Separation of Propranolol Hydrochloride Enantiomers by Preferential

Aug 17, 2007 - Separation of Propranolol Hydrochloride Enantiomers by Preferential Crystallization: Thermodynamic Basis and Experimental Verification...
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Separation of Propranolol Hydrochloride Enantiomers by Preferential Crystallization: Thermodynamic Basis and Experimental Verification Daniel Polenske,*,† Heike Lorenz,† and Andreas Seidel-Morgenstern†,‡

CRYSTAL GROWTH & DESIGN 2007 VOL. 7, NO. 9 1628-1634

Max-Planck-Institut fu¨r Dynamik komplexer technischer Systeme, Magdeburg, Germany, and Otto-Von-Guericke-UniVersita¨t, Magdeburg, Germany ReceiVed January 23, 2007; ReVised Manuscript ReceiVed July 17, 2007

ABSTRACT: Preferential crystallization is an attractive technology to separate racemic mixtures of conglomerates in the pure enantiomers due to the advantage of obtaining directly a solid product and economic considerations. In case of racemic compound forming systems, a hybrid process may be performed consisting of an established separation technique capable of providing a certain enantiomeric enrichment and a subsequent preferential crystallization to produce the pure enantiomer(s). In previous work, the applicability of preferential crystallization in such a hybrid process was demonstrated for the example of mandelic acid. To evaluate the extensibility of the results to other pharmaceutically relevant systems, in this work propranolol hydrochloride is studied. Solubility and metastable zone width data determined in the ternary systems of (R)- and (S)-propranolol hydrochloride in water and methanol are shown and discussed. The eutectic composition of the enantiomers as an important characteristic value could be identified as ∼45:55 and ∼55:45, respectively. The potential of preferential crystallization to produce the pure enantiomer from partially resolved mixtures of (R)- and (S)-propranolol hydrochloride in water is demonstrated. Introduction Typically, a 50:50 mixture of both enantiomers is produced during the chemical synthesis of chiral systems. The resolution of such a mixture is difficult because the scalar chemical and physical properties are identical. Interactions with linear polarized light and other chiral substances are the exceptions. The importance and the application ranges of enantioseparation increase continuously in the pharmaceutical, agricultural, and food industries.1,2 Since 1990, the portion of traded pure enantiomer drugs exceeds the portion of racemic mixtures.3 Well-known technologies to separate racemic mixtures are preparative chromatography, enzymatic resolution, crystallization via the formation of diastereomeric salts, and preferential crystallization.2 Further possibilities to separate enantiomers are supramolecular complexation with chiral molecules,4 the application of molecularly imprinted polymeric membranes,5 and the use of optically active solvents.6 Preferential crystallization is an attractive technology to produce pure enantiomers due to economic considerations and the advantage of obtaining directly a solid product.7,8 However, the direct crystallization of pure enantiomers from racemic solutions is limited to conglomerates (5-10% of all chiral systems).9 Unfortunately, the major part of the chiral substances belongs to the racemic compound forming systems. In this case, a preferential crystallization might be performed in the two three-phase regions of the ternary phase diagram. A first conformation of this concept has been recently published.10,11 Examples of the enantiomeric separation for the mandelic acid/ water system performed in an isothermal batch and cyclic operation mode were given. In the case of racemic compound forming systems, the preferential crystallization step can be integrated in a hybrid * To whom correspondence should be addressed. Address: Max-PlanckInstitut fu¨r Dynamik komplexer technischer Systeme, Sandtorstrasse 1, D-39106 Magdeburg, Germany. Phone: (0049) 391-6110-283. Fax: (0049) 391-6110-617. E-mail: [email protected]. † Max-Planck-Institut fu ¨ r Dynamik komplexer technischer Systeme. ‡ Otto-von-Guericke-Universita ¨ t.

