Co-Crystals of Etravirine by Mechanochemical Activation

The co-crystals formation of etravirine with three carboxylic acids was investigated. New co-crystals of etravirine with adipic acid, benzoic acid, and 4-hydroxybenzoic acid have been synthesized by wet milling of ingredients for 120 min. The novelty of these solid forms was first evidenced by powder X-ray diffraction. Their different morphology was evidenced by SEM microscopy. Spectroscopic analyses (FT-IR, MAS-NMR, and XPS) highlighted the hydrogen bonds between etravirine and co-formers, as a result of the solid-state reaction of the ingredients by wet milling. Thermal analyses pointed out that the milling process caused in co-crystals a reduction in the fusion enthalpy and the melting temperature, compared to the values obtained for etravirine. These co-crystals are stable up to four months on storage under extreme conditions, excepting the co-crystal with benzoic acid which begins to transform into a polymorph of etravirine after 30 days. The UV absorption spectra of the samples tested in three simulated physiological media with pH values of 6, 6.3, and 7 have evidenced the conformation change of etravirine due to hydrogen bonds between etravirine and carboxylic acids. (C) 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Automated summary

This study investigated the co-crystals formation of etravirine with three carboxylic acids. New co-crystals of etravirine with adipic acid, benzoic acid, and 4-hydroxybenzoic acid were synthesized by wet milling and their novelty and different morphology were confirmed by various analyses. The wet milling process resulted in a reduction in fusion enthalpy and melting temperature of the co-crystals. These co-crystals showed stability during storage, except for the co-crystal with benzoic acid. UV absorption spectra revealed conformational changes of etravirine due to hydrogen bonds with carboxylic acids.