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

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30. L. Saerens, L. Dierickx, B. Lenain, C. Vervaet, J.P. Remon, T. De Beer. Ramanspectroscopy for the in-line polymer–drug quantification and solid statecharacterization during a pharmaceutical hot-melt extrusion process. Eur J PharmBiopharm. 77(1) (2011) 158-63.31. Pharma Polymers, 51st International, EUDRAGIT® Workshop, March 14-16,Degussa AG, Business Line Pharma Polymers, Darmstadt, Germany, 2006.32. E.L. Parrott. In Lieberman, H. A., Lachman, L., Schwartz, J.B., (eds.),―Pharmaceutical Dosage Forms: Tablets Vol. 2,‖ 2nd ed., Marcel Dekker, New York,1990 pp. 201—243.33. Y.X. Bi, H. Sunada, Y. Yonezawa, K. Danjo. Evaluation of rapidly disintegratingtablets prepared by a direct compression method. Drug Dev Ind Pharm. 25 (1999)571-81.34. P. Kocbek, S. Baumgartner, J. Kristl. Preparation and evaluation of nanosuspensionsfor enhancing the dissolution of poorly soluble drugs. Int J Pharm. 312 (2006) 179–186.63 | P a g e
CHAPTER 4: TASTE MASKING OF PARACETAMOL BY HOT MELTEXTRUSION: AN IN VITRO AND IN VIVO EVALUATION1.0 IntroductionThe taste masking of bitter APIs is a major challenge especially for the developmentof orally disintegrating tablets (ODT) in pharmaceutical industry. Several approaches havebeen reported which involve fluidized-bed coating, supercritical fluids and coacervationapproaches where effective taste-masking is achieved by applying polymeric coating layer tocreate a physical barrier around the drug [1, 2] . Other alternatives involve the use ofcomplexing agents (cylcodextrins, ion exchange resins) through the formation of inclusioncomplexes or resonates [3] . Recently, taste masking approaches have employed tastesuppressants molecules by blocking the gap junction channels ad hemichannels and thussuppressing the drugs taste [4,5] . However, there is an enormous need for more robust, costeffective and easy to scale – up taste masking technologies. HME is a continuous, one stepprocess that has been used for the development of solid dispersions of active substances forvarious applications [6, 7] .Hot-melt extrusion (HME) has been employed as a novel technique for theformulation of oral solid dosage forms in pharmaceutical industries in the last decade. It wasinitially used in food and plastic industry but has attracted significant interest in thepharmaceutical manufacturing for the development of robust formulations. HME can be usedto develop various formulations such as sustained release matrices [8–11] . It has also beenintroduced for taste masking purposes of bitter APIs by involving the use of taste maskingpolymers that create solid dispersions to prevent bitter drugs from coming in contact with thepatient‘s taste buds [12–15] .Taste masking can be achieved through intermolecular forces (e.g. hydrogen bonding)between the active substance and the polymer matrix by processing oppositely chargedcompounds [1, 2] . In addition, solid dispersions in which the drug is molecularly dispersedwithin the polymer matrix have shown effectivenes for masking of the drug‘s unpleasanttaste. Successful taste masking requires development of HME processing conditions,drug/polymer ratio and selection of the appropriate formulation components (Hansensolubility parameters). HME can be used for the development of robust formulations withincreased patient palatability and compliance. Taste masking evaluation of pharmaceuticaldosage forms is usually carried out by human taste panels (volunteers) and it can be used forfurther product optimization. However, the taste assessment is subject to the individuals64 | 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)
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8.5d A plot of the logarithm of HCS
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L100Eudragit L100L100-55 Eudragit L
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Maniruzzaman M, Rai D, Boateng JS.
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Maniruzzaman M, Boateng JS, Bonnefi
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CHAPTER 1: INTRODUCTION1.0 Backgrou
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Table 1.1: HME and other convention
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homogenize but also compress the ex
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properties of polymers and excipien
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particles‘ wettability [46] . A v
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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 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
Page 126 and 127: Physical mixtures (PM) and extruded
Page 128 and 129: Fig. 5.2c: Thermograms of CTZ and V
Page 130 and 131: masking effect for active concentra
Page 132 and 133: Fig. 5.5b: Distance and discriminat
Page 134 and 135: 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
Page 140 and 141: scale or lower. XPS is more accurat
Page 142 and 143: patterns were identified after ener
Page 144 and 145: 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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