TY - JOUR

T1 - Relative Stability of Pyrazinamide Polymorphs Revisited: A Computational Study of Bending and Brittle Forms Phase Transitions in a Broad Temperature Range

AU - Dubok, Aleksandr S.

AU - Rychkov, Denis A.

N1 - Funding: This research was funded by the Russian Science Foundation, grant number 21-73-00094, (https://rscf.ru/project/21-73-00094/, accessed on 7 March 2023).

PY - 2023/4

Y1 - 2023/4

N2 - Pyrazinamide may exist in at least four known polymorphic forms, which were obtained experimentally. One of these polymorphs, (α), shows outstanding mechanical properties, demonstrating a significant anisotropic plasticity in a three-point bending test, while the δ form was brittle. Despite a δ → α transition as well as β and γ behavior being experimentally studied, the relative stability of pyrazinamide polymorphs remains unclear and even controversial. In this work we provide a pure computational study of the thermodynamic relationships between all four polymorphs as a function of temperature using periodic DFT calculations. It was shown that the β but not the δ form is the most stable at low temperatures. Moreover, the relative stability of the δ form in comparison to α is questioned, showing that the “brittle to bending” δ → α transition was kinetically hindered in the experiments. We show that α and γ polymorphs were stabilized at higher temperatures due to an entropy term. Finally, the calculated stability of the bending α form of pyrazinamide at room temperature was in perfect agreement with previous experiments, which showed a transformation of all other forms to α during six month storage or grinding.

AB - Pyrazinamide may exist in at least four known polymorphic forms, which were obtained experimentally. One of these polymorphs, (α), shows outstanding mechanical properties, demonstrating a significant anisotropic plasticity in a three-point bending test, while the δ form was brittle. Despite a δ → α transition as well as β and γ behavior being experimentally studied, the relative stability of pyrazinamide polymorphs remains unclear and even controversial. In this work we provide a pure computational study of the thermodynamic relationships between all four polymorphs as a function of temperature using periodic DFT calculations. It was shown that the β but not the δ form is the most stable at low temperatures. Moreover, the relative stability of the δ form in comparison to α is questioned, showing that the “brittle to bending” δ → α transition was kinetically hindered in the experiments. We show that α and γ polymorphs were stabilized at higher temperatures due to an entropy term. Finally, the calculated stability of the bending α form of pyrazinamide at room temperature was in perfect agreement with previous experiments, which showed a transformation of all other forms to α during six month storage or grinding.

KW - DFT

KW - bending crystals

KW - computational study

KW - drug stability

KW - polymorphism

KW - pyrazinamide

KW - relative stability

KW - temperature induced phase transitions

KW - thermodynamic relationship

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85156198595&origin=inward&txGid=e39ecd2e68f86c32ce8e3a372f68cc24

UR - https://www.mendeley.com/catalogue/ff933c51-6c83-31a5-b394-a2e1c09cc2ae/

U2 - 10.3390/cryst13040617

DO - 10.3390/cryst13040617

M3 - Article

VL - 13

JO - Crystals

JF - Crystals

SN - 2073-4352

IS - 4

M1 - 617

ER -