Crystal polymorphism is encountered in all areas of research involving solid substances. Its occurrence introduces complications during manufacturing processes and adds another dimension to the complexity of designing materials with specific properties. Research on polymorphism is fraught with unique difficulties due to the subtlety of polymorphic transformations and the inadvertent formation of pseudopolymorphs. In this report, a summary of thermodynamic, kinetic and structural considerations of polymorphism is presented. A wide variety of techniques appropriate to the study of organic crystalline polymorphism and pseu-dopolymorphism is then surveyed, ranging from simple crystal density measurement to observation of polymorphic transformations using variable-temperature synchrotron X-ray diffraction methods. Application of newer methodology described in this report is yielding fresh insights into the nature of the crystallization process, holding promise for a deeper understanding of the phenomenon of polymorphism and its practical control.

Crystalline Polymorphism of Organic Compounds

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 piroxic...

Cocrystals of Piroxicam with Carboxylic Acids

Characterization of piroxicam crystal modifications.

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.

Polymorphism in Piroxicam

In previous work, it has been shown that the crystal nucleation of salicylic acid (SA) in different solvents becomes increasingly more difficult in the order: chloroform, ethyl acetate acetonitrile, acetone, methanol, and acetic acid. In the present work, vibration spectroscopy, calorimetric measurements, and density functional theory (DFT) calculations are used to reveal the underlying molecular mechanisms. Raman and infrared spectra suggest that SA exists predominately as dimers in chloroform, but in the other five solvents there is no clear evidence of dimerization. In all solvents, the shift in the SA carbonyl peak reflecting the strength in the solvent–solute interaction is quite well correlated to the nucleation ranking. This shift is corroborated by DFT calculated energies of binding one solvent molecule to the carboxyl group of SA. An even better correlation of the influence of the solvent on the nucleation is provided by DFT calculated energy of binding the complete first solvation shell to the S...

Investigating the role of solvent-solute interaction in crystal nucleation of salicylic acid from organic solvents.

Piroxicam (4-hydroxy-2-methyl-N-2-piridyl-2H1,2-benzothiazine-3-carboxamide1,1-dioxide), belongs to the class of acidic, nonsteroidal antiinflammatory (NSAI) drugs (Wiseman et al., 1976). Piroxicam is an effective analgesic agent in rheumatoid arthritis, ankylosing spondylitis, and acute pain in muskuloskeletal disorder and episiotomy. It can diminish or inhibit the development of all symptoms of inflammation no matter what its reason (Brogden et al., 1981). Piroxicam crystallizes in two modifications o~ and/3 (Fig. 1), in space groups Pca21 with Z = 4 and P21/c with Z = 4 (Reck et al., 1988; Kojir-Prodi6 and Ruzir-Toros, 1982), respectively. The conformation of the molecule in both structures is approximately planar and rigid, owing to the strong intramolecular hydrogen bonding O ( 1 7 ) H . . . O ( 1 5 ) of lengths 2.526(2)A (cr and 2.561(5),~ (/3). The crystals with the c~ modification exhibit more or less disorder (Reck et al., 1988) depending on crystallization conditions. The c~ structure is rigid owing to the formation of the infinite chains of the weak bifurcated intermolecular hydrogen bonds O ( 1 7 ) H . . . O ( 1 2 ) of the length 3.007 A,. The free N(16)--H groups have the intermolecular distances close to the van der Waals' (Reck et al., 1988). The/3 structure contains the cyclic dimers with the intermolecular hydrogen bonds N(16)--H 9 9 9 O(11) of

M. Janik

Papers

Influence of solvent effect on polymorphism of 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1, 1-dioxide (piroxicam)