Quantification of Four Azido Impurities in Losartan Potassium API using LCMS-8045

Significance of the topic

The detection and quantification of trace azido impurities in Losartan potassium API is critical due to the potential mutagenic and toxic nature of these compounds. Azido intermediates used in the synthesis of angiotensin receptor blockers such as Losartan are classified as first-class poisons and carry a theoretical cancer risk even at low levels. Regulatory guidelines demand highly sensitive and reliable analytical methods to ensure patient safety and product quality.

Objectives and overview

This study aimed to develop and validate a simple, robust, and rapid LC-MS/MS method for the direct quantification of four specific azido impurities (AZBT, AZLS, AZBC, AZIM) in Losartan potassium API. Key goals included achieving low limits of quantitation, linear response over a defined range, and minimal sample preparation.

Methodology and used instrumentation

A Shimadzu Nexera™ XS UHPLC system was coupled to a Shimadzu LCMS-8045 triple quadrupole mass spectrometer with ESI interface. Separation was achieved on a Shim-pack™ Scepter Phenyl-120 column (150×4.6 mm, 3 µm) at 45 °C using a water/ammonium formate mobile phase and methanol gradient at 0.4 mL/min. Multiple reaction monitoring (MRM) transitions were optimized for each impurity. Calibration standards (1–16 ppb) were prepared in water:methanol (10:90). Losartan peaks were diverted to waste to prevent source contamination.

Main results and discussion

Linearity was demonstrated from 1 to 16 ppb (equivalent to 0.667–10.667 ppm in the 1.5 mg/mL sample) with correlation coefficients (R²) exceeding 0.996. Limits of quantitation for all impurities were 0.667 ppm (S/N ≥10). Repeatability at LOQ (n=6) showed %RSD below 10%. Sample analysis revealed 3.55 ppm AZBT and 409.69 ppm AZLS; AZBC and AZIM were below LOQ. Recovery studies at LOQ levels ranged between 81% and 127%, meeting acceptance criteria (70–130%).

Benefits and practical applications

• The method requires no complex sample pretreatment, reducing analysis time and potential errors.
• High sensitivity and selectivity enable detection of mutagenic impurities at sub-ppm levels.
• Fast polarity switching and rapid scanning on LCMS-8045 support high-throughput QA/QC workflows.

Future trends and possibilities for application

Further trends include expansion to other sartan APIs, automation of sample handling, and integration with in-line impurity monitoring. Advances in ion source design and data processing algorithms could further lower detection limits and improve method robustness.

Conclusion

A straightforward UHPLC-MS/MS approach on Shimadzu Nexera XS and LCMS-8045 offers a reliable solution for quantifying four azido impurities in Losartan potassium API. The validated method meets stringent regulatory requirements, ensuring drug safety and quality.

Reference

No external literature references were provided in the original document.