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

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Fdid ,Vi F2pip , p( Ehi/ ViVi )i = structural groups within the molecule = the total solubility parameter.F di = molar attraction constant due to molar dispersion forcesF 2 pi = molar attraction constant due to molar polarization forcesE hi = hydrogen bonding energy.Vi = group contribution to molar volumeThe average molecular weight was used to determine the solubility parameter of differentpolymeric excipients while the Bagley advanced solubility parameter equation and diagrams [24]were used to investigate the effect of hydrogen bonding compared to the combined solubilityparameters (dispersion forces and polarization forces).2.3 Preparation of formulation blendsThe dry drug/polymer powders (100 g) were blended thoroughly in a Turbula TF2 mixer(Basel, Switzerland) for 10 min. As shown in Table 2.1, the drug content for the binary blendsvaried from 20 – 40%. For the FMT/VA64, FMT/S630 and INM/S630 the drug content did notexceed 20% due to the difficulty with extruding the powdered formulations.Table 2.1: Drug/polymer percentages of the HME processed formulations.Drug Polymer Drug(%, w/w)Polymer(%, w/w)FMT SOL 20 80FMT SOL 40 60FMT VA64 20 80FMT S630 20 80Drug Polymer Drug Polymer21 | P a g e
(%, w/w) (%, w/w)INM SOL 20 80INM SOL 40 60INM VA64 20 80INM VA64 40 60INM S630 20 802.4 Hot-melt extrusion (HME) processExtrusion of all INM and FMT formulations was performed using a single screwRandcastle extruder (Model RC 0750, Cedar Grove, NJ) with a 0.2 mm rod die. The temperatureprofile from the feeding zone to the die was 105°C/113°C/118°C/122°C/120°C for allformulations with 15 rpm screw speeds. The extrudates (strands) were milled for 5 min toproduce granules using a Pulverisette 6 ball mill (Fritsch, Germany) with 400 rpm rotationalspeed. The micronized particles were then passed through a 250 µm sieve.2.5 Thermal analysisA Mettler-Toledo 823e (Greifensee, Switzerland) differential scanning calorimeter(DSC) was used to carry out DSC analyses of pure actives, physical mixtures (PM) andextrudates. 2-5 mg of samples was placed in sealed aluminium pans with pierced lids. Thesamples were heated at 10°C/min from 0°C to 220°C under dry nitrogen atmosphere. Inaddition modulated temperature scanning calorimetry (MTDSC) studies were performed from30 o C to 150 o C temperature range with an underlying heating rate of 1 o C/min to further analyzethe samples. The pulse height was adjusted to 1-2 o C with a temperature pulse width of 15-30 s.2.6 X-ray powder diffraction (XRPD)XRPD was used to determine the solid state of pure active substances, physical mixturesand extruded materials using a Bruker D8 Advance (Germany) in two-theta (2) mode. A copperanode at 40 kV and 40 mA, parallel beam Goebel mirror, 0.2 mm exit slit, LynxEye positionsensitive detector with 3° opening (LynxIris at 6.5 mm) and sample rotation at 15 rpm were22 | P a g e
Page 3 and 4: DECLARATION“I certify that this w
Page 6 and 7: 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 56 and 57: used. Each sample was scanned from
Page 58 and 59: Furthermore, by means of thermodyna
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
Page 108 and 109:
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
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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
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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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