Predicting the Formation of Multiple Hydrates for a Complex Zwitterionic Drug Compound

A complex pharmaceutical compound that is stable in its zwitterionic form has been found to exist in five different pseudo-polymorphs that differ in the hydration state ranging from the anhydrous desolvate over hemihydrate, dihydrate, and tetrahydrate forms to the pentahydrate. The formation of the higher hydrates leads to undesirable tablet cracking at higher humidities. In this work, particle-based simulation techniques are used to explore the hydrate formation as function of humidity. It is found that a simulation strategy employing Monte Carlo simulations in the isobaric-isothermal and Gibbs ensembles and the transferable potentials for phase equilibria (TraPPE) force field, that is not parameterized against any experimental data for this compound, is able to yield very satisfactory crystal structures for the anhydrate and pentahydrate and to predict the existence of all five hydrates.