Pinheiro Mariana S, Viana Gil M, Vieira Bárbara de A Abrahim, de Souza Alessandra Mendonça Teles, Rodrigues Carlos Rangel, Marins Rita de Cássia E E, Cabral Lúcio M, de Sousa Valéria P
Department of Drugs and Pharmaceutics, Faculty of Pharmacy, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho, 373, CCS, Bss, sl15, Rio de Janeiro, RJ 21941-902, Brazil; Department of Pharmaceutical Sciences, Federal University of Espírito Santo, Av. Maruípe, 1468, Vitória, ES 29043-900, Brazil.
Department of Drugs and Pharmaceutics, Faculty of Pharmacy, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho, 373, CCS, Bss, sl15, Rio de Janeiro, RJ 21941-902, Brazil.
J Pharm Biomed Anal. 2017 May 10;138:126-133. doi: 10.1016/j.jpba.2017.02.012. Epub 2017 Feb 6.
The present study reports the degradation behavior of roflumilast (RFL), a new drug developed for the treatment of chronic obstructive pulmonary disease. The degradation of RFL was tested under various stress conditions as per the guidelines of the International Conference on Harmonization. The degradation products (DPs) of RFL were identified, characterized and in silico predictions were made of their pharmacokinetic properties, absorption, distribution, metabolism, excretion and toxicity (ADMET). RFL was subjected to various stress conditions including photodegradation, alkaline and acidic hydrolysis, oxidative and metallic degradation. After analysis by HPLC-DAD, the DPs were isolated by preparative TLC and characterized by high resolution mass spectrometry (HRMS), H NMR, C NMR and infrared (IR) spectroscopy. RFL tablets were prepared by the addition of solid stressing substances such as excipients and storage in an accelerated stability chamber (40°C; 75% r.h.) for sixteen months. Resulting DPs from the tablets were analyzed by UFLC-QTOF. The most drastic degradation conditions for RFL were 5M NaOH, 6M HCl, 7.5% v/v peracetic acid, which resulted in the isolation of four DPs. However, milder degradation conditions (1M NaOH and photolysis) generated six DPs (DP-1, 2, 3, 5, 7 and 8), and are more similar to the actual conditions the drug will be exposed. For tablets containing RFL exposed to an alkaline reagent, two DPs were formed: DP-1 and DP-11. Whereas RFL-containing tablets exposed to acid and oxidizing agents, formed one product DP-11. Forced degradation of RFL led to the formation of eleven DPs, seven of which have never been previously reported. RFL is stable under metallic stress and it is relatively stable during photodegradation testing. The UFLC-QTOF methodology detected a greater number of DPs that formed during the stress conditions tested when compared to the HPLC-DAD methodology. In silico prediction of the ADMET properties of the RFL degradation products and metabolites produced in this study are potentially hepatotoxic.
本研究报告了罗氟司特（RFL）的降解行为，RFL是一种用于治疗慢性阻塞性肺疾病的新药。根据国际协调会议的指导方针，在各种应激条件下测试了RFL的降解情况。鉴定并表征了RFL的降解产物（DPs），并对其药代动力学性质、吸收、分布、代谢、排泄和毒性（ADMET）进行了计算机模拟预测。RFL经受了各种应激条件，包括光降解、碱性和酸性水解、氧化和金属降解。通过HPLC-DAD分析后，通过制备型TLC分离DPs，并通过高分辨率质谱（HRMS）、1H NMR、13C NMR和红外（IR）光谱进行表征。通过添加辅料等固体应激物质制备RFL片剂，并在加速稳定性试验箱（40°C；75%相对湿度）中储存16个月。通过UFLC-QTOF分析片剂产生的DPs。RFL最剧烈的降解条件是5M NaOH、6M HCl、7.5% v/v过氧乙酸，这导致分离出4种DPs。然而，较温和的降解条件（1M NaOH和光解）产生了6种DPs（DP-1、2、3、5、7和8），并且更类似于药物实际会暴露的条件。对于暴露于碱性试剂的含RFL片剂，形成了两种DPs：DP-1和DP-11。而暴露于酸和氧化剂的含RFL片剂，形成了一种产物DP-11。RFL的强制降解导致形成了11种DPs，其中7种以前从未报道过。RFL在金属应激下稳定，并且在光降解测试期间相对稳定。与HPLC-DAD方法相比，UFLC-QTOF方法检测到在测试的应激条件下形成的更多DPs。本研究中产生的RFL降解产物和代谢物的ADMET性质的计算机模拟预测可能具有肝毒性。
