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. 2012 Jun 20;134(24):9872-5.
doi: 10.1021/ja302601f. Epub 2012 Jun 12.

Nonamorphism in flufenamic acid and a new record for a polymorphic compound with solved structures

Vilmalí López-Mejías  1 , Jeff W Kampf, Adam J Matzger
Affiliations

Nonamorphism in flufenamic acid and a new record for a polymorphic compound with solved structures

Vilmalí López-Mejías et al. J Am Chem Soc. .

Abstract

The unprecedented polymorphism of the non-steroidal anti-inflammatory drug (NSAID) flufenamic acid (FFA) is described here. Nine polymorphs were accessed through the use of polymer-induced heteronucleation (PIHn) and solid-solid transformation at low temperature. Structural elucidation of six of these forms, in addition to the two previously known forms, makes FFA indisputably octamorphic. Although the structure of at least one other form of FFA remains elusive, the occurrence of most of these polymorphs under one crystallization condition through PIHn illustrates that a fine interplay exists among the kinetic factors that lead to phase selection in this NSAID.

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Figures

Figure 1
Figure 1
Molecular structures of highly polymorphic compounds in the CSD, illustrating the torsion angles (τ, bonds in blue) differing among the conformers. In parentheses is the number of structurally characterized polymorphs for each molecule. In some instances the number of polymorphs experimentally observed is greater than the values reported here reflecting additional forms lacking structural characterization.
Figure 2
Figure 2
Molecular structures of NSAIDs flufenamic acid (FFA), tolfenamic acid (TA), mefenamic acid (MA), and other structural analogues illustrating torsion angles (τ1 and τ2 in blue) differing among the forms. In parentheses is the number of structurally characterized polymorphs for each molecule. In some instances the number of polymorphs experimentally observed is greater than the values reported here reflecting additional forms lacking structural characterization.
Figure 3
Figure 3
Molecular packing and hydrogen bonding motifs of FFA polymorphs. (a) form I viewed along the a-axis, (b) form II viewed along the a-axis, (c) form III viewed along the a-axis, (d) form IV viewed along the a-axis, (e) form V viewed along the b-axis, (f) form VI viewed along the a-axis, (g) form VII viewed along the b-axis, and (h) form VIII, ordered molecules only, viewed perpendicular to the bc-plane.
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