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
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
