Application of preferential crystallization for racemic compound integrating thermodynamics, kinetics and optimization 1

APPLICATION OF PREFERENTIAL CRYSTALLIZATION FOR RACEMIC COMPOUND INTEGRATING THERMODYNAMICS, KINETICS AND OPTIMIZATION LU YINGHONG NATIONAL UNIVERSITY OF SINGAPORE 2008 Application of Preferential Crystallization for Racemic Compound Integrating Thermodynamics, Kinetics and Optimization LU YINGHONG (B. Eng., Sichuan University M. Eng., Xian Jiaotong University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMICAL & BIOMOLECULAR ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2008 Acknowledgment I would like to thank for support, advice and encouragement from many people who made completion of this theses possible. First, I greatly appreciate my supervisor, Professor Chi Bun Ching, for providing me the opportunity to pursuer my research interests and for his scientific guidance and kind support and encouragement in my work. Lots of thanks go to Prof Zeng Huachun for his kind assistance. Special thanks go to Dr. Wang Xiujuan for her valuable scientific discussion and many critical comments on my research work. It is also my pleasure to express my gratitude to all the staff and students in Prof. Ching’s group for their friendship, helps and encouragement. In addition, I would acknowledge National University of Singapore for providing me this opportunity to pursue my PhD degree and the research scholarship. At last, I wish to thank my husband, my parents and my little baby girl for their consideration, help and encouragement, which are huge support behind this work. I Table of contents Acknowledgment I Table of contents . II Summary VI List of tables VIII List of figures .X Nomenclature .XV Chapter Introduction Chapter Literature review .8 2.1 Enzymatic separation .10 2.2 Separation by chiral chromatography 11 2.3 Chiral crystallization 14 2.3.1 Characterization of the racemic species 15 2.3.2 Resolution by crystallization of diastereoisomers 18 2.3.3 Optical resolution by direct crystallization .20 2.3.3.1 Separation of enantiomers by direct crystallization of their racemate .20 2.3.3.2 Preferential crystallization of enantiomeric enrichment of racemic compound .24 2.3.4 Process of preferential crystallization .28 2.4 Objective of the present research work 30 Chapter Characterization of two kinds of racemic compounds: Mandelic acid and Ketoprofen 37 3.1 Introduction 38 II 3.2 Materials and methods .39 3.2.1 Materials .39 3.2.2 Fourier Transform Infrared Spectroscopy (FTIR) 40 3.2.3 Raman spectroscopy .40 3.2.4 Powder X-ray Diffraction (PXRD) .40 3.2.5 Differential Scanning Calorimetry (DSC) 41 3.3 Results and Discussion 41 3.3.1 Characterization by analytical spectroscopic techniques 41 3.3.1.1 Fourier Transform Infrared Spectra .42 3.3.1.2 Raman spectroscopy 44 3.3.1.3 Powder X-ray Diffraction 45 3.3.2 Characterization by thermal analysis and binary phase diagram 47 3.3.2.1 Binary phase diagram of mandelic acid .47 3.3.2.2 Binary phase diagram of Ketoprofen .54 3.4 Conclusion .59 Chapter Crystallization thermodynamics: solubility and metastable zone width of mandelic acid and ketoprofen 64 4.1 Introduction 62 4.2 Method and Experiments .65 4.2.1 Apparatus 65 4.2.2 Solubility and metastable zone width (MSZW) 66 4.3 Results and discussion .68 4.3.1 Solubility and metastable zone width for the mandelic acid 68 4.3.1.1 Solubility and ternary phase diagram for mandelic acid .68 4.3.1.2 Metastable zone width for the mandelic acid 71 4.3.2 Solubility and metastable zone width for ketoprofen .76 4.3.2.1 Solubility and ternary phase diagram for ketoprofen 76 4.3.2.2 Metastable zone width for ketoprofen .80 4.3.2.3 Fractional Experiment Design .81 4.3.2.4 Analysis of the effects influencing metastable zone width of ketoprofen 84 III 4.4 Conclusion .91 Chapter Crystallization kinetics of mandelic acid and ketoprofen 93 5.1 Introduction 94 5.2 Mathematical model .97 5.2.1 Method of moment analysis 97 5.2.2 Method of Laplace transformation 99 5.3 Experimental Procedure .100 5.4 Results and discussion .101 5.4.1 Crystal nucleation and growth kinetics for the (S)-MA and (RS)-MA 101 5.4.1.1 Crystal suspension density and supersaturation .101 5.4.1.2 Crystal size distribution (CSD) 104 5.4.1.3 Kinetic evaluation on the measured data .106 5.4.2 Crystal nucleation and growth kinetics for the (S)-Kp and (RS)- Kp .110 5.4.2.1 Solubility 110 5.4.2.2 Crystal size distribution .112 5.4.2.3 Crystal growth and nucleation kinetics evaluation 114 5.5 Conclusion .118 Chapter Systematic preferential crystallization process of mandelic acid 120 6.1 Introduction 121 6.2 Experiment .123 6.2.1 Semi-preparative HPLC separation of mandelic acid .123 6.2.2 Direct crystallization operation .123 6.3 Results and discussion .124 6.3.1 Semi-preparative HPLC