Enabling Enantiopurity: Combining Racemization and Dual-Drug Co

Article Cite This: Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Enabling Enantiopurity: Combining Racemization and Dual-Drug Cocrystal Resolution Bram Harmsen and Tom Leyssens* Institute of Condensed Matter and Nanosciences, Université Catholique De Louvain, 1348 Louvain-la-Neuve, Belgium S Supporting Information *

ABSTRACT: A new process methodology to obtain enantiopure (S)-Ibuprofen has been designed. Starting from racemic Ibuprofen, co-crystallization with Levetiracetam is used as a resolution tool to obtain only the target enantiomer, (S)-Ibuprofen, in the solid state. The resulting mother liquor, enriched in (R)Ibuprofen, is recovered and submitted to a racemization cycle, after which another co-crystallization step is introduced. Levetiracetam can be recovered from the co-crystal phase and reused, resulting in an economical use of the resolution agent. Overall, a novel approach to transform a racemic compound into enantiopure material has been developed.

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INTRODUCTION In the pharmaceutical industry, chirality is of key importance. Where one enantiomer has the desired effect, the other can be inactive or in other scenarios even have detrimental effects.1−3 Some well-described examples are thalidomide4−6 (the R enantiomer works as a sedative, whereas the S enantiomer has teratogenic effects), ethambutol4,7 (the S,S enantiomer is a tuberculostatic, whereas the R,R counterpart causes blindness), and dopa4,8 (the L enantiomer is used to treat Parkinson’s disease, whereas the D enantiomer causes granulocytopenia). To prevent issues like this, regulatory instances prefer drugs to be marketed in enantiopure form,9 which circumvents the potential adverse effects.10,11 To obtain enantiopure drugs, the drug is either synthesized in an enantiopure manner or obtained from a racemic mixture by applying a postsynthetic physical chiral separation process. Common synthetic approaches are the chiral pool approach (using enantiopure starting materials) or the asymmetric approach (in which the reaction preferentially leads to one enantiomer).12−17 Alternatively, the separation is performed using a physical separation step after the synthesis. The most common physical separation processes are crystallization-based (mainly diastereomeric salt formation) or chromatography-based.18−23 The downsides of these methods are apparent: chiral chromatography is expensive, and diastereomeric salt formation is feasible only when the compound is salsifiable (i.e., forms a salt). More importantly, in both cases the enantiomers are separated, and thus, a 50% loss (unwanted enantiomer) occurs. To prevent such a loss, one would have to transform the unwanted enantiomer into the desired one, which can be achieved through racemization. Racemization of organic molecules typically occurs via two pathways or combinations thereof:24−26 a basic pathway (proton abstraction), where the intermediate structure is a carbanion in which the lone pair can exhibit inversion, or an acidic pathway, which involves protonation followed by © XXXX American Chemical Society

displacement of the now-protonated group, resulting in stereoinversion. Over the recent decade, racemization has been combined with crystallization processes to lead to one-pot deracemization processes, which ultimately lead to enantiopure material with a theoretical 100% transformation. Viedma ripening (conglomerate resolution),27−29 preferential dynamic crystallization30,31 and crystallization-induced diastereomeric transformations32 have been described for the transformation of a racemic mixture into enantiopure material. As each of these methods remains subject to limitations (e.g., requirement to form a conglomerate, salsification ability, etc.), such a one-pot deracemization procedure is not always feasible. In such cases, an alternative approach is to introduce a stepwise deracemization procedure in which the separation and racemization steps are performed separately. In this work, we develop such a stepwise transformation process for (RS)-Ibuprofen, for which no one-step single-pot deracemization has been described to date, via the use of cocrystallization. To do so, we start by using enantiospecific cocrystallization from solution, a recently introduced resolution technique for compounds that do not form salts.33−35 Enantiospecific co-crystallization occurs when only one enantiomer of the target active pharmaceutical ingredient (API) is able to co-crystallize with the resolving agent. Recent findings have shown such behavior to be more commonplace for co-crystals compared with diastereomeric co-crystal formation.33,36−38 In a recent contribution, we showed how resolution through co-crystallization can be used in a dual-drug approach, separating (R)- and (S)-Ibuprofen using (S)-2-(2oxopyrrolidine-1-yl)butanamide (Levetiracetam).34 In that contribution, we showed how enantiopure (S)-Ibuprofen can Received: March 23, 2018 Revised: April 16, 2018 Published: April 23, 2018 A

DOI: 10.1021/acs.cgd.8b00438 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

be obtained upon enantiospecific co-crystallization followed by dissociation of the co-crystal to yield the pure (S)-Ibuprofen. The maximum theoretical (S)-Ibuprofen recovery of such a process would be 50%. In the present contribution, we go beyond this by combining this resolution process with a racemization process for the opposite enantiomer. After racemization of the undesired enantiomer and recovery of the resolution agent, a second co-crystallization resolution can be performed by feeding the starting materials back into the system. By looping this system, ultimately a zero-waste process in terms of APIs is achieved.

