Abstract
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.
Highlights
Tolterodine tartrate (2-{(1R)-3-[di(propan-2-yl)amino]-1-phenylpropyl}-4-methylphenol 2,3dihydroxybutanedioic acid (1:1) salt, C22H31NOC4H6O6) is an antimuscarinic drug that is used to treat overactive bladder and symptoms associated with voiding such as urge urinary incontinence, urgency, and frequency
The present study describes the isolation and characterisation of N,N des diisopropyl tolterodine, as well as the development and validation of a stability-indicating RP-Ultra Performance Liquid Chromatography (UPLC) method for the estimation of degradation and process-related impurities of tolterodine tartrate, namely N,N des diisopropyl tolterodine, impurity A, imp B, imp C, imp D, and imp E (Table 1)
Stress studies were performed at the 500 μg/mL concentration of tolterodine tartrate on the drug product to provide an indication of the stability-indicating property and specificity of the proposed method
Summary
Tolterodine tartrate (2-{(1R)-3-[di(propan-2-yl)amino]-1-phenylpropyl}-4-methylphenol 2,3dihydroxybutanedioic acid (1:1) salt, C22H31NOC4H6O6) is an antimuscarinic (muscarinic receptor antagonist) drug that is used to treat overactive bladder and symptoms associated with voiding such as urge urinary incontinence, urgency, and frequency. It controls bladder incontinence by controlling contractions [1,2,3]. Reported methods have not mentioned the formation of a new degradant, des-N,N-diisopropyl tolterodine. This unknown impurity was detected in the drug product during stability sample analysis, which crossed the identification threshold. Various analytical instruments and advanced hyphenated techniques [25,26,27,28,29,30,31,32,33,34,35,36] are routinely used to carry out the impurity profile study
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