Synthesis and characterization of supramolecular assembly probenecid cocrystal

Abstract

To improve the bioavailability and provide a lead compound for developing formulations of the highly water-insoluble prodrug probenecid (PRO), enhancing its solubility is a crucial challenge that needs to be addressed. Herein, we report the synthesis and solid-state characterization of a new pharmaceutical cocrystal, PRO-BPE, synthesized using trans-1,2-bis(4-pyridyl)ethylene (BPE) to improve the solubility of PRO. The PRO-BPE cocrystals were characterized using various analytical techniques, including differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy, Fourier transform-infrared spectroscopy, and X-ray powder diffraction. Single-crystal X-ray diffraction was performed to determine the crystal structure of PRO-BPE. PRO-BPE crystallized in the triclinic crystal system P-1 space group and its asymmetric unit consists of half a BPE molecule and one PRO molecule. The N1 atoms located at both ends of the BPE molecule form stable hydrogen bonds with two PRO carboxyl hydrogens through N1···H4—O4 (1.777 Å, 166.78°) interactions, whereas the O3 atoms of the carboxylic groups form C1—H1···O3 (2.479 Å, 132.10°) hydrogen bonds with two pyridyl hydrogens, resulting in a stable seven-membered ring structure. Furthermore, these fragments are further assembled via C—H···O intermolecular interactions to form a two-dimensional layered structure. Interestingly, the two pyridyl rings of each BPE molecule engage in π···π interactions with the benzene rings of two other non-coplanar PRO molecules. Finally, a three-dimensional framework structure is formed through intramolecular non-covalent interactions. Comprehensive characterization analyses provided further information regarding PRO-BPE cocrystal formation. Based on the equilibrium solubility results, the water solubility of the PRO-BPE cocrystal was superior to that of pure PRO, with an increase of 2.43 times. In summary, this study provides the first evidence that cocrystals could enhance the solubility of PRO and offers valuable insights into the solid-state properties of PRO-BPE cocrystals.