Benadryl Manufacturing Process Simplification and Use of Triumvirate (1) [Unit processes, Sociochemicology and Unit operations]

For every chemical process development and commercialization, the following age old routine that has been used from the lab to the plant floor. Briefly the process starts from the paper chemistry to laboratory confirmation, some optimization to pilot plant and final commercialization. These are sequential events and have been successfully used for most chemicals and their processes. They have been practiced and mastered from the day we consider bulk production of chemicals. They have become routine. However, they need continuous refreshing for improvement and simplification. 

 

Inclusion of the Village ⁽¹⁾ along with incorporating elements of Triumvirate ⁽²⁾ from inception can significantly impact the development and commercialization process. These, in my estimation, are included randomly but not in a regimented way in the development of chemistries and processes. Regimented inclusion along with our imagination and creativity can, if practiced routinely, can simplify processes and reduce use of solvents and excess amount of chemicals i.e. costs are reduced and environmental impact will be minimized. Several such chemistries have been discussed ^(3,4,5,6). In my experiences inclusion of Triumvirate always leads to significant simplification of processes for life extending and life facilitating chemicals. Once we incorporate such practices, they become addictive.  

 

Synthesis of Benadryl:

 

Different chemistries (too many to cite) have been proposed for the manufacture of diphenhydramine hydrochloride (Benadryl). Laboratory process ⁽⁷⁾ was selected for its simplicity. Its review suggests that elements of triumvirate ⁽²⁾ and knowledge of village ⁽²⁾can be used to further simplify commercialization of a continuous process ⁽⁸⁾ and totally eliminate/minimize solvent use (Figure 1). This would be quite a deviation from the suggested laboratory process ⁽⁷⁾. Possibilities are reviewed. 

 

Authors ⁽⁷⁾ call for reacting benzhydrol with hydrochloric acid to produce chlorodiphenylmethane which is then reacted with dimethylethanolamine to produce diphenhydramine hydrochloride (Benadryl) Figure 1. Since the isolation of benadryl is not discussed in the paper ⁽⁷⁾ it is expected it would be separated processed as a solid. 

 

Using process chemistry ⁽⁷⁾, Figure 1, and capitalizing on physical and chemical properties of each raw material, intermediates and the final product, Table 1, one can easily postulate, test and commercialize a simplified continuous process, Figure 2 and is discussed.

 

 

Figure 1: Benadryl Process Chemistry ⁽⁷⁾

Physical properties (Table 1) suggest that all of the chemicals except, for the final product benadryl, are liquid above melting point of benzhydrol. By carrying the reaction above 70 °C need for any organic solvent can be eliminated. Liquid Benzhydrol can be metered and the reaction stoichiometry controlled using off the shelf commercial process controllers. Nothing new has to be invented. We can eliminate solvent use. In addition, choosing higher reaction temperature accelerates the reaction rate, reduces the reactor size i.e. investment: an excellent opportunity. 

 

Based on my experiences ^(3,4,5,6) excess of reactants can be minimized. This practice has been routinely used in many reactions ^(3,4,5) for the manufacture of many chemicals that improve life style and extend life. 

Chemical	Benzhydrol	Hydrochloric acid	Chlorodiphenylmethane	Dimethylethanolamine	Diphenhydramine
Formula	(C6H5)2CHOH	HCl	(C6H5)2CHCl	C4H11NO	C17H21NO
MW	184	36.5	202	89	256
CAS No.	91-01-0	7647-01-0	90-99-3	108-01-0	58-73-1
MP °C	65-69		15-20	-59	166-170
BP °C	297		270	134

Table 1: Physical Properties

Diphenhydramine hydrochloride (benadryl) being a solid at the room temperature provides an excellent opportunity to produce the solid product using well-known commercially available methods such as crystallization or wiped film evaporators.  

 

Based on my experiences ^(3,4,5) Figure 2 is my rendition of a simplified process flow diagram. Every chemical engineer and/or chemist will totally understand the process schematic and the associated equipment. 

 

Plate and frame heat exchanger ⁽⁹⁾ or electric heaters ⁽¹⁰⁾ instead of traditional jacketed reactors can used as a reactor. Since electric heaters do not require heating fluid the process economics improves significantly. Suggested alternate reactors have value and every experienced chemical engineer and chemist, business manager, manufacturing manager will agree and understand. 

                          

Figure 2: Simplified block diagram for Benadryl production

Based on physical properties molten benzhydrol and hydrochloric acid will be metered in a properly designed plate and frame heat exchanger ⁽⁹⁾ or electric reactor ⁽¹⁰⁾ where the residence time and temperature will be controlled. Using process controls stoichiometry and operating temperature etc. processing conditions will be controlled. 

 

Dimethylethanolamine, a liquid, will be metered to produce diphenhydramine hydrochloride. Since diphenhydramine hydrochloride (benadryl) is a solid at room temperature it will be processed as a solid using well known commercial methods such as crystallizer or a wiped film evaporator. 

 

Methods, equipment and technologies have been commercial for over 70+ years will be used to control the process. 

 

Perspective presented is based on my experience and village. It will have to be reviewed and tested in the laboratory to make sure that the elements of the triumvirate ⁽²⁾ as suggested can be exploited to create and commercialize an excellent ecofriendly simple with no/minimal impact. Every experienced chemist/chemical engineer will understand. It is possible that they might make additional improvements to create a simpler process. 

Every process chemistry has its own creation story. How we use our creativity and imagination is our story.

 

Girish Malhotra, PE

EPCOT International

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

2.     Malhotra, Girish: The Process Development Triumvirate: Profitability Through Simplicity

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

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, Profitability through Simplicity  

6.     Malhotra, Girish: Sociochemicology; Its birth and Value, Profitability through simplicity

7.     Konkol et.al. On the synthesis of diphenhydramine: Steady state kinetics, solvation effects, and in-situ Raman and benchtop NMR as PAT https://doi.org/10.1016/j.cej.2024.152159

8.     Continuous Process

9.     Alfa Laval: Gasketed plate-and-frame heat exchangers

10.  Process Technology Frontier Inline Heater

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