Influence of additives on ethylcellulose coatings

INFLUENCE OF ADDITIVES ON ETHYLCELLULOSE COATINGS ONG KANG TENG (B.Sc. (Pharm.)(Hons.), NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2006 ACKNOWLEDGEMENTS With great gratitude, I wish to thank my respectful supervisors, Associate Professor Paul Heng Wan Sia and Associate Professor Chan Lai Wah for devoting much time and effort in supervising and guiding me in my higher degree pursue. They have given me an education that is worth a lifetime. I could not have carried out my study without the generous financial supports from the National University of Singapore and the use of research facilities in the Department of Pharmacy and GEA-NUS Pharmaceutical Processing Research Laboratory. I wish to thank the laboratory officers in the Department of Pharmacy, especially Teresa and Mei Yin, who have never failed to render me their technical assistance whenever needed. My heartfelt thanks go to all my friends and colleagues in the Department of Pharmacy and GEA-NUS, especially Celine, Tin Wui, Chit Chiat, Liang Theng, Sze Nam, Gu Li, Wai See and Qiyun. They have not only shared with me their valuable experiences but also provided me with their friendship. My parents and siblings have showered me with much love and supports which kept me going, especially through difficult times. This journey has been blessed with many prayerful and spiritual supports of saints both at home and aboard, for whom I thank God for. All thanks and glory be to God the Father and Lord Jesus Christ, to whom I owe all things. Kang Teng Jan 2006 i TABLE OF CONTENTS CONTENTS ACKNOWLEDGEMENTS i CONTENTS ii SUMMARY vii List of Tables xii List of Figures xiv I. INTRODUCTION A. Film coating 1. Reasons for coating 2. Film coating polymers 3. Organic versus aqueous coating systems 4. Aqueous coating systems a. Latex and pseudolatex i. Emulsion polymerization ii. Emulsion - solvent evaporation iii. Phase inversion iv. Solvent change b. Suspension B. Mechanism of film formation C. Substrates for film coating D. Drug release mechanisms of coated pellets 10 1. Diffusion - controlled systems 11 2. Swelling - controlled systems 14 3. Chemically - controlled systems 15 4. Osmotically - driven release systems 16 ii TABLE OF CONTENTS E. Performance of film-coated products 17 1. Substrate 17 2. Coating formulation 19 a. Nature of the polymer 19 i. Cellulose derivatives 20 ii. Acrylic polymer 22 b. Additives 23 i. Plasticizers 23 ii. Colorants and opacifiers 29 iii. Surfactants 30 iv. Anti-tack agents 30 v. Hydrophilic additives 31 3. Coating process variables F. Analysis and comparison of dissolution data 31 35 1. Zero order equation 36 2. First order equation 37 3. Hixson – Crowell equation 37 4. Higuchi equation 38 5. Baker and Lonsdale equation (Higuchi's model for spherical matrices) 40 6. Hopfenberg equation 40 II. OBJECTIVES 45 Part 1. 46 Part 47 III. EXPERIMENTAL 50 A. Materials 50 iii TABLE OF CONTENTS 1. Drugs, polymers and additives B. Methodology 50 53 1. Preparation of film forming dispersions 53 a. EC and acrylic dispersions containing plasticizers 53 b. EC dispersions containing polymeric additives 53 2. Preparation of films 53 3. Evaluation of film properties 54 a. Surface morphology 54 b. Film transparency 55 c. Mechanical properties 55 d. Puncture test 56 e. Plasticizer content 57 f. Percent weight change of film 58 g. Moisture content 58 h. Water vapour permeability 59 i. Thermal properties 60 Glass transition temperature 60 Thermal mechanical spectra 61 j. Drug permeability 62 k. Swelling and leeaching of film 65 4. Preparation of pellets 66 5. Coating of pellets 67 a. Coating with Aquacoat 67 b. Coating with Surelease 68 6. In vitro dissolution studies 69 iv TABLE OF CONTENTS 7. Assay of drug content in coated pellets IV. RESULTS AND DISCUSSION Part 1. Influence of plasticizers and storage conditions on properties of films 69 70 70 A. Film morphology 70 B. Mechanical properties of films 73 1. Comparison between different polymeric films 73 2. Influence of plasticizers on properties of films 74 3. Influence of storage time on properties of films 75 4. Influence of storage humidity on properties of films 84 5. Water vapour permeability 87 C. Drug release 88 1. Influence of plasticizer on dissolution profiles of pellets coated with Aquacoat 88 2. Influence of storage conditions on dissolution profiles of pellets