Investigation of a Chiral Additive Used in Preferential Crystallization

Article pubs.acs.org/crystal

Investigation of a Chiral Additive Used in Preferential Crystallization Linzhu Gou,*,† Heike Lorenz,*,† and Andreas Seidel-Morgenstern†,‡ †

Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstrasse 1, D-39106 Magdeburg, Germany Otto-von-Guericke-University, Department of Chemical Engineering, Universitätsplatz 2, D-39106 Magdeburg, Germany

‡

ABSTRACT: It has been observed in a previous study that small amounts of the chiral substance hydroquinine-4-methyl-2-quinolylether (HMQ) increased the yield of the preferential crystallization processes of (+)-(S)-mandelic acid without contaminating the solid product. In this work, systematic investigations were performed to verify the influence of HMQ on the nucleation and crystal growth of mandelic acid. It has been found that HMQ inhibits both primary nucleation of the enantiomer and the racemate. Besides, it leads to a retarded crystal growth rate of the enantiomer with an increased amount of HMQ. Further, a series of preferential crystallization runs with varied HMQ amounts were conducted, and the enhancement of the yield was quantitatively evaluated. Different from common cases, the additive suppresses primary nucleation of both enantiomers and the racemate.

1. INTRODUCTION Besides the direct chiral resolution of racemic conglomerates,1 preferential crystallization is also a cost-effective method for the purification of enantiomers from slightly enriched solutions of racemic compound-forming systems.2,3 The latter application makes this method attractive to complement other separation processes which are limited in achieving high enrichments with acceptable concentrations. The combination with a subsequent preferential crystallization step allows an efficient production of pure enantiomer crystals. Since racemic compound-forming substances represent the majority (90−95%) of all chiral substances,4 it is of great importance to develop new methods which separate cost-efficiently this class of racemates into enantiomers. The above-mentioned hybrid concept, combining preferential crystallization with a pre-enrichment process, is a promising approach, since crystallization processes are cheap and highly selective. In our previous work,5 membrane separation has been proven to be a possible first resolution step supplying an enantiomeric enrichment by exploiting the presence of chiral selectors. A remarkable phenomenon was discovered in parallel: the presence of a small amount of the chiral selector used in the membrane step, hydroquinine-4-methyl-2-quinolylether (hereafter HMQ), also increased the yield of enantiopure mandelic acid crystals (MA) in preferential crystallization. The chemical structures of HMQ and MA are presented in Figure 1. A systematic study of applying additives for preferential crystallization was undertaken by Addadi et al.6 Based on the theory of “tailor-made additives”,6,7 his group searched in the literature for kinetic resolutions of racemic conglomerates performed in the presence of chiral additives and found a number of examples, such as the separation of glutamic acid, aspartic acid, and γ-methyl glutamate from their racemic solutions with the enantiomers of malic acid or asparagine as additive, which fit the “rule of reversal”. According to this rule, © 2012 American Chemical Society

the stereochemical structural similarity of the additive to the undesired enantiomer is responsible for the enhancement of yield, since the additive can be adsorbed on the surface of the undesired enantiomer cluster and thus suppresses its nucleation and crystal growth. This type of additive was later applied to enhance the yield of selective crystallization of racemic compound-forming systems.8,9 Addadi also mentioned that there may exist a variety of other mechanisms of additives in preferential crystallization processes, such as chiral solvent effects or ligand exchange interactions.6 Since the effect of enhanced yield is of great interest for optimization of the preferential crystallization process, the influence of HMQ on the preferential crystallization of mandelic acid is investigated systematically in this work. To plan a crystallization process, solubility data of the mandelic acid/water system in the presence of HMQ are essential. The phase diagram of mandelic acid in pure water has been published in a previous work.10 Adding different amounts of HMQ leads to an increase of solubility which was below 10% of the corresponding pure water value; the new phase diagram is used in this work, and the details are not given here. The preferential crystallization process has been described in several references; in particular, Jacques et al. and Collins et al. have given a comprehensive review about this kinetically controlled process.4,11 The driving force for preferential crystallization is usually generated by cooling the solution. After seeding, the solution composition exceeds normally the metastable limit of the secondary nucleation of the desired enantiomer but is still within the metastable range of the primary nucleation of the counter-species. This leads to nucleation and crystal growth of only the desired seeded Received: January 12, 2012 Revised: September 9, 2012 Published: September 12, 2012 5197

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Figure 1. Chemical structures of hydroquinine-4-methyl-2-quinolylether and mandelic acid enantiomers.

enantiomer. Shortly before the metastable zone of primary nucleation of the counter-species is exceeded, the process must be stopped; otherwise, the product will be contaminated with the counter-species (in our case, racemic mandelic acid). Since preferential crystallization comprises events of nucleation and crystal growth, in the first part of this work, the influence of HMQ on both mechanisms will be investigated respectively. Afterward, various amounts of HMQ are applied in preferential crystallization processes to quantitatively evaluate its impact and effectiveness on the overall process.

