Pyrazinamide Polymorphs: Relative Stability and Vibrational Spectroscopy

Abstract

The stability of four polymorphs of pyrazinamide, α, β, γ, and δ, was studied under solvent-mediated crystallization, neat and liquid-assisted grinding, polymorph seeding, and ambient storage conditions. In contrast to a recent report that the δ polymorph is the most stable modification (Castro et al. Cryst. Growth Des. 2010, 10, 274), we find that the α polymorph is the thermodynamic form. β, γ, and δ transform to the α phase in the above-mentioned conditions as monitored by infrared, near-infrared, and Raman spectroscopy, differential scanning calorimetry, and X-ray powder diffraction. Transformation to the high temperature γ phase is monitored by thermogravimetric analysis-infrared (TG-IR) spectrometry. A semischematic energy−temperature diagram consistent with phase transformation experiments, thermal measurements, and crystal structure data gives the order α < δ < γ < β at 25 °C (α is the most stable form), whereas at 160 °C γ < α < δ < β (γ stable modification), but at absolute zero δ < α < β < γ (δ stable modification). Even though the δ polymorph has the lowest free energy at absolute zero temperature, the α polymorph is the thermodynamic form under the ambient conditions regime more relevant to crystallization and handling of pharmaceuticals. The intrinsic dissolution rate of the γ form is faster than α and δ polymorphs, but α is the preferred polymorph of pyrazinamide considering both stability and bioavailability criteria. We also report high quality X-ray crystal structures of all the four polymorphs of pyrazinamide (R = 0.0387, 0.0340, 0.0392, and 0.0372 for α, β, γ, and δ).