Separation of Propranolol Hydrochloride Enantiomers byPreferential Crystallization: Thermodynamic Basis andExperimental Verification

Daniel Polenske,*,† Heike Lorenz,† and Andreas Seidel-Morgenstern†,‡

Max-Planck-Institut fu¨r Dynamik komplexer technischer Systeme, Magdeburg, Germany, andOtto-Von-Guericke-UniVersitat, 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 pureenantiomers due to the advantage of obtaining directly a solid product and economic considerations. In case of racemic compoundforming systems, a hybrid process may be performed consisting of an established separation technique capable of providing acertain 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. Toevaluate 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 andmethanol are shown and discussed. The eutectic composition of the enantiomers as an important characteristic value could be identifiedas ∼45:55 and∼55:45, respectively. The potential of preferential crystallization to produce the pure enantiomer from partiallyresolved mixtures of (R)- and (S)-propranolol hydrochloride in water is demonstrated.

Introduction

Typically, a 50:50 mixture of both enantiomers is producedduring the chemical synthesis of chiral systems. The resolutionof such a mixture is difficult because the scalar chemical andphysical properties are identical. Interactions with linear polar-ized light and other chiral substances are the exceptions. Theimportance and the application ranges of enantioseparationincrease continuously in the pharmaceutical, agricultural, andfood industries.1,2 Since 1990, the portion of traded pureenantiomer drugs exceeds the portion of racemic mixtures.3

Well-known technologies to separate racemic mixtures arepreparative chromatography, enzymatic resolution, crystalliza-tion via the formation of diastereomeric salts, and preferentialcrystallization.2 Further possibilities to separate enantiomers aresupramolecular complexation with chiral molecules,4 the ap-plication of molecularly imprinted polymeric membranes,5 andthe use of optically active solvents.6

Preferential crystallization is an attractive technology toproduce pure enantiomers due to economic considerations andthe advantage of obtaining directly a solid product.7,8 However,the direct crystallization of pure enantiomers from racemicsolutions is limited to conglomerates (5-10% of all chiralsystems).9 Unfortunately, the major part of the chiral substancesbelongs to the racemic compound forming systems. In this case,a preferential crystallization might be performed in the twothree-phase regions of the ternary phase diagram. A firstconformation 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 cyclicoperation mode were given.

In the case of racemic compound forming systems, thepreferential crystallization step can be integrated in a hybrid

process. At first, an established separation technique (e.g.,simulated moving bed chromatography) can be applied toprovide a certain enantiomeric excess (ee) (enrichment). Sub-sequently, preferential crystallization can be used to producethe desired pure enantiomer(s) and the racemic compound as abyproduct. The racemic compound can then be recycled to theenrichment step. Thus, the loss of valuable feedstock can beavoided.

In this work, the pharmaceutically interesting system ofpropranolol hydrochloride enantiomers is studied. Generally,propranolol hydrochloride is a nonselectiveâ-adrenoblockingagent with a broad spectrum of actions. It is used in the treatmentof high blood pressure, angina pectoris, prevention of migraineheadache, and tumors of the adrenal gland. (S)-Propranololhydrochloride is approximately 100 times as potent as (R)-propranolol hydrochloride in blocking beta adrenergic recep-tors.12 For (R)-propranolol hydrochloride side effects arereported.13,14 Further, no extensive information is availableregarding the enantiospecific toxicity in aquatic systems.12

Propranolol hydrochloride is distributed as a racemic mixture,but for medical applications (R)-propranolol hydrochloride isnot necessary and just ballast for the environment. Propranololhydrochloride was described over a long time as a conglomerateforming system.15-17 However, further publications14,18and ourown results19 indicate propranolol hydrochloride to belong tothe racemic compound forming systems with an eutecticcomposition of enantiomers of∼45:55 or∼55:45, respectively,i.e., eeEut ) ∼10%.19 Polymorphic forms for the racemiccompound are known,19-22 but only the desired stable modifica-tion was observable during the experiments reported.

At first in the following, the ternary systems (R)- and (S)-propranolol hydrochloride/water and (R)- and (S)-propranololhydrochloride/methanol will be characterized by determinationof the ternary phase diagrams. The eutectic composition of theenantiomers in the ternary, solvent containing system will beverified. The shape of the solubility isotherms and the metastablesolubility lines are discussed. Further, metastable zone widthdata for both systems will be shown. Subsequently, results of

* To whom correspondence should be addressed. Address: Max-Planck-Institut fur Dynamik komplexer technischer Systeme, Sandtorstrasse 1,D-39106 Magdeburg, Germany. Phone: (0049) 391-6110-283. Fax: (0049)391-6110-617. E-mail: polenske@mpi-magdeburg.mpg.de.

