A comparison of the experimental and theoretical charge density distributions in two polymorphic modifications of Piroxicam.

28 April 2016

Experimental charge density distribution studies of two polymorphic forms of piroxicam, β- piroxicam (1) and piroxicam monohydrate (2), were carried out via high-resolution single crystal X-ray diffraction experiments and multipole refinement. The asymmetric unit of (2) consists of two discrete piroxicam molecules, (2a) and (2b), and two water molecules. Geometry differs between (1) and (2) due to the zwitterionic nature of (2) which results in the rotation of pyridine ring around the C(10)–N(2) bond by approximately 180°. Consequently, the pyridine and amide are no longer co-planar and (2) forms two exclusive, strong hydrogen bonds, H(3) …O(4) and H(2) …O(3), with bond energy of 66.14 kJ mol-1 and 112.82 kJ mol- 1 for (2a), 58.35 kJ mol-1 and 159.51 kJ mol-1 for (2b) respectively. Proton transfer between O(3) and N(3) in (2) results in significant differences in surface electrostatic potentials. This is clarified on calculation of atomic charges in the zwitterion shows the formally positive charge of the pyridyl nitrogen is redistributed over the whole of the pyridine ring instead of concentrated at N-H. Similarly, the negative charge of the oxygen is distributed across the benzothiazinecarboxamide moiety. Multipole derived lattice energy for (1) is -304 kJ mol-1 and that for (2) is -571 kJ mol-1, which is in agreement with the experimentally determined observations of higher solubility and dissolution rates of (1) compared to (2).