coated with plasticized Aquacoat 92 a. Citric acid esters (TEC and ATEC) 92 b. Phthalic acid esters (DEP) 101 c. Glycerol acid ester 104 3. Effect of storage temperature on drug release Part 2. Influence of polymeric additives 107 109 A. Thermal and dynamic mechanical properties 109 B. Film morphology 121 C. Mechanical properties - tensile test 126 D. Mechanical properties - puncture test 131 E. Water vapour permeability 135 F. Drug permeability 137 v TABLE OF CONTENTS 1. Effect of polymer additives on drug permeability 138 2. Effect of drug properties on drug permeability 147 G. Correlation between physicomechanical properties and permeability of composite EC films 149 H. Release kinetics of pellets coated with EC and polymeric additives 151 1. Effect of coating levels on drug release from EC coated pellets 151 2. Effect of curing on EC - coated pellets 161 3. Influence of PVP on EC - coated pellets 164 4. Effect of curing on drug release from EC-PVP coated pellets 181 5. Influence of PV/VA on drug release from EC - coated pellets 183 V. CONCLUSION 188 VI. REFERENCES 193 VII. APPENDICES 207 Symbols 207 Published communications and presentations 211 vi SUMMARY SUMMARY Many polymeric film coats applied onto dosage forms have been reported to undergo changes in mechanical properties upon storage. The extent of these changes is influenced by several factors, such as the amount of plasticizers added, type of plasticizers used, film forming conditions, film storage temperature and humidity. Changes in film mechanical properties may ultimately influence the drug release, stability and other physicochemical properties of the coated dosage forms. Ethylcellulose and acrylates are among the most commonly used polymers in the production of coated controlled-release dosage forms. Several researchers have studied the effects of different types of plasticizers on the mechanical properties of Aquacoat films. Plasticizers, such as dibutyl sebacate, tributyl citrate, acetyl tributyl citrate and oleyl alcohol were found to produce ethylcellulose films that showed greater elongation upon stretching, after the films had been stored under conditions of elevated humidity. However, the actual mechanisms that caused the above change and the extent of influence by the different types of plasticizers have not been reported. The primary objective of this study was to investigate the effects of different types of plasticizers on the stability and other properties of the films exposed to different storage conditions. Attempts were made to elucidate the mechanisms responsible for the changes observed and correlate these changes in film properties to the release profiles of coated pellets. This study demonstrated that ethylcellulose film stability is influenced by several factors, including type and amount of plasticizers remaining in the film, as well as the storage conditions. Plasticizers interact with ethylcellulose and affect its film properties primarily in the following three ways. Firstly, plasticizers with low permanence, such as glycerin triacetate and diethyl phthalate can cause formation of vii SUMMARY brittle films as these plasticizers are volatile or degrade on extended storage. Secondly, the extent of coalescence or ageing on ethylcellulose films varies with different plasticizers. In addition, the stability of ethylcellulose films under different storage conditions is also dependent on type of plasticizers used. At a commonly applied concentration of 30 percent, the citrate ester plasticizers, particularly triethyl citrate, have been shown to interact well with Aquacoat, while glycerin triacetate and diethyl phthalate were not able to plasticize Aquacoat films as effectively. Exposing the film membrane to low humidity or high temperature accelerates loss of bound water, thus enhancing the coalescence or fusion of polymer molecules. Storage environments with high moisture content, on the other hand could delay and reduce the coalescence of films but not prevent it. With the exception of glycerin triacetate, chlorpheniramine release from pellets coated with plasticized Aquacoat films were affected to varying degrees by storage conditions. Higher storage temperatures tend to cause greater changes for pellets coated with Aquacoat containing citric acid class of plasticizers (triethyl citrate and acetyl triethyl citrate) compared to other plasticizers. This