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Scheme 1. Chemical Structures of (S)-2-(2-Oxopyrrolidin-1yl)butanamide (Levetiracetam) and (S)-Ibuprofen

MATERIALS AND METHODS

Materials. Leviracetam (or (S)-Etiracetam) was purchased from Xiamen Top Health Biochem. Tech. Co., Ltd. (RS)-Ibuprofen was purchased from HoaHua Industry Co., Ltd. (S)-Ibuprofen was purchased from Thermo Fisher Acros Organics. Acetonitrile was purchased from VWR International S.A.S. Octane (98%) was obtained from Sigma-Aldrich Co. LLC. Triethylamine (>99.5%) was obtained from Honeywell FlukaFisher Scientific. All of these materials were used without further purification. Instrumentation. X-ray powder diffraction (XRPD) characterization was done on a Siemens D5000 diffractometer equipped with a Cu X-ray source operating at 40 kV and 40 mA. A secondary monochromator allowed for the selection of Cu Kα radiation (λ = 1.5418 Å). A scanning range of 2θ values from 2° to 72° at a scan rate of 0.6°/min was applied. Chiral high-performance liquid chromatography (chiral HPLC) measurements were performed on a reversed-phase Waters Alliance 2695 system with a photoarray detector (Waters 2998) at 210 nm. Samples were measured using a 1 mL flow of 50/50 H2O/MeCN with 0.1% formic acid added on a Lux 5 μm Amylose-1 250 mm × 4.6 mm column from Phenomenex, Inc. The samples were dissolved in 50/50 H2O/MeCN. 1 H NMR spectroscopy measurements were performed on a 300 MHz Bruker Avance spectrometer and used to determine the ratio of Levetiracetam to Ibuprofen (see section 3 in the Supporting Information). DMSO-d6 was used as the solvent. Enantiospecific Crystallization Conditions. Typically co-crystal seeds were created via ball milling by adding (S)-Ibuprofen and Levetiracetam together in a 1:1 molar ratio, followed by milling at 30 Hz for 60 min (see section 1 in the Supporting Information). A typical co-crystallization process is as follows: (RS)-Ibuprofen (10.394 g, 50.4 mmol) and Levetiracetam (8.575 g, 50.4 mmol) were added to 100 mL of acetonitrile, and the mixture was heated until dissolution was complete. The solution was left to cool to −10 °C and subsequently seeded with the solids in the system (1 wt %). A second seeding (also 1 wt %) was done 24 h after the initial seeding event. The seeding material contained mainly crystalline co-crystal solid. Amorphous material present did not impact the thermodynamic outcome of the experiments. Deviations from this starting ratio and other process changes are listed in section 2 in the Supporting Information. Standard conditions are used in the text unless mentioned otherwise. The yield after each step was calculated by comparing the total input of solid material to the output after crystallization.

conditions, the addition of Levetiracetam to a solution of racemic Ibuprofen can lead to co-crystal formation and consequently to opposing enantioenrichment in the solid and liquid phases. To identify the appropriate process conditions, ideal phase diagrams are constructed. In our earlier work,34 we constructed such a diagram (shown in Figure 1) for the Ibuprofen/Levetiracetam co-crystal system. As the temperature, pressure, and amounts of (R)- and (S)-Ibuprofen, Levetiracetam, and solvent can be varied, these diagrams can become very complex. Even when the temperature and pressure are fixed, one technically ends up with a quaternary phase diagram (amount of solvent, amounts of (R)- and (S)-Ibuprofen, and amount of Levetiracetam), which is hard to represent graphically. To reduce the complexity further, the total amount of solvent was fixed (95 mol % in our case), as described in our earlier work. This results in a ternary diagram as shown in Figure 1. The edges correspond to (R)-Ibuprofen, (S)Ibuprofen, and Levetiracetam in a suspension composed of 95 mol % solvent and 5 mol % overall in other compounds (solids). The vertical line in the middle (the leftmost line) corresponds to the racemic line, represented by an (S)Ibuprofen:(R)-Ibuprofen (S:R) ratio of 50:50. Going upward along this line from the base of the triangle to the top, the only variable is the amount of Levetiracetam with respect to the amount of racemic compound. Along this line, the nature of the solid state that is stable in suspension changes according to the ratio of Ibuprofen to Levetiracetam. When no Levetiracetam is present, (RS)-Ibuprofen is stable in suspension. For small amounts of Levetiracetam (up to at least 20% of the overall solid composition) (RS)-Ibuprofen is the only stable phase in suspension. Increasing the amount of Levetiracetam even further (40−60% of overall solid composition), one enters a zone where three solid phases are stable in suspension: (RS)Ibuprofen, Levetiracetam, and the co-crystal of (S)-Ibuprofen with Levetiracetam. For even higher amounts of Levetiracetam (80% of the overall solid composition), Levetiracetam is the only solid phase stable in suspension. Following a nonracemic mixture for Ibuprofen (e.g., an S:R ratio of 60:40 or 70:30), new zones emerge. Along the 60:40 line, increasing amounts of Levetiracetam successively result in the following zones: (RS)Ibuprofen; (RS)-Ibuprofen and co-crystal; co-crystal and Levetiracetam. Along the 70:30 line, increasing amounts of Levetiracetam successively lead to the following zones: (RS)Ibuprofen; co-crystal; co-crystal and Levetiracetam. The width

