Toward Novel Solid-State Forms of the Anti-HIV Drug Efavirenz: From Low Screening Success to Cocrystals Engineering Strategies and Discovery of a New Polymorph

Efavirenz is a first-line anti-HIV drug largely used as a non-nucleoside reverse transcriptase inhibitor as part of antiretroviral therapies. However, there are few reports on its solid-state structures and behaviors. Besides that, crystal engineering strategies have not been well-exploited for this drug and screening methods have been low promising as a source of new solid forms. To the best of our knowledge, only two efavirenz cocrystals have been reported thus far. On the basis of one of the two known cocrystals, namely, that with 4,4′-bipyridine, here we have used a rational approach for coformer selection and prediction of structurally defined multicomponent molecular crystals. Two 4,4′-bipyridine-like coformers, whose heterocycles are spaced by either an ethylene or an ethane moiety, were cocrystallized together with efavirenz into solid-state forms isostructural with respect to that of the drug cocrystal with the antecedent coformer. The formation of a three-molecule supramolecular entity based mai...