How To Crystallize Anhydrous Racemic Tartaric Acid from an Ethanol

Article pubs.acs.org/IECR

How To Crystallize Anhydrous Racemic Tartaric Acid from an Ethanol−Water Solution Xiaofang Wang,† Leping Dang,*,† Simon Black,‡ Xiangyang Zhang,† and Hongyuan Wei† †

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

‡

ABSTRACT: Racemic tartaric acid (TA) exists in the solid state as an anhydrate and a monohydrate. In this paper, a method to obtain the anhydrate at lower temperature by adjusting the water activity, aw, through introduction of ethanol is proposed. The influence of aw on the phase conversion temperature of TA was investigated by the determination of the ternary phase diagrams for the system of water−ethanol−TA at varying temperatures. The result shows that the anhydrous TA can be obtained at ambient temperature by lowering the water activity and that the conversion rate from monohydrate to anhydrate appears to increase with decreasing water activity. The result can be extended to the application of other anhydrate and hydrate systems. Meanwhile, the process of anhydrous TA crystal formation from ethanol−water solution was investigated by using microscopy and HPLC.

1. INTRODUCTION During the process of crystallization, water may become incorporated into the crystal structure to form a hydrate when water is involved in the crystallization medium. Anhydrates and hydrates may exhibit different properties, such as density, solubility, and physical and chemical stability. Furthermore, the bioavailability and product performance may also be varied.1,2 It is, therefore, of vital importance to control the solid phase that crystallizes during the development and manufacture of fine chemicals and pharmaceuticals. Previous studies on hydrates and anhydrates of organic molecules have demonstrated the importance of the water activity3,4 in controlling whether hydrates or anhydrates are the stable phase. It has been proved that the hydrate is the most stable form when the water activity is higher than the equilibrium activity and the anhydrate is the stable form if the water activity is lower than the equilibrium activity. The use of phase diagrams to aid crystallization process design from aqueous solvents has been illustrated for carbamazepine5,6 and an active pharmaceutical ingredient.7,8 Those approaches are also developed further by considering the effects of temperature as well as solvent composition. In the present work, racemic tartaric acid (TA) was selected as a model system that forms both an anhydrate and a monohydrate. TA is an important and versatile organic acid which is widely used in several fields.9−12 Generally, anhydrous TA is obtained from aqueous solution when crystallization takes place above 70 °C.13 A separate study of the solubility of TA in water14 does not give a transition temperature. On the basis of the reported studies,3,5,7,8 anhydrous TA should be obtainable at ambient temperatures by adding a second solvent such as ethanol to reduce the water activity. The main aim of this study is to crystallize anhydrous TA at ambient temperature by changing the water activity as proposed. First, the investigation of the influence of water activity on the phase conversion temperature was performed, and the conversion rates of monohydrate to anhydrate in terms © 2012 American Chemical Society

of water activity were studied. Moreover, to investigate the transformation mechanism, the crystallization process of anhydrous TA in a mixture of ethanol−water was studied by means of microscopy. 1.1. Theory: Water Activity. Commonly, the stability of anhydrate/hydrate depends on the temperature in pure aqueous solution. However, the conversion temperature for many cases is relatively high, which results in reduced efficacy of active pharmaceutical ingredients (APIs) and higher operation costs. For such situations, a mixture solvent could be considered;15 i.e., a change of solvent may trigger the occurrence of phase transformation at lower temperature. The formation of hydrated crystals from anhydrous crystals may be represented by the following equilibrium:2,16,17

A(solid) + mH2O ⇔ A· mH2O(solid) Kh =

a[A· mH2O(solid)] a[A(solid)]a[H2O]m

(1)

(2)

where Kh is the equilibrium constant for the process shown in eq 1, and a[A·mH2O(solid)], a[A(solid)], and a[H2O] are the thermodynamic activities of the hydrate, the anhydrate, and water, respectively. When Kh > 1, the hydrate will be more stable than the anhydrate. The anhydrate will be more stable than the hydrate in the inverse situation. If the standard states of unit activity of A (solid) and of A·mH2O (solid) are represented by their pure solid phases, eq 2 can be simplified to the following equation:

