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Published on: April 23, 2019
Analysis of Major Impurities in Tolterodine Tartrate Tablets by 2D-UPLC-Q-TOF/MS
Fangfang Pan1, Zhuyu Jin1, Donghai Xu1
1Zhejiang Institute for Food and Drug Control, National Medical Products Administration Key Laboratory for Core Technology of Generic Drug Evaluation, Zhejiang Key Laboratory of Biopharmaceutical Contact Materials, Hangzhou, China.
Rationale:
Impurity profiling is critical for the quality control and safety assessment of pharmaceutical formulations. Tolterodine tartrate tablets contain unknown impurities that are not documented in standard literature or pharmacopoeias. Identifying these impurities and determining their origin is essential for optimizing the manufacturing process and ensuring product stability.
Methods:
A comprehensive two-dimensional liquid chromatography-mass spectrometry (2D-LC/MS) method was developed. The first-dimension separation used a Waters XBridge C18 column (4.6 × 250 mm, 5 μm) with gradient elution (mobile phase A: acetonitrile/water/perchloric acid, 200:800:1.5, v/v/v; mobile phase B: acetonitrile) at 65°C and 1.0 mL·min-1. The second-dimension analysis employed an Agilent Poroshell 120 EC-C18 column (2.1 × 100 mm, 2.7 μm) under isocratic conditions (acetonitrile/20 mmol·L-1 ammonium formate, pH 3.0, 45:55) at 30°C and 0.3 mL·min-1. Detection was performed using an Agilent 6538 Q-TOF mass spectrometer with ESI in positive ion mode (capillary voltage: 4000 V; nebulizer pressure: 35 psi; drying gas: 10 L·min-1 at 350°C; scan range: m/z 50-1000). Impurity structures were elucidated by comparing their fragmentation patterns with tolterodine and considering the synthesis pathway. A comparative stability study of the API and tablets under stress conditions was conducted to trace impurity origins.
Results:
Three primary impurities were detected and characterized in tablets from three different manufacturers, including the originator product. One previously unreported impurity (Impurity 1) was identified. Stability studies indicated that this impurity is a degradation product generated specifically during the tablet formulation process, not from the drug substance itself.
Conclusions:
The established 2D-LC/MS method is effective for the structural elucidation and source tracking of impurities in tolterodine tartrate tablets. The identification of a process-related degradation product provides direct insights for enhancing formulation strategies and implementing targeted quality control measures.
