注射用哌拉西林钠他唑巴坦钠的含量测定及其配伍稳定性的考察
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摘要
目的:考察三个厂家生产的注射用哌拉西林钠他唑巴坦钠的主药和杂质含量及其与0.9%氯化钠注射液的配伍稳定性。
方法:本实验研究采用高效液相色谱法(HPLC)测定三个厂家生产的哌拉西林钠他唑巴坦钠的主药和杂质的含量及与0.9%氯化钠注射液配伍稳定性。该法采用HYPERSIL BDS-C18色谱柱,甲醇:四丁基氢氧化铵水溶液(pH3.5,50:50)为流动相,流速0.8ml/min,检测波长为220nm,室温下进行检测。
1.溶液的配制
1.1标准品储备液的配制
分别精密称定哌拉西林钠标准品和他唑巴坦钠标准品,以50%(V/V)甲醇的水溶液配制成16mg/ml的哌拉西林钠及2mg/ml他唑巴坦钠的标准储备液。
1.2含量测定的样品溶液的配制
分别取美国惠氏制药有限公司、华北制药集团和珠海联邦制药有限公司生产的注射用哌拉西林钠他唑巴坦钠,用50%(V/V)甲醇的水溶液配制成10mg/ml哌拉西林钠,1.25mg/ml他唑巴坦钠溶液。
1.3配伍稳定性考察的样品溶液配制
分别取上述三家药厂生产的注射用哌拉西林钠他唑巴坦钠,用0.9%氯化钠注射液配制成10mg/ml哌拉西林钠,1.25mg/ml他唑巴坦钠溶液。
2.方法学的考察
2.1专属性考察
分别取哌拉西林钠标准品溶液,他唑巴坦钠标准品溶液及两种标准品的混合溶液进样,进样量1μl,比较所得色谱图。
2.2线性关系的考察
分别精密量取标准品储备溶液适量,以50%(V/V)甲醇的水溶液稀释至哌拉西林钠浓度为2、4、8、10、12和16mg/ml及他唑巴坦钠浓度为0.25、0.5、1、1.25、1.5和2 mg/ml的溶液。分别精密量取各浓度标准液1μl注入色谱仪,记录峰面积,以峰面积(Y)对浓度(C)进行线性回归。
2.3精密度的考察
精密量取8mg/ml的哌拉西林钠及1mg/ml的他唑巴坦钠标准品溶液,连续进样5次,记录峰面积,计算RSD值。
3.样品的含量测定
分别取上面三种含量测定的样品溶液1μl注入色谱仪,记录峰面积,计算哌拉西林钠及他唑巴坦钠的含量。
4.样品的配伍稳定性实验
分别取上面三种配伍稳定性考察的样品溶液1μl,于0h,0.5h,1h,2h,3h,4h,5h和6h注入色谱仪,记录峰面积,计算哌拉西林钠、他唑巴坦钠及杂质的含量。同时用肉眼观察在室温放置6h的外观变化(颜色、浑度、沉淀)。
结果
1.专属性试验结果
哌拉西林钠和他唑巴坦钠的保留时间分别为9.566min和4.561min,两峰分离良好,无干扰。
2.线性关系结果
哌拉西林钠在2～16mg/ml、他唑巴坦钠在0.25～2mg/ml范围内,浓度与峰面积呈良好的线性关系(R值分别为1.0000、1.0000)。
3.精密度考察结果
该法测定哌拉西林钠和他唑巴坦钠的RSD值分别为1.4%、0.2%。
4.样品的主药及杂质的含量测定结果
三种样品的哌拉西林钠含量分别为标示量的102.9%、96.4%、103.1%;他唑巴坦钠含量分别为标示量的100.1%、92.8%、97.9%;杂质的含量分别为1.65%、2.75%、1.83%。
5.样品与0.9%氯化钠注射液的配伍稳定性结果
三种配伍样品液放置6h,均无外观变化(变色、产生浑浊或沉淀);主药含量变化与0h相比均低于±2%。
结论本实验结果表明,三个厂家生产的注射用哌拉西林钠他唑巴坦钠的主药与杂质的含量均符合药典规定。与0.9%氯化钠注射液的配伍溶液6h内均无外观变化,主药含量变化均低于±2%,配伍稳定。
Objective: To study content of the main drugs and theirimpurities injectable piperacillin sodium and tazobactam sodium of three manufacturers and compatible stability with 0.9% sodium chloride injection.
