Application of Preferential Crystallization for Different Types of

Jul 2, 2009 - was saturated with respect to Eu-MA at 25.5 °C based on the solubility measurements of Eu-MA at different temperatures. Similarly, for ...
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Application of Preferential Crystallization for Different Types of Racemic Compounds Yinghong Lu,† Xiujuan Wang,*,† and Chi Bun Ching† Department of Chemical and Biomolecular Engineering, National UniVersity of Singapore, Singapore, and DiVision of Chemical and Biomolecular Engineering, School of Chemical and Biomedical Engineering, Nanyang Technological UniVersity, Singapore

A systematic approach was developed and applied to the preferential crystallization of a racemic-conglomerateforming system in our previous work. In this work, we extended and modified the strategy for two typical types of racemic-compound-forming systems, namely, mandelic acid and ketoprofen, taking into account the crucial different thermodynamics and crystal structure properties between a racemic compound and a conglomerate. System thermodynamic aspects such as binary melting-point phase diagram and ternary solubility phase diagram were measured. The metastable zone widths of mandelic acid with different compositions in water under different cooling rates were determined with a Lasentec focused beam reflectance (FBR) probe. The crystal nucleation and growth kinetics were measured by s-plane analysis. Based on the solubility and the metastable zone width diagram, the maximum limits of practicable operating ranges for conducting preferential crystallization to obtain enantiomerically pure products was defined. Different operating profiles were applied, and the solution supersaturation was analyzed for the crystallization processes. The optical purities, yields, and crystal size distributions of the final products were examined and compared. 1. Introduction With the increasing market for pure enantiomers of chiral drugs because of regulatory requirements and considerations of improved therapeutic effects, enantioselective technology is a very promising area.1-7 Preferential crystallization is one of the most straightforward and efficient separation and purification processes given its advantages involving low costs and solid products.6-13 Typically, preferential crystallization has been used for the separation of the enantiomers of racemic conglomerates. Many successful applications of this type have been reported.14-21 However, only 5-10% of crystalline racemates are conglomerates. The majority of chiral substances are racemic compounds, including 90-95% of all racemates. Therefore, the applicability of preferential crystallization to racemic compounds would significantly widen the potential of typically inexpensive crystallization-based techniques for enantioseparation.22-27 Moreover, with the great development of asymmetric synthesis and simulated moving bed (SMB) chromatography, it has become easier to obtain an enantiomeric enrichment exceeding the eutectic composition in the racemic-compound-forming system, which sets the threshold for a subsequent enantioselective crystallization process. Direct crystallization for an enantiomeric enrichment can be applied to further purify the partially resolved racemic compound.1,11,12,25,27,28 In our previous work,9,10 we introduced the concept of critical supersaturation control for preferential crystallization and applied the strategy to a racemic-conglomerate-forming system. For a racemic-conglomerate-forming system, this approach requires control of the different crystallization rates 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 growh * To whom correspondence should be addressed. E-mail: wangxj@ ntu.edu.sg. † National University of Singapore. † Nanyang Technological University.

of the desired enantiomer 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 racemiccompound-forming system. The solution structure and properties of a system forming a racemic compound are different from those of a system forming a conglomerate. The solution consists of molecules of the racemate and one excess pure enantiomer instead of molecules of two pure enantiomers. The eutectic composition is usually not superimposable on the racemate. In view of thermodynamic aspects, it is crucial to keep the freedom of supersaturation of the racemate in its metastable zone to avoid its spontaneous nucleation and growth on the seed crystals of the desired enantiomer. Therefore, the solubility diagrams and supersaturation data are the thermodynamic basis for the preferential crystallization of a 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 could easily initiate the spontaneous nucleation of its racemate. In addition, the crystal size distribution (CSD), which is greatly affected by the supersaturation control, is an important factor affecting the production of high-quality crystal products and determining the efficiency of downstream operations. To control the supersaturation, the thermodynamic data, crystal nucleation and growth kinetics, and crystal population balance are needed to combine together to model and predict the operating concentration/temperature profiles. According to their binary/ternary phase diagrams, racemic compounds can be classified into three cases as shown in Figure 1: the solubility of the racemate is lower than that of pure enantiomer (unfavorable), such as for ketoprofen;29 the solubility of the racemate is greater than that of the pure enantiomer (more favorable), such as for mandelic acid;30 and the special case of propranolol hydrochloride (most favorable).27 In a previous work,27 we attempted to employ the strategy of preferential crystallization to a special case of racemic compound, namely, propranolol hydrochloride, whose eutectic composition is almost superimposable on the racemate composi-

