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

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Gibbs free energy change before and after mixing [21] . It has been reported in the literaturethat F-H theory could successfully be applied in order to determine the interaction parametertherefore signifying the interactions strengths between two compounds during their melting.A small molecule drug–polymer pair is analogous to a solvent–polymer system and haspotential to be described by the F–H theory. The recent publications applying the F–H theoryin this area focus on obtaining the F–H interaction parameter, , by the melting pointdepression method [22, 23] . Extractions of the maximum information out of the F–H theoryand prediction of the thermodynamics of pharmaceutical binary systems is still of greatinterests in pharmaceutical research and developments.In this study, both the FT-IR and XPS were used to identify the strength and types ofthe possible drug-polymer interactions. Similarly the F-H interaction parameter of the modelsystem determined at two different conditions using the Nishi–Wang [24] equation based onmelting point data and Hildebrand and Scott [25] correlation, respectively was furtherevaluated to interrelate them with the taste masking efficiencies of two different anionicmodel polymers (Eudragit L100-55, Eudragit L100) in the extruded solid dispersions ofpropranolol HCl and diphenhydramine HCl.2.0 Materials and methods2.1 MaterialsPropranolol HCl (PRP) and Diphenhydramine HCl (DPD) were purchased fromSigma Aldrich (London, UK). Eudragit L100 (L100) and Eudragit L100-55 were kindlydonated by Evonik Pharma Polymers (Darmstadt, Germany) and Colorcon Ltd respectively.The HPLC solvents were analytical grade and purchased from Fisher Chemicals (UK). Allmaterials were used as received.2.2 Hansen solubility parameters: prediction of drug/polymer miscibilityThe Hoftyzer and van Krevelen method was used to calculate all drug polymersolubility parameters by considering the chemical structural orientations [26] and two –dimensional approach introduced by Bagley et al. [27] was used to predict the combinedthermodynamic effects on the drug-polymers miscibility over hydrogen bonding energy.[Please see Chapter 6, Section 2.2 for more details].129 | P a g e
2.3 Flory Huggins (F-H) theory for the prediction of drug/polymer interactionparameterThe F–H interaction parameter, , was correlated with temperature dependence, as inmany simplified cases. The interaction parameter of the model system was determined at twodifferent conditions using the Nishi–Wang [24] Eq. 7.1 equation based on melting pointdepression data and Hildebrand and Scott [25] Eq. 7.2 correlations with solubility parameter,respectively. The F-H interaction parameter () for all of the drug/polymers binary mixtureswere calculated by using the following equations. The value determined by Eq. 7.1 representsthe interactions between the two substances, specifically at the melting temperature, whichmay not be extrapolated to other temperatures.1 1 Rdrug12 [ln (1 ) (1 ) (1 ) ]0 drug drug drugpolydrugT T Hmmmdrugpolypoly(7.1)Where, is the molar volume of the repeating unit, m is the degree of polymerization, isthe volume fraction and is the crystalline– amorphous polymer interaction parameter, T mand T o m is the crystalline melting peak and amorphous Tg in the system, respectively.F-H interaction parameter () can be also estimated by the method developed byHildebrand and Scott according to Eq. 7.2 [25] .( drug poly) RT2(7.2)Where, R is the gas constant, T is the absolute temperature, and v the volume per lattice siteand drug and poly are solubility parameters of drugs and polymers respectively.2.4 Differential Scanning Calorimetry (DSC)The physical state of the pure drug, physical mixtures and extrudates were examinedby using a Mettler-Toledo 823e (Greifensee, Switzerland) differential scanning calorimeter.Samples were prepared in sealed aluminum pans (3-5 mg) with a pierced lid. The sampleswere heated at 10 o C/min in a temperature range between 0 and 220 o C under nitrogenatmosphere.130 | 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
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
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 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 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
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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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