Changes in the conformational structure, microscopic and macroscopic pKas of meloxicam on complexation with natural and modified cyclodextrins

Spectroscopic and phase solubility techniques have been used to study the complexation of neutral meloxicam (Mel) with alpha-, beta-, gamma- and HP-beta-cyclodextrins (CDs). The results indicate that neutral Mel has two conformational structures, enol and zwitterions, with the latter more dominant in water. The two pK(a)s of Mel were found to change in the presence of beta-CD, where a blue shift in lambda(max) was observed but not in the presence of alpha, HP-beta- and gamma-CD. Rigorous analysis of phase solubility diagrams indicate that beta- and HP-beta-CD form 1:2 Mel/beta-CD type complexes with Mel while alpha- and gamma-CD form only 1 : 1 complexes. The fact that the overall 1:2 Mel/CD complex formation constant (beta(12)) was found significantly higher for beta-CD than for HP-P-CD, combined with further spectroscopic studies, indicate that beta-CD favors inclusion of the neutral enol form over the zwitterion. Unlike alpha-, HP-beta- and gamma-CDs, the hydrophobic microenvironment of a tight 1 :2 Mel/beta-CD complex was found to mimic those of organic solvents, thus favoring inclusion of the enol rather than the zwitterion, and hence shifting the tautomerization equilibrium towards the enol conformer.