1. 2DS01 Statistics 2 for Chemical Engineering lecture 5

2. 2 Contents high-throughput screening combinatorial chemistry overview of previous lectures

3. 3 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)www.symyx.com –Avantium (www.avantium.com)www.avantium.com

4. 4 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?

5. 5 combinatorial synthesis approach

6. 6 Multireactor vessels

7. 7 Overview of experimental strategies scientific understanding chemical intuition chemical/physical knowledge factor/level determination polynomial models first-principles equations semi-empirical models combinatorial methods screening designs optimal designs for non-linear models response surface methods

8. 8 Multistage screening

9. 9 Multireactor vessels

10. 10 Combinatorial explosion: example 2 nd 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: 50  C-120  C, steps of 10  C 3 choices for both X and R 1 6 choices for R 2 Total number of possibilities: 3.3 * 10 7 R 1 -BY 2 + R 2 –X R 1 -R 2

11. 11 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

12. 12 Experimental strategies: materials development currently descriptors less well developed (complex interactions / processing) need for other strategies Common approaches: 1.High-speed array strategies 2.True combinatorial design strategies

13. 13 High-speed array strategies 1.gradient arrays 2.quaternary mask arrays 3.high-speed versions of conventional experimental designs

14. 14 Gradient arrays 100% B 100% A 100% C continuous spread point techniques uniform spacing? data analysis?

15. 15 Quaternary mask arrays 4^5 = 1024 possibilities in 20 sputter operations!!

16. 16 Detail quaternary masks

17. 17 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 3 rd 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)

18. 18 True combinatorial design strategies split-and-pool / split-and-combine representational strategy index library strategy all 2-way combinations strategy

19. 19

20. 20 Representational strategy similar to one-factor-at-a-time strategy will not identify interactions

21. 21 Index library strategy is limited strategy like representational strategy

22. 22 All 2-way combinations strategy 19*18/2 = 171 for all 3-way combinations: (19*18*17)/(1*2*3) = 969 runs

23. 23 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

24. 24 Some WWW sites on combinatorial chemistry http://www.combichem.net/ Homepage of Furka: http://szerves.chem.elte.hu/Furka/http://szerves.chem.elte.hu/Furka/ http://www.aae.enscm.fr/anciens/94-mc/combchem.htm http://www.combinatorial.com/ Molecular diversity page: http://www.5z.com/divinfo/http://www.5z.com/divinfo/ Links to several papers: http://chemengineer.miningco.com/cs/combinatorialchem /index.htm http://chemengineer.miningco.com/cs/combinatorialchem /index.htm

25. 25 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.