Kh = a[H2O]−m Received: Revised: Accepted: Published: 2789

(3)

August 29, 2011 January 5, 2012 January 13, 2012 January 13, 2012 dx.doi.org/10.1021/ie201935t | Ind. Eng.Chem. Res. 2012, 51, 2789−2796

Industrial & Engineering Chemistry Research

Article

where a[H2O], which is abbreviated to aw, is the water activity and m is the number of moles of water taken up by 1 mol of the anhydrate in the stoichiometric equation. According to eq 3, the stability of anhydrate/hydrate in the surrounding medium, for example, in a crystallization medium, at a specific temperature depends on the water activity. Namely, the phase conversion temperature changes at a specific water activity. Zhu et al. have proven the hypothesis that the dissolved drug in the aqueous solvent mixtures influences aw to a much smaller extent when the concentration of the dissolved drug is not high.3,4 Values of aw in mixtures can be calculated by the following equation: a w = γw x w (4) where xw is the mole fraction of water in the mixture, which can be adjusted by changing the composition of an appropriate water−organic solvent mixture, and γw is the appropriate activity coefficient. Although aw can also be expressed by xw using eq 4, Zhu et al. emphasizes the fact that the water activity in the crystallization medium is more important than the water concentration in determining the nature of the phase (anhydrate or hydrate) that crystallizes. Furthermore, due to the solution theory, the water activity depends not only on the composition but also on the solvent. Therefore, the value of the water activity at equilibrium should change with the solvent. That is, when the solvent changes, the water content in the mixed solvent is different at the transition water activity, which is invariable at constant temperature and pressure. For example, at aw = 0.25, corresponding to xw = 0.2 in a methanol + water mixture and xw = 0.08 in an IPA + water mixture, theophylline anhydrate is in equilibrium with theophylline monohydrate.4 Moreover, the influence of dissolved drug in the aqueous solvent mixtures on aw can be ignored when the concentration of the drug is low compared to the concentration of water.3,4 Therefore, water activity, aw, instead of water composition, xw, was used in our work. 1.2. Solubility of TA in Water. Solubility data for TA in water have been reported previously as part of a larger data set,14 which also includes data for other hydrates. Figure 1 shows the solubility of TA in water. As expected, the solubility of TA increases with increasing temperature. The data were fitted in two different ways. The data were fitted across the entire temperature range using a simple two-parameter exponential fit (Figure 1a), as in ref 18. This assumes that all the data refer to the same solid phase. According to ref 12, there is a transition temperature in the region of 70 °C.13 This suggests that the data should be fitted to two separate curves above and below this temperature. This is shown in Figure 1b: The data at lower temperatures (triangles) are assumed to refer to the hydrate, whereas the data at 80 and 100 °C (squares) are assumed to refer to the anhydrate. Extrapolation of both curves as shown suggests that the transition temperature may be closer to 60 °C. This suggests one strategy for isolating anhydrous TA, namely, from water at elevated temperatures by phase transformation, which is usually driven by the difference in solubility between the two forms. This is likely to be difficult to achieve in practice, particularly if the elevated temperatures have to be preserved during filtration and washing. Therefore, the use of ethanol to lower the water activity was investigated.

Figure 1. Solubility of TA in aqueous solution: symbols, experimental results; lines, fitted according to ref 17.

purity is above 99.5%. Ethanol used for the experiments was supplied by the Tianjin Damao Chemical Reagent Factory (China), with purity higher than 99%. Double-distilled water was used in all the experiments.

