Capitalizing on Mutual Behavior and Chemical Reactivity of Chemicals

Fine/specialty chemicals and its family members such as additives, flavors and fragrances and active pharmaceutical ingredients have a commonality. They use similar/same chemicals and equipment for their synthesis for their production but are separated by end use and application. Their differentiation starts from how the same and/or different raw materials are reacted to produce the desired intermediates and products. They also have different quality standards and expectations. 

Solvent/water reduction per kilo of the product has always been a part of the process design but not emphasized. Discussion here centers around the opportunities chemists and chemical engineers have to reduce the solvent/water use and simplify processes. My discussion is based on actual experience of how by capitalizing and augmenting the reactivity and method of addition of chemicals, reactions can be optimized and can result in significant reduction of reaction facilitators (solvent/water). Discussion is not influenced by any regulatory, non-profit and for profit organization.  

Among the organic chemicals which includes petrochemicals, fine/specialty chemicals, active pharmaceutical ingredients (API) and their formulations have the highest emissions per kilo of product ⁽¹⁾. In recent years “Net Zero” ⁽²⁾  has become a mainstream topic. There is conversation but an effort on how we can reduce the solvent use for the production of APIs and their formulations, a subset of fine/specialty chemical product classification that cure diseases is least discussed. With emphasis on lowering emissions per kilo, process developers, when it comes to development have to act and react differently from what we are taught or practice. Solvent recovery and reuse is not enough or sufficient to get to “Net Zero”. Solvent use/reduction is critical for our planet. Creativity and imagination is needed. Volumes can be written on the subject. 

 

We are taught fundamentals of physical properties of the chemicals used and produced. How these can be used to reduce/minimize solvent use in various chemical synthesis are not taught in our universities and colleges. At least we were not taught. They are learnt and experienced on the job during development, scale-up, commercialization of the developed processes. During process development out of the box thinking is required. They are on the job training and developer’s EUREKA moments. Collective creativity ^{(3, 4, 5, 6)} helps to optimize processes and reduces solvent use. 

 

Some of the methods to optimize and reduce solvent use could be called magical tricks but they are not. They are pure and simple exploitation and manipulation of physical and chemical behavior. Physical properties of chemicals tell and teach us of their social behavior ⁽⁷⁾. It is up to us to decide how we can and are able to exploit them to create excellent processes. 

 

Diazotization is a chemical reaction that every chemist and chemical engineer is taught in Organic Chemistry and is used as an illustration. This reaction is about 100 years old and has been the building block of most Dyes in Germany ⁽⁸⁾ and worldwide. It is also used to produce many other products. Learnings of this and/or similar reactions can be incorporated and implemented to many other chemical reactions. Other examples are reviewed ^{(3, 4, 5, 6)}.  

 

In the illustrated reaction an amine is converted to its diazonium salt which is reacted further with appropriate molecule to create the desired intermediate/product. Focus here is on the diazonium salt production (Eq. 1). 

Aromatic Amine+ 2HCl + Sodium Nitrite  --->  Diazonium Salt + H₂O + NaCl     (1)

 

Diazo formation reaction is exothermic. To contain the exotherm, i.e. prevent any explosion or run away reaction, it recommendation has been to conduct it at low (0-5°C or lower) temperatures. In early process development reaction exotherm was generally controlled by adding ice to the reaction. This diluted the reaction mass. This was due to unavailability of jacketed reactors or heat exchangers. Reaction product, generally a dye, was filtered and filtrate disposed in river streams as it was the simplest thing to do ⁽³⁾. Impact of effluents on water, fauna and soil was not a consideration. These came later. Heat exchangers were tremendous help in that effort.

 

About seventy years ago Maumee Chemicals, Maumee Ohio developed a continuous ⁽⁹⁾ diazotization process for one of its products. This reaction was carried out at 35-40°C., quite an anomaly from the tradition of those and earlier days. This minimized the water/solvent use and improved the productivity of the process. Due to cost considerations hydrochloric acid was the acid of choice. Company commercialized many other chemistries that were novel for their time and were way ahead of even present day conservation considerations. 

 

Illustration of exploitation of mutual behavior of chemicals, reaction mechanism and kinetics is illustrated using Diazo reaction (Eq. 1). Amines are generally a basic chemical. To convert an amine to a diazo salt, it is reacted with an acid. Resulting product is subsequently is reacted with sodium nitrite to produce the respective diazonium salt. Equations 2 & 3 illustrate the reaction mechanism of the diazo reaction. It is acknowledged in most organic chemistry books ⁽¹⁰⁾. This sequence can be simulated in the laboratory and in pilot plant.

 

              RNH₂ + HCl       ⎯>                RNH₂.HCl                                (Eq. 2)  

 

RNH₂.HCl + NaNO₂ +HCl    ⎯>  RN₂Cl +2H₂O + NaCl              (Eq. 3)      

 

Amine reacts with hydrochloric acid to produce a hydrochloride (Eq. 2) with subsequent reaction with nitrous acid (generated by sodium nitrite and acid reaction) to produce a diazo compound (Eq. 3) that is reacted with a chemical to produce the desired product. This reaction sequences can be capitalized on in a plant by sequential feeding of raw materials, controlling the exotherm and reaction residence time.   

 

In the reaