Tautomerisation and polymorphism in molecular complexes of piroxicam with mono-substituted benzoic acids

Abstract

A series of nineteen piroxicam (PX) molecular complexes with mono-substituted benzoic acid co-molecules are reported. The piroxicam molecule can exist in two possible tautomers, one of which is zwitterionic; the PX tautomer obtained in these complexes is not related to the type of substituent or substitution position. Instead, a correlation is seen between the pK_a of the benzoic acid co-molecule and the preference towards a particular PX tautomer. The complexes with 2-, 3- and 4-fluorobenzoic acids exhibit the rare phenomenon of tautomeric polymorphism. DSC measurements have been used to identify the most thermodynamically stable polymorph in these cases and this has been rationalised by consideration of the intermolecular interactions in the crystal structures. The complexes containing zwitterionic piroxicam (PXZ) display a highly predictable and reproducible four-molecule tetrameric hydrogen bonding pattern whereas the complexes containing non-ionised piroxicam have more than one possible hydrogen bonding synthon.