Effect of added halide ions and pH on the solubility of nebivolol hydrochloride and the evaluation of selected, discriminating dissolution media
10.16438/j.0513-4870.2018-0865
- VernacularTitle: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
- Author:
Da-chuan ZHAO
1
;
Yu-han QIU
2
;
Wen-xia CUI
1
;
Jie-min HAO
1
;
Hai-xia ZHAO
1
;
Wei PAN
1
;
Wei CAO
1
;
Hong-chun QIU
1
;
Yun TIAN
1
;
Wen-jian CAI
1
;
Tai-jun HANG
2
;
Xiao-di GUO
3
Author Information
1. Prinbury Biopharm Co. Ltd, Shanghai 201203, China
2. China Pharmaceutical University, Nanjing 210009, China
3. Prinston Pharmaceutical, New Jersey 08512, US
- Publication Type:Research Article
- Keywords:
solubility;
salt;
common-ion effect;
salting-out effect;
issolution;
bioequivalence
- From:
Acta Pharmaceutica Sinica
2019;54(1):54-60
- CountryChina
- Language:Chinese
-
Abstract:
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 hydrochloride 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).
