Thermodynamic Stability of Crystal Forms in Pharmaceutical Formulations

Active pharmaceutical ingredients (APIs) are preferably administered orally as solid formulations. The API may be formulated as an amorphous form, crystalline polymorph, or a crystalline form with an additional component present in the crystal lattice (hydrate, solvate, co crystal (CC), or salt). The form with the optimal properties, such as high aqueous solubility or desired API release profile, is selected for the formulation. However, the beneficial properties of a specific solid form might also result in a decreased physical or chemical stability, which must be guaranteed over the entire period of production, transport, storage, and administration. Typically, expensive and time-consuming stability tests must be performed for each formulation candidate to evaluate the environmental influence of temperature, light, and relative humidity (RH).
This work proposes an approach to predict the stability of formulations based on thermodynamic calculations with the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). Thus, predicted phase diagrams are used to determine the critical stability parameters temperature and RH for different formulation types (amorphous or crystalline).
The developed approach allows evaluating different formulation strategies based on a minimal number of experiments without expensive and time-consuming long-term stability tests. Thus, PC-SAFT proved to be a valuable model to predict the stability of pharmaceutical formulations.