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

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Table 5.1: Sample preparation for taste masking analysisCode Type Description Drug Placebo Drug Placebo Total Final pH(%) (%) (mg) (mg) (mg) Volume(ml)AD100 Active CTZ 100 0 100 0 100 25 3.8PDA90 Placebo EZE 0 90 0 900 900 25 5.8ADA10 A. Form CTZ/EZE 10 90 100 900 1000 25 3.4PDE90 Placebo L100 0 90 0 900 900 25 3.0ADE10 A. Form CTZ/L100 10 90 100 900 1000 25 1.8AP100 Active VRP 100 0 100 0 100 25 3.3PPA90 Placebo EZE 0 90 0 900 900 25 5.8APA10 A. Form VRP/EZE 10 90 100 900 1000 25 2.6PPE90 Placebo L100 0 90 0 900 900 25 2.8APE10 A. Form VRP/L100 10 90 100 900 1000 25 1.72.9 In vitro drug release studiesIn vitro dissolution study was carried out by using a Varian 705 DS dissolution paddleapparatus (Varian Inc. North Carolina, US) at 100 rpm and 37 ± 0.5 o C. The dissolutionmedium pH was maintained as 1.2 by using 750 ml of 0.1 M hydrochloric acid for 2 hr. After2 hr operation, 150 ml of 0.20 M solution of dehydrogenate sodium ortho phosphate wasadded into the vessel to give the final pH of 6.8 that has been equilibrated to 37°C. Atpredetermined time intervals, samples were withdrawn for HPLC assay. All dissolutionstudies were performed in triplicate. The difference in the release profiles of differentformulations were investigated by calculating the similarity factor (f2) The f2 value (Eq. 1) isa logarithmic transformation of the sum-squared error of differences between the test Tj andreference products Rj over all time points (n=6).f1 50 log[{1 (nn2 0.52 ( R ) )j 1 jTj}100](5.1)89 | P a g e
2.10 HPLC analysisThe release of CTZ and VRP was determined by HPLC. An Agilent Technologiessystem equipped with a HYCROME 4889, 5 m x 150 mm x 4 mm column at 276 nm and266 nm was used for the CTZ and VRP HPLC assay, respectively. The mobile phaseconsisted of methanol/water/ triethylamine (70:30:0.25, v/v). The flow rate was 1.5 ml/minand the retention time of CTZ and VRP was about 4 minutes. The CTZ and VRP calibrationcurves (R 2 = 0.999), at concentrations varying from 10 µg/ml to 50 µg/ml, were used toevaluate all the samples with 20 µl injection volume.3.0 Results and discussion3.1 Solubility parameters and extrusion processThe theoretical approach derived from the solubility parameter suggests thatcompounds with similar values are likely to be miscible. The reason is that the energy ofmixing from intramolecular interactions is balanced with the energy of mixing fromintermolecular interactions [21, 22] . Greenlagh (1999) demonstrated that compounds with 10 MPa 1/2 were likely to beimmiscible [23] .As it can be seen in Table 5.2 the difference between the calculated solubilityparameters of the polymers and the drug indicate that both CTZ and VRP are likely to formsolid solutions with both polymers. By using the Van Krevelen/Hoftyzer the values forCTZ/L100, CTZ/ EZE, VRP/L100 and VRP/EZE are 2.07, 0.97, 3.4 and 2.3 MPa 1/2 ,respectively.Furthermore, a more advanced two dimensional approach proposed by Bagley et al.[20] was used also to predict drug – polymer miscibility as shown in Table 5.2. By using thetwo – dimensional approach Bagley et al. introduced the volume – dependent solubilityparameter, v, where v2d 2p(5.2)90 | 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
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 120 and 121: (dispersion forces and polarization
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
Page 170 and 171: 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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