New Solid Forms of the Anti-HIV Drug Etravirine: Salts, Cocrystals, and Solubility

Thirteen
new solid forms of etravirine were realized in the process
of polymorph and cocrystal/salt screening to improve the solubility
of this anti-HIV drug. One anhydrous form, five salts (hydrochloride,
mesylate, sulfate, besylate, and tosylate), two cocrystals (with adipic
acid and 1,3,5-benzenetricarboxylic acid), and five solvates (formic
acid, acetic acid, acetonitrile, and 2:1 and 1:1 methanolates) were
obtained. The conformational flexibility of etravirine suggests that
it can adopt four different conformations, and among these, two are
sterically favorable. However, in all 13 solid forms, the active pharmaceutical
ingredient (API) was found to adopt just one conformation. Due to
the poor aqueous solubility of the API, the solubilities of the salts
and cocrystals were measured in a 50% ethanol–water mixture
at neutral pH. Compared to the salts, the cocrystals were found to
be stable and showed an improvement in solubility with time. All the
salts were dissociated within an hour, except the tosylate, which
showed 50% phase transformation after 1 h of the slurry experiment.
A structure property relationship was examined to analyze the solubility
behavior of the solid forms.