A STUDY OF HPMC-PEG MATRIX AS DRUG CARRIER IN SPRAY CONGEALING OH CHING MIEN B.Sc. (Pharm.) (Hons.), NUS A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2014 DECLARATION I hereby declare that this thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. ______________________________________________ Oh Ching Mien 31 July 2014 ii ACKNOWLEDGEMENTS First and foremost, I would like to extend my sincere gratitude to my supervisors, Assoc. Prof. Chan Lai Wah and Assoc. Prof. Paul Heng, for their continued stimulation of curiosity and their total dedication, guidance and supervision. Without their inspiration and motivation, this work would not have been possible. My appreciation is also extended to the Head of Department, Assoc. Prof Chui Wai Keung, for use of the facilities at the Department of Pharmacy, National University of Singapore (NUS). I am also grateful to NUS for the NUS Research Scholarship and NUS Industry Relevant PhD Scholarship. I am grateful to Dr Kurup and Dr Celine Liew for their invaluable advice during my candidature, Teresa and Mei Yin for providing excellent technical assistance throughout my course of research and my fellow GEANUSians, past and present, in particular Wong Xin Yi and Carin Siow, for their ideas, help and friendship. My deepest appreciation to my wife, Ker Yun, whose patience and continual love encouraged me throughout this period and my son, Ethan, for always giving me joy and good cheer. I also owe an immeasurable debt to my family for their understanding and support. Finally, I would like to thank my Heavenly Father for the grace and blessings, and without whom, I would not be where I am today. Ching Mien July 2014 iii TABLE OF CONTENTS DECLARATION ii ACKNOWLEDGEMENTS . iii SUMMARY . ix LIST OF TABLES xii LIST OF FIGURES . xiv LIST OF ABBREVIATIONS xix INTRODUCTION A. Spray congealing 1. The process of spray congealing 2. Advantages and disadvantages . 3. Influence of matrix materials . 4. Influence of active pharmaceutical ingredients (APIs) 11 5. Influence of additives . 14 B. Solid dispersions . 19 1. Significance of solid dispersions . 19 2. Crystallisation and amorphism 21 3. Screening of formulations using melting method 23 C. Modification of drug release . 23 1. Design of modified release drug delivery systems 24 2. Advantages and disadvantages of modified release dosage form . 26 3. Polyethylene glycols as matrix material 27 4. Excipients for drug delivery system modification . 28 4.1. Hydroxypropyl methylcellulose . 28 4.2. Methylcellulose 29 4.3. Ethylcellulose . 29 4.4. Polyvinylpyrrolidone . 30 D. Polymer rheology . 30 1. Importance of polymer rheology in the pharmaceutical industry 30 2. Application of multivariate analysis in polymer rheology 31 HYPOTHESIS AND OBJECTIVES 34 EXPERIMENTAL 37 iv A. Materials . 37 1. Active pharmaceutical ingredients 37 2. Matrix materials and additives 37 3. Dissolution media 38 B. Methods 38 1. Preparation of physical mixtures . 38 2. Preparation of molten mixtures . 38 3. Preparation of microparticles by melting method and milling 39 3.1. Preparation of solid dispersions . 39 3.2. Conical screen milling of solid dispersions . 39 4. Preparation of microparticles by spray congealing . 40 5. Preparation of tablets with spray congealed microparticles 41 6. Characterisation of the physical mixtures, molten mixtures and microparticles 42 6.1. Particle size analysis of particles produced by melting method and milling . 42 6.2. Particle size analysis of microparticles produced by spray congealing . 43 6.3. Determination of total yield and useful yield of spray congealed microparticles 43 6.4. Assessment of morphology of microparticles 44 6.5. Swelling analysis of microparticles . 44 6.6. Viscosity measurement of molten mixtures . 45 6.7. Thermal analysis 45 6.8. X-ray powder diffraction (XRD) analysis . 46 6.9. Raman spectroscopy 46 6.10. Fourier transform-infrared spectroscopy (FT-IR) 47 6.11. Determination of solubility of metronidazole in PEG . 48 6.12. Determination of drug content and encapsulation efficiency 48 6.13. Construction of Beer-Lambert plot 49 6.14. Drug release study of microparticles . 49 7. Characterisation of tablets . 50 7.1 Tablet thickness 50 7.2 Tablet hardness . 50 v 7.3 Disintegration time 50 8. Statistical analysis . 51 RESULTS AND DISCUSSION . 