Kattel Krishna, Clogston Jeffrey D.
Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702
Various organic solvents are used in the synthesis of complex drug products (for example, nanomedicines) and in the manufacturing/purification of drug substances and other excipients. Residual organic solvents may originate from the purification of drug materials and cleaning/maintenance of equipment used to manufacture the drug products. These residual organic solvents are considered drug product impurities having no therapeutic benefit. High or inconsistent concentrations of these volatile residual impurities not only pose health risks for patients but also affect the product’s quality. In addition, residual organic solvents can affect the physicochemical properties of therapeutics, such as particle size, dissolution and wettability [1]. The amount of residual organic solvent tolerated in final drug products is well-described in pharmacopeias such as United States Pharmacopeia (USP) and European Pharmacopeia (EP), and is closely monitored by regulatory agencies. The International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and the US Food and Drug Administration (FDA) have released a guideline for Residual Solvents Q3C approach for their classification [2]. The residual solvents were evaluated for their possible risk to human health and were placed into one of three classes based on their toxicity data and environmental impact. Class 1 solvents such as benzene, carbon tetrachloride, dichloroethane, and trichloroethane are highly suspected human carcinogens and must be completely avoided. Class 2 solvents such as acetonitrile, chlorobenzene, chloroform, cyclohexane, hexane, and methanol produce non-genotoxic carcinogens and induce neurotoxicity. Class 3 solvents such as acetone, ethanol, ethyl acetate, formic acid, heptane, and propanol have low toxic potential. Class 3 solvents are typically limited to 5000 ppm or 0.5% (w/w). Class 2 solvents have their own individual limits; the acceptable levels of residual solvents are specified by ICH Q3C [2]. Headspace-Gas Chromatography (HS-GC) is the preferred technique for analysis of residual organic solvents in nanoformulations/drug products because it offers several advantages over direct injection GC. In using HS, only volatile components are introduced into the GC system, resulting in extended column lifetime and reduced instrument maintenance, providing superior sensitivity and reproducibility. Headspace sampling is conducted by placing a liquid or solid sample in a sealed vial until a thermodynamic equilibrium between the sample and gas phase is reached. A known aliquot of the gas phase analyte is then transferred to the gas chromatograph for analysis. This protocol outlines procedures for quantitative determination of various residual organic solvents using headspace-gas chromatography.
各种有机溶剂用于合成复杂药物产品（例如纳米药物）以及原料药和其他辅料的制造/纯化过程中。残留有机溶剂可能源于药物原料的纯化以及用于制造药物产品的设备的清洁/维护。这些残留有机溶剂被视为没有治疗益处的药物产品杂质。这些挥发性残留杂质的高浓度或不一致浓度不仅会给患者带来健康风险，还会影响产品质量。此外，残留有机溶剂会影响治疗药物的物理化学性质，如粒径、溶解性和润湿性[1]。最终药物产品中允许的残留有机溶剂量在美国药典（USP）和欧洲药典（EP）等药典中有详细描述，并受到监管机构的密切监测。人用药品注册技术要求国际协调理事会（ICH）和美国食品药品监督管理局（FDA）发布了关于残留溶剂Q3C分类方法的指南[2]。对残留溶剂进行了人体健康风险评估，并根据其毒性数据和环境影响分为三类。第1类溶剂如苯、四氯化碳、二氯乙烷和三氯乙烷是高度可疑的人类致癌物，必须完全避免使用。第2类溶剂如乙腈、氯苯、氯仿、环己烷、己烷和甲醇会产生非基因毒性致癌物并诱发神经毒性。第3类溶剂如丙酮、乙醇、乙酸乙酯、甲酸、庚烷和丙醇的潜在毒性较低。第3类溶剂通常限制在5000 ppm或0.5%（w/w）。第2类溶剂有各自的限量；残留溶剂的可接受水平由ICH Q3C规定[2]。顶空气相色谱法（HS-GC）是分析纳米制剂/药物产品中残留有机溶剂的首选技术，因为它比直接进样气相色谱法具有多个优势。使用顶空进样时，只有挥发性成分被引入气相色谱系统，从而延长了色谱柱寿命并减少了仪器维护，提供了卓越的灵敏度和重现性。顶空进样是通过将液体或固体样品置于密封瓶中，直至样品与气相达到热力学平衡来进行的。然后将已知等分的气相分析物转移到气相色谱仪中进行分析。本方案概述了使用顶空气相色谱法定量测定各种残留有机溶剂的程序。
