Separation of Etiracetam Enantiomers Using Enantiospecific Cocrystallization with 2-Chloromandelic Acid

Abstract

Chirality plays an important role in the pharmaceutical industry since the two enantiomers of a drug molecule usually display significantly different bioactivities, and hence, most products are produced as pure enantiomers. However, many drug precursors are synthesized as racemates, and hence, enantioseparation has become a significant process in the industry. Cocrystallization is one of the attractive crystallization approaches to obtain the desired enantiomer from racemic compounds. In this work, we propose a chiral resolution route for an antiepileptic drug, S -etiracetam ( S -ETI), via enantiospecific cocrystallization with S -2-chloro- S -mandelic acid (CLMA) as a coformer. The experiments indicate that the system is highly enantiospecific; S -2CLMA cocrystallizes only with S -ETI but not with R -ETI or RS -ETI. Therefore, the chiral purification of S -ETI can be achieved efficiently with a 69.1% yield and close to 100% enantiopurity from the racemic solution. Additionally, structural simulations of the S -ETI: S -2CLMA cocrystal reveal that the cocrystal structure has higher thermodynamic stability than that of R -ETI: S -2CLMA by about 5.5 kcal/mol (per cocrystal formula unit), which helps to confirm the favorability of the enantiospecification in this system.

On the pairwise cocrystallization of racemic compounds

“…The cocrystal of S -2-chloromandelic acid-levetiracetam has recently been used in the context of an enantiospecific resolution. 37…”

“…The cocrystal of S-2-chloromandelic acidlevetiracetam has recently been used in the context of an enantiospecific resolution. 37 All other combinations led to the formation of full racemic compounds (both enantiomers of both compounds present). The cocrystal between flurbiprofen with etiracetam led to the formation of a cocrystal that might be considered a co-drug.…”

Chiral resolution methods for racemic pharmaceuticals based on cocrystal formation

“…The devised system was extremely efficient and enantiospecific, resulting in the coformer just co-crystallizing with S -etiracetam with a yield of 69.1% and an enantiomeric excess close to 100%. 52…”

“…The devised system was extremely efficient and enantiospecific, resulting in the coformer just co-crystallizing with S-etiracetam with a yield of 69.1% and an enantiomeric excess close to 100%. 52 Enantiospecific cocrystallization procedures are also employed for spontaneous chiral resolution and dual pharmaceutical molecule formulation. In this regard, Leyssens et al 8 cocrystallized racemic ibuprofen, a nonsteroidal anti-inflammatory drug, with S-etiracetam or levetiracetam as a coformer and made an enantiospecific cocrystal of S-ibuprofen-levetiracetam with an 87.6% ee (Fig.…”

Case of Chiral Resolution through Converting Two Racemic Compounds into a Conglomerate

“…Different enantiomers of a chiral drug have different or opposite properties in terms of physiochemical and biochemical effects in the pharmaceutical industry. , Regulatory agencies increasingly require that chiral drugs should be used in the optically pure form . Generally, there are two main approaches to obtaining pure enantiomers: (a) asymmetric synthesis of one enantiomer and (b) chiral resolution of racemates.…”