10.1021/ie801344s CCC: $40.75  2009 American Chemical Society Published on Web 07/02/2009

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Figure 1. Ternary phase diagrams for a racemic compound: (a) unfavorable, (b) more favorable, (c) most favorable.

tion. To explore the general strategy of preferential crystallization for racemic-compound-forming systems, in this work, we extended the study to members of the two more commonly encountered classes of racemic compounds (Figure 1a,b): mandelic acid (MA) and ketoprofen (Kp). Mandelic acid is a widely used reagent in classical resolution. Some efforts have been made to study the crystallization process and measure relevant data for MA because of its relatively low price and favorable phase diagram characteristics for preferential crystallization. For example, the coupling process of liquid chromatography and preferential crystallization was suggested for mandelic acid in aqueous solution by Lorenz et al.25 The binary and ternary phase diagrams of mandelic acid enantiomer in water were constructed.30,31 Profir and Rasmuson reported that metastable conglomerate mandelic acid racemate crystals can be formed upon primary nucleation in water and acetic acid; after a time lag, the conglomerate was transformed into the stable form of the racemic compound. The time-lag range depended on the operating conditions and decreased wih increasing concentration or temperature and in the presence of micrometersize particles.8,26 Simple crystal growth kinetics assuming no nucleation was evaluated using the isothermal method.32 Ketoprofen is a potent nonsteroidal anti-inflammatory drug (NSAID) currently marketed as the racemate. It is equally as potent as NSAIDs, or even more so, with respect to antiinflammatory and analgesic activity.33 What is most important is that the biological activity of ketoprofen resides with the S enantiomer whereas (R)-ketoprofen is therapeutically inactive.34 Some methods have already been applied for ketoprofen enantioseparation, including chiral chromatography35-37 and enzymatic separation.38 However, very few attempts have been reported to systematically study the practical preferential crystallization process combining the aspects of thermodynamics, kinetics, optimal operation, and in situ monitoring. This work presents a systematic study of the solubility, metastable zone, kinetics, and supersaturation control profile to obtain crystal product with good quality for racemic-compound-forming system. The binary melting-point phase diagram and ternary solubility phase diagram of mandelic acid in water were measured. The metastable zone widths of mandelic acid with different compositions under different cooling rates were measured with a Lasentec focused beam reflectance (FBR) probe. Through use of the classical s-plane analysis, both crystal nucleation and growth kinetics of the pure enantiomers and racemate mandelic acid can be extracted during batch crystallization. Three different typical cooling profiles were applied to the preferential crystallization process. The optical purities, yields, and crystal size distributions of the final products were examined and compared. Under the optimal controlled cooling profile, the crystallization progression was analyzed and elucidated in terms of the solubility and metastable zone width (MSZW) diagrams. The new modified strategy was also applied to examine the other

type of racemic compound, namely, ketoprofen, based on the thermodynamic solubility phase diagram, MSZW, and optimal operation aspects. 2. Experimental Setup and Methodology 2.1. Materials. (S)- and (RS)-mandelic acid and (S)- and (RS)-ketoprofen were purchased from Sigma-Aldrich (Singapore) and used without further purification. Ultrapure deionized water was obtained through a Millipore ultrapure water system (Milli-Q Gradient A10 System). high-performanceliquid-chromatography- (HPLC-) grade isopropanol, ethanol, trifluoroacetic acid (TFA), n-hexane, and n-heptane were purchased from Aik Moh Paints and Chemicals Pte Ltd. (Singapore). 2.2. Apparatus. The crystallization experiments were carried out in an automatic laboratory reactor system equipped with a 1-L glass jacketed crystallizer as described in our previous work.9,10 2.3. Solubility and Metastable Zone Width (MSZW). The polythermal method was used to determine the solubilities of mandelic acid at different mole percentages of (S)-MA (100, 80, 70, and 50 mol %) in water. The experiments were performed in the temperature range between 5 and 35 °C. The metastable zone widths of these solutions were determined at different cooling rates of 2, 5, and 10 °C/h at a constant rate of 300 rpm. The maximum allowable subcooling (Tdissolution Tnucleation) was determined as the MSZW. Nucleation and dissolution were detected with a Lasentec S400A FBR probe. 2.4. Crystallization Kinetics Measurement. 2.4.1. Method. In the enantioseparation crystallization process, the supersaturation of the enantiomeric mixture solution should be carefully controlled to inhibit spontaneous crystal nucleation and growth of the undesired isomer. Kinetic data such as the crystal growth rate G and the nucleation rate B are essential for the design and optimization of the crystallizer. Because crystal growth and nucleation are almost simultaneous processes, it is difficult to determine their kinetics separately. Therefore, scientists have proposed many methods to estimate the kinetics of the growth and nucleation processes simultaneously.39-55 Among these methods, one of the most classical methodologies is the s-plane analysis. Using this method, both the crystal nucleation and growth kinetics can be extracted from the population curves obtained during batch crystallization. The classical equation for determining the kinetics of the crystallization process is the population balance equation Qi ∂(Gn) d(ln V) Q ∂n + +n + n ) B' - D' - ni ∂t ∂L dt V V

