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Showing posts with label #Manufacturing. Show all posts
Showing posts with label #Manufacturing. Show all posts

Sunday, February 22, 2026

SOCIOCHEMICOLOGY: Designing Chemical Processes by Exploiting the Social Behavior of Molecules

A Personal Note from Girish Malhotra

 

For more than sixty years, I have practiced Sociochemicology — the deliberate exploitation of the mutual behavior of chemicals to simplify manufacturing.


This is not theoretical chemistry. It is the product of decades of careful observation, experimentation, and disciplined thinking. I have seen countless processes burdened by unnecessary steps, wasted energy, and avoidable complexity. I have also seen the profound benefits when simplicity, creativity, and understanding of molecular behavior are applied intentionally.


I share this work not for recognition, nor to claim discovery, but to pass on what I have learned before I leave this planet. My hope is that others — chemists, chemical engineers, and curious minds — will engage with these ideas, challenge them, improve them, and carry them forward.


Science progresses not just through reaction mechanisms or calculations, but through insight, imagination, and disciplined observation. Sociochemicology is my attempt to capture that essence and make it practical.


If even a few minds are inspired to think differently, question inherited norms, and design processes more intelligently, then this work will have served its purpose.


For more than sixty years, I have practiced a method of process design that I later named Sociochemicology — the deliberate exploitation of the mutual behavior of chemicals to simplify manufacturing.


  • It is not a new branch of chemistry.
  • It is not theoretical abstraction.
  • It is applied physical chemistry used intentionally to eliminate unnecessary process burdens.


Most process development begins with a reaction scheme and builds outward. The emphasis is on conversion, yield, and purity. Existing equipment is a facilitator rather than a strategic design variable. Product quality deviations are managed.


Sociochemicology begins differently. It asks:


How do these molecules behave together under realistic manufacturing conditions — and how can that behavior be used to eliminate steps rather than create them?


The Central Premise


Chemicals do not behave in isolation. They interact socially — through solubility differences, phase behavior, crystallization tendencies, density differences, acid-base relationships, thermal characteristics, kinetic preferences, and other physical property differences.


In many industrial processes, we ignore this “social behavior” during early design. As a result:


  • We dissolve what we later must separate.
  • We overreact and then purify.
  • We neutralize only to re-acidify.
  • We introduce solvents that complicate recovery.


Then we add equipment, controls, and validation layers to manage the complexity we created.


Sociochemicology reverses this logic. Instead of forcing chemistry and managing consequences, we allow molecular behavior to guide sequencing and staging from inception.


Profitability Through Simplicity

For decades, I have advocated what I call Profitability through Simplicity (1). Not minimalism for its own sake, but disciplined elimination of non-value-adding operations.


Simplicity in manufacturing yields:


  • Thoughtful capital investment
  • Reduced energy consumption
  • Fewer separations
  • Less waste
  • Minimal solvent use
  • Shorter cycle times
  • Improved robustness
  • Lowest cost 


Yet simplicity is often resisted. Complexity creates institutional comfort. Departments form around managing problems.  Validation structures grow around inherited designs.  

Elimination can feel disruptive. But industrial progress rarely comes from adding steps. It comes from questioning 

why they exist.


Sociochemicology in Practice


Sociochemicology does not require exotic technology. It requires disciplined observation and creative application of physical chemistry principles.

It means designing processes around:

  • Differential solubility rather than brute-force purification
  • Controlled precipitation rather than evaporative concentration
  • Selective crystallization rather than chromatographic rescue
  • Mutual phase behavior exploited intentionally
  • Equipment used as a behavioral amplifier rather than a containment vessel


In site-based chemistries such as Omeprazole, Phthalimide, Metformin, Modafinil, Gabapentin and other active ingredients, simplification did not come from discovering new reactions. It came from reordering steps, staging additions differently, and allowing inherent molecular tendencies to perform separations naturally (2,3,4).

The chemistry was known. The behavior was underutilized. The innovation lay not in reaction discovery, but in interaction management. Alternative routes to established processes needed to be exploited — and we did.


Why It Is Rarely Taught

 

Academic training emphasizes reaction mechanisms, kinetics, thermodynamics, unit processes and unit operations. These are essential foundations.