2. CHEMICALS (+)-(S)-Mandelic acid (S-MA), (−)-(R)-mandelic acid (RMA), and (R,S)-mandelic acid (RS-MA) with purities >99% were purchased from Merck Darmstadt, Germany. Hydroquinine-4-methyl-2-quinolylether (HMQ) with purity >99% was obtained from Sigma-Aldrich, Germany. All substances were directly used in experiments without further purification.

Figure 2. Schematic representation of the experimental setup to measure the growth rate of single (+)-(S)-mandelic acid crystals.

3. EXPERIMENTS

T2, while vessel 1 was set at a lower temperature T1. The growth cell was steadily set at the equivalent temperature of T1. The solution was pumped from vessel 2 to vessel 1 to create a supersaturated S-MA solution as a condition for crystal growth. The degree of supersaturation was modified by adjusting temperatures T1 and T2. It is defined as S = C/Ceq, where C represents the saturation concentration of the solution in vessel 2 and Ceq the saturation concentration in both vessel 1 and the grow cell. To start the experiment, the supersaturated solution was continuously pumped from vessel 1 to the growth cell, in which a single S-MA crystal was glued on the pin head of a crystal holder, to promote the growth of this single crystal. Afterward, the solution was transported back to vessel 2 in order to compensate the mandelic acid consumed by crystal growth. In this way, a stable degree of supersaturation was guaranteed during the whole process. The growth of the fixed crystal was followed by taking pictures using a microscope (type Stemi2000C, company Carl Zeiss) every hour. 3.3. Application of HMQ during Preferential Crystallization. Pure enantiomers can be obtained from an enantiomerically enriched supersaturated solution under certain conditions by providing seeds of the same enantiomer. Preferential crystallization has been recently verified to be a promising process to gain enantiopure crystals from racemic compound-forming systems.12 To qualify and quantify the effect of HMQ as an additive for this process, different amounts of HMQ were added to the starting solution. The enantiomeric excesses of the initial solutions were fixed at 43 ee %, i.e. slightly above the composition of the polysaturated solution characterized by a value of 40 ee%. The start temperature was chosen as 30 °C. Since the maximum solubility of HMQ in a 33% wt aqueous polysaturated mandelic acid solution at 30 °C is around 1 wt %, the HMQ amount was increased step by step from 0 up to 1 wt % in altogether seven runs. The experimental conditions are summarized in Table 2. The solutions were kept at 30 °C at the beginning of the runs (t = 0 min) until all solids were dissolved. Then the solutions were cooled down to 28.5 °C, reaching a supersaturated state. After stabilizing for

3.1. Investigation of the Influence of HMQ on Mandelic Acid Nucleation. To reveal the influence of HMQ on primary nucleation, 10 mL of saturated solutions of S-MA, R-MA, and RS-MA in water were prepared at 20 °C, respectively. These solutions were afterward cooled down with a rate of −6 K/h to a minimum temperature of 2 °C. The onset of the nucleation shower was detected with a turbidity probe, and the corresponding temperature at which the nucleation took place was documented. To enhance the reliability of the results, each experiment was repeated 10 times. The same procedure was then conducted in the presence of 0.1 wt % HMQ, keeping the other conditions constant. The change of solubility of mandelic acid in water caused by the addition of 0.1 wt % HMQ is slight and can thus be neglected. 3.2. Investigation of the Influence of HMQ on the Crystal Growth Rate. Crystal growth is essential for preferential crystallization, since the added seeds and formed nuclei of the desired enantiomer grow in the supersaturated solution. The growth rate of single S-MA crystals was measured in the presence of varied concentrations of HMQ and for varied supersaturation degrees. The detailed experimental conditions are summarized in Table 1. The experimental setup used for investigating growth rate is illustrated in Figure 2. The two vessels and the growth cell are double jacketed, enabling the regulation of temperature by circulated water provided by thermostats. Vessel 2 contained a saturated solution at temperature

