Improving the properties of pharmaceutical powders using supercritical anti solvent processing

IMPROVING THE PROPERTIES OF PHARMACEUTICAL POWDERS USING SUPERCRITICAL ANTI-SOLVENT PROCESSING LIM TAU YEE, RON NATIONAL UNIVERSITY OF SINGAPORE 2012 IMPROVING THE PROPERTIES OF PHARMACEUTICAL POWDERS USING SUPERCRITICAL ANTI-SOLVENT PROCESSING LIM TAU YEE, RON (B. Eng. (Hons.), UNIVERSITY OF BATH, U.K.) (M. Eng., NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMICAL AND BIOMOLECULAR ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2012 DECLARATION I hereby declare that this thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. Lim Tau Yee, Ron 29th January 2013 ACKNOWLEDGEMENT Firstly, I would like to express my sincere gratitude to my supervisor, Prof. Reginald Tan and my co-supervisor, Dr. Ng Wai Kiong for their advice and patient guidance to me throughout the candidature. I am very grateful to Agency for Science, Technology and Research (A*STAR) for providing me the scholarship during my study in NUS. I am also very grateful to Dr. Keith Carpenter, Executive Director of Institute of Chemical and Engineering Sciences (ICES) for supporting me throughout the candidature. I also like to thank Prof. Satoru Watano, Prof. John Dodds, Dr. Jerry Heng, Dr. Gerry Steele and Dr. Simon Black for giving me very useful advice in my research work. I wish to thank Dr. Elisabeth Rodier and Ms. Sylvie for their advice and study in DSC. The colleagues and fellow students at the ICES have been most supportive to me. I would like to thank Dr. Martin Wijaya Hermanto, Mr. Ng Jun Wei, Ms. Tan Li Teng and Ms. Agnes Nicole Phua for their invaluable support in analytical studies. I wish to thank Dr. Effendi Widjaja for his support in Raman characterization and analysis. I also like to thank Mr. Jerry Wisser, Thar USA Engineering Support Manager for his constant help and support on the operation of Super Particle SAS50 system. My wife, Shu Yen, and my family have been most understanding to my long research hours. I would like to thank the Science and Engineering Research Council of A*STAR Singapore for awarding me the Scientific Staff Development Award (SSDA) and providing financial support to this research project. i TABLE OF CONTENTS ACKNOWLEDGEMENT . i TABLE OF CONTENTS ii SUMMARY . vi NOMENCLATURE ix ABBREVIATION xi LIST OF FIGURES . xiv LIST OF TABLES xvii 1. 2. Introduction . 1.1 Research Background . 1.2 Research Objectives . 1.3 Organization of Thesis Literature Review 10 2.1 Drug Development and Delivery 10 2.2 Drug Solubility and Dissolution Rate . 12 2.3 Formulation Strategies to Enhance Dissolution Rate . 13 2.3.1 Micronization 13 2.3.2 Amorphous Form/Solid Dispersion Material 18 2.4 Co-milling . 24 2.5 Supercritical Fluids Technologies 25 2.5.1 Physicochemical Properties of Supercritical Fluids 27 2.5.2 SCF as Solvent Process . 30 2.5.2.1 RESS Process . 30 ii 2.5.3 SCF as Solute Process . 32 2.5.3.1 PGSS Process . 32 2.5.4 SCF as Anti-solvent Processes (GAS, SAS and SEDS) . 33 2.5.4.1 GAS Process . 33 2.5.4.2 SAS Process . 35 2.5.4.3 SEDS Process . 38 2.6 3. Characterizations of Solid Dispersion 40 2.6.1 X-ray Powder Diffraction (XRD) . 41 2.6.2 Scanning and Transmission Electron Microscopy 41 2.6.3 Differential Scanning Calorimetry (DSC) . 42 2.6.4 Physical Stability Evaluation 42 2.6.5 Gravimetric Vapour Sorption (GVS) 43 2.6.6 Fourier Transformed Infrared and Raman Spectroscopy 44 2.6.7 Inverse Gas Chromatography (IGC) . 44 Material and Methods . 47 3.1 Model Compound . 47 3.2 Preparation of Physical Blends . 48 3.3 Milling 49 3.3.1 Co-milling of IDMC with PVP . 49 3.3.2 Cryo-milling to Generate Amorphous Form of IDMC . 49 3.4 SAS Experimental Set-up and Procedures . 49 3.5 Powder Characterizations . 52 3.5.1 X-ray Powder Diffraction (XRD) . 52 iii 3.5.2 Scanning Electron Microscopy (SEM) . 52 3.5.3 Differential Scanning Calorimetry (DSC) . 52 3.5.4 USP Dissolution Tester . 