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 α-, β-, γ- and HP-β-cyclodextrins (CDs). The results indicate that neutral Mel has two conformational structures, enol and zwitterions, with the latter more dominant in water. The two pKas of Mel were found to change in the presence of β-CD, where a blue shift in λmax was observed but not in the presence of α, HP-β- and γ-CD. Rigorous analysis of phase solubility diagrams indicate that β- and HP-β-CD form 1 : 2 Mel/β-CD type complexes with Mel while α- and γ-CD form only 1 : 1 complexes. The fact that the overall 1 : 2 Mel/CD complex formation constant (β12) was found significantly higher for β-CD than for HP-β-CD, combined with further spectroscopic studies, indicate that β-CD favors inclusion of the neutral enol form over the zwitterion. Unlike α-, HP-β- and γ-CDs, the hydrophobic microenvironment of a tight 1 : 2 Mel/β-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.