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

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The observed melting peaks are shifted to lower temperatures and the peak shapes arebroader compared to those of pure PMOL suggesting the presence of crystalline PMOL. Theobserved melting peak of PMOL occurred between 143–152 o C which is due to the presenceof Form I PMOL in the polymer matrix. However, the shifts of the melting endothermicpeaks can also be attributed to possible PMOL–EPO interactions without any changes in thecrystal modifications. The presence of Form I was confirmed by the X–ray characterizationstudies as described below. If the PMOL/EPO components are miscible the Tg of theextruded samples can be derived by the Gordon – Taylor equation [35] and it will show asingle Tg that varies between the Tg of the pure components. The EPO glass transitiontemperatures for the PMOL loaded samples (30-60%) are shifted at lower temperatures(45.9 o C, 44.1 o C, 41.7 o C) and are slightly different from the estimated Gordon – Taylortheoretical values at 36.0 o C, 33.7 o C, 31.6 o C respectively. In addition, only a single Tg wasobserved for all PMOL/EPO ratios while the Tgs decreased with increase in PMOLconcentrations showing partial drug – polymer miscibility and PMOL plasticization effect. Intotal, the shifts of the melting PMOL peaks and EPO glass transition temperatures suggest theco–existence of molecularly dispersed and crystalline PMOL within the polymer matrix.Similar observations were reported by Qi et al. [36] for PMOL/EPO extrudates where PMOLwas presented in two physical forms simultaneously. The calculated amorphous/crystallinitydegrees [37] of the extruded formulations are shown in Table 4.2. It is obvious that thepresence of crystalline PMOL is increased with the PMOL loading in each formulation.Table 4.2: Crystalline/amorphous percentage of the extruded PMOL formulationsFormulationAmorphousCrystallineTgTm(%)(%)( o C)( o C)PMOL/EPO 40% 79.5 20.5 45.9 143.3PMOL/EPO 50% 75.5 24.5 44.1 148.5PMOL/EPO 60% 52.0 48.0 41.7 151.5PMOL/VA64 30% 100.0 - 85.8 -PMOL/VA64 40% 100.0 - 95.2 -PMOL/VA64 50% 100.0 - 93.5 -Tg: polymer glass transition, Tm: PMOL melting pointIn contrast, the PMOL/VA64 extrudates showed two Tg peaks, one close to the Tg ofbulk VA64 (105 o C) and the other between 27 – 42 o C depending on the PMOL loadings. Pure71 | P a g e
VA64 showed a baseline shift at 105 o C which is reported as Tg and there is anotherendothermic peak visible at about 200 o C which correspond to decomposition of the polymer.As Fig. 4.1c shows the low temperature Tg is related to the PMOL loading with descendingorder of PMOL (30%)>PMOL (40%)>PMOL (50%) (41.1 o C, 37.7 o C, 27.6 o C) and areelevated at higher temperature in comparison to amorphous PMOL Tg (25 o C). Thetransformation of PMOL from Form I to amorphous is supported by the disappearance of themelting endothermic peak at 169 o C. As a result we could rule out the presence of molecularlydispersed PMOL within the VA64 matrix which can be recognised by the presence of onesingle mixed–phase Tg. In our case, the two consecutive glass transitions indicate thepresence of amorphous mixtures and an amorphous/amorphous phase separation. Thisobservation is not unusual as similar results have been observed for itraconazole/EPO100solid dispersions [38] .Fig. 4.1c: MTDSC thermograms of PMOL/VA64 extrudates at different PMOL loadings.XRPD was employed to investigate the crystalline state of PMOL within the polymermatrices. The standard XRPD patterns of pure PMOL, physical mixtures with EudragitEPO, and extrudates are depicted in Fig. 4.2a.72 | 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
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 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
Page 120 and 121: (dispersion forces and polarization
Page 122 and 123: Table 5.1: Sample preparation for t
Page 124 and 125: Table 5.2: Solubility parameters ca
Page 126 and 127: Physical mixtures (PM) and extruded
Page 128 and 129: Fig. 5.2c: Thermograms of CTZ and V
Page 130 and 131: masking effect for active concentra
Page 132 and 133: Fig. 5.5b: Distance and discriminat
Page 134 and 135: Table 5.4: Mean standard deviation
Page 136 and 137: Fig. 5.6b: Release profiles of VRP
Page 138 and 139: 17. Woertz K,Tissen C, Kleinebudde
Page 140 and 141: scale or lower. XPS is more accurat
Page 142 and 143: patterns were identified after ener
Page 144 and 145: 3.3 Differential scanning calorimet
Page 146 and 147: Fig. 6.3a: Diffractograms of PRP fo
Page 148 and 149: good agreement with the anticipated
Page 150 and 151: Since L100 contained higher proport
Page 152 and 153: 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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