Exploitation and Capitalization of Mutual Behavior of Chemicals (Sociochemicology) and Process Equipment for the Manufacture of Propofol

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 

Use of Tradition, Creativity, Imagination and Technology Innovation in Propofol Manufacturing

Title in itself can be questioned by some or many for any and every discussion. It should not be, if we look at everything that is manufactured. Everything starts from rudimentary paper concepts  with subsequent intervention of humans and science that makes the products and their manufacturing process elegant, useful and easy to use. It is well known that creativity and imagination when applied to any product and/or process leads to excellent results. Perspective presented is my own and there is no relationship or influence of any profit, nonprofit organization or regulatory body.

 

Methodologies used for process development and manufacture of fine/specialty chemicals which includes active pharmaceutical ingredients (API) are same. APIs are younger cousin of fine/specialty chemicals. However, they are treated differently even when exactly the same/similar chemicals, processes and equipment are used to produce each of the molecules. The only difference is API’s cure a disease whereas fine/specialty chemicals enhance lifestyle ⁽¹⁾. It is true that APIs have to follow stricter regulations as they are used to cure diseases. Pseudo-assumption that APIs are nobler than their older cousin, fine/specialty chemicals, is unnecessary and very convoluted. 

 

If one traces a chemical molecule being developed in a laboratory equipment and has been synthesized It uses same/similar in every process development. Paper chemistries are tested and tweaked to create a process that the developer considers to be economic and optimum. Real test of this hypothesis comes when the process is commercialized.  

 

Every chemical entity for its production has a defined process and method. Even though I have reviewed and presented my perspective ^(1,2,3), it is never redundant to re-visit and share steps I would take to develop and commercialize a product. My team “THE VILLAGE” ^(1,2,3) will include a chemist, a chemical engineer, an accountant (can be a chemist and/or chemical engineer who is well versed in cost analysis), quality control, purchasing and manufacturing. Extent of their involvement will vary as the project progresses.

 

Every fine/specialty chemical plant that includes active pharmaceutical ingredient (API) should follow the outlined or equivalent path/s ^(1,2,3). There is value in this methodology or similar practices. They are documentation of reason and rationale for the process design and its basis. They assist in every regulatory filing and facilitates every trouble shooting and expansion if needed. 

 

Village ^{(1, 2, 3)} has to address each of the following items. If a village is not involved from inception, costs can be higher and commercialization can be delayed.

1.     Product volume per year 2.     Physical, chemical properties, mutual behavior and toxicity of raw materials, intermediates  3.     Mass balance 4.     Process chemistry and manufacturing methods/procedures (unit processes) 5.     Process equipment and metallurgy (unit operations) 6.     Method/s used to feed the raw materials and transfer intermediate reaction products 7.     Raw material and Product specifications 8.     Effluent/waste treatment

 

Table 1: Information needed for an excellent chemical synthesis process

 

Collected information ^(1,2,3) Table 1 gives significant clues about the process. To every experienced chemists and chemical engineer it gives clues about how to finesse and capitalize on mutual behavior of chemicals. This information influences product cost and process economics. If the process involves multiple reaction steps and can be fitted in the existing equipment, it is very likely that the process will be inefficient and repeated analysis of process intermediates and the final product would be necessary, a characteristic of a classical batch process. Such processes for APIs would have low asset utilization ⁽⁴⁾.

 

If a product is a high volume product and the process involves multiple steps i.e. sequential processing steps without interruption, it can be conducive to a continuous process. Every village ^{(1, 2, 3)} team member has to be familiar with the development and commercialization process. Such processes are economic. However, generally this methodology has not been part of the API landscape. For a process to be a continuous process ⁽⁵⁾ product has to have sufficient volume (Kg/year) to operate 24 hours per day, seven days per week and about 50 weeks per year with some allocated downtime for maintenance. For such processes equipment design will be product specific.   

 

Based on my experiences any product that has multiple synthesis steps when fitted in the existing equipment  is generally a batch process. Fitting processes in existing equipment have inherent drawbacks of poor design and less than efficient asset utilization. Excess solvents, water or organic/s, are needed to assure proper processing. They have high emissions ^{(6, 7)}. Along with low process productivity process yields are generally less than optimum. 

 

Continuous processes are not adopted by the brand pharma companies. Reason is simple. Speed to market. Once the product’s efficacy is recognized, it is submitted for regulatory approval. That is the key. Since the market size is not defined, batch process is the selected process. Any process changes require regulatory reapproval and that can be very expensive. In addition, village is not involved in their business model. This can delay the commercialization of process. For the generics many APIs of high volume can be produced using continuous process but will necessitate different business model. Only an outlier company will consider such options ^{(1,2,3, 8)}. 

 

Manufacture of Propofol: 

 

Five alternate refenced chemistries ^{(9,10,11,12,13)} for the manufacture of Propofol are presented. Items discussed in Table 1 have to be incorporated. Village team should review each of the experiments in the lab to get a feel for the process, flow of materials and mutual behavior of chemicals. This can unleash their creativity and imagination and would facilitate the scale up and commercialization of an excellent process. Raw materials should be of commercial grade quality and do not need to be pharmaceutical grade i.e. high purity. They are expensive and add unnecessary cost and may not be any different from the commercially available raw materials. Quality of the final product has to be the final driver. 