 

However, curricula often do not emphasize free thinking in process staging — the art of asking:

       What happens if we change the order?

       What if we avoid dissolving this component?

       Can we precipitate selectively before impurity formation?

       Can the equipment environment be used to influence behavior?

 

Industrial design frequently follows precedent. Once a route is validated, it becomes institutionalized.

 

Sociochemicology challenges inherited structure. It suggests that many “necessary” unit operations and unit processes are artifacts of early decisions rather than chemical inevitabilities.

 

Not Magic — Discipline

 

Sociochemicology (1) is sometimes misunderstood as intuitive or anecdotal. It is neither.

 

It is rooted in:

         •        Solubility parameters

         •        Thermodynamic equilibria

         •        Acid-base interactions

         •        Mutual solubilities and insolubilities

         •        Mass transfer behavior

 

The difference is not scientific rigor — but emphasis. Traditional development asks: “How do we make this reaction work?”

 

Sociochemicology asks: “How do we make the entire sequence self-organizing?”

 

A Practical Test

 

Consider any multi-step API manufacturing process.

 

For each step, ask:

         1.       Does this operation exist because of intrinsic chemistry?

         2.       Or does it compensate for an earlier design decision?

 

If it is compensatory, simplification may be possible. Often the greatest improvements come not from new molecules or new platforms, but from eliminating what should never have been introduced.

 

The Future Opportunity

 

Artificial intelligence and modeling tools may facilitate and optimize defined process structures. However, optimization assumes that the structure itself is appropriate. Simplification requires something different -  deliberate understanding of mutual physical behavior and the willingness to question inherited laboratory sequences.

 

No algorithm replaces thoughtful interrogation of molecular behavior. Imagination and disciplined understanding of physical properties remain essential.

 

The opportunity ahead is not merely automation of existing complexity — but redesign grounded in behavioral exploitation. Sociochemicology provides a framework for that redesign.

 

Sociochemicology provides a framework for that redesign. It is not revolutionary chemistry. It is disciplined attention.

 

Invitation

 

I have practiced the principles of Sociochemicology since early 1960s, long before the term was coined. Many real-world applications are described in my published work and articles.

 

But the concept gains power only through discussion. If you believe a process step cannot be simplified, I welcome the example.

 

Progress begins with conversation. 


Editorial refinement support provided by AI tools.  

 

Girish Malhotra PE

 

EPCOT International

 

References:

 

1.     Malhotra, Girish Blog 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

Thursday, March 21, 2024

Use of Tradition, Creativity, Imagination and Technology Innovation in Propofol Manufacturing

Title in itself can be questioned by some or many for any and every discussion. It should not be, if we look at everything that is manufactured. Everything starts from rudimentary paper concepts  with subsequent intervention of humans and science that makes the products and their manufacturing process elegant, useful and easy to use. It is well known that creativity and imagination when applied to any product and/or process leads to excellent results. Perspective presented is my own and there is no relationship or influence of any profit, nonprofit organization or regulatory body.

 

Methodologies used for process development and manufacture of fine/specialty chemicals which includes active pharmaceutical ingredients (API) are same. APIs are younger cousin of fine/specialty chemicals. However, they are treated differently even when exactly the same/similar chemicals, processes and equipment are used to produce each of the molecules. The only difference is API’s cure a disease whereas fine/specialty chemicals enhance lifestyle (1). It is true that APIs have to follow stricter regulations as they are used to cure diseases. Pseudo-assumption that APIs are nobler than their older cousin, fine/specialty chemicals, is unnecessary and very convoluted. 

 

If one traces a chemical molecule being developed in a laboratory equipment and has been synthesized It uses same/similar in every process development. Paper chemistries are tested and tweaked to create a process that the developer considers to be economic and optimum. Real test of this hypothesis comes when the process is commercialized.  

 

Every chemical entity for its production has a defined process and method. Even though I have reviewed and presented my perspective (1,2,3), it is never redundant to re-visit and share steps I would take to develop and commercialize a product. My team “THE VILLAGE” (1,2,3) will include a chemist, a chemical engineer, an accountant (can be a chemist and/or chemical engineer who is well versed in cost analysis), quality control, purchasing and manufacturing. Extent of their involvement will vary as the project progresses.

