Title:Determination of Two Potential Genotoxic Impurities in Crisaborole API
by UPLC-MS/MS
Volume: 19
Issue: 6
Author(s): Mengmeng Zhang and Qiaogen Zou*
Affiliation:
- Department of Pharmaceutical Sciences, Nanjing Technology University, Nanjing, 210009, P.R. China
Keywords:
UPLC-MS/MS, Crisaborole, genotoxic impurities, quality control, quantitative analysis, 4-(4-Bromo-3-formylphenoxy)- benzonitrile, 4-(4-(4-bromo-3-formylphenoxy)-3- formylphenoxy)benzonitrile.
Abstract:
Background: Atopic dermatitis (AD) is an allergic skin disease that can be inherited.
Crisaborole is a specific drug developed to deal with this disease. The compounds of 4-(4-
Bromo-3-formyl-phenoxy)-benzonitrile and 4-(4-(4-bromo-3-formylphenoxy)-3- formylphenoxy)
benzonitrile are the representative impurities in the synthesis of Crisaborole active pharmaceutical
in gradient (API). Owing to the genotoxic impurities that could lead to cancer and gene
mutations, it is necessary to develop a simple, efficient, sensitive, and accurate method to detect
these impurities. In this study, the 4-(4-Bromo-3-formyl-phenoxy)-benzonitrile and 4-(4-(4-
bromo-3-formylphenoxy)-3-formylphenoxy)benzo- nitrile present in Crisaborole API were detected
using UPLC-MS/MS.
Methods: The separation was made on a ZORBAX Eclipse XDB-Pheny column (4.6 mm
×75mm, 3.5 μm) with the mobile phase of acetonitrile solution containing 0.1% trifluoroacetic
acid (A) and water containing 0.1% formic acid (B) in gradient elution mode. Quantification was
performed using positive ion electrospray ionization (ESI), and the contents of two compounds
were determined using the multiple reaction monitoring (MRM) modes.
Results: The quantitative analytical method was fully validated with respect to linearity (r >
0.9998), sensitivity, precision, accuracy (the average recovery of two impurities was 84.1% to
90.7%), and robustness.
Conclusion: Three batches of samples were detected by UPLC-MS/MS, indicating that the proposed
approach was applicable for the quality evaluation of Crisaborole.