(1)

For a well-mixed batch crystallization process, with Q ) Qi ) 0, in which crystal breakage and agglomeration are negligible,

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the population balance equation for size independent of growth rate is given by Randolph and Larson39 as ∂n ∂n +G )0 ∂t ∂L

(2)

Tavare and Garside43 first reported that an experimentally determined population density can be converted into the Laplace transformed response with respect to size L as nj(t, s) )

∫

∞

0

n(t, L) exp(-sL) dL

(3)

Then, transformation of the population balance equation using eq 3 as dnj(s, t) + G[snj(s, t) - n(0, t)] ) 0 dt

Figure 2. Raman spectra of (RS)- and (S)-MA.

(4)

In eq 4, n and G both are function of time t, when the time interval is small enough, their value can be expressed by the j. average value on this time interval, nj and G j nj(0, t) ) B j G

(5)

∆nj(s, t) j snj(s, t) + B j ) -G ∆t

(6)

Therefore

Over an optimal range of the Laplace transform variable, a plot of ∆nj(t,s)/∆t versus snj(t,s) for eq 6 should yield a straight line with a slope of -G and an intercept of B. The estimated nucleation rate B and growth rate G can then be correlated with the degree of supersaturation ∆C and slurry density MT by regression of the data by the linear least-squares technique G ) KG∆Cg

(7)

B ) KBMTjGi

(8)

2.4.2. Procedure. Batch crystallization experiments were carried out to measure the crystallization kinetics of (S)-MA and (RS)-MA. The loading of the crystallizer was 600 mL of saturated solution at 35 °C for (S)- and (RS)-MA. In both experiments, the operating temperature range was 20-35 °C. During each run of the crystallization experiments, 3-5 mL samples were withdrawn and filtered every 15-25 min. Based on these samples, the crystal size distribution was measured using a Malvern Mastersizer 2000 instrument with a Hydro 2000 µP dispersion unit cell with analytical hexane as the liquid dispersion medium. The sample filtrate was used for solute concentration analysis. The concentration was measured using a Shimadzu 2450 UV-visible spectrophotometer. The crystal slurry concentration was calculated by mass balance. 2.5. Preferential Crystallization Operation. Three types of cooling profiles, namely, controlled cooling, linear cooling, and forced cooling, were used on three separate batches of direct crystallization of mandelic acid. The starting point of all three experiments was the same solution, which was an 80 mol % (S)-MA saturated solution at 35 °C. The crystallizer was kept at 40 °C for 0.5 h to attain a completely clear solution. After that, the temperature of the crystallizer was decreased to 34 °C, which was slightly below the saturated temperature of 35 °C, and maintained for 0.5 h. Then, pure (S)-MA crystal seeds prepared by fast cooling from a solution of pure (S)-MA were added into the solution. The cooling crystallization experiments

Figure 3. Binary phase diagram of MA.

