(124e) A Comparison of Methods for Capturing Hydrate-Anhydrate Transition Thermodynamics

A key milestone in the small molecule drug development pipeline is the selection of a solid form for both research and commercial development. One of the main deliverables from the solid form selection process is to identify a solid form of the Active Pharmaceutical Ingredient (API) that is physically stable and unlikely to undergo a solid form change during a later stage of manufacturing, transportation, and storage. One significant physical transformation that can occur in a drug product is a conversion from an anhydrous to a hydrate form because a hydrate can have a lower aqueous solubility and dissolution rate by over an order of magnitude relative to the corresponding anhydrous form.

Computational models of hydrate-anhydrate transitions can reduce the risk of unintended transformations during late-stage development. Recent molecular modeling approaches have been developed to compute the stability of anhydrous polymorphs pairs over a range of experimentally relevant temperatures. Here we extend this work to the comparison of anhydrous forms to their corresponding hydrates over a range of temperature as well as ambient humidity levels. The stabilities of multiple different small molecule hydrate-anhydrate pairs are computed using a variety of classical potentials including OPLS, GAFF, and the polarizable AMOEBA force-field. Additionally, the interstitial waters are modeled with the TIP3P, TIP4P, and AMOEBA water models. Overall, we find that the estimated entropy differences between forms are significantly less sensitive to the force-field than the corresponding enthalpy differences. In addition, the entropy differences are in decent agreement with experimental measurements derived from coexistence points. This result suggests that quantitative prediction of the transition temperature could be achieved in conjunction with a sufficiently accurate enthalpy difference estimate at a single temperature.