INVESTIGATIONS ON CO-MILLING OF ACTIVE PHARMACEUTICAL INGREDIENTS BALANI PRASHANT NIRMAL (M. Pharm., University of Mumbai) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2010 ACKNOWLEDGEMENTS A successful compilation of PhD thesis needs consistent support and guidance of many people throughout the candidature. The decision to aspire for PhD degree wouldn’t have been possible if not for continuous support, motivation and help provided by my family, relatives and friends in India. I deeply appreciate their faith, patience and confidence in my abilities. It would not have been possible if not for them. I would like to showcase my deepest gratitude and respect for my supervisor Associate Professor Chan Sui Yung for her constant motivation, encouragement, sound advice and giving me an opportunity to pursue my research work at Crystallisation & Particle Science (CPS), Institute of Chemical and Engineering Sciences (ICES), A*STAR (Agency for Science, Technology and Research), Singapore. The research work wouldn’t have been possible if not for valuable suggestions, guidance, and support of my co-advisors Dr Ng Wai Kiong, Research Scientist and Associate Professor Reginald B.H. Tan, Programme Manager, CPS, ICES. The most important thing which I learnt from my supervisors was the concept of “training of mind”, which has helped me to remain patient and focused throughout my research work and also during compilation of the PhD thesis. I sincerely acknowledge National University of Singapore for providing the research scholarship and the Science and Engineering Research Council of A*STAR, Singapore for supporting my project. Every PhD project needs learning of experimental techniques to acquire desired results. I am deeply indebted to Dr Widjaja Effendi, Mr. Lim Seng Chong, Mr. Ang i Benjamin, Mr. Ng Junwei, Miss Tok Ai Tee, Miss Goh Xue Ping, Mr. Kwek Jin Wang, Mr. Liu Gary, Miss Hoong Adaline, Mr. Ng Mark, Miss Phua Agnes, Miss Tan Li Teng, Miss Seo Angeline of ICES, Miss Wong Shi Yin, Mr. Tan Bing Xun of the Department of Pharmacy, NUS for providing training as well as assistance in carrying out experiments and creating an ideal working and amiable atmosphere during my PhD project. Finally, I would like to acknowledge Mr. Pasikanti Kishore, Mr. Nema Tarang, Mr. Nayak Tapas, Mr. Karande Atul, Miss Azarbayjani Anahita, Dr Chourasia Manish and other seniors, colleagues and friends, at NUS Department of Pharmacy; Dr Poornachary Sendhil, Dr Kanaujia Parijat, Dr Dong Yauncai and other research colleagues and friends at ICES; Mr. Tiwari Ravi, Mr. Choudhury Deepak, Mr. Sachdeva Nikhil, Miss Sarkar Natasha, Miss Shah Shreya and other friends for their continuous support, suggestions and motivation throughout the PhD candidature. ii Investigations on Co-milling of Active Pharmaceutical Ingredients TABLE OF CONTENTS Acknowledgements……………………………………………………………………… i Summary………………………………………………………………………………….vii List of Tables………………………………………………………………………………x List of Figures………………………………………………………………………… xi List of Abbreviations…………………………………………………………………… xvi List of Symbols………………………………………………………………………….xviii Chapter Introduction…………………………………………………………… …….1 1.1 Particle Science and Technology……………………………………… …….1 1.2 Milling………………………………………………………………… …… 1.2.1 Wet and Cryomilling…………………………………………………… ……3 1.3 Theory of Milling………………………………………………………….….7 1.3.1 Griffith Theory………………………………………………………….…… 1.3.2 Thermodynamics………………………………………………………… 10 1.4 Pharmaceutical Applications and Limitations…………………………… 12 1.4.1 Achieving Desired Particle Size…………………………………………… .12 1.4.2 Improvement in Solubility……………………………………………….… .14 1.4.3 Limitations of Milling…………………………………………………… .15 1.4.3.1 Polymorphic Transformation……………………………………………… 16 1.4.3.2 Amorphous Transformation……………………………………………… 16 1.4.3.3 Dehydration……………………………………………………………… .17 1.4.3.4 Chemical Instability……………………………………………………….