A study on the roller compaction of undulated flakes by real time process monitoring of compaction and cone milling of flakes

A STUDY ON THE ROLLER COMPACTION OF UNDULATED FLAKES BY REAL-TIME PROCESS MONITORING OF COMPACTION AND CONE MILLING OF FLAKES ASIM KUMAR SAMANTA (M.Pharm. (First Class), Jadavpur University (India)) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2012 ACKNOWLEDGEMENTS I wish to express my deepest and most sincere appreciation to my supervisors, Associate Professor Paul Heng Wan Sia and Dr. Lawrence Ka-Yun Ng (Center for Scientific Review, National Institutes of Health, USA), for their patience and advice throughout the course of my research work. They have shared with me their invaluable experiences and it has definitely enriched my professional and personal life. I wish to thank Professor Lucy Wan, Associate Professor Chan Lai Wah and Assistant Professor Celine Valeria Liew for their invaluable advice in life and research. I would specially like to thank Head of the Department of Pharmacy and National University of Singapore for providing the facilities and research scholarship, respectively. Thanks to Mrs Teresa Ang and Ms Wong Mei Yin for their help in providing technical assistance whenever needed. My stay in NUS would not be as enjoyable and enriching if not for the wonderful company and help from all friends in GEA-NUS Pharmaceutical Processing Research Laboratory, especially Sze Nam, Likun and Atul. Last but not least, I am truly appreciative of my parents, new parents (fatherand mother-in-law) and relatives for their love, blessings, continuous support and encouragement. Special thanks to my wife Neelam for her help, patience and mental support. Thank you. Asim Kumar Samanta January 2012 i Dedication To my late father Kalipada Samanta. His words of inspiration and encouragement in pursuit of excellence, still linger on. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS………………… … .…….……… .i TABLE OF CONTENTS……………………………… .… … …… iii SUMMARY………………………… ………… .………………… ix LIST OF TABLES………………………… ………… …………… .x LIST OF FIGURES………………………… …… .……………… .xi LIST OF SYMBOLS AND ABBREVIATIONS……… .……… .xvi INTRODUCTION . 1.1 Roller compaction 1.1.1 Factors affecting roller compaction process 1.1.1.1 Raw material properties 1.1.1.2 Roller compactor design . 1.1.1.3 Processing variables . 1.1.2 Critical quality attributes (CQA) of roller compacted flakes . 12 1.1.2.1 Relative density 12 1.1.2.2 Tensile strength 14 1.1.3 Why there is need to monitor CQA of roller compacted flakes? 15 1.1.4 Monitoring of roller compaction process and formulation variable 15 1.1.4.1 Near infrared (NIR) spectroscopy . 17 1.1.4.2 Application of NIR spectroscopy 25 1.2 Comminution of roller compacted flakes 26 1.2.1 Forces involved in size reduction . 26 1.2.2 Factors affecting the comminution process . 29 iii 1.2.2.1 Equipment type and flake property . 29 1.2.2.2 Process parameters . 31 1.2.3 Evaluation of comminution process parameters 32 1.2.3.1 Significance of granule size, size distribution, and amount of fines . 32 1.2.3.2 Energy requirement for milling . 34 1.2.3.3 Milling rate . 35 1.3 Research gaps . 35 1.3.1 Real-time NIR monitoring of undulated roller compacted flake and post-milled granule attributes . 35 1.3.2 Conical screen milling of undulated roller compacted flakes 37 HYPOTHESES AND OBJECTIVES 39 2.1 Hypotheses . 39 2.2 Objectives . 41 EXPERIMENTAL . 42 3.1 Study I: Investigation of the factors affecting NIR real-time monitoring of content uniformity and flake attributes of undulated roller compacted flakes . 42 3.1.1 Materials 42 3.1.2 Methods . 42 3.1.2.1 Powder blending . 42 3.1.2.2 Roller compaction of powder blends . 43 iv 3.1.2.3 Flake density measurement . 44 3.1.2.4 Flake strength measurement . 45 3.1.2.5 Flake thickness measurement ……… .….… …………… 46 3.1.2.6 NIR spectroscopy . 46 3.1.2.7 Off-line NIR monitoring set-up 48 3.1.2.8 Calibration model development from the off-line NIR spectral data 50 3.1.2.9 Validation of the calibration models . 50 3.1.2.10 Real-time monitoring set-up . 51 3.1.2.11 Real-time monitoring using online Unscrambler Predictor (OLUP) software…………………………………………… 52 3.2 Study II: Selection of the cone milling process parameters for the comminution of undulated roller compacted flakes by adopting minimal fines, milling energy and higher milling rate approach 53 3.2.1 Materials 53 3.2.2 Methods . 54 3.2.2.1 Powder blending . 54 3.2.2.2 Roller compaction of powder blend 54 3.2.2.3 Comminution of flakes . 54 3.2.2.4 Energy consumption . 58 3.2.2.5 Milling rate . 60 3.2.2.6 Characterization of granules . 