Survey of Crystallographic Data and Thermodynamic Stabilities of Pharmaceutical Solvates: A Step toward Predicting the Formation of Drug Solvent Adducts

Solid
form screens of active pharmaceutical ingredients are a key
component of drug development. Beyond forming multiple neat crystal
structures, also known as polymorphs, drugs can also crystallize with
a variety of solvent molecules to form solvates. They can display
physiochemical properties different from the solid form selected for
development. Hence, using computational crystal structure prediction
(CSP) methods to predict the formation of solvates would be valuable
to the pharmaceutical industry. However, CSP for solvate prediction
faces a range of obstacles. This work addresses two important challenges:
the determination of a computationally feasible search space for CSP
on pharmaceutical solvates and the extent to which the formation of
these adducts is driven by thermodynamics. First, a survey of ∼12,000
solvates of druglike molecules extracted from the Cambridge Structural
Database revealed that a majority of them have stoichiometries and
numbers of constituents in the asymmetric unit that are routinely
accessible by CSP. Then, quantum mechanical calculations performed
on a subset of solvates of drug molecules demonstrated that their
formation is generally driven by thermodynamics: ∼80% are more
stable than their constituents by an average of 6.6 kJ·mol–1. The implications on the potential of CSP on pharmaceutical
solvates are discussed.