Selective quantitation of B₂Pin₂ and B₂(OH)₄ in active pharmaceutical ingredients by gas chromatography- mass spectrometry

This paper describes a sensitive and selective method for the simultaneous determination of bispinacolato diboron (B₂Pin₂) and tetrahydroxy diboron (B₂(OH)₄) in a small molecule Active Pharmaceutical Ingredient (API) by gas chromatography - mass spectrometry (GC-MS). These reagents are commonly used in the Suzuki-Miyaura coupling reaction and analytical methods are typically required to monitor these reagents at the Threshold of Toxicological Concern (TTC) level since they are Class II impurities based on ICH M7 guideline. In this study, hexylene glycol was added to derivatize B₂(OH)₄ before direct injection to the GC-MS, and B₂Pin₂ is analyzed in the same analysis without derivatization. Under the optimal conditions, the limit of detection (LOD) and the limit of quantitation (LOQ) were 65 ng/mL and 130 ng/mL respectively. Average recoveries of the analytes spiked in the drug substance at the 13 ppm (LOQ) and 104 ppm (TTC) levels were in the range of 77.9 %-85.3 % with relative standard deviations (RSDs) of 2.8 %-6.8 %. The linearity for both analytes was established in the range of 0.130-2.080 μg/mL with a correlation coefficient (r) of 0.9998 and the derivatization reaction is very rapid and complete within 15 minutes.