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

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scale or lower. XPS is more accurate and sensitive to presents precise surface analysis resultsof different type complexes compared to that of NMR and FTIR.The types of the interaction to form polymeric complexes in the solid dispersionswould normally depend on many factors such as nature of the polymer, degree ofsubstitution, polymer chain configuration and length [13] . The H-bonding would also be moreprominent in the longer side-chain polymers, where a larger number of groups are availablefor the interaction to occur. Furthermore, HME processing has been proved to facilitate drugpolymerinteractions leading to increase solubility of water insoluble drugs, taste masking ofbitter actives and stable solid dispersions.Therefore, in order to investigate the type of potential drug-polymer interactions acomprehensive study was carried out using two model cationic drugs (propranolol HCl anddiphenhydramine HCl) with with the anionic polymers, Eudragit L 100-55, Eudragit L100.The identification and understanding of this type of interactions can find ground in thedevelopment of solid dispersions in pharmaceutical industry2. Experimental sections2.1 MaterialsPropranolol HCl (PRP) and Diphenhydramine HCl (DPD) were purchased fromSigma Aldrich (Gillingham, Kent, UK). Eudragit L100 (L100) and Eudragit L100-55 (L100-55) were kindly donated by Degussa (Evonik, Germany) and Colorcon Ltd (Dartford, UK),respectively. The HPLC solvents were analytical grade and purchased from Fisher Chemicals(UK).2.2 Determination of drug-plymer miscibility by Hansen solubility parameters ()The partial solubility parameters () of PRP and DPD as well as the anionic polymerswere calculated by using Hoftyzer and Vankrevelen method [14] considering their chemicalstructural orientations in order to determine the theoretical drug/polymer miscibility. [Pleasesee Chapter 5, section 2.2 for details].2.3 Hot-melt extrusion processPrior to the extrusion process, the dry drug/polymer powders (100g) were blendedproperly in a Turbula TF2 mixer (Basel, Switzerland) for 10 minutes. The drug polymercompositions consisted of PRP/L100 and PRP/L100-55 in the ratio of 10/90 (% wt/wt).Similarly, DPD/L100 and DPD/L100-55 were used in the ratio of 10/90 (% wt/wt). Extrusion107 | P a g e
of all PRP and DPD formulations was performed using a single screw Randcastle extruder(RCP 0625, Cedar Grove, NJ) with a 0.2 mm rod die. The temperature profile from thefeeding zone to die was 100°C/150°C/150°C/160°C/155°C for all formulations with L100and L100-55 with 15 rpm screw speed. The extrudates (strands) were milled for 5 min toproduce granules using a Pulverisette 6 ball mill (Ritsch, Germany) with 400 rpm rotationalspeed. The micronized particles were then passed through a 250 µm sieve to separate out theparticles to use under this threshold.2.4 Scanning electron microscopy (SEM)SEM was used to study the surface morphology of the 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–palladium, andmicroscopy was performed using a LEO Supra 35 (Cambrdige Instruments, S360) operatingat an accelerating voltage of 5 kV.2.5 Thermal analysis by differential scanning calorimetry (DSC)A Mettler-Toledo 823e (Greifensee, Switzerland) differential scanning calorimeterwas used to carry out DSC runs of pure actives, physical mixtures and extrudates. Sealedaluminium pans were used to prepared sample. 2-5 mg of samples was prepared with aunpierced lid. The samples were heated at 10°C/min from -40 o C to 220 o C under nitrogenatmosphere.2.6 X-ray powder diffraction (XRPD)XRPD was used to determine the solid state of pure active substances, physicalmixtures and extruded materials using a Bruker D8 Advance (Germany) in two theta-theta(2) mode. For the study purposes a Cu anode at 40 kV and 40 Ma, parallel beam Goebelmirror, 0.2 mm exit slit, LynxEye Position Sensitive Detector with 3° opening (LynxIris at6.5 mm) and sample rotation at 15 rpm were used. Each sample was scanned from 2 to 40° 2with a stepsize of 0.02° 2 and a counting time of 0.1 seconds per step; 176 channels activeon the PSD making a total counting time of 35.2 seconds per step.2.7 Molecular modellingThe monomeric structures of L100, L100-55, PRP and DPD were constructed byprogram Gaussview (Frisch‘s group, Gaussian Inc. Wallington CT) [15] . Hydrogen bonding108 | 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
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 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 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
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
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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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