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

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2.5 Hot-melt extrusion (HME) processingDrug/polymer blends were blended in 100 g batches for 10 min each with a Turbula(TF2, Basel) mixer. The extrusion of all bathces was performed using a Randcastle singlescrewextruder (RCP0625) equipped with a 5 mm rod die at100°C/150°C/150°C/160°C/155°C (Feeder --> Die) temperature profiles and screw speeds at15 rpm. The drug-polymer composition consisted of PRP/L100, PRP/L100-55, DPD/L100and DPD/L100-55 at ratios of 10/90 wt/wt. The produced extrudates (strands) were grindedby using a Ball Milling system (Retsch, Germany) to obtain granules (< 500 µm at arotational speed of 400 rpm for 5 min.2.6 Particle morphology and size distributionSEM was used to study the surface morphology of all hot-melt extrudates. Thesamples were mounted on an aluminum stage using adhesive carbon tape and placed in a lowhumidity chamber prior to analysis. Samples were coated with gold, and microscopy wasperformed using a Leica Cambridge Instruments (S360F), SEM operating at an acceleratingvoltage of 5 kV.In order to determine the particle size distribution of the micronized extrudategranules a dry sieving method was applied. The method involved stacking of the sieves ontop of each other and then placing the test powder (100 g) on the top sieve. The nest of sieveswas subjected to a standardised period of agitation (20 min) in order to give the weightpercentage of powder in each sieve size range.2.7 In vivo taste masking evaluationIn vivo taste masking evaluation for pure APIs, polymers and all active extrudedformulations was performed in accordance to the Code of Ethics of the World MedicalAssociation (Declaration of Helsinki) [28] . Six (6) healthy volunteers of either sex (age 18–25)were selected (Male = 3, female = 3) from whom informed consent was first obtained(approved by the Ethics Committee of the University of Greenwich, Ref: UG09/10.5.5.12)and trained. The equivalent of 100 mg of pure DPD, PRP or DPD/PRP extrudates (containingequal amounts of APIs) were held in the mouth for 60 seconds and then spat out. Theselection of samples was random and in between of two samples analysis mineral water wasused to wash each volunteer‘s mouth. The bitterness was recorded immediately according to131 | P a g e
the bitterness intensity scale from 1 to 5 where 1, 2, 3, 4 and 5 indicate none, threshold,moderate, bitter and strong bitterness.2.8 In vitro taste masking evaluation: TS-5000Z sensing systemThe assays were realized on TS-5000Z taste sensing system equipped with a BASICsensor set (for pharmaceutical analysis) which are suitable for basic APIs composed of 10specific sensors (AAE, CT0, CA0, C00, AE1, AC0, AN0, BT0, GL1 ) on a 48-positionsautosampler using 25 ml beakers. Acquisition times were fixed at 120s with a BT0 negativelycharged sensor. All the data generated on TS-5000Z system were treated usingmultidimensional statistics. Each solution was tested on TS-5000Z at least 4 times andtriplicates were taken into account for the statistical treatment. Sensors were then cleaned upin references solutions (30 mM KCl + 0.3 mM tartaric acid) between each samplemeasurement. The samples were dissolved in 50 mL of 10 mM KCl aq. solutions and furtherdiluted to prepare 0.03, 0.1, 0.3, and 1 mM solutions as standards. Then solutions werefiltered with Buchner funnel fitted with filter paper at 2.5 µm pore size.2.9 Molecular modellingThe monomer of L100, dimer of L100-55, PRP and DPD were constructed byprogram Gaussview [29] . Hydrogen bonding patterns were identified by placing the drugmolecule within the proximity of the L100 and L100-55, respectively and thenenergy optimised at the B3LYP/6-31G* level using Gaussian09 [30] . Based on these optimisedconfigurations of drug-polymer interactions, the binding energy was calculated using E binding =-[E complex -(E drug +E polymer )] with each energy term obtained at the M06-2x/6-31G** level [31]after single point calculations. A counterpoise procedure [32] was employed to correct for theeffect of basis set superposition error (BSSE). In all of the drug/polymers combinationsprimarily two different H bonding were detected with the donor-acceptor distance at ~2 Å.All possible H bondings were shown in dash line in Table 4.2.10 Fourier Transform Infra-Red (FT-IR) analysisFTIR analysis was performed on the drug, polymer, drug_/polymer physical mixtures,and complex using Perkin Elmer PE1600 (Massachusetts 02451USA) Fourier Transform Infrared Spectra according to the KBr disc method from 400 – 3600wavelength/cm -1 range.132 | 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
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Fig. 4.2a: Powder XRPD patterns of
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Interestingly, no difference was ob
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7 Astree sensors Taste masking effi
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The in vitro e-tongue evaluation wa
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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
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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
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Page 140 and 141: scale or lower. XPS is more accurat
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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
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Page 154 and 155: Finally, the XPS analysis confirmed
Page 156 and 157: Fig. 6.6b: 1 H NMR spectra of all P
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Page 160 and 161: 26) Vandencasteele, N.; Reniers, F.
Page 162 and 163: Gibbs free energy change before and
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,
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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
Page 206 and 207: Supp. Fig. 2: XPS O 1s peaks for PR
Page 208 and 209: Supp. Fig. 4: O 1s BE peaks for L10
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Page 212 and 213: 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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