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

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taste masking effect of the processed formulation was evaluated in vivo by a panel of sixhealthy human volunteers. In addition, in vitro evaluation was carried out by an Astree e-tongue (Alpha MOS) equipped with seven sensors and Taste Sensing System TS5000Z(INSENT), respectively.The taste and sensory evaluation in human volunteers demonstrated that the formulationmasked the bitter taste of the APIs and improved tablet palatability. In addition to that thetaste sensing technology demonstrated taste improvement for all polymers by correlating thedata obtained for the placebo polymers and the pure APIs alone. The e-tongue results were ingood agreement with the in vivo evaluation. Molecular modelling (Gaussian 09) predicted theexistence of two possible H-bonding types while Fourier Transform Infra-Red (FT-IR) andNMR studies confirmed drug-polymer interactions between the functional groups of bothcomponents (cationic drugs–anionic polymers). Furthermore, the intermolecular interactionsevaluated by Flory-Huggins interaction parameters theory and X-ray photoelectronspectroscopy (XPS) showed stronger interactions between drug-polymer in L100 systemscompared to that of L100-55 systems. The mechanism of the intermolecular interactionsderived from this research showed the presence of H bonding between the amine group of theactive substances and the carboxylic groups in the polymer.Hydrocortisone (HCS) was also embedded and extruded with ethyl cellulose N10 (EC N10)or ethyl cellulose Premium 7 (EC P7) in order to develop sustained release tablets processedby HME. The compressed tablets were subsequently coated with an enteric coating polymer,Eudragit ® S100 (15-20%), which showed sustained release over 12 hrs with a lag time of2 hrs. Further analysis of the release mechanism of HCS from tablets was performed byimplementing five different kinetic release models which confirmed that the release of HCSfrom both coated and uncoated tablets followed a first order kinetic model.v | P a g e
CONTENTSContentsPage NoTITLE PAGE.....................................................................................................................iDECLARATION................................................................................................................iiACKNOWLEDGMENTS.................................................................................................iiiABSTRACT........................................................................................................................ivCONTENTS........................................................................................................................viTABLES AND FIGURES...............................................................................................xvABBREVIATIONS........................................................................................................xxviPUBLICATIONS…………………………………………………...………..………xxviiiCHAPTER 1: INTRODUCTION1.0 Background ...................................................................................................................11.1 Hot-melt extrusion: Process technology........................................................................11.2 Equipment: single screw and twin screw extruder.........................................................31.3 Advantages and disadvantages of HME ......................................................................61.4 Applications of HME ....................................................................................................71.5 Formulation research and developments to date...........................................................81.6 HME in commercial products......................................................................................121.7 Summary.......................................................................................................................121.8 Aims and objectives………………………………………………………………….131.9 References....................................................................................................................13vi | P a g e
Page 3 and 4: DECLARATION“I certify that this w
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 =
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used. Each sample was scanned from
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Furthermore, by means of thermodyna
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3.2 Particle size morphology and pa
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Fig. 2.4a: Diffractograms of INM fo
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However, the DSC thermograms of the
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Fig. 2.5b: DSC thermograms of INM a
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Fig. 2.5e: DSC thermograms of FMT a
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Nevertheless, more than 80% FMT was
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6. Caron V, Tajber L, Corrigan OI,
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CHAPTER 3: DEVELOPMENT AND EVALUATI
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2.2 Hot-Melt extrusionHot-melt extr
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Committee of the University of Gree
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The PM of formulation II (40% IBU)
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Fig. 3.3: DSC thermograms of pure I
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As a general rule, the powder compr
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Fig. 3.4: Schematic diagram of ODT
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Fig. 3.5: Schematic diagram of ODTs
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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
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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
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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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