† Max-Planck-Institut fu¨r Dynamik komplexer technischer Systeme.‡ Otto-von-Guericke-Universita¨t.

CRYSTALGROWTH& DESIGN

2007VOL.7,NO.9

1628-1634

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

two enantiomeric resolution experiments in the system propra-nolol hydrochloride/water are presented. Finally, the potentialof preferential crystallization to produce the pure enantiomerfrom partially resolved mixtures of propranolol hydrochlorideis demonstrated and critically analyzed.

Performance of Preferential Crystallization for Enantio-separation of Racemic Compound Forming Systems in aBatch Mode. Figures 1 and 2 show schematically the ternarysolubility phase diagrams of the enantiomers (+)-E and (-)-Eof a chiral system in a solvent A. The different possible areasin the phase diagram are illustrated in Figure 1. The performanceof the preferential crystallization process for enantioseparationin a isothermal batch mode is shown in Figure 2.

The presence of a stable racemic compound (Rac) ischaracteristic for a racemic compound forming system. In thiscase, both enantiomers are integrated together into the crystallattice. Three two-phase regions (white areas) and two three-phase regions (gray areas) exist below the solubility isothermin the ternary phase diagram of racemic compound formingsystems (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 phaseare in equilibrium. In the two three-phase regions always asaturated solution containing the enantiomers in eutectic com-

position (Eut) and two solid phases consisting of one of theenantiomers ((+)-E or (-)-E) and the racemic compound coexistin equilibrium.

Figure 2 shows the performance of preferential crystallizationto gain, e.g., the pure (+)-enantiomer ((+)-E) in the case ofracemic compound forming systems. The crystallization processstarts with a saturated solution of the enantiomers at thetemperatureTsat. The initial composition of the enantiomers can(a) correspond to the eutectic line (black dashed line connectingthe solvent corner with the eutectic composition in the binarysystem (+)-E/Rac or (b) exhibit a certain ee (e.g., point A inFigure 2). After the clear solution was cooled down to thecrystallization temperatureTc (which should not exceed themetastable zone width to avoid spontaneous nucleation), thesolution is supersaturated. This clear solution is seeded withcrystals of the pure (+)-enantiomer ((+)-E). Now in the idealcase pure (+)-enantiomer ((+)-E) is crystallized. The idealcrystallization path follows the trajectory line Af B. Fromthe thermodynamic point of view, the crystallization of the (+)-enantiomer ((+)-E) is finished at point B. Thus, the virtualcrystallization limit is given by the metastable solubility lineof the enantiomer, as discussed later. Subsequently, the racemiccompound (Rac) nucleates and crystallizes until all supersatu-ration is consumed and the equilibrium is reached (i.e., pointC). Nevertheless, a real crystallization process would run alonga curved trajectory Af C. The asymptote is represented bythe straight line AB and the final point is C. To identify theoptimal crystallization parameters, it is important to know wherethe process trajectory starts to deviate from the straight line ABto get pure product. Our recent studies10,11 have confirmed thefeasibility of preferential crystallization to gain alternating pureenantiomer and the racemic compound for the system mandelicacid in water. To verify the transferability of the results to othersystems, i.e., as a “proof of concept”, the application ofpreferential crystallization to separate the propranolol hydro-chloride enantiomers is studied here. The eutectic compositionsof the enantiomers in the binary and ternary phase diagramsare essential characteristics for applying preferential crystal-lization in racemic compound forming systems. In the binarychiral systems mandelic acid and propranolol hydrochloride theeutectic compositions were found to be∼30:70 and 70:30,respectively10,11,23and∼45:55 and∼55:45, respectively.19 Forthe 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)-propranololhydrochloride ((S)-Pr‚HCl) were supplied from Merck KGaA, Darm-stadt, 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 classicalisothermal method was used. Calculated amounts of the enantiomer,racemic compound, or different mixtures of both were weighed andfilled in small glass vessels (5 mL total volume). Definite amounts ofsolvent, not sufficient to dissolve all the solid, were added with asyringe. The suspensions were stirred at 400 rpm at constant temperatureusing a thermostated double jacket. After 24 h, the suspensions werefiltered. The liquid phases were weighed before and after evaporationat room temperature. The solubility was calculated in weight percentw [wt %] by

