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

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v2d 2p(4.1)Table 4.1: Calculated solubility parameters of drug/polymersSample d(MPa 1/2 ) p(MPa 1/2 ) v(MPa 1/2 ) h(MPa 1/2 ) t(MPa 1/2 )PMOL 19.43 9.71 29.14 13.88 25.77 - -∆ DistanceR a(v)EPO 17.89 0.65 18.54 6.08 18.91 6.86 13.16VA64 18.0 0.64 18.64 7.73 19.60 6.17 12.17Ra[( ) ( )2( v)v2v1h2h12]This method was further developed by Breitkreutz [31] and Albers [32] and used inpredicting the duration of intestinal absorption for various drugs. The two–dimensionalapproach can provide more accurate prediction of the drug–polymer miscibility. The drugpolymer miscibility can be predicted by the distance (R a(v) ) using the Pythagorean Theoremand the two components are condidered miscible when R a(v) ≤5.6MPa 1/2 . In our case it isobvious from Table 4.1 that the p values of the drug – polymer combinations differsignificantly indicating an effect on the predicted miscibility. HME quite often requires theaddition of a plasticizer to lower the glass transition temperature of the polymers and thus toconduct the extrusion process at lower temperatures [6, 24] . However, plasticizers were notincorporated in our studies as both polymers present low glass transition temperatureallowing samples to be processed at low extrusion temperature ranges. The absence ofplasticizer did not affect the extrusion process.3.2. Thermal analysis and X – ray solid state characterization studiesDSC studies were performed to investigate the physical state of the drug within thepolymer matrix. As can be seen in Fig. 4.1a the DSC thermogram of pure PMOL (calibratedby the peak onset) showed a sharp melting peak at 169 o C (fusion enthalpy 33.40 J/g) with anonset of peak at 168 o C where the amorphous EPO showed an endothermic peak at 48.4 o C(onset 44.1 o C) which corresponds to the glass transition temperature (Tg).69 | P a g e
Fig. 4.1a: MTDSC thermograms of pure PMOL (inset) and Eudragit EPO, Kollidon VA64Previous studies [33–34] of pure PMOL reported the existence of three crystal forms, theForm III which is highly unstable (melting point at 148 o C), the metastable orthorhombic(Form II) with melting point at 160 o C and the stable monoclinic (Form I) with melting pointat 170 o C while the amorphous form has a glass transition at 23 o C. The polymorphic form ofPMOL that was used in the current study was the monoclinic Form I. The DSC scans of thePMOL/EPO extrudates (Fig. 4.1b) showed melting endotherms at 143.3 o C, 148.5 o C and151.5 o C, respectively that correspond to 40, 50 and 60% PMOL loadings.Fig. 4.1b: MTDSC thermograms of PMOL/EPO extrudates at different PMOL loadings.70 | 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
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 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 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
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
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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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