separation of mandelic acid .124 6.3.2 Preferential crystallization operation for mandelic acid .127 6.3.2.1 The progression of preferential crystallization 127 6.3.2.2 Optimal operation profile .132 6.3.2.3 Optical purity and crystal size distribution 137 6.3.2.4 Seed size effect on crystal size distribution .143 IV 6.4 Conclusions 145 Chapter Application of direct crystallization for racemic compound ketoprofen .147 7.1 Introduction 148 7.2 Experiment and methods 150 7.2.1 HPLC collection of ketoprofen .150 7.2.2 Direct crystallization process 150 7.3 Result and discussion .151 7.3.1 Semi-preparative HPLC separation of Ketoprofen .151 7.3.2 Preferential crystallization operation for ketoprofen 153 7.4 Conclusion .161 Chapter Conclusions and Future work .162 8.1 Conclusions 163 8.2 Future work 166 References .168 List of publications .193 V Summary In comparison to other chiral separation methods, the preferential crystallization is one of the simplest and most efficient processes. Typically, it was used for the enantioseparation of a racemic conglomerate. However, the applicability of preferential crystallization to racemic compounds would significantly widen the potential of crystallization based techniques for enantioseparation because racemic compounds occupy 90-95% of all racemates. For a racemic compound system, it is crucial to keep the freedom of supersaturation of the racemate in its metastable zone to avoid its spontaneous nucleation and control the supersaturation of the target enantiomer as the spontaneous nucleation of the target enantiomer may easily initiate the spontaneous nucleation of its racemate. In our group’s previous work (Wang and Ching, 2006), the concept of critical supersaturation control for preferential crystallization was introduced and the strategy was applied to racemic conglomerate. Therefore, in this dissertation, the objectives are to extend and modify this strategy to two kinds of racemic compound systems: mandelic acid and ketoprofen. A systematic preferential crystallization was studied on solubility, metastable zone, kinetics and supersaturation control profile to obtain crystal product with good quality. Two typical types of racemic compounds, namely favorable racemic compound (mandelic acid) and unfavorable racemic compound (ketoprofen), were characterized by various spectroscopic techniques, thermal analysis and phase diagrams construction. The solubilities and metastable zone widths (MSZWs) were studied for both systems. The MSZWs of racemate are different from those of pure enantiomer for a racemic compound system. The MSZWs of mandelic acid were favorable for VI preferential crystallization process, while the MSZWs of high mole percent (S)ketoprofen were narrow, which indicated it was hard to control the supsaturation level of pure enantiomer to inhibit its spontaneous nucleation to induce nucleation of racemate during the crystallization process. The classical Laplace transform analysis and moment analysis were used for deriving the crystal growth rate and nucleation rate in the batch crystallization process for enantiomer and racemate of mandelic acid and ketoprofen. The enantiomer and racemate show different characteristics in crystal nucleation and growth. Through the study on the direct crystallization progression for the mandelic acid and ketoprofen system, it was found that the optically pure product could be obtained by direct crystallization with seeding within certain safe supersaturation limit for a racemic compound. So, it is important to control supersaturation degree in preferential crystallization. Based on the thermodynamic and kinetic consideration, an optimal temperature control profile was derived to control the critical supersaturation in order to inhibit the induced nucleation of the racemate for the mandelic acid. Compared with the forced and linear cooling profile, the final crystal products of the proposed control cooling profile were almost optically pure with high yield and good crystal size distribution. The results suggest that it is crucial and helpful to combine thermodynamics and kinetics to establish the control strategy. This is especially critical for the unfavorable ketoprofen system due to its high eutectic composition and narrow metastable zone widths, which cause narrow feasible region and more difficulty to control for direct crystallization. Direct crystallization alone could be less effective and less economical as an enantioseparation process for the ketoprofen system. VII List of tables Table 2.1 Resolution methods Table 3.1 Thermodynamic properties of (S)- and (RS)- MA .51 Table 3.2 The melting temperature and eutectic temperature of different mole fraction of (S)-MA 53 Table 3.3 Thermodynamic properties of (S)- and (RS)- Kp .57 Table 3.4 The melting temperature and eutectic temperature of different mole fraction of (S)-Kp .58 Table 4.1 Solubility data (g/ml) for different mole percent of (S)-MA .69 Table 4.2 Solubility data for different mole percent of (S)-Kp 78 Table 4.3 Levels for each of four factors .83 Table 4.4 The design of L9 with coded levels of factor 83 Table 4.5 The solubility data of (RS)-Kp, 0.94 mole fraction of (S)-Kp, and (S)-Kp (mg/ml) .84 Table 4.6 Worksheet for a L9 design for metastable zone widths .85 Table 4.7 Calculation average responses for three-level experiment for (RS)-Kp .86 Table 4.8 Calculation average responses for three-level experiment for 0.94 mole fraction of (S)-Kp and (S)-Kp 87 Table 5.1 Crystallization kinetics measurement of (S)-MA 102 Table 5.2 Crystallization kinetics measurement of (RS)-MA 102 Table 5.3 Estimated (S)-MA crystal nucleation rate B and growth rate G with s plane analysis from the experiment 106 Table 5.4 Estimated (RS)-MA crystal nucleation rate B and growth rate G with s plane analysis from the experiment 107 Table 5.5 Solubility of (RS)-Kp and (S)-Kp 111 Table 5.6 The estimated linear growth rate and nucleation rate for (RS)-Kp 114 VIII Zaugg (1955) described the simultaneous crystallization of the enantiomers of methadone. “50 g of racemate is dissolved in 145ml of petroleum ether. Through slow evaporation at 40 oC (125h), two crystals of (+) - methadone weighing 13.0 g and two crystals of (-) - methadone weighing 13.1 g develop from two seeds of each isomer deposited in the solution at the onset.” A further improvement of the above procedure is to allow the supersaturated solution of the racemate to circulate over R and S seeds, which now are physically separated from one another, for instance, by means of fritted glass plates. Several pieces of apparatus have been reported for the resolution if various conglomerates by this dynamic method. For instance, the device used for the resolution of lysine 3,5dinitrobenzpatewas constructed from two columns arranged in parallel and each loaded with either R or S seeds in relatively large quantities (Sato et al., 1969), in contrast with the static method. A similar device in which the two columns are arranged in series has been described for the resolution of 3-fluoroalanine-2-d benzene sulphonate (Dolling et al., 1978). Hydrobenzoin has also been resolved by the same method, using a slightly different apparatus with only one crystallization column and a single seed, so as to obtain a large monocrystal of a pure enantiomer (Brugidou et al., 1974). This method has been used to prepare the α-methyl-L-dopa and for the C3-sython glycidyl-3-nitrobenzenesulfonate etc (Merk, 1965; Challener, 2001). b) Preferential crystallization Preferential crystallization involves introducing seed crystals of the desired enantiomer into a cooling saturated solution of the racemic mixture and harvesting the 21 crystals that grow on the seeds (Harada, 1986; Shiraiwa, 1998). It is a practical variant of nonequilibrium crystallization carried out under carefully specified conditions designed to prevent the spontaneous crystallization of the undesired enantiomer during the controlled crystallization of its chiral partner (Eliel et al., 1994). In the preferential crystallization method, one manages to promote the crystallization of one of the enantiomers while keeping the other in supersaturated state. Application of this process therefore rests on the mastery of the crystallization rate of the two enantiomers, and implies the utilization of ternary phase diagrams (Collet et al., 1980). Fig. 2.3 represents a solubility isotherm ternary phase diagram for a conglomerate. The region (NPMQ) of the phase diagram where the preferential crystallization can take place is located in the vicinity of the eutectic point E, where the degree of supersaturation of R and S enantiomers is not too high, so as to delay their spontaneous crystallization. In this area, seeding of a supersaturated solution with crystals of one of the enantiomers is expected to trigger the crystallization of this crystal, without disturbing the supersaturation of the other. The path A, B, A’, C indicates how the composition of the solution changes during the course of the crystallization in Fig. 2.3 (a). If the optical rotation of the solution is used to observe the change of solution, some results can be found as followed. At the onset A, a racemic solution is enriched artificially by adding a pure enantiomer or a partially resolved solution obtained by a different method. he solution is laevorotatory (or dextrorotatory). It becomes zero at B, and then begins to change the sign. At A’, the dextrorotatory (or laevorotatory) solution reaches a rotation opposite to the starting value. Then, the rotation of the solution reaches its maximum positive value (C point), and the R enantiomer starts crystallizing spontaneously. The 22 system slowly goes toward its equilibrium state, corresponding to the racemic solution E. (a) (b) Fig 2.3 A solubility isotherm ternary phase diagram for a conglomerate; (a) the composition of the solution changes during the course of the crystallization; (b) Preferential crystallization procedure. 