Understanding pellet filler interactions in compression of coated pellets

UNDERSTANDING PELLET-FILLER INTERACTIONS IN COMPRESSION OF COATED PELLETS CHIN WUN CHYI NATIONAL UNIVERSITY OF SINGAPORE 2011 UNDERSTANDING PELLET-FILLER INTERACTIONS IN COMPRESSION OF COATED PELLETS CHIN WUN CHYI B.Sc. (Pharm.) Hons, NUS A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE ACKNOWLEDGEMENTS I would like to express my heartfelt thanks to my supervisors, A/P Paul Heng Wan Sia and A/P Chan Lai Wah for their patience, guidance, encouragements and opportunities given by them throughout my candidature. I am also thankful for their time and effort spent in correcting and improving this thesis. It has been an enriching experience working with them. I would also like to thank Dr Celine Liew for her suggestions to improve my work and for being so approachable. I wish to thank National University of Singapore for providing the research scholarship and resources for research. My sincere appreciation goes to my colleagues and friends in GEANUS for their support, help and company: Zhihui, Dawn, Sook Mun, Stephanie, Atul, Likun, Christine, Kou Xiang, Srimanta, Asim, Bingxun, Poh Mun, Yien Ling, Teresa and Mei Yin. They have made my graduate life more enjoyable and meaningful. I am grateful and indebted to my parents and sister for their constant love, support, patience and faith in me. Without them, I will never be able to come this far. Thank you. I am also thankful to brothers and sisters in Christ who have been supporting me through prayers. Last but not the least, I wish to express my gratitude towards my Lord and Saviour, Jesus Christ, who “causes all things to work together for good to those who love God, to those who are called according to His purpose” (NASB, Romans 8:28). Wun Chyi July, 2011 TABLE OF CONTENTS TABLE OF CONTENTS .i SUMMARY v LIST OF TABLES .vii LIST OF FIGURES viii LIST OF SYMBOLS .xii 1. INTRODUCTION 1.1. Background .2 1.2. Coating of multiparticulates 1.2.1. Polymers for coating .4 1.2.2. Coat thickness .8 1.3. Coating core .9 1.4. Compact fillers 12 1.5. Proportion of coated pellets .23 1.6. Compression pressure 26 1.7. Protective overcoat and undercoat 26 1.8. Methods for assessing the coat integrity of compressed pellets 30 2. HYPOTHESES AND OBJECTIVES 41 3. EXPERIMENTAL .44 3.1. MATERIALS 44 3.1.1. Pellet cores and coating materials 44 3.1.2. Compact excipients .44 3.2. METHODS 46 3.2.1. Preparation of coating materials 46 3.2.2. Pellet coating .46 i 3.2.3. Preparation and characterization of compacts 48 3.2.4. Dissolution studies 49 3.2.5. Analysis of drug release data 50 3.2.6. Disintegration test .51 3.2.7. Evaluation of the densification behaviour of materials 51 3.2.8. Determination of particle true density 52 3.2.9. Determination of material bulk density, tapped density and Hausner ratio 53 3.2.10. Particle size reduction of lactose 53 3.2.11 Particle size determination of compact fillers .54 3.2.12. Particle size and coat thickness determination of pellets 54 3.2.13. Method of retrieving pellets from compacts .55 3.2.14. Scanning electron microscopy (SEM) 56 3.2.15. Stereomicroscopy 56 3.2.16. Surface profilometry .56 3.2.17. Determination of pellet core osmolality .56 3.2.18. Determination of pellet mechanical strength .57 3.2.19. Statistical analysis .57 3.2.20. Multivariate data analysis .58 4. RESULTS AND DISCUSSION 60 PART A. UTILIZATION OF LACTOSE FILLERS IN COMPACTS CONTAINING COATED PELLETS 60 A.1. Influence of lactose filler particle size on the extent of coat damage during compression .60 A.2. Influence of disintegration time on UC/C values 62 ii A.3. Other methods of assessing coat integrity of pellets compressed with lactose filler of different particle size 65 A.3.1. Stereomicroscopy 65 A.3.2. Scanning electron microscopy (SEM) .68 A.3.3. Surface profilometry .71 A.5. Utilization of micronized lactose in reducing the extent of coat damage during compression .75 A.5.1. Relationship between disintegration time and UC/C 77 A.5.2. Effect of lactose blend particle size 77 A.5.3. Effect of proportion of micronized lactose in the blend .79 A.5.4. Critical pellet volume fraction .85 A.6. Conclusion 86 PART B. INFLUENCE OF FILLER TYPE AND PELLET VOLUME FRACTION IN COMPACTS CONTAINING COATED PELLETS 89 B.1. Physical characteristics of fillers and their influence on the extent of coat damage during compression 89 B.2. Relationship between the material compressibility and extent of pellet coat damage .99 B.3. Comparison of the extent of coat damage in uncured and cured coated pellets 102 B.4. Influence of disintegration time on UC/C values .103 B.5. Influence of compression pressure and pellet volume fraction 105 B.5.1. Influence of compression pressure and disintegration time on different dissolution parameters .105 B.5.2. Relationship between compact characteristics and UC/C 111 iii B.5.3. Influence of compression pressure on UC/C 112 B.5.4. Influence of pellet volume fraction on UC/C 120 B.6. Influence of compression speed on the extent of coat damage .129 PART C. INFLUENCE OF PELLET SIZE AND PELLET TYPE IN COMPACTS CONTAINING COATED PELLETS 133 C.1. Dissolution profiles of uncompressed pellets .133 C.1.1. Differences in drug release from coated MCC pellets and sugar pellets .133 C.1.2. Differences in