Application of preferential crystallization for racemic compound integrating thermodynamics, kinetics and optimization 6

Chapter Application of direct crystallization for racemic compound ketoprofen 147 7.1 Introduction As mentioned before, the direct crystallization for partially resolved enantiomers can be used for the racemic compound. According the phase diagram, whether we can obtain the desired pure enantiomer depends on the partially resolved mixture’s initial position and eutectic composition. When the crystallization initial solution composition is located inside the existence region of pure enantiomers, this crystallization process will afford a pure enantiomer. In the last chapter, a systematic preferential crystallization process was successfully applied for the favorable racemic compound mandelic acid. In this chapter this strategy was extended to another racemic compound system: unfavorable racemic compound. For this compound, 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. Ketoprofen was chosen for this study. There were some methods already applied for the ketoprofen enantioseparation, including chiral chromatography and enzymatic separation. For a chromatography, several direct/indirect liquid chromatographic methods involving a variety of chiral phases have been reported for the ketoprofen enantioseparation and its enantiomer analysis. For example, a new chiral stationary phase using flavoprotein, a glycoprotein present in chicken egg-white, was developed for high-performance liquid chromatography by Nariyasu et al. in 1992. The column with this chiral stationary phase could achieve baseline separations for ketoprofen. Also, Zhu (1999) reported that β-cyclodextrin (CD) and its derivatives HP- β -CD, DM- β -CD, and TM- β -CD had been employed as chiral selectors for the separation of ketoprofen by capillary zone electrophoresis. And also, Pehourcq (2001) found that 148 flurbiprofen and ketoprofen were resolved from their racemic forms using a vancomycin chiral stationary phase known as ChirobioticV. In addition, according to Aboul-Enein (2003), ketoprofen was also resolved on Kromasil tartardiamide-DMB chiral stationary phase. In this process, optimum resolution was achieved using a mobile phase consisting of hexane: tert-butyl methyl ether: acetic acid (75 :25: 0.1 v/v/v) at flow rate of ml/min. An enzymatic separation can be used for ketoprofen enantioseparation too. Antona et. al. (2002) observed that Immobilized lipase from Candida antarctica (Novozym 435) can catalyze the enantioselective etherification of (RS)-ketoprofen. He found that the use of methanol in dichloropropane allows large scale separation for ketoprofen. This method gave the desired (S)-ketoprofen with 96% ee as unreacted enantioform. The (R)-enantiomer, recovered as ester, can easily undergo chemical racemising hydrolysis and can be reused in the process. Though several chiral separation methods were used for the enantioseparation of ketoprofen, few studies have reported on using direct crystallization for partially resolved enantiomers to get the pure (S)-ketoprofen. And there is little information available on whether the coupling the directly crystallization with chromatography could be used for chiral separation of ketoprofen. Therefore, this chapter presents a study to obtain a enantiomerically enriched ketoprofen by using the HPLC with a semi-preparative column for the subsequent systematical study of direct crystallization process. The critical supersaturation control strategy and crystallization progression were investigated. 149 7.2 Experiment and methods 7.2.1 HPLC collection of ketoprofen The collection experiments were carried out with a Shimadzu chromatographic system and used a chiralpak preparative HPLC AD-H column (dimension 250mm L x 10mm I.D) to collect ketoprofen whose mole fraction should be more than 0.96. The mobile phase contained 90%hexane and 10% IPA. The temperature was 25oC and flow rate was 3.5ml/min. 7.2.2 Direct crystallization process The crystallization experiments were carried out in the same crystallization setup as described in Fig. 4.2. The controlled cooling profile (convex) was used on the batch direct crystallization operation of ketoprofen. The start point was the same enantiomeric composition with the partially resolved ketoprofen from HPLC collection. It was the 96% mole percent (S)-MA saturated solution at 20 oC in the mixed solvent ethanol and water with volume ration 0.9/1.0. Five batches direct crystallization experiments were carried out starting from the same solution with different modes, which are (a) Exp_01: with seeding and final temperature at 10 oC; (b) Exp_02: with seeding and final temperature at 7.3 oC; (c) Exp_03: with seeding and final temperature at 6.0 oC; (c) Exp_04: with seeding and final temperature at 0.7 o C; (f) Exp_05: without seeding until nucleation occurred. The optical purity of crystal products were also measured by using HPLC. For HPLC, the analyze AD-H column was also used to analyze product ee values. The 150 separation conditions are as followed: hexane/IPA (90/10 v/v) as mobile phase, at 25°C column temperature, flow rate of 0.8ml/min and UV-Vis detection at 254nm. 7.3 Result and discussion 7.3.1 Semi-preparative HPLC separation of Ketoprofen As discussed in chapter 6, the loading capacity of ketoprofen on Chiralcel ADH was determined by injecting different amount of sample onto the column. It was found that ketoprofen shows partial separation when sample loading reaches to 5.0mg, shown in Fig. 7.1. Fig 7.1 Partial separation of Kp on Chiralcel AD-H semi-preparative HPLC column (dimension 250mm L x 10mm I.D) at loadings 5.0mg per injection using hexane/IPA (90/10 v/v) as mobile phase, at 25°C column temperature, flow rate of 3.5ml/min and UV-Vis detection at 254nm. Through semi-preparative chiral HPLC separation, the 96% mole percent S enantiomer and pure R enantiomer of Kp were obtained by collecting two different 151 fractions at two different retention time, t =17-22 mins and t =15.3-17mins, as presented in Fig. 7.2. The optical purity of 96% mole percent S enantiomer collection was analyzed on analytical chiral column with hexane/IPA (90/10 v/v) as the mobile phase and a flow rate of 0.8ml/min, shown in Fig. 7.3. Then, the volume enough 0.96 mole fraction S Kp can be obtained by using continuous HPLC separation with an antosampler and automated fraction collector. Fig 7.2 Fraction collection under semi-preparative HPLC separation of Kp on Chiralcel AD-H column (dimension 250mm L x 10.00 mm I.D.) under separation conditions: hexane/IPA (90/10 v/v) as mobile phase, at 25°C column temperature, flow rate of 3.5ml/min and UV-Vis detection at 254nm.Fraction (a) collected at retention time 15.3-17 minutes and fraction (b) is collected at 17-22 minutes. 152 Fig 7.3 Chromatogram of fractions (b) obtained through semi-preparative HPLC separation of ketoprofen on Chiralcel AD-H analytical column (dimension 250mm L x 4.6 mm I.D.) under separation conditions: hexane/IPA (90/10 v/v) as mobile phase, at 25°C column temperature, flow rate of 0.8ml/min and UV-Vis detection at 254nm. 7.3.2 Preferential crystallization operation for ketoprofen Based on the phase diagram of Kp in the chapter 4, if we want to get the pure S enantiomer, the initial composition of the cooling crystallization should be between pure S and eutectic composition. At first, three different start compositions (96%, 94%, and 92% mole percent S ketoprofen) were tried at same cooling process in order to determine from which one pure S enantiomer products can be obtained. The HPLC analyzing results for the final crystal products of different initial composition are shown in Fig. 7.4. 153 (a) (b) (c) Fig 7.4 The HPLC analyzing results for the crystal products of different initial composition, (a) 92% mole percent (S)-Kp; (b) 94% mole percent (S)-Kp; (c) 96% mole percent (S)-Kp. 154 The first peak in these figures presents the R enantiomer of ketoprofen, while the second one is S enantiomer. We can see from these HPLC results that the first peak area was almost negligible compared with the second peak only in Fig. 7.4 c. That means only final crystal product from 96% mole fraction (S)-Kp initial composition was almost pure S enantiomer considering the measure error in HPLC and impurities in products. It can be explained by the Fig. 7.5 (Lorenz and Seidel-Morgenstern, 2002). If we want to get the pure (S)-Kp, the system point should locate inside the pure enantiomer existence region at ending temperature. When start point P cooling to a lower temperature T2, the pure S enantiomer will come out. Then, The start point at high temperature, such as T1 should be higher than the eutectic point. The bigger the cooling temperature range, the higher the start point. Generally the start point always need higher than the eutectic point. Therefore, in this work, the crystallization operations with start composition of 92% and 94% can not produce the optical pure ketoprofen, though their start composition was higher than eutectic point. 155 Fig 7.5 Cooling process to obtain pure enantiomer. The start composition for the preferential crystallization of ketoprofen was the saturated solution at 20oC with 96% mole percent S enantiomer. 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Lu Yinghong, Wang Xiujuan and Ching Chi Bun, Application of preferential crystallization for different types of racemic compounds, Industrial & Engineering Chemistry Research, Revision submitted. 193 [...]... experiment data The shape of binary phase diagrams of mandelic acid and ketoprofen both show the typical shape of racemic compound system, just the more favorable racemic compound system for mandelic acid and unfavorable racemic compound system for ketoprofen From the binary phase 163 diagram, the eutectic point was determined as 70% of (S)-MA for mandelic acid and 91 .6% of (S)-Kp for ketoprofen In chapter 4,... process for the ketoprofen system 161 Chapter 8 Conclusions and Future work 162 8.1 Conclusions In this present work, the preferential crystallization process itself was studied for the two racemic compound systems, namely more favorable racemic compound mandelic acid and unfavorable racemic compound ketoprofen, combining the aspects of thermodynamics, kinetics, and optimal operation A systematic preferential. .. method and the kinetic results of moments analysis are comparable with those of Laplace transform analysis for ketoprofen The enantiomer and racemate show different characteristics in crystal nucleation and growth for racemic compound mandelic acid and ketoprofen In chapter 6, a systematic preferential crystallization combining the solubility, metastable zone, kinetics and supersaturation control profile... different between the pure enantiomer and racemate for the mandelic acid and ketoprofen, which indicates that the mandelic acid and ketoprofen both belong to the racemic compound Through the thermal analysis and calculation, it was found that the ∆G0 was negative and the enthalpy of fusion difference between (RS) and (S) were positive for both of mandelic acid and ketoprofen Their ∆Tf were both far away... identification of batch crystallization processes (estimate of kinetic-parameters of Sodium-Perborate precipitation), Comput Chem Eng., 1995, 19, 241-2 46 Lorenz H., Perlberg A., Sapoundjiev D., Elsner M.P and Seidel-Morgenstern A., Crystallization of enantiomers, Chem Eng and processing, 2006a, 45, 863 -873 Lorenz H., Polenske D and Seidel-Morgenstern A., Application of preferential crystallization to resolve racemic. .. the preferential crystallization of mandelic acid in the chosen solvent is more favorable as temperature decreases All the MSZW results of mandelic Acid were higher than 5 oC which are favorable for preferential crystallization process Its ternary phase diagram showed a typical shape of more favorable racemic compound, which further proves that the mandelic acid is a kind of more favorable racemic compound. .. feasible supersaturation control range compared with 0.027g/ml for mandelic acid It suggests that it is more difficult to control the supercooling for the preferential crystallization for ketoprofen and the nucleation of enantiomer and racemate of ketoprofen may be easy to occur On the other hand, considering the crystal growth kinetics of the ketoprofen (Eq 5-23), the crystal growth rate should be very small... Press, 1994 Harada K., Optical resolution of monoammonium DL-Malate by preferential crystallization, Chem And Indu, 19 86, 20, 68 -69 Harrington P.J and Lodewijk E., Twenty years of naproxen technology, Org Process Res Dev., 1997, 1, 72- 76 Henderson G M and Rule H G., A new method of resolving a racemic compound, J Chem Soc., 1939, 1 568 Heydron W.E., Developing racemic mixtures vs single isomers in the... properties in solution were studied for the mandelic acid and ketoprofen using the Lasentec FERM The solubilities, ternary phase diagram and metastable zone width at different mole percent of S enantiomer were obtained for mandelic acid in water and ketoprofen in mixed solvent of ethanol and water with volume ration 0.9:1.0 For the case of mandelic acid, the solubility ratio of (RS) to (S)-MA decreases with... However, the MSZW of high mole percent ketoprofen are still not satisfied even in the optimal condition derived by fractional experiment design 164 In chapter 5, the classical Laplace transform analysis was used for deriving the crystal growth rate and nucleation rate in the batching crystallization process for both (S) and (RS) mandelic acid and ketoprofen Also the kinetics of (S) and (RS)-Kp were . for the two racemic compound systems, namely more favorable racemic compound mandelic acid and unfavorable racemic compound ketoprofen, combining the aspects of thermodynamics, kinetics, and. shape of racemic compound system, just the more favorable racemic compound system for mandelic acid and unfavorable racemic compound system for ketoprofen. From the binary phase 164 diagram,. determined as 70% of (S)-MA for mandelic acid and 91 .6% of (S)-Kp for ketoprofen. In chapter 4, the thermodynamic properties in solution were studied for the mandelic acid and ketoprofen using the