were performed according to the different temperature profiles within the range of 35-20 °C. During these experiments, several samples were taken at certain time intervals to examine the optical purity of the crystal products, the solute concentration in the liquid phase, and the crystal size distribution. The optical purities of the crystal products were measured using a Mettler Toledo 822e differential scanning calorimeter (DSC), a JASCO P-1020 digital polarimeter equipped with a quartz cell of 50mm path length, and an Agilent 1100 series HPLC system with a Chiralcel AD-H analytical column (dimensions 250 mm length × 4.6 mm i.d.) under the following separation conditions: hexane/TFA/isopropanol (IPA) (95/0.1/5 v/v/v) at 25 °C column temperature, flow rate of 1.0 mL/min, and UV-vis detection at 210 nm. 3. Results and Discussion 3.1. Characterization of Racemic Species of Mandelic Acid. Mandelic acid was reported to be a racemic compound by Li and Lorenz.5,8,11,12,25,26,30 Here, we conducted a Raman spectroscopic analysis and melting-point measurements to further confirm its racemic nature and eutectic composition. The Raman spectra of (RS)- and (S)-MA are shown in Figure 2. Significant differences can be found in the range of Raman shifts of ca. 500-1300 cm-1. The experimental binary melting-point phase diagram of MA is shown in Figure 3, and the calculated liquidus curve is illustrated as well. From the phase diagram, the experimental results obtained by DSC measurements were in good agreement with the calculated results. The eutectic point was obtained as 70 mol % (S)-MA, which was close to the reference value.30 The Raman spectra and the shape of the binary phase diagram can further confirm that mandelic acid is a racemic compound. 3.2. Solubility and Metastable Zone Width (MSZW). The solubilities of 50, 70, 80, and 100 mol % of (S)-MA in water were determined by the polythermal method using FBR detection. With consideration of possible metastable conglomerate formation and the high transition rate into the stable form of the racemic compound under the studied experimental condi-

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j2 the limits on the values of s used should be constrained by sfL j ≈ 1-2 where L2 is the population-average size at time t2. j 2 ≈ 0.1-0.5 was most However, in our analysis, the relation sfL suitable and gave a better linear regression. The results of the analysis of a typical set of data are shown in Figure 7. The kinetic expressions for the crystal growth and nucleation of (S)- and (RS)-MA were obtained by regression of the data in Tables 1 and 2 by the linear least-squares technique (S)-MA: G ) 3.21 × 10-16∆C2.04 Figure 4. Solubility of MA with different mole percentages in water.

tions,8 the measurement of the saturation temperature was given sufficient time to reach equilibrium with respect to the stable form of the racemic compound. The solubility values were also verified by the isothermal method using gravimetric analysis. All results are shown in Figure 4. According to the solubility data, the ternary phase diagram of MA in water was derived, as shown in Figure 5. It was also found that the solubility increased greatly with temperature over the experimental range from 20 to 35 °C, which indicates that the chosen solvent is suitable for the crystallization operation and that the cooling preferential crystallization method can be used for mandelic acid. As for our previous discussion,9 the solubility ratio of (RS)- to (S)-MA decreases from ca. 3.3 at 35 °C to ca. 1.6 at 20 °C. As the solubility ratio of (RS)- to (S)-MA decreases, the destabilization process of the solution is decreased, and the possibility of spontaneous nucleation of the undesired racemate is slowly increased. This suggests that the preferential crystallization of mandelic acid in the chosen solvent is more favorable as temperature decreases. The ternary phase diagram of mandelic acid in Figure 5 shows the typical shape of a racemic compound, which further indicates that mandelic acid is a type of racemic compound (case b in Figure 1) with a higher solubility for the racemate (RS)-MA than for the pure enantiomer (S)-MA. The metastable zone widths of mandelic acid with different mole percentages of (S)-MA (100, 80, 70, and 50 mol %) were determined by FBR, as illustrated in Figure 6. From these plots, it can be seen that the cooling rate and the saturation temperature have a great influence on the metastable zone widths of mandelic acid. When the cooling rate was increased, the MSZW also increased. A possible reason for this observation is that the growth of a nucleus to a detectable size requires a finite time after the solution reaches the supersaturated region. Hence, a larger MSZW can result when the cooling rate is relatively high during the MSZW measurement process.56 When the cooling rate was constant, the metastable zone widths had a tendency to become narrower at higher saturation temperatures. All of the measured MSZWs of mandelic acid were higher than 5 °C, making them favorable for the preferential crystallization process. 3.3. Crystal Nucleation and Growth Kinetics. The method of Laplace transform analysis was used to obtain the crystallization kinetics for (S)- and (RS)-MA. The estimated growth rate and nucleation rate results are given at Tables 1 and 2. One of the obvious advantages of using the Laplace domain is that the sensitivity to experimental errors in the determination of the experimental response is greatly reduced, provided that a suitable value of the Laplace transform variable s is used.44 j and B j from eq In formulating a linear regression to estimate G 6, the limits on the optimal values of s must first be known. The selection of the optimum Laplace transform parameter in the analysis of crystal growth dispersion in a batch crystallizer has been reported by Tavare and Garside.44 They indicated that

