Kalariya Pradipbhai D, Talluri M V N Kumar, Patel Prinesh N, Srinivas R
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education & Research, IDPL R&D Campus, Balanagar, Hyderabad, Andhra Pradesh 500 037, India.
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education & Research, IDPL R&D Campus, Balanagar, Hyderabad, Andhra Pradesh 500 037, India.
J Pharm Biomed Anal. 2015 Jan;102:353-65. doi: 10.1016/j.jpba.2014.09.033. Epub 2014 Oct 5.
The present study reports the degradation behavior of a new antidepressant drug, vilazodone, under various stress conditions as per International Conference on Harmonization guidelines (ICH, Q1A(R2). The investigation involved monitoring decomposition of the drug under hydrolytic (acidic, basic and neutral), oxidative, photolytic and thermal stress conditions and identifying degradation products. A rapid, precise, accurate and robust ultra high performance liquid chromatography (UPLC) method has been developed on a Waters CSH Phenyl-Hexyl column (100 mm × 2.1 mm, 1.7 μm) using gradient elution of 10mM ammonium acetate buffer (pH 5.0) and acetonitrile as mobile phase. The drug was found to be degraded in hydrolytic (acidic and basic) and oxidative conditions, whereas it was stable under neutral hydrolytic, photolytic and thermal stress conditions. The method was extended to quadrupole time-of-flight mass spectrometry (QTOF-MS) for the structural characterization of degradation products. It has been observed that isomeric N-oxide degradation products were formed under oxidative stress condition. The exact location of N-oxidation in the drug was investigated using atmospheric pressure chemical ionization (APCI) due to the formation of characteristic fragment ions. These fragment ions resulted from Meisenheimer rearrangement owing to thermal energy activation at the vaporizer of APCI source. All degradation products were comprehensively characterized by UPLC-ESI-MS/MS and UPLC-APCI-MS experiments. The most probable mechanisms for the formation of degradation products have also been proposed. The method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per ICH guidelines.
本研究报告了一种新型抗抑郁药物维拉唑酮在根据国际协调会议指南（ICH，Q1A(R2)）规定的各种应激条件下的降解行为。该研究包括监测药物在水解（酸性、碱性和中性）、氧化、光解和热应激条件下的分解情况，并鉴定降解产物。已开发出一种快速、精确、准确且稳健的超高效液相色谱（UPLC）方法，使用沃特世CSH苯基-己基色谱柱（100 mm×2.1 mm，1.7μm），以10mM醋酸铵缓冲液（pH 5.0）和乙腈的梯度洗脱作为流动相。结果发现该药物在水解（酸性和碱性）和氧化条件下会降解，而在中性水解、光解和热应激条件下稳定。该方法扩展至四极杆飞行时间质谱（QTOF-MS）用于降解产物的结构表征。已观察到在氧化应激条件下会形成异构体N-氧化物降解产物。由于形成了特征性碎片离子，使用大气压化学电离（APCI）研究了药物中N-氧化的确切位置。这些碎片离子是由于APCI源蒸发器处的热能激活导致的迈森海默重排产生的。所有降解产物均通过UPLC-ESI-MS/MS和UPLC-APCI-MS实验进行了全面表征。还提出了降解产物形成的最可能机制。该方法根据ICH指南在特异性、线性、准确性、精密度和稳健性方面进行了验证。
