Simultaneous Chiral Resolution of Two Racemic Compounds by Preferential Cocrystallization**

Abstract

We tap into an unexplored area of preferential crystallization, being the first to develop simultaneous chiral resolution of two racemic compounds by preferential cocrystallization. We highlight how the two racemic compounds RSmandelic acid (MAN) and RS-etiracetam (ETI) can be combined together as enantiospecific R-MAN•R-ETI and S-MAN•S-ETI cocrystals forming a stable conglomerate system and subsequently develop a cyclic preferential crystallization allowing to simultaneous resolve both compounds. The developed process leads to excellent enantiopurity both for etiracetam (ee > 98 %) and mandelic acid (ee % 95 %) enantiomers.

Mechanochemical Synthesis of Cocrystal: From Mechanism to Application

“…This is well illustrated in the case reported by Eddleston, where racemic malic acid can be transformed into two distinct diastereomeric cocrystal phases by trituration with the single enantiomer of tartaric acid. 155 It was later validated in countless cases, including L-proline/RSmandelic acid, 154 RS-mandelic Acid/RS-etiracetam, 156 and Lmalic acid/RS-praziquantel. 157 Ionic cocrystal is unquestionably a viable method for realizing chiral resolution via mechanochemistry.…”

“…This makes sense, given that the process (Figure 11a) is typically thermodynamically driven and the products are frequently more stable and less water-soluble. 153,154 For mechanochemistry, it has the potential to supplement conventional solution-based cocrystal chiral resolution techniques by providing a quick and simple method for screening candidate coformers for chiral resolution. This is well illustrated in the case reported by Eddleston, where racemic malic acid can be transformed into two distinct diastereomeric cocrystal phases by trituration with the single enantiomer of tartaric acid.…”

Chiral resolution methods for racemic pharmaceuticals based on cocrystal formation

“…54,55 Crystal engineering techniques are used to convert racemic substance systems into conglomerate systems, such as cocrystal formation using achiral agents (coformers, acids or bases) or conglomerate salts, which were effectively created by combining racemic amines and racemic carboxylic acids. 5 To do this, chiral seed crystals are utilized to recrystallize conglomerates and resolve enantiomers via various methods, such as seeding procedures 2,54,56 like seeded isothermal preferential crystallization (SIPC), seeded polythermal preferential crystallization (S3PC) and autoseeded polythermic programmed preferential crystallization (AS3PC), as well as the presence or absence of in situ racemization, referred to as second order asymmetric transformation. 57 Generally, a dissymmetry with a chiral coformer is induced when forming multicomponent crystals, and outcomes can be either diastereomeric pairs of enantiopure phases or enantiospecific systems, that is, only one enantiomer forms a new multicomponent crystal.…”

“…High enantiopurity for both etiracetam (ee > 98%) and mandelic acid (ee > 95%) enantiomers was achieved by the established technique. 5 Finally, in a study, compressed CO 2 was employed as an antisolvent to create conglomerate cocrystals. Subra-Paternault and colleagues examined the cocrystallization of racemic naproxen with achiral nicotinamide as a coformer.…”

“…Meanwhile, the R,R-enantiomer causes blindness, and naproxen's S-enantiomer is a nonsteroidal antiinflammatory agent, whereas the R-enantiomer results in liver poisoning. 4,5 Moreover, the chiral form of drugs may even have different pharmacokinetic and metabolism properties, e.g., dissimilar pharmacokinetics and drug interactions have been reported for ofloxacin and its S-isomer (levofloxacin). 6 In addition to the biological factors already mentioned, the development of enantiopure compounds is being recommended by regulatory guidelines as there is a growing number of enantiopure chiral drugs on the market.…”