An anti-solvent/solvent mixture approach for pharmaceutical cocrystals and salt at pilot-scale

Abstract

Cocrystals have generated a lot of interest due their ability to influence: physiochemical properties, optical properties etc. These properties are important in the pharmaceutical and food industry.
In this thesis, the scale up of cocrystal synthesis is studied using a novel slurry cocrystallisation approach involving an anti-solvent and solvent mixture. The anti-solvent composition is typically > 97 %, with the solvent comprising the rest. This counter-intuitive approach resulted in > 95 % caffeine-oxalic acid cocrystal yield in less than 2 hrs. The mixed anti-solvent/solvent approach was applied successfully to four other cocrystal systems and a salt.
The level of caffeine-oxalic acid cocrystal yield observed varied with the solvent used in the mixture. Using statistical analysis, it was shown that the hydrogen bonding Hansen solubility parameter (δH) of the solvent and oxalic acid solubility were the two most important factors for increasing cocrystal yield. The parameter Ra/(Oxalic acid) , however, showed even better correlation (94.2 %) with caffeine-oxalic acid cocrystal yield than both δH (78 %) and oxalic acid solubility (88 %). Ra is the Hansen solubility distance between the solvent and the coformer (oxalic acid) and includes all three Hansen solubility parameters (δD, δP, δH).
Four new cocrystals (A-D) of 2-aminopyrimdine-glutaric acid were crystallised from three different solvents and their crystal structures reported. Two of them (A and B) are 1:1 polymorphs. The glutaric acid molecule in A has a linear conformation but it is twisted in B. Variable temperature PXRD analysis indicates that A and B are monotropic polymorphs, with A transforming to B at ≈73C, prior to the melting of B. D is a cocrystal-salt hybrid. D was crystallised from the same solvent as cocrystal B supporting the idea of a cocrystal-salt continuum when both the neutral and ionic forms are present in appreciable concentrations in solution.