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

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Physical mixtures (PM) and extruded formulations (EF)PM( o C /H, Jg -1 )EF( o C /H, Jg -1 )PM( o C /H, Jg -1 )CTZ/L100 113.60 105.72/6.85 222.90/31.23CTZ/EZE 73.19 64.78/2.64 187.55/9.74VRP/L100 113.68 74.73/8.15 146.41/14.39VRP/CTZ 72.98 64.11/3.42 161.30/11.95The DSC scan of pure CTZ and VRP in Fig. 5.2a showed an endothermic peakcorresponding to its melting point at 225.6 o C (H = 104.2 J/g) and 145.9 o C (H = 106.5 J/g),respectively. Similarly, the pure polymers showed a Tg at 83.97 o C corresponding to EudragitL100-55 and 164.83 o C corresponding to Tg of L100, respectively (Fig. 5.2a).Fig. 5.2a: DSC thermograms of pure APIs and polymers.There was also a sharp melting peak present in EZE diffractogram at 59.2 o C (data notshown) which could be due to the presence of crystalline plasticizers and other ingredients inthe co-processed formulation of Acryl-EZE. Later, this melting peak was also visible inphysical mixtures (PM) of both drugs (Fig. 5.2 b-c). Eventhough, all binary physical93 | P a g e
drugs/polymers blends exhibits endothermic peaks (Fig 5.2b-c) corresponding to the initialsubstances at slightly shifted temperatures indicating the drug existence in its crystallineform, the melting peaks were absent in all extruded formulations.Fig. 5.2b: Thermograms of CTZ and VRP in L100 polymers sytems.Furthermore, the extruded formulations exhibited a broad Tg peak ranging from 64 to105 o C indicating the conversion of the originally crystalline drugs into their amorphous formsduring the HME process The range of one single Tg in the extruded formulation is in betweenthe Tgs of drugs (CTZ at 55.36 o C and VRP at 51.65 o C) and polymers. This also confirms theformation of solid dispersions of drugs into the polymer matrices [21, 26] and also thedrug/polymers miscibility. According to the Gordon Taylor equation, the miscibledrug/polymers extrudates would exibit a broad single Tg at the intermediate position of theTgs of amorphous drug and polymers [22] . Nevertheless, the characteristic peak of CTZ andVRP cannot be found in the thermograms of the extruded formulations, indicating thatextruded formulation is different in physicochemical properties from the physical mixture ofdrug/polymer. This could be attributed to the amorphous dispersion of the drugs in molecularbasis onto the polymer matrices.94 | 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
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
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 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
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
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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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