Methods: Use HPLC to Determine the content of piperacillin sodium, tazobactam sodium and impurities and Investigate Content changes of piperacillin sodium, tazobactam sodium with 0.9% sodium chloride injection from three manufacturers samples,the chromatographic column was HYPERSIL BDS C18“4.6 mm×250 mm,5μm”, the mobile phase was methanol and tetrabutyl ammonium hydroxide (pH3.5 ,50: 50)at a flow-rate of 0.8mL/min, the detection wavelength was 220nm.
1. Solution preparation
1.1 Preparation for standard solutions
The piperacillin and tazobactam sodium standards precisely weighed were dispensed by 50% (V/V) methanol aqueous solution respectively, then two stock solution of 16mg/ml for piperacillin sodium and 2mg/ml for tazobactam sodium were prepared respectively
1.2 Preparation for Sample solutions for assaying
The piperacillin sodium and tazobactam sodium obtained from Wyeth Pharmaceuticals Co., Ltd., North China Pharmaceutical Group and Zhuhai United Laboratories Co., Ltd were dispensed by 50% (V/V) methanol aqueous solution respectively, then 10mg/ml piperacillin sodium, 1.25mg/ml tazobactam sodium can obtained.
1.3 Preparation for Sample solutions for compatible stability investigation Piperacillin Sodium And Tazobactam Sodium For Injection from the above three manufactures were dispensed by 0.9% sodium chloride respectively, then 10mg/ml piperacillin sodium, 1.25mg/ml tazobactam sodium can obtained.
2. Method validation
2.1 Selectivity investigation
The standard solution of piperacillin sodium, tazobactam sodium and the mixed solution of above two standard samples were analysed by HPLC respectively, the corresponding chromatograms then obtained.
2.2 Calibration investigation
The standard stock solution prepared above was serially diluted with 50% (V / V) methanol solution to standard concentrations of 2,4,8,10,12 and 16mg/mL for piperacillin and 0.25, 0.5,1,1.25,1.5 and 2 mg / ml solution for tazobactam respecively. 1μL of above standard solution was injected into the chromatograph, and the peak area was recorded. According to the peak area and concentration, linear Regression analysis was carried out.
2.3 Prescion investigation
The variations and accuracy for prescion study were assessed by integrated peak area attained from the continuous injections of 8mg/ml piperacillin sodium and 1mg/ml tazobactam sodium for 5 times, then the relative standard deviation (RSD) were calculated to assess the prescion of the methods.
3. Contents assaying in sample solutions
Sample solutions for assaying were injected into the HPLC system with 1μl injection volume, the integrated peak areas were obtained and used for calculating the contents of piperacillin sodium and tazobactam sodium in sample solutions.
4. Investigation of compatible stability
The sample solution for compatible stability after preparing for 0 h, 0.5 h, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 5.0 h and 6.0 h were injected into the HPLC system, and the peak areas were obtained, then the contents of piperacillin sodium, tazobactam sodium, and the impurities were calculated. At the same time, the appearance changes such as color, turbidity, and precipitation after 6h in room temperature were observed with naked eye.
Results
1. Selectivity
The retention times of piperacillin sodium and tazobactam sodium were 9.566min and 4.561min, the peaks were well separated, and did not interfere with each other, or with the impurities.
2. Calibration
The standard calibration curve for piperacillin sodium and tazobactam sodium were linear in the concentration ranges of 2~16 mg/ml, and 0.25~2mg/ml, respectively. The correaltion coefficients (R) of piperacillin sodium and tazobactam sodium were 1.0000 and 1.0000, respectively.
3. Precsion
The RSDs of piperacillin sodium and tazobactam sodium were 1.4% and 0.2%, respecitively.
4. The contents of piperacillin sodium, tazobactam sodium and impurtities
The content of piperacillin sodium in three sample solutions were 102.9%, 96.4% and 103.1%, respecively. The content of tazobactam sodium in three sample solutions were 100.1%, 92.8% and 97.9%, respecively. The content of impurties in three sample solutions were 1.65%, 2.75% and 1.83%, respecively.
5. Compatible stablity
There had no color changes, no cloudings, and no precipitations in the sample solutions for comopatible stablity after preparing for 6 h, and the contents of piperacillin sodium, tazobactam sodium, and the impurities were lower than±2%, compared with those prepared at 0 h.
Conclusions
The results showed that the contents of piperacillin sodium, tazobactam sodium and impurities in the products of three manufacturers were in accordance with the related requirements of the Chinese Pharmacopoeia. The products were compatible with 0.9% sodium chloride within 6 h after preparing, supported by the evidences that there had no appearance changes, and the contents of piperacillin sodium and tazobactam sodium were all lower than±2%, which suggested that the piperacillin sodium and tazobactam sodium for injection were compatible with 0.9% sodium chloride.