The enantiomeric composition of the equilibrated liquid phases was

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

Figure 2. Performance of the preferential crystallization process forenantioseparation in a isothermal batch mode (Tc, crystallizationtemperature,Tsat, temperature of the saturated solution,∆T, subcool-ing).10,11

w [wt % ] )mdry - mempty

msolution- mempty100 (1)

Separation of Propranolol Hydrochloride Enantiomers Crystal Growth & Design, Vol. 7, No. 9, 20071629

analyzed by HPLC using a Chirobiotic T stationary phase (column:250 × 4.6 mm, 5µm particles, Astec). As eluent, methanol with 0.1vol % triethylamine was used. The chromatographic separation wasperformed at 20°C and an eluent flow rate of 1 mL/min. Thewavelength used was 280 nm. The solid phases of all samples wereanalyzed by X-ray powder diffraction (diffractometer X’Pert Pro,PANalytical GmbH, Germany; equipped with a high-speed X’Celeratordetector) to identify the type of the species and to check themodification. The enantiomeric compositions of the solid phases werealso determined by HPLC (method described above).

The standard deviations of the solubility data, stdv, and the idealsolubility, xA,7 are calculated according to eqs 2 and 3.

The melting enthalpy (∆Hf) and the melting temperature (Tf) of thepure compound data (A) are used to calculated the ideal solubilities(xA) for different temperatures (T).

Metastable Zone Width Measurements.Metastable zone widthdata for primary nucleation were determined for racemic propranololhydrochloride in water and methanol using the polythermal method asdescribed by Nyvlt et al.24 The experiments were performed in amagnetically stirred batch crystallizer of 60 mL volume in a temperaturerange between 20 and 30°C. Saturated solutions of about 25 g wereused. At different cooling rates, the maximum possible subcooling wasdetermined. Nucleation was detected by an inline-turbidity sensor (QR-System; BASF AG, Ludwigshafen, Germany) and a Pt-100 temperaturesensor.

Preferential Crystallization Experiments. Two isothermal pref-erential crystallization experiments were performed in the crystallizerdescribed above. The crystallization process was monitored by offlineHPLC and refractive index measurements. For the experiments, 50 gof 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. Theinitial composition of both enantiomers corresponds to the eutecticcomposition (eeEut ) 10%) with a certain ee∼ 11.5%, represented bypoint A in Figure 2. The prepared mixtures of the enantiomers andsolvent were heated up to 40°C. To be sure that all particles aredissolved, the mixtures were maintained about 60 min at that temper-ature. After the sample was cooled down to the crystallizationtemperature (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 werewithdrawn at definite time intervals to observe the course of the processtrajectory 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, processproductivity, and yield, should be gained. No samples were taken, andthe process was stopped before nucleation of the counter species (Rac-Pr‚HCl) as obtained from the first experiment. The crystallizationproduct was separated (filter pore size∼2-12 µm) and washed with20 mL of ice water to remove the adhering mother liquor. X-ray powderdiffraction was applied to identify the solid phase present, and HPLCwas 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 thepropranolol hydrochloride/water system.

Results and Discussion

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

data of the pure enantiomers, racemic compound, and eutecticmixture of propranolol hydrochloride in water and methanol,respectively.

In Figure 3 the measured solubility data of the enantiomersand racemic compound are compared with ideal solubilitiescalculated according to the simplified Schroeder van Laarequation (eq 3). The pure substance data used were∆H(R)-Pr·HCl

f ) 37224 J/mol,T(R)-Pr·HClf ) 468 K, ∆H(Rac)-Pr·HCl

f

) 36277 J/mol, andT(Rac)-Pr·HClf ) 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 areshown.

