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

Emtricitabine (ECB), a nucleosidereverse-transcriptase inhibitor,is commonly used to prevent and treat HIV infection in both adultsand children. The drug is categorized as a member of the BiopharmaceuticsClassification System (BCS) class I with high solubility and moderatepermeability. In continuation of the published research work on ECBcocrystals with para-substituted benzoic acids, multicomponentsolid form screening was extended with aromatic carboxylic acids inorder to improve the diffusion behavior of the native drug. Solvent-assistedgrinding of equimolar ECB and aromatic carboxylic acids resulted inthree anhydrous cocrystals with meta-hydroxybenzoicacid (MHB), vanillic acid (VAN), and ferulic acid (FER), in additionto three more cocrystal hydrates with para-methylbenzoic acid (PMB), para-chlorobenzoic acid (PCB),and para-nitrobenzoic acid (PNB). The cocrystalswere characterized by single-crystal XRD, powder-XRD, DSC/TGA, andFT-IR spectroscopy. In all three cocrystals, the 2-aminopyrimidine center dot center dot center dot carboxylicacid heterosynthon was found to be prevalent similar to the reportedECB-benzoic acid cocrystal. In ECB-VAN and ECB-MHB,the ECB hydroxyl group was hydrogen-bonded to the hydroxyl groupsof the coformers as well as to the carbonyl groups of other ECB molecules,and in ECB-FER, it was interlinked to the ECB carbonyl moietyonly. In the other cocrystal hydrates, the ECB-OH group formed hydrogenbonds with water only. The solubility study in a pH 6.8 phosphatebuffer indicated the solubility order of ECB > ECB-MHB >ECB-VAN> ECB-FER; i.e., the cocrystal decreased the solubilityofthe native drug. The diffusion study of ECB and its cocrystals wascarried out using a Franz diffusion cell in a pH 6.8 buffer mediumwhich suggests that ECB cocrystals decreased its diffusion rate comparedto its native drug due to reduced concentration gradient/solubilityand higher hydrophobic interactions. Emtricitabinecocrystals with vanillic acid, 3-hydroxybenzoicacid, and ferulic acid were confirmed by their crystal structures.The cocrystals exhibited similar or lower dissolution/diffusion propertieswhich correlated with the concentration gradient, higher nonpolarcontacts, and higher energy.