Dual-Drug Chiral Resolution: Enantiospecific Cocrystallization of (S)-Ibuprofen Using Levetiracetam

Abstract

In this work we show the feasibility of resolving a racemic drug substance with a second chiral drug. Via enantiospecific cocrystallization a dual-drug cocrystal is obtained. Such a method can be useful not only for chiral resolution but also for the parallel creation of dual-drug formulations. Here, racemic ibuprofen is resolved using levetiracetam through the formation of an enantiospecific cocrystal. Cocrystallization is utilized as a resolution tool for (in this case) (S)-ibuprofen, the active enantiomer. To find the right conditions to resolve the system, the appropriate ternary and quaternary phase diagrams were constructed. Since these diagrams are governed by thermodynamics, where the kinetic forms are prevented via seeding, the system is robust under scale-up conditions and is an interesting alternative to chiral chromatography or enantioselective synthesis for the pharmaceutical industry.

Cocrystal of Ibuprofen–Nicotinamide: Solid-State Characterization and In Vivo Analgesic Activity Evaluation

“…The formation of cocrystalline phase of ibuprofen with other carriers has also been reported. These include 2-aminopyrimidine and other pyridine derivatives [ 15 , 20 ] and levetiracetam [ 21 ]. However, nicotinamide is considered as better carrier, as it is categorized as GRAS (generally recognized as safe).…”

Cocrystal design by network-based link prediction

“…21 Furthermore, it has recently been shown how enantiospecific cocrystals (i.e. a cocrystal that is formed preferentially with one of the enantiomers by the addition of a chiral coformer) can be used to separate a racemic compound forming molecule, 22,23 essentially being the neutral analogue of the widely used resolution via diastereomeric salts. Hence, cocrystallization also has large potential for applications regarding chirality, and could become a key element in enabling resolution.…”

Ionic Co‐Crystal Formation as a Path Towards Chiral Resolution in the Solid State

“…S ‐2‐(2‐oxopyrrodin‐1‐yl) butanamide, successfully co‐crystallized with S ‐mandelic or S ‐tartaric acid, although—surprisingly—did not co‐crystallize with either R ‐mandelic or R ‐tartaric acid . Similar results have been obtained upon co‐crystallisation of levetiracetam with S ‐ibuprofen: no co‐crystallisation with R ‐ibuprofen was observed . Furthermore, a search in the CSD, followed by targeted laboratory co‐crystallization experiments, estimated that 85 % of co‐crystal systems behave enantiospecifically .…”

“…[8] Similar results have been obtained upon co-crystallisation of levetiracetam with S-ibuprofen:n oc o-crystallisation with R-ibuprofen was observed. [9] Furthermore, as earch in the CSD, followed by targeted laboratory co-crystallizatione xperiments,e stimated that 85 %o fc o-crystal systems behave enantiospecifically. [6] To the best of these authors'k nowledge, these are the only studies describing conglomerate formation via co-crystallization in all-organic systems.…”