Enantioseparation of beta blocker drugs for pharmaceutical applications

ENANTIOSEPARATION OF BETA-BLOCKER DRUGS FOR PHARMACEUTICAL APPLICATIONS WANG XIN (B. Eng.; M. Eng., Tianjin Univ., P.R. China) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMICAL & ENVIRONMENTAL ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2004 Acknowledgements I would like to express my sincere gratitude to my thesis supervisor, professor Ching Chi Bun, for his guidance, emotional and financial support of the project. His comments and criticisms have been highly beneficial and most stimulating. Without his support, the completion of this thesis would not have been possible. Thanks are also to all the staff members in the department and our chiral separation group, especially, Dr. Bai Zhen Wu, Mdm Fu Ping, Dr. Ong Teng Teng and Dr. Chen Lei, for their technical assistance and discussion in the chiral synthesis field; Ms Wang Xiu Juan for the cooperation in the chiral crystallization area. The discussion with my friend Dirk-Uwe Astrath is sincerely appreciated. I am also grateful to my colleagues, Dr. Yu Hong Wei and Dr. Wu Yan Xia, for their kind discussion and support. I would also like to take this chance to express my sincere appreciation to Professor D.M. Ruthven, for his precious suggestions of my work, to Professor M. Morbidelli, Professor M. Mazzotti, Professor G. Guichon and Dr. Y. A. Beste for the valuable discussions and/or providing the reprints of papers. Special thanks go to my dearest wife, Zhang Huayun, and my parents for providing the inexhaustible emotion support and love. In particularly, the thesis could not be finished without the encouragement and support of my wife. Last but of course not least, I would like to thank the National University of Singapore and the Chemical Process Engineering Center (CPEC) for providing the financial support for this research and for providing finial support to attend various regional symposium on chemical engineering held in Thailand (1999), Singapore (2001) and Beijing (2002) as well as the 9th Asian Pacific Confederation of Chemical Engineering (APCChE 2002) in New Zealand. i TABLE OF CONTENTS Acknowledgement i Table of content ii Summary viii Nomenclature xii List of Figures xvii List of Tables xx Chapter 1. Introduction 1.1 General Background 1.2 Scope of the work Chapter 2. Literature Review on Chiral Separation 13 2.1 Background on chiral separation 13 2.2 Chromatographic techniques 13 2.2.1 Indirect HPLC method using chiral derivatizing agent 14 2.2.2 Direct method using chiral stationary phase (CSP) 15 2.2.2.1 CSP based on small synthetic chiral molecules 16 2.2.2.2 CSPs based on immobilized proteins 17 2.2.2.3 CSP based on polysaccharides and derivatives 18 2.2.3 2.3. Chiral mobile phase additives Crystallization techniques 2.3.1 Direct crystallization 19 20 22 2.3.1.1 Separations based on the simultaneous crystallization of the enantiomers 22 ii 2.3.1.2 Resolution by preferential crystallization 24 2.3.2 Crystallization of diastereomers 28 2.3.3 Characterization of the racemic species 30 Chapter 3. Racemic Characterization of β-Blocker Drug Propranolol 32 3.1 Introduction 32 3.2 Experimental and Methods 36 3.2.1 Materials 36 3.2.2 Thermodynamic Properties of Propranolol Hydrochloride 37 3.2.3 Differential Scanning Calorimetry, Powder X-ray Diffraction Pattern, Fourier Transform Infrared Spectroscopy and 13C Solid State Nuclear Magnetic Resonance Spectroscopy 40 3.2.4 Solubility and Metastable Zone Width of (R, S)- Propranolol Hydrochloride in the Mixed Solvent of Methanol and Acetone 40 Ternary solubility phase diagram 41 3.2.5 3.3 Results and discussions 3.3.1 42 3.3.2 X-ray Diffraction (XRD), FTIR Spectra and 13C SSNMR Spectra 45 3.3.3 Solubility and Metastable Zone Width of Racemic Propranolol Hydrochloride in the Mixed Solvent of Methanol and Acetone 48 The Ternary Phase Diagram 48 3.3.4 3.4 Enthalpy, Entropy and Free Energy of Formation of Propranolol Hydrochloride 42 Conclusions 52 Chapter 4. Preparation of Perphenylcarbamoylated β-Cyclodextrin Based Stationary Phase 53 4.1 Introduction 53 4.2 Syntheses 58 iii 4.2.1 General overview 58 4.2.2 Syntheses Procedures 60 Chapter 5. Liquid Chromatographic Retention Behavior and Enantiomeric Separation of β-Blocker Drug (Nadolol) 64 5.1 Introduction 64 5.2 Materials and Methods 65 5.3 5.4 5.2.1 Materials 65 5.2.2 Apparatus and chromatographic conditions 65 Results and discussions 67 5.3.1 Elution order of the enantiomers of nadolol 67 5.3.2 Effects