53 3.5.5 Accelerated Physical Stability Evaluation 53 3.5.6 Gravimetric Vapour Sorption (GVS) 53 3.5.7 Fourier Transformed Infrared Spectroscopy (FTIR) . 54 3.5.8 Inverse Gas Chromatography (IGC) . 54 3.5.8.1 Experimental Apparatus . 54 3.5.8.2 Evaluation of Surface Energies of Powders . 56 3.5.8.3 Evaluation of Surface Structural Relaxation 59 3.5.9 4. Raman Microscopy Mapping (RM) 59 3.5.10 Thermogravimetric (TGA) 60 3.5.11 Gas Chromatography (GC) 60 Results and Discussion . 62 4.1 Solid-State (XRD) 62 4.2 Morphology (SEM) 66 4.3 Glass Transition Temperature of Co-precipitates (DSC) . 68 4.4 Dissolution Rate Evaluation . 71 4.5 Accelerated Physical Stability Evaluation 74 4.6 Moisture Sorption Isotherm (GVS) 78 4.7 Drug-Polymer Interactions (FTIR) . 85 4.8 Surface Energy Properties (IGC) 89 4.8.1 Dispersive Energy . 89 iv 4.8.2 4.9 Specific Polar Energy 92 Surface Structural Relaxation (IGC) 94 4.10 Raman Mapping (RM) 97 4.11 Drug Content in COM and SAS Co-precipitates (TGA) 100 4.12 Residual Solvents in SAS Processed Samples (GC) 102 5. Conclusions . 104 6. Future Recommendation Work . 107 REFERENCES . 109 APPENDICES 129 A1. List of Publications 129 A2. Conferences 130 v SUMMARY Recently, the increase in the number of newly discovered poorly water-soluble drug candidates has heightened the interest in developing novel methods to improve solubility of active pharmaceutical ingredients (APIs). Amorphization is an emerging technique to enhance the dissolution of poorly water-soluble drug. In amorphous form the ordered crystalline lattice is not presence, thus providing the maximal solubility advantages as compared to the crystalline and hydrated forms of a drug. There are several strategies to generate amorphous drug substances such as solvent evaporation, co-milling (COM), melt-extrusion, spray-drying, melt-quenching and supercritical fluids technology. In this thesis, the effectiveness of a low-cost and easily scalable process COM was compared with the high-cost and precise-controlled supercritical anti-solvent (SAS) process to amorphize indomethacin (IDMC) with a water-soluble polymer excipient poly(vinylpyrrolidone) (PVP) to improve the aqueous-solubility as well as physical stability of IDMC amorphous form. Both COM and SAS co-precipitation were conducted at IDMC to PVP ratios of 60:40, 50:50 and 20:80. The untreated, COM and SAS powders were characterized using scanning electron microscopy (SEM, morphology), X-ray powder diffractometry (XRD, crystallinity), thermogravimetric analysis (TGA, composition), differential scanning calorimetry (DSC, glass transition temperature (Tg)), USP dissolution tester, gravimetric vapour sorption (GVS, moisture isotherms), Fourier-transform infrared spectroscopy (FTIR, drug-polymer interactions), inverse gas chromatography (IGC, surface energetic and structural relaxations) and Raman mapping (RM, spatial distribution). The residual solvent content in SAS processed samples were evaluated vi using gas chromatography (GC). Accelerated stability stress tests were also conducted on COM and SAS co-precipitates in open pans at 75%RH/40oC. Amorphous forms of IDMC produced by COM and SAS have significantly improved the dissolution rate of IDMC as compared to the crystalline form and its physical blends, respectively. SAS IDMC-PVP co-precipitates with PVP contents at more than 40wt.% were X-ray amorphous form and remained stable after more than months of storage at 75%RH/40oC. COM IDMC-PVP samples with PVP contents less than 50wt.