2. EXPERIMENTAL SECTION 2.1. Chemicals. Anhydrous racemic TA was purchased from Tianjin Guangfu Technology Co. Ltd. (China). The 2790

dx.doi.org/10.1021/ie201935t | Ind. Eng.Chem. Res. 2012, 51, 2789−2796


Article

2.2. Experimental Apparatus. 2.2.1. Powder X-ray Diffraction (PXRD). The X-ray diffractograms of the anhydrous/monohydrate TA crystals were recorded using X-ray powder diffraction (D/MAX 2500) with Cu Kα radiation of wavelength 1.5405 Å at 100 mA and 40 kV with 2θ increasing at the rate of 8 deg/min. Counts 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. Differential Scanning Calorimetry (DSC) Analysis. A differential scanning calorimeter (module 910, Netzsch, Germany) equipped with a data station (Thermal Analyst 204, Netzsch) was used to record the thermograms of the samples. The thermal behavior was studied in an aluminum pan with a pore under a dry nitrogen purge at a heating rate of 2 °C/min. 2.2.3. Thermal Gravimetric Analysis (TGA). A thermal gravimetric analyzer (module SF/817, Netzsch) was used to determine mass loss upon heating. Anhydrous TA and monohydrate TA were heated in an open aluminum pan from 30 to 300 °C at 10 °C/min under a nitrogen purge. 2.2.4. High-Performance Liquid Chromatography (HPLC) Analysis. A high-performance liquid chromatograph equipped with a UV detector (Agilent) was used offline to determine the concentration of anhydrous TA. 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. The velocity of the mobile phase was set to 1 mL/min, and the analysis was conducted at 20 °C and 210 nm of UV light. 2.2.5. Microscopy. An Olympus CX31 microscope equipped with a 3CCD (three charge-coupled device) digital camera was used. Photomicrographs were taken using the SIGE300 software. 2.3. Experimental Setups and Procedures. All the experiments were performed in a vessel with a jacket (Figure 2).

ensure enough time for the crystal growth. Suspension samples were finally withdrawn from the crystallizer for analysis using PXRD and DSC−TG patterns. Figure 3 shows the PXRD

Figure 3. PXRD spectrum of TA obtained from experiment (top) and the monohydrate TA obtained from the Cambridge Crystallographic Data Centre (bottom).

spectrum of TA obtained from the experiment is in agreement with that of the monohydrate TA obtained from the Cambridge Crystallographic Data Centre (CCDC). The characteristic peaks are at 11.7 and 12.6. Figure 4 shows the DSC−TG

Figure 4. DSC−TG patterns of TA obtained from experiment.

patterns of TA obtained from experiment. The onset temperature of dehydration of TA obtained from experiment was found to be about 64 °C, which is consistent with the theoretical transition temperature of monohydrate TA. PXRD and DSC−TG show that the hydrate obtained above is a monohydrate. 2.3.2. Determination of Binary and Ternary Phase Diagrams. As the transformation behavior is involved at higher temperature, and only two solubility data of TA above 60 °C have been reported in ref 14, the solubility of each phase (monohydrate and anhydrate) was then measured to determine the accurate transformation temperature. The solubilities of anhydrous and monohydrate TA in water and ternary phase diagrams of TA−water−ethanol were all determined by equilibrating the solute (anhydrous TA) in the same setup described above for 72 h. The temperature was controlled by a PT100 sensor with an accuracy of ±0.05 K, and

Figure 2. Schematic diagram of the experimental apparatus for measurements of solubility: 1, water bath; 2, magnetic stirrer; 3, vessel with jacket.

