Polymorphism and Particle Formation Pathway of Carbamazepine during Sonoprecipitation from Ionic Liquid Solutions

In this work, liquid antisolvent precipitation of carbamazepine (CBZ), an anticonvulsant and antiepileptic drug, was carried out from its solutions in an ionic liquid (IL), [BMIM]­[Cl], using water as an antisolvent. Precipitation was carried out in the presence of ultrasound and additives such as hydroxyl propyl methyl cellulose (HPMC), bovine serum albumin (BSA), and polyvinylpyrrolidone (PVP). In-situ Raman spectroscopy was employed to uncover any polymorphic transformations that might occur in the solution during precipitation. It was found that the dihydrate (DH) form of CBZ precipitated from IL solution irrespective of the additive or the mixing condition. However, characterization of the freeze-dried CBZ powders obtained from liquid antisolvent (LAS) precipitation revealed that the DH CBZ underwent dehydration and transformed selectively to anhydrous Form III (P-monoclinic) and Form I (triclinic) in the absence and presence of additives, respectively. The additives were found to influence the final polymorphic outcome by “kinetically entrapping” the metastable Form I during dehydration. The morphology of CBZ particles obtained under all conditions was found to be long needle-like where each individual needle appeared to have been formed by aggregation of several smaller needles. Time-resolved scanning electron microscopy studies show that the morphology of CBZ particles is a result of a non-classical particle formation pathway followed by secondary nucleation and growth.