Improving the Solubility of 6‑Mercaptopurine via Cocrystals and Salts

An antitumor drug, 6-mercaptopurine monohydrate, has a low oral bioavailability (about 16%) due to its poor aqueous solubility. To improve its solubility, two cocrystals of 6-mercaptopurine with 4-hydroxybenzoic acid (<b>1</b>) and 2,4-dihydroxybenzoic acid (<b>2</b>), as well as two salts with piperazine in 1:1 (<b>3</b>) and 2:1 (<b>4</b>) stoichiometry, respectively, were obtained and characterized by infrared spectra, powder and single crystal X-ray diffraction. The structures of <b>1</b>–<b>4</b> are assembled via N–H­(pyrimidine)···O­(carboxyl), N–H­(pyrimidine)···N­(imidazole), O–H­(carboxyl)···S, O–H­(hydroxyl)···N­(imidazole), N–H­(pyrimidine)···S, O–H­(carboxyl)···O­(carboxyl) and N–H­(piperazine)···N­(imidazole) hydrogen bonds. After the formation of cocrystals and salts, the solubility of 6-mercaptopurine monohydrate is much improved, and the apparent solubility values of <b>1</b>–<b>4</b> in the phosphate buffer of pH 6.8 are approximately 1.6, 2.0, 14.0, and 4.2 times as large as that of 6-mercaptopurine monohydrate. Interestingly, <b>3</b> transformed to <b>4</b> at 40 °C/75% RH within one month