Physical transformations in solvated pharmaceuticals

Understanding the properties of solid-state compounds, especially solvated drugs, is very important during process/product development. The stability and performance of such solvated drugs can vary drastically with variations in processing and storage conditions. Therefore, it becomes imperative to properly document and control the crystal form present in the formulation. A systematic attempt to characterize phase transformations in solvates and hydrates has thus been presented as a part of this dissertation. Two model compounds, cytosine and indomethacin, are chosen to study the solvation and desolvation pathways in the solid-state. The first study involves the study of solid-state hydration of cytosine using water sorption and X-ray powder diffraction. The effect of processing and relative humidity was studied on the hydration mechanism. Upon quantitative analysis, cytosine hydration in the solid-state gave excellent fits to a combined nucleation-growth equation. Based on the kinetics, hydration can be hypothesized to be a two step-mechanism; the first step entails the formation of hydrate nuclei and the second step involves the growth of these nuclei in a manner governed by the geometry of the crystals. Statistical analysis showed that processing the crystals either by grinding or seeding enhances nucleation and increasing % RH enhances growth of these nuclei. The second study involves the study of desolvation of indomethacin (IMC), a potent non- steroidal anti-inflammatory agent. It exists in three true polymorphic forms (a, Form III and γ) and an amorphous form. It also forms solvates with stoichiometric and non-stoichiometric amounts of enclosed solvent. The desolvation kinetics of two solvates, methanolate and tert-butyl alcohol (TBA) were studied. It was found that the methanolate has an activation energy (34.1 kcal/mol) almost twice that of the TBA solvate (17.6 kcal/mol). The rank order of activation energy of the two solvates correlated well with the hydrogen-bonding strength, crystal packing, and relaxation studies measured using solid-state NMR. FTIR studies of the polymorphic transitions of these solvates indicate that the TBA solvate desolvates to the γ form at all temperatures (60--100°C), whereas the methanol solvate desolvates to an anhydrous metastable form (Form III), which finally transforms to the a form at all the temperatures studied. These trends illustrate how one can manipulate the final crystal form by varying the solvent used in the final purification step