Designing Co-Crystals of Pharmaceutically Relevant Compounds That Crystallize with Z′ > 1

Molecules which crystallize with Z ′ > 1 show a markedly stronger tendency to form co-crystals than compounds that crystallize in the pure form with Z ′ = 1. The proportion of bioactive compounds with Z ′ = 1 which form co-crystals is 4.8% as opposed to 7.1% for compounds crystallizing with Z ′ > 1 in the pure state. Moreover, the Z ′ > 1 percentage of the distinct set of molecules in the entire Cambridge Structural Database (CSD) that form co-crystals is 17.7% compared to the CSD average for organic molecules of 11.5%. This tendency is demonstrated experimentally by the design and preparation of a new 1:1 co-crystal of Ornidazole ( Z ′ = 3 in pure form) with 3,5-dinitrobenzoic acid. Two new pure structures with Z ′ > 1 are also predicted and prepared from molecules known to form co-crystals, namely, 2,3,4-trihydroxybenzophenone and 6-phenyl-3(2H)-pyridazinone. These compounds crystallize in their pure form with Z ′ = 2 and 3, respectively.