Chitosan Loaded Mucoadhesive Microspheres of Gliclazide - Journal

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ABSTRACT RGUHS Journal of Pharmaceutical Sciences Effect of Different Acids on the Formation of E and Z Isomers of Dothiepin 1 2 1 3 Gopal Krishna Rao* , Ramesha A.R , Amit Kumar Jain and Sanjay Pai P.N 1 Department of Pharmaceutical Chemistry, Al-Ameen College of Pharmacy, Bangalore, Karnataka, India 3 Dept. of Quality Assurance, Al-Ameen College of Pharmacy, Bangalore, Karnataka, India 2 R.L.Fine Chemicals, Yelahanka, Bangalore, Karnataka, India Dothiepin is an antidepressant drug useful in the treatment of mild to moderate endogenous depression. The synthesis of dothiepin involves dehydration of alcohol using acid catalysis leading to the formation of E- and Z- isomers. So herein, we report the use and effect of various acid catalysts on the formation E- and Z- isomers. Characterization of both the isomers was achieved by using HPLC and NMR. Both NMR and HPLC analysis showed the formation of E-isomer as the major component. Keywords: Dothiepin, E and Z isomer, NMR and HPLC INTRODUCTION Many important and widely used drugs are marketed as mixture of optical isomers that often differ in pharmacological, toxicological and pharmacokinetic 1 properties . Qualitatively and quantitatively enantiomers may have similar or different pharmacological effects. This may be related to stereo selective pharmacokinetics or pharmacodynamics. The terms 'eutomer' for the more potent isomer and 'distomer' for the less potent one have been often used. No generalizations can be made concerning enantiomers since they exhibit varied effects, e.g., cyclophosphamide and flecainide for equipotent enantiomers; one enantiomer with all or most of the activity as exhibited by NSAID's and β-blockers; both enantiomers active with similar therapeutic and toxic effects but different magnitude as shown by warfarin and both enantiomers active but with quantitatively different therapeutic and toxic effects 2 as evidenced by verapamil . Hence efforts in formation of one of the isomers of high pharmacological importance during the synthesis itself can be of immense value. Dothiepin, chemically is N,N-dimethyl-3-(dibenz[b,e] thiepin-11(6H)-ylidene) propylamine. It also differs in structure from amitriptyline by the presence of sulphur atom in the central ring, which leads to the formation of E and Z isomer. Of the two isomers, E isomer is predominant in its 3 composition . Dothiepin, a tricyclic antidepressant possesses marked anticholinergic and sedative properties and is also known to prevent reuptake of noradrenaline and serotonin at nerve terminals. The tricyclic antidepressants are particularly 4 useful in the treatment of endogenous depression . RGUHS Journal of Pharmaceutical Sciences Received: 6/4/2011, Modified: 12/5/2011, Accepted: 21/5/2011 172 Original Research Article In continuation of our efforts in understanding the catalytic effects of various acids on the formation of E and Z isomers of 5 doxepin and encouraging results obtained therein, we hereby report the effect of various acids on the formation of E and Z isomers of Dothiepin. Dothiepin was synthesized using different acid catalysts on (11RS)-11-[3-(Dimethyl amino) propyl]-6,11dihydrodibenzo[b,e] thiepin-11-ol (Compound A). Using NMR technique we were able to identify the isomers and confirm the E- and Z- isomer formation in the experiments involving use of various acids. This study was confirmed by HPLC to know the percentage of both the isomers in 6 dothiepin . MATERIAL AND METHOD The chemicals and reagents used in the present project were of AR grade and LR grade and were purchased from Lancaster, Sigma, NR Chem etc. Melting points of the synthesized compounds were determined in open capillary 1 tubes