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

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Nevertheless, more than 80% FMT was released from all drug/polymers formulationsafter 300min. Similar to INM the FMT/SOL granules at 40% loading showed faster dissolutionrates to the 20% loading which was attributed to the drug‘s plasticization effect.Furthermore, the difference of the release profiles of different formulations wasinvestigated by calculating the similarity factor (f2). According to the FDA guidelines, releasecurves are considered similar when the calculated f2 is 50–100 [30] . The formulation containingpure APIs differs significantly from that of the active extruded formulations as all of thecalculated f2 values fall into 10-20.07 range (Table 2.4).Table 2.4: Similarity factor (f2) for comparing release curves with respect to drug loading ofINM and FMT formulationsFormulationsDifference Factor (f2)INMFMTINM/S630 20% 18.67 -INM/VA64 20% 20.07 -INM/VA64 40% 13.48 -INM/SOL 20% 17.91 -INM/SOL 40% 12.10 -INM PURE Ref -FMT/S630 20% - 17.27FMT/VA64 20% - 12.72FMT/SOL 20% - 11.63FMT/SOL 40% - 10.09FMT PURE - Ref37 | P a g e
4.0 ConclusionsIn the current chapter HME processing was employed as a means to increase thedissolution rates of two water insoluble drugs. INM and FMT were extruded with SOL, VA64and S630 at different loadings up to 40% without the presence of traditional plasticizers. Theextrusion process was optimized to produce amorphous solid dispersions of the drug substances.Further physico-chemical characterization studies confirmed the theoretical drug – polymermiscibility for all binary mixtures as predicted by Greenhalgh and Bagley approaches. Inaddition, INM and FMT demonstrated plasticization effects and were found to be molecularlydispersed within the polymer matrices. Increased aqueous solubility was observed in both APIsmixtures with all three polymers and the extruded solid dispersions resulted in greaterdissolution rates over the bulk drugs.Therefore, through the appropriate selection of a polymeric carrier solid dispersions ofboth INM and FMT can be prepared by hot-melt extrusion to improve the dissolution propertiesof the poorly water-soluble drugs. Further work is warranted to determine whether the oralbioavailability of INM/FMT is increased for the solid dispersions with enhanced dissolutioncharacteristics.5.0 References1. Leuner C & Dressman J. Improving drug solubility for oral delivery using soliddispersions. Eur J Pharm Biopharm 2000; 50: 47–60.2. Hong SW, Lee BS, Park SJ, Jeon HR, Moon KY, Kang MH, Park SH, Choi SU, SongWH, Lee J, Choi YW. Solid dispersion formulations of megestrol acetate withcopovidone for enhanced dissolution and oral bioavailability. Arch Pharm Res 2011;34(1):127-35.3. Dittgen M, Fricke S, Gerecke H, Osterwald H. Hot spin mixing: a new technology tomanufacture solid dispersions. Pharmazie 1995; 50(3): 225–226.4. Breitenbach J. Melt extrusion: from process to drug delivery technology. Eur J PharmBiopharm 2002; 54(2): 107–117.5. Sekikawa H, Fukyda W, Takada M, Ohtani K, Arita T, Nakano M. Dissolution behaviorand gastrointestinal absorption of dicumarol from solid dispersion systems of dicumarolpolyvinylpyrrolidineand dicumarol-beta-cyclodextrin. Chem Pharm Bull 1983; 31(4):1350–1356.38 | 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
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 52 and 53: CHAPTER 2: DISSOLUTION ENHANCEMENT
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 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
Page 106 and 107: Fig. 4.2a: Powder XRPD patterns of
Page 108 and 109: Interestingly, no difference was ob
Page 110 and 111: 7 Astree sensors Taste masking effi
Page 112 and 113: The in vitro e-tongue evaluation wa
Page 114 and 115: 3. K. Woertz, C. Tissen, P. Kleineb
Page 116 and 117: 25. B.C. Hancock, P. York, R.C. Row
Page 118 and 119: 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
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26) Vandencasteele, N.; Reniers, F.
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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)]
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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
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Fig. 8.5c: A plot of the cubic root
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when n > 0.89. From the results of
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14. Lam PL, Lee KKH,Wong RSM, Cheng
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Furthermore, HME has successfully b
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Supp. Fig. 2: XPS O 1s peaks for PR
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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
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Supplementary table 1: Solubility p
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N = 55000/ 219.2 = 250.912Density:
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(4) Eudragit L100, N = (125000/202
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