. Ptl,/, 

posnivc Equn€ eDdication as well s h€aling, Th. proion punp inhibito6 belong lo a tcw 

clN or stirErory $bsrituicd b€uioi&al* l5l3l. 

,,""ct-F!+a(": G"'i,r7"^* 

Onspreolc is a slbstioled beEimidMole (rhethox]-2-L[(4-netfiox]J, 5 dine$tl_2. 

plridinyl) nerhyll sulnnyu-lH-beMimidele), wbich cd be applied to the treahenr ol 

ssric acid relared disrdN {89, Irl. Il sork th6!d iinihiting th. (H', K'}AT?& in lb. 

lEslric pdiekl cells ro rcsult in a diminulion ol gsltic tcid s@tion, s otrs dng ce bc ed 

ef€clivcly ro conbl rh€ 841ric eidity in pdien$ nol4sponding sdisf&rorily b H,RA slch 

as rhosc suflcdng fron ZollingetsEllis. syndmme [5141.

for de a@tifiedon of omep@le, scal mcrhods sEh 6 volunm.trv [515], TLc 1516, 

5l?1. spedrophotomerry [518-520] &d HPLC [52]-s32] 

bovc beo rcPoded 

I an$prdolc or 2 {(l'ncrhyl'412,2,2-rinuoethoxy)_2_pyridyl) nerhvll sulfinvl' 

b.uimiddole. is one of lhc proton pmp in]tibno6 (PPIS) dar innibtu erstic eid KEtion 

$rough dn inlenclion wnh (rl'/K')-aTPse in srsfic pri.bl cells [53!] Thh ddg, which 

ha3 e dymmetric aulnr i. iti ch€mi@l sEwlc, is clinically adninisreied 6 a lenic 

mixruE of R (+) - and s ( ) €nanione^ Js3.l,89,2lll. 

spccrmphol{}metr} ls3s-s.lll and HPLC 1512- 5t71. 

l- Sr.rins / EMG4oA R.ducr.!€ lnbibno6 

Lmsoprele ws detmined bv Uv_ 

Sbrins inbibn chol6t ol synthesis in the liv€r bv blocki.g 3_nvdrexv_3-ncthvlslutaryl 

oo.nzymc A (HMC-CoA), indrc ostcobldt aclivilv dd lead lo bon fomaion [548-5541' 

'lhcy dc $e no$ comonly pr€elib.d agefls for lhe treatm€nl of hvpe(holeslerolenla 

h.cau$ ol rheir efnctc] in educinS low densnv lipotrclein (LDL) dd thcn cxcncnt 

rtcrability and saaely [555-55?] 'Itev de also iic,Ieclivs in nodifving lhe sid ed densnv 

ofLDL (5581. 

Surins conlain a h.xahydio haphthalene !in8,lovasladn diff€ts froF mevdulin bv addilion 

or, mdhyl gnnp at cebon I Th@ e lwo major side chains. o'e is a nethvl butvBle 'sl€r 

.nd .rher conuins a hydbx! .cid lhal can fom asix_menb.rcd maloS oflh€ inicmedialc in 

$. HMG coA r€ducle @crion tnvrnad. and 3inr6utin d€ admini$ecd in dE le|ohe 

fom, a,ier absorttion, the l41o.e nns opeD ih lhc liver b, ch'nidl or e'zvnaic hvdolvss 

dd lhe activ. hydroxy rcid h go€rated Pavslnin h adiioisleEd a e eid &d is pcs'nl 

in rhe activc fom. FhElslin is, svn$elic @npoud 6al conlais e indol€ {iU a m'thvl 

.skr atul luoloph.nyl side chain wi$ a h.ptenoic acid which foms a slrEtlbl mlog ol 

llMG co^ 'nt medi e shins nav ds all€r thc.oMtdtions of othr drugs' sucn s 

wdrf&in or digoxin, Ieadins rc altedtions in erecr or r€quiins clini@l monnorinB [ss9l 

-fhe onbimtion of sbri6 wir! ce.lain dro$ th.| m CYPIA4 i'bbno6 or subsldtcs 

increses fte rhk of myopathy. presumablv bv inhibilins the melabolisr of thc statin tnd 

in.rcdint ns bbod conccnlr.lio.. llEse drues irclude cvclcporiic [560] cynrcmvc'n 

1s61, s2l. cldnhrcdrcin [s63] and nibeiadil 1564] Fibdres and niacin aho increasc rhc 

lisk oi statin-ihdwed nyoparhv vi. a mechdis $ do6 'ol incicse pl6na $axn 

coiehrdions [565, 566]. Myopa0ty hG be. EDon€d oilh Pavtsltin ero lholCl n n noi

md.boliad sig.ifi@dy by CYP [56?l- Shtins with ed yirhour CYP merabolism have b€en 

usEd salilyin lor doFs in @nbimtion wnh cyclGponne in h.an rrespldni parienk [568]. 

Arowdradi h Ii{Rl, n1)l-214-nuorcph€nyl)-0. 6nihydbxv'5- (l_n thvhnvl}}phovl'4 

tohcnylmirc) caihonyll'lH_p}1rcl._l_hcprrmic &id [8t1. ll .l.vares nitos oxide 

producrion. reduce the size of ath€ros.leotic lesion &d dereNe vsular snooth nuscle Gll 

ptulifer.tion i. ir-trto modcl [569i 

Exisring @alt{ica! methods for ato(stati. includcd sFclrcPhoion.tric l5tG5?51 &d hiel'- 

penbmmce liquid ctuorutogaphi. [576-582] nethods 

simvssorin or l s ll-alPba. l-alpha.7 bera,8 b.t2 (2 sr' 4 S{), sabelall_2.2- 

dim.$ylbuGnoi@id1,2,3.?,8,8a-hdahydGl,?iidclhvl{_12'(ldEnvdre-r|'hvdoxv'6{xc 

2 H-p)@-2-yl).lbyll-l-naphlhal4yl csi.rr is a HMG-CoA 6dn @ inhibnoi that ha been 

sho*n ro be €fi*dve s d edlipid.mic agmt h G adninist.Gd s a ptodrug, in rhc livei il 

n hydrolt?ed to fie Fhydmxyeid tom [89, t3ll- Sdml mdnods havc b'cn cpotrol for 

sinuslarin by Uv*pecltopholom€ft, [5E3-s85] dd liquid chtoEarosdPhv [s86_s9!]' 

Pravaslarih or l s- 0alpha(beb Sr, delta sl,2alPha,6slpha.8b!t'(R*),8aalphall_ 

1.2.6.7.8.8a-Hexalrydro-b.la,&llE6{ihydexy_2_n.thvl-8_(2'nclhvl_l'oxobntoxv)'l' 

42

ph$alfthepBnoic eid monosodim sll. del€4s chol*lml l€wl' ll is d innibilot or 

uM(; CoA reduclasc eEyme vtich catalv*s HMG{oA inb me!.lomtc 189' 594-5961 

Prav6ladn is detmined by nelhods which includ€ capilldv ion el*lophoresis [59?]' 

IlPl.C 1598-6011 qirh lssFi.dwed n@re*M d.Lctor [602] Lc/tddm .N 

spcclromcty [603, 601] ln addnion ro thc* d.thods. an LC me$od usins alnosphcnc 

ptssur€ chcmiEt ioniation n6s sFcron t v t6{51 dd e6 chrcmatog6ptic me$od 

edployi.s chenical ioniztioo ha$ sp€cuonetrv [606] hdve b€ei ued' 

M obi..tia of PEsdt rloti 

Pr*nt *od n bas.d on dru8irug inL..cdon sudi's olc'Dirctu wi$ AcE 

'nnibnod' 

anlioxiddls. essenlial ed lrace elenenls cd_cl'snnel bl6ke6 Hr{ec€plot dagohnls Hr 

E.Plor dbgoniis, hvpoSlvcemic asdt . mn'sldoidal dtijnflmrulorv dNer pmron 

punp i.nibiros and *arins. Difletenl lvp.s ol drug inrcradions iav occui wh€n padenls @ 

ftaGd silh nnhiPlc dngs Anlibiolics e the largcsl grouPs of drus which & coMonlv 

pcscribed and may undeigo snch tvpe of inler&rioB' 

l hes inkiaclions olcefPnonc wnh abole dehtioned drugs leR invesiigatsd in sinulole'1 

g6tnc juice (!H l), butrd of pH 4. 74 ed 9 tt l? trd 6o"C usitre Uv/visible 

spslropnobnelry dd revdc Phe high pafomece liquid chomaloglaphv (RP_HPLC)' 

Prior ro i.lctuiion sludi.s Nav nclhodt ofefpirene atd inetuiing dru8s q4 dev'lop€d 

dd optimi,id on Uv/visibl€ speclto9hotom€l€r dd RP'HPLC whicb w@ lhd apPli'd to 

intmclions. In order io find out th' m1ue of binding b€t*em efpiome a'd inl€t'ditrg 

dru8s, kinclic studi.s w.!€ did oll ar 37 @d 60oC in all int@mg nd'uns 

Funhemore, cefpion€ @hPlexcs w'F svflhesizld wilh all i't@rins dru85 dd 

chdacten4d b' !-v_vis. tTlR ed |H-NMR sFcltospv En€tgv ninimizdon slud'$ *rc 

ako cdticd out to detelnine the bihdinssit€oi'cfpnone dd int'dclinS dru8s Andbelcnal 

acivnics of cefptome sd celpironenrus contlex6 $€d ale €val@ted asriNl o@_ 

positive and Gdn_negative orgdisns 

4l

EXPERIMENTAL

IiXPERIMI]NTAI- 

cefpione (c.fromo 1g) ws a gin fom Aventis Pharmaceulical. capbPril ( ccropril& 25 

ms) fmn Tjld Phmaccutic.l kboEtories (Pra) Lrd. cnslapril (C'onec"lo mg) fbn Nabi 

Qrsim lndustri$ and lhiiop l (Lkinopilr 5 ng) li.d Arco Loboabrics l-d Anlioxidrnrs 

usd wrc vihin A fren Galxo smilh Klift Pakiste Ltd. vildin E. c and sdiud 

neladisulfile wcrc oblain€rl foh Phdmclo Phda. Dillien (Ti@do 60 m8) verapadil 

(cralan sRr 240 ng) ad @lodipi.e (s.lv$'5 ms) wde taken rren rlillo. Phama. s.lrle 

Pharmr and wilen s Pharmaccuricals rcspdilcly fhc essmial md lde clcments u*d 

wrc in $e lom of fteir hyddlcd el$ s Mgncsim chlonde. calciuh chbnd'. chbmilm 

chlo dc. manSdes chloride, feric chlotide, @bah chlorid.. nickcl chloride coppcr 

chloridc,2jnc chbndc 6d cadmim chlodde ot sFl},1ical gad. C.d.izine (Rigixllo ng). 

l.voceririzine (lrozina 5 og) and fexofoMdi.e (Iexelt 50 nel *cE obtained fton Ali Cohur 

Phadac.uricab (Pu.) I-ld. UcB Fmhim sA. Swilzerldd md ceD Pnatm Pakish (P\l) 

Ltd rdpeclivcly. Cim€lidine ( fagmslr 200 md frcm Calxo Smnh Kline P'tistan I td' 

lamolidine (ltilcr' a0 hg) tton Celz Phama Patisun (P\4) Lrd ud tdilidihc (lh Rec' 150 

ne) w€re obt ined liom zara Phm&.lli€al Labonroti.s (Prl) Lld GIiquidone (cluenoro 

l0 n8) frcn Phmatcc Pal'stan (P{) Ld, Pioslilazone iPioar! lo ns) aid nefomin 

Neodipes 250me) w€t oblain€d fron Alenlis Pidm Ns'\lDs usDd wer' dicloicnac 

$diun {Voltalr 50 fllg) lrom Novanis Pharfra. I utbipro'cn {Svnslgo' lO0 md fiom 

PladnuF Phm&euricsls (Pvl) Ltd, neloxim (M€lfdo l5ng) fron Ali Goh& 

Phadaceuricals (P{.) l,tt and mcfenadic &id {Ponsbr 

250 ng) wE oblained fioh Partc_ 

Dayis & Co Ld) Lt

orrhophosphatc. sdid chloride. mnonium chloride. anmonia solution 26 '/" and butlar 

oblec ol tll 4 Md 7, 4d and nulricnl bro$ ol Mere\. lt rmsladl, (;cmanv labolllory 

suppli.s. Dcionized vater @ used U@gh out tn. sik 

( EquipneDt rnd gla3rP.re 

tilecrrol bddc( lns 5lgn. d-!,Olngl. lMel|16 Tolcdo AB54l. pH mecr lM€(l€t 

'lblcdo Ml220l. UV Visible doublc bem spcc!rcpholomeld {Shimodtu 160l), I cm 

rccrmg'nd qlanz cells, greud glN dislillalio! Mblv (Quickno d€_ionid (Stda 

(s\\ 100), \arcr dislillarion unir (Gr-L lrF ?001,. No. 10791600C)- nchins poinr 

appd,lus (Oalhnranp), FTIR sp.clropholodctcr (Nicolcl Avalar 310). proton NMR 

(Brukr). HPI,C. Pmp 

Shimadzu LC'l0 AT VP. SPD_lO Av VP Uv_visible d€l€olor' LC 

20 AT vP, SPD-20 AV VP Uv-Visible d€tecor CBM-102 Bu Modul' imestabt lll r4A 

OD-5 lOO. Crr (5sn, 150 x 46 nm) collm, Pdosphcr Smn Cr (5!m 250 x 46 m) 

column- Medn@€ Cr (5Fn. 25 x O {6m) collnm trd Nuclsil l20 Cr(5!m 125 x 

All fie glswe wt of Pyrcx A gFdc, wshcd vith chonic eid followd bv rhtuugt) 

s.shing sith traier and {inallt nn*d snh dolblc dinilled 'r d'ionitcd walq- whtch vls 

fdshly prepded in th€ laboetolY. 

Disslutior Tst APP.dtus 

'lhe dislution equipmflt l23tl was ndufactucd 10 lhe 8 P 200? I2!ll sl'ndards which 

i.cluded lhe di$lution noror and leable spced ontoller with a sbinlt$ stel bosket 

a$enbly lhc lop of tne bskd w6 modified dd Fplaccd bv a conical he"d in ord'r to 

climide !n dra9'n nt dunne diselution whrch is noi inconsbr'nl with lh' presl 

uppardd dceriPrion. 'lhe diseludon @nraincr E ! iltl'bo om€d 816 lcsl with m 

lnkhal diddclcr of l0O nn dd wnh a capacirv ofone litc! dh$ludon nuid ftc la'able 

speed noror wG modi6.d !o rcdw. unwdtcd vibdrions bv ino4xmrion of 1000 210 sF 

!,pacitorin lhc speed conlrol cinuil and ss nainbi'ed ui{hin !0 5 % of the Equircd speed 

Rolalioh of thc baslet as$nblv was lixed al 100 1 rpm $ioushod rhe 'xpedm'nl $c 

disnnnlioh ns--nbl! \as imme6ed in *a(€t blrh ai l? i () l "C Aliqmls ol5 il q€E 

wnhdrdwniermntenllyal15nihulcstineinloNalforI80ninuFsandtssavedforlhedtug 

co.t nr aner appopri.t dilution Tn€ volune of disoluion fluid vd nainlained bv adding

d equival€ moul of disluiion fluid wnhdrasr! *nich ha p.cviouly b@ minrdn€d at 

samc lemp€rsrulc in rhe su. barh. Th. smpl.s \@ scon d in th. rdg€ of 200"?00 nn 

alainst Gagent blanl dd thc absibancc wa Gcorded. 

D 

Ddonktrt $1a: Dei@iz.l \\d.r *s lcpsr.d by psing ttouble dinillcd *als threustt 

Pr.porolioa oJ 0,1 M hriro.hloric @A $in,r'.ud s6ni. jtb.): 9 mL hvdr@hlonc acid of 

andlyrisl srade (16 %, I I N) lru kt n i. a ljter volumeric n$k &d the volme ws made 

up lo lhe lMt {i$ de-ionized w&r' 

Buf.t oJ pE a (cttotut bufr.l: ti wa tEpa8i bv dislline 3 ?25 s or porassim 

ohloride in a deionircd warci io one lit r, th€ pH was.djused wilh 0l N hvdrochloric acid 

sulJer of pE 7,1 (ptotphat. b6..); O 6 g oa pora$iM dihvdtogen orthophosph'te. 6 l s o' 

disldiun hydrogen onhophosphate dd 5.85 g of $drm chlotide es dksolved in sumcienl 

&ionircd sld lo prod@ 1000 nrl- ltd pH adjul€d it nadsaiv 

EuntoJp 9 (Mtuniu bulJ.4r Dhsolvc 498g of mmoniufr chloride in 1000 nL of 

d.ionizedsalerddadjustpHb9with l0%dnonia 

Ccipnome (00662 s) sas accmlcly scighed dd lrmsf€n d in 100 mL volumedc nasl' 

disellql dd the volm€ wd tDde with O.l N hvdruhloric eid Sinilelx e|ltiotr w 

prcpded in bulfes oa pH 4, 7.4 ed 9 ep@i.lv Thc conenlraion of thee primtv 

elurioB ss I hM Frem lhe prinury elndotu, worlins st dLrd elutios (0 01_0 1 mM) 

t@ pEpaEd hy.pprcprili. dilutions ii gs$rcjui@. in buficb o{PH 4, ? 4 md 9 

c4ubt'tiu .tNs of c4pinre in stnutdt d e6tti. iuicz (pH I) o'd h b'nd ol pH t' 

Th. .bove prcp.r.d wotking st nd.rd eludons w€E $ann d io th' dgion 200_700 tn dd 

absnbdce mdina ed @oded ar 211.769, 265 

^d 266 om ia sinllllcd sasuic juie. in

uffcr ol Dll .1- 71 rd 9 esFclively. The calibntion cudc trd obtained bv plotiog 

absorbuce of $eF solutions lcBus @nentdrion gers taw w6 ob€yed at all 

concenradoN, epsilon vdlu€s wete thcn calculatd at 5ll abovc descnbed pH lalEs 

II C.libntiotr .ud6 of irt.nctug dnll 

Cdlihtttion cury6 ol captoptil, eôloptil Md lisi,opril 

For ihe pepdrion of calibErion cwe, primary $l$ons of ImM dd mrkiry srdtdd 

solutuns di each conccnlradoh fom O.|)l |).l nM w€re p@p.Rd indilid@llt in sinulated 

sdic juice md b!ffcu of pH 4, ?.4 &d 9. A poPup sce of 0 l nM solulion 6 latcn in 

$e egion of2o0-?00 nm lor $ese $lurioB agaiN rhe Easmt bla.t The ftdina aPpaEd 

ar zol nn in simularcd garricjuice andpH ?.4,206 nfr al PH 4 dd 204 fln atpH 9 aSarnsl 

toagcnl blMk lorcaplopril, The L. for €mlapdlwas obsed€d at 206' 207.208ed 203 nm 

in sinulatd s6ficjuic. ed bufic6ofpH4 ?-4and9 rBpetiv.lv LisinoPtil mqim sE 

ob*r,-ed ar ?06 m in butreB of pH 4. ?.4 dd 9 Gnphs *G Ploned for aberbane againsl 

concenuation md a staighl line wd oblained which ob€ved the Beefs ltw EDsilon valu€s 

rvm €alculaEd al each pH. Simild pt@edN w6 adopl€d fo! otner inle6cring druss at $en 

cotihrntio, .uM ol dltiazrn, wtap.dit 4nd ohlottipite 

For dilliaen od ve6puil thc mdina app.4d al 216 od 229 nm in sinulded gdric 

ruu.n'l buiac6 of pll4.?4and9rcspec(ilclt ThelDrof amlodipinc wd 219 nn in 

simulaul sdric juicc dd bullcs of pH 4, 7 4 and 9 

Catibtutnn.un* o! clnaidqe,! n tdihe qntl Nni. li". 

The), '. ws obscd al216.26? dd 225 m in simuL €dga|ricjlie 218 267 and 223 

nm in butle.oapH 4. dl2l?.26?and228nnin PH 74and al216.267and 229 m ih bufcr 

ofpH 9rslin$reagenr blank iorcimeidine, famoidihe and dnitidine iesp*lrlelv 

c'tibt.tion cu'€ of dictoJenft, !tub*,oJa, wtfunn: @id and dtdi'M 

workihs elandard solulions ofech concenlradon frcm O'09 to 018 nM were prep@d 

th. calibrarion cune ofdiclofemc sodiun sd n.xima was Rcord€d ar 2ll m in bufi'r 

pH 4. aI276 m in blllcrs olpH 7.4 and 9

l'lurbiprolen. worki4 stardard $lutions of oncotmdon fmm 002 lo 065 mM wet 

prcFred i. buflds of pH 4. 7.4 &d 9. Th€ I ddinM eG ob$t€d al 247 nn in bulIer pH 

.1. 7.4 and 9 Whil. for fr.fenamic scid calibiaion rdge M 0 01-0 1 nM wilh I ndiia of 

285 nn in buicN ofpH ?.4and 9i loi neloxicd the onenliarion ra.ge was 001 to0lmM 

harne 1, 

"^ ar 162 hm in b!f&!s of pH 4. ?.4 dd 9 

CeIbNnu .uM ofon P..zok 

Cal'brarion curvcsot onepruolc werc ptptcd in lhe rdge 0l-I0 nM in sinulatd gatric 

joicc- bulfc's of pH 4. ?.4 ad 9. The ndi@.pFard ar 284 nn in sinulalcd galricjuie. 

291 m in bufld pH 4. 2?6 nn in buff€r pH ?.4 md pH 9 against cagem blanl 

|ll r, vtm cv.ihbilitiB of cefpircn€ .rd int nctiog dru$ in limultt€d g.slric itrice 

ind in bure6 of pH 4, 7.! .nd 9 

thc in !iko lvail.bihies ol cutpnone, AcL-inhibnon (aplopril. cmhpnl ed lisinopiil). 

Ca-chmel bloke6 (dilliusn, verapmil ed mlodipine), H.receptor antlgonisrs 

(cimctidine, irnolidine and tuiidine), NSAIDS (dicloftu edim, nubipbfn, ncftuic 

*id dd m.loxicm) dd prcton pmp inlibiror (onep@ol.) Ef@nce $andddr *.E 

srudied individually in sinulat d g6rt juicc (pH l) md ii bufets of PH 4 (pH of tull 

sbndch). 7.4 (bl@d pH) dd pfl 9 Gioultlcd ihtesdoaljuico on a modilicd BP 2007 

dieldion appaElus de*tibed cdli6 IO ng of cefoirome, AcebpnP (caFopril) 25 ms. 

( on€@ (nalapril) l0 ns, Lisi.opdlo 0ninopnl) 5 ms, Ti&m@ (dihien) 60 m& calm 

sRa (\€rapamil) 240 dg, sofvaso (mlodipine) 5 hg, Taee.lo (cin€tdiie) 2OO ng, Hil€!6 

llirnDridi|c).10 nrs. Hr R{o (rdiidine) l5O ng. voltal@ (diclofenac sodiun) 50 ns. 

stnalso' (nurbitrro,en) l0o mg. M.lfdo (m.loxican) lJ m8. Ponslto {@aenamic acid) 

ItO me and Riseko (omep@ole) 20 ng lablers w€e epaotely added in l'1, dis$lrion 

medim alrcady naintai.ed ai specifiet lehp.6tw (37oc) at lhe st.n of ih€ €xp€nmenl 

Aliquols of t mL smpl€s w.rc withdEM p€nodi.ally at findn ninn s tn int nds ibt 

180 fti.ures usinS sl6s piD.tlc vith a fih.r tip frem dis$lltion n dium &d Edaed 

inmediarely wilh the sne volune of the n diun mai .ined al $e smc rehFEluE Thc 

amounr oi drug rcleded w3 delemined spectmpbobnefically al its Lnax diseluioo

Inlsrction sludi$ of c.fDhob. wiln Acf,-inhibitoB, Cr-ch.nml block.G Hr 

reccpior rnrrgoni r, HrreceptorrnrrSonilk, hypoglyc.nlc rg€nls, noNl.roidrl 

rnti-in0.nb ory dn$ (NSArDt, prcton-Nnp itrhibitoE r.d rbrb. urirg 

UV,!i! roetmpbotoD.rrt rd h'€h l.rtomme lqrid .toE.tornphy(HPlr) 

lvA Inr.ncrions by Uv/vis *pectrophotoh.try 

/, r,/,? i craclion $udies of cefpirone witi AcE-innibitols (captopril, enalapril and 

lisinop.i.). Ca{hdnd blel.6 (dildem, v.€trnil and @lodipire), H?sceptor 

dragohisrs icineddim, fmotidine &d @nidiro. NSATDS (diclof.M $dim, nurbiprof.n. 

nefenamk eid and neloxham) aid Foton plnp inhibitor (on.p!@ol.) Befe cadied our 

indnidually in sinulated gaslric juice &d ii bu0eu ofpH 4. 7 4 and 9 al 37 and 60qC on a 

B.P 2007 Disslutio. App6Er6 dscnb€d cdlid. ln @h sets of cxperinent$ l0 hs of 

cclpiom. rd added to fie disslution nediM at am tiDe while e€lopdl GapbpriU 25 

ne. conec (enalapril) l0 n8, lisinopdl {ltinoflil) 5 n& tiu€n (diltiu€m) 60 me, calah sR 

(vcrapamil) 240 ng, sofv.$ (analodipine) 5 ms, ugmel (cim€tidine) 200 mg, Hiler 

(arnoridinc) 40 ng- Hr R( k nitidin€) 150 m8. voltBl (diclofcnac {diunl 50 ng, 3yMlgo 

(llurbipntcn) 100 ns, m€lr:* (m.bncm) 15 mg, poNtan (m.Lnmic ftid) 250 mg ed 

iek (oncpraole) 20 hg bblcts w€r€ spamlely added for indiridul inleFction sludies aner 

I 5 minutcs inteNal 10 efpiome in I liler dissolution mediud aheady maintlined ar specifi€d 

t€npeErurc (37'C md 60oC ) at lhe stan ofihe erp.rinenl. Aliquols of5 ml seples s@ 

$irhdatrn peiiodicaxy at fin*n ninutes tinc inl*als for I80 minltes aing gl4s piFtt 

snh. ihrr rit fmm dissolurion nediun and (placed innedi.t ly wi$ rne smc volume of 

the nednrN maintaihed at the sme tehpcdture, Tne drug cont€nrs seE detemined 

spedopholometrically at rbeir respeile l-, usinS the dGelution m€dim 6 blel. A gt pn 

sts ploncd for lhe % drue available v6s limc in rch s ofcxFrimenl. 

IVB D*clopmetrt ofHPLC nerhods lor.cfpirune r irt.ncrirydrus! 

.umber of sinple, sensiliv.. reliable dd rapid reveêd phs. hiBh-perfommce liqnid 

chonabgEphic netDds for lhe d€reminadon dd qwlifiqtion of efpircme od 

inr@ring druss (c.tlopril, cnalapril, lisinopril, dihiazd, v@pmil, mlodipi@, eddzire- 

levoceririzine. texofemdinc. cimeidine, dniidine. fmoridioe, gliquidone, n.rfomin. 

pioghaano, diclofenac sodiun. flu.biprofen. toefenmic acid, neloxicm. omoprazole.

ldsoprMle. atonasudn, sihvdtatin od pdvslalin) fom dosage fotns have b€en 

dc\cloped and lalidded which *de fie. applicd b dng_ddg int mdion studi's 

a h,onotoe ptic .ondinons lo. .4pitu e or.l id@a.nns droSt 

Mcrhod developnent- lalidation ,nd intettcdon sodies weie cdried oul on a liquid 

{hnrn,roaraphic s!{Ln consisrins of shinadd nod€l LC'IoAT VP punp. a Shino&u 

nodcl SPD-IOA-I VP, vdiabl. g.rctdglh Uv.vkible del*(or' Cbmmtographic svslen 

\us in(cgrarcd vid Shimadzu modcl CBM-102 Comnuicalion Bus Modulc to. Pentim 4 

l,(. S.pmlion of ccfpnode ad esscntial ad l@e elements wa cdied out on Bl'l4A OD_ 

5-100. Cr (lJo x 4.6 m) colum al dbie knp€8tuq mixtw ofndh&ol and *aot 

(15185. v/vl w6 used as a nobile phe. B.foE deliv@n8 irto lh€ svslen, il was filt€ed 

mugn a 0.45!n millitore filler dd degsscd in e lllrenic bath- Thc sdples w€r. 

inl(iuced dmuBh d inj{tor valv€ *nn a 20-|rL mPle lep at a now ale of I mL ni. l 

usins i$craric pump stsrem sd chomatoSrds we €cord€d at 265 nn Sme procedu( 

was repeatd for d$.r druesi however, colunn! nobil€ phasc, flo{ nte and UV delection 

Sepmrion of ccfpiren€ wnh AcE-inhibilors (capbPnl, eMlapril and lisinopnl) was 

conducred on a Purospher Starl, Crs (5[m, 250 x 4.6 nn) colum. ealylical revee_phasc 

column al anbicnr lenp.arue. 'lne nobil. ph6e foi cefpimnc. Qptoptil atd emlaPril 

consisted of nc$anol: {atd (80:20. v/v): pH B adjct d to 3-3 Mth orthcphcphofic lcid 

lo! lisinopiil. mobile pn6e co.sistcd of ne$dofMler (40:60. v/v. pH 3 3) which was 

pumped ar a flo{ rdle of I mL min i. Chronalogrtu were @o.d.d 5t 225 nm. 

^nri\iddrs chroDarosraphy $as conduclcd on a M€dil€fr..a Cr (5Fn.25x 0'l6nn) 

colum( nobilc phas co.sisrcd olSOj?O m.tha.ol: watet. Flow Ble wd I nL ninrMd UV 

d.t€tor v4 ser al 265 m. 

S.pddion of cctpnore sd dili@m (Ca-cbmel bhr.t wG cni€d ou on. Nmlosil 

120. C s (5!m. 12 5 x 0.46 nh). Mobile phase onsisled of melhmol water (30:70. !/!) 

\hich l-a\ punlFd { a now mrc oao.5 mL nin' For ccfpibme ad veraDMil mobile phac 

conpos€d ol m€$eol: @ler (70:30, v/v) *hit. (80:20, v/v) for cefpimnc tnd mlodipi*, 

nobile pn* @ pup€d at flow ral€ of t dL min I. Th€ d.Lcrion ws cdi€d out .t 248. 

210 and 240 nF for diltiem. !€rapamil md afrlodipine respe.tiv€ly.

Sinilarly. $e spmlion of cefpione with Hr-eepror etagonisl3 (cetitizine, l€v@efiiz'ne 

and lcrotinddinc) anlasonisls was p€rfomed on a Nucleosil 120. Cr (tsn. I2.5 x 0 46 nm) 

eal.{ical Evse phN column aI mbiql t mp€Etue Tn mobil. phN consislcd ol 

m€thdol: warer (65:15, v/v), *eronitrild wdd (75: 25. v/v) nor cctitizine ed lry@airizim 

esF.cti!.ly. F.xofenadine spantion wd cdi.d out on a PuGph.r Slan, Cr {5Id, 250 r 

r a, n,n) colLLhn xnd mobilc ph.sc consnted ofmclhsnol: waler(?010. v/!). pH was adlusred 

ro 1.5 *nh onho-pnosphoric acid. The mobil€ phe rd pmped al a flo* 6t of 1 ml, nin 

usins sradicnt 

puFp sysrcm dd emuds wrc nodbFd d 212 nm 

Analysis of cefpion€ *hh Hrtecepor elagonists v6 conduct d on a Nu.lesil 120. Cr! 

(rpn- ll5 r 046 nm)column usins mobile phae nerhdol: w6le(20i80, vh)ed pumPed 

d , Ilou rur ot I nl ni.i oring gndienr punp synen. ]n. emucf,ts veE nonnorcd at 

2il. 26t and 247 nm lbf cimeridin., fmolidin trd tuiridinc Esp€ct'vcly. 

sepdaion ol hypoglycenic agc.rs (gliquido.., n ltonin dd piogliia&ne) wih cefpiohe 

{s co.duded oh a Mednetu a cr s (5Fn, 2s x 0.a6 nn) col|m Mobile phde consistcd 

da meth.noli qarer (80:20. !/l. pH 3.l)- (30:70. !^. pH 3.4) ed (60:a0. v/v, pH 3.4) adjlstcd 

wft onhophospnoric eid rbr sliquidone, mtfomin sd pioslikzon. EsFctird' Mobil€ 

phase wd pumFd al a now dle ofO.9O (for lliquidon€) and I mL minr (fot pioglirdone 

aid n.!bmin). Th€ €flluenK were no.iloftd al 268. 240 ed 279 m foi gliquidon.. 

netlodin dd piogli@onc r.sp€ctiv€ly. 

In rhc scl){ratio of cefpituhc wilh NSAlDs. a Mednmnea Cr (5Fm. 25 x 046 mn) 

column wN used, mobile phM anshled ofa nixtucofmelhanol: water (80:20, v/v).nd PH 

ld]usrcd ro 3.1 with orlbophosphoric &id. Assy qd t domed at dbient leopemue ar a 

!lo$ r.rc oa I mL nir'' and emudrs wrc monilord at 265 M- 

ln thc spaotion of celbnohc with polon-pmp iinibnos (ohep@le a.d lmep@ile). a 

M.dircmnca C { (5+m,25 x 0.46nn) column w6 ued, nobilc phase etrnted ofMeOHl 

Hr() (80i20, !/!). whose pH 3.5 M adjusted *i$ onltophdphoric &id Mobile phde w4 

p@pcd ar a now me of 0.85 mL min ' .nd UV dctection w p€rfomed al 291 and 278 M 

for om.pMlc md laMpr@oL 6p6livcly. 

Sen.rRrior ofcefriotoe silh n6fns was conducied on aPuosnh.t Stan. C s (5Fm.250 x 4.6 

mm) column. mobile phsc consisred ofmelhanol: waler (80:20. v/v. pH l.a) for cclPilome

arodslarin. prarsrarin dd wr.i m€thdol: eclonitile (20:60:20 v/v) (PH q6 adjN€d to 

l..r ri$ onhophosphonc 4id) for €fuirene dd simvasl,rin Mobik phN wd pump€d ar a 

flow are of I nL min-l md UV deleclio. *as done at 240 m 

Pftpontion of rt'nd'd and w,*ias sotutins of ..hnN a44 idt Nthe.bugs 

sr@k solurion ol cefpircme (lOO ,rs mL L) ws squ€diany dilulcd virh d€io.ned wte' ro 

yield. 1 0, 2 0. 4.0. 5 O, lO.O and 50 ltg nL worldng shddrd solltio$ for Pepdation of 

srck solurions (l0O }e mLr) of cefpiroft &d enalapnl $€R diluled wirh mobilc phe ro 

1 25. 2.5. 5 0. l0 (].25 f8 mL r Capbpril st@k soludon (100 pg fr L') wa dilut d to I 12, 

6.25. 12 5. 25.0. 50.0 pg nLiwhile lisinoPril dilule.l lo I O,2 0.40, 8.0, 500 ps tLr 

qorking $andard eldions for $e PEPantion of@libEtion cw6. 

srock $lulntns of ccfpnome and diltadn conlaining IO0 Fg mLr w.r. pEpd€d bv 

dnsnringrhcm in freshlr prcn.€d d€ionied water. Th€* weE lhen dilured 1o1 25.2 5.5 0. 

oa ctlibalion cm€' 

| 0 o dd 2t.0 !g ml-r wo*ing srudtrd slurions for rh. PEPdlion 

Sbck elutions of vcEpdnil dtd dlodipinc wGE Fepared in n $ml dd itr|ha dilul€d lo 

I 25,2 5.5 0. lO 0.25 (] dd 0.625, 1.25,2 t,5.0, l0,O,50 pg mLrresp€crively 

stct solunons oa celitom€. €elirizin€ dd lcvcririnne (lOO llg mLr) w€ pepared bv 

dis$nine d.n in fEshly plepd€d deionicd waEr Trl€* wrc then dilded lo 0 25. 0 j0. 

1.0,2.0.1,0,4.0, s 0,6.0 50, lO,O ed 50 Fg nLr. Fexofoadin€ stock soluion (lOO |g mLr) 

N6 p.epdcd in nobile phs Aliq@ts werc dilutd lo 0.5. 1.0.2.0.4.0,7.5, 15.0 md 50 !g 

Cefunonc and cimeridine, la.itidin€ dd fmoidi.e st@t solulions (1(]o pe ml r) {€re 

flnhei diluled wnh deionizcd laler ro prepde 1.0.2.0, 50, 10.0.250 ed 50 ps nll 

sFnridd sohtions (l0o Fs ml,r) of cefuitutu. pioglitdone dd merfomin wcrc pcpaEd in 

rhen rcsDecrile dobile ohre The* stddard solulions werc diluEd to 0 78, I 5, 10. 60, 

12.5 250dd 50 Fe 6L'(celpircme sliquidonc 

pioCli@ne) while neiformiD w6 dilutd to

078. lt6-:l12.6.25. I2.5 25.0 and 50 tg ml-'wrking soluions wilh $en Espedive 

Srrk solnrion ( I 00 Fg mL r 

) of cefrione ws dilukd wilh dislilled wair lo yi.ld 0.25, O 5. 

1.0. j.0. 12.t. 25.0 ad t0 rc nL' mrting arard.rd elutio.s lor pGp.Flion ofcalibnlion 

cuF es Sbiddd nock mlution of I OO llg nL r of NSAIDS (dictof..e sodiun, Uubipnfen 

m.r'.nmic .cid and mcloxicam \€re pEpeed by dissolving rnem in mclhmol, tbe* sere 

subseq@tly nsed in lbe pr€pdatio. ofwo{iog stdddds (0.25.0.5, I 0, 5.0, 12.5,25.0 a.d 

50 rc nL ') by iulder dilulion with n€lbdol. 

Appoprial€ moum of eapibm€. oneptdk 4d ldept€zlc sd ItId to pttde 

shdard elutioN of lO0 fg mr'in mclhdol, C.bircme and oncp@le el off l@ 

tunh€r dilued o t0. 21.0, I 2.50, 6.0. 1.0 sd Lto Fg nL {hile l$opr@le $lulio. m 

dilurd ro 50,25.0, 12.50.6.0, LO, l.5O dd 0,7t pg mLr. Th€* solulions werc tn€n mixed 

Slandard elurions ofcehimmc. atononatin, pEldlatin dd sinvlsralitr conlainins 100 lrg 

nL' reE pr.p6Ed by disslvinS *h of lbd spatately in ncthdol. Thc elulioG of 

cefpiome. prat6b$n wft dilded 1o 20.0. 10.0, 5.0, 2.5. 1.25 ad 0 625 llg mL', while 

aroNsrldn and simvsradn see dilut d ro 15,0, 14.0, ?.0,1.5 od l,?5 u mL". 

hr.nrr @blers c&h ol Aetoprilr (eFopril 25 mg). Coi4' (mol.pril lO ns), Lisino9iil! 

rh$nopnl i mgr. liuem! rdilriMm 60 mgl. Cdd SR! rvmpmil 2aO ms).1rvdnleli 

Gimdidine 2oo ms). Hiler! (fdoridinc 40 m0. Hr Rc6 G&itidin€ l5o md, Glllmoi 

(sliquidone l0 ng). Pioz/ (pioeliluon l0 ng) Neodipd€ (m€tfomir 250 md. Voltrtl! 

(diclofenac ediun5o mg). Syhalgo@ (flubippfen IOO dC), Melfax! (mcloxicm 15 69). 

Ponsb'(metinmic acid 250 ne). Ri*!! (omeprele 20 dg), PDloal* (lffipruole 30 

nl!). Arona' (doâsbin 20 md. Lipix! (iidvadalin 20 m$ dd Phv&hol! (pnsbtin 

20 ng) wrc wiBhed &d firely sound€d. An amour equival4t ro eeh table' m wi3h€d, 

rdsfcftd lo a 100 mL lolmeuic fl6k, dksolvcd by sliring lor l0 minut€s ed lhe fin2l 

volume nade up {ith methaol, while nefomin ws disslved in walo Tnis primdy stoct 

nnrrion *"s lillcrd rhrnugh whahan 42 llllcr papcr a.d $e fillrate was funner dilded lo

peparc a *ond.ry stGt elnion. Ariquois of llE sond.ry slar $lulioro wr diluted to 

their esDe.fiv€ onc.ntntior dd lhe @plcs \rc erlyzd sirS llcn prcpos€d m.tl'od. 

v Cefpirom. drug int.n tion.tudl€ by d.e pbs. high pcrlom.n.. liq{id 

ch.omrlogr.Dhy (RP-HPLC) 

In second ser or exp.rim€nrs, srock soluions (100 Fs mL ) of cehibme dnd iht Ectins 

druss [AcE-inhibilo6 {aplopril, en lap.il dd lisinoFil), Ca-chmel bloct 6{diltimm. 

r€npmil dd amlodipin€). HFReplor eragonisls (einnne. levctirizinc fld 

re\orenadinc).llrKcplor fltagonisls (cincidine. mnidinc $d fmotidine). hypo8lyccmic 

aecns (gliqlidonc. melaomin dd paoglihan.). NSAIDS idiclof@ac ediM. nurbipoteim.femic 

eid &d n€loxicd). pJo|on-pmp iitribnob (oneFal. md ldsp@ole) dd 

sbtiru (aroruastatin! simvdain .nd phvNatin)l qee pepared in simul cd gdki. juice, 

buffc^ ofpll4, ?,4 and 9 individlally. Th6e soludons seF nixed in l:l ratio in Edenfteler 

flasls indnidulllt ond kcF on a wler ba$ al l7'C for the hous. The samples "€E 

wilhdram after l0 minulcs 1im€ inlnal &d drug conlent wre 6her€d tbrouSi a millipoE 

filtr (0.45!) ond af,rltzed by RP-HPLC. A gragh w6 ploned for th€ % dru8 avlilable rc6us 

dde in e&h *l of *e.ihenr 

C.lp i ro N t L t a n tiNidt, E 

Srsk solurbns ol 100 p3 mL ofcefpirche, vitffiins A, C, E and edim netabisllnle in 

deionird watr were prepd€d, diluted wi$ dejonizbd watd lo produce 50 Fg ml, I of each. 

cebnone and lihins slntions we nixed in lil 61io individuUy sd plaed on a mler 

ba$ al llc for halld hou- The&ugonr. s *c fillered drd dalyzed by RP.I{PLC. 

C.lpituft vitt .saniol tnd ift. .t ents 

sl] j4 mt, I of c.hnomc solution s6 pEpded in d€iohizcd *€t€r. I O mL of lhis solulion $6 

added in 0.58 of clch mehl sahi and wc kepl al 37"C for hall ao hour wi$ occdional 

sritriig dd filrced. Tbe @ enrs {de Mlydd by RP-HPLC. 

Srnrh.rnol.erpimDe. iDcncdoadrugj 

Complcxd of efpione with all int BrinB dtuss l,@ symhesized. Fo. rhis tulpGe 

equimol& elutioN ofcfoircn€ dd inreEcrins dtuss weE pr@aied ir app.opriate elve s

(mcdanol and wtt t). To cefpiome elutio.3. inl@ring drugs elurions wtt 'dd€d 

individudlly md rcflued for I hos on a saln b h .l 80pC {ilh on$anr niEnS Thc 

Fsuling poducls wer€ filtered $d leff @n |€npcdN for ctstalliztion Mchin3 

poinh and physical characrcrislics of thc* complex* wee nored Soiubilitv ol all the 

conplcxes wos caried oul i. diifere.l solvents as waler, methdol. €thanol, chlorotom and 

vlI Spc.lrtl ltrdi6 of .oEPl.t6 

rjv-visiblc sptcra w€'€ dord€d using Uv_visiblc sp€ctrophorom€E h is a double bcm 

sp..lrophobmaE, simlllaom6lv smpl. and bl4k quanz celh placed in thc insmmcnt 

The insmment was calibdted ed adj*ted the bas. li.e wilh the we elvcnl plior lo ftcord 

$e rcadings. lhc sp.clra weE scm€d in lhc tege ol2o0_700 @ All olth' emplcs weE 

lreaFd in rhc en. ranner. 

