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Stability indicating assay method for acotiamide: separation, identification and characterization of its hydroxylated and hydrolytic degradation products along with a process related impurity by UHPLC‐ESI‐QTOF‐MS/MS

Rationale

The presence of impurities and degradation products will affect the pharmacokinetic, pharmacodynamic properties and alter the safety of the drug. Hence, development of stability indicating assay method is an integral part of quality product development and is crucial for the regulatory approval of drug products.

Methods

Acotiamide was subjected to stress degradation under hydrolytic, oxidative, photo and thermal stress conditions. The resulted degradation products (DPs), as well as process related impurity (IMP), were selectively separated from the drug on Waters Acquity HSS cyano column (100 × 2.1 mm, 1.8 μm) with mobile phase containing a gradient mixture of 0.1 % formic acid and acetonitrile (ACN) at flow rate of 0.25 mL min‐1.

Results

The drug was found to degrade in hydrolytic (Acidic and basic), oxidative and photolytic stress while it remained stable in neutral hydrolytic and thermal stress conditions. The seven degradation products (DPs) and one process related impurity (IMP) were observed. All the DPs and process IMP were well separated by the developed UHPLC method and subsequently characterized by UHPLC‐ESI‐QTOF‐MS/MS. The proposed UHPLC method was validated with respect to specificity, linearity, accuracy, precision and robustness as per ICH guideline, Q2 (R1).

Conclusion

All the observed DPs were new and formed by hydrolysis of an amide bond, phenyl ring hydroxylation and hydrolysis of methoxy group the phenyl ring. The despropyl process impurity was observed and well separated from the drug. The proposed UHPLC mass spectrometric method has greater utility in the identification of degradation products in much less time with great selectivity.

Authors:   Mohit Thummar, Prinesh N. Patel, S. Gananadhamu, R. Srinivas
Journal:   Rapid Communications in Mass Spectrometry
Year:   2017
Pages:   n/a
DOI:   10.1002/rcm.7968
Publication date:   24-Aug-2017
Facts, background information, dossiers
  • impurities
  • Hydroxylation
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