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

Subham Ranjan,C. Malla Reddy,Ramesh Devarapalli,Shubham Deolka,Venu R. Vangala,Subhankar Saha,Sudeshna Kundu

doi:10.1107/s205225251901604x

Subham Ranjan, C. Malla Reddy + Show 5 more

Open Access

https://doi.org/10.1107/s205225251901604x

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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-di-methyl-amino-pyridine (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 di-methyl-formamide (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.

Highlights

In crystal engineering, the aspects of isostructurality and polymorphism have always been intriguing for implications on the crystal packing and the potential impact on the properties of crystalline solids
Two crystals are said to be isostructural if they have the same crystal structure but not necessarily the same cell dimensions nor the same chemical composition, whereas two crystalline solids are isomorphous if both have the same unit-cell dimensions and space group (Kalman et al, 1993)
We have seen the close match between the powder X-ray diffraction (PXRD) patterns of the same molar ratio pairs of multicomponent solids of tolfenamic acid (TFA) and mefenamic acid (MFA) (e.g. 1:1 salts of TFA and MFA)

Summary

Introduction

The aspects of isostructurality and polymorphism have always been intriguing for implications on the crystal packing and the potential impact on the properties of crystalline solids. Two crystals are said to be isostructural if they have the same crystal structure but not necessarily the same cell dimensions nor the same chemical composition, whereas two crystalline solids are isomorphous if both have the same unit-cell dimensions and space group (Kalman et al, 1993). Coles et al recently demonstrated a counterintuitive case of two polymorphic forms with close structural resemblance which they called isostructural polymorphs (Coles et al, 2014; Fabian & Kalman, 2004). This term has been used in a different (rather unfitting) context to describe isostructural relationships between two forms of polymorphic analogous molecular pairs (Nath et al, 2008)

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