study demonstrated that the physicochemical properties of the plasticizer coupled with the storage conditions have an important influence on the stability and performance of the final film coat. Hence it is important to exercise caution in the selection of plasticizers for film coating in order to ensure good product stability and performance. Ethylcellulose is used in controlled released preparations because of its good mechanical properties and poor permeability to water vapour. However, these properties strongly retard drug release and thereby limit the application of pure ethylcellulose coating as controlled release coating. Studies were undertaken to modify drug permeability through ethylcellulose coatings by reduction in thickness of viii SUMMARY the coating layer, formation of pores using organic solvents and hydrophilic additives. Polyvinylpyrrolidone is a water - soluble, physiologically inert synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, with varying degree of polymerization which results in polyvinylpyrrolidone of different molecular weights. Viviprint 540 is a molecular – composite polyvinylpyrrolidone, which is formed by in situ incorporation of insoluble crosslinked polyvinylpyrrolidone nanoparticles into soluble, film–forming polyvinylpyrrolidone polymer. Hence molecular – composite polyvinylpyrrolidone has much larger molecular weight than polyvinylpyrrolidone and is less soluble in water. Plasdone S-630 copolyvidonum is a synthetic watersoluble copolymer consisting of N-vinyl-2-pyrrolidone and vinyl acetate in a random 60:40 ratio. All the water-soluble polymers discussed above are potential polymeric film modifiers for achieving improved drug release. However, to date, their potentials have not been explored. In this study, the interaction between ethylcellulose and polyvinylpyrrolidone was found to be dependent on the molecular weight, concentration and chemical nature of the additives. When added to ethylcellulose, low molecular weight polyvinylpyrrolidone would be randomly distributed in the ethylcellulose matrix as a disperse phase. Increased concentration up to 30 %w/w did not alter the phase distribution. 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STP Pharma Science (1994) 122 – 127. 206 APPENDICES VII. APPENDICES Symbols a0 initial radius for a sphere or cylinder or the half-thickness for a slab a1 a constant incorporating structural and geometric characteristics of the dosage form A area through which diffusion occurs or effective area for mass transfer Acs cross-sectional area of the film Ai initial cross-sectional area of the sample AIC Akaike information criterion AUC area under the curve Cb, Cs concentration of drug at drug-coating interface and the bulk respectively Cd concentration of the drug Cfs drug solubility in the liquid surrounding the matrix Ci , Cm interior and media drug concentrations respectively C0 initial concentration of the drug in the polymer matrix. Cr concentration of the drug in the receptor fluid (g/cm3) Ce solubility of drug in dissolution medium Cs solubility of drug in the matrix cw water concentration in the system Dp displacement of the probe from point of contact to point of puncture D diffusion coefficient or diffusivity De Deborah number Deff effective diffusion coefficient Diw diffusion coefficient of drug through the pores Dm diffusion coefficient across the membrane Dr diffusivity of the drug through the membrane dC/dx gradient in concentration (C) in the x direction. dL/dm slope of the linear potion of the elastic deformation dM/dt rate of diffusion E’ storage modulus E” loss modulus EL percent elongation at break (tensile test) 207 APPENDICES EM elastic modulus EXC amount of extracted components, f1 difference factor f2 similarity factor ft fraction of drug released at any time t. F load required for puncture hm thickness of the membrane K partition coefficient Kf filtration coefficient ke erosion rate constant K0 zero order release rate constant K1 first order release rate constant KH Higuchi release rate constant Ks a constant incorporating the surface–volume relation for Hixson and Crowell model K′ a constant related to the surface, the shape and the density of the particle Kβ Hixson and Crowell release constant. Is swelling index j flux per unit area J total flux li initial gauge length Lmax maximum load M mass change Md, Ma the respective