硫酸新霉素软膏的质量评价

目的评价硫酸新霉素软膏的质量现状并分析存在的问题。方法按法定标准检验与探索性研究相结合,对原料及国家计划抽验的2批次制剂进行检验,通过对软膏及原料的粒径、晶型、有关物质、杂质谱、含量测定方法等的考察,分析原料及制剂的质量状况及质量标准合理性。结果按法定标准检验2批次硫酸新霉素软膏,合格率为100%。探索性研究显示软膏含量均匀性欠佳,进一步分析原因,发现原料粒径大小及分布均欠均匀,且原料在存放及制剂过程中易发生转晶;针对质量标准中缺失的有关物质检查项,建立了硫酸新霉素含量测定及有关物质检查的HPLC-PAD方法,并对杂质谱进行研究;初步完成了HPLC-PAD法替代微生物检定法测定硫酸新霉素效价的量效一致性研究。结论国内硫酸新霉素软膏质量总体良好;原料粒径不均匀及易发生结晶形态的转变,可能导致制剂含量均匀性欠佳;建议原料及软膏现行标准中增订有关物质检查项,用HPLC-PAD法替代传统的效价测定;建议原料药企业对原料工艺进行优化,以进一步提高产品质量。     

A Newly Identified Impurity in Polysorbate 80, the Long-Chain Ketone 12-Tricosanone,Forms Visible Particles in a Biopharmaceutical Drug Product

Visible particles linked to polysorbates (PSs) used in biopharmaceutical drug products (DPs) have been observed repeatedly in recent years as an industry-wide issue, with PS degradation and insoluble degradation products, especially fatty acids and fatty acid esters, being suspected as root cause. We have shown that the visible particles observed in a monoclonal antibody DP solution in vials after 18 months of long-term storage at 5 ± 3°C were neither linked to reduction in PS (PS80) concentration nor to any known PS degradation product, but consist of 12-tricosanone, an impurity present in the raw material PS80, not a degradation product. The occurrence of visible 12-tricosanone particles in DP correlated with the usage of specific PS80 raw material lots, where 12-tricosanone was found as impurity at elevated levels. The quantities detected in these PS80 lots directly translate into the amount found in the respective monoclonal antibody DP batches. This is the first time that a clear correlation between the occurrence of the impurity 12-tricosanone in PS80 and the occurrence of visible particles in DP batches is reported. The observation and techniques described enable the control of this ketone in PS raw materials, providing means to prevent respective visible particle formation in DP.     

氨苯喋啶片质量分析

目的对氨苯喋啶片101批样品进行法定标准检验及探索性研究,对该品种的质量状况作出总体分析及评价。方法法定标准检验依据《中国药典》2010年版二部,其质量标准设定有性状、化学反应鉴别、溶出度、重量差异、UV法测定含量。探索性研究参照BP2010年版氨苯蝶啶原料项下有关物质检测方法,采用优化后的HPLC法考察各企业提供的氨苯蝶啶原料及101批片剂中的有关物质;采用HPLC法测定5个企业的样品在4种不同pH值介质中的溶出曲线,并与日本橙皮书中氨苯喋啶片溶出曲线进行比较;建立了溶出度测定的非标方法,并对全部样品进行检验;为考察辅料及各有关物质对氨苯蝶啶含量测定的影响,建立了HPLC法测定氨苯蝶啶片含量的方法。结果法定标准检验：101批样品,5批次不符合规定,不合格率为5%,不合格项目均为溶出度检查。探索性研究：有关物质研究表明制剂中的杂质来源于原料,检验101批样品,均检出已知杂质B、C和一个未知杂质,均未检出已知杂质A;溶出曲线及溶出度研究比较了该制剂在4种不同pH值介质中的溶出曲线,5家生产企业制剂溶出曲线与日本橙皮书上的相似性差异大,有3家生产企业的自身批间均一性相对较好;含量测定结果说明辅料及各有关物质对氨苯蝶啶含量测定基本无影响。结论各生产企业氨苯蝶啶片的质量参差不齐,总体质量状况与日本药品有差距,建议进一步进行生物等效性研究,改进制剂工艺,提高质量。     