The temperature of the vessel was kept constant by circulating water in the jacket from a thermostatic bath. The stirring rate was kept constant for all the crystallization experiements with an electromagnetic stirrer. 2.3.1. Preparation of Monohydrate TA. To prepare monohydrate TA, an anhydrous TA solution (40 g/100 g of H2O) was first heated to 60 °C to allow complete dissolution of the solid. The solution was then cooled to 30 °C at a fixed constant rate (1 °C/min). After the temperature finally reached 30 °C, the suspension was continuously stirred for 4 h to 2791



Article

the uncertainty of the measured temperature was ±0.1 K, which was calculated from the standard deviations of repeated experimental measurements. After equilibration was reached, the sample was extracted by an injector (membrane filtration with an aperture of 0.2 μm) from the surface of the solution and diluted with double-distilled water. The concentration was analyzed by HPLC (Agilent), and the solid was analyzed by XRPD and DSC−TG to verify the solid form present at equilibrium. 2.3.3. Conversion Rate Analysis. To investigate the influence of the water activity on the conversion rate of TA from monohydrate to anhydrate, calibration curves of overall enthalpy as a function of monohydrate mass content19 were established as follows. Mixtures of monohydrate and anhydrate TA with different compositions were prepared and then analyzed by DSC. The result is listed in Figure 5. It is noticed

The results prove the existence of two different solid phases and that monohydrate TA is the stable form below the transition temperature and anhydrous TA above the transition temperature. 3.2. Correlation of the Water Activity of Anhydrous and Monohydrate TA and Temperature in an Ethanol− Water Mixture. The values of γw in ethanol−water mixtures at different temperatures have been reported previously,21 and aw can therefore be calculated by eq 4. The values of aw were fitted to polynomials in xw and are listed in the Table 1. Table 1. Functions of xw and aw in an Ethanol + Water Mixture at Different Temperatures temp/°C 15 20 25 30

adj R2

function aw aw aw aw

= = = =

−0.03716 −0.04281 −0.03582 −0.04914

+ + + +

3.04574xw 2.99956xw 3.00382xw 3.19715xw

− − − −

4.28259xw2 4.00192xw2 4.00009xw2 4.40933xw2

+ + + +

2.29792xw3 2.05521xw3 2.03958xw3 2.27396xw3

0.99985 1 1 1

The mass fraction solubility data of anhydrous or monohydrate TA in a mixture solvent are listed in Table 2, in which “A” and “M” represent anhydrous and monohydrate TA at equilibrium, respectively. On the basis of the data of solubility, the ternary phase diagrams for the system of ethanol−water−TA at different temperatures are plotted in Figure 6. As shown in Figure 6, each ternary phase diagram can be divided into four regions representing different stable states by the solubility curves of the anhydrous and monohydrate TA. First, the solubility curve a−b−c represents the equilibrium between the substance and solvent compositions, and the intersection of different solubility curves can be used to confine the eutectic point marked as b shown in each ternary phase diagram. xw of the solution at point b can be obtained, and then the corresponding aw can be obtained and is shown in Table 3. As to the different regions mentioned before, region 1 represents the undersaturated solution in which no crystalline phase exists, regions 2 and 3 are the saturated solution in equilibrium with monohydrate and anhydrous TA crystals, respectively, and region 4 is the saturated solution of invariable composition in equilibrium with monohydrate and anhydrous TA crystals. At point g in Figure 6a, for example, there is a solution equal to the composition of point h and solid anhydrate TA present in the solution. The solution composition of regions 2 and 3 is then equal to those of corresponding points on curves a−b and b−c, and that of region 4 is equal to that of point b. Thus, eutectic point b can be confirmed to be the transition point; i.e., both the anhydrous TA and monohydrate TA are stable at point b. The monohydrate TA is the most stable form when the water activity is higher than the transition water activity, i.e., region 2, and the anhydrate is the stable form if the water activity is lower than the transition, i.e., region 3. As shown in Figure 6 and Table 3, the corresponding values of aw at various temperatures from 15 to 30 °C are 0.7590, 0.7844, 0.8090, and 0.8042, respectively. That is, the anhydrous/monohydrate TA is stable when aw < 0.7590 (xw < 0.6366) and aw > 0.8402 (xw > 0.7780) at various temperatures over the range from 15 to 30 °C. There is a transition temperature when 0.7590 ≤ aw ≤ 0.8402 at temperatures in the range from 15 to 30 °C. The conversion rate at different water activities will be discussed later.

