Investigating the Effect of Emtricitabine Cocrystals with Aromatic Carboxylic Acids on Solubility and Diffusion Permeability

Emtricitabine (ECB), a nucleoside reverse-transcriptase inhibitor, is commonly used to prevent and treat HIV infection in both adults and children. The drug is categorized as a member of the Biopharmaceutics Classification System (BCS) class I with high solubility and moderate permeability. In continuation of the published research work on ECB cocrystals with para-substituted benzoic acids, multicomponent solid form screening was extended with aromatic carboxylic acids in order to improve the diffusion behavior of the native drug. Solvent-assisted grinding of equimolar ECB and aromatic carboxylic acids resulted in three anhydrous cocrystals with meta-hydroxybenzoic acid (MHB), vanillic acid (VAN), and ferulic acid (FER), in addition to three more cocrystal hydrates with para-methyl benzoic acid (PMB), para-chlorobenzoic acid (PCB), and para-nitrobenzoic acid (PNB). The cocrystals were characterized by single-crystal XRD, powder-XRD, DSC/TGA, and FT-IR spectroscopy. In all three cocrystals, the 2-aminopyrimidine···carboxylic acid heterosynthon was found to be prevalent similar to the reported ECB–benzoic acid cocrystal. In ECB–VAN and ECB–MHB, the ECB hydroxyl group was hydrogen-bonded to the hydroxyl groups of the coformers as well as to the carbonyl groups of other ECB molecules, and in ECB–FER, it was interlinked to the ECB carbonyl moiety only. In the other cocrystal hydrates, the ECB-OH group formed hydrogen bonds with water only. The solubility study in a pH 6.8 phosphate buffer indicated the solubility order of ECB > ECB–MHB > ECB–VAN > ECB–FER; i.e., the cocrystal decreased the solubility of the native drug. The diffusion study of ECB and its cocrystals was carried out using a Franz diffusion cell in a pH 6.8 buffer medium which suggests that ECB cocrystals decreased its diffusion rate compared to its native drug due to reduced concentration gradient/solubility and higher hydrophobic interactions.