Table 1. Experimental Conditions To Study the Influence of HMQ on Crystal Growth (Degree of Supersaturation and Concentration of HMQ) deg supersat S [−] 1.06 1.11

concentration of HMQ [wt %] 0 0

0.07 0.07

0.14 0.14 5198

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4.2. Influence of HMQ on the Crystal Growth Rate. The arising question now is whether HMQ influences the crystal growth rate of the seeded enantiomer. Therefore, growth rates were determined in single crystal experiments by measuring the change in outer crystal dimensions at a certain time interval. Since a single S-MA crystal exhibits a hexagonal shape, an average growth rate of the crystal can be defined as the mean value of the growth rates of six normals as shown in Figure 3.

Table 2. Conditions of Preferential Crystallization Runs with Varied HMQ Amounts run

msolution [g]

wHMQ [wt %]

wmandelic acid [wt %]

eeinitial solution [%]

1 2 3 4 5 6 7

200 200 200 200 200 200 200

0 0.1 0.2 0.3 0.4 0.5 1

33 33 33 33 33 33 33

43 43 43 43 43 43 43

10 min, the seeds were introduced (4.8 g of ground S-MA with a mean maximum Feret diameter of 200 μm measured via light microscopy). As far as seeded (t = 10 min), the cooling program was started with a rate of −6 K/h to generate an additional driving force for crystallization. Cooling was applied until 4 °C to observe the occurrence of primary nucleation of the counter-species. Offline refractometry was used to provide the concentrations of the mother liquor at certain time intervals, and offline HPLC analysis was used to provide the corresponding enantiomeric composition (column: Chirobiotic T, 250 mm × 4.6 mm, 5 μm particles, Astec, USA; eluent composition: 1% TEAA/methanol (80/20, v/v) at pH = 4). Also, focused beam reflectance measurement (FBRM, Mettler Toledo, USA) was used to follow crystallization events.

Figure 3. Determination of the crystal growth rate.

Due to the fact of growth rate dispersion, every experiment was repeated at least five times to gain a reliable result. The mean crystal growth rates for different conditions determined are presented in Table 4.

4. RESULTS AND DISCUSSION 4.1. Influence of HMQ on the Primary Nucleation of Mandelic Acid. Without HMQ, significant turbidity signals were detected during cooling of the three solutions (S-, R-, and RS-MA) due to primary nucleation. The results are summarized in Table 3 using the degree of supersaturation S = C0/Ceq as

Table 4. Mean Crystal Growth Rates for Varied Conditions

Table 3. Primary Nucleation of the Differently Composed Mandelic Acid Solutions without or with HMQ

The influence of HMQ on the growth rate can be quantified with the Kubota−Mullin model,13 which is based on assuming the occurrence of Langmuir adsorption (eq 1). This model describes theoretically the crystal growth rate as a function of the amount of additive, in our case HMQ. The model parameters α and K were determined using the experimental data. Figure 4 shows the model function along with the experimental data; the error bars were calculated from the results of five independent experiments.

without HMQ

with HMQ

S-MA

R-MA

RS-MA

mean value of S

1.224

1.225

1.302

standard deviation of S

0.011

0.013

0.014

no nucleation

no nucleation

no nucleation

criterion, which describes the driving force for nucleation, where C0 is the initial concentration (saturation concentration at 20 °C) and Ceq refers to the saturation concentration at the temperature as nucleation occurs. Without HMQ, primary nucleation occurred as the supersaturation degree reached a range between 1.2 and 1.3 for all solutions. The corresponding temperature of the nucleation was approximately 13 °C. When 0.1 wt % HMQ was present in the solutions, no nucleation occurred, even when the temperature fell down to the minimum at 2 °C (corresponding to a degree of supersaturation of around 1.6). It can be concluded that HMQ suppresses primary nucleation of the mandelic acid enantiomers and the racemate, which are both beneficial for preferential crystallization. First, during seeded enantioselective crystallization, primary nucleation of the counter-species RS-MA is undesired and any inhibiting effect on it contributes to the robustness of the separation process. Additionally, the inhibition of primary nucleation of the desired enantiomer allows for higher initial supersaturations and, thus, also supports performance of preferential crystallization of the desired enantiomer.

wHMQ [wt %]

0

0.07

0.14

mean growth rate at S = 1.06 [mm/h] mean growth rate at S = 1.11 [mm/h]

