Dodging matrix effects in liquid chromatography tandem mass spectrometric assays—compilation of key learnings and perspectives

Abstract

Triple quad liquid chromatography mass spectrometric assays (LC/MS/MS) have revolutionized the analysis of drug(s)/metabolite(s) with exceptional speed, sensitivity and selectivity features. From inception to date, several new and innovative features have been regularly proposed by researchers to further enhance the value in the applicability of this analytical tool. However, owing to such compressed run times and scanty sample preparation procedures, LC/MS/MS assays that are not fully optimized generally have issues of matrix effects, where ionization potential is either suppressed or enhanced due to the presence of other materials (endogenous/exogenous) in the matrix. By definition, even co-medications, isomeric or isobaric impurities, and drug excipients used in dosing solutions could also potentially contribute to matrix effects. This article captures some of the interesting work carried out by researchers to understand and handle matrix effects. Additionally, it provides perspectives to effectively deal with matrix effects.

The impact of phospholipids and phospholipid removal on bioanalytical method performance

“…For example, with highly hydrophilic compounds that are not easily recovered through LLE, adding high concentrations of salt to increase the polarity of the aqueous phase while using a water-miscible solvent can lead to superior phase separation, aiding in quantification of analytes from biological samples in a process referred to as salt-assisted LLE or SALLE (Bylda et al, 2014). In a 2008 review, Srinivas cautioned against discarding a possible LLE solvent based on its reputation for enhancing matrix effects (Srinivas, 2009).…”

Bioanalytical assay validation parameters re‐visited: perspectives on stability studies

“…If this information is known before hand, one may be cautious in not attempting to analyze the NCE beyond third F/T cycle; however, it should be noted that it is not often that compounds will be analyzed beyond the third F/T cycle. As observed from the recent literature on potentially dubious data generation due to matrix effects (Srinivas 2009;Peoples et al, 2008;Chambers et al, 2007), it is unknown subjecting the matrix to multiple F/T cycles further aggravates the situation of the observed matrix effects. There has not been a specific evaluation of this effect performed and reported in the literature.…”

Dealing with matrix effect: should there be a cut‐off limit for signal ion suppression in quantitative assay validation?

“…Evaluation of matrix effect is an important and integral component of assay validation involving liquid chromatography mass spectrometric methods (LC/MS, LC/MS/MS), regardless of the type of assay being developed (Srinivas, 2009;Chambers et al, 2007;Dams et al, 2003;Matuszewski et al, 2003). The study of matrix effect is applicable without regard to single or multiple analytes being quantified inclusive of internal standard.…”