Celpibme and ils codpleteswE cha6lcnzd 

4o04ooo cmn. ArR (arcnualed loirl Efladon) or Sisn perfofter r€esory wc uscd lor 

the samplc (mininufr .nounr) 

ni Pruton NlltR stu.li6 

Pdon NMR slldics sft camdl oul on d Brukr iturm€nl 

fld chlorofod usingTMS 6 d int€nial $andltd 

vllt Arribrcl.ri.l3rudi6 

by FT-IR sFctropbolon€lr in fic tgion of 

'. 

deu&tatd wler. ndhuol 

lor dtib&t rial studics, disk $$@ribililv l*htiqE 6 enploved TlE diltusion l{hnqle 

develop.d by B.w d al 160?l re@nmend.d bv tne FDA [608] has b€eh ado/cd which hd 

nosr widcly becn lsed in the clinical hbodod€s 16091 

l hc orlsnisii cmployed in rhes sudi6 wrc diff.Enl clinical ielales of Gdm tositiv' 

(9opltltoc.us duew,cort eb@tdiun hoJtun,ii StePtocEM f@'alis a4l BEiII6

.,p.cirJ) and Gm-negativ. oeaniffi (Klebsiella pneutu,i@, Klebsiela rP.i9s. Shigella 

l$!ntc/t, s.hetichiu coli Pseudonorus a{uginoso Prokus nirabilis, Cihobader species 

Pe8rdion ot MadhLHbtfi tgq 

MucllcFtiinlon agd ws prcpded by dis$lving 18 gtms ofdgd lowdcr in 1000 mt of 

dciohi^d warer a.d cohplctely dissolved by heating on a waler balh. Thc agar soluion ot 

mcdiun vas lhen dhtribut d in oni@l flasks in desjred qmtily (18 mL). pluesed with 

couonandsrerilized inmautoclav€at i2l'Ced l5 Psi for l5ninui€s. 

P,.pa.ttiD ql nattur, brat, 

Nulrienl broth was prepd€d by disolving conpldely 13 grm of nutncnt broth powd$ in 

looo frL ofdeionized wal€r. l0 mL of b@lh wes ta.slened inlo lesl lubcs plussed silh 

rbsorbcnr cotbn od rhce wrc autoclaved for I t minut€s al l2l "C &d I 5 Psi. 

Pr.pomnu oJ tLi..l p.Ao .lE 

AccordinB to Federal Drus Adoinhllation St ndoids tbc 6lter tdper uscd for thc prcpmtion 

oldislt lor sns*plibilily ssays should weigh 30 mg + 4ng/cn'dd should absrb 2 to 3 

rlmcs ns ow veigh! in wler. Disl pcpand fbn thh fihd 9ap.r should bc 6.15 mn in 

dimcrs 16119l. Disks wrc pepr€d *nn lhc llelp of rubber hole puncn€t shos intenal 

didelf f,6 6.i5 nn, wr rh€n inneed in 2.5. 5. lO. 20 ud 40 FB nlr $enliad 

slution of cefpirone and ils conplex4. wd€ dti.d md€t ldind flo* snd stor€d in aidighl 

conrainer conraining silica gcl. 

Papantion oJ ontini.tubn l pleta 

Slsilizcd asrr ss addcd ( | 8 mL) ir the sr€riliz€d Fri dish6 od wd lclt to $lidify 

Pepantion otno.k add w inq elutio$ 

ccllrircme sroct $lution (lOO tg mLr) was Feped in (].l N HCI and funher diluted wilh 

sme elvenr !o prep@ 2.5. 5.0. I0.0, 20.0 md 4O.O |rg ml- r $lulions.

ln ordd ro sludy fi. mlibsldial lctivirie of afpitsm @mdq6. thcy qft trrldc sluble 

i. mall Dou.r oadimdnyl s'nfoxid. (DMSO) ed find vdM€ I ha& up *ith 0. I HCI 

b prepaa smk $hioro (loo Fg nl-r). Th€ stek solodois wrc finher dilur.d wirh 0.lN 

IICI to prpac 0.25.5, lO.20 ed40 rc mLrelutions, 

orSmisms studicd *€E tat€n lion thc sl&r wiln ln. h.lp ofNiE loop od wer. inn.^.d 'n 

fte ob. @nraining nu|riot brcth dd dE lubc w6 imubatd a13?oc for 4-6 hE $t lnc 

turbidnt excadcd th.t of 0.5 M&Fdland s1dd.id. t6r0l, The orgEnism (d@dy greM in 

.utien both) v* slle.rel @ inc sufae of .gd of ppp@d Fei dishcs vith th. h.lp of 

n riliz.d *nc loop The disk ofcomplcxd atd dru8 of sm€ concoFations ftc pl&cd on 

the agar plarc and were covered by othcr retn dkh*. All work was canied oul under l.mins 

l ow Thce p€tri dishes w€r€ incubat€d ai 3?'C for 24 hous md lhe 2on€ of inhibitio. wd 

measued rvirh rhc hclp ofvmid cslipcr.

RESULT AND DISCUSSION

RESULIS AND DISCUSSION 

/r ,.rt Inr.ndio. Strdi6 ot C.himD. qtt l.t n airg Drugs by Uv/vi.ibt. 

spdtos.opy .rd Rd.B.d Ph.s Hisl P.rforD.n.. Liquid Cbrom.roanphy 

Cefpnomc h a C-J qutenary mno.iun cephalospori. which beds a 2. l"cyctope mo 

pyddrn'um at the C-l posnioh of the cepheD .ucleus. Ir 

be.rs a carboxyLio 8rout, an mino$i@lc ing ed /"-n 

nerhory goup afa.hcd lo the nirrosen, eplbl. ro fom "n* 

irt nal hydrego bond yith the mid. hydmSd. It ha 

biord sFctnfr of &tiviiy againsr ndy C@-positirc md 

Gdfr-ne8ativ. ba.reria [83] As di$6s.d rylier. efpiren€ 

sperophoonlrry. porenriom€rry [9?] md HPLC I92,98n011. 

The bioavailabilily of drugs ar their sit of &tion cs be afiered by int€racrion wirh ouer 

drues S€vcdl studies conemed th€ biocn€mical &d phmologicat elfecr of eihicrobiat 

reenG vh€n 8it.n wnh oth6 dogs 16l l l. Vuios int @rio.s Eponed inwlvc mdy f&roB 

1612. 613 | bd such i.l@lions my be p@dcd by d@rca$d dislurion poor aberprion. 

Dru-q intemctions ommonly occur itr Dsrimls @iving lretrnot $ilh muhiple mcdi€io.s. 

All dru8 inl.@tions have a ph@acotindic or phsm&odtrrdic hNis od @ pFdi.rable. 

DruBs aE melebolized in hnne body i. diff.cnt woyst thcy de oxidizcd, Gduced or 

conjLr8alL'd lhcy also hale electron donatins dd anracting siles to which oth€r elehe.r or 

dtug tesenl In thc me envnom.nr @y inrc@t. Dru$ nosr liable lo po* pobl.ms ft 

rhN h,lins con*ntaaon-dependent toxicny wilhin 6r clo* t6 rhe deratculic tug.; thos 

with sl€ep dos-rsponr cw.si rho* havinS high fiBl,pds metabolin or tho* *iih a 

sin8le, inhabitabl. oule of elimiDtion. Xrowing which drugs poss $c* ifiriisic 

chamcknsrics. rogcihcr with lmvledee oi h.pdic cltochone P450 n.hbolhn ud 

connon enzymcrnducing ed eDyme-inhibiting drugs M er.ady a$jsl ir pFdicriig 

lnlemcrions lhat mal be clinically relevsl. h h of Breat importflc€ to predicl in vi!, 

phmacokinetics in hunds baed on t ytuo d.ra i614 6151. 

Literatw suêy Eveal€d inlen.tion of cephalosponB wilh minoSlycosid.s, diuctics, 

mhids and Hrc.plor drasonisls [l]I201. Howv.r. tllc is m rcpofl€d i c@don of

nr.r.crion {udics of ceftnon. wilh AcE-inhibiro6 (captoFil. enalapnl and lisi.op.il). 

Mioxiddls (rihins A, C md E and snium ncrrdis'I6r), hldbr€d salrs of csnlial {d 

l@c el@o$ (nagnesiw, calciM, chronim, n@grnse, f.Ec, €oball, nickcl, copp€r, 

zinc md cadmium), Ca-cnmhel bl@k c (dilie.E.v€rapmil ed dlodipine), HF@epbr 

rtrraconisrs (.crni?ine.lcreernDinc ed texoffladi.e). Hfeceplor ulasonists (cimelidinc. 

r.nnidim ed limoddinc), btpo8lycemic asenu (Sliquidone, m€lfomin dd pioglilaane). 

nohsreroidal &i-i.nslmalory dru8s (NSAIDt (diclofenm sodiud, flubiprof.. mefendic 

acid md meloxic@), pmloh punp innibitos (onep@ole dd lesoprele) ed stalins 

l.r.^?srarin. iimlaslalin and pmvanat.) wE cmied oul usins Uv/visible 

spectophotomety md hieb Frfomee liquid chtunatoghphy (HPLC). 

I Inr.rr.rion Sttrdi$ by Uv/vtuible Sp.crrephotoh.try 

A Cttibntion.M oJnJM.. stu.bdt oJtl,ugs 

'l he UV specrroscopy nelhod was develop€d for $e q@tilalive 6sy of efpimoe, whnh is 

:clsln.. scnsililc. rapid dd trccise dd enployed lo. ou $udies SDecmpholonelenc 

D!fte{ is sinrplc !s oDpared (o othct nerhods. This dpel of sFcttopholonekic s.ltsis is 

ol nrajor rnteresr ih ulltiql chcni$y sine il ofeB dislincr Possibilitv in th. ssav or a 

panicub componenl in conplex dossse fomulations The eag.nls used in lhe pepoed 

nNhod .rc chciacr- rcadil-\ aviilable and $e r@edute docs not involYe tcdious smple 

p(pdrio. for $e 6e, ol elpiomq stdl $lltios of lmM wrc prcp&ed in o.lN HCI 

(simulared sasfic juie), buffd ol pH 4 Gimulating tull s!om&h), bulier of pH ?4 

(simulatinsbl@d pH) odpH 9 Gimulaling intc$inal pH) ed dilu|d lo ance dtion rme€ 

of o 09 b o.l mM sing the sn $lvat A popup $e of st@t elutioG wa M in th€ 

rceion of 200-700 f,m asainsl lhc Mg.ni bldL 

lhe ih" $as obserued at 2?1.269,265 ed 266 nm in 0.lN HCl. buller ofpH 4 7,4 dd pH 

I espedinely Thc absorbdce at L- sd rccoded ibble 3 l) dd calibration cuo€ of 

ob6orbdce againsr @n€enhtio. w.rc plored which ob.yed B€ s law (fi3ut I l) in fi. 

co.ccntdion nnSc 0.09 lo 0.I nM Mole absry(vili€s N€E atso colculaled (labh 3 I ). 

wodi.ssolurioB seE pEpared in dE concentrtio. rese 0.05-0.14 nM ior caPlopril dd 

0 0l'0.1 mM for cn.l.p.l ed lisinopnl from sr@k elulions. Th.$ $@ ihd s@ftd in rhe

ljvîsihle EEion aS.insl lhe rcr8.nl blank. Thc ndiM of celopril apFlrd dl20l M in 

simulalcd gdtric juice, ar 206 nm in pH 7.4 dd ar 204 nn in pH 4 ad pH 9 Emlapril 

show.d mdima at 206 m in sinulated 86rric juic€, 207 m in pH 4. 208 in pH 7.4 &d 201 

nm in nl I 9 I isinopril s ndima @ r@rd.d at 206 nr in rll bulfc6. cEpbs weE plorkd 

aor ab$Ibd.e asainn @ncendlion md a st6i8hl line w6 oblaincd shich obcyed de B!.is 

la$ aL ull pH (fi8nres 1.2-1.4). Epsilon valG wee calculakd en @h pH whichee snown in 

calbralio. c@es Iq Ca{hmel bl@k6 (dilti@n, vdp@il ed alodipire) wee lin d 

in th. @ncenhrion @g€ of0.01.0.1 ntM. A popup s@ of sroct elution ot@h of lh.* 

JruSs $as run in lltr rcgion of:00-700 m againsl $e eag€nl blsnt. The 1,.'. of dillimm 

was obsened at 236 nm in simular.d g6rricjuice ed aU bufiec v€npdil 3howed ndind 

d 229 'h in simulakd g6lic juic. dd blff.6 of pH 4. 7.4 sd 9 AmlodipiE a!$rption 

naxim. appesd !r 239 M in simuldl€d sNtric jui@ ed bufl4 The nolsr ab$'ltilities 

and lh. naxima ob*d.d @ giveo i. lable l.l lnd ploned in lig@s 3 5-3 7 

lt, -M.ptu Mtqoniut 

l,or validdion pur'os r€f€Ence slard&d solutions of Hd€ccplor etaSonhts (cihetidine, 

raniridin. ed fdoridire) Bft sludied. Th. s16k elutios (ltrtM) w.rc pEp€td 

indrdurllt in snnulaL.d Sstic juicc &d builc6 ofPH 4, ?.4 ud 9 workinS slulioc frcn 

rhese qere pEped in the @ncentr.lion rd8€ O 0l_O lmM for cimetidine and reilidine and 

0.01 (). l: .lll lor feDlidin€ Th.sc *crc rnch $m.d in thc rcgion 200 ?00 m aaaiNt lh. 

sgem blant. All lh. tttre desonisls obey.d &.ls l.w i. ih.ir @rc6@tion dse 

ln simuldred gslric juice $d b!fc! ofpH 9, cidctidile absoPlion ndiha *as al216 nm 

rlo$.\.r. rn bullert of pH 4 dd 7.4 lwim Bd al 218 and 2l? m EsFcivelv Tnc 

.'1\!{rrl(tr, r\inr of dnilidinc lppcaFd ar 225 nn in simulatd Sdncjuicc, 

d 228 m in 

buffcrolpll,l md pll7.4 &dat229 min pH 9 ln c& of famoridi ne, ,bsorption maxima 

E rccorded al 16? hm in sinulatd ga5ric jui.e ,nd all buffcs EFilon !alu* wrc 

c,lculd.d ar ech pH lor @h dtug (bble l-4 ngNs l 8-l l0).

5 Nnll.toidolMtiislahdototrdNst(NsAIDs) 

Due b $en iNohbility i! simuld€d Eeic juie, NSAIDe wE asy.d in buff6 of PH 4, 

7.J ed 9. ln buller of DH 4, d'cloL@ sodiM shoued lberplion nuim al 271 m. 

llurhipiofcn !1247 nm and meloxicam at 162 m. while in bufle6 olpH 7 4, md 9 dicloltn& 

$dium rberb€d ar 276 m. iurbipblen ar 247 m, mef.ndic eid ar 285 m . d 

mdoxicm al 162 m. Dicloa€Ec $dih ed mcfmic eid obev€d Beei s law in fie 

concentrarion rdge 0,09-0.18 ed o.0l-0.1 mM rcsp€ciivelv wbilc meloxicu md 

nurbiprcf.n in $e @ftcntlllon nn8.0.Ol-0,1 ald 002'065 6M in.ll hff4. Mde 

aberDrivili.s of a€h drug wft calcul.tcd {hble 1.5) md ploircd in figuEs 3 l l _1. | 4 

Wortine $lurions ofom.pEol€ *@ pEpaed in ihe ondnitation dgc of 0 014 l0 nM 

from the stoct slutions 6d rhen cdibntion .wes \@ fosd ro be lin a (fis@ I I 5) The 

dina opFed ai 284 M in sioul.l€d s6:lric juice, ar 29lm h pH 4 lrd ar 276 m in pH 

7.4 dd 9 respeclv.ly Mold absor ivn, val@s wet ctlculat d ar €ach pH (table 1 6)' 

Trblc J l 

Releurce ealdard oJczhno^. k sindakd sshi. juic. lp t ) dd wk6 htlf^ 

0.321 

I ll8 1.221 

0.t33 

o.264 

0.ttl 

0522 

0.620 

0 8rl 

o.2tl 

lm35

0_0t 

T.bL!.! 

R(f@kce ldnaod afAcE i,hibitar! i, sin dedqei. j,iea1dwtoabtfe^ 

0t2 L053 

0.01 

0.08 

0.231 

r.091 

1215 

0.33r 

l.0ll 

3615 

0.490 

L253 

0162 

0.6,13 

Lt0l 

L25t 

t.5?r 

pH ?.il DH9 

0,5l2. 

0.610 

0,782 

0.879 

1,152 

|.202 

r,29 

0.t99 

0.171 

0.362 

t.206 

I lll 

l.J2l 

0,172 

0731 

tt533 

o.632 

t.032 

|.266 

0.531 

93ll 

1.127 

t.502 

r8390 

0.320 

r.2t1

0.03 

008 

0.01 

0_m 

T.bt JJ 

k4eror! rdAtd oICa .tnmt bter. in sinutd?.1 Eastic j'icz and w'oa bufqs 

0 r36 

| 217 

0 r91 

0.591 

0.158 

l.t0l 

r 2tl 

|.an 

0.320 

t051 

LlTl 

0 t23 

0.136 

0.2r1 

0.527 

0531 

0.r30 

0.155 

0.7t1 

L24t 

1.597 

0,t26 

026 

0.136 

0.t71 

0.010 

0.160 

0.22r 

0.275 

0.121 

0.382 

0.542 

0.173 

0.'0 

1.,56 

I 513 

|.gr2 

0.Ltl 

0.321 

o.921 

t.039 

trSr 

r2215 

0.t36 

0.u3 

0.511 

0.593 

6t28 

o-t17 

0.511 

0.?28 

r.288

o.2 

0.1 

T.ble 3.4 

tufuo,a ldtntur olHr2elu dtdsu^B in tinulated 3@i. 

0.200 

0.365 

0.591 

|,311 

|.567 

t.7t5 

0l 0.178 

0.182 

0.519 

I 

0.591 

l. t72 

I36l 

0.r68 

0130 

1.107 

16531 

0.373 

0.561 

t.037 

Llt3 

0.333 

l0ll 

|.261 

1.393 

2124 

0.212 

0.314 

t2a2 

t6533 

1,152 

jui9 t tdwio8 hqdt 

1.033 

1.253 

1.355 

1.573 

0.224 

1.020 

I t62 

0,863 

t.ll3 

1.212 

1.311 

D&13 80? | 6ll t137&

Concctrtrdion ptl4 pH7.4 

Mx 10 271nm 276 nm 

rl 

l5 

1.0t3 

|.296 

t.336 

2 

3 0.421 

r.hh 3.5 

Reharce tmdatd oI Ns,atDs B vdio8 b4^ 

llrT 

1 325 

| 4!2 

1.5t7 

l0B7 

0.Bl 

0.131 

0.501 

t.221 

|.75t 

0.2.57 

0.195 

1.062 

l 221 

1.35J 

I 176 

1.67t 

conccndarion pH 7.4 pH 9 

-M.f.nmiccid- 

5 

9 

0 220 

0,t03 

0.153 

0522 

0.732 

7'l1 

- Flubiprcf.t 

C@@nhrioi DHr DH74 PH9 

M r rtr' 24? m 2.47 nm 241 an 

2 

2.5 

l 

1.5 

Ll70 

0.331 

0.347 

1.032 

|.272 

t7452 r.l t5 t t359t 21650

02 

ol 

06 

0t 

0l 

I 

Lrbta 

r'Jdid'ldd 4 qd. b e',,'d Edi P.td *IN &' 

Pll I pH4 sr ?.1 Pt|9 

02'i 

o-ar9 

0.558 

0.6l' 

oa26 

0,96t 

r!'2 

r:$ 

0,lt l 

0rt,l 

0.559 

0,704 

tfit 

tt$ 

r3a 

t.az, 

t,65t 

0,060 

olt2 

0.1?6 

022t 

0& 

0.!36 

03r0 

(I5|l 

0546 

0,ll2 

03't 

0.tx 

0lt6 

o,aro 

ot7t 

0,614 

0m 

oaat 

0,9!5 

rott l@t9 5612 9':lt

e 

? 

B 

ktrx * otahtr t *ed @ ata d tu t tta 

qie tu d.q.Fr,*'btc t*t|'b dtu tqtt, 

cdbryr'r1 

ur6e ldrt6#@t qd'q4h 

*"

a 

I 

g 

i- 

,.brE e{btdrtutltb 

,4@*dM.-tu'{*tddtut$r. 

e.b"a e 4@4 t -rt...d@ sd 6e tt6

I 

t 

I 

3 

a 

t 

I 

br.e d q'bat* r - dt r& ra a * tdu 

6ddb|xrrJ) 

ho@ e r! d.i6' b,bd.6 !'E d tu t'th 

ir.', 

lved.IbetMarnd-erdtn

!" 

2 

a 

t 

.: 

,44aeotdn-dBabd@r.tt 

tutaa at,c.td.t N&.t5. @ t4b 

ocrdbi(Mr ro! ) 

tutwtud,t66a.k& b t4t4olPE 1t d e

t 

I 

I 

{ 

&IawtuqI,M btut'lr' 

a4'e-.b'd.tMrtd"4tn 

RthQrQ addd oto.o@h q t|tuha F* j* a w8 rda

8 ln tbtu te aUIMa ol c4pl@e, ACE-ldhWo^, Ca4nnDd U@ka, Hr 

r4.No. atu,.onbrt, NS,lIDt Md prcton panp lrhlbitd 

Prid to druC inl.etiois si!di6, u rtuo rvail.bilili.e of c.ftituh. dd ini.dctin8 dNSs 

wE sndi.d in ihci! dosrc fmulaiiom. For thL tlrtos eflirenc. AcE-inlibitoa, Ca- 

chontrcl blckc6. Hrrcc.pror dragonbrs. NSAID. 8d pbron pmp inlibiroi wE lddcd 

!p!ntl) in onc lits di$lution mcdiun (iinllrt d Sanic 

jui.c (0. I N HCI), bufc6 of pH 

.1. 7.4 or 9 in iMilidul cxp.rih.nb) didrjrcd d l?oc- AliquoG of 5 nL *ft wilhdr.M 

Friodically d fin&tr miNlls dm. inLful3 fd 180 minut6, Thc vdlm of thc disbnon 

nedim B tuinr.ined by adding .n cquiv.lc tuur of dislutiq fluid withdFq, 

sdich @r n.intdftd ll th. s. t nDaiiE i. thc a.m disltnio. !p!.r.tE nE 

abslbme ral*s of all the aliqw$ EE ledcd by Bing W-vis spstrcplDtorcr.r !r 

$eir cpccrivc Edin. which showd thc drus a!.ilabihy .t p€nicula dmc. 

In. .v.ihbility of ccfrimc at 3/C iicrlr!.d innidly 

deoa*l to 77.91,70.90.66.58. trd 75.60%in simuht d 

bot !t lh. .nd of dpdinc'n it 

8lnric jtic ed in butrcB of pH 

'1. 7.4 Nd 9 cspccrivclt, l-h.* dsults @ ptlst d in r$lc 1.7 .rd ploucd infisml.16. 

'l he alaihbihy of cllropril tu8.d 6m 92,88-100,E3 % in rimlld.d 8|iic 

j!i.., pH 4, ?.4 

dd e. {rablc 3.8) an.l (fiaw l.l7)- Simil&ly, cn l.Fil wa.v.jlablc upto 97.6?, 102.?0. 

95,91 and l0l.8l 9/. in sidul.r.d glsrric juie, pH a, ?-4 sd 9 Esperiv.ly (rabl.3.9) 8d 

(liguE Ll8). LtinoFil avaibbihy I in th. mg. 107.2+84,24 %, 106,81.101.5t % &d 

I 07.6?- 102.l2 % in burcB of pH 4, ?.4 and 9 nsD..tircly {tabl. l. | 0 ad fisw L l9). 

l)ilriozm al$ showcd imrcas i..vail.bihy as shom in bbl.3,ll .nd plon d in figuE 

1.20, Av{ilabiliry of ver.!6mil incc.s.d to 84.1E,91.84, 101.38 &d 93,01 70 in simlllt d 

s$tic juie, bufis ofpH 4,7.4 rid 9 EeFcriv.ly (hbl.3.l2 &d IisG 3.21). In ce of 

mlodipi!., avdlability wa | 15.15 7. in sihulat d g!$ric juic., | 29.91 7o in b!trd of pH 4,

7l .16 % in pH 7-4 .rd 103.69 % iD buff.. of pH l. Th4 rlsultr !f shom in bbl. 3.l3 ud 

l0 Hr@yo nngorlrs 

cimcridine w6 avoihblc upro l@ ed 99,J4 % in simuld.d g4rric juie ed pH ?.4 

rrsplcu\.1). lldsrlcr, il d€c@d ro 12.? % i. pH 4 sd 67.16 % in pH 9. Th.* avoilability 

rosults N prc*flcd in t bl. l,l4 &d plo{.d in fig@ 1.21. Simih.ly, mitidin. w6 

avaiLblc in sinuhcd gairlic juie &d pH ?.4 rnd 9 upto 9.9E, 100 .d EE.0l % 

r$rcdi\clJ shilcdcco*d b 10.22%inrH4(t btcl.l5rnd ligc 1.24). Fmolidirc wa 

av.il$lc upro 100, l@.49.rd 99.?4 v. in simuLrcd Ssirricjoie, btfIcB of pH 4 ed ?-4 

6p@1i!clt whilc de@!.d to | ,09 % in pH 9 (Lblc I 16. ligw 1.25). 

tt Non-sktuidal.r&irlbdiear,4tqsAlDt) 

Diclot€ru sodim 6 .vailrblc in dl nEdims '9lo 96,22, 95.57 ad 104.04 % Bpelrvdy 

(ubl. I l 7 dd in lisuc 1.26). Fllrbiprefo E .v.ihbL up to 95.90, l0l.02 rnd 95.66 % in 

blftd ot pH 4. 7 rnd 9 EsF.tircly (tablc 3.lE .nd fi8m 1.27). M.f.mic rid w6 

.vailcble in fic Mg€ ol12.64-98.91 in pH 7.4 rnd 9,a shoM in obl.3.l9 dd plot d in 

fi8u€ 1.28. Sinildly. availability of mloxi@ in.llm.di@s (pH 4, 7.4 lrrd 9) B 95.90, 

96,3? and 97.?7 % Esp€crir€ly (trblc 1.20 rnd lig@ 1.29), 

12 Proto"-rattphhlbltd 

I hc avail.bihy of otup@.lc sa 87.62 sd 164.69 % in 3imulrt d Satric jui6 &d bufr4 

of pH 4. *niL n d..c!$d to 17.78 atd 3.2A i^pH7,4 trl9. The cadr3 c pllgLd 

i. labl.l.2l ud plou.d in figlr.1.30.

T.tL J.7 

lNitdhitut oJ ehiM in tiadd.a aNrE JttN tpH L dd i" wiN b64t d 37"c 

Absd-??lnn %Avlil. 269nm %Avil. 255nm 

lTin.{ni6)+ pH | +

Trbl.l.9 

f,vdhb it, ol etu\aqi| in :isuta.d 8lshr jtic. lpE 1J dd i, wioa W.B d 37'L 

abs..r+ 206 nn %Avail. 20?nm %av.il. 

ffine{fri',s) 

1t5 

43.31 

62 ta 

33.29 

0.272 

0353 

0.388 

0.4t5 

70.22 

7688 

80 r5 

83 26 

86.21 

39.11 

91.94 

02ll 

0,242 

0.235 

0,30t 

0.1r3 

0.333 

0.155 

0 t72 

0191 

51.34 

fr.52 

3l t4 

,\hs db$ rncq "/. tvail = % avlillbl.i En.hpril .dr.d = 2 65 x lo!Mol.s 

.\bs ar - ?06 nn %Avial. 

llin.(mint< pH4 

-> 

t30 0.327 

T.U.l,l0 

Atu'lobilitr ol |itkoptit k wio8 b!&B d J7"c 

0.399 

0.163 

t0t.r7 

r05.12 

l0t.tt 

0.311 

ak - sb{'nanc.: % av'i! = % aviil.bLi LbinoFl .dd.d = ,1 60 r lot Mol6 

0.13t 

33. t4 

101.31

T.bt r.ll 

.tnitahilh'of dilien i, wiN brfi.'s o! 37't: 

,\br.d . z16nn % Av.il 216 nm %Av.il. 

lTin. (mins)

l0 

7t 

T.bt.3JJ 

/t\ uitohititf ol dnt.dipire o linttated sdtth j"ic? a1d in votw bulfuA at 37eC 

0., 1 

0.378 

Av.il. 239 nm %Avlil. 

-+pH4+ 

ll Ll3 

t20.t3 

0.4t1 

|]9.l I 

t!7.04 

tt4.o2 

129.93 

0.39t 

0.434 

o,,r]8 

70.11 

1t.11 

Ahs Ab:orbrnoq%av.il=%,voilablqAnlodipin rdd.d = 1.25 x l0)Mol.s 

r.t|.f,.la 

o3m 

0.340 

lwilabiLtyofci@direitti.,t'Ld4rge4rtcjtt at l @ioa WIls d J1'c 

61.6t 

,2.25 

4132 

t00.32 

lol.0, 

Abs,.r- 2f5nn %A$il. 2l3nm %Ahil. 2l7nn % Anil. 2l6n .AAril, 

lTid.(ni )< pHl+< pHa+ +pH7.4-> < -pH9+ 

t20 

lt5 

130 

L 115 

L 427 

1432 

t.452 

r..r53 

t,459 

91.83 

98. r7 

93.31 

r.65 r 

1.7t3 

t.t94 

|.122 

l98t 

8.60 t.651 

9.t2 L651 

11,2t 1,655 

10.92 1.652 

.23 L665 

lo,9 1.668 

| 1.0! ts7) 

r2_m r.682 

99.01 

Abs-lbcotb.e:%.v!il=%.v!il.bt :CinEridiG.?.93 x lorMol6 

0.190 

0,276 

I,06I 

1.063 

t.073 

5.04 

I t.34 

38.22 

56.21 

66,15 

67.01 

67,t6

T.bt.3.15 

tw abnool reiudiE k situtak t eAnk juie ddwioq blteB d t7"c 

Abs-:r - rtnm %Avlil. ,3m %Av.il. 223nm %Av.il. 229m %Avlil. 

lTim. (mi6x- pH I 

120 

135 

-> 

95.27 

< rH9- 

t.633 

1.556 

2.210 

t.523 

t.715 

2 t.05 

2t,a2 

2 t,08 

11,27 

21,63 

24.5t 

2121 

t0.22 

0.135 

0752 

9713 

93.30 

Abl ,be'harq % av.il = % .!rilrbl.: Raitidin. Addcd = 4.77 x l0- 

T.bL.l,t6 

0.72? 

,lruitlhitrD oJJmttutk? i' sin aed E/ek juk. atd wioa Wds d jTdL 

8?28 

Ab5 ir- 267nm % Arail. 261nn %Arril. 267im ,.awil. 261.n t/oAwillTinc 

(nint< pH I >+pH4+ +tH ?.,1--.J < pH9- 

6A 0.|2 

105 0ll9 

120 0. t2r 

D5 0.122 

&3.17 

0.323 t48.29 

0.479 157.32 

r.050 188.07 

0 tll 

0 t39 

0,149 

0.152 

o,t52 

0,rt? 

bs ab*brnce % av.il = % a!.il.blq lmo dirc rd(H. l.19 r l0r Moks 

90.?3 0.t02 0.91

,^be. d - :tlnn %At.il. 

lTim (mi.sF- pH,l + 

l0 

?i 

It 

5 

t3 

0,217 

0]ol 

0.70E 

t.oal 

t.030 

l. I 

T.tL l.l7 

twitabiti, oldi.t&M ediu it wiru MbB d 37oC 

5.23 

r8,79 

t1.1t 

6t_12 

51.51 

90.25 

96.72 

0.680 

l.t06 

1.518 

1.631 

I.650 

|.611 

0.51 

ao.l I 

65.21 

90.11 

97.26 

0,122 

t,316 

t.660 

t.701 

l,?05 

t.63ff) 

r.6?8 

t,?00 

l5.rl 

I0t.53 

t0a.t5 

101.43 

r02,6t 

102.75 

Abt _ lbsorh.M: % .nil - % .{iLbh: DaloL* ediuD .dd.d - Lt? r lor Mol6 

t0t 

t20 

Il5 

r50 

165 

rdk 3.ra 

twildbilitt olrubipqn n waa bqbn d 37'c 

Abr. { - :a7nm !t Av.il. 

lTiic(fri6)

Trbt.t19 

ltvitabititf .tf tuIMic qid k btdt pH 7.4 ana e d 371: 

0.031 

t264 

t3 53 

25 63 

2304 

290r 

4335 

55.26 

62.t6 

32.83 

0.t22 4243 

0.692 92.12 

Abs = ab*b.k; o/o lvril = t !vdl.bL, M.f.Mic rcid !dd.d - l.{X x I0' Md6 

Abs. at - 162 nm % Avlil. 

lTine (nint 

r8.16 

13.16 

22.57 

25.52 

0056 

5613 

57.02 

Abs= rb$rb.n@i % rvril= %.!.il.blci M.loricM add.d =4.27x l0rMd6 

75.42 

33.35

T.hbul 

lnitahitii, of.ttp\olc tt tonnacd edfi.Jtta a,.l wloa ME^ d 37'c 

\l'\ d - lslnn %avril 2sltrm % rlil 276im % Avtil 2T6nn %Avail 

lTim (mint< pHl++pH4- 

t5 

60 

115 

0.t26 

0.557 

.5l 

t5.51 

68,11 

33.01 

0.61 

0,655 

0.718 

0.73 

0.681 

0 

0.713 

0.6t2 

16.51 

43,99 

5?.84 

62,8 

69,22 

66.00 

0 

+PH?4+ 

0,002 

0 

0,0u 

0.06 

0.9t5 

0,05t 

0,52 

0 

t4,6 

18.3 

292,22 

l?,?8 

Abs = !b6d.ne: % lqil = % .v.iLblq oln.,.@l. .dd.d - 1,79 x l0'Moks 

-pH9- 

o,0l 

0.01 

0,o2 

0.(D 

2.0t 

2.al 

l.?3

,Mtrt ol'bh. h hed.etk tpE , d tu' tr'ad 3rf 

I 

: 

\\ 

--,x, 

'. \\..t.--_.- 

.. ... r.I..*r:"_)._) 

fii, 

h.bt t 44...t r -aba Fr rs d w t4hd tk 

ldda ot6.44, dild.e rb a. tu t4b d ut 

32

a 

I 

a 

I 

{ 

! 

A,btet ql&. 

.vbntt.:/@.tut'l.ctft 

-d.* tE d tu Nb d ra 

,ffit,/|q.. r -d 1^ rdnJ.rrtrrtt 

,- r-': 

,..-.-'t-''-' " 

'.-.-.''.-.'-2,-=....-./ 

... ----1--- 

';"-t :-fi1 

at

[3.ng 

)rtt"b 4/-ta9- \-r/'c.drtu d.tu t4b1. t7! 

t 

I 

t- 

I 

t" 

-=41-t^"*- 

@.t*.*.h-.t-.d* -.t e *tt .t 'c 

/ntr'.l'*.t.. -a t*te - t tu 1b.- tR

dhb&t qltdtu k hed.e ttu d b tu$ 14&6 d r< 

b 

; 

.Fnl'' 

ltuutdtE!6*.tu4b.d ra 

)>- 

hMtE or6v.tn btu6{2' d u.

€ 

! 

€" 

I 

tuNtrd!-48td. tltb'qltd 1., ded rrt 

-t-/ 

lpbtbdtuttur6n.3R 

//--'/- 

A4en4qlq@L d -tu.'dra 

d t 4d aQ d t4

C Sir ult r@6.Ltznitatw olelpvotu 6d ht ,tdlag dtuSt 

!n order lo n 6uE the queriti* of inre@ n8 druss by Uv/vtibl. sF.rophoromelry 

simulan€ons equations weE enployed. Mold absorptive val@s of cefpirone md all 

inr@rihg drugs wre calcule cd .t €&h dNg s lru s well 4 .t interaling drugt l,-. &td 

th. q@lni$ of .rch dru8 in lb. sm. eludon wft n@ud sihullandBly by cmploi.g 

following equtiotu. which EE devcloFd by nodifying Bal3 hw. wherc, 

whft- A = aberbance. s = mdd aberptivily or .p6ilon. b = p.lh lcn8th of thc cell (l cm in 

ow .xlqin€irs) dd c = conc.nlration of slution- wl|n more thd ore componcr s 

pEsenl in a solutio.. which absoibs at fie smc wsvele4th bu1 to a difl4e .xl€ni. theo tn€ 

cqudion (l)mrl bc stinei as 

whee. c, ed cb de concentorjons oflw compomnls presdt in $e eludon i,.., cefpiom€ 

dd inGiacdrg drugs md r ud r' 1@ tc nole ab$rltiviiies of d€ tw conpone.h 

oblained from $e calibdtion cw. ofsldtlard slu6o6. 

Borh afrimn. ed ca9lopril absib ar 2?l m and 206 M Bpstiv€ly. Ld C, be irE 

qmcenration of cefpirone and Cb $e coieimrion of captopril. Now €qution 2 cd bc 

wher, a, ad a2 were rtc abs@tiviri.s ofcebibne ar 271 md 206 m, while br md h 

were lhe mola! absootivilies of captopril ar 271 @d 206 m rcspetively. By muhipiying 

cqualion I wirh a: dd equllao! 4 wirh !1 w€ gerl 

A,r h Ae_bl 

Equtions 5 sd 6 @ b. uFd lo n 6urc lhe q@lity ol cefpitonc &d caplopril 

simdtareouly pEst in . $lulion ard ale.nployed ior a$ireme and othd inEmctin8 

drugs prcsent in solutio.s. 

a7 

l

ll l .rttiarolc4pnoweith ACE-irtibitoR 

InkEclion of cefpnome with cllbpnl dbplil &d lbinopdl @ @ied ou ar 37"C &d 

60t in sinnlatcd gNnicjtrie ald buft B ofpH 4, ?.4 dd L h the prse ofcarbpril at 

l7'C, efpircme s availaDility M ircrc&d !o l5l,l7, 133.E6 &d 286.98 o/o in simulaEd 

$stric juicc &d buffeE of pH 4 &d 9 Gp€ctivcly rhik n d€cwd 10 t5.83%inbufaof 

pH 7.4 (lable 122- figurc l.3l). In ord.r to study th. kinetic ollh. reaction the @e 

inleracrio. seE cmied out al @el.nLd t mpcratu€ (60oC) Cefpirene avilabilit, 6 

compmtiv€ly d{lwd in sinulated gastlic jui@ ind pH 7,41o 112.92 ed 516.10 % but 

i.cteded in pH 4 dd 9 to 88.98 and 155.56 yo (!.blc 3.23, fi8nrc l.l2) 

ctfpt nc drailabil4 wa rho enhenced in fte prc*ncc oa cnalapril to 268.11, 188.52. 

374.00 md 196.61 % in siBnlared gast icjlice, tH 4,7,4 ed 9 res!4rively al l7'C ed aho 

ioceded a1 60"C to 121.09, 105.71, l?5.81 od 158.79 rcspelively. Th€s Bdrs de 

sulMizd in tables 3-243.25 &d ploncd in fig6 3.33-3-14. 

sinildl}. incl€a in eibiFme s av.ilabihy wa rls ober$d in lhe pe*rc ol lisimp'il 

b | 14.01.236.27.344.79 y" ar l?"C rnd 282.01.316,31 ad ll6.3l % ar 60"C in buft6 of 

pH 4. ?.4 dd 9 Espetively (iabl.s l.?6.1.27.,igNs l.15-1.16). 

me inc'%al or high availability of .cfpiem€ is du ro chdSc trar'fer conpld fomation 

\nh inrciaciing dtue dd lhc nolar absorptiviry values of conpl€x€s fomed wre sr€aler 

rhan rhd of c€hnome. .s a Bulr availabilityofc.fpirone incdcd Howev€!, the decEAed 

or lo* availabiliiy of cefpnome is due to suppresion of cefpirone s driliiy by interacting 

drue or may be a complex having low nole absr/ivny h6 fome4 Th€s Esulls showd 

inte@tionof cefDiooe Rih AcE-innibios, 

t4 Int*action oleehinw dtt cr-.h.nn.l U6I.a 

Availahility of efpimme in the pesen e of dilli&d al l7'C *d incr6ed lo 281.4:1. 

985.19 dd l7l0.ll % in sinula!..d grstric jrie, pH ?.4 ed 9 al rcspetively. my be dre !o 

conplex aonatioD bul it rc les avaibbl. i! blller of pH 4 (124.63 7t 6 @npaEd to 

diliiffi (bbl€ I23. tig@l l7). Ho@vei al 60eC. eftion€ availabilny w6 d€c@ssl in 

simulaled s6ric juie. bufreB ofpll4 dd 7.4 to 9t.91. ?6.58 md J4.77 o/" Bpetirely 

(bbl. 1.29. fi8re l.l8). my b. beaue efpiohc is suppressed by diliiem or nay be a 

88

@npl.x having low mold.bsorylivity fom.d or may b€ the complex fomd ws uDslablc 

at 60'c. Bd n inc@d o 2?26.46 % i! bufci of pH 9. Wh.n e$ibmc iitc@t d wnn 

(dpanil. cefpnom. alailabiliiy wd also incrcae

pH 9 ('46.27 %) esFcrilcly (table 3.19, fisw 1.48). This ligh availability orefpiomc is 

.uinly due lo lhe fomalion ofch&g€ lusfer onpl.res eirh H2-@plor mbeonists elil. 

d{rcMd availabiliry is duc ro imrability or dissGiaion of complex.s at hiell lmpeErurc. 

These Esults led ro conclusion lbar th€E b s interedon bdween efDibne tud H2-receDtor 

16 tnt tution oJ c4pimw iith nwtkmind tnti-idJldMtory drtgs 

c.fpirone ine@iion with diclofm sdiM in buffd of pH 4, 7.4 ed 9 showed . 

significanr is in avdilability of cefpirone boih at 37"c dd 60'C. ln bufer of pH 4, 

selhnome availabiliry was 182.62 % while in buflets of pH 7.4 dd 9i it ss ?20.91 sd 

599.66 9. nsp@tirelt. At &c.l.r.td icnp.6tw (60 C). simild b€h.tior E obsrycd and 

availabiliry i.c@sed b E72.59, 155.?2 and 157.07 vo in butr 6 pH 4, ?.4 and 9 cpetiely 

(able$ 1.40'3.41, lisws 3.49-3.50). I. the pr€s.ne of flurbiPrefen, cefpitune availabihy 

al$ increased to 185.87.59596 ed 846 % in pH 4,7.4 md 9 al 17"C, whercas al 

a.ccledled tenpealnE, availability o{ cefpnonc decE ed to 55 96 % in pH 4 ed incEasd 

in pll7.4 @d pH 9 to ?53.89dd 817.49 % Gs!.cliv€ly (labl€s 1.42_3 43. fi8us 3 51-1.52). 

lhft w6 6l$ a nF in av.ilabihies ot c€biren. wltn inle@rcd with hefal@ic acid in 

buff.6 of pH 7.4 dd pH 9 io 229.23 md 152.38 % ai 3/C h rhe simild way. availability of 

cchiome indea$d ar 60 C to 92.9\ r/a (9H 7 4) and l4t 46 r/, (pH 9), a shaM in lablcs 

1.44-145 md ploned in figuasl.5l-1.54. 

Similelt, celpnone avdhbilny wd at$ ircEls.d h tbe plt$e of n€loxid in buftd 

ofDH 4. ?.4 and 9 al l7'C. to 145.?6. ?5.00.nd 49.28 o/. Esletiv.lv (1abL 3.46, fi8uG 

I 55), Ho$evet, al.cceledtcd lenpmlE, a!6ilabiht ofefpimnc decrcGed to4l 06,_6 6l 

dd-67,68 % i. pH 4,7.4 sd 9 EsFclilely (trb|. 3.4?, n8re 3 56). 