B ) 6.46 × 104MT1.15G0.17 (RS)-MA: G ) 1.24 × 10-21∆C3.10 B ) 3.52 × 1011MT1.76G1.68

(9) (10) (11) (12)

The same analysis was performed for (S)- and (RS)-Kp, and the resulting kinetic expressions are (S)-Kp: G ) 3.02 × 10-15∆C2.01 B ) 5.86 × 1010MT0.17G0.35 (RS)-Kp: G ) 8.91 × 10-24∆C3.29 B ) 8.36 × 1011MT1.44G1.07

(13) (14) (15) (16)

3.4. Progression of Preferential Crystallization and Implications of the Phase Diagram for Different Types of Racemic Compounds: Mandelic Acid and Ketoprofen. Preferential crystallization experiments were carried out for two different types of racemic compounds, namely, mandelic acid and ketoprofen, and the experimental results were systematically elucidated based on the thermodynamic solubility phase diagram, MSZW, and kinetic aspects. A typical loading for the preferential crystallization of mandelic acid was a saturated solution with 80 mol % of (S)MA at 35 °C. As the components of solute in the solution could consist only of the eutectic composition (Eu-MA), pure enantiomer [(S)-MA], or racemic composition [(RS)-MA], to demonstrate and analyze the subsequent progress and limits of the preferential crystallization process for a racemic-compoundforming system, we regard the initial saturated solution with 80 mol % of (S)-MA as a combination of Eu-MA and (S)-MA or of (RS)-MA and (S)-MA. If the initial saturated solution was formed by Eu-MA and (S)-MA, the concentration of Eu-MA was calculated accordingly. Then, this initial saturated solution was saturated with respect to Eu-MA at 25.5 °C based on the solubility measurements of Eu-MA at different temperatures. Similarly, for the combination of (RS)-MA and (S)-MA, the initial solution was saturated with respect to (RS)-MA at 23.3 °C. This means that only S enantiomer is supersaturated in the temperature range of 23.3-35 °C. From the thermodynamics viewpoint, according to the MSZW data in Figure 6, the supersaturation should be kept within ca. 5 °C to avoid spontaneous nucleation of both the enantiomer and the racemate. Also, the applicable supersaturation for the RS racemate is 5.5-25 °C. Therefore, it is acceptable to set the final targeted temperature at 20 °C. Because the MSZW should be narrower in the solution with seed crystals and the supersaturated solution was unstable in a relatively higher second metastable region where RS racemate nuclei could form, the supersaturation should be kept lower than that measured under homogeneous conditions. In this work, a critical supercooling was chosen to

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Figure 5. Ternary phase diagram of MA in water.

Figure 6. Experimental MSZWs of different mole percentages of (S)-MA in water at different cooling rates: (a) (S)-MA, (b) 80 mol % (S)-MA, (c) 70 mol % (S)-MA, (d) (RS)-MA. Table 1. Estimated (S)-MA Crystal Nucleation Rate B and Growth Rate G with s-Plane Analysis from Experiments B (min-1 · m-3) 1.94 × 10 9.66 × 108 9.61 × 108 4.98 × 108 8

G (m/min) -7

1.88 × 10 8.94 × 10-8 8.61 × 10-8 3.25 × 10-8

∆C (g/m3)

MT (g/m3)

T (°C)

2.06 × 10 1.43 × 104 1.20 × 104 9.18 × 103

1.65 × 10 2.21 × 104 3.30 × 104 4.24 × 104

24.43 23.21 22.40 21.70

4

4

Table 2. Estimated (RS)-MA Crystal Nucleation Rate B and Growth Rate G with s-Plane Analysis from Experiments B (min-1 · m-3) 3.48 × 10 4.40 × 109 2.23 × 109 1.18 × 109 9

G (m/min) -7

1.43 × 10 1.24 × 10-7 7.24 × 10-8 4.85 × 10-8

control at around 2.5 °C. The corresponding ∆C value should be ca. 0.027 g/(mL of water), and the growth rate is 0.35 µm/min (eq 9). The classical simplified equation correlating temperature with

∆C (g/m3)

MT (g/m3)

T (°C)

3.58 × 10 3.08 × 104 2.71 × 104 2.53 × 104

2.43 × 10 3.22 × 105 3.51 × 105 3.72 × 105

28.29 25.75 24.06 22.86

4

5

time (eq 17) derived by Nyvlt et al.46 for optimal batch cooling crystallization with seeds was applied here in the preferential crystallization of mandelic acid to control the supersaturation. This

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Figure 9. Three different cooling profiles.