and are uncorrected. H NMR (400 MHz) spectra were recorded in deuterated chloroform in Amx-200 liquid state NMR spectrometer (Astra Zeneca, Bangalore) using TMS as internal standard. HPLC chromatograms were recorded on Shimadzu SPD10 A UV-visible detector, Ray Chemicals Pvt Ltd,Yelahanka,Bangalore. STEP-1: General procedure for preparation E- & Z- isomers of N,N-dimethyl-3- (dibenzo[b,e]thiepin- 11(6H)ylidene) propylamine (1a-g) ( 1 1 R S ) - 1 1 - [ 3 - ( D i m e t h y l a m i n o ) p r o p y l ] - 6 , 1 1 - 9 dihydrodibenzo[b,e]thiepin-11-ol [Compound A] (10 g, 0.0311 mol) was taken in a 500 ml round bottom flask, to which acid (0.0377 mol) and toluene (100 ml) was added with stirring at 110 °C. The reaction mixture was stirred for a RJPS, Jul - Sep, 2011/ Vol 1/ Issue 2
period of 6-8 h. After the reaction, the reaction mixture was extracted with toluene and poured in to 150 ml of water and made basic to pH-9. The aqueous and toluene layers were separated. Toluene was distilled out to form a semisolid product. Acetone was added and made acidic to pH-2 by the addition of acid to obtain the final product. -1 IR (KBR) cm :3068(ArC-H str), 2951(aliph C-Hstr), 1629(C=C, str), 1469(C-S-C str), 1081(C-N str) (Compound GKRA-13). 1 HNMR (TMS) δ: 6.96-7.33{m, 8H,Ar-H};5.90 {t,1H, Unsat. C=CH-E-isomer};5.83{t,1H, Unsat. C=CH-Zi s o m e r } ; 4 . 7 8 - 4 . 8 5 { t , 2 H , N C H 2 } ; 3 . 3 8 - 3 . 4 5 {t,1H,CH 2};3.08{m, 2H, CH2-S-C }; 2.53-2.70 {s, 6H, 2 х CH 3 }[Compound GKRA-13 obtained from p-Toluyl sulphonic acid] (Fig. 1). Compounds GKRA-07 to GKRA-12 were obtained in the similar manner by using various acids (Table 1). Determination of percentage of (E- and Z-) N,Ndimethyl-3- (dibenzo[b,e]thiepin-11(6H)ylidene) propylamine hydrochloride by High performance liquid chromatography Test solution: Dissolved 0.02 g of the N,N-dimethyl-3- (dibenzo[b,e]thiepin-11(6H)ylidene) propylamine hydrochloride in the mobile phase and dilute to 20 ml with the mobile phase. 1 ml of this solution was diluted to 10 ml with the mobile phase. Chromatographic Procedure Separation was carried out on Wakosil II (SGE) C-18 column, length 10cm and internal diameter 0.5 cm, particle o size 5µ. Column oven was set at 50 C and detection was carried out at 254 nm. Mobile phase comprised of a mixture 1 Fig 1: H-NMR spectrum of GKRA-13 Gopal Krishna Rao et al./ Effect of Different Acids on the Formation of E and Z Isomers of Dothiepin 1 HNMR (TMS) δ: 6.96-7.33{m, 8H,Ar-H};5.90 {t,1H, Unsat. C=CH-E-isomer};5.83 {t,1H, Unsat. C=CH-Z-isomer};4.78- 4.85{t,2H,NCH 2};3.38-3.45 {t,1H,CH 2};3.08{m, 2H, CH2-S-C }; 2.53-2.70 {s, 6H, 2 х CH 3 }[Compound GKRA-13 obtained from p-Toluyl sulphonic acid] Scheme - 1 173 of 30 volumes of methanol and 70 volumes of a 30 g/l solution of sodium dihydrogen phosphate, previously adjusted to pH 2.5 with phosphoric acid. Procedure 20 µl of the test solution was injected. The system sensitivity was adjusted so that the height of the principal peak is at least 50 % of the full scale of the recorder. The test is not valid unless the resolution between the first peak (E-isomer) and the second peak (Z-isomer) is at least 1.5 (Fig. 2). The percentages of both the isomers formed are tabulated in (Table 2). RESULT AND DISCUSSION The percentage of E-isomer is found to be higher than Zisomer in all the experiments. The conversion of (11RS)-11- [3-(dimethylamino) propyl]-6,11-dihydrodibenzo[b,e] thiepin-11-ol (Compound A) to E- & Z- N,N-dimethyl-3- (dibenzo[b,e]oxepin-11(6H) ylidene) propylamine (Compounds 1 and 2) was complete as shown by IR spectra -1 with appearance of C=CH peak at 1602 cm . SCHEME 1 E-isomer 1 CH 3 S OH (A) N CH 3 CH 3 Acid catalyst toluene S S N CH3 H3C H3C N Z-isomer 2 RJPS, Jul - Sep, 2011/ Vol 1/ Issue 2
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