The present invention relates to a method and system for selecting best case set of factors for a chemical reaction. Particularly, the invention is directed to a method and system for defining an experimental space and conducting a combinatorial high throughput screening (CHTS) of the experimental space to determine a best case set of reaction factors.
In experimental reaction systems, each potential combination of reactant, catalyst and condition must be evaluated in a manner that provides correlation to performance in a production scale reactor. Combinatorial organic synthesis (COS) is a high throughput screening (HTS) methodology that was developed for pharmaceuticals. COS uses systematic and repetitive synthesis to produce diverse molecular entities formed from sets of chemical xe2x80x9cbuilding blocks.xe2x80x9d As with traditional research, COS relies on experimental synthesis methodology. However instead of synthesizing a single compound, COS exploits automation and miniaturization to produce large libraries of compounds through successive stages, each of which produces a chemical modification of an existing molecule of a preceding stage. A library is a physical, trackable collection of samples resulting from a definable set of processes or reaction steps. The libraries comprise compounds that can be screened for various activities.
The technique used to prepare such libraries involves a stepwise or sequential coupling of building blocks to form the compounds of interest. For example, Pirrung el al., U.S. Pat. No. 5,143,854 discloses a technique for generating arrays of peptides and other molecules using, for example, light-directed, spatially-addressable synthesis techniques. Pirrung et al. synthesizes polypeptide arrays on a substrate by attaching photoremovable groups to the surface of the substrate, exposing selected regions of the substrate to light to activate those regions, attaching an amino acid monomer with a photoremovable group to the activated region, and repeating the steps of activation and attachment until polypeptides of desired lengths and sequences are synthesized.
The methodology of COS has been slow in application to screening to develop chemical production scale reactions because of the difficulty in emulating such reactions on the combinatorial micro-scale. For example, catalyst testing is typically accomplished in bench scale or larger pilot plants by contacting a feed to a continuous flow reactor with a catalyst under near steady state reaction conditions. Rapid combinatorial screening of reactants, catalysts, and associated process conditions requires that a large number of reaction and/or catalytic systems be tested simultaneously. The large number of systems are parameters that can define a very large, multidimensional experimental space.
For example, even a simple commercial process may have five or six critical factors, each of which can have 2 to 20 levels. These factors can include reactants, catalysts and processing conditions. As shown in FIG. 1, the number of possible combinations of factors can become very large, depending on the number of levels. In addition, little may be known about the reaction kinetics and the role of a catalyst. Accordingly, it may be necessary to search hundreds or thousands of combinations to find a handful of xe2x80x9cleadsxe2x80x9d (i.e., combinations that may lead to commercially valuable applications).
T. E. Mallouk et al. in Science, 1998, 1735 showed that effective ternary combinations can exist in a system in which none of the binary combinations are effective. As shown in FIG. 2, investigating binary combinations alone can result in completely ineffective exploration of an experimental space. However, as seen in FIG. 1, the number of tertiary, 4-way, 5-way, and 6-way combinations rapidly becomes extremely large. It is extremely difficult to examine all possibilities of such a complex space even with a very productive high throughput screening (HTS) system. There is a need for improved methods for rapidly, yet effectively investigating a complex experimental space relating to these process combinations.
Accordingly, the invention is directed to a method and system for sampling an experimental space for combinatorial high throughput screening (CHTS). CHTS is an HTS methodology that incorporates characteristics of COS. The definition of the experimental space permits a CHTS investigation of highly complex systems. The method selects a best case set of factors of a chemical reaction. The method comprises defining a chemical experimental space by (i) identifying relationships between factors of a candidate chemical reaction space; and (ii) determining a chemical experimental space comprising a table of test cases for each of the factors based on the identified relationships between the factors with the identified relationships based on researcher specified n-tuple combinations between identities of the relationships. A CHTS method is effected on the chemical experimental space to select a best case set of factors.
In another embodiment, a system for selecting a best case set of factors of a chemical reaction, comprises a processor, reactor and an evaluator. The processor defines a chemical experimental space by (i) identifying relationships between factors of a candidate chemical reaction space and (ii) determining the chemical experimental space comprising a table of test cases for each of the factors based on the identified relationships between the factors with the identified relationships based on researcher specified n-tuple combinations between identities of the relationships. The reactor and evaluator select a best case set of factors from the chemical experimental space by a CHTS method to select a best case set of factors.