氟康唑氯化钠注射液的质量评价

目的 对国产氟康唑氯化钠注射液的质量状况进行评价。方法 采用法定标准检验结合探索性研究,对检验结果进行统计分析。结果 按法定标准检验158批样品,合格率为100%。探索性研究采用文献报道的有关物质测定方法,对样品进行检测,合格率为95.4%;采用LC/MS对主要杂质进行结构确认,并进行来源分析;氟康唑氧化降解杂质为主要杂质,部分企业的原料和制剂中存在未知的弱极性杂质,优化后的有关物质系统可对其同步控制。结论 国产氟康唑氯化钠注射液的整体质量较好,各企业产品存在不同程度的质量差异。原料工艺控制水平是影响本品质量的关键因素,相关企业应对原料进行优选并提高生产工艺控制水平。现行标准无法有效控制弱极性杂质,pH值及渗透压摩尔浓度的限度范围有待规范,标准亟待修订。     

硫酸庆大霉素注射液质量评价

目的通过对抽验结果数据进行统计分析,评价国产硫酸庆大霉素注射液的质量现状。方法依据现行法定质量标准,对全国范围内的硫酸庆大霉素注射液进行法定标准检验,运用多种统计学方法,分析国内硫酸庆大霉素注射液的质量总体水平,比较不同生产企业产品质量;根据专题调研、文献检索和检验结果及分析等情况,开展了杂质谱、组分纯度和离子色谱法测定有关物质等探索性研究,探讨了有关物质、组分纯度和效价的关系。结果本次抽验中涉及的318批次样品标准检验,其中,2批溶液的颜色超标,8批有关物质不符合规定,1批含量不符合规定。杂质谱研究结果显示,各企业杂质谱基本固定,原料和对应制剂杂质个数和杂质含量均一致;解决了用高效液相色谱法测定庆大霉素组分纯度的问题。结论目前绝大部分国产硫酸庆大霉素注射液生产工艺成熟,质量状况较好;杂质谱研究有助于产品的质量控制,进而促进产品质量的提高;新建组分纯度测定方法可更直观地反映产品的质量状况。     

HPLC测定盐酸克林霉素原料和制剂的有关物质

摘要：目的 建立盐酸克林霉素有关物质HPLC测定方法,并比较国产盐酸克林霉素杂质含量的差异。方法 采用CAPCELL PAK C18(250mm×4.6mm,5μm)色谱柱,以0.05mol/L磷酸盐缓冲液(pH7.5)为流动相A,以乙腈为流动相B,按线性梯度洗脱,柱温为30℃,检测波长为210nm,流速1.0mL/min,测定9批盐酸克林霉素原料及75批制剂中的杂质含量。结果 3种已知杂质[林可霉素、克林霉素B(RRT 0.80)、7-差向克林霉素(RRT 0.89)]和其余未知杂质及克林霉素峰间的分离度大于1.5。林可霉素校正因子为0.68,采用外标法计算含量。国内仅1个生产企业不同批次的盐酸克林霉素胶囊杂质水平差异较小,其余生产企业杂质水平批间差异均较大。结论 本方法灵敏度高,分离效果好,能同时测定盐酸克林霉素原料及制剂的杂质。     

国产四环素片质量分析

目的 综合评价不同企业生产的四环素片的质量。方法 采用现行法定标准检验结合探索性研究结果，对市场上24家企业生产的200批四环素片的质量进行系统比较，通过对原料药和制剂含量测定、有关物质及水分等项目的考察，结合稳定性试验，分析不同企业产品的质量差异。结果 法定标准检验200批四环素片，合格率为100%；探索性研究显示，法定标准中有关物质及水分检查项的缺失，导致质量控制不到位。结论 国内四环素片整体质量一般，现行质量标准有待提高。     

Radiolysis characterization of cetostearyl alcohol by gas chromatography-mass spectrometry

Methods for sample preparation, assay test and impurity test were established. Degrees of cetostearyl alcohol (CSA) radiolyses in pure state, ointment base and in chloramphenicol eye ointment (CAPEO) were determined at doses of 25 and 50 kGy. Radiolyses of CSA occur in all cases. The degrees are directly proportional to the irradiation dose in each case. Forty-two impurities and radiolysis products were identified using gas chromatography-mass spectrometry. The radiolysis products were assigned to be n-alkane, n-aldehyde and 2-methyl-1-alcohol. Accordingly, the degradation pathways of cetosteary alcohol were elucidated. Radiolysis behaviors of CSA in pure state, eye ointment base and CAPEO were studied by assay and impurity analyses. The influence of eye ointment matrixes is modest and chloramphenicol molecule exhibits slight scavenger function for cetostearyl. Both qualitative and quantitative data confirm that the radiolysis products of CSA do not cause safety concerns for human use.     

