卤离子及pH对盐酸奈必洛尔溶解度的影响及对区分性溶出介质的探究

Effect of added halide ions and pH on the solubility of nebivolol hydrochloride and the evaluation of selected, discriminating dissolution media

药物的溶解度既是开发药物口服固体制剂满足漏槽条件、有区分性的体外溶出度方法的基础,也是影响药物体内外相关的重要因素。本文测定了盐酸奈必洛尔在不同pH、不同卤盐及不同盐浓度下的溶解度。在pH 5.0～1.0内,盐酸奈必洛尔的溶解度随着pH值降低而降低、且随着加入的NaCl、NaBr和NaI浓度升高而降低。在酸性介质中,盐酸奈必洛尔的溶解度高于漏槽条件的下限。加入适量的盐可使盐酸奈必洛尔的溶解度降低到漏槽条件的下限。通过检测研发阶段的仿制药处方的溶出度,发现漏槽条件下限的介质有区分性,且与空腹条件下的体内数据有一定的相关性(体内生物等效性试验方案获得伦理委员会审查批准)。

The solubility of nebivolol hydrochloride was determined in acidic aqueous media in the absence and presence of different concentration of NaCl,NaBr,or NaI at 37℃in order to facilitate proper selection of dissolution media that have adequate discriminating power for enhancing the likelihood of a generic drug product to successfully pass in-vivo bioequivalence test.In the range of pH 5.0 to pH 1.0,the solubility of nebivolol hydro-chloride decreased with the decrease in the pH of aqueous solution,and the solubility of nebivolol hydrochloride further decreased with the increase in the concentration of added sodium chloride.The solubility decrease of a few weakly basic drug molecules in acidic media and in higher concentration of added chloride was published previously by other researchers,and the observed decrease in the solubility in the presence of higher chloride concentration was interpreted in terms of common-ion effect.However,the results in this paper showed that the solubility of nebivolol hydrochloride also decreased when sodium chloride was replaced with sodium bromide or iodide.The approach described in this paper(i.e.substituting sodium chloride with sodium bromide or iodide)provides an effective method to verify whether common-ion effect is the true(or at least the sole)driving force behind the observed decrease in the solubility of nebivolol hydrochloride in the presence of sodium chloride.The solubility decrease reported in this paper can be interpreted in terms of salting-out effect of sodium chloride,bromide,and iodide.For hydrochloride salt of a weakly basic drug molecule like nebivolol hydrochloride,its solubility in an acidic dissolution medium can be purposely decreased to the lower end of sink condition by adding sodium chloride to make the resulting medium more discriminating.As shown in this paper,a medium at pH 1.2 with added sodium chloride is discriminating and this medium is shown to be bio-relevant to the in-vivo data collected under fasting condition(in-vivo study protocol was approved by Institutional Review Board).