Why Chemistry, Properties, and Equipment Must Work Together from the Onset
Every chemical—whether a lifestyle-enhancing and/or life-extending product—has a theoretical and practical legacy and pathway through which it is developed, scaled up, and commercialized.
Exploitation of the following triumvirate impacts the overall process, product quality, economics, and environmental outcome.
• Process chemistry (unit processes)
• Sociochemicology (physical and chemical properties)
• Process equipment (unit operations)
Paper chemistries (unit processes) show us the theoretical pathway. Laboratory experiments validate them. How the “VILLAGE” (chemist, chemical engineer, manufacturing, purchasing, and accounting) exploits these using the triumvirate to create an excellent process depends on collective imagination, creativity, and the ability to harness the mutual behavior of the physical and chemical properties (Sociochemicology) of raw materials, intermediates, and final products, along with the capabilities of process equipment (unit operations).
Once the village realizes the benefits and success of such collaborative efforts, they become committed advocates.
In my 60+ year career, I have been fortunate to work with and learn from members of such a “VILLAGE.” Thoughtful inclusion and application of the elements of the triumvirate have consistently resulted in economic processes. In many cases, capital investment was also reduced compared to processes where chemistries were forced into existing equipment—what I describe as “fitting a square plug into a round hole.”
Exploitation of Sociochemicology is of tremendous value. Learnings from reaction kinetics and thermodynamic properties must be fully utilized (as discussed in my books and blogs) 1,2,3,4. Differences in solubility and density can reduce reaction volumes, leading to smaller equipment and lower capital investment. Solvent usage can often be reduced or eliminated, and overall productivity is generally improved.
Triumvirate-based designs are simpler and more productive compared to designs where chemistry is forced to fit existing equipment. They also generally result in higher profitability.
Laboratories are excellent for proving chemical feasibility. However, translating this into a simpler and more economical process requires imagination, creativity, and full exploitation of Sociochemicological behavior along with appropriate use of process equipment. All elements of the triumvirate must be considered and integrated.
Paper chemistry is a good starting point. The laboratory can demonstrate feasibility, but it cannot replicate what imagination and the collective contribution of the village (chemists, chemical engineers, manufacturing, accounting, purchasing, and maintenance) can achieve. For every successful process, imagination and creativity are essential.
Process development typically begins in round-bottom flasks, and process schemes are demonstrated at the laboratory bench. Due to tradition, the elements of the triumvirate are often not fully exploited. This is due to equipment limitations, established practices, and initial resistance when new ideas are proposed. However, with success, skeptics often become strong supporters.
The following case illustrates this point (additional examples are discussed in my publications 1,2,3,4.
A company, whose identity is not disclosed, successfully commercialized products using triumvirate-based thinking. Encouraged by this success, it developed and commercialized a continuous process that had not previously been conceived.
Every organic chemistry textbook discusses diazonium reactions and suggests that, due to their exothermic nature, they are generally carried out at around 0°C. The following reaction is well known:
R–NH₂ + 2HCl + NaNO₂ → RN₂Cl + NaCl (1)
Due to the instability of the diazo intermediate, it is typically reacted immediately with subsequent reagents. However, breaking the reaction into steps suggests the following:
R–NH₂ + HCl → R–NH₂.HCl (2)
R–NH₂·HCl + HCl + NaNO₂ → RN₂Cl + 2H₂O + NaCl (3)
This stepwise nuance of chemistry was commercialized over 55 years ago by an assembled “village” as a continuous process. It operated at approximately 40°C for about 7,200 hours per year. Each intermediate was immediately converted to the next intermediate to the final product through subsequent reactions (sulfation, chlorination, amidation, etc.), followed by isolation and purification. Some patents discuss similar chemistries. If they were commercialized is not known.
A batch methylation was converted to continuous process resulting is significant reduction of solvent use. Other chemistries can also be similarly exploited to create simpler processes. In many cases, solvent usage can be significantly reduced or eliminated. Several such examples are discussed 1,2,3,4. We must challenge traditional ways in which chemistries have been and continue to be practiced.
Learnings from these and other successes show that triumvirate-based approaches can be extended to a wide range of chemical processes. Yes, naysayers can be convinced—it often takes just one success. In my 60+ years in process development, commercialization, and manufacturing, I have seen many change their perspective.
The question we must ask ourselves is: “Is there an alternate way?”
To summarize, triumvirate-based designs are simpler and more productive than those that force processes into existing equipment. They generally deliver higher profitability. Such processes are inherently simpler, supporting the principle that: “Profitability is Simplicity.”
Girish Malhotra, PE
EPCOT International
References:
- Malhotra, Girish: Blog Profitability through Simplicity
- Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
- Chapter 4 “Simplified Process Development and Commercialization” in “ Quality by Design-Putting Theory into Practice” co-published by Parenteral Drug Association and DHI Publishing© February 2011
- Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022
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