The current United States Pharmacopeia–National Formulary(USP–NF) includes more than 250 monographs of fixed dose combinations(FDCs), and some of them need to be updated due to incompleteness of impurity profiles an...The current United States Pharmacopeia–National Formulary(USP–NF) includes more than 250 monographs of fixed dose combinations(FDCs), and some of them need to be updated due to incompleteness of impurity profiles and obsolescence of analytical methodologies. A case study of metoprolol tartrate and hydrochlorothiazide tablets is presented to summarize challenges encountered during the USP monograph modernization initiative of FDCs and to highlight an "adoption and adaptation" approach employed for method development. To this end, a single stability-indicating HPLC method was developed to separate the two drug substances and eight related compounds with resolution 2.0 or higher between all critical pairs. Chromatographic separations were achieved on a Symmetry column(C18,100 mm*4.6 mm, 3.5 mm) using sodium phosphate buffer(pH 3.0; 34 mM) and acetonitrile as mobile phase in a gradient elution mode. The stability-indicating capability of this method has been demonstrated by analyzing stressed samples of the two drug substances. The developed HPLC method was validated for simultaneous determination of metoprolol tartrate and hydrochlorothiazide and relevant impurities in the tablets. Moreover, the developed method was successfully applied to the analysis of commercial tablet dosage forms and proved to be suitable for routine quality control use. The case study could be used to streamline USP's monograph modernization process of FDCs and strengthen compendial procedures.展开更多
Aryloxypropanolamine is an essential structural scaffold for a variety of b-adrenergic receptor antagonists such as metoprolol.Molecules with such a structural motif tend to degrade into α,β ehydroxypropanolamine im...Aryloxypropanolamine is an essential structural scaffold for a variety of b-adrenergic receptor antagonists such as metoprolol.Molecules with such a structural motif tend to degrade into α,β ehydroxypropanolamine impurities via a radicaleinitiated oxidation pathway.These impurities are typically polar and nonchromophoric,and are thus often overlooked using traditional reversed phase chromatography and UV detection.In this work,stress testing of metoprolol confirmed the generation of 3-isopropylamino-1,2-propanediol as a degradation product,which is a specified impurity of metoprolol in the European Pharmacopoeia(impurity N).To ensure the safety and quality of metoprolol drug products,hydrophilic interaction chromatography(HILIC)methods using Halo Penta HILIC column(150mm×4.6 mm,5 μm)coupled with charged aerosol detection(CAD)were developed and optimized for the separation and quantitation of metoprolol impurity N in metoprolol drug products including metoprolol tartrate injection,metoprolol tartrate tablets,and metoprolol succinate extended-release tablets.These HILIC-CAD methods were validated per USP validation guidelines with respect to specificity,linearity,accuracy,and precision,and have been successfully applied to determine impurity N in metoprolol drug products.展开更多
目的观察酒石酸美托洛尔片联合瑞舒伐他汀对高血压合并2型糖尿病(T2DM)患者血压变异性(BPV)及糖脂代谢的影响。方法选取2018年1月至2021年1月空军第九八六医院收治的108例高血压合并T2DM患者为研究对象,根据使用的药物不同分为单药组和...目的观察酒石酸美托洛尔片联合瑞舒伐他汀对高血压合并2型糖尿病(T2DM)患者血压变异性(BPV)及糖脂代谢的影响。方法选取2018年1月至2021年1月空军第九八六医院收治的108例高血压合并T2DM患者为研究对象,根据使用的药物不同分为单药组和联合组,每组54例。单药组给予酒石酸美托洛尔片(每次25 mg,每日3次)治疗,联合组给予酒石酸美托洛尔片(方法同单药组)联合瑞舒伐他汀(每次10 mg,每日1次)治疗,两组均连续用药8周。比较两组治疗前后血压[包括日间收缩压(dSBP)、日间舒张压(dDBP)、夜间收缩压(nSBP)、夜间舒张压(nDBP)、24 h收缩压(24 h SBP)、24 h舒张压(24 h DBP)]、BPV参数[包括日间收缩压标准差(dSSD)、日间舒张压标准差(dDSD)、夜间收缩压标准差(nSSD)、夜间舒张压标准差(nDSD)、24 h收缩压标准差(24 h SSD)、24 h舒张压标准差(24 h DSD)]、血脂[包括三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)]、血糖[包括空腹血糖(FBG)、餐后2 h血糖(2 h PG)]以及两组不良反应发生情况。结果治疗前后血压(dSBP、dDBP、nSBP、nDBP、24 h SBP、24 h DBP)、BPV参数(dSSD、dDSD、nSSD、nDSD、24 h SSD、24 h DSD)、血脂(TG、TC、LDL-C、HDL-C)、血糖(FBG、2 h PG)的主效应差异有统计学意义(P<0.01);不考虑测量时间,两组间血压、BPV参数、血脂、血糖的主效应差异有统计学意义(P<0.05或P<0.01);血压、BPV参数、血脂、血糖的时点间与组间存在交互作用(P<0.05),治疗后血压(dSBP、dDBP、nSBP、nDBP、24 h SBP、24 h DBP)、BPV参数(dSSD、dDSD、nSSD、nDSD、24 h SSD、24 h DSD)、TG、TC、LDL-C、血糖(FBG、2 h PG)水平均低于治疗前(P<0.05),而HDL-C水平均高于治疗前(P<0.05),但两组血压、BPV参数、血脂、血糖的变化幅度不同,联合组变化更明显(P<0.05)。两组不良反应总发生率比较差异无统计学意义(P>0.05)。结论酒石酸美托洛尔片联合瑞舒伐他汀治疗有助于降低高血压合并T2DM患者的血压、血脂、血糖,且不良反应少。展开更多
