Microbatch under-oil salt screening of organic cations: single-crystal growth of active pharmaceutical ingredients

Abstract

Multicomponent solid forms of active pharmaceutical ingredients represent a modern method of tuning their physicochemical properties. Typically, salts are the most commonly used multicomponent solid form in the pharmaceutical industry. More than 38% are formulated as organic cations. Salt screening is an essential but demanding step when identifying the most appropriate formulation. The microbatch under-oil crystallization technique of proteins has been combined with the previously developed high-throughput vapour-diffusion screening for use as a novel method of primary salt screening of organic cations. The procedure allows the set up of about 100 crystallization experiments per 30 min. This requires between 17 and 564 mg of screened cationic active pharmaceutical ingredients, which were of moderate to very high water solublity. Five distinct organic salts, three of them diverse active pharmaceutical compounds or the other enantiomer thereof, in the form of chloride salts were tested. The screening was extremely successful; at least two new single-crystal structures could be obtained for each particular compound and many more salts as single crystals were formed compared with our previous vapour-diffusion method.