Successful Computationally Directed Templating of Metastable Pharmaceutical Polymorphs

Abstract

A strategy of using crystal structure prediction (CSP) methods to determine which, if any, isostructural template could facilitate the first crystallization of a predicted polymorph by vapor deposition is extended to the fenamate family. Mefenamic acid (MFA) and tolfenamic acid (TFA) are used as molecules with minimal chemical differences, whereas flufenamic acid (FFA) shows greater differences in the substituents. The three crystal energy landscapes were calculated, and periodic electronic structure calculations were used to confirm the thermodynamic plausibility of possible isostructural polymorphs to experimentally obtainable crystals of the other molecules. As predicted, a new polymorph, TFA form VI, was found by sublimation onto isomorphous MFA form I, using a recently developed technique. MFA and TFA form a continuous solid solution with the structure of MFA I and TFA VI at the limits, but the isomorphous MFA/FFA solid solution does not extended to a new polymorph of FFA. The novel solid solution structure of TFA and FFA was found, and a new isomorphous polymorph TFA VII was found by sublimation onto this new solid solution template. Sublimation of TFA onto a metal surface at the early stage of deposition gave TFA form VIII. We rationalize the formation of new polymorphs of only TFA.

Crystal structures of tolfenamic acid polymorphic forms I and II with precise hydrogen-atom positions for nuclear magnetic resonance studies

“…Tolfenamic acid (TFA; 2-[(3-chloro-2-methylphenyl)amino]benzoic acid; C 14 H 12 ClNO 2 ) is a non-steroidal anti-inflammatory drug (NSAID). It is frequently used as a model for crystallography studies because it displays interesting polymorphism, with eight forms identified to date (Andersen et al, 1989;Ló pez-Mejías et al, 2009;Case et al, 2018). Moreover, its small size and simple crystal structures permit timely computational calculations, which is advantageous for studies investigating its behaviour by nuclear magnetic resonance (NMR).…”

“…A search for crystal structures containing TFA explicitly in its protonated state was performed within the Cambridge Structural Database (CSD version 5.41, update November 2019; Groom et al, 2016). There are eight polymorphs of pure TFA (CSD reference codes KAXXAI, KAXXAI01-07, Andersen et al, 1989;Ló pez-Mejías et al, 2009;Case et al, 2018) and six co-crystal forms (EXAQIE, Fá biá n et al, 2011; SIMDOK/01 & SIMFUS/SIMGAZ/SIMGED, Case et al, 2018; UZUZIA & UZUZOG, Bouanga Boudiombo & Jacobs, 2016; XOWKAX/01, Surov et al, 2015, Wittering et al, 2015. In all cases, the internal hydrogen-bond equvialent to N7-H7Á Á ÁO15 in the present structures is present and the hydroxyl hydrogen atom is attached to the corresponding O16 equivalent.…”

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization

“…A recently discovered form V of indomethacin was found to stabilize in nanoconfinement of the controlled porosity silica (Nartowski, Tedder, Braun, Fábián, & Khimyak, 2015). Metastable polymorphs of olanzapine (Warzecha et al, 2017), tolbutamide (Zhang et al, 2011) and mefenamic acid (Case et al, 2018) were also successfully crystallized using different heterosurfaces.…”

A simultaneous X-ray diffraction–differential scanning calorimetry study into the phase transitions of mefenamic acid

“…Since degradation has been ruled out, the additional reflections must arise from a new polymorph of MA. In an attempt to identify this, predicted crystal structures were explored (Case et al, 2018). None of the low-energy structures provide a good match to the unassigned reflections (Fig.…”