and l-Tartaric Acid and Their Importance for Enantioseparation

Article pubs.acs.org/jced

Solid−Liquid Equilibrium of D- and L-Tartaric Acid and Their Importance for Enantioseparation Xiaofang Wang,† Xiangyang Zhang,† Simon Black,‡ Leping Dang,*,† and Hongyuan Wei† †

School of Chemical Engineering and Technology, Tianjin University, 300072 Tianjin, China Pharmaceutical Development, AstraZeneca, Macclesfield, SK10 2NA, United Kingdom

‡

ABSTRACT: The solid−liquid phase equilibrium of D- and L-tartaric acid (TA) was investigated in this work. Based on the solubility data, the dissolution enthalpy and entropy of the monohydrate racemic tartaric acid (race-TA) and enantiomer were calculated using van't Hoff plots. Binary melting point phase diagrams of D- and L-TA and ternary phase diagrams of D-TA/water/L-TA were also described. The results show that TA exhibits a racemic compound behavior. Furthermore, the influence of temperature on the eutectic points between enantiomer and racemic compounds was investigated. Finally, the importance of solid−liquid equilibrium on the purification and separation of enantiomers was discussed.

and enantioselective catalysts.14,15 However, the selectivity of asymmetric synthesis is not high enough, and further enantiomer purification will be required, which also causes a large interest in an efficient separation process. In recent years, many methods to separate enantiomers have been proposed.13,16−18 Among them, preparative chromatography is a powerful and flexible technology, and the theoretical understanding of chromatographic processes operated under overloaded conditions has been significantly improved.19,20 Furthermore, the development of simulated moving bed technology increases the application of the chromatographic technique to achieve an enantiomeric enrichment sufficient for a subsequent crystallization.21,22 However, chromatographic separation has a characteristic in which productivity drops when the requirements on purity increase. To achieve a product with both high productivity and purity, a hybrid process coupling chromatography and crystallization has recently been proposed.23 As the solid−liquid phase diagrams of enantiomeric systems were rarely reported, crystallization processes of chiral products are often carried out just on the basis of experience. In this paper, TA was selected to demonstrate the importance of solid−liquid equilibrium on the separation of enantiomers. First, the solid−liquid equilibrium was investigated, which provides the theoretical basis for crystallization process. Meanwhile, the interaction of D- and L-TA in aqueous solution was discussed using the ternary phase diagram of the D-TA/water/L-TA system.

1. INTRODUCTION Since more than 50 % of pharmaceutical active substances are known to be chiral1 and especially that 9 of the top 10 drugs have chiral active ingredients,2 enantioseparation and racemate resolution are of much interest. Under certain circumstances, crystallization is the best choice for the purification or separation of enantiomer because of its comparatively low expenses and simple process equipment technology. The design and optimization of these crystallization processes require the knowledge of the fundamental solid−liquid equilibrium in the ternary system of two enantiomers in a solvent. Tartaric acid (TA) is an important and versatile organic acid which is widely used in several fields.3−5 For example, it can be used in carbonated beverages, effervescent tablets as a mordant, silvering mirrors,6 and so forth. TA has three types, namely, D-, L-, and mesomeric tartaric acid (meso-TA). D- and L-TA are a pair of enantiomers, and meso-TA is an achiral form. 50:50 mixtures of enantiomers are called racemic tartaric acid (raceTA). L-TA is distributed in plants, especially enriched in grapes. D- and meso-TA have not been found to occur in nature. Also, in chiral drugs, it is well-established that one enantiomer generally exhibits biological activities different from those of the other enantiomer because the target receptors or enzymes are chiral.7−12 In some cases, the inactive enantiomer has no effect or can even elicit undesirable side effects, which can be avoided by the development of the pure enantiomer rather than the racemate. As a medicine intermediate, obtaining a pure enantiomer is a serious important issue in pharmaceuticals.13 Obtaining pure enantiomeric TA can be achieved by two methods, that is, asymmetric synthesis and separation of enantiomers by chromatography or crystallization. Asymmetric synthesis enjoyed tremendous progress over the last few decades because of the development of asymmetric reactions © 2012 American Chemical Society

Received: February 9, 2012 Accepted: May 3, 2012 Published: May 11, 2012 1779

dx.doi.org/10.1021/je300170y | J. Chem. Eng. Data 2012, 57, 1779−1786

Journal of Chemical & Engineering Data

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2. MATERIALS AND PROCEDURE 2.1. Materials. Race-TA monohydrate and anhydrate (99.5 % in mass fraction) and L-TA (99.5 % in mass fraction) were purchased from Tianjin Guangfu Technology Co. Ltd. (China). Double-distilled water was used in all of the experiments. 2.2. Apparatus and Procedures. All of the experiments except for the measurement of solubility using the dynamic method were performed in a crystallizer with jacket (Figure 1).

Figure 3. Graphical example of time versus turbidity and temperature.

experimental measurements. After reaching equilibration, the sample was extracted by an injector (0.2 μm PTFE filter, Shanghai Victory Fluid Technology Co., Ltd., China) from the surface of the solution and diluted with double-distilled water. The concentration was analyzed by an Agilent high-performance liquid chromatography (HPLC) equipped with a UV detector. The mobile phase was a buffer solution of monopotassium phosphate at 0.025 M, the pH value of which was adjusted by phosphoric acid to 2.0. The velocity of mobile phase was set to be 1 mL·min−1, and the analysis was conducted at 20 °C and 210 nm UV light. The solid was analyzed by X-ray powder diffraction (D/MAX 2500) with Cu Kα radiation of wavelength of 1.5405 Å at 100 mA and 40 kV with 2θ increasing at the rate of 8°/min and thermogravimetry/ differential scanning calorimetry (TG-DSC) to verify the solid form present at equilibrium. Counts of X-ray powder diffraction (XRPD) were accumulated for 1 s at each step. The instrument was operated between an initial and a final 2θ angle of 5° and 50°, respectively, in increments of 0.02°. 2.2.2. Determination of the Binary Melting-Point Phase Diagram. The binary melting-point phase diagram of two enantiomers was determined using DSC25−27 (module 910, NETZSCH, German) equipped with a data station (Thermal Analyst 204, NETZSCH, German) under atmospheric pressure. Samples [(3 to 6) mg] of mixtures prepared at varying composition were weighed with a METTER AB265-S balance with an accuracy of 0.01 mg and then placed in sealed aluminum pans (aluminum capsules, 00026763, Perkin-Elmer

Figure 1. Experiment setup for solubility measurement. 1, water bath; 2, magnetic stirrer; 3, vessel with jacket; 4, thermocouple.

The temperature of the crystallizer was kept constant by circulating water in the jacket through a thermostatic bath, and the fluctuation of the temperature in the vessel was less than 0.1 K. The stirring rate was kept constant for all of the crystallization experiments with an electromagnetic stirrer. 2.2.1. Solubility Analysis of Monohydrate Race- and L-TA. The solubility was measured by two methods: the dynamic method and static method. Dynamic measurement was performed in parallel synthesis (HP PolyBLOCK, HEL, UK) shown in Figure 2, which offers full, independent control and logging of all parameters such as temperature, stirrer speed, turbidity, and so forth. A certain mass of L-TA and water was transferred in the crystallizer and then heated up to specific temperature (± 0.05 K). The turbidity during crystallization process was recorded to determine the dissolving point of Land monohydrate race-TA. A graphical example of parallel synthesis is shown in Figure 3. The solubility was also measured using a static method.24 An excess amount of anhydrous race- and L-TA was suspended in water at a certain temperature under stirring. The temperature was controlled by a PT100 sensor with an accuracy of ± 0.05 K, and the uncertainty of the measured temperature was ± 0.1 K which was calculated from the standard deviations of repeated

Figure 2. Experiment equipment (parallel synthesis). 1, oil bath; 2, charge pump; 3, thermostatic bath; 4, poly block; 5, PC; Tu, turbimeter; RT, temperature of the reactor; ZT, temperature of the zone. 1780



