(600c) A Comparison of Methods for Computing Relative Hydrate-Anhydrous Stability with Molecular Simulation

The spontaneous transformation of a pharmaceutical solid from an anhydrous crystal into a hydrated form represents a significant risk to the performance of oral drug products due to the potential impact on stability, bioavailability, and solubility among other properties. Here, we explore 10 classical free energy simulation protocols to evaluate the thermodynamic stability of hydrated crystals relative to their anhydrous forms. Molecular dynamics simulations are used to calculate the Gibbs free energies of the crystals of three pharmaceutically relevant systems using two fixed-charge potentials, GAFF and OPLS, as well as the polarizable AMOEBA model. In addition, we explore a variety of water models, including TIP3P, TIP4P, and AMOEBA for both the interstitial waters and for the effects of ambient humidity.

The AMOEBA model predicts free energy values closest to experimental measurements among the models examined. Despite this improved accuracy, we find that no single model produces reliable phase-boundaries between hydrated and anhydrous crystals from theory alone. However, we show here that accurate phase diagrams can be recovered from the simulations by introducing a single known coexistence point determine from experiments. Using this single coexistence point, the phase boundaries for the three systems in this work are predicted to within 10% humidity along the temperature range of 15 °C to 75 °C. Furthermore, we show that with this hybrid experimental-theoretical modelling approach, the differences between the various potentials and water models become insignificant and all models yield accurate phase boundaries. An analysis of the dipole moments in the crystalline system suggests that this insensitivity to polarization results from significant cancellation of errors when using the fixed-charge potentials.