Figure 5. Overall enthalpy as a function of the monohydrate mass content.

that the overall heat was proportional to the content of monohydrate TA. The excess monohydrate TA (2 g) was added to 10 mL of an ethanol−water mixture at varying composition at 25 °C. To determine the conversion rate and the solubility at different times, the upper solution and deposit were analyzed at set intervals. The solid phase withdrawn was filtered and then measured using DSC, and the content of monohydrate in anhydrate/monohydrate solid samples can be calculated using calibration curves. The concentration change of the solution was analyzed by HPLC.20 2.3.4. Crystallization Process of Anhydrous TA from Ethanol−Water at 25 °C. To investigate the transformation mechanism, the crystallization process of anhydrous TA in an ethanol−water mixture was monitored by HPLC and microscopy. The excess monohydrate TA (2 g) was added to 40 mL of the ethanol−water mixture at aw = 0.26 and aw = 0.59 at 25 °C. The concentration of the solution was analyzed by HPLC, and the solid crystals harvested at the end of the batch crystallization were analyzed by microscopy.

3. RESULTS AND DISCUSSION 3.1. Solubilities of Monohydrate and Anhydrous TA. The solubilities of monohydrate and anhydrous TA are shown in Figure 1c. Furthermore, they are fitted according to ref 18, and a transformation temperature of 60.2 °C can be clearly observed. To determine the composition of these solid phases, samples, before and after experiments, were analyzed by XRPD. 2792



Article

Table 2. Mass Fraction Solubility Data of Anhydrous or Monohydrate TA in a Mixture Solvent at Temperatures in the Range between 15 and 30 °C 15 °C

20 °C

ethanol

TA

water

xw

aw

ethanol

TA

0.9709 0.7259 0.6238 0.4581 0.3344 0.2396 0

0.0291 (A) 0.0656 (A) 0.0816 (A) 0.0987 (M) 0.1058 (M) 0.1102 (M) 0.1364 (M)

0 0.2085 0.2946 0.4432 0.5388 0.6102 0.8636

0 0.4235 0.5471 0.7122 0.8047 0.8669 1

0 0.6592 0.7236 0.7899 0.8380 0.8818 1

0.9706 0.7420 0.6257 0.5459 0.4703 0.4419 0.3170 0.1723 0

0.0294 (A) 0.0705 (A) 0.0976 (A) 0.1093 (A) 0.1138 (M) 0.1156 (M) 0.1222 (M) 0.1310 (M) 0.1534 (M)

ethanol

TA

water

xw

aw

ethanol

TA

0.9696 0.9094 0.8472 0.7771 0.7286 0.6168 0.5345 0.5012 0.4201 0.3031 0.1644 0

0.0304 (A) 0.0446 (A) 0.0564 (A) 0.0756 (A) 0.0873 (A) 0.1104 (A) 0.1278 (A) 0.1316 (A) 0.1406 (M) 0.1530 (M) 0.1673 (M) 0.1839 (M)

0 0.0460 0.0964 0.1473 0.1841 0.2728 0.3377 0.3672 0.4393 0.5439 0.6683 0.8161

0 0.1146 0.2255 0.3265 0.3926 0.5308 0.6178 0.6521 0.7279 0.8211 0.9123 1

0 0.2587 0.4615 0.5895 0.6504 0.7366 0.7741 0.7876 0.8178 0.8628 0.9236 1

0.9642 0.5975 0.5275 0.4146 0.2981 0.2314 0.1899 0.1604 0

0.0358 (A) 0.1211 (A) 0.1361 (A) 0.1565 (A) 0.1746 (M) 0.1837 (M) 0.1861 (M) 0.1909 (M) 0.2122 (M)

