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首页> 外文期刊>The Internet Journal of Pharmacology >Determination of Organic Volatile Impurities in Active Pharmaceutical Ingredients
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Determination of Organic Volatile Impurities in Active Pharmaceutical Ingredients

机译：活性药物成分中有机挥发性杂质的测定

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Organic solvents such as acetone, ethyl acetate, isopropyl alcohol, methanol, tetrahydrofuran and toluene frequently used in pharmaceutical industry for the manufacturing of Active Pharmaceutical ingredients (APIs). GMP conditions commands to control adequately the quality of APIs. A selective Gas Chromatographic (GC) method has been developed and validated as per ICH guidelines for residual solvent analysis in 16 different APIs. Residual solvents in APIs were monitored using gas chromatography (GC) with Flame Ionisation detector (FID). The separation was carried out on BP 624 column (30m X 0.53mm i.d. X 0.25mm coating thickness), using GC 17 A Shimadzu, with nitrogen as carrier gas in the split mode by direct injection method. The method described is simple, sensitive, rugged, reliable and reproducible for the quantitation of acetone, ethyl acetate, isopropyl alcohol, methanol, tetrahydrofuran and toluene at residual level from intermediates and APIs. Introduction Organic Volatile impurities (OVIs) 1 are residual solvents that are used in and are produced during the synthesis of drug substances, or in excipients used in the production of drug formulations. Many of these residual solvents generally cannot be completely removed by standard manufacturing processes or techniques and are left behind, preferably at low levels. These impurities encounter during manufacture, storage of API, excipients and drug products. ICH 2 has given limits for the presence of OVIs in APIs 3 .In manufacturing drug substances, organic volatile impurities (OVI’s) arising from the final purification by recrystalization, and also from one or more steps of the synthetic process, can be retained in the end products. Very often these solvents, referred to as residual solvents, are carried to the pharmaceutical preparation concerned, making their determination mandatory 4 . During the manufacturing process, certain types of formulations like Gel extrusion module tablet (GEM) is exposed to several organic volatile chemicals. Ethanol, isopropyl alcohol and acetone are commonly used during granulation process. Methanol may be present in certain grades of ethanol. Ethanol and acetone are also used in the preparation of the polymeric coating of GEM tablets 5 .Isopropyl alcohol may be used in the crystallization of the active ingredient while ethyl acetate is a process solvent for the gel forming polymer 6.Low levels of these organic solvents are inevitably present in the GEM drug product even after drying process. OVIs, not only affect physiochemical properties of a drug, such as particle size, dissolution rate and stability, but also can present a serious potential health hazard. Methods for the quantification of OVI’s are reported by the United States Pharmacopoeia (USP) 7 and European Pharmacopoeia (EP) 8 , where the wide spread but relatively expensive automated head space gas chromatography (HS-GC) instrument is used. With these methods relative standard deviations RSDs as high as 15% are allowed 78 . However the methods mentioned in the USP and EP are dedicated to the determination of residual solvents in drug substances, excipients or drug products. The content of residual organic solvents in pharmaceuticals is routinely measured by gas chromatography (GC). Routine GC applications include the analysis of samples of active pharmaceutical ingredients and their intermediates to comply with good laboratory practices (GLP) and good manufacturing practices (GMP), as well as in- process testing for residual solvents to optimize the drying process 9 . Over the last decade, several GC methods to monitor residual solvents in pharmaceutical samples have been reported in the literature 1011121314 . Several of these GC methods tend to have long run times and are very specific for a limited number of OVI’s. There are several methods reported for the determination of residual solvents. Residual solvents are detected using Hewlett Packard (Agilent, Wilmington), MODEL 68
机译：制药工业中经常使用的有机溶剂，例如丙酮，乙酸乙酯，异丙醇，甲醇，四氢呋喃和甲苯，用于制造活性药物成分（API）。 GMP使用条件命令来充分控制API的质量。已开发出一种选择性气相色谱（GC）方法，并已按照ICH指南对16种不同API中的残留溶剂进行了验证。使用带有火焰离子化检测器（FID）的气相色谱仪（GC）监控API中的残留溶剂。使用GC 17 A Shimadzu在BP 624色谱柱（30m X 0.53mm内径×0.25mm涂层厚度）上进行分离，并使用氮气作为载气以分流方式通过直接进样法进行分离。所描述的方法简单，灵敏，坚固，可靠且可重现，可用于从中间体和原料药中定量分析丙酮，乙酸乙酯，异丙醇，甲醇，四氢呋喃和甲苯。简介有机挥发性杂质（OVIs）1是残留的溶剂，用于药物物质的合成或在药物合成过程中或在药物制剂生产中使用的赋形剂中产生。通常，这些残留溶剂中的许多残留溶剂不能通过标准的制造工艺或技术完全除去，并且优选以低水平残留。这些杂质在原料药，赋形剂和药品的生产，储存过程中会遇到。 ICH 2对API 3中OVI的存在给出了限制。在生产原料药时，可以保留重结晶最终纯化产生的有机挥发性杂质（OVI），以及合成过程的一个或多个步骤产生的有机挥发性杂质。最终产品。通常将这些溶剂（称为残留溶剂）带到有关的药物制剂中，使其确定为必不可少的4。在制造过程中，某些类型的配方（例如凝胶挤出模块片剂（GEM））会暴露于几种有机挥发性化学物质中。制粒过程中通常使用乙醇，异丙醇和丙酮。甲醇可能以某些等级的乙醇存在。乙醇和丙酮还用于制备GEM片剂5的聚合物涂层。异丙醇可用于有效成分的结晶，而乙酸乙酯是形成凝胶的聚合物的加工溶剂6这些有机溶剂的含量低即使在干燥过程之后，GEM药物产品中也不可避免地存在这些化合物。 OVIs不仅会影响药物的理化性质，例如粒径，溶出度和稳定性，而且还可能会严重危害健康。美国药典（USP）7和欧洲药典（EP）8报道了OVI定量方法，其中使用了分布广泛但相对昂贵的自动顶空气相色谱仪（HS-GC）。使用这些方法，相对标准偏差RSD可以高达15％78。但是，USP和EP中提到的方法专用于测定原料药，赋形剂或药品中的残留溶剂。药物中残留有机溶剂的含量通常通过气相色谱法（GC）进行测定。常规GC应用包括分析活性药物成分及其中间体的样品，以符合良好的实验室规范（GLP）和良好的生产规范（GMP），以及对残留溶剂进行在线测试以优化干燥过程9。在过去的十年中，文献1011121314中已经报道了几种监测药物样品中残留溶剂的气相色谱方法。这些气相色谱方法中的几种趋于运行时间较长，并且非常适用于有限数量的OVI。报告了几种测定残留溶剂的方法。使用Hewlett Packard（Agilent，威尔明顿）的MODEL 68检测残留溶剂

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