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of ± 0.05 K, and the uncertainty of the measured temperature was ± 0.1 K which was calculated from the standard deviations of repeated experimental measurements. After reaching equilibration, the sample was extracted by an injector (0.2 μm PTFE filter, Shanghai Victory Fluid Technology Co., Ltd., China) from the surface of the solution and diluted with double-distilled water. The total concentration was analyzed by HPLC (Agilent, T = 25 °C, λ = 210 nm, inj. volume = 20 μL, flow rate = 1 mL·min−1), and each concentration of L- and DTA was determined by an automatic polarimeter with an accuracy of ± 0.005° (SGW-1, T = 13 °C, λ = 589 nm). Furthermore, the solid were analyzed by XRPD to verify the solid form present at equilibrium. As all of the specific rotations were measured at 13 °C, the calibration curve of concentration of L-TA range from (0.25 to 3.0) g·L−1 versus specific rotation at the temperature of 13 °C in water was then established and shown in Figure 6.

model). During the scanning operation, high-purity nitrogen gas was flushed throughout the DSC furnace to avoid condensation. These samples were heated to the final temperature at a fixed heating rate. To determine the suitable heating rate of DSC, the melting points were measured at the heating rate of 10 °C·min−1, 5 °C·min−1, 2 °C·min−1, and 1 °C·min−1, respectively. The results are shown in Figure 4, and the corresponding melting

Figure 4. DSC patterns of anhydrous race-TA at different heating rates.

points are 211 °C, 209.7 °C, 206 °C, and 201.9 °C, respectively. Among them, the measured melting point at the heating rate of 2 °C·min−1 is in agreement with that proposed in the literature [(205 to 206) °C].28−30 The deviations measured at higher heating rate can be explained by the simultaneous occurrence of decomposition during the melting process, which lowers the accuracy of the measured melting point. For example, Figure 5 shows the TG-DSC pattern of TA,

Figure 6. Calibration curve of concentration of L-TA versus specific rotation.

3. RESULTS AND DISCUSSION 3.1. Characterization of Race-TA (Anhydrate and Monohydrate) and Enantiomer. The thermal characteristics of chemicals was determined by PXRD and DSC, and the patterns were shown in Figures 7 and 8, respectively. Figure 7 shows the PXRD patterns of L-TA and anhydrous and monohydrate race-TA. The characteristic peak of L-TA is at 11.58, and those of anhydrous and monohydrate race-TA are at

Figure 5. TG-DSC patterns of anhydrous race-TA. Heating rate: 10 °C·min−1.

and it can be clearly noticed that the decomposition occurred during the melting process at the heating rate of 10 °C·min−1. As to the error measured at the heating rate of 1 °C·min−1, it can be attributed to the heat loss. Therefore, DSC analysis in this paper was taken at the heating rate of 2 °C·min−1. 2.2.3. Measurement of the Ternary Phase Diagram of DTA/Water/L-TA System. The ternary phase diagrams were determined by equilibrating the solute (L-and D-TA at various ratios) in the setup shown in Figure 1 for 72 h. The temperature was controlled by a PT100 sensor with an accuracy

Figure 7. PXRD patterns of L- and race-TA: (a) monohydrate raceTA; (b) anhydrous race-TA; (c) L-TA. 1781



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Figure 8. DSC patterns of L- and race-TA. Heating rate: 2 °C·min−1. L, M, and A represented the L-TA, monohydrate race-TA, and anhydrous race-TA, respectively.

Figure 10. Solubility of monohydrate race-TA in water. ●, ref 29; ○, measurement by static method; ▽, measurement by parallel synthesis.

(9.8 and 14.2) and (11.7 and 12.6), respectively. As shown in Figure 8, the melting point of L-TA is 170.2 °C, and the melting points of anhydrous and monohydrate race-TA are both 206 °C (Table 1).

As shown in Figures 9 and 10, the solubilities of monohydrate race- and L-TA in water show an obviously increasing tendency with temperature. The solubility of L-TA is higher than the monohydrate race-TA. The reasons are that in a crystal each enantiomer has a greater affinity for molecules of the different enantiomers than for that the same enantiomers. The van’t Hoff equation was used to correlate the mole fraction solubility in water with temperature (Figure 11).

