Lacroix P M, Dawson B A, Sears R W, Black D B, Cyr T D, Ethier J C
Office of Compliance and Regional Liaison, Therapeutic Products Directorate, Ottawa, Ont, Canada.
J Pharm Biomed Anal. 1998 Nov;18(3):383-402. doi: 10.1016/s0731-7085(98)00051-x.
HPLC methods for drug content and HPLC and NMR methods for related compounds in fenofibrate raw materials were developed. The HPLC methods resolved 11 known and six unknown impurities from the drug. The HPLC system was comprised of a Waters Symmetry ODS column (100 x 4.6 mm, 3.5 microm), a mobile phase consisting of acetonitrile water trifluoroacetic acid 700/300/l (v/v/v) at a flow rate of 1 ml min(-1). and a UV detector set at 280 nm. Minimum quantifiable amounts were about 0.1% for three of the compounds and less than 0.05% for the other eight. Individual impurities in 14 raw materials ranged from trace levels to 0.25%, and total impurities from 0.04 to 0.53% (w/w). Six unknown impurities were detected by HPLC, all at levels below 0.10%, assuming the same relative response as fenofibrate. An NMR method for related compounds was also developed and it was suitable for 12 known and several unknown impurities. It requires an NMR of 400 MHz, or greater, field strength. Individual impurities in the raw materials analyzed ranged from trace levels to 0.24%, and total impurities from trace levels to 0.59%. Several lots contained small amounts of unknown impurities at trace levels. Three lots, all from the same manufacturer, contained an unknown impurity, not detectable by HPLC, which was not present in the other raw materials. It was estimated to be present at a level greater than 0.2%. The results for related compounds by the two techniques were consistent. The main differences stem from the low sensitivity of the HPLC method for some of the related compounds at 280 nm, or from the higher limits of quantitation by the NMR method for several other impurities using the conditions specified. A fifteenth raw material was not homogeneous in its content of impurity VI, a synthetic intermediate and possible degradation product. The HPLC/MS results provided information on the peak purity (number of components) for minor HPLC peaks, as well as structural data such as the molecular ions and diagnostic fragment ions. The HPLC/MS results showed that there were five unknown drug related impurities, for which there were no standards available. Results for the assay of 15 raw materials by HPLC were within the range 98.5-101.5%.
建立了非诺贝特原料药中药物含量的高效液相色谱（HPLC）方法以及有关物质的HPLC和核磁共振（NMR）方法。HPLC方法分离出了药物中的11种已知杂质和6种未知杂质。HPLC系统由沃特世Symmetry ODS柱（100×4.6 mm，3.5μm）、流动相（乙腈-水-三氟乙酸，700/300/1，v/v/v）组成，流速为1 ml·min⁻¹，紫外检测器设置在280 nm。三种化合物的最小可定量量约为0.1%，其他八种化合物小于0.05%。14种原料药中的单个杂质含量从痕量水平到0.25%不等，总杂质含量从0.04%到0.53%（w/w）。通过HPLC检测到6种未知杂质，假设其相对响应与非诺贝特相同，则所有杂质含量均低于0.10%。还开发了一种有关物质的NMR方法，该方法适用于12种已知杂质和几种未知杂质。它需要400 MHz或更高场强的NMR。所分析原料药中的单个杂质含量从痕量水平到0.24%不等，总杂质含量从痕量水平到0.59%。几批样品含有痕量水平的少量未知杂质。三批样品均来自同一制造商，含有一种HPLC无法检测到的未知杂质，其他原料药中不存在该杂质。估计其含量大于0.2%。两种技术测定有关物质的结果一致。主要差异源于HPLC方法对某些280 nm处有关物质的低灵敏度，或源于在规定条件下NMR方法对其他几种杂质的较高定量限。第15种原料药中杂质VI（一种合成中间体和可能的降解产物）的含量不均匀。HPLC/MS结果提供了次要HPLC峰的峰纯度（组分数量）信息以及分子离子和诊断碎片离子等结构数据。HPLC/MS结果表明存在5种未知的与药物相关的杂质，尚无这些杂质的标准品。15种原料药的HPLC含量测定结果在98.5 - 101.5%范围内。
