One of the goals of crystallization processes is to obtain a pure form, especially when treating with active pharmaceutical ingredients (API). Different forms of these latter may be accessible (polymorphs of the pure compound, salts/hydrates/co-crystals ...). One form may differ significantly from another by its physicochemical properties, such as its solubility or bioavailability. A multitude of drug substances are marketed under salt form. As salt formation mainly depends on pKa differences between base and acid, an acid/base interacting with a given chiral API is also expected to interact with the racemic version of the API (containing both enantiomers). However, one can question whether this still holds for co-crystals, as these compounds, mostly depend on hydrogen-bonding interactions, which are directional.

We therefore decided to perform a systematic co-crystal search for the enantiopure and racemic version of a given compound, that does not form a salt. We recently identified a series of co-crystals for Levetiracetam, which is an anticonvulsant drug used in the treatment of epilepsy. Levetiracetam is the biologically active enantiomeric form of (RS)-2-(2-oxopyrrolidin-1-yl) butanamide.

Here we identified several co-crystals of Levetiracetam and the racemic equivalent using solvent drop grinding and a wide variety of coformers. XRPD was used to detect co-crystals. X-ray single crystal diffraction analysis was carried out to confirm positive hits. 20 co-crystals of the enantiopure compound were obtained, whereas 29 of the racemic compound were identified. Out of these, 17 share a common coformer.

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1. Amino acids as zwitterionic co-formers for cocrystallization