53 Part I. Screening of matrix material and additives 53 A. Rheological properties of PEG with/without MNZ 54 1. Influence of molecular weight of PEG on viscosity . 54 2. Influence of temperature on viscosity of the molten PEG with/without drug 55 3. Influence of viscosity and PEG grade on drug crystallinity in congealed matrix at different drug concentration . 57 B. Crystallinity of PEG 59 C. Impact of different grades of PEG on MNZ stability in solid dispersions . 60 D. Rheological impact of additives on molten PEG 3350 61 E. Summary for Part I . 63 Part II. Impact of HPMC on rheological properties of binary/ternary PEG melt suspensions . 64 A. Nature of PEG melt suspensions 64 B. Effects of various concentrations and grades of HPMC and temperature 66 C. Effect of HPMC particle size 71 D. Effect of water content in molten PEG . 79 E. Summary for Part II 81 Part III. Evaluation of polymer rheology using principal component analysis 81 A. Assessment of principal component analysis as a suitable analytical tool to evaluate viscosity profiles of melt suspensions . 82 B. Evaluation of ternary polymer melt suspensions using principal component analysis . 87 C. Sprayability of ternary melt suspensions 90 D. Summary for Part III . 90 Part IV. Impact of various grades and concentrations of HPMC on the properties of congealed matrix with drug . 91 A. Appearance of molten mixtures, solid dispersions and milled particles 91 vi B. Relationship between particle size and the mechanical properties of congealed matrix with drug . 93 1. Effect of HPMC concentration . 93 2. Effect of viscosity . 96 C. Effect of HPMC on MNZ crystallinity at high drug concentration 100 D. Summary for Part IV 102 Part V. Impact of HPMC on spray congealed PEG microparticles with/without drug 103 A. Total yield and useful yield 103 B. Characterisation of spray congealed microparticles . 106 1. Morphology of microparticles 106 2. Size and size distribution of microparticles 107 3. Solid state properties of MNZ in the spray congealed microparticles 110 4. Drug content and encapsulation efficiency . 123 C. Drug dissolution of MNZ 124 D. Summary for Part V 126 Part VI. Swelling effect of different grades and concentrations of HMPC 127 A. Extent of swelling . 128 B. Rate of erosion 133 C. Swelling effect on dissolution of rifampicin . 136 D. Summary for Part VI 138 Part VII. Effect of HPMC on MNZ crystallinity in spray congealing and during storage . 138 A. Impact of HPMC particle size on MNZ crystallinity . 138 B. Summary for Part VII . 142 Part VIII. Modification of drug release from spray congealed microparticles and the feasibility of developing the microparticles into tablets 142 A. Dissolution of microparticles containing various additives 144 B. Screening of tablet formulations using manual tablet press . 147 C. Optimisation of rotary tablet press parameters . 150 D. Production and characterisation of MNZ tablets 151 vii E. Summary for Part VIII 154 CONCLUSION . 157 FURTHER STUDIES . 161 REFERENCES . 164 APPENDICES 177 LIST OF PUBLICATIONS AND PRESENTATIONS . 180 viii SUMMARY Spray congealing has been used over decades to produce particulates by the food and pharmaceutical industries. The latter have used this technology to develop specialised drug delivery systems with meltable materials. Various types of polymeric admixtures and additives may be incorporated into the melt carrier matrix to modify the final product properties, in particular, the drug release. In this study, various grades of polyethylene glycol (PEG) and types of additives commonly used in formulating modified release dosage forms were screened for their suitability as a meltable matrix and matrix modifier, respectively, for spray congealing. The impact of grade and concentration of selected additives on the properties of the molten mixtures, metronidazole (MNZ), PEG matrix and spray congealed microparticles were investigated. Suitable formulations were then selected for the production of spray congealed microparticles, which were then compressed into tablets as the final dosage form. The grade of PEG used was found to affect the crystallinity and thermodynamic stability of MNZ. Viscosity of the molten mixture had also played an important role in affecting the crystallinity of MNZ. Screening of the additives showed that hydroxypropyl