SGMS Meeting 2001

Using the Mass Spectrometer for Triggering a Fraction Collector. Various aspects of MS directed autopurification

Gerard Bondoux, Jing Lin
Waters European Headquarter, BP 608, 78056 St Quentin Yvelines, France

It's only a few years ago that the first papers were presented on the use of a mass spectrometer for the automated purification of compounds libraries. With the increasing use of combinatorial chemistry in the drug development process, researchers were faced with new challenges: verify the synthesis of the large number of molecules generated by combinatorial chemistry, and purify hundreds of samples per week.

Mass spectrometry was naturally the technique of choice for the characterisation of the combinatorial chemistry libraries. The information provided was mainly the verification of the molecular weight. UV or ELSD detection was used to provide the purity information.

When the molecular weight of the molecule is known, using MS as a detector for the purification is very attractive. The expected benefit is the reduction of the number of collection tubes and fractions to handle, since it is possible to collect only peaks with the expected molecular weight. Large pharmaceutical companies (Pfizer, Abbott, Dupont…), combinatorial chemistry libraries suppliers and instrument manufacturers were involved in the developments. First papers were published in 1998, demonstrating automation possibilities.

Today, MS is widely accepted in the purification/isolation work. The main application domain is still in the early drug discovery stage (leads discovery, leads optimization), but new applications are appearing. One of them is the purification of multi-charged molecules (peptides, oligonucleodites). Another one is the isolation of small chromatographic peaks (impurities, metabolites) for further characterization.

In that paper, we will discuss and illustrate the various advantages and aspects of MS directed autopurification. We will present various application examples, and show how to optimise the mass load and throughput by careful selection of the instrument configuration and separation conditions. Software aspects and implementation into the laboratory environment will be also presented.

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