A STUDY ON BOTTOM-SPRAY GRANULATION AND ITS POTENTIAL APPLICATIONS ER ZHI LIN DAWN NATIONAL UNIVERSITY OF SINGAPORE 2010 A STUDY ON BOTTOM-SPRAY GRANULATION AND ITS POTENTIAL APPLICATIONS ER ZHI LIN DAWN B.Sc. (Pharm.) Hons., NUS A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2010 ACKNOWLEDGEMENTS I would like to express my heartfelt thanks to my supervisors, Asst. Prof Celine Liew and A/P Paul Heng for their guidance and the opportunities they have given me to learn and grow during the course of my study. I am indebted to NUS for providing me with a research scholarship to fund this higher degree, and to the Department of Pharmacy and its administrators for the facility and support during my candidature. I also wish to thank A/P Chan Lai Wah for her concern and advice throughout my candidature. Special thanks to Mrs Teresa Ang, Mr Peter Leong and Ms Wong Mei Yin, the laboratory technologists during my course of study for their technical assistance. I am fortunate to have been in the company of a group of supportive and helpful fellow postgraduates in GEA-NUS PPRL. They have made the laboratory a very pleasant and conducive place to work in. I would like to especially thank Elaine, Zhihui, Sook Mun, Yihui, Atul, Likun, Stephanie, Wun Chyi and Christine for their invaluable friendship. Finally, my deepest gratitude belongs to my dear family and friends, especially to my parents, for their faith and belief in me. I am grateful to my beloved husband, Dale, for his loving support and patience during this work. I will also like to thank my best friend, Serena, for her constant encouragement. Dawn, 2010 ii DEDICATION For my parents, Chin Lam and Hwee Kiang iii Table of contents TABLE OF CONTENTS ACKNOWLEDGEMENTS .ii DEDICATION . iii TABLE OF CONTENTS iv SUMMARY . x LIST OF TABLES .xii LIST OF FIGURES xiv LIST OF SYMBOLS .xvii I. INTRODUCTION . 2  A. BACKGROUND 2  A1. Significance of granulation . 2  A2. Types of granulation . 4  A2.1. Dry granulation processes . 4  A2.2. Wet granulation processes . 5  B. FLUIDIZED BED GRANULATION . 9  B1. Techniques of spray 11  B2. Advantages and challenges . 14  B3. Parameters influencing the process and granule quality . 16  B3.1. Material related factors 17  B3.2. Process related factors during the liquid binder addition phase . 20  B3.3. Process related factors during the drying phase 22  C. RECENT ADVANCES IN FLUIDIZED BED GRANULATION 25  C1. Process analytical technology (PAT) in fluidized bed granulation . 25  C1.1. Moisture content 26  iv Table of contents C1.2. Particle size 27  C1.3. Composition of bed material . 28  C1.4. Solid state transformations 28  C2. Fluidized bed granulation methods . 29  C2.1. Fluidized bed melt granulation 29  C2.2. Fluidized bed binderless granulation . 31  C2.3. Bottom-spray granulation 32  II. HYPOTHESIS AND OBJECTIVES 40  A. HYPOTHESIS 40  B. OBJECTIVES . 41  III. EXPERIMENTAL . 44  A. MATERIALS 44  A1. Feed material . 44  A2. Liquid binder . 44  A3. Model drugs 44  A4. Tablet excipients . 45  A5. Chemicals for dissolution media preparation and high performance liquid chromatography (HPLC) analyses . 46  B. METHODS . 47  B1. Feed material . 47  B1.1. Blending of powder . 48  B1.2. Determination of powder particle size . 48  B1.3. Determination of powder flow with angle of repose . 48  B2. Liquid binder . 49  B2.1. Micronization of HCT . 49  v Table of contents B2.2. Determination of particle size of micronized HCT . 50  B2.3. Preparation of HCT-incorporated liquid binder 50  B3. Granulation process . 50  B3.1. Real-time measurement of process conditions 52  B3.2. Determination of process drying efficiency 54  B3.3. Determination of granule bed temperature profiles . 54  B3.4. Determination of capacity for moisture removal . 55  B3.5. Determination of granule bed moisture content profiles . 55  B3.6. Determination of air velocity within partition column 56  B3.7. Determination of process yield 56  B4. Characterization of granules 57  B4.1. Granule size . 57  B4.2. Granule shape 57  B4.3. Granule surface morphology . 58  B4.4. Granule flow 58  B4.5. Granule porosity 59  B4.6. Granule friability . 59  B4.7. Content determination of HCT in granules . 60  B4.8. Dissolution of HCT from granules 61  B4.9. Amount of ASA degradation . 61  B5. Compaction process 63  B5.1. Heckel plot analysis . 64  B6. Characterization of tablets . 65  B6.1. Tablet surface morphology and roughness 65  B6.2. Tablet porosity . 66  vi Table of contents B6.3. Tablet tensile strength 67  B6.4. Disintegration of tablets . 67  B6.5. Dissolution of HCT from tablets . 67  B7. Statistical analyses . 68  B7.1. Design-of-Experiment and response surface modelling 68  B7.2. Multivariate data analysis 69  B7.3. Regression analyses . 69  B7.4. Other data analyses 70  B7.5. Level of significance 70  IV. RESULTS AND DISCUSSION . 