The Portfolio Method of Chemical Process Development

More efficient chemical process development is possible but it requires the addition to the team of someone with an unusual combination of bench experience, book learning, creativity, electronic search skills, and communication. This person acts as an assembler of the initial literature folio.

The method would work as follows:

As soon as a Process Development Project has been accepted all the client’s pertinent information is provided to the folio assembler. The longer the period between project acceptance and the planned start of the bench-work the better. The shorter the period, the more critical the assembler’s timeline becomes. The folio assembler works with the senior research chemist for the project. It is the folio assembler’s job to provide a stack of pertinent literature to the senior research chemist as quickly as possible of such a quality that after reading through it the senior research chemist will say, “The solution is obvious.” 

The early bench work of junior team members should concentrate on the development of ‘in situ’ assays for product and starting materials and sometimes known impurities. 

The senior research chemist, the folio assembler, and often other senior scientists conceive and rank possible synthetic routes.

 By the time the actual process work begins at the bench, the senior research chemist has read a wide variety of articles pertinent to the various critical aspects of the process problem. Thus the early work period is not spent just keeping junior people busy or making mistakes that could have been avoided with basic literature familiarity. Once new pertinent literature examples become difficult to unearth, the folio assembler moves on to a different priority. Searching becomes more focussed once bench results start coming in and the Senior Research Chemist should decide what new information will address the problem.

This methodology will work efficiently because:

• Reliable chemical data is pains-taking to acquire at the bench.

• It is much faster to learn methodology from a publication than de novo.

• A comprehensive set of pertinent references would be useful as close to the beginning of the process development experiments as possible.

• Early experiments are usually poorly chosen and waste time

• It takes more time to find a key paper than to read it.

Models for Ideal Chemical Processes

Any process has the possibility of continual incremental improvement but practically a point will be reached when it is not worth further effort and one’s time and talents are better expended elsewhere. 

 In process development how does one judge the good and the better?  A good process meets its quality and quantity requirements. The better process does this and goes further. The better process must be rugged. In a rugged process, if human error, mechanical failure, or equipment inadequacy creates some small deviations from the prescribed procedure, the result does not suffer seriously either in quality or quantity.

We judge a process by its costs and these include the labor expended, the time utilized in the special equipment, the price of the starting materials, and the price of waste disposal or recycling. A costing not only provides an indication of the efficiency with which inputs are used but it also provides a running assessment on the specific shortcomings that contribute most to the overall expense. A preliminary costing is an important tool in developing any process because it ranks areas where one might invest whatever limited time one has to achieve improvement.  

Trost has philosophized that the ideal process would be a single step and that there should be no co-product. That is, all the atoms in the reacting substances are retained in the products. Nothing then is thrown away. This is an interesting idea to contemplate.  It dramatically highlights that atom economy, as he calls it. It has the benefit of high weight throughput and low waste disposal but it is far from reality in terms of what can be actually practiced.  Every process is indeed ideally only a single transformation but the problem is starting materials for this ideal process are not commercially available- and because of this, the process creator must move retro-synthetically one step at a time until we do reach such commercial precursors.

Another useful idealized conception of a process is a sequence of chemical steps in which the reaction mixture from each step is simply treated over and over again with the reagents for the next transformation until the material which is the synthetic goal is present in the mixture; then, in one isolation operation, this product is separated pure from the complete complex mixture containing all the by-products and co-products of all the prior steps. This model dramatizes that it is most important to eliminate isolations because it is isolations that usually consume the most time and resources in a process.   In practice, of course, there are very valid reasons for performing isolations before the final isolation.

Valid reasons for isolation are:

1. To remove non-productive mass (ballast)
2. To change solvent for reaction optimization
3. To achieve needed purification through phase shifting
4. To correct stoichiometry and so save reagents
5. To provide convenient stopping points for campaign processing
6. To provide rework opportunities for rugged processing