process. At first, an established separation technique (e.g., simulated moving bed chromatography) can be applied to provide a certain enantiomeric excess (ee) (enrichment). Subsequently, preferential crystallization can be used to produce the desired pure enantiomer(s) and the racemic compound as a byproduct. The racemic compound can then be recycled to the enrichment step. Thus, the loss of valuable feedstock can be avoided. In this work, the pharmaceutically interesting system of propranolol hydrochloride enantiomers is studied. Generally, propranolol hydrochloride is a nonselective β-adrenoblocking agent with a broad spectrum of actions. It is used in the treatment of high blood pressure, angina pectoris, prevention of migraine headache, and tumors of the adrenal gland. (S)-Propranolol hydrochloride is approximately 100 times as potent as (R)propranolol hydrochloride in blocking beta adrenergic receptors.12 For (R)-propranolol hydrochloride side effects are reported.13,14 Further, no extensive information is available regarding the enantiospecific toxicity in aquatic systems.12 Propranolol hydrochloride is distributed as a racemic mixture, but for medical applications (R)-propranolol hydrochloride is not necessary and just ballast for the environment. Propranolol hydrochloride was described over a long time as a conglomerate forming system.15-17 However, further publications 14,18 and our own results19 indicate propranolol hydrochloride to belong to the racemic compound forming systems with an eutectic composition of enantiomers of ∼45:55 or ∼55:45, respectively, i.e., eeEut ) ∼10%.19 Polymorphic forms for the racemic compound are known,19-22 but only the desired stable modification was observable during the experiments reported. At first in the following, the ternary systems (R)- and (S)propranolol hydrochloride/water and (R)- and (S)-propranolol hydrochloride/methanol will be characterized by determination of the ternary phase diagrams. The eutectic composition of the enantiomers in the ternary, solvent containing system will be verified. The shape of the solubility isotherms and the metastable solubility lines are discussed. Further, metastable zone width data for both systems will be shown. Subsequently, results of

10.1021/cg0700770 CCC: $37.00 © 2007 American Chemical Society Published on Web 08/17/2007

Separation of Propranolol Hydrochloride Enantiomers

Figure 1. Different phase areas for a racemic compound forming system, presented in a ternary solubility phase diagram (+,- and ( refer to the pure enantiomers and the racemic compound in the solid phase).

Figure 2. Performance of the preferential crystallization process for enantioseparation in a isothermal batch mode (Tc, crystallization temperature, Tsat, temperature of the saturated solution, ∆T, subcooling).10,11

two enantiomeric resolution experiments in the system propranolol hydrochloride/water are presented. Finally, the potential of preferential crystallization to produce the pure enantiomer from partially resolved mixtures of propranolol hydrochloride is demonstrated and critically analyzed. Performance of Preferential Crystallization for Enantioseparation of Racemic Compound Forming Systems in a Batch Mode. Figures 1 and 2 show schematically the ternary solubility phase diagrams of the enantiomers (+)-E and (-)-E of a chiral system in a solvent A. The different possible areas in the phase diagram are illustrated in Figure 1. The performance of the preferential crystallization process for enantioseparation in a isothermal batch mode is shown in Figure 2. The presence of a stable racemic compound (Rac) is characteristic for a racemic compound forming system. In this case, both enantiomers are integrated together into the crystal lattice. Three two-phase regions (white areas) and two threephase regions (gray areas) exist below the solubility isotherm in the ternary phase diagram of racemic compound forming systems (Figure 1). In the two-phase regions, the (+)-enantiomer ((+)-E), the (-)-enantiomer ((-)-E), or the racemic compound (Rac) as stable solid phases and a corresponding liquid phase are in equilibrium. In the two three-phase regions always a saturated solution containing the enantiomers in eutectic com-