23 Only the linear segment AA’ of the diagram is used to set up a preferential crystallization procedure. This process (Angelov et al., 2006) is described in Fig. 2.3 (b). A supersaturated solution M (equivalent to A) is seeded with the S enantiomer and allowed to crystallize until it reaches composition N (equivalent to A’). At this point, the S crystals are harvested by filtration. Then the same mass of racemic mixture as that of the collected S crystals is added into the filtrate. The new supersaturated solution P is created. It is symmetrical to point M. When R crystals are seeded, it initiates the crystallization of R enantiomers. The crystallization process is stopped until Q and the R crystals are collect. Addition of racemate then gives solution M, and so on. There are many reports about the success use of preferential crystallization. For example, Histidine hydrochloride was resolved by preferential crystallization above 45oC consistent with the phase disgram (Eliel et al., 1994). The 4-chloro-3methylphenyl ester (+)-3 (Yamada et al., 1998) and 4-hydroxy-2-pyrrolidone (Wang and Ching, 2006) were found to exist as a conglomerate. Their pure R and S enantiomers were reported to be obtained by optical resolution of preferential crystallization. In addition, Shiraiwa’s group has extensively application of preferential crystallization for racemic amino and other compound (Shiraiwa et al., 1996, 1997a, 1997b, 1998, 2002, 2003, 2005). 2.3.3.2 Preferential crystallization of enantiomeric enrichment of racemic compound As discussed above, preferential crystallization was typically used for the enantiomer separation of a racemic conglomerate. However, only 5%-10% of 24 crystalline racemates are conglomerate. The majority of chiral substances are racemic compounds which occupy 90-95% of all racemates. Therefore, the applicability of preferential crystallization to racemic compounds would significantly widen the potential of usually cheap crystallization based techniques for enantioseparation (Jacques et al, 1981; Brock and Dunitz, 1994; Kinbara et at., 2001; Lorenz et al., 2001; 2006a; 2006b; Profir et al., 2002). Moreover, with the great development of asymmetric synthesis and SMB chromatography, it becomes relatively easier to obtain an enantiomeric enrichment exceeding the eutectic composition in the racemic compound system, which sets the threshold for a subsequent enantioselective crystallization process. The preferential crystallization for an enantiomeric enrichment can be applied to further purify the partially resolved racemic compound (Lorenz et al., 2001; 2006; Polenske et al., 2007). It is easy to understand for the racemic compound in the binary phase diagram, shown in Fig. 2.4. Fig 2.4 Binary phase diagram for a racemic compound. 25 Compared with conglomerate, the racemic compound has the more complex situation. When heating, a partially resolved mixture (M or M´ in Fig. 2.4) begin to melt at TE, which is now different from that the racemate melting point. At a temperature just above the TE, one obtains a two-phase system consisting of a liquid and a solid, as same in the conglomerate case. However, here the nature of the solid depend on the sample composition and, more precisely, on its composition with the respect to the eutectic. In case of mixture M´, the solid phase is the racemic compound, whereas it is one of the pure enantiomers when the original compound is M. In the case of crystallization from the solution, a mixture of two enantiomers and a solvent can be represented in a ternary phase diagram (Fig. 2.5). In the case of an achiral solvent, the shape of the solid–liquid equilibrium line in the ternary phase diagram is very often similar to the one in the binary melt diagram. Also, the composition in the binary system of the two enantiomers at the eutectic point in the ternary phase diagram (point E in Fig. 2.5) is nearly always equal to the concentration at the eutectic point in the melt diagram. In most cases, the eutectic points at different temperatures are situated on a line. Assuming that the ternary system has a temperature T3, the area above the equilibrium line W3–E3–E′3–W′3 represents the one-phase area; the one below that line is the two-phase area, in which a liquid is in equilibrium with a solid phase. Optically pure crystals can only be obtained if the overall composition of the system is situated within the triangle W3–E3–(+). The point F, i.e., consists