Sociochemicology: Its Birth and Value

Sociochemicology ⁽¹⁾ is THINK DIFFERENT ⁽²⁾ phrase in the chemical world. Since most are not be familiar with the term and its evolution, it has its own journey. It is my journey also. It is practical inclusion of characteristics and behavior of chemicals in process design. It is not peer reviewed as there is no set charter, course or class room curriculum. Nothing new has been discovered. It is just based on how the chemicals behave with each other under the process conditions. We learn and use them to create excellent manufacturing processes. 

 

My Journey:

 

Unknown to me my SOCIOCHEMICOLOGY ^(1,3) journey started in eighth grade chemistry class. The fact that different color gases evolve when acids react with metals intrigued and fascinated me/us. I needed to see this. I coaxed fellow students to join in my project. Since we did not have glassware, we used concrete steps of the house as the test tube. We collected different acids and metal pieces and poured acids on different metals/coins to see the colors of gases produced and smelled their pungency. Experiments were a great success but were reprimanded for pitting the concrete. This w as my first experience with chemicals showing their behavior. 

 

I entered our college organic chemistry laboratory Fall of 1959 and for the first time saw lab benches with stands, round bottom flasks, magnetic and propeller agitators, condensers and beakers etc. Euphoria sank in that we are going to be experimenting with chemicals that we have been studying in the chemistry classes. Our professor gave us a tour of what is what. The fume hood and the Bunsen burners: how to lite them ON and turn them OFF etc.. It was exhilarating. Safety tips, handling of chemicals and the glassware suggested that we are going to be scientists and engineers. 

 

Our teacher’s first instruction was NEVER add water to the acid but do it the other way i.e. slowly add acid to water. Explanation was that when strong acid is added to water with inadequate mixing it generates heat and contents can boil over causing injury. Acid should be added slowly to water to absorb the heat of solution. Heat will dissipate in the water and will not boil over and cause a chemical accident by erupting water. It made sense. This was our first lesson about how the physical and chemical properties of chemicals influence and interact with each other chemical but did not fully understand this value till an incident happened in our lab. 

 

One of the fellow student must have not heard our professor or paid attention. He did exactly the opposite of what the professor had told us not to do and added water to concentrated sulfuric acid. The mix boiled out of the test tube and flew like a rocket to the ceiling and splashed over many students. Commotion set in and the lab emptied out in a hurry. No one was hurt but few days later our clothes had holes. Lesson learnt was respect chemicals, use them wisely and they can be our friend. 

 

During my sophomore chemical engineering year, our organic chemistry lab our professor gave me the responsibility to manage the laboratory, chemicals, reagents and the lab supplies. In return, I was given permission to experiment and test different synthesis routes for dyes and chemicals from our organic chemistry book. This allowed me to test reactions listed in the book and beyond as long as they were safe. This freedom allowed me to learn more than what was part of the curriculum. Unknown to me seeds of “Think Different ⁽²⁾” were planted/reinforced/strengthened/bolstered. These experiments helped me later in my career.  

 

For the last 60+ years, I have been involved in various roles in petrochemicals, fine/specialty chemicals, coatings, flavors and fragrances and other chemical industries. Roles have included reviewing chemistries, process development and design, commercialization, manufacturing, patent reviews and consulting clients at many different companies to simplify their manufacturing practices etc. This has been a continuous process. All along my career I had realized that each chemical has its unique and different behavior for each other and how we use them in our processes. 

 

With time I learnt that we can manage and manipulate physical properties to simplify processing conditions by manipulating their physical state, how and where we add these reactants to the process. This facilitated and simplified our processes. This was/is similar to social manipulation of behavior of chemicals like human behavior to create friendships and relationships, Sociology ⁽⁴⁾. So in 2013 I appropriately coined mutual behavior of chemical relationships as “SOCIOCHEMICOLOGY ⁽¹⁾. Its use has grown from benchtop experiences, experiments and application of components of triumvirate ^(3,5) to critical elements of actual commercial processes. Due to lab equipment limitations, behavior and benefits of many chemicals cannot be easily tested and/or measured easily in laboratory. However, using chemical engineering design principles, behavior of chemicals can be used in process designs and processes simplified. Without their incorporation most commercialized processes are larger version of the round bottom flask experience. 

