注射用头孢硫脒杂质谱分析及质量控制

摘要：目的 对头孢硫脒原料及制剂中杂质进行定性分析,比较原料晶型的异同。方法 采用HPLC及柱切换HPLCMS 方法对4个厂家头孢硫脒原料以及12个厂家注射用头孢硫脒杂质谱进行分析。采用粉末X-射线衍射方法对原料晶型进行 分析。结果 共检出6种主要杂质,并对杂质的结构及来源进行了分析,确认了关键指针性杂质。测定了不同厂家原料的晶 型。结论 对头孢硫脒杂质以及晶型的分析可用于监控原料及制剂降解情况以及工艺控制的合理性。     

近红外光谱法快速分析注射用头孢硫脒

摘要：目的:利用近红外（NIR）光谱技术,建立定性和定量通用模型,实现注射用头孢硫脒的快速鉴别与含量、水分检测。方法:采用聚类分析法与模式识别模型对注射用头孢硫脒原料来源进行快速分类鉴别,用偏最小二乘法（PLS）建立注射用头孢硫脒含量和水分的定量分析模型。结果:聚类分析法与模式识别模型对原料来源分类识别结果一致,准确性好。注射用头孢硫脒含量模型的最终优化结果如下:交叉验证相关系数（R2）为60.88,校正集均方根误差（RMSEE）为0.004 68,相对分析偏差（RPD）为1.6,偏差为0.000 5;水分模型的最终优化结果如下:R2为65.12,RMSEE为0.169,RPD为1.69,偏差为-0.042 8。含量和水分模型预测相对偏差分别为0.012%和0.301%。结论:所建定性与定量分析方法可用于注射用头孢硫脒的快速分析,方法简单、准确可靠。     

不同晶型头孢硫脒的制备及稳定性研究

目的 研究头孢硫脒在不同溶剂中的结晶情况,得到稳定性高的结晶产品.方法 采用外观分析、热重分析和粉末X-射线衍射法分析晶型特点,采用高效液相色谱(HPLC)法对晶型的稳定性进行测定和比较.结果 在不同溶剂中制备得到的产品外观上有簇状和针状两种形态;它们的热裂解温度存在明显不同,最大相差20℃;制备得到的产品分别是晶型Ⅱ和一种新的晶型;不同溶剂中得到的头孢硫脒晶体稳定性由高到低依次为异丙醇、丙酮、四氢呋喃、乙腈.结论 首次发现一种头孢硫脒新晶型,得到稳定性高的结晶条件,为工业生产中选择最佳结晶工艺提供依据.     

注射用头孢硫脒的稳定性探讨

目的:探索注射用头孢硫脒在不同pH溶液中的稳定性.方法:应用抗生素微生物检定法测定头孢硫脒在不同pH溶液中的抗金黄色葡萄球菌效应,分别于溶解12h,24h和48h后测定其效价.结果:注射用头孢硫脒溶解于0.9%氯化钠溶液中最为稳定.结论:临床使用头孢硫脒时应以中性溶液稀释.用0.9%氯化钠注射液为佳.     

乙醇-水溶剂体系结晶阿奇霉素的晶体差异分析

目的探索不同条件下乙醇-水溶剂体系产生的阿奇霉素晶体差异。方法以乙醇-水为溶剂体系,采用不同的结晶条件制备阿奇霉素晶体,运用差热分析(TDA)和X-ray衍射法(XRD)对阿奇霉素晶体进行初步研究,并用核磁共振(C-NMR)对阿奇霉素样品进行了确证。结果得到了4种具有不同DTA和XRD特征的晶型阿奇霉素样品。结论获得了阿奇霉素多晶型相关的热力学数据、XRD特征、不同晶型的结晶条件(温度、压强、析晶方式等),为晶体结晶方法的研究开阔了思路。     