….18 1.5 Co-milling and Applications………………………………………………….18 1.6 Amorphous Solid Dispersions……………………………………………… .19 1.6.1 Drug-polymer Solubility and Miscibility…………….……………………….24 1.7 Electrostatics………………………………………………………………….26 1.8 Research Objectives and Approach………………………………………… 30 1.8.1 Mitigating Milling-induced Amorphization of a Crystalline Pharmaceutical Active……………………………………………………………………… 30 1.8.2 Stabilization of a Milled Amorphous Form of SS…………………………….31 1.8.3 Investigation on Electrostatic Properties of Milled and Co-milled APIs…… 32 iii Investigations on Co-milling of Active Pharmaceutical Ingredients Chapter Experimental Methods and Analytical Techniques…………………………34 2.1 Model APIs…………………………….…………………………………… 34 2.1.1 Salbutamol Sulphate (SS)……… .……………………………………………34 2.1.2 Clarithromycin (CAM)……… .………………………………………………35 2.1.3 Ibuprofen (IB)…………………………………………… .………………… 36 2.2 Studies on SS……………………………………………………………… 36 2.2.1 Characterization of Unmilled SS.………………………………………… .36 2.2.1.1 Bulk Density……………………………………………………………… 37 2.2.1.2 Tapped Density……………………………………………………………… 38 2.2.1.3 True Density………………………………………………………………… 38 2.2.1.4 Powder Compressibility………………………………………………………38 2.2.1.5 Moisture Content………………………………………………………… .38 2.2.1.6 Particle Size Measurement……………………………………………………39 2.2.1.7 X-ray Powder Diffraction (XRPD)………………………………………… .39 2.2.2 Sieved (unmilled) Fractions of SS………………………………………… .39 2.2.2.1 Jet Milling of SS………………………………………………………… 40 2.2.2.2 Scanning Electron Microscopy (SEM)……………………………………… 40 2.2.2.3 Brunauer-Emmett-Teller (BET)………………………………………………40 2.2.3 Particle Size of Excipient for Co-milling………………………………… 41 2.2.3.1 Sieving of LAC…………………………………………………………… .41 2.2.3.2 Jet Milling of LAC……………………………………………………………41 2.2.3.3 Wet Dispersion Method………………………………………………… .41 2.2.3.4 Dry Dispersion Method…………………………………………………… .42 2.2.3.5 Ball milling of LAC………………………………………………………… 42 2.2.3.6 Sonic Sifting and SEM of Milled LAC…………………………………… .43 2.2.4 Co-milling…………………………………………………………………….44 2.2.4.1 Preparation of Co-milled Mixtures with Jet-milled LAC………………… .44 2.2.4.2 Preparation of Co-milled and Physical Mixtures with Ball-milled LAC… 44 2.2.4.3 Preparation of Cryo co-milled Mixture…………………………………… .44 2.2.4.4 Milling of Other Excipients………………………………………………… .45 2.2.4.5 Preparation of Co-milled Mixtures with Excipients………………………… 45 2.2.4.6 Preparation of Co-milled Mixtures with LAC and PVP………………… ….45 2.2.5 Physical Stability of Stored Samples………………………………………….46 2.2.6 Analysis of Co-milled and Physical Mixtures…………………………… ….46 2.2.6.1 X-ray Powder Diffraction (XRPD)………………………………………… .46 2.2.6.2 Dynamic Vapor Sorption (DVS)…………………………………………… .46 2.2.6.3 High Sensitivity Differential Scanning Calorimetry (HSDSC)………………47 2.2.6.4 Scanning Electron Microscopy (SEM) .………………………………… .47 2.2.6.5 High Performance Liquid Chromatography (HPLC)…………………………47 2.2.6.6 Infra-red Spectroscopy (FT-IR)……………………………………………….47 2.2.6.7 In situ Raman Spectroscopy………………………………………………… 48 2.2.6.8 Raman Microscopy (RM)…………………………………………………… 48 2.3 Studies on CAM and IB………………………………………………… … 49 2.3.1 Characterization of Unmilled CAM……………………………… ……… 49 2.3.1.1 X-ray Powder Diffraction (XRPD)… .…………………………… ……… 49 2.3.1.2 Differential Scanning Calorimetry (DSC)…………………………………….49 iv Investigations on Co-milling of Active Pharmaceutical Ingredients 2.3.1.3 Determination of Tg…………………………………………………….…… 49 2.3.2 Sieving of IB……………………………………………………………… .50 2.3.3 Milling and Cryomilling………………………………………………………50 2.3.3.1 Ball Milling of CAM………………………………………………………….50 2.3.3.2 Cryomilling of CAM………………………………………………………….50 2.3.3.3 Preparation of Co-milled and Physical Mixtures with Excipients……………51 2.3.3.4 Preparation of Cryo co-milled Mixtures with Excipients…………………….53 2.3.4 Physical Stability of Stored Samples……………………………………….…53 2.3.5 Analysis of Mixtures and Excipients………………………………………….53 2.3.5.1 Scanning Electron Microscopy (SEM)… .………………………………… .53 2.3.5.2 Particle Size Analysis…………………………………………………… 54 2.3.5.3 Brunauer-Emmett-Teller (BET).