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Furthermore, by means of thermodynamic considerations Bagley et al. [24] concluded thatthe effects of d and p show close similarity and so introduced the combined solubilityparameter v , wherev2d 2p(2.3)The parameter for components of intermolecular hydrogen bonding h and the combinedparameter v are plotted in a diagram to project the three-dimensional solubility parameter spaceinto a two-dimensional plot which is called Bagley diagram (Fig. 2.1).Fig. 2.1: Location of polymers (open symbols) and APIs (closed symbols) within the Bagleyplot.The two – dimensional approach through plotting the Bagley diagram can provide moreaccurate prediction of the drug – polymer miscibility. The drug polymer miscibility can bepredicted by the distance (R a(v) ) using the Pythagorean theorem in the Bagley diagram and thetwo components are likely to be miscible when R a(v) ≤5.6MPa 0.5 [28] . WhereRa[( ) ( 2( v)v2v1h2h1)2](2.4)Only small differences can be observed for FMT and INM and all three polymers wherethe R a(v) values are less than 5.6MPa 0.5 suggesting again drug – polymer miscibility for eachformulation (Table 2.2). The estimated R a(v) value for the FMT/VA64 is 5.87 MPa 0.5 suggesting25 | P a g e
immiscibility of the two components. However, the difference from the value given by Albers(2008) is marginal and the components were considered miscible.Table 2.2: Calculated solubility parameters of drug/polymers and compound distances in Bagleydiagram.Sampled(MPa 0.5 )p(MPa 0.5 )v(MPa 0.5 )h(MPa 0.5 ) average(MPa 0.5 )∆ (INM)(MPa 0.5 )∆ (FMT)(MPa 0.5 )Ra(v)INM(MPa 0.5 )Ra(v)FMT(MPa 0.5 )INM 18.99 7.37 20.34 10.34 22.84 - - - -FMT 11.93 15.00 19.17 13.49 23.44 - - - -VA64 18.0 0.64 18.01 7.73 19.60 3.24 3.84 3.49 5.87SOL 15.14 0.45 15.15 12.18 19.43 3.41 3.99 5.54 4.23S630 13.0 8.80 15.70 9.17 18.18 4.66 5.26 4.79 5.54Nevertheless, both approaches confirmed the miscibility of the binary mixtures for allformulations. It is worth mentioning that the manufacturing of solid dispersions via HMEdepends also on the processing parameters such as temperature profile and screw rotation speedwhich are not taken into account in the estimated solubility parameters by Van Kreveln/Hoftyzeror Bagley. Thus, further process optimization is required for the manufacturing of soliddispersions in order to increase drug solubility.As can be seen in Table 1, no plasticizer was incorporated in the binary mixtures due tolow glass transition temperatures of the selected polymers. All formulations were easily extrudedat temperatures around 120 o C even at high drug loadings.[Please see supplementary chapter 10, section 10.2 for examples of the calculation ofsolubility parameters of different drug and polymers by using Van Krevelen/ Hoftyzer equation]26 | P a g e
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DECLARATION“I certify that this w
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taste masking effect of the process
Page 8 and 9: CHAPTER 2: DISSOLUTION ENHANCEMENT
Page 10 and 11: 3.2 Powder and ODT characterization
Page 12 and 13: 3.7 In vitro drug release profiles
Page 15: 3.1 Solubility parameters and extru
Page 18 and 19: polymers.7.2 DSC findings of all AP
Page 20 and 21: 2.4b Diffractograms of FMT formulat
Page 22 and 23: 4.3 Schematic representation of the
Page 24 and 25: 55 exrudates (b) DPD/L100-55 PM (c)
Page 26 and 27: 8.5d A plot of the logarithm of HCS
Page 28 and 29: L100Eudragit L100L100-55 Eudragit L
Page 30 and 31: Maniruzzaman M, Rai D, Boateng JS.
Page 32 and 33: 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 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 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
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Interestingly, no difference was ob
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7 Astree sensors Taste masking effi
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The in vitro e-tongue evaluation wa
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3. K. Woertz, C. Tissen, P. Kleineb
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25. B.C. Hancock, P. York, R.C. Row
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CHAPTER 5: AN IN VIVO AND IN VITRO
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(dispersion forces and polarization
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Table 5.1: Sample preparation for t
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Table 5.2: Solubility parameters ca
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Physical mixtures (PM) and extruded
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Fig. 5.2c: Thermograms of CTZ and V
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masking effect for active concentra
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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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