 

Every fine/specialty chemical plant that includes active pharmaceutical ingredient (API) should follow the outlined or equivalent path/s (1,2,3). There is value in this methodology or similar practices. They are documentation of reason and rationale for the process design and its basis. They assist in every regulatory filing and facilitates every trouble shooting and expansion if needed. 

 

Village (1, 2, 3) has to address each of the following items. If a village is not involved from inception, costs can be higher and commercialization can be delayed.


1.     Product volume per year

2.     Physical, chemical properties, mutual behavior and toxicity of raw materials, intermediates 

3.     Mass balance

4.     Process chemistry and manufacturing methods/procedures (unit processes)

5.     Process equipment and metallurgy (unit operations)

6.     Method/s used to feed the raw materials and transfer intermediate reaction products

7.     Raw material and Product specifications

8.     Effluent/waste treatment

 

Table 1: Information needed for an excellent chemical synthesis process

 

Collected information (1,2,3) Table 1 gives significant clues about the process. To every experienced chemists and chemical engineer it gives clues about how to finesse and capitalize on mutual behavior of chemicals. This information influences product cost and process economics. If the process involves multiple reaction steps and can be fitted in the existing equipment, it is very likely that the process will be inefficient and repeated analysis of process intermediates and the final product would be necessary, a characteristic of a classical batch process. Such processes for APIs would have low asset utilization (4).

 

If a product is a high volume product and the process involves multiple steps i.e. sequential processing steps without interruption, it can be conducive to a continuous process. Every village (1, 2, 3) team member has to be familiar with the development and commercialization process. Such processes are economic. However, generally this methodology has not been part of the API landscape. For a process to be a continuous process (5) product has to have sufficient volume (Kg/year) to operate 24 hours per day, seven days per week and about 50 weeks per year with some allocated downtime for maintenance. For such processes equipment design will be product specific.   

 

Based on my experiences any product that has multiple synthesis steps when fitted in the existing equipment  is generally a batch process. Fitting processes in existing equipment have inherent drawbacks of poor design and less than efficient asset utilization. Excess solvents, water or organic/s, are needed to assure proper processing. They have high emissions (6, 7). Along with low process productivity process yields are generally less than optimum. 

 

Continuous processes are not adopted by the brand pharma companies. Reason is simple. Speed to market. Once the product’s efficacy is recognized, it is submitted for regulatory approval. That is the key. Since the market size is not defined, batch process is the selected process. Any process changes require regulatory reapproval and that can be very expensive. In addition, village is not involved in their business model. This can delay the commercialization of process. For the generics many APIs of high volume can be produced using continuous process but will necessitate different business model. Only an outlier company will consider such options (1,2,3, 8)

 

Manufacture of Propofol: 

 

Five alternate refenced chemistries (9,10,11,12,13) for the manufacture of Propofol are presented. Items discussed in Table 1 have to be incorporated. Village team should review each of the experiments in the lab to get a feel for the process, flow of materials and mutual behavior of chemicals. This can unleash their creativity and imagination and would facilitate the scale up and commercialization of an excellent process. Raw materials should be of commercial grade quality and do not need to be pharmaceutical grade i.e. high purity. They are expensive and add unnecessary cost and may not be any different from the commercially available raw materials. Quality of the final product has to be the final driver. 

 

Raw materials for Propofol synthesis (9,10,11,12,13) Table 1 influence process design and selection. Chemistries described (9,10,11,12) are similar. In reference (13), the starting material is different. De-carboxylation step is executed differently. For process selection each of the outlined process chemistry needs a thorough review. 

Execution of laboratory processes in the plant will be very different from what is being discussed in these papers and patent. Again, each process has to reviewed carefully. Described chemistries (9, 10, 11, 12)  present an excellent opportunity for a continuous process (5). Purification or distillation of Propofol is based on chemical engineering distillation practices and there is no novelty. 

 

Items of Table 1 can be applied to select the best and the simplest process. Since 4-Hydroxybenzoic acid is solid at room temperature, its addition can be controlled if it is used as a melt or in a solvent that has high solubility. Scheme one (9)because of its simplicity could be the most likely candidate for a continuous process. 