…………………………………………… .55 2.3.5.4 Moisture Content…………………………………………………………… .55 2.3.5.5 Electrostatic Measurement……………………………………………… 55 2.3.5.6 X-ray Powder Diffraction (XRPD)… .………………………………… 55 2.3.5.7 Differential Scanning Calorimetry (DSC)… …………………………….… 56 2.3.5.8 Infra-red Spectroscopy (FT-IR)…………………………………………… .56 2.3.5.9 High Performance Liquid Chromatography (HPLC)…………………… 56 2.3.5.10 Inverse Gas Chromatography (IGC)……………………………………… .57 Chapter Mitigating Milling-induced Amorphization or Structural Disorder of a Crystalline Pharmaceutical Active……………………………………… .58 3.1 3.2 3.3 3.3.1 3.3.2 3.4 3.4.1 3.4.2 3.5 3.6 3.7 Characterization of Unmilled SS…………………………………………… 60 Selection of Sieved (unmilled) Fractions of SS…………………………… 61 Selection of Appropriate Excipient Size for Co-milling…………………… .62 Particle Size Analysis…………………………………………………… 63 Comparison of Ball-milled and Jet-milled LAC…………………………… 64 Co-milling…………………………………………………………………….65 Co-milling of SS with Jet-milled LAC…………………………………….…65 Co-milling of SS with Ball-milled LAC…………………………………… .66 Understanding Behind Amorphization Reduction……………………… 73 Stability Studies of Mixtures of SS and LAC…………………………… .81 Summary………………………………………………………………… .84 Chapter Stabilization of Milled Amorphous Form of Salbutamol Sulphate……… 86 4.1 Effect of Co-milling on Crystallinity of SS………………………………… 88 4.1.1 X-ray Powder Diffraction (XRPD) .…………………………………… 88 4.1.2 High Sensitivity Differential Scanning Calorimetry (HSDSC) …………… 89 4.1.3 Infra-red Spectroscopy (FT-IR)……………………………………………….93 4.1.4 Raman Microscopy (RM)…………………………………………………… 95 4.2 Stability Studies of Mixtures of SS and PVP…………………………………98 4.3 Summary…………………………………………………………………… 105 v Investigations on Co-milling of Active Pharmaceutical Ingredients Chapter Investigation on Electrostatic Properties of Milled and Co-milled APIs.106 5.1 5.2 5.2.1 5.2.2 5.3 5.3.1 Introduction…………………………………………………………….… 107 Selection of Excipients for Co-milling………………………………… ….111 Clarithromycin (CAM)…………………………………………………… .111 Ibuprofen (IB)………………………………………………………………112 Milling and Co-milling of CAM………………………………………… 112 Effect of Milling and Co-milling on Solid-state and Physico-chemical Properties………………………………………………………………… 112 5.3.1.1 X-ray Powder Diffraction (XRPD)……………………………………… .112 5.3.1.2 Infra-red Spectroscopy (FT-IR)………………………………………… 119 5.3.1.3 Differential Scanning Calorimetry (DSC)………… …………………… 127 5.3.2 Effect of Milling and Co-milling on Triboelectrification……………….… 135 5.3.3 Effect of Milling and Co-milling on Surface Energetics………………… 141 5.3.3.1 Inverse Gas Chromatography (IGC)……………………………………… 141 5.3.3.2 Changes in Surface Energy on Co-milling of CAM…………………… 143 5.4 Milling and Co-milling of IB…………………………………………… .150 5.4.1 Effect of Milling and Co-milling on Solid-state properties…………… 150 5.4.2 Effect of Milling and Co-milling on Triboelectrification………………… .151 5.5 Summary………………………………………………………………… .155 Chapter Conclusions and Future Work………………………………………………158 6.1 Conclusions………………………………………………………………… 158 6.1.1 Co-milling with Crystalline Excipients Mitigated Amorphization of Milled API……………………………………………………………………… .158 6.1.2 Co-milling with Amorphous Excipient Stabilized Milling-induced Amorphization of API…………………………………………………… .158 6.1.3 Co-milling with Amorphous Ionic Polymer Produced Amorphous Dispersion of API ……………………………………………………………………… 159 6.1.4 Co-milling Produced Physically Stable Amorphous mixture with Reduced Triboelectrification of API……………………………………… 159 6.2 Future Work……………………………………………………………… .160 6.2.1 Study the Change in Triboelectrification of Stable Amorphous Co-milled Mixtures of IB… ……………… .…………………………… .160 6.2.2 Study the Change in Triboelectrification of Wet Milling API with Polymers.