New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms

The asthma therapeutic theophylline exists in at least
three anhydrous
polymorphs and a monohydrate. The single-crystal X-ray structure of
the high-temperature polymorph form I is presented for the first time,
and the energetic relationship between forms I and II is investigated
using the partial charges and chemical hardness analysis (PACHA) algorithm.
It is shown that the interactions in the form I crystal network are
stronger, especially the hydrogen bond. The single-crystal neutron
structure of the monohydrate demonstrates static disorder of the water
molecule as well as dynamic disorder of the methyl groups. PACHA investigations
based on the neutron coordinates reveal that the homomeric interactions
in this form are stronger than the interaction of the water with the
host molecules. The dehydration of the hydrate should thus leave the
theophylline network intact, explaining the isomorphic powder X-ray
diffractograms of the monohydrate and its dehydrated form III.