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RESULTS AND DISCUSSION Discussion of the System Used. (S)-Ibuprofen (the active enantiomer)39,40 forms an enantiospecific co-crystal with Levetiracetam (the active ingredient of Keppra, an anticonvulsant).41,42 The chemical structures of both compounds are shown in Scheme 1. A co-crystal does not form between Levetiracetam and (R)-Ibuprofen, which means that Levetiracetam serves as a chiral discriminator.34 This also implies that Levetiracetam can be used as a chiral resolving agent for chiral resolution from solution. We designed such a dual-drug resolution process in our earlier work.34 Under appropriate B



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Figure 1. Ternary phase diagram for (RS)-Ibuprofen ((RS)-Ibu), the co-crystal (Cc), and Levetiracetam (Lv) (5 mol % total) with acetonitrile as the solvent (95 mol %) at −10 °C (adapted from ref 34; copyright 2017 American Chemical Society). The starting point in Scheme 2 corresponds with the exact center of this figure ((R)-Ibu:(S)-Ibu ratio of 0.5, amount of Lv = 0.5).

Scheme 2. Flowchart Showing a Two-Step Process for Enantiopure (S)-Ibuprofen with a Racemization and Recycling Route (Waste Stream)

Levetiracetam. Along the 60:40 and 70:30 lines, this also occurs for the zones where the co-crystal is among the phases that are stable in suspension, as denoted by crosses (only the co-crystal is stable), solid dots (the co-crystal and (RS)Ibuprofen are stable phases) and solid diamonds (the co-crystal and Levetiracetam are stable phases in suspension). Toward Enantiopure (S)-Ibuprofen. On the basis of the phase diagram shown in Figure 1, the scaled-up process shown in Scheme 2 has been designed, which ultimately affords enantiopure (S)-Ibuprofen through a combination of race-

of the zone where the co-crystal is the only solid form emerging increases as the starting Ibuprofen composition moves toward the S-enriched direction, as could be expected. To obtain an imbalance of enantiomeric excess between the solid and liquid phases, one requires the crystallization of the co-crystal phase (as it contains only (S)-Ibuprofen). Starting from racemic Ibuprofen, the only relevant zone where this would occur is given by the area where three solid forms are present, as shown by the solid squares in Figure 1: (RS)Ibuprofen, co-crystal (contains only (S)-Ibuprofen), and C



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mization and co-crystallization. In the product stream, the starting point is the exact center of Figure 1 (racemic Ibuprofen with Levetiracetam in a 1:1 ratio with 95 mol % acetonitrile solvent). The solids were dissolved by heating to 40 °C, after which the solution was cooled to −10 °C and seeded with cocrystal (1 wt %), which triggered the crystallization of all forms. The suspension was seeded again 24 h after the initial seeding event. After a 1 week isothermal hold, the crystals were harvested, washed twice with 20 mL of cold (−10 °C) acetonitrile, and filtered, and the enrichment of the solid phase was determined via chiral HPLC. Simultaneously, the overall composition of Ibuprofen with respect to Levetiracetam was determined via 1H NMR spectroscopy. This solid phase obtained from step 1 in Scheme 2 has an average S:R ratio of 64:36 and a yield (weight of solid recovered with respect to weight of solids initially introduced) of 31% (see Table 1).