…………………………………………………………………… 160 6.2.3 Dissolution Studies of Stable Amorphous Co-milled CAM-EPO mixtures…161 6.2.4 Use of Other Ionic Polymers for Co-milling with APIs………………… …161 6.3 Summary…………………………………………………………………… .162 References……………………………………………………………………………… 163 List of Publications……………………………………………………………………… .196 vi Investigations on Co-milling of Active Pharmaceutical Ingredients SUMMARY Milling is commonly used in pharmaceutical secondary manufacturing for reducing particle size of crystalline active pharmaceutical ingredients (APIs) as it is difficult to achieve a narrow particle size distribution via crystallization alone. However, milling leads to generation of thermodynamically unstable amorphous regions on particle surfaces which undergo re-crystallization on storage of pharmaceutical drug products. This reversion affects physicochemical properties of APIs such as solubility, physical stability, flow properties and aerosolization behavior eventually affecting performance of the drug product. Literature reports the use of co-milling in effectively improving solubility and physical stability of various APIs. This research explores new approach of co-milling. In the first part, co-milling with crystalline excipients, lactose, adipic acid and magnesium stearate, reduced the amorphization of salbutamol sulphate. These excipients acted as seed crystals to induce re-crystallization of amorphous salbutamol sulphate formed by milling. During co-milling, both salbutamol sulphate and lactose became predominantly amorphous after 45 but re-crystallized after 60 min. The use of crystalline excipients mitigated the amorphous content of an API to below detection limits. The results provide a new dimension to the potential application of co-milling in handling the challenges of the unstable amorphous state of milled APIs and possibly other materials. In the second part, studies on co-milling with use of an amorphous excipient polyvinyl pyrrolidone were conducted. Probable hydrogen bond interaction between salbutamol sulphate and polyvinyl pyrrolidone by infrared spectroscopic analysis and homogeneous distribution of salbutamol sulphate and polyvinyl pyrrolidone by Raman microscopy vii Investigations on Co-milling of Active Pharmaceutical Ingredients analysis suggested formation of a stable amorphous molecular dispersion of salbutamol sulphate with a minimum of 80% polyvinyl pyrrolidone content on storage for a period of days under accelerated stability conditions (22°C/75% RH). It demonstrates that a stable and homogenous amorphous dispersion of API can be obtained with the addition of sufficient amorphous excipient. In the third part, stabilization of the milled amorphous form of clarithromycin, a poorly soluble antibiotic, with Eudragit EPO and co-povidone (Kollidon VA64) polymers was investigated. Milled clarithromycin is partially amorphous, unstable and re-crystallizes under accelerated storage conditions (40°C/82% RH) within days. Results showed that only co-milled mixtures with Eudragit EPO remained stable for a period of 90 days under accelerated storage conditions of 40°C and 75% RH. Infrared spectroscopic analysis and differential scanning calorimeter studies with co-milled mixtures containing EPO indicated that the drug-polymer ionic interactions produced stable amorphous form of API on comilling and for subsequent storage. In the last part, the potential of stable amorphous co-milled mixtures in reducing triboelectrification of clarithromycin was explored. Stable co-milled mixtures of clarithromycin containing Eudragit EPO showed a reduction in surface electrostatic charge in comparison to milled clarithromycin. An increase in surface basicity studied using inverse gas chromatography correlated to surface electrostatic charge in milled and comilled clarithromycin samples. In comparison, crystalline co-milled mixtures of Ibuprofen with magnesium stearate charged to a greater propensity in comparison to physical mixtures. In addition, Ibuprofen-colloidal SiO2 co-milled and physical mixtures showed an increase in electrostatic chargeability. 