methylcellulose (HPMC) was the appropriate matrix modifier as it dispersed uniformly in molten PEG and the molten mixture had low viscosity, which is amendable to spray congealing. An understanding of the rheological behaviour of polymer melt suspensions is crucial in pharmaceutical manufacturing, especially for spray ix congealing. Rheological studies showed that the amount and particle size of HPMC, besides temperature, affected the viscosity of PEG melt suspensions. Using principal component analysis, the ternary melt suspensions consisting of PEG, MNZ and HPMC of different grades were classified into three clusters, namely low, moderate and high according to their final melt suspension viscosities. The classification of formulation viscosities allows the selection of an appropriate grade and concentration of HPMC to achieve the desired spray viscosity for spray congealing. Formulations in the low viscosity cluster were found to be the most easily sprayable. The impact of various grades and concentrations of HPMC on the properties of the PEG matrix and MNZ was subsequently studied using the melt solidification method and by spray congealing. The addition of HPMC decreased the size of the microparticles obtained, indicating a decrease in mechanical strength of the PEG matrix. The reduction in MNZ crystallinity was due to the presence of HPMC and not the viscosity of the molten mixture. HPMC was successfully incorporated into spray congealed PEG-MNZ microparticles. Spherical and free-flowing microparticles with good yield and high encapsulation efficiency of MNZ were obtained. The HPMC concentration influenced the viscosity of the molten mixture and size of the resultant microparticles. Particle size of HPMC exerted a significant effect on MNZ crystallinity. The amorphous and molecularly dispersed MNZ in the microparticles was stable thermodynamically during storage. The swelling extent of microparticles was influenced by the grade, particle size and number of HPMC particles employed. Drug dissolution was influenced by matrix erosion of the microparticles. A fast rate of erosion x Christoffersson, K.E., Sjöström, M., Edlund, U., Lindgren, A., Dolk, M., 2002. Reactivity of dissolving pulp: Characterisation using chemical properties, NMR spectroscopy and multivariate data analysis. Cellulose 9, 159-170. Ciron, C.I.E., Gee, V.L., Kelly, A.L., Auty, M.A.E., 2011. 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Matrix materials, active principles and additives employed in spray congealing. Matrix materials Active principles Carnauba wax Cetostearyl alcohol Glyceryl behenate Glyceryl palmitostearate Glycerol tripalmitate Glyceryl tristearate/tristearin Hydrogenated castor oil Aminolevulinic acid Aspirin Atenolol Avobenzone Azithromycin dehydrate Benzoic acid Chitosan Ethylcellulose Lecithin Phosphatidylcholine Poloxamer Polyethylene Bovine serum albumin Hydrogenated palm oil Hydrogenated soybean oil Microcrystalline wax Bupivacaine Caffeine Polyoxyethylene sorbitan monooleate Rosin Silicon dioxide Palmitic acid PEG 4000 Clarithromycin Crystalline human insulin Diclofenac Econazole nitrate Estradiol cypionate Felodipine Fenbufen Glimepiride PEG 5500 PEG 6000 Poloxamer Polyorthoester Stearic acid Stearoyl macrogol glycerides Stearyl alcohol Trimyristin Witepsol H15 Carbamazepine Indomethacin Lidocaine hydrochloride Mesalazine Piroxicam Praziquantel Propafenone hydrochloride Salbutamol sulphate Silybum Marianum Sulfamethylthiadiazole Sulfathidole Sulfathylthiadiazole Tetracycline hydrochloride Theophylline Verapamil hydrochloride Vitamin E 177 Additives Sodium carboxymethylcellulose Sorbitan monooleate Appendix 2. Properties of various grades of HPMC. HPMC grades Methoxyl Hydroxypropyl Nominal substituent (%) substituent (%) Viscosity (mPa.s) K100M 22 8.1 100000 K15M 22 8.1 15000 K4M 22 8.1 4000 K100 LV 22 8.1 100 E4M 29 8.5 4000 E50 LV 29 8.5 50 E15 LV 29 8.5 15 F4M 28 5.0 4000 F50 LV 28 5.0 50 - - [...]