药学学报, 2019, 54(1): 54-60
引用本文:
赵大川, 邱妤涵, 崔文霞, 郝杰敏, 赵海霞, 潘伟, 曹伟, 邱宏春, 田芸, 蔡文健, 杭太俊, 郭晓迪. 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[J]. 药学学报, 2019, 54(1): 54-60.
ZHAO Da-chuan, QIU Yu-han, CUI Wen-xia, HAO Jie-min, ZHAO Hai-xia, PAN Wei, CAO Wei, QIU Hong-chun, TIAN Yun, CAI Wen-jian, HANG Tai-jun, GUO Xiao-di. Effect of added halide ions and pH on the solubility of nebivolol hydrochloride and the evaluation of selected, discriminating dissolution media[J]. Acta Pharmaceutica Sinica, 2019, 54(1): 54-60.

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
赵大川1, 邱妤涵2, 崔文霞1, 郝杰敏1, 赵海霞1, 潘伟1, 曹伟1, 邱宏春1, 田芸1, 蔡文健1, 杭太俊2, 郭晓迪3
1. 普霖贝利生物医药研发(上海)有限公司, 上海 201203;
2. 中国药科大学, 江苏 南京 210009;
3. 美国普霖斯通制药公司, 美国 新泽西 08512
摘要:
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)。
关键词:    溶解度            同离子效应      盐析      溶出      生物等效性     
Effect of added halide ions and pH on the solubility of nebivolol hydrochloride and the evaluation of selected, discriminating dissolution media
ZHAO Da-chuan1, QIU Yu-han2, CUI Wen-xia1, HAO Jie-min1, ZHAO Hai-xia1, PAN Wei1, CAO Wei1, QIU Hong-chun1, TIAN Yun1, CAI Wen-jian1, HANG Tai-jun2, GUO Xiao-di3
1. Prinbury Biopharm Co. Ltd, Shanghai 201203, China;
2. China Pharmaceutical University, Nanjing 210009, China;
3. Prinston Pharmaceutical, New Jersey 08512, US
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).
Key words:    solubility    salt    common-ion effect    salting-out effect    dissolution    bioequivalence   
收稿日期: 2018-09-16
DOI: 10.16438/j.0513-4870.2018-0865
通讯作者: 赵大川,Tel:86-21-51323331,Fax:86-21-51323339,E-mail:david.zhao@prinburybiopharm.com;郭晓迪,E-mail:xiaodi.guo@prinstonpharm.com
Email: david.zhao@prinburybiopharm.com;xiaodi.guo@prinstonpharm.com
相关功能
PDF(430KB) Free
打印本文
0
作者相关文章
赵大川  在本刊中的所有文章
邱妤涵  在本刊中的所有文章
崔文霞  在本刊中的所有文章
郝杰敏  在本刊中的所有文章
赵海霞  在本刊中的所有文章
潘伟  在本刊中的所有文章
曹伟  在本刊中的所有文章
邱宏春  在本刊中的所有文章
田芸  在本刊中的所有文章
蔡文健  在本刊中的所有文章
杭太俊  在本刊中的所有文章
郭晓迪  在本刊中的所有文章

参考文献:
[1] Huang Y, Zhan XC, Lv FJ, et al. Air humidity solubility assay[J]. Acta Pharm Sin (药学学报), 2016, 51:1472-1475.
[2] Nemichand SK, Laxman SD. Solubility enhancement of nebivolol by micro emulsion technique[J]. J Young Pharm, 2016, 8:356-367.
[3] Avachat A, Raut V. Solubility and dissolution enhancement of nebivolol hydrochloride using hydrophilic carriers[J]. Asian J Pharm Sci, 2012, 7:337-345.
[4] Sweetana S, Akers MJ. Solubility principles and practices for parenteral drug dosage form development[J]. Pda J Pharm Sci Technol, 1996, 50:330-342.
[5] Li S, Wong SM, Sethia S, et al. Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH[J]. Pharm Res, 2005, 22:628-635.
[6] Serajuddin ATM, Jarowski CI. Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical bases and their hydrochloride salts I:Phenazopyridine[J]. J Pharm Sci, 1985, 74:142-147.
[7] Streng WH, Hsi SK, Helms PE, et al. General treatment of pH-solubility profiles of weak acids and bases and the effects of different acids on the solubility of a weak base[J]. J Pharm Sci, 1984, 73:1679-1684.
[8] Serajuddin ATM. Salt formation to improve drug solubility[J]. Adv Drug Deliv Rev, 2007, 59:603-616.
[9] Pudipeddi M, Serajuddin A, Grant D, et al. Solubility and dissolution of weak acids, bases, and salts[M]//Stahl PH, Wermuth CG. Handbook of Pharmaceutical Salts Properties, Selection, and Use. Zürich:Wiley-VCH, 2008:19-40.
[10] Miyazaki S, Inoue H, Nadai T, et al. Solubility characteristics of weak bases and their hydrochloride salts in hydrochloric acid solutions[J]. Chem Pharm Bull, 1979, 27:1441-1447.
[11] Hyde AM, Zultanski SL, Waldman JH, et al. General principles and strategies for salting-out informed by the hofmeister series[J]. Org Process Res Dev, 2017, 21:1355-1370.
[12] United State Pharmacopeia 37, especially the sink conditions as defined in subsection entitled Medium in <1092>[S]. Rockville:United States Pharmacopeial Convention, 2014.
[13] Lindahl A, Ungell AL, Knutson L, et al. Characterization of fluids from the stomach and proximal jejunum in men and women[J]. Pharm Res, 1997, 14:497-502.
[14] Hörter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract[J]. Adv Drug Deliv Rev, 2001, 46:75-87.
[15] Bakatselou V, Oppenheim RC, Dressman JB. Solubilization and wetting effects of bile salts on the dissolution of steroids[J]. Pharm Res, 1991, 8:1461-1469.
[16] FDA. Guidance for Industry:Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations[M]. Rockville:Food and Drug Administration, 2003.
相关文献:
1.殷一凡, 李卓越, 李慧, 郭阳, 张强, 张烜.氟灭酸对索拉菲尼纳米骨架给药系统中索拉菲尼溶解度、溶出度和体内药动学行为的影响[J]. 药学学报, 2019,54(1): 48-53
2.范玉玲;崔福德;杨明世;季宇彬.利用球晶造粒技术盐析方法制备齐酞酸钠肠溶微球[J]. 药学学报, 2005,40(3): 267-273
3.魏欣;丁黎;高家敏;李君;张胜强;沈建平;张银娣.盐酸乙哌立松片在健康人体内的药代动力学及生物等效性[J]. 药学学报, 2004,39(4): 309-311
4.高丽红;刘洪来;蔡水洪;柴逸峰;刘荔荔;吴玉田.两对非对映体盐和两种氨基酸在二氧化碳近临界区的溶解行为[J]. 药学学报, 2002,37(5): 355-358
5.郭建兰;经广纬;曹德善;李瑶卿;何海燕;林力行;李忠.盐酸维拉帕米渗透泵片溶出度与人体生物利用度研究[J]. 药学学报, 1993,28(9): 714-720
6.胡效亚;冷宗周.Nafion修饰玻碳电极阳极溶出伏安法测定盐酸异丙嗪[J]. 药学学报, 1992,27(4): 283-286
7.马建华;倪维骅;刘植蔚.盐酸硫胺两种结晶变体及其稳定性研究[J]. 药学学报, 1983,18(12): 938-944