Table 1. Dissolution Enthalpy and Entropy of TA in Water at 101.32 kPa ΔHd (KJ·mol−1) ΔSd (J·K−1) melting point (°C)

monohydrate race-TA

L-TA

26743.96 58.65 206

7518.77 9.36 170.2

3.2. Solid−Liquid Equilibrium. 3.2.1. Solubility of Monohydrate Race- and L-TA. The solubilities of monohydrate race- and L-TA in water are shown in Figures 9 and 10.

Figure 11. van't Hoff plot of logarithm mole fraction solubility of monohydrate race- and L-TA. ●, L-TA; ○, monohydrate race-TA.

ln x = −

ΔHd ΔSd + RT R

(1)

where x is the mole fraction solubility (mol/mol solution) of anhydrous L-TA or monohydrate race-TA, T is the temperature of solution, ΔHd and ΔSd are the dissolution enthalpy and entropy, respectively, and R is the gas constant. The dissolution enthalpy and entropy can be obtained from the slope and the intercept (Table 1). As listed in Table 1, the dissolution enthalpy is much higher than entropy. This observation emphasized the fact that the dissolution enthalpy is more important than entropy in determining the solubility of TA in water. The enthalpy of monohydrate race-TA is higher than L-TA, which are all agreement with the results of solubility. 3.2.2. Thermal Analysis and Binary Phase Diagram of Anhydrous Race- and L-TA. Generally, the binary phase

Figure 9. Solubility of L-TA in water ●, ref 29; ■, ref 30; ○, measurement by the static method; ▽, measurement by parallel synthesis.

The data are consistent with the literature data. Figure 9 shows that the maximum deviation of the solubilities of L-TA in water in this work and in the literature is less than 0.005 mass fraction. The result of monohydrate race-TA has a similar trend with the L-TA. The max deviation of two methods is less than 1.0 %. Consequently, the solubilities of L- and monohydrate race-TA can be obtained with high accuracy and repeatability using the two methods mentioned above. 1782



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3.2.3. Ternary Phase Diagram. Figure 13 shows the ternary phase diagram of the system D-TA/water/L-TA at 40 °C. As

diagram of the racemate and the corresponding enantiomers has traditionally been used for identifying the type of the racemate.31−33 The mixtures of different composition between the anhydrous race-TA (x = 0.5) and pure L-TA (x = 1) were prepared and analyzed by DSC. The liquidus curve can be predicted from the melting point and enthalpy of fusion by the expression of a simplified Schröder−van Laar equation: ln x =

ΔHm ⎛ 1 1⎞ − ⎟ ⎜ R ⎝ Tm T⎠

(2)

In the case of a racemic compound, the liquidus curve between the racemic mixture and the corresponding eutectic (xeu < x < 1) in the phase diagram can be predicted by using the Prigogine−Defay equation:34 ln(4x(1 − x)) =

ΔHm,rac ⎛ 1 1⎞ ⎜⎜ − ⎟⎟ R ⎝ Tm,rac T⎠

Figure 13. Ternary phase diagram at the temperature 40 °C and 101.32 kPa.

(3)

where x is the mole fraction enantiomeric composition, ΔHm and Tm are the melting enthalpy and melting temperature of pure enantiomers, and ΔHm,rac and Tm,rac are the melting enthalpy and melting temperature of anhydrous race-TA. As the melting points of the two enantiomers are equivalent, the binary melting point phase diagram of two enantiomers is symmetric.35 Therefore, only one-half of the phase diagram is shown in Figure 12.

