制备型高效液相色谱法在药物杂质研究中的应用

制备型高效液相色谱法是一种使用高压、大流量液体输送系统在高分辨率、大内径、高载量分离柱上进行样品高纯度分离的液相色谱制备方法。应用该方法分离的产品在纯度、回收率、分离效率等方面远远优于传统的制备方法,因此在药物研究、生产领域得到广泛应用。介绍制备型高效液相色谱法的研究概况,特点,影响制备型高效液相色谱分离纯化的因素,以及在药物杂质研究中的实际应用,并对制备型高效液相色谱技术存在的问题与发展方向进行总结。     

ICP-MS法测定注射用头孢美唑钠中31种元素杂质的含量

摘 要 目的：建立电感耦合等离子体质谱（ICP-MS）法,测定注射用头孢美唑钠中的31种具有潜在风险的元素杂质：砷（As）、镉（Cd）、汞（Hg）、铅（Pb）、钴（Co）、镍（Ni）、钒（V）、金（Au）、铱（Ir）、锇（Os）、钯（Pd）、铂（Pt）、铑（Rh）、钌（Ru）、银（Ag）、硒（Se）、铊（Tl）、钡（Ba）、钼（Mo）、铬（Cr）、铜（Cu）、锂（Li）、锑（Sb）、锡（Sn）、硼（B）、铝（Al）、硅（Si）、钛（Ti）、锰（Mn）、铁（Fe）,锌（Zn）的含量。方法：采用Agilent 8900 ICP-MS Triple Quad电感耦合等离子体质谱仪,运用碰撞模式消除双电荷干扰,以高基体样品进样系统模式进样,通过在线内标方式消除基质效应,样品稀释直接进样测定。结果：该方法能同时测定31种元素杂质含量,其线性关系良好（r ＞ 0.99）、重复性试验的RSD小于20%（n = 6）、回收率在70%～140%（n = 9）,均满足USP 43 < 233 > 方法学验证碰撞模式的要求。应用该方法测定了20批来自不同生产企业的国产制剂及1批原研制剂中上述元素的含量。结论：国产及原研制剂中元素杂质含量均低于限度的30%,风险可控;所建立的方法操作简便,准确灵敏,专属性强,重复性好,可为化学药品中元素杂质控制方法提供参考。本试验对国评样品的元素杂质迁移情况开展筛查,不仅能够掌握注射用头孢美唑钠质量整体水平,并且可以为监管部门对上市后药品再评价提供技术储备和数据支持。     

Synthetic origin of illicit methylamphetamine in Australia: 2011–2020

The National Measurement Institute's Methylamphetamine Profiling Program has evolved over the last 15 years to address analytical challenges faced with changes in illicit methylamphetamine production. The program involves organic and inorganic analysis of methylamphetamine to determine the precursors and synthetic route used in manufacture. This paper discusses changes in the methylamphetamine chemical profile for samples received at this laboratory during January 2011 to December 2020. In particular, changes observed in the methylamphetamine purity, potency, synthetic route, precursor and precursor synthetic origin are discussed. Over 13,180 samples were analysed during this period consisting of samples seized on the streets and the Australian border. This paper shows correlations between methylamphetamine seizures at the Australian border with international clandestine laboratory and precursor seizures trends. As the illicit drug landscape changes so too must our approach to chemical profiling if we are to confidently determine the synthetic origin of methylamphetamine.     

Developing an Injectable Formula Containing an Oxygen-Sensitive Drug: A Case Study of Danofloxacin Injectable

The purpose of this study was to assess the impact of impurities in formulation components, antioxidants, formulation pH, and processing/packaging on the extent of color change associated with oxidation of danofloxacin injectable. The methods used in this study include reversed-phase HPLC, UV-VIS spectrophotometry, atomic absorption spectroscopy, visual observation, and iodimetric titration for quantification of the antioxidant. The results from this study revealed that trace impurities from two different excipients significantly contributed to color change associated with oxidation. Polyvinyl pyrrolidone (PVP) introduced trace levels of peroxides into the solution. A second excipient also had a significant impact on stability because it introduced trace metal impurities into the product. The minimization of oxygen levels alone in the solution and headspace was not sufficient to completely eliminate the product instability. The addition of an antioxidant, monothioglycerol (MTG), resulted in a formulation less sensitive to processing variables. The impact of pH on the performance of MTG was also studied. At pH 7.5, MTG resulted in significant improvement in stability; however, at pH 6.0 it was not effective as an antioxidant. Process modifications alone may not be sufficient to prevent oxidation. Chemical approaches, such as pH control, addition of an antioxidant, and control of components should be considered first as means of enhancing stability of oxygen-sensitive solutions.     

