Solubility Measurements and Correlation of Modafinil in Neat Solvents and Binary Solvent Mixtures

Abstract

The solubility of modafinil (MOD) form I, an antinarcoleptic drug, was measured at temperatures ranging from 278.15 to 333.15 K in ten neat solvents (acetone, acetonitrile, dimethylformamide, ethanol, ethyl acetate, methanol, methylethylketone, 1-propanol, 2-propanol, and water) and two binary solvent mixtures (acetone + water and methanol + water). The results employing the polythermal method demonstrate that the solubility increases with increasing temperature in the neat solvents and at constant composition in the binary solvent mixtures. Moreover, the MOD solubility decreases with an increasing mass fraction of water (antisolvent) in the binary solvent mixture methanol + water. In the binary solvent mixture acetone + water, the solubility exceeds its solubility in neat acetone and water, reaching a maximum at a water mass fraction of ∼20 wt %. Based on the calculated average relative deviation (ARD %), the experimental solubility data agree with the correlated data using the modified Apelblat and λh equations. Additionally, powder X-ray diffraction confirms that the recrystallized solid in the neat and binary solvent mixtures was the commercial MOD form I, except for 2-propanol. Thus, the presented solubility data provide a pathway to engineer crystallization processes for MOD toward integrated manufacturing from flow synthesis to crystallization.