drug release from coated sugar pellets of different particle size 138 C.2. Influence of pellet core material on the extent of coat damage .139 C.3. Influence of sugar pellet size on the extent of coat damage .144 5. CONCLUSION 149 6. REFERENCES .153 iv underwent a longer phase of particle rearrangement than MCC fillers. As a result, this allowed the pellets to undergo spatial adjustments at higher compression pressures, reducing the forceful pellet-filler interactions. In addition, the compressibility studies also showed that compressible materials could result in higher pellet coat damage due to greater reduction in compact volume during compression. Hence, material compressibility acted as a double-edged sword. On one hand, it could reduce the extent of indentations caused by coarser filler particles through particle deformation. On the other hand, the reduction of compact volume due to material compressibility resulted in greater extent of pellet coat damage. Depending on the compression pressure applied, the pellets underwent different compression phases leading to different levels of coat damage. Overall, there were three main phases, with two critical transition points. Minimal coat damage was observed in the initial lag phase where the particles underwent mainly rearrangement. The first critical point, which was found to be associated with the pellet volume fraction range of 0.33 to 0.39 depending on the filler type, corresponded to the bond percolation threshold of the compact components. Beyond this point, extensive particle deformation occurred, resulting in acceleration of pellet coat damage with increase in compression pressure and pellet volume fraction. This constituted the second phase. The pellet volume fraction at the second critical point was approximately 0.48 for all the fillers. It corresponded to the percolation threshold for the coated pellets. Beyond the second critical point, pellet fusion and formation of larger pellet aggregates occurred, resulting in longer disintegration time and thus, slower drug release. This constituted the third phase. At almost all the compression pressures tested, UC/C value for compacts containing micronized lactose was the lowest, followed by PH105, PH200 and lactose 80M. Compared to the other filler 150 types, the coated pellets compressed with micronized lactose were less sensitive to the changes in compression pressure, pellet volume fraction and compression speed. In contrast to sugar pellets, the extent of coat damage of MCC pellets was not dependent on the filler particle size. The compressibility of the filler seemed to be the dominating factor affecting the extent of coat damage. Except micronized lactose, the extent of coat damage of MCC pellets was lower than that of sugar pellets. These observations were attributed to the greater mechanical strength of MCC pellets and differences in the main mechanism of pellet deformation. Sugar pellets would undergo brittle fragmentation under pressure while MCC pellets would undergo densification and shape deformation under pressure. Consequently, MCC pellets were more resistant to surface indentations. In addition, the coat damage for MCC pellets was more gradual than sugar pellets as they were less brittle. Unlike sugar pellets, coat damage for MCC pellets was mainly dependent on the extent of core densification during compression rather than surface indentation and pellet fragmentation. Hence, the most suitable filler might not be the same for different coated pellet cores, especially when the pellets deform differently. A greater extent of coat damage was found in sugar pellets of smaller particle size. This was attributed to the greater specific surface area of smaller pellets in contact with the filler particles. Furthermore, the mechanical strength of the smaller pellets was lower than that of larger pellets. The smaller pellets exhibited a lower threshold to fragmentation during compression. 151 PART 6: REFERENCES 152 6. REFERENCES Abrahamsson, B., Alpsten M., Jonsson U.E., 1996. 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Particle slippage and rearrangement during compression of pharmaceutical powders. Journal of Pharmacy and Pharmacology, 1978, 6-10. York, P., 1979. A consideration of experimental variables in the analysis of powder compaction behaviour. Journal of Pharmacy and Pharmacology, 31, 244-246. Yuasa, H., Takashima, Y., Omata, T., Kanaya, Y., 2001. Studies on stress dispersion in tablets. III. Suppression of fracture of coated film by an excipient during the preparation of tablets containing coated particle. S.T.P Pharma Sciences, 11, 221-227. 164 LIST OF PUBLICATIONS Poster presentations • W. C. Chin, L. W. Chan, P. W. S. Heng, A study on the phases of pellet coat damage during compression, AAPS Annual Meeting and Exposition, Washington D.C., USA, 23-27 October 2011 • W. C. Chin, L. W. Chan, P. W. S. Heng, Utilization of micronized lactose in reducing the extent of pellet coat damage during compression, AAPS Annual Meeting and Exposition, Los Angeles California, USA, - 12 November 2009 • W. C. Chin, L. W. Chan, P. W. S. Heng, Exploring methods to reduce damage to pellet coat under compression, Coating Workshop, Lille, France, 11 September 2008 • W. C. Chin, L. W. Chan, P. W. S. Heng, Influence of diluent particle size and compression force on coat integrity of pellets, Asian Association of Schools of Pharmacy Conference, Makati City, Philippines, October 25 - 28, 2007 Journal publication • X., Lin, W.C. Chin, K. Ruan, Y. Feng, P.W.S. Heng. Development of potential novel cushioning agents for the compaction of multi-particulates by co-processing micronized lactose with polymers. European Journal of Pharmaceutics and Biopharmaceutics (article in press). Oral presentation • W.C. Chin, L.W. Chan, P.W.S. Heng, Influence of pellet core properties on the extent of coat damage during compression, PharmSciFair, Prague, Czech, 13-17 June 2011 165 [...]