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

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used. Each sample was scanned from 2 to 40° 2 with a step size of 0.02° (2) and a countingtime of 0.2 seconds per step; 176 channels active on the PSD making a total counting time of35.2 s/step.2.7 Particle size morphology and distributionScanning electron microscopy (SEM) was used to study the surface morphology of thehot-melt extrudates. The samples were mounted on an aluminum stage using adhesive carbontape and placed in a low humidity chamber prior to analysis. Samples were coated with gold, andmicroscopy was performed using a Jeol 5200, SEM operating at an accelerating voltage of 5 kV.The particle size distribution of the micronized extrudate granules of all formulations wasmeasured by dry sieving. The method involved stacking of the sieves on top of each other andthen placing the test powder (100 g) on the top sieve. The nest of sieves was subjected to astandardised period of agitation (20 min) and then the weight of the material retained on eachsieve was accurately determined to give the weigh percentage of powder in each sieve sizerange.2.8 In vitro drug release studiesIn vitro drug release studies were carried out in 750 ml of 0.1 M hydrochloric acid for 2hr using a Varian 705 DS dissolution paddle apparatus (Varian Inc. North Carolina, US) at 100rpm and 37 ± 0.5 o C. After the 2 hr operation, 250 ml of 0.20 M solution of trisodium phosphatedodecahydrate were added into the vessel (buffer stage, pH 6.8) that had been equilibrated to 37°C. At predetermined time intervals, samples were withdrawn for HPLC assay. All dissolutionstudies were performed in triplicateFurthermore, the difference of the release profiles of different formulations wasinvestigated by calculating the similarity factor (f2). The f2 value (Eq. (2)) is a logarithmictransformation of the sum-squared error of differences between the test Tj and referenceproducts Rj over all time points (n = 5).f1 50 log[{1 (nn2 0.52 ( R ) )j 1 jTj}100](2.2)23 | P a g e
2.9 HPLC analysisThe release of INM and FMT was determined by using HPLC, Agilent Technologiessystem 1200 series. A HYCHROME S50DS2-4889 (5 µm x 150 mm x 4 mm) column was usedfor both active substances. The wavelength was set at 260 nm and 267 nm for INM and FMTrespectively. The mobile phase consisted of methanol/water/acetic acid (64/35/1 by volume) andthe flow rate was maintained at 2 ml/min and the retention time was 4-5 min. For INM and FMTcalibration curves (R 2 = 0.999) were prepared with concentrations varying from 10 µg /ml to 50µg/ml and 20 µl injection volumes.3.0 Results and Discussion3.1 Miscibility studies by calculating solubility parameters ()The estimation of the solubility parameters () was used to predict the miscibility of theactive substances and the polymeric carriers [12,25,26] . Calculated solubility parameters indicatethe probability of a drug molecule to be miscible with a large polymer molecule. In thecalculation of solubility parameters three different forces are considered. It is believed that thecompounds with similar values for solubility parameters are likely to be miscible because themiscibility is caused by balancing the energy of mixing released by inter molecular interactionsbetween the components and the energy released by intra molecular interactions within thecomponents [27] . The Hansen three dimensional solubility parameters are calculated by groupcontributions of dispersion forces, polar forces and hydrogen bonding forces using the VanKrevelen/Hoftyzer (1976) method [25] .The estimated solubility parameters are depicted in Table 2.2 and it can be seen that forall drug – polymer combinations the values vary from 3.2 – 5.2 MPa 0.5 as derived by the VanKrevelen/Hoftyzer approach. Greenhalgh [26] classified compounds according to their differencein solubility parameters. The authors found out that compounds with a < 7 MPa 0.5 were likelyto be miscible, but likely to be immiscible with a >10 MPa 0.5 . Since the determined solubilityparameter differences between each drug and polymer are less than 7 MPa 0.5 , all three polymersare likely to be miscible with both of the APIs. Interestingly the values for INM and the twovinylpyrrolidone copolymer grades are slightly different although both appear to be miscible.This was attributed to the different molecular weights and the degree of cross – linking of thetwo polymers. Similar differences can be observed for FMT and the vinylpyrrolidonecopolymers.24 | P a g e
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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 54 and 55: Fdid ,Vi F2pip , p( Ehi/ ViVi )i =
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
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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
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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
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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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