of Mobile Phase Composition 67 5.3.3 Effects of pH 72 5.3.4 Effects of Ionic Strength 74 5.3.5 Effects of Flow Rate 75 5.3.6 Effects of Temperature 77 Conclusions 83 Chapter 6. Kinetic and Equilibrium Study of The Enantioseparation of Nadolol 84 6.1 General Background 84 6.2 Theoretical background 86 6.3 6.2.1 Theories for multi-component liquid chromatography 86 6.2.2 The rate models for chromatography 88 6.2.3 Moment analysis 92 Model parameters 94 6.3.1 Bed voidage 94 6.3.2 Axial dispersion coefficient 96 iv 6.4 6.5 6.6 6.3.3 Kinetic data 97 6.3.4 Adsorption isotherm 98 Materials, Instrumentation and Experimental Procedure 101 6.4.1 Materials and apparatus 101 6.4.2 Experimental procedure 102 Results and discussion 103 6.5.1 Determination of bed voidage 103 6.5.2 Determination of axial dispersion 104 6.5.3 Determination of equilibrium data 106 6.5.4 Determination of mass transfer coefficient 107 6.5.5 Simulation results 110 Conclusions 111 Chapter 7. Determination of Competitive Adsorption Isotherms of Nadolol by Improved H-Root Method 113 7.1 Introduction 113 7.2 Theoretical 117 7.3 7.4 7.5 7.2.1 Adsorption isotherms 117 7.2.2 Methodology of the improved h-root method 118 Materials, instrumentation and experimental procedure 126 7.3.1 Materials 126 7.3.2 126 Experimental procedure Results and discussions 127 7.4.1 Determination of competitive Langmuir coefficients 127 7.4.2 Validation of Adsorption Isotherms of nadolol 132 Conclusions 134 v Chapter 8. Continuous Counter-Current Separation of Nadolol Enantiomers of Competitive Adsorption 8.1 8.2 General introduction 135 135 8.1.1 Cross-current process 138 8.1.2 Counter-Current process 139 8.1.3 Simulated moving bed (SMB) technology in chiral separations 142 Theory 8.2.1 144 Four-zone counter current chromatography and basic design principles 144 8.2.2 Two design approaches for counter-current separation process 149 8.2.3 Binary and multi-component SMB separation in nonlinear region 157 8.2.4 Optimal and robust operation of SMB process 166 8.3 Five-zone SMB separation of ternary mixture 161 8.4 Experimental 171 8.5 8.6 8.4.1 Chemicals 171 8.4.2 Separation unit 172 8.4.3 Flow control system 173 Results and discussions 176 8.5.1 Robust and optimum operation of the SMB 178 8.5.2 Operation of the SMB for 2-extract configuration 186 8.5.3 Nonlinear separation of multi-component nadolol 191 Conclusions 200 Chapter 9. Modeling and Simulation of Continuous CounterCurrent Separation of Nadolol 202 9.1 Modeling of steady state behavior of Counter-Current Process 202 9.2 Results and discussion 206 vi 9.3 9.2.1 Model parameters 206 9.2.2 Cyclic steady-state behavior 209 Conclusions 211 Chapter 10. Conclusions and Recommendations 212 Reference 221 vii SUMMARY In this thesis, chiral separations of β-blocker drugs were studied by both crystallization and chromatographic processes. Specially, among beta-blockers, propranolol belongs to the most important one since a variety of analogous compounds have been developed based on it. Nadolol is another β-blocker drug widely used in the management of hypertension and angina pectoris, unlike propranolol, its chemical structure has three stereogenic centers that allow for eight possible stereoisomers. However, the two-hydroxyl substituents on the cyclohexane ring are fixed in the cisconfiguration that precludes four stereoisomers, which allows for the presence of four stereoisomers for this drug. These two drugs were chosen as the target substances in this study. In this study, combination of different techniques such as thermodynamic calculations, structural studies as well as ternary solubility diagram was proposed and demonstrated to be a powerful and reliable method to identify the nature of chiral drugs. The thermodynamic properties of enthalpy, entropy and Gibbs free energy of formation of racemic compound of propranolol hydrochloride and the entropy of mixing of the (R)-, (S)- enantiomers in the liquid state for conglomerate of propranolol hydrochloride were calculated. The structural studies such as powder X-ray diffraction patterns, infrared spectra and solid-state NMR spectra were utilized to characterize the crystalline nature of (S)- and (R, S)- propranolol hydrochloride and noticeable differences between enantiomer and racemate suggesting racemic compound nature of propranolol hydrochloride. The ternary solubility phase diagram of (R)-, (S)- propranolol hydrochloride and the mixed solvent of methanol and acetone in a volumetric ratio of 1:4.11 was