Theoretical and experimental cocrystal screening of temozolomide with a series of phenolic acids, promising cocrystal coformers

The virtual cocrystal screening approach based on molecular electrostatic potential surface (MEPS) maps is a fast and feasible computational method to estimate the probability of cocrystal formation by calculating the difference in the interaction site pairing energies of monomers and that of their assemblies prior to experimental screening. In this paper, we report 12 cocrystal forms of temozolomide with mono-, di-, and trihydroxy benzoic acids, namely, 3-hydroxy-, 2,4-dihydroxy-, 2,5-dihydroxy-, 2,6-dihydroxy-, 3,4-dihydroxy-, and 3,4,5-trihydroxy-benzoic acids, as well as benzoic acid, as pharmaceutical coformers for the first time. 10 single crystals out of the 12 cocrystal forms were obtained and unequivocally determined by single-crystal X-ray diffraction, which clarified spatial arrangements, molecular conformations, and supramolecular synthons. MEPS further gains some insights into the sites of hydrogen bonding interactions for exploring combination patterns in these assemblies. Modulated stability of TMZ was successfully achieved by cocrystallization with these acids.