HPLC法测定盐酸丙酰左卡尼汀原料药及其制剂的含量和有关物质

目的:建立测定盐酸丙酰左卡尼汀原料药及其制剂含量和有关物质的方法。方法:采用高效液相色谱法测定3批盐酸丙酰左卡尼汀原料药及注射用制剂中主成分及杂质A、B、C的含量。色谱柱为Angilent Eclipse XDB-C18,流动相为0·006mol·L-1辛烷磺酸钠溶液(pH3·0)-甲醇(95:5),流速为1·0mL·min-1,柱温为30℃,检测波长为210nm。结果:盐酸丙酰左卡尼汀色谱峰与杂质峰能完全分离,主成分检测浓度线性范围为1·0036～20·072mg·mL-1(r=0·9997);低、中、高浓度平均回收率分别为99·92%、100·62%、100·25%,RSD为1·68%、2·41%、2·12%(n=9);最低检测限为0·03888mg·mL-1;6批样品中总杂质含量均小于1·930%。结论:本法简单、灵敏、专属性强、结果准确,适用于测定盐酸丙酰左卡尼汀原料药及其制剂的含量和有关物质。     

HPLC-UV/MS2法考察国产莫匹罗星软膏的杂质谱

建立了同时适合莫匹罗星软膏杂质谱定性和定量研究的HPLC-UV/MS2方法。采用Agilent zorbax SB-C8色谱柱,以四氢呋喃-0.1 mol·L^-1的乙酸铵溶液（28∶72）为流动相;检测波长240 nm;柱温35℃;流速1.0 mL·min-1;进样体积20μL。建立的色谱条件可以使莫匹罗星与相邻杂质基线分离,在0.50~200.0μg·mL^-1范围内线性关系良好（r=1.000）;检测限为4.26 ng。对13批不同有效期的莫匹罗星软膏进行了有关物质测定,从中检出了16个杂质,采用LC-MS对主要杂质结构进行了推定,其中5个杂质为EP报道的杂质,方法简便,结果准确。     

Determination of assay and impurities of gamma irradiated chloramphenicol in eye ointment

A sample preparation method was developed to isolate chloramphenicol and its radiolytic products from an oily ointment base. The isolation method suspended the eye ointment in n-hexane at 45 degrees C, and isolated the target compounds as residue by centrifugation. It was found that the main element to ensure a satisfactory isolation was keeping the sample solution at 45 degrees C during sample preparation. Linearity, precision, accuracy and suitability of the method were confirmed valid for both assay and impurity tests. This isolation method was ideal for assay, unique for extraction of unexpected and complex radiolysis products, and had a number of advantages compared to the pretreatment methods described in The United Stares Pharmacopoeia and British Pharmacopoeia, in terms of accuracy, precision, and easy handling. The effect of gamma-irradiation on chloramphenicol eye ointment was studied by HPLC, after applying the developed sample preparation method. The present assay and impurity test methods with HPLC were confirmed to be suitable for irradiated chloramphenicol in eye ointment. Formation of radiolytic products induced by gamma-irradiation was evidenced by the impurity test. The assay test showed that active ingredient of chloramphenicol eye ointment decreased by 3.3% at an irradiation dose of 25 kGy and by 11.1% at 50 kGy.     

水合氯醛有关物质分析方法优化与稳定性检测

目的 建立水合氯醛中有关物质检查方法,提高水合氯醛相关产品的质量标准与控制限度。方法 建立水合氯醛三氯甲烷与卤代羧酸的检测方法,并通过稳定性监控水合氯醛的杂质变化。结果 经对比研究,本文建立的有关物质方法可满足相关法规要求,同一方法可准确检测原料及其制剂中的4种杂质。结论 本文为水合氯醛及其制剂的质量标准提升提供技术支持,通过水合氯醛杂质检测以及本品在高温、光照的稳定性对比,对实施制剂研究与生产过程中的杂质监控非常必要,可更大程度保障人民群众用药安全。     

中药川楝子炮制前后总三萜的含量变化研究

目的 采用紫外-可见分光光度法测定中药川楝子炮制前后总三萜的含量变化。方法 以川楝素为对照品,5%香草醛-冰醋酸溶液和高氯酸显色后,在515 nm处测定其吸光度值。结果 川楝子生品中总三萜含量为9.223 mg·g^-1,3批炒制品中总三萜含量平均值为8.584mg·g^-1。结论 川楝子炮制品中总三萜含量较生品有所降低,此试验结果可为川楝子的炮制减毒机制提供理论参考。     

