A study on the side spray fluidized bed processor with swirling airflow for granulation and drug layering

    A STUDY ON THE SIDE-SPRAY FLUIDIZED BED PROCESSOR WITH SWIRLING AIRFLOW FOR GRANULATION AND DRUG LAYERING WONG POH MUN B.Sc (Pharm.) 1st Class Hons., National University of Singapore A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2013         DECLARATION     ACKNOWLEDGEMENTS I would like to express my highest gratitude to my supervisors, Assoc Prof Paul Heng Wan Sia and Assoc Prof Chan Lai Wah for their supervision, advice and guidance during the course of my study Their motivation and guidance helped me tremendously in the completion of this study and preparation of the thesis I would also be grateful to Dr Celine Valeria Liew for her invaluable advice and help during my candidature I am also indebted to National University of Singapore for the kind award of NUS Research Scholarship that had supported me during my candidature I would also like to express my thanks to the Department of Pharmacy and its administrators for the support during my candidature I would like to express my special thanks to Ms Teresa Ang and Ms Wong Mei Yin for their ready assistance I would like to thank my helpful and supportive colleagues and friends in GEANUS Pharmaceutical Processing Research Laboratory The quality time that we spent for discussions, exchanging opinions was one of the best moments I had during my candidature Finally, I am grateful to my family for their support and understanding during my candidature I would like to express my appreciation to my wife, Siew Teng, for being a supportive and patience partner Poh Mun, 2013 I    Table of contents Summary   V  List of tables   VIII  List of figures   X  List of symbols and abbreviations   XIII  I Introduction   2  A Background   2  A.1 Granulation  2  A.1.1 Dry granulation   3  A.1.2 Wet granulation   4  A.2 Particle coating   10  B Types of fluidized bed processor  12  B1 Top-spray fluidized bed processor   13  B2 Bottom-spray fluidized bed processor   15  B3 Side-spray fluidized bed processor   16  C Factors influencing fluidized bed granulation and product quality   18  C.1 Effect of raw materials on granulation and coating  18  C.1 Effect of process parameters on granulation and coating   28  D Fluidized bed processor with swirling airflow- FlexStreamTM fluidized bed processor  . 34  E Design of experiments   40  II Hypothesis and objectives   44  A Hypothesis  . 44  B Objectives  . 46  III Materials and methods   50  A Materials   50  B Methods   50  B.1 Granulation process   50  B.2 Design of experiment (DOE)   56  B.3 Preparation of coating solution  59  B.4 Drug layering of non-pareil beads   61  B.5 Recording of particle movement  . 63  II    B.6 Size analysis   64  B.7 Assessment of flow properties and compressibility   66  B.8 Shape analysis   67  B.9 Determination of friability   68  B.10 Determination of density  . 69  B.11 Measurement of coating formulation viscosity  . 69  B.12 Drug content and content uniformity   70  B.13 Determination of weight gain of drug layered beads   71  B.14 Preparation of coating film   71  B.15 Optical microscopy of coating film  . 72  B.16 Scanning electron microscopy of drug layered beads   72  B.17 Statistical analysis   72  IV Results and discussion  . 76  Part A Examination of the particle movement in FS processor   76  Part B Understanding and optimization of FS process by DOE   80  B.1 Group 1: first DOE by central composite design   82  B.2 Group 2: second DOE by Box-Behnken design   94  Part C Comparison between FS granulation and TS granulation   98  C.1 Physical properties   98  C.1.1 Granule size and size distribution   98  C.1.2 Granule shape  . 105  C.1.3 Granule friability and density  . 106  C.1.4 Granule bulk density and flow properties   108  C.1.5 Granule compressibiliy   110  C.2 Chemical attributes   112  C.2.1 Drug content  . 112  C.3 Comparison of process time   113  Part D Effects of spray rate and coating formulations on drug layering of small nonpareil beads in FS processor  . 114  D.1 Effect of spray rate   115  D.2 Effect of coating formulation viscosity  . 116  D.3 Friability index of uncoated and coated beads   124  III    D.4 Drug content of drug layered beads   127  Part E Drug layering on small beads using FS processor   127  E.1 Optimization of formulation for drug layering on small beads for one-to-one weight gain   128  E.2 Drug layering of small beads for one-to-one weight gain   129  E.3 Physical examination of drug layered beads with one-to-one weight gain  . 131  E.4 Chemical analysis of drug layered beads with one-to-one weight gain   133  V Conclusion  . 