T1$ inseaed in cefDirum. .v.ilabiliry is dE lo 0! aotmtion of chdg. llmfer @nplexes 

bcl\on cefpimne dd NS tDs *hich po*$ high bole absrFivilt 6 @nped ro 

cetDiomc. On the otner hdd. dfteased sailab'hy is dE lo inslabilitv of th.s conPlq6 al 

hish renperatM or nay be a @nplex b.ving low nole absotpiilirv hs fomed. 

l unhcnnoc. rhcse rosult shoted inlermtion of cefpimne with NSAIDS

11 Int nctior o! cqpirud. with ptutonttnp ir'ibitor 

In pr€ene of oftpl@le al l7'C, ehircne aEilability del.ed !o 42.85 .nd 71.51 6l'l" 

ii simulated gdltic juia dd in b!ffcr ofpH 7.4 whilc incea.d ro 112.91 nd 119.241/' in 

pH 4 ed s cspecdvdy. Simil{ b.havior was obseFed al 60'c ad cehiohe avoilability 

d€ctued to 218.50 &d 41.18 % io sidulated r,r$ric juie ad bufier ofpH 7.4 How€rer, il 

incEa*d b I10.20 dd 1021.74 % in bufeB of pH 4 &d 9 sF.iively (1abl6 1.48-1.49 4d 

fiEurcs 1.57.1 58). IIiEh availabilily of cefpircmc shoved $e fomalion of cheB€ lrmsfcr 

contlex with omep@ole whilc d.creased availability showed th. dksialion o! ihslabilily 

of .onpler Th€* rcsulii d€lcd inieFcdoi bclren @Sibmc tnd ompep@le . 

r5 

10 

r65 

ll5 

0.255 

0.?21 

T.bL lJl 

Monitorks ofcehitun-cdpbp tnl,rctia$ b, Uv d 37r 

0.932 

03ll 

0.329 

t35.91 

134.30 

t60.13 

t55 96 

t5l t7 

157.30 

l52.ll 

ll,t.l5 

lll.9l 

121.99 

417,91 491.61 

1.57 l?3.31 

31.52 !69.24 

0.173 

0.t12 

0166 

0.t62 

cdprc-edoded- 93\ '0'.apropnldded I15l 0 Vole' 

9l 

0,5J1 

0,503 

0,502 

0.673 

0.692 

0_1t2 

0.8!7 

\ia.25 t26.25 

l]7 t] 1r:15 

225.72 12t.29 

2t3.a7 126.24 

2!7 3t t t0.12 

Ba32 111.22 

2A698 157.21

Abs .r- 271nh 203 nm 

I Iimo (0,nt< - 

t5 

l0 

B5 

130 

t5 

l0 

120 

l&0 

0.117 

0.151 

0lt0 

0.127 

T.ble,,23 

M@i\di,s ofc.hiw4rrytoptil id@tio8 by W d 64.. 

-PH 

0.552 

0.553 

1t2'93 

100.53 

100.57 

100.57 

t0231 

103.73 

t07.22 

|2.92 

lll,34 210.30 

416_71 X345 

-5!5.4t 227.68 

-616.10 264.10 

I2l0l 0.093 

125.52 0.099 

l?5.52 0.101 

125.19 0.101 

125.50 0.105 

129.62 0,106 

89.t6 0.115 

0.112 

c.fpnom. add.d - I 08 r lo'. clpbpil tld.d - | 15 x lor vol.: 

92 

206 nn %Avlil % a!.il 

o.J2l 

0,525 

0.525 

0.525 

0.525 

05ll 

0.534 

0.519 

0.t?8 

0..r8r 

0,520 

0.t24 

0.5t3 

0.612 

0.633 

79,91 -41.52 

33.98 -50.03 

\61.24 12673 

ll5.t2 103.33 

llt.rl ll217 

l]5.21 11r.33 

155.56 114.40

t5 

t05 

r20 

llt 

130 

t30 

0.624 

0.611 

0.352 

0.622 

0625 

0.45 

0.61| 

T.ble l2a 

MultdinE of celpnom-Nlaptil iturctiot hy UV at 37'C 

0.710 

0.326 

0.862 

0.373 

0.334 

0ia) 

0.925 

0,?18 

0.731 

0 820 

0 821 

0.310 

0.333 

0.395 

142.69 

l3l.t9 

r90.81 

192.20 

191.22 

710.75 

261.24 

263.11 

335.80 

348.82 

l5t.6l 

J51.09 

16106 

16435 

36t.12 

365,20 

367.44 

69.22 

30.32 

31.90 

42.27 

33.10 

42.t5 

62.31 

0.512 

0.515 

0,510 

0.513 

0,30r 

0.1t0 

0.13 

0.119 

0.1t3 

0.1t9 

o321 

0.123 

0.123 

.(rp'rume rdded Lq3 \ lO': !..l0pil'dded t 6t I l0' vol.e 

9l 

207 n0 % Avtil. %Av.al. 

0,913 l7l.t3 102.10 

t72.0tt to2.79 

17,1.98 l0l.l2 

0.625 

0,1t2 

0,7r8 

0.762 

l?6.63 105 5l 

t73.lt t06.5 | 

t3l t3 6.46 

t33 52 r2r 14 

181.08 40.62 

133.39 42.31 

I9t.8r 53.57

T.bL 3la 

lh'itNna oJ..hi@-tut4pfil ii!tuiM bt W d 6o'c 

C€f Em C.a 

Abs. at - 271n0 206nm %Av.il, 207 nm %Av.il. %Avail. 

lTime(mint+pH 

t50 

t65 

t30 

t5 

7S 

r05 

ll5 

0.ll ! 

0.156 

0.1t6 

0162 

0.271 

0 273 

o.2u 

0.286 

0.246 

0.311 

0.4c2 39.m 

49.12 

0.656 

0.711 

r05.80 

rit9_89 

L4l 

r I r.8l 

IB.l0 

122.39 

121.09 

tt4 05 

162,31 

t62,62 

162.46 

162.25 

t6t.5l 

t75.31 

1626 

't7.12 

't5.t7 

33.43 

39.13 

40.29 

4t.01 

46.27 

91.10 

,15.1t 

98.85 

102.71 

129.09 

0.235 

0239 

0.239 

0.109 

0.1ll 

0.!2 

0 t9l 

0.205 

0.215 

0.235 

0.235 

0.213 

0.242 

o.254 

0.210 

Ccflircme dd.d - L93 r loj; Emhpit !d\d = 2,65 x 10" MolB 

0.58,1 

0,6t0 

0.623 

0,614 

0.65 | 

0.663 

0,672 

0.682 

0.636 

0.?t5 

0.729 

0,167 

0,80] 

0,8t5 

0.817 

0.393 

95.71 8312 

95.30 35.31 

103.52 39.73 

1.02 90.22 

133.17 33.09 

113.64 8872

l0 

105 

t20 

ll5 

t5 

t0 

135 

0.311 

0l t3 

0,122 

0.J23 

0.132 

0l5l 

0.29t 

0.321 

T.bt l:6 

Mon onnE ofcehircneJkihopd inttmtia6 b, Uv d J1Y 

Ln C.t Li! C.f Lis 

%A€il. 269m 206 nm %Avlil, % aYlil 

0.862 

0,905 

0,599 

0.6rJ 

0,669 

0.922 

0.956 

I173 

l04.ll 

105.t3 

|o.12 

l .6l 

6.24 

|l8.01 

31.59 

32.0.1 

31.t9 

117.01 32.91 

18,1.42 11.03 

l9l.t2 33.03 

262,28 53.66 

)2102 10.9 

0,373 

0.332 

0.33t 

0.333 

(ero'rcm.odded 1.93rlo;INinooil.dd.d 4 60r l0 Vor.s 

95 

0.7 

0.332 

I l17 

210 t3 21.t2 

217,St s3.21 

2t9,21 60.45 

22t.11 16.54 

224.29 3t 3t

l0 

150 

t65 

l0 

120 

0.711 

0.742 

0 752 

0.270 

0335 

T.bL 3:7 

Moaito.ksalcelpttudeli\i.opr tfrwtia8 b, Uv at 6aY 

0.762 

0143 

0518 

0.732 

0.784 

0,752 

0.742 

0.323 

210.91 

257.t1 

25277 

256,16 

259.62 

265.25 

282.0t 

12.3t 

20.55 

2.42 

3.14 

l.9l 

16l I 53.91 

t63.92 60.03 

170.23 ()59 

20t.68 53.05 

210.16 60.14 

0.502 

0.t22 

Celpnom.!dd.d I oE\ lOr. | 'srnop.il !d.Ld 460r10'Vd6 

96 

2Oi nn %Avril. %Av.il. 

0.713 

0.n2 

0.753 

0.783 

0.335 

0.855 

0.393 

0.958 

231 42 3123 

251.00 35.?6 

26[.72 t5.07 

277.22 15.44 

238.48 13.13 

10981 46.67 

116.3t 54.02

T.bl.l,28 

Monjtotins oJ .qrnotuaiikiE k l"krdiDs by Uv al 37'c 

Cef Dil C.f 

Abs..t - 271Dm 236nn % Av.il. 

l1imc(mins)+ 

105 

120 

r50 

t65 

0 r25 

0 t29 

0.lll 

0.133 

0.11l 

0.120 

0,251 

-PH 

0.625 

t.05s 

0.973 

r88.55 

t72.16 

r86.43 

193 05 

I95.q) 

197.31 

< PH71 - 

436.13 

492.51 

4t9.62 

353,19 

385.0? 

919.t2 

75.33 

117.57 

132.30 

199.22 

202.42 

2M.42 

207.11 

28.50 

221.02 

252.28 

262.64 

219.t6 

2t216 

210,98 

0 093 

0,113 

0.121 

1.93 x l0 iDili@mldded=1.39x l0 Molcs 

Dil 

Dil 

216D 9! Av.il ToAv{il. 

0.256 

0.27r 

0234 

0234 

0,284 

0,29r 

0.]02 

0.103 

0.19t 

0.t07 

0.358 

0.r63 

0.3?5 

0.t11 

nl3t t63.41 

\t!36 111.71 

ll3.t5 130.41 

1t34.65 

I152,66 

t3t8.t] 

-1119.21 

.1462.2t 

l593.ll

45 

t20 

130 

l0 

105 

t?0 

B5 

130 

0.031 

Trbl.3.29 

Mni!tui.s of.4pi@eniki@6 tnktutiN br Uv d 60'c 

216nn %Av.il. %Av'il. 

prr! 

0520 

0.524 

62.38 

1f.9a 

32.80 

33.1? 

j}r.52 

92.43 

.71.ll 

-?0.39 

-5t.]0 

r50.7t 

r52.02 

156.22 

154.24 

r6r.5t 

161.56 

153.62 

136J0 

133.71 

197.13 

198.56 

C.l Dil C.f Dil 

269 nm 236nm %Amil %Auil 

< --pH4 

0.075 

0.032 

0.072 

0.073 

| .98 x 105; Dihi@n !dd.d = 3,89 x l0' Mold 

93 

0_221 

0.261 

o.214 

0,217 

0.233 

0.281 

0.292 

0,296 

0231 

0.25t 

o,271 

0,275 

0,281 

0.286 

0.]|5 

0,123 

51.30 

55.39 172.91 

2091.15 

21?4.4X 

2264.43 

22a1,18 

2121.21 

215465 

2l93.tl 

t3t.l4 

l3l.?3 

136.0,6 

,t114.95

t05 

t20 

B5 

0. t2l 

0.J70 

0.511 

TibL l30 

Maitoktofcehinre-vraqnil i qntiM br Uv 4 37"c 

0.103 

0. 2 

0.t25 

0. t29 

0.170 

tl.42l 

0.523 

122.54 

t22.74 

1,19.25 

I5l.l5 

153.33 

t91.36 

202.66 

202.75 

816.06 

310.26 

99204 

t0l2.3l 

ll.5l 

11.25 

13.18 

19.,13 

20 26 

2l ll 

23 77 

2451 

63.32 

0.065 

0.067 

0.0?l 

0.032 

0,032 

0.033 

(dDi'om.lddcd 93 r l0 : V.ddm'ladded - 5.2"x l0 Moles 

229 nm % Avlil. %A{il. 

0.031 

0.039 

0.112 

0.114 

0.1t5 

113.19 4.86 

14"437 A.2A 

145.90 3.53 

t53. t3 t0. t9 

l3l.r9 ll.3l 

2l r.61 56,45 

131.45 158.70 

193.25 l7t. t6

lTim(minsF- 

t20 

t35 

130 

B5 

. 

- 

T.ble3,ll 

Mantinsof @hi@wpMi! itutuiN bt w d 6crc 

0 022 0 022 

0.033 

0112 

pH 

75 t3 

3t.32 

35.71 

33.17 

pH?.4-> 

22.30 

26.25 

23.11 

!29) 

35.93 

41.42 

6.ll 

t363 

22.t4 

2353 

60.65 

0.032 

0 052 

0.04) 

0.ll! 

0.021 0.026 

0.023 

(efpiT'ncadded l.oBx 0j. ve'sptn,l.dded-5 27x l0{ vol.s 

100 

0.072 

al29 

86.17 

0.0t 

t02 

l.t6 

5.t3

T.ble 3.!2 

Y'''i@hE ofeIpirutva to.tiprt rkrd'ionr b! Uv d 376(' 

Ccf Anl Cef 

Abs rr- 271 nm 239.m "/" Av.il, 239rn %Avail. %Avril. 

lTmern'nr+pH 

t&0 

llt 

t50 

t65 

0 l 

0.123 

0.Bl 

0.546 

0.55t 

0.551 

0.532 

0.6t1 

0.251 

0.592 

0.593 

0.623 

0415 

0.478 

0.48' 

0.523 

0.571 

23t. 

193.20 

412.21 

411.35 

?47 39 

2t2.01 

2t6.tl 

2it.21 

Ba.l2 

261.03 

252.64 

257.il 

258.12 

26t.33 

262.67 

7n2.45 

97.2! 

107.73 

123.93 

B0.ll 

135.51 

t33.97 

t1t 27 

0.532 

0.6t3 

0.626 

0.161 

0201 

0.22\ 

4.224 

Ccfpilrrm .dd.d = 1.93 r | (''; Amlodipinc 'dded = I 22 x I0i Mol.s 

l0l 

0.512 

0,523 

0.511 

0,512 

0.t27 

2f2.07 t28.99 

236.| ll0. 

731.21 tt5.5l 

213.t2 134.94 

261.04 t4t.21 

t522.61 

1J60.19 

r566.21 

tu0.25 

t187o 

r828,?9 

I854.52 

-2Jt7.49 

-23J7.95 

-71t8.21 

26.10.13 

-27L1|

t5 

l0 

ll5 

150 

130 

75 

150 

Trble 3.31 

Monitoiry ol..hiw@loAipiN intqdtion! h, UV d 60"c 

o.126 

0215 0.471 

0.652 

0.733 

0523 

0533 

0.t21 

0325 

0.3!7 

0.316 

722.64 

126.56 

755.Il 

811.30 

365.53 

902 50 

353 t3 

35943 

359,06 

l6,l,l6 

1J7.88 

t62.64 

352.06 

153.33 

36J.18 

133.36 

195.36 

r96.06 

t3.51 

41.58 

t5.25 

93.12 

96.9t 

0.453 

0.453 

0255 

0.263 

0,271 

o.x1t 

0.26 

0.293 

0.319 

c.ipircne added = 1.98 x l0!i Adlodipin. dd.d' 1,22 x l0'Moro! 

102 

2l9nn %Avlil Yo Auil. 

0.190 

0,343 

0.352 

0.362 

0.169 

20t,92 -72.27 

209.15 -16.22 

2t3.28 40.20 

220.81 -33.14 

251.98 -112.10 

ll32l5 

l2ll.31 

t254.24 

t210.51 

t322.88 

r493.t3 

1523.63 

l33l t4 

-2060.t I 

-2064.91

,Dk lL 

Mdittks of cehircwrinaidk. intedioc by W d 37'c 

C.l Cim C.f 

Abs. r i 271nm 216nn %Av.il. 2l8m %AwiL %Avlil. 

lrrft (mint

T!bl.3.3S 

MMitNks of c?hinwninaidk ht @io[ b, wd 60

90 

165 

B5 

0.t35 

0.|]3 

0.D9 

0.15: 

0.621 

T.ble JJ6 

Monlt*ks ofcqhiftm-MiliAitu interntio$ bt Uv 4t 37'c 

0,981 

Lt8l 

Lt99 

l.2I 

1.253 

1.265 

|.217 

t.l l5 

r.t20 

|.221 

|.217 

1.245 

1.251 

| 259 

| 270 

t.l t? 

t.ll5 

219,25 

213.61 

2t9.29 

229.69 

232.41 

235 72 

231.t1 

241_26 

251.10 

:53.08 

254.38 

261.20 

1023.19 

r080.36 

1030.53 

1090.16 

lll2.l3 

29.33 

1.24 

IB.0l 

115.96 

117.41 

t2\.64 

93.32 

l 07 

1t2.21 

18.30 

117.03 

t2t.74 

0.117 

0 423 

0.415 

c.fpim,itd.d = 198 x |0_': Rdnidin..dd€d = 4 77 x |0'Mok 

l0t 

t.022 

r.025 

t.092 

.ll6 

.160 

|.t11 

L184 

Llq) 

L199 

t.212 

l2tt 

| 226 

132.09 lll.M 

13?.09 2.51 

131.t3 112.42 

1t9 7t 111.15 

t12.2t |r1l3 

142.66 Il3.5l 

-13.22 11923 

,ll.l9 121.30 

-13.21 t1t.6l 

-t!.37 l2'.9l 

-25 88 l27.ll 

,1891 127.41

llrmc(n,nt- 

It 

75 

r35 

r80 0.032 

l5 

r20 

130 

0.252 

0.236 

0.239 

0.125 

T.bL 3J7 

Mannatins o.f c.lpnone@itjdk inter@tions by Uv a1 60'c 

L013 

t.023 

t.0l I 

0.30t 

0 817 

0.313 

0.332 

0.332 

pH I 

175.73 

tTan 

179,35 

Itz.t2 

146.42 

-56.31 

-6t.35 

42.31 

45_20 

10t.69 

104.52 

91.11 

93 37 

101.22 

0.3,r3 

0.355 

0.t61 

0,155 

0.211 

0.273 

0291 

C.fp'bme ddd - | e8 \ lO 1, Re['dmc ldded - a 77 x lO' Mol.r 

106 

223 nn Y. Avdl 9/. Av.il. 

0.337 

| 072. 

Ll12 

1.t25 

Lll I 

0,393 

0.733 

0.8J1 

0.331 

0,371 

.142.72 124.41 

-12A.02 126.t1 

-t0600 t2J.5l 

-73.25 t25.25 

-ll.r0 124.t7 

4.13 121,95 

9,2t 126.65 

I1.49 128?4 

618,51 61.30 

42.16 lt7.4l 

1t9303 125.23 

1172.04 ltz.24 

t136 61 133.47 

1l1l.l4 tl9.4l

T.bL 3J3 

Mqitdi,E olcehnone-fMdidin. aktdio8 by w ot 37cc 

267 an % Aqil. yoAvait. 267 htu Yo Avtil. Y.Arril 

llimelminsr+pH 

130 0.513 

0.523 

0513 

0.562 

0.4?0 

0.432 

0.513 

.41.21 

48.78 

30t 

5_05 

I t5.29 

lt5.3l 

6.13 

173.92 

108?.59 I t7.t6 

1092_2A 12421 

1t04.t2 125.7a 

1t03.70 123.63 

0.251 

0_255 

0.253 

0.253 

(efpircm.rdded - LaS r t0 : rmoridiEdd.d - t.ta r t0, Mote! 

0.412 

0.4t3 

0.421 

0.427 

209334 463.69 

2t2a.1t 17t.!5 

2133.07 -472.30 

2|]6.40 41t,t8 

22.10 

t3.19 

26.48 

24.41 

24.63 

92.10 

9J.28 

91.51 

9l3t

T.bL ijt 

ttDni@iaq of.elpm-lMAiN itu4tiN bt Ov d 60'c 

C.l Fm Cef 

,\bt . lTlnm 167nn %Avlil. 

tTinc(mins)+pH 

30 

B5 

l0 

0.132 

0.412 

0.411 

0.251 

o257 

0 262 

0.268 

0.711 

0,280 

0.142 

0.4f2 

0.I l 

0.t21 

0.324 

o.326 

0.317 

0.131 

91.15 

94.88 

l0l.8l 

197.6t 

136.t3 

r95.79 

210. t3 

2t0.29 

2t4.41 

22!.19 

\|72 

57.91 

t0?.93 

110.39 

5.ll 

71.52 

72.16 

73 68 

7633 

76.31 

79.15 

0.t80 

0.4t2 

0.271 

022t 

0.239 

0253 

0 271 

o.243 

r e pnrnc added . og \ lu J. I amoridine doed. Lto r tO' Vot.e 

t0E 

0,361 

0.4t1 

0.413 

0,357 

0,363 

0..r68 

333.t5 -t3t.39 

192425 432j2 

1927.76 4t2.63 

lqt7.20 -41.1.35 

t62.27 1t 9a 

t3.t3 8t,90 

t5.42 83 7l 

tl.l2 91.7t 

:26.03 l't .32 

2r.31 10t.63 

-2.09 t05 84

tTin.(minri< 

l5 

135 

130 

120 

0.264 

0236 

0.343 

0.431 

TibL 3 40 

Mui@i,E of ehnm.-db@ne ituewtiN b, 0v d 37\: 

0.209 

02t6 

0.225 

0.251 

0.298 

--Pn 

106.26 

r4857 

n8.19 

239.33 

16t 57 

342.62 

tE.l I 

t3.31 

4.98 

-12.21 

-13.28 

t3.t6 

563.42 t22.ta 

561.44 t23.41 

571.01 t23.43 

0.5t1 

0 563 

0.582 

0 589 

0.612 

0,627 

c.iDnom. addei = 1.98 x l0': Diclofeuc edded = L5? x I0' Mol.s 

109 

216n6 % Ardil. % Arîl 

0,58r 

0.590 

0.602 

0.672 

0.621 

512.89 165.3,1 

569.91 t69.05

5 

l0 

t20 

r35 

15 

t20 

t30 

0265 

T.bl.aal 

nonnuins of.4pin'enli.tohe inl?ratunr bt Ul d 60 r 

0 t35 

020t 

0.228 

0.211 

0.256 

0.288 

0233 

0?33 

0.289 

0.247 

0.332 

8.87 

613.57 

326.23 

827.t0 

328 65 

372.59 

It6.tl 

1l].57 

127.62 

121.46 

D2 3l 

tt2.67 

-91_22 

-83.67 

-3t_M 

t432 

l6.ll 

t629 

t6.73 

l9.ll 

0 251 

02t3 

0.2t8 

0.259 

0.266 

Cefpiromc added 1.98 x l0 'i Di.lofenac.dd.d = L57 r l0' Md6 

ll0 

276 nm %Avlil. % A!.il 

o2u 

0 271 

0.280 

0,280 

0.282 

0,286 

0,287 

0.294 

t22.27 Al al 

t22-62 91.21 

t25.62 9l5l 

t26.24 94.t6

Il5 

l5 

t30 

0.151 

0.162 

0.167 

0. t70 

0,th 

0.t33 

0.202 

0.2ll 

0.2t6 

0?t0 

hb|.3,42 

MMTEaC oleehielnbitorta iMiN br W d t7t 

0.140 

0.154 

0.t61 

0.442 

0..t39 

0.522 

143,36 

160,08 

r6t.95 

r62.5r 

r63.t2 

t12,6t 

l80,tl 

135.37 

3t 50 

12.35 

!4.41 

35.14 

t5.t4 

36.14 

13.96 

70.00 1a.11 

72.6to 1927 

31,60 84,30 

u_60 85.12 

0.161 

0.166 

0.r68 

0.t70 

CefpiDm. ddcd = L98 x rO ri FturbiDbfo rdded = a.09 r lon Mo'6 

l 

0341 

0.156 

0.163 

0.363 

0.371 

0.375 

0,330 

53?.ll 59.63 

542!2 68.15 

545.11 69.32 

579.5t 70,90 

53t.25 7r,63

120 

130 

t20 

t35 

tt0 

165 

0. t31 

0.224 

0.231 

0.211 

0.201 

0 211 

TtbL l.l3 

tlonitdq olcehnoe.ltubiryortn kk/dio6 b, Uv d 6!aC 

0.]32 

0521 

0.526 

0.636 

0.501 

0.503 

0.531 

4?|l 

3323 

33.34 

t9.83 

4033 

4l !2 

5t.t6 

1@,16 At.2l 

40597 83.72 

315.50 8t.(D 

0.2t0 

0.211 

0.213 

o.220 

0.229 

c.r'pimnc.dded - t.93 x t0 ri Ftu.birof.n .dd€d = 1.09 x tor Motca 

ll2 

127.01 36X2

Abr at- :65nm 235 nm 

Itinr(mint< 

r35 

t65 

t30 

0.1t4 

01r3 

0|]l 

0 136 

Trblel,,L 

Monit*i,E oJ.elpi6re-tukhai. eid itutuiN b, W d 37'c 

-pH 

0.t01 

0.162 

0.t17 

o.tg2 

0.133 

o.2t0 

0 225 

74 

r55.96 

Dt.ll 

I60.51 

201.92 

207j0 

208.99 

8.94 

25.11 

41.5 | 

51.61 

5t28 

0.89 

0.t53 

0.r58 

0.169 

0.171 

0_133 

0.193 

0.136 

o.224 

o.251 

0.253 

0.26t 

o.274 

0.215 

0.231 

0323 

CcfpiM? added = |.93 r t05; M.Ln.mic eid sddcn = | O.t x tor Mot6 

T.tn.l.as 

Mnibhg of.zhitow-wl.nani. qid intetdtioB b! av at 60cC 

%Avail. %Avail. 266 nn 

LTime(minr+pH 7 

75 

t05 

Bt 

t65 

0.r26 

0.166 

0. t32 

0.136 

02lt 

0221 

0.210 

o.251 

0.233 

6t.58 

57.20 

53.11 

6t.53 

61.13 

81.62 

88.63 

89.81 

92,91 

37.27 

54.72 

61.5t 

67.26 

0.120 

0.153 

0.2t1 

0.2t1 

0.211 

0.216 

0.1t3 

0.253 

0.29t 

0 317 

0.324 

0.123 

0.339 

0.141 

0.146 

(L'promldded Ie3y.n . vcrcn'm( r'd dd.d . t.01 r t0 vob 

ltl 

t5l.l? ?17.73 

113.23 954.53 

152.33 1267.00 

86.13 50.2a 

33.92 77.23 

113.53 9t.54 

t29.26 91.59

LhL l,a6 

Manitutig o.f ..lpituntwtotuan idersttons b! w d 37oC 

abr. d . 269nn 16.l nn %Avail. 

tlim. (ni6)

T.bh J.a? 

M@itori"s of cehnon4ketdi.dk int rutins bt w d 60oC 

Y.Aviil 26tnm 162 nm 

lT'm.(mnt

l0 

105 

t35 

t5 

t!0 

i35 

130 

0 rl5 

0.r51 

0.lt,r 

0. 8 

0.125 

0.r12 

0.131 

0.135 

I.bl.3 l||| 

ibnitdins ol.elpinweqdol. idz@tio6 hy W d 37.c 

0.212 

0 t02 

0l|l 

0.1t3 

0.120 

0.123 

0 126 

0.lm 

0 t29 

0.ll I 

0.136 

0.137 

0.118 

pHl 

12920 

l]81r 

126.13 

I I t.64 

80.0r 

43.9r 

42.35 

PH 74-> 

ll0,t7 

23.39 

65.33 

69.3t 

4114 

61.35 

82.45 

t05.43 

114.21 

155.8t 

2.4012 

253.50 

257.32 

253.61 

259.30 

0.115 

0.t17 

0.12, 

0.12t 

0.DE 

(.fdirem..ddcd' | 93 x l0': on.Dt?.l. ldded = 5 79 x lu> Mol.s 

lt6 

0.031 

0. |l2 

0. |l3 

0.121 

0.123 

-u.52 tt.12 

14a.99 t2.27 

l5l.17 t3.14 

t58.27 l5.ll 

159.91 16.rl 

t60.t4 \'1.74 

169.7t I3.0? 

t71.76 l3.lt 

t27.12 a998 

\52.55 17232 

165.65 185 S5 

t?1.41 t93.14

lTin.(min\l+ 

r?0 

r30 

t35 

0.1l0 

0.112 

0 4 

0.|]2 

TrbL 3,a9 

iton@i'ry olc4pinweFeol. itudiM by w d 60'c 

On. C.f Ore C€f Om. 

234nm%Av.il. %At.il. 269.m 291nm 

0. t0l 

0112 

0.|]3 

0. t55 

pH I 

28.09 62.24 

10.t3 n.6 

-218.50 219.04 

' pH14 ' 

33.01 

67.44 

41.23 

18 .25 

2M.91 

2l l-ll 

221.41 

]r0 31 

0.088 

0.w2 

0. 0 

C.fDimm. idded = | ,93 x l0"t On.ltr.lc .ddd - 5.79 x I0 , Mot.g 

II? 

0.055 

0.093 

0.ltl 

lt3.,t0 5.15 

1.52 5?9 

|]1.00 ?.lt 

|]0.20 10.36 

69 38 U.91

lqbrttt.tqhtu, @tu.t444, z6td 

l|'brurr.r.4tu. u w qt@Fa h a6ha 

Eff 

t* 

ir:.*-r

tuttu!, rtdhbr.6 N@ dtwbtu k a&N1 

lw,bttut, ot6t 6. q wQ olthr@H b tu$ 

/vbtt otet'tu b tu@ olte.Fit d xtue 

||9

1p614 ql nb*.. a@ 4M., d&.d 

: 

F.^.-.+-E!:-:-= 

rk.n * 

tubtr'otc.td.. Fw {ab .&tet 

I 

: 

lvernq otdt tu. '|.m', k P.oe 4@Fr - d6hnl 

: 

-h.-. j---==_:: 

120

avh'ib otflhhi. b rt,B. olwqwt k dti., 

! 

3 

.vhroehttu? hFrcotlqdw F 

daiqd abhb, .dn^, o t fr 

)tu,t@ o/..ttu., w,Jqtu1*, 

darm'Mtu-tet,d4i 

t2l

5& 

,d 

1'&M4 oJQtPbr. h Pnc^4 oldidMw B 

dt*dMt6ndqa,.1,r 

iil:-:-:--:=---' 

1-etn, ol.tttu. b Fn otdndMb. h 

d6tu@M-aqq'.1,0r 

/ w & tt rt ol c.htu. k w d! tutuh h dotu| 

t22

E 

3 

t 

lYbbv at..tbhn. h 4'4ita'ntu 4 

aa.rn z@6 3e.'.1.K 

tubbt.tnttuhe@4t e. 

d&ddtu.tu,.ttft 

Ec!-F+?**'_. 

)ElbtrD otc.t tu, k Ne.th'de h 

ddtdtbtuntu'crN 

t3

t btdttdtattu h F.xoldtot*h 

4tutuLtu.e'dtt 

t* 

\ 

--.' 

1- "u-'- -' '" - 

,|.tbtto otnhtu. h F8. oldkqlm btu 

to 

*E;:::::::_ 

tdetorattu r@4t 4r4r, 

E@ 

s=F.+: 

124

' 

.Mtrr'/.dd..@'st .t*" 

)-,:.=.-;=-:::: 

t'=::===-:- 

ra6|.| 

t$ts' 

tr$*t.lqrtut'G'.d,rt dat 

I 

|'nr,. 

t*tb/dhlt'ce'.d..d, 

I 

IE

tnb*t4&w.@of.etut 

t: 

, 

I 

....-.\.. 

*,:==o=* 

r' 

,-btttdc&tuh@4.ebt 

7 

126 

,2

! 

tu6t4.t.ttu t@oIq@Ln 

coed dbhb n./6t d tft 

I 

kbrnq{ct@rb@dN@Lb 

aotuddh.6'd6

D Xi,.ti. studl8 ofc.hitutu.lrts int tu.nont br Uvbh sp..toprtoton lry 

lhemodymic studies nrnhd suptoned the eulls ol int r.clion sMies. To colculate $e 

slability consl4r of conpler, * !s.d B.ncsi.Hildebnnd .qErim [516], lh€ Miation 

connait of charec transfer compl.xcs l@ calculared using $. ab$rbd.e of@mpler.-lh. 

equalion depends on $e expeimcnlal condilions that one oa th€ two conponenl specics 

should b. p@nt in cxcs. Eiihq dond or @ptor @nqr.rion should b. llr8cr th& th. 

olh.r. ltre Miation @nsldts \Nd €valut d !t mElcnllh ot fom.d @mplex fq 4h 

drus (donot ad @cptor uiis th. eqlation below [6u]: 

lr)nl,\ r/Krlôl- rh lAol/A: l/({rhl+ l/r 1 

where: [Aol = cohenrrarion ofeceplor, Do = coh@nrratioh ofdo.or, A = absolbme of 

complcr. c molar.bsoptivily ofconpler, K = subili9 onslenl ofcomplex. 

Oi plotdng $c valuca [Do] /A vc6us l/ [Ao], straidt lines *cc ohair€d frch whjch mol& 

ahsomrivnies and sbbilitv constanh were calcultated 

CoBideri4 lh€ deFndoe of binding @n$anr on toFnlw, a lhmodyMic p@s 

wa considered io bc responsibl. lor tn€ fo@lion of €ompl€x. Hoe, rh. rhemodtMic 

tanmcles depend on tenpe.dw ed w.E .nalrzed ro chealerik $e adry force 

bersc.n cctjrirene !d intdriog dngs The *d4 foEs iftlud. hydrcgd bond, Vm d€t 

waah force. electrc$aric forc. ahd hyd@phobk int.nclion force [618]. 

Thc shndtrd enlhalpy cnmge (AHo) w6 obrain d fron equrioi 2 by plorling lre Iq againsl 

rhc Rilbcal or ahslute renp.6te T' s+fr ir 6 calculared from $c alope of rhc 

LogK"=- dH' /2 303RT + constanl 

whce R is lhe Cs conslinl &d T is lemFEtuE if, K€lyin. 

shil&ly, Gibbs s l.e energy (AO') ad dc.ntropy (AS') EE cabrrarcd Grp€.tirly frcn 

dC' = -RT ln lq 

^c" = dtf ,TdSq 

1he bindirg studies qere 6ied out et 310 md 331K. 

l0

ta C.himw with AcEi"hblt^ 

'rhc rcsarilc lalu.s of fiee ensSt (lablc 1.50) showed lhat inlerelion bdwcen cefpiDm. 

and AcE-innibitoB is spontatrdG. Thc .esotirc volue ol sthtlpt in simuhl€d er$ic juicc. 

buffcs of pll ,1,74 ed 9 and higl value of stabilny consia indicat d tn suength of 

bohding belsen cefpilome od AcE-irfiibilors. This also showed fie hirl' slability of che8. 

lrdsfu conplcxcs in lheF mediuhs [619]. Thc n€satile vah. of.nrn lpy in sinulsed 

sai.ic jui.e. buileB ot pH 4, 7,4 cxcept efpnone{aptopril @npld) od 9 indid.d tn€ 

Thc posnirt ral@ of en|opt in buIr.6 of pH .| (for efpinmc

!0 C4pnon eith E?Eepto. anltgoiatts 

lhe lalues o, thc stabilily @nstanr md th.lmodynmic pdhet€^ lor celptonc dd Hr 

@eplor drlgonists de sModized i. 6ble 1.52. The negaive AG vrlu€ in simulst€d g6llic 

ju'e, bur1c6 of pH 4, 7.4 rnd 9 indic.red dw dE in@rion b.1@ @fuinnc.d H- 

aepror anlo8onisrs (cimelidin.. tuitidine dd fmolidine) it spontanoE. The pcitiv€ 

lalues ol cnlh0lpy (AH') in simulatd gstic juic€ aor cefpirome-cimetidine, rMitidine sd 

lamotidine complex€s and in butf.r of pH 9 for €fpiome-.imelidine ed rMitidine 

complexcs slDwed tnal r@lion is endodmic md ahpynriv.n. 

I he negatl!. value of dlhalpy ed hid valu€ of stabiliiy @Bldt in bufi6 of pH 4. 7 4 (for 

elpiromecimctidine. cefuiomc+annidine and cefpirone-fmotidine comphxa) and 9 (ior 

cefpimne-amoridine onpl.x) sho$€d thc $dgth of bondine b.t*ed ceftion. dd H, 

@0r.r dragonists and lhc hiSh slability of chr8. tnsfer cohplcx in rh* bull€E. The 

negarive valu.s of enthalpy also showd d. hydogen bodin8 bawn cefpibm. dld H. 

reepror mlagonisrs 1619l. 

2l C.lpi,w,ith,tukmiddtnti-hjbwttto.r&azs(NSAIDs) 

'llE rslues ol srabiliry constanr ad rhnody.mic pameles calculared fon inrcEclion 

bdwen celinonc and NSAIDS in buileu ol pH 4, 7.4 Md 9 dt l7 "C dnd 60 t re 

treenred 

in t.ble 3.51. The ftsarire v.lues ofihe AGo sho{ed lbar the inreEcrion bctween 

(he ebibne dnd NSAIDS E rponlan@u. Th. negaov€ valw oa mthalpy for c.fpiom.- 

diclofenac sodium (pH 4, 74 rnd 9), efpionefluibipiofen (pH a &d 9). ccfpirone- 

ndoxbffi (pH4l md cefpitohe-nefe.mic did complexes (pH 74 ed9)&d hilhvalEs 

of si.bihv conslld indicat d rh. sftnefi of bodi.s berweo efpione dd NSAIDS md the 

hich sbbilny of Oce charse Lesfcr @nplex {6191. 

Negadve talue of enthalpy (AH') for cefpircm. conplexs witb diclofenrc. flurbiplolen md 

mclo\icam itr bufc^ olpH 4, t.a (for cefpnonc{iclofe.ac ad cefttomc-n.f.nanh &id 

onpl€xes) ed 9 (for efpironeii.loGn&. efpnooc-nurbipoaen dd c.fpircne- 

neloxicam comrlcx.s) indic.t d that do@r eccflor cmpl€x.s w.F lmcd du b nydogm 

binding. Morcover, positive value of enlropy in buff.6 of pH 4 (for c€fpirom€-UurbiFofen 

md efpircnc-mdoicm omplexs). ? a (for c.$ionenubipofeq €fpimhenefemic

acid md ceri'imn.-reloxicah chplcxs) ed 9 (for cefuiom..mcfcnMic and efpircne 

ncloxicdn cdnrplcxes) indicat€d nydmphobic int.@tion [618, 620]. 

22 

klpi@ ,ith ynon-punp inhinnt 

Ilt ralucs ol &. AO', All" and AS'toi c.fpiom{m€pl@le inFhction ar lrrcC &d 60"C 

in sinulared gasrric ad bunc6 of pH 4, ?.4 ed 9 e give. in t.bl. L54. -nE n garive valE 

or dc" in sinulated e6tdc juie. bulfe6 or pH 4. 7.4 dd 9 rclcaled fiat inremrio. berween 

eDibmc ed omcpr@le * E$d.nos. Tlr posiriv€ valws of €nthalpy (AH) ii 

sinulard g$rric juice. buflc6 of pH 7.4 md 9 indiel€d intcdrion in lhee ncdilms 6 

cnlropy-dnv€n. Posirive Elu€s of.nlhalpy also indicat d { endoth.mic @tion; th.EfoE, 

$e increase of tenpentur€ is in favor ol the foNad dircclion of lhe r€action, esulting in 

biger values of bindiq const.nl Tn€ n gadv. vllue of enthalpy dd nish value of stability 

conslanl in bullcr of pH 4 indisle thc atqglh of bondinS b.two elpidhc md 

onep@ol€ &d tn€ high srlbility ofchdge tr nsfq compl€x [619]. The posniv€ v.lucs of 

enrropt in sinulaled gasuic iuicc. bufieB ofpH 7.4 and 9 indicarcd hydrophobic int raction 

berseen ccfpiene od oncprel€ whil€ neg.lilc €nlopy valE i. bufld of pH 4 shoMd 

hrdogci boid b.tq€n ebiroh. nd omepEal. [61E, 620]. 

(K) 

T.bL 3,5O 

stubiti\ !,^!itt: u.! thltnk btumn ptonetn lot relF;tona-1cE-i"hibito itudlions 

lt0 

l3l 

lt0 

ll3 

3010 

15139 

r r?t3 -64.q) 

75943 231 -5219 

-702\ 

96t3 422 

-10333 -|l 05

Trbh 3Jl 

skthttio nton^ ant thrmodlr'onr poohd* kr cehirum carnomel th.ktr: inlsdtion3 

(K) 

tll 

3t0 

3ll 

ltl 

310 

333 

lt0 

133 

5J27 

96128 

pHl 

-5263 

|50 -5721 

54t5028 -to2n 

13953 -6330 

125t 22,51 

-2418 2158 

-5710 ll 29 

-6t56 t036 

-10228 .54.92 

-125t7 .72.16 

l0|l9 2.21 

1.h1.J.52 

tz41 

133 

a25I 

4t5 tl 

t52 

-5611 -t9351 

-1514 -Ztl25 

,4522 2613 

-t2t1 -2661 ta22 

.1631 .858 Il..|1) 

-55i1 -t4t25 19.40 

-70t2 -15t39 -26.24 

,3036 -407?5 ,t09.70 

-4379 -43749 109.99 

Stuhiltv .ahrdts tuJ themodnmn parartt.B f* celpnne- H.kcepk, Mtoqonis^ 

(K) 

lt0 

10 

331 

ll0 

ll0 

331 

310 

333 

t243705 -3613 

t3247 

t281072 

688 

5866 

-5329 

-5122 

t94 29 

-12261 -t49.40 

,r9053 ,.48 52 

:20468 -44,28 

2aq4 -6307 -22941 -5! 66 

l33r:]| 3473 24645 43.55 

19373 -6504 -42505 -n6.04 

4743663 -t0l33 t -45662 -r066r 

f6.2) -X2N '20J$ 54.54 

357.U -3374 -2t375 -54.04 

t242072 -9275 

20t52t6 -39t2 

12414442 -10175 

1t544 l7t.t2 

-t620a -11.54 

-t74122 -19.91

T.bk 3.3J 

9obitit, .oLtuh ehd thztmdtuni. pnhct ^ kn .elpnon -Ns,tDs itutdiN 

(K) 

ll0 

lt3 

310 

lr0 

3t3 

lll 

3t3 

tll 

l2t7 

. t2506 

Tlltl 

-5|]4 

-530t -'20 

-28299 6760 

.2722 4855 

2.26r10" -t42ot 

uo dso & OC. 

{Jmol Kr) (nol ) (Kjnol') 

-20230 41.2 

982 18.9 

1055 t9.2 

-4tm3 -t23 

18166 .125 

-5421 ,1.33 

-5426 -1,67 

-t22! Zl,1t 

,132 21.76 

56951 22t.60 

6tlAl 226.39 

T.bL 3J. 