硫酸氨基葡萄糖固体口服制剂质量、企业执行标准评价及质控方法探索性研究

目的 评价国内目前市售的硫酸氨基葡萄糖固体口服制剂的质量,考察现行标准中存在的问题,为生产和质量控制提供参考。方法 对硫酸氨基葡萄糖固体口服制剂进行国家药品抽检（共73批,涉及8家生产企业）,采用现行各企业执行的注册标准（共9个标准）对抽检样品进行法定检验。同时对产品进行探索性研究,表观溶解度参照《美国药典》（USP）1236通则;含量测定方法参照USP43硫酸氨基葡萄糖氯化钠项下相关方法;有关物质方法参照原研企业标准;囊壳铬含量测定方法按照《中国药典》2020年版明胶空心胶囊项下相关方法;建立近红外光谱一致性检验模型。结果 73批次硫酸氨基葡萄糖制剂合格率97.3%,2批样品有关物质检查项目不合格。各家质量标准存在一定差异,个别企业质量标准不完善,有待提高,质量标准中部分重要项目检测方法待改进。此外,个别企业应考虑制剂配方工艺的合理性、包装材料的密封性和防潮措施等。探索性研究结果显示,目前各企业执行标准中均没有原料药溶解性检验,建议企业关注晶型等可能影响溶解度的因素;法定检验采用C₈色谱柱的结果较探索性结果整体偏高,采用氯离子作为主成分峰进行含量控制方法不专属,紫外可见分光光度法操作复杂、结果偏差较大,建议改为更为简便和专属的HPLC法;原料药为非复盐的受试批次制剂的杂质检出种类、已知杂质果糖嗪和脱氧果糖嗪含量、其他已知杂质类别和总杂含量高于其他受试企业样品,推断原因为其易吸湿;泡腾片中果糖嗪含量较高,未知杂质数量多于其他剂型,推测原因为辅料较多;与胶囊剂相比,片剂含有的杂质更多,提示片剂生产过程中制粒、整粒等温度较高的步骤会对产品质量产生一定影响;可按生产厂家建立近红外光谱一致性模型或相关系数模型,补充本品的快速筛查方法。结论 各企业质量标准尚存在一定差异,个别企业质量标准不完善,有待提高,质量标准中部分重要项目的检测方法有待改进。应建立统一的国家标准,建立专属性强、准确度高的检测方法。     

玉红膏指纹图谱研究及质量标志物预测分析

目的：建立玉红膏指纹图谱并进行聚类分析及主成分分析,并对其质量标志物进行预测。方法：在古方记载方法基础上加以改善,制备玉红膏样品;采用HPLC色谱法测定21批样品,色谱柱Sepax Bio-C₁₈（4.6 mm×250 mm,5 μm）;流动相为乙腈-0.1%磷酸水溶液;流速：1.0 mL·min^-1;柱温：25℃;检测波长：278 nm,进样量：20 μL。采用"中药色谱指纹图谱相似度评价系统（2012版）"软件对21批样品图谱进行相似度评价及主成分分析,结合主成分分析（principal component analysis,PCA）、正交偏最小二乘判别分析（orthogonal partial least squares discriminant analysis,OPLS-DA）对玉红膏进行整体质量评估,并对其质量标志物进行预测分析。结果：玉红膏的HPLC指纹图谱中21批样品（S1~S21）的相似度>0.940,通过PCA、CA和OPLS-DA,将21批样品聚成3类,S1~S7、S15~S21为第一类、第三类（2019年6月实验室自制、2020年1月实验室自制）;S8~S14为第二类（源自长春中医药大学附属医院）;并从10个共有峰中确定差异较大的3个共有峰,分别为3号峰（芝麻酚）、5号峰（甘草苷）、9号峰（左旋紫草素）。结论：建立的玉红膏HPLC分析方法简便、准确、稳定、灵敏,体现了玉红膏的整体化学成分特征,可用于该制剂的质量控制,也为经典名方发展为现代制剂提供了一定的参考依据。     

乳糖酸阿奇霉素注射液质量评价

目的 评价乳糖酸阿奇霉素注射液的质量。方法 按国家评价性抽验的总体要求，采用法定标准检验方法与探索性研究相结合，对抽验样品进行研究，统计分析检验结果。结果 按现行质量标准检验6批次样品，合格率为100%。探索性研究建立了专属性强、灵敏度高、简便快速的HPLC法测定有关物质和含量。杂质研究表明注射液中降解产物未知杂质III为注射液中特有杂质，含量远超出限度；注射液中杂质含量显著高于注射用粉针制剂和原料，注射液pH值在6.0~7.0范围内以及低温贮藏条件下降解程度相对降低，但不能抑制降解过程；应用高分辨质谱对未知杂质进行了结构确证和来源分析；已知杂质活性研究提示仅少部分杂质具有一定抑菌活性。结论 目前乳糖酸阿奇霉素注射液的产品质量状况差，现行质量标准需提高。注射液产品中杂质显著高于注射用粉针制剂和原料，对现有条件的优化不能有效避免降解反应的发生，该剂型安全性存在较大风险。     