Figure 14. Ternary phase diagrams for the D-TA/water/L-TA system at the temperature between (20 and 60) °C and 101.32 kPa. All axis scales are in weight percent. M represents the composition of the monohydrate race-TA.

shown in Figure 14, TA exhibits a racemic compound type, which is in agreement with the result of the binary phase diagram. Moreover, mirror image symmetry can be clearly observed. There are two euteutic points and marks as H and H′ shown in Figure 13, at which three phases, namely, D-TA/ (monohydrate race-TA)/liquid or L-TA/(monohydrate raceTA)/liquid, coexist. The point M represents the composition of monohydrate race-TA. According to Parry,28 monohydrate race-TA was obtained from aqueous solution when crystallization takes place below 70 °C. So the ternary phase diagrams of D-TA/water/L-TA were measured at the temperature range between (20 and 60) °C. The mass fraction solubilities for the D-TA/water/L-TA system at the temperature ranging from (20 to 60) °C at atmospheric pressure were shown in Table 2. All of the experiments were repeated three times at each temperature, and experimental uncertainties in the measured data were less than 0.005 mass fractions for all solubilities measured at different temperature at range between (20 and 60) °C. Based on these data, the schematic ternary phase diagrams are plotted in Figure 14. As shown in Figure 14 the equilibrium

Figure 12. Binary melting point phase diagram of the TA enantiomers: ●, liquidus curve (experiment data); ○, liquidus curve (predicted data by ref 34); ▲, solidus curve.

The type of solid−liquid phase diagrams of enantiomer systems have been first described in a pioneering work of Roozeboom. 36 The racemic species is likely to be a conglomerate if the melting point difference approaches −30 °C.37 For TA, the melting point difference reaches as high as 35.6 °C, which means TA could not form a conglomerate system. Besides, Figure 12 exhibits obvious eutectic points at 167.7 °C with the two enantiomers at a ratio of 97:3, which clearly verifies that the binary TA mixture is a racemic compound forming system according to the Jacques et al.34 The affinity between molecules of different enantiomers is greater than that of the same enantiomer, which results in that the melting point of racemate is higher than that of the enantiomers, but the solubility is lower. It was agreement with the Wallach's rule.38 1783



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Table 2. Mass Fraction Solubilities for the D-TA/Water/L-TA System at the Temperature Region of (20 to 60) °C at 101.32 kPaa 20 °C

30 °C

D-TA

water

L-TA

solid phaseb

D-TA

water

L-TA

solid phase

0 0.005 0.0089 0.0098 0.0106 0.0162 0.0277 0.03372 0.07674

0.4095 0.4082 0.6638 0.5205 0.5917 0.7188 0.7702 0.80085 0.84653

0.5905 0.5868 0.3273 0.4697 0.3977 0.265 0.2021 0.16543 0.07674

L L, Race(M) Race(M) Race(M) Race(M) Race(M) Race(M) Race(M) Race(M)

0 0.0076 0.0141 0.0134 0.0236 0.0425 0.0747 0.0777 0.1044

0.3814 0.3755 0.5105 0.6424 0.6841 0.7472 0.7680 0.7678 0.7912

0.6186 0.6169 0.4754 0.3442 0.2923 0.2103 0.1573 0.1545 0.1044


40 °C

50 °C

D-TA

water

L-TA

solid phase

D-TA

water

L-TA

solid phase

0 0.0105 0.0183 0.0241 0.0406 0.0601 0.0815 0.1102 0.1370

0.3542 0.3447 0.4724 0.5979 0.6611 0.6849 0.7109 0.7212 0.7260

0.6458 0.6448 0.5093 0.3780 0.2983 0.2550 0.2076 0.1686 0.1370


0 0.0108 0.0138 0.0308 0.0371 0.0516 0.0768 0.1345 0.1686

0.3294 0.3243 0.3239 0.4713 0.5348 0.5804 0.6075 0.6455 0.6627

0.6706 0.6649 0.6623 0.4979 0.4281 0.3680 0.3157 0.2200 0.1686

L L L, Race(M) Race(M) Race(M) Race(M) Race(M) Race(M) Race(M)

60 °C

a

D-TA

water

L-TA

solid phase

0 0.0126 0.0185 0.0329 0.0430 0.0572 0.0859 0.1350 0.1721 0.2018

0.3035 0.2955 0.2926 0.3607 0.4158 0.4664 0.5200 0.5669 0.5858 0.5965

0.6965 0.6919 0.6889 0.6064 0.5412 0.4764 0.3941 0.2981 0.2421 0.2017

L L L, Race(M) Race(M) Race(M) Race(M) Race(M) Race(M) Race(M) Race(M)

The uncertainty is estimated to be ± 0.005 mass fraction and ± 0.10 K. bL and M represent L-TA and monohydrate race-TA, respectively.

