Sociochemicology (1,2,3,4) is an important member of the triumvirate (5) necessary for the development of every life style (additives) and life span (pharmaceuticals) improvement chemical. Physical state of chemicals used and produced in the process along with the equipment used play a significant part in process selection and their design. Each has its say and influence in process development. From my perspective these phenomenon are very much recognized but may and/or not fully capitalized on.
Purpose of this note is not to be critical of the lab development and commercialization process/es but allow us to understand and capitalize on how the influence of state of materials used and produced in chemical processes provide us the process simplification opportunities and clues. Unit processes and operations can be and need to be exploited to simplify the process. Chemistry and process of propofol is used as an example.
Commercialization: Batch vs. Continuous Process:
We have to accept and acknowledge chemical processes have a definition to be a batch process or a continuous process (1,2,3,4). Chemistry processed in any processing equipment that is not specifically designed for the process is generally a batch process. In such processes intermediate products are held over time for further processing. Equipment specifically designed to produce a product and processed without being held for time for the next reaction process step operates 24x7x350 hours per year, is a continuous process. Claiming a lab or plant process where intermediate reaction product is held to be processed for some time is a batch process and calling it a continuous process is mis-representation of reality.
Each product’s raw materials and intermediates along with physical and chemical properties and nuances of process equipment need to be exploited. Any experienced process design chemist and/or chemical engineer, i.e. part the village (1,2,3,4,5) once exposed to the chemistry in the lab can create simple processes if they are well versed in exploiting social behavior of chemicals and process equipment. It is emphasized again that laboratory just shows the pathway. Economic processes are build. Imagination, creativity and experience of chemists and chemical engineers are of vital importance (1,2,3,4,5). Impact on environmental conservation can be effortless and efficient.
Propofol Manufacture:
Table 1 outlines four alternate propofol synthesis routes. These chemistries are similar and involvement of Village (1,2,3,4) and triumvirate (5) is necessary from the onset. Information can be used to select the most economical process. Ease of availability of the raw materials, their prices and business strategy drive the selected process. One will have to test the selected pathway using knowledge and experience. Based on global volume of propofol active ingredient the synthesis and its formulation can be a continuous process.
Friedel-Crafts reaction generally use aluminum chloride. It is a challenge to handle in the lab and the plant. Significant investment is needed to have a safe process. Production of Propofol (6, 7, 8, 9) uses Propofol uses concentrated sulfuric acid instead of aluminum chloride in their Freidel Craft reaction. This is much safer route. Each of the referenced process uses solvents.
For each case discussed in Table 1 creative and imaginative chemical engineer and chemist with the help of village (1,2,3,4,5) can easily select and design a manufacturing process that can be modulated to meet variable global production demand and even be used to produce other products if equipment modifications are needed.
Each cited chemistry in Table 1 is very similar except for some of the reactants. Paths (6,9) use hydroxy benzoic acid and 2-ethoxyethanol or ethyl alcohol for the decarboxylation step to produce propofol. Paths (7,8) use methylparaben as the starting raw material and use ethylene glycol for the decarboxylation step (8). Physical properties can be exploited to simplify the process and create an all liquid process that can be totally controlled using commercially available control technologies. Several other published routes are not discussed.
Pramanik Process (6) | |
H2SO4 + IPA | NaOH +2-ethoxyethanol |
4-hydroxy benzoic acid ----------------> 3,5-diisopropyl-4-hydroxybenzoic acid -------------------------> Propofol | |
Vinet Process (7): | |
H2SO4 + IPA | NaOH +2-ethoxyethanol |
Methyl paraben -----------> 3,5-di-isopropyl-4-hydroxybenzoic acid ---------------------------------> Propofol | |
Chodankar (USP 11,767,281 B2) (8) | |
H2SO4 + IPA | NaOH +2-ethoxyethanol |
Methyl paraben -----------> 3,5-di-isopropyl-4-hydroxybenzoic acid ---------------------------------> Propofol | |
Coeuillas A. et.al (9) | |
H2SO4 + IPA | NaOH +ethyl alcohol |
4-hydroxy benzoic acid ----------------> 3,5-diisopropyl-4-hydroxybenzoic acid -------------------------> Propofol | |
Table 1: Process chemistries of Propofol
Table 2 is compilation of properties of the chemicals used in various propofol processes. Economics and ease of manufacturing process indicates that process based on methyl paraben route due to its lower raw material price and reaction temperatures could be the preferred route. Methyl paraben can be used as a melt and reacted with sulfuric acid and isopropyl alcohol to produce 3,5-Diisopropyl-4-hydroxybenzoic acid. By products produced would be water soluble and they can be separated using a differential gravity decanter to produce excellent feed for the distillation step.