Crystal Growth & Design, Vol. 7, No. 9, 2007 1629

position (Eut) and two solid phases consisting of one of the enantiomers ((+)-E or (-)-E) and the racemic compound coexist in equilibrium. Figure 2 shows the performance of preferential crystallization to gain, e.g., the pure (+)-enantiomer ((+)-E) in the case of racemic compound forming systems. The crystallization process starts with a saturated solution of the enantiomers at the temperature Tsat. The initial composition of the enantiomers can (a) correspond to the eutectic line (black dashed line connecting the solvent corner with the eutectic composition in the binary system (+)-E/Rac or (b) exhibit a certain ee (e.g., point A in Figure 2). After the clear solution was cooled down to the crystallization temperature Tc (which should not exceed the metastable zone width to avoid spontaneous nucleation), the solution is supersaturated. This clear solution is seeded with crystals of the pure (+)-enantiomer ((+)-E). Now in the ideal case pure (+)-enantiomer ((+)-E) is crystallized. The ideal crystallization path follows the trajectory line A f B. From the thermodynamic point of view, the crystallization of the (+)enantiomer ((+)-E) is finished at point B. Thus, the virtual crystallization limit is given by the metastable solubility line of the enantiomer, as discussed later. Subsequently, the racemic compound (Rac) nucleates and crystallizes until all supersaturation is consumed and the equilibrium is reached (i.e., point C). Nevertheless, a real crystallization process would run along a curved trajectory A f C. The asymptote is represented by the straight line AB and the final point is C. To identify the optimal crystallization parameters, it is important to know where the process trajectory starts to deviate from the straight line AB to get pure product. Our recent studies10,11 have confirmed the feasibility of preferential crystallization to gain alternating pure enantiomer and the racemic compound for the system mandelic acid in water. To verify the transferability of the results to other systems, i.e., as a “proof of concept”, the application of preferential crystallization to separate the propranolol hydrochloride enantiomers is studied here. The eutectic compositions of the enantiomers in the binary and ternary phase diagrams are essential characteristics for applying preferential crystallization in racemic compound forming systems. In the binary chiral systems mandelic acid and propranolol hydrochloride the eutectic compositions were found to be ∼30:70 and 70:30, respectively10,11,23 and ∼45:55 and ∼55:45, respectively.19 For the ternary systems propranolol hydrochloride in the solvents, these compositions have to be verified in the following. Experimental Procedures Materials. (()-RS-Propranolol hydrochloride ((Rac)-Pr‚HCl), (+)(R)-propranolol hydrochloride ((R)-Pr‚HCl), and (-)-(S)-propranolol hydrochloride ((S)-Pr‚HCl) were supplied from Merck KGaA, Darmstadt, or Aldrich Chemical Co. with purities of >99%. As solvent, methanol (Merck KGaA, Darmstadt) and deionized water were used. Solubility Measurements. For solubility measurements, a classical isothermal method was used. Calculated amounts of the enantiomer, racemic compound, or different mixtures of both were weighed and filled in small glass vessels (5 mL total volume). Definite amounts of solvent, not sufficient to dissolve all the solid, were added with a syringe. The suspensions were stirred at 400 rpm at constant temperature using a thermostated double jacket. After 24 h, the suspensions were filtered. The liquid phases were weighed before and after evaporation at room temperature. The solubility was calculated in weight percent w [wt %] by

w [wt % ] )

mdry - mempty 100 msolution - mempty

(1)

The enantiomeric composition of the equilibrated liquid phases was

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Polenske et al.

analyzed by HPLC using a Chirobiotic T stationary phase (column: 250 × 4.6 mm, 5 µm particles, Astec). As eluent, methanol with 0.1 vol % triethylamine was used. The chromatographic separation was performed at 20 °C and an eluent flow rate of 1 mL/min. The wavelength used was 280 nm. The solid phases of all samples were analyzed by X-ray powder diffraction (diffractometer X’Pert Pro, PANalytical GmbH, Germany; equipped with a high-speed X’Celerator detector) to identify the type of the species and to check the modification. The enantiomeric compositions of the solid phases were also determined by HPLC (method described above). The standard deviations of the solubility data, stdv, and the ideal solubility, xA,7 are calculated according to eqs 2 and 3.

stdv[wt %] )

x

ln(xA) )

Table 1. Averages of Solubility Data of the Pure Enantiomers, Racemic Compound and Eutectic Mixture, Number of Measurements (no.) and Standard Deviations of the Solubility Data (stdv) for Propranolol Hydrochloride in Water Tsat enantiomer stdv Rac stdv Eut stdv [°C] w [wt %] no.a [wt %] w [wt %] no.a [wt %] w[wt %] no.a [wt %] 10 20 25 30 35 40

2.1 2.7 3.0 3.4

22R 31S,2R 31S,2R 41S,3R

6.0

22R

0.0 0.2 0.2

5.2 8.6 11.3 14.4 21.2 27.2

2 7 4 5 3 4

0.8 1.0 0.7 0.9 0.2

5.2 9.5 11.7 15.2

22R 31S,2R 44R 21S,1R

1.2 0.3

27.3

33R

0.4

a

1

Number of measurements together with the enantiomer used (R)-Pr‚HCl or (S)-Pr‚HCl.

n

∑ (w - wj )

2

i

(2)

( )

