阿莫西林中高分子杂质的测定与质量分析

目的 比较不同厂家阿莫西林原料、胶囊、混悬剂中高分子杂质的含量.方法 采用Ohpak SB-802.5HQ(聚合基柱)高效液相凝胶色谱系统进行分离分析.结果 21批阿莫西林样品中高分子杂质的测定结果均为1%以下.结论 国产与进口阿莫西林中的高分子杂质含量无显著差异.     

阿莫西林胶囊聚合物杂质测定中的异常情况研究

目的研究阿莫西林胶囊聚合物测定中出现的异常情况。方法按照2005年版《中国药典》规定的分子排阻色谱法原理，采用高效液相色谱（HPLC）法和AKTA^TM LC抗生素高分子专用分析系统两种方法进行分析。结果采用HPLC法时聚合物杂质含量超出药典规定范围。采用AKTA^TM LC抗生素高分子专用分析系统法进行复核时出现双杂质峰现象，即聚合物杂质峰出现异常分离情况，以第1个杂质峰作为聚合物杂质进行计算，发现聚合物杂质含量小于0．2％，在药典规定范围内。结论有条件的实验室应使用AKTA^TM LC抗生素高分子专用分析系统与较大柱床体积的色谱柱来检查阿莫西林胶囊聚合物，检查时若出现聚合物杂质峰异常分离，应以第1个杂质峰作为聚合物杂质进行计算。     

凝胶色谱法测定阿莫西林颗粒中的高分子杂质

目的：建立测定阿莫西林中的高分子杂质（阿莫西林聚合物）的方法。方法采用凝胶色谱法。色谱柱为Sephadex G-10（40～120mm）凝胶柱，流动相A为0．2mol／L磷酸盐缓冲液（pH8．0），流动相B为水，流速为1．0ml／min；检测波长为254nm。结果阿莫西林颗粒中的高分子杂质含量，均小于0．1％。结论方法灵敏、准确、简便，可用于本品的质量控制，对提高临床有效性及安全性有利。以此方法测定已在国内上市的两个厂家阿莫西林颗粒的高分子杂质，结果发现，南京长澳制药有限公司的产品高分子杂质含量低于香港联邦制药厂的产品。     

阿莫西林胶囊中高分子杂质含量的凝胶色谱法测定

目的 应用凝胶色谱法测定阿莫西林胶囊中的高分子杂质。方法 以高分子杂质为指标，对阿莫西林胶囊中的高分子杂质含量进行测定，采用凝胶色谱法，使用Sephadex G-10（40-120μm）柱，流动相为磷酸盐缓冲液（pH7．0），检测波长：254nm。结果 测定了市售15个批号阿莫西林胶囊中高分子杂质的含量。结论 方法简便，结果稳定，可用于阿莫西林胶囊的质量控制。     

注射用头孢唑林钠中高分子杂质的检查法

目的 对注射用头孢唑林钠中高分子杂质进行分离分析。方法 采用以Sephadex G-10为填料的凝胶色谱系统，以自身对照外标法对头孢唑林钠中高分子杂质进行定量测定。结果缔合物在Sephadex G-10凝胶色谱系统中的色谱行为和高分子杂质一样，都在Kay=0处表现为单一的色谱峰，可精确对高分子杂质峰进行定量。结论 方法简便，结果可靠。     

加替沙星中高分子杂质的分离分析与测定

目的：探讨加替沙星中高分子杂质的分离分析与测定。方法：用高效液相色谱法（HPLC），以葡聚糖凝胶G-10填充柱为色谱柱，以磷酸盐缓冲液为流动相，流速1.0mL/min，检测波长298nm。结果：利用高效液相色谱系统能分离高分子杂质，采用自身对照法能测定出加替沙星中高分子杂质的含量。结论：方法简便，可用于喹诺酮类高分子杂质的测定。     

超声处理对β-内酰胺类抗生素高分子杂质含量的影响

目的:考察超声前处理方法对β-内酰胺抗生素高分子杂质含量的影响.方法:采用葡聚糖凝胶(Sephadex)G-10高效液相色谱系统对不同厂家的注射用头孢曲松钠和阿莫西林胶囊进行分析.结果:采用超声前处理的方法可导致注射用头孢曲松钠和阿莫西林胶囊的高分子杂质含量出现不同程度的降低(5.5%～14.8%).结论:检测β-内酰胺类抗生素的高分子杂质含量时应尽量避免强烈的超声处理.     

注射用头孢唑林钠中高分子杂质的检查法

目的对注射用头孢唑林钠中高分子杂质进行分离分析。方法采用以SephadexG10为填料的凝胶色谱系统,以自身对照外标法对头孢唑林钠中高分子杂质进行定量测定。结果缔合物在SephadexG10凝胶色谱系统中的色谱行为和高分子杂质一样,都在Kav=0处表现为单一的色谱峰,可精确对高分子杂质峰进行定量。结论方法简便,结果可靠。     

安美汀中高分子杂质的分离分析与质量控制

目的 :建立对安美汀 (阿莫西林 /克拉维酸钾 )中高分子杂质进行分离分析与质量控制的方法和指标。方法 :采用以SephadexG - 10 ,SephadexG - 15 ,TSK2 0 0 0SW ,TSK2 5 0 0PWXL等为填料的一系列凝胶色谱系统。结果 :确定了TSK2 5 0 0PWXL凝胶分离系统 ,采用对高分子杂质总量 (Kav <0 3)和分子量最大的杂质量 (Kav <0 1)进行联合控制的质控方法 ,其检测指标依据临床免皮试研究用样品的高分子杂质的检验结果而制订。结论 :方法简便 ,结果可靠 ,现已用于我国药品质量标准中对安美汀高分子杂质含量的控制。     

高效液相色谱法测定阿莫西林颗粒中的高分子杂质

目的:建立一种高效液相色谱法测定阿莫西林颗粒中高分子杂质的方法.方法:采用高效液相色谱法.色谱柱为Sephadex G-10凝胶柱,流动相A为0.1 mol/L的磷酸盐缓冲液(pH=7.0),B为水,流速0.6～0.9 mL/min;检测波长为254 nm.结果:阿莫西林颗粒(再林)中杂质含量小于0.1%.结论:高效液相色谱法灵敏、准确、简便,可用于本品的质量控制.     

Isolation and characterization of some potential impurities in ropinirole hydrochloride

Three impurities in ropinirole hydrochloride drug substance at levels approximately 0.06-0.15% were detected by reverse-phase high performance liquid chromatography (HPLC). These impurities were isolated from the drug substance. These impurities were analyzed using reverse-phase HPLC. Based on the spectral data (IR, NMR and MS), structures of these impurities were characterized as 4-[2-(propylamino) ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride (impurity-A), 5-[2-(diropylamino) ethyl]-1,4-dihydro-3H-benzoxazin-3-one hydrochloride (impurity-B) and 4-[2-(diropylamino) ethyl]-1H-indol-2,3-dione hydrochloride (impurity-C). Synthesis of these impurities is discussed.     

Isolation and identification of process impurities in trimethoprim drug substance by high-performance liquid chromatography, atmospheric pressure chemical ionization liquid chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy

Twenty-two lots of recently synthesized trimethoprim drug substance, from five different manufacturers, in three different countries of origin, China, Israel and the United States, were investigated for the presence of impurities. A liquid chromatographic system, using gradient elution, and a mobile phase consisting of 0.25% TEA/0.1% formic acid (pH 5.8)--acetonitrile, was used to separate and detect two significant, recurring impurities in trimethoprim drug substance. The two impurities were isolated by preparative liquid chromatography and identified, using a combination of liquid chromatography/mass spectroscopy and nuclear magnetic resonance, as 2,4-diamino-5-(4-ethoxy-3,5-dimethoxybenzyl) pyrimidine and 2,4-diamino-5-(3-bromo-4,5-dimethoxybenzyl) pyrimidine. These impurities were not detected by the compendial method and were present at significant levels in 17 of the lots tested. Total impurity concentrations were in the range of 0.1-2.1%.     

Chromatographic determination of high-molecular weight impurities in amoxicillin

The separation of high molecular weight impurities in amoxicillin has been examined by three methods of gel filtration chromatography (GFC) and reversed phase liquid chromatography (RPLC). Specificity of GFC was checked by applying the method for the determination of amoxicillin and its related impurities and linking of GFC and RPLC. The result shows that for the determination of polymers the gel filtration chromatography is a rather simple separation mode as compared to RPLC. Regarding the three gel filtration chromatographic methods, the separation on the Superdex peptide column is advantageous over other methods of determining amoxicillin polymers.     

Identification of Pharmaceutical Impurities in Formulated Dosage Forms

Structure elucidation of pharmaceutical impurities is an important part of the drug product development process. Impurities can have unwanted pharmacological or toxicological effects that seriously impact product quality and patient safety. This review focuses on current analytical strategies for chemical and structural identification of pharmaceutical impurities. Potential sources and mechanisms of impurity formation are discussed for both drug substance and drug product applications. The utility of liquid chromatography–mass spectrometry (LC/MS) for providing structure-rich information is highlighted throughout this review. Other hyphenated analytical techniques including LC/nuclear magnetic resonance, gas chromatography/MS, and size-exclusion chromatography/chemiluminescent nitrogen detectors are also discussed, as LC/MS alone sometimes cannot reveal or confirm the final structures as required during dosage form development.     

