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

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Table 1.1: HME and other conventional processing techniques; advantages and disadvantages.Technologies Advantages DisadvantagesHot-melt extrusion [1-6] - Solvent free- Fast and continuous process- Low cost- Small footprint- High recovery- In line monitoringSpray Drying [5] - Fast process- Flexible particle sizesFreeze drying [5] - Mild condition- Suitable for thermolabilemolecules- Temperature(thermolabile molecules)- Downstream processing- Solvent residues (toxicityissue)- Processing parameters- Small yield- Cost- Solvent residues- Cost- Longer processing time- Cry protecting- Suitable solvent withhigh freezing point forsublimation process.Supercritical fluid - Mild conditions - Limited solubility of CO 2processing [5] - Cost- Time- Phase separation duringevaporationSolvent evaporation [5] - Mild condition - Solvent residues- Cost- Time- Suitable solvent- Phase separation duringevaporation1.2 Equipment: single screw and twin screw extruderA single screw extruder consists of one rotating screw positioned inside a stationarybarrel at the most fundamental level. In the more advanced twin-screw systems, extrusion ofmaterials is performed by either a co-rotating or counter-rotating screw configuration [9] .Irrespective of type and complexity of the function and process, the extruder must be capable ofrotating the screw at a selected predetermined speed while compensating for the torque and sheargenerated from both the material being extruded and the screws being used. However, regardlessof the size and type of the screw inside the stationary barrel a typical extrusion set up consists ofa motor which acts as a drive unit, an extrusion barrel, a rotating screw and an extrusion die [13] .A central electronic control unit is connected to the extrusion unit in order to control the process3 | P a g e
parameters such as screw speed, temperature and therefore pressure [14] . This electronic controlunit acts as a monitoring device as well. The typical length diameter ratios (L/D) of screwspositioned inside the stationary barrel are another important characteristic to consider whetherthe extrusion equipment is a single screw or twin screw extruder. The L/D of the screw either ina single screw extruder or a twin screw extruder typically ranges from 20 to 40:1(mm). In caseof the application of pilot plant extruders the diameters of the screws significantly ranges from18-30 mm. In pharmaceutical scale up, the production machines are much larger with diameterstypically exceeding 50 - 60 mm [15] . In addition, the dimensions of a screw change over thelength of the barrel. In the most advanced processing equipment for extrusion, the screws couldbe separated by clamps or be extended in proportion to the length of the barrel itself. A basicsingle screw extruder consists of three discrete zones: feed zone, compression and a meteringzone (Fig. 1.2). Under the compression zone which is basically know as processing zone couldbe accompanied by few other steps such as mixing, kneading, venting etc [13, 15] .Fig. 1.2: Schematic diagram of a single screw extruder [10] .The depth along with the pitch of the screw flights (both perpendicular and axial) differwithin each zone, generating dissimilar pressures along the screw length (Fig. 1.3). Normally thepressure within the feed zone is very low in order to allow for consistent feeding from thehopper and gentle mixing of API, polymers and other excipients and therefore the screw flightdepth and pitch are kept larger than that of other zones. At this stage of the process the pressurewithin the extruder is very low which subsequently gets increased in the compression zone. Thisresult in a gradual increase in pressure along the length of the compression zone effectivelyimparts a high degree of mixing and compression to the material by decreasing the screw pitchand/or the flight depth [9, 15] . Moreover the major aim of the compression zone is not only to4 | 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 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 54 and 55: Fdid ,Vi F2pip , p( Ehi/ ViVi )i =
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
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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
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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
Page 114 and 115:
3. K. Woertz, C. Tissen, P. Kleineb
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25. B.C. Hancock, P. York, R.C. Row
Page 118 and 119:
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
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
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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
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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.
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Gibbs free energy change before and
Page 164 and 165:
2.5 Hot-melt extrusion (HME) proces
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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
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Table 7.4: Binding energy calculati
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PRP/ polymers extruded in compariso
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atom as NH + 4 . This observed N 1s
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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
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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
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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
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N = 55000/ 219.2 = 250.912Density:
Page 218 and 219:
(4) Eudragit L100, N = (125000/202
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