amounts of diffusing substance in the donor and acceptor compartment when t = MDT mean dissolution time n value in order to characterise different release mechanisms or number of dissolution data points N number of particles p number of the parameters of the model P permeability constant Peff effective permeability coefficient 208 APPENDICES Pm permeability coefficient of the polymer membrane Q amount of drug released in time t per unit area, Q0 initial amount of drug in the solution Qt amount of drug dissolved in time t, r radius of a sphere ro radius of the device r2 correlation coefficient R radius of the film exposed across the open screw cap Rj percent dissolved of reference products at each time point j Rtot total resistance Rm membrane’s diffusional resistance Rwvp water vapour permeation rate R1, R2 aqueous resistance T absolute temperature t time tL lag time tx% parameter corresponds to the time necessary to the release of a determined percentage of drug Td dissolution time Tj percent dissolved of test products at each time point j Ts tensile strength W total amount of the drug per unit volume of the matrix Wd weight of the dried polymer film We weight of the film that was dried to constant weight wi optional weighing factor W0 initial amount of drug in the dosage form, Ws weight of the swollen film Wt amount of drug in the dosage form at time t WSSR weighed sum of square of residues v Poisson’s ratio V volume of the receptor fluid V1, V2 molar volumes Vd, Va volumes of the donor and receptor compartments. 209 APPENDICES Vm total volume of the mixture ε void fraction (porosity) τ tortuosity of the membrane θ one-half the angle of coalescence (contact angle) θd diffusion time η viscosity of the spheres β chain immobilization factor λ relaxation time ∂ % elongation (puncture test) δ solubility parameter δc coating thickness δd thickness of the diffusion layer δs cross-head speed σ reflection coefficient of the coating ω work of failure φ volume fraction ∆π osmotic pressure difference ∆αcubic difference between the thermal cubical expansion coefficients of the coating and the tablet core ∆E energy of vaporization ∆E/V cohesive energy density (CED) ∆G Gibbs free energy of mixing ∆H heat of mixing ∆lb increase in length at break point ∆p vapour pressure difference ∆S entropy pf mixing ∆W amount of water vapour permeated through the film γ surface tension γp puncture strength 210 APPENDICES Published communications and presentations The following have been published or presented in advance of this thesis. PUBLICATIONS (PAPER) 1. Heng, P.W.S., Chan, L.W., Ong, K.T., Influence of storage conditions and type of plasticizers on ethyl cellulose and acrylate films formed from aqueous dispersions. Journal of Pharmacy and Pharmaceutical Science (2003) 334344. 2. Chan L.W., Ong K.T., Heng P.W.S., Novel film modifiers to alter the physical properties of composite ethyl cellulose films. Pharmaceutical Research 22 (2005) 476-489. PUBLICATIONS (POSTERS) 1. Heng, P.W.S., Chan, L.W., and Ong, K.T., The influence of storage humidity on pseudolatex films. American Association of Pharmaceutical Scientists Annual Meeting and Exposition, Canada, 2002 2. Ong, K.T., Chan, L.W., Heng, P.W.S. The influence of storage conditions on polymeric films. 11th International Pharmaceutical Technology Symposium on “Intelligent Drug Delivery Systems Better and Safer Therapy” Istanbul, Turkey (9-11 September 2002) 3. Heng, P.W.S, Er, D.Z.L., Ong, K.T., Chan, L.W., A Study of Composite Ethylcellulose Films. 31st Annual Meeting and Exposition of the Controlled Release Society, Hawaii, US, 12-16 June 2004. 4. K.T. Ong, Paul W.S. Heng and L.W. Chan. Influence of polyvinylpyrrolidone and its derivatives on properties of ethylcellulose films American Association of Pharmaceutical Scientists Annual Meeting and Exposition, Baltimore, US, 2004. 5. K.T. Ong, Paul W.S. Heng and L.W. Chan. Investigation on effect of storage conditions and type of plasticizers on drug release from ethylcellulose coated pellets. American Association of Pharmaceutical Scientists Annual Meeting and Exposition, San Antonia, US, 2006. 211 [...]