Survey of Chlorinated Hydrocarbons and Other Organic Volatile Impurities in Captopril Raw Materials and Tablets

Pharmaceutical Research -     

Experiments on the carcinogenic effect of ortho-toluol-sulfonamid (OTS)

Summary Ortho-toluol-sulfonamid was applied to male and female Sprague-Dawley rats in daily doses of 200 mg/kg and 20 mg/kg bodyweight respectively. The maximum dose applied amounted to 17 g/kg. A shortening of the average life expectation was not observed in comparison to the control animals. The incidence of malignant tumors in the animals treated with OTS was identical with the one of the control animals. We did, however, find one animal in the test groups that had a carcinoma of the urinary bladder and seven animals with papillomas of the bladder.The results obtained by experiments in rats allow the conclusion that the essential ingredient of the saccharin impurity, OTS, may possibly have a week carcinogenic effect.     

硝苯地平及有关杂质的HPLC测定法

用HPLC法同时测定了硝苯地平原料药及片剂的含量及杂质A,B,C。以尼泊金乙酯作内标物。     

Evaluation of tetracycline raw materials and finished products found on the Kenyan market

Contents of tetracycline, its degradation products (epitetracycline, epianhydrotetracycline, anhydrotetracycline) and a fermentation impurity (2-acetyl-2-decarboxamidotetracycline) were determined in four raw materials, 12 batches of six ointment products, four eye ointment products and nine batches of five capsule products, all sampled from the Kenyan market. The analytical method was liquid chromatography on a column packed with a poly(styrenedivinylbenzene) material (8-μm PLRP-S 100 Å). All raw materials and finished products had tetracycline contents and impurity levels within the prescribed compendial limits.     

LC determination of glimepiride and its related impurities

Five impurities in glimepiride drug substance were detected and quantified using a simple isocratic reverse phase HPLC method. For the identification and characterization purpose these impurities were isolated from a crude reaction mixture of glimepiride using a normal phase HPLC system. Based on the spectroscopic data like NMR, FTIR, UV and MS these impurities were characterized and used as impurity standards for determining the relative response factor during the validation of the proposed isocratic reverse phase HPLC method. The chromatographic separation was achieved on a Phenomenex Luna C8 (2) 100 Å, 5 μm, 250 mm × 4.6 mm using a mobile phase consisting of phosphate buffer (pH 7.0)–acetonitrile–tetrahydrofuran (73:18:09, v/v/v) with UV detection at 228 nm and a flow rate of 1 ml/min. The column temperature was maintained at 35 °C through out the analysis. The method has been validated as per international guidelines on method validation and can be used for the routine quality control analysis of glimepiride as active pharmaceutical ingredient (API).     

Isolation and structure characterization of related impurities in 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H) bulk drug and quantitation by a validated RP-LC

10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a novel active derivative of ginkgolide B, is a platelet-activating factor antagonist which is being under clinical trial. Two unknown related impurities were observed in analysis of XQ-1H bulk drug. A scaling up preparative liquid chromatography (Prep LC) was used for isolation of the two impurities. Based on LC–MS/MS and nuclear magnetic resonance (NMR) spectra, they were characterized as 10-O-(N,N-dimethylaminoethyl)-11,12-seco-ginkgolide B (imp-1) and 10-O-(N,N-dimethylaminoethyl)-11,12,2,15-diseco-3,14-dehydroginkgolide B (imp-2), respectively. A reversed-phase liquid chromatography (RP-LC) was developed for simultaneous determination of XQ-1H as well as imp-1 and imp-2. Main variables that significantly influence the chromatographic procedure were optimized and efficient chromatographic separation was achieved on a CN column with mobile phase consisting of 5 mM dipotassium hydrogen phosphate (pH 7.5) and methanol delivered in a gradient mode at the flow rate of 1.0 mL min⁻¹. The method was validated and found to be suitable to check the quality of bulk samples of XQ-1H at test concentration of 5.0 mg mL⁻¹ for a 20 μL injection volume.