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

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As a general rule, the powder compressibility decreased when the amount ofsuperdisintegrants was increased in all formulations (Table 3.2). In many cases the presenceof MCC (disintegrant nature) and mannitol (soluble diluents) has been reported to facilitatetablet disintegration. However, this was not observed in our studies as the formulationsprepared in the absence of superdisintegrants showed high disintegration times (data notshown). As a result the improved disintegration times observed in this study should not beattributed to the existence of the aforementioned excipients.Table 3.2: Physical properties of powder blends and compressed tablets (n = 3).F2 F6 F7 F10 F11 F13 F14Bulk density 29.00 35.00 36.30 33.70 37.30 38.30 42.30(g/cm 3 )Tapped 25.00 30.30 31.70 30.30 32.00 34.30 38.00density(g/cm 3 )Density 1.35 1.40 1.40 1.35 1.33 1.36 1.35(g/cm 3 )Carr‘s Index 13.8 13.40 12.60 10.10 14.20 10.44 10.16(%)Tensile 6.05 10.40 9.44 8.97 7.21 9.73 9.93strength(kP/cm 2 )Porosity 0.14 0.13 0.13 0.16 0.13 0.15 0.15As is shown in Table 3.1 superdisintegrants with concentrations varying from 5-20%,under different compaction forces, were tested to evaluate their effect on the ODTsdisintegration times. In general, the concentration of a superdisintegrant influences therelationship between the applied compaction force and the disintegration time [32] . For thepurposes of the study four different grades of crosslinked N-Vinylpyrrolidone (XL, XL10,CL, CL-SF) and sodium croscarmellose (Vivasol ® ) were evaluated. The selectedsuperdisintegrants differ in their particle size distribution, particle shape, porosity,compressibility, flowability and disintegration mechanism. The CL and CL-SF grades act as51 | P a g e
disintegrants by absorbing water and the subsequent swelling leads to separation of the tabletparticles. In contrast, XL10, XL and croscarmellose promote wicking via capillary action dueto their high porosity. Subsequently, water is rapidly absorbed and disrupts the interparticularmatrix bonds causing the tablet to fall apart [33] .The superdisintegrant concentration versus the compaction force profiles in Fig.3.4(a-d) showed interesting results regarding the disintegration time performance of eachsuperdisintegrant. At first, it can be seen that XL10 outperformed all superdisintegrants atlow levels (2-5% wt/wt) while XL outperformed at high levels (10-20% w/w) respectively.The disintegration performance can be arranged in descending order for low levels asfollows: XL10>XL>Vivasol>CL-SF>CL, while for high levels the order isXL>XL10>Vivasol>CL-SF>CL. For XL10 the optimum concentration level was between 5-10% w/w with disintegration times varying between 8-20 sec while for 20% w/wdisintegration times were increased without exceeding 60sec. On the other hand, XL‘soptimum level was at 10–20% (wt/wt) showing substantial reduction to the disintegrationtimes (Fig. 3.4C). The better performance of XL10 at low levels can be attributed to thesmaller particle size of XL10 (30-50µm) compared to XL (100-130 µm) facilitating fasterwater absorbance. On the contrary, high XL10 levels led to increased disintegration times.Vivasol showed good disintegration times at high levels (10-20% wt/wt) and betterdisintegration times at compaction forces of 10-20 kN. Interestingly the addition of KollidonCL–SF presented excellent disintegration times at concentrations of 2% w/w withcompaction forces of 8 or 12 kN. This also could be attributed to the particles morphologyfacilitatiung faster water absorptions.Further addition of CL – SF amounts led to prolonged disintegration times but muchlower than 60 sec. In contrast, the Kollidon CL grade showed poor performance for allconcentrations and the entire range of compaction forces. This behaviour can be explained tosome extent because of the small CL–SF (10-30µm) particle size compared to the CL grade(110 – 130µm) similar to the other two crosslinked N-Vinylpyrrolidone grades (XL, XL10).However, the different disintegration times of the five superdisintegrants are mainlyattributed to the different disintegration mechanisms and the tablet porosities. ThePolyplasdone (XL10, XL) and Vivasol grades posses both swelling and wicking properties.All the disintegration studies were carried out at pH 5.6, where these cross-linked polymershave similar swelling capacities (92, 90 and 85% respectively).52 | 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
Page 34 and 35: CHAPTER 1: INTRODUCTION1.0 Backgrou
Page 36 and 37: Table 1.1: HME and other convention
Page 38 and 39: homogenize but also compress the ex
Page 40 and 41: properties of polymers and excipien
Page 42 and 43: particles‘ wettability [46] . A v
Page 44 and 45: Table 1.2: Different hot-melt extru
Page 46 and 47: 1.8 Aims and objectivesThe purpose
Page 48 and 49: 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 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 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
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Table 5.4: Mean standard deviation
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Fig. 5.6b: Release profiles of VRP
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17. Woertz K,Tissen C, Kleinebudde
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scale or lower. XPS is more accurat
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patterns were identified after ener
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3.3 Differential scanning calorimet
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Fig. 6.3a: Diffractograms of PRP fo
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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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