Figure 7. Typical s-plane analysis to estimate crystal nucleation and growth rates for (S)-MA. sL ) 0.1, G ) 3.25 × 10-8m/min, B ) 4.98 × 108 min-1 · m-3.

Figure 10. Concentrations of both enantiomers in the liquid phase and corresponding process trajectory for a controlled cooling process. Table 3. Optical Purities of the Final Crystal Products of MA from the Progression Experiments optical purity of product (% S enantiomer) experiment

DSC temperature (°C)

Figure 8. Progression of direct crystallization of mandelic acid.

from HPLC

cooling degree

99.8 100 99.6 100 93.0

within ∆Tcrit

91.1

primary nucleation occurred

With Seeds

model determines the optimal cooling curve for a batch crystallizer with an arbitrary seeding and nucleation ratio. It should be noted that other numerical methods can also be applied here to combine the metastable zone data, crystallization kinetics (eqs 9-16), population balance (eq 2), and mass and energy balances to predict the optimal cooling profiles. (T0 - T)/(T0 - Tf) ) (t/tc)3

from polarimeter

Exp_01 Exp_02 Exp_03 Exp_04 Exp_05

As the mean size was ca. 230 µm for the seeds and 527 µm for a target product, the operating time can be calculated as tc ) (527 - 230)/0.35 ) 848 min. Six batches of direct crystallization experiments were carried out starting from the same solution with different modes, which are (a) Exp_01, with seeding and a final temperature of 28 °C; (b) Exp_02, with seeding and a final temperature of 25.5 °C; (c) Exp_03, with seeding and a final temperature of 24 °C; (d) Exp_04, with seeding and a final temperature of 23.3 °C; (e) Exp_05, with seeding and a final temperature of 22.9 °C; and (f) Exp_06, without seeding until nucleation occurred. As described in Figure 8, a saturated solution with 80 mol % of (S)-MA at 35 °C is represented by point A. The corresponding saturated points of Eu-MA and (RS)-MA are represented by points B and C, respectively. When the controlled cooling profile (as shown in Figure 9a) was applied, the solution was seeded with (S)-MA and cooled to different temperatures, including 28, 25.5, 24, 23.3, and 22.9 °C, as shown in Figure 8 as well. It was noted that the product crystals were almost pure S enantiomer when the end temperature was higher than 23.3 °C

99.7 99.3 100 99.8 92.8

outside ∆Tcrit

Without Seeds Exp_06

(17)

132.5 132.5 132.5 132.5 128.5 127.5

91.1

(Exp_04). In this region, only (S)-MA is supersaturated. This implies that the pure enantiomer product can be obtained by well-designed and -controlled direct crystallization. However, when the crystallization final temperature was lower than 23.3 °C, such as in Exp_05 at 22.9 °C, (RS)-MA began to supersaturate, and the product crystals were in the form of a mixture of (RS)-MA and (S)-MA. This was observed in both solution components of R- and S-enantiomer concentration profiles (Figure 10) and crystal product analyses (Table 3). From Figure 10, it can be seen that the crystallization process can be divided into two stages: stage 1 (a-b) and stage 2 (b-c). In stage 1, the concentration of the (S)-MA component decreased properly, and the concentration of the (R)-MA component remained almost constant. This suggests that the product crystals obtained from stage 1 should be in the form of pure (S)-MA. However, when the process entered stage 2, referring to point b, the temperature reached 22.9 °C, and the concentration of (R)-MA in solution began to decrease. This means that (RS)MA, including the (R)-MA component, began to crystallize accordingly. Therefore, if the S enantiomer of mandelic acid is

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Figure 11. FBR data on the number of fine counts with a controlled cooling profile.

acid cannot crystallize as a stable compound from solution. Therefore, during the preferential crystallization process for mandelic acid, the crucial controlling factor should be the supersaturation of (S)- and (RS)-mandelic acid, which controls the competition of the crystal nucleation and growth rates between the S enantiomer and the RS racemate. Furthermore, the optical purities of crystal product were measured and verified by HPLC, polarimeter, and DSC. Prior to the optical purity analysis of the crystal product, a polarimeter calibration curve with different mole percentages of (S)-MA was determined as shown in Figure 12. The relationship between the concentration of pure S enantiomer C and the optical rotation R is expressed as R ) 0.7448 × 100C

