Pan Changkang, Liu Frances, Ji Qin, Wang Wei, Drinkwater Donald, Vivilecchia Richard
Pharmaceutical and Analytical Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA.
J Pharm Biomed Anal. 2006 Feb 24;40(3):581-90. doi: 10.1016/j.jpba.2005.08.020. Epub 2005 Oct 20.
Understanding drug degradation in the formulated product is critical in pharmaceutical development as it has significant impacts on drug efficacy, safety profile and storage conditions. As a result, identification of degradation compounds has taken an important role in the drug development process. In this study, various hyphenated analytical techniques, such as liquid chromatography mass spectrometry (LC/MS), gas chromatography mass spectrometry (GC/MS), and liquid chromatography nuclear magnetic resonance with a solid phase extraction interface (LC/SPE/NMR), have been applied to the identification of a drug degradation product which grew over time in the stability study of the drug product. The target unknown is less polar and more unsaturated than the drug substance based upon reverse phase HPLC relative retention time and UV spectra. It is not ionizable by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) in either a positive or a negative mode. The unknown was isolated by an HPLC fraction collector and enriched by solid phase extraction. GC/MS with chemical ionization (CI) was employed to determine the molecular weight of this compound. Its fragmentation pattern was determined by CI-MS/MS using an ion trap mass spectrometer. The isolated material was also analyzed by LC/SPE/NMR, from which the structure of this compound was further characterized. The study utilizes a combination of various hyphenated analytical techniques to obtain complimentary information for structure elucidation of the unknown. The combination approach is critical for unambiguous impurity structure elucidation in drug degradation studies of pharmaceutical drug products.
了解制剂产品中的药物降解在药物研发中至关重要，因为它对药物疗效、安全性和储存条件有重大影响。因此，降解产物的鉴定在药物研发过程中发挥了重要作用。在本研究中，各种联用分析技术，如液相色谱 - 质谱联用（LC/MS）、气相色谱 - 质谱联用（GC/MS）以及带有固相萃取接口的液相色谱 - 核磁共振联用（LC/SPE/NMR），已被应用于鉴定一种在药品稳定性研究中随时间增长的药物降解产物。根据反相高效液相色谱相对保留时间和紫外光谱，目标未知物的极性比原料药小，不饱和程度更高。它在正离子或负离子模式下均不能通过电喷雾电离（ESI）或大气压化学电离（APCI）电离。未知物通过高效液相色谱馏分收集器分离，并通过固相萃取进行富集。采用带有化学电离（CI）的气相色谱 - 质谱联用（GC/MS）来测定该化合物的分子量。使用离子阱质谱仪通过CI - MS/MS确定其碎片模式。分离得到的物质也通过LC/SPE/NMR进行分析，从而进一步表征该化合物的结构。本研究利用多种联用分析技术的组合来获取用于阐明未知物结构的互补信息。这种组合方法对于药品药物降解研究中杂质结构的明确阐明至关重要。
