Pharmaceutical Solid-State Studies

Physicochemical characterization of an active pharmaceutical ingredient (API) in preclinical development is one of the major activities supporting the investigational new drug (IND) application. Furthermore, obtaining the physicochemical profile is key to understanding the API performance attributes, (e.g., absorption, stability, processability) and in setting the direction of the formulation design.

The physical properties assessed for APIs include crystallinity, polymorphic form, particle size and habit, melting and decomposition temperatures, solvent content, and hygroscopicity. A specialized single-crystal X-ray structure determination that proves the atomic connectivity, enhances the understanding of the solidstate nature and strengthens the regulatory and legal filings may also be pursued.

In addition to solid-state assessment, solubility, and stability (both chemical and physical) as a function of pH are determined in aqueous buffers. These data are utilized to determine pKa and the amenability of the API to form salts. Furthermore, solubility data are also obtained in media relevant to the administration route. For oral solid dosages (OSDs), dissolution in water and simulated biorelevant (salivary, gastric, and intestinal) fluids are considered in the context of solubility, or dissolution-rate limited absorption, using the Biopharmaceutical and Developability Classification Systems (BCS/DCS). For solution dosages, which often support toxicological studies and parenteral formulations, solubility in water, co-solvent, and solubilizing agents is obtained.

The knowledge of the polymorphic landscape and the physical stability of the progressed solid form in the relevant solvents/media is required, irrespective if the intended formulation is solid or liquid. Therefore, solids isolated from pH solubility or biorelevant solubility studies are analyzed to determine if a conversion occurred to a more stable hydrate, or in the case of salts, to disproportionated pure free form or counterion. For solution formulations, it is important to ensure that the drug concentration is below the equilibrium solubility of the most stable solid-state form in that formulation.