The solubility of an active pharmaceutical ingredient (API) in various solvents is extremely important for its manufacturing and development as a drug. In this work, the solubility of two polymorphs of clopidogrel hydrogen sulfate (CHS) in the solvents of isopropanol (IPA) and ethyl acetate (EA) has been experimentally measured and theoretically predicted. The nonrandom two-liquid (NRTL) and universal quasichemical (UNIQUAC) models have been employed for the solubility prediction. The results show that, the solubility of both polymorphs generally increases with the temperature and the content of isopropanol in the mixed solvent, and meanwhile polymorph I has a higher solubility than polymorph II which demonstrates that polymorph I is a metastable form. Through taking into account that the binary interaction parameters a(ij) (i not equal j) are temperature-dependent, both NRTL and UNIQUAC can well predict the solubility of the polymorphs of clopidogrel hydrogen sulfate in organic solvents with the average relative deviation of 0.0545 and 0.0417, respectively. Finally the free energy difference between two polymorphs, Delta G, indicating their transformation tendency, has been calculated as a function of temperature, and in this way the transition temperature between two polymorphs is obtained as T = 384.4 K. (C) 2015 Elsevier Ltd. All rights reserved.