59f | 5t32 

158101 -1t172 

-5078 ll.9 

Stubility cN@B atd ttt,nodt'Mi. pM.kB rt c4pirewadeFud. tntaim 

(K) 

tll 

338646J 

2ll9350 

pHl 

-9230 

< pH74 

c.f,o,nelt0 t5433473-t0162 

3tl 40oot0 .3107 

42.98 

.42,05 

39772 -6502 

15433478 -10915 

-33t0 

.66t2 

32qt i9

u C.rpircn. Dtug I .n tior Studks bt Rw.E.d Ph* Ui$ P.rfor.nc 

Liqutd ChrcD.rosnDbY (RP-HPL) 

A lr.wlorld^t dnd vtli.hti.n of .rttti@l nzthods tor tt. ti^rttan@u 

^ 

d.|minattar of cehimre wlth ittfu.ting drtgs 

ratid and scnsilive nerhod has been deleloped and lalidat€d foi de deteminaioh sd 

qmtificadon of (fpnom€ fem phmceutical fomulaion In ord€r to studv th' inttacion 

of ccfpnomc wilh c€-innibilots (caPlopril, emhpnl sd lisinoPnl) dlioxidanls (vibnin 

A, t, c dd $dim neLdi$llile), C{_ch@el blckd (dili@n. vcBpmil ed 

@lodipift). cl.mcnls.ssndal ro hmd body (Mgttsiun! c,lciuiL chmmim. mdgos. 

ledic. cobalt. niclel, copper, zinc md cadnium), Hr @eptor dhgonisrs (cainzine 

levcelirizine and fexofenadin€). HrEc@lor st gonists (cideudinc tdnidine md 

rmoidine), hyposlyc€nic ag€nrs (cliquidon , hctfomin dd piogliwono non{temidal 

dri-i.ltammatory dlu8s (NSAID' (diclofenac, fludiprcfen nelendic &id and 

m?lo\ican). ti.l.n-rump inhihn n (omcpr.Tolc and larsoprele) and slalins (gtooa$aiin' 

sin\Elalin dd pmvdlatin) by Ev€B€d phe hid Frfonre liquid chtomatoedpbt (RP 

HPLC)- a numb.r of simple ssitave, Eli.blc ad Epid RP-HPI-C Ndods for lhe 

sinulraneous d.Lminadon dd q@dfiedo! of.efuiome with inledcine dru8s lion 

rhamacerical dosage foms have b€en dev.lopcd and validaled Tlles nctho& w lben 

applied lo drug-drug inleraction $udies of cfpiomc with all inrerrcting drugs Theie ae no 

rcponed melhods D hcrorurc lbr simutr.nsous dcl€minatio. of celiJirome wid intencrin8 

sinult .6us det mimlion hG a nmbq of !dveLs.s: {l) ndtiPle dsss @ b' &'lFcd 

usins lhe enc sp@lion co.dilion; (2) is conv.nic lot clinicd ed phm4utial bltrne 

analjsis: (l) id.nification of the p€ak of ddgs @ b. @ied oul MuBrelv md 

crpc.liriousl) b) usin8. sindlMmus mlrlical syslem; &d (4) cd be €hploved ih drus 

Optihizotion o! k. .hatuto9.aphic cor.litiont 

Itr uL.lu Looplnlize E opcrdr nrts coDd iLions for ccfpnoN erd intcrdli'!ddgs anunbcrol 

pommelets such 4 colum llT€. nobile phs conposilion. pH elfecroB (orlhophosPhoric or 

aceric acid) dd flow dlc $trc veied Co.diiohs giving shonesr denion dne Cr E!ers'd-

phas anallLical colunn. mobile phas mrios. pll (adi6rd qnh onhophdphonc aid) ed 

flow rar. *lccled aor wtk *rc cho$n 6 opli@l 

Como.ly used slv€ s in RP_IIPLC m m.thdot $alei 'cdonnrit md leldnvdrofudn 

I he p.(.nlasc of orssic aolv.nr i. mobil€ pha. conuot the Gr'nlio' lide of lhe d'l"e 

and have a diamdc efect on selslivitv ln lhis €gdd €trahvdofua is songer lhd 

aceronirrile. which in tum is sonsd thd melhdol Howevcr. tcftdhvdrcnnd h nol 

conmonl! uv! du€ 1o ns briciry sd its le.dcmy lo fom p€oxid.s 162 | I 

Mdy dtu$ have €ilh€r &idic or 6asic turcrioMl 8tuup6 md cd crisl in slulioE in ioniz'd 

.r non'io.i&d foms Th. ionic slal€ ed degEe of ioniation gearlv affecl theh 

UuonuLosraphi. eentiol ih RP_HPLC. Tlpicsllr, lhe ionic iom d@s not panition vell into 

rhe h-\dophobic sbliotry Phsc &d lhe@loe hs siBnincedv loscr * thm the he ral. un_ 

iooized aom. Buffe6 m cohnonly ued to conuol lhe pH ol rne hobib pn8 for the 

spanrioh olacidic or hsic anal)'les. A nobil. phase ai rcidic pH (2 5_l) is gmd s|anrng 

point for acidic dalries b*au* pH suppEsFs rhc iodiztio. [622] Howev€r' in ou srudv, 

bu|f* wcre f,ol sed a a mobile phe, 6 $.y mav choke olmn. Momler. deerc ot 

io.izarion is conlrolled hy adjustins pH offie nobil€ ph4 wilh onhopnospnoric acid' 

RP-HPLC is a powerfnl r@l lot lhe oalysG ofdrugs lhe ldvdtagd ofshod Etedtion rimc 

merhod Bliabilir), sensitivity.nd drue sp(ificily iusdfv the us ofHPLC for vdious grouPs 

Wh€n . mc$od ha ben dcv.lop.d ir is idporltnt to laii

Accuract of & oalttcal proc.duE expreses th. closen€ss of osRd.nt b.tren lhe valG 

which is rcceprsl eitb* as a .oNentioml true v.luc ot cfft.c€ value dd lhc val@ fou.d 

I'Nisbn of an antlyriol Fc.duE expEst the clo*nes of ae'em.nl b.t@n a sri€s of 

nNdur.n s obt ined ltom muhiplc smpling of $. sm€ homogcn@u spl. udq dre 

pr*ribed condirio.s. 11 my b€ @nsid€rcd al lhc levels: r€Fatabililv' intemediarc 

pRisioh md rcpbducibilily. lhe p@ision of d ealtrical PMedu. k expEsed a th. 

variance or relativc slerd6d dcliadon of6 eries of me6u€Ddis 

Spccincity is rhe abi[y ro s6s urquiveauy lh. ealtt in lnc pGFncc of cohpon'nts 

which may be expecl.d to bc pEenl Ttliolly $cse nislt i@tud. ihPuiiei d'8Eddl3 

marix, elc, Lack ofspccificity ofe indilidulanalytical poceduE nay be cohp€nsated for 

by orhe! supponins analylic.l ptoccdurqs). 

1 Lidn old.L.1ion (LoD) ond qnntudi6 (Log) 

Thc derection linit ofo individual aialylicat Poc.dG 

is th€ lowsl dolnl ofmalyft in a 

sahple which cd b. d.t€cted but noi n.c.csilv qm ared d d cxact valre' Th' 

quanrirarion limil ofan individual analtlical pdeduc is tl'e lowsl ddount ol ml'le in a 

sontle *hich cm be qumtil,lively d€l€min d wi$ suitable tscision dd @uev Thc 

|.oD ..d LoQ d crlclllLd 6: 

I (lD 1:Jd,',S and l.OQ 

con eflrarioh md s h rh. 

lOoS wn€E q is th. 3hddd dcvialion ol the lowcsl iandard 

3lop. ofth€ standard cw., 

Th{ bbusbess of e @lytical prccede i! . nc4m of its caleilv to emdn unnf*ted bv 

shall. bui delibeac vdllions in n€lhod psl'mr€R dd Pbvid6 d indi@don of ils 

lclirbi|nt durins nomal ussc 

mpid and sdsitivc high pefollM€ liquid chronatogaphv D.thod hd ben dseloF+d 

.nd \ alidltd for lne detcminalion ol efpnoE. fom pfidl@ulidl fomnlation Sepdalion 

l16

of efpimnc vts p.lfomed on Bl44A, OD.5-100, Ctr (tto x 46 m) @l'm ard mbile 

nha\. consie.d of ndnanol: salq ( I 5:85- Vv). Mobile ph$ B pMFd .l a lloe 6tc of I 

ml, nin ' with llv d.t clion al 265 nn. hitially, m.lhod wd optiniz€d by vtio6 n.theol: 

war.r iarios (20:80. 15:85 dd 30:70, r/v). The ladation in lhe mobilc ph.s. leads to 

considerable chdgcs in d. chromolosdphic Pdm.tcs, like Fak synnetry md r€tcnio. 

ine. Howcv(. $c r.lio of 15:85 (v/v) yieldcd b.st Esults- Crs @luo ws wd instad ofa 

Cr column $ it gavc betEr sep@lion ofcefpiod.. 

a omp€ri$n of Gponed and ou nelhod it givo in 1abL l.55. l2ck of *nsilivilv. 

conplicaLd.bbil€ phe ed sracdon pd.d@ mad€ the Eporled n.tho& lcs 

atplicablc in phme.utiol induLi6. nE signincd advotases of ou m.thod m 

sinplicny. accur&y. p@ision {d sreitcity, e uing thol il h suitable for the ddmjndion 

of cefpiode in phama€.ulicsl fomulaion 

Linedit! sas delcmined in the r&8. l O-50 lrgnl I Peat ma \€sus €cfpiome 

conccnr.rion $as subjelcd ro lcd sqlm linee Esrcsion riabsis A lincs resEssion line 

(y = 0.9804x + 0.0E49) M ohai*d wilh @cladon @mcient (l) of 0 9999 The linit of 

det.ction and quetficadon w d.lcmin d fom rh. c.libration cwe Bi.g Oc following 

cquarion: L{)l) 3 ld/S ahd LOQ =lod/t whdc o is lhe slrndard d€vi.tion md J is the 

slope of $c standard cwe. The limits of dd{tion and q@lificatioh weE 0 01 llg nL and 

002 Ag mL r srecrively. 

T.bt 3l5 

cohtpoitN oJrepM.d Nthodt ud os tuttut 

I v dctdiontnm)Conc En8c 

265 

l)7 

I931 

0,6 ngl ' [99] 

l9ll

Pdisbn oilhe pBposcd melhod ras detemin.d bv rcpeaiabilirv (intr.'dav p€hion) Md 

int mediste F4Gion (intra-.lay precision) Pdhioi ws expEsed a rclative sundad 

d.!i.rio. {RSD %). Difi.rcnl .onoiraliom of c.fpimne in lhe lind Mge wer mlt*d 

on th. soft day (inta{.Y PEcisio!) - 

and thd cotrsuriv€ d.Ys (iirdiaY I 

pr.rision). !r.D $npl. sd inF.tcd - 

threc imes. Bolh ihlE- dd i €FdaY I A 

RsD varucs uef 'n de @seooor 'o "] i\ 

O.()? %. confimins good PFcision I ] \ 

.l 

Mcrhod acumcv Ms *dut€d s lhe 

Nrc.ntase of recolcty ol knoM 

moub of €hircmc to th€ 

cttututos@ ol4hinw 

phammuri€l f@ulation (l.O-510.0 !g ml-r) All m.ss*ndts ecG made ir lriplicat s 

lnh- dd ind {hy Mlmy @g€d 98.0-loo.0 % Thc E$ns @ rtc$ted in table 156 

lX. low RSD vllws ed high Emvery irdic.r.d thar dE nethd hG ! hisll degr or 

Trbl.3.36 

htt an ! idqna, paxid Md@cstc, olc4itircn in Phsffiati.d funutdiN 

L99 99,85 

r00.ll 

1.99 

RsD = Relativc standdd deviatia\rlt tcc = % r.cordv 

138 

003 

0,02 

0.01 

0.01

lr was perfomed by makinS shall chdges in thc pcrcotag€ of mclhdol or wlet in mobile 

phos md now rate @und optinu oodnions. which trov€d qune sDbl. When a pdmeler 

$d delihedely chmged +5% (in mobile phe) sd a0 2"/o (in flow rc) ftom ill oprinum 

condnion, |he snifting in fGnrion rine of efpircn. $6 lss Th.* rctulls indi€ral b'n€t 

mhustnes ol the d€leloFd method. 

21 celtb@ unh AcE-intinit6 

Ccfpimme wnb AcE.inhibito6 (caplopiil, ensl.Pril &d lisinop'il) M Mlvzed o' a 

Pubspher Sd. Cr (5!m,250 x 4.6 nn) @lnn. Mobile phe for lhc epMtion o' 

efpircme, .a$opdl dd cn lapdl osistcd of hdlalol: @rcr (80:20. v/v. pH l-3) Ior 

ceapiom. ed lisiiopril, (40: 60. v,rv) mi aining no* 6r. !r I nL min n and UV d€reio' 

'lhe calibration cud6 we lin€{ in the laogc 

| 25 to 20 dd I 1o 50 !8 mL I for celpionc, 

captopril, oalapril 4d lisinopril Bpelivcly 

*itn coftlatioo ccmcic s (l)or >099. 

Suris c.l $Ils&€ ws ucd lo g€rcdre lined 

rogrcssion equalions for all calibEdon cufl.s 

'Ih. lalucs oi LoD lid LOQ we,e 001.0.1?, 

0.05 a.d 0.02 Fg nL I for cefpircme dplopril. 

oalapril fld Iisinopril 0.04. 0.51, 0.15 ed 007 

llgnL r dpetively (t ble3.5?). 

Inna- dd inter-day pcckion of the popos.d 

toethods were evaludtcd s rcp@tabililv ed 

inr.mediare psision Espelivelv l h.F 

crpennehr vft rcp. ed over thft drys 

Friod ro €r€t@re int nncdiare PEbion lnmddy 

vo RSD valn s of thc neGwhors of dl 

an.lytes ranged betwcen 002-073 % wh'lc 

inleFiay % RSD ol $c nethod ws nol grcatr 

tha.2.70 % (bblc 3.58), 

ll9 

,l 

"il, lll 

i 

"- .- 

Figur.1.6{ 

ch/otuosans tl cclPitan?' ud talDprit 

lo) refpnore'tud .tu|aqit A)

T.b|. 1.57 

Lihk ol det..tid dd qmtilbdid d..hnme 

1"ff;;l; "*""t" "*'t" ' 

@d .|cLhhibi@s 

LOD LoQ 

l.15-25 r-57753i+6021,7 09091 001 004 

LI2-J0 y =252.61x -13 

t.25.2o !=17t.ttr+77lo.t 0.999,{ 005 0lt 

r.O.to y=ll546x+806.54 0.9999 002 0.07 

Conc . Concentdion. I =Cor.ldion coetnci.nt, LOD = Limitof dderion, 

LOQ - Limit of qumliff otion 

Ttbl.3.a8 

A..w od p.rtsim of . elpnon aMt tc E-inhiulds i' PleMeitat fonrutdiw 

r.t5 

2.5 

J.t2 

6.2t 

|].5 

\.25 

t0.0 

2.0 

t.l2 

25.01 

2.5 

RSD 

0,10 

0.26 

0.20 

0.02 

0.r3 

0.50 

0.0? 

93.50 

2.51 

3.07 

629 

t2.6 

140 

5.02 

1.93 

7.92 

RSD 

0.53 

98.39 

too-43 

t$.12 

100.2

ccury of rhc ptupo*d meihods wd expEsd 4 Frcent Sc E@lery ard 'l 96 

delemined by addnion ofloos douts of efp,rcEq captoFil. .nalapril and lisimFil inlo 

knom concentBtion of phmMui.al fomulations. Th€ n6 @overy volEs w€re 98.40lo0l5 

% for inlra-day od 98.39n01.0 % for in&.nay (t!bl. 3.50. EiSh pocentas€ 

rccordd of rh. proposd ncrho& indicar€d sufficic dlmy (Lbl€ 1.58) ed speificily. 

trohusrne\s ., rhc mcrhods Nas .h{ked by m.lins small delib.taie cndses in th€ mobile 

Dhas (+5 "/0), pH lnd l ow rat€.'l hese vriations hdd a dinoi eif.d in opeEting condnioN. 

,5 C4pircn Nith Ct

lNlrt.s (octpiruntc. diltium, v€rapmil sd 6 odipin€) in rhe phmeuical 

fomulotions. All ma@md|3 v@ p.rfom.d in Eiplierd 

|.25 

7.5 

50 

1.5 

20.0 

Tilt l,59 

Linit\ olde@iM ond qdlldioa olehno@ ud c4hnnl bkxt$ 

LOD LOQ 

,iilli:l" "**'-""".-' 

1.25-25 

t.2s-20 

T.bh 1,60 

Ac.wu, ot'd praitiN ot..hiw @td cklmd blukrs in phefudkot l*nulatiN 

2.52 

|.25 

|.25 

0,25 

0.ll 

\42 

|.24 

25,01 

2,48 

2.tl 

20.0 

1.23 

2.15 

0.33 

0_22 

0.22 

0.03 

t00.30

The iftanay precision (% RSD) lalues mged fbn 0.01 to 0 64 % {i$ accuBcy of 98 00_ 

IOO 5l %, while intriay prEisior M 0.01-l.?9 % *ilh Muwy of 98.00_10o 80 '^ (bble 

l.60) lhc* values indicat€d lhat the proposcd nernod hd hislt p@bion ed acutsy, 

which shovcd th€ suir.bility of $. meihod. Thc ihlra-day ptcchion (% RSD) valu$ mged 

0 0l-0.64 o/. with &c\rey of 98.00-100.51 %, shile int r{tt p@isio. wG 0.03-1.79 % 

\irh arc0ru) o19800-100.30 i/" (Lblc 160) Thcs uluca i.dicotd thar lhe proPoscd 

he$od h6 hiSn pr€cision ad ecuracy, which shoqed the suilrbilily of lhe mdhod. 

ln orde. lo cval@b |he sDecincny of lnc m.tiod, dosge fom of Ca{haml blckd w 

mllud. The chooarogres showcd no excipiots inllafctcnce, lnus the prcceduG was 

sunibl. for dcremimrion of Ca.channel bloclcB i. pEence of excipienG. 

Tnc mbushcss of thc toposed h.lhod was .val@led by influcne of shau variadons of 

orEarihg psrderen such as nobil. phae, pH .nd now de. On€ pardeler wd chdg.d i. 

rh€ exp.rimenr aI s dhe ed oalyFs w€E cdi.d oul in tripliql€. Thc rcsulh did nol show 

26 Cqpirom with It rr..eptor antaConkB 

Scpantiotr \r$ p€rfodcd on aNuclesil 120, Ctr (5lln, I2.5 x 0.46 nm) RP-olllm, mobile 

phde @6bted oI h.lhaol md wr.r (65:35, v/v), metonitril. dd *atet (75: 25, v/v) for 

cetirizin. and leva.lirizine Bpetively Fcxofcnadine ep@tion w4.died oui on a 

Purosphcr Slart, Cr (5Fn. 250 r 4.6 m) olmn, 6ing ncth&ol &d wtd (70:10, v/v) a a 

nobilcphasc. pll{as adlustd ro I5, ln allcass, nobil€ phase was pumpcd al a tlo* ra|e or 

I nLnin ed emuenG weE noniloFd al2l2 nm. 

calibhion cunes wcrc .omtructd qith m*ins stan.Lrds d*l B@ foud lind (l 

> 0.9S9) lor cmh of the anal)les over th€n qlibratio. @g$. Thc linedil, qas evalualed by 

$e lesl s4uaE rcsrssion method !,rd the pop6.d mernods wrc evalutcd by ib 6r.ldion 

cdfide dd i.terc.pl value. The linits ol dekction t.d qustifi€.tion of celpiohe, 

osttizine. levoceftizinc ad f€xofenadine re shom in lablc 3.61 . 

Inhiay (Epetabilily) ed inta{!, peidon (inldftdi.lc p@isio.) m Ms.d by 

calcularins fi. rclariv. sbndard ddiaiio. (RSD 7") ror three detcminatoB ar .!ch 

concennarion in rhe linedii, rsgc. The inoa- sd i ernay pecision ol $e nelhods wd 

lound b b. les (hs 3 %. Melhods @mcy M deredi.cd by calcul.li4lhe *tinaled 

conccnualons s p€ro.nr ol rhe nominal con€enk dons 1 bc in@- od intcriay &cutcy or 

t43

the netlod! .ansed 98.01.100.59 %. Th. high rcovri€s and lo* RSD % coilimed the 

nrnabih,' of te pmFkd dclhods (irble l-62). 

SFcificnt of the prcFsd me$o& 6 .xeined by mlytry rh. ph@cdrrcal 

lbmuladons, nr€ chrcm.1oe@s of HFEeptor ot68o.ilts qee not int.f€ed by $e 

excipimrs plt$t i. thc dosge fod. -nE cfid of mobilc pt@ onPosition ad PH on 

scpaFdon olcefpiome 4d ErdePlor eiagonhl5 w@ also optimiz.d 

'l 

lt 

-l 

tl 

't i 

-tri 

iii 

t-j 

; 

I 

li 

_JI 

FEUF J.62 

ctu.natosun of eerpirune' ad c.",','tr:?fr

TrbL 3.62 

A.cod! and precitin of.ehnone ud E Fe.eztat @losoi44 in pl@n@dicol lornutdioht 

50.0 

2.02 

t.29 

r1l 

lr3 

2.19 

1.53 

l.9l 

0.15 

0.12 

025 

001 

93.10 

t00.23 

r0016 

ro0.ol 

100.!? 

98.01 

99.75 

145 

0.2t 

0.5 

l.0t) 

50.0 

1.00 

1.98 

1.93 

3,98 

tt_01 

RSD 

0.71 

0.33 

LJ6 

Ll3 

t.ll 

2.53 

2.3\ 

2.21 

L32 

0.ll 

0.t2 

0,25 

100.2

21 c4pitM pA H.tuNor rmogfiba 

Ccfpimne and Hfseplor &tagonbts ealysis wd condded on a Nlcleosl I2O, Ctr (5Fm, 

12.5 x 0.46 mm) oolum dd mobile phase sG m.thmol dd wat r (20:80. v/v) Flow mle 

$6 |] 5 nL min r dd Uv dclstor ws sl al 231, 247 Dd 2& M for cim€lidi*, rannidi.e 

&d fmlidine dpetilely. 

l he linediry of rhe cslibraion ca€s for cefpitome 

lnd Ilr re@plor aflagonisls werc 6s6ed in $e 

.cnsc of L0-50 |18 mL I. The coftlaron @effici.nls 

(l). linib or dckcrion dd qurilicrtior d.tcmiftd 

lBm c.libnton cuncs e€ smh&ikd in 1abl. L63. 

l,rcchion wai cvaluar.d ar the rcpealabilny (inrcts 

d{r_) ond inrfm.diab pEcision (intcriay) lcv.l. 

Rcp.arabiliry w6 studied on th. w€ day "tile 

if,rcmediar. pr.cision on the dif€r€nl days The 

iiEanay F@isioD 

(% RsD) of efpibne ss tured 

0.02-0.1i % virh ulmy o4 99.85-100-20 o/. and 

inrsr dq RSD \ras 0.0: 0.1? % $ilh rcuracy oa 

99.10-100.10 % l he inlra-dat prsision (% RSD) of 

Hrr.ceplor .nhgonists tug.d 0,01-0.26 % whilc 

sautuy w 97.90-103-0 vo.ll. i qnay pdision 

$ai 002-1.4! % wilh scMcy of 97.00 -101.0 % 

snecificiry of fie ndhod wa ob*tu€d by ealyzing 

$e phamaceutical fomulatotu. Thc excipids did 

nor inre.fee wilh lhe peal ofH:-Ec.plor dlagonisl3, 

ln order ro study the mbushcss ofln metnods, snall 

.harycs in l o$ rdc (1 0.2 mL nin ') 4d mbile 

ph6e conpGnion *erc o.d.. Mimr €ha8es in tlE 

now Ete and mobik phe composilion did no! have 

,nt sis.ifi€ant clTer on peal arca ed Elention time, 

,] 

Fr"-, 

t 

FkoF 3,6J 

chnnatosan of.ejbitune' od cinit rke , 

ta). Cehnotu' dd rmitidinr' @, cehnotu 

andfndidk ' (c)

T.bL !.63 

t.ir'r: oldetu.i@ an t q@i.trdid oJc4piore aa Erte4t aagat* 

.i;ffry **"-*"'.l- I TOD LOQ 

1.G50 

LG50 

y=34!l3x+7@s.4 0.9991 

' 6143,8r +421.71 0 9990 

y- 1202.4r+ 1559 7 09991 

y-753t.1x+21149 0.998 

I.bL l.6a 

autn.t utul rt?tisiu ol tllpttntu od tI: - Pcelt ontasîs^ in zhotkueutiNt Jtntnotiont 

10.0 

25.0 

2t.0 

50.01 

l0l 

50.01 

5.02 

0.02 

0.12 

0.02 

t00_m 

t.00 

2t.01 

201 

2.02 

5.02 

0.12 

0.03 

0.02 

0.10 

0.01 

t00. t0 

9.33 

100.3 

98.0

2A celpituw wrth htqgbc.dt asur' 

(:lbmatos6pht \5 pcrfomed on a Mcdnmca Ctr (5sn' 25 x 0 46 mi) col6n Mobilc 

phae cohsislcd ofnelhdol; wtcr (8or2o, v/!, pH 3 l) neth6ol: wtd (60:40, v/v pH l4) 

pioslit'hoe ed mtfomin *ilh 

and methdolr Mter (10:?0. v/v, pH 1.4) for sliquidone 

ccfpiren. Bpedwly. MobiL ph!* ws pwPcd !l ! flov FL of090 dd I mL nin-l 

rcsD.cdvely Uv ddeclor {s sel al 268. 240 dd 2't9 m fot Sliquidone 

pnrglibTone r$PecivelY. 

Tnc me$ods wft lire{ ovcr a tr8c 0 75-50 

!g ml-i br cefpircnc, 1.5_50 fg mlrfot 

gliquidone, pioglihrcne sd 0 78'50 lrg mL' 

for mefomin wirh co'.larion @mcios (l) 

greorer 6m 0.999 Thc LOD md LoQ values 

r.nscd $i!in 0.02-0.3 sd 0 05 o 09 llg hL l 

6p€.1ivel, {ubtc 3-615) 

The pmision of the ncihods for del.minaiion 

of @$imn. ud hr?ogly@n'c .gors w6 

srldicd using rh€ paBm€leB as Epc.rabililv 

(inr6nay) and idem.di e prciion (in1er_ 

day). h M cxp6$d 4 rclativ. n4datd 

d.viarion (RsD %) ar *tics or n4ur€menrs. 

Repeahbihy ol lhe* m€lhods wd sludi.d on 

rhe se day and imcmcdiate pFition *6 

de&mined on ihe @nseculve days 

Aeumy of lbe n.tlbd wG d€lmired bY 

rpliete aMlysi! of six *ls of spl.s spi*ed 

wirh six diffei€nl levcls ol cefPnone rd 

htpoSlyc.nic agenb (0 t5, 1 5. 1 0. 6 0. I 2 0. 

25.0. 5o.oFg nL') dd @mpding $e 

difcrcne b.twes sPil.d valc 4d thal 

&rslly found (Eblc 1 66) 

I43 

.-i[t 

n€{omin ed 

ctuonatosals ol c.httNe d') 

stiq'idon' tot ciPnow,ad 

mtldnt'/lbt, c4|t6w 6d

Trbl.3.6t 

Linik .! A.kcti@ ana gun'ificttin ofc.hiare md bp.stve^n t8edt 

ff;i" *"o*'*"'u- LOD LOQ 

r-1306.1i+45603 

0 0990 

y = 4156.5x+621.97 0 9999 

y-32t22x+lO0l8 0 9991 

, - 2596 3r + 2ll.a.9 0.9991 

TrbL !.56 

Arwu, Mi ptnkion of cehituft o'd hnnqlr.enh as.rts in pho@'dxot ttu'tdiN 

0 73 0.730 

Llz I 120 

I0 2.99 

lto 250: 

RSD 

013 

020 

2.93 

12.44 

L5t 

2.95 

2501 

19,53 

1.510 

1.073 

6244 

12.47 

50.0r 

0.lo 

99.33

The inrn- md interd.y % RSD wB l.ss lhd I % fot all amlt'lcs while % &cuev tuged 

irofr 98-loo "/0 (bblc I66) speificitv ol lhe md$ods ws evaluated lhrougb a'alvsis of 

phmrc.ulical fomul.lioN dd thc F$hs wE Gv.l@|ed bv .n lvtng wilh standdd {d 

empl. elulion of hyPoglycnic tS.nls No int.rfdnce in lhc peaks shoald de$nbed 

nelhods n specific. Asey robushc$ ws 6s.scd bv maling small vdi'donr in mobile 

oompsirion (+ i%). pH (r 0.5%). dd now nt (+0.2 %) Results rc6 'val@lcd bv RsD % 

ol ltat aRadnd Rtcnti.nline $hichddnol sho* mNh vaitrion 

29 Celpinn ||ith nonatqorltl ann'iaJLnndlott dtues (NSAID, 

A Mcdilcm€a Cr (5pn.25 x O46hh) col6n E dplov'd lor thc scpanlion ol 

cetpimnc wirh NSAIOS- Mobil€ phs coNisted of a nixtuE ol me0r@l ed Mler (80:20' 

r/v, pH l.l). Assy was Perfomed al anbienl rcnp.dre a1' noq rate of I mL nin' The 

cmNnls $crc moniu.d dlnm 265 nh 

CalibEtion cw6 for ccfuireme .nd NSAIDS *c lind ovcr the otuordion mgc of 

o.2t-50 |]g mL L. The med egression equarions fbm,.or'larion coelficients (/) ed linns 

ofdctection an l q@tilicadon vducs @ shoM in t ble 3 6? 

'lh. pNhion or poposed nerhod qs 4alulcd $tuucl| inFlnav (Epe't'bihv) ud inr€F 

da) (lrlcrmcdiatc pBcision) Thrcc rcplicatcs {eF nadc for inlra_ ed i e'dav sludv Tt' 

precision is experscd d pc@nlage rcrarv' 

sbndrd deviarion (vo RSD) and it s tug.d 

O02-216oh?i4O0l'1.54o/' Ioi inlra_ ed i e'day 

rcspectively (lable 3 68) To evalu!. 

ecuract ol the pbPoed melhod rccovery tesl3 

ntr all !n!l!es wcrc pcrlbm.d b, addiog knoM 

dolnts of stande.d eluions lo smpLs 

folloltd by dalysis usirg popostd nellod 

Accu@y v6 dp€s.d G Frcot!8e 'gv€ry 

lnd dctnnnrcd in ftc li.6nv rdgc lnta ud 

inrcFday pdcenlsg. recolery dnged 98 00_ 

IOz.Ol % and 9?.00_102-0 % Espe[rclv- Th6' 

€suts e r@ntcd 

iD i.ble 3.68 

lt0 

FiAtrE 3.65 

( hrcmrto3rom of (.rprbme , meb\n8m 

nurb,prcf.n . dn loGm sLdDm' md md.mmrc

sneci6cn!, srudy of lhc prcF*d maM denonnfl.d $at the cxcipi'm fiom lh' tabl'ls did 

not imdfce qirh lhe chrcnalogrms of ehimm. &d NSAID' FunlamoE wll'lslved 

pcdLs indicakd lhc specilicily md suitabililv of$. prcpos'n he$od for the iLlehimtion of 

I|x dbosurcss oa lhc n.thod Na3 culuted bt tsiaions in the nobil' phN comPos't'on' 

I and no$ drc .t wbicn cetpnone md NsAIDs Malvsis wre p'rfomed Measur€ments 

werc cnied oul in lripli@t€ dd l.$ vdiation was obseryed' indicaring obch'ss of lbe 

T.tL ! 6? 

Qttihrdit unvt ant li i^ .tekdiah d'd qtudifudtian of'4?irctu atd NSA|DS 

iil";$r *.**'-"0-ll"" . 

0.2t 50 

y=1(x3.?6x+?2527 0 9994 

v d3l.90x+ 180 l8 0.997 

i =966.21x + t35.10 09s46 

v =t236.40x + 479,21 09993 

i =r5r8 2Ox+ 3t4,37 0.9995 

I 

LOD LOQ

0.:5 

:.5 

Tlb|.3.63 

A..vE d'.t pe.iti[ ot.ehim and Ns'rlDs k phewet'i'et ft*tuldk's 

150 

t0l 

12.0 12.5 

25.0 24.91 

0.52 

?.51 

RSD 

2.26 

0.13 

t2t 

0.32 

0.65 

0.1? 

0.12 

1.15 

031 

L23 

t.2t 

1.23 

o.t2 

0.2 

0.25 

l0tt 

t01.03 

102.01 

0.2t 

2.50 

5.00 

1250 

o.2t 

250 

t2 49 

250 

5.00 

12.5r 

t52 

12.500 

RSD 

0.ll 

o.22 

0.22 

0.01

!\t C.Ipro^. rith Pmto"Ainp i"hititors 

'| h. olum. usd aor $poration ss a Moiirerdq C r (sfm 25 t 0 46nn) co|lmn hobile 

phaseconsisied ofnethanol: walct (80:20, v/v, pH 3 5) Asar5 w.tc perfom€d at a flow Ele 

010,85 mL ninr dd chrcmatogrms were @rd.d al29l dd 278 nn for on€Dtele md 

Six ditl@ conccnmrion lw.k iO?5, 15,IO.60 l25 25O dd 500 18 DL-r) lr@ 

oholned ofcach s{andald elulion Each solution ws ibj€ctd in th' chrcmtogaphrc svslem 

(r 3) ed m6 valcs of p€al &e6 w@ plolt€d against 'onc'nhtio6 Cudcs were 

rdjusr.d b! lituar e8Esion wirh l.!sl n@ sq@s method. indi€ting a high d'8r of 

linceiy for all ealttes. Tt. limil of deldtion &d qwlifiolioh of all @lrtes dd 

aHcldioncocfllcicnt(r:) lalucs olc smmdizcd in (able I69 

Pdcision ol $e me$od *6 d.t mined with rc8rtd 

b horh inFa (rcFlr.bility) dd inlcr{av pE ision 

(inidn€diarc prcokion) which is .xPesed s Glatve 

starddd ddilion (RsD "/O lnd ils M valu. 

rmongsr r€pli€r. Espoh*s B ls tb4 20 %. 

indicarins sood pdision oflhe mclhod. 

Accurcr oa th. proposd netbod wa sesed bv 

adding knoM dours of stada.d eludons ro 

smple follo*d by antltsis sing lhe popos.d 

ndhod. I he Ecolcry lalnes *d. b.tw€en 98 0 aid 

l00O 91,- rotrftr1in8 Bodl 

accurrov of the proposcd 

lbc medod s speific,6 no i .rfemes fom 

crcipie.h were obseped duing lhe deiemimtion of 

NfiJnome and trolon_punp 

inhibiloB Robu$n.$ of 

rlN Nlhdl \as sludicd b! rari,tion in p'{. nrobile 

phe onposiLion ud ilow rarc' Tbe vriatio. of I 

0.5 % in pH. a 0.2 % in flow ratc dd a 5 % in nobilc 

phase did nor .ft*t si8nilicetlv on op.dting 

l5l 

Chrcnatosan oIefunore | t) ud 

oneztdoh 12) (a) @hitune ud 

LuNNeot.lb)

25.0 

1.0 

TrbL3,69 

Linitt of detectin and q,@tiftahm o.f ..hitotu atd p@'Punp khL\ibs 

lff;fi,* "n*'-*-'- 

T.bt 3.m 

LOD LOQ 

,a.cur@ md p€chion al ahnMe @d protfl'punP tnhibitott in phun@dicdlamlnatiN 

100 

r2.50 

r2 5l 

0.02 

0031 

t.30 

t2.493 

3.01 

r2.50 

0,75 

t54 

98.67 

100.31

3l C4pitffivlt ttdirt 

Sep@rio. pd caried oul on a Purosphd Sl!n, Ctr (51D, 250 x 4 6 m) colunn nobilc 

phase consiskd of melhdol qaler (80i20, vr, pH 34) ior cefpimm€. atoflarali' 

pBlGtatin dd w.tcr: neth@l: a.elonitrile (20:60:20 v/v' pH 34) for cefuircn' ed 

simvAlalin. Flow ole m s st I nL min ' sd dcr@tion B 4hi'vcd with Uv d'lcclor !t 

l-inearity wd dcnonslhled al conc.DlEtions fom 0 625 to 20 lg DL- lor cefpnome &d 

pnrNarin. from I ?5 ro 50 18 ml-r for aloNdlttin and {nvstdtin Tne LOD' LOQ dd 

nd ESrssion c4@ioo frem six dpliored elibnrion c@€s of efpioft dd statiis @ 

shoMinllble 3.?L Tn orelarion oemcienrs (/) *@ sreater 

Pdision of lh. n€$ods wa d.remined 

inrmedi{c prccision (inlqiat pdision). al 

difcmt concstdlion lerets Pdision ws 

cxprcssed as RsD o/0. Repeabbility sludv wd 

F.fotrcd 

by inj.clion of tbE. Gplicales al 

six diff@nr @BnFation l.lcls widin . 

single day whilc imcm€diare ptccision M 

cvalualed on thr.c dif€renl days (lable I ?2) 

detem'md fiom 

phdt@un.d fodutarios of efpircrc .!d 

3uim. *6 exPAed 6 Frccnt 

g. @Y€rY 

lhN Eollcat$ were nadc lbr each 

conccntalion, Ih. n.4 r€@vcti.s found tbr 

ccfpibm€ and srdins wE in ln. tu8. 98-G 

lhe s!.cificily srudy Evealed th€ abeme of 

crcitisb inlolcdcc 6 none of lhe peats 

intcrf.re in Elcniior line of mltl€i 

Robu$ne$ w.s studied by makinS chmges in 

llow rate, mobih Ph6e md pll of hobile 

phr$, l8 vsi.tior we ob6d\td. 

r55 

than 0 999 

by repeatabitity (i '!nay PEcisio!) md 

l|lrrc 3.5? 

Crrctuosrotu ol cehise atoMedin' 

atd p,Mtot @rc4pi,@' tud 

si'Mdint 6)

1.5 

TrbL l.Tl 

Iinits ol.hkdid and qm'rftotid oJe.hntu a'Lt idiB 

eocq& R.sKDn!+.!M LOD L,OQ 

0.625.20 

T.ble 3 7t 

*lurdr ud prechtm oJ cehnane atrd satins in plwmeuti.al l.'nuldiN 

0.62 

125 

2.50 

RSD 

0,0t1 

0.0t3 

0.030 

0.10 

t00.02 

t0012 

0.61 

r2l 

t75 

7,01 

r56 

0.62 

2,50 

2.01 

0.t7 

0. 

0.32 

r00.8 

99.20 

t00.5

B Dnqi"t t .lior sto.li.t of..fpinn 

l drdq b c&r! our rhc inlcdtio. sludies of cefpinne bv his)l p€rfolrme liquid 

cfiohatography. nock $lutions (100 rc nlr) of cefpnome sd intct&tin8 dags wrc 

pEprred individually in simulated gsdc juh€ aid bulfe6 ofpH 4, t4 md 9 These {eG 

mixed in cquimold Elio io En.meyer tldks dd kept on a wald balh al l7'C {i$ 

occ,sbnrl shdlins loi $u nou6. Sdples \ere witMam at l0 minutcs tine inhal. dru8 

conknb wd lilcrcd lnrcugl a niuiporc lilter (0-45p) ed tfllv$d bv RP_HPLC AII 

separ ions wcrc Frloftcd 

using rheir resp.cliv. chbnalognPhic @nditioDs h €ach c6c 

wavelength ws selecled by lakinS uv cul olf poinl of cefpircme with inte@li.3 drugs 

lnrctacri.n rgulls "crc contuled fmn p€ak rcs of ccfpimm. and intracting drogs crath 

$.s plorhd fo. fi. % ddg available veGs tine in ..ch er oI expcdmcnl 

32i h,tc.o.lion of ..lpi,one with,'tcE-inhibith 

ln prcsne ol capbpil, c.fpiode\ .vailability ind€ded in bufie6 of pH 4 &d 91r 194 8l 

ed 141.99 %. while it was @mporalively le$ available ir simula&d gatdc juice ( 125 3l %) 

and h{ffcr oftll ?.4 (124.46 d/") (ltble l.?1. fi8ui6 368a.169) ln prcssce of enalapnl. 

rchnoN rmilabilil) incrcNli in simulaled Sstic juie. b!$es of nH 4. ?4 md 9 to 

l82.Ol. 199.79. 195.49 $d 196.62 % resp€cti!€ly (tablc 3.?4. fisut s 3 68b. 1 70) Similar 

r4ulb wore obs cd {hen ccipioo€ ihloadcd wirh lisinoPril Th. incrcM in celpironc 

availabiliry (conptralivelt) *as 84.?1, 93.85 ed 8885 % in botf.rs of pH 4. 7.4 dd 9 

rcsFctircl! These Esulls arc $mnwitd in rabl. 3 ?5 dd ploned in figufts 168c. l ?l 

I his incre in ceipiome alailabilily is drc rc lh. fomalion of chd8e transler conplcx *ilh 

AcF-nrhibiro6. shich resuhs in high nold absoqdlny lhd lhe p!rcnl drug (cetpibmc) 

ilowcvcr, $c deceascd avdilabiliry oa @apircnc is d@ to lbmation of lov nolar 

absoptilhy conplex or suppi.ssion oI €hnonct .clivnv bv AcE-inhibilou The incEas 

or llrruo* avdilabihy showdd lhc inrenction bctqc! c€fpiom€.nd AcF.inhibito6' 

ii, S]D$.si! o!.elpitod. tith AcE-inhibilo6 

In ordcr ro furlhq €rplotc lhe resuhs of i.€ra.tion studies. ceftitom€ conplexes wcd 

slnlhe$Ad nr equmold ratio wi$ all inte@ting drugs in netheol except metfonin 

(war.r) To efpnome solulions, i.tereing drugs $lutions $@ added indilidullv and 

r.nlxcd foi I ho6 on a warer balh al 8O"C oit cons6m stirins. liftcrcd. cry$'llizd dd 

mclrin! poinrs Eorded. Thc solubihy of $ese complcxcs w6 ch4l.d in Mlf ncrbdol. 

t57

c$!nol. rebnn.ih od dimcrhylsuloxide (DMSO).'nr @mplex6 werc foud $luble onlt 

in DMSO. Th€s compl.x6 woe chd&triz.d by spectros@pic Ehniques such s 

Uv/vhible. F_ a-lR and H-NMR. The physical and specuo$opic dala dc Siven in tlble 1.76. 

Soluti('n\ ofc.mplc\.s in DMSO Nm {anned in rhc (lvlvis rceion againsl rcag.ht bldk. 

( rrinonc sa\€ )"8. al 264 .n. wbcl@ rhe ompl.x.s showd difeFnt L* whicb m giv€t 

in $ble 1.76. the shi ff of lhc* complexes |oa long.t wavele.glh indicaEs thal thc mol4dd 

slrucruG ol rhc conplex ba a hiSh$ @njusation ftm thal of cefpnone. l-he chege in lhc 

marina suggesred an inlenction or fomatio. ofcharge ttahslir conpl€x. 

llt srud\ is a aunhcr supponing evidence forcomplcxation o! i.leraclion bctwccn cctpiome 

ddi cffrinS dtues. lR sFcrra ofc€fpnon€ showcd m aberption peak ar l5O4 cn I which 

q6 antihur€d ro NH1 slr.lching dd @respondine bciding vibBlion al | 582 cn I l61a I. A 

sharp a.d sell Esolved peak l?41 chr {d ssign d to pl&rm cltbonyl [62s] shile 

M.k s-H bdd qd obscpcd ar 2566 cn | [624] (able l.?6, figur€ 1.72) In capbpril, pealc 

ar l?47 and l59l cd wE assighed lo cdbonyl sltlching vibralion of*rboxylic acid dd 

rnid. rcsp(tirely t6261 ln onalapril. lR pe.ks ar l?50 and 1645 cmr wcrc duc lo C=O of 

cdboxylic acid dd dide ctFcrively {6271. Simildlt i. lisinoPfll. gbonyl slrerchine ol 

kni&t mide *6 obFtu d al lg2 cm'dd Gymtutric €rboxylic sltEtching ai 1582 oi 

16281 l]lee rcsulls d€ given in lable 3 76. 

In lR sp€cta ol ceipione.Ac!-ihhibibn conplcxcs, NH, band dispp$rcd. ]hcre was a 

lhin in carhonvl perk of amide lo lowr frequencics al 1722- 164? and 161l cnr in 

.ehnome{aplopnl, cefpionrnalatril dd cc&ion€-lisinoDnl 6npl.x.s ep€.rivelv 

Thc* EstrlIs suggestcd e inrc actior or @hPlcxtlio. thbuglt 9_le|,h nntogd of 

ce fpioEe $ith mid€ c&bontl oaoploFil, dmary di!. of efuione wnn srbonvl dide 

ofcnaladl and carbonyl (anid.) of cefpiome wilh p.inary amine of lisino[il (able 3 76. 

Thc rll-NMR srudid funh.r confimed 0E$ inLdtion Esnlls Thc |H_NMR (cDroD) 

sp.cuun of cehircne shoEd rhe folloins sisntls: d 2 l'L2.ll (2H m. cvclopentene)- 

l.16.l t5 (6H. n. cyclopdt.nc, SCH,,1.95 (lH, !. -N-O{H]).5 11-5 15 (lll. d. cephan 6_ 

l l). 5.4 1 (2H. s. CHrN). 5.82'5.81 (2H. s. cepham_?-H ). 6 81 { l H. s. thielvl prol6') 7 22 

(2H, br.s, NHr. ?.7t?.80 (lH, dd,.,= 7 H2, ptridine).8 28'8 31(lH. d J- 7 Hz. pvtidihe) 

ll 76'8.78(lll,d.J Tllz,pyridine),9.:(Irl.dd,J=7112,7!_NH) 

158

Caplopril: H-NMR (CDCIT)|, 1.53 (lH, dd, SH), LI7 (3H, d, cHt,282 (2H, m, sCHt. 

l,l1( lll- d- q- cllco).l.6l (lH- n.6 cH,).2 07 (lH. n r_CH,.),2 01(lH. m. p_CHr).4 60 

(lll. . u Crr).9.31 (lll. s. COOII) [629 ]. 