注射用头孢硫脒的稳定性研究

目的考察注射用头孢硫脒的稳定性。方法按药典规定的方法进行考察。结果在不同条件下注射用头孢硫脒的性状、含量、酸度、有关物质、澄清度与颜色、水分、不溶性微粒等均符合规定。结论注射用头孢硫脒具有良好的稳定性。     

注射用头孢硫脒细菌内毒素检查方法探讨

目的对注射用头孢硫脒进行鲎试剂检查法实验,以替代热原检查,建立注射用头孢硫脒细菌内毒素检查。方法参照《中国药典》2010版(二)部附录细菌内毒素检查法及其指导原则进行试验。结果注射用头孢硫脒稀释至2.5g/L及以下时可消除对鲎试剂与内毒素凝集反应的干扰。结论注射用头孢硫脒可以通过细菌内毒素检查法来控制细菌内毒素的含量。     

注射用头孢硫脒与替硝唑配伍稳定性临床观察

目的探讨注射用头孢硫脒与临床常用药物配伍稳定性。方法采用模拟临床用药浓度,测定注射用头孢硫脒与替硝唑注射液配伍后8h内的含量和pH变化,同时观察配伍液外观变化情况。结果配伍8h内头孢硫脒和替硝唑的含量、配伍液pH和外观均无明显的变化。结论注射用头孢硫脒与替硝唑配伍后稳定性良好,值得临床推广应用。     

注射用头孢硫脒的稳定性研究

目的考察注射用头孢硫脒的稳定性。方法建立注射用头孢硫脒的含量测定方法,并进行加速试验及室温留样试验,考察其外观、含量、pH值等变化。结果加速试验及室温留样试验中其样品各项指标与0d相比无明显变化。结论注射用头孢硫脒具有良好的稳定性。     

LC-MS法分析头孢硫脒中的主要杂质

目的对国内四家头孢硫脒制剂产品进行检测,确证超过报告限度(>0.05%)杂质的结构。方法采用HPLC法、LC-MS法及NMR法对头孢硫脒进行了强制降解杂质研究、长期留样杂质研究、杂质谱研究。结果存在四个超过报告限度的杂质,降解杂质为去乙酰头孢硫脒和头孢硫脒内酯,其他杂质为7-溴乙酰胺头孢烷酸(7-BCA)、头孢硫脒Δ2异构体。结论为头孢硫脒的质量控制和稳定性研究提供了重要依据。     

注射用加替沙星与头孢硫脒的配伍稳定性考察

目的:考察注射用加替沙星与头孢硫脒在0.9%氯化钠注射液和5%葡萄糖注射液中配伍的稳定性。方法:分别观察及测定配伍液在室温(20±1)℃下放置8h内的外观、pH值变化,并用紫外双波长分光光度法测定其含量。结果:2药在0.9%氯化钠注射液、5%葡萄糖注射液中配伍后8h内外观、pH值、含量、紫外吸收峰形无显著变化。结论:注射用加替沙星与头孢硫脒可以在0.9%氯化钠注射液、5%葡萄糖注射液中配伍使用。     

注射用头孢硫脒与注射用阿昔洛韦的配伍稳定性考察

目的:考察注射用头孢硫脒与注射用阿昔洛韦分别在0.9%氯化钠注射液和5%葡萄糖注射液中的配伍稳定性。方法:在室温(25±1)℃、不避光条件下,观察并测定6h内配伍液的外观和pH值变化,采用高效液相色谱法测定2种药的含量并考察有无新物质生成。结果:2种药在0.9%氯化钠注射液、5%葡萄糖注射液中配伍后6h内外观呈现淡黄色并随时间延长颜色有逐步变深的趋势,pH值逐渐下降,头孢硫脒含量显著下降。结论:注射用头孢硫脒不能与注射用阿昔洛韦在0.9%氯化钠注射液、5%葡萄糖注射液中配伍使用。     

