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

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2.2 Hot-Melt extrusionHot-melt extrusion was carried out using a 18 mm Leistritz twin-screw extruder. Screwswere co-rotated at a speed of 200 rpm; the temperature applied was 140°C. At this temperature,dissolution of the IBU in the polymer occurred. The drug-excipients composition consisted ofIBU/EPO/Talc and IBU/EPO/Talc at a ratio of 25/25/50 and 50/40/10(% wt/wt). The extrudateswere collected as strands with diameter of approximately 1.5 mm and milled under cryogenicmilling (Retsch ZM 200 Ultracentrifugal, Germany) conditions (6000 rpm, 10 min) to obtain thefinal taste-masked granules.2.3 Particle size distribution measurementsThe particle size distribution of the produced IBU granules was measured by dry sieving.The method involved stacking of the sieves on top of each other and then placing the test powder(100 g) on the top sieve. The nest of sieves was subjected to a standardised period of agitation(20 min) and then the weight of the material retained on each sieve was accurately determined togive the weight percentage of powder in each sieve size range.2.4 Tablet preparationDevelopment batches were prepared using batch sizes of 200 g. All materials were passedthrough a mesh sieve with an aperture of 800µm before use. The batches were blended withsodium stearyl fumarate (0.5%) in a Turbula TF2 mixer (Basel, Switzerland) for 5 minutes.Blends were directly compressed on a Flexitab trilayer tablet press (Oystar - Manesty,Germany) using 13 mm normal flat punches. Dwell time was set at 30 ms and the compactionforce varied from 4-12kN.2.5 Flow properties and compressibilityCompressibility index I (Carr‘s index) values of the different formulations weredetermined by measuring the tapped bulk and poured bulk volumes of the powders aftersubjecting to 100 taps in a graduated measuring cylinder using the following equation [21] :VI ( 1) 100V o(3.1)V is the freely settled volume of a given mass of a powder and V o is the tapped volume of thesame mass of powder.43 | P a g e
2.6 Evaluation of tabletsThe prepared tablets were evaluated for the uniformity of thickness, hardness (Erweka TBH28, Frankfurt, Germany), friability (Erweka friabilator, model A3R, Frankfurt, Germany), anddisintegration time (Erweka, model ZT4, Heusenstamm, Germany) according to USP22tests/2010. The diametral compression test defined by Fell and Newton [22] was used todetermine the tensile strength T, using the formula:T2P Dt(3.2)Where P (kP) is the applied stress, D (cm) is the diameter of the tablet, and t (cm) is the tabletthickness. Three tablets from each batch were subjected to tensile strength determination.The solid fraction (SF) and porosity ( ) were calculated based on the true density ( true ), tabletvolume (v), and tablet weight (Wt) as below [23] :SFw t true(3.3) 1SF(3.4)2.7 In vitro tablet disintegration testThe tablet disintegration test was carried out using a TA-XDPlus texture analyzer (StableMicro Systems) similar to a recent study [24] . The apparatus was calibrated with a 5 kg load celland fitted with a flat-bottomed cylindrical stainless steel probe (P/25, 12mm in diameter and25mm in height). In summary, the completely dry tablet is placed on the perforated grid and it isnot in contact with the disintegration medium. The probe descends until a trigger force isdetected where it gets in contact with the tablet placed on the grid and pushes the whole systemdownwards. The tablet then touches the medium and starts disintegrating. At this point, the TAapparatus is set to maintain a predetermined nominal force (50 g) for a given period of time (60s). For all the disintegration studies artificial saliva (pH 5.8) was used as a solvent medium inorder to simulate oral disintegration.2.8 In vivo tablet disintegration and bitterness evaluationIn vivo disintegration and taste masking evaluation was performed on 10 healthy humanvolunteers [25, 26] from whom informed consent was first obtained (approved by the Ethics44 | 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)
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 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 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
Page 110 and 111: 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
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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
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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
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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
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Fig. 6.6b: 1 H NMR spectra of all P
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6) Bonferoni, M.C.; Rossi, S.; Ferr
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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
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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)]
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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
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14. Lam PL, Lee KKH,Wong RSM, Cheng
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Furthermore, HME has successfully b
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Supp. Fig. 2: XPS O 1s peaks for PR
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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
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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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