Changes in the conformational structure, microscopic and macroscopic pK(a)s of meloxicam on complexation with natural and modified cyclodextrins.

ABSTRACT

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 lambdamax 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 12 Mel/beta-CD type complexes with Mel while alpha- and gamma-CD form only 11 complexes. The fact that the overall 12 Mel/CD complex formation constant (beta12) was found significantly higher for beta-CD than for HP-beta-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 12 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.