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.

Graphical abstract

中文翻译：

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盐酸雷洛昔芬的质子分解平衡及pH、环糊精和聚山梨酯80对溶解度影响的研究

研究了雷洛昔芬的酸碱平衡以及pH值和助溶剂对盐酸雷洛昔芬溶解度的相互影响。雷洛昔芬的表观电离常数 (p K _a *) 在甲醇-水混合物 (45%-55% w/w) 中通过电位测定法测定，p K _a值 (p K _a1  = 7.21 ± 0.02，p K _a2  = 7.86 ± 0.02，p K _{a3 = 9.97 ± 0.04）通过将 p} K _a * 值外推至 0% 甲醇 来定义水介质中的电离。将获得的 p K _a值分配给相应的电离中心。根据本研究中获得的电离常数，计算了雷洛昔芬的平衡形式的分布。研究了在存在和不存在β -CD、HP- β -CD 和聚山梨酯 80 的情况下，盐酸雷洛昔芬在 0.01 M HCl、醋酸盐缓冲液 pH 4.5 和磷酸盐缓冲液 pH 6.8 中的溶解度。0.01 盐酸雷洛昔芬最有效的溶解度增强剂M HCl 为浓度为 0.5% 的聚山梨醇酯 80，而该增强剂在 pH 6.8 磷酸盐缓冲液中的影响可以忽略不计。在 10 ^–3  M HP- β- CD存在下，盐酸雷洛昔芬在乙酸盐和磷酸盐缓冲液中的溶解度达到最高，在 0.01 M HCl 和乙酸盐缓冲液中溶解度高 1.3 倍，在磷酸盐缓冲液中溶解度高 2.3 倍。 10 ^–3  M β -CD的存在。

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