... excessively deformable during compression in order to maintain the original uncompressed pellets drug release profiles 10 With regard to the size of pellets, smaller pellets coated to the same weight gain as bigger pellets had faster drug release due to the larger specific surface area of smaller pellets and thinner film coats applied A greater extent of coat damage was also found for smaller pellets (Béchard... length of particle rearrangement phase with respect to the compression pressure It was also dependent on the rate of increase in pellet coat damage with compression pressure and pellet volume fraction in the acceleration phase In order to investigate the influence of pellet size and pellet core material on the extent of pellet coat damage, sugar pellets of different size fractions and MCC pellets were coated. .. cushioning material was added (Wagner et al., 2000a) The absence of change in dissolution profile could be due to the incomplete disintegration of the coated pellets, and the faster drug releasing pellets compensated by slower released, undamaged pellets In order to cushion the coated pellets, especially those in direct contact with the die and punches, as well as to ensure disintegration of the tablet in. .. Stereomicroscope images of uncompressed coated pellets and coated pellets compressed with different grades of lactose “I” denotes pellets retrieved from the interior of the compacts; “S” denotes pellets from the surface of the compacts 66 Figure 10 SEM photomicrographs of (A) uncompressed pellets, as well as coated pellets compressed with (B) lactose 100M and (C) lactose 450M (retrieved from compact interior) ... stay intact during compression Tunon et al (2003a) concluded that the use of more porous and deformable pellets was more advantageous in terms of preserving the drug release profile after compression compared with hard, non-porous pellets It was suggested that cracking of pellet coat and hence, increase in drug release, could had resulted from a built-up of local high stresses during compression at pellet- pellet... characteristics of the pellets, as well as the mechanical strength and elastic recovery of the compacts containing only Surelease coated pellets (Maganti and Celik, 1994) It was concluded that coating pellets with Surelease changed the deformation characteristics of the pellets from being elasto-brittle to elasto-plastic With an increase in the coat thickness, the total ability of the pellets to deform... lactose (□) and lactose 80M (■) formed at different compression speeds .132 Figure 39 Drug release profile of MCC pellets (▲), Group I sugar pellets (♦), Group II sugar pellets (■) and Group III sugar pellets (Δ) 135 Figure 40 SEM photomicrographs of coated (A) Group I sugar pellets, (B) Group II sugar pellets, (C) Group III sugar pellets and (D) MCC pellets at (1) 200 and (2) 1000 times magnification... Plots of (A) apparent volume (B) porosity and (C) pellets volume fraction of compacts containing lactose 80M (■), micronized lactose (□), PH200 (▲) and PH105 (Δ) against the average mean pellet diameter of sugar pellets .146 xi LIST OF SYMBOLS ε: Porosity of the matrix σo: Yield strength in psi τ: Tortuosity factor of the capillary system A: Y-intercept of extrapolated line from the linear portion of. .. elastic coating used in the study done by Tunon et al (2003a), the brittle coat used was unable to adapt to the shape and volume changes in the soft pellets during compression In addition, since hard pellets have been reported to have a higher resistance to deform and fracture compared to soft pellets (Salako et al 1998), the greater degree of deformation by softer pellets could have resulted in a larger... characteristics of pellets coated with Surelease were studied by Maganti and Celik (1994) It was found that Surelease imparted plasto-elastic properties to the original brittle and elastic nature of uncoated pellets Increase in rate of compression also reduced the plastic flow and extent of consolidation, resulting in weaker compacts In addition, the sustained release properties were lost at low compression . UTILIZATION OF LACTOSE FILLERS IN COMPACTS CONTAINING COATED PELLETS 60 A.1. Influence of lactose filler particle size on the extent of coat damage during compression 60 A.2. Influence of disintegration. INFLUENCE OF PELLET SIZE AND PELLET TYPE IN COMPACTS CONTAINING COATED PELLETS 133 C.1. Dissolution profiles of uncompressed pellets 133 C.1.1. Differences in drug release from coated MCC pellets. UNDERSTANDING PELLET- FILLER INTERACTIONS IN COMPRESSION OF COATED PELLETS CHIN WUN CHYI NATIONAL UNIVERSITY OF SINGAPORE 2011