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

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at ~533.01 eV is the combination of C-O/-O-O bonds from polymer/drug and represents C-O-O-C or C(O)-O-O bonds [27, 28] .The N (1s) binding energy (BE) of ~402.035 eV (Fig.6.5d) in PRP suggests theprotonation of the NH + group while Cl (2p) energy of ~198.035 eV significantly supports thatconclusion [26] . The N (1s) energy of ~402.8 eV in PRP/L100 extrudates represents further+protonation effect of N atom as NH 4 which is described by the equation (ii) below. The N(1s) binding energy (BE) of ~402.6 eV (Fig. 5d) in DPD suggests similar effect in relation tothe protonation of the NH + group while the slightly reduced Cl (2p) energy of ~197.495 eVcompared to pure PRP also significantly supports the statement.N-H+ NH 4 + / NH 2 + (next to electron withdrawing group) ...................... (ii)The N 1s peak at BE= ~402.80 eV is in good agreement with the previously observedprotonation of amide group by Beamson and Briggs [16] . The BE peak at ~402.80 eV (higher+than typically observed for amines BE= ~399 eV - 400.5 eV and much more for –NH 2+group) for N1s is an indication of C-O-NH 2 structure whereas the O atom peak at ~534.40eV shows the same [16] . These results strongly indicate an interaction between the amidegroup of the API and ester/carboxyl group of the polymer (L100) through the available H-interactions or hydrogen bridges (Fig. 6.5d).Fig. 6.5d: N 1s peaks of PRP and DPD formulations.119 | P a g e
N 1s peaks from PRP/L100-55 and DPD/L100-55 also complement the observationsfrom PRP/L100 and DPD/L100 formulations. The N (1s) energy of ~402.9 eV in DPD/L100formulation represents a positive shift of the peak position to the right by +0.40 eV. This isdue to the additional protonation effect of N atom converted to NH + 4 . The N 1s peak at BE=~402.90 eV suggests protonation of the amide group as observed for the PRP/L100+formulation. The BE peak at ~402.90 eV for N1s is an indication of C-O-NH 2 structure withlonger peak shift than that of PRP/L100. As before, we concluded that a strong interactionbetween the amide group of API and ester/carboxyl group of polymer through the availableH-interactions has taken place.The protonation effects of N 1s in the extruded formulations were significant andshowed high peak shifts which are summarised in Table 6.2. From the binding energyassignments determined by XPS it is presumed that the higher the peak shifts the moresignificant the protonation [29] , therefore stronger intermolecular interactions.Table 6.2: N 1s peak shifts in all extruded formulations with both drugsPRP FormulationsDPD FormulationsForm.Peak PositionNet shiftForm.Peak PositionNet shift(eV)( eV)(eV)( eV)PRP Pure ~ 402.04 - DPD Pure ~ 402.5 -PRP/L100 ~ 402.80 + 0.76 DPD/L100 ~ 402.9 + 0.40PRP/L100-55 ~ 402.47 + 0.43 DPD/L100-55 ~ 402.77 + 0.27From Table 6.2 it is obvious that the peak shifts of N 1s in PRP/L100 arehigher compared to the other formulations demonstrating the a high protonation effect andthus stronger drug – polymer interaction. The ascending order of the protonation effects inthe extudates is PRP/L100>PRP/L100-55>DPD/L100>DPD/L100-55. Therefore, eventhough both drugs were found molecularly dispersed through DSC studies the XPS analysisshowed different magnitude of interactions even with counterpart polymer grades. The XPSobservations demonstrate a direct relation of the drug – polymer miscibility andintermolecular interactions.120 | 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
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 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 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,
Page 196 and 197: ate and time on the basis of Eq. (8
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
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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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