MALDI Matrices for the Analysis of Low Molecular Weight Compounds: Rational Design, Challenges and Perspectives

The analysis of low molecular weight (LMW) compounds is of great interest to detect small pharmaceutical drugs rapidly and sensitively, or to trace and understand metabolic pathways. Matrix‐assisted laser desorption/ionization mass spectrometry (MALDI MS) plays a central role in the analysis of high molecular weight (bio)molecules. However, its application for LMW compounds is restricted by spectral interferences in the low m/z region, which are produced by conventional organic matrices. Several strategies regarding sample preparation have been investigated to overcome this problem. A different rationale is centred on developing new matrices which not only meet the fundamental requirements of good absorption and high ionization efficiency, but are also vacuum stable and “MALDI silent”, i. e., do not give matrix‐related signals in the LMW area. This review gives an overview on the rational design strategies used to develop matrix systems for the analysis of LMW compounds, focusing on (i) the modification of well‐known matrices, (ii) the search for high molecular weight matrices, (iii) the development of binary, hybrid and nanomaterial‐based matrices, (iv) the advance of reactive matrices and (v) the progress made regarding matrices for negative or dual polarity mode.