constructed at 20 °C, which is helpful to understand the viii nature of racemic mixture and can be used as a guideline for choosing crystallization operation conditions to produce pure enantiomers of propranolol hydrochloride. Since direct crystallization can only be applied to resolve racemic conglomerates and is not suitable for racemic compounds that account for the vast majority of racemic species, chromatographic process was used as the major approach in this study for direct separation of chiral drugs. The study concentrated on the threechiral center β-blocker drug, nadolol, due to the separation of binary mixtures (i.e., one chiral center racemate) by SMB process has been widely investigated. Novel and facile methodologies for the preparation of two series of βcyclodextrin (CD)-based chiral stationary phase (CSP) by immobilization of mono or heptakis(6-azido-6-deoxy)-perfunctionalized-β-CD on amino-functionalized silica gel have been reported and patented by our group. In this study, heptakis (6-azido-6deoxy-2, 3-di-O-phenylcarbamolyted) β-CD bonded CSP was synthesized and packed into suitable size of columns in our lab. Complete resolution of three components of nadolol was achieved (two stereoisomers eluted together and overlapped in the first peak of the chromatogram) and the most active enantiomer (RSR)-nadolol was completely separated from other components. Various factors that affect the enantioseparation, including the mobile phase composition, pH, ionic strength, mobile phase flow rate and temperature were examined systemically. The optimum separation conditions for the mobile phase were also determined. The preparative column packed with the perphenyl carbamoylated β-CD bonded onto 15 µm spherical silica gel was characterized by the parameters of bed voidage and axial dispersion coefficient. Kinetics of mass transfer and equilibrium constants were evaluated by moment analysis on the basis of solid film linear driving force model for the given chromatographic system. 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Wu Yanxia, Xin Wang and Chi Bun Ching. “Computational Fluid Dynamics (CFD) Simulation of the Adsorption Separation of Three Components in High Performance Liquid Chromatography (HPLC).” Chromatographia, 55, pp. 439-445. 2002. 3. Xin Wang and Chi Bun Ching. “Kinetic and Equilibrium Study of the Enantioseparation of a Three Chiral Center Drug (Nadolol) on a Perphenyl Carbamoylated β-Cyclodextrin Bonded Chiral Stationary Phase by HPLC.” Sep. Sci. & Tech, 37, pp. 2567-2586. 2002. 4. Xin Wang and Chi Bun Ching. “Liquid Chromatographic Retention Behaviour and Enantiomeric Separation of Three Chiral Center β-Blocker Drug (Nadolol) Using heptakis (6-azido-6-deoxy-2, 3-di-O-phenylcarbamolyted) β-Cyclodextrin bonded Chiral Stationary Phase.” Chirality, 14, pp.318-324. 2002. 5. Xin Wang and Chi Bun Ching. “Determination of the Competitive Adsorption Isotherms of Nadolol Enantiomers by an Improved h-Root Method.” Industrial & Engineering Chemistry Research, 42 (24), pp.6171-6180. 2003. 6. Xin Wang and Chi Bun Ching. “Chiral Separation and Modeling of Three Chiral Centre β-Blocker Drug (Nadolol) By Simulated Moving Bed Chromatography.” J. Chromatogr. A, 1035, pp 167-176. 2004. 7. Xin Wang, Xiu Juan Wang and Chi Bun Ching. “Implications of Chirality for the Physicochemical Properties and Crystallization of Chiral Drugs”. Symposium on Challenges in Novel Separation & Purification. Singapore. October 29-30, 2001. 8. Xin Wang and Chi Bun Ching, “Determination of Competitive Adsorption Isotherms of Nadolol on A Perphenyl Carbamoylated β-Cyclodextrin Bonded Chiral Column”, presented at the 9th Asian Pacific Confederation of Chemical Engineering (APCChE), Christchurch, New Zealand. September 29-October 3, 2002. 9. Chi Bun Ching and Xin Wang. “Chiral Separation of Three Chiral Centre beta-Blocker Drug (Nadolol) By Simulated Moving Bed Chromatography.” AIChE Annual Meeting. November 16-21, San Francisco, CA. USA. 2003. PAPERS SUBMITTED 10. Xin Wang and Chi Bun Ching. “Chiral Separation of β-Blocker Drug (Nadolol) By Five-Zone Simulated Moving Bed.” Submitted to Chem. Eng. Sci (Revised version). 2004. 11. Xin Wang and Chi Bun Ching. “Two Design Approaches for Countercurrent Chromatographic Separation Process.” Submitted to Sep. Sci. & Tech. 2004. [...]