THERMODYNAMICS OF CHOLESTEROL COMPOUNDS IN SUPERCRITICAL CARBON DIOXIDE: EXPERIMENTAL AND MODELING STUDIES HUANG ZHEN NATIONAL UNIVERSITY OF SINGAPORE 2003 THERMODYNAMICS OF CHOLESTEROL COMPOUNDS IN SUPERCRITICAL CARBON DIOXIDE: EXPERIMENTAL AND MODELING STUDIES HUANG ZHEN (M. ENG., TIANJIN UNIVERISTY) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMICAL & BIOMOLECULAR ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2003 Acknowledgements ACKNOWLEDGEMENTS First of all, I would like to thank my principal advisor Professor Yee C. Chiew for his invaluable guidance and never-stopping encouragement throughout the span of my doctoral research at the National University of Singapore. His unmatched supervision and his spirit and soul as a real scholar, which make my research scholar experience undoubtedly the most impressive in my life, is highly appreciated. I also take this opportunity to thank A/P S. Kawi my co-supervisor for his admirable dedication to my thesis work during the time when Prof. Chiew has been on leave for years. I also would like to thank A/P W.K. Teo and A/P S.S. Feng for their insightful suggestions and comments on my PhD study. I would like to express my heartfelt thanks to the Department technicians: Samantha, Choon Yen, Mr. Boey, Mdm. Li Xiang, Mdm. Koh, Mdm. Chiang, Mdm. Tay and Ms. Ng for their pleasing willingness while rendering help for my experimental work. Special thank must go to Mr. Ng Kim Poi for his great support during the setup of my experimental apparatus. I wish to mention my thanks to my senior colleges Wang Xiaoyan and Lu Weidong, and my junior colleges Zhou Hong, Wu Ning and Wen Hanzhen, as well as my friends Effendi Widjaja, Chen Shaoping, Liu Xueming, Zhao Lingyun, Peng Zanguo, etc., for providing a friendly and pleasant environment to live and study at NUS. Their helps done in the lab are also highly appreciated. Last, but not least, I would like to show my affectionate regards to my family members for their love and support while I have been studying overseas. My beloved mother has always shown me her love and supported me silently with her affection. I i Acknowledgements feel deeply grateful to my parents-in- law for their kindly caring my child and all the moral support that they have given me. I am also greatly obliged to my wife and later my son for their closely accompanying with me and making my stay in Singapore pleasant, colorful and perfectly satisfactory. Finally, I want to express my highly appreciation to the National University of Singapore for funding my pursuit of a PhD degree in the last three and a half years and supporting my attending AIChE 2000 annual meeting at Los Angels, CA USA. ii Tables of Contents TABLES OF CONTENTS ACKNOWLEDGEMENTS i TABLES OF CONTENTS iii SUMMARY ix NOMENCLATURE xi LIST OF FIGURES xvii LIST OF TABLES xxiii CHAPTER ONE Overview 1.1 Introduction 1.2 Scope of work CHAPTER TWO Theoretical Background and Literature Review 2.1 Introduction 2.2 Background on pure supercritical fluid 2.2.1 What is the supercritical fluid? 2.2.2 Physical properties of supercritical fluids 11 2.3 2.2.2.1 Tunable density 11 2.2.2.2 Fast mass transfer rate 12 2.2.2.3 Other merits 15 2.2.3 Choices of supercritical fluids 15 2.2.4 Advantages and disadvantages of CO2 16 Solid-supercritical fluid equilibrium 18 2.3.1 Experimental methods 18 iii Tables of Contents 2.3.2 Solubility characteristics of supercritical solutions 19 2.3.2.1 Typical solid solubility characteristics 19 2.3.2.2 Solid partial molar volume 21 2.3.2.3 Structure of supercritical solutions 23 2.3.3 Solid solubility behavior in pure SCFs 24 2.3.4 Cosolvent effect on the solid solubility behavior in SCFs 26 2.3.5 Cosolute effect on the solid solubility behavior in SCFs 27 2.3.6 Thermodynamic modeling for the supercritical fluids 31 2.4 Cholesterols 35 2.5 Rapid expansion from supercritical solution (RESS) process 37 2.6 Conclusion 41 CHAPTER THREE Modeling Method 42 3.1 Introduction 42 3.2 Equation of state approach 43 3.2.1 Enhancement factor 43 3.2.2 Cubic equation of state approach 44 3.2.3 Mixing rules 46 Density-based correlations 48 3.3.1 The ln y i vs. ln ρ or ρ linear models 48 3.3.2 Pressure and temperature dependent density models 50 Summary 52 3.3 3.4 CHAPTER FOUR Property Estimation 4.1 Introduction 53 53 iv Tables of Contents 4.2 Vapor pressure 55 4.3 Molar volume 57 4.4 Critical temperature and pressure 58 4.5 Acentric factor 59 4.6 Summary 60 CHAPTER FIVE Solubility of Cholesterol and its Esters in Pure Supercritical CO2 66 5.1 Introduction 66 5.2 Experimental methodology 68 5.2.1 Materials 68 5.2.2 Experimental procedure 69 5.2.2.1 Solubility determination 69 5.2.2.2 Non-aqueous reversed phase HPLC 71 5.3 Data correlation 72 5.4 Results