(3)

n - 1 i)1

∆HfA 1 1 R Tf T A

The melting enthalpy (∆Hf) and the melting temperature (Tf) of the pure compound data (A) are used to calculated the ideal solubilities (xA) for different temperatures (T). Metastable Zone Width Measurements. Metastable zone width data for primary nucleation were determined for racemic propranolol hydrochloride in water and methanol using the polythermal method as described by Nyvlt et al.24 The experiments were performed in a magnetically stirred batch crystallizer of 60 mL volume in a temperature range between 20 and 30 °C. Saturated solutions of about 25 g were used. At different cooling rates, the maximum possible subcooling was determined. Nucleation was detected by an inline-turbidity sensor (QRSystem; BASF AG, Ludwigshafen, Germany) and a Pt-100 temperature sensor. Preferential Crystallization Experiments. Two isothermal preferential crystallization experiments were performed in the crystallizer described above. The crystallization process was monitored by offline HPLC and refractive index measurements. For the experiments, 50 g of the initial solutions according to the solubility data (Tsat ) ∼30.5 °C, wsat ) 15.7 wt %, initial composition (R)-Pr‚HCl/(S)-Pr‚HCl ) ∼55.75/44.25) and the metastable zone width data were prepared. The initial composition of both enantiomers corresponds to the eutectic composition (eeEut ) 10%) with a certain ee ∼ 11.5%, represented by point A in Figure 2. The prepared mixtures of the enantiomers and solvent were heated up to 40 °C. To be sure that all particles are dissolved, the mixtures were maintained about 60 min at that temperature. After the sample was cooled down to the crystallization temperature (TC ) 10 °C), the supersaturation present was 10.5 wt %. At the crystallization temperature, a defined amount of seed crystals (125 mg of (R)-Pr‚HCl, powder, purity > 99%) was added. During the first experiment, several samples of ∼100 mg were withdrawn at definite time intervals to observe the course of the process trajectory and to identify the nucleation time of the counter species (Rac-Pr‚HCl). In the second experiment, performed under the same conditions, further results, such as mass and purity of the product, mass loss, process productivity, and yield, should be gained. No samples were taken, and the process was stopped before nucleation of the counter species (RacPr‚HCl) as obtained from the first experiment. The crystallization product was separated (filter pore size ∼2-12 µm) and washed with 20 mL of ice water to remove the adhering mother liquor. X-ray powder diffraction was applied to identify the solid phase present, and HPLC was used to determine the product purity (methods described above). The two experiments are used to demonstrate the general feasibility, reproducibility, and the potential of preferential crystallization in the propranolol hydrochloride/water system.

Table 2. Averages of Solubility Data of the Pure Enantiomers, Racemic Compound and Eutectic Mixture, Number of Measurements (no.) and Standard Deviations of the Solubility Data (stdv) for Propranolol Hydrochloride in Methanol Tsat enantiomer stdv Rac stdv Eut stdv [°C] w [wt %] no.a [wt %] w [wt %] no.a [wt %] w [wt %] no.a [wt %] 0 10 20 30 40 a

12.6 13.6 16.3 19.4 23.9

2 2 3 2 2

0.4

16.3 20.2 24.4 30.0 36.0

2 4 5 4 5

0.2 0.3 0.8 0.5

17.1 19.5 23.9 29.1 37.9

2 2 3 2 4

0.1 1.7

Number of measurements as enantiomer (R)-Pr‚HCl was always used.

data of the pure enantiomers, racemic compound, and eutectic mixture of propranolol hydrochloride in water and methanol, respectively. In Figure 3 the measured solubility data of the enantiomers and racemic compound are compared with ideal solubilities calculated according to the simplified Schroeder van Laar equation (eq 3). The pure substance data used were f f f ) 37224 J/mol, T(R)-Pr·HCl ) 468 K, ∆H(Rac)-Pr·HCl ∆H(R)-Pr·HCl f ) 36277 J/mol, and T(Rac)-Pr·HCl ) 436 K as determined in previous work.19 In Figures 4 and 5 ternary solubility phase diagrams of (R)and (S)-propranolol hydrochloride in water and methanol are shown. The solubilities in water are significantly lower than those in methanol (Tables 1 and 2, Figures 3-5). In both ternary systems, the solubilities of the pure enantiomers, racemic compound, and eutectic mixture increase with increasing temperature. Generally, for ideal systems the eutectic composi-

Results and Discussion Solubility Data and the Influence of the Shape of the Solubility Isotherms and Corresponding Metastable Solubility Lines on the Preferential Crystallization Process. (a) Solubility Data. Tables 1 and 2 present the results of the solubility measurements and standard deviations of the solubility

Figure 3. Solubility curves of the enantiomer and racemic compound for propranolol hydrochloride in water, methanol and the ideal case as function of the temperature (ideal solubilities calculated after eq 3).