25 °C

xw

aw

0 0.3926 0.5308 0.6177 0.6934 0.7192 0.8190 0.9118 1

0 0.6423 0.7292 0.7675 0.7982 0.8091 0.8585 0.9231 1

water

xw

aw

0 0.2814 0.3364 0.4289 0.5273 0.5849 0.6240 0.6487 0.7878

0 0.5464 0.6199 0.7258 0.8190 0.8661 0.8937 0.9118 1

0 0.7523 0.7801 0.8179 0.8609 0.8897 0.9095 0.9240 1

water 0 0.1875 0.2767 0.3448 0.4159 0.4425 0.5608 0.6967 0.8466 30 °C

Figure 6. Ternary phase diagram for ethanol− water−TA at atmospheric pressure: (a) t = 15 °C; (b) t = 20 °C; (c) t = 25 °C; (d) t = 30 °C. All axis scales are in weight percent. 2793



Article

Table 3. Transition Water Activity (at Point b) at Different Temperatures ethanol concn (wt %) TA (A + M) concn (wt %) water concn (wt %) xw aw

15 °C

20 °C

25 °C

30 °C

0.5381 0.0934 0.3685 0.6366 0.7590

0.5056 0.1112 0.3832 0.6597 0.7844

0.4598 0.1385 0.4326 0.7065 0.8090

0.3493 0.1709 0.4788 0.7780 0.8402

The variation of the transition water activity as a function of temperature is plotted in Figure 7. It can be noticed that the

Figure 7. Water activity as a function of temperature.

water activity increases linearly with the temperature as given by the following equation:

a w = 0.0054T + 0.6774

(5)

Figure 8. Conversion rate versus time at different solvent compositions.

The linear fit is consistent with the assumption made earlier that the transition water activity is not affected significantly by the presence of variable amounts of the solute. Extrapolation of this line suggests a transition temperature of 60.2 °C at a water activity of 1, consistent with the discussion in section 3. The water activity at a specific temperature can then be calculated on the basis of eq 5, and consequently the composition of the solution. 3.3. Influence of the Water Activity on the Conversion Rate between Anhydrous and Monohydrate TA at 25 °C. As discussed before, the conversion from monohydrate to anhydrate occurs when the water activity is lower than that of point b. Therefore, the points at aw = 0, 0.26, 0.46, 0.59, and 0.65 in Figure 6c (the corresponding water activity at point b is 0.809) were selected to investigate the transition behavior at different water activities, and the results at other temperatures shown in Figure 6a,b,d express a similar tendency. The conversation rates between monohydrate and anhydrate at different water activities are shown in Figure 8. The conversion rate shows a tendency to decrease with increasing water activity. This can be explained by the fact that the thermodynamic driving force increases with the content of ethanol. Figure 9 shows the time evolution of the TA concentration during the transformation from monohydrate to anhydrate. The solute concentration increased to a maximum and then decreased at aw = 0, 0.26, and 0.46 (Figure 9a). As shown in Figure 9b, first, the solution became saturated and the solute concentration remained unchanged and, second, the concentration increased to a maximum and then decreased. These

phenomena can be recognized when considering Figure 8. The conversion rate at aw = 0 and aw = 0.26 is higher than that at aw = 0.59 and aw = 0.65. The phenomena above may be explained by the process of dissolving monohydrate and crystallization of anhydrate. Therefore, the transformation from monohydrate to anhydrate at aw = 0.26 and aw = 0.59 was selected to investigate the crystallization process of anhydrous TA. 3.4. Crystallization process of anhydrous TA from Ethanol−Water at 25 °C. Morphological examinations have shown that crystals of monohydrate TA belong to the triclinic system and anhydrous TA is a polycrystalline mass formed by multiple twinning.13 The difference in crystal shape was used to identify which crystalline form of TA coexisted with an equilibrated liquid solution and thereby determine which form is more stable.22 Taking the water activity at 0.26 and 0.59, for example, the crystallization process of anhydrous TA from ethanol−water at 25 °C was investigated. The photomicrographs of the anhydrous and monohydrate TA are shown in Figure 10. As shown in Figure 9, the solution concentration increased to a maximum quickly an then decreased at aw = 0.26 (Figure 9a). However, the solution concentration increased to 10.3 g/100 g of mixed solvent, then increased to a maximum slowly, and then decreased at aw = 0.59 (Figure 9b). The difference between the solute concentration curves at aw = 0.26 and aw = 0.59 may be accounted for by the difference in conversion rate. The crystallization process of anhydrous TA from ethanol− water solvent can be divided into three steps: (1) dissolution of 2794



