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

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2.6. In vitro drug release studiesIn vitro drug release studies were carried out in 750 ml of 0.1 M hydrochloric acid for2 hr using a Varian 705 DS dissolution paddle apparatus (Varian Inc. North Carolina, US) at100 rpm and 37 ± 0.5 o C. After 2 hr operation, 250 ml of 0.20 M solution of trisodiumphosphate dodecahydrate were added into the vessel (buffer stage, pH 6.8) that has beenequilibrated to 37°C. At predetermined time intervals samples were withdrawn for HPLCassay. All dissolution studies were performed in triplicate.2.7. HPLC analysisThe release of PMOL was determined by HPLC. An Agilent Technologies systemequipped with a HICROM S50DS2, 5 m x 150 mm x 4 mm column at 276 nm was used forthe PMOL HPLC assay. The mobile phase consisted of acetonitrile/water (1% acetic acid)(50:50, v/v). The flow rate was 1.5 ml/min and the retention time of PMOL was 3.6 minutes.The PMOL calibration curves (R 2 =0.999), at concentrations varying from 10 µg/ml to 50µg/ml, were used to evaluate all the samples with 20µl injection volume.2.8. In vivo taste masking evaluationIn vivo taste masking evaluation was performed on 6 healthy human volunteers[22, 23]from whom informed consent was first obtained (approved by the Ethics Committee of theUniversity of Greenwich, Ref No: UG09/10.5.5.12). The study is also in accordance to theCode of Ethics of the World Medical Association (Declaration of Helsinki). The healthyvolunteers of either sex (3 males and 3 females, age 18–25) were selected, trained and theextruded granules were evaluated (no exclusion criteria). The equivalent of 200 mg of purePMOL or PMOL extrudates (containing equal amounts of PMOL) were held in the mouth for60 seconds and then spat out. The selection of samples was random and in between twosamples analysis mineral water was used to wash each volunteer‘s mouth. The bitterness wasrecorded immediately according to the bitterness intensity scale from 0 to 5 where 0, 1, 2, 3,4and 5 indicate none, threshold, slight, moderate, bitter and strong bitterness, respectively.2.9. In vitro taste masking evaluation: Astree e-tongueThe assays were realized on Astree e-tongue system equipped with an Alpha M.O.S.sensor set #2 (for pharmaceutical analysis) composed of 7 set of sensors (ZZ, AB, BA, BB,CA, DA, JE) on a 48-positions autosampler using 25 ml-beakers. Acquisition times werefixed at 120s. All the data generated on the Astree system were processed using67 | P a g e
multidimensional statistics on AlphaSoft V12.3 software. Each sample (granules) was testedon the Astree e-tongue at least 4 times with three replicates for each sample for the statisticalanalysis. The average values between 100 and 120 s were used to build the maps. Astreesensors were cleaned up in deionised water between each sample measurement. Each samplewas diluted for 60 seconds under magnetic stirring in 25 ml of deionised water to reach APIconcentration corresponding to a final PMOL dose of 200 mg. The mixtures were filteredwith Buchner funnel fitted with filter paper of 2.5 µm pore size.3.0 Results and Discussion3.1. Solubility parameters and extrusion processThe PMOL miscibility with EPO and VA64 was investigated prior to extrusion byestimating the Hansen solubility parameter using the method of Hoftyzer and van Krevelenfor pure PMOL and both polymers. The prediction of drug/polymers miscibility in soliddispersions has successfully been achieved by the solubility parameters () [24-27] . Thismiscibility is caused by balancing the energy of mixing released by inter-molecularinteractions between the components by the energy released by intra molecular interactionswithin the components [21] . Three dimensional partial solubility parameters by Hansen (1969)calculated by group contributions of dispersion forces, polar forces and hydrogen bondingforces was provided byVan Krevelen/Hoftyzer (1976) and Fedors (1974). The theoreticalapproach of the solubility parameter suggests that compounds with similar values are likelyto be miscible. The reason is that the energy of mixing from intramolecular interactions isbalanced with the energy of mixing from intermolecular interactions. It was demonstratedthat compounds with < 7 MPa 1/2 were likely to be miscible and compounds with > 10MPa 1/2 were likely to be immiscible [28] . Thus, solubility parameters provide a simple andgeneric capability for rational selection of carriers in the preparation of solid dispersions [29] .As can be seen in Table 4.1, the difference between the calculated solubility parameters ofthe polymers and the drug indicate that PMOL is likely miscible with both polymers. Byusing the Van Krevelen/Hoftyzer the values for PMOL and EPO/VA64 are 6.86 and 6.17respectively.However, a two dimensional approach proposed by Bagley et al. [30] was used also topredict drug – polymer miscibility as shown in Table 4.1. By using the two – dimensionalapproach Bagley et al. observed that p and d have similar thermodynamic effects in contrastto h and introduced the volume – dependent solubility parameter, v, where68 | 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
Page 50 and 51: 56. International Conference on Har
Page 52 and 53: CHAPTER 2: DISSOLUTION ENHANCEMENT
Page 54 and 55: Fdid ,Vi F2pip , p( Ehi/ ViVi )i =
Page 56 and 57: used. Each sample was scanned from
Page 58 and 59: Furthermore, by means of thermodyna
Page 60 and 61: 3.2 Particle size morphology and pa
Page 62 and 63: Fig. 2.4a: Diffractograms of INM fo
Page 64 and 65: However, the DSC thermograms of the
Page 66 and 67: Fig. 2.5b: DSC thermograms of INM a
Page 68 and 69: 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 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 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
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Since L100 contained higher proport
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at ~533.01 eV is the combination of
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Finally, the XPS analysis confirmed
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Fig. 6.6b: 1 H NMR spectra of all P
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6) Bonferoni, M.C.; Rossi, S.; Ferr
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26) Vandencasteele, N.; Reniers, F.
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Gibbs free energy change before and
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2.5 Hot-melt extrusion (HME) proces
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2.11 X-ray photoelectron spectrosco
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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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