Separation of Propranolol Hydrochloride Enantiomers

Figure 4. Ternary solubility phase diagram for (R)- and (S)-propranolol hydrochloride in water.

Figure 5. Ternary solubility phase diagram for (R)- and (S)-propranolol hydrochloride in methanol. (Only points on the (R)-Pr‚HCl side are shown.)

tion of the enantiomers in the binary and ternary phase diagrams are identical. In previous work,19 the eutectic composition in the binary phase diagram was determined as ∼45:55 and ∼55: 45, respectively. The same composition was found for the ternary system propranolol hydrochloride/water. For the propranolol hydrochloride/methanol system only the solubility isotherms at 0 and 40 °C clearly indicate an eutectic composition at ∼45:55. Solubilities of the racemic compound in water match the ideal solubility curve well (Figure 3). For the enantiomers, the differences in the solubility data compared to the ideal solubility curve increase with increasing temperature. The solubility data in methanol for the enantiomer and racemic compound are higher than in water and thus much higher than the ideal values. The shape of the solubility isotherms for the enantiomers is significantly different in the propranolol hydrochloride/water and propranolol hydrochloride/methanol system (Figures 4 and 5). In water, the solubility isotherms of the enantiomers are steeper than in the methanol system. This behavior is particularly pronounced at higher temperatures. The importance of the shape of the solubility isotherms of the enantiomers and racemic compound for planning of crystallization experiments is discussed later. The standard deviations give a first impression of the error of the solubilities (Tables 1 and 2). The highest standard deviations observed in water and methanol are (1.2 wt % (Table

Crystal Growth & Design, Vol. 7, No. 9, 2007 1631

Figure 6. Course of the metastable solubility lines at different slopes of the solubility isotherms for racemic compound forming systems.

1, eutectic mixture, 20 °C) and (1.7 wt % (Table 2, eutectic mixture, 40 °C). Sometimes the solubility data determined for the eutectic mixture in the propranolol hydrochloride/methanol system were lower than for the racemic compound (Table 2, Figure 5; 10, 20, 30 °C solubility isotherms). This could indicate the presence of a (metastable) conglomerate. Wang et al.17 reported for propranolol hydrochloride a conglomerate forming system in a methanol/acetone mixture (volumetric ratio 1:4.11). However, all solid phase analyses performed confirmed the presence of the racemic compound; a (metastable) conglomerate was never seen. Solubilities determined for compositions close to the eutectic mixture, for example, 20 °C, do not differ sufficiently (Tables 1 and 2, Figures 4 and 5). Taking into account the standard deviations obtained in the solubility measurements (Tables 1 and 2), the solubilities are in the error range. (b) Influence of the Shape of the Solubility Isotherms and Corresponding Metastable Solubility Lines on the Preferential Crystallization Process. The importance of the shape of the solubility isotherms and corresponding metastable solubility lines for preferential crystallization experiments is discussed in the literature for conglomerates7,25 and in the following part for racemic compound forming systems. The metastable solubility lines are the extensions of the solubility isotherms, as shown in Figure 6. Further, the metastable solubility lines are the virtual crystallization limits, and in this way they have a significant influence on the theoretical and practical yield of a preferential crystallization process. For conglomerates, the slope of the solubility isotherms of the enantiomers and thus the corresponding metastable solubility lines can be described with the help of the molar solubility ratio (Rmol) definite as the solubility of the racemic mixture divided by solubility of enantiomers.7,26 High values indicate a big difference between the solubilities of the enantiomer and the racemic mixture; that is, the eutectic mixture and low values characterize the opposite. For a molar solubility ratio (Rmol) higher, equal, and lower than 2 the final composition of the mother liquor for a preferential crystallization of one enantiomer is found generally in the three-phase domain in the ternary phase diagram. Only for a molar solubility ratio (Rmol) significant lower than 2 it was reported that the finally liquid-phase composition can be in the two-phase domain. An example is given by Levillain et al.25 Thus, the highest yields of a preferential crystallization should be obtained at low molar solubility ratios. As shown in Figure 6 for racemic compound forming systems the slope of the solubility isotherms of the enantiomers and

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Polenske et al.

