Chiral Resolution of RS-Baclofen via a Novel Chiral Cocrystal of R-Baclofen and L-LEMandelic Acid

Baclofen is a drug currently sold in a racemic form, despite R-baclofen having far higher pharmacological activity than S-baclofen. The objective of this study is to find new cocrystals of baclofen suitable for application in a complete resolution process to obtain pure baclofen enantiomers, using the difference in the solubilities of the two cocrystals formed with a particular chiral coformer. Cocrystals were screened using both neat and solvent-assisted grinding. By screening 20 potential coformers, only a single diastereomeric cocrystal system was found between the enantiomers of baclofen and L-mandelic acid. Although both baclofen enantiomers formed cocrystals with this coformer, only R-baclofen:L-mandelic acid, one of the pair, formed crystals suitable for X-ray diffraction. The crystal was identified as a zwitterionic cocrystal: baclofen was in its zwitterionic form while L-mandelic acid was in the free acid form. The choice of solvent for cocrystallization was found to be vital since in most solvents the solubility of mandelic acid was far higher than that of baclofen. A suitable solvent for the resolution of RS-baclofen with an equimolar amount of L-mandelic acid via slurry crystallization was a mixture of 12:1 water/acetic acid, which gave a maximum theoretical yield of 74.8%, calculated from the eutectic point in the phase diagram of the diastereomeric cocrystals. Slurry crystallization experiments performed under these conditions resulted in a product of 95% enantiomeric purity with a 40.8% yield. The baclofen enantiomer was easily separated from the cocrystal product by dissolution in methanol, which dissolved mandelic acid and recrystallized baclofen, to obtain 96.7% enantiopurity of baclofen polymorph B. A method involving liquid-assisted grinding followed by dissolution is also proposed. The two diastereomeric cocrystals were conveniently formed by liquid-assisted grinding; then, dissolving the less-stable S-baclofen:L-mandelic acid cocrystals using the same solvent used in the slurry crystallization method gave the same result within a shorter time.

Automated summary

This study aims to find suitable cocrystals of baclofen to achieve separation of its enantiomers. After screening 20 potential coformers, only one diastereomeric cocrystal system between the enantiomers of baclofen and L-mandelic acid was found. Slurry crystallization experiments with a 12:1 water/acetic acid mixture resulted in a product with 95% enantiomeric purity.