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

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medium pH was maintained as 1.2 by using 750 ml of 0.1 M hydrochloric acid for 2 hr. After2 hr operation, 150 ml of 0.20 M solution of dehydrogenate sodium ortho phosphate wasadded into the vessel to give the final pH of 6.8 and the temperature equilibrated to 37°C. Atpredetermined time intervals, samples were withdrawn for HPLC assay and replaced withfresh dissolution medium. All dissolution studies were performed in triplicate.2.9 HPLC analysisThe release of HCS from the prepared tablets was determined by HPLC. An AgilentTechnologies system equipped with a HYCROME 4889, 5 m x 150 mm x 4 mm column at243 nm was used for the HCS HPLC assay. The mobile phase consisted of methanol/water/acetic acid (54:45:1, v/v/v). The flow rate was 1.5 ml/min and the retention time of HCS wasabout 4 minutes. The HCS calibration curve (R 2 =0.999), at concentrations varying from 10µg/ml to 50 µg/ml, were used to evaluate all the samples with 20 µl injection volume.2.10 Analysis of drug release mechanismZero order kinetics, first order kinetics, Hixson–Crowell, Higuchi and Korsmeyer–Peppas models were used for the analysis of the dissolution mechanism taking the rateconstant obtained from these models as an apparent rate constant. The drug release patternsfrom both coated and uncoated tablets were analyzed by release kinetics theories [18-22] , asfollows:Zero order kinetics: F K t (8.1)toWhere F t represents the fraction of drug released in time t and K 0 the apparent release rateconstant or zero order release constant.First order kinetics: ln( 1 F ) K (8.2)1 tWhere F represents the fraction of drug released in time t and K 1 is the first order releaseconstant.Higuchi model: F K t 1/ 22(8.3)Where F represents the fraction of drug released in time t and K 2 is the Higuchi dissolutionconstant.1/3 1/30 t stHixson–Crowell model: W W K (8.4)155 | P a g e
Where, W 0 is the initial amount of drug in the pharmaceutical dosage form, Wt is theremaining amount of drug in the pharmaceutical dosage form at time t and Ks is a constantincorporating the surface volume relation.3Dividing Eq. (8.4) by W and simplifying: 1F )1/ 3 1 K t (8.5)1/0(3Where F=1− (W t /W 0 ) and F represents the drug dissolved fraction at time t and K 3 is therelease constant). When this model is used, it is assumed that the release rate is limited by thedrug particle dissolution rate and not by the diffusion that might occur through the polymericmatrix.nKorsmeyer–Peppas model: F K t (8.6)4Where K 4 is a constant incorporating the structural and geometric characteristics of the drugdosage form, n is the release exponent (e.g. zero order release when n = 1, for tablets n =0.89), indicative of the drug release mechanism and F represents the drug dissolved fractionat time t. This model is generally used to analyze the release of which mechanism is not wellknown or when more than one type of release phenomena is involved.3.0 Results and discussion3.1 Solubility parameters and extrusion processThe calculated solubility parameter of HCS, EC N10 and EC P7 were 22.60, 25.61and 25.27 MPa 1/2 , respectively. The difference between the calculated solubility parametersof the polymers and the drug indicates that HCS is likely to form solid dispersions with bothpolymers EC N10 and EC P7. By using the Van Krevelen/Hoftyzer equation, the valuesfor HCS/EC N10 and HCS/EC P7 were 3.01 and 2.67 MPa 1/2 , respectively.3.2 Scanning electron microscopy (SEM)Surface morphology was examined by SEM for both the drug and extrudates. Theextrudates containing both polymers exhibited no drug crystals on the extrudate surface withHCS (Fig. 8.1). Similarly, the absence of HCS crystals on the surface in all drug/ polymerextrudates indicates the presence of amorphous solid dispersions of the API into the polymermatrices [13] . Thus, the SEM observations were quite sensitive to elucidate the presence ofdrug/polymers amorphous solid dispersions by complementing the thermal investigations(DSC, XRD).156 | 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
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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
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 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 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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