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

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2.11 X-ray photoelectron spectroscopy (XPS) analysisX-ray photoelectron spectra (XPS) were measured on a Kratos Axis Ultra-DLD usinga monochromatic Al K X-ray source (120 W) and an analyser pass energy of 160 eV (surveyscans) or 20 eV (high resolution scans); the pressure during analysis was 1×10 -9 Torr. Alldata were referenced to the C(1s) signal at 285.0 eV attributable to unsaturated C-C/C-Hbonds [33] . Quantification and curve fitting was performed in CasaXPS TM (Version 2.3.15)using elemental sensitivity factors supplied by the manufacturer.3.0 Results and discussions3.1 Predictions of drug/polymer miscibility: solubility parametersThe calculated solubility parameters of APIs and polymers are shown in Table 7.1.The difference between the calculated solubility parameters of the polymers and the drugindicate that both PRP and DPD are likely to be miscible with both polymers since thedifference of the calculated solubility parameters are not more than 7MPa 1/2 .Table 7.1: Solubility parameters calculations summery for both drugs and polymersComp.p d h v ∆ ∆(MPa 1/2 ) (MPa 1/2 ) (MPa 1/2 ) (MPa 1/2 ) (MPa 1/2 ) PRP DPDR a(v)PRPR a(v)DPD(MPa 1/2 )(MPa 1/2 )PRP 3.67 19.30 9.90 19.64 21.94 - - - -DPD 4.05 16.39 5.44 16.89 17.75 - - - -L100 0.41 19.31 12.03 19.31 22.75 0.81 5.0 3.26 4.67L100-55 0.25 18.22 11.69 18.22 21.65 0.29 3.9 3.59 4.22Rav22(v2 v1) (h2h1)Being slightly diverted from the Van-Krevelen equation, Bagley proposed a moreadvanced two dimensional equation to predict the drug-polymers miscibility known asBagley equation [27] .The two – dimensional approach can provide more accurate prediction of the drug –polymer miscibility by calculating the distance (R a(v) ) in Bagley diagram using the133 | P a g e
Pythagorean Theorem. In this theory two components are considered miscible when R a(v)≤5.6MPa 1/2 [26] .3.2 Flory Huggins (F-H) theory for the prediction of drug/polymers interactionparameterIn order to determine the F-H interaction parameter between both drugs and polymersthe heat of fusion of crystalline PRP and DPD as well as the Tg of both polymers and meltingpeaks of APIs (Table 2) were determined by DSC experiments. In the DSC thermograms thepure PRP and DPD showed a sharp melting peak at 166.65 o C and 170.83 o C, respectivelywith a net heat of fusion / enthalpy (H) values of 126.25 J/g and 124.59 J/g, respectively.The Tg observed for both polymers are at 164.38 o C for L100 and 83.97 o C for L100-55 (AcrylEZE).Molecular volumes of the two different polymers L100 and L100-55 as well as activesubstances were estimated from functional group contribution. As shown in Table 7.2 themolecular volumes of PRP and DPD are 269.96 cm 3 and 284.24 cm 3 , respectively. Byimplementing both the Eqs. 7.1 & 7.2, the average value of is calculated as shown in Table7.3.In this case, since the drug content is essentially low (, Drug = 10%), the accuratedetermination of the onset point of the melting endothermic peak became difficult. However,accurate interaction parameter by using F-H theory has successfully been implemented in ourstudy as the interaction parameter depends on multiple factors such as crystalline meltingtemperature of APIs, Tg of polymers, molecular volumes and degree of polymerisations etcwhich have successfully been determined from the thermal analysis of drug-polymer binarymixtures. The negative interaction parameter in Table 7.3 indicates that there is a netattraction force between species in a binary mixture which is favourable for all compositionsat observed melting temperature of both APIs and also same for the Tg‘s of both polymers[34] . Therefore the higher the absolute value of , the stronger the interactions betweendrug/polymers species. In Table 7.3, it can be seen that L100 facilitates stronger interactionswith both the drugs compared to those of L100-55. To make the case stronger thisobservation was confirmed by both approaches (Nishi-Wang and Hildebrand-Scott).134 | 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
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6. Caron V, Tajber L, Corrigan OI,
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CHAPTER 3: DEVELOPMENT AND EVALUATI
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2.2 Hot-Melt extrusionHot-melt extr
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Committee of the University of Gree
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The PM of formulation II (40% IBU)
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Fig. 3.3: DSC thermograms of pure I
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As a general rule, the powder compr
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Fig. 3.4: Schematic diagram of ODT
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Fig. 3.5: Schematic diagram of ODTs
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Fig. 3.7: Schematic diagram of ODTs
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F2 0 0.5 0 1 0 1F6 0 0.5 0 1 0 2F7
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6. M.F. Al-Omran, S.A. Al-Suwayeh,
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30. L. Saerens, L. Dierickx, B. Len
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leading to significant variations w
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2.6. In vitro drug release studiesI
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v2d 2p(4.1)Table 4.1: Calculated so
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The observed melting peaks are shif
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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
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
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 168 and 169: Table 7.2: DSC findings of all APIs
Page 170 and 171: 3.4 In vivo and in vitro taste mask
Page 172 and 173: Fig. 7.3c: Normalised DI (%) of all
Page 174 and 175: Table 7.4: Binding energy calculati
Page 176 and 177: PRP/ polymers extruded in compariso
Page 178 and 179: atom as NH + 4 . This observed N 1s
Page 180 and 181: 8.0 ConclusionsThe presence of inte
Page 182 and 183: 20. Davies MC, Wilding IR, Short RD
Page 184 and 185: CHAPTER 8: SUSTAINED RELEASE HYDROC
Page 186 and 187: 2.3 Preparation of formulation blen
Page 188 and 189: medium pH was maintained as 1.2 by
Page 190 and 191: Fig. 8.1: SEM images of [(a), (b)]
Page 192 and 193: Fig. 8.2b: DSC transitions of HCS/E
Page 194 and 195: in the range of 10-12 kP. However,
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Page 198 and 199: Fig. 8.5c: A plot of the cubic root
Page 200 and 201: when n > 0.89. From the results of
Page 202 and 203: 14. Lam PL, Lee KKH,Wong RSM, Cheng
Page 204 and 205: Furthermore, HME has successfully b
Page 206 and 207: Supp. Fig. 2: XPS O 1s peaks for PR
Page 208 and 209: Supp. Fig. 4: O 1s BE peaks for L10
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Page 212 and 213: 12.2 s 9.0 s 6.2 s 3.8 s 1.8 s
Page 214 and 215: 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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