The solubilities in water are significantly lower than thosein methanol (Tables 1 and 2, Figures 3-5). In both ternarysystems, the solubilities of the pure enantiomers, racemiccompound, and eutectic mixture increase with increasingtemperature. Generally, for ideal systems the eutectic composi-

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[°C]

enantiomerw [wt %] no.a

stdv[wt %]

Racw [wt %] no.a

stdv[wt %]

Eutw[wt %] no.a

stdv[wt %]

10 2.1 22R 5.2 2 5.2 22R

20 2.7 31S,2R 0.0 8.6 7 0.8 9.5 31S,2R 1.225 3.0 31S,2R 0.2 11.3 4 1.0 11.7 44R 0.330 3.4 41S,3R 0.2 14.4 5 0.7 15.2 21S,1R

35 21.2 3 0.940 6.0 22R 27.2 4 0.2 27.3 33R 0.4

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

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[°C]

enantiomerw [wt %] no.a

stdv[wt %]

Racw [wt %] no.a

stdv[wt %]

Eutw [wt %] no.a

stdv[wt %]

0 12.6 2 16.3 2 17.1 210 13.6 2 20.2 4 0.2 19.5 220 16.3 3 0.4 24.4 5 0.3 23.9 3 0.130 19.4 2 30.0 4 0.8 29.1 240 23.9 2 36.0 5 0.5 37.9 4 1.7

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

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

stdv[wt %] ) x 1

n - 1∑i)1

n

(wi - wj )2 (2)

ln(xA) )∆HA

f

R ( 1

TAf

- 1T) (3)

1630 Crystal Growth & Design, Vol. 7, No. 9, 2007 Polenske et al.

tion of the enantiomers in the binary and ternary phase diagramsare identical. In previous work,19 the eutectic composition inthe binary phase diagram was determined as∼45:55 and∼55:45, respectively. The same composition was found for theternary system propranolol hydrochloride/water. For the pro-pranolol hydrochloride/methanol system only the solubilityisotherms at 0 and 40°C clearly indicate an eutectic compositionat ∼45:55.

Solubilities of the racemic compound in water match the idealsolubility curve well (Figure 3). For the enantiomers, thedifferences in the solubility data compared to the ideal solubilitycurve increase with increasing temperature. The solubility datain methanol for the enantiomer and racemic compound arehigher than in water and thus much higher than the ideal values.The shape of the solubility isotherms for the enantiomers issignificantly different in the propranolol hydrochloride/waterand propranolol hydrochloride/methanol system (Figures 4 and5). In water, the solubility isotherms of the enantiomers aresteeper than in the methanol system. This behavior is particularlypronounced at higher temperatures. The importance of the shapeof the solubility isotherms of the enantiomers and racemiccompound for planning of crystallization experiments is dis-cussed later.

The standard deviations give a first impression of the errorof the solubilities (Tables 1 and 2). The highest standarddeviations observed in water and methanol are(1.2 wt % (Table

1, eutectic mixture, 20°C) and(1.7 wt % (Table 2, eutecticmixture, 40°C). Sometimes the solubility data determined forthe eutectic mixture in the propranolol hydrochloride/methanolsystem were lower than for the racemic compound (Table 2,Figure 5; 10, 20, 30°C solubility isotherms). This could indicatethe presence of a (metastable) conglomerate. Wang et al.17

reported for propranolol hydrochloride a conglomerate formingsystem in a methanol/acetone mixture (volumetric ratio 1:4.11).However, all solid phase analyses performed confirmed thepresence of the racemic compound; a (metastable) conglomeratewas never seen. Solubilities determined for compositions closeto the eutectic mixture, for example, 20°C, do not differsufficiently (Tables 1 and 2, Figures 4 and 5). Taking intoaccount the standard deviations obtained in the solubilitymeasurements (Tables 1 and 2), the solubilities are in the errorrange.

(b) Influence of the Shape of the Solubility Isotherms andCorresponding Metastable Solubility Lines on the Prefer-ential Crystallization Process.The importance of the shapeof the solubility isotherms and corresponding metastable solubil-ity lines for preferential crystallization experiments is discussedin the literature for conglomerates7,25 and in the following partfor racemic compound forming systems. The metastable solubil-ity lines are the extensions of the solubility isotherms, as shownin Figure 6. Further, the metastable solubility lines are the virtualcrystallization limits, and in this way they have a significantinfluence on the theoretical and practical yield of a preferentialcrystallization process.

For conglomerates, the slope of the solubility isotherms ofthe enantiomers and thus the corresponding metastable solubilitylines can be described with the help of the molar solubility ratio(Rmol) definite as the solubility of the racemic mixture dividedby solubility of enantiomers.7,26 High values indicate a bigdifference between the solubilities of the enantiomer and theracemic mixture; that is, the eutectic mixture and low valuescharacterize the opposite. For a molar solubility ratio (Rmol)higher, equal, and lower than 2 the final composition of themother liquor for a preferential crystallization of one enantiomeris found generally in the three-phase domain in the ternary phasediagram. Only for a molar solubility ratio (Rmol) significant lowerthan 2 it was reported that the finally liquid-phase compositioncan be in the two-phase domain. An example is given byLevillain et al.25 Thus, the highest yields of a preferentialcrystallization should be obtained at low molar solubility ratios.