Effect of the admixture of tetracycline and nadifloxacin ointments on their stability and their antibacterial activity

Impetigo contagiosa staphylogenes is commonly treated by administering a combination of nadifloxacin and tetracycline ointments. However, it is not clear whether nadifloxacin and tetracycline are stable after mixing. The purpose of this study was to evaluate the stability of these agents in combination. We also evaluated changes in antibacterial activity after mixing. Mixing the two ointments caused tetracycline to change from yellow to brown in the admixture. Furthermore, the tetracycline content in the ointment decreased in a time-dependent manner, to about 40% at 288 h after mixing. In addition, the nadifloxacin content in the ointment did not change 288 h after mixing. In an alkaline environment (pH 9.0 and 11.0), the tetracycline content decreased and the color of tetracycline changed to brown. These results suggest that sodium hydroxide, which is an additive in nadifloxacin ointment, influences the content of tetracycline. We evaluated the chemical sensitivity of Staphylococcus aureus using disk tests. Nadifloxacin and tetracycline ointment showed the largest radius of inhibition circle, followed by the admixture 0 h after mixing and the admixture 72 h after mixing. These results suggest that the antibacterial activity is inhibited by the admixture. We propose that pharmacists should avoid mixing nadifloxacin with tetracycline ointment in the treatment of impetigo contagiosa staphylogenes and should take care to avoid interactions caused by additives in the ointments.     

Investigation of the chemical equivalence of the trypanocidal products, Samorin and Veridium

A procedure for the evaluation of chemical equivalence of proprietary formulations of isometamidium is described. The method combines the analysis of the principal component (isometamidium), HPLC profiling of related substances and determination of the inorganic impurity, ammonium chloride, using a modification of the Berthelot (Indophenol) reaction. Application of these procedures to analyses of commercially available sachets from four different batches of Samorin and four different batches of Veridium has demonstrated that there are marked qualitative and quantitative differences between batches from these two sources. Whilst Samorin samples showed inter-batch consistency of composition, there was considerable inter-batch variation between the samples of Veridium.     

Structural Rheology of a Model Ointment

A model ointment consisting of white petrolatum, mineral oil and microcrystalline wax was studied using rheology, microscopy and thermal techniques. Rheograms studied over a temperature range of 25-40°C indicated that the overall rheogram shape changed little as the temperature increased. However, two inflections gradually disappeared as the temperature increased. Thermal optical analysis showed that the temperature range over which these inflections disappeared correlated with the melting transition of the components forming the secondary structure. Another series of rheograms obtained from ointments with different combinations of the raw materials showed the rheology of the ointment is primarily controlled by the white petrolatum and mineral oil and that the microcrystalline wax acts to build-up the structure by incorporating itself into the existing white petrolatum structure. Thermal optical analysis of comelts of the raw materials proved that the ointment network structure is essentially a recombination of the naturally occurring components in differing ratios. The knowledge obtained from these studies is applied to a discussion of the thermal and mechanical stresses encountered in the filling operation.     

注射用盐酸大观霉素的质量评价

目的评价国内原料与原研原料的质量差异及国内不同企业的注射用盐酸大观霉素的质量。方法按法定标准检验与探索性研究相结合,对国内原料、原研原料及国家计划抽验的31批次制剂进行检验,通过对有关物质、含量、粒径、包材相容性、苯甲醇注射液等的考察,分析国内和原研原料的质量差异及国内制剂的质量状况。结果法定标准检验31批次注射用盐酸大观霉素,合格率为100%;探索性研究揭示原研原料有关物质个数与总杂含量低于国内原料,效价含量高于国内样品,粒径较国内原料的小且分布均匀集中。影响因素结果显示,1个国内制剂企业的内包装玻璃材质对产品颜色有影响。苯甲醇注射液作为附带的溶解液,其使用必要性有待商榷。结论国内原料与原研原料在有关物质、含量及粒径方面质量不一致;国内制剂整体质量较好;建议现行标准增订4R-双氢盐酸大观霉素的限度标准;建议国内企业对原料工艺进行优化,以提高产品质量,并考察苯甲醇注射液使用的必要性。