Emtricitabine (ECB) afforded dimorphic cocrystals (Forms I, II) of benzoic acid (BA), whereas p-hydroxybenzoic acid (PHBA) and p-aminobenzoic acid (PABA) resulted in high Z″ cocrystals. Intriguingly, the Z″ of cocrystals are trends from 2 to 14 based on the manipulation of functional groups on the para position of BA (where the H atom is replaced with that of OH or NH2 group). The ECB–PABA cocrystal consists of six molecules each and two water molecules in the asymmetric unit (Z″=14) with 2D planar sheets representing the rare pharmaceutical cocrystal. The findings suggest that the increment of H bond donor(s) systematically via a suitable coformer is in correspondence with attaining high Z″ cocrystals. Further, solid state NMR spectroscopy in conjunction with single crystal X-ray diffraction is demonstrated as a significant tool to enhance the understanding of the number of symmetry independent molecules in the crystalline lattice and provide insights to the mechanistic pathways of crystallization.

Emtricitabine (ECB) is an anti-retroviral drug that inhibits HIV reverse transcriptase and prevents transcription of RNA to DNA. ECB exhibits high solubility and low permeability (log P < 0). To modify the diffusion behavior of ECB, a high throughput cocrystal screening has been carried out with coformers that contain carboxylic acid/amide functionalities via solvent assisted grinding. The screening study resulted in the formation of cocrystals with benzoic acid (BA), caprolactam (CPR), and salts with 2,6-dihydroxybenzoic acid (DHBA), malonic acid (MLN), maleic acid (MLE), and saccharin (SAC), which were confirmed with single crystal X-ray diffraction. In addition, 15N solid state NMR spectroscopy was exploited to define the ionization state of the multicomponent systems. The 2-aminopyrimidine homodimer of the cytosine analogue in the ECB is replaced by aminopyrimidine···carboxylic acid/amide in the cocrystals and aminopyrimidinium···carboxylate/saccharinate heterosynthons in the salts. The terminal hydroxyl group of the ECB forms a hydrogen bond with its carbonyl group, which is consistent in the ECB–BA cocrystal, ECB–DHBA and ECB–MLN salts. In addition, the hydroxyl group of ECB is hydrogen bonded with the relatively stronger acceptors like the carbonyl/sulfonyl group of caprolactam, maleate, and saccharinate in their corresponding multicomponent crystals. The diffusion studies of ECB multicomponent crystals using a Franz diffusion cell suggest that the ECB–BA cocrystal exhibited an enhanced diffusion and flux compared to that of native drug and other multicomponent crystals. An inverse correlation was observed partially between the flux values with crystal densities and binding energies of the ECB multicomponent systems.

Lesinurad (systematic name: 2-{[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, C 17 H 14 BrN 3 O 2 S) is a selective uric acid reabsorption inhibitor related to gout, which exhibits poor aqueous solubility. High-throughput solid-form screening was performed to screen for new solid forms with improved pharmaceutically relevant properties. During polymorph screening, we obtained two solvates with methanol (CH 3 OH) and ethanol (C 2 H 5 OH). Binary systems with caffeine (systematic name: 3,7-dihydro-1,3,7trimethyl-1H-purine-2,6-dione, C 8 H 10 N 4 O 2 ) and nicotinamide (C 6 H 6 N 2 O), polymorphs with urea (CH 4 N 2 O) and eutectics with similar drugs, like allopurinol and febuxostat, were prepared using the crystal engineering approach. All these novel solid forms were confirmed by XRD, DSC and FT-IR. The crystal structures were solved by single-crystal and powder X-ray diffraction. The crystal structures indicate that the lesinurad molecule is highly flexible and the triazole moiety, along with the rotatable thioacetic acid (side chain) and cyclopropane ring, is almost perpendicular to the planar naphthalene moiety. The carboxylic acid-triazole heterosynthon in the drug is interrupted by the presence of methanol and ethanol molecules in their crystal structures and forms intermolecular macrocyclic rings. The caffeine cocrystal maintains the consistency of the acid-triazole heterosynthons as in the drug and, in addition, they are bound by several auxiliary interactions. In the binary system of nicotinamide and urea, the acid-triazole heterosynthon is replaced by an acidamide synthon. Among the urea cocrystal polymorphs, Form I (P1, 1:1) consists of an acid-amide (urea) heterodimer, whereas in Form II (P2 1 /c, 2:2), both acidamide heterosynthons and urea-urea dimers co-exist. Density functional theory (DFT) calculations further support the experimentally observed synthon hierarchies in the cocrystals. Aqueous solubility experiments of lesinurad and its binary solids in pH 5 acetate buffer medium indicate the apparent solubility order lesinurad-urea Form I (43-fold) > lesinurad-caffeine (20-fold) > lesinurad-allopurinol (12-fold) ' lesinurad-nicotinamide (11-fold) > lesinurad, and this order is correlated with the crystal structures.

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Metaxalone forms isostructural cocrystals with nicotinamide and salicylamide that offer a solubility advantage compared to the native drug. A drug–drug homosynthon is retained in all the cocrystal structures.