72  A. ROLE OF FLUID DYNAMICS AND WETTING ON GRANULE FORMATION IN PG 72  A1. Factors influencing air velocity within the partition column 73  A2. Factors influencing characteristics of granule batches . 77  A2.1. Influence of variables on process yield . 77  A2.2. Influence of variables on granule size and size distribution 85  A2.2.1. Influence of variables on fines . 85  A2.2.2. Influence of variables on lumps . 88  A2.2.3. Influence of variables on modal size fraction 89  A2.2.4. Influence of variables on MMD . 89  A2.2.5. Influence of variables on span . 91  A2.3. Influence of variables on granule shape 91  A2.4. Influence of variables on granule flow 95  B. APPLICABILITY OF PG AND TG FOR SPRAY DEPOSITION OF DRUG DURING GRANULATION . 96  vii Table of contents B1. Drug content and drug content uniformity of PG and TG granules 96  B2. Impact of particle circulation pattern and fluid dynamics in PG and TG on granule growth 99  B2.1. Resultant mode of granule growth in PG and TG . 102  B2.2. Process sensitivity to binder spray rate and the resultant influences on granule growth . 106  B2.3. Process sensitivity to particle size of feed material and the resultant influences on granule growth . 112  B3. Drug release properties of PG and TG granules . 117  B4. Flow properties of PG and TG granules 119  C. COMPACTIBILITY STUDY ON PG AND TG GRANULES . 120  C1. Compaction behaviour of PG and TG granules 120  C1.1. Influence of compactibility of granules on tablet properties . 126  C1.2. General relation between granule characteristics, granule compactibility and tablet properties . 136  C2. Compaction behaviour of PG and TG granules with tablet excipients . 142  C2.1. Influence of compactibility of granules on disintegrant efficacy . 145  D. INVESTIGATIVE STUDY ON THE ABILITY OF PG TO GRANULATE MOISTURE SENSITIVE DRUGS 150  D1. ASA stability in PG and TG during processing 150  D1.1. Impact of particle circulation pattern and fluid dynamics in PG and TG on ASA stability 155  D1.2. Influence of inlet air temperature and binder spray rate 158  viii Table of contents D2. Factors influencing processing conditions and ASA stability in PG 161  D2.1. Influence of AAI diameter . 163  D2.2. Influence of inlet air temperature 164  D2.3. Influence of binder spray rate 165  V. CONCLUSION . 168  VI. REFERENCES . 172  VII. LIST OF PUBLICATIONS 211  ix References Rasanen, E., Rantanen, J., Jorgensen, A., Karjalainen, M., Paakkari, T., Yliruusi, J., 2001. Novel identification of pseudopolymorphic changes of theophylline during wet granulation using near infrared spectroscopy. J. Pharm. 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Pharm. Sci. 64(11), 1869-1873. Zuurman, K., Riepma, K.A., Bolhuis, G.K., Vromans, H., Lerk, C.F., 1994. The relationship between bulk density and compactibility of lactose granulations. Int. J. Pharm., 102(1-3), 1-9. 209 PART VII: LIST OF PUBLICATIONS 210 List of publications VII. LIST OF PUBLICATIONS Journal publications 1. Liew, C.V., Er, D.Z.L., Heng, P.W.S., 2009. Air-dictated bottom spray process: Impact of fluid dynamics on granule growth and morphology. Drug Dev. Ind. Pharm. 35(7), 866-876. 2. Er, D.Z.L., Liew, C.V., Heng, P.W.S., 2009. Layered growth with bottom-spray granulation for spray deposition of drug. Int. J. Pharm. 377(1-2), 16-24. Conference presentations 1. Er, D.Z.L., Liew, C.V., Heng, P.W.S. A comparative study on the compactibility of granules prepared by bottom-spray and top-spray granulation. Poster presentation. American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition 2009, 8th to 12th November 2009, Los Angeles, California, USA. 2. Er, D.Z.L., Liew, C.V., Heng, P.W.S. Air-dictated bottom spray process for granulation of moisture sensitive drugs. Oral presentation. ASEAN Scientific Conference in Pharmaceutical Technology 2008, 1st to 3rd June 2008, Penang, Malaysia. 3. Er, D.Z.L., Liew, C.V., Heng, P.W.S. A study on granule growth behaviour in top and bottom fluidized bed granulations. Poster presentation. Asian Association of Colleges of Pharmacy (AASP) Conference 2007, 25th to 28th October 2007, Makati City, Philippines. 211 List of publications 4. Ng, Y., Er, D.Z.L., Liew, C.V., Heng, P.W.S. Influence of the characteristics of starting material on fluidized bed granules properties. Poster presentation. 2nd AAPS-NUS Student Chapter Symposium, 5th March 2007, Singapore. 5. Er, D.Z.L., Liew, C.V., Heng, P.W.S. Precision granulation: a promising bottom spray fluid bed granulation process. Poster presentation. Asian Pharmaceutics Graduate Congress, 25th to 27th September 2006, Singapore. 6. Er, D.Z.L., Liew, C.V., Heng, P.W.S. A comparative study of the influence of fluid dynamics and thermodynamics on the properties of granules prepared by precision granulation. Poster presentation. American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition 2006, 29th October to 2nd November 2006, San Antonio, Texas, USA. 7. Er, D.Z.L., Liew, C.V., Heng, P.W.S. Cocurrent and countercurrent binder spray orientation on growth kinetics in fluid bed granulation processes. Poster presentation. Asian Association of Colleges of Pharmacy (AASP) Conference 2005, 14th to 17th November 2005, Bangkok, Thailand. 