Prakash Lakkireddy, Himaja Malipeddi, Vasudev Rudraraju
Department of Analytical Research and development, Dr. Reddy's, Laboratories Ltd, IPDO, Hyderabad, 500072, Telangana, India; Pharmaceutical Chemistry Division, School of Advanced Sciences, VIT University Vellore-632014, TN, India.
Pharmaceutical Chemistry Division, School of Advanced Sciences, VIT University Vellore-632014, TN, India.
Sci Pharm. 2014 Sep 8;83(1):65-83. doi: 10.3797/scipharm.1407-18. Print 2015 Jan-Mar.
A short and sensitive stability-indicating gradient RP-UPLC method was developed for the quantitative determination of process-related impurities and degradation products of tolterodine tartrate in pharmaceutical formulations. The method was developed by using the Waters ACQUITY UPLC™ BEH shield RP18 (2.1 × 100 mm, 1.7 μm) column with a mobile phase containing a gradient mixture of solvent A and B at a detection wavelength of 210 nm. During the stress study, the degradation products of tolterodine tartrate were well-resolved from tolterodine and its impurities and the mass balances were found to be satisfactory in all the stress conditions, thus proving the stability-indicating capability of the method. The developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection and quantification, accuracy, precision, ruggedness, and robustness. During the stability (40°C/75% RH, 3 months) analysis of the drug product, one unknown impurity was detected by the above stability-indicating method. The unknown impurity was isolated by preparative HPLC and subjected to mass and NMR studies. Based on the spectral data, the unknown impurity was characterised as 2-(3-amino-1-phenylpropyl)-4-methylphenol (des-N,N-diisopropyl tolterodine). Structural elucidation of the impurity by spectral data is discussed in detail.
开发了一种快速灵敏的稳定性指示梯度反相超高效液相色谱法，用于定量测定药物制剂中酒石酸托特罗定的工艺相关杂质和降解产物。该方法采用沃特世ACQUITY UPLC™ BEH shield RP18（2.1×100 mm，1.7μm）色谱柱，流动相为溶剂A和B的梯度混合物，检测波长为210 nm。在强制降解研究中，酒石酸托特罗定的降解产物与托特罗定及其杂质得到了很好的分离，并且在所有强制降解条件下质量平衡均令人满意，从而证明了该方法的稳定性指示能力。按照ICH指南对所开发的方法进行了特异性、线性、检测限和定量限、准确度、精密度、耐用性和稳健性等方面的验证。在药品的稳定性（40°C/75%相对湿度，3个月）分析中，通过上述稳定性指示方法检测到一种未知杂质。通过制备型高效液相色谱法分离出该未知杂质，并对其进行了质谱和核磁共振研究。根据光谱数据，该未知杂质被鉴定为2-(3-氨基-1-苯丙基)-4-甲基苯酚（去-N,N-二异丙基托特罗定）。详细讨论了通过光谱数据对该杂质进行结构解析的过程。