61 v 3.3 Study III: Real-time monitoring of post-milled granule attributes, milling energy and milling time 61 3.3.1 Comminution of flakes . 61 3.3.2 Energy consumption . 62 3.3.3 Milling rate 62 3.3.4 Characterization of granules . 62 3.3.5 Calibration model development 62 3.3.6 Validation of calibration models . 63 3.3.7 Real-time analysis of post-milled granule attributes, effective specific milling energy and milling time 63 RESULTS AND DISCUSSION . 64 4.1 Study I: Investigation of the factors affecting NIR real-time monitoring of content uniformity and flake attributes of undulated roller compacted flakes . 64 4.1.1 Flake properties 64 4.1.2 Linear effective surface area scanned by different NIR probe . 70 4.1.3 Effect of sampling mode on NIR spectral feature and calibration models . 71 4.1.4 Effect of pre-processing method on calibration models . 79 4.1.5 Effect of probe position on calibration models 80 4.1.6 Effect of probe diameter (spot size) on calibration models 84 4.1.7 Selection of best calibration models for real-time analysis 86 4.1.8 Application of best calibration models for real-time roller compaction process analysis 90 vi 4.1.8.1 System performance of real-time application 90 4.1.8.2 Real-time analysis of flakes 90 4.1.9 Continuous quality monitoring of the roller compaction process . 95 4.2 Study II: Selection of the cone milling process parameters for the comminution of undulated roller compacted flakes by adopting minimal fines, milling energy and higher milling rate approach 96 4.2.1 Preliminary studies and results . 96 4.2.2 Effect of impeller sidearm shapes and screen types on the granules size and size distribution at different impeller speeds . 98 4.2.3 Effect of impeller speeds and types with different screens on the percentage of fines generated during milling .106 4.2.4 Cone mill no-load power requirement .111 4.2.5 Effect of impeller speed, screen type and impeller type on total specific energy …………………………………………………111 4.2.6 Effect of speed, screen type and impeller type on effective specific energy…………………………………………………………….115 4.2.7 Effect of screen type, impeller type and impeller speed on milling rate .117 4.3 Study III: Real-time monitoring of post-milled granule characteristics, milling energy and milling time .120 4.3.1 Post-milled granule size, size distribution and fines .120 4.3.2 Effect of drug concentration and RF on total and effective specific milling energy……………………………………………………126 4.3.3 Effect of drug concentration and RF on milling rate 129 vii 4.3.4 Validation of the calibration models 131 4.3.5 Real-time analysis .136 CONCLUSIONS .139 REFERENCES .144 LIST OF PUBLICATIONS 156 viii The factors of beam size and spectra preprocessing method also played a major role in designing a more sensitive and accurate calibration model. Therefore, the best calibration models for real-time monitoring of content uniformity and CQA of undulated flakes were resulted from SNV followed 1st derivative dynamic spectra captured using QR 400 probe from the under side of the moving flakes over the conveyor belt. Adequacy of these best calibration models for real-time roller compaction process monitoring was visible from RMSECV, SEP and external validation results. Finally, the best calibration models performed well in real-time monitoring of the roller compaction process and showed smallest degree of variation in the prediction results. Second part of the study demonstrated the evaluation of cone milling process parameters for the comminution of roller compacted flakes, in terms of granules qualities (size, size distribution and amount of fines), energy consumption and milling rate. From this study, it appeared that both the type of impeller and screen had played important roles in determining the quality of milled granules and milling rate. The impeller and screen, which have prebreaking and shearing actions due to their special geometric configuration, were best for the comminution of flakes. I-2 impeller and grater screen were found to possess these requisites. Either one of them when present in any mill setting was found to shorten the residence time of flakes inside the milling chamber and resulted in the production of granules of better quality from flakes, in terms of granules size, size distribution and fines. On the other hand, effective specific energy was mainly influenced by screen type and impeller speed. Grater screen and impeller speed around 2000 rpm were found to have 141 the best combination for low energy consumption during milling. No significant effect of impeller type was