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 (1) and 2,4-dihydroxybenzoic acid (2), as well as two salts with piperazine in 1:1 (3) and 2:1 (4) stoichiometry, respectively, were obtained and characterized by infrared spectra, powder and single crystal X-ray diffraction. The structures of 1–4 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 1–4 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, 3 transformed to 4 at 40 °...