Quantum Chemical Study on Mefenamic Acid Polymorphic Forms

Three polymorphic structures of mefenamic acid, which is a very popular drug, have been studied using quantum chemical methods. It has been shown that the centrosymmetric dimer formed due to two O-H center dot center dot center dot O hydrogen bonds is a complex building unit in all of the polymorphic structures under study. On the basis of an analysis of the pairwise interaction energies between molecules, the polymorphic forms I and II are classified as columnar-layered while the polymorphic form III has a columnar structure. The stabilities of the three polymorphic forms of mefenamic acid under ambient conditions (I > II > III) correlate with the degree of anisotropy of the interaction energies between columns (primary basic structural motifs) formed due to stacking interactions. The shear deformation modeling of strongly bound layers in all of the polymorphic structures has not revealed any possibility for deformation of the crystal structure. The construction of the shift energy profiles and calculation of the energy barriers for the displacement along the (100) crystallographic plane in the [100], [010], and [011] crystallographic directions make it possible to explain the experimental data obtained for commercially available polymorphic structure I in a diamond anvil cell. The absence of any local minimum near the starting point on the shift energy profile and the extremely high energy barrier can be considered as criteria for the impossibility of a crystal structure deformation under pressure.

Automated summary

Three polymorphic structures of mefenamic acid were studied using quantum chemical methods. It was found that a centrosymmetric dimer formed by two hydrogen bonds is present in all of the polymorphic structures. Analysis of the interaction energies revealed that polymorphic forms I and II are columnar-layered while form III has a columnar structure. The stabilities of the three polymorphic forms correlate with the degree of anisotropy of the interaction energies between columns.