Development of hot-melt extrusion as a novel technique for the ...

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14. Lam PL, Lee KKH,Wong RSM, Cheng GYM, Cheng SY et al. Development ofhydrocortisone succinic acid/and 5-fluorouracil/chitosan microcapsules for oral andtopical drug deliveries. Bio Med Chem Lett 2012; 22:3213–3218.15. Abrahamsson B, Alpsten M, Bake B, Jonsson UE, Eriksson- Lepkowska M, LarssonA. Drug absorption from nifedipine hydrophilic matrix extended-release (ER)tabletcomprison with an osmotic pump tablet and effect of food. J Contr Rel 1998; 52:301–310.16. Li SP, Mehta GN, Grim WN, Buehler JD, Harwood RJ. A method of coating nonuniformgranular particles. Drug Dev Ind Pharm 1988; 14: 573–585.17. Hayashi T, Kanbea H, Okada M, Suzuki S, Ikeda Y, Onuki Y, Kaneko T, Sonobe T.Formulation study and drug release mechanism of a new theophylline sustainedreleasepreparation. International Journal of Pharm 2005; 304:91–10.18. Hixson AW, Crowell JH.Dependence of reaction velocity upon surface and agitation.Ind Eng Chem 1931; 23: 923– 931.19. Higuchi T. Mechanism of sustained-action medication. Theoreticalanalysis of rate ofrelease of solid drugs dispersed in solid matrices. J Pharm Sci 1963; 52: 1145–1149.20. Gibaldi M, Feldman S. Establishment of sink conditions in dissolution ratedeterminations—theoretical considerations and application to non disintegratingdosage forms. J Pharm Sci 1967; 56: 1238–1242.21. Korsmeyer RW, Gurny R, Doelker EM, Buri P, Peppas NA. Mechanism soluterelease from porous hydrophilic polymers. Int J Pharm 1983; 15: 25–35.22. Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur JPharm Sci 2001; 13: 123–133.23. DiNunzio JC, Brough C, Hughey JR, Miller DA, Williams III RO, McGinity JW.Fusion production of solid dispersions containing a heat-sensitive active ingredient byhot melt extrusion and Kinetisol-dispersing. Eur J Pharm Biopharm 2010; 74: 340–351.24. Zheng X, Yang R, Tang X and Zheng L. Part I: Characterization of Solid Dispersionsof Nimodipine Prepared by Hot-melt Extrusion. Drug Dev Ind Pharm 2007; 33:791–802.25. Maniruzzaman M, Hossain MA, Abiodun A, Douroumis D. Chrono – Delivery ofHydrocortisone Tablets Processed by Hot-Melt Extrusion (HME). 39 th CRSexposition 2012b; Canada.169 | P a g e
CHAPTER 9: CONCLUSIONS AND FUTURE WORK9.1 Overall conclusionsHot-melt extrusion (HME) has proved to be a robust method of producingseveral drug delivery systems and therefore it has been found to be useful in thepharmaceutical industry enlarging the scope to include a range of polymers and APIs that canbe processed with or without plasticizers. In this current study HME processing wasemployed as a means to increase the dissolution rates of three water insoluble drugs. INMand FMT were extruded with SOL, VA64 and S630 at different loadings up to 40% withoutthe presence of traditional plasticizers while IBU was extruded and embedded withinEudragit EPO polymer matrix. The extrusion process was optimized to produce amorphoussolid dispersions of the drug substances. Further physicochemical characterization studiesconfirmed the theoretical drug – polymer miscibility for all binary mixtures as predicted bythe theoretical approaches of Greenhalgh and Bagley. Increased aqueous solubility wasobserved in both API mixtures with all polymers, and the extruded solid dispersions resultedin greater dissolution rates compared to the bulk drugs. The in vivo taste-masking evaluationof extruded IBU formulations showed that HME processing can be used to efficiently maskthe taste of bitter active substances without compromising tablet palatability. The ODTsdeveloped displayed disintegration times and crushing resistance similar to commercialNurofen® tablets but improved tablet friability. Finally the increased IBU release rates of thedeveloped ODTs were faster than the commercial Nurofen® tablets.PMOL was found to exist in either the crystalline or amorphous state depending onthe polymer used for extrusion. The optimized formulations were evaluated in terms of tastemasking efficiency both by in vivo human panellists and an electronic tongue. The extrudedformulations of VA64 demonstrated better taste masking compared to those of EPO while thee-tongue was found to be a valuable tool for taste masking assessments and formulationdevelopment. Similarly, DPD, PRP, CTZ and VRP were found to be in the amorphous stateafter extrusion due to the formation of solid dispersions. The optimized formulationsevaluated by both in vivo and in vitro taste masking tests correlated with each other very well.The extruded formulations of L100 demonstrated better taste masking compared to those ofEZE while the e-tongues were found to be a valuable tool for taste masking assessments andformulation development.170 | P a g e
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DECLARATION“I certify that this w
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taste masking effect of the process
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CHAPTER 2: DISSOLUTION ENHANCEMENT
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3.2 Powder and ODT characterization
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3.7 In vitro drug release profiles
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3.1 Solubility parameters and extru
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polymers.7.2 DSC findings of all AP
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2.4b Diffractograms of FMT formulat
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4.3 Schematic representation of the
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55 exrudates (b) DPD/L100-55 PM (c)
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8.5d A plot of the logarithm of HCS
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L100Eudragit L100L100-55 Eudragit L
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Maniruzzaman M, Rai D, Boateng JS.
