Isomorphism: `molecular similarity to crystal structure similarity' in multicomponent forms of analgesic drugs tolfenamic and mefenamic acid

Abstract

The non-steroidal anti-inflammatory drugs mefenamic acid (MFA) and tolfenamic acid (TFA) have a close resemblance in their molecular scaffold, whereby a methyl group in MFA is substituted by a chloro group in TFA. The present study demonstrates the isomorphous nature of these compounds in a series of their multicomponent solids. Furthermore, the unique nature of MFA and TFA has been demonstrated while excavating their alternate solid forms in that, by varying the drug (MFA or TFA) to coformer [4-dimethylaminopyridine (DMAP)] stoichiometric ratio, both drugs have produced three different types of multicomponent crystals, viz. salt (1:1; API to coformer ratio), salt hydrate (1:1:1) and cocrystal salt (2:1). Interestingly, as anticipated from the close similarity of TFA and MFA structures, these multicomponent solids have shown an isomorphous relation. A thorough characterization and structural investigation of the new multicomponent forms of MFA and TFA revealed their similarity in terms of space group and structural packing with isomorphic nature among the pairs. Herein, the experimental results are generalized in a broader perspective for predictably identifying any possible new forms of comparable compounds by mapping their crystal structure landscapes. The utility of such an approach is evident from the identification of polymorph VI of TFA from hetero-seeding with isomorphous MFA form I from acetone-methanol (1:1) solution. That aside, a pseudopolymorph of TFA with dimethylformamide (DMF) was obtained, which also has some structural similarity to that of the solvate MFA:DMF. These new isostructural pairs are discussed in the context of solid form screening using structural landscape similarity.

Methods for easy recognition of isostructurality – lab jack-like crystal structures of halogenated 2-phenylbenzimidazoles

“…Molecular placement and molecular conformation of flexible molecules may adjust to the chemical and supramolecular features, thus isostructural crystals can be achieved. 9,10 This way we may succeed to produce a series of crystal structures with a gradual transition in crystal packing arrangements through chemical change. Isostructural crystals are highly similar in their packing arrangement, but may differ to a lesser or greater extent in chemical properties, like seeding and crystal growth, recognition processes, stability, and biological activity.…”

The unexpected discovery of the ninth polymorph of tolfenamic acid

“…30,[33][34][35][36] The other polymorphs (III-VIII), in contrast, have only been reported in a few studies, and their discovery was only possible by crystallisations performed on templating agents, either in solution or by sublimation. [37][38][39] Despite the numerous studies and explorations on the polymorphism of TFA, to our surprise, we came across a new form which was readily crystallised from isopropanol (IPA) by simple fast cooling crystallisation. The new form, form IX, appears concomitantly with the stable form I and the metastable form II from pure TFA solutions in IPA.…”

Quasi-Isostructural Co(II) and Ni(II) Complexes with Mefenamato Ligand: Synthesis, Characterization, and Biological Activity

“…It is often described by the term isostructurality [10] and is profoundly associated with intermolecular interactions and often prompted by symmetry restrictions. A given packing arrangement may tolerate tiny molecular geometry adjustments while keeping the crystals almost isostructural [11,12]. However, certain crystals of coordination compounds which diverse metal ions are characterized by the same chemical constituents may not be classified as entirely isostructural due to subtle differences in their interaction arrangement [13].…”