... permeability of EC and MA films Comparison of plasticizer content in Aquacoat films exposed to storage conditions of 50 %RH, 30 °C and 75 %RH, 30 °C Comparison of percent weight change of films exposed to storage conditions of 50 %RH, 30 °C and 75 %RH, 30°C Pearson correlation for films exposed to storage conditions of 50 %RH, 30 °C and 75 %RH, 30 °C Comparison of percent change in moisture content of films... separation of adjacent chains to permit passage of a drug Another mechanism of release is configurational diffusion that involves the movement of drug through the polymer chains The rate of diffusion is therefore dependent on polymer parameters such as degree of crystallinity, size of crystallites, degree of cross-linking, swelling and molecular weight of the polymer The release rate of a non-porous... as diffusion - controlled, swelling - controlled, osmotically - controlled and chemically - controlled systems 1 Diffusion - controlled systems In these systems, drug release is governed by molecular diffusion along a concentration gradient across the polymer film coat The latter may be porous or nonporous Porous controlled release systems contain pores that are large enough for diffusion of drug through... Surelease (EC): (a) continuous phase of EC film without polymeric additives (b) minor component existing as random spheres/crevices in the continuous phase of EC (c) minor component existing as random spheres/crevices of larger size in the continuous phase of EC (d) minor component forming a separate continuous phase (e) overcoat of one continuous phase over another Water vapour permeability of Surelease (EC)... Fujita equation: Ddrug = Ddo exp{- α (β - cw)} (6) where α and β are two characteristic constants of the polymeric system and cw is the water concentration in the system 3 Chemically - controlled systems Drug diffusion is controlled by the erosion of the polymer matrix (Figure 4d) The polymer may undergo bioerosion and/or biodegradation Biodegradation refers to 15 INTRODUCTION the breaking down of polymer... aqueous coating systems Stricter environmental legislation, in conjunction with the high cost of controlling organic solvent emission, has forced researchers to find alternative ‘environmentally friendly’ coating systems 4 INTRODUCTION The current USP lists only three sustained release coatings that function as a rate controlling membrane – cellulose acetate, ethylcellulose and methacrylic acid copolymer... 1991) In a membrane-controlled system, the drug diffuses from the core through the rate-controlling membrane into 10 INTRODUCTION the surrounding environment The rate of diffusion may depend on membrane porosity, tortuosity, geometry and thickness In circumstances where film coat is insoluble in the dissolution media and in the absence of additives or where the influence of additives on drug release is... 75 %RH Effect of storage conditions on elastic modulus of EC films: Surelease and Aquacoat films plasticized with DBP, DEP, TEC, ATEC, ATBC, GTA stored at 30 °C, 50 %RH and 30 °C, 75 %RH Effect of storage conditions on work of failure of EC films: Surelease and Aquacoat films plasticized with DBP, DEP, TEC, ATEC, ATBC, GTA stored at 30 °C, 50 %RH and 30 °C, 75 %RH.) Dissolution profiles of Aquacoat coated...SUMMARY concentration Increased molecular weight of additives also accelerated the formation of separate layers Addition of polyvinylpyrrolidone increased the glass transition temperature, water vapour and drug permeabilities, as well as strengthened the mechanical properties of composite ethylcellulose films However, the magnitude of change was not consistent in all cases For instances,... microscope images of wetted composite EC films: (a) EC-PV/VA (7:3), (b) EC-PVP K29 (7:3), (c) EC-PVP K60 (7:3), (d) EC-PVP K90 (7:3) Dissolution profiles of pellets coated with different levels of Surelease Effect of coating level of Surelease on (a) Baker-Lonsdale release rate constant (b) T50% (c) MDT50% of chlorpheniramine, theophylline and paracetamol pellets Dissolution profiles of theophylline . of films 73 1. Comparison between different polymeric films 73 2. Influence of plasticizers on properties of films 74 3. Influence of storage time on properties of films 75 4. Influence of. plasticizers. In addition, the stability of ethylcellulose films under different storage conditions is also dependent on type of plasticizers used. At a commonly applied concentration of 30 percent,. humidity on properties of films 84 5. Water vapour permeability 87 C. Drug release 88 1. Influence of plasticizer on dissolution profiles of pellets coated with Aquacoat 88 2. Influence of storage