observed on energy consumption. The last part of the study focused on NIR-PLS1 calibration model development and real-time monitoring of the post-milled granule attributes, effective specific energy consumption and milling rate for specific mill settings optimized in second part of the study. Real-time analysis revealed good agreement between the real-time prediction values and the reference values. In conclusion, with the proposed set-up, simultaneous determination of content uniformity, CQA of the flakes, post-milled granule attributes, effective specific milling energy and milling rate from undulated roller compacted flakes in a rapid, efficient and non-destructive manner could be achieved. Overall, findings of these studies are a step forward towards achieving the objectives laid out by the PAT guidelines. The studies conducted had revealed many important findings regarding the establishment of NIR reflectance spectroscopy as a real-time process monitoring tool for undulated roller compacted flakes and controlled size reduction of these flakes. However, this research work can be extended for better real-time monitoring of the CQA of undulated roller compacted flakes by installing distance measurement probe alongside with the NIR probe. Measurement of distance between probe and flake surface concurrently during NIR spectral acquisition could help to modulate the NIR spectra according to spatial distances and minimize the variations in spectra due to undulations, curvatures or variations in flake thickness more precisely. In addition, a 142 temperature probe may also be installed together with other probes during monitoring of roller compaction. This proposed custom built set-up for offline and real-time NIR spectral acquisition could be modified accordingly and applied for real-time monitoring of tabletting process, especially for embossed or concave shaped tablets. Therefore, it is possible to gain insights into the effects of processing and formulation variables on the tablet characteristics from the in-process data obtained using NIR spectroscopy. The conical screen mill has been successfully employed to mill the undulated roller compacted flakes. Further application in size reduction of flakes should be explored using different formulations. 143 REFERENCES Adeyeye, M. C., 2000. Roller compaction and milling pharmaceutical unit processes: Part I. American Pharmaceutical Review, 3, 37-42. Alderborn, G., 1996. Granule properties, In: Alderborn, G., Nystrom, C. (Eds.), Pharmaceutical powder compaction technology. Marcel Dekker, New York, pp. 245-282. Armstrong, N. A., Palfrey, L. P., 1989. 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Pharmaceutical Research, 23, 1898-1905. Wu, S. J., Sun, C., 2007. Insensitivity of compaction properties of brittle granules to size enlargement by roller compaction. Journal of Pharmaceutical Sciences, 96, 1445-1450. Zinchuk, A. V., Mullarney, M. P., Hancock, B. C., 2004. Simulation of roller compaction using a laboratory scale compaction simulator. International Journal of Pharmaceutics, 269, 403-415. 155 LIST OF PUBLICATIONS Publications in Journals 1. A.K. Samanta, K.Y. Ng, P. W. S. Heng, Cone milling of compacted flakes: Process parameter selection by adopting the minimal fines approach. Int. J. Pharm. 422, 17-23, 2012. (doi:10.1016/j.ijpharm.2011.10.015) 2. A.K. Samanta, A.D. Karande, K.Y. Ng, P. W. S. Heng, Application of near infrared (NIR) spectroscopy in real-time monitoring of content uniformity, tensile strength, Young’s modulus and density of undulated roller compacted flakes . To be submitted. International conference presentations 1. A.K. Samanta, K.Y. Ng, P.W.S. Heng, Influence of feed flowability and process parameters of roller compaction on the characteristics of granules from milled ribbons, 4th Asian Association of School of Pharmacy, 9th Malaysian Pharmaceutical Society Pharmacy Scientific Conference 2009 (AASP-MPSPSC 2009), 10-13 June 2009, Penang, Malaysia. 2. A.K. Samanta, A.D. Karande, P.W.S. Heng, Multivariate analysis of roll pressure, ribbon component and granule properties in roller compaction using NIR and Raman spectroscopy: A comparative study, FIP Pharmaceutical Sciences World Congress 2010 in association with the AAPS Annual Meeting and Exposition, 14-18 November 2010, New Orleans, Louisiana, USA. 3. A.K. Samanta, E.L. Cheah, L. K. Ng, P.W.S. Heng, Controlled size reduction of roller compacted ribbons: a high-throughput, minimal fines approach, 2009 AAPS Annual Meeting and Exposition, 8-12 November 2009, Los Angeles, California, USA. 156 [...]