of pure (+)-crystal and a saturated liquid phase of composition S. If the overall composition is situated within the triangle (+)–E3–R, i.e. F′ or P′′, a liquid phase of composition E3 is in equilibrium with a mixture of pure and racemic crystals. Within the triangle E3–E′3–R (i.e., P′), a solid phase with racemic composition is in 26 equilibrium with a liquid phase (for P′ this is S′). With decreasing temperature, the solubility usually decreases and the one phase area is reduced. It can be seen that there is a minimum temperature for a given feed concentration, so that the crystallization process still yields pure crystals. For an overall composition of F, this minimum temperature is T2. If the temperature is lowered to T1, being smaller than T2, F is situated in the triangle (+)–E1–R and the solid phase is not optically pure anymore (Ströhlein et al., 2003). This is the reason why it is important and useful to know the type of racemate species. When it is racemic compound, we need to determine, at least roughly, the position of the eutectics in the phase diagram. Fig 2.5 Ternary phase diagram for a racemic compound (Ströhlein et al., 2003). 27 2.3.4 Process of preferential crystallization Typically, isothermal condition is the conventional method in the application of preferential crystallization process (Jacques et al., 1981). Coquerel’s group (Coquerel et al., 1995) introduced an isothermal approach named as Classical Seeded Isothermal Preferential (SIPC) programme. In this method, the saturated solution is cooled to the target temperature with seed added in the supersaturated solution. The solution is kept for a time period and finally the crystals are filtrated out. However, this isothermal method is not suitable for all preferential crystallization. In the optical resolution of (±)-N-acylnorfenfluramine derivatives, the preferential crystallization failed mainly because of unfavorable solubility ratio α of racemate to enantiomer (Coquerel et al., 1990), which is crucial for the preferential crystallization process (Watanae and Noyori, 1969; Collet et al., 1980). A smaller solubility ratio will result in a more favorable preferential crystallization operation. Therefore, an Auto Seeded Programmed Polythermic Preferential Crystallization (AS3PC) was proposed and applied to the preferential crystallization (Coquerel et al., 1995; Ndzie et al., 1997; Beilles et al., 2001; Courvoisier et al., 2001, 2002; Dufour et al., 2001). The results show that AS3PC process is more efficient than SIPC process for purity, yield, scale-up and filtration. The simplified mathematical description was used in the preferential crystallization and the optimal initial conditions for isothermal preferential crystallization were also studied (Elsner et al., 2005; Angelov et al., 2006). In addition, the crystallization process was monitored by the on-line polarimetry (Rodrigo et al., 2004) and an on-line density meter. From the engineering point of view, people had investigated on the synthesis of chiral crystallization process by considering the 28 separation steps in the flowsheet as movements on phase diagrams (Berry and Ng., 1997; Wibowo and Ng, 2000; Schroer et al., 2001). As discussed before, the simple preferential crystallization for partially resolved enantiomers without using the resolving agent can be directly applicable to the racemic compound, but the partially resolved enantiomers need to be achieved by other methods such as enzymatic separation and chromatography. In most case, Coupling of chromatography and direct crystallization is suggested for efficient enantioseparation of racemic compound. There are a few literature reported on this combination. A first attempt to realize such a combination has been published by Lim et al. for the Praziquantel system (Lim et al, 1995a, b). Enantiomerically pure (-) Praziuantel, an anthelmintic drug, was resolved by coupling a continuous chromatographic process and a multistage crystallization. Blehaut and Nicoud (1998) demonstrated improvement in productivity and eluent consumption for the separation of chiral ester LS2904 in heptane/2-propanol solution. Lorenz et al. (2001) indicated the possibility of productivity improvement in the combined process for the separation of the enantiomers of mandelic acid in aqueous solution. Ströhlein et al. (2003) worked in the development of a design method for this process. Amanullah and Mazzotti (2006) presented an analysis of a hybrid process consisting of SMB chromatography and crystallization and studied its performance for the separation of the Tröger’s base enantiomers. 