If the co-crystal is not the wanted phase, the API can be dissociated from the co-crystal by slurrying the entire amount of solid recovered in step 2 in 50 mL of water. Ibuprofen is insoluble in water, whereas Levetiracetam dissolves readily, which means the remaining solid phase after filtration consists solely of Ibuprofen. At this stage a 94% (S)-Ibuprofen solid phase is still recovered. To come to enantiopure Ibuprofen, a literature-based approach was used in which Ibuprofen was first transformed into its sodium salt.45 Ibuprofen is characterized by a eutectic at around R:S = 90:10 (the ratio varies slightly depending on the solvent used), whereas the sodium salt has a eutectic at 62:38. The use of the sodium salt will therefore lead to an increased yield during the enantiopurification. The salt is synthesized by dissolving the Ibuprofen in acetone (10 mL per gram of material) and adding 0.5 molar equivalent of NaOH. Unlike in the literature,45 the suspension was heated to 50 °C to aid dissolution. After dissolution was complete, the solvent was left to evaporate, and the residue was triturated with diethyl ether (10 mL per gram of material) and filtered to yield >99% pure (S)-Ibuprofen sodium salt as determined via HPLC. At this stage the Ibuprofen salt can be recovered for use as the final API product, or alternatively, an acidic workup (using 1 M HCl) followed by filtration gives the liberated final enantiopure (S)-Ibuprofen. In Scheme 2, waste is generated at various stages during the product stream. As we aim for an economically viable process, all of the waste is collected at these specific points and processed in a respective waste stream. This allows recovery of not only the resolving agent (Levetiracetam) but also the Renriched Ibuprofen. Through racemization, the latter is transformed into a racemic Ibuprofen mixture, which can in turn be reinjected into the process, thus leading to an overall deracemization process. The waste stream at point 1 uses an orthogonal solvent strategy in which Levetiracetam precipitates from the concentrated mother liquor when octane is added. The R-rich Ibuprofen octane solution is racemized with triethylamine in octane under reflux conditions (2 mL of octane per millimole of material, 2 equiv of triethylamine, 15 h reflux)46 followed by an acidic workup. The solvent is evaporated, and racemic Ibuprofen is obtained. A similar process is performed with the waste stream at point 3. The only difference here is that no removal of Levetiracetam is required. The waste stream at point 2 contains only Levetiracetam, which can be recovered by concentration of the solvent and reintroduced into the product stream. The advantage of the proposed product and waste streams is that almost no waste is generated. The racemized Ibuprofen and separated Levetiracetam are recycled and reintroduced in the product stream, reducing the amount of material needed and achieving the ultimate goal of transforming (RS)-Ibuprofen into its enantiopure counterpart. The process described in Scheme 2 was repeated multiple times, and the results are shown in Table 1. Table 1 shows the percentage of (S)-Ibuprofen with respect to the total amount of Ibuprofen in the solid phase recovered after each step. The yields were calculated from total solids in versus total solids out. The yields per compound (and per enantiomer for Ibuprofen) are described in section 3 in the Supporting Information. Even though there was some variation in the amount of Levetiracetam versus Ibuprofen in the step 2 experiments, in all cases pure co-crystal was obtained as a solid solution with S:R = 94:6 (see section 2 in the Supporting Information).34 Individual experiments are detailed in section 2 in the

Table 1. Percentage of (S)-Ibuprofen upon Completion of the Process Steps Shown in Scheme 2a starting composition 2.5 mol % (RS)-Ibuprofen, 2.5 mol % Levetiracetam, and 95 mol % acetonitrile

enrichment after step 1b

enrichment after step 2

64% (S)Ibuprofen (avg of 7 expts.) 31% yield (avg of 7 expts.)

96% (S)Ibuprofen (avg of 3 expts.) 34% yield (avg of 3 expts.)

a

The yield is given as the total mass of solids recovered upon crystallization with respect to the total mass of solids introduced initially in the specific step. bInterestingly, stirring (at 200 rpm) seemed to have a strong negative influence on the enrichment of the process. The average enrichment after step 1 without stirring (as listed in Table 1) is 64%, whereas the average with stirring was 53% (average of 8 experiments). The reason for this difference was not investigated because it is outside the scope of this article, but it is likely that the agitation prevents the co-crystal from forming.

