(723f) Investigations on Co-Milling of Pharmaceutical Cocrystals Via Characterization and Physico-Chemical Stability Evaluation

Active pharmaceutical ingredients (APIs) are most commonly formulated and delivered to the patient in solid state forms. In recent years an alternative API solid-state form has witnessed increasing interest, namely cocrystals of APIs. Cocrystals of APIs have the ability to tailor the physicochemical as well as mechanical properties of an API, whilst retaining its biological function. Therefore cocrystals of APIs provide exciting opportunities in the pharmaceutical industry. The most current literature is based on discovery of novel cocrystals systems and improvement of their physicochemical properties. Despite its widespread research in the field of cocrystals, development of end product formulation is less viable in literature. Drug product manufacturing includes complex mechanical stress associated processing steps such as milling, granulation, and tableting, all induce solid-state phase transformations (polymorph, solvate) further cocrystals may dissociate into its individual components. In order to enhance understanding of cocrystals API solid state processing, in this study we first introduced co-milling of an API cocrystal with tablet excipient, and then studied the stability of the co-milling product. Furthermore molecular level analysis of cocrystals constituents and excipients was evaluated using molecular modelling (Density functional theory calculations).

A 1:1 stoichiometric amounts of THP and 4ABA with different ratios of tablet excipients (PEG, HPMC, PVP, MCC and Lactose) were placed in 25-ml grinding jar at 30 Hz for predetermined periods of time. Co-milled samples were characterised for formation of cocrystals and phase transformation using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and particle size analysis. The study has demonstrated that co-milling in the presence of the HPMC and PEG yielded pure cocrystals. More importantly, such prepared THP-4ABA pharmaceutical cocrystals were also stable under milling conditions.