29 2.4 Objective of the present research work As reviewed in this chapter, racemic compound represents 90-95% of crystalline racemates. Therefore enantiomer resolution for racemic compound presents a great challenge in pharmaceutical industry. The applicability of preferential crystallization to racemic compounds would significantly widen the potential of usually cheap crystallization based techniques for enantioseparation. In this work, the application of preferential crystallization to the racemic compound system will be explored coupling with chromatography. In Ching’s group previous work (Wang and Ching, 2006), the concept of critical supersaturation control for preferential crystallization process was introduced and this strategy was applied to racemic conglomerate system. It is understood that for a racemic conglomerate system, it requires controlling the different crystallization rate of the two enantiomers. Crystal nucleation and growth rates are closely associated with supersaturation. Therefore, it is crucial to carefully control the supersaturation of the two enantiomers to promote the desired enantiomer to grow and keep the undesired enantiomer in its metastable zone to avoid its spontaneous nucleation or growth on the target enantiomer crystals. In this work, we attempt to extend this strategy to a racemic compound. For a racemic compound system, the solution structure and properties are different from a conglomerate. The solution consists of racemate and one excess pure enantiomer molecules instead of two pure enantiomer molecules. The eutectic composition is usually not superimposable with the racemate. In view of thermodynamics aspects, it is crucial to keep the freedom of supersaturation of the racemate in its metastable zone to avoid its spontaneous nucleation. Therefore, the solubility diagrams and supersaturation data are the 30 thermodynamic basis for preferential crystallization for the racemic compound. On the other hand, it is also important to control the supersaturation of the target enantiomer as the spontaneous nucleation of the target enantiomer may easily initiate the spontaneous nucleation of its racemate. In addition, crystal size distribution (CSD) is an important factor in the production of high-quality products and for determining the efficiency of downstream operations. The feasibility and yield of pure enantiomer obtainable by direct crystallization depend on the characteristics of the phase diagrams of the system and initial enantiomeric composition of the feed to the crystallizer (Collet et al., 1980; Jacques et al., 1981; Lorenz et al., 2001). There are three typical classes of racemic compounds based on the binary/ternary phase diagrams, shown in Fig. 2.6. As discussed above, a pure enantiomer can only be produced by direct crystallization when the initial solution composition is located inside the existence region of pure enantiomers, indicated by AED or A’E’L in Fig. 2.6. For the unfavorable case (Fig. 2.6 a), the solubility of racemate is smaller than that of pure enantiomer and it shows the most narrow operation region to obtain pure enantiomers by crystallization. The Fig. 2.6 b shows the more favorable case, the solubility of racemate is greater than pure enantiomer for this case. The operation region to obtain pure enantiomers for this case is much wider than the unfavorable case. The most favorable case, shown in Fig2.6 c, is the special case which exhibits the maximum operation region and ideal phase diagram, eg. Propranolol hydrochloride (Wang et al., 2007). 31 Fig 2.6 Ternary phase diagrams for a racemic compound: (a) unfavorable; (b) more favorable; (c) most favorable. S: solvent; D, L: two form of enantiomer; R: racemate; E. E’: two eutectic point; A, A’: enantiomer saturated point in the solvent. Because the most favorable racemic compound is just a special case, the model racemic compounds in this study are chosen as mandelic acid (MA) for the more favorable case and ketoprofen (Kp) for the unfavorable case, respectively. (R)-mandelic acid (S)-mandelic acid Fig 2.7 Chemical structure of (R)- and (S)- mandelic acid. Mandelic acid, shown in Fig. 2.7, has long been used in the medical community as an antibacterial, particularly in the treatment of urinary tract infections, as well as an oral antibiotic. Lately, mandelic acid has been receiving greater attention as a topical skin care treatment. Dermatologists now suggest Mandelic acid as an appropriate treatment for a wide variety of skin concerns, from acne to wrinkles; it is especially good in the treatment of adult acne as it addresses both of these concerns. It 32 is also recommended is a pre- and post-laser treatment, reducing the amount and length of irritation caused by laser resurfacing. Ketoprofen (Fig. 2.8) is a potent nonsteroidal anti-inflammatory drug (NSAID) being currently being marketed as the racemate. (R)- Ketoprofen (S)- Ketoprofen Fig 2.8 Chemical structure of (R)- and (S)- ketoprofen It is equally or more potent than other