Received October 23, 2006

Revised February 20, 2007

Abstract:

A crystal engineering method was used to investigate cocrystal formation of piroxicam with pharmaceutically acceptable carboxylic acids. Forming cocrystals of piroxicam can potentially result in solid forms with increased bioavailability. A total of 50 unique cocrystals containing piroxicam and a guest carboxylic acid were identified in screening experiments. Each of the 23 guest molecules tested formed at least one cocrystal with piroxicam. In addition, the three known polymorphs of piroxicam were observed. Raman data for the piroxicam cocrystals can be sorted into three distinct groups based on spectral similarity. These groups are differentiated by the piroxicam tautomer present in the cocrystal and the presence or absence of a strong hydrogen bond donor interacting with piroxicam's amide carbonyl group. X-ray powder diffraction data revealed six isostructural piroxicam cocrystals. Single-crystal structure determination revealed that this isostructural series is a host-guest system in which the piroxicam forms a well-ordered host containing disordered guest compounds. Crystal structures of eight piroxicam cocrystals and a dioxane solvate of piroxicam are reported. All carboxylic acid guest compounds are non-ionized in the cocrystals, and piroxicam is present as the non-ionized or zwitterionic tautomer. Of special interest are two 1:1 piroxicam/4-hydroxybenzoic acid cocrystal polymorphs. While the unit cell contents are identical, one polymorph contains the non-ionized piroxicam tautomer plus the guest, while the other contains the zwitterionic tautomer plus the guest. In a related phenomenon, a 4:1 piroxicam/fumaric acid cocrystal is reported that contains one zwitterionic tautomer, one non-ionized tautomer, and one-half of a non-ionized fumaric acid in the asymmetric unit.

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