Piroxciam is a polymorphic drug. However, reports on the number and nomenclature of the polymorphs of piroxicam and the complete hydrogen-bonding patterns of piroxicam molecules in the crystal forms are in conflict and are sources of confusion, which we attempt to clarify. The difference in energy of the two polymorphs, I and II, of piroxicam arises predominantly from the difference between their lattice energies, rather than between their conformational energies. The detailed hydrogen-bonding networks of the two polymorphs are described and compared. Despite stabilization of the polymorphs by hydrogen bonds, a loss of polymorphic memory was observed upon cryogrinding the two polymorphs, leading to differences in recrystallization behavior between amorphous piroxicam prepared from polymorphs I and II.

Structural and solid-state changes of piroxicam in its crystalline form under mechanical stress were investigated using cryogenic grinding, powder X-ray diffractometry, diffuse-reflectance solid-state ultraviolet-visible spectroscopy, variable-temperature solid-state (13)C nuclear magnetic resonance spectroscopy, and solid-state diffuse-reflectance infrared Fourier transform spectroscopy. Crystalline piroxicam anhydrate exists as colorless single crystals irrespective of the polymorphic form and contains neutral piroxicam molecules. Under mechanical stress, these crystals become yellow amorphous piroxicam, which has a strong propensity to recrystallize to a colorless crystalline phase. The yellow color of amorphous piroxicam is attributed to charged piroxicam molecules. Variable-temperature solid-state (13)C NMR spectroscopy indicates that most of the amorphous piroxicam consists of neutral piroxicam molecules; the charged species comprise only about 8% of the amorphous phase. This ability to quantify the fractions of charged and neutral molecules of piroxicam in the amorphous phase highlights the unique capability of solid-state NMR to quantify mixtures in the absence of standards. Other compounds of piroxicam, which are yellow, are known to contain zwitterionic piroxicam molecules. The present work describes a system in which proton transfer accompanies both solid-state disorder and a change in color induced by mechanical stress, a phenomenon which may be termed mechanochromism of piroxicam.

No abstract

The local structures of amorphous phases of piroxicam were studied to explain differences in their recrystallization behavior, which we reported earlier (Sheth, A. R.; Bates, S.; Muller, F. X.; Grant, D. J. W. Polymorphism in piroxicam. Cryst. Growth Des., in press). The differences between the structures of form I (P I ) at 25 and at 160 °C are consistent with anisotropic thermal expansion (R x ) 2.85 × 10 -5 K -1 , R y ) 1.96 × 10 -5 K -1 , R z ) 5.26 × 10 -6 K -1 , volume thermal expansivity of the unit cell ) 4.92 × 10 -5 K -1 , increase in unit cell volume ) 2.01%).