Enatapir: \I-NMR (D:o): d 5.18 (NH), ?.11.7.1? (mmadc pobB), l.2l (cllr26), 123 

(cH,-22).2.54{cll-14). 3.79(cH-l2a),4.17(CH-25) 1630,631} 

Lninopril ll.NMll (llDO) d 7 tl (phcDylrihs prolont,.l,l4 (H 2), 1 15(ll_2). 1 84 (H_21, 

:r 62lt-5).:t 06 I6 ). ?.85 (ll-4 1.2.11(H-3',).2.03Ol-l).l.?101-t).160(l{-4)16321. 

ln cefpibm€-captoptil conplex. efpibme eph€n &H ptolon (6 5 13_5 1 5 ppn) w.s snined 

to upfi.ld (r 4.23 pp6) &d CHCO prclon (d 2.44 pFn) of eFopnl I ale shift.d lo 

upfield (r 2.18 pprn). The eul|s showld tht involvm€nl of Flelln nitrog.n of 

celtn nc Md carhonyl .xycen.fcE oFil (tabl. ].76). IlE shin ofNH, tmlon id 7 22 

ppm) ol cctiriromc ro doMlicld (d 7.2? ppn) sd NH prolon (r 5.18) ofenalapril lo upfield 

(d 4 8l) in efpiromFenalap.il conplex shov.d th. inlerstion at mino goup of cefPircme 

and cdbo.rl oxysen ol enalapril (hble l.?6). In 4fpircne-lisinopril @nplex, proton of7{ 

NH (d 9.2 ppn) olc.biooeand H4 preron (d 2.85 ppm) of lhimpril qe thifi.d lo,9.99 

ppn dd {t 1.02 rDnr (doMlield) r€sp€ctiEly whicb indicated fomarion of conplcx al uEs 

iii En.rp mirihiuliod studi6 

ln order b find the binding siL of efpnone ed inlemting druss. en€rgy ninimiation 

srudies wei€ cuicd oul usinS Chem lDa Uhra t€6ion 8.03 nolecule nodelinS ond an.lvsis 

sonsarc fron ( anbridge solisac Coipomion. Cambtidg. USA 

Itr Drd€r ro srudy 0. cnarge lrdNler cohplex lomarion b€lwen €fpirche ard caPtopnl fou 

prcDo*d siles ol .lecrronic atutlioc ar cefpiorc wc evaluted ad .nerev w6 cohpurot 

aor romarion of complcx (rable 1.77). I. filsl ce (fi8w 3.?6a) betwco pintry mno 

nnDg€n ofacrl sid€ chain of cefptome. h $€ *ond case (fig@ 1.76b), cleion deffcient 

nirr.gen of3-cyclopcntenopyridinium nilosen al C-3 of celpnone wnh carbonvl oxvgen of 

mcrcaploDropdoyl sid. chain of caplopril. In lhe thnd cae (fisure l 76c). melhoxtidino 

nirrc-qfl oa actl sid. chain of c€fu,ome ed cdbonyl oxysm of netcaploPropa.ovl side 

chain of capropdl. In rh. foMh 6e (li8e 3.?6d) bdds.'hsd nnros@ of dchvdbrnidire 

and Pr&bD ring of ccfpiren€ ed cdbonyl oxygen ol DeMltopoFnovl side chain of 

.r olnl. TnissltucnrE (1.7&) sho$€d nioimun .nerey thm otheB and th@foE fo@tion 

159

ol co'npLcr !l nntugen ol plackm ring oi cefpion. and carbonvl oxvS€n of 

mercaproprop&oyl is most littly -hich is also .viden lom total .ftr8J (t ble l.??). 

On $ce lEss. structws of o$Gr cha.g. lfosf.r comd.B of e$irenc witn dbPtil od 

lisinodl \r(.lso rmposed (figuB 3 77 and 3 ?8 ttediv€ly) rnd d.reJ mihimiuions 

*er. c.lcrhled (hhles I 78) 

'IrbleJ.7J 

Mo"rtkE ol ebimropt.ptit inte@tio$ br MJlrLc 

125.t2 

1l5.tl 

135.14 t84616 19169 

r19.37 167009 76150 

r2r.29 t723r6 39',79? 

t46.92 196515 99595 

155.17 193913 l0l l5l 

157 27 240500 !130?3 194 81 l3l t6 

153052 rl4tl5 123.01 

l)0lil 3ll16 lll70 

r5()45 t05139 l22.lt 

r5223t t0?019 123.15 

t52673 107715 12!.61 

15t647 I|]205 t2.t.46 11153n 15252 

142.36 1t299

t20 

t30 

t0 I26.56 

L lime (mins)

i E 

F 

: 

s 

t: T 

s 

5 

t 

E 

E 

c 

3 

E: 

J,= 

I 

a 

E:Z t9f-al 

^t na.('ct d,4w ttth'1sid',{,'dt44pt*r vth.qtoFi (4, *!4,it' (b) od 

l6l

1'9btuo otaah.. b * @d olqita -tutrthd 

tt0 

ett 4 qttu. - * w oldt+!' wp rqfr 4 d 

i : 

..tE''l 

k$er, ol4btu. t * @ 4bq4' tu httb.l 

t6

.F 3., ,9..r! d.6ow 

raftaBVet6d@aata 

laF3"'aWr4@a'fu 

165

,3erl3rtu''tt*rti'qntcry,4 

*ft#?=b 

fr6!-.ta Fodb,t 4 cttzp tsfu d4L taw 4n* ad .4pit d 7t*v 

sib eotp d efiiw tit *rt tl 8nd ol4.oFWtI ti.b At,'' 6 

F|'at16 Fo*aao o! d'at bt* & dm ded d'Ld 'e44 4 3' 

.*@rie', ,t,'.'6 c ca .! &a* rt @t@r dtt t 6 

Mq,.tptWtttr*aAr{ryi 

t6

''" ---+'-'"'--o-*" 

rtatn3.16ir tdtutun ot .lw$ n^14 anpt* b.tuQr bri&.'lPdd ,i|osd ol 

&@dhiain ad Ftot@ ine .J cehb@ dd @bon l ovsa ol 

Rrcaptop,optof tie.tsi' of .aPtopil 

Trblc 3.77 

Emtrt nininiaim d.ttdiMr lot t\Mio" ot.,htw-caflop chqetmsl.t@nptet 

IEUEI ?d FEIEl.76b Fi8uEl76c FiSuE 176 

623 

2tt,4l 

-24.29 

22.16 

-r08,00 

c\

i'' 

Futuioa olcteee hmjbt conple, b.tuu' c.rrpibw atd lhtuprjl d .tbonll 

o"gen dcelpibn. 6d prikdr @t"o crcu2 dl6i@pril 

Trbl. J.73 

Erew uitn.dhn ..lc,lutio"t lot Johdhn ol.ehircneraploptil chuse ta3l?r unpte! 

.',1 trt nctiod olelpinn. ith rniori.b,6 

8,66 1.32 

-f.50 -11.22 

Cebnod. ioleradioc wilh .ntioxiddts 3ch a vnmin A, C, E dd sodi@ @odGllphn€ 

*cre individually caried out at 37'C by EnuxinS cetbironc wit antioxideh for halfan 

houi Chronarognphic analysis w6 6.duclcd of, a Medne@ea Cr (5tm,25x 0.46nm) 

coltrmni nobilc phls coNist.d ofne$dol .nd slf (30:?0. v/v). punp€d al a now nlc or 

I dL min ' dd chbmlog@s *r. mrd.d !l 265 m. 

Th€ avoilabiliry ofcehiddc d.crcMd in lbe pr.*nce of mtioxidsts. In lhe pEsncc of 

vihmitr A. aftiremet lvtihhility $€s 58.9? % Sinilarlt, in thc prc*nce of vhmin C, 

vihin E .nd $diuD hct disulphik. e&ireh. ohilabil'ty d@Es.d 10 49.85, 50.51 4d 

50 15 % EsD€crively This datsse in auihbility (lable 3.79, ngues 1.79. 1.80) i.dicat.d 

intcraction bctweencefpituh. ed elioxideli 

t6E

3ti 

T.h|.Lt 

tIN i@ira 6 c.hiw d ld kbtrt it@ct E* bl RP - EP Il 

27\264 

229301 

232373 

220103 

&= Rer@tion timi AUC = AFa und.r th. cwe 

C*a+Yrit - 

I 

*1*t 

53.97 

50,51 

50.r5 

pa-.R 

Ftse t.19 cbowrogm showtts i,1t?eti@ ol@hbw eith didi.tds 

Iar..atlian ol..tplrtu vlrt Ct r6n l bloc,.6 

Inl€Fction ofcefirirem€ wilh diltia,m shovld thll rlE av.jlabiliry ofegimne incMsd in 

sin'nad SNliic jui@, bufid ofpH 7.4 &d 9, which *s fobd ro be 82,t9, 303,60 &d 

233.16 5 % Ep€lively; it d€crrsed i. pH 4 (99,l8 7t (tdlc 1.80 ed fiCl6 l,8t a. 3.82). 

In plwne of v@lanil afll dlodipirc, alail.bility of eftinDe inc€$d in all i.ceting 

n dil@ (si6ula&d gdEic juic., bull.F or pH 4, 7.4 .d 9), for v@ranil, dis ircrss€d in 

cfpiNbe auilalility M 88.34, 100.97, E0.E9 ed EE.to % in sinutared sa*ic juie. 

hd6 of pH 4,74a{d 9 '6!*tiEly (t bl.3.81, fu|E l.8lb,l-El). 

t69

Whil. in Ihe nreence ofamlodipine. il qs l68.lE. 141.04. 145 96 and 134 33 % dvailabl. in 

siinrl0lcd gdsticjuice, pH.1. ?..1md I rcspcc(ivcly (6blc I82. figures l8lc l84) Ilis 

hiSh slaildbilil, ol celpinne is mainly due to $c fodaion ofch&ge toslcr cohplcxds 

sith Ca{hd.nel blockeB dd indicatd int€ra€$on 

ii Srnh.sis ofcehitum eitt CHhon".l btoc*.6 

stnrh.sis of celtinm. contlexes *ilh ca_ch.rml blmkeu {dilriem. rcapanil tnd 

amlodipift) ws cdied out 4 distsd cdli.r D li@n show€d @bonvl slrElch'ng al 

1682 cnn. $,hil€ C=C, C{ stdchins &d C'tl b.nding *cE ohsdled al 1512 l25? sd 

IOll cnr [611 epecrilely. C=C Pcat ir IR sP.citlm of !@pmil wd at 158? cn r' 

srrcrchirg ofC-O and C-H bendins was obsePcd 5l 1253 and 1026 cn- Bpectivdv 16331' 

Ii aNlodipinc. strething and bendihS of Pdha.r aminc (Nllr) were ob*wed al l4l0 cm 

ahrl 1609cm resFctilely.P€at{5r1689chr*asssign€dlocdhohvlsrretchingandp'aks 

.t 3018 and l48l cn rw.r€ signed to C-H str.tchin8 dd C=C Eslctivelv 16341 

IR 3p(rrun of ce&ione_Ca{hmct blekd compl.x€s show€d no NH, p€ak be$'cr 

]lo0'3t00 cm r. A sharp ad slrong qbonyl p.ak appcarcd al 1750 cn | (hieher ftcquc'cr) 

in ccfpiom.nili@n conpl€x *tets in ccfpibn€-v@pmil @mplq it M @l at 

I7!s cn-r (high.. f(qtrdcy). How€t. cehion dlodiPinc @mPlq showed cabonvl 

pcat 3r lowcr frequency (16?6 cDr) (tabl. l83), The shifting of F laclm cqbonvl P'ak 

indic,&d inoBclion !t niroge. of PlaclM ringofcefpione md nitog€n ofdiniz'm and 

lcdrsmil vhile anino group of anlodipine conPlexed al placlah carbonvl oxrgcn ol 

ccfpiromc (tabk 1,81, nsu$ 3.85_3 8?) 

Dilriu.mr r 

lt-NMR ictrclr): d l.9o ppn (3H. s, CHrCO_). 2 90 (6U s. (CHt:N-). 1 25 ( l H' 

m). 1.55 (lll. n). 1.84 (lH.s. cHro-). 4 45 (lH. h). 4 55 (lH, m) 5 01 (lH d J=5'E Hr)' 

5.12(lll,d.J=5.8H2),691 (2H. d.F5.8llz. Ar).712 (2H n Ar) 716(2ll d / 5811/' 

,4r).?.56 ( I H. d. Ar). 7.69 { I H. d. At) [6351 

vcmFnil: rH-NMIr (cDroD):,0?l22 ppm (lH. d. cHt l26_2'45 (6H n cH cHt' 

2.82 {lH. s. N-CH', 2.?5_3.40 (1H, n CHr. 3 ElJ.86 (3H s, CHrG) 66G715 {lH n' 

^hrodirine H NMR (CDCb) 7.37-6.98 r,pm {4H. m, Ar), s 18 (1H, s 4H),473(2H dd r 

16.6, 16.6 tl?. -CIIIOCH:CH,NHt. 4 02 (2H,m, _CO:CrltCHr), 1 76 (! 2H J_ 4 9 tlz _ 

l?0

CH,oCHiCH)NH,), 3.59 (3H. s. -COrCHt.2.96 (2H, r, ./ = 4.9 Hz, {H,OCH]CH,NH', 

2.ll (111, s. 5{H3), 2.05 {tr.2H. -CHTOCH,CHTNH', L l6 (3H, m,-co,cH,cHt [634]. 

ln cetpion.iilri@n complex. aph.n 6-H prelon (a 5.ll-5.15 ppn) ol efPnome is 

,hin.d b.J 5.08 ppm (unficld) whilc N(Clll)? (d 2.82 Ppm) pbton of dilrim wG ale 

shincd lo dosnncb (r 2.90 ppm), indicating compl.x.tion al Fl*lrn nibgd ofehired. 

&d niibem of dili@n (bbl€ l.8l). Simil&ly, in @bibnc_vdalanil 6mplq, chose in 

rhedical shin w6ale ob*wed cephen 6-H pDlon (.r 5.1l-5.15) ofcefPnomc lo d48t 

.nd N {CHrz (',2.82 ppm) of vmpdillo r 2.72 pph (upfield) (tablc 183) ln cerpircd._ 

anlodiline complex. cephm 7-H prcton (d 5.82-5,81 ppm) P€ak wa shift.d lor 524 ppn 

( uplield ) while -CHTOC HzcH1NHz peak of ffilodipite disaPp*d (table 1 83). 

iii Eh.tp niîa4orion studizs 

Dilriazcn and veEpamil conplexed with cqfpionc thrcugb bddge_head .iltog.n of 

drhydnrhirine dd plmum nns (6suEs 1.88. ]E9). However, ih c6e ofcefpiode.nd 

mlodipine n qs tttoleh cdbonyl oxygen of di& of efpione (nsm 190) The 

minimiadon enerci* ofrne smdq.s wrE c.lcul.l.d (nble 1 34). 

Trbl. J.&, 

vdtituins of .ehinne

30 

t20 

t50 

t20 

150 

26826 

235364 

213154 

T.bL !.31 

Lkni@t E ofcdpi@-wq.nn ituio8 bl RP-EPLC 

15 35 36.35 

151t74 37.92 

nH'1 

166984 ?t.90 

60.11 

60.91 

61.16 

61.31 

67.42 

T.hL lr2 

233!02 

2El79t 

t7tBI 

132116 

232612 

240591 

24589t 

2t6A 

t52152 

153320 

l75t3l 

t33033 

pHa 

74 2a 61.42 

t5516X 74.71 

159|]2 76.15 61.15 

naDitiaz.IcdpinMtod\k itua|ions l,y M-EPLC 

231735 53675 

t65 t46 53236 

t04.12 

r01.82 

t05.52 

t40. t3 

r68. r8 

3 t.t8 

5I,]I 

13,46 

98,07 

I t9.22 

l.7 94.t3 

12,55 

73rE 

t72 

239194 13713 

2190 23093 

t24525 53692 

376818 79124 

292325 s7499 

255752 532t9 

269256 55920 

712995 58304 

795120 62UA 

15E953 7l 4 

39.51 21.91 

14 t.04 t0134

t 

* 

r 

t 

;s 

* 

5 

I 

2 

i 

JE 

3g ssigs} 

:E 

e4 

.. \2 

5 

a, 

S i 

d q 

:g ESgRFT 

-ai 

Ir I 

e i€ i F 

-:Jd6 

!ta$ 

IEiEg 

36d,id 

E 

113

&hld. - 

tbi|d == 

rt E 3r1c&{rerose lrorfu ht@dd dc4ptttet tt$.rLl@,| (e) *.q*it' (b) 

6tddldtbl G) 

t74

'nu 

ffiot4

ttuls+d'd.di.c&..."48 

Rn!*.9d!q/o#*F4-{oo.rb 

lbF ltt.$dr 4/.d'.cdo*r,.rd- 

t15

trtrft t8 Fmim { cls'a. tu{.r dtdd b.^td Mdt .,c..r nituAd o[ 

&WdhiaiEa'd PIdd rtntolelpiM d,inqa ofditti@ 

fiatBtAq Funutia' of thrt ttu^tf{ erVl* baNv., brute.-kad nitugd oI 

lt h dhhEn a',.t Ftaa aagoJdhirc* @d.th.84 4*,qadil 

,"-ar-l^*# 

\ l-iocHr 

cr 

ti4dft t.n rtuiu oI ctws. hdfu .dnpta [.M. dre!, of Ntd. olehi@ .nd 

Mltu gtotP oI@nlodiPitu 

t17

T.bLata 

E Etp nn,ini.di@ Nh,tdkts !* lbtuloh .lciPircn .Cahet I bttr.B chary. 

n&.odM 

5t.l I 

7,02 

.9,tl 

-1.t7 

4,25 

Fig[E 1,96 Fiaut ].o7 

252 

54.25 

t6.47 

2t.21 

-1.29 

77,5t 

3s ttEndbn olcqlri'w,A eatu$ate.t e.,t 

7tt 

rt,6t 

.6.21 

lt.6l 

tbr ccfpi@m. .nd tutll in|cicriom. Bl,l4A. OF5-100. cr (150 x 46 hn) colMn wa 

us.d d dbicnr lGnD. !E vit rerhsl ad vrid(|5:E5, v/v).s. mbilc Dlr puDFd 

$ | rb* 6r. of I nL mitr r. Cllw||ngntB wr! |@d.d .t 265 nh. 

CclDitoic inlc@tioB 9i$ *ntirl {!d tru daml! 94 c$n d out .l 3?"C fd h.lf $ 

hou. Lilc olhq etibiolica, tllc inr.tudon eirh Ed k . chchtion @li@ in@lving lljc 

c.dsxtlarc loup on rhc ..biMc mld!|c B.fot inrcefio|! efpilrm tpFlFd !l 

rcntion rim. of 5.9 miMca (lise 3.9h) b .nq int d.tios, @Ddc, is fom.d which 

.pp€d.d ar ditfcE r.t@lion tin€ .6 shoM in Iig|G 3.9lb.nd Sglc Tlr 6ulll ot 

inr*rion e shom in Lblc 3.E5 {d plotcd ii li$E 3 92 TlE ndimm @pl.x.tion 

@ur.d vith fdic dd chrcmim chtdi& !d .mPlq6 hld rdanio dm of 1.3 .d I 29 

nrinur* Npecivcly. In @ of iFn 9.06 % drsS-rdd @npld ws tfficd !i 0 91 % of 

fic dtug $s bn. Inc popo!.d sllucrc ot fcqtpibnc complq ie shovn in ligG 3.93 In 

c4of chroniM 89.|I % drug vrs cmPlcxcd, qidt 6p9.r EdE.d dE dru8 lo 53.23 % 

Nickcl fod.d only 22.23 % conpl.x. In .rF of ms!.sid .nd c.l.iu 97'99 % drua sa 

ardt.bl. which 3lDwd lcgdi@ tution, *iile i! c& of ctdniu'! 2irc {d nug&6., 

dede ii thc.mou of dtug indiclt d th. @mpLx!tun. bd tl! |lsddna Mplcx could 

&r bc dcrstcd. tlo$crcr. in ce ot ob6h chlorid., @ndq ws ful tomcd !.d lh.6tiE 

178

D 

*a*..-.fld-.r. 

39ettr ctro'.4doldpr*r.fu. dttat,4.(a) ctt'i.,,!ld! 6 

4r* & t .at rtadb (, d,.r.) 

r.tr.1! 

,b,W.e.r*b*-al tadta nP-EP E 

Dq/Mca.l R.aldir AUC 

f{[D 6Ot 

c(ru) 6J9 

o{[) 627 

N{||) 6.1 

c(rD 5.6r 

z(ft) sta 

Mdtr) 5.r5 

Mr(X) 5t! 

c{n) 5s 

c([) 6t 

291511 

27lt 

!lzu 

t37t9o 

22rfi5 

n|rn 

2|n6|' 

7t,/'34 

2$mt 

t2t91 

td) 

f. 

0,9! tjl 

fott, tz, 

4:ft tjl 

n.1t t29 

91.71 Cddddddd 

96J1, C.dar*ddi.(.d 

9732 Cdp&r...dc.s.d 

99.@ t35 

l(|i).l5 Co.pb(.dded 

li9 

r5t0r2,a 0t,41 

@59136 5t23 

lztfi 22.23 

s731 291 

252i 0,,O

..._{.J_rj." 

r"tr 

FlEnft a.93 Ptupdcd c.hircntFe @nplet 

hneruction oJ.4pitotu ,nh Ertu lo odt,gonis8 

ln pEsce of HrmcFor dlasonbt! (c.tirizi.., l.vdctitizi.e md rdofc.adinc). 

efpimmt aEilalility inqe*d dd foMd |o b.92.17,84.41, 84,84 and 102.00 % in 

simularcd sstric juice pH 4,7.,1dd 9 rspccliv.ly in fi. plt$ce of eririnn (bb1.3.86. 

fisures 1.94a :l 95) Sinildly. i! the prcemc of l.dclni2ift. n w* I0l.l0, 8l.91. I | 0.71 

dd 105 ?9 v. in all n€dims rcsFcliv.ly iabl. 1.87. fig!rcs 1.94b. 3.96) vhil€ in pNnce 

of fexofoadin€, @fpircoet avaibbilily w E5.42, 91.54. 90.22, ard 105.20 7o io ,ll 

nedim especdvely (lable 3.8E, nsurcs 3.94c, 3.9?). Tlc ilciled lv.il.bility of erpiome 

shoNed the inr€raclion with H f@flor anrlgonhb. 

ii Sr h6itof@fpituhevitt ErEc.pto,dnto|onitls 

Cefpiome conplqes weE sy h*iz€d with @tirizin€. le!@elirizin€ md fexoietudine (H _ 

Thc IR speclrun of cednzine or levocetirizinc sho{.d a! OH strctching no

nono+ubstnulion (1078 cnr) al p4fa-posidon wi$. rinS slELh bd@n 165GI495 cr'. 

Tnc pE$nce of two adjmmt b€Een ri.Es k 3hoM ar 844-808 cm-r, whi'c rhc carboxylic 

bond rrequ€ncy ws ar 1456-1319 and 1275-1242 cn-r. rhe.lipharic chain C-O bond in 

CHTCHT(XHICOOII app€6 !t l 186 dd at T40 cn 163Tl.ln fexofenadine, c&hoxylic peak 

sls obsdnrd ar l?00 cm r, whilc C-O ar l42O and ('ll h.nding ar I I50 cn I 16ll. 

C€fpnone-Hrrec.pror mrogonisl cohpl.xes showcd the dispFatscc of NIl, bdd The 

slElching bed ol Mrbonyl sbined b lowi fr.qucnciB 1654 cm Gcfpnone{eftizine 

conrplex)j 1670 cmL {efpirom+levocefitine corplcr) md I54O cnr (etpiome- 

iexofenadine complex). DisappearMce of NH? showd intcraclion at mino group oI 

cefpiome and csbo\ylic grout ot celnizine or lcldclirizinc Oxysen of lexolenadine 

inreadcd wilh melhoxyinino nilrogen ol acyl sidc chain of cefpircmc llable 1.89. figuts 

3.98-l.t0o) 

ceinzineor levoceririzin : |H-NMR (CDj):SO:d 2E ppn (2H...lor tne cHr athched lo N 

in rhe NCH:CtlrO)- 1.21 1.47 (tH. s. pinc@inc pmlons).l.6t_l86 (2H. r CHr near $e O in 

CH,CH,O).4.6 (lH, br.s, CH in th. mcthyldiPhcnyl), ?.1_?.6 (9H. n. eharic 

nnss).I0 8(lH, b.s, COOH [637]. 

Fqor€nadi.d |H-NMR (Do): d 1.52 ppm ((cnrlc), 2.0 (NH preion).2 19 (cH,N), 2 2e 

(CIIrCllrN).I l6 (CII,O).4.95(Oll). ?.1l-7.l? (s, mdalic prolof,s). 

In rhe oton NMR spetiun ofc.fpnon.{.[nzin. a.d cefpimmc_lqocetrizinc, cehoxvlic 

(COOF) (a lO.8 ppn) dd NCH, poto! {d 2.8) ppn oa elirizine a.d leveetiritne 

disppeared. b cefpioDeeti.izii. compl.x NH: Folon 

(, ? 22 ppd) of c.fpnome also 

disapp€ard while in cefpionelercc.tirizit. conpler it vs obs €d at d 7.24 ppm (able 

189). Thc disappeard.e of prorons showcd cohplcx ion In celpimme_fexofenrdinc 

complex. pcaL due lo N-O-CHr (J 3.95 Ppn) oi c.fpiome wd missing and CH:O (d 216 

ppm) or fexofe.adine shified io downfield (d 2.9E ppm). showins i.kr&tion or complexation 

ar tlres posniomof cefpnonc dd fexof€nadin€ (6ble 3 89) 

iii Enerp nitinizatiry sttrLt 

The fodalion of chdge $dsfcr comPlcx belwcen ccfpibme dd ceftizine or levaelirizine 

Gcured rhmugh pdmary dino nitmg€n of eyl side chain of cefpirome and dboxvlic 

smlp of cdirizift dd lcvcelirizinc. Whilc ccfpiodc aid f.xofenadine conpl€xed ai 

l8l

n.rhoxyinino nihgen of &yl side chain of afpionc. nee cnrge lresfq €onplqB ad 

shos in figws L l0 | -1.l0l dd d.ir mi.inaarion €n..8is m giv.n in table I 90 

t20 

r30 

tt0 

t30 

l0 

120 

145672 233643 

I r336t 125547 

T.bL !.t6 

Ltt ni@irs oJczhircdeaintiw kt.4tiN h, M-EPLC 

19 52 

33 13 43 25 

3632 1653 

92.17 5l.62 

7t.00 !6.51 

T.!l.3lt 

Monitoing o|c.lpitun Jcw.|ihln. iture|io's by M-EPLC 

1t4264 a1B6 

t2t706 3t8?7 

3t.53 

t0.23 

t0.61 

'l.95 

16.73 

tt.t2 

40. t2 

182 

33245 

9t846 

95621 

47452 

51651 

5t542 

96872 53735 

63.11 35.32 

c 

79.11 

3t.91 

?2.* 

33.1t

l0 

60 

I20 

t50 

lt0 

JO 

120 

r80 

t bL ll8 

Ma'ibi,s ddh'tutufttol.din2 h{Mia by RP-EPLC 

n t 271685 

?t8841 1032t9 

PH 

?9.tE 

&n7 

U_t9 

86.53 

a7.21 

33,58 

37.15 

$.t5 

18.8t 

11.76 

45,t0 

56.9 8622& 

38.15 885346 

6a.80 913642 

67.09 930,128 

183 

?!548t 3t5371 

1at2t6 v2519 

?927a1 1517t1 

8t6t91 X12694 

139174 398.t51 

193673 

212644 

239451 

24424 

285921 

86.5r 

33.t6 

&.t3 

9t.92 

53.1S 

97.06 3 t.30

i 

g 

ts 

! ! 

a: 

rs i 

.E 

s 

{ 

E I 

I 

6 

z 

E 

E> 

J.a 

j 

b 

3 

5 

,e -itr '!tr ae 

Ee€ e€ E 

i{* ip Fi 

r$ +5E 15[ 9X 

-A; 

g 3€ 

t: 

t: 

l:" 3 

I 

.! 

E 

I 

lE4 

l 

E 

, 

d 

! 

d

.hnrracbd.r'drrdttu{#'(,&rurl (4, t ,,j'n.' ft) 

rawk) 

lt5

lI19 

/r.bdt 44tu.. * N 4e.tu,4t' d 

i" 

I 

.ttnr.r. 

k'br&t '/4Ptu. a e tmd olhatu. itu' 

llEU 

/*thqt4tu.-@t!r*.tu'dd 

IE6

tDlr$drCCl-..-l*'..tb 

E-l.t ll.dnd.*.r**r-.r* 

It7

ftanre3.r0r Fandian o!.hdg. bdl.r con'!t* btu.u cehnone md ..tuizke d ptitu y 

Mirc snlp of.elpircre enh cdnot :li. sa'q dQttri'itu 

Fiatrc3.r02 Fotnation ol .huse tdth ronpls b.tue.n .erhtune ard hwelnhtu d 

pridary Nko srup of.2hnM eit, cehotni. qrctq of tewetijtk. 

Ftatt 3,103 Fottuiq of .had. tuskt cnpld betueen wthot idino nitos.. aJ qtl sizte 

chaih oJeIpnow o'a o'!34 oJ fdoJ.rodk 

T.bL 3,9i, 

ENtsJ "nninizatiq @lculdihs hiwtim oJc4pim-Erreept* ntal.nkk ch@se tMIt 

@Dlplu4 

-4.3t 

r0.83 

-103.19 

4.82 

t1.66 

188 

FiSuE l 109 Figrcl ll0 

3.24 

54.51 

10.83 

-t03]9 

-l t.56 

7.52 

63.35 

14.32 

27.58

31i l"ktution of c4pitw *ith E,rcuptor Mtaenita 

After inldrion wid cineliditu, cefuionc avail.bilily @ conp,mrivelv inc@d in all 

inlcmcrins mcdiums ln simulaled gaslric, pH 4. ?,4 md 9. n was 89.95.94 54.82 0] and 

89.89 % rlailabl€ rcspecdlely (lable 3.91. figures I 1044 1.105) Similady, in lbc presn@ 

of runidine, cefpimmc's aqilabilily inc@sed lo 106.69, 86.20 ed 79 41 % i! sim aled 

Sddc juic€, buffcrs of pH 4 ad ?.4 Gpctiv.ly, but d*lwd lo 64 73 % in pH 9 (table 

l.92, lleuesI 104b,3.106). 

Ilo$!!cr in nrcence of amoridinc. cefpnomc\ availabililt dccrcascd in simulakd grsaic 

juie (50.57 %) dd bnfier of pH 9 (66-11 7o) while incMs.d to 88 25, and 10?.42 % in 

hlffeu of pH 4 and ?.4 r$petir.ly (loble 1.91, tigurcs 3 10&. l. l0?) This high avaihbilit-v 

ol ccipircme showed de suppE$ion of Hf4.plor dagonhts by cefpione Howevd. 

dccrcNd arailability in simul.tcd s!$nc juic. (in rhe pE*nce of rmotidinc) a.d pH 9 (in 

fic pesdce ol oilidine dd lamoddim) is de lo supP€sion of c€apidm. in $* 

mediums by i&iiidine &d fdotidine. Tb6e rcsults indicaled intcdcdon ofcdpirone wilh 

ii stntiob of eha@ rlree4o.utatabx 

lR spdR of cindidin. showed N-H peak al 1226-31'17 cnr, CnN dd C=N pcaks werc 

obscned al218T. 1622 cnr uplclivelt [638].ln ranilidinc, NOzasvnnelic and svnnetric 

sElchinCr $rc ob$ped at 1620 ed I 5?0 cn-r. Pats al I t 92 dd 1220 cn-r scE 6igr€d 

ro C-H b€nding dd CO t6331. In fmotidine. Gynuctric ard symcuic pcars of NH, l|@ 

obsryed ar 1506 dd 3401-3337 tespdiv€ly whil. NH, b€nding al l60l_1513 co Peaks at 

29ll dd 16lgcnrwrcdue!ocHrs dd N-C=N epetiv€ly [6391. 

ftc tT IR spcctE of efuionc-H-@epror shgonisr conplex.t showd .o Nll. b.nd In 

c€lpnone-cimeridin€, cefpiom€-tuilidine dd cefpion -fuolidine compl.x. cabonvl 

pcak sbiied to lower fiequcncy at l@?, 1654 od 1619 cnrrcspeclivclv lhcse Fsllt 

indid€d inl.@tion at @bonyl oxye€n of olldam nng dd NH goup of rmilidin€ dd 

lamoridi.e ln lhc complqci dispp.aie of N-H ped dd shi8ing of carbontl pear to 

lower frequ.ncy susseskd an inrenction orconplexation bctween c€lpnome and I h_dcpror 

antagonisls (llb1. 3.94, fi3ur€s L l 08-1. I l0). 

cinetidjre:d'l1.74ppn(s,NH,.),7.a5(s,CHt,7.14G,NH_16'Il),163GcHrll)3'21 

(n CHrll),2.70 (d, cHr'16),2 55 C, cHrl2).2 1| G, cH3_51) [63E] 

139

Rdnidihe: |H-NMR (ctrclr): d 2.24 ppn {6H. s. (CHrhN'). l0 (lH. d. CHrNH).1.40 (lH. 

m. CII,NI I), 1.50 12H.s. CH?N), 1.72 (2H, s, n $vlcne bndgc linking the nng lo $e snltur 

abm), 6.22 (lHd, dng prcron ar c I posnion),6.26 (lH, d,.ing prcton at C'4 posnion) 656 

(lH.s,CHNo, L6a0l. 

tanoridinc: d 8.21 ppn (2H. s. Ntlr-t8), ?.ll(2H, s, NHrl5),6.E0 (2H' s, N|Jr8.9)- 

6.47(lH.d-CH). 1.59(2H.s.CHrl0).268(2H, m.CH.l2)244 (2H.m.CHr ll) 16'll 

ln cefpnonc-cimetidine conplcx. N-o-cHr (d 1.95 ppm) pcal ol cefpione w6 shined to 

upfield (, 1.70 ppn) while CHrl6 poton (d 2 70 ppn) peal of cim.tidine wa shi'ted to 

dom field (r 2.98 ppm). It cehioft_@iddin. 6mplex, cePhcm ?_H poron {d 5 82-5 81 

ppn) m shiftcd lo npteld (d 5,55 ppn) a.d CHrNH (, l0 tpm) pedk of dnnidine 

disppared (ldle 1.94). Sinildly, in efpiromc{uotidine @nPlcx, cephem 7-H pioloo (' 

t.s2-j.8j ppD of .rfpirohc w6 dispF €d ed NH? (, 6 80 ppn) pek of aooridire sa 

shined to .lom fiGld (, ?.74 ppn) nrs 6ulrs sleg5lcd complexodon o. i.L@rion or 

cefpircne wirh Hrdeptor dLgonh$ (r.ble 3 94) 

iil En.ryt niht"izotior ttwli6 

Ccfpiodc cohplcxol with cid€lidin. ar nc brtini.o triltogm of its &tl sidc chain 

Fomaton ol ch{se id6fcr conplex of efpircD. with fmotidine &d runidin' occured 

rhtoueh c&bonyl oxyg€n of P-ladtn ring Th6e chdge umsf€t €odplexes e shoM in 

figu6 3- l I l -l,l l 3 and their minimiulion cndgi.s e siven 

190 

in bhlc :l 95'

t20 

t20 

180 

30 

120 

t50 

t30 

t0 

T.bl.J,9l 

Muitt*irg ol cthtun -cinetidine interutio|s bt E?'nPLL 

123639 l?0t63 

93t62 95835 

118561 939t3 

1202t3 6,1,16t 

8452t 67216 

159326 ?0156 

162i04 72131 

54.22 

55.92 

32.03 

58.59 

62.53 

29.12 

30.26 

T.bL lJl 

ll2516 

t5l65l 

r60256 

t642t3 

112536 

ll395l 

t52681 

r69831 

155361 70.t5 

t75511 33.t6 

t49156 8031 

Mtutdns ol .ehtunetmitidine tntetuctions bv RP'HPLC 

t20815 64523 

33.41 

105.06 

5tin 

58.70 

5t.ll 

53.53 

55 92 

l9l 

111123 44732 

3l]07 

319r5 

86.20 

6l5l 

53.91 

16.51 

333r

T.tltlB 

Mtildus of dhiw.IMtidh. htfttioB b, RP-EPLC 

lTirs(nint < - pHl '+pH 

l0 

I20 

t50 

r80 

30 

1n 

150 

l3I) 

15236 

15956 

17,t63 

19112 

80t47 

80tt2 

1t256. 

112t46 

t49524 

tt0lt6 

162t84 

t7025E 

125196 algl 

t31072 .9.13 

tt 21a $,11 

r458lt 50,82 

152164 50,t? 

u129 atnl 

9oJ6. atr3 

9rt43 9|.r4 

c2ElE 94,n 

94254 102.45 

9617t t01.42 

12l! 

17_57 

49,6t 

s2,19 

55,28 

57,15 

55.9t 

t125 

34_tl 

t5,21 

15,?1 

16,.15 

t9z 

89&5 

9251 

lt|65t2 

rt6245 

r2t846 

ll98?5 

94581 

tdtl 

9642 

r0l2?0 

l0aE2l 

I I t532 56.69 

ll8at7 59.,t? 

122t56 5122 

t31t25 11.t1 

t49t24 79.11 

158514 88,25 

tTt235 

r?8521 

l89t64 

190215 

191542 

6t.t6 

62,It 

62,81 

63.89 

66.13 

11.11 

52.24 

56.5J 

67,67 

72.10

tl 

I 

3 

) 

rs 

a 

1 

E 

e 

EE 

)= 

I 3 

! I 

:- =- :r ! 

6! sr 3'* ti 

- b 3*a 

$* :* n3 EF 

3 

s9s8 

It 

n li i E 

5.EA 9,5 

t 

?g € € 

T,E E E 

EEE E g 

d ':,i 3 d 

t9l

It E 3.101 Chtdog8 tutdE dtqdb, d 4d 

4tttutb.G) 

l9 

te'.tuId,/ (o),tudi.bt ) (b)

|tubal*tu t*w4{ehtut tb'a 

g! 

' -,r/ 

-2..' 

rFr,.!* 

hbtt".J nttu a e @ ola'a-' tu httD a 

rn 

t 

rh.n .t 

rtubnrt qlqbtu. d & w 4hFotu n @, &t n 

t95

nar r l!drd

(N','-V".:. 

F:--.2 

Fiav.3.rrr Forwtion of charyt nhslet .tupla b.tueen ndhoainiho ,itqen al6rl tid4 

.hok olceknore ald nittus.n ol.irctidi@ 

FiBtnt.\r2 Fotmid ol.hua. tatJet conplq b,tu*h.ehinne and .antidttu at cdhon,'t 

attteh of &tdan n4.lcelpnanc ond httu*h oJrMitidirt 

'"

tEi tnkuti.n oJeJpttutu vrh hlpogtrc$ti. 4s.,8 

Rcsults of efpircm. int!.t!.tim Mth 8liquidonc r.r..l.d thlt th. .vlilabihy of 4$irone 

incd!.d ro I lt.l4, I48.36. I I1.96 &d Il5.5O % in simulrkd etsiic juics, bufi.6 ofplI4 

pH ?,4 od pH 9 rcapeiiv.ly (|'b1. 3.96, llguts 3.ll4a. ud 3.115), On lhe oher hud. 

efpionc avaibbiliry ddt !.d in pllqe of 4dfomin to 64.4?,6?ll od 67.85 % in 

simllcrcd s6ric j!i4. buff.E of pH 4 ed 7.4 cspcctiv.ly. How.ver, in blflcr tH 9. 

.vlilability ofbo$ drugs iNqed (t bL l.9?, figca l.l l4b, 3.I | 6) 

Howv.r. in rhc p@tu. of pioelitaaE. inct!@ in efPibmc avlil$ihy wa ob*rycd in 

.ll inrcmtiry ncdiuN. In simula|d 88lric juie, pH 4, ?.4.nd pH 9, il*a found 7l1,48. 

102,25,642.21 &d 624,29 % rcsp€ctiv.lt (lAbte 3,9E. ligG l. I l&, I l | 7) ]lle incds.d in 

cchiom. daihbility is dE lo lh. fod jon of chr8. lr&sf.r @mplexes b.lwcn 

e&ionc aid hrToglr@ic .gcnis. Tl** cdpla6 htvc hid 6dd ab$+tivitv d 

compard !o efpireD., s a Buh alailabilny im|!gd. o'r $. od.r hod, dctred 

avail.biliry is de lo supp6io. of c.$ioc\ .ctiviiy by mtrfomin. Th* €uhs Elol.d 

itrr@rio. bctEo c.fpidm. dd ht?oglyemic .ghlr. 

at Stnthdis ofc4dM eA LDocltc.dir q.tn 

In od4 to sy.tlEsia 6npl.xe ot e$irerc wilh ht?ogltcnic !8cnG (gljqoidone 

Derfomi. ard pio8lilezo*), lh.n $lutions in.quinole 6tio wG mix€d individuall} wnh 

ehircme dd Enucd for thc hou's. M.llinS Poin$ wd dord.d lrd @mpl.xd Eft 

ch@tciiz.d by Uv.vkiblc, FT-IR dd H-NMR tchliqud. 

IR sp€.tt of gliquid,oft showcd rrc 3t!o.g lbsotption p.!k !t | 7oo cm r Bign d lo mid. 

Croup. Ti. dondic nn8 F.l qs obed.d d 1530 .n r whilc a.yl .th.r sfidching p€.t al 

I160 cnr. P.d! il 1285 and 1295 cd' w.E du. !o 3ulfondidc ed C N bond.Gpstivelt 

t6$1. Ininc F r of mctfomin w6 obs.d 1580,c-osr lo75cmrsdc=N p€sk wrs 

obefrtd ar 1620 cmi [6421. Pioglit zorc slbwld F.Li st 3358 ed 298 cdr for NH, ed 

aliphatic C-H nElching qhilc cdbonyl (C=O) $ynn.ric and sFm.lric pcal Ms obsaed 

ar 1742 ed l?05 cm r epelivcly, P.ak.t 1610 6d I lEl cmr*c ssiln.d lo c=c fld 

CO s|clch csD€cively [6.13]. 

198

ln cefpione-Sliquido.e conplcr. NH, pak dhappearcd dd cdbonyl sphting F.k Nas 

obstued ar 1654 cnr(low€r fuquenct). Hos.vq, in cefpircne_neraomin conplex. NH: 

stcrchine M obsryed at 33OO cn r dd @bonyl p€ak M shiied to low.r fEqu€ncy (1600 

cn r). Simildly, in cse of cefpiome-pio8liEon., Ntl, p.al ws obsery€d al 1500 cn . 

rnib cebolyl peat shifted to lowd fcq@ncy ar 1697 cnr (*c.li bed) Th.s indiations 

aboul shifiing or dnappedance of p.ats suSgested compl€xation or interaclion ar ctrbonyl 

oxysen ol gliquidone and pioghaone end nilrogcn ol ccfpnoie. while ininc goup of 

neribmin complexed d carbonyl oxyecn (dmido of cefPnone (table 1.99. figur€s Ll18 

1.r20). 

Cliquido.e: H-NMR (CHTOD): d 1.64-1.68 ppn (10H. m, cyclohexde nnCr). 1.79_18l 

(lH. m. CHr). I 36 (lH. s, CHrCO-), 2.99-1.02 (211. |. Ctll in mnatic ing), 4.22 (2H. s. 

CHzofOCNHCH:)- 6.4 (2H, S,-CONH). ?.16-7.?8 (lH, s. Ar). 

Merfomin: rH NMR (t ro): 2.72-1.07 ppn (n, cHl NH) 16!l I. 

Piosliua..: rH-NMR (CHTOD): r' l.24 ppn (3t1, I CHt, 2.59 (2H, ! CH, ol pyridi.e nns). 

l.lo (2H. n. CHt, l.l4-1.59 (CH, ptoton ol arcmalic rins) 4.27(3H, OCHt 8 60 (lH. s- 

pyndine), 6.72-7 0 (l H, m, Ar), 10.0 (2H, s, -SCONH), 

In efuinnesliqnid,t.e omp!.x, {ONH pdon (, 6,4 ppm) P€at of sliqlido.e ws shift€d 

b it 6.79 ppm (domfidd) while NHr (, 7.22 ppm) p€sk of c.fpiome wd shin€d !o a 7 14 

ppn (upfield) (tabl€ 1.99). How€v€r, i. c€fPircnenelfodin .ofrplex, ?o-NH peak (n 92 

ppm)of eapimmedispp€md and NH (, 2.72J.0? ppn) F.I 

of nefomin Ms appedtd 

atJ LO2 pph (ablc 1.99). ProlonNMR spetdn ofceapiome-pioglitazoncconplex showed 

a chmge al N-O-CH3 (d 3.95 ppd) of cefptone dd peal was ob*ded al d l.?9 ppm while 

peat of -SCONH (, 10.0 pph) of pioglit@ne ws snifted lo , 8 4? ppm These rsluh 

shoved conplexation ar $ese sitcs (lable 3.99). 

iit En rg! mirinizotiot sudi^ 

Tbe lolmtion of .ofrplcx b.tEn cfpircm. &d gliqlidone muned though thielvl 

nihss of cefpnone (ngu. l.!21), whsc$ bdwn @fPion€ od netfomin occuned 

$rouC! cdbonyl oxtgn of did. (fi8u8 1.122). Ccfpircne omplqed siih pioelilzone at 

ndhoxyinino nirrogen ol actl sidc cbain of c.fpnomc (figuc 3. I 2l dd 6ble 1.100) 

l9

Cef Oli 

tTimc(nint

30 

t20 

lt0 

180 

30 

t20 

lt0 

l.bl.trc 

Mdibins oJehiM-ppslit@. t"@iN tt RP-HPLC 

pHl 

16l,103 75?01 6,10.79 

t61t61 TEltt 611_@ 

t55213 79332 656.(n 

163233 31,147 668.13 

111331 93161 6@,13 

\7920a t17736 7ll.4a 

r pH74 - 

t53416 

t57622 

t003t4 6t3.t2 

1r.11 t619t8 19t12 

t6417 ata29 

,t3,66 

t12t68 11949 

r?t97 82545 

t7688! 96932 

6San2 

636.3r 

698.13 

102.25 

52,55 150967 

54.15 t532tl 

5l t0 153297 

55.11 rr3137 

56.a9 1t3626 

56,51 151246 

201 

15.12 

52.94 

56.33

i* 

F 

s 

t 

s 

a 

E 

T 

: 

€ 

; 

E 

5 

s?E Ee !i EB 

,. ii b 

,r4qr:-a9r:a 

-,..t 

I 

EEE 

E EE E i 

'Ir 

sl E ! 

