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

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Fig. 7.3c: Normalised DI (%) of all drug/L100-55 formulations in four different time scale.The taste graph shows significant discrimination between all active formulations andactive substance solutions (Fig. 7.3c). The bitter taste of DPD has successfully been maskedup to 35% (DI 65%) while for PRP only 5% (DI 95%). EZE has demonstrated its tastemasking efficiency for both the APIs but not as significant as L100.Liquid sensors are able to detect the presence of the drug in the coated formulations(up to 0.3 mM API). Focusing on pure drug in reference solution (artificial saliva) thecomplex with L100 (Fig. 7.3b) at 90% shows a better taste improvement compared to AcrylEZE coating (Fig. 7.3c). This could be highly attributed to the pH dependency of bothpolymers. L100 is soluble in pH above 6.5 while L100-55 (EZE) is soluble in slightly lowerpH range therefore in the artificial saliva solutions the electronic tongue sensor did perceivethe taste of bitter APIs from the dissolved polymer matrices.Sensory correlated models were built to evaluate the correlation with sensory scores.The correlation model is considered as valid and fits with panel perception (Fig 7.3d; R² >0.9). However, the correlation studies show the same conclusions: sensory panel was sensibleto taste perception with Eudragit L100. The correlation studies depicted in fig. 3d alsocomplemented the sensory findings from the panelists score to conclude the statement thatL100 has better taste masking efficiency than L100-55 (EZE).139 | P a g e
Fig.7.3d. Relationship between results of taste sensors and human taste scores for similartastes (the standard deviations on the x- and y-axes are the difference between the panelists‘scores and measurement error (n = 6), respectively).In Fig. 7.3d, TS-5000Z taste sensing system (INSENT, Japan) showed differentsensitivity to each sample with a high correlation (0.94) to the taste scores, suggesting thatthis sensor responds selectively according to bitterness intensity and does not detect justquantitative information.3.5 Molecular ModellingMolecular modelling results indicated that both the hydroxyl group and amine groupwithin the drug molecule could form strong hydrogen bonds with the monomeric form ofL100 and L100-55, as indicated by the optimal distances between the H-bond donor andacceptor (Table 7.4). However, presence of the chloride ion could disrupt the H-bondbetween the hydroxyl group and the carboxylate group (data not shown). PRP showed a totalbinding energy ranging from 6.0 -15.9 kcal/mol with both of the polymers used. DPD showeda similar range (8.6 – 17.5 kcal/mol) as shown in table 7.4. In addition, both drugs requirehigher binding energy to interact with L100-55 in comparison to L100, as indicated by thebinding energy calculation. Higher binding energy is indicative of more energy required tobreak the H bonds apart, therefore enhanced stiffness of the drug/polymer binary mixturesthat may result in less movements of the molecules during the extrusion to form significantinteractions. All conformations showed very strong binding energy specifying stronginteraction possibilities between both drugs and polymers.140 | 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
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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
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 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
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,
Page 196 and 197: ate and time on the basis of Eq. (8
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
Page 210 and 211: 8.2 s 6.2 s 3.8 s 1.8 s 200 msS
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
Page 216 and 217: N = 55000/ 219.2 = 250.912Density:
Page 218 and 219: (4) Eudragit L100, N = (125000/202
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