% re-crystallized after days of storage at 75%RH/40oC. FTIR also revealed there were interactions between IDMC and PVP in both COM and SAS co-precipitates and PVP may influence the re-crystallization kinetics by preventing the self association of indomethacin molecules. IGC studies also revealed that the two different preparation methods have an effect on its physical stability in terms of surface structural relaxation as well as having different surface energetics. Overall the surface structural relaxation of SAS co-precipitate was slower than COM samples indicating that SAS co-precipitate was physically more stable than COM sample. Raman mapping results showed the presence of crystalline γ-IDMC phase in COM sample, which may has acted as the precursor for the re-crystallization of COM sample. The Raman spatial distribution mapping suggested that co-linearity in composition between PVP and amorphous IDMC in SAS sample, which resulted in the reconstruction of single component spectrum that are resemblance to Raman peaks of PVP and amorphous IDMC pure component references. It was demonstrated that the drug to polymer ratio influenced the amorphous content of the SAS co-precipitates. By using different polymer ratios, the morphologies of a drug- vii References [88] Lee, B.-M.; Jeong, J.-S.; Lee, Y.-H.; Lee, B.-C.; Kim, H.-S.; Kim, H.; Lee, Y.W., Supercritical antisolvent micronization of cyclotrimethylenetrinitramin: Influence of the organic solvent Ind. Eng. Chem. Res. 2009, 48, 1162-1167. 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Y.; Tan, R. B. H., Recent developments in process analysis for gas-solid fluidization. In Advances in Chemistry Research; Taylor, J. C., Ed. Nova Publisher: 2011; 10, 143-176. 129 Appendices A2. Conferences [1] Lim, R. T. Y.; Ng, W. K.; Tan, R. B. H., Effect of co-precipitation on crystallinity of pharmaceutical compounds using supercritical anti-solvent process. AIChE The 2008 Annual Meeting, Philadelphia, PA, 15-21 November 2008. [2] Lim, R. T. Y.; Ng, W. K.; Tan, R. B. H., Amorphization of pharmaceutical compounds by co-precipitation using supercritical anti-solvent process. 9th International Symposium on Supercritical Fluids (ISSF9), Bordeaux, France, 18-20 May 2009. [3] Lim, R. T. Y.; Ng, W. K.; Tan, R. B. H., Influence of supercritical anti-solvent coprecipitation on the solid-state properties of pharmaceutical compound. 9th Conference on Supercritical Fluids and Their Applications, Sorrento, Italy, 5-8 September 2010. [4] Lim, R. T. Y.; Ng, W. K.; Tan, R. B. H., Dissolution enhancement of indomethacin via amorphization using supercritical, co-precipitation and co-milling. Engineering Conferences International (ECI): Particulate Processes in the Pharmaceutical Industry III, Gold Coast, Australia, 24-29 July 2011. [5] Lim, R. T. Y.; Ng, W. K.; Tan, R. B. H., Physical stabilities of indomethacin via amorphization using co-milling and supercritical co-precipitation processing. 10th International Symposium on Supercritical Fluids (ISSF10), San Francisco, California, USA, 13-16 May 2012. 130 Appendices [6] Lim, R. T. Y.; Ng, W. K.; Widjaja, E; Tan, R. B. H., Amorphization of pharmaceutical compounds using co-milling and supercritical co-precipitation processing. 5th Asian Particle Technology Symposium (APT 2012), Singapore, 2-4 July 2012. [7] Hoong, Y. J. A.; Lim, R. T. Y.; Ng, W. K.; Widjaja, E.; Tan, R. B. H., Investigating milling-induced amorphization effects on properties of an active pharmaceutical ingredients (API). AAPS Annual Meeting and Exposition, Chicago, Illinois, USA, 14-18 October 2012. 131 [...]... forms can be obtained using these technologies by modifying the molecular structure of the crystals The amorphous state of the drug can be stabilized by dissolving the drug into the polymer matrix at molecular level and restricting the mobility of the drug molecules, thus hindering the re-crystallization process There are a number of different methods to generate the amorphous form of APIs and/or amorphous... that leaves the surface of drug and dissolved into the solution per unit time Based on the modified Noyes-Whitney equation, the dissolution rate (dm/dt) is proportional to the surface area available for dissolution (A), the diffusion coefficient of the solute in solvent (D), the concentration across diffusion layer (concentration of the solute at saturation (C ) - concentration of the drug in the bulk... substances The effect of a polymer on the re-crystallization rate of amorphous substances is generally expressed in terms of properties of the meta-stable amorphous form such as the molecular mobility, the glass transition temperature (Tg) and the interactions 2 Chapter 1 arising between the drug and the polymer Substances with higher entropy and enthalpy than the steady crystalline form, such as the amorphous... improve the dissolution of APIs These methods apply new concepts based on the use of supercritical fluids or liquefied gases as solvent, antisolvent or cryogenic medium [24, 27] Supercritical fluid (SCF) technology presents a new and interesting route for particle formation, which avoids most of the drawbacks of the conventional methods (Table 2.2 and Figure 2.1 [74]) A substance is termed as a supercritical. .. heightened the interest of pharmaceutical researchers in developing new patents and novel techniques to improve oral bioavailability of APIs either in the areas of enhancing solubility and dissolution rate of poorly water-soluble APIs or enhancing permeability of poorly permeable drug Hence, in our studies the work is focused on enhancing the dissolution rate of a poorly water-soluble drug (BCS Class II) using. .. measure the solubility of substance at a meta-stable equilibrium The solubility measured under these conditions is known as apparent solubility and is higher than the intrinsic solubility Normally, the retention time for an API passes in digestive system is quite limited and thus, the absorption is governed by kinetic factors instead of thermodynamic properties The dissolution rate is the amount of active... and understand the nature of amorphous IDMC in PVP generated by COM and SAS co-precipitation process using Raman microscopy and FTIR, IV To study the surface energetic properties of amorphous solid generated by COM and SAS processes using IGC and V To investigate the surface structural relaxation of amorphous COM and SAS co-precipitated powder using IGC 1.3 Organization of Thesis This thesis is organized... precipitate the drug to microparticle There several methods to induce supersaturation in a solution such as thermal treatment (heating and cooling), evaporation and addition of a third component (anti- solvent, precipitant or reactant) Some of these techniques are spray-drying, solvent- evaporation and liquid anti- solvent Rasenack and Muller [69] conducted in-situ micronization of poorly water-soluble drug using. .. calcium generated using both anti- solvent and spraying processes was improved as compared to the raw material However, these techniques may present several disadvantages, such as contamination of the particles with organic solvents or other toxic substances, high energy requirement, generation of large volumes of solvent waste and may require multiple crystallization steps [73] Beneath the conventional... and commercialization of new pharmaceutical products The main objective of formulation chemistry is to improve bioavailability, stability and convenience of the APIs to the patient (preferably in solid dosage form) Bioavailability means the rate and extent to which the active substance or therapeutic moiety is absorbed from a pharmaceutical form and becomes available at the site of action [25] Moreover, . IMPROVING THE PROPERTIES OF PHARMACEUTICAL POWDERS USING SUPERCRITICAL ANTI- SOLVENT PROCESSING LIM TAU YEE, RON NATIONAL UNIVERSITY OF SINGAPORE 2012 IMPROVING. SINGAPORE 2012 IMPROVING THE PROPERTIES OF PHARMACEUTICAL POWDERS USING SUPERCRITICAL ANTI- SOLVENT PROCESSING LIM TAU YEE, RON (B. Eng. (Hons.), UNIVERSITY OF BATH, U.K.) (M. Eng.,. fluids technology. In this thesis, the effectiveness of a low-cost and easily scalable process COM was compared with the high-cost and precise-controlled supercritical anti- solvent (SAS) process