Combinatorial data quality

This initial parallelization of the purity analysis for combinatorial chemistry has demonstrated the considerable benefits of such an approach in terms of reduction of overall analytical time with no compromise of data quality. However, for a system that mirrors current practice in the majority of laboratories, and to obtain more information about the identity of the analyte, a parallel approach using MS detection must also be present. 

In this chapter we will discuss current approaches for analytical characterization of combinatorial libraries in a pharmaceutical industry environment. Recently, several analytical groups have presented very similar strategies for analysis of libraries [7-9]. As will be shown later, the key to successful analytical characterization of a combinatorial library is to perform analytical and chemical work in parallel with the library development. The accumulation of data and analytical experience during this process results in an assessment of library quality with a high level of confidence, even if as little as 5-10% of the library components are analyzed. Utilization of the strategy will be demonstrated using two examples analysis of a library synthesized on a robotic station in spatially addressed format and analysis of a library synthesized in accordance with split-and-mix technology. 

The term chemical assessment describes the process through which the reaction scheme to arrive at a target molecule is combinatorialized. This process may include the transfer of a reaction from solution onto SP and/or the adaptation of the reaction conditions to the use of many monomers with different reactivities and stabilities for library synthesis. Monomer rehearsal is an accurate check of the reactivity of a monomer set in the synthetic scheme for the buildup of the library so that the unreactive/difficult monomers are removed from the set. A model library is a small set of discretes, or a small pool, that is prepared using the planned synthetic route for the library and is fully characterized by the appropriate analytical tools Only if the results are satisfactory is the library synthesis carried out. Quality control determines the analytical profile of a library as a single entity, but data from each library individual, or a significant percentage of library individuals, are acquired. A library with 80% confirmed pure compounds is a good-quality library, but the 20% of samples that are... 

In the late 1980s Frechet showed that high quality 13C NMR data of swollen gels could be readily obtained by MAS using a standard MAS probe (34-36). The first use of13 C MAS NMR data for combinatorial chemistry demonstrated that a potential reaction complication, the production of two similar compounds, could be monitored (37). The reaction of norbomane carboxylic acid... 

As stated earlier, LC has emerged as the technique of choice for assessing the quality of combinatorial libraries. While this trend will certainly continue, LC, either alone, or in combination with other techniques, will continue to evolve. The trend towards shorter, smaller internal diameter columns will continue, however hardware limitations such as pressure limitations, system volume, injection overhead times and data storage must be overcome. A balance be-... 

DOS) which offer convenient routes to much larger numbers of compounds. If there is one thing that should be learnt from the early days of combinatorial chemistry, it is that chemists should always judge the quality of these libraries on the chemical structures and biological data produced, not on the elegance of the synthetic chemistry, nor on the unsubstantiated claims of their proponents. 

The purification of combinatorial libraries on a Berger system is deseribed by Farrell et al. at Pfizer for their parallel solution-phase syntheses. The overall process employs as well analytical SFC in combination with mass spectrometry and nitrogen chemiluminescence deteetion off-line of the preparative-scale SFC systems. Pre-purification analytical SFC/ MS/CLND allows the triage of samples for purification, and an in-house software package analyzes data for predicted quality based on an evaluation of UV and MS data for the potential of co-eluting peaks during purification. This same software package selects a collection time window for purification, which is necessary to limit the number of fractions per sample. This system accommodates the purification of samples up to 50 mg... 

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