 

Raw materials for Propofol synthesis ^{(9,10,11,12,13)} Table 1 influence process design and selection. Chemistries described ^(9,10,11,12) are similar. In reference ⁽¹³⁾, the starting material is different. De-carboxylation step is executed differently. For process selection each of the outlined process chemistry needs a thorough review. 

Execution of laboratory processes in the plant will be very different from what is being discussed in these papers and patent. Again, each process has to reviewed carefully. Described chemistries ^{(9, 10, 11, 12)}  present an excellent opportunity for a continuous process ⁽⁵⁾. Purification or distillation of Propofol is based on chemical engineering distillation practices and there is no novelty. 

 

Items of Table 1 can be applied to select the best and the simplest process. Since 4-Hydroxybenzoic acid is solid at room temperature, its addition can be controlled if it is used as a melt or in a solvent that has high solubility. Scheme one ⁽⁹⁾because of its simplicity could be the most likely candidate for a continuous process. 

Stoichiometry and process conditions can be precisely controlled and make an excellent case for a continuous process ⁽¹⁾. Depending on the process selection (batch vs. continuous) design, feeding of aluminum chloride ⁽²⁾ has to carefully thought through. 

Chemical	4-Hydroxybenzoic              acid	3,5-di-isopropyl-4-hydoxybenzoic acid	Methylparaben	Propofol
CAS No.	99-96-7	13423-73-7	99-76-3	2078-54-8
Formula	C7H6O3	C13H18O3	C8H8O3	C12H18O
Mol. Wt.	138	222	152	178
Melting point, ºC	214.5	146	~ 125	18
Boiling point, ºC		345	~ 299	256

Table 2: Properties of Reactants and Propofol 

Yearly production volume is a very important criterion for selection of a batch or continuous process. Since propofol is a widely used for anesthesia its global use would be high. Sales of finished Propofol speculated by many, too many to cite. For Propofol as API no numbers were available. With consultation of Dr. Albinus D’Sa ^(16), it is estimated that between 250,000 to 300,000 MT per year would be needed to meet global needs. 

 

Since Propofol is a generic product only a new entrant in the business would use what has been described but the principles and methodology can be used by any fine/specialty and API business. 

 

 We have to remember that every multiple step chemical synthesis is an opportunity to simplify the process. This is easier said than done. Total knowledge and command of the chemicals used and produced in the process is a MUST. Knowledge of the unit operations ⁽¹⁴⁾ and chemical and physical properties ^{(1, 2, 3)} is essential. Application and inclusion of the knowledge simplifies the process and give command to produce quality product whether it is a batch ⁽¹⁵⁾ and/or a continuous process ⁽⁶⁾. A distinct advantage of a continuous process is that it can be ramped up to meet sudden surge in product demands. 

 

Some of the discussion above has been reviewed earlier ^{(1, 2, 3, 8)}. Use and inclusion of parameters outlined in Table 1 allows proper process equipment ⁽¹⁾ design and can reduce investment. Since Propofol is already commercial most likely not much will change unless an outlier company decides to enter the business. For any outlier it would be necessary to know the yearly demand for the Propofol API.

For process selection (batch vs. continuous) global how much active Propofol is produced is not available. Only number available is projected speculation of finished product. That does not give a reliable number. After consultation and discussion with Dr. Albinus D’Sa ⁽¹⁶⁾, different anesthesiologists, published information ^{(17, 18)} and world population ⁽¹⁹⁾ best number has been calculated, Table 3. Total Propofol active molecule needed is large enough to have an excellent continuous process. Continuous operations can be ramped to meet fluctuating active molecule need. 

Sweden Population	10 million (18)
Yearly use, kg	394
Global population	8.1 billion (19)
Yearly Global Propofol need, kg	250,000 to 305,000

 

Table 3: Estimated Global Propofol Active Ingredient need

Similar analysis can be done for many other products. Options exist for continuous processes for many other products exist and need a review along with business model change. They can be used to alleviate shortages. 

 

Girish Malhotra, PE

 

EPCOT International 

 

References:

1.     Malhotra, Girish:  Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022

2.     Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability  John Wiley & Sons, February 2011 

3.     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

4.     Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharma Manufacturing Sep 19, 2007

5.     Continuous Processing Accessed February 12, 2024

6.     Burke, J. What does net zero mean?, May 2, 2019 Accessed April 27, 2021

7.     Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry, 2017, 19, 18-43 Accessed February 17, 2021

8.     Profitability through Simplicity

9.     Pramanik  C. et. al. Organic Process Research Development, 2014, 18, 152-156

10.  Mougeot, R. et al Continuous Flow Synthesis of Propofol. Molecules 2021, 26, 7183

11.  Guilherme M. Martins et. al. Scaled up and telescoped synthesis of propofol under continuous-flow conditions Journal of Flow Chemistry (2022) 12:371–379 , 

12.  SCHNEIDER, Jean-Marie et.al. Process for producing Propofol WO/2023/111488  

13.  USP 11,767,281 B2

14.  Unit operations of Chemical Engineering, McCabe, W.L. Smith et. al McGraw Hills Inc. 1993, Accessed February 17, 2024

15.  Batch Production Wikipedia Accessed July 6, 2017

16.  D’Sa, Albinus Dsa Pharma Associates,

17.  Braun B: Miljöinformationen för propofol är framtagen av företaget Aspen Nordic för Diprivan 

18.  Sweden population https://www.worldometers.info/world-population/sweden-population/

19.  World population https://www.worldometers.info/world-population/