文摘The current United States Pharmacopeia–National Formulary(USP–NF) includes more than 250 monographs of fixed dose combinations(FDCs), and some of them need to be updated due to incompleteness of impurity profiles and obsolescence of analytical methodologies. A case study of metoprolol tartrate and hydrochlorothiazide tablets is presented to summarize challenges encountered during the USP monograph modernization initiative of FDCs and to highlight an "adoption and adaptation" approach employed for method development. To this end, a single stability-indicating HPLC method was developed to separate the two drug substances and eight related compounds with resolution 2.0 or higher between all critical pairs. Chromatographic separations were achieved on a Symmetry column(C18,100 mm*4.6 mm, 3.5 mm) using sodium phosphate buffer(pH 3.0; 34 mM) and acetonitrile as mobile phase in a gradient elution mode. The stability-indicating capability of this method has been demonstrated by analyzing stressed samples of the two drug substances. The developed HPLC method was validated for simultaneous determination of metoprolol tartrate and hydrochlorothiazide and relevant impurities in the tablets. Moreover, the developed method was successfully applied to the analysis of commercial tablet dosage forms and proved to be suitable for routine quality control use. The case study could be used to streamline USP's monograph modernization process of FDCs and strengthen compendial procedures.
文摘Aryloxypropanolamine is an essential structural scaffold for a variety of b-adrenergic receptor antagonists such as metoprolol.Molecules with such a structural motif tend to degrade into α,β ehydroxypropanolamine impurities via a radicaleinitiated oxidation pathway.These impurities are typically polar and nonchromophoric,and are thus often overlooked using traditional reversed phase chromatography and UV detection.In this work,stress testing of metoprolol confirmed the generation of 3-isopropylamino-1,2-propanediol as a degradation product,which is a specified impurity of metoprolol in the European Pharmacopoeia(impurity N).To ensure the safety and quality of metoprolol drug products,hydrophilic interaction chromatography(HILIC)methods using Halo Penta HILIC column(150mm×4.6 mm,5 μm)coupled with charged aerosol detection(CAD)were developed and optimized for the separation and quantitation of metoprolol impurity N in metoprolol drug products including metoprolol tartrate injection,metoprolol tartrate tablets,and metoprolol succinate extended-release tablets.These HILIC-CAD methods were validated per USP validation guidelines with respect to specificity,linearity,accuracy,and precision,and have been successfully applied to determine impurity N in metoprolol drug products.
文摘目的观察酒石酸美托洛尔片联合瑞舒伐他汀对高血压合并2型糖尿病(T2DM)患者血压变异性(BPV)及糖脂代谢的影响。方法选取2018年1月至2021年1月空军第九八六医院收治的108例高血压合并T2DM患者为研究对象,根据使用的药物不同分为单药组和联合组,每组54例。单药组给予酒石酸美托洛尔片(每次25 mg,每日3次)治疗,联合组给予酒石酸美托洛尔片(方法同单药组)联合瑞舒伐他汀(每次10 mg,每日1次)治疗,两组均连续用药8周。比较两组治疗前后血压[包括日间收缩压(dSBP)、日间舒张压(dDBP)、夜间收缩压(nSBP)、夜间舒张压(nDBP)、24 h收缩压(24 h SBP)、24 h舒张压(24 h DBP)]、BPV参数[包括日间收缩压标准差(dSSD)、日间舒张压标准差(dDSD)、夜间收缩压标准差(nSSD)、夜间舒张压标准差(nDSD)、24 h收缩压标准差(24 h SSD)、24 h舒张压标准差(24 h DSD)]、血脂[包括三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)]、血糖[包括空腹血糖(FBG)、餐后2 h血糖(2 h PG)]以及两组不良反应发生情况。结果治疗前后血压(dSBP、dDBP、nSBP、nDBP、24 h SBP、24 h DBP)、BPV参数(dSSD、dDSD、nSSD、nDSD、24 h SSD、24 h DSD)、血脂(TG、TC、LDL-C、HDL-C)、血糖(FBG、2 h PG)的主效应差异有统计学意义(P<0.01);不考虑测量时间,两组间血压、BPV参数、血脂、血糖的主效应差异有统计学意义(P<0.05或P<0.01);血压、BPV参数、血脂、血糖的时点间与组间存在交互作用(P<0.05),治疗后血压(dSBP、dDBP、nSBP、nDBP、24 h SBP、24 h DBP)、BPV参数(dSSD、dDSD、nSSD、nDSD、24 h SSD、24 h DSD)、TG、TC、LDL-C、血糖(FBG、2 h PG)水平均低于治疗前(P<0.05),而HDL-C水平均高于治疗前(P<0.05),但两组血压、BPV参数、血脂、血糖的变化幅度不同,联合组变化更明显(P<0.05)。两组不良反应总发生率比较差异无统计学意义(P>0.05)。结论酒石酸美托洛尔片联合瑞舒伐他汀治疗有助于降低高血压合并T2DM患者的血压、血脂、血糖,且不良反应少。