Table 3. Metastable Zone Width Data for the Propranolol Hydrochloride/Methanol and Water Systems methanol

water

Tsat [K]

∆Tmax [K]

∆cmax [wt %]

∆Tmax [K]

∆cmax [wt %]

20 25 30

12 10 7

4 3.5 2.5

>15 >20 >25

>4 >7 >10

corresponding metastable solubility lines can be described similar to the conglomerate case. For solubility isotherms of the enantiomers with a lower slope (black lines) the extension of the solubility isotherms (thus the metastable solubility lines) enter the two-phase domain of the racemic compound; that is, the virtual crystallization limit lies in the two-phase domain of the racemic compound. Consequently, for an enantiomer crystallization it should be possible that the final liquid-phase composition contains the enantiomers in a 50:50 ratio and the complete enantiomeric initial enrichment can be crystallized. Obtaining a mother liquor composition in the two-phase domain is less probable at steeper slopes of the solubility isotherms and eutectic compositions close to an ee of 50% (dark gray lines, Figure 6). In this case the metastable solubility lines enter the three-phase domain. The virtual crystallization limit lies in the three-phase domain of the pure enantiomer and racemic compound. Thus, only a part of the initial enantiomeric enrichment can be crystallized, and low yields are obtained. A cyclic preferential crystallization as shown for the mandelic acid case11 with racemic compound as byproduct would be necessary. According to the shape of the solubility isotherms and the metastable solubility lines for the propranolol hydrochloride enantiomers in the ternary phase diagrams (Figures 4 and 5), at lower temperatures for both solvents the same behavior should be observed. The final mother liquor composition could enter the two-phase domain, and the complete enantiomeric initial enrichment should be crystallized. On the other side, at higher temperatures and for a stronger slope of the solubility isotherms (as it is the case for propranolol hydrochloride in water) the mother liquor composition would enter the three-phase domain. In that case the border between the two- and three-phase region is the maximal final liquid-phase composition that can be reached, represented by point B in Figure 2. Metastable Zone Width Data. In Table 3 the results for the propranolol hydrochloride/methanol and water systems are summarized. It was found that the maximal possible subcooling ∆Tmax and the maximum possible nucleation-free supersaturation ∆cmax of racemic propranolol hydrochloride in methanol decrease with the increase of the temperature. In case of water as solvent ∆Tmax and ∆cmax increase with temperature (Table 3). It was possible to cool down a saturated solution to about 3 °C without observing primary nucleation in the studied temperature range. The fact that the propranolol hydrochloride/water system shows such a wide metastable zone makes this system favorable for preferential crystallization. The maximum possible yield of the pure enantiomer should be significantly higher than in the propranolol hydrochloride/methanol system. Preferential Crystallization Experiments. On the basis of the measured solubility and metastable zone width data first resolution experiments of propranolol hydrochloride in water were planned and performed. The width of the metastable zone in water (Table 3) favors this system for a preferential crystallization compared to the propranolol hydrochloride/ methanol system. Further, at low crystallization temperatures the two-phase domain can be entered, and thus the total initial enrichment might be gained (described above). In Figure 7 the calculated weight percents of both enantiomers

Figure 7. Calculated weight percents of both enantiomers in the liquid phase and the corresponding process trajectory a f b (f c) for both experiments in a quasi-binary phase diagram.

Figure 8. Enantiomeric excess, calculated masses for (R)-Pr‚HCl and (S)-Pr‚HCl as a function of time for the first experiment. The stop time of the repeating experiment 2 is indicated (a,b,c refer to Figure 7).

in the liquid phase and the corresponding process trajectory a f b (f c) for both experiments in a quasi-binary phase diagram are presented. Figure 8 shows the ee and the calculated masses of crystallized (R)-Pr‚HCl and (S)-Pr‚HCl as function of the time for the first crystallization experiment. The ee at the stop time of the repeating experiment 2 is indicated. The initial composition of the enantiomers is marked as point a in Figures 7 and 8. On the basis of the measurement data (HPLC and refractive index data) the concentrations, ee’s, and masses were calculated. After cooling down of the clear solutions and seeding with (R)-Pr‚HCl seed crystals the concentration of (R)-Pr‚HCl in the solution decreased, whereas the concentration of (S)-Pr‚HCl remained constant (Figure 7 a f b). Analogous, the ee decreased to zero (i.e., racemic composition of the enantiomers in the liquid phase), the calculated mass of (R)-Pr‚HCl increased, and the calculated mass of (S)-Pr‚HCl remained almost zero for the first ∼70 h (Figure 8 a f b). At first the eutectic line is crossed (process trajectory Figure 7; ee Figure 8). Later the racemic line is reached (Figures 7 and 8 point b). At the racemic line, the racemic compound nucleated and thus crystallized. Both concentrations decreased