and discussion 73 5.4.1 Testing reliability of experimental SCF technique 73 5.4.2 Solubility investigation 74 5.4.3 Modeling results 81 5.5 5.4.3.1 Enhancement factor 81 5.4.3.2 Peng-Robinson equation of state 83 5.4.3.3 Partial volume consideration 87 5.4.3.4 Density-based correlations 90 Conclusion 97 CHAPTER SIX Solubility of Cholesterol and its Benzoate in SCF CO2 with Cosolvents 99 v Tables of Contents 6.1 Introduction 99 6.2 Experimental setup 100 6.3 Modeling 102 6.4 Results and discussion 104 6.4.1 Cosolvent consideration 104 6.4.2 Solubility enhancement 105 6.4.3 Modeling results by PR EOS approach 111 6.4.4 Modeling results by density-based correlations 116 Conclusion 122 6.5 CHAPTER SEVEN Behavior of Mixed Cholesteryl Butyrate and Benzoate in Supercritical CO2: Effect of Pressure Induced Structural Transition 123 7.1 Introduction 123 7.2 Experimental section 128 7.2.1 Equipment setup and experimental conditions 128 7.2.2 Bed composition consideration 128 7.2.3 HPLC analysis of collected solid mixture 129 7.2.3.1 HPLC instrumentation 129 7.2.3.2 Preparation of standard solutions 130 7.2.3.3 Chromatographic condition 130 7.2.3.4 Analysis procedure 131 7.2.4 Thermal analysis of mixed cholesteryl esters 133 7.2.4.1 TGA analysis 134 7.2.4.2 Differential scanning calorimetry (DSC) analysis 134 7.2.5 XRD analysis of mixed cholesteryl esters 135 vi Tables of Contents 7.3 Results and discussion 136 7.3.1 Solubility behavior 136 7.3.1.1 Solubility of mixed cholesteryl esters at 1:1 mass ratio 136 7.3.1.2 Effect of bed composition 7.3.2 Phase studies of CBU-CBE mixture 7.4 140 144 7.3.2.1 TGA results 144 7.3.2.2 DSC results 145 7.3.2.3 X-ray diffraction results 156 Conclusion 161 CHAPTER EIGHT Modeling the Polar Solid Solubility in SCF CO2-Polar Cosolvent Mixture with a New Peng-Robinson EOS plus Association Model 164 8.1 Introduction 164 8.2 The Peng-Robinson plus association equation of state model 166 8.3 Results and discussion 169 8.3.1 Aspirin-SCF CO2-ploar cosolvent systems 170 8.3.2 Naproxen-SCF CO2-polar cosolvent systems 174 Conclusion 178 8.4 CHAPTER NINE Application of the Perturbed Lennard-Jones Chain Equation of State (PLJC EOS) to Solute Solubility in Supercritical Carbon Dioxide 179 9.1 Introduction 179 9.2 PLJC equation of state for mixtures 183 vii Tables of Contents 9.3 9.4 Results ad discussion 187 9.3.1 Supercritical solvent 187 9.3.2 Binary solid-CO2 system 189 Conclusion 199 CHAPTER TEN Formation of Aspirin and PLGA Particles through Rapid Expansion of Supercritical Solutions (RESS) Technique 200 10.1 Introduction 200 10.2 Experimental apparatus and procedure 202 10.3 Results and discussion 205 10.3.1 Precipitated aspirin particles 205 10.4 10.3.1.1 Effect of nozzle diameter 207 10.3.1.2 Effect of extraction temperature 208 10.3.1.3 Effect of extraction pressure 211 10.3.2 Precipitated PLGA (85:15) particles 212 Conclusion 217 CHAPTER ELEVEN Summary and Recommendation 218 11.1 Summary of results and conclusions 218 11.2 Recommendations for further research 222 References 224 Appendix 252 viii References Lee, H.K., C.H. 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After serving as a lecturer in Tanjin University of Commerce for two years, he came to Singapore in October 1998 as a full-time postgraduate to pursue a Doctorate of Philosophy in Chemical Engineering at The National University of Singapore (NUS). In May 2002, he continued his career as a Research Engineer in Chemical and Process Engineering Center (CPEC) of NUS involved in ABB Lummus industrial project. One year later He joined the Department of Chemical and Environmental Engineering as a Research Fellow to further develop his career. 252 Appendix APPENDIX B: PUBLICATIONS Mutually decreased solubility behavior of mixed cholesteryl esters in supercritical CO2, (in preparation) Solubility of aspirin in supercritical carbon dioxide/alcohol mixtures: Experimental data and modeling using a Peng-Robinson plus association equation of state, Ind. Eng Chem. Res. (in preparation) Solubility of aspirin in supercritical carbon dioxide with/without acetone, J. Chem. Eng. Data (accepted), 2004 Formation of aspirin and PLGA particles through rapid expansion of supercritical solutions (RESS), (in preparation) Application of the Perturbed Lennard-Jones Chain equation of state (PLJC EOS) to solute solubility in supercritical carbon dioxide, Fluid phase Equilibrium, 216: 111122, 2004 Solubilities of cholesterol and its esters in supercritical carbon dioxide with/without cosolvents, J. Supercritical Fluids (accepted), 2003 Solubilities of cholesterol and its derivatives in supercritical carbon dioxide, Presented at AIChE 2000 annual Meeting, Los Angeles, California, USA, November 12-17, 2000. Solubility of aspirin in supercritical carbon Dioxide with and without methanol, Presented at Chemical and Process Engineering Conference (CPEC) 2000, Singapore, December 11-13, 2000. 