TAUTOMERISM OF PHENINDIONE IN NONAQUEOUS SOLVENT SYSTEMS

The phenindione molecule shows great sensitivity to solvent and solute basicity in mixed nonaqueous media and therefore is useful as a model for solute-solvent, acid-base interactions in pharmaceutical systems. This study is an investigation of the prototropic equilibrium between the diketo and enol isomers of the (beta)-dicarbonyl carbon acid, phenindione (2-phenyl-1,3-indanedione) in a saturated hydrocarbon solvent, cyclohexane. The study deals with the alteration of the tautomeric equilibrium between isomers of phenindione by the addition of dipolar aprotic solvents and solutes, which promote the formation of the enol isomer. The study also investigates the hydrogen bonding interactions in the formation of molecular complexes, since the promotion of the enol isomer by basic cosolvents and solutes is ascribed to a hydogen bonding interaction. Hydrogen bonded complexation, or acid-base behavior in solvents of low permittivity provides information as to how these interactions may improve or inhibit the performance of pharmaceutical formulations in optimum drug delivery.; Several techniques for studying such molecular interactions have been employed in this investigation. The association equilibrium between phenindione and various electron donors, basic solvents and solutes, in cyclohexane was conveniently measured spectrophotometrically. The spectrophotometric method required measuring the spectrum of a solution of phenindione of constant concentration (5 x 10('4)M) in varying concentrations of basic cosolvent-cyclohexane mixtures. Thermodynamic parameters, (DELTA)G(DEGREES), (DELTA)H(DEGREES), and (DELTA)S(DEGREES) were determined from the variation of the equilibrium constant with temperature. The rate of complex formation was also determined for selected basic cosolvent- or solute-cyclohexane systems. Finally, the equilibrium association was studied by phase solubility analysis of the association between phenindione at saturation solubility in various concentrations of basic cosolvent- or solute-cyclohexane mixtures.; The visible absorbance spectrum and the spectral shifts observed for phenindione in the presence of basic solvents and solutes in cyclohexane indicate that hydrogen bonding of the enol is the major mode of interaction. The thermodynamic parameters are also consistent with hydrogen bond formation.; The 1:1 association constants experimentally determined for the formation of enol complex, correlate well with other measures of cosolvent or solute basicity in non-solvating inert solvents, e.g. the para-fluorophenol hydrogen-bonded complex formation constant measured by R. W. Taft and E. M. Arnett. Not only does the data show an excellent free-energy relationship with Taft's basicity scale but phenindione as a base indicator shows greater sensitivity to base strength than p-fluorophenol.; The rates of hydrogen-bonded enol complex formation are indeed indicative of the "slow" prototropic tautomeric equilibria associated with keto-enol interconversion. The nature of the interacting base, not only basicity as determined by the 1:1 association constant, determines the rate of complex formation.; The investigation presented here also reveals higher order base interactions with the enol complex and/or the diketo form of phenindione, the nature of which are not clear. Also, indications are that the formation of enol complexes do not exclusively account for all increases in solubility. The higher order interactions and unaccounted for increases in solubility only occur at the higher concentrations of base or phenindione. The enhanced solubility of phenindione in cyclohexane-basic cosolvent or solute mixtures appears to have contributions from other interactions which may include diketo:base associations. The relative importance of the enol:base interaction to the solubility of phenindione increases as base strength increases and is the major contributor to solubility for strong bases.