Table 3. [X]eut and eeeut of TA at the Temperature Range of (20 to 60) °C at 101.32 kPaa temperature (°C)

[rac]b

[ep]b

αc

[X]eutd (calcd)

[X]eutb,f

eeeute (calcd, %)

eeeutf (%)

20 30 40 50 60

0.0212 0.0306 0.0431 0.0573 0.0748

0.1469 0.1623 0.1789 0.1956 0.2148

0.14 0.19 0.24 0.29 0.34

0.1477 0.1638 0.1815 0.1998 0.2213

0.1482 0.1664 0.1858 0.2002 0.2249

98.96 98.24 97.13 95.80 94.12

98.04 97.55 96.79 95.90 94.79

The uncertainty is estimated to be ± 0.005 mass fraction and ± 0.10 K. bConcentration in mole fraction. cAccording to eq 3. dAccording to eq 4. According to eq 5. fResults of the experiments.

a e

data determined in the ternary system D-TA/water/L-TA at the temperature between (20 and 60) °C are summarized and presented in the typical equilateral triangle-shaped diagram. It can be clearly seen that the ternary phase diagram depends on temperature. The ternary solubility phase diagram exhibits a eutectic point, the composition at which can be predicted by the equation as follows:39 α=

[rac] [ep]

where [rac] and [ep] are the solubilities of monohydrate raceand L-TA, respectively. ⎛ α2 ⎞ [X]eut = [ep]⎜1 + ⎟ 4 ⎠ ⎝

(5)

4 − α2 4 + α2

(6)

eeeut =

where [X]eut and eeeut are the total solution concentration of compound TA and enantiomeric excess at the eutectic point.

(4) 1784



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provided, and the influence of temperature on the eeeut was discussed. It can be noticed that eeeut decreases with temperature. The data obtained from calculation are in good agreement with those from experiments. Thus, the pure TA enantiomer can be crystallized from enriched solution with higher concentrations of enantiomer than the eutectic.

The results obtained from calculation and experiments are shown in Table 3, and the rmsd is about 0.6 %. The variation of enantiomeric excess at the eutectic point as a function of temperature is plotted in Figure 15. It can be noticed that eeeut decreases with temperature as given by eq 7: y = −0.0010x 2 − 0.0032x + 98.5040

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(7)