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Investigation and physicochemical characterization of clarithromycin-citric acid-cyclodextrins ternary complexes. Drug Dev. Ind. Pharm. 33:163-171. Zheng, X., Yang, R., Tang, X., Zheng, L., 2007. Part I: Characterization of solid disperions of nimodipine prepared by hot-melt extrusion. Drug Dev. Ind. Pharm. 33:791-802. Zhu, K., Tan, R.B.H., Ng, W.K., Shen, S., Zhou, Q., Heng, P.W.S. 2008. Analysis of the influence of relative humidity on the moisture sorption of particles and the aerosolization process in a dry powder inhaler. J. Aerosol Sci. 39:510524. 195 Investigations on Co-milling of Active Pharmaceutical Ingredients LIST OF PUBLICATIONS Journal 1. Balani PN, Ng WK, Chan SY, Tan RBH. 2010. Influence of excipients in co-milling on mitigating milling-induced amorphization or structural disorder of crystalline pharmaceutical actives. J. Pharm. Sci. 99(5); 2462-2474. 2. Balani PN, Wong SY, Ng WK, Widjaja E, Tan RBH, Chan SY. 2010. Influence of polymer content on stabilizing milled amorphous salbutamol sulphate. Int. J. Pharm. 391(10); 125-136. Presentations 1. Balani PN, Ng WK, Chan SY, Tan RBH. 2007. Stabilizing crystalline salbutamol sulphate by co-milling. [Poster] American Association of Pharmaceutical Scientists (AAPS) Annual Meeting; November 11-15; San Diego. 2. Balani PN, Ng WK, Chan SY, Tan RBH. 2007. Effects of co-milling on crystallinity of salbutamol sulphate using adipic acid. American Institute of Chemical Engineers (AICHE) Annual Meeting; November 4-9; Utah. 3. Balani PN, Wong SY, Ng WK, Chan SY, Tan RBH. 2008. Control of crystalline and amorphous properties of solids through co-milling. Crystallisation and Particle Science (CPS) group Research and Strategy Day; Institute of Chemical and Engineering Sciences (ICES); March 25; Singapore. 4. Balani PN, Wong SY, Ng WK, Chan SY, Tan RBH. 2008. Can Crystalline and amorphous properties of pharmaceutical actives be controlled? An insight into a new application of co-milling. Frontiers in science symposium; Oct 15; Singapore. 5. Balani PN, Ng WK, Chan SY, Tan RBH. 2008. Magnesium stearate reduces 196 Investigations on Co-milling of Active Pharmaceutical Ingredients amorphization of salbutamol sulphate on milling. [Poster] American Association of Pharmaceutical Scientists (AAPS) Annual Meeting; November 16-20; Atlanta. 6. Balani PN, Wong SY, Ng WK, Chan SY, Tan RBH. 2008. Use of co-milling to improve physical stability of amorphous salbutamol sulphate. [invited oral presentation] American Institute of Chemical Engineers (AIChE) Annual Meeting; November 16-21; Philadelphia. 7. Balani PN, Wong SY, Ng WK, Chan SY, Tan RBH. 2009. Co-milling, a potential technique to minimize or stabilize milling induced disorders. th PharmSci@Asia; May 27; Nanjing. 8. Balani PN, Tan BX, Ng WK, Chan SY, Tan RBH. 2010. Effect of pre-milling conditioning on electrostatic chargeability of ibuprofen. A-Star Scientific Conference; Oct 28; Singapore. 9. Balani PN, Ng WK, Chan SY, Tan RBH. 2010. The use of inverse gas chromatography to assess acid base contributions to surface electrostatic charge of a milled pharmaceutical active. PharmSci@India10; Feb 25; Mumbai. 197 [...]... efficacy of CAM 109 Characteristic absorptions, functional groups of CAM, excipients and changes in CAM : excipient mixtures Effect of milling and co- milling on triboelectrification of CAM Changes in particle size and surface area on milling of CAM Effect of cryomilling on surface energetics of CAM 121 Table 5.2-5.3 Table 5.4 Table 5.5 Table 5.6 54 90 136 136 144 x Investigations on Co- milling of Active Pharmaceutical. . .Investigations on Co- milling of Active Pharmaceutical Ingredients LIST OF TABLES Table Title Page Table 1.1 Mechanism of milling, advantages and disadvantages of mills used for API milling 4 Table 1.2 Changes in co- milling of APIs with additives 20 Table 2.1 Information of SS, CAM and IB 35 Table 2.2 Characterization of