Gökekin Yasin, Bulut Mehmet, Çetin Ersen Büşra, Güleli Müge, Çalışkan Cem
World Medicine İlaç San. Tic. A.Ş, 15 Temmuz Mah. Camiyolu Cd. No:50, K.4, 34212 Bağcılar, İstanbul, Türkiye.
World Medicine İlaç San. Tic. A.Ş, 15 Temmuz Mah. Camiyolu Cd. No:50, K.4, 34212 Bağcılar, İstanbul, Türkiye; Institute of Graduate Programs, Department of Chemistry, Ankara Hacı Bayram Veli University, Ankara 06500, Turkey.
Eur J Pharm Biopharm. 2025 Nov;216:114844. doi: 10.1016/j.ejpb.2025.114844. Epub 2025 Sep 14.
Bromobutyl rubber stoppers are widely used in the primary packaging systems of many different drug products. However, different additives are added to provide the existing properties of these synthetic elastomeric stoppers. The most important additives are curing agents, activators, plasticizers, fillers, antioxidants and accelerators. However, these components are not covalently bonded to the polymer chains and have the potential to leach from the rubber stopper material to the drug product during its shelf life. Therefore, since they may adversely affect the product's safety, efficacy and stability, they should be identified and monitored through extractable studies. In addition, regulatory authorities such as the US Food and Drug Administration (US FDA) and the European Medicines Agency (EMA) require the submission of Extractables and Leachables (E&L) information to examine the risks. For this purpose, E&L originating from bromobutyl rubber stoppers was examined within the scope of the study. Two different sample preparation methods were used to extract volatile, semi-volatile and non-volatile components at the highest level. The microwave assisted extraction methods, which are relatively widely used and provide faster and less solvent consumption than Soxhlet and also provide longer and continuous contact with the packaging matrix, were compared with the conventional Soxhlet extraction method. The results show that the number of components obtained by microwave assisted extraction method is higher. In addition, different solvent environments (IPA + water, pH 3.5 solution and pH 9.5 solution) were used to expose the matrix to extreme conditions to obtain non-volatile components. The extractable components obtained were identified by using the library databases of the relevant gas chromatography-Mass Spectrometry (GC-MS) and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF) analytical devices. Elemental impurities were quantitatively determined by inductively coupled plasma mass spectrometry (ICP-MS) and evaluated within the scope of possible additives. In addition, six different drug product formulations using bromobutyl rubber stoppers in container-lid systems were investigated within the scope of leachable studies. The results show that the presented methodology is successful in the E&L analysis of different therapeutic products. Moreover, it is adaptable to the analysis of different primary packaging products to ensure product quality and patient safety, while also offering a new approach to E&L analysis for both the literature and the pharmaceutical industry.
溴化丁基橡胶瓶塞广泛应用于许多不同药品的初级包装系统。然而，为了赋予这些合成弹性体瓶塞现有的性能，会添加不同的添加剂。最重要的添加剂有硫化剂、活性剂、增塑剂、填料、抗氧化剂和促进剂。然而，这些成分并非共价键合在聚合物链上，在药品保质期内有从橡胶瓶塞材料中沥出到药品中的可能性。因此，由于它们可能会对产品的安全性、有效性和稳定性产生不利影响，应通过可提取物研究对其进行识别和监测。此外，美国食品药品监督管理局（US FDA）和欧洲药品管理局（EMA）等监管机构要求提交可提取物和可沥出物（E&L）信息以审查风险。为此，本研究范围内对源自溴化丁基橡胶瓶塞的E&L进行了考察。采用两种不同的样品制备方法以最高水平提取挥发性、半挥发性和非挥发性成分。将相对广泛使用的微波辅助萃取方法与传统的索氏提取方法进行了比较，微波辅助萃取方法比索氏提取更快、溶剂消耗更少，且能与包装基质进行更长时间的持续接触。结果表明，微波辅助萃取方法得到的成分数量更多。此外，使用不同的溶剂环境（异丙醇+水、pH 3.5溶液和pH 9.5溶液）使基质处于极端条件下以获得非挥发性成分。通过使用相关气相色谱-质谱联用仪（GC-MS）和液相色谱四极杆飞行时间质谱仪（LC-Q-TOF）分析设备的谱库数据库对获得的可提取物成分进行鉴定。通过电感耦合等离子体质谱仪（ICP-MS）对元素杂质进行定量测定，并在可能的添加剂范围内进行评估。此外，在可沥出物研究范围内，对六种在容器-瓶盖系统中使用溴化丁基橡胶瓶塞的不同药品制剂进行了研究。结果表明，所提出的方法在不同治疗产品的E&L分析中是成功的。而且，它适用于不同初级包装产品的分析，以确保产品质量和患者安全，同时也为文献和制药行业的E&L分析提供了一种新方法。
