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

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CHAPTER 1: INTRODUCTION1.0 BackgroundOver the last three decades hot-melt extrusion (HME) has emerged as an influentialprocessing technology in developing molecular dispersions of active pharmaceutical ingredients(APIs) into polymer matrices and has already been demonstrated to provide time controlled,modified, extended and targeted drug delivery resulting in improved bioavailability [1, 2, 3, 4] .HME has now provided opportunity for use of materials in order to mask the bitter taste ofactive substances [4] . Since the industrial application of the extrusion process back in the 1930‘s,HME has received considerable attention from both the pharmaceutical industries and academiain a range of applications for pharmaceutical dosage forms, such as tablets, capsules, films andimplants for drug delivery via oral, transdermal and transmucosal routes [5] . This makes HME anexcellent alternative to other conventionally available techniques such as solvent evaporation,freeze drying, spray drying and so on (Table 1.1). In addition to being a proven manufacturingprocess, HME meets the goal of the US Food and Drug Administration's (FDA) processanalytical technology (PAT) scheme for designing, analyzing as well as controlling themanufacturing process via quality control measurements during active extrusion process [6] . Inthis chapter, the hot-melt extrusion technique is reviewed based on a holistic perspective of itsvarious components, processing technologies as well as the materials and novel formulationdesign and developments in its varied applications in oral drug delivery systems.1.1 Hot-melt extrusion (HME): Process technologyJoseph Brama first invented the extrusion process for the manufacturing of lead pipes atthe end of the eighteenth century [7] . Since then, it has been used in the plastic, rubber and foodmanufacturing industry to produce items ranging from pipes to sheets and bags. With the adventof high throughput screening, currently more than half of all plastic products including bags,sheets, and pipes are manufactured my HME and therefore various polymers have been used tomelt and form different shapes for a variety of industrial and domestic applications. Thetechnology has proven to be a robust method of producing numerous drug delivery systems andtherefore it has been found to be useful in the pharmaceutical industry as well [8] . Extrusion is theprocess of pumping raw materials at elevated controlled temperature and pressure through aheated barrel into a product of uniform shape and density [9] . Breitenbach first introduced thedevelopment of melt extrusion process in pharmaceutical manufacturing operationshowever, Follonier and his co-workers first examined the hot melt technology to manufacture1 | P a g e[10] ,
sustained release polymer based pellets of various freely soluble drugs [11] . HME involves thecompaction and conversion of blends from a powder or a granular mix into a product of uniformshape [9] . During this process, polymers are melted and formed into products of different shapesand sizes such as plastic bags, sheets, and pipes by forcing polymeric components and activesubstances including any additives or plasticisers through an orifice or die under controlledtemperature, pressure, feeding rate and screw speed [9, 12] . However, the theoretical approach tounderstanding the melt extrusion process can be summarized by classifying the whole procedureof HME compaction into the following [13] :1) feeding of the extruder through a hopper,2) mixing, grinding, reducing the particle size, venting and kneading,3) flow through the die, and4) extrusion from the die and further down-stream processing (Fig. 1.1).Fig. 1.1: Schematic diagram of the HME process [12] .The extruder generally consists of one or two rotating screws (either co-rotating orcounter rotating) inside a stationary cylindrical barrel. The barrel is often manufactured insections in order to shorten the residence time of molten materials. The sectioned parts of thebarrel are then bolted or clamped together. An end-plate die is connected to the end of the barrelwhich is determined according to the shape of the extruded materials.2 | 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 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 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
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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,
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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
Page 104 and 105:
The observed melting peaks are shif
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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
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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
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
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3.3 Differential scanning calorimet
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Fig. 6.3a: Diffractograms of PRP fo
Page 148 and 149:
good agreement with the anticipated
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Since L100 contained higher proport
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at ~533.01 eV is the combination of
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Finally, the XPS analysis confirmed
Page 156 and 157:
Fig. 6.6b: 1 H NMR spectra of all P
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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
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2.5 Hot-melt extrusion (HME) proces
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2.11 X-ray photoelectron spectrosco
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Table 7.2: DSC findings of all APIs
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3.4 In vivo and in vitro taste mask
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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
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20. Davies MC, Wilding IR, Short RD
Page 184 and 185:
CHAPTER 8: SUSTAINED RELEASE HYDROC
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2.3 Preparation of formulation blen
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medium pH was maintained as 1.2 by
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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,
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ate and time on the basis of Eq. (8
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Fig. 8.5c: A plot of the cubic root
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when n > 0.89. From the results of
Page 202 and 203:
14. Lam PL, Lee KKH,Wong RSM, Cheng
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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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8.2 s 6.2 s 3.8 s 1.8 s 200 msS
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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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