Electronic structure analysis of isomeric preferences of canonical and zwitterionic forms of lornoxicam

Lornoxicam, is a non-steroidal anti-inflammatory drug (NSAID) and has analgesic, anti-inflammatory and antipyretic activity. Various polymorphic forms of drugs belonging to oxicam class are known in the literature and study of their polymorphic behavior has become a research interest over the past few years. Due to the differences in the conformational arrangement of the molecules in the crystal lattice, polymorphic forms of a drug substance can exhibit different physicochemical properties–solubility, density, dissolution, pKa, etc. Density functional (DFT) study has been carried out on various canonical and zwitterionic forms of lornoxicam. The electronic level details revealed that, the existence of polymorphism in lornoxicam can be traced to the prototropic exchange which helps in the interconversion of one polymorph to the other. Electronic structures of all the probable isomers of lornoxicam at HF, B3LYP and M06L levels using 6-31 + G(d) basis set have been analyzed. The comparative analysis of their relative Gibbs free energies in the gas, solution and explicit water phase revealed that the form of global minimum structure differs with respect to the varied conditions. Microsolvation calculations show that three water (3W) molecules are sufficient to stabilize the zwitterion ZO. Therefore, transition of canonical to zwitterionic form can happen under the influence of explicit water molecules. Further, transition state studies point out easy conversion between the two zwitterionic states (ZN ↔ ZO). This phenomenon can be attributed to the observed polymorphism in lornoxicam.