Isolation and identification of ester impurities in RG7128, an HCV polymerase inhibitor

RG7128 is a di-ester prodrug of a cytidine analog for the treatment of hepatitis C virus (HCV) infection. The structures of nine low level impurities (0.05–0.10%) in RG7128 drug substance were elucidated. The majority of the impurities were formed during the synthesis of the prodrug from the parent drug. Structural elucidations of the impurities were achieved either by enrichment of the impurities using preparative chromatography followed by spectroscopic techniques or by confirmation with a reference sample. Heart-cut and recycle chromatographic techniques were applied to purify closely eluting isomers of RG7128.     

国产阿莫西林克拉维酸钾片质量评价

目的:考察现行质量标准的科学性,评价国产阿莫西林克拉维酸钾片的质量现状及存在的问题。方法:采用现行标准对抽验样品进行法定检验;建立并完善了用于探索性研究的多个方法:(1)采用中国药典2010年版中梯度条件代替原标准中的方法对抽验样品进行有关物质检查;(2)采用LC-MS法[Agilent 1100 LC/MSD Trap液质联用仪,Shim-pack CLC-ODSC18(4.6 mm×150 mm,5μm,日本岛津公司)]研究本品的杂质谱,根据该研究结果,建立了分区域计算有关物质的方法;(3)采用交叉验证法验证和完善了现有的NIR定性定量模型并新建了NIR水分定量模型;(4)采用自动取样溶出仪(SOTAXAT7 Smart)进行溶出试验、采用新建立UPLC法(Agilent Technologies 1920 Infinity型超高压液相色谱仪)测定溶出量,研究国内外口服制剂溶出行为的差异。结果:法定检验显示,本次抽验样品绝大多数批次符合标准规定;杂质谱研究结果显示,口服制剂中有19个潜在杂质,不同来源的杂质具有明显分区,与阿莫西林有关的杂质主要集中在克拉维酸主峰后,而与克拉维酸有关的杂质则集中在克拉维酸主峰前,采用杂质归属分区域法检测杂质含量,得到的杂质含量更合理;本品溶液状态稳定性较差(温度>25℃时,3h降解2.0%～3.1%,尤其是克拉维酸组分);验证并完善了现有的NIR定性、定量模型并新建了NIR水分测定模型;新建的UPLC快速检测方法使两组分在1分钟内出峰完毕,满足了快速测定的要求;不同生产厂家片剂之间溶出行为差异显著,与进口片剂溶出曲线也明显不同。结论:目前绝大部分国产阿莫西林克拉维酸钾片的产品质量能符合现行标准要求;现行标准存在缺陷,如有关物质检查的计算方法不尽合理;新建计算方法能有效弥补现行标准的缺陷,测定结果能更真实地反映药品质量,有助于发现目前产品中的质量问题,进而促进产品质量的提高。     

阿莫西林颗粒中特定杂质的研究及控制

目的建立阿莫西林颗粒有关物质检查方法,用于控制产品中特定杂质及其他有关物质。方法以十八烷基硅烷键合硅胶为填充剂（4.6 mm×100 mm,5μm）;以2.72 g/L磷酸二氢钾溶液（2 mol/L氢氧化钾溶液调节pH值至5.1）为流动相A,以甲醇为流动相B,梯度洗脱;检测波长为210 nm;柱温40℃。结果主成分与各相关杂质峰均能有效分离,各杂质线性关系良好（R≥0.9996）,各杂质检测限≤12 ng。结论该方法专属性强、灵敏度高、重复性好,可用于阿莫西林颗粒中特定杂质及其他有关物质的控制。     

Identification and structural elucidation of process impurities generated in the end-game synthesis of taranabant (MK-0364) via cyanuric chloride

Taranabant (MK-0364) is a highly potent and selective cannabinoid-1 receptor (CB-1R) inverse agonist. It is being developed at Merck & Company to treat obesity. The chemical synthesis of MK-0364 drug substance involved the direct coupling of chiral amine and pyridine acid side chains mediated by cyanuric chloride. Four major process impurities were observed and characterized using high performance liquid chromatography (HPLC) coupled with ultraviolet (UV) and electrospray ionization (ESI) mass spectrometry (MS) detectors. The exact mass data was used for structural elucidation which suggests that the impurities are derivatives of cyanuric chloride formed in the coupling step. Owing to the reactive nature of these impurities, an interesting degradation phenomenon was observed during stability testing of MK-0364 drug substance when stored at 40 °C/75% RH and 25 °C/60% RH conditions. Degradation pathways were proposed to explain the changes observed in the HPLC impurity profile. Forced degradation experiments were also conducted to confirm the degradation pathways and assess the stability of the impurities. Finally, the complete stability data of the bulk drug are reported to support the hypothesis.