XRPD data show that all three forms ((RS)-Ibuprofen, cocrystal, and Levetiracetam) are present, as expected from Figure 1. From Figure 1, one observes that in principle for an S:R ratio of 64:36, one could add an appropriate amount of Levetiracetam so that (RS)-Ibuprofen no longer crystallizes (solid diamonds in Figure 1). The solids of step 1 are redissolved again using 95 mol% acetonitrile solvent (see section 3 in the Supporting Information), and if needed, Levetiracetam is added to arrive in the area where the co-crystal is the only stable form in suspension. As enrichment has occurred, the redissolved solid ratio is no longer racemic for Ibuprofen and has moved to the right in Figure 1. Furthermore, since the composition obtained in step 1 is known (via chiral HPLC and 1H NMR spectroscopy), the expected outcome can directly be read from Figure 1 on the basis of the input composition. Another heating, cooling, and seeding procedure similar to step 1 is followed in step 2, and after another 1 week isothermal hold period the solids are again harvested, washed, filtered, and analyzed. The resulting enrichment after the second dissolution and crystallization cycle appears to be the limit for our system (94% (S)-Ibuprofen as a solid solution of the co-crystal). This means that a nearly enantiopure end state is achieved in only two cycles. At this point the co-crystal (which forms a partial solid solution with S:R = 94:6) could be used as potential drug form, since Levetiracetam and Ibuprofen exhibit synergistic behavior, as also shown for other co-crystal drugs.43 When they are combined, the effect of Ibuprofen improves up to 11-fold.44 D



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procedures. In two steps, nearly enantiopure (S)-Ibuprofen is obtained in the form of the co-crystal as a partial solid solution. After further optional purification (S)-Ibuprofen is obtained with >99% enantiopurity. The resolution agent is recovered during the process and can be reused as such, whereas the (R)Ibuprofen-enriched waste is recovered and fully racemized, so that it can also be recycled into the stream. This ultimately implies that the entire amount of (RS)-Ibuprofen can be successfully transformed into the desired enantiopure (S)Ibuprofen end product. Interestingly, this process can be interrupted at different stages, as the co-crystal and the sodium salts of Ibuprofen are also viable solid states. The process developed here is thermodynamic and can theoretically be applied to all co-crystal-forming compounds with no limitation to conglomerate formation or salt formation.

Supporting Information. In step 1, the average of seven experiments was taken, and in step 2, three experiments were averaged. When the starting composition was created using recycled material obtained from the waste stream in Scheme 2, the outcome of step 1 did not change and gave enrichment in (S)Ibuprofen as expected. This shows that the compounds from the mother liquor(s) after waste processing can be reused without problems in the product stream. After the second crystallization step in the product stream, the Ibuprofen salt was created as described earlier,46 but the suspension was heated to 50 °C to complete the dissolution of sodium hydroxide (unlike the literature). The washed product of the concentrated sodium salt (the concentrate was initially slurried until evaporation was complete and then washed and filtered twice via displacement) was enantiopure as expected, but no yields were recorded. When Ibuprofen was liberated via an acidic workup, an enantiopurity of >99% for (S)-Ibuprofen was obtained. The overall average yield over the two crystallization steps is low (11%) and has not been fully optimized, as the goal of this work was to demonstrate a working process that does not utilize diastereomeric salts or separation via chiral column. However, since we showed that the API and resolving agent are fully recovered via the waste stream (no API material is lost or discarded), this low yield is not a limiting issue, as one can cycle through the process multiple times. For example, Levetiracetam is used as the chiral resolving agent and does not get consumed at all during the entire process. The undesired (R)-Ibuprofen (and the (S)-Ibuprofen remaining in solution) also gets recovered and racemized, achieving full transformation of (RS)-Ibuprofen into the enantiopure counterpart. The only product leaving the system is the final pure (S)-Ibuprofen, with all of the remaining material being reused. As the whole process is thermodynamically controlled, further scale-up is possible as long as seeding is done consistently. When the process is compared with known methods such as separation via chiral column or diastereomeric salt formation, the differences become apparent. For preparative chiral column separation, the throughput is mainly limited by the column size, specifically the inner diameter. For example, a separation of 500 g to 1.5 kg of racemate per kilogram of chiral stationary phase per day has been reported on pilot scale.47 The limiting factor is thus the amount of stationary phase. No such limit exists for our process in terms of sizethe limiting factor here is time needed for the formation of the enantiospecific co-crystal. Time is also the limiting factor when chiral separation is achieved via diastereomeric salt formation. For example, separation in supercritical CO2 takes up to 5 days to obtain 60% ee under harsh and difficult-to-scale conditions (200 bar).48 Salt formation of an equimolar mixture of racemic Ibuprofen with N-methyl-D-glucamine has been reported to give a yield of 18.4% with a purity of 94% (S)-Ibuprofen after 30 min. 49 Longer crystallization times show reduced enantiopurity because the opposite diastereomer also starts to crystallize, limiting the yield that can be obtained. For our enantiospecific co-crystal system, the opposing combination of enantiomers does not form,34 and thus, the yield is not influenced.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.8b00438. Raw data and individual experiments, together with a more detailed explanation of (analytical) methods (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Telephone: +32 10 47 28 11. Fax: +32 10 47 27 07. E-mail: [email protected]. Address: Place Louis Pasteur 1, bte L4.01.03, 1348 Louvain-la-Neuve, Belgium. Website: http://www.uclouvain.be/leyssens-group. ORCID

Bram Harmsen: 0000-0002-5422-3926 Author Contributions

The manuscript was written through contributions of both authors. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank UCL and FRIA (FC 02573) for financial support.