E€ E -H 

E IE I ! 

E 3E E E 

3 dd 3 (5 

202 

t

ligon3,lL Cttotdogw sltflila dttadLn 6 ',rhdh@ kt,*&^r,'O)

..tE'I|. 

/-.t9.!4tu. * F 4.ta.b. tu da 

t6 

: 

--;zL- 

AvMrE ot ebtu. b e @.h.&dh tu Mtq' d 

I 

lrLt t 4#4 

{- 

I 

.'n'lo 

r - @ ntt ts-.tu 

'l 

t4b 

ma

,4{.e3.rra &ere 4 eht*4|lod&E 6*, 

r{!e trra Sp.o. d&b*i,&'ri, @'sta 

' '4 ',i. * _ j 

W.RaJ'/! *.nt 6e&t *pbslitw @npkt 

tu5

*f+t"'-u -' 

/"t i 

vf ari 

'"^.# 

fiatrt 3,r2r FotutM ot ctw|. t^tzt nnptt O

39i IDt rttin oJ.4pitutu,ith ntu4.milal antinnJlwdlort dnes (NSAIDS) 

Whch c€fpimne {E @ctcd wilh NSAlDs. u irt6.d i. iis availabilily 6 obFned. In 

pGence oldiclofene sdiun, ccfpnone arailabilily w.s comparativ€ly incEased lo 49.18, 

61..t2 &d 88.97 % in buflr otpg 4, ?.4 dd 9 rcsp.clively (table l.l0l, tiguts I I24a 

3.125). While. in pEsene of oubipofen, c€fpirome availabilily ws incr€sed !o 74.81 (pH 

4),85.16 (!H 7.4), md 83.14 o/o (pH 9) (labl. L102, figues 3,124b.3.126). 

Simildlt, cehirome availability aho inc@sed in pEsence of nefendic acid i. bulies of 

pH7.4Qa.62o)and9\17.01%)(lable3.103.ndfrsures3.124c,Ll2?).simildbehaliorof 

ccfpirome was obsned in lhe pr€sence ofneloxicam,an incredse in celpiome's alailabihy 

w6 ll4.9l, 140.84 md 138 53 % in bullea ofpH 4, 74 dd s espectilely (hble I 104, 

licurs, I 124n. 3.128). Ite high availability ol cfpione showed the fonation of chlge 

r@saer compl.x fomstion b€lrec..efpidm. a.d NSAIDS or.lecr€e NSAIDS aclivity in 

rhc pr.encc of ccapiome. Thc high or los availabihy of ccfpiomc sho$ed j.rciacrion 

b.t*en cebion€ and NSAIDS 

n srart6is of c.hitutu brh N&aIDt 

C.&inme @mptdes wi$ NSAIDT we synlhdizld in melnnol in equinol& dio bv 

€Iluxing for drce ho6- The di.loi.mc sp.ctnn sho$ed $. NH slrctching peal d 127? 

cni t6a!l Thc mmali. rins p€ak is ob$o.d ar 1604.? ro 1189 cmr signed b lhe 

substrued ph€nyl grcups. Th. 1454 dd 870.621 cmrbdds ihdiste a dihalogoatd 

subsnubd benane ;ng. Bmds at 7?2-748 cm r, ssiEn.d !o the pcFne of the adjent 

hydmsen alons. The 1605 cmi bmd is ossign.d to an ,tro_disubsdution. Th€ 1.2_ 

subinution in lhe scond f,n8 is shoM al 1234-1202 cnr dd 41683_41? cm-r' The carbonvl 

Broup [64s] appeds bdwi ls00 md l9t0 cnr as a weak ab$rbmce ud again as th€ 

ncutnliud enrny of lhe ceboxylic acid in the dgcs l6l0-1555 &d l4l0-1292cto [63?1. 

The FTIR spe.tro of fllrbiprofeh showcd chadci.rislic brcad p*k in lhe dnge o12500_ 

l5oo cnI du€ lo hydogen boodinS. ft€ ch@t rislic P€als ot nurbiptofen al 1698 cn-r dd 

2920 cd'r wo. dDe lo @bonyl md byd@xyl sti.rchin8 respccivelv [646] li nela.mic 

&id. N-H slretching 4d b.ndinS w* obsocd at 3300 &d 1572 cm r !6Fclivelv Paks at 

1647 dd 1504 cnrwrc dE to cdbonyl (C=O) and C{ strelchitg while donadc 

srrctchins \6 obedcd at ?57 cm i 16.17l, M.loxicd shostd a distinct Deat at l29l trd 

201

1620 cnr duc ro N-H srerchirS dd bendins EsFcdvely, *tilc c{bonyl (C=O) Fal at 

r58o cni 16481. 

Cefpiome-dilcofcn* sodiuh compl.x showed N-H slrelchi.g .l 3300 cmr sd carbonyl 

F.l m shincd b lower fEqumy il54l cnr). ln @fpimmc-flubipmfen onplcx,. srl 

NH, srrErchins ws obsdcd ar loecr fFqwrcy (looo mr) &d sharp cdbonyl Flr ws 

shifted lo lower iEqu€ncy (1659 cn r), How.lci in cs of c€apibmenefehamic rid 

complex, thcr wN no NH, pcat &d @bonyl pcai( shited 10 1646 cn ' (lower tcqucncy). In 

c4 ol efpirone-meloxi@, Ntl, Far M vcry v.!r .t l3OO cm r sd cabonyl Fol w6 

al 165l cm-t. Th€ shiiine or dispFamc. of NH? or cdbonyl p€ak annb es to m 

intedction ar prihsry dino group of cefpiomc md cdboxylic or N-H Sroup ofNSAIDs 

(lable 1.105. ligurc 3.129-1.132). 

Diclofmc: rll-NMR (cDrhsoi , l.4l ppn (2H, s, cH:coo). 6.21-7.47 (7H. h. ammaric 

poront, 10.50 ( I H, brs, emaric NH polo. b.twn dE c'N'H curctunots.) [63?l 

Flnlbipiofen: IH-NMR (cDclr) I 159 ppn (d, rH, J=73 Hz, CHr. l.s5(q, lH, J=7 r Hz, 

cH).7.14-7 24 (m,2H, H-Pn). 7.38,7.60 (m, 6H, H,Ph) [649]. 

Meieiamic acid: TH,NMR (cDclr):,2.18 ppn (s.2LcHr,2.14G. t-cHt,6.6qdd. H4). 

6.69(dd, H-6), ?.28(r, H-5), ?.10 (n, H4),7.10 (m, H-5').710 (m, H-6 ),8.01(( Hl).9.1I(s, 

NH) [6s0]. 

M€loxico: |H-NMR (Dro): d?.7app,n (dd, H.l).766 (d. tl4).7.75(d H-5),7.95(dd, 

ll 6r.2 77(r Cll"l0).6 aqd.ll-llL 2.)8(d. CIrr-r8) l6srl 

In cefpircmc-diclofena @mplcx, cephen 7-H poto. (d 5.82-5.81 prm) or ccfptone dd 

CHTCOO Doto. (d 1.4 ppm) peak of diclofeo.c shined lo upncld (d 4.8a ed 1.30 ppn 

Esp€clively). In cefpircne-0urbipbf.n @nplq, Oimlyl prclon (r 6.81 ppm) of cclpione 

and CHr poton (, 1.59 pFn) of lulbipofen s?s shined b l'7.20 and .t1.79 ppm 

resFcively, The proton NMR specmn of ccfpibmsmef€n@ic mid compl€x showcd a 

chdee ii chcnicalshift of thielyl polon (d 6,81 ppn) of €efpirom€ lo 5 6.67 ppm ed NH 

prcbn (d 9.I I ppm) ofn€l:imic eid to 6 8.81 ppn (hble 1.105). 

NII, peat (5 7.22) of c€foionc in ceftibm.-h.loxim @npl.x was shined ro lpfield (, 

7.14 ppm) and CHrlo prclon (6 2?7 ppn) ofmcloxicad peal< was snift€d to downield (t 

19 ppn). Thc* r€sults suggestcd inre@tion b€uee. eipircnc &d NSAIDS ($blc 3 105J. 

208

iii E!.r6t Eitrioir.lio. lldie 

The fomaliof, of charge ffisfer conplex bqt&en e$ircmc md diclof@c occuftd 

drcush cehonyl oxyss of didc (plrlln ring) $d @boiylar. s.lt ot diclo&m (ligle 

3.I ll). whilc fttbipofo a.d rcfcimic &id @mplcx.d wnn c.hiren. $muEJl nihg€n of 

rhi@lylof ccfrtome (ng@s 3.114. Ll35). Tl'c fomtion of compl.x bei$M c.fpircn. 

md nelo{cm cftd thbuSh pnmdy Mino ditroscn of &yl sidc .hain of @fpircnc ed 

cartonyl orygcn of n€loxio (few L 136), ninimiadon cncrgict of IhN onplex.s aE 

Irbl.3.l0l 

i4o'1bi"3 o!.4pi@ndole@ todns ndtuiM br RP-HPtl: 

t03754 497t3 

I r0215 55381 

n7166 13?650 

t59468 r5ll?0 

159t3 | 1590?? 

21t076 167075 

4l.lt 

4t.63 

1.15 

t3.33 

2145 

66.59 75.16 

3?.27 31.19 

88.97 31.33 

209 

135196 213977 

tJ64a 211111 

55.92 

55.26 

58.16 

59.51

l0 

90 

tm 

150 

130 

120 

T La.l02 

Mditoirz olc.hitune lwbiptul.n tntetdiN b, RP'HP LC 

2826,16 l r 3928 

'!23316 6t0424 

128J89 6180?5 

t34t82 713792 

t31716 7501C2 

lt6r6t 753331 

,60228 765150 

64,36 

?1.63 

74,8t 

52.1t 

61.2t 

r6,9t ?&39 

at,t5 19.11 

82,03 80.07 

8t.r4 e0,29 

Ttbl.l.lo:t 

110640 7573rt 

354107 7a5062 

75.29 

30.73 

35.16 

M@itdks olcelpnow-mlemnh utd idetdtitu! bt RP-HP Lc 

Aucari268nh % Amil. %Ahil, 

lTirc(mid+pH7.r 

- 

30 

120 

130 

223266 r51ot8 

22t216 tTza4 

222691 t1taag 

1tt258 t&4941 

248414 20ll5l 

5 t,3 

10,62 

t26627 202|9 

73.13 

8r.98 

82.31 

81.46 

8].51 

%At.il. %Avlil. 

40.24 150317 2.tt286 

56.31 

t6t6a 251625 

53.23 

161411 2&242 

6t,67 

t12at9 2773t\ u,7t 

210

C.f M.l 

lTihe(nins)+pH 

30 

t20 

130 

l0 

t20 

130 

20d367 

20r0{l 

2032t1 

204169 

2t5t29 

r86406 

25031| 

252521 

267682 

tt2al 

T.bb3.llx 

Ilo"iwi'g oJ.ehim-wLai@ a'd itutuiN bt M-EPLC 

tJ2499 

116560 

t19656 

t59291 

t2t70l 

t23951 

tJ22t9 

171552 

10t.57 

r0226 

r03.0r 

lM.ot 

56.11 

58_05 

59_t1 

6l_81 

126.39 54,59 

t23.01 54.32 

83.51 57.20 

,lt 

221423 

268662 

269281 

2t11l2 

215t22 

tt726a 

121007 

12t561 

l2UAt 

|]6_50 5l.63 

tt1_60 52n7

ii 

iF 

i 

d 

I 

t T 

: 

* E 

'I is 

'i B 

! 

1 

e 

E 

E 

l? 

: 

g 

z 

.t 

a 

3 

:-E 

.!! 

FRXF 

t 

f,:- 

rgE 

866 

'Ei: 

2t2 

'6

lte!.3.rr1c,'o'dJst'/'*i,e@t{erpbd,Vd.4.,d tq.t"Etda' 

A),,t@ctt(dddtd.d (q 

2t3

nrE 

t*q {qr*. - r.a.r*tb. n 4r. d 

a 

t" 

r...rl|- 

.*.tqrtu...@4Fd..turFz 

r.!.lJ' 

.{4 {qt*,,.. p 4+b a r tdbr 4 

t. 

t. 

e 

211

.[ll| 

,*.rqb-. - r-...itu. * a*' 

tim 

'"--.:*":tF 

ItlrJt*-rCdh.Jd*-..da 

2t5

31c.E ,"rao W. 4..hb*tt tt d6.a..eta 

We tr$eada@dqt r 

|3e3.t3r+,6'qy'.di*@sa)a 

2t5

Fl.ra,ri' Fs"di6 of ctss. balt @pl6 b.M." ahitutu .td di"t6'* tt"*8h 

cobdiv! 6txd 6 61r't (bla@ tu@ oiehiM attd tut$rt& tdt ql 

{} {}{ 

':. 

fErt. r,$4 Fotddton oJ chos. ndtl.r .o"vt , b.N..n c.hwm md nobwol'h th'oqh 

oltht@M nitus., ol..lp,M. od @bdvh. snuP oJ ltbtryohn 

zoc r,Bs Fo"na'ton ol chosP tu14 @6*r b.tue.n c.lpircd' atd d'kME throqh 

ol tht@tyt mnos.n o! lhibw 8d ntiasq oJ d4flMn dtd 

Fkt!t.l!6 Fmiu 4.tasc MI,, coidu .,@r "hbw dtd *Iut@ tl@4h 

' Fnwt mwnirncn d;oa tid..hai, olelqw '"d@b'ryI"a34 

of eldka 

211

Irbl.3,t06 

Enssv nimnndion cohulotians fot fundi@ ol cehircneNsAlDs chuse 1rtuIlr.onplea 

F'gurel.lll Figurcl lla FiglEl.llt FiSu(l l16 

3.01 

4.31 

-3.4t 

3.21 

3.27 

57.2t 

15.22 

-l t,95 

-r3,21 

401 tnt mction oI .a[pimw eit, prcton-Pudp hhlb,toa 

10523 

-1.9\ 

I1.55 

l5 t3 

,12.51 

Alrq cefpircme dd omeprele intehcdon in sinuldled eslric 

!.24 

51.84 

686 

-r3.03 

juice, pH 4, 7 4 and 9 Therc 

*6 d(us in .ef!ion.'s availdbilit 10 6.81 ed 54.58 % i. sinllat d Sasdc juice md 

buf.' ofpH ?.4 Esp.crivcly. or lhe olhd hdd. n inc@s.d to 92 22 sd 721t % in tif'6 

ofpH 4 dd 9 Bpetiv.ly s @mpded to om€p'i&!. (toble l.l0?. fisuEs 3 ll?a. l l38) 

Itowever, i. preene of lesoPMle, ccfpircm. alailabilitv conpdaiivelv incrced in 

sihulared gdllh juice, buffeE oI pH 4 74 ed 9 10 6420, 8513, 7436 dd 6893 

r*p€clively (bble 3.108, ligws 3 13?b, 3 ll9) Thn incFse in cefuiomds alailabililv n 

due to sulp@ion of prcton-Pup inhibitols activiiv bv cehitom' qhile d{E sed 

.uilabihy in simulatcd gastric iuie dd blllc ol pH 7 4 (in llte pE*ncc ol om€PMle) 

sho*ed tbe $pp6sion ol ehibme s &livily b! on pt!,le. TlEs 6ults $8Aesl€d m 

intracion beMen cefpiremc sd prclo._pmp inhibiios 

slntt5i:t oI ilp one 'nh pM-punP hhttit6 

Synrh.ls of €efpiron. *ith poron-pmP inlibito6 ws ceied ont 6 di$used ealier' 

OmeD@L showed C=N par ar 1626 4d b.Einid@L at 1566 cBrwnib S{ pdk w6 

obsRed at lo?5 cn | 16521 srm,lrly. h loepl@|. c N peal w6 ob6'rcd at I58? cml 

and b.hzimideole d 1464 cr'. Pesks al I I 15 Dd l04O cmr w@ ssign'd lo S:O dd C_F 

213

A sfething bmd al 3500 cn' i. cebiom.-polon pwp iinibitos complexB w4 asi$cd 

ro NH:. How.ver, very qcal cdbonyl peat wd obseFed ar 1635-1616 cnr(lorer 

t qn hcy) h both $e ehibneprolon-pmp complcxes. Th€ shilling of Pnnory dino 

pe.k indi.ar.d i.te@rion at uino gmup of cefDim€ ad nitmAen of Foton-pmp 

ihnibitoB (r.ble 3.I09, fulas 1.140, 3. l4l ). 

onep@ol€: rH-NMR (acebne D6): , 2.23 ppm (6H, t 1.72 (lH, t, 3.86(3H, d). 4.88 (2H. 

t.6.95 (lH, t, ?.18 (ltI, r.7.tl(lH, s, H-17) E.l6(lH, t, 12.16(lH, t [654]. 

raepru.lc TH,NMR (cDclr): a 8ia ( | H, d) ?,65 (2II, br), 7.35( I ll. d, H-I6). ?.10 ( I ll, 

d),6.67(lH,d),4.74(2H,q),4.40{lH,d)4.32(lH.d),2.21(lH,s)16531. 

ln proton NMR sFcmn of c.fpiom.-omeprazole @nphx, NHr Poton (6?.22) peak of 

ce{piose wa shifkd to domli.ld (t.40 Ppn) ed H_17 prcton (67 51 ppm) of omep@ole 

ro 

'/.66 

ppm (do*detd) (ilblc Ll09) Sinilaly, in ebirencideplule omplcr. NH: 

ptuloi (67.22 ppn) Fak ofcc$ircm. h shiff.d io uPfield (r7 20 ppm) md H_16 Poroi (d 

t.35 ppn) of lmopEole 1o doMfield (, 7.48 Ppm) which shovld @nPldarioh bd*een 

e&tome and p'otoh-pmp inhibilos (bble 3.109). 

iti En.rg,6itidiuti6dr.tia 

The fomtion of complex bdecn eryrcme and prcion pmp innibiioa iom.pdolc and 

lan$prazole) occuftd lhough priEary mino goup of cefpirone and nilrcgen of polon_ 

pmp inhibitoG. (fisws 3.142. l.l4l). Tne endgy nininiztion of tbce comPlcxes soc 

carc arcd .nd s\lmrized in tabl€ L l l0 

\9

l0 

t30 

t30 

2|11 

25226 

Tdk3.l07 

Lknading of celpinne^.Fdol. i,@rctiM bf RP-HPLC 

r35236 4l t365 

215M6 3.36 

2r8r80 3.55 

2181t0 1.21 

l25lo9 521 

224623 6.31 

43.33 

54.53 

Cef tln C. 

AlC d - 273n6 

lTim. tm'nt+ 

pH I 

r20 

130 

120 

130 

6135 

64.13 

57.93 

Trbl.3,llr€ 

261949 t034t 

269193 23l 

2a3515 t4361 

432523 

33,51 

Md rtins o!. elpnonala6aPtuote tnk ru.l ions bv M' H P LC 

117239 l00l 

111652 30865 

341427 4906t 

62.71 

53.14 

62.59 

62.31 68,9' 

220 

7a1141 al22 

396721 al72 

432334 3463 

7l.73 

35.t1 

6t.13 

65.53 

263 

55.25

: 

! 

I 

.i.5 

l5 

x 

1 

g 

I 

x 

E> 

).E 

! 

n 

,Ee € 

5!3 E 

:81 

iEt 

r €: e 

e!A.ee 

3 dd d 

221 

6

xntna.ral c@.@ttvttts br@t@ {d&noilt edtdF@i (d) o'td 

i(rad 

h.,,r|,' 44b. - * M er*@t r d- t4h 

1

.*44,-,,JlSi!*.*.b, 

t: 

4r.ua9d!t.i!|aqd..o.?b 

tl-l.t{|ltsErC.li.E{.rt{.r..tb

Fi.t* a.tar Fomdion of chatse t@tlt conpld bctuah cehitue atut M'prmte th"rsh 

FErR !.ra Futud o!.hot nMfu.anpk\ bew?a aA tNopr@h prw 

' 'dPmw 

tdno A4ta oJ ehircn. ad hftosd ol lNp42otP 

Trbl'!ll0 

En Bt nininidii ..lcutatitu lq[ottuit oJcelpton'ptobn p'D'p inhibitds chnse conqer 

c6pt*' 

4ri Intet6tionoJ.4ptron vthttaltns 

F'8uE 1.142 F,3uE I l4l 

5.11 

56t 

1.23 

-\t.12 

AiLr efpiromc ud slaiiN intcFclioG. u inc6!s' in cefpiome s availabililv M obsed 

in all intereling 6.dim. ln pGetuc of aloddtain, c'fpinnc avoilabihv inciesed 10 

226.16. 142.!5.169 42 md I10 84 % in sinulatcd Salric juice' buff€6 pH 4 ? 4 tnd 9 

RsD4ri\el) (Eble I lll li8uc' l l44a. ' 145) Sin'lslv rn prc*n(e ol s'mr6b'in 

avai!.bititr ofcfpirenc vs 14218 c/o (in simllaled g6tnc juie) 160 1I 7q (in buffs of 

224

pH 4). ll8.0l % (in bufier ofpH ?4) dd l78.Ol % (in bufin ofpH 9). d shown in tablc 

L I l2 anl liBures 3.144b. l. 1,16. Sinild b.hsvior ws ob*Fed in prcenc€ ofpdtasari' and 

increded in cefpirone s availability was 15999.8894 13693end I0?55 % in simulalcd 

s6tricjuicc.bnlT€rofpH4,?4.dd9GFctivdv{lablell13,figl63l4-4''Il47)Th' 

indeGed or high alailabilily of @fpiome is due lo charSe trssler complex (i'te@ion) 

b.tren dfpircne 4d !rad6. s a csnh avsilabililv of efpiome inc66d 

il Srdth6it ot.qlpiton wnhsbti"s 

Syn$6n of elpiton€ wi$ statins ws @ricd oul in €quimold ratio in meth&ol' 

Atonzsl!$n shosd F5k! ar 1652 dd l5O9 cni Gisned b arboxvlic dd C=C 

dpdively [6s5,624] simvslarin showcd chdacreisric p€aks ar l55l ed l01l cd 

6riened lo GH s.l olelinic c-H 3uethiry vibolio' mpeiiElv Methvl &d m'thvl6e c_ 

H asynnctic sd syme$ic slet hing vibdlion *as obscry€d al 295? 'nd 2878 cn I Rhilc 

bcnding vibdtion 6 d t453 dd l l8l m' Espeliv€lv Pe&s't l7l9 aftl ITOI cn r we 

due ro lacrone and est€r *retch. Peaks at 126?, 1222 ll?3 ed 1080 cd weE dss'8n€d lo 

ladone and €$er C O_C b€nding vibd'oh 1656l lR sp€cM of palahtin showc" 

ceboxylic leal at 1780 €h r, C=C at l59O €mr ed C_H be'ding at 1200 cn ' 162'l' 6331' 

A brcad Nllx stekhing of cesnomealoN6ladn cohplex vd oberv€d ai lowd frcquencv 

(1285 ch r) and carbonvl shap p..I al 164? €m r(lo*€r fdqn'nct) How'v€r' in c€lptone- 

sinvasladn conplcx, NH: Fal diepFffid and cdbonvl p'ak ws obs@ed 'l bwer 

fr.qMcy (1695 cmr). In efpiren€_pEvsr.tin 6nplei. brcsd NH'? Fd( 

w6 obed'd at 

1205 cd (lowq ftquencv) and cdbonvl pesk a1 l?08 cmr' Shifting ofNH: peak ot 

diepp€dfte snoqql inkdnon of efpiMe with slaliN lhFlgh pnmlrv drno gmuP oI 

ccfpirodea.dhydtuxvlorcdbonyl groupof$ains(lablel 114''igsI l48"l'150) 

Aiorvsldlin: rH-NMR,' 7555.98 ppn (l4rr4'ls (2H. s, H-?a md H-l) l9l(lH m ll. 

7b), 1.6? (lH, fr , H'5), l 40 (lH n. H_14) 2 16 (lH dd' l=lo 2' 4 8Hz H_2a) 2 26 (lH dd 

J10.2,2,4 Ha H_2) 1 70 (2H, n H_6) l 60 (lH. n, H_a) 1 50 (6H d l=7 2 Hz H_l5 H_16)' 

l 4l (lH,m,H4)[65?1. 

sinvaslarin LH-NMR,, o.9l ppm (H_21), l.l2(Hjo) 1 56 {H-2?)' 2 56 (H'17) 260 (H_s) 

5.14 (H-r5), 5.51(H-18), 5 98(H-!2) 16311 

p6v6lari!: LH NMR, d 0.90 ppm (H_13) 

0{-l6a),4 46 (H-9). 5.81(H_5). 5 92 (H_6) 

r.]l (H.26) l.8t (H_3), l.2O (H-l?. 19, 25) 3 94 

163ll. 

)25

The probn NMR sFcta ofcefpiom€{tofl61a1in conpl.xes show.d shiliing ofNHl prolon 

(O 7.22 rpm) orccfpireme to r 7.l9 Ppm (doMli.ld) ed OH pblon orarodslarin lo 

' 3'lE 

opm (upfield)(r$le Ll14) Simil&ly, in c.lbiom._sinv6lslin complex pcal ofNHz poron 

(6722 ppm) ofccapionc sd shifted to upfield (6 ?05 ppm) sd H-5 polon (6 260) o' 

simrautin b 6 2 88 Pph iDble I I 14) ln prcton NMR 3p€cM of celptrome_pravdkrin 

@nplcr, th€ P.at for OH pbbn (6 320 ppm) of pnvasLlin dtlPp€dd due lo 

conDleiatior at N_OCtlr po$tion of efpione shilc pelt o'N-OCHr (6 195 tpm) shincd 

lodoMfidd(d4.II Pph) (labl. I lIa) 

iii Ed.ts ditiniz.tid stt li.s 

Th€ lomation of conplex belwn @fpirom€ and st4titr occured brcugh pflndv m'no 

soup of cebiFDe dd bydMv (!to*di!tin) or c'rbonvl stoup Gimvdatii) or sbbns 

*hil€ @nplexadon bd@n .cfPirche ud pnv6Ltin o4ued lhroud mdnoxvim'no 

nitrcsen of acyl side chain of c.fpibn. and hvdDxv gow of pnva3Erin Thc €ne4v 

minimiztio.s of th€e @otlexs \N@ calculated (table 3 I 15 figlEs l l 5 l '3 

lTrme (f isr-pH 

t:0 

t30 

t20 

Tible3,llr 

MDilti,ts of c.hinwaoMbnn int2trctio6 bv F?'ttPLc 

214031 91623 

212a32 945!5 

+PH14> 

t21152 

%Avlil. %Awil 

135.3 

112.4t 

r 31.2 

2t2,14 

92 t2 

118.25 

t69.42 

34.31 

15.34 

15.36 

7l l5 

71.29 

226 

225244 

t38451 

200153 

149303 19821| 

t61213 199261 

lo4ll 

110.32 

t1l.l6 

133.01 

1 5l) 

65 52 

t0].15 71.16

Trble3.t12 

)tdi@hs ol.chi@-sne6dia ituerctiM bv RP-HPLC 

C.f Sim 

lTime(mint+PH 

130 

t20 

180 

t56876 7t2t' 122,18 

164617 15126 124.31 

168723 ?6379 112.05 

169264 81024 13247 

169738 88665 112.33 

t81670 106671 142.13 

- PH14- 

t60862 213927 

t64196 2,la52a 

I6849a 225756 

lTin.(dins)

{: 

iE 

! 

I 

I 

n 

6 

i 

1 

I 

s 

E 

t 

I 

E 

l! 

E> 

: 

'E 

€fs 

!I 

r.a 

fE f- f.r El 

za zz z; 

crx 

!H :! pi :5 

I 

s 

!3 

iE 

}J 

e 

6 

gE 

EE 

9E 

g!i 

;4i.3 

364 

E.= 

E' 

aa 

dd 

224 

3 

1

-2 

naeaJl,Ct otuosG t tnbg@i@ d@sd,rheaddnl @, 

ttwedd/@.tdF@tdt (O 

229 

D

ld|ttt d.atu. h * w./Mt 

: 

,/ 

',.'.. 

//' 

--' ''---t"" 

,-ar 

.__--.---*'J_---. 

t tu Mkd 

lnbrbt,t4tu| h e w qr'-6. tu Mt, 

/ebb, olQttu. h * '!ltf,I.? @.t p.e r tu d46 

a 

.--.-- 

2t0

W.ntr.tr &M d.@b.tu wb,'co"da 

We 3,re &61 idhh*r/'a6i'.onpt' 

lranLll.&dud.dlrqcFrxdcr.q&t 

231

narft r.Ar FdtuiM oI ct@se tdJer cohpld b.Na, elpitow o'd otoMtdin ttuo,sh 

yinaty ani,o gnuP of ehiw Md Wto,, smp otMtck 

FranFa.rsz Fottuioh oI .r-ase nNler c@ph, b.tueen cehintu atd sin@din thnush 

?inat, ani,o Atory of c?hnm. and ctbo,yt oas.n oJ simattotin 

':f 

Fra!rc},ri} F.rnotioh o!.hase h@sJet .onpla b.tu*n.ehnDe and ptawiatin thmuEh 

nahorrtnko titrosen oJ ocrl sid. chdk oJ c?himne atA Wtutr snlp .f 

T.bL 3.llt 

Eneryt nkihidiM @t,tdiNfu lqtuion olehitututuia.,8t btuJ* co'tpl$ 

F'8ur3.l5l Fig{El.l52 Figucl l5l 

513 

51.76 

4.92 

||.8l 

3.t2 

-6.21 

212 

427 

't.11 

ltr.25 

Ll9 

-3.73 

758 

3.31 

5,15 

-4.17

Ill 

As di$usd orlir. efpiome has broad sD.clrum of dribaclqi6l &livil, agaist C!d- 

Dosnivc ud cm-nesativc orgdisns. Thc i, vit'o driberedal rclivily or erpitunc and 

cefpircmc-intcd.iing dru8 anplexd w@ .vsluakd agairot vdiou Ctm-positilc 

(skiphrbcoew dte6, Cotyrebrckiw hofMnnti, St/eptNoqut hecatis anl B@tllrt 

ry..&r) ed Cm-n.gnri!. qr8eistr (Kl.bsiela Wunotue, 

Klebsielta species, ShlE lla 

.tse,Erf, Scherichia coli, Pset.lonM @ruEi@sa, PrcteB nnabilit, Cit,obater tpc.icl 

cad Stlnon. a rypht) | hG* stld'es w cmcd out in conenu.oon rmgc 2.5-40 Fg mL 

Cefunone showqi dtibeL.ial &livity ag.iml .ll th€* orgmisbs (table 3.116) Thee 

esul$ Gv.al thal an€ of inhibition of cefDircm. incrcsd vilh incr.a3ing oncehtnlion 

Howcr. when eribactcri.l &$vny oleirironc complexd Bs sludicd, th€E @ oo @ne 

or inhibirion agaiN my Clm-Fsniv€ and CM-n 9(v. orSoism, vhich showd lh. 

antagonisE erd of cefpion€-€onplexes. 

T.bt r.116 

oJ i,hibitid tM) ol.elUitutu aaai8t Gw-patitjw tut Gw-Natu|. Nsaka 

'aon 

cortnebtutm MMn, 

8 

t0 

l5 

l3 

r2 

213 

It 

l3 

l3 

tl 

t8 

2l 

t3 

2l 

2l 

20 

25 

2a 

27 

26 

t3 

21 

24 

29 

32 

)3

lv 

Rcsuhs of intelacrioo $udies ofefuioie sith AcE inhibitoB drioxidmls essential a'd 

tracc elemenls. Ca-chahn€l blockes. Hrr.ccDbt anueonists, Hrrcceptor mtagonist, 

htpoglyedic agenrs, NSAIft, ptoron Pup inlibitoB ed stalins tct.alcd thal availabililv 

of c.foiom€ inc@5.d in mosr c.g. Howvo, in pren@ of dlioxiddts *ntal a 

rocc clcncns efDion€ avlilabilitv dec@d Th. intcdction Esulls weE well coftlaLd 

by dilfeed lshniques i..., Uv/visiblc spdmpnobm€t.v ed alced phde high 

D(fomancc liquid chomaiogr.phy. Kin€tic sludies sho*d lhc tvp.s of forcs (hvdogei 

bond 6d hydrcpnobic inte6ction) beisen c.fPircme ed interaciinS drugs. Funnemoe 

efpnome @npl.xcs wilh all inteactinr d$g! w.s synth*izld sd ch{aclerizcd bv 

lJv/ siblc. Fr IR ed |H-NMR. Binding sirc of orcs @nplex€s ra &lmincd bv m€tgv 

mininiarion sludi€s. R.sults of Uv/visiblc. FTIR and |H_NMR funher sDPponed $e 

int.Ecrion. Anibadenal a.ivny ot c.fpiom. od ils conplexes *cG aho evaluatd againn 

Clam-Dosnive od Gnm-posilive orgdisms, CdPitone compl€xes showd lbe augoDrt 

cffccl a conpded penl dru8. Ir th€ lighl of sbov€ esulls, il cd be co.cluded thd 

efpircre should .or b. co-.dmini$lrcd with diioxid.nrs dd 6F.tial $d tBe el@cnts 

HowcEi in cG.dninismton of eli,ibm€ *i$ o$a druls, rhcE should he a PmFr 

214

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' - 

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rJr V.hrmmed L Iu!.nc Lnd Allctr | t l,2UO5r \nulbneouvldrn'ndrn or 

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"prop'ilind s' 

'4o Khcdr a rd Elsh?ner H rleo8, l Bbmomdhvlprcpnh'M": *,1 

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16l P.;6k.v6 C , Atl!-Pdlnd J 6d Kspp.ft M {2002) sp"lrophoromdi' dereminatio-i or 

le' 365- 

'" 

il.i".pir I" "iri' *r.c r nmc2'r-di;i;obodc Eg' i Pho Bioncd ^nar 

.62 E"Yarbi 14, AMrne HH and shslan RA rlgoa' \De'ro?{rmd'r md 

-- 

,*""n*.t*i. ne$ods fd rhe of h'inotnl in d mulrômpo"'n( 

^si) 'n8le 

;;.eu!@ldo*s. r(ms J Phm B'om'd Anrl tc Bl+327 

163 Hillt.n S. Nduse K dd Vtn dd Bw (2001) Sinulb@s ddmi'dion of 

'"' i"l.Jr.'io;,ra" *a *vcml inhibibd of '4iotnsinsnvenine enrym' bv c'pilr'ry 

?i.JophoFi\ J Chrcmato3r' a 9t4 4rc 4r'9 

'M ^trdhamulu ^B d Panrulu aRR 'laqjr ua hqu'd chrcndop'lphL 'nnd'on 'r 

lk'i@nl in fi Dhma ed 'c'l dosS. toms lnd't Drug5 J0' 64644 

'-' ii-"i. licls ana Uiol.xic.l fluidslhouri rdm'lt wl$ nitmus acid Miltdhioioa Ack 

165 El-Endy N. Bchl F ud Al-OhDdn S Cml) PoLtosdphic ddemindion of lisinopril 'n 

166 srn.R.l.\alilecR.D.thnurhI M SinghsR andsodhi R rlo9zl s'nulbn@us 

r' ph'mac'urrc'r prp'nrion' 

rirL r dd.m;i.n or t'.inophr.nd h)dchrorcrh!''d' 

"om 

Indiair,rue. 2rril2)553r60 

lo Albn 1., Alpdoga- C tnd Su-elr ) r20o_t Fi8' pEsre liquid ch{_noL'ap\tr 

'",.l.'i'*ir'.'r,r'i"r-o''mp'Ercen4tonlne'oluuonlkbihqorlnmopnL Reric$sin 

^mlnidl ch.misrY, 26(l ) t564 

24J

163 F:lEmamA.A.. HlnenS.H. MousfaM. El-AshryS M md Elsh'dinvDl {2004) 

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l7l Crrciadudio^..ogr"tre.admotorbehaUoumldeli!irs$[hblueb'rD \pim l' 

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l15 lvirBovichMl.(2OOO)Anricincopop.nicsofitunstndvcgehblesHonicuhurcscience35' 

176 Lhdn'tr K. lnd Hdilh C K (20OlJ Anrroldeb itr lrurb md \'g'obl'crh' millenn'ums 

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i09 Lot..b.n 1 w . Rol,nd B l .ndwilsSl ' 99otClo''ieMdrueron'letpasionorth' 

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llo H.!s ll. ind Prul. P. (200r) Th.6l. ofhisuni.c lnd rhl rub'm'nill'ry nucl'us tn rhc 

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Jll Yol.'llmi H. (2001, n* oh ol4nhl hitu'mlgrc n'ud rvtum a m mticonvuLnc 

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SK&I91944 (ren.la$ine), a novel hi$minc HrHepror tnbgoDii snh neglisibl' lb'liry ro 

p.net{. the c. ntal ncdous svnem Ar' r' Pitm.col 3T' 56+573 

ll3 Calc AD. Oero TW., walker KR, Lo yS. Wehr'ad w I Jrques L'W Johnsoi AI 

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i.""""aC,r',mr-r.c *d Johnsn DN (1989) B'nzcand pttido l 4{reepiil_orer md 

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uiiiiin.on"i,.". -o ,e.*u_nt"ahiea rvrtrns vot Phmaol60 rIII Ila: 

llt LoR R.. Chu(h M K ed I'Aliald.h M (200?t H a'tihitu'i6 inr'M aSois lnti 

inninmtrory.criosandcadieefias.Clin E\p AIl"g/.12 439!93 

116 Koba B,A. rd CuY6 M w ldihi'bmiEt in lhticdio and A'aiedeM- ltsi' n6s 

- - iin"aii*i* -a s, *.ihituiGs in lll.rsic di* 2''d M,el Dc,*er' Nd Yo :' 

B.s !4e-236 (2002) 

ll7 \| rnd.(r A a . B.m*in l l a.d C@dm,n Dl ':O0lr rh' diasnsF md mrtglm'd d 

"nic.,i':, dm(ice Domnde' I A,ur. un'CrritlngD.drm Anr Arlcr$ A(hn! rmnuFr' 

35.525Jll. 

ll3 SimoNf,ER (2001) Prevenrion ofdclre uni'cnir in roung 

AllctlvClin lmnunol.107. ?03 706 

319 KlplanaP (20{2) Chonic Dfridii dd mgio{den' N Engl J Med 3'16 175_lr9 

251 

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lZ0 Brcneron D.L. (196) Cdnizine *uus hydrcx' vzinc .nd pleebo in chonic idiopar[i' 

uni.aia. a.n Phmacorhci30. l07t'1079 

l2l Finn A. F J, Kapldn A.P.. FEtsll R., Qr R od ldnSI (|999) A doublcbliid Pleebc 

conhll.d tialotf*oLn.diE llcl in rh. nmcnl of choic idioD.rhic uniBia i all.rs/ 

Clan lnmunol lo,Ll07l'10?3 

112 Di I oEnm G., Paco. M.L. .nd Mtmudo P. {2OOa) R.trd@ird plt .bo

138 zurd M.F - Tahbotband Y.R. and Nljib N M (2002) RP_LC melhod ror $. ddminalion or 

.dnizN in srum. J. Pham.Biomed Adl,t2.719'744 

ll9 Chong.Ket K, Klr l.Y, Eunma B, Myu4Jr H..,in'Ki K., MFKlans K. S!_Eon.r md 

,cons-Smk P. 12005) Nrllw boE hi8t D.rlmrncc tiquid chdmaroeE hic mdhod for rhc 

ddcm,indaon ofcetirizin. in lum,n plasna usinAcolunn slnchinB l Ph.m Biomed Aml'- 

l4O Mac.k I - Pbek P. ond KliN , ( l9t9) D.rcmiididi of ceinzine in honan phqa b) hrlh_ 

p.dmuce liquid .htumotqnphy l Chrcn ogt 0 Aioncd S.i Appl . 736 23 | 215 

lll Rossl M.T rd l,lebvrc R.A. (l9l) D.l.minotion of c.ttanrc in hunM uine hv his!_ 

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343 A4 A.. Badwe N., KaulP, snd Sethi PD (1995) tisimarion ofCetrizine dihvdrNhloidc n 

lyrups Indian Drugs,:12, 409-4l0 

144 Brsvaiah K. S.ilaih I M. and Swany (1999) SFctmphotonetic detcmindion ofccr'rizine 

hJdro.hrorld. iilh Al&ri R.d s.lahnr!. !0,337-392 

l,l5 Prak sh MS, Sundmpandian M. Mmo S. tnd Nagamjd Ms (20001 Sp{tophotom€tic 

deLmin{io. of cetnizinc dihyd@hloridc in bulk ddg ond phamaceurical fomulariois 

Indirn DruBs.3?,211 212. 

116 Co{d, BC. Mcltrln*i MB and S{rih.nm.pp. J (2001) Exhctvc sp€'tophoronct'c 

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147 M.lMiki M B. Serhtnmlpp! J 'nd Cord. B.G (2001) Spetdnuo'inftic dermin'tion or 

dni2i* hydchlor t an thmr.uridl ts Pmiio.i Chem' anal. '6 331_337 

1,13 MiMtl G. aDd Paw B (2001) atultsis of em. .nrihisminc dogs ii nodal pha* 

chnmarqnphic t5r€ms J Pllne Chbmltogt. Mod. 1 LC . ll' '30_414 

119 Mokhijr S.N. lnd vavia P.R. (2001) Stbilirv i ic.ri4I{PTLC rdhod for rhe simulhneous 

dekr;inlrion of pseudoephedin. rnd ccriizinc in phlrmeeltical fomulaions I Ph'nn 

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350 wihon and Grhwold\. lnhibirion of hislliiic rcle|s' Isrr'ook 'J Osnr l'ledi'inat 'nt 

Phuntdeunal chenittry.LipptncoFRav.n Publishcr, n!3e 675 ( I Er9) 

' 

15l ( D'i"d't{ \'zr-moA dd I$!oM{ '200ar l.\(erri''ne 'TDm\e na{ obrru'ro1 

-[ ."0,L". t.rt. p.*'n pcucrR $ir *sonal tl''8tr lh'nri' t pror iud\ 

'n 'l'n 

txP. Alle4r,. 3'1. 953 64. 

151 Cmdon J M. and Alldn H (2005) Iic[ of.fied ofsi|8l. and rep'akd doss oflevoarttiie' 

! rcw mrihhr.manic dn& on..eniliY. lid p3 lhomoro. tuturiots in h'ahhvvolunreB Rl l' 

Cli! Ph.dml . 54. tl-3 

r

ijj lloir!trtr lj. Scil$ M. Dftsch( S .nd rrcm M F (2002) Deremin'rioi offcxofcn'dine 'n 

hlmo plasm..rd urin. by liquad ch@nsto3aphv'n.s sp.chnerrv J Chbntrogt B ?65' 

221-\Jt 

156 lio T.- Yrsui'fuokdi N., Talohe I. sog.wea K .nd Tarcishi l (2001) L'quid 

chom.to3dphic dct mimrion of Gxof.$dinc ii humln pl6ma Nith fluocsdcc &retion l' 

Pham. Bion.d. Adl 35, 93r-942. 