NSAIDs with respect to antiinflammatory and analgesic activity (Ceschel et al, 2002). And ketoprofen is stable if screened from light and not sensitive to temperature variations, but it may start to decompose above 340oC (Espitalier, 1997). What is most important is the biological activity of ketoprofen resides with the (S)-enantiomer while (R)-ketoprofen is therapeutically inactive (Thirumala et al, 1998). So, chiral separation for the 33 ketoprofen to get the pure S enantiomer from its racemate is important for its therapeutic effects. In this work, the preferential crystallization process itself was studied for these two racemic compound systems, combining the aspects of thermodynamics, kinetics, optimal operation and in-situ monitoring. This thesis presents a systematic study on solubility, metastable zone, kinetics and supersaturation control profile to obtain crystal product with good quality. The chapter contents are introduced as below: In Chapter 3, two kind of racemic species, namely mandelic acid and ketoprofen, will be characterized by the various spectroscopic techniques, thermal analysis and thermodynamic calculation. The binary melting phase diagrams will be also constructed for the mandelic acid and ketoprofen based on Schröder-Van Laar equation and the Prigogine-Defay equation for characterization purpose. All these results suggest that the mandelic acid and ketoprofen are in form of racemic compound. But for the case of mandelic acid, the melting temperature of racemate is lower than that of enantiomer. It indicates that the mandelic acid may be a kind of more favorable racemic compound. On the contrary, the melting temperature of racemate is higher than that of enantiomer for ketoprofen, which suggests ketoprofen could be an unfavorable racemic compound. In Chapter 4, the solubilities, ternary phase diagrams and metastable zone widths at different mole percent of S enantiomer will be obtained for mandelic acid in water and ketoprofen in mixed solvent of ethanol and water with volume ratio 0.9:1.0. The lasentec FBRM is used to detect nucleation and dissolution. Based on the solubility, MSZW data and the properties of ternary phase diagram, it can be found that mandelic acid is a kind of more favorable racemic compound which is favorable for the preferential crystallization resolution, while ketoprofen show the typical 34 properties of an unfavorable racemic compound system with narrow MSZW. The main four effects of MSZW are to be studied for the ketoprofen by fractional experiment design in order to enhance the MSZW. For the Chapter 5, the classical methods of moments analysis and Laplace transform analysis for derive the crystal growth rate and nucleation rate in the batch crystallization process will be introduced. The crystallization kinetics of (S) and (RS)MA are to be obtained by moments analysis and the crystallization kinetics of (S) and (RS)-Kp are derived by using both methods. The enantiomer and racemate of mandelic acid and ketoprofen show different characteristics in crystal nucleation and growth. These kinetics data are useful to control the critical supersaturation and optimize the crystallizer in batch operation. In Chapter 6, the enantiomerically enriched mandelic acid will be obtained from a racemic composition by using an HPLC with a semi-preparative chiral column. Through the study on the direct crystallization progression for the mandelic acid system, it will be found that the optical pure product can be obtained by direct crystallization with seeding within certain safe supersaturation limit. In addition, a systematic study on solubility, metastable zone, kinetics and supersaturation control profile to obtain crystal product with good quality is proposed for the mandelic acid. Based on the thermodynamic and kinetic consideration, the mandelic acid is favorable for the preferential resolution. An optimal temperature control profile will be proposed to control the critical supersaturation in order to obtain the good quality pure product. As for the Chapter 7, a system preferential crystallization will be applied for the unfavorable racemic compound ketoprofen coupling with the HPLC. The partially resolved Kp is still obtained by HPLC collection with semi-preparative column. 35 Based on the solubilities and MSZWs of ketoprofen, the direct crystallization progression is to be clearly investigated. It could be found that the optical pure product is obtained by direct crystallization with seeding within certain safe supersaturation limit. However, for the unfavorable racemic compound ketoprofen, the whole coupling process with HPLC and direct crystallization would be less effective and less economical as an enantioseparation process. Because the metastable zone width of S enantiomer for ketoprofen is narrow and the ketoprofen eutectic point is high about 92% more percent (S)-Kp. These result shows that the ketoprofen system is unfavorable for the preferential resolution. In the last Chapter 8, some conclusions will be drawn and some future suggestions will be introduced. 