方法:本实验研究采用高效液相色谱法(HPLC)测定三个厂家生产的哌拉西林钠他唑巴坦钠的主药和杂质的含量及与0.9%氯化钠注射液配伍稳定性。该法采用HYPERSIL BDS-C18色谱柱,甲醇:四丁基氢氧化铵水溶液(pH3.5,50:50)为流动相,流速0.8ml/min,检测波长为220nm,室温下进行检测。
1.溶液的配制
1.1标准品储备液的配制
分别精密称定哌拉西林钠标准品和他唑巴坦钠标准品,以50%(V/V)甲醇的水溶液配制成16mg/ml的哌拉西林钠及2mg/ml他唑巴坦钠的标准储备液。
1.2含量测定的样品溶液的配制
分别取美国惠氏制药有限公司、华北制药集团和珠海联邦制药有限公司生产的注射用哌拉西林钠他唑巴坦钠,用50%(V/V)甲醇的水溶液配制成10mg/ml哌拉西林钠,1.25mg/ml他唑巴坦钠溶液。
1.3配伍稳定性考察的样品溶液配制
分别取上述三家药厂生产的注射用哌拉西林钠他唑巴坦钠,用0.9%氯化钠注射液配制成10mg/ml哌拉西林钠,1.25mg/ml他唑巴坦钠溶液。
2.方法学的考察
2.1专属性考察
分别取哌拉西林钠标准品溶液,他唑巴坦钠标准品溶液及两种标准品的混合溶液进样,进样量1μl,比较所得色谱图。
2.2线性关系的考察
分别精密量取标准品储备溶液适量,以50%(V/V)甲醇的水溶液稀释至哌拉西林钠浓度为2、4、8、10、12和16mg/ml及他唑巴坦钠浓度为0.25、0.5、1、1.25、1.5和2 mg/ml的溶液。分别精密量取各浓度标准液1μl注入色谱仪,记录峰面积,以峰面积(Y)对浓度(C)进行线性回归。
2.3精密度的考察
精密量取8mg/ml的哌拉西林钠及1mg/ml的他唑巴坦钠标准品溶液,连续进样5次,记录峰面积,计算RSD值。
3.样品的含量测定
分别取上面三种含量测定的样品溶液1μl注入色谱仪,记录峰面积,计算哌拉西林钠及他唑巴坦钠的含量。
4.样品的配伍稳定性实验
分别取上面三种配伍稳定性考察的样品溶液1μl,于0h,0.5h,1h,2h,3h,4h,5h和6h注入色谱仪,记录峰面积,计算哌拉西林钠、他唑巴坦钠及杂质的含量。同时用肉眼观察在室温放置6h的外观变化(颜色、浑度、沉淀)。
结果
1.专属性试验结果
哌拉西林钠和他唑巴坦钠的保留时间分别为9.566min和4.561min,两峰分离良好,无干扰。
2.线性关系结果
哌拉西林钠在2～16mg/ml、他唑巴坦钠在0.25～2mg/ml范围内,浓度与峰面积呈良好的线性关系(R值分别为1.0000、1.0000)。
3.精密度考察结果
该法测定哌拉西林钠和他唑巴坦钠的RSD值分别为1.4%、0.2%。
4.样品的主药及杂质的含量测定结果
三种样品的哌拉西林钠含量分别为标示量的102.9%、96.4%、103.1%;他唑巴坦钠含量分别为标示量的100.1%、92.8%、97.9%;杂质的含量分别为1.65%、2.75%、1.83%。
5.样品与0.9%氯化钠注射液的配伍稳定性结果
三种配伍样品液放置6h,均无外观变化(变色、产生浑浊或沉淀);主药含量变化与0h相比均低于±2%。
结论本实验结果表明,三个厂家生产的注射用哌拉西林钠他唑巴坦钠的主药与杂质的含量均符合药典规定。与0.9%氯化钠注射液的配伍溶液6h内均无外观变化,主药含量变化均低于±2%,配伍稳定。
Objective: To study content of the main drugs and theirimpurities injectable piperacillin sodium and tazobactam sodium of three manufacturers and compatible stability with 0.9% sodium chloride injection.
Methods: Use HPLC to Determine the content of piperacillin sodium, tazobactam sodium and impurities and Investigate Content changes of piperacillin sodium, tazobactam sodium with 0.9% sodium chloride injection from three manufacturers samples,the chromatographic column was HYPERSIL BDS C18“4.6 mm×250 mm,5μm”, the mobile phase was methanol and tetrabutyl ammonium hydroxide (pH3.5 ,50: 50)at a flow-rate of 0.8mL/min, the detection wavelength was 220nm.
