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

Comments & Feedback to USFDA on Distributed and POC Manufacturing (FDA-2022-N-2316)

USFDA has sought feedback on Distributed and Point-of-Care Drug Manufacturing. It makes the following statement for Distributed and POC Manufacturing ⁽¹⁾. Focus of DM and POC is US based. Perspective and comments presented are my own and not influenced by any profit and non-profit making organization.  

 

“Pharmaceutical manufacturers have generally produced drugs at large fixed-location facilities, but some are now developing smaller, mobile drug manufacturing processes that can be deployed to multiple locations, including at the point of care, such as at a hospital or clinic. These novel distributed manufacturing (DM) and point-of-care (POC) manufacturing technologies have the potential to improve the reliability and robustness of the drug supply chain. The U.S. Food and Drug Administration is keenly interested in these technologies because they could potentially provide flexibility for drug manufacturers to enable rapid and localized response to changing demand and increase timely access to quality drugs for U.S. patients.”

 

Underlying question is that using FDA’s current review and approval scenario how much time it would take to set up and fill the “rapid and localized response”. What would be considered reasonable and who is going to be held accountable? There are questions and comments that need to be addressed/considered. 

 

1.    Has USFDA considered and reviewed the patient volume need for such manufacturing and distribution in USA from company’s business perspective? It is critical that it be done. 

2.    Who would prioritize the drugs and their quantities? Who would manufacture the prioritized drugs? What would it take? What if due to lack of profitability no company wants to produce the drugs. What has FDA done or do to expedite availability ^(2,3) of the needed products? 

3.    What has USFDA done for the companies to facilitate avail such business opportunities i.e. has it simplified its approval processes from multiple years to few months ^(2,3)? 

4.    DM and POC opportunities have existed for a long time. What has stopped companies from capitalizing on such profit making opportunities? Is it the regulations or the investment each company has to make for each specific drug (limited volume) for them to have sufficient return? 

5.    Since there are not very many generic API production facilities in US, DM and POC business opportunities will be limited. Has USFDA considered this limitation? Approval times and regulations will have to be simplified ^(2,3).  

6.    For the brand drugs (API and their formulation) being produced in US, why would the companies not use their existing facilities to serve the DM and POC needs. No additional manufacturing plant would be needed. No one wants to have additional “white elephants” that will be used sparingly ⁽⁴⁾. This holds true for the generic drug producers also. 

7.    Cost of drugs produced at USA located DM and POC will be higher than the current prices. This will be due to higher overall costs compared to China and India and PBMs (pharmacy benefit managers) and associates wanting to retain their profit margins. Only direct distribution to patients would lower prices ⁽⁵⁾. PBM et.al. will strongly oppose such move. Alternate business models and proposals discussed ⁽⁶⁾ can be searched (key word: alternate business) and need to be considered. 

8.    Based on review of the discussion paper for DM and POC post ⁽⁷⁾ it seems that the filing and approval requirements for even for limited quantity DM and POC business would be the same as they are for the current NDAs and ANDAs. This will be an obstacle as the drugs will not be available when needed, even in emergencies. Drugs could be available by bringing DM and POC manufacturing home. This could be done by significantly reducing NDA (new drug application) and ANDA (abbreviated new drug application) approval times. Pathways are available ^(2,3). It is recognized that drug safety and efficacy cannot be compromised but to bring pharma manufacturing home approval time reduction is critical. Companies need to be held responsible and if do not comply there could be business consequences. 

9.    Pharmaceutical companies who want to establish manufacturing facilities in USA and participate in DM and POC or any similar opportunity, based on the current landscape, will have to internally prove their innovative methods (e.g. continuous or modular or mobile ^{(8, 9)} ) to assure the product quality will be as designed. They will be challenged for time to commercialize as each process will have to be proven internally and then to USFDA. This would pose an enormous burden on acquiring experienced chemists and chemical engineers and time. Brand companies due to patent expiry time limitations do not have the time for such process developments unless they start such effort from the onset ⁽⁹⁾. Batch processes will stay as the routine method. To use continuous or mobile processes business model change would be needed ⁽⁹⁾ and need to be considered Generics will have to review their short and long term business model for each product but will be similarly challenged. Another serious question of confidentiality will be there and it is why FDA personnel should be taught the details of confidential chemistries and methods as long as the company guarantees quality product.  

10. Introduction of every new processing method at companies and USFDA, based on recent six years needed for Continuous Direct Compression ⁽¹⁰⁾ from FDA, suggests that innovation incorporation at companies will be a tough sell internally and no company will innovate. Every process could include different unit operations and that means it will delay approval. Companies do not have such time luxuries. Question is why the companies have to go through such processes if they guarantee product quality and consistency and have fast approvals of NDA and ANDA. Companies innovate but teaching USFDA the technologies they use should not be needed. Product quality , efficacy and consistency should the underlying requirement.

If USFDA can address, simplify and shorten its processes ^(2,3) not only it will make Distributed and Point of Care manufacturing possible but also would set an environment to bring pharmaceutical manufacturing home, comply with the Executive orders ^{(11,12, 13)} and alleviate shortages. This along with direct selling to patients will lower drug prices. All this will require an alternate business model that could lead to “net zero emissions” in pharma ⁽¹⁵⁾.  However, to these to happen two entities (USFDA and PBMs) will put significant resistance ^(5,14).   

 

Girish Malhotra, PE

 

EPCOT International 

References 

 

1.     FDA Seeks Feedback on Distributed and Point-of-Care Drug Manufacturing https://www.fda.gov/news-events/fda-voices/fda-seeks-feedback-distributed-and-point-care-drug-manufacturing October 14, 2022 Accessed November 15, 2022

2.     Malhotra, Girish: Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Profitability through Simplicity, March 25, 2017 Accessed November 10, 2022 

3.   Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity, October 24, 2018  

4.     Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharmaceutical Manufacturing, September 7, 2007 Accessed November 12, 2022  

5.     Malhotra, Girish: Improving Drug Affordability for the United States Populous through Alternate Business Models, Profitability through Simplicity, May 4, 2018, Accessed November 10, 2022

6.     Malhotra, Girish: Profitability through Simplicity Accessed November 14, 2022 

7.   Distributed Manufacturing and Point-of-Care Manufacturing of Drugs, Discussion Paper, October 18, 2022 Accessed November 4, 2022

8.     Continuous production Cambridge Dictionary, Accessed November 19, 2022 

9.     Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter.com Accessed June 10, 2022

10.  ETP Graduates its First Technology February 22, 2022 Accessed November 16, 2022  

11.  Executive Order 13588 Reducing Prescription Drug Shortages, October 31, 2011, Accessed August 31, 2020 

12.  Executive Order 13944 https://www.govinfo.gov/content/pkg/FR-2020-08-14/pdf/2020-18012.pdf Accessed April 26, 2022

13.  Executive Order on America’s Supply Chains https://www.whitehouse.gov/briefing-room/presidential-actions/2021/02/24/executive-order-on-americas-supply-chains/  Feb. 21, 2021 Accessed May 30, 2022

14.  Malhotra, Girish: Innovation in Pharmaceuticals Manufacturing Technologies, Distribution & Regulations: Are they Easy or a Challenge? Profitability through Simplicity, September 26, 2022 Accessed November 10, 2022  

15.  Malhotra, Girish: Climate Change and Greening of Pharmaceutical Manufacturing Profitability through Simplicity January 24, 2022 Accessed November 15, 2022