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 mainly on the NH hydrogen bonding donation from two efavirenz molecules to both pyridyl nitrogens of each coformer unit was kept in the three efavirenz cocrystals. Nevertheless, the introduction of the spacer groups in the coformers has altered the pattern of weak nonclassical hydrogen bonds of the type C-H center dot center dot center dot O and was also related to the formation of a g pi-pi stacking interaction between pyridyl rings of the ethane-spaced coformer. In addition, a polymorphic form of the drug with only one molecule in the asymmetry unit of a C-centered monoclinic lattice is reported for the first time here. It resembles a known orthorhombic form also with Z' = 1 in terms of conformation and assembly of helical hydrogen-bonded catemers, but their organization is unlike.
