The pressure-temperature phase diagram of tetramorphic pyrazinamide by vapour pressure and synchrotron Xray diffraction under pressure

Ivo B. Rietveld (1) , Kangli Li (1, 2) , G. Gbabode (1)

1 SMS - Sciences et Méthodes Séparatives
2 Zhejiang Shaoxing Institute of Tianjin University

The phase behaviour of drug molecules is important to control the desired polymorph in drug formulations, whether it is to ensure better stability of the formulation or better solubility (solubilization) of the drug. In the case of pyrazinamide, a drug against tuberculosis, four polymorphs are known to exist labelled α, β, γ, and δ [1,2]. Stability studies of this active pharmaceutical ingredient have been complicated due to the very slow transition kinetics observed in DSC measurements [1,2]. Using vapour pressure measurements, in which the reluctance of phase transformation is in fact an advantage, all solid-solid phase transformation temperatures have been determined. This method has been key to map the phase behaviour of pyrazinamide. The use of high-pressure measurements with synchrotron X-ray diffraction at several temperatures from room temperature up to 120 °C has allowed to construct the pressure-temperature phase diagram of the four solid phases of pyrazinamide and the liquid phase (Figure 1). The equations of state of the four polymorphs have been determined at various temperatures in addition to the thermal expansion.

Keywords: Thermodynamics; Phase diagram P-T; Phase behaviour; Active pharmaceutical ingredient

Domains: Chemical Sciences; Cristallography; Chemical Sciences; Theoretical and/or physical chemistry

Ivo B. Rietveld, Kangli Li, G. Gbabode. The pressure-temperature phase diagram of tetramorphic pyrazinamide by vapour pressure and synchrotron Xray diffraction under pressure. 33rd European Crystallographic Meeting, Aug 2022, Versailles, France. ⟨hal-03807993⟩