Article

1 and 3, and the subsequent decrease of the solution concentration is mainly caused by the conversion of monohydrate TA. The variation of the concentration curve at aw = 0.26 and 0.59 shown in Figure 9 can be explained by the difference in the conversion rate, which exhibits a tendency to increase with decreasing water activity. For example, the lower conversion rate at aw = 0.59 results in slow dehydration of monohydrate TA, and consequently, a slower increase of the solution concentration by dissolving more monohydrate or anhydrous TA can be observed. Furthermore, microscopy photos have been taken during the conversion process and are shown in Figure 11. The conversion

Figure 11. Some snapshots taken during transformation at 25 °C with a microscope: (a)-1, aw = 0.26, t = 10 min; (a)-2, aw = 0.26, t = 40 min; (b)-1, aw = 0.59, t = 60 min; (b)-2, aw = 0.59, t = 220 min.

Figure 9. Solute concentration profile during the transformation process at varying water activities at 25 °C: (a) aw = 0, 0.26, and 0.46; (b) aw = 0.59 and 0.65.

process was already accomplished before 40 min at aw = 0.26, while coexistence of both monohydrate and anhydrous TA can be observed after 220 min at aw = 0.59. this is in agreement with the results discussed above.

4. CONCLUSIONS The ternary phase diagrams of the water−ethanol−TA system at different temperatures ranging from 15 to 30 °C were determined to investigate the influence of the water activity on the phase conversion temperature. The result shows that anhydrous TA can be obtained at ambient temperature by lowering the water activity through increasing the content of ethanol in the mixed solvent. The solubility of TA also decreases as more ethanol is added. The data on the transition water activity should apply equally to mixtures of other solvents with water. The crystallization process of anhydrous TA from ethanol− water solution includes two steps, namely, the dissolution of monohydrate and the crystallization of anhydrate. The phase conversion rate appears to increase with decreasing water activity at a certain temperature; i.e., the difference between the real water activity and the equilibrium water activity can be considered to be the driving force of the transformation. The solubilities of monohydrate and anhydrous TA in pure water have also been remeasured in this study, and the

Figure 10. Morphology of anhydrous and monohydrate TA: (a) anhydrate; (b) monohydrate.

monohydrate TA; (2) conversion of monohydrate TA to anhydrous TA; (3) as a result of the dehydration in step 2, an increase of the water content in the solvent, which is in favor of the dissolution of monohydrate or anhydrous TA. The first and third steps cause an increase of the solution concentration, while the dehydration process in the second step decreases the solution concentration due to the lower solubility of anhydrous TA. The increase of the solution concentration at aw = 0.26 and 0.59 shown in Figure 9 can be explained by the control of steps 2795



Article

(18) Black, S.; Muller, F. On the effect of temperature on aqueous solubility of organic solids. Org. Process Res. Dev. 2010, 14 (3), 661− 665. (19) Caillet, A.; Puel, F.; Fevotte, G. Quantitative in situ monitoring of citric acid phase transition in water using Raman spectroscopy. Chem. Eng. Process. 2008, 47 (3), 377−382. (20) Kitamura, M.; Abe, T.; Kishida, M. Mechanism for the release of the industrial biocide CMI from clathrate crystal. Chem. Eng. Res. Des. 2008, 86 (9), 1053−1058. (21) d’Avila, S.; Silva, R. Isothermal vapor-liquid equilibrium data by total pressure method. Systems acetaldehyde-ethanol, acetaldehydewater, and ethanol-water. J. Chem. Eng. Data 1970, 15 (3), 421−424. (22) Luk, C. J.; Rousseau, R. W. Solubilities of and transformations between the anhydrous and hydrated forms of L-serine in watermethanol solutions. Cryst. Growth Des. 2006, 6 (8), 1808−1812.

transition temperature was obtained in pure water, which is consistent with the data obtained in mixed solvent systems.