157 Oliv.nr D.C.. WoiSch A and Rolim C M.A. (2007) Simpl€ a'd relidle HPLC amlvisor 

fexofeadinc bdo;bdde in rablds and ils dpplicorion ro dissolurion iudlcs Phainrzie' 

jj3 C.uunr J.ll. Wcimirk PA.. N3.dellr PA.. Wah$ SM md Oke olm RA(1991) 

D.r.min.rior of Ld.nadin. ond trf.ntdin. rcid m.6bolir€ in pl6na rsi!3 solid pha$ 

.xiEclio' lnd higFp.'fm.nc. liquid chtoMloldphv wirh flmE*'ic' dcr(lon r' 

Chom.to3t.,5'0(l) l19 143 

lj9 BGi6 A.R.. Prin C.S.. M.n goh J. St rp. M id S.hpov'l EB (209) D'v'lopme tnd 

ulid.rion of ! liqlid chhdogmphic ;.thod aor 

"xoloadin' 

hrdEhldid' in crprule( I 

AOAC 1m..315) 1093_lm7 

160 Radhakishna l lnd Oh RC (2002) simulbnsus d.teminatioi of ieiolciad''e and is 

Elarcd compou.dsbtHPLC J Pharm Biomcd.Anol.29(4)631490' 

16l Masaromo M, Iruk& U, TomonoriT sid Toshio S (2007) Decflindion ol nxolcnadi't 

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16.: 5u*\h KK.. R,\tchindnn t Moh.n MR ft)lgu R md Dhrirht A i2006) 

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16l Niido.c W., Shou W.Z, Addisd T. M.l.[i S ffd ii'dS X (?00]) liqDd 

-'- 

.r""*i,'""ont n"a". 

hiMdl)$' u{ns nom'ltha* column\ }trh 

;nov.loppd(hor'"m'n'rin3't'ptrilonmddd{Nron 

"""i""'.i"i','i."t'r.O*. 

.;; ,n eo.:".11 sPE. Ra;id @-un v;ei spcrcF ld20r rs6!lo?< 

ro4 ne'tud. V, Iucnre. J.A ,nd fedtnd€.Alr.'$ V\ Hhhmine uDrcLuhre' 

')00r' 

' pr'.'-pr'oai.""*. rV "-*'tJ '"U 

sltcelkftmughH dcepro' r'mu'!'ion&r qVPinlrtue 

Med. sci. Monit.9(6)21 l-213 

i65 Mclincs G.f dd Brcdie M.i. {1933) Drug irrcriclions thd mdne' A 'tuicll ElpDmisl 

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166 sdrc[Ja A .nd Mudv M (193?) Phomokiiaic inrdions of cid'din' Clin 

Pham@kintl ttl5) l2l'16. 

167 Mnchsd M. H&k A md Mulli4'r AM (193?) Rrnnidine drug intencrionf l&mruE 

revieu. Ph.Mol Ther'.32. 291_325. 

163 ced*MC, I.iwadi GA.Ced€tN tid aiinchine IR (19351 Drtr3 lnkrccriotrs wirh 

Li'nridi( upddle lhanneol Thor,2T(3)151 370 

169 PosanenM.Ad.l.PindPeltonenO(1986)tiff'd'lfircshdurillvdive6'H)depror 

a;bsonisto.drugnerabolish Bi@hem Phthi'ol. J5(24) 1457-'1461 

370 D.smonn P.V.. M6hford 

6i din.ddcimdidiG 

M.L. sd Hmd P.r' (1984) DeEas€d oBl *lrfrin cl'dnce 

'ne' 

Clin. PhamMl. Ti.r',35, ll3. 

n3 cvr(hbd' P4'0 

"' uYfi:"ili:i)ff :,':s*'ftilx,,ftr'd;,1"s6:1; T#' 

254

in 

t7t 

334 

t35 

t86 

srcinb.rs w,M' tAit r.H. !d kr. D.M. ( 1982) Afi.nL inhibit .bdDrid ofcimdidim N 

Ens. ,. Mcd' 3lt(7) 4090.1, 

Mcl.n6 G.T. dd aodi. MJ. (1913) Drus i'n r*rions tld nftr' a ctiliol opcni{L 

Sorss)i A. ud Mumy M. (l9t?) Ph@kin.lic incnctids or cim.ridirc' Clin 

Pft lMolid., l215l 12l-166. 

17t Gusld R.. Bdid M .id Sm6|i a { 198l) InFiEd cinddF lborFion dE b rtrcnk sd 

mcr@loDnhd., Eur. J. Clin. Ph.mMl , lo(l)225_l2t 

t75 6.d!fii N.. Cfti C,. Ci@ F. .nd P.us E (1989) lnFiEd 6iovlil.bilnv of f.noridi* 

siv.n-oioH 

311 

y *idr. FMrEid.,,Clin Phm$l,29(7) 6?M?2 

Lii J.tt.. chEmd A. .nd K@skt S- (r98?) Erat. ol uEid! sd food d lbleDrid ol 

frdidinc, l- cli.. Pt.lll@|., 24. 5t l -t51. 

't7a 

179 

l30 

331 

182 

l3l 

Doin K.H.. Esh.lnr F.N. ..d Pltchdlo l R (t98!) Tn .ffe|5 ol.n[.id nd D'ot!nlh'r'n' 

d $. .bearion 6l oEl mitidif. Phmdh.dpt (2) 89'92 

Mih.ly C. w.. Msino A. T. &d W.!d.r LK (1982) Hidr doc of DEid (Mvhr ll) t'dus 

bio.viiLbiliry ormiridir, 8.. M.d. 1., 2115, 998. 

MdiEc.. Albd c.. A.undrJ.^., Hffi E., Ceillo J.A. Mtiq@ M BdikJ .ndOnit 

r.A. rl999r Conddiw rn vito sd in vi{ i.hibirioo of cvtehoft P450 CYP|A2. 

c YPin6. ond CYPia br Hrd.trd ubs@RB cr'i Phm.6l Tlti a5. r69_t?6 

N@h S. t200J) CifttidiE A Evi* of rlE @nt dcEloc|rcns tnd rto'B in cuumul 

n dicim,Dcn.bloa/ Orlii. Joudl. 9(2) 4 

Shdiour M. Jrhli F. sd H.ghSao s (2002) Ptp.Etid ol ! cididiF io *L'rit' 

.i.;i. sd iB .oDlhr'q ro ,h;-sd{i r.l}si' J mm gid*d an'l 2t(6' 367_8?! 

cftmni G.. crGriui f.. Nurchi v .'i Silt rni l (199t) A 0'Gr iod'tic 

r"""i.aror.i'*i"oa 'H NMR !|!dt d d* inhctid ol cinclidirc. |.tolidin' "d 

nnnidi;. eith Dhlinunlll) .nd D.ll.diun{lr)trlrim3Polvh.dMl'{rl)l5l7-15r0 

€lfis D.. PllF M. .!d Tctld E C ( lt9t) S€p.tnioi ol cinctidi" !d El'r'd m'rcri'b bv 

.q!o6 ud mF.qwB opill.ry.h.nophGi. r- Ch|ldlog A' t'q l_2) 269'275 

Luls i. ud I@i. DJ. (lr5) D.Ldi..rh. olciddidiE in huItr pLdn' bv 

brc .f.croprmis. ,. ChENtog'. B,6t(2)t2l'j21 

'c {pilhtt 

cci! M.. Albqo M. sel@PbdED c id Abuh6b. M. (2003) Spdiolhod*lric 

a.-i""ii* 

"r cididirc in Dhl'|M.lntth lnd u.irc 6ina h'rch 'nd fl6$_ 

injetionm.$o&. ,. Pt m. Bion.d. an.l . !14s) rO03_ 1010. 

18? B.&r M,, fls!.d M , Kmv M .id Fdnt T ( 1991) sp'chrhMri' ddmin'tioi ot 

cim.ridin. in dE d!t.@ ol r cid_indcd &annnid Fldudt' 

133 J.ttr D.C. Edmrd T F. Mrr R S. D|fl t( !d Ldv C A (20fl1 Ddmin'ti@ of 

Dhr'r|l*sriol coDpo{nd! in {rtte dd !rcmd*e spl6 bv $rd'ph'* drtrEn 'no 

irio-c,rre fiquid chomban v+lcr'lqprry ioidid n6 lpemmrv r' 

Cibnrblr ^, tsl(1 2) l7l_180 

139 llllmot 2.. Sanhv C . Srlik J . Cshi V.4rK.HonrhP Kirl'trM Domu' G Ncm' 

-"' 

i ."a'c-.- s ri"riie"idion or impurii PDlil'r ordE8! md Ehr'd drdi'le Pd lt 

ia."i'i*.ri"".or.;. i'p";,i. in , Ph- sio'"r'' l5(l) l_5 

",n*ridi* ^-l 

255

390 H.lali N.rnd Mo*r L. (2006) Sinulr.|@s &rcminarion of cndidin. tid cl.red 

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Chon..qnphia 63(9- | 0) 425 430 

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lsl tuhinl.Chd!trS.K.MinoriK.CilbenC.N !trd lhomrs C D (1004)Vdlidorotr ola 

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chrcmaroSrphylilh uhdviolerd.r.crion. J Chrcnarogr. 8. t99(2) ll7l4l. 

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ChMdqr A. $d 253-259 

194 Mlud I l. t l99O) Chmm.rognphy of hisnim ll'_.nd ll, @pror bldkc6 in bioemolc\' l 

Cnrc ah!r. B.531.169-,t05 

195 Yousn Ml.. hm.d FAY lnd Ati AM {2005) Cond@romelic d'r'mindion of 

D-cnliproptnohhin. HCl dnr'd'nc HCl h)o:c)n$cHB' lnd btu'ne HCI'n$'trPud \orc 

rnd Drm'ntc.urtr DRpad"on\ It Fmn&o,60\6j) 5llra6 

le6 Ric;d P. fomlM.r.0nd Munoz-va[.s F (1994) Pokogr.ph ic bebv r tnd dercrm'mron 

'ou 

olBtriridineirph.mscuricalfomuldionscnduine An,lv$ rlq llTl 

197 Pcrcz R. 1 .. Lobno C M , Tod6 v.. Bmvo 6 md Cll€d R (2002) Diftd d'bmin{ior 'r 

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tbm{l0rionr.J.l'i!m Biomed Anal-lO.l05t_1061 

193 Yins C.. Yiling'| . Xauhu! S.. Xue_Ao Y . Oiu X- 6. M and E*'g W (2m6) ttt'd'un$ 

oa ;iiridinc li fin. bv apillttr .lahpn@si*tectehcmiltrmitu$c't &htio" 

Chromdo3t. B, 332, 21G240 

199 Kel.ni K.M . Mousuaa a A M, H4rzy M.A .nd Adel F L (2002) Uv{pstothorom'r'c 

shb'l'h ind$hr mdhod ror UF quan'ibtn. dd.m'nd'on of ''nd'd'ne fdnoridinc I-d 

*-'l;"h'd-.;b"de'rDE*"ceorftenorrdanlcden\r'nc5 

Anal tnr'Js 0

406 Su!i$m! A.. Srbh V , Tttahtm A , N.&mud Y , Sfiinia_Sase M . Srto S , Mi,ttt K 

rJihshimolo K {20{3) Fmdidine dcs nd indue los QT s}ndmft: exparim'ihl 

evidenr. f$n in vitm and in rirc rd s)s!cns. Eur' .,. Phamacol . {66( l _2) I 17 146 

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409 Rami NR, Prubhavdhi K., Bhrskar RYV ed chrkaldhv lE (2006) A it* 

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sci.N.r.6fl(5)641617. 

41o Amtral \.k.. sh'vmhlndm K Sindr LN rnd R o B l (l@)r \Fcwphoro'ndrtr 

d;m,nrhon orf.mridin. in oh.trc*l*t o"p"-t.* |PhJm B'omed 

^ntl lltT)5:l 

511. 

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412 llehli N . I)adhourh F.and Mon*.I. (2004) RP HPL,C ridemi'dioi of lamoridiN dnd hs 

Do(eiul impu;nics in phamscuricft. ctuon6losr0phh. 6(7-3) 455 460 

4ll Zendelovsl€D. Sioeskls, Perrcv S. aid MilosevskiP (2002) A snsirive mdhod for 

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srudies. Aco Ph.mreuiq 52(2) I l3-120, 

rr1 rhon! l..nd Y.h X( (lea3, D..m'n"rioi of f.nohd'm r hdmrn pla1m b) h'gh 

*,rci'-* r"uia *-.aoe*phv si$ column lsichins ' Ph,m B''n'd ^n'l 16{6) 

rr ( /lrohi A. Shlfsrr' a. t omuhn \ v 3nd Khodd?m 4 r"0O

4:4 Ma2um! V 1.. Nolik A.A.. Nagib.vich OA. Romash.vskii B V. Gulirv! I V and Kur8rora 

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425 Podduzlov. B.lnd Kiueva D. (1992)Conbin.dlhc6t, wnh insulin/Aliquidon'(chrrcnom) 

ln hr.2 di.her6 rner@imenr failuE uriig omla idiabclic rgei6 vnilr tik'.33(10)963 

416 Ahync M S., Najm. S. and Agha 

det.minalion ofeliquidone 'n bulk 

J Pham. S.i.- l9ll), 132-135 

'r:7 Maudr l l.l l.. Knt^ch c.. Km.mer r. P.LG lj T .!d w.b€. A A (200?) s.Eenins. libED' 

!$isr.d id.nifictr ion dd v.l idtted qunt if*tr id of odl dt id i'b€tics of lh rnlfontlumrvpc 

'n nhsn! bt dmosDheric rsuE ch.micrl 'onr4tio liquid (hrcmab8Ephv m's 

'simd* jchm-,ioe'BA*ly l-hml Sidn d I ir.v' 7?ril161 7l 

t23 cuo l'. Li Z W. Ch.n C.ll. D€ng S P .id Tr't3 SC. (1992) Di€t injdrion of phni ro 

dekminc !liq! doc in ptlsma usin-q Hl'l-C colunn sen hin8 icchniqu' Yao Xuc Xlr Ba'' 

429 Sener , Al&0n A.C, and Malaiss. W J ( 1995 ) Sbnd.rditd pcedurc for rl'c assy aM 

idc fictiior oihlpdslrccmic sulfonyluree in humti plasma AchDiabdol 32(l)64'63 

r10 I'ngY. \.-Orn \. /huo_Ron8 l ,nd Sh,o_HonB J r200-r D'v'opmerr ol a FPHPlC 

..". a' _ *"-.g p."r'"ttr."unred.it 0nti_dcb.n(drugs l ( \omroB' 8 35!1 2'254' 

lll SchcNn . and l cftbYto P 

125 236. 

Z.M. (2006) spetophorometic nerh.d |or qu0nrirdrvc 

drug, ph rmlc.uiical lorm u larions rd humin $rum Pak 

(lees)OnlAnrdDhcn! ^S.nh A 3u'de 'o €lAirm Dn'Fs S5(:l 

412 SchciA.r.{1996)Clini€l hmmtin.ricaolndfomin ( l'. I'fi,mcal|@.J0 lteJrl 

4ll Sam bol N C ( I c96) pn'm*o*i.clics phimlcodvn.o ics of ndfomin in hctlth! subj66 

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"'""i.-. -"-".-,,1 r"lior'h'p{hn-o"ndD' r'v' 

\biblesohroD' {oner4 q_tv1(t.h'mica \-u J73ri Ir 'e r I 

415 Ashours .nd K.bbaniR. (2001) DiEd spc.lophoromedc deciminarion ol mcnbmin 

hrdrehloridc in puE lom.nd in druBformul.tiotu Analvlical Leh 33{2)16l-370' 

rld Pm hP.P.. MtshruR( srlth! MC md Sr.h)t va r/00i' spekophoton'ric 

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ll7 H6ei', A.. Abolhen A..M P'isG (IOot) D.tmin'rio of merf@in plrsma 

''nuNn 

bthigh-p.rfomaneliquidchrcmarogmphv.lChrcfrroe. B a2'(I'2)Il9_122' 

ll3 ( hinq.t dlt indChenHr'C i 0o l t lxtem'nd''n of ncrromin humrn plt\n' b! hilh 

- 'n 

;;;?i';;; r,q;'o *-.a.c-phr "rh lp.dbpho'om'uic der6ron r' chmmarcsra 

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419 lrlemlM P. Simon. CS Eunice K K ttunicc EK. Y$a PA. K@o F aid (}krint H RS 

,:,,,,ii ,rn...' r dckm,nr'on or 

pra'ra r'' rp(r''d n tr 

.i.',i,. i,'""t. -a *ce {r die" rPh^m F \nr' 4d 41 r^_ 

".*." 

"ncd ' 

1.|o l X.. Voncmoo ,r'. voshivama Y . NaklmuB-t . Aia*a M FujiraY andNkhikawtT 

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"rram Ddv.linlrion of aniihlp€rglvcenic bigunid's in *tum rd unn' Drn! on patr 

'n 

,"i,0.*"" -*"." '-t'"'q;l"ll;""d bJ HPLC_Uv on ! Fnunuooph3n'lpoDI (orumn 

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442 Mmt K A. l evine B. Tirus J.M. Fo*lo D R (2001) trrllsh of Berfomin ii rnlci$noi 

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441 T*hc 1,.. Dlvid v.. FM A and M.dv.dovici a (2001)HPta DAD d.Gmination of 

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Di.n,. Mi.dhen l. 6a{l) ll_19 

.144 tllupDoncn R., Ojah-Konsn P.. Routu J lnd (ul! M ( 1992) Det ninldon of mdromin i" 

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1.16 LirM(-.-l-i',J.ll.aidwenKC(:O0l)Ddcdionandd.lenniidioiofphenfdminiiChiff5c 

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14? lnoh.tr | AfdNftlM (lq?Om.lfonnin dfmctitrDin ir pksms at th.mpedic levels hv 3s 

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143 Li, l,AboolL.eiD,HY..nd OuPbVK. (200?) Analvsis of mdromin ircn dosgc 

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rrilh Ihrcu3hpd scft.nin& l0(7)61 l-615 

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454 K?nn Y. Htromi V., Oludr I and Mrh'o M rl{6r H'Sh perfomanlc liqr'd 

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rou-"r oicl'-.r.rr!Ov s ei;'cdsls.i.16.nd ^pplqtion' 67'(|'l4l 146 

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"'''jli',""i ""a' "' ,ro etr\c -.rsbrirc< 'd humn ora ms b) rrPrr v\ r' 

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rc'rn'rk1.l\u'd Jromoro!'0pnLiu!! olct me'hod ro dJ*nrnror of d'cl fena!a'J i 

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476 Moncri.lfJ 

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bpi!'l Ns^llr pakh rlnrr idid 

'€n\urrn.uu\ nudiprorcnr rndo'rldh lofennnrh' r@rryd l.r* 

P.heunlrol. l6{ l ) 2tl L 

a3l rh"uh.r C\' \ingh\i | ,no Choudhun P|\ lo0"r 5p*rDphdom'tE deremindrio o' 

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-- 

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' 

"ii,^...,i*r 'omulrt'utr! br t\ 'p''tc'pho@mdr) 'nd 'q-'d hrcadNrrupr) 

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434 uBeoud0ln . v$ltnton6 sL rlgoSr An alkrun!' h'8h_perfomd'', hqu'd 

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^*r Lr hFnd.g' B B'oned s.' Apol 7{ql' lle 125 

436 Pho!rcq F.,lnry c and Btnnvanh B (2001) chnd resolurion offubipbler mdlcloprckn 

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specrrcphorom.trr. lndior Joumal ol Phalreeuiql S.itnces, 63( I ) 55J? 

r'] G,ru.:t$drlths and S.nfs '100?rS'nulrrncou, e{imrrun af melen4( mid rtrd 

dh.m5'ltrt in t bl.b Indirn JoumrlofPtrm.(.utic.ls"'n!e\' 69!2':79 ?31 

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497 Mohdmid-Ro R. Ali 4.. Y.ld. Hei.ad.h a tnd FrlhEdin A (200{) Liq!'d 

'' 

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' ;,';-t.,'",-,' .. I q;,d (h;o.doe*pht *tu vordlrd'l) rmp"n'ed Pol)ne a' rh( 

493 (h'n-Y H indlhinsCh'in!H r2o03r Anil)" or t\doP'or{ rnd VeG-'m( Acid bJ 

shlionrd PhB. Joum;l orchon.ros.thic s.i.m.. 46 (9) 3l3 3 | 3 

Wid M'd w6h'n*hr' 

'nhibirion 

499 Bcubld E. (200, Ptmmlo&| of cvcl@rvg'ne 2 

r00 V'cnadur/o \l ( Btchrno PM and Kcufmrn tS Mcthod derelopncnr rnd 

^" '''003r 

';il;;;" 

i"'-il ,ili"""ous dercminario! or m.roxi€m and p dinor mesvrde usir Rp' 

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501 a.c J.\v.. Kin MJ. J.nB CC od IE SY. (200?) D'rcmindion oi meloxiam in h m'n 

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I ch'.mrtoa'. B: An' T(hnolaiomed L'f. sr!r' 839(|)6a 7r' 

502 Pon' v.. F:tu H.c., sou4 T M DL. KrnoEK's'acHDs (2005) D*minrion or 

-"';;-;;;i"h,.,;i*."bvrrPLc'roum'lofPhin'ccuric'rs'i'nc's'f(2)2r5222 

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rM B.nsh H., L'F, A, Kot l.nGFdnl H ond Pchtla | 12004' A vlld'rcd llPt-c '5$) for 

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503 H\! Yl. tlv. wl. Voung H K- Dong w i. md HF s L (2005) Sinulbn'ou3 

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5r9 Ssrrr cs.P., N.idu PY .id Munv ssN. (199?) spelnphabdric ncdmds ior the 

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pr'amc.urol b,.,la o^ I Phar B'on.d Aill Jol'' llll l !z 

rll \lue{ctr C.w..tonrl D and cdm\ l ll l20ol t On'pD'/oh dekm'n'ncn unng llPl' trih 

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522 Chor FC. Ho Yl .ndHu4|C (1m2) Dd'mm'iion md phmrotindrc pblilc of 

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521 Lxrsin' s. A1'lluru v v.nl .$n M Md tuj' I k (20olrsrmh,tKu\ 'n'nrton or 

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Nr;.-snce Iqtr'.l.hR'mar.smrh 

r' F'omar'lr B 3J'rl 'll -' 

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5ll luo C.. Moldo$n V, Pop, 4'nd k*ub S E l2o03r Vrl'diuon of HPI C l'V dhod ftr 

.;h.,.d omdE^h htd{N.oltr' mebbohre 'n hJm'n ph'ma ttmc'r s6tr2s{' 

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'nd 

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515 7.1!in N 11999) D.Gmindiion of tssdpnmlc in ph'mreuticdl doslgc roms bv rwo 

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516 Brevli:h K.- Rrm'kisni! V.. Anil Kun'r (J R md Ku'ffi U {2005) Sp6l6ph@dtc dtd 

_ - 

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'n 

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-- 

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'ouh'l 

539 llaeraiih K, Ramdrishn. v. Anil Kumr UR somshcl! Bc (2007) 

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'n 

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Phlmlc.uriol ScieEs. t0( | ) 102-105 

542 M.$romo M.. HnGhi T .nd loshio S (2OOl) Sinulbous ddtmidrion af ldspBtl' 

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'4J Yrn{. \ \'eJ.\.|'B SunYH ldns.lL Liu\ aldHe/! ')00o' I{'' 'nd'on"r 

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Chbm.tognphy and R.trt.d TRhmloAies- ll{ l4) 2159'2 r 71 

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c..di;b&r.l0l(r)q l7 'nk* 

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'' pi" -a -.-"t-t on siiskno; pnamlcotintrics of HMc'coA Educh$ itrhibitor 

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eur,snicared drlconplcxorihisa ihvpen.Nilcage( l Inor8 Biodrm 9? 3?0 176 

6!7 WrnAS..l.inSindChcnT(2001)RedaonkindicsofFlid{btccvdianionof€mbpnl 

mal.;ic inv6riSrcd by isolh.mil FT]R mic@opic s'cLn Ch.n Phm Bull . r9(4) 40?_ 

623 Wrm S.L.- Chuns C.H.. LIN S.Y (2002) pH_dcp€ndcnl c@dii.rion of mct'l lhinopril 

comDlci irv.srisatn bt lnciudcd ror'l rll(ion/fdd$ ttrsfom infmd \Fcro$opt' 

aher Pham B!ll. s0(l) 73-32 

679 r|tyK A"ol.rtitol Prolbr of Drry tuhionret vol.!l.AcademicPrc$.\.*Yo .londdn 

p6s6 ?9 rll(1932) 

610 Ariatu 2.. Marcolo L .nd Marceh L. (2005) Qudribriv. 3nllysis of€nalaprilbv H NMR 

sp..rrcscopy in t{ble6. Joumal ol Ph0meeulieil tnd Bionodical AdFis , 3t(l) 62?_610 

6lll Adv.nce Ch.mttry D.vdoFtri In . lll Richmond Sr' w.st Sun.605 Tmnb ON MiH 

2Ll Canada. Vc6ioi 4 03, 1999 

617 Ha\- G H..4"t|ni.ol Ptofk' of DruA Subaances 'd cx.ipi.nts vol 2l. Acrdemic Press. 

Ne\ Yo'k- bndon. Fg6 2ll 173 (1992). 

61t Clntke s Analyir a! Dng: and Po6r,r, l( ed., Phamreuricrl P6 Lrndon. 20fi. 

634 S.ok{han X.. Kw.d Min C and Cht}Seong C. (2002) Synthesis olAnlodipin. UsinB Aa 

Di.le^ldd R@ctio. Bull. K@d Ch.n Se'rl(l) l4r'144 

515 Adisono v, llrelia P.. Coo R., Leoni A md Crvin v (2001) Phdonabilo.nd 

phodoxiciry sGiesoi diltiazrm J Phom Bidm.d. Anal. Z5(1 4) 539197. 

636 FtoE, K ,1Ml i..l Pmltlet af Dnt Subrlawt vd, 11, Aczdemic Pres N.tr Yod( rindon. 

p,g{r641617 (r933). 

6l? Ihsrtr M. K.. Blrsun N. B.and M.ha A. Y. (2005) Dog.drug inrcmcrion bdMci dicof.nac. 

cctnizin. ond mnilidine. lounal of Ph.mduli{l ed Biom.di@l Anrlysii 314)65566 | 

613 On@ C.B, Moreno V., FrcGi4.r ti. .nd LipFd B (2002) Pd(ll! and h(ll)

645 Acll.my LI The In bftd S'a.tm ol C.,vtet Molr,isr vol. t. Ch.pron & tlt l'td. NY 

646 nanr P..M.nish M..Ann K.T Bhllrr C.id K'd'm S.S Cml) PEp.dlion 'nd 

. haftcteizlt ion of fl u rbiDBf$ b€:& bv Meh slidificarion tcchniq* AAPS Phtm Sci lech 

647 OceliD V.D.. Mruduh B an! Ni*hil K {2003) r, v/tu dd i, vtD.vtlulion ofdetntmic 

.cid rnd its mmol.res whh 0.Cycloddtin lnd XP-Fcvclod.xkin asim Joumrl of 

I'hrmaccurics. ra ll l()'40. 

643 Mohoed H,O D. ..d Moh.mmd J. {2006) Impoing dislurioi of tuloxic.n using slid 

disp.6ion$. lranian Jolnrl olPhimacouriql Rsieh. 4't]l 213 

d9 Pdnzia S.. Aleendr 8.. Cynthia., l-ucia C., V.lerio F., Dicgo R. tnd Fmnccsco M (2007) 

R.sluiaon of (Xjlnudiprcf.n dlyed by drt mt*li! in o4rnic elvcnt Tetrth.dbn 

6t(45) 005 ll010. 

650 Dimnd K.D.. ve D., Zbtni.r C.. Nikoltus K. dd MaDudis A.D. (2002) oryrnorin 

Gf.n.nac c@plcx+Feptdrims. spetuopic iudi6 rnd .rFbl n.duE of a rriDh.nvhin 

cio.f mcfeiamic r.id: nov.l inrilub.rculosh.gen6. Appl. o'ganometallic cfem. 16. l6{ 

65 | guchi N.N.. Chold.ry K.P.R- Murrfiy (,v R , S.D€My.'s V.. H.tntn A.R. lnd Bft&d C 

(2004) Physi@heni.al chldte'iarion ed di!$ldion pop€dirs ol meloiic,m{vclodextin 

binor! syslcms. J.Phsm.Biom.d Anal.,3(l) 75-36. 

6t2 G.n'd C.M.. Nd. ElDi.n F.A., sh.bu M,K., ali. s.M- (2003) M.6l dpLres of 

.nepr.zole Prcparalion. spcctrcscopic rd thcmal .hlnctrizrion .nd biolo8ical .divitv. 

.,olmsl of ( oordin.tion Chcmlstry. 6l- l-10. 

6tl Ks$gjiyln A, Hlkwm K., Jeong R. K., Sd C.1., Tr. S K. Hyon T S. 'nd C.tn J.1,. 

(2002) A rcw synrhcic prae$ oa |tnopEzol.. Bull. Korcan chem se , 2.i(4) 62ft28 

65-4 Rone Y. lnd Sr€ph.. C S. (t003) Acid-h{$ lh.misty of omep@le in rqlds eluions 

Analtric.Chirica Ada,4Al(l) 155-154. 

655 Di'niaa S. d Chftios G K. (2003) ldenlification ed quanlilstivc detemin.rion of 

'tmiidin.alciunDolymoDh 

in rablds using FT-Rin.tr sptrro*or! Tllrnt.7{, 106.}1070 

6j6 Rale$ P. dnd M.dhohh'i p (2003) pcpaBtioi. cha€cterirlrion rd dissohnn' b€hlfnn or a 

kniddrpcbion ol siflvaiarii ! polyerhllctrc gllco 1000.trd polyvinylpyroliJo ,! Klo 

Jsn'rl rr'DNp€îun S!ieM.nd Tehnolus. l0.lo1 104. 

657 Flivio C.. Mein. D,G. Mii! R.t., SlB M, Lucio P, dd F.bio T. i2006) Phol@h.mic 

b.hlvior of the dn3 doasdin in w!!.r.Te!ah.don. 62(3 I ) 7390'7195. 

271

PUBLICATIONS

ORIGINALARTICLE 

A RP-IIPLC METHOD TOR IHE ASSAY OT CEFPIROME 

,TND ITS APPLICATIONIN DRUG.METAL INTERACIION STUDIES 

M. SAEEO ARAYNE, NAJMA SULTANAT AND M' NAW^Z 

t)NP,tud {ch.nB'ry t^M6itr o! 

*stttt tlntu. olPtwtui.d s.kE ' Dcpdtu 4Plwtuxd ch.nda 

FdD E P^'w-. Lawstt 4 x@h 

$nirs RP HPLC n.ri.d fd d'. dimaio. oret'iint in ft pEld' 

sbpd,nd-|ii,d'(.rpim.qs. 

rut lhh . mobilr thc 6$iiti8 or M.oH:Ho (r 5:35- % tv) '' r flo\ 

nldr.s qd. bftlr.d b dffi;. ric dds ir $dedric oneirrnon i 

' ";r,.\' rr ({rrrl.(r'd.drr''.ftmft'omo'!1od*Tt.c!,o\}L.sNpor'hedcrDdm'hiur 

ins hs moG b idins caplc'ty aldjk ro odd sDup rh{ $tmlnts tt. ddg @ 

diblllx'i.i.xyiniml et'l'riblrodoxy-3{xc 

5 rr!.r.ubiqrolr:01 od rrn ]rrl dyll'6,r- 

bM4tFdru rrr hdrc 0r-h 

ftspnabry rmr, slin iid $n ftsu. idedions c.rilbn. 

c sFt\. ,004) Meny rc*lR 

rhnmdr sl fomlrdioc,fd ii hum:nson(BGrh, 

or- reo: slsrorr., a/. reao: rp, M d o/, r99o. rhd. 

!frp|fiEdnobikp6!5ol 

otHPLC Prctidd iiv6ris'm (Btu.r,t. res,,oB 

d qr' - re&. Mur d, a/.. rtt7. s.ibd . d , r9r1) hrE 

{fD'renq1\o tudi6 (Mas.' I, 

o/ , rt!?) Eron.d d. pim'okin.ri6 or E P,bn. ii 

dii$runbyBiig 

i'strFiromhft Liqlld .hDntusapty (FLa) rgv tor 

rd +el,i46r0rr6i.m.ri d'ym@g'wd.@m 

. b!.eF of is {nsnivig rid @rcdEitilirv. Th. 

.*\A 

Aiiibbrio G rrcnr 

Mirciry.ondB|Bd|ivr 

to Ddy inErurioff *ir' orhd drug! 

iafued'/'|9q6]. 

ons (^rynr ? d 

:005). na $dl.birity of..rhrlo6Fin 

bp*tdn|ygsHny.rrd$.. 

ftdinry.m'|wicdEpci.d5Utdrc'li'.id 

'@fD|gd|@dfdg'jEdMhodfd 

ii. qu!!@ oteQ'-. r'd iB n 

Th.NFdMdhI 

b*n vrridn d ird ia lN LoD Oo ns) nd Loq 120 i3)

R&r!\,IPhh),ht^, \nh t @ vt h,tbl,E 

Tru. l: P.rcdl &cufuyrE6sly o| ll 

G c.flircn. rr.r.d'o rm. - 6 $ nrdd)-> 

r$* t: hb&y @vsJ, d Eg*id crddiijB orpopd n.rr.d fo. ertM. 

dr silNne {&s obbind frcm 

P. hsn U( Linird. Eisrhd A[ Rlsac ufd *.rc of 

HP|C &rd.. Mdhmr sndidr gdd. (M.cr, !sr) xd 

HPLC s.rd. *rd lft ,5.d b rN di. mbih r6c, 

^[ odF 'qt6! '!.d Kt of $tuooPic !'nc d 

.[]rriol !|d. rrd oh.iEn ftm BDH rno.di6 

Surrli6 {8DH cnaioi Lrd, tuolq Ux ) 

D. riquid .hbmmsnrhi. rtu 6Gisr.d of shin.da 

sPt}ro^T vP, wnbk wrEtosri uv,vnibb d.lcbr 

connlilsrioi 3s Moduk. Amlysk wa ondmkn oi r 

Br44A, OD.tr00,c{ (r50 x 4.6 mm) arryricd Fv.{+ 

,,"*uyo+i 

\ )-/, 

Ft !: Prlrc.d ccfrimm.nodad. @rrq 

Th. ihtih pr'e ffii*n ol fttbmlrb (rrr5 

trvd). 8.rm d.riEiD! itu rh. ,y. 

DmqlJI i o!5p n ir 

odGd rirc!8i 

iijdor vnE wih a 20lL mrt. ro. 

Biis srrdi^r punr rsh. 

vP srinrd4 uv-viiibk da*r.

.bh I Outiuioi.re$iM.6!rlffiPl*6 bv th! tip6'd n'rhod 

^r ;;dd qdd.d b 5,00 '! or ..Dlnm 6 

fd dk-!.d h ar rv tE:rd 

drsiud rd ii r r()onr slrMir n.{ b l..dc . 

!.0,4.0.20:ql r, rtml ol $'ritr! Fhtio.to.53 or 

,d!t slr es v.i3h.d dud.rv in r5d Blahcvt 

|l!r ^.llor &lsior oa eftircn. ( loml fEn 50 ts'/nl 

-rd'oiiw ddd 6 .rd 0!L rh.t turt vc r.r ii 

r .oBtd tnxtrbE Dri i ItC tu hir , ior hb 

cdd emi4 ri. oiG6 orrF flar 6 nll6d 

rhblsh . nilliroE find {0 45!) -d inicd dqlh I 

rE !: typi.i .hMr&tm ot..tP'M 

^ 

8A 

d*odym ol 2o|tl ro., b HPLC tv6 a d& b.d 

R'SULTS AND DISCUSSION 

Ti. innik D[.r dii*d or n rhdl xd vG 

( Itr5) 

bd wiN his (20:34, l5:lt, 10:70 v/v) v$ de eic 

r tui'{ slEd ror 3y*i eiitilil' &d} ft. diim 

d th. hobik d4 ladr b 66ddk dr!6 n m 

.hffihi. tsm.qa lik! Fd ivnittv rd 

l.nfu d;.. rio*lE. !F dtr of 

h.tr B!l!. T1E ie nd i6 d.t els 'l*n ii !bl6 I

R.N.^ olphtdhin' tuh teb.t4btmik 

rir.: cblnesm! ,hdii3 itudioB or.lrrjmn. vi$ ftlr! 

rE, 3 chmnriosmi $olh3 InbFoii or.dp'mm *'6 ndll 

0.s ird ! sddrrn ddhrim or>0.00rt. 

c.flnoftnbdn*fu 

dibidiq d. itldim bd*6 srii'm .nd n.rk ili 

I cr.r.is Edjm. Ih8 dioE, cDi* 

fo.s iini d.lft lidr dE 'r'e etode adt .r 

ihirddhizE nB dd Flrhn rlsm (tuuE ,). 

B.fF r.brii|dim..rpim .'.u d ddrio rift 

0159 niifts (fi3uE r), viih.frs 

iicE*. in ndclrr vi'g,I( d'c ndd mner.es aFd 

, | - t niNrc B ds. in fisE 4 d 5. n. obxrd 

d.r!6 iD j6rio .nG rn' i@rrorc witl' qc, hsl 

& tsr ii !!L r. Ink !bl. . 

sd.x.d d da kn i d c. Ti. Iuirui 

6m|g,im@!'.dfibft'icdfuilmddid. 

xd.4|d4Fj.dn6'im|i

ere'.d"ddcofF.

R.tuh* 4 etrhalMtu,ih 

r -Nqdt1lhnin 

in nnmK /dthbah /9. 

Ls ( 1934) /, vto 

t'ivi}d|HR3|0.irt{ccptrd6Fft,',.r,, 

ch.ns AFBlr9'rL 

n id I'isr'{.fmba liqlid .hM3n l . !r, 

^ lc (l.p'frt. .dpi6[c 4d n!!F.n J ,di'nro, 

jGRN'fuil.ryc.Bq^1.^rRL'B'Ms. 

lM. R.rld LB d sodn.6 HM ( r9&r. Dkr difiGio. 

6liig'q{|ji,.ffi| 

FhDorHRs|0'afud€4dnle'|os'olii. 

M!$ L, MrL.rc4k v, v.d'o M. s'j 

rik*rN (1937). Dos lira'ig dins of inhrcmB 

rrpiEn. (HR 310),. mv.l clphslospo n ddivltiv. 

v ald vc,h M 119371. 

ftfpi@nc (HR 3r0), i m{ 

rd htrR.msry 6 r'dr'r'y br!fl..B /,/4ro, 13: 

Mir.rc4t v. M!6 L. vdo M. Hij 

tui3m*ah R (1937). 

Fhhdkidis of rftsq: sfrrhm. (rR fi0).: 

ma|cph'lBFfid('ai!/4,.f,id|5|?|l:|1' 

s.ib.n c, Linbd M, wi |d I d Dicr 1(!ert. nr 

o'ibeddirl *'ivi9 _,'"a- dd tslabu *biri'y 

of rr' [v qtdryi tsR tro ii 6Ip'ioi *iil' 

fiEd'l'd.9h.|o.,dim 

ibltftr arivjg or callndir. M.!rc6&!6: 

^ 

cdniun Par r Pb, &i., rq r)i 16.., 

s!8ior,T.AsoT.o']|Gnt|'iY.$uriE.s|io^. 

KurikiT, shidrrr M bd sri6 K (190). stbiliiy nd 

d.sr.ddidn p,n.n or etimm. (HRllo) ii a@s 

&tltian.ckn Phdh N , !3l1): teer-r000 

h|jhm9l.,6'vo|9i|,J}4

Icld,setrr. v.L lo.l{a 1,2!04 rul 

A Nd lI"EtLC M.rhod for Modloiilt d Ai.lolol! ADllh.iio! to lr6olol 

M.t l llt E.rtoo Saud&. 

|I{A,MA SULT/INA,IiUSAMMAD SAIAD ARAYNE 

IBEIIISH IFnKIlAi 

AND TMUI|AMMADNAVAZ 

'R.t@d ldttt'h {ttn.ddndl tuq D''dM {rtwn@Icd ctetbt, 

Fedt4Pbtqt Ltut' 4xadl PeM 

'DeM dct6tar, L@afxtttl xtdtL7t7o, P&4d 

cd rf .d16r,'ld |.ban) 

nry 

^ r-.s! trrnd..lld. e{{ d E Hr.d L e 

&fuddiE..d 

drad.. d d r.rd n dtc { r I r!.td. rrt c! (ra rro r 

.r r) .d- ra rara to 0t: r!, * rr' dd rt- d cr r r{-a r ut 

i c6n r44,c{.!r.- r+.6.hd, I r.bs w 

riF..rdi:rf @rnrd 

LdnbrrH.*b6 

@e dfq i de4 

- d I F. ddd.. {.i Dr d 

Dr..6qE6dtidh 

rE d co.dod- t...rc ri5 d 

&>-d>rt>ld.>q!.|.> 

t derrD '!..'ro. .!!adtr h|E.. rld Ntledir.l loolrioo lltlll S@ 

rEiEd @!e cu.lal |@i.! tqa ol wl6! F o.r.d 6. d4Eidi! of rkir'lbd 

6.&.f'6er b d. hrqFr olhyFbdo., d .dtq.l@bl t! r!.L hL.d n9-201. 

ioFs dr,i& n!.rL.r r.dF 6. rylrtod dt Co4ldo [.t.nd hs !td b bn@ 

l-t dn!., i!r.m ft!6rtl.*b, &d bioLdql Fw ild c @l d.p6t!d Pl. 

& dG!. bL@ lddL ..d *rb 2q. 

N.Eh.t !a Dry d!9 !.t r . 

^@rol ob l) 6 a.B&rL{F'- (r- Eodt ddild4 efir tlod!. c@4, 

dhybyD th.l l.! rr b@!eld. lr ! - & .d nq rvti.t .16o ih.t tddd I! o 

ddtydc,adlaaraci; &t| byt .D idld. L ED.l, ti-lo!, d. d. .do old ld 

tFrddir* .riyi.t lt0l. l. . .L Dd.ly. r@ of !h. drua, {..d it tL !@ oa 

bod b de. dGh od tx onrn &u! i! el{.t-t|.rdtcob.qD||i!.rldtho 

br..d) Iril d ord. dlr i..liri!&4 i,'lit ccd.E rl).êirhrFblo.t r.s!. 

Gr;r.d ft.d, Dr !r{t dta htF rllFr SoodruPborrhntP.,!.fudidslo..tF 

vir'[.UdDy02l, I .d znE @iot' r.slt P$3 U 

i.o 

,, Th.r+b.r.6 h @ot t!. &!!| d 

Q rid.t E d b th. h6!.!t o, bFtoi.. !d 

6.ddtn@wlrwn.tdl .llldtd 

l&rd& or ielol enb 6dL! o'l @ 

.l.ea s mpLldo or dr.Ll yti co''., 

zL. ud ftEL & r.ro.i.a pt rl. 

fta n runlo of !|bdhq |ws! 

win .drlsDons F!361 od ,!.tdt 

qdrlB di rld linLd n-l..|hs p7), T!. 

.v|jLulry or &!3! { t .dlccl by tb

ll rcro'sc Prr. vol r0' Na r',00t 

coft@ itrsdrion of dJUg3 .mD' i3m 

orims l n irpdriv. to bl r*e or 

$.e 'v'lmr intdiG I. PE@r PlPq *. d.*no' ! 

id lnd comdumbk m$od fot th. qur idtd 

or d.mlor'nd G m.bl.mpkE tith 

'*nhi 

nd @ .Lm.nb, ehi.i n.v .ilh.i b. plled h 

rd cmadioN io hum b.dv d mv b. 

ingc$.d c r @lt ofnu[ith dna th.dpv 

M4hod D*hPMt .td r.ttdct@ 

Th. @hiL Pls 6oii.d ol iEdqol 

nn f.k ([0: 20) ,th pH 2.1t, blr wis ds 

20 ?l: 2l r0 D. r/ t) 6 .lto E!&d ! 

's: ;mn! eld ta r*h .uiubilit' dudr' Tt 

di.!6 i! rl* D.siL Phs lad: b .d4!|M 

Fi, 2. Crmn&ld or&,t l bhkr 

b of &br E ! .!.lt! Frtrd !4LJ i. 

d4li.a. !d !.d ..4.d. -eE c, rtaB 

ud nobik !6a roMnc C..dnci.! ofwtE 

(cU (o -.) ft. .ll 016. {,q16 ftr *h ld w 

Ls thd 2,0 % Ldidiot &..r.rblo obr66! 