136  VI References   138  VII List of publications and presentations   158    IV    Summary The use of swirling airflow in fluidized bed processor has not been fully explored although it has been extensively studied in other industries In an innovation to the fluidized bed processor, the FlexStreamTM (FS) fluidized bed processor adopted a swirling airflow instead of employing axial airflow which is typical of a conventional fluidized bed processor This new FS processor is the main focus of this study Two response surface approaches were employed to understand and optimize the process of FS fluidized bed granulation Parameters such as amount of binder solution delivered, binder solution spray rate and distance between spray nozzle and powder bed were studied using the central composite design while other parameters such as inlet airflow rate, atomizing air pressure and distance between spray nozzle and powder bed were studied using the Box-Behnken design Statistically significant models were developed to describe the relationship between these parameters with some important granule properties, such as mass median diameter, span, lumps and fines Following from the developed models, the process was optimized to produce granules with desired properties Granules prepared by the FS processor were compared with granules made by conventional fluidized bed processor at various spray rates Granules made by this processor were generally smaller and possessed more medium sized granules at higher spray rates (60 g/min to 80 g/min) compared to granules prepared by topspray granulation This was brought about by the better drying capacity of the swirling airflow in the FS fluidized bed processor However, under-granulation V    was observed for FS granulation at a low spray rate (21 g/min) but not in the topspray granulation FS fluidized bed processor was explored for drug layering onto small beads (355 – 425 μm) by spray coating Coating formulations containing two grades of hydroxypropylmethyl cellulose (HPMC), HPMC E3 and HPMC VLV, were used to layer coat small beads at different spray rates HPMC VLV was found to be better than HPMC E3 due to the possibility of a higher useful yield in the product Subsequently, prolonged small bead drug layering was carried out with HPMC VLV as main film forming agent and metformin hydrochloride as the model drug One-to-one weight gain runs for the drug layered beads were completed in about h without stopping the process Examination of these drug layered beads after h continuous layering found that a high useful yield (about 90 %, w/w) could be achieved The enhanced drying capacity with an elevated attritive condition caused by the airflow in the FS processor and the selection of suitable coating formulation had contributed to the good drug layering results Swirling airflow was found advantageous for the fluidized bed processor The swirling airflow had resulted in a better drying capacity for the processor and had enabled it to tolerate higher liquid spray rates This had translated into shorter process time without impairing the quality of granules produced In addition, the higher attritive conditions caused by the swirling airflow and atomizing air had help to reduce agglomeration in the long coating time involved for drug layering VI    Hileman, G.A., 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publication Wong, P.M., Chan, L.W., Heng, P.W.S., 2013 Investigation on side-spray fluidized bed granulation with swirling airflow AAPS PharmSciTech 14, 211221 (DOI: 10.1208/s12249-012-9906-0) Poster presentations Wong, P.M., Heng P.W.S., Chan L.W.,  Optimization of FlexStreamTM— A novel fluid bed processor for granulation 3rd PharmSciFair, 13th to 17th June 2011, Prague, Czech Republic Wong, P.M., Chan L.W., Heng P.W.S., Comparison of swirling airflow fluidized bed granulation with top-spray fluidized bed granulation at high and low binding solution spray rates Asian Federation for Pharmaceutical Sciences Conference, 9th to 12th December 2011, Kuala Lumpur, Malaysia 158    .. .A STUDY ON THE SIDE- SPRAY FLUIDIZED BED PROCESSOR WITH SWIRLING AIRFLOW FOR GRANULATION AND DRUG LAYERING WONG POH MUN B.Sc (Pharm.) 1st Class Hons., National University of Singapore A THESIS... extrusion granulation was a more robust process and was minimally affected by variations in the particle size and morphology of the ingredients Fluidized bed granulation A popular granulation process... of the coating formulation on a tablet surface Nadkarni et al (1975) reported that increasing surface tension of the coating formulation increased the contact angle of the coating formulation on