212 [...]... linear term (partition gap) in response surface equation XS linear term (binder spray rate) in response surface equation XAA squared term (air accelerator insert × air accelerator insert) in response surface equation XPP squared term (partition gap × partition gap) in response surface equation XSS squared term (binder spray rate × binder spray rate) in response surface equation XAP interaction term (air... in which a positive correlation to granule size was exhibited The partition gap played an important role in transporting particles into the spray granulation zone, whereas the binder spray rate affected granule shape Unlike conventional top -spray granulation, fluid dynamics in the bottom- spray process can be easily modulated by using different air accelerator inserts and partition gaps to allow for... (air accelerator insert × partition gap) in response surface equation xix List of symbols XAS interaction term (air accelerator insert × binder spray rate) in response surface equation XPS interaction term (partition gap × binder spray rate) in response surface equation Xaf linear term (airflow rate) in regression equation XAAI linear term (air accelerator insert) in regression equation Xheat linear... of (a) AAI diameter and partition gap (hold values at binder spray rate = 21 g/min) and (b) binder spray rate and partition gap (hold values at AAI diameter = 29.5 mm) on aspect ratio 93 Figure 13 Mean drug content of PG and TG granules: PG/small ( ), PG/medium ( ), PG/large ( ), TG/small ( ), TG/medium ( ) and TG/large ( ) when (a) binder spray rate and (b) lactose powder blend were varied... practical application, attributed to inherent problems such as loss in compactibility (Li and Peck, 1990) and poor homogeneity of the formed compact (Badawy et al., 1999) A2 .2 Wet granulation processes Some common examples of wet granulation processes include wet massing, high shear granulation, pan granulation, extrusion-spheronization, spray drying and fluidized bed granulation Of particular interest... postioned at side of chamber Perforated metal plate Powder particles Rotating plate Fluidizing air Gap air (c) Product chamber Partition column Powder particles Perforated air distribution plate Fluidizing air Spray nozzle positioned at bottom of chamber Figure 3 Schematic diagrams of (a) top -spray granulator, (b) tangential -spray granulator: double chamber rotary processor and (c) bottom- spray granulator... commonly present and its presence better regulates particle fluidization and flow into the spray granulation zone (Ishida and Shirai, 1975) Binder solution is sprayed in the same direction as the air flow Essentially employed for coating purposes and less so for granulation (Dixit and Puthli, 2009), there were few reports on its use for pharmaceutical granulation in the 1990s (Flogel and Egermann,... granulation of inorganic materials (Freitag and Kleinebudde, 2003), granulation of dry herbal materials (EggelkrautGottanka et al., 2002; Soares et al., 2005), compaction of tablet formulations (Mollan and Celik, 1996; Skinner et al., 1999) and production of controlled release formulations (Ohmori and Makino, 2000; Juang and Storey, 2003; Mitchell et al., 2003) However, there are limitations to its practical... increases, particle deformation occurs and creates more points of contact for bonding to occur With an additional increase in the 4 Introduction compaction force, fragmentation of particles takes place and the number of potential bonding sites is further increased Lastly, particle-particle bonding results, together with plastic deformation and fragmentation Roller compaction has found application in the granulation. .. have understandably gained more attention 3 Introduction A2 Types of granulation Several manufacturing techniques are used for producing granules, and they can be broadly divided into dry and wet granulation processes A2 .1 Dry granulation processes In dry granulation processes, power particles are brought together by mechanical force The binders used exist in solid form A major advantage of dry granulation . A STUDY ON BOTTOM-SPRAY GRANULATION AND ITS POTENTIAL APPLICATIONS ER ZHI LIN DAWN NATIONAL UNIVERSITY OF SINGAPORE 2010 A STUDY ON BOTTOM-SPRAY. factorial design. 78 Figure 11. Response surface graphs of the effect of (a) AAI diameter and binder spray rate (hold values at partition gap = 26 mm) on fines and (b) AAI diameter and partition. granulation 2 A2 . Types of granulation 4 A2 .1. Dry granulation processes 4 A2 .2. Wet granulation processes 5 B. FLUIDIZED BED GRANULATION 9 B1. Techniques of spray 11 B2. Advantages and challenges