Study on protolytic equilibria and the effects of pH, cyclodextrins and polysorbate 80 on solubility of raloxifene hydrochloride

The acid–base equilibria of raloxifene and the mutual influence of pH and solubility enhancers on the solubility of raloxifene hydrochloride were studied. The apparent ionization constants (pK_a*) of raloxifene were determined potentiometrically in methanol–water mixtures (45%-55% w/w), and the pK_a values (pK_a1 = 7.21 ± 0.02, pK_a2 = 7.86 ± 0.02, pK_a3 = 9.97 ± 0.04) defining ionization in aqueous media were obtained by extrapolating the pK_a* values to 0% of methanol. The obtained pK_a values were assigned to the corresponding ionization centers. Based on the ionization constants obtained in this study, the distribution of the equilibrium forms of raloxifene was calculated. The solubility of raloxifene hydrochloride in 0.01 M HCl, acetate buffer pH 4.5 and phosphate buffer pH 6.8 was studied with and without the presence of β-CD, HP-β-CD and polysorbate 80. The most effective solubility enhancer of raloxifene hydrochloride in 0.01 M HCl was polysorbate 80 at a concentration of 0.5%, while the influence of this enhancer in phosphate buffer pH 6.8 was negligible. The highest solubility of raloxifene hydrochloride in acetate and phosphate buffer was achieved in the presence of 10^–3 M HP–β-CD which was 1.3-fold higher in both 0.01 M HCl and acetate buffer and 2.3-fold higher in phosphate buffer than in the presence of 10^–3 M β-CD.