1. Statistics 2 for Chemical Engineering lecture 5
2DS01
Statistics 2 for Chemical Engineering
lecture 5

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

3. Breakthrough in experimentation
robotic sample preparation
miniaturization of reactors
high-level automatization of sensors
pharmaceutical industry:
routine creation and testing of 1000 to distinct compounds (libraries)
techniques are now also being applied in material development
new companies:
Symyx (
Avantium (

4. High-throughput screening
typical cycle of experimentation:
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. combinatorial synthesis approach

6. Multireactor vessels

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

8. Multistage screening

9. Multireactor vessels

10. Combinatorial explosion: example 2nd year project
R1-BY2 + R2 –X
R1-R2
4 different catalysts, 10 continuous change equivalence: , with mixtures:
4 different bases, 10 continuous change equivalence: , with mixtures
3 solvents
temperature: 50C-120 C, steps of 10 C
3 choices for both X and R1
6 choices for R2
Total number of possibilities: 3.3 * 107

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

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

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

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

16. Detail quaternary masks

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
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)

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

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

21. Index library strategy
is limited strategy like representational
strategy

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

23. N-way combinations gain possible by noting that 1 2 3 4 5 contains
orthogonal arrays
Latin squares

24. Some WWW sites on combinatorial chemistry
Homepage of Furka:
Molecular diversity page:
Links to several papers:

25. Literature
J.N. Cawse, Experimental Strategies for Combinatorial and High-Throughput Materials Development, Acc. Chem. Res. 34 (2001),
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),
W.A. Warr, Combinatorial Chemistry and Molecular Diversity. An Overview, J. Chem. Inf. Comput. Sci. (37) 1997,