Virtual Screening Identifies New Cocrystals of Nalidixic Acid

Formulation of solids as cocrystals
offers an opportunity to modulate
physical properties, so identification of cocrystal formers (CCFs)
for an active pharmaceutical ingredient is an area of significant
interest. Exhaustive experimental screening would be time-consuming,
but we have developed a computational method for identifying CCFs
that have a high chance of success based on calculated functional
group interaction energies. This virtual screening tool has been applied
to nalidixic acid cocrystals. Calculations on a library of 310 compounds
identified the 44 most promising CCFs for formation of nalidixic acid
cocrystals. Six of these compounds were already known to form cocrystals,
and experimental work was undertaken on the remaining 38 compounds.
X-ray powder diffraction (XRPD) of mixtures obtained from grinding
experiments identified seven CCFs that form new solid phases with
nalidixic acid. Infrared spectroscopy and differential scanning calorimetry
confirm that these new solid phases are different from the pure components.
Further structural characterization was not possible for the skatole,
2,4-dihydroxybenzoic acid, and 3,4-dihydroxybenzoic acid cocrystals,
but X-ray crystal structures were obtained from single crystals of
the 1:1 tert-butylhydroquinone cocrystal and of the
1:1 propyl gallate cocrystal and from the XRPD pattern for the 1:1
2-phenylphenol cocrystal and for the 1:2 indole cocrystal. The results
suggest that success rates in cocrystal screening can be significantly
improved by application of computational filters to select the most
appropriate CCFs for experimental study.