253 [...]... SUMMARY Knowledge of equilibrium solubility in supercritical fluid is of great importance to practical SCF process design In this work, a continuous-flow system was set up to measure the solubility of cholesterol and its acetate, butyrate and benzoate in supercritical CO2 Experimentally determined solubility isotherms in pure supercritical carbon dioxide were obtained over a range of operating conditions... supercritical region of CO2 10 Figure 2.2 Variation in density of CO2 in the vicinity of its critical point 12 Figure 2.3 Diffusivity behavior of carbon dioxide in the vicinity of its critical point (McHugh and Krukonis, 1994) 13 Figure 2.4 Viscosity behavior of CO2 over a wide pressure and temperature range (Stephan and Lucas, 1979) 14 Figure 2.5 Solubility behavior of solid naphthalene in supercritical. .. CBE-CBU binary mixture (obtained from 154 heating T profiles of Series C) Figure 7.17 Phase diagram of CBE-CBU binary mixture (obtained from 154 heating T profiles of Series A) 143 150 xx List of Figures Figure 7.18 Phase diagram of CBE-CBU binary mixture (obtained from 155 heating T profiles of Series B) Figure 7.19 X-ray powder diffraction patterns of CBU/CBE solid 157 mixture prepared by the melting... 9.5 Experimental solubility of progesterone in supercritical CO2 197 and correlation with PLJC EOS model Figure 9.6 Experimental solubility of phenanthrene in supercritical CO2 197 and correlation with PLJC EOS model xxi List of Figures Figure 9.7 Experimental solubility of 1,10-decanediol in supercritical 198 CO2 and correlation with PLJC EOS model Figure 9.8 Experimental solubility of pyrene in supercritical. .. pressures of cholesterols obtained by Klincewicz and Reid method 63 Table 4.5 Estimated acentric factors of cholesterols obtained using Han and Peng’s method 64 Table 4.6 Required physical properties of all compounds used 65 Table 5.1 Sources and purity of all compounds used 68 Table 5.2 Solubility of cholesterol in pure SCF CO2 (mole fraction) 75 Table 5.3 Solubility of cholesteryl acetate in pure SCF... Advancements in this area will provide data for a better understanding of the phase equilibria of multi-solute mixtures which is of relevance to the design and development of processes involving supercritical fluids In addition to the above, academic and industrial researchers have been interested in developing theoretical models to quantitatively describe phase equilibrium of solid/multi-solid in supercritical. .. decaffeination of coffee and tea, refining of cooking oils, recovering of flavors and pungencies from spices, hops, and other plant materials A compilation of proven and potential applications using supercritical CO2 for extraction from natural materials has been detailed elsewhere (Mukhopadhyay, 2000) Other applications of 7 Chapter 2 Theoretical Background and Literature Review supercritical fluids including... and Reid, 1986) 20 Figure 2.6 Chemical structures of cholesterol and its three esters 36 Figure 5.1 Schematic of the experimental apparatus used in measuring the solid solubility in supercritical CO2 69 Figure 5.2 Effect of carbon dioxide (liquid based) flow rate on the solubility of cholesterol at 318.15 K, 160 bar 73 Figure 5.3 Comparison of cholesterol solubility in SCF CO2 75 Figure 5.4 Determination... using several equations of state including the PengRobinson equation of state, a modified Peng-Robinson equation which accounts for polar association between molecules, and the Perturbed Lennard-Jones Chain equation of state –a molecular model based on the perturbation theory of liquid state physics; and (3) to investigate the formation of fine particles of aspirin and PLGA through rapid expansion of. .. 10%) Besides single solute solubility measurements, several studies examining the solubility behavior of solid mixtures in supercritical fluids have been reported in the literature Knowledge of solute solubility of multi-solid systems is of importance 2 Chapter 1 Overview since most substances encountered in practical engineering and industrial situations usually exist as mixtures containing several . NATIONAL UNIVERSITY OF SINGAPORE 2003 THERMODYNAMICS OF CHOLESTEROL COMPOUNDS IN SUPERCRITICAL CARBON DIOXIDE: EXPERIMENTAL AND MODELING STUDIES . THERMODYNAMICS OF CHOLESTEROL COMPOUNDS IN SUPERCRITICAL CARBON DIOXIDE: EXPERIMENTAL AND MODELING STUDIES HUANG ZHEN. acetate, butyrate and benzoate in supercritical CO 2 . Experimentally determined solubility isotherms in pure supercritical carbon dioxide were obtained over a range of operating conditions from