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ABBREVIATIONS HPLC, high-performance liquid chromatography; NMR, nuclear magnetic resonance; XRPD, X-ray powder diffraction; wt %, weight percent

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REFERENCES

(1) Sánchez, C.; Bergqvist, P. B. F.; Brennum, L. T.; Gupta, S.; Hogg, S.; Larsen, A.; Wiborg, O. Escitalopram, the S-(+)-Enantiomer of Citalopram, Is a Selective Serotonin Reuptake Inhibitor with Potent Effects in Animal Models Predictive of Antidepressant and Anxiolytic Activities. Psychopharmacology (Berlin) 2003, 167 (4), 353−362. (2) Kuusela; Raekallio; Anttila; Falck; Molsa; Vainio. Clinical Effects and Pharmacokinetics of Medetomidine and Its Enantiomers in Dogs. J. Vet. Pharmacol. Ther. 2000, 23 (1), 15−20. (3) Wibe, a.; Borg-Karlson, a.-K.; Persson, M.; Norin, T.; Mustaparta, H. Enantiomeric Composition of Monoterpene Hydrocarbons in Some Conifers and Receptor Neuron Discrimination of a-Pinene and Limonene Enantiomers in the Pine Weevil, Hylobius Abietis. J. Chem. Ecol. 1998, 24 (2), 273−287.

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CONCLUSION A novel process to transform racemic material into enantiomerically pure material based on co-crystallization principles was developed as an alternative to known E



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(4) Kasprzyk-Hordern, B. Pharmacologically Active Compounds in the Environment and Their Chirality. Chem. Soc. Rev. 2010, 39 (11), 4466. (5) Eriksson, T.; Björkman, S.; Höglund, P. Clinical Pharmacology of Thalidomide. Eur. J. Clin. Pharmacol. 2001, 57 (5), 365−376. (6) Fabro, S.; Smith, R. L.; Williams, R. T. Toxicity and Teratogenicity of Optical Isomers of Thalidomide. Nature 1967, 215 (5098), 296−296. (7) Karlson, A. G. Therapeutic Effect of Ethambutol (Dextro-2,2′[Ethylenediimino]-Di-L-Butanol) on Experimental Tuberculosis in Guinea Pigs. Am. Rev. Respir. Dis. 1961, 84 (6), 902−904. (8) Sheldon, R. A. Chirality and Biological Activity in Chirotechnology: Industrial Synthesis of Optically Active Compounds; CRC Press: Boca Raton, FL, 1993. (9) Muñoz Solano, D.; Hoyos, P.; Hernáiz, M. J.; Alcántara, A. R.; Sánchez-Montero, J. M. Industrial Biotransformations in the Synthesis of Building Blocks Leading to Enantiopure Drugs. Bioresour. Technol. 2012, 115, 196−207. (10) Slováková, A.; Hutt, A. J. Chiral Compounds and Their Pharmacologic Effects. Ceska Slov. Farm. 1999, 48 (3), 107−112. (11) Nguyen, L. A.; He, H.; Pham-Huy, C. Chiral Drugs: An Overview. Int. J. Biomed. Sci. 2006, 2 (2), 85−100. (12) Nicolaou, K. C.; Pappo, D.; Tsang, K. Y.; Gibe, R.; Chen, D. Y.K. A Chiral Pool Based Synthesis of Platensimycin. Angew. Chem., Int. Ed. 2008, 47 (5), 944−946. (13) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Double Asymmetric Synthesis and a New Strategy for Stereochemical Control in Organic Synthesis. Angew. Chem., Int. Ed. Engl. 1985, 24 (1), 1−30. (14) Herdeis, C.; Hubmann, H. P.; Lotter, H. Chiral Pool Synthesis of Trans-(2S3S)-3-Hydroxyproline and Castanodiol from S-Pyroglutamic Acid. Tetrahedron: Asymmetry 1994, 5 (1), 119−128. (15) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. Direct Catalytic Asymmetric Synthesis of Cyclic Aminals from Aldehydes. J. Am. Chem. Soc. 2008, 130 (47), 15786−15787. (16) Savile, C. K.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam, S.; Jarvis, W. R.; Colbeck, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P. N.; Huisman, G. W.; Hughes, G. J. Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture. Science (Washington, DC, U. S.) 2010, 329 (5989), 305− 309. (17) Rudolph, J.; Hannig, F.; Theis, H.; Wischnat, R. Highly Efficient Chiral-Pool Synthesis of (2 S, 4 R)-4-Hydroxyornithine. Org. Lett. 2001, 3 (20), 3153−3155. (18) Ying, Z.; Ling, L.; Kunde, L.; Xinping, Z.; Weiping, L. Enantiomer Separation of Triazole Fungicides by High-Performance Liquid Chromatography. Chirality 2009, 21 (4), 421−427. (19) Tachibana, K.; Ohnishi, A. Reversed-Phase Liquid Chromatographic Separation of Enantiomers on Polysaccharide Type Chiral Stationary Phases. J. Chromatogr. A 2001, 906 (1−2), 127−154. (20) Frank, H.; Nicholson, G. J.; Bayer, E. Rapid Gas Chromatographic Separation of Amino Acid Enantiomers with a Novel Chiral Stationary Phase. J. Chromatogr. Sci. 1977, 15 (5), 174−176. (21) Bereczki, L.; Pálovics, E.; Bombicz, P.; Pokol, G.; Fogassy, E.; Marthi, K. Optical Resolution of N-Formylphenylalanine Succeeds by Crystal Growth Rate Differences of Diastereomeric Salts. Tetrahedron: Asymmetry 2007, 18 (2), 260−264. (22) Kinbara, K.; Sakai, K.; Hashimoto, Y.; Nohira, H.; Saigo, K. Chiral Discrimination upon Crystallisation of the Diastereomeric Salts of 1-Arylethylamines with Mandelic Acid or P-Methoxymandelic Acid: Interpretation of the Resolution Efficiencies on the Basis of the Crystal Structures. J. Chem. Soc., Perkin Trans. 2 1996, 12, 2615. (23) Guangyou, Z.; Yuquing, L.; Zhaohui, W.; Nohira, H.; Hirose, T. Resolution of β-Aminoalcohols and 1,2-Diamines Using Fractional Crystallization of Diastereomeric Salts of Dehydroabietic Acid. Tetrahedron: Asymmetry 2003, 14 (21), 3297−3300. (24) Jencks, W. P. When Is an Intermediate Not an Intermediate? Enforced Mechanisms of General Acid-Base, Catalyzed, Carbocation, Carbanion, and Ligand Exchange Reaction. Acc. Chem. Res. 1980, 13 (6), 161−169.

