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
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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)。
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).
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).
引文
[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 JPharm 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 func-tion 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]H?rter 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 Consid-erations[M].Rockville:Food and Drug Administration,2003.
[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 JPharm 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 func-tion 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]H?rter 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 Consid-erations[M].Rockville:Food and Drug Administration,2003.
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