As shown in Figure 6 for racemic compound forming systemsthe slope of the solubility isotherms of the enantiomers and

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

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

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

Separation of Propranolol Hydrochloride Enantiomers Crystal Growth & Design, Vol. 7, No. 9, 20071631

corresponding metastable solubility lines can be describedsimilar to the conglomerate case. For solubility isotherms ofthe enantiomers with a lower slope (black lines) the extensionof 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 ofthe racemic compound. Consequently, for an enantiomercrystallization it should be possible that the final liquid-phasecomposition contains the enantiomers in a 50:50 ratio and thecomplete enantiomeric initial enrichment can be crystallized.Obtaining a mother liquor composition in the two-phase domainis less probable at steeper slopes of the solubility isotherms andeutectic compositions close to an ee of 50% (dark gray lines,Figure 6). In this case the metastable solubility lines enter thethree-phase domain. The virtual crystallization limit lies in thethree-phase domain of the pure enantiomer and racemiccompound. Thus, only a part of the initial enantiomericenrichment can be crystallized, and low yields are obtained. Acyclic preferential crystallization as shown for the mandelic acidcase11 with racemic compound as byproduct would be necessary.

According to the shape of the solubility isotherms and themetastable solubility lines for the propranolol hydrochlorideenantiomers in the ternary phase diagrams (Figures 4 and 5), atlower temperatures for both solvents the same behavior shouldbe observed. The final mother liquor composition could enterthe two-phase domain, and the complete enantiomeric initialenrichment should be crystallized. On the other side, at highertemperatures and for a stronger slope of the solubility isotherms(as it is the case for propranolol hydrochloride in water) themother liquor composition would enter the three-phase domain.In that case the border between the two- and three-phase regionis the maximal final liquid-phase composition that can bereached, represented by point B in Figure 2.

Metastable Zone Width Data.In Table 3 the results for thepropranolol hydrochloride/methanol and water systems aresummarized. It was found that the maximal possible subcooling∆Tmaxand the maximum possible nucleation-free supersaturation∆cmax of racemic propranolol hydrochloride in methanoldecrease with the increase of the temperature. In case of wateras solvent∆Tmax and ∆cmax increase with temperature (Table3). It was possible to cool down a saturated solution to about 3°C without observing primary nucleation in the studied tem-perature range. The fact that the propranolol hydrochloride/watersystem shows such a wide metastable zone makes this systemfavorable for preferential crystallization. The maximum possibleyield of the pure enantiomer should be significantly higher thanin the propranolol hydrochloride/methanol system.

Preferential Crystallization Experiments. On the basis ofthe measured solubility and metastable zone width data firstresolution experiments of propranolol hydrochloride in waterwere planned and performed. The width of the metastable zonein water (Table 3) favors this system for a preferentialcrystallization compared to the propranolol hydrochloride/methanol system. Further, at low crystallization temperaturesthe two-phase domain can be entered, and thus the total initialenrichment might be gained (described above).

In Figure 7 the calculated weight percents of both enantiomers

in the liquid phase and the corresponding process trajectory af b (f c) for both experiments in a quasi-binary phase diagramare presented.

Figure 8 shows the ee and the calculated masses of crystal-lized (R)-Pr‚HCl and (S)-Pr‚HCl as function of the time for thefirst crystallization experiment. The ee at the stop time of therepeating experiment 2 is indicated.

The initial composition of the enantiomers is marked as pointa in Figures 7 and 8. On the basis of the measurement data(HPLC and refractive index data) the concentrations, ee’s, andmasses were calculated. After cooling down of the clearsolutions and seeding with (R)-Pr‚HCl seed crystals the con-centration of (R)-Pr‚HCl in the solution decreased, whereas theconcentration of (S)-Pr‚HCl remained constant (Figure 7 afb). Analogous, the ee decreased to zero (i.e., racemic composi-tion of the enantiomers in the liquid phase), the calculated massof (R)-Pr‚HCl increased, and the calculated mass of (S)-Pr‚HClremained almost zero for the first∼70 h (Figure 8 af b). Atfirst the eutectic line is crossed (process trajectory Figure 7;ee Figure 8). Later the racemic line is reached (Figures 7and 8 point b). At the racemic line, the racemic compoundnucleated and thus crystallized. Both concentrations decreased

