The phase relationship between the pyrazinamide polymorphs α and γ

Abstract

Pyrazinamide is an active pharmaceutical compound for the treatment of tuberculosis. It possesses at least four crystalline polymorphs. Polymorphism may cause solubility problems as the case of ritonavir has clearly demonstrated; however, polymorphs also provide opportunities to improve pharmaceutical formulations, in particular if the stable form is not very soluble. The four polymorphs of pyrazinamide constitute a rich system to investigate the usefulness of metastable forms and their stabilization. However, despite the existence of a number of papers on the polymorphism of pyrazinamide, well-defined equilibrium conditions between the polymorphs appear to be lacking. This paper focusses on the phase behavior of the so-called a and g polymorphs of pyrazinamide, its liquid phase and vapor phase. The melting points and enthalpies of both solid phases have been determined. The equilibrium temperature between a and g was experimentally found at 392(1) K. Moreover, vapor pressures and solubilities of both phases have been determined, clearly indicating that form a is the more stable form at room temperature. High-pressure thermal analysis and the topological pressure-temperature phase diagram demonstrate that the g form is stabilized by pressure and becomes stable at room temperature under a pressure of 260 MPa. File list (2) download file view on ChemRxiv pyrazinamidePhaseBehavior-alpha-gamma-OA.pdf (1.93 MiB) download file view on ChemRxiv Supplementary Materials-OA.pdf (344.86 KiB)

Crystal Structure of Polymorph II and the Pressure–Temperature Phase Diagram of the Dimorphic Anesthetic Butamben

“…The mean expansivity with eq becomes α v,II = 1.98(9) × 10 –4 K –1 , which virtually matches the average value of 2 × 10 –4 K –1 for the expansivities reported for solids of organic compounds in general and for pharmaceuticals. ,,− The expansivity of form I, obtained from eq (α v,L = 3.4(3) × 10 –4 K –1 ), is considerably larger than this average and the expansivity of form II, which is most likely caused by the small temperature range at which the expansion has been determined in addition to the fact that this range lies close to the melting point of form I.…”

The pressure–temperature phase diagram of tetramorphic pyrazinamide

“…Single crystals of α were obtained by sublimation. 2 The γ form was obtained by heating the commercial sample above the α-γ transition temperature (see introduction). δ was obtained by cooling crystallization from 1,4-dioxane 5 and β by cooling crystallization from chloroform.…”

“…1 The solid-state behaviour of pyrazinamide (PZA) has received a lot of attention, because of its four known solid phases, α, β, γ, and δ, and the fact that it has not been clear whether form α or form δ is the most stable form at room temperature. [2][3][4][5][6][7][8][9][10][11][12] Moreover, the phase transitions between these phases exhibit large hysteresis, making it difficult to interpret the thermodynamics behind the transition behaviour. 4,9,10,13 A consensus exists in the literature that form γ is the hightemperature form and that form α is stable at lower temperatures, probably down to room temperature, while form δ is most likely stable below room temperature.…”

“…Considering the large hysteresis in transition temperatures for pyrazinamide samples studied by DSC (differential scanning calorimetry), 2,9,10 the high sublimation pressure of pyrazinamide [14][15][16][17] can be used to obtain information about which phase is the most stable at a given temperature, provided that the solid phase does not transform into another phase. The latter condition appears to be met for pyrazinamide because of the large hysteresis in the system, so this disadvantage in the DSC becomes an advantage for the sublimation pressure measurements.…”

“…In Table 1, previously published data on the phase behaviour of forms α and γ in relation to each other and the liquid can be found. 2 The vapor (V) pressures of forms α and γ reported previously are mentioned here as they will be used in the phase diagram calculations: 2 α → V : ln P = −94 945(1024)/RT + 32.3 (4) (1) γ → V : ln P = −92 192(2024)/RT + 31.5 (7) (2…”