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

Role of Village and Triumvirate in Process Development of Isoniazid :- a Tuberculosis Drug

In the past I have discussed how the Village and Triumvirate [unit processes, Sociochemicology and unit operations] ^1,2,3,4,5 can assist in developing, expediting and commercializing excellent processes that maximize profits and have minimal environmental impact. Purpose of this post is to share how commercially available equipment not used in the chemical and or pharmaceutical manufacturing along with sociochemicology can be exploited to create significantly simple manufacturing processes.   

In this post I have reviewed synthesis of Isoniazid [isonicotinic acid hydrazide]. Two alternate processes are reviewed. Readers should not be bound by my perspective and can use their own knowledge and experiences to commercialize an excellent process. 

 

Chemistries mentioned in routes ^{(6, 7, 8, 9)} are similar. 4-cyanopyridine is reacted with caustic to produce isonicotinamide which is reacted with hydrazine hydrate to produce isonicotinic acid hydrazide (Isoniazid) Figure 1.

                                Figure 1

	4-Cyano pyridine	50% NaOH	Isonicotinamide	Hydrazine hydrate	Isoniazid
Chemical Formula	C6H4N2	NaOH	C6H6N2O	N2H4	C6H7N3O
MW	104	40	122	50	137
MP °C	76-79		155-157	2	171-173
BP °C	196	140-145	334	114	252
CAS	100-48-1	1310-73-2	1453-155-157	301-01-2	54-85-3

 

Table 1: Physical Properties of Figure 1 reaction components

 

In another process ⁽¹⁰⁾ isonicotinic acid is reacted with thionyl chloride and ethyl alcohol to produce an ester which is reacted with hydrazine hydrate to produce isoniazid. 

                                                                Figure 2 ⁽¹⁰⁾

 

	Isonicotinic   acid	Thionyl chloride	Ethyl alcohol	Ethyl isoniconitate hydrochloride
Chemical Formula	C6H5NO2	SOCl2	C2H6O	C8H10ClNO2
MW	123	119	46	187
MP °C	310	-104.5		167
BP °C	Sublimes	75	78.5
CAS	55-22-1	7719-09-7	64-17-5	58827-14-8

 

Table 2: Physical Properties of some of the components in Figure 2  

 

Based on Village and Triumvirate ^(1,2,3,4,5) analysis pathway since solvent use will be necessary, isonicotinic acid process (10) was not considered for further evaluation.  

 

It surprising to note that European Patents ^(8,9) are based on the chemistry that had been in the public domain ^(6,7) before their patent filings and are not acknowledged.  This can potentially make their validity questionable. Details of cited batch processes are not known. 

 

European Patent ⁽⁸⁾ claims to be a laboratory based continuous process and suggests use of microreactors. Continuous process has an established definition ⁽¹¹⁾ and laboratory processes are never a continuous process. Microreactors are well known miniaturized version of plate and frame heat exchangers that have been used in chemical synthesis for over 70 years and are not a novelty. Flow chemistry is “new name” in the reaction chemistry domain for flow of fluids flow which happens to be the fundamental processing method of every chemical reaction since the advent of chemical processing. In my opinion filing ⁽⁸⁾ is not a new manufacturing process or method or chemistry and should not be acknowledged such. 

What can the Village ^(1,2,3,4,5) do to simplify the 4-cyanopyridine based process? 

 

Based on traditions of at least the last eighty plus years first instinct to commercialize the isoniazid process would be to start with a commercial agitated jacketed reactor. There are other methods however they are not considered. Since I do not have access to a laboratory to test the proposed process, it is suggested my perspective be reviewed, tested and modified, if necessary. 

Based on my experiences of applying learnings from Village, Triumvirate ^(1,2,3,4,5) and chemistry of Figure 1 I have proposed the following flow diagram, Figure 3, as a potential pathway. 