Stoichiometry and process conditions can be precisely controlled and make an excellent case for a continuous process (1). Depending on the process selection (batch vs. continuous) design, feeding of aluminum chloride (2) has to carefully thought through. 

Chemical

4-Hydroxybenzoic  

           acid                  

3,5-di-isopropyl-4-hydoxybenzoic acid

Methylparaben

Propofol

 

CAS No.

99-96-7

13423-73-7

99-76-3

2078-54-8

Formula

C7H6O3

C13H18O3

C8H8O3

C12H18O

Mol. Wt.

138

222

152

178

Melting point, ºC

214.5

146

~ 125

18

Boiling point, ºC

 

345

~ 299

256


Table 2: Properties of Reactants and Propofol 

Yearly production volume is a very important criterion for selection of a batch or continuous process. Since propofol is a widely used for anesthesia its global use would be high. Sales of finished Propofol speculated by many, too many to cite. For Propofol as API no numbers were available. With consultation of Dr. Albinus D’Sa (16), it is estimated that between 250,000 to 300,000 MT per year would be needed to meet global needs. 

 

Since Propofol is a generic product only a new entrant in the business would use what has been described but the principles and methodology can be used by any fine/specialty and API business. 

 

 We have to remember that every multiple step chemical synthesis is an opportunity to simplify the process. This is easier said than done. Total knowledge and command of the chemicals used and produced in the process is a MUST. Knowledge of the unit operations (14) and chemical and physical properties (1, 2, 3) is essential. Application and inclusion of the knowledge simplifies the process and give command to produce quality product whether it is a batch (15) and/or a continuous process (6). A distinct advantage of a continuous process is that it can be ramped up to meet sudden surge in product demands. 

 

Some of the discussion above has been reviewed earlier (1, 2, 3, 8). Use and inclusion of parameters outlined in Table 1 allows proper process equipment (1) design and can reduce investment. Since Propofol is already commercial most likely not much will change unless an outlier company decides to enter the business. For any outlier it would be necessary to know the yearly demand for the Propofol API.


For process selection (batch vs. continuous) global how much active Propofol is produced is not available. Only number available is projected speculation of finished product. That does not give a reliable number. After consultation and discussion with Dr. Albinus D’Sa (16), different anesthesiologists, published information (17, 18) and world population (19) best number has been calculated, Table 3. Total Propofol active molecule needed is large enough to have an excellent continuous process. Continuous operations can be ramped to meet fluctuating active molecule need. 

Sweden Population 

10 million (18)

Yearly use, kg

394

Global population 

8.1 billion (19)

Yearly Global Propofol need, kg

250,000 to 305,000 

 

Table 3: Estimated Global Propofol Active Ingredient need

Similar analysis can be done for many other products. Options exist for continuous processes for many other products exist and need a review along with business model change. They can be used to alleviate shortages. 

 

Girish Malhotra, PE

 

EPCOT International 

 

References:


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

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

3.     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

4.     Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharma Manufacturing Sep 19, 2007

5.     Continuous Processing Accessed February 12, 2024

6.     Burke, J. What does net zero mean?, May 2, 2019 Accessed April 27, 2021

7.     Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry, 2017, 19, 18-43 Accessed February 17, 2021

8.     Profitability through Simplicity

9.     Pramanik  C. et. al. Organic Process Research Development, 2014, 18, 152-156

10.  Mougeot, R. et al Continuous Flow Synthesis of Propofol. Molecules 2021, 26, 7183

11.  Guilherme M. Martins et. al. Scaled up and telescoped synthesis of propofol under continuous-flow conditions Journal of Flow Chemistry (2022) 12:371–379 , 

12.  SCHNEIDER, Jean-Marie et.al. Process for producing Propofol WO/2023/111488  

13.  USP 11,767,281 B2

14.  Unit operations of Chemical Engineering, McCabe, W.L. Smith et. al McGraw Hills Inc. 1993, Accessed February 17, 2024

15.  Batch Production Wikipedia Accessed July 6, 2017

16.  D’Sa, Albinus Dsa Pharma Associates,

17.  Braun B: Miljöinformationen för propofol är framtagen av företaget Aspen Nordic för Diprivan 

18.  Sweden population https://www.worldometers.info/world-population/sweden-population/

19.  World population https://www.worldometers.info/world-population/