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

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patterns were identified after energy optimisation at the B3LYP 6-31G* level using Gaussian09. In all of the drug/polymers combinations primarily two different H bonding were detectedwith up to 2 °A distance. All possible H bondings were shown in dash line in theconstructed figures.2.8 X-ray photoelectron spectroscopy (XPS) analysisX-ray photoelectron spectra (XPS) were measured on a Kratos Axis Ultra-DLD usinga monochromatic Al K X-ray source (120 W) and an analyser pass energy of 160 eV (surveyscans) or 20 eV (high resolution scans); the pressure during analysis was 1×10 -9 Torr. Alldata were referenced to the C (1s) signal at 285.0 eV attributable to unsaturated C-C/C-Hbonds [16] . Quantification and curve fitting was performed in CasaXPS TM (Version 2.3.15)using elemental sensitivity factors supplied by the manufacturer.2.9 Nuclear magnetic resonance (NMR) studiesNMR spectra were recorded on a Jeol ECA 500 NMR spectrometer, incorporating a5mm inverse probe (The 1 H operating frequency was 500 MHz). 1 H NMR spectra of thedrugs, polymers and drug/polymer formulations were recorded using the standard Jeol pulsesequence. All samples were dissolved in CD 3 OD, degassed and then maintained at 25 o Cduring data acquisition. Samples were referenced with respect to the solvent. The solutionconcentration of the drugs was 2 mg/ml, the polymer was18mg/ml, and the drug/polymerformulation was 20 mg/ml (the overall drug content in the formulations was 10%).1 H T 1relaxation experiments were recorded for all samples using a standard inverse recoveryexperiment. Recovery delays () were investigated between 10 ms and 20 s. The relaxationdelay was set to be > 5T 1. T 1 s were calculated from curve fitting, peak intensities, obtainedfrom the spectra recorded for different recovery delays. Jeol, curve fitting software wasutilised during this process.3. Results and discussion3.1 Determination of drug-polymer miscibility by Hansen solubility parameters ()To predict the miscibility of the active substances and the polymeric carriers theHansen solubility parameter was used [14, 17, 18] . According to the Vankrevelen/ Hoftyzerequation the calculated solubility parameters for PRP and DPD are 21.94 MPa 1/2 and 17.75MPa 1/2 , respectively whereas the solubility parameters for L100 and L100-55 are 22.75MPa 1/2and 21.65 MPa 1/2 , respectively. Since the determined difference in solubility109 | P a g e
parameters between each drug and polymer are less than 7MPa 1/2 (about 0-5 MPa 1/2 ), bothpolymers are likely to be miscible with both of the APIs [19] . Thus, miscibility studies bysolubility parameters provide a simple and generic approach for rational selection of carriersin the preparation of solid dispersions through the intermolecular interactions. In the miscibledrug-polymers based solid dispersions cationic active substances (PRP, DPD) can interactwith the functional groups of the negatively charged polymers. These interactions facilitatethe creation of hydrogen bonding between the active amide group of the APIs and carboxylicgroup of the polymers and consequently mask the API‘s bitter taste [20] .3.2 Scanning electron microscopy (SEM)SEM was used to examine the surface morphology of the drug and extrudates. Theextrudates containing L100 and L100-55 exhibited no drug crystals on the extrudate surfacewith PRP (Fig. 6.1). Similarly, no DPD crystals were observed on the surface of polymericextrudates in all drug/ polymers extrudates, indicating that DPD is also high miscible withboth anionic methacrylate co-polymers. Thus, the SEM observations were also quite sensitiveto elucidate the presence of drug/polymer miscibility by complementing DSC and XRPDinvestigations.Fig. 6.1: SEM images of (a) PRP/L100 (Magnification x 2000), (b) PRP/L100-55(Magnification x 10K), (c) DPD/L100 (Magnification x 500) and (d) DPD/L100-55(magnification x 10K) extruded formulations.110 | 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
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 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 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
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)]
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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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