Changes in the conformational structure, microscopic and macroscopic pK(a)s 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 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 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 (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 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.

Thermodynamics of propylparaben/beta-cyclodextrin inclusion complexes.

The aim of this study was to develop models for rigorous analysis of phase solubility diagrams, particularly the descending portion, in order to obtain individual thermodynamic complex formation and solubility product constants. Additionally, the effect of varying the initial solute concentration St, in excess of the optimal solubility Sm, on the general shape of the plateau and descending portions of the solubility diagram was investigated. The solubilities of propylpapraben (Seq) were measured against initial beta-cyclodextrin concentrations (Lt) at different temperatures and different St. Equilibrium concentrations (Leq) were also measured. The only effect observed was a broadening of the plateau region with increase in St with no discernible effect on Sm. Simultaneous rigorous analysis of the rising as well as the descending portions of the phase diagram could only be interpreted in terms of formation of two soluble complexes: SL and S2L. Rigorous analysis of the descending portion allowed the determination of individual formation constants K11 (SL) and K21 (S2L) in addition to the solubility product of the less soluble complex KS11 (SL). Thermodynamic analysis of the individual solubility of propylparaben and beta-cyclodextrin was carried out in water at different temperatures. In aqueous beta-cyclodextrin solutions, however, the solubility of propylparaben is enhanced due to the formation of both SL (delta G11(0) = -26.4 kJ/mol) and S2L (delta G21(0) = -46.4 kJ/mol) soluble complexes. Formation of the SL-complex is favored both by enthalpy (delta H11(0) = -20.7 kJ/mol) and a slight increase in entropy (delta S11(0) = 18.6 J/mol.K). Formation of S2L from SL apparently involves stronger solute-SL binding (delta H21(0) = -45.9 kJ/mol) yet is retarded by a net decrease in entropy (delta S21(0) = -86.3 J/mol.K). The solubility of the SL-complex is highly endothermic (delta HS11(0) = 55.8 kJ/mol), and although is accompanied by much randomization (delta SS11(0) = 101.8 J/mol.K), its solubility remains quite low (delta GS11(0) = 25.5 kJ/mol). Molecular mechanical modeling of propylparaben/beta-cyclodextrin interactions in water revealed that the S2L-complex formation is energetically more favored.