■

AUTHOR INFORMATION

Corresponding Author

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

■

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

■

xw x γw aw T Kh

■

NOMENCLATURE mole fraction of water mole fraction solubility of TA activity coefficient water activity temperature (°C) equilibrium constant REFERENCES

(1) Bechtloff, B.; Nordhoff, S.; Ulrich, J. Pseudopolymorphs in industrial use. Cryst. Res. Technol. 2001, 36 (12), 1315−1328. (2) Khankari, R. K.; Grant, D. J. W. Pharmaceutical hydrates. Thermochim. Acta 1995, 248, 61−79. (3) Zhu, H.; Grant, D. J. W. Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase. 2. Ampicillin. Int. J. Pharm. 1996, 139 (1−2), 33−43. (4) Zhu, H.; Yuen, C.; Grant, D. J. W. Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase. 1. Theophylline. Int. J. Pharm. 1996, 135 (1−2), 151−160. (5) Li, Y.; Chow, P. S.; Tan, R. B. H.; Black, S. N. Effect of water activity on the transformation between hydrate and anhydrate of carbamazepine. Org. Process Res. Dev. 2008, 12 (2), 264−270. (6) Qu, H.; Louhi-Kultanen, M.; Rantanen, J.; Kallas, J. Solventmediated phase transformation kinetics of an anhydrate/hydrate system. Cryst. Growth Des. 2006, 6 (9), 2053−2060. (7) Black, S. N.; Phillips, A.; Scott, C. I. Crystallisation design space: Avoiding a hydrate in a water-based process. Org. Process Res. Dev. 2008, 13 (1), 78−83. (8) Bohlin, M. J., H.; Black, S. New developments in scale-up and QbD to ensure control over product quality. Am. Pharm. Rev. 2009, 52−57. (9) Jain, M. K. Organic Chemistry; Shoban Lal Nagin Chand and Co.: Jalandhar, India, 1991. (10) Mukherjei, S. M.; Singh, S. P.; Kapoor, R. P. Organic Chemistry; Wiley Eastern Ltd.: New Delhi, 1993. (11) Pine, S. H.; Hendrickson, J. B.; Cram, D. J.; Hammond, G. S. Organic Chemistry, 4th ed.; McGraw-Hill: New York, 1985. (12) Windholz, M.; Budavari, S.; Stroumtsos, L.; Fertig, M. The Merck Index: An Encyclopedia of Chemicals and Drugs; Merck & Co. Inc.: Rahway, NJ, 1976. (13) Parry, G. The crystal structure of hydrate racemic acid. Acta Crystallogr. 1951, 4 (2), 131−138. (14) Mullin, J. W. Crystallization; Butterworth-Heinemann: London, 2001. (15) Kuhnert-Brandstatter, M.; Gasser, P. Solvates and polymorphic modifications of steroid hormones. I. Microchem. J. 1971, 16 (3), 419− 428. (16) Grant, D. J. W.; Higuchi, T. Solubility Behavior of Organic Compounds; Wiley-Interscience: New York, 1990; Vol. 21. (17) Shefter, E.; Higuchi, T. Dissolution behavior of crystalline solvated and nonsolvated forms of some pharmaceuticals. J. Pharm. Sci. 1963, 52 (8), 781−791. 2796


How To Crystallize Anhydrous Racemic Tartaric Acid from an Ethanol

Recommend Documents