... driving force model Figure 6.2 Molecular structure of TTBB Figure 6.3 Plot of mean retention time of TTBB versus inverse of mobile phase flow rate Figure 6.4 Plot of HETP of TTBB versus interstitial velocity of mobile phase on the column Figure 6.5 Plot of first moments of three components of nadolol versus inverse superficial velocity of mobile phase on the column Figure 6.6 Plot of HETP of enantiomers of. .. Immobilization of 7PPHCD onto aminised silica gel Figure 5.1 Effect of mobile phase composition on (a) the retention time of nadolol; (b) the logarithm of the capacity factor of nadolol; (c) the resolution of nadolol Figure 5.2 Effect of pH on (a) the retention time of nadolol; (b) the resolution of nadolol Figure 5.3 Effect of ionic strength on (a) the retention time of nadolol; (b) on the resolution of nadolol... separation performance of 2-extract 5-zone SMB Figure 8.9 Regions of separation for a ternary mixture (nadolol) in four-zone SMB (feed concentration is 0.25 mg/min) Figure 8.10 Effect of changing feed concentrations on the region of complete separation for separation of ternary mixture by four-zone SMB Figure 8.11 Effect of changing feed composition on the region of complete separation for separation of ternary... Diameter of the column (cm) dP Particle diameter (µm) F Phase ratio, equal to (1-ε)/ε fi j Definition in Chapter 8, f i j = m j c ij − q ij ∆G 0 Gibbs free energy of formation of racemic compound hi H-root (dimensionless) xii H Equilibrium constant (dimensionless), defined by Equation 8.21 ∆H 0 Enthalpy of formation of racemic compound ∆H Enthalpy of fusion of racemic compound f ∆H lm Enthalpy of mixing of. .. spectra of (S)- and (R, S)- Propranolol Hydrochloride xvii Figure 5.4 Effect of flow rate on (a) the retention time of nadolol; (b) the resolution of nadolol Figure 5.5 Effect of temperature on (a) the retention time of nadolol; (b) the resolution of nadolol Figure 5.6 Chromatogram of nadolol in the optimal chromatographic conditions Figure 5.7 van't Hoff plot of nadolol in the temperature range of 15-40oC... mixture of nadolol by four-zone SMB Figure 9.1 Complete separation regions of the four-zone SMB for separation of nadolol Figure 9.2 Steady state concentration distribution profile in the four-zone SMB xix List of Tables Table 1.1 Comparison of biological activity of pharmaceutical products Table 1.2 Sales of chiral therapeutics in 1995 (sales in $ billions) Table 3.1 Physicochemical Properties of Propranolol... Scope of this work Beta- blocker drugs (a k a beta- adrenergic blocking agents or betaadrenoreceptor blocking agents) competitively bind to beta- adrenergic receptor sites on the heart (cardiac) and /or nonvascular smooth muscle They reduce the force of the heart muscle contraction and tend to reduce the heart rate under many circumstances The clinical uses were previously reviewed (Meyers, 1980) Beta- blockers... approach has been used to simulate the operation and performance of a simulated moving bed process for separation of nadolol in a fourzone SMB The simulation of the pseudo-binary separation was conducted on the basis of the shortcut method constituted only of the weak-key and strong key components The performance of the cyclic steady state behavior of the separation unit is predicted reasonably well The... Table 8.2 Different definitions of the two approaches in counter-current chromatographic process Table 8.3 Design criteria of flow rate ratios for the five-zone SMB Table 8.4 Definition of process performance parameters for 2-raffinate 5-zone SMB Table 8.5 Operating conditions of SMB experiments for 2-raffinate configuration Table 8.6 Operating conditions of SMB experiments for 2-extract configuration... sales of chiral drugs in 1995 alone were $59+ billion, which was about 40% of the total sales of therapeutics (chiral and non-chiral) for those areas The growth rate for these sales has been about 20% for the last 5 years The regulatory requirements, vastness of the chiral pure drug market and recent technical advances suggest that chiral technologies will continue to be a very lucrative area of biopharmaceutical . ENANTIOSEPARATION OF BETA- BLOCKER DRUGS FOR PHARMACEUTICAL APPLICATIONS WANG XIN (B. Eng.; M. Eng., Tianjin Univ., P.R. China) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR. nature of chiral drugs. The thermodynamic properties of enthalpy, entropy and Gibbs free energy of formation of racemic compound of propranolol hydrochloride and the entropy of mixing of the. Enthalpy of formation of racemic compound f H ∆ Enthalpy of fusion of racemic compound m l H∆ Enthalpy of mixing of enantiomers in the liquid state m s H∆ Enthalpy of mixing of enantiomers