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Maniruzzaman M, Boateng JS, Bonnefi
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CHAPTER 1: INTRODUCTION1.0 Backgrou
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Table 1.1: HME and other convention
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homogenize but also compress the ex
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properties of polymers and excipien
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particles‘ wettability [46] . A v
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Table 1.2: Different hot-melt extru
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1.8 Aims and objectivesThe purpose
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29. Zheng X, Yang R, Tang X and Zhe
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56. International Conference on Har
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CHAPTER 2: DISSOLUTION ENHANCEMENT
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Fdid ,Vi F2pip , p( Ehi/ ViVi )i =
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used. Each sample was scanned from
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Furthermore, by means of thermodyna
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3.2 Particle size morphology and pa
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Fig. 2.4a: Diffractograms of INM fo
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However, the DSC thermograms of the
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Fig. 2.5b: DSC thermograms of INM a
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Fig. 2.5e: DSC thermograms of FMT a
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Nevertheless, more than 80% FMT was
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6. Caron V, Tajber L, Corrigan OI,
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CHAPTER 3: DEVELOPMENT AND EVALUATI
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2.2 Hot-Melt extrusionHot-melt extr
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Committee of the University of Gree
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The PM of formulation II (40% IBU)
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Fig. 3.3: DSC thermograms of pure I
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As a general rule, the powder compr
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Fig. 3.4: Schematic diagram of ODT
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Fig. 3.5: Schematic diagram of ODTs
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Fig. 3.7: Schematic diagram of ODTs
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F2 0 0.5 0 1 0 1F6 0 0.5 0 1 0 2F7
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6. M.F. Al-Omran, S.A. Al-Suwayeh,
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30. L. Saerens, L. Dierickx, B. Len
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leading to significant variations w
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2.6. In vitro drug release studiesI
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v2d 2p(4.1)Table 4.1: Calculated so
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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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Page 154 and 155: Finally, the XPS analysis confirmed
Page 156 and 157: Fig. 6.6b: 1 H NMR spectra of all P
Page 158 and 159: 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
Page 164 and 165: 2.5 Hot-melt extrusion (HME) proces
Page 166 and 167: 2.11 X-ray photoelectron spectrosco
Page 168 and 169: Table 7.2: DSC findings of all APIs
Page 170 and 171: 3.4 In vivo and in vitro taste mask
Page 172 and 173: Fig. 7.3c: Normalised DI (%) of all
Page 174 and 175: Table 7.4: Binding energy calculati
Page 176 and 177: PRP/ polymers extruded in compariso
Page 178 and 179: atom as NH + 4 . This observed N 1s
Page 180 and 181: 8.0 ConclusionsThe presence of inte
Page 182 and 183: 20. Davies MC, Wilding IR, Short RD
Page 184 and 185: CHAPTER 8: SUSTAINED RELEASE HYDROC
Page 186 and 187: 2.3 Preparation of formulation blen
Page 188 and 189: medium pH was maintained as 1.2 by
Page 190 and 191: Fig. 8.1: SEM images of [(a), (b)]
Page 192 and 193: Fig. 8.2b: DSC transitions of HCS/E
Page 194 and 195: in the range of 10-12 kP. However,
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Page 198 and 199: Fig. 8.5c: A plot of the cubic root
Page 200 and 201: when n > 0.89. From the results of
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
Page 210 and 211: 8.2 s 6.2 s 3.8 s 1.8 s 200 msS
Page 212 and 213: 12.2 s 9.0 s 6.2 s 3.8 s 1.8 s
Page 214 and 215: Supplementary table 1: Solubility p
Page 216 and 217: N = 55000/ 219.2 = 250.912Density:
Page 218 and 219: (4) Eudragit L100, N = (125000/202
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