36 [...]... measurement of (RS)-Kp .11 3 Fig 5 .11 Crystal size distribution of (S)-Kp in kinetic measurement of (S)Kp 11 3 Fig 5 .12 Typical s-plane analysis to estimate crystal nucleation and growth rate for (RS)-Kp s f L 2 =0 .1, G=2 .10 5 10 -8m/min, B= 5. 216 10 9#/min.m3 11 5 Fig 5 .13 Typical s-plane analysis to estimate crystal nucleation and growth rate for (RS)-Kp s f L 2 =1. 5, G =1. 959 10 -8m/min,... G =1. 959 10 -8m/min, B= 5.2379 10 9#/min.m3 11 5 Fig 5 .14 Typical s-plane analysis to estimate crystal nucleation and growth rate for (S)-Kp s f L 2 =1. 0, G =11 .22 10 -7m/min, B= 7.5679 10 8#/min.m3 11 7 Fig 5 .15 Typical s-plane analysis to estimate crystal nucleation and growth rate for (S)-Kp s f L 2 =0 .1, G=8.39 10 -7m/min, B=7.3593 10 8#/min.m3 11 7 Fig 6 .1 Partial separation of. .. 13 9 Fig 6 .11 DSC results for the final products and pure (S)-MA 14 0 Fig 6 .12 HPLC results of final products and pure (S)- and (RS)-MA 14 0 Fig 6 .13 Crystal size distribution of (S)-MA seeds and crystal products from different cooling profiles .14 2 Fig 6 .14 Effect of seed size on the final CSD of preferential crystallization for MA 14 4 Fig 7 .1 Partial separation of Kp on Chiralcel... rate and nucleation rate for (S)-Kp 11 6 Table 6 .1 The optical purity of the final crystal products with different cooling degree for mandelic acid 13 0 Table 6.2 The optical purity of final crystal product 13 9 Table 7 .1 The optical purity of the final crystal products with different cooling degree for ketoprofen .15 9 IX List of figures Fig 1. 1 A pair of chiral enantiomorphic forms... crystal nucleation and growth rates for (RS)-MA s f L 2 =0 .1, G =1. 43 10 -7m/min, B= 3.48 10 9#./min.m3 10 9 Fig 5.8 Typical s plane analysis to estimate crystal nucleation and growth rates for (RS)-MA s f L 2 =1. 0, G=2 .19 10 -7m/min, B= 3.58 10 9#./min.m3 10 9 Fig 5.9 Solubility of (RS)-Kp and (S)-Kp with different temperature 11 2 Fig 5 .10 Crystal size distribution of (RS)-Kp in kinetic... MSZWs of (RS)-MA in water at different cooling rates .75 Fig 4.9 Ternary phase diagram of (S)-Kp and 0.9 :1. 0 (vol) mixture solvent of ethanol and water, ■, 15 oC; ♦, 20oC; ▲, 25oC; ●, 30oC 79 Fig 4 .10 Solubility and Metastable zone width of 50% and 75% mole .80 Fig 4 .11 Effect chart of L9 design for (RS)-Kp 88 Fig 4 .12 Effect chart of L9 design for 0.94 mole fraction of (S)-Kp and. .. (95/0 .1/ 5 v/v) at 25°C column temperature, flow rate of 1. 0 ml/min and UV-Vis detection at 210 nm .12 7 Fig 6.4 Progression of direct crystallization of mandelic acid 12 9 Fig 6.5 Three different cooling profiles 13 4 Fig 6.6 The concentration of both enantiomers in the liquid phase and corresponding process trajectory for controlled cooling process .13 5 Fig 6.7 The concentration of. .. diagram for a racemic compound .27 Fig 2.6 Ternary phase diagrams for a racemic compound: (a) unfavorable; (b) more favorable; (c) most favourable .32 Fig 2.7 Chemical structure of (R)- and (S)- mandelic acid .32 Fig 2.8 Chemical structure of (R)- and (S)- ketoprofen .33 Fig 3 .1 The FTIR patterns of the pure (S)-MA and (RS)-MA 43 Fig 3.2 Infrared spectra of (S)-Kp and (RS)-Kp... distribution in kinetic measurement of (RS)MA 10 5 Fig 5.5 Typical s plane analysis to estimate crystal nucleation and growth rates for (S)-MA s f L 2 =0 .1, G=3.25 10 -8m/min, B= 4.98 10 8#./min.m3 10 8 XI Fig 5.6 Typical s plane analysis to estimate crystal nucleation and growth rates for (S)-MA s f L 2 =1. 0, G=5 .16 10 -8m/min, B= 5 .15 10 8#./min.m3 10 8 Fig 5.7 Typical s plane... (269 of the top 500 drugs) (Stinson, 19 97, 19 98, 19 99) In addition, between 19 92 and 2002, the world market for optically pure chemical compounds increased from $30 billion to an estimated $10 0 billion According to a survey, the global sales of single enantiomer compounds are expected to reach about $15 billion by the end of 2009, growing annually by 11 .4 % (Rouhi, 2004) 6 With the development of the . nucleation and growth kinetics for the (S)-Kp and (RS)- Kp 11 0 5.4.2 .1 Solubility 11 0 5.4.2.2 Crystal size distribution 11 2 5.4.2.3 Crystal growth and nucleation kinetics evaluation 11 4 5.5. Conclusion 11 8 Chapter 6 Systematic preferential crystallization process of mandelic acid 12 0 6 .1 Introduction 12 1 6.2 Experiment 12 3 6.2 .1 Semi-preparative HPLC separation of mandelic acid 12 3. distribution 14 3 V 6.4 Conclusions 14 5 Chapter 7 Application of direct crystallization for racemic compound ketoprofen 14 7 7 .1 Introduction 14 8 7.2 Experiment and methods 15 0 7.2 .1 HPLC collection