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

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Fig. 6.6b: 1 H NMR spectra of all PRP and DPD formulations.To investigate the potential interactions found within the drug/polymer formulation,1 H NMR inverse recovery experiments were carried out to analyse spin relaxation times [31,32] . Differing relaxation rates of nuclear spins can be related to aspects of molecular structureand additionally to internal molecular motion. The rationale of these experiments was to lookat potential changes of the drugs molecular motion, before and after HME processing. Indeed,it would be assumed that the free drug (with a low molecular weight) would have quite a highmolecular motion leading to fairly high T 1 relaxation delays. After extrusion, any possibleinteractions between the drug and polymer would result in a decrease in the amount ofmolecular motion observed for the drug. T 1 relaxation times are particularly sensitive tointermediate molecular motions which result in short T 1 s. Molecules which have fast or slowmolecular motion can have comparable T 1 s (Supp. Fig. 5-8).In Table 6.4, significant changes (p>0.05) between the T 1 relaxation times for thedrugs and the drug/polymer solutions can be observed. It is expected that low molecularweight present relatively fast molecular motion in solution. The decrease in T 1 of the extrudeddrug – polymer blends indicates a slowing in the molecular motion of the compounds. Thisresult would infer that there is some type of molecular interaction between the drugs andpolymers in methanol solutions, although the proximity of the interactions cannot beelucidated.123 | P a g e
Table 6.4: A comparison of T 1 relaxation times for drug and drug/polymer solutions.SamplePropanolol HClPropanolol HCl/ Eudragit L-100Diphenhydramine HClDiphenhydramine HCl / Eudragit L-1001 H NMR T 1 range of drug protons1.0 - 3.7 seconds0.05 – 0.5 seconds1.5 – 4.3 seconds0.4 – 1.6 seconds4.0 ConclusionsHME has successfully been employed as a robust technique to form solid dispersionsof both APIs into polymer matrix through intermolecular interactions. The existence ofamorphous APIs into the polymer matrices has been confirmed by thermal analysis. TheNMR method and molecular modelling indicated the presence of intermolecular interactionsbetween drug and polymer molecules. The XPS analysis has finally confirmed themechanism of the interaction through H-bonding between the carboxyl group of the anionicmethacrylate co-polymer and the amide group of the active substances.5.0 References1) Maniruzzaman, M.; Rana, M. M.; Boateng, J. S.; Mitchell, J. C.; Douroumis, D.Dissolution enhancement of poorly water-soluble APIs processed by hot-meltextrusion using hydrophilic polymers. Drug Dev. Ind. Pharm. 2012. In press.2) Lakshman, J. P.; Cao, Y.; Kowalski, J.; Serajuddin, A.T. Application of meltextrusion in the development of a physically and chemically stable high-energyamorphous solid dispersion of a poorly water-soluble drug. Mol Pharm. 2008, 5(6),994-1002.3) Bekturov, E. A.; Bimendana, L.A. Interpolymer complexes. Adv. Polym. Sci.1981,43, 100-147.4) Tsuchida, E.; Abe, K. Interactions between macromolecules in solution andintermolecular complexes, Adv. Polym. Sci. 1982, 45, 1-119.5) Pavli, M.; Baumgartnera, S.; Kosa, P.; Kogejc, K. Doxazosin–carrageenaninteractions: A novel approach for studying drug–polymer interactions and relation tocontrolled drug release. Int. J. Pharm. 2011, 421, 110– 119.124 | 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
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v2d 2p(4.1)Table 4.1: Calculated so
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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 152 and 153: at ~533.01 eV is the combination of
Page 154 and 155: Finally, the XPS analysis confirmed
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
Page 202 and 203: 14. Lam PL, Lee KKH,Wong RSM, Cheng
Page 204 and 205: 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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