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CHAPTER 2: DISSOLUTION ENHANCEMENT OF POORLY WATER-SOLUBLEAPIs PROCESSED BY HOT-MELT EXTRUSION (HME) USING HYDROPHILICPOLYMERS1.0 IntroductionWith the recent start of high throughput screening of potential therapeutically activeingredients, the number of poorly soluble drug candidates has increased sharply (about 25% to40%). The availability of water insoluble APIs into systemic circulation is highly controlled anddependent on its aqueous solubility and therefore increasing the solubility/dissolution of poorlysoluble subtances for oral delivery is a challenging task in pharmaceutical processing anddevelopment. The manufacture of solid dispersions is considered one of the most attractiveapproaches to increase solubility and thus bioavailability of poorly soluble APIs [1] . Soliddispersions have been prepared by employing various approaches such as co-evaporation [2] , hotspin mixing [3] , roll-mixing or co-milling [4] , freeze-drying [5] , spray drying [6,7] and supercriticalfluid processing (SFP) [8] .Hot-melt extrusion (HME) is considered as an effective process in pharmaceuticalindustry for the formation of molecular dispersions in order to improve the bioavailabity of drugcomponents which have low water solubility [9] . The melt extrusion process offers variousadvantages over conventional approaches such as it is a solvent-free process and thereforeenvironmental friendly. Relatively low heat sensitive substances can be easily processed byHME as the exposure of the APIs is very short and processing temperatures can be lowered byselecting the appropriate drug carrier. Moreover, the melt extrusion process helps to convertcrystalline active substances into the amorphous state as well as offers a chance to dissolve thedrugs in the inert polymer matrix through the formation of solid solutions. Different case studieshave been reported to increase solubility of various poorly soluble drugs [10] by HME includingnifedipine, tolbutamide, lacidipine [11, 12] , itraconazole [13, 14] and nitrendipine [15] .Famotidine (FMT) is a histamine H2-receptor antagonist (H2RA) mainly used for thetreatment of gastric-duodenal ulcers, symptomatic gastro-oesophageal reflux disease (GERD),erosive oesophagitis, management of hypersecretory conditions [16, 17] for paediatric populations[17] . According to the Biopharmaceutical Classification System (BCS) FMT is classified as aclass IV drug (low solubility, low permeability) [18] . Indomethacin (INM) is a non-steroidal antiinflammatorydrug (NSAID) used to treat rheumatoid arthritis, osteoarthritis, alkylosing19 | P a g e
spondylitis, tendinitis and headaches [19, 20] . It is known as a Class II active substance whichexerts high permeability and low bioavailability [19] due to the poor water solubility. The twodrugs were chosen to represent the two classes and to compare the effect of HME on increasingtheir percent loading and dissolution properties which are important for improving theirbioavailability. To the best of our knowledge, this is the first study comparing two differentpoorly water soluble drugs from two BCS classes for drug loading and drug dissolutionproperties.Both FMT and INM have been reported to be molecularly dispersed in various polymermatrices in order to provide quick release profiles [16,19,20,21] . In the present study, soliddispersions of relatively high loadings of INM and FMT (up to 40%) embedded in hydrophilicpolymers such as SOL, VA64, and S630 were prepared using hot-melt extrusion in order toachieve faster dissolution profiles. The in vitro dissolution properties and physico-chemicalproperties of the solid dispersions were investigated and compared with the physical mixturesand the pure APIs alone.2.0 Materials and Methods2.1 MaterialsIndomethacin (INM) was purchased from Sigma Aldrich (London, UK) and Famotidine(FMT) was donated by Colorcon Ltd (Dartford, UK). Soluplus and cross-linkedpolyvinylpyrrolidone kollidon VA64 were kindly donated by BASF (Germany). Plasdone S630was obtained from ISP. All HPLC solvents were of analytical grade and purchased from FisherChemicals (UK).2.2 Drug-polymer miscibility study by Hansen solubility parameters ()The Hansen [22] solubility parameters () of both drugs as well as the polymers werecalculated by considering their chemical structural orientations. In order to determine thetheoretical drug/polymer miscibility, the solubility parameters were calculated by using theHoftyzer and van Krevelen method [23] according to the following equation: 2d 2p 2h(2.1)Where,20 | P a g e
Page 3 and 4: DECLARATION“I certify that this w
Page 6 and 7: taste masking effect of the process
Page 8 and 9: CHAPTER 2: DISSOLUTION ENHANCEMENT
Page 10 and 11: 3.2 Powder and ODT characterization
Page 12 and 13: 3.7 In vitro drug release profiles
Page 15: 3.1 Solubility parameters and extru
Page 18 and 19: polymers.7.2 DSC findings of all AP
Page 20 and 21: 2.4b Diffractograms of FMT formulat
Page 22 and 23: 4.3 Schematic representation of the
Page 24 and 25: 55 exrudates (b) DPD/L100-55 PM (c)
Page 26 and 27: 8.5d A plot of the logarithm of HCS
Page 28 and 29: L100Eudragit L100L100-55 Eudragit L
Page 30 and 31: Maniruzzaman M, Rai D, Boateng JS.