 

             Figure 3: 4-Cyanopyridine based Process Flow Diagram for Isoniazid

After the initial feasibility is proven, instead of using and/or suggesting use of conventional reactors and heat exchangers, I am suggesting processing equipment that incorporates, exploits and uses every element of the Triumvirate ^(1,2,3,4,5). Since I have used similar equipment, I am comfortable discussing the suggested equipment. Anyone wanting to use similar equipment needs to exploit attributes of Triumvirate ^(1,2,3,4,5) for the best process. Benefits are small overall footprint, higher profits and flexibility to meet market demands. 

 

The process instead of using a conventional reactor for the production of isoniazid can use commercially available inline tubular electric process heater ⁽¹²⁾ as reactor/s.  Since this is an electric tubular heater, compared to conventional reactors, the heat input can be precisely controlled/modulated. Like conventional thermal fluid heaters or steam or hot oil systems are not required. Investment would be significantly lower and will have a very small foot print. Due to their performance flexibility, production rate can be modulated to meet variable production demand.  

 

Every chemical engineer well versed in chemical process design will understand the following proposal. There are two potential ways to introduce 4-cyanopyridine in the process and produce isonicotinamide. It could be educted as a solid using circulating caustic reactant mix or introduced as a melt ^{(13, 14)}. Caustic solution would be metered and may be preferred as its water will provide the needed fluid for the process. Conventional reactors and processing equipment can also be used. 

 

Produced isonicotinamide would react with hydrazine hydrate to produce isoniazid in a similar tubular heater ⁽¹²⁾ which would be crystallized using known methods with methanol as a solvent. Stoichiometry would be controlled by commercial process controllers. Economics of both routes should be compared.

 

Methanol could also be used from the start as it is needed for crystallization of isoniazid. However, this might lower the productivity due to solvent use. Water of caustic or additional amount could be added to the reaction mass. Suggested process would need to reviewed. Major advantage of this route is minimum solvent and energy use compared to conventional reactors based processes. Figure 3 suggested process has an additional advantage as the production rates can be modulated to meet every variable global demand. 

Due to FDA’s lack of experience in process development and commercialization, it is very likely that inclusion of better and simpler manufacturing methods will not be included for the foreseeable future. FDA has basically hamstrung pharmaceutical industry in continuous shortage and antique manufacturing mode. Question we all need to ask FDA “does it have vested interest in technologies they float and/or promote”? I hope not. However, it seems that way. 

My wishful thinking is someday rationality will sink at FDA and US Legislators and pharma manufacturing will move from “STONE AGE” to “Actual Intelligence” Age by following what the TRIUMVIRATE⁽⁵⁾ has been telling us about process manufacturing simplification. A change to better technologies has to happen and it will lead to lower prices, shortages and significantly reduce emissions. 

Girish Malhotra, PE

EPCOT International

References:

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

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

3.     Malhotra, Girish: Blog Profitability through Simplicity 

4.     Malhotra, Girish: Use of Tradition, Creativity, Imagination and Technology Innovation in Propofol Manufacturing Profitability through Simplicity, March 21, 2024

5.     Malhotra, Girish: The Process Development Triumvirate: Profitability Through Simplicity, Profitability through Simplicity,March 24, 2026

6.     Gasson E. J. USP 2,830,994 Process for manufacture of isonicotinic acid hydrazide from pyridine nitrile

7.     Sycheva, T.P., Pavlova, T.N. & Shchukina, M.N. Synthesis of isoniazid from 4-cyanopyridine. Pharm Chem J 6, 696–698 (1972). https://doi.org/10.1007/BF00771896

8.     Watts Paul, EP 4041712 B1 WO 2021/069975/PCT

9.     USP 6,734,309

10.  CN 111138355 A

11.  Continuous Process

12.  Process Technology

13.  Malhotra, Girish: Imagination, Creativity and Sociochemicology (1) in Chemical Process Development. Profitability through Simplicity, January 10, 2026

14.  Malhotra, Girish: SOCIOCHEMICOLOGY: Designing Chemical Processes by Exploiting the Social Behavior of Molecules,Profitability through Simplicity, Feb. 26, 2026