 

We used elements of sociochemicology profusely for every batch ⁽⁶⁾ and continuous processes ⁽⁷⁾. Their inclusion allowed us to simplify processes. Some of the unit processes ⁽⁸⁾ were e.g. continuous/batch diazotization, sulfation, sulfonation, amidation, chlorination, nitration and alkylation. In addition, our processes included batch and continuous unit operations ⁽⁹⁾ e.g. decantation, filtration, crystallization and spray drying to name a few. 

 

Sociochemicology ⁽¹⁾ delivers simplicity: an ultimate sophistication and a creator‑centric philosophy.

 

Sociochemicology’s Path and Considerations:

 

We have to recognize that the process chemistry shows us the feasibility of the reaction path and process. What generally works in the lab has to be modified and fitted in the existing equipment or new equipment has to designed for the process. Final commercialized process has to be safe and economical. 

We are taught, know and have all the tools to create excellent processes but still are stuck in 80+ years old “round bottom flask” mode especially in pharmaceuticals. Why? Simple answer. We are willing to pay for inefficient processes and in the process do not care how we leave the Earth when we leave i.e. highest emissions. This is especially true for pharmaceuticals ⁽¹⁰⁾. It is up to us to challenge ourselves. If we do not, we will be stuck in the tradition of bull going around in circles⁽¹¹⁾. Food and Drug Administration (FDA)⁽¹²⁾ also has to change its ways if it/we want manufacturing technology innovation in pharmaceuticals. If a DARK HORSE using methods shared ^{(13, 14,15,16, 17)} can show how to change the landscape, there can be a domino effect. 

 

The following needs to be considered for commercial processes and the village has to be an integral part ^{(13,14,15,16, 17)}. There are other ways. There is not enough space to enumerate every option. Product volume plays a significant role in process selection, equipment sizing and use. Traditions of using what equipment is available in-house and from the vendors has to be evaluated, not an easy choice. Equipment vendors will challenge options. In addition, we have to always scout equipment that is used in other industries/applications and can be used in the chemical manufacturing. There will be considerable resistance from within the companies as well as users. These can be overcome through higher profits and better product quality.

 

We have to be always mindful in our process development/design of the fundamental fact is that every reaction happens in liquid phase. Thus, our intention has to be how to create all liquid phase. Village ^{(13,14,15,16, 17)} offers its input and expertise. Some of the considerations are enumerated. Creativity and imagination is necessary.

 

1.     Solid raw materials as a melt offer opportunities to control process stoichiometry and can reduce solvent need. Fluid flow and process temperatures can be controlled. Excess solvents facilitate the process but can become unnecessary as they occupy reactor equipment space, a prime real estate. Heat of the molten liquids speed the reaction rate.

2.     Can the solid raw material instead of dissolving in solvent can be educted in the process thereby minimizing additional solvent? This cannot be tested in the lab. 

3.     Gas can be used as liquid not only it can reduce solvent use but also can facilitate reaction rate. Gas, if added as liquid, can be used to control the reaction temperature and heat of exotherm as the liquid converts to gas. We exploited physical and chemical properties to our advantage. 

4.     Exotherms of the reactions cannot be exploited in the laboratory to facilitate and speed the reactions. Labs generally do not have the equipment or the set up to test. Ingenuity like raising the laboratory process reaction temperature comes in handy. In actual production set up using proper unit process ⁽⁸⁾ and unit operation ⁽⁹⁾, exotherms can be exploited in many ways leading to reduced solvent use, equipment size and investment. 

5.     Mutual solubilities or their lack of cannot be exploited in the lab development set up. They can be tested. However, they can be used in a commercial process to facilitate the process. There are creative ways to exploit.  

 

Unknown to our equipment vendors we used plate and frame heat exchangers (now called micro or flow reactors) and crystallizers differently. Other equipment was also used differently than the suggested use. Each company has to decide how it can capitalize on mutual behavior of chemicals i.e. sociochemicology of the reactants to have an optimum process. Overall economics has to be evaluated.  

