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 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···O
and was also related to the formation of a π–π
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.