2DS01

Statistics 2 for Chemical Engineering

lecture 5

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Contents• high-throughput screening• combinatorial chemistry• overview of previous lectures

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Breakthrough in experimentation• robotic sample preparation• miniaturization of reactors• high-level automatization of sensors• pharmaceutical industry:

– routine creation and testing of 1000 to 1000000 distinct compounds (libraries)

• techniques are now also being applied in material development

• new companies:– Symyx (www.symyx.com)– Avantium (www.avantium.com)

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High-throughput screening• typical cycle of experimentation:

– thousands of reactions in few hours– few hours of statistical analyses– thousands of reactions in few hours– few hours of statistical analyses– ---

• new chemical may be developed in 3 weeks rather than 3 years

• Which statistical techniques are important?• How do the classical techniques of the previous lectures fit

in?• Which new techniques are necessary?

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combinatorial synthesis approach

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Multireactor vessels

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Overview of experimental strategies

scientific understanding

chemicalintuition

chemical/physicalknowledge

factor/level determination

polynomial models

first-principles equations

semi-empirical models

combinatorial methods

screening designs

optimal designs for non-linear models

response surface methods

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Multistage screening

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Multireactor vessels

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Combinatorial explosion: example 2nd year project

• 4 different catalysts, 10 continuous change equivalence: 0.01-0.10, with mixtures:

• 4 different bases, 10 continuous change equivalence: 0.01-0.10, with mixtures

• 3 solvents• temperature: 50C-120 C, steps of 10 C• 3 choices for both X and R1

• 6 choices for R2

• Total number of possibilities: 3.3 * 107

R1-BY2 + R2 –X R1-R2

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Experimental strategies: combinatorial organic synthesis

• structural descriptors are calculated for each compound

• similarity coefficients are calculated between compound pairs

• compounds are selected using multivariate methods (based on clustering, dissimilarities, etc.)

Possible because target is single compound

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Experimental strategies: materials development

• currently descriptors less well developed (complex interactions / processing)

• need for other strategies

Common approaches:1. High-speed array strategies2. True combinatorial design strategies

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High-speed array strategies1. gradient arrays2. quaternary mask arrays3. high-speed versions of conventional

experimental designs

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Gradient arrays

100% B

100% A

100% C

• continuous spread

• point techniques• uniform spacing?• data analysis?

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Quaternary mask arrays

4^5 = 1024 possibilities in 20 sputter operations!!

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Detail quaternary masks

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High-speed versions of conventional designs

• cost of experimentation is low• high resolution designs are possible

– full factorials– central composite designs– special cubic mixture designs

• 3rd and higher order interactions are important !

• use in second stage of screening (after “hit” has been found)

• complicated experiments may require extra statistical features (nesting, random effects)

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True combinatorial design strategies• split-and-pool / split-and-combine• representational strategy• index library strategy• all 2-way combinations strategy

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Representational strategy

• similar to one-factor-at-a-time strategy• will not identify interactions

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Index library strategy

is limited strategylike representationalstrategy

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All 2-way combinations strategy

• 19*18/2 = 171 • for all 3-way combinations: (19*18*17)/(1*2*3) = 969 runs

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N-way combinations• gain possible by noting that 1 2 3 4 5 contains

– 10 2-way combinations– 10 3-way combinations – 5 4-way combinations

• orthogonal arrays• Latin squares

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Some WWW sites on combinatorial chemistry

• http://www.combichem.net/ • Homepage of Furka:

http://szerves.chem.elte.hu/Furka/ • http://www.aae.enscm.fr/anciens/94-mc/combche

m.htm

• http://www.combinatorial.com/ • Molecular diversity page:

http://www.5z.com/divinfo/ • Links to several papers:

http://chemengineer.miningco.com/cs/combinatorialchem/index.htm

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Literature• J.N. Cawse, Experimental Strategies for

Combinatorial and High-Throughput Materials Development, Acc. Chem. Res. 34 (2001), 213-221

• R. Hoogenboom et al., Combinatorial Methods, Automated Synthesis and High-Throughput Screening in Polymer Research: Past and Present, Macromol. Rapid Commun. 24 (2003), 15-32

• G-J.M. Gruter et al., R&D Intensification in Polymer Catalyst and Product Development by Using High-Throughput Experimentation and Simulation, Macromol. Rapid Commun. 24 (2003), 73-80.

• W.A. Warr, Combinatorial Chemistry and Molecular Diversity. An Overview, J. Chem. Inf. Comput. Sci. (37) 1997, 134-140.