Village’s (1,2,3,4,5) creativity, process engineering and reaction kinetics would be needed to have an all liquid process. My conjecture is that the higher reaction temperatures will keep the reaction mass as a melt, speed the reaction and minimize solvent use. Each route would have to be tested in the laboratory and piloted to commercialize the most economic process.
| FORMULA | MOL. WT. | MP °C | BP, °C | CAS NUMBER |
4-Hydroxy benzoic acid | C7H6O3 | 138 | 214.5 |
| 99-96-7 |
H2SO4 | H2SO4 | 98 | 10.2 | 337 | 7664-93-9 |
Iso propyl alcohol | C3H8O | 60 | -89 | 82.6 | 67-63-0 |
3,5-Diisopropyl-4-hydroxybenzoic acid | C13H18O3 | 222 | 146 | 343.5 | 13423-73-9 |
Methyl Paraben | C8H8O3 | 152 | 131 | 265 | 99-76-3 |
NaOH 50% | NaOH | 40 | 12 | 140 | 1310-73-2 |
2-Ethoxyethanol | C4H10 | 90 | -70 | 135 | 110-80-5 |
2-Ethylene glycol | C2H6O2 | 62 | -12.9 | 197.3 | 107-21-1 |
Ethyl alcohol | C2H6O | 46 | -114 | 78.2 | 64-17-5 |
Propofol (2,6-Diisopropylphenol) | C12H18O | 178 | 18 | 256 | 2078-54-8 |
Table 2: Physical properties of chemicals used in synthesis of Propofol Process
Based on the global demand (1) unformulated propofol can be produced using modular plants. Validity of process patent (8) due to similar chemistries being on the public domain might need a review.
Commercialization:
Each product’s raw materials and intermediates along with physical and chemical properties and nuances of process equipment need to be exploited. Any experienced process design chemist and/or chemical engineer, i.e. part the village (1,2,3,4,5) once exposed to the chemistry in the lab can create simple processes if they are well versed in exploiting social behavior of chemicals and process equipment. It is emphasized again that laboratory just shows the pathway. Imagination, creativity and experience of chemists and chemical engineers are of vital importance (1,2,3,4,5). Impact on environmental conservation can be effortless and efficient.
In each of the cases discussed above every creative and imaginative chemical engineer and chemist with the help of village (1,2,3,4,5) can easily select and design a manufacturing process which can be modulated to meet variable production demand and even used to produce other products if equipment modifications are needed.
We have to accept and acknowledge chemical processes have a definition to be a batch process or a continuous process. Chemistry that can be processed in any processing equipment that is not specifically designed for the process is a batch process. Generally in such processes intermediate products are held over time for further processing. Equipment specifically designed to produce a product and is processed without being held for time for the next reaction process step operate 24x7x350 hours per year is a continuous process. Claiming a lab or plant process where intermediate reaction product is held to be processed for some time is a batch process and calling it a continuous process is mis-representation of reality.
It is emphasized that we with the inclusion of village (1,2,3,4,5) have to review each process chemistry and by exploiting their chemical and physical properties can commercialize excellent environmentally friendly economic processes.
Girish Malhotra, PE
EPCOT International
References:
1. Malhotra, Girish Profitability through Simplicity
2. Malhotra, Girish Malhotra, Girish Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022
3. Malhotra, Girish Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
4. Malhotra, Girish 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
5. Malhotra, Girish: The Process Development Triumvirate: Profitability Through Simplicity, March 24, 2026
6. Pramanik C. et.al. Commercial Manufacturing of Propofol: Simplifying the Isolation Process and Control on Related Substances Org. Process Res. Dev. 2014, 18, 152−156
7. Vinet, Laurent et.al. Process Intensive Synthesis of Propofol Enabled by Continuous Flow Chemistry Org. Process Res. Dev. 2022, 26, 2330-2336
8. Chodankar N.K. USP 11,767,281 B2 Manufacturing and Purification Technology for High Purity Propofol September 23, 2023
9. Coeuillas A. et.al. Process Intensified Continuous Flow Synthesis of Propofol December 24, 2025