特索鲁汀，芦丁的天然类黄酮 O-羟乙基衍生物的混合物：化学稳定性和分析方面。
Troxerutin, a mixture of O-hydroxyethyl derivatives of the natural flavonoid rutin: Chemical stability and analytical aspects.
机构信息
Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.
Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.
出版信息
J Pharm Biomed Anal. 2018 Feb 20;150:248-257. doi: 10.1016/j.jpba.2017.12.018. Epub 2017 Dec 9.
Troxerutin (TRX) is a mixture of semisynthetic hydroxyethylrutosides (Hers) arising from hydroxyethylation of rutin, a natural occurring flavonoid. TRX is commonly used for its anti-oxidant and anti-inflammatory properties in chronic venous insufficiency and other vascular disorders. In recent studies, the protective effects of TRX in Alzheimer's disease, colon carcinogenesis and hepatocellular carcinoma are emerged. However, the chemical stability of TRX has never been studied. Hence, the aims of the work were to study the TRX chemical stability through a forced degradation study and to develop and validate a new stability indicating LC-UV method for determination of TRX. In order to perform the study, TRX stability was tested in various stress conditions analysing the degradation samples by LC-MS. Three degradation products (DPs; D1, D2 and D3, 3',4',7-Tri-O-(β-hydroxyethyl)quercetin, 3',4',5,7-Tetra-O-(β-hydroxyethyl)quercetin and 3',4'-Di-O-(β-hydroxyethyl)quercetin respectively) arising from degradation in acidic conditions were identified and synthesized: among them, D1 resulted the stability indicator for hydrolytic degradation. Furthermore, a stability-indicating LC-UV method for simultaneous determination of triHer (3',4',7-Tri-O-(β-hydroxyethyl)rutin, the principal component of the mixture) and D1 was developed and validated. The LC-UV method consisted in a gradient elution on a Phenomenex Kinetex EVO C18 (150 × 3 mm, 5 μm) with acetonitrile and ammonium bicarbonate buffer (10 mM, pH 9.2). The method was linear for triHer (20-60 μg mL) and D1 (5.1-35 μg mL). The intraday and interday precision were determined and expressed as RSDs: all the values were ≤ 2% for both triHer and D1. The method demonstrated also to be accurate and robust and the average recoveries were 98.8 and 97.9% for triHer and D1, respectively. Moreover, the method resulted selective and specific for all of the components present in the degradation pattern of TRX (diHer (3',4'-Di-O-(β-hydroxyethyl)rutin), triHer, tetraHer (3',4',5,7-Tetra-O-(β-hydroxyethyl)rutin), D3, D1 and D2) and it was successfully applied for the stability studies of both drug substances and drug products.
曲克芦丁（TRX）是芦丁羟乙基化的半合成羟乙基芦丁（Hers）混合物，芦丁是一种天然存在的类黄酮。TRX 通常因其抗氧化和抗炎特性而用于慢性静脉功能不全和其他血管疾病。最近的研究表明，TRX 对阿尔茨海默病、结肠癌发生和肝细胞癌具有保护作用。然而，TRX 的化学稳定性从未被研究过。因此，本工作的目的是通过强制降解研究研究 TRX 的化学稳定性，并开发和验证一种用于测定 TRX 的新的稳定性指示 LC-UV 方法。为了进行这项研究，在各种应激条件下测试了 TRX 的稳定性，通过 LC-MS 分析降解样品。在酸性条件下降解产生了三种降解产物（DPs；D1、D2 和 D3，分别为 3'，4'，7-三-O-（β-羟乙基）槲皮素、3'，4'，5，7-四-O-（β-羟乙基）槲皮素和 3'，4'-二-O-（β-羟乙基）槲皮素），并进行了鉴定和合成：其中，D1 是水解降解的稳定性指标。此外，还开发和验证了一种用于同时测定三羟乙基芦丁（混合物的主要成分 3'，4'，7-三-O-（β-羟乙基）芦丁）和 D1 的稳定性指示 LC-UV 方法。LC-UV 方法包括在 Phenomenex Kinetex EVO C18（150×3mm，5μm）上进行梯度洗脱，使用乙腈和碳酸氢铵缓冲液（10mM，pH9.2）。该方法对三羟乙基芦丁（20-60μg/mL）和 D1（5.1-35μg/mL）均呈线性。日内和日间精密度均以 RSD 表示，并确定为精度：三羟乙基芦丁和 D1 的所有值均≤2%。该方法还表现出准确性和稳健性，三羟乙基芦丁和 D1 的平均回收率分别为 98.8%和 97.9%。此外，该方法对 TRX 降解模式中存在的所有成分（二羟乙基芦丁（3'，4'-二-O-（β-羟乙基）芦丁）、三羟乙基芦丁、四羟乙基芦丁（3'，4'，5，7-四-O-（β-羟乙基）芦丁）、D3、D1 和 D2）均具有选择性和特异性，并成功应用于药物物质和药物产品的稳定性研究。
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