Production of the metastable δ-polymorphic form of pyrazinamide by isothermal internal seeding anti-solvent crystallization

Abstract

Pyrazinamide, an important drug for treatment of tuberculosis, crystallizes in four different polymorphic forms: commercially available needle-like α-polymorph, plate-like metastable δ-polymorph, prism shaped γ-polymorph, and the highly unstable β-polymorph. Since the fine needle shaped crystals of α-form of pyrazinamide easily agglomerate rendering downstream processing inefficient, the manufacture of plate-like δ-form of pyrazinamide is of significant importance in pharmaceutical industries. In this work, an isothermal internal seeding anti-solvent crystallization is proposed to selectively obtain metastable δ-polymorph of pyrazinamide with desired particle size distribution. The polymorphic purity and the final crystal size distribution can be influenced by careful selection of solvents, anti-solvents, anti-solvent addition rate, stirring rate, and seeding. After a series of screening experiments, 1,4-dioxane and cyclohexane were chosen as solvent and anti-solvent, respectively for the isothermal anti-solvent crystallization at 30 °C. The solubility of pyrazinamide in various 1,4-dioxane-cyclohexane mixtures in the range of 0–50 wt% of cyclohexane was determined gravimetrically at a temperature of 30 °C. A central composite design was then employed to investigate the effects of important process variables such as anti-solvent addition rate, stirring rate, and internal seeding on the process yield and the final crystal size distribution. An empirical model was developed that correlated the mean particle size with these variables and such a model can be used to determine the operating parameters for obtaining a target product size.