Figure 12. Calibration curve of optical rotation with concentration for pure (S)-MA. Table 4. Optical Purities of the Final Crystal Products of Kp from the Progression Experiments

experiment

optical purity of product (% S enantiomer) from HPLC

cooling degree

With Seeds Exp_01 Exp_02 Exp_03 Exp_04

99.3 99.2 99.8 96.1

within ∆Tcrit outside ∆Tcrit

Without Seeds Exp_05

85.0

primary nucleation occurred

desired, the operation range should be within the limits of stage 1. The temperature at the end of stage 1 for the controlled cooling profile was about 23.3 °C, which was the saturated temperature of (RS)-MA. This is also observed from the FBR detection in Figure 11. The counts of fine chord lengths of 1-5 and 10-24 µm increase steeply at 47300 s, 22.9 °C, and the counts of chord lengths of 29-86 µm also suddenly increase. This might indicate that there is no selectivity of crystal growth of the pure enantiomer and racemate for a racemic compound when both S and RS reach supersaturation, which was first observed in the crystallization of propranolol hydrochloride (special case c).27 When the solution was cooled to 21.5 °C without seeding as in Exp_06, the primary nucleations occurred. The products were always in the form of (RS)-MA and (S)MA. This could be due to the crucial characteristic of a racemic compound, namely, no selectivity of nucleation between the pure enantiomer and the racemate for a racemic compound. More importantly, it was found that, even though the end temperature was reached below the Eu-MA saturated temperature of 25.5 °C, pure S enantiomer crystals were still obtained, and the eutectic component crystal of mandelic acid did not precipitate from solution, as in Exp_02 and Exp_03. It can be explained that the eutectic mandelic acid could be still in the metastable zone area, even though the end temperature already surpass its saturated temperature, or that the eutectic mandelic

(18)

Table 3 lists the optical purities of the final crystal products, which were derived by the methods mentioned above. Only 92.8 and 91.1 mol % of (S)-MA can be obtained from Exp_05 and Exp_06, respectively. Also, two peaks were found in the DSC thermograms and HPLC chromatograms in these two operations. This indicates that the crystal nucleation and growth of racemic (RS)-MA could occur. On the other hand, we also employed the above crystallization strategy to ketoprofen in a solvent mixture of ethanol and water in a volume ratio of 0.9:1.0. According to the solubility and MSZW diagrams reported in our previous work,29,57 the eutectic composition of Kp is around 92 mol % of (S)-Kp. The MSZW of high-mole-percent (S)-Kp is ca. 2 °C. The chosen experiments were conducted starting from a saturated solution at 20 °C with 96 mol % of the S enantiomer. This saturated solution was saturated in the eutectic composition of Kp at 7.3 °C and saturated in (RS)-Kp at 0.7 °C. Similarly, for the controlled cooling profile, five experiments under different cooling modes were conducted: (a) Exp_01, with seeding and a final temperature of 10 °C; (b) Exp_02, with seeding and a final temperature of 7.3 °C; (c) Exp_03, with seeding and a final temperature of 6.0 °C; (d) Exp_04, with seeding and a final temperature of 0.7 °C; and (e) Exp_05, without seeding until nucleation occurred. The optical purities of final products of ketoprofen obtained by the HPLC chromatograms are reported in Table 4. It can be seen that it was more difficult to obtain pure enantiomer product because of the narrower MSZW and unfavorable phase diagram for Kp. Again, it was found that there was no selectivity of crystal nucleation and growth for the racemic compound Kp with an unfavorable phase diagram (Figure 1a). 3.5. Progression of Direct Crystallization Process under Different Cooling Profiles. For comparison purposes, the linear and forced cooling profiles, which result in higher supersaturations, were studied with mandelic acid as well. The temperature profiles are presented in Figure 9b,c. The corresponding concentrations of both enantiomer components in solution and process trajectories for forced and linear cooling processes are illustrated in Figures 13 and 14. It was found that all three crystallization process can be divided into two stages: stage 1 (a-b) and stage 2 (b-c). The range of operation stage 1 was longest for the controlled cooling profile and shortest for the forced cooling profile. This implies that the controlled cooling profile is the optimal operation for obtaining a high-yield crystal product. Indeed, based on the difference between the initial and final solution concentrations, ca. 65% yield was obtained for the controlled cooling operation, whereas ca. 58% was obtained for the forced cooling operation and 62% was obtained for the linear cooling operation. The optical purities of product crystals were measured by HPLC, polarimenter, and DSC as listed in Table 5. The pure S

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Table 5. Optical Purities of Final Crystal Products from Different Cooling Profiles

experiment

DSC temperature (°C)

polarimeter sample concentration [g/(100 mL of water)]

controlled cooling forced cooling linear cooling

132.5 121.8 129.9

0.2845 0.2089 0.3992

enantiomer products were obtained only by controlled cooling experiments. Only 80.6 and 95.5 mol % of (S)-MA can be obtained by the forced and linear cooling crystallization operations, respectively. This suggests that the controlled operation was successful and that the induced nucleation of racemate was effectively inhibited by controlling the supersaturation of the S enantiomer within the critical value. The crystal size distributions of the final crystal products under different cooling profiles are presented in Figure 15, and the CSDs of seeds prepared by fast cooling are shown as well. It was found that the final product obtained by the controlled cooling operation exhibited a larger particle size with a narrower

optical purity of product [mol % of (S)-MA] R (°)

from HPLC

from polarimeter

0.2119 0.0598 0.2706

100 80.6 95.5

100 80.6 95.5

distribution. The two most representative parameters describing a crystal size distribution are the weight-mean size and the coefficient of variation (CV) (width of the distribution).39 The crystal-weighted mean size for the controlled operation was 527 µm with a 53% coefficient of variation, whereas the crystals had a 362-µm weighted mean size with a 70% coefficient of variation for the forced operation and a 457-µm weighted mean size with a 60% coefficient of variation for the linear operation. Based on the optical purities and crystal size distributions of the final products, it was indicated that the proposed controlled cooling profile was successful in obtaining pure S enantiomer. During this preferential crystallization process, it is essential to control the supersaturation of the S enantiomer within a critical range to prevent the nucleation of the RS racemate. 4. Conclusions

Figure 13. Concentrations of both enantiomers in the liquid phase and corresponding process trajectory for a linear cooling process.

Figure 14. Concentrations of both enantiomers in the liquid phase and corresponding process trajectory for a forced cooling process.

Figure 15. Crystal size distribution of (S)-MA seeds and crystal products from different cooling profiles.

The preferential crystallizations of the racemic compounds mandelic acid from water and ketoprofen from the mixture of ethanol and water (0.9:1.0 v/v) were studied in detail. The solubilities and metastable zone widths of different enantiomeric compositions for both systems were analyzed. The crystal nucleation and growth kinetics were estimated from batch measurements. The crystallization progressions for different types of racemic compounds were first systematically studied and elucidated based on the nature of crystal structure, solubility, MSZW, and supersaturation operating profile. Both product crystals and solution compositions were examined. It was demonstrated that the maximum operating supersaturation limit was defined to obtain pure enantiomer product, and there was no selectivity of crystal nucleation and growth between the pure enantiomer in excess and the racemic compound beyond this limit. To control this supersaturation limit, thermodynamic data and crystallization kinetics are the basis for modeling and hence predicting the optimal cooling profiles to obtain pure product crystals with good quality. This work shows that the modified critical supersaturation controlling strategy can be successfully applied to the preferential crystallization of racemic-compound-forming system with different characteristics. Nomenclature B ) nucleation rate, min-1 · m-3 B′ ) birth function, min-1 · m-4 ∆C ) supersaturation solution concentration, g/m3 D′ ) death function, min-1 · m-4 g ) kinetic parameter G ) crystal growth rate, m/min i ) kinetic parameter j ) kinetic parameter KB ) nucleation rate constant KG ) growth rate constant L ) crystal size, m MT ) suspension density, g/m3 n ) population density, m-4 ni ) population density of feed (m-4)

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Q ) volumetric flow rate of output, m3/s Qi ) volumetric flow rate of feed (m3/s) s ) Laplace transform variable with respect to size, 1/µm t ) time, min tc ) final operation time, min T ) temperature, °C T0 ) initial temperature, °C Tf ) final temperature, °C V ) volume of suspension, m3 Greek Symbol R ) angle of rotation of plane-polarized light, °

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ReceiVed for reView September 7, 2008 ReVised manuscript receiVed April 16, 2009 Accepted June 2, 2009 IE801344S