title: A comparison of the experimental and theoretical charge density distributions in two polymorphic modifications of piroxicam.
abstract: 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 the 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 energies of 66.14 kJ mol-1and 112.82 kJ mol-1for (2a), and 58.35 kJ mol-1and 159.51 kJ mol-1for (2b), respectively. Proton transfer between O(3) and N(3) in (2) results in significant differences in surface electrostatic potentials. This is clarified by the calculation of atomic charges in the zwitterion that shows the formally positive charge of the pyridyl nitrogen which is redistributed over the whole of the pyridine ring instead of concentrating at N-H. Similarly, the negative charge of the oxygen is distributed across the benzothiazine carboxamide moiety. The multipole derived lattice energy for (1) is -304 kJ mol-1and 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).
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia. david.hibbs@sydney.edu.au.
authors.forename: Felcia
authors.initials: F
authors.lastname: Lai
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia. david.hibbs@sydney.edu.au.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Du
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia. david.hibbs@sydney.edu.au and School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Williams
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia. david.hibbs@sydney.edu.au.
authors.forename: Linda
authors.initials: L
authors.lastname: Váradi
authors.affiliation: Rigaku Oxford Diffraction, Oxford Industrial Park, Yarnton, Oxfordshire, OX5 1QU, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baker
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia. david.hibbs@sydney.edu.au.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Groundwater
authors.affiliation: Department of Chemistry, Center for Materials Crystallography, Aarhus University, Langelandsgade 140, Aarhus C, 8000, Denmark.
authors.forename: Jacob
authors.identifier: http://orcid.org/0000-0001-6492-7962
authors.initials: J
authors.lastname: Overgaard
authors.affiliation: School of Chemistry, Cardiff University, P.O. Box 912, Cardiff, CF13TB, Wales, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Platts
authors.affiliation: Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia. david.hibbs@sydney.edu.au.
authors.forename: David E
authors.identifier: http://orcid.org/0000-0002-2635-2990
authors.initials: DE
authors.lastname: Hibbs