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

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CHAPTER 5: AN IN VIVO AND IN VITRO TASTE MASKING EVALUATION OFBITTER MELT EXTRUDED APIs1.0 IntroductionThe taste of a pharmaceutical formulation has major influence on patient complianceto the medication and therefore the taste masking of bitter APIs is a major challengeespecially for the development of orally administered dosage forms in pharmaceuticalindustry [1] . In reality, most or many of the active pharmaceutical substances have either anunpleasant taste, such as bitterness, sourness or saltiness. Some of them may often cause anirritating mouth feeling, including metallic and/or spicy taste or astringency. For thesereasons, the need for a pleasant taste becomes a key aspect for patient palatability [2] . Tastemasking of various bitter active ingredients can be carried out using various techniquesdepending on the type of APIs and the type of formulation [3] .Currently, various taste masking methods are available. The most commonly usedconventional methods are film coating [4] and adding sugars, flavours or sweeteners[3]which are often limited due to regulatory requirements. Freeze-drying[1] , microencapsulation [5, 6] , fluidized bed coating [1] , high shear mixing [7] , supercritical fluids[8, 9]and spay drying [10] have been reported to be used as successful techniques for thepurposes of taste-masking various bitter active subtances. In addition to the afore mentionedconventional methods, different advanced and chemical taste masking approaches such asdrug complexation by cyclodextrines [11, 12] , ion exchange resins [13] , prodrugs and differentsalt formations [14] have been reported in the literature. Similarly, HME was introduced asuseful tool to produce polymeric extrudates with taste masking properties in a continuousprocess [15] . Different polymeric systems have already been implemented for taste maskingpurposes via the hot-melt extrusion (HME) processing and have been proved effective tastemaskingapproach by applying polymeric coating layer that creates a physical barrier aroundthe drug.Gryckze et al. (2011) successfully claimed taste masking of ibuprofen was achievedthrough intermolecular forces (e.g. hydrogen bonding) between the active substance and thepolymer matrix by processing oppositely charged compounds [2] . Later, similar results wereobserved by Maniruzzaman et al. (2012) where the authors successfully managed to mask thebitterness of paracetamol by applying the same mechanism [1] . In addition, solid dispersionswhere the drug is molecularly dispersed within the polymer matrix have shown effectivemasking of the drug‘s unpleasant taste. Successful taste masking requires development of85 | P a g e
HME processing conditions, drug/polymer ratio and selection of the appropriate formulationcomponents. HME can also be used for the development of robust formulations withincreased patient palatability and compliance.Taste masking evaluation of pharmaceutical dosage forms is usually carried out byhuman taste panels as well as electronic taste sensing systems which can be employed topredict the taste of pharmaceutical formulations [1] . Commercially available electronictongues such as a Astree e-tongue have been well studied and evaluated for taste maskingpurposes which showed very good correlation with human taste panels, reproducibility, lowdetection limits and high sensitivity [16, 17] . Furthermore, in comparison to final extrudedformulations the Astree e–tongue (AlphaMOS, France) has been systematically used toevaluate the bitterness of pure active substances.Cetirizine HCl (CTZ) and Verapamil HCl (VRP) are white crystalline powders withvery bitter taste mainly used as antihistaminic group drug and used for treating high bloodpressure, chest pain, and irregular heart rhythms, respectively. In this study both CTZ andVRP were used as model drugs for the purpose of taste masking.The purpose of this study was to develop and optimize CTZ and VRP based melt extrudedgranules in order to mask the bitter tastes. The extrudates were evaluated both by in vivo andin vitro studies where an electronic tongue analyzer was employed that captures the globaltaste profile correlating the in vivo data.2.0 Materials and methods2.1 MaterialsCetirizine HCl (CTZ) and Verapamil HCl (VRP) were purchased from Sigma Aldrich(London, UK). Eudragit L100 (L100) and Eudragit L100-55 (Acryl EZE-EZE) was kindlydonated by Evonik Pharma Polymers (Darmstadt, Germany) and Colorcon Ltd respectively.The HPLC solvents were analytical grade and purchased from Fisher Chemicals (UK). Allmaterials were used as received.2.2 Calculation of soubility parametersThe Hansen solubility parameters () of both drugs as well as the polymers werecalculated by using the Hoftyzer and van Krevelen method [18, 19] as described in Chapter No2 (section 2.2). Bagley advanced solubility parameter diagrarms [20] were used to investigatethe effect of the hydrogen bonding compared to the combined solubility parameters86 | 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
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1.8 Aims and objectivesThe purpose
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29. Zheng X, Yang R, Tang X and Zhe
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56. International Conference on Har
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CHAPTER 2: DISSOLUTION ENHANCEMENT
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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
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
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 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
Page 146 and 147: Fig. 6.3a: Diffractograms of PRP fo
Page 148 and 149: good agreement with the anticipated
Page 150 and 151: Since L100 contained higher proport
Page 152 and 153: at ~533.01 eV is the combination of
Page 154 and 155: Finally, the XPS analysis confirmed
Page 156 and 157: Fig. 6.6b: 1 H NMR spectra of all P
Page 158 and 159: 6) Bonferoni, M.C.; Rossi, S.; Ferr
Page 160 and 161: 26) Vandencasteele, N.; Reniers, F.
Page 162 and 163: Gibbs free energy change before and
Page 164 and 165: 2.5 Hot-melt extrusion (HME) proces
Page 166 and 167: 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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