反相高效液相色谱法考察注射用头孢硫脒与注射用卡络磺钠配伍稳定性

目的考察室温条件下头孢硫脒与卡络磺钠在0．9％氯化钠注射液中的配伍稳定性。方法采用反相高效液相色谱法分别测定配伍液中头孢硫脒与卡络磺钠0～6h内的含量变化,并观察配伍液的外观及pH值。结果头孢硫脒与卡络磺钠的检测波长分别为254、364nm;头孢硫脒与卡络磺钠的回归方程分别为Y硫=9335．3X硫-8315．1（r=0．9996,n=6）和Y卡=31133X卡＋7013．7（r=0．9995,n=6）,头孢硫脒在25．0～250．0mg／L、卡络磺钠在8．2～82．0mg／L浓度范围内与峰面积呈良好的线性关系;精密度试验测得头孢硫脒和卡络磺钠峰面积相对标准偏差（RSD）分别为0．55％和0．63％;重复性试验测得头孢硫脒峰和卡络磺钠峰面积RSD分别为0．81％和0．90％（n=6）;稳定性试验测得头孢硫脒与卡络磺钠峰面积RSD分别为0．99％和0．76％（n=6）。6h内配伍液外观无明显变化、pH及含量均变化明显。结论在室温下、6h内,注射用头孢硫脒与注射用卡络磺钠不宜在0．9％氯化钠注射液中配伍使用。     

注射用头孢硫脒与四种常用注射液的配伍稳定性考察

目的 考察注射用头孢硫脒在4种临床常用注射液中的配伍稳定性.方法 根据《中华人民共和国药典》(2010版)规定的注射液pH值的上下限,调节0.9％氯化钠注射液、5％葡萄糖注射液、10％葡萄糖注射液以及5％葡萄糖+0.9％氯化钠注射液的pH值,并按临床常用剂量,配制头孢硫脒与上述注射液及原pH值注射液的配伍溶液,考察上述12种配伍液于0、0.5、1、2、3、4、5、6h的pH值、颜色和澄明度等外观变化,用高效液相色谱法考察在上述时间点下配伍液中头孢硫脒的含量变化.该方法采用BDS-C18(250 mm×4.6 mm,5 μm)色谱柱,磷酸盐缓冲液:乙腈(80∶20)为流动相,检测波长为254 nm,柱温为30℃,进样量1μl.结果 头孢硫脒专属性好,能达到基线分离,线性范围为1～12 mg/ml(R=1.0000),日内精密度相对标准差＜2.0％,12种配伍液在6h内峰面积变化均＜4％.结论 头孢硫脒与不同pH值的0.9％氯化钠注射液、5％葡萄糖注射液、10％葡萄糖注射液以及5％葡萄糖+0.9％氯化钠注射液配伍后稳定,临床上可配伍使用.     

Application of TZERO calibrated modulated temperature differential scanning calorimetry to characterize model protein formulations

The objective of this study was to evaluate the feasibility of using T(ZERO) modulated temperature differential scanning calorimetry (MDSC) as a novel technique to characterize protein solutions using lysozyme as a model protein and IgG as a model monoclonal antibody. MDSC involves the application of modulated heating program, along with the standard heating program that enables the separation of overlapping thermal transitions. Although characterization of unfolding transitions for protein solutions requires the application of high sensitive DSC, separation of overlapping transitions like aggregation and other exothermic events may be possible only by use of MDSC. A newer T(ZERO) calibrated MDSC model from TA instruments that has improved sensitivity than previous models was used. MDSC analysis showed total, reversing and non-reversing heat flow signals. Total heat flow signals showed a combination of melting endotherms and overlapping exothermic events. Under the operating conditions used, the melting endotherms were seen in reversing heat flow signal while the exothermic events were seen in non-reversing heat flow signal. This enabled the separation of overlapping thermal transitions, improved data analysis and decreased baseline noise. MDSC was used here for characterization of lysozyme solutions, but its feasibility for characterizing therapeutic protein solutions needs further assessment.     

