Manipulating Solubility and Dissolution through Multicomponent Crystallization.

Abstract

Chemical entities can be arranged into different packing motifs, leading to variation in properties of solid materials. Therefore, solid form optimization is a critical approach to material development. Here crystallization systems with multiple components are investigated to improve performance of materials.

Cocrystallization is a technique to optimize solid forms by introducing a neutral coformer to form multicomponent crystal with the target molecule; this method shows great potential to improve the dissolution of poorly soluble compounds. A novel carbamazepine /p-aminobenzoic acid 4:1 cocrystal is discovered and structurally characterized. Phase stability data demonstrate that it is a thermodynamically unstable form. According to the dissolution experiments, cocrystal stoichiometry is not the only factor that determines the dissolution rate; intermolecular interactions within the crystal play a vital role.

Solid state studies of a class of nitric oxide releasing S-nitroso-N-acetyl-D-penicillamine (SNAP)-doped polymer materials are conducted to investigate the stability mechanism. Crystalline SNAP is detected in polymers and a crystallization based theory is proposed wherein SNAP molecules are partially solubilized in polymers, and the excess SNAP beyond the solubility limit crystallizes and embeds in the polymer. Solubility of SNAP in polymer has been determined by PXRD analysis. It is proposed that the lattice energy of crystalline SNAP is the key to the stability improvement, while the solubilized SNAP is more reactive that decomposes and releases NO. This crystallization based hypothesis has been tested in other SNAP/polymer composites.

It is proposed that the unsuccessful cocrystallization between target compound and a poorly soluble coformer with accessible synthons can be a kinetic result of the coformer solubility limit, which favors the formation of single component crystals that compete with the hypothetical cocrystals. In order to retain a high degree of coformer supersaturation in solution favorable for cocrystallization, soluble polymeric additives were employed. It was demonstrated that solubility and metastable limit of poorly soluble compounds can be altered in presence of soluble polymers. Therefore, utilization of polymer additives is a feasible approach to adjust the metastable zone width which is a potential strategy to facilitate the growth of unattainable cocrystals.