Ternary solid-liquid equilibria for crystallization of pharmaceutical components

Isothermal titration calorimetry (ITC) has been used to develop a method to construct the solid-liquid equilibrium line in ternary systems containing the solute to precipitate and an aqueous mixed solvent. The method consists in measuring the heat of dissolution of a solid component (the solute) during successive additions of the liquid solvent. The cumulated heat, resulting from the successive heat peaks obtained for the different injections of known volumes of solvent, plotted vs. the ratio of the numbers of moles n (solvent) /n (solute) is represented by two nearly straight lines. The intersection of the two lines gives the solubility limit and the corresponding enthalpy of dissolution of the solute in the solvent. Phase diagrams have been established at 303.15 K in binary mixed solvents ethanol-water over the whole concentration range for four components of pharmaceutical interest, namely: caffeine, nicotinamide, nicotinic acid and salicylic acid.