1.3 4.8

0.3 1.4

0 0.71

Figure 4. Fitted curve based on the Kubota−Mullin model (eq 1) along with the mean growth rate of a (+)-(S)-mandelic acid crystal in the presence of different amounts of HMQ. 5199

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Crystal Growth & Design ⎛ αKw ⎞ ⎟ G = G0⎜1 − ⎝ 1 + Kw ⎠ K = 27. 5 [wt %−1]

Article

with

α = 1[‐]

species enhances with an increasing amount of HMQ. The more HMQ was present, the more retarded the counter-species nucleated and the lower was the ee value at the inflection points. Also runs 3 and 5 (not included in Figure 5 for a clear illustration) supported this result. The nucleation events were further observed inline by FBRM detecting the particles with a chord length smaller than 10 μm (Figure 6). The onsets of the counts signal refer to the points in

and (1)

The Kubota−Mullin model is well suited to describe the influence of HMQ on the crystal growth rate of (+)-(S)mandelic acid, and it can be evaluated under two aspects: (a) An increase of the HMQ concentration leads to reduced growth rates of the desired enantiomer, and this effect can be quantitatively interpreted by this model. (b) Considering the above-described inhibition effect of HMQ on primary nucleation, a higher initial supersaturation of the solution is feasible for preferential crystallization separation, which in turn allows for higher growth rates and, hence, might counterbalance the reduced S-MA growth in the presence of HMQ. Since both aspects interact and influence the growth rate simultaneously, a predictive estimation of the effect of HMQ on the preferential crystallization process is complicated. In the next section this influence will be experimentally evaluated. 4.3. Application of HMQ as an Additive in Preferential Crystallization. Part of the results of the HMQ influence on preferential crystallization are shown in Figure 5. Based on the

Figure 6. Temperature profile and particle numbers counted by FBRM for preferential crystallization processes with varied HMQ amounts (runs 1−7).

time when nucleation showers of undesired counter-species occur. The corresponding temperatures are marked in Figure 6 for each of the seven runs. The FBRM results are in good agreement with the crystallization trajectories in Figure 5 and thus verify that the nucleation of counter-species is suppressed by HMQ. This suppression effect increases with HMQ content. These series of experiments were repeated once, and all runs were stopped in time by solid−liquid separation before the counter-species nucleated. The crystals of each run were then washed with 10 mL of ice water and dried at ambient conditions for 3 days. Solid samples from the crystals were taken to perform a purity analysis by HPLC. Table 5 contains essential process parameters, i.e. process time (tend) and final temperature (Tend), the final total solution concentration, and the enantiomeric composition of mandelic acid in the solution (wtotal‑MA,liq and eeend,liq). Besides, product parameters, such as mass of the target crystals (mS‑MA,solid), yield, and purity of the product crystals are also listed. The purity is defined as content of S-MA in the solid product. The HPLC results further revealed that in all runs the product is not contaminated with any HMQ. As mentioned before, the maximum solubility of HMQ under the conditions used is 1 wt %. In a range of 0−1 wt % of HMQ, the yield of the process increases with the amount of HMQ significantly while the purity remains higher than 96%. The yield of preferential crystallization (yieldPC) in this work is hereby defined as the mass of the crystals excluding the seedsmass (mprod) related to the mass of the enantiomer in excess in the initial solution (mexcess,enan) according to eq 2: mprod 100% yieldPC = mexcess , enan (2)

Figure 5. Results of preferential crystallization with varied HMQ content comprising the trajectories of the enantiomeric excess and the applied temperature profile (conditions in Table 2).

transient values of concentration and enantiomeric composition, the enantiomeric excess (ee) of the mother liquor (defined as the difference of the concentrations between two enantiomers relative to the sum of them) can be calculated and, thus, the crystallization trajectory can be discussed along with the temperature profile. The transient of the ee is often used in practice to assess preferential crystallization processes. The inflection points in the ee curves indicate that the undesired counter-species started to nucleate. To gain pure enantiomer crystals, the crystallization process must be stopped at least a few minutes before this point occurs. From the results shown in Figure 5, two remarkable conclusions can be drawn: (a) In run 1 with no HMQ, the inflection point occurred at the 22nd minute at a temperature of 26.5 °C, indicating the crystallization of the counter-species. In contrast, during run 7 with 1 wt % HMQ, the ee decreased steadily, indicating that no nucleation of counter-species occurred within 160 min. It can be concluded that HMQ inhibits the nucleation of counter-species RS-MA significantly, which is in agreement with the results of section 4.1. (b) The inhibition effect of HMQ on the nucleation of the counter5200