Page 32 and 33: Maniruzzaman M, Boateng JS, Bonnefi
Page 34 and 35: CHAPTER 1: INTRODUCTION1.0 Backgrou
Page 36 and 37: Table 1.1: HME and other convention
Page 38 and 39: homogenize but also compress the ex
Page 40 and 41: properties of polymers and excipien
Page 42 and 43: particles‘ wettability [46] . A v
Page 44 and 45: Table 1.2: Different hot-melt extru
Page 46 and 47: 1.8 Aims and objectivesThe purpose
Page 48 and 49: 29. Zheng X, Yang R, Tang X and Zhe
Page 50 and 51: 56. International Conference on Har
Page 54 and 55: Fdid ,Vi F2pip , p( Ehi/ ViVi )i =
Page 56 and 57: used. Each sample was scanned from
Page 58 and 59: Furthermore, by means of thermodyna
Page 60 and 61: 3.2 Particle size morphology and pa
Page 62 and 63: Fig. 2.4a: Diffractograms of INM fo
Page 64 and 65: However, the DSC thermograms of the
Page 66 and 67: Fig. 2.5b: DSC thermograms of INM a
Page 68 and 69: Fig. 2.5e: DSC thermograms of FMT a
Page 70 and 71: Nevertheless, more than 80% FMT was
Page 72 and 73: 6. Caron V, Tajber L, Corrigan OI,
Page 74 and 75: CHAPTER 3: DEVELOPMENT AND EVALUATI
Page 76 and 77: 2.2 Hot-Melt extrusionHot-melt extr
Page 78 and 79: Committee of the University of Gree
Page 80 and 81: The PM of formulation II (40% IBU)
Page 82 and 83: Fig. 3.3: DSC thermograms of pure I
Page 84 and 85: As a general rule, the powder compr
Page 86 and 87: Fig. 3.4: Schematic diagram of ODT
Page 88 and 89: Fig. 3.5: Schematic diagram of ODTs
Page 90 and 91: Fig. 3.7: Schematic diagram of ODTs
Page 92 and 93: F2 0 0.5 0 1 0 1F6 0 0.5 0 1 0 2F7
Page 94 and 95: 6. M.F. Al-Omran, S.A. Al-Suwayeh,
Page 96 and 97: 30. L. Saerens, L. Dierickx, B. Len
Page 98 and 99: leading to significant variations w
Page 100 and 101: 2.6. In vitro drug release studiesI
Page 102 and 103:
v2d 2p(4.1)Table 4.1: Calculated so
Page 104 and 105:
The observed melting peaks are shif
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Fig. 4.2a: Powder XRPD patterns of
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Interestingly, no difference was ob
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7 Astree sensors Taste masking effi
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The in vitro e-tongue evaluation wa
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3. K. Woertz, C. Tissen, P. Kleineb
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25. B.C. Hancock, P. York, R.C. Row
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CHAPTER 5: AN IN VIVO AND IN VITRO
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(dispersion forces and polarization
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Table 5.1: Sample preparation for t
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Table 5.2: Solubility parameters ca
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Physical mixtures (PM) and extruded
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Fig. 5.2c: Thermograms of CTZ and V
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masking effect for active concentra
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Fig. 5.5b: Distance and discriminat
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Table 5.4: Mean standard deviation
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Fig. 5.6b: Release profiles of VRP
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17. Woertz K,Tissen C, Kleinebudde
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scale or lower. XPS is more accurat
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patterns were identified after ener
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3.3 Differential scanning calorimet
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Fig. 6.3a: Diffractograms of PRP fo
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good agreement with the anticipated
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Since L100 contained higher proport
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at ~533.01 eV is the combination of
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Finally, the XPS analysis confirmed
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Fig. 6.6b: 1 H NMR spectra of all P
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6) Bonferoni, M.C.; Rossi, S.; Ferr
Page 160 and 161:
26) Vandencasteele, N.; Reniers, F.
Page 162 and 163:
Gibbs free energy change before and
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2.5 Hot-melt extrusion (HME) proces
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2.11 X-ray photoelectron spectrosco
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Table 7.2: DSC findings of all APIs
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3.4 In vivo and in vitro taste mask
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Fig. 7.3c: Normalised DI (%) of all
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Table 7.4: Binding energy calculati
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PRP/ polymers extruded in compariso
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atom as NH + 4 . This observed N 1s
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8.0 ConclusionsThe presence of inte
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20. Davies MC, Wilding IR, Short RD
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CHAPTER 8: SUSTAINED RELEASE HYDROC
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2.3 Preparation of formulation blen
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medium pH was maintained as 1.2 by
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Fig. 8.1: SEM images of [(a), (b)]
Page 192 and 193:
Fig. 8.2b: DSC transitions of HCS/E
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in the range of 10-12 kP. However,
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ate and time on the basis of Eq. (8
Page 198 and 199:
Fig. 8.5c: A plot of the cubic root
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when n > 0.89. From the results of
Page 202 and 203:
14. Lam PL, Lee KKH,Wong RSM, Cheng
Page 204 and 205:
Furthermore, HME has successfully b
Page 206 and 207:
Supp. Fig. 2: XPS O 1s peaks for PR
Page 208 and 209:
Supp. Fig. 4: O 1s BE peaks for L10
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8.2 s 6.2 s 3.8 s 1.8 s 200 msS
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12.2 s 9.0 s 6.2 s 3.8 s 1.8 s
Page 214 and 215:
Supplementary table 1: Solubility p
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N = 55000/ 219.2 = 250.912Density:
Page 218 and 219:
(4) Eudragit L100, N = (125000/202
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