 

We all know that without flow of liquids, centuries old practice, no reaction takes place. Since flow of fluids in lab equipment is not directly translatable to commercial equipment, what does “Flow Chemistry” really mean and what is its value. Similarly “Micro-reactors” are a fancy name for plate and frame heat exchangers that have been around and used since mid-fifties. Their use in lab development processes is not directly translatable to commercial processes. Each application and inclusion in a commercial process has to be justified. Thus suggesting “flow chemistry and micro-reactors” are new process advances in chemical and pharmaceutical manufacturing is like dressing an old house with a new coat of paint and calling it a new house, a misconception. 

 

Rational for giving new names to the traditional methods and equipment is not clear. In addition, especially micro reactors are expensive and may not fit every process. Each need has to be justified. Some of the existing commercial equipment can be used to accomplish the same objective and simplify the processes. Scale up of round bottom glassware (laboratory) to a commercial vessel (manufacturing) is not directly translational. 

 

Incorporation of the above is very possible in fine/specialty chemicals that enhance life style but not in API as the equipment/process. This is due to regulatory stranglehold and/or our inaptitude. We can practice creative designs but since the process has to be re-validated by FDA ⁽¹²⁾ after initial approval, a time consuming and expensive process each company has to share its intellectual property. No company wants to invest in better methods. Current regulatory approval methods have to change to allow incorporation of innovative processes ⁽¹³⁾. Simpler method would be that companies be allowed to proceed as long as they make sure that the product quality and performance is not compromised from the established specs. This would bring much needed manufacturing technology innovation to pharmaceuticals.

 

Process improvements and enhancements that come from inclusion of sociochemicology practices is difficult to test in the laboratory equipment. They are designed in commercial processes and are based on application of mutual social behavior of chemicals and used equipment. In addition any sociochemicology based designs being proprietary would not be published. 

 

Since FDA and other regulators are not familiar with many of the nuances of sociochemicology and if they insist on scrutinizing new and innovative methods before a drug manufacturing can be approved, no one will include and/or simplify their manufacturing processes as is the case now. From experience we included sociochemicology based designs. 

Due to limitations of the laboratory equipment, it is not easy to test mutual social behavior of the chemicals. Test of behaviors of chemicals can be a challenge but are doable if the experiments are properly designed. Creativity, imagination and knowledge of mutual behavior of the chemicals has to be included in design of such experiments. Stoichiometry i.e. the product cost and quality will be optimum. Process designed using the generated information will meet and/or exceed FDA stipulated product specifications. This would be a stark change from the current practices and the most difficult to accept and implement at the companies and FDA ⁽¹²⁾. If we want innovation in chemical/pharmaceutical manufacturing we have to be an outlier and THINK DIFFERENT ⁽²⁾. FDA’s methods have to change ⁽¹⁸⁾, a hard thing to implement and accept. 

Again to re-emphasize commercial process is judicious inclusion of the Triumvirate ⁽³⁾: unit processes ⁽⁸⁾, sociochemicology and unit operations ⁽⁹⁾. The THREE DOTS ⁽¹⁹⁾ have to be connected. So let us STAY HUNGRY and STAY FOOLISH ⁽¹⁹⁾ and “Think Different ⁽²⁾” thereby creating excellent manufacturing processes that are green and economical. It is best if all of the above comes internally from each company as they define and select its own pathway. 

Incorporation of TRIUMVIRATE ⁽⁵⁾ in pharmaceutical manufacturing will result in manufacturing technology innovation, significantly reduce emissions per kilo of product and that will be a game changer.  

 

Girish Malhotra, PE

 

EPCOT International

 

References:

 

1.     Malhotra, Girish: Sociochemicology

2.     Apple Think Different

3.     Malhotra, Girish: Sociochemicology: Redefining Chemical Process Design for Efficiency and Sustainability, Profitability through Simplicity

4.     Sociology

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

6.     Batch Process   

7.     Continuous Process

8.     Shreve, R. Norris: Unit Process in Chemical Engineering, Ind. Eng. Chem. 1954, 46,4,672

9.     Unit Operation

10.  Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry   

11.  Bull going around in circles  

12.  FDA

13.  Malhotra, Girish: Profitability through Simplicity

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

15.  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

16.  Malhotra, Girish: Report: Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredient (API) Manufacturing Processes, March 2017

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

18.  Malhotra, Girish: For Domestic Pharma Manufacturing: Reorganize CDER, Profitability through Simplicity

19.  Steve Jobs Stanford Commencement Address 2005  

 

 

 

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