... released at a higher rate than crystalline drug (Savolainen et al., 2002) Encapsulation of praziquantel in a hydrophilic stearyl macrogol glyceride matrix increased its dissolution rate (Passerini et al., 2006) Drug release was significantly enhanced at drug load of 5 and 10 %, w/w of praziquantel Further increase in drug load to 20 and 30 %, w/w of praziquantel resulted in reduced release rate from... which was not 9 seen when tristearin or stearic acid was used (Albertini et al., 2013) This was attributed to the affinity between drug and lipid material Taste masking is often required for pharmaceutical oral dosage forms because a large number of drugs have bitter or unpleasant taste Spray congealing is a useful technique for taste masking Yajima et al (2002; 2003; 1996; 1999) had undertaken extensive... Influence of matrix materials For spray congealing, the matrix material must be a molten liquid at an elevated temperature and when atomised, forms fine droplets that congeal in the cooled chamber (Deasy, 1984) When assessing the suitability of a matrix material for spray congealing, two important properties must be considered, namely the melting temperature and heat stability of the matrix material The matrix. .. et al., 1995; Maschke et al., 2007; Schwendeman et al., 1996; Sinha and Trehan, 2003; Taguchi et al., 1992; Wanasundara and Shahidi, 1995), increase flowability (Lee, 1981), mask taste (Deasy, 1984; Yajima et al., 2002; Yajima et al., 2003; Yajima et al., 1996; Yajima et al., 1999), reduce gastrointestinal irritation (Frenkel et al., 1968) and/or alter release properties (Bodmer et al., 1992; Deasy,... Thus, any coating attempts by spray drying may be adequate for taste masking and other purposes but not for controlled drug release (Deasy, 1984) Conversely, particles produced using spray congealing are generally dense, spherical and smooth surfaced as there are no internal evaporative effects on 5 the spray congealed products (Hincal and Kaş, 1994) The properties of spray congealed particles make them... result in increased drug dissolution and vice versa Formation of the barrier and the grade of HPMC used affected the rate of erosion of microparticles and modified the release of rifampicin Further modification of drug release of spray congealed PEG -HPMC microparticles could be achieved with the incorporation of other additives, such as dicalcium phosphate Formulation and operation parameters of the rotary... hydrated in aqueous medium and their hydration capacity was reduced by sorbitan monostearate As a result, the drug release process was impeded In addition to drug release, surfactants were found to affect other properties of microparticles It was reported that lecithin affected the phase transformation of the lipid matrix (Eldem et al., 1991) Lecithin was incorporated into the crystalline lattice and... drugs/active principles, encapsulation of proteins, vaccines and other solid particles has been attempted with a variety of matrices using the spray congealing technique The core material to be encapsulated may be suspended, melted or dissolved in the molten matrix Drugs possessing certain properties such as heat stability, small particle size and regular particle shape are more amenable to spray congealing. .. Deasy, 1984; Park et al., 2004; Passerini et al., 2003) of the active principles Over the last few decades, researchers had explored the application of spray congealing to various matrix materials and active principles to produce particles of different size, shape and solubility (Appendix 1) Figure 1 Distribution of drug within spray congealed particle A schematic diagram of the spray congealer and the process... (Cavallari et al., 2005; Deng et al., 2003; Passerini et al., 2002; Rodriguez et al., 1999) The amount of microparticles obtained per unit time was found to decrease with increasing drug load The atomisation process was depressed by the incorporation of drug in the matrix material and a longer sonication time was required to atomise the same amount of feed material Consequently, the feed material was exposed . xix INTRODUCTION 2 A. Spray congealing 2 1. The process of spray congealing 2 2. Advantages and disadvantages 5 3. Influence of matrix materials 7 4. Influence of active pharmaceutical ingredients. spray congealing. The addition of HPMC decreased the size of the microparticles obtained, indicating a decrease in mechanical strength of the PEG matrix. The reduction in MNZ crystallinity was. research study provided insights into the impact of PEG and HPMC as a drug carrier in the formulation of spray congealed matrix for modulating drug release. The work also had contributed to a deeper