SS 37 Table 2.3 Preparation of physical and co- milled mixtures... ball-milled IB-colloidal SiO2 physical mixture, (g) IB-colloidal SiO2 co- milled mixture Electrostatic charges of IB-MgSt and IB-colloidal SiO2 mixtures Particle size distributions of a) IB-MgSt mixtures, b) IB-colloidal SiO2 mixtures 151 152 153 xv Investigations on Co- milling of Active Pharmaceutical Ingredients LIST OF ABBREVIATIONS AA Adipic acid AA-2G Ascorbic acid 2-Glucoside API Active Pharmaceutical. .. Non-Steroidal Anti-Inflammatory Drug PAA Polyacrylic Acid PVP Polyvinyl Pyrrolidone RS Raman Spectroscopy RM Raman Microscopy SEM Scanning Electron Microscopy SiO2 Silicon Dioxide SMCR Self-Modeling Curve Resolution SS Salbutamol Sulphate SS-NMR Solid State Nuclear Magnetic Resonance Wt Weight XRPD X-ray Powder Diffraction xvii Investigations on Co- milling of Active Pharmaceutical Ingredients LIST OF. .. deformation Er Energy for particle size reduction F Carrier flow rate fc Crushing strength of the material ∆GAB Specific energy of adsorption of a polar probe with solid material γSd Dispersive component of solid surface energy γSl Surface tension of the adsorbate γSV Surface energy γSVe Effective surface energy γpl Plastic deformation xviii Investigations on Co- milling of Active Pharmaceutical Ingredients. .. sorption and second sorption cycle of ball-milled X-ray amorphous SS at 30% RH Na Avogadro’s number p/po Relative pressure R Gas constant S1 Specific surface before milling S2 Specific surface after milling T Temperature Tg Glass transition temperature tv Retention time of the probe tm Retention time of the reference methane probe VN Net retention volume Wi Work index xix Investigations on Co- milling of. .. obtained after milling under ambient conditions BET Brunauer-Emmett-Teller βCD Beta Cyclodextrin BTEM Band-Target Entropy Minimization BuMA n-Butyl Methacrylate CA Citric Acid CAM Clarithromycin Co- milled Co- milled product obtained after milling under ambient conditions Cryo-milled Milled product obtained after milling under cryogenic conditions Cryo co- milled Co- milled product obtained after co- milling under... electron-donor to the electron-acceptor parameter ratios [KD/ KA] of cryo-milled and co- milled samples, as a function of their 146 137 139 148 xiv Investigations on Co- milling of Active Pharmaceutical Ingredients Figure 5.19 Figure 5.20 Figure 5.21 electrostatic charges Powder X-ray diffractograms of (a) ball-milled IB, (b) MgSt, (c) colloidal SiO2, (d) ball-milled IB-MgSt physical mixture, (e) IBMgSt co- milled... pharmaceutical secondary manufacturing (Chikhalia et al., 2006; Mackin et al., 2002a; Begat et al., 2003) as they allow controlled reduction of the particle size The following section discusses the reported pharmaceutical applications of milling 1.4.1 Achieving Desired Particle Size Solution crystallization is normally used for crystallization of pharmaceutical actives However particle size or shape control... Mechanism of milling, advantages and disadvantages of mills used for API milling 4 Chapter 1 Introduction Type of Mill B Shear action mills Mechanism of milling Gravity feeding of mill charge into a multiple grinding sections having vertically stacked pair of rollers Size reduction occurs by induced stress or shear action between rollers (Colombo et al., 2009) Advantages Generation of fewer fines as compared . List of Publications……………………………………………………………………… 196 Investigations on Co- milling of Active Pharmaceutical Ingredients vii SUMMARY Milling is commonly used in pharmaceutical secondary. for their continuous support, suggestions and motivation throughout the PhD candidature. Investigations on Co- milling of Active Pharmaceutical Ingredients iii TABLE OF CONTENTS Acknowledgements………………………………………………………………………. size reduction of the ingredients and components is required. Count: 553 words Investigations on Co- milling of Active Pharmaceutical Ingredients x LIST OF TABLES