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

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(dispersion forces and polarization forces) derived from Bragley equation. [Please seeChapter 4, Section 2.2 for details].2.3 Preparation of formulation blends and hot-melt extrusion (HME) processingCTZ and VRP formulations with L100 and EZE to be extruded were mixed properlyin 100 g batches for 10 min each. A Turbula (TF2, Basel) mixer was used to blend thepowder formulations. The drug-polymers composition consisted of CTZ/L100, CTZ/EZE,VRP/L100 and VRP/EZE at a ratio of 10/90 wt/wt. Extrusion of all CTZ and VRPformulations were performed using a Randcastle single-screw extruder (RCP0625) equippedwith a 5 mm rod die in 100°C/150°C/150°C/160°C/155°C (Feeder Die) temperatureprofiles. The screw speed maintained for all extrusion was 15rpm. The produced extrudates(strands) were grinded by using a ball milling system to obtain granules (
otation at 15rpm. The sample was scanned from 2 to 40 degrees 2-theta with a step size of0.02 degrees 2-theta and a counting time of 0.2 seconds per step; 176 channels active on thePSD making a total counting time of 35.2 seconds per step.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). 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 CTZ, VRP or CTZ/VRP 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 tothe 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: Astree E-TongueThe assays were realized on an Astree e-tongue system equipped with an AlphaM.O.S. sensor set #2 (for pharmaceutical analysis) composed of 7 specific sensors (ZZ, AB,BA, BB, CA, DA, JE) on a 48-positions autosampler using 25 ml beakers. Acquisition timeswere fixed at 120 s. All the data generated on Astree system were treated usingmultidimensional statistics on AlphaSoft V12.3 software. Each solution was tested on Astreee-tongue at least 4 times. 3 replicates were taken into account for the statistical treatment. Theaverage values between 100 and 120 s were used to build the maps. Astree sensors werecleaned up in deionised water between each sample measurement.2.8.1 Sample preparation for Astree e-tongueIn vitro taste masking evaluation was carried out with an Astree e-tongue equippedwith 7 different sensor sets. To be as close as to the panellists taste‘s conditions, each drugwas diluted for 60s under magnetic stirring in 25 ml of deionised water to reach APIconcentration corresponding to a final dose of 100 mg. Then solutions were filtered withBuchner funnel fitted with filter paper at 2.5µm pore size (Table 5.1). One single analysiswas done for each API.88 | 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
Page 70 and 71: Nevertheless, more than 80% FMT was
Page 72 and 73: 6. Caron V, Tajber L, Corrigan OI,
Page 74 and 75: CHAPTER 3: DEVELOPMENT AND EVALUATI
Page 76 and 77: 2.2 Hot-Melt extrusionHot-melt extr
Page 78 and 79: Committee of the University of Gree
Page 80 and 81: The PM of formulation II (40% IBU)
Page 82 and 83: Fig. 3.3: DSC thermograms of pure I
Page 84 and 85: As a general rule, the powder compr
Page 86 and 87: Fig. 3.4: Schematic diagram of ODT
Page 88 and 89: 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 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 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
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3.4 In vivo and in vitro taste mask
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Fig. 7.3c: Normalised DI (%) of all
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Table 7.4: Binding energy calculati
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PRP/ polymers extruded in compariso
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atom as NH + 4 . This observed N 1s
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8.0 ConclusionsThe presence of inte
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20. Davies MC, Wilding IR, Short RD
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CHAPTER 8: SUSTAINED RELEASE HYDROC
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2.3 Preparation of formulation blen
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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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