Table 3. Metastable Zone Width Data for the PropranololHydrochloride/Methanol and Water Systems

methanol water

Tsat [K] ∆Tmax[K] ∆cmax[wt %] ∆Tmax[K] ∆cmax [wt %]

20 12 4 >15 >425 10 3.5 >20 >730 7 2.5 >25 >10

Figure 7. Calculated weight percents of both enantiomers in the liquidphase and the corresponding process trajectory af b (f c) for bothexperiments 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 timeof the repeating experiment 2 is indicated (a,b,c refer to Figure 7).

1632 Crystal Growth & Design, Vol. 7, No. 9, 2007 Polenske et al.

(Figure 7 bf c), and the ee and the calculated masses of bothenantiomers increased (Figure 8 bf c). In that period of time,the mass of the (S)-Pr‚HCl increased more strongly than themass of the (R)-Pr‚HCl. This behavior is only explainable whenconsidering simultaneous crystallization of the racemic com-pound and dissolution of the (R)-enantiomer. The crystallizationprocess runs in the two-phase domain of the racemic compound,where the enantiomer is not stable. This phenomenon wasalready discussed in the literature for conglomerates25 and inthis 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 sameconditions as the first, but stopped after about 41 h, that is,shortly before the racemic line was reached (compare Figure 7and 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. Theproduct purity was satisfying with a value of 96.4%. A productpurity of 100% was not expected since the purity of the seedswas just∼99%. Further, solid/liquid separation of the very fineproduct powder could cause adhering mother liquor at the crystalsurface and thus lowered purity. A part of the product stuck inthe crystallizer and on the filter, which accounted for a massloss of about 28%. The productivity of the process (mass ofproduct [g]/time [h]‚mass of the solution [kg]) was calculatedto be 0.38 g/h‚kg. This value is low due to the long crystal-lization time. The yield (defined as mass of product [g]/massof initial enriched enantiomer [g]‚100) of 68% is satisfying andcould be close to 95% in the case of an optimized solid/liquidseparation. The composition of the mother liquor at the end ofthe process was 51.2% (R)-Pr‚HCl to 48.8% (S)-Pr‚HCl. Thisconfirms that it is possible to crystallize almost the completeinitial enrichment when the crystallization process is stoppedbefore nucleation of the undesired racemic compound.

Conclusions

The results show that a hybrid process can be an interestingtechnology for enantioseparation in case of the racemic com-pound forming system propranolol hydrochloride. It could beshown that preferential crystallization is feasible to gain the pureenantiomer. Thus, the results confirm again the applicability ofpreferential crystallization for racemic compound formingsystems after the proof for the mandelic acid system. Further,it was shown that it is feasible to gain almost complete initialenrichment. It was demonstrated that crystals of pure enantiomerkeep crystallizing and remain pure even when entering the two-phase (existence) region of the solid racemic compound.

There is still a potential of optimizing the preferentialcrystallization step for propranolol hydrochloride in water.Working at higher temperatures or supersaturations could leadto higher productivities, based on faster crystallization kinetics.A further option could be the application of an autoseededprogrammed polythermic preferential crystallization process(AS3PC)27,28 in the propranolol hydrochloride/methanol (orwater) system. Significant improvements should be feasiblewhen optimizing the solid/liquid separation. A scale-up withoutusing magnetic stirrers should produce coarser particles andavoid problems in solid/liquid separation.

Acknowledgment. The authors thank I. Eyole-Monono, T.Sperlik, J. Kaufmann, and L. Borchert at the Max-Planck-Institutin Magdeburg for the help in the experimental work. Thanks

are also given to the group of Prof. Gerard Coquerel atUniversity of Rouen for fruitful discussions. The financialsupport of Max-Buchner-Forschungsstiftung (MBFSt-Ken-nziffer: 2619) and Fonds der Chemischen Industrie is gratefullyacknowledged.

Notations

Symbols

Rmol ) molar solubility ratio, [-]∆H ) enthalpy change, [J/mol]i ) indexm ) mass, [g]n ) number of measurementsR ) 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 compounddry ) vessel with dry substanceempty) empty vesself ) fusionsolution) vessel with filtrate

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