This is a reprint of the first blog article on this site. In retrospect, I think the original purpose has been served, yet many of my readers may not have properly understood the perspective.
In 2006, I started a blog called ’KiloMentor’. The goal was to provide training and updating in the methods for chemical process development emphasizing scale-up of organic synthesis, particularly scale-up of high-value pharmaceutical products. I recognized that there were textbooks, symposia, and courses for this purpose but they were expensive and not equally available in different places in the world.
Moreover, in academia, the treatment of chemical process development was neither widespread nor generally thorough. The KiloMentor blog was free and available wherever access to the worldwide web was possible. My blog was originally hosted at a site called Chemical Blogs. Later the articles were transferred to a different, dedicated site. A few years ago this site was shut down when I did not pay for the web address. This Google blog will be a republication and supplementation of those articles.
Below is a revision of one of the earliest articles from the original KiloMentor archives. The original was written in 2007. This article restates for new readers the core idea of the Kilomentor process development philosophy and offers an approach that I think leads consistently to valuable considerations, if not complete solutions.
In synthesis, we talk about assembling, building, or constructing a molecular structure. This is a misleading metaphor because we are comparing activity in the nano-world to an activity in the macro-world. Operating in the macroscopic world, for example in building a house, we handle the pieces, we position the pieces, and we join the pieces.
In chemical synthesis, we do none of these. The substructures we are endeavoring to unite are atomic in scale: too small to touch, to align, or even to see.
In chemical synthesis, the chemist adjusts macroscopic conditions: solvent ratios, stoichiometry, stirring, temperature, duration of exposure, etc. then the chemist presents the proposed reaction partners to each other under the orchestrated conditions and they interact, as their nature dictates, but hopefully this is also as we have planned. How is this perspective different from the conventional one? Chemical process development is simply efficiently making these parameter choices that cause nature’s choice to comply with what we want the outcome to be. Nature- to be commanded, must be obeyed.
Separation as the Focus of Chemical Process Development
According to the academic, synthetic chemistry tradition, synthetic accomplishments are judged on the basis of the number of synthetic steps, the yield per step, and the overall yield for the combination of steps. High yields are good. A short sequence is good. The combination is elegant. According to this traditional perspective, the focus is on the reactants, the plan for reactant transformation, and the overall yield output from that plan. Separation of unreacted starting materials, by-products, co-products, catalysts, solvents, salts, and other excipients are in the background (the attitude is that it can be done and will be done BUT these are not pertinent criteria to evaluate the quality of the synthesis). The giveaway phrase of those who harbor this philosophy is “the product was isolated in the usual way.”
From the KiloMentor perspective, in this age of online substructure searching, coming up with creative transformations with strong literature analogies is no longer the domain of the synthetic genius but has come within the scope of good synthetic chemists. We do not have to depend upon our neuronal computers alone anymore. Now it is creative ideas for separation and purification that are not easy to search that have become the art element of the project. The deconstruction of the chemical soup and the fishing out of the desired product in an adequate state of purity has become paramount.
Is there any particular value in this way of looking at the process rather than the traditional way which was focusing on the series of chemical reactions and taking the separation of intermediates as obvious, merely technical, work?
My perspective rather emphasizes:
- The work involved setting up and controlling the necessary reaction conditions.
- The work involved quenching the reaction condition/then working up the reaction and finally isolating the desired product.
The value in this KiloMentor perspective is that in chemical synthesis, the money, manpower, and resources consumed during the reaction phase, while A & B are reacting with each other, is minuscule compared to the money, manpower, and resources expended preparing for the reaction and recovering pure product from the reaction.
The clash of these perspectives can be focussed by the question, “Which would I rather do- a four-step synthesis in which every conversion has many parameters that must be rigorously controlled and from which each intermediate must be isolated by gradient column chromatography and evaporated to a foam OR an eight-step synthesis which is rugged and forgiving of process deviations and from which each intermediate can be cleanly extracted in a separatory funnel, crystallized or distilled to give a practical purity intermediate adequate to use directly in the next step".
People have personal preferences and this is as it should be in a pluralistic society. Still, I pick the second sequence and as the need for larger quantities and higher quality intensifies, I increasingly prefer the second route.
Please note- I am not saying the number of chemical steps doesn’t matter. I am not saying that the overall yield or the yield in individual steps does not matter. I am saying that elegance also encompasses simplicity, ruggedness, time economy, and scalability.
OK, so what. How does this insight change our behavior in the synthetic laboratory, office, or library?
Based on an examination of what really goes on in a chemical process step a method of rating the difficulties of the separation are proposed as a quantitative tool to rank the challenges of a process scale-up.
We should evaluate or rate synthetic schemes using more criteria:
1. Number of Chemical Steps
2. Isolated overall Yield
3. Yields of the Individual Steps
4. Difficulty Rating for Each Reaction Mixture Separation
5. Number of ‘Phase Switches’ in the Synthetic Process
6. Intermediates that are Acids or Bases
7. Ease or Difficulty in reaching Practical Purity
How could we execute these ratings? We could classify work-ups.
A. The product can be separated practically pure by simply liquid-liquid extraction (ie acid-base pH or other phase switching)
B. The product can be separated by crystallization or precipitation as a filterable solid.
C. Product can be separated by atmospheric or vacuum distillation assessed from an approximated difference in boiling points (based on molecular weights)
D. The product can be separated based on chemical reactivity (formation of a reversible, simply separable, derivative, or destruction of a contaminant by reaction)
E. The previously unknown product must be crystallized to free from unknown impurities
F. The product seems likely only to be separable in practical purity by chromatography.
Clearly, as process chemists, we want to face more A-C separations and fewer D-F type separations.
‘KiloMentor’ articles will offer up particular tactical tools that fit into its distinctive strategy of pharmaceutical or chemical process development. It will also review considerations particularly important for plant-scale processing as contrasted with laboratory-scale syntheses.
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