(25) Cram, D. J.; Mateos, J. L.; Hauck, F.; Langemann, A.; Kopecky, K. R.; Nielsen, W. D.; Allinger, J. Electrophilic Substitution at Saturated Carbon. VI. Stereochemical Capabilities of Carbanions 1. J. Am. Chem. Soc. 1959, 81 (21), 5774−5784. (26) Kice, J. L.; Large, G. B. The Relative Nucleophilicity of Some Common Nucleophiles toward Sulfenyl Sulfur. The Nucleophile- and Acid-Catalyzed Racemization of Optically Active Phenyl Benzenethiosulfinate. J. Am. Chem. Soc. 1968, 90 (15), 4069−4076. (27) Viedma, C.; McBride, J. M.; Kahr, B.; Cintas, P. EnantiomerSpecific Oriented Attachment: Formation of Macroscopic Homochiral Crystal Aggregates from a Racemic System. Angew. Chem., Int. Ed. 2013, 52 (40), 10545−10548. (28) McLaughlin, D. T.; Nguyen, T. P. T.; Mengnjo, L.; Bian, C.; Leung, Y. H.; Goodfellow, E.; Ramrup, P.; Woo, S.; Cuccia, L. A. Viedma Ripening of Conglomerate Crystals of Achiral Molecules Monitored Using Solid-State Circular Dichroism. Cryst. Growth Des. 2014, 14 (3), 1067−1076. (29) Addadi, L.; Weinstein, S.; Gati, E.; Weissbuch, I.; Lahav, M. Resolution of Conglomerates with the Assistance of Tailor-Made Impurities. Generality and Mechanistic Aspects of The “rule of Reversal”. A New Method for Assignment of Absolute Configuration. J. Am. Chem. Soc. 1982, 104 (17), 4610−4617. (30) Coquerel, G. Preferential Crystallization. Top. Curr. Chem. 2006, 269, 1−51. (31) Lorenz, H.; Polenske, D.; Seidel-Morgenstern, A. Application of Preferential Crystallization to Resolve Racemic Compounds in a Hybrid Process. Chirality 2006, 18 (10), 828−840. (32) Brands, K. M. J.; Davies, A. J. Crystallization-Induced Diastereomer Transformations †. Chem. Rev. 2006, 106 (7), 2711− 2733. (33) Springuel, G.; Leyssens, T. Innovative Chiral Resolution Using Enantiospecific Co-Crystallization in Solution. Cryst. Growth Des. 2012, 12 (7), 3374−3378. (34) Harmsen, B.; Leyssens, T. Dual-Drug Chiral Resolution: Enantiospecific Cocrystallization of (S)-Ibuprofen Using Levetiracetam. Cryst. Growth Des. 2018, 18 (1), 441−448. (35) Lee, T.; Chen, H. R.; Lin, H. Y.; Lee, H. L. Continuous CoCrystallization As a Separation Technology: The Study of 1:2 CoCrystals of Phenazine−Vanillin. Cryst. Growth Des. 2012, 12 (12), 5897−5907. (36) Habgood, M. Analysis of Enantiospecific and Diastereomeric Cocrystal Systems by Crystal Structure Prediction. Cryst. Growth Des. 2013, 13 (10), 4549−4558. (37) Koscho, M. E.; Spence, P. L.; Pirkle, W. H. Chiral Recognition in the Solid State: Crystallographically Characterized Diastereomeric Co-Crystals between a Synthetic Chiral Selector (Whelk-O1) and a Representative Chiral Analyte. Tetrahedron: Asymmetry 2005, 16 (19), 3147−3153. (38) Bock, D. A.; Lehmann, C. W. Chirality Determination from XRay Powder Datadiastereomeric Co-Crystals of Mandelic Acid and Proline Amide. CrystEngComm 2012, 14 (5), 1534. (39) Bonabello, A.; Galmozzi, M. R.; Canaparo, R.; Isaia, G. C.; Serpe, L.; Muntoni, E.; Zara, G. P. DexIbuprofen (S(+)-Isomer Ibuprofen) Reduces Gastric Damage and Improves Analgesic and Antiinflammatory Effects in Rodents. Anesth. Analg. 2003, 97 (2), 402−408. (40) Chhabra, N.; Aseri, M.; Padmanabhan, D. A Review of Drug Isomerism and Its Significance. Int. J. Appl. Basic Med. Res. 2013, 3 (1), 16. (41) Shorvon, S. D.; Lowenthal, A.; Janz, D.; Bielen, E.; Loiseau, P. Multicenter Double-Blind, Randomized, Placebo-Controlled Trial of Levetiracetam as Add-On Therapy in Patients with Refractory Partial Seizures. Epilepsia 2000, 41 (9), 1179−1186. (42) Cereghino, J. J.; Biton, V.; Abou-Khalil, B.; Dreifuss, F.; Gauer, L. J.; Leppik, I. Levetiracetam for Partial Seizures: Results of a DoubleBlind, Randomized Clinical Trial. Neurology 2000, 55 (2), 236−242. (43) Yeh, K. L.; Lee, T. Intensified Crystallization Processes for 1:1 Drug−Drug Cocrystals of Sulfathiazole−Theophylline, and Sulfathiazole−Sulfanilamide. Cryst. Growth Des. 2018, 18 (3), 1339−1349. F