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Table 5. Process and Product Parameters of Preferential Crystallization Experiments with Varied Amounts of HMQ as Additive 1 2 3 4 5 6 7

tend [min]

Tend [°C]

wtotal‑MA,liq [wt %]

eeend,liq [%]

mseed/mproduct [−]

mS‑MA,solid [g]

yieldPC [%]

purity [%]

17 45 60 80 85 115 160

27.8 25.0 23.5 21.5 21.0 18.0 13.5

28.7 27.8 27.4 26.8 24.7 23.8 22.2

36 32 31 29 23 20 14

0.69 0.51 0.47 0.40 0.28 0.26 0.21

7.0 9.4 10.2 12.0 17.0 18.8 23.0

24 32 35 41 59 65 79

99 98 99 96 98 97 98

water as solvent. Its methodology and results will be presented in a further work.

We define the yield in this way, since preferential crystallization applied for racemic compound-forming systems can in principle just deliver the enantiomeric excess provided by presteps such as chromatography,2 enantioselective liquid− liquid extraction,14 or membrane processes.5 Thus, a yieldPC of 100% means that all of the available enantiomer in excess in the solution subjected to preferential crystallization can be harvested as enantiopure crystals. The yield increased from 24% to 79% due to the additive effect with highest yield for the highest usable additive amount of 1 wt %. This more than 3fold gain in yield is connected with an almost 10-fold increase in crystallization time. Particle size analysis using light microscopy revealed a mean maximum Feret diameter of 220 μm vs 260 μm for product crystals of run 1 compared to run 7. Thus, in agreement with section 4.2, growth of S-MA in the presence of HMQ occurs but is retarded.

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AUTHOR INFORMATION

Corresponding Author

*Phone: (0049) 391 6110 293. Fax: (0049) 391 6110 524. Email: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to DFG (German Research Foundation) for the financial support through Grants SE 586/16-1 and SE 586/16-2, and also to our project partners in Karlsruhe and Aachen for the intensive collaboration. The authors thank Dr. Matthias Stein, Dr. Ronald Zinke, and Dr. Leonhard for fruitful discussions.

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5. CONCLUSION AND OUTLOOK The chiral substance hydrochinin-4-methyl-2-quinolylether (HMQ) was demonstrated to be a suitable additive allowing for preferential crystallization of S-MA with a more than 3-fold enhancement in yield compared to conventional preferential crystallization without additive. This is mainly due to the inhibiting effect of HMQ on nucleation of the counter-species RS-MA that allows for longer process times and, thus, lower final temperatures in cooling crystallization. Different from conventional chiral additives, HMQ also inhibits primary nucleation of the desired S-MA to almost the same extent. In return, this enables during the controlled cooling process a higher overall supersaturation, which is consumed by crystal growth and secondary nucleation of the seeds. Generalizing the results, the yield of preferential crystallization could be increased by an additive that unselectively inhibits the primary nucleation of both the desired and the counter-species. Seeding with the desired enantiomer crystals induced secondary nucleation and crystal growth that consumes the overall supersaturation while primary nucleation of undesired species was strongly inhibited. In this way, the additive contributes to improve the robustness of preferential crystallization and, thus, enhances the process performance. Besides gaining S-MA, preferential crystallization of R-MA using HMQ has been performed quite recently. Likewise, an approximately 3-fold enhancement of yield has been obtained by seeding R-MA, which agrees with the results discussed above. It is assumed that HMQ can build relatively strong hydrogen bonds to the mandelic acid molecules leading to the inhibition of primary nucleation. The authors are now carrying out detailed molecular modeling that particularly deals with the dimerization of the additive and mandelic acid molecules in

LIST OF SYMBOLS AND ABBREVIATION HMQ hydroquinine-4-methyl-2-quinolylether MA mandelic acid S-MA (+)-(S)-mandelic acid R-MA (−)-(R)-mandelic acid TEAA triethylammonium acetate ee enantiomeric excess [%] G growth rate of (+)-(S)-mandelic acid in the presence of HMQ [mm h−1] G0 growth rate of (+)-(S)-mandelic acid in pure solution without HMQ [mm h−1] α effectiveness factor of HMQ [-] K constant in the Langmuir adsorption isotherm [wt %−1] w mass fraction of HMQ [wt %] yieldPC yield of the preferential crystallization

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REFERENCES

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