The solid-liquid phase equilibrium solubility of doxycycline hyclate (DH) in 10 pure organic solvents and cosolvent mixtures DMF (1) + ethanol (2), DMSO (1) + ethanol (2) and acetone (1) + ethanol (2) at a temperature range from 278.15 to 323.15 K was measured and discussed. The results indicated that the experimental mole fraction (x) of DH in 10 neat solvents followed this order: acrylic acid > acetic acid > 1-butanol > 1-pentanol > tetrahydrofuran > isobutyl alcohol > isopropyl alcohol> propanoic acid > acetone > acetonitrile, and temperature affected obviously the solubility especially in acetic acid. Moreover, the experimental mole fraction (x) of DH increased with mass concentration rising of DMF or DMSO in DMF (1) + ethanol (2) or DMSO (1) + ethanol (2), and decreased gradually with mass concentration rising of acetone in acetone (1) + ethanol (2). The experimental solubility in all solvents was correlated better lower values of RAD and RMSD.