Article

(44) Tomić, M. A.; Micov, A. M.; Stepanović-Petrović, R. M. Levetiracetam Interacts Synergistically With Nonsteroidal Analgesics and Caffeine to Produce Antihyperalgesia in Rats. J. Pain 2013, 14 (11), 1371−1382. (45) Manimaran, T.; Stahly, G. P. Optical Purification of Profen Drugs. Tetrahedron: Asymmetry 1993, 4 (8), 1949−1954. (46) Manimaran, T.; Impastato, F. J. Preparation of Optically Active Aliphatic Carboxylic Acids. U.S. Patent: US5015764A, 1991. (47) Francotte, E. R. Enantioselective Chromatography as a Powerful Alternative for the Preparation of Drug Enantiomers. J. Chromatogr. A 2001, 906 (1−2), 379−397. (48) Bánsághi, G.; Székely, E.; Sevillano, D. M.; Juvancz, Z.; Simándi, B. Diastereomer Salt Formation of Ibuprofen in Supercritical Carbon Dioxide. J. Supercrit. Fluids 2012, 69, 113−116. (49) Lam, W. H.; Ng, K. M. Diastereomeric Salt Crystallization Synthesis for Chiral Resolution of Ibuprofen. AIChE J. 2007, 53 (2), 429−437.

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