... by the use of roller compacted granules instead of powders Lastly, the bulk density of powders can be increased by roller compaction, thereby improving material handling and transport by minimizing the overall bulk volume 1.1.1 Factors affecting roller compaction process The fundamental mechanisms of roller compaction are complex, and like other manufacturing processes, product quality and performance... flakes? Conventional roller compaction process is generally evaluated based on the characterization of granule or tablet properties which in turn depends on flake properties (Falzone et al., 1992; Inghelbrecht and Remon, 1998b; Murray et al., 1998; Adeyeye, 2000) Therefore, evaluation of flake use performance cannot be made by just assessing flakes manufactured by a conventional roller compactor Maintenance... region (Guigon and Simon, 2003) Also, heat may be generated in the compaction region from friction between the rolls and compacted powder, causing variation in properties of the flakes during long compaction runs (Ghorab et al., 2007) Therefore, it is important to identify and develop a better understanding of the critical factors that affect the roller compaction process, so that they can be accounted... accounted for in the formulation design and be monitored during the manufacturing process A deeper understanding of the process is needed to reliably and consistently maintain desired quality and product performance across a range of environments as part of a quality -by- design (QbD) approach (FDA, 2006) 1.1.4 Monitoring of roller compaction process and formulation variable In September 2004, FDA issued guidelines... method and beam size In the second section of the study, the cone milling process for undulated roller compacted flakes was studied Impeller sidearm shape, screen surface profile and impeller speed showed significant influence on granule attributes, fines generated, energy consumed and milling rate A study on the applicability NIR real- time monitoring for the prediction of the post-milled granule attributes,... Maintenance of constant process parameters throughout the entire roller compaction operation does not necessary guarantee a homogenous flake For example, the motion of the last flight of the spiral feed screw has been shown to create periodical sinusoidal density variations across the flake width and along the flake length (in the direction of flake output motion) as it delivered powder to the compaction. .. spectral acquisition from the upper side of the flakes (A) and the under side of the flakes (B) 49 Figure 7: Schematic diagram of in-line NIR monitoring set-up for real- time roller compaction process 52 Figure 8: Cross-sectional view of impeller sidearms along with the position of screen and direction of impeller rotation 55 Figure 9: Surface profile of screens: (A) smooth and. .. indicate the calibration samples and in red colour are test set validation samples 89 Figure 28: PLS1 predicted values of µCPM concentration from the NIR data collected during real- time monitoring of roller compaction 93 Figure 29: PLS1 predicted values of RD from the NIR data collected during real- time monitoring of roller compaction Values determined using reference method as diamonds... rearrangement of particles; (b) compaction zone, where the pressing force becomes effective and the particle deform plastically and/ or break; and (c) extrusion zone, where pressure eases and compact is released The boundary between the feeding zone and the compaction zone to the midpoint between the rolls is called the nip or gripping angle (Guigon and Simon, 2003) Nip angle size is mainly affected by. .. changing µCPM concentration and RF on TS of undulated flakes prepared according to the 52 full factorial experimental design 67 Figure 13: Effect of changing µCPM concentration and RF on E of undulated flakes prepared according to the 52 full factorial experimental design 68 Figure 14: PCA of process parameter, formulation parameter and flake properties in correlation loadings plot . A STUDY ON THE ROLLER COMPACTION OF UNDULATED FLAKES BY REAL- TIME PROCESS MONITORING OF COMPACTION AND CONE MILLING OF FLAKES ASIM KUMAR SAMANTA (M.Pharm. (First Class), Jadavpur. Application of best calibration models for real- time roller compaction process analysis 90 vii 4.1.8.1 System performance of real- time application 90 4.1.8.2 Real- time analysis of flakes. Continuous quality monitoring of the roller compaction process 95 4.2 Study II: Selection of the cone milling process parameters for the comminution of undulated roller compacted flakes by adopting