A multicomponent crystal approach with increased permeability of cocrystal of emtricitabine with zwitterionic l-proline†

Abstract

This investigation reports the synthesis and structural characterization of a zwitterionic cocrystal comprising anti-retroviral emtricitabine (ECB) and L-proline (PRL), explicitly designed to enhance intestinal permeability. The cocrystal was synthesized via a liquid-assisted grinding (LAG) methodology, utilizing PRL as a naturally occurring amino acid to modulate the physicochemical attributes of ECB. Comprehensive characterization was performed using multiple analytical techniques, including infrared (IR) spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and powder X-ray diffraction (PXRD), with the crystal structure elucidated through Rietveld refinement of high-resolution PXRD data. The crystal structure (P2₁2₁2₁, Z = 4) indicates alternate packing arrangements involving 2-aminopyrimidine (ECB)⋯ammonium carboxylate (PRL) and hydroxyl (ECB)⋯carboxylate (PRL) heterosynthons. In vitro diffusion studies conducted in pH 6.8 phosphate buffer demonstrated superior permeation characteristics compared to the parent drug, which is correlated with its enhanced solubility and alternate packing motif. Notably, the zwitterionic cocrystal exhibited enhanced diffusion properties with a 1.2-fold increase in flux compared to the native drug. This study provides pioneering insights into the structural aspects of the first zwitterionic amino acid cocrystal with ECB.