1. Solution preparation
1.1 Preparation for standard solutions
The piperacillin and tazobactam sodium standards precisely weighed were dispensed by 50% (V/V) methanol aqueous solution respectively, then two stock solution of 16mg/ml for piperacillin sodium and 2mg/ml for tazobactam sodium were prepared respectively
1.2 Preparation for Sample solutions for assaying
The piperacillin sodium and tazobactam sodium obtained from Wyeth Pharmaceuticals Co., Ltd., North China Pharmaceutical Group and Zhuhai United Laboratories Co., Ltd were dispensed by 50% (V/V) methanol aqueous solution respectively, then 10mg/ml piperacillin sodium, 1.25mg/ml tazobactam sodium can obtained.
1.3 Preparation for Sample solutions for compatible stability investigation Piperacillin Sodium And Tazobactam Sodium For Injection from the above three manufactures were dispensed by 0.9% sodium chloride respectively, then 10mg/ml piperacillin sodium, 1.25mg/ml tazobactam sodium can obtained.
2. Method validation
2.1 Selectivity investigation
The standard solution of piperacillin sodium, tazobactam sodium and the mixed solution of above two standard samples were analysed by HPLC respectively, the corresponding chromatograms then obtained.
2.2 Calibration investigation
The standard stock solution prepared above was serially diluted with 50% (V / V) methanol solution to standard concentrations of 2,4,8,10,12 and 16mg/mL for piperacillin and 0.25, 0.5,1,1.25,1.5 and 2 mg / ml solution for tazobactam respecively. 1μL of above standard solution was injected into the chromatograph, and the peak area was recorded. According to the peak area and concentration, linear Regression analysis was carried out.
2.3 Prescion investigation
The variations and accuracy for prescion study were assessed by integrated peak area attained from the continuous injections of 8mg/ml piperacillin sodium and 1mg/ml tazobactam sodium for 5 times, then the relative standard deviation (RSD) were calculated to assess the prescion of the methods.
3. Contents assaying in sample solutions
Sample solutions for assaying were injected into the HPLC system with 1μl injection volume, the integrated peak areas were obtained and used for calculating the contents of piperacillin sodium and tazobactam sodium in sample solutions.
4. Investigation of compatible stability
The sample solution for compatible stability after preparing for 0 h, 0.5 h, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 5.0 h and 6.0 h were injected into the HPLC system, and the peak areas were obtained, then the contents of piperacillin sodium, tazobactam sodium, and the impurities were calculated. At the same time, the appearance changes such as color, turbidity, and precipitation after 6h in room temperature were observed with naked eye.
Results
1. Selectivity
The retention times of piperacillin sodium and tazobactam sodium were 9.566min and 4.561min, the peaks were well separated, and did not interfere with each other, or with the impurities.
2. Calibration
The standard calibration curve for piperacillin sodium and tazobactam sodium were linear in the concentration ranges of 2~16 mg/ml, and 0.25~2mg/ml, respectively. The correaltion coefficients (R) of piperacillin sodium and tazobactam sodium were 1.0000 and 1.0000, respectively.
3. Precsion
The RSDs of piperacillin sodium and tazobactam sodium were 1.4% and 0.2%, respecitively.
4. The contents of piperacillin sodium, tazobactam sodium and impurtities
The content of piperacillin sodium in three sample solutions were 102.9%, 96.4% and 103.1%, respecively. The content of tazobactam sodium in three sample solutions were 100.1%, 92.8% and 97.9%, respecively. The content of impurties in three sample solutions were 1.65%, 2.75% and 1.83%, respecively.
5. Compatible stablity
There had no color changes, no cloudings, and no precipitations in the sample solutions for comopatible stablity after preparing for 6 h, and the contents of piperacillin sodium, tazobactam sodium, and the impurities were lower than±2%, compared with those prepared at 0 h.
Conclusions
The results showed that the contents of piperacillin sodium, tazobactam sodium and impurities in the products of three manufacturers were in accordance with the related requirements of the Chinese Pharmacopoeia. The products were compatible with 0.9% sodium chloride within 6 h after preparing, supported by the evidences that there had no appearance changes, and the contents of piperacillin sodium and tazobactam sodium were all lower than±2%, which suggested that the piperacillin sodium and tazobactam sodium for injection were compatible with 0.9% sodium chloride.
引文
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