J,Cr.!,Sel!l6v ro,Nc lr00l ll3 

ft. n rhd dld lor lhd o, tubbb &vi.rio h 

wnl non e?bhL linits, 

IF ncrd..r tdF .bLl d 

D.d|! b r.!.rdilt ta.dc Ir it td&bd rid 

ri. nddvid cai(E c@h rni ft hyd!ry 

r!.14!.1F4. @ d. raolol dldL(Fit 3), 

B.f@ !d6e &d|o| epa.ql i Ettdo 

dd of2,07 mid!6 €i& a) ti .l!4 i@rdo., 

FIr,3. Pr!9os.d miod@ ud bia.@ 

.mr.r of ftmlol. u/tc L ir .hLr 

Fl&.. A rypnl .hlnlfugm of eobl 'itfi nurbiDFra (inhrl 6rdrd)

116 rtul{.hr- v.r !4 x4 LLi 

F'3,5,ChM&|ntu tlFrltg jilldiGor elol *irht@15 

Fi& 6. Ct|l)!er,u thdq ubn rjos of |Mld *irh naL 

.mpLr h.b.d +F.d { dtu d redbn 

itu a shom i! FisB 5 ed 6 Ix. lexid 

bdE tte 4di! rd @ .kdsa ud 

.rolot @ $om nr Tdh 3 Ii. dnM 

.oddi@ @rnd rth oottE, fttn Dd 

chrunu .,hldirt d .@!|.t |,rd..t . 

td of 2J6, 2.54 .rd 2J, d!@ 

'tdi. ,cediEtn,tt .bng. nd.ddds n d6 

o ft.Dlto! of otpLr .nd t{.6i&bili9 of &!l 

.lr. ileE d. In * of ,!nq ftrs .!.1 odd 

tt hiLbiliy in!! .lr. i@a!.d b &6Jt,'196,06 

ut 57696 c!.dEly. Ir e of !-t l 

E SGriu, h.s'le ..d od&im $ rY.tiht of 

&tg s inoBr.d b 136.32. Itt,6l, ll0.?l lld 

r29-7a ta. I' dg of 6Li6 dly lJ2 t( &r

T.bl63: Qediuam of |hlor mul @9krci 

R.fee o!dr! ol .hlol s 

olbitr d tw Eod D[@ (hO LlL Nl 

,es4 ued @ of IIILC 3r.d.. Mcl&.| 

Srldb! Sr& (uSA T.db) .!d Hll4 tdtL 

|& }s '!.d b Ft!.. tu !.biL dr* Alr 

dha l!@E u5.d rE of,rdar.o'ir rB,. d 

dlyti€l ,rd. :nd oloir.d ns AD|i 

Ih? &!id .tFo&stplic t b 

@isr.d of stio.dr n d.l rCloAT vP 9uc'D, 

. shnllna ,n d.i sPtroaT vP, Yti.5l. 

*.ELinb w-vilibL d.tu (Shind! 

corrddi@ Kyoro, J.po). cnrmgnphh 

, .ysh 6 ircSrlcd vii shindzu ddlol cBM. 

102 C@aidid aB Modul. A!.ltti. *! 

.idirctd oo r Plcpha Su4 Cn (tF4 2t0 r 

45 m) colum b|]rriol Fveplurd ol+n.. 

CtuMsap ccoin iM 

TL nobilc pbB coislsbd of mthrmlvd6 

(30:20 %v/v); pH *o i4u*d b 2.3t *inr 

dhern6phoric Eia ft. {!Pl6 }w 

inildu.d rkoulb D inj.e hlE vitn.20-Jr! 

s4lc lo.p .r a l* nb of t Dvoir Ei!3 

bErdc sbp sytu- clr@eEu *s 

d 224 m 6ht SPDIoAT vP Shin.da 

'6rd.d 

J.ctrs4trr. Yol Jo,It. Lteoa ru 

An tu .quiv.lctrr b 10.00 !E of 

eblol w! @uel, *.i3hod Dd diselv.d i! 

tuthool i o . 100 frl slffiio flesr b Ptud@ 

. lndlrd oluuoo ol 100.0 lr3/ nl. Aliqm 9w 

dilu&d b 50, 30, 15, 7.5. 4, 2, l, 0,5, ed 015 !a / 

nl. 0.53 of Ml !.h rG weiSh.d a..l@ly h 25 

ml Erl.dnsts flak. l0 ml of rMlol soldion (50 

!r' nD w! lddd L r.h fird. T1E i{rt wE 

14 h r o$bnr bor.r'M b.rh d 3? rc fd @ 

nd wlh .srd llnriq. Th. s@ of lno 

n6k v.F nltR! dmurh . mirrird! 6r.. (0.a5d 

od hjd"bd rlfdtj| r '6odrs of 2q[ bop 1o 

HPrc !116 r &sib.(| $.rc. 

FiE bbld of |@bf loo bg 6od 

Bdd I'bd (Pn) u4 '* wigH b otej! 

d. .€.!. !bl* wBbl Fdltd .d 

frlfdEd rid l0 . of oc!|el b I00 hl 

w&!Ei. nll T[i! dt oldio s filF.d 

&d adib!.ib.|Bn ddladi@ 

^ n i4 rGi'c r.bt ld d d 

k i ri@ .djnill Rr,.llPl, Dd.d f* dt 

oldidiF .!d q@ridiE dlyt! of @lol h 

bull dE! rld plrlr!.diel ftrE d@r ia 

bd d.wlopcl &d dldn d D. t Q...d RF 

HPLC mdhod alhkJ lloultldE ira.rEritlim 

of .@rd !d i! a4ll MrLs rith o.tl 

Fkf,tio iiJrc.f ls d{ a Ei'c. T1F &64 

F@oE w loud o b. liDa oG . qid. 

di.adtion Ms. 0.2t30 lrrrl. Rdtht *E 

e!* .trd pEi& ed w ooilid.d b, rl* 

3ldniol p'mc4. R.u$ility, n9idr6 

ritldvity, ..mmiel ourc Sood tsEy ind 

psirid ofrhlt llPlc m.lhod 8is ir e .('!d.g. 

ov{ rh. orhd E!.n!d HPLC ndlDd. 

L E. J. ELhlFrL C. M. tte$b Dd J. H. Baftt" 

J,1k, CalL C@dlol,u. t32, \1994), 

2, M. l. Firn r, S. S, Godiob rd G- D. Phet I 

t, /tr. CoL CsAoL rl,943 11994). 

3. S, L, l/oodLy, E. M. Gilb.t ed ,, L 

Andqr.q./. ct /dia 3a.2426 (lr9l),

llt J,cr.rlorP.l v.L r0, xc t,1{6 

..M'n-Bri@'l's-coffilldE'M-ailb.ll, 

J - C t61di4 a9, | 532 lnt94' 

5. M. Mda M. Nrda, n- ciurbini .nd L D c5, 

r. ta.t tL cqztot.aj t673 Qet.t. 

5. H. I(s.\ L D Sckna-&eii rld f, L. 

ao|dsjdr, ci.rddi4 'll, 1499 ( r9r). 

7. F. wss*t! M. n- Bdnw rd l( S. 

w.db.rs. r@,3lo, r44t 0993), 

3. CIB|S licrig.b d conmirc!. J, 

cr@l4nx, es, 1765 \tee4). 

9. C. E. Fowll ,i L H. Sh!f, J Pr4m.ot 

E p.11,0, \Lj 43o (tesl). 

I0. A. M. Bmq R. Hull, D. L L..dtrt sd C. J 

Sqtrir9,J Cde4 73, 120313 (r970). 

ll. ry. K'.n ed K G, 6ds END, ./. Dzs 

it4ab. Phud" 7,at (\932). 

12, PC. Rubln, w. P. J. s€ll K M.rr6, A. 

P.'tl4 D. Rq J, L R.id, B. v C.ot!. z. 

Mikora.-MirLr4 H. Ho6M, r. K!ni;, M 

slcbl4 F. Kajrq ^. N.cr and N. shdi., 

J le P r,n _ Jwo d d. t3' 7 It 931). 

B. M. I. MrsrEeui e M. Ake 4d R. M. 

Ji,,.eJc]'@d4|'a:B|@.d'lpl'd7.' 

14. ll. O. w.ddt , N. a. Edei' d D. M. 

willi4J' rrd. s.r_ 6?Jor1 (1973). 

15. T. A. Kob.h, F. ?t 6t 'nd \v. cotsd* I 

Pt@_ Bi'n n. h.t'1, t7n t9,9l 

16'M.r.L.l.bE 

CMin Lrra Ss. Phen. trg, 2t9 

17. A. G. G@q M. H. A4l!s D'l c. A. 

r$)dn,J PhM., r2a,l19 (1995). 

13. S,V. &e sd H. P. TiDnis, ,drr, d.!sr, 2t 

t9. R MtLt6 ad B, Gtui\ J. phud. BiMrn, 

20 f, Mil|a {d B. cu*tu, J L@. Cr@ad.. 

2r, ch. N&hcq p, R BoDich*, B. Eiimv! ud 

o, tr6of , r. cnh. phmno.?3y]3 Q9t3). 

2?. M. Apder4 P. f aonrhc( c, N&t&v, r 

sin,-va. 1 r.r.r rdi. atut 4s, | 35 ( | 99?) 

2].P'R'llonl6.v.c.N&h.{M'^FrohYa'1, 

snrov. G oldcjovic rnd sioil &,E 

r..na. untu. P'a, 8.dbr. .P.361tt s, 

2.. M. ap6rotov4 c. NictEv, M. Kotm, p. R. 

Aokh.v . i. K.rEiov, ,atd4 ,t6,3?, 

K. H. A. ch@, A. E. 

Mkh,tsl, ed c. Ton z4 I ldc. trJ4d, 

Mcd. siot , rr, I lteeT). 

26, P, R. BdnB, c. co.he, B. Evtimov., rl. 

Kdu ed c' Nac1l*' l '49' 3i'.,'''' .4 

27. V. T. Gdov4 L P. B.nchov, D. R. 

Mchodjhv, V. skurrld , P. R. 8o&h.v 

P a lr'tb& o n, 2a, I 93 t (2gJ5t. 

23 H vdi@v, C. Nachw. I. KindjM.nd M. 

Aponolova Pmcrdiig! of 2nd rnl.mriml 

zn. s$p6ium,1"*qa p. 13 (lee3). 

?9. J. r. R. F. d. Sitv. L J p. wiltim, Tt 

Biorosklr ch.nnby of 118 dmdlq 2nd 

Fln,ctu nto| Pte, orIdd.p.s{t (tee3). 

r0. P. R. Bmrhry, r. N. P.nrch4 G P.coclEv, 

D. R. M.hrdji.v ddD. s r@ov, rzsl? 

r,td.t cka ,23, te6l2sn) 

lr. L, Ll KL€y,,., Clir. *.,U,1a 

r?. P. & Bodch.v, L N. p.'Eh.E, B. rr:mv: 

.trd D.R M.l,!dji*,I ar& c/s,.,2q 106 

3r. P. & Ao..h*, H. XrdDq B. Eriboq q 

N&hd, E z'.ch.v4 D. Ebedjj.v dd D. 

t@, r.Inary. RiNh.d" t& t53 (9m| 

14 i. P{khlva P. e Bd&hcv, C. N&ncv, C. 

Ordt jovic .rd A. Sift, ll@. Icr,. U,ir 

Pa, ttut:tdo. p.2oe (tee1), 

l5 M. S, Araym, N. sulba nd M. Na*q p!}. 

r. Phdn. sd, te, 3e 12006). 

s. w. t , R. L. c,he. J. L. 

rllippich, G, Mc34 

Dlckwnh,./. Pr,u'. J.i., 3s, 303 ( t996). 

Sulrm! and F. Hu$iii, J. 

t ry 4. & Dng kk.rc,rr, |7 a$r. 

^

ARTICLES 

Simultan€ous Quantification of Cefpirome and Cetirizine 

or Levocetirizine in Pharmaceuticrl Formulations and Human 

Plasma by RP-HPLCI 

M. S. Anyns, N. Sullanr,, .'d M. Nrvtt 

" DlNtu\t.lchawD, unb.Ritr al 

'R^k]dLh,l&'afPhlu|ludi4lscbne5'epnn1.||dP,lndqv|id|ch 

dcrfrfunoimdqudiicJ|iotrorc.r'i 

e4hic*Fnob*npc/udotr! 

0mdeIiq!id.hRidoln'hi(Frr 

lbsiglrchMfk,gFphic.ondtrio 

o i 10 !!/nr- ('. > 0 q99) Th. ri;ir or J.cdh 0,oD) md qunin€bn (LoQ 

Milsr mt i'drlorndd'o r.r|utnlAndyLhr llowry rton 

'd 

C.ftiDn., a rounh l.Enton aminorhidroyl 

lrphrlorporin (Fig I)- is Ep{n d bhN.m extended 

\psru or di{ry aSan$( cnm.p6niv. 3nd crd} 

fllirlc bxdtr'a lnri arc rcs$rN ro .etoralh. lnd 

c.fiuzidimell 5l. Itis.xolidql$.ctru'iof @tiviry 

ased lbr rhc tsrhen( ol in,ic 

'ndcs n $ 'o?crve 

tronr iLi trir'crllt illp*drs m!nl3. 

un$ l6l. cdlnom. n r p.ciri.lly rrluablc an!micrc 

btdl !!.u rur us 'n infrnb ard .hildr.n [7, [] 

A nu'Dbd of nerhodr hN. b..n Epod.d fo. thc 

qu.niirn:rion or efptud. A nlntE or tffh.a 

fo. dE set ot atDiffi by 

Uv{F.roftay. pH poti.ion.iry I9l, ,nd by HPLC 

nil[. uri'E ll0. l?1. d *tom t3, ll-13] Fdicr 

nNsrisatoR l, li hlve ako involy.d vinoDsnicobi. 

ol.g Ksay ftdods, rcluding both microdiluhotr 

irrrrrMi'l nf. ro qMnlv c.li r.he. Two {0di.s 

rNn.d Lr4. r5lrhe phamdorii.ricsofefpnone ii 

rdulh altr qurtiricariotr ol rhc co 

ui,a! HPLC,rer fd *h'ch spe,6 

C.anziE dinyddhbnd. Gi& 2) is r lms ding 

iotrsdionE mtihirtmie wirh em. mat{elr iabi 

Lrn! r' \ ,) rd F u(d r.r,h. ryhd.ni'n clnlnr 

Jrrr!\ tu.dr o^ mclulins dini dd chrcnic udi 

c.ni l16l, As r bulr maknal c.rnDit e.,sey.d by 

@id br€ firarjoi tr7. l3l rnd HPLC Ile,:ol 

tr'qu6 v.n.u! HPtr ndhod( fot rh. i\\ry of certt '..h 

in. in vrous phao@euticul ri'murdioN t?l-25 

hmM prasm, 126 ?91. nn $in. lrr)l !a qonrd 

Tnc$ livolve 

phs$ or 'ndhods blile^ rha( b.ooretiv.t, rl'.col"mn 

or ft. now syiDm or HPLC. 'nay Cunnins,n phol.eu 

ric limuldions *6 al$ &(.hin d by dner kh 

qE\ {ch i\ ultriv'old |pehpho'onc'D Pr rll 

5F(mnumne'D lr:, ]\1. crlorinc|r) Irl rlr6l 

.nd ion-*rdire ar4rr!d8 ll7l. TLc 2nd HPILC 

ftrhod. !.a ,le Epon.d for rh. d.r.mina:icn ol 

oftizine $ r bull nu.ill and in lnmlhioi\ 

Lulocrniz'ie dihtd!{hloidc (Fi3. l), the acrive R 

enlnnon* or celnzi"c. ir 1 €ld 

blekcr rhat coibid( arihi\rmi'i! prcpenic! aM n 

*jJYir

î-"-.-" 

nGrsNlEdqldlim 

u\ed rormn4eiircmikdaid p€Kiscnr !lle4ic lhii- 

!r Ir az krioN md rclriy.lypol!rand.rhu\.ddh 

nor t'lidre 'he blood bnt n rcadily l4ol h nenrctivr 

ir ftlie!ing trdal!ttr'prom!, imprcv'ns msd$rla, 

r.ducing l.u.eyrc inlihmrion. lnd dnnlnithing rhc 

cyrokin. leEl. ich rlllrs in .vid.d@ of rh. efi..riv.n.s 

of levdnnii. in *ren.l alleBic diiiris 

llll {i'horplodtr irs$yd.kEnoN.fredm.qni 

nyd aid psychmlic fondiois cMpsEd viln. ph' 

c.l'r 'i h.rrhy mar. whni6 la2l rha is m 

n |bi rrJ trulrql r!tr Llr utrrl) i of ldccrnizinc Tlt 

r'c\fl ne'hodw.rrual\ d.v.lopcd in our labon'o. 

ica rff dtuB-riire 'nrcBUi'm nId'esirahtrom. dd 

cdntii.orlp(dniz i. ii o^].f r d|he.ffRIor 

cdrL"c of lslclrnizin or D !!!il!bilny oi .ci 

prcnE such a wus n.cd.d for rh. .o'!dm iiie 

ria(on of bdn dnss 'mrhod k posible in muhipl. diug th.! 

uy lid rheE n no s(h n.rhod cpoietl in dE lireE 

a c.rinzir e l.@rnizin.. Funh€mr., an lhn 

pipci w. rcpon an r speinc a.d etrsirile HPLC 

|'iom 

cll Fepanrions aid hum'n ph$ni. 

rnd elnirnr d l.{rcfitin in phlrnrelri 

L{PERIMENTAL 

Indrum ltion .d .ntly.lol condld.B. Th. 

fttunato€nphic \r\E cu\i3r.d o 

LC-l0AT vPFmp rith ! sPD.l0A,nd Uv v*iblc 

ddt..o. Chrcniotmphic !)ion e6 nncencd Yir 

l02ConfrunicdidB{5Mod 

Nudonl 120 C, (5 um, ll.5 rJ46 mml Jirly'ical 

icvere pha{ ..luni n hhnir cnr.dturc Tnc 

ionpLrs w{e DrnnuceJ Ihough l rhsdyne 

v r sirh!2OrL$nrl)h loop The'nobileph8tcon. "lccror 

snbd olcH€N: Hro (7J :2t, vr) md pumFd d a 

6d nr of I mumin uring rgnd 

Tne nobih Dre *6 6lrEd rhrcuo a 0..r5 Fn Milli 

Fr ilrd md desc*'l ulkDunrally bdorc u*. Tt 

M.r..i'k rd F&nt . CerpiDme. cdiriziE. aid 

hwdnizin cfcrcncc sbidldr se& obtain.d troir 

PRh.on lrl( l,'mied. Ei!rm,t. AGP Phrmi (Pvol-td 

nM rrcB Farhin SA. Svirzcrland. Lszin! hbl.rt 

cd oinitrg l.vEdnizine ecE Purch6ed rrom a l*01 

r^N"-ovcoo'I' 

F1.fs'A'6dblRfrlE 

n!*d. All reas.'h ukd wdE ol malyri.al BEdc rid 

sen obrrn.d iitrD Mcfl k lcermany). Merhrror 3ru'll 

.nr gradd (T.dl( USAI .rd de on 

Pr.p€did orsrdt dd norkln3 sollthns. SrNl 

slutioG or arpircft, €dnzin.. ed Lr@ nuin. 

conbining lm rgn! ot e eryc *m pEpr€d by 

dislving E sdpordr ir fEshly pcpfi.d &iotrizd 

*e. Th. $lorioB €a rh 

10.G, 5.G..1.G.2.d. l.G. lnd o.5'mp/'nl e iit 

nrd&d eluron! ror rhd p'+rar,on .r caribnn.n 

Lu e!. nr {o.k nrlurorr vlrnorcd !r-?0'C. 

Srnrl. pEpdr0on Tcn leozin" r$le$ Grch coF 

!trD r! 5 '4 le!€e&!l'E) *.t weished and firdy 

sampla conkinins rh. l.b.Ld arotr 

*s adju{ed {nh ris lnd rh. re! 

ioniclr.d rd 5 hin A ponitn 0rdE$npl."rsrh 

lilErd rhough ! wh,hm lilcr prps no 4r rid 

dilured ro the d*iEd .qr.nhtiotr 

Dn4.dsn slutldB Tne rov.rt or cerp,to . 

lnd levoc&jzm rrcm l)&lcd humd plrMa Rrs 

ddcnrii.d hy thc sarcd chn,mlroBrupha cond('ons. 

MrrtrDk b {d smDr.r {r0 mll of h h.5 rhy '.tr. 

lnord \oludeA lonlrng 'n r3e lrom 22-15 r.ibl 

ir) dd ior bling 

n 3ru.r.n 3b* 

t!be! Th. blo.d var 6.n ccndrus.d r 1r, lDn for 

l0 dir dd rhc plrem *panrql !'d deprctimtd b) 

aeroDirdl.. The 5utsm.tant otui@d *a nx.dd 

in ! dio of I : I *irh rhr d.as $ru 

-20'C p.nding drut rMlyrh 

RESTJIj| S ND DTSCUSSION 

The RP HPLC ncthod !d de€lopal rnr.rpitum. 

anjdzk. and l.vadint 

tun\cn'enrl' .mplolal Id rh. rcur 

non hu'M sd'n. Th. .htunttosaphtc coidirions 

seE oprim%d ii ordcr to pr.vidc r 3ood pertarfrrNc 

df rh. ssry rn ordc. ( obh n rhd b.{ $prrurior 

bcrvrs ..frnone dnd l.vdeftizi 

lrdph ic .ondirions *stoprimiad To dcYcrop r sui

MdikPig,albdtrwdgifo:6'i 

ydit,trt'.dfuDLl.cl'& 

SIJNIJLTAJ!FOUS QUANTIFICANO 

ablea mbot t-c ftrhod for rh. dcEmindim otef. 

pimn. ind lrlcd.nzin.. didsit mobil. phr*s .nd 

$d csolurion Th. n'.thod dev.lop 

wirh r Nucldnil l20.Ci column $itr88 mobile pha* 

co'sirriuof&eronirril.: sarr (?5 r 25, v/v) punp€d 

{ r I mr-/'n tr f,o* nG. bur rhdd.nrionriheofcd: 

pnonc od lcve! inew4.hoir(09lTd 1.3mir. 

GFariEly) and |,x Fr Eelutio 

Jnd F [.ymtrtry *r rrrFB.4r. Trhl.l). FsB 

4b rM 4 erb* rhe chmm{ofnnr ol r blank pla$l 

and pralnr iij{r.'r *irh rh. dru3r. E\Fcrifly. ln 

d'drr rr rnptule rhe p. \rnDtD Esulurion and 

cap'.iry ibdor. rring th. snc mobil. ph6.. lnorho 

Cr ChunFrk col nn was dnploy.d. Undd ihis .oi. 

d t4 $c clurion was brcrd lbr rglBhzine (F g. 4d). 

rn order b lhift (h. pdrs md in b!. tn. Goluhon, 

rh. mobiL phr$ (merhdol : worr 30, 20. v/v), nN 

Br. (0 65 'num'n). rid @lurn *.E .h4.d. Th. 

op{inizrion of ft n@ @ i! criric 

ofrhc rory{udind bmld.nins is jiE 

fl*nkorrhcmotil.d,r In rh. cr$ ar hish or lN 

n's'd.\,o'idal.Dn.ofrhdp€ nidubbikdrr 

$c pr $ymnery rl,cror dev'arc\ rilm unir). Tvo 

.ftn C ! Mcdirermea ard Ps.ospn r srff colnmtr 

weE usd scpanoon oD rh. Mcdicfllc! column 

wasb.tr*(Fis.4.)rhanonlnl PufiphoSrrcoluDn 

( Fig. 4f). On dE PuDspher Sd colu 

pdlia d dt@ !d l.lNinzic @ cs olon8 ar 

erni.ii. *cul5 eld.d (F s..kr 

eririlin., rnd lrcanziic wt injettr {nuharN 

yioF etinzji. md l.voeri 

lupFi It sam wo* {ur,lso p.nthrd on a cN column,bd 

rhr pe of rhc ccri,lromc lnd hvmdnizi"L 

ndE.rl. Th. rc\uxs ofrhd ncrhodionCr.olmis ii. 

lnod.rtooptini4sd minin'iz itrnruft nbr rruc. 

ru:rdr. rha vrwldslh ol th. ddes s6 ako !!n.d 

P.!r e.s o( th. dmss *ft '|E3ucd Nr r wid. 

rmsr slnound'ns 2rl m. i.c.. 227. ?17- 2J2, lid 2{',t 

nm (Tlbl.2) Ine nulr'v d. dak ohrtncn Id ri 

anrlyticalin{nnedhrE h.en pbp6.d ror rhe diminrrioi 

dl rhc djsadvantas* ol siigle durd p'de*i',s 

'Ir,is ft(hod 0mvid.s r hoE $nj 

b..ous rh. caknlatio.r at onc {..ihc *'velenSrh 

mrr bnn! cm6 fo' rh. sinMrio 

nd.qdionr lhc mirion.d p'llmEx rff.c' thc 

Guh or dE ntlysL aJ'd al5 D'!da 

E[rsion.qdian. which n b6

H*4 dN w*lcl3|n h& b..n.ls.D ro. $. penr 

A *n-Fint ..lihrrion .!tu @\ con{d4 

*iln *drnu! ibnd!'ds lal sa round h b. lind (i > 

0.999) ror 4h or rh. .nalyl.s oEr |hcn cahbilDtr 

dg6 Th. lin@iry wr olulel b' dr ka!1@s 

EsEsion rtthod !d dF Fopo!.d Erhod wr mr 

ura by irs coftldiu cfitci4r &d inrarpl vdE

Chitrtn('c pannerdG fd. EsEssid .{! ion (J 

= 

,! + r) ol rhd HPLC m.rhod obrdned by rh. Las 

\qures tr ah. of tn BDlrs wd us.d to mnfim 

rhc li'miry ol rhc mrhod dcvelop.d. Ir'. lnir or 

'ldanon (LOD) 

o]T|llrnr in th. 

*fln. G@.a*ly: I' lffrirtzire. it 15 o2:r lnd 

0.65. r.ri.riEly Th€ qmnfrdion umn GoQ) ror 

ehin,ft rh. ph,mnunal rom dimrd sn 

'n 

wn o.17 :nd Lm lrg,tnl. rtspdtjE 

in.. h u tr 0.r5 lnd 0 9r a' mrc.nrrions *hcE 

rhc qnl.!'iois di6 'rynl *tr .q 

r\Ilcdnlry. Tllc calcllatd LoD aDd LoQ valxi cdi. 

rif,n.a rhI rh. ftrhrr\ s* rtrm.i.drly ktrsni!.. 

wnhii.nay pE$on (Ep.iubilry) *as d.r.r 

:nidd b, colculdins rhe Elarive r 

(RsD'r) rd tbur ddem'nrions !t sch corc.mfttoi 

ol rh. smnlcs dd ir sN round to be le$ rhii 4%, 

Bdw.cn'diy pcilion and ecurcy weE a$c$ed by 

.n\a{ng \dmD|.] [' tr'oh.ak on ft 

j i rfu.hur nr. j;i \^r 0eh'.d; RsDsl. 

ucs (l{so en) Asry accur6y, r'\.escd r)y c!r.ur'.ie 

$. $rimd.d concenratons a! ! p.&nr!gc or rhc 

ioniral .omentunons, wft b.b MoNvei th. RSD 

(l.s viiatio.) !hd.d r Sood pi..ision lb. .h. d.El. 

dprd HPLCedod (Tablesl 5). 

No chrtrs. wd obsed in d. chmmarqh of 

bv@lntiE in rh. rt !.c of co 

Th. chrumirogdn of ! p!ft d c smple *as hthcd 

kllhcnFd.tcdllmulionTh.sFihcil'*a5il$ 

dd.min d br scdng fr!. difieanr bth.s or r Mhllat 

hun.n Drtina dd .l$ aions *irh $. r(muhriM 

ThcE ss N nr.IfcMe ot df pl&sm Flrs 'n 

$cJru!-ph.ro smpr.' Fi8ut\ .lb rnd .k mptril 

lhtuniulnm! or $. blrnl plaru ,fl1 rh. pl6nr 

.onhin,ns h.rh dnis\. EsFdiEly. Th.Efm. th. trc. 

!.*d mc od n \F.ific 8nd kldiw ftr the dtos. 

Tt. Nrhod ruslenn.s *6 doonstrsr.d usitrs 

rwo urlyrA by an r$!! oi $petu lot ofefpnon. 

rnd lcwrchrtii! Eoch sialvn preFred qmol* in 

trrpli.& ni(t us.d s.Pmat. in{tu'nc 

c . rnJ nib,lcphr* ,ulurlii\ Tn.RsDsrr=4)ror 

ul Idei'rple\lureJrhld$eFl.$rhr]0q{ inJi 

cari4 ii acspuble rugged.es. 

^ r|!{ihc. *nsi.iv.. dd prccis HPLC A*y 

io' rhc imultundur d.r.mnarion ^pid. or cerp,rcm. ind 

odnizitr or l.ddiri.ift was de 

d.r.d. th. n $ibble toj rhe m ysn or dn8s 

'n.rhod 

'n 9iE rom. doss. fmrl,rim' md plsm !mnr.\ 

T\. rtkn' m rift uh{n.d ll. rh"n 5 nitr) 

!llo* for dE nDid dclminario or dE mdrEi 

rhi.hi\ inFndfrquicl.i,lr!is Irr m.rhod pc 

ds ! \ htctor! muay and p.ekion *ith lN 

n'Dirtorddenod rndqo ihanion 

*A .ulr.sfully lppli.d ro asyinl rhl comm.t'rr 

SIMULTANEOUS OUANTIFICATION OFCEFPIROME 

T$h 3. wirrii &, rM h.rwenily rc!tuy ad pn! 

idifollh.&@nhnreiolefp]mrudhlclB[!n

REFERENCES 

(nbAyfua.frok.|'|'91.d'21\N2.p'2n 

ldERx'Tht6b.ry.c'Bq'Ar''^y4L. 

sosn.c. Linb.n,M,winIleil,andDici,r,/4tr 

utuy ff rhe d.kmiidio of efpii'i 

n*dd rÎtuB Diw" te,6t. t .re l,p 361 

H46h. H.Y'n hh.r. NdD.r. Hq' r, x.jin' 

not,'taitirnnr a*2tu1.7 :t2,\9t te.no 5,r 105 

3'Bbllldsah'l'M'Ml@dodddJ7.n' 

dd Gd;i. Liprcrw'llsm!rM)rrtr :0.. 

9. va$ilir,E.,Ts ili(*oulidotrA.rdMi.hi.l x J 

r2. Uihldn,M.Kr*LN.:riSsgcrK,t/.d4.rtir-

SIMULT^NEOIS OU^MFICATION OF CEf?IROME 

Mr$. ! . r.&br4l. v. \tftq M,, H.Jdq P, s*l6. K . 

:d {kr. N.6/drh rer?.sr. rr.p D 

M*R4L! M6\L.!!tu M . Brr{ P. Kkl r., 

Modttuk rh. tin te Dtu. R4q.w, P.lnn, x, 

b4@?NMwb' 

|9.sualtuFil.Mv.Rcdl''s.P.l.sFd4d.a'LD' 

znir,\I-tjqii!|,\,J.rh\|l.a.rdsbDi',3.â, 

P,l. Pld.. ?ml. td 5&r :L 

owrllJ'A'|]v'rmn,iM^'E!aiDd'^'d 

?rnprr. s s . Hrrru, u t. dd tuE, s3 . /d. D4r. 

onrqt, A. rt k Por trp ,20c0. ni 5?.p. r7l 

rrq 0., Mj rr. G. Hdprrr. ll.. u'r Dre/n r.. rra^ 

J|! i A.M.Y, Ar s*nr.. u a, Al orti, M M, d 

udsD'^'^'.J'',,4,i.'?d.,d.2m.8|']6' 

2d. Metur. r.. /. .xMorr & rry:, wr. t33. m. t. 

z!d!r r, F:, lih!.uNid. Y.R., u'd N.i,b. N.M, I 

9 arr A-^ , M4ob, ll.. E Y&ni. r^., Fr szFtr. v ^ 

lln,4.|9,9'$'Jo. 

Pzrd. M-s, Sldnodm. v. kni. s, 'd 

N46js, M s.. d D4i m. ldr r?. P rr I 

Mrhti.s.N.xdv r. PR. r Pt'M. ,id.a iel 

*ik* rtu 6^*bur r.n M o! o@n Mdklot 

.[4E'rl.4J':||).'!d]rp9q

.yelopDeDa ard vclldealoD of.liqsid dlonrtogruphtc nethod for tbe 

.rniDrtioD of doptdogrel fron phsrn ceutical dolege forn 

.uhd.., M. s. 

M. N$' 

^nra/, 

'D.gfumo'Phl@4lj.r|cienntry.rr@nyo' 

p&rnflr or ch'ntri. unredy or xrachi. (m.hi75170. p*k!n 

!dl&alEdl'|e'4'!ad 

, ,@, oe?d te tueêt 2N 

rtri,qtud r &nddi (4 d o,B lrl* @o, d rdd- lds @oar 

u9jdo&rcr (Fi8. r) or (+)-(s).herryl ?,(2. 

phrrr216.7-nihr!nii@tr, 2 

colD 

uE$|Ph,E'n.d'a0'yridiJE&d4dE'I'it 

IENEIW€yf€]ddnf.v.h@bcnpij. 

md'fd6.d?Emi':l'loofdopidotclbpb*'pH'dne'6 

nm or dopi&tEl hG bd' lnHdslbd rr n,D Bins 

(0.010 / bdln dibyd'isq pno6rbr!_ .rt r.o) d 

.@n!:J. (3r : 65, /v), ubndc I picpbr burfE 

(50 | ro, vr, pr{ 3.0). lov or hish nw n6 (o I rd 4 0 

nl.il! ') d qen rrD:n LoQ Ei6 (0.r l]3 nL ' 

d r.l2 |]. nlr -d 0.12 d 0.39 !s !:!r) 

Tl)tiefe'dE.jhord!fudy*Ibddllopr 

indcb'jdo8El''!d'hm';crrd@rfm'^ 

oDPuitro''d|i!ll.del.d*i6Milm''oEd

chdd Ir d. otdoun *Fdim or dE 6npord. 6 

onpHPrelid.dEl|dlEdpab'clmaogruof 

.rald.sEl ild Len,t jldd ! lbm i! fo. 1v[.r 

borl e r:rr '. '!u @lv'l lld Ebtd d d 

al-rd 6.a mL nifr ErpE ircly 

LaH'ity oi d. sdythd trrhod wt *du!d re 

ins ri,l]llffitdr $Dll|l& it & u$ or 0 25_50 13 

nr|fure@dEd'lrtlb.&Elrl@B 

of aci.ffiid ciibnd@ o'c*smrtum 

ri lld drimrtit w cbrii.d tdlg b Flr 

@ndoord.9idocn'b'i.dlb.i,E'rllte 

ddlh.dG'loidilg.tjd4dlid'T}.l.'Bbd 

rtu Eptuddbilid.t ot rll t.lDasd dnod w.c 

*|lu&{ by c0Ky sudir In $n 3todv e lrd'ry 

:

o s-'de-btu(A 

sdM a or. : Dp&ouor td vJidrbtr ot t L{uid ch'@&enpdjc @M 2' 

4!,d.9'dfqEoMBfll.dddiff.d@ 

Fid kl5 n 'bE ftdi..B ldi d itrEdt a_ 

tu,.y vr..lo!&d s rh. Gn of 6. im d'd* 

.,@yd.!midi@'tfr'udiffij.'@. 

' .r Dlgd rrd 96 (!ror'5i d es rs tt'9ls F 

I ddr (rrL r, r& PGis@ dpd u ' cuF 

Edo'vdrddlcv)'€ddutdb'.1d|.'l''3ft 

!d inEjrv. FMr certuid ol vtidid of ft * 

c";* rdnd b b€ 2.r0-2.36n .nd r'13-r0ret 

LoD - jf !d Loo = iwh.F 

d h rl'. t ldrd d.virrio of rb. b*d i'M 

Midrlo. rd s it r!. tbp? of lnl ,!tu @' 

Tnl LoD !d LOa ol clotidolnl bY & PqM 

sFituity wd lYducd bv Pr"zd4 dflg md 4 

itrru& avicd ph Mg' 

.iri.; mrurim' rb hntu! 

Mdun.k*F'h}diq}Plopy|ftriy't!l|uM.hce 

rdmruuftn.Tltd.E'op.dfu6oddd.'Btadgd 

It!ublllyof.bPidqnlh$bdotrd4@ 

|despB$Gltr'BD6F'm'T&4b 

rd cn6t.d rnd 3 d4iE dry3 of srl! d E 

dM c s9.!d viD ft€LtY Pqrd e@E F 

d! s ri. ctl@.d ot vtnam Yrl6 otdv *G 

rd.d 6 b. t ro* 2 ot. iodqtnu & *britv ot 

dodrosd i! rt Erud.. for 3 at' 

To dddiE dr ldl,l6 or 6. diod. E a 

'n@lodil'nlftn..ib'teEm'pHof& 

ll.ti} rhr 6 |lEld 3ri!hd, Motik F offfi 

mlld*&$'hao]20@biDnoDdpgs'.8 

told stubh ld rh. &nDidis oI cla;6srd d 

T'.3ytE0tujubi|ily'rl:lMaro6ropc.d 

did orrs, Fd dtu rd 'al!M Tt' mb'r dr 

u'oc&d9|&!w865|9rd$(pdl.uiliigiodb 

h|,20'Ti.E&luiiotrofdErdb.dwafdodoe 

3.5t, indtain3 @nPlrG '.!@rio or d'e rft c'ry 

Croolc.sr.l bldPhr. d!ffi ',fud sa hndr' 

doMrdbyG.aP6ldlPqlLd'(rtrbi'l,fu 

clorid4!.| ebl.! orribd 6 seh 75 ns ckpdceEr) 

&n obiti.d f6n lo.d mrki s'l@a sd w'c o' 

HPLC qldiry dc alEoj3ds *rc ol "rllric't gnd! 

AnHgr,cUfn'imsifidln.|0A1vP)il 

ro^.vP) rld clzis4c $ inqE ($i'nd KFb

Jr!&) for de.o ..dm tud itusdib w6 us.n. rL. 

tubsnph. r.puriG or chpidold !d i.cnrt 

t|:fulftr@olnh.d6iic'Purwfu4c'3 

(5 r. Ito x ..6 'ED @r!fl. tu Dorit !.& 6 

sj,.d or E turer :d fr. (rH % dj6!d b 3.. 

lid q'r4ioebd do i. i ..!bnrnm or 30 : 20, 

,9'&fodubinbih0b'!d.!:dtdfi| 

d duald: r 0.41 |6 m@. Md pbr B plryd 

dIndedld[mru$!@icn@@[ 

d.[a! *c 6i@d n ??,J @. 

s4k erurid ol.laidold .nd i.Emt ddrd 

(ro $ mL r) }4 prcplEd by dj3rlviis t0 nu ir 

nlti.slre,@rsludotrolc|opidogd@$b$ 

quirr) u*'l ii r* p@nd6drqliostud (0 :5_ 

rh. on@ of Rdy Nolpl{ Ebb (a.h .lmlnji3 

75 nt.r.?ldo!d) E! ea&ry *ieb.d {d rdy 

b.' 6 71 4 of clopid3cr % w(eh.4 hBidEd b 

.t00'rc|lqi'd(qdi€n''ddrelo 

pndry rer .rudm E fild tuc \r'htuD fir_ 

E'.Fll'..l12deflmmnldgdib'.d 

'!ou,bP'l'.,..g!d'y5Els|uid.^liqb! 

ddFsdrys@Le|u'jm"@dilutd6'.reF 

drid' of 0.2r-50 rs b|-i ud rr. sdpr6 rft .u, 

|,!du!ir!,r.'o*drE'hd' 

lrelrlf &!ibh, 'r7. r. D 

9'xNsfu'P',l@idli&|d']|h'

add.!dor 

Corrcclio$tnd ms.Broqu..id bv E em,l ErDi"r 

Ph.lt l [Br titl.: Drus-Dru8 Intcnclion Snidi.t ofccftimne 

I PrSe no 2. lNi Peaghph line no 4 

scherichis coli sholld be Eld $ Esch.richia coti 

2 P.ge no 16.smndpdasEphliG2!dl 'll thid gddtion onpou!& @ 

suiiable only lor Psentdal ldminBlralio! 

'ftis should be €3d s 

all rhird gcneradon compou

psdirr trd Clm-negadle orSanistu incl&Ed Klebsie z Ptuudohik Klebtiela sp.ciet 

tihigetlo dlsenter'. Escheri.hia @li Peudomn$ aerugitusd Ptote"s nirabili! 

ciooba.te. spe.ies ,nd salmo/.lta ttphi ccfpione conpl.xes *ilh AcE_ihnibito6 

G. onnl. en.bpnl and tbimpdl), Ca-chdcl bloclcs (dilriuen veaptnil md 

mlodipirc). Hr-'4ptor eLgonisis (elidtnc. l.vccfizinc &d f.rof'n!dinc), HrK'plor 

anrae isrs (cineridin€. renidibe dd rmolidin ). hvposlvanic aBcnc (BliqddoF 

frqronnin ud piosliuaE), mslsoidal &tninnamnalory droB! dSArDg (diclofo& 

sodiunr. llubiprol€n nethmic eid dd n loxic@), proton Pmp innibno6 (orep@lc 

dd ldoplule) &d shrios (atonst tin, sibvdratin dd prNdratin) NeE subjet'd ro 

$ljbdreiial sludies sd conped with liP pd.nl dtue afpirom' A! ln's @nplcY's 

shored no actirily aSoinsl thee orS,trisns 

ln 6e lighl of th€s rcsnhs, it is th€rcfoe, rc€iftended ths ccfuibme should not b' co- 

rdDnrisraled *ith anlioxiddG dd €sential and lree ehndl3 ln c6' is n4esdv ro 

adrninisrer c.fptone with otlE drugs a pep.r inl'ftal should b' tu'nta'ned 

Rcsuhs ot incaction $udies ol ceapirene wirl Ac!'inhibilos' mtioxidsls' sFnlrdl md 

@c. el€n.nrs. Ca{hdel blocl.s, grrceptor ulsgonis(! HrEepbr eiagon$t5' 

h)posl)ceniic 4enrs. NSAIDS Proion pwp inhibitors dd slatins ev€led d8t avaiLbnitv 

ol cefpironc incHsed in mosr cases Howver' in prc*n@ of dtioxidet' essnlial rnd 

rae elenehrs celpitome availabililv d*Esed llE interaction results l@ wll coNlaled 

bt dilleEnl rechniques ie, Uv/visible sD€crrophob ct" dd rev'n€d ph6e hig' 

perfdananc. liquid chrcnabsrapht Ki'dic $ndies showd the rvpes o' fo@s (hvdosen 

bond and hyd'ophobic inkraiior) bdwd *fPiomc dd inL6ctins dngs FunhemoE' 

cchnom€ @mptexet wilh all inc@ting dtuet qw tvnlh*izd a'd ch@rfliad bv 

Uuvisible, ! | -lR dd lll_NMR Bilding snc of Ue @npLxd wG d'tmin'd bv 4'r&v 

minimiztion stldies Rdulls of Uv/visiblc, FT'IR ed |H'NMR tunb'r support'd |}'c 

Antib.ct rial flivn, of elpnom' dxl i!5 @nPld's sE tle 'valuted a*ailst C'm 

positir. anl Crd ncgatit. microo'geisff Gd posiliv' o€&isms in'luded 

Shph)to.od^ rua6' (:orlnebetditn holmaknii Ste4o9"6 Jd'calir sd aacilr'r 

ry{cter ed Grm_negativc orgrnishs includ'd X1e'ri'lla P"noniae Klebliella sPecie! 

Shi3ella tllsukrt. Es&erichia 'oli PAudonona! derugitusa Proteus hirdbilk

Cinohd.ter tptcies dd Salnoretla tqhi C.fpiom' @nplcxet vid AcE_inhibnou 

lcaDtoDril, oEl.prit sd tisinoprit), Ca4hamt bl@kqs (dilri@m v'nFnil md 

amlodigine). HrEcptot dllgonist! (cetidziic, lcvocdirizinc md fdof6'dinc)' HrEc'plor 

inheonists (cineiidin., dnitidine ud fdotidite), ht"oelvcdic lgdtt (8liquidon' ' 

uclfonin Md pioetirdono nonstctoidal eti_inllmn.lory druss (NSAlDt (dictofoac 

$dim. flnbiDrof€n m.fMic a€id ed icloxi@) ptobn pmp innibnos (oncP@ole 

and ldsopr@lc) and slalid (alofl4latin, simv4latin lnd p6vslatin) lrw sbj€cted to 

etibdt.rial sludies md coEpsld vith the p{rdt drus c'fpirem' AIl lbde conPld6 

showed no {tility asansloPs ors.rosns 

In rhr hshr ol Lh.* Rsulb. n 13 d6toE. @m'ntt'd thlt 4tprom' should d b€ coadnintulrcd 

vilh sliotid4l5 ttrd snti'l dd lr@ 'lmrs ln ce il k nd€gt b 

adnrinisler c.fpnon. sith other dru$, a popq in|cntl slbtid h' naint'ined

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