AUTHOR INFORMATION

Corresponding Author

*Tel.: +86-22-27405754. Fax: +86-22-27400287. E-mail: [email protected]. Funding

We thank the financial support by the AstraZeneca UK, Tianjin Municipal Natural Science Foundation (11JCYBJC 04600), and the Seed Foundation of Tianjin University for their financial assistance in this project. Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Brown, M.; Gallagher, P. K. Handbook of Thermal Analysis and Calorimetry; Elsevier: New York, 1998. (2) Thayer, A. M. Trial separations. Chem. Eng. News. 2005, 83 (36), 49−53. (3) Jain, M. K. Organic Chemistry; Shoban Lal Nagin Chand and Co.: Jalandar, 1991. (4) Mukherjei, S. M.; Singh, S. P.; Kapoor, R. P. Organic Chemistry; Wiley Eastern Limited: New Delhi, 1993. (5) Pine, S. H.; Hendrickson, J. B.; Cram, D. J.; Hammond, G. S. Organic Chemistry, 4th ed.; McGraw-Hill: New York, 1985. (6) Windholz, M.; Budavari, S.; Stroumtsos, L.; Fertig, M. The Merck index: An encyclopedia of chemicals and drugs; Merck: Whitehouse Station, NJ, 1976. (7) Casy, A. F. Medicinal Chemistry, 3rd ed.; Wiley-Interscience: New York, 1970; Vol. I. (8) Daniels, T.; Jorgensen, E. Central nervous system depressants. Textbook of organic medicinal and pharmaceutical chemistry; Lippencott: Philadelphia, 1971; p 395. (9) Friberger, P.; Aberg, G. Some physiochemical properties of the racemates and the optically active isomers of two local anaesthetic compounds. Acta Pharm. Suec. 1971, 8 (4), 361. (10) Himori, N.; Ishimori, T.; Taira, N. A further study on antihypertensive action of beta-adrenoceptor blocking agents in conscious, renal hypertensive dogs. Arch. Int. Pharmacodyn. Ther. 1979, 242 (1), 115. (11) Dayer, P.; Leemann, T.; Gut, J.; Kronbach, T.; Kupfer, A.; Francis, R.; Meyer, U. A. Steric configuration and polymorphic oxidation of lipophilic beta-adrenoceptor blocking agents: in vivo-in vitro correlations. Biochem. Pharmacol. 1985, 34 (3), 399−400. (12) Wainer, I. W. Drug stereochemistry: analytical methods and pharmacology; CRC Press: Boca Raton, FL, 1993; Vol. 18. (13) Zhang, X. Y.; Févotte, G.; Zhong, L.; Qian, G.; Zhou, X. G.; Yuan, W. K. Crystallization of Zinc Lactate in Presence of Malic Acid. J. Cryst. Growth 2010, 312, 2747−2755. (14) Collins, A. N.; Sheldrake, G.; Crosby, J. Chirality in industry; John Wiley & Sons, Inc.: New York, 1992. (15) Collins, A. N.; Sheldrake, G.; Crosby, J. Chirality in industry II: Developments in the commercial manufacture and applications of optically active compounds; Wiley: New York, 1998; Vol. 2. (16) Kodama, S.; Yamamoto, A.; Matsunaga, A.; Hayakawa, K. Direct chiral resolution of tartaric acid by ion-pair capillary electrophoresis using an aqueous background electrolyte with (1R,2R)-(−)-1,2diaminocyclohexane as a chiral counterion. Electrophoresis 2003, 24 (15), 2711−2715.

Figure 15. Enantiomeric excess as a function of temperature.

3.3. Importance of the Ternary Phase Diagram of DTA/Water/L-TA for Enantioseparation of Enantiomers. Once the eutectic composition at the temperature of interest is determined and the solubility of the pure enantiomer is obtained, a rational separation process can be designed. A recent work discussed in great detail the process design and demonstrated this approach in several industrial cases.40 There is literature evidence to show that chiral resolutions may be performed successfully by using kinetic control in some instances. Producing pure enantiomers via crystallization is only feasible when the solution composition exceeds the eutectic point such as the points H and H′ in Figure 14. In other words, to obtain enantiopure products the initial solution composition must be located inside the enantiomer existence region such as the region AFH or BF′H′. In these areas the composition of the liquid phase moves toward the eutectic, and the solid phase consists of pure L- or D-TA after crystallization, respectively. For the process of the resolution of racemate, a preliminary enrichment achieving an enantiomeric excess higher than the eutectic composition via chromatography is required. Then, pure enantiomer can be obtained by enantioseparation via crystallization. This is a theory of the hybrid process, as stated above, consisting of chromatography enrichment and crystallization.

4. CONCLUSIONS The solubilities of monohydrate race-TA and the enantiomers were measured by two methods. The results show that the solubility of L-TA is higher than that of monohydrate race-TA. Further, the dissolution enthalpy and entropy of the monohydrate race- and L-TA were determined using van't Hoff plots based on the measured solubility data. From the binary phase diagram, the TA enantiomeric system could be identified as a compound-forming system with a melting point of the racemate higher than the enantiomers. The melting point phase diagram exhibits obvious eutectic points at 167.7 °C with the two enantiomers at a ratio of 97:3. Moreover, the ternary phase diagrams at the temperature from (20 to 60) °C were 1785



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and l-Tartaric Acid and Their Importance for Enantioseparation

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