Solubility measurements and thermodynamic modeling of pyrazinamide in five different solvent-antisolvent mixtures

Abstract

Pyrazinamide, an important first line drug for the treatment of Mycobacterium tuberculosis, has different polymorphic forms among which the plate like metastable δ-polymorphic form is desirable for ease of downstream processing. Pyrazinamide has reasonably good solubility in acetone, 1,4-dioxane and methanol; but very low solubility in toluene and cyclohexane. Also, the δ-polymorphic form of pyrazinamide can be obtained by antisolvent crystallization using any of these five solvent-antisolvent pairs. In this work, the solubility of pyrazinamide in acetone-toluene, acetone-cyclohexane, 1,4-dioxane-toluene, 1,4-dioxane-cyclohexane and methanol-toluene mixtures is measured by gravimetric method within the temperature range of 283.15 K to 333.15 K over antisolvent composition upto 70 wt%. The solubility of pyrazinamide increases with increase in temperature for all systems at constant antisolvent (toluene and cyclohexane) composition and decreases with increase in antisolvent composition for the given temperature range for all systems except methanol-toluene system. The solubility of pyrazinamide in methanol-toluene system increases with increase in toluene composition upto 40 wt% and then decreases with increase in toluene composition. Three thermodynamic models namely UNIQUAC, NRTL, and Wilson are used to correlate the solubility of pyrazinamide in above solvent-antisolvent mixtures. A nonlinear optimization technique was used to determine the adjustable parameters of various models. The accuracy of the model correlation has been evaluated on the basis of relative average deviation, root mean square deviation and Akaike Information Criterion. All the models represented the experimental solubility data with good accuracy, the maximum root mean square deviation being 5.21. The dissolution enthalpy and dissolution entropy of pyrazinamide in above solution mixtures were calculated from the slope and intercept of van't Hoff equation which shows that solvation of pyrazinamide in these mixed solvents is endothermic and enthalpy-driven.