我院4种常用抗菌药物与转化糖注射液的配伍稳定性

目的:探讨转化糖注射液与常用抗菌药物配伍的稳定性,减少用药错误,促进临床合理用药。方法:采用高效液相色谱法测定配伍溶液中药物含量,观察我院4种常用抗菌药物头孢硫脒、头孢西丁钠、头孢美唑钠、克林霉素磷酸酯在5%、10%转化糖注射液中与对照溶媒(5%葡萄糖注射液)中不同时间点的药物外观性状、pH值、不溶性微粒、含量等变化。结果:4种抗菌药物与5%、10%转化糖注射液配伍后,性状和含量均无显著改变。头孢西丁钠与转化糖注射液配伍后pH值呈升高趋势,且放置时间越久,pH越高,同与5%葡萄糖注射液配伍的pH变化趋势一致。头孢硫脒与转化糖注射液配伍后随放置时间延长,pH逐渐降低。克林霉素磷酸酯、头孢美唑钠与转化糖注射液配伍的稳定性较好,不溶性微粒符合要求,外观、pH、含量均无明显变化。结论:头孢硫脒、头孢西丁钠、头孢美唑钠、克林霉素磷酸酯可以与转化糖注射液配伍使用。建议头孢西丁和头孢硫脒与转化糖配伍后在2 h内使用。     

Quantifying crystalline form composition in binary powder mixtures using near-infrared reflectance spectroscopy

The objectives of this study were to assess the utility of near-infrared reflectance spectroscopy (NIRS) in differentiating crystalline forms of pharmaceutical materials and determine the accuracy of this technique in quantifying crystalline forms of solids in binary mixtures. Various crystalline forms of sulfamethoxazole, sulfathiazole, lactose, and ampicillin, independently characterized with other methods, were analyzed qualitatively and quantitatively. The observed differences in near-infrared (NIR) spectra of crystalline form pairs were interpretable on the basis of the features of their crystalline and molecular structures and mid-infrared spectra. NIR spectra of binary physical mixtures of crystalline form pairs were obtained directly through glass vials over the wavelength range of 1100-2500 nm. The calibration lines were constructed using an inverted least-squares regression method. The ratio of the response of the second derivative of the reflectance spectra at two wavelengths was plotted versus crystal form composition. The correlation coefficients for plots of predicted versus theoretical composition were generally greater than 0.99 and standard errors were all low. Parallel studies comparing the NIRS method to a quantitative x-ray powder diffraction method using sulfamethoxazole and sulfathiazole confirmed the accuracy of the results. Additional NIRS studies were conducted in the 0-10% composition range with ampicillin and sulfamethoxazole. These results indicated that prediction down to the 1% level was possible. This study demonstrates that NIRS can be used as a quantitative physical characterization method, is comparable in accuracy to other techniques, and is capable of detecting low levels of one crystal form in the presence of another.     

Use of CP/MAS solid-state NMR for the characterization of solvate molecules within estradiol crystal forms

To investigate the solvate molecules within estradiol crystal forms, four crystal forms of estradiol (EM, ET, EP and EC) were obtained by recrystallization from various organic solvents such as methanol, ethanol, isopropanol and acetone, and their physicochemical properties were characterized using XRD, TGA, DSC and solid-state NMR. The XRD patterns showed that the estradiol crystal forms were composed of high crystallinity and their degrees of crystallinity were nearly identical. The solvent phases and solvate molecules within the estradiol crystal forms were detected by thermal analysis and the solvate molecular structures were identified by further observation using solid-state NMR. Estradiol typically tends to crystallize in form of its hemihydrate by the solvate molecules from the mother solvents used for recrystallization. The residual solvent might be incorporated into the estradiol molecules to change the local chemical environment and cause the observed ¹³C CP/MAS NMR spectral changes. These results suggest that the thermal analysis and CP/MAS solid-state NMR spectroscopy could be useful at the dried solid state to characterize the solvate molecule within the recrystallized estradiols.