Separation of Propranolol Hydrochloride Enantiomers

(Figure 7 b f c), and the ee and the calculated masses of both enantiomers increased (Figure 8 b f c). In that period of time, the mass of the (S)-Pr‚HCl increased more strongly than the mass of the (R)-Pr‚HCl. This behavior is only explainable when considering simultaneous crystallization of the racemic compound and dissolution of the (R)-enantiomer. The crystallization process runs in the two-phase domain of the racemic compound, where the enantiomer is not stable. This phenomenon was already discussed in the literature for conglomerates25 and in this work (in Figure 6) for racemic compound forming systems. The crystallization process finally reached (after ∼6 days) thermodynamic equilibrium (Figures 7 and 8 point c). From the second experiment, performed under the same conditions as the first, but stopped after about 41 h, that is, shortly before the racemic line was reached (compare Figure 7 and 8), product related characteristics such as the product mass, product purity, mass loss as result of solid/liquid separation, productivity, and yield have been evaluated. The mass of product (gained product mass [g] minus seed mass [g]) was 0.77 g. The product purity was satisfying with a value of 96.4%. A product purity of 100% was not expected since the purity of the seeds was just ∼99%. Further, solid/liquid separation of the very fine product powder could cause adhering mother liquor at the crystal surface and thus lowered purity. A part of the product stuck in the crystallizer and on the filter, which accounted for a mass loss of about 28%. The productivity of the process (mass of product [g]/time [h]‚mass of the solution [kg]) was calculated to be 0.38 g/h‚kg. This value is low due to the long crystallization time. The yield (defined as mass of product [g]/mass of initial enriched enantiomer [g]‚100) of 68% is satisfying and could be close to 95% in the case of an optimized solid/liquid separation. The composition of the mother liquor at the end of the process was 51.2% (R)-Pr‚HCl to 48.8% (S)-Pr‚HCl. This confirms that it is possible to crystallize almost the complete initial enrichment when the crystallization process is stopped before nucleation of the undesired racemic compound. Conclusions The results show that a hybrid process can be an interesting technology for enantioseparation in case of the racemic compound forming system propranolol hydrochloride. It could be shown that preferential crystallization is feasible to gain the pure enantiomer. Thus, the results confirm again the applicability of preferential crystallization for racemic compound forming systems after the proof for the mandelic acid system. Further, it was shown that it is feasible to gain almost complete initial enrichment. It was demonstrated that crystals of pure enantiomer keep crystallizing and remain pure even when entering the twophase (existence) region of the solid racemic compound. There is still a potential of optimizing the preferential crystallization step for propranolol hydrochloride in water. Working at higher temperatures or supersaturations could lead to higher productivities, based on faster crystallization kinetics. A further option could be the application of an autoseeded programmed polythermic preferential crystallization process (AS3PC)27,28 in the propranolol hydrochloride/methanol (or water) system. Significant improvements should be feasible when optimizing the solid/liquid separation. A scale-up without using magnetic stirrers should produce coarser particles and avoid problems in solid/liquid separation. Acknowledgment. The authors thank I. Eyole-Monono, T. Sperlik, J. Kaufmann, and L. Borchert at the Max-Planck-Institut in Magdeburg for the help in the experimental work. Thanks

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are also given to the group of Prof. Gerard Coquerel at University of Rouen for fruitful discussions. The financial support of Max-Buchner-Forschungsstiftung (MBFSt-Kennziffer: 2619) and Fonds der Chemischen Industrie is gratefully acknowledged. Notations Symbols Rmol ) molar solubility ratio, [-] ∆H ) enthalpy change, [J/mol] i ) index m ) mass, [g] n ) number of measurements R ) universal gas constant, 8.314 [J/(mol‚K)] stdv ) standard deviation, [wt %] T ) temperature, [°C] or [K] w ) solubility, weight percent, [wt %] x ) solubility, mole fraction or percent, [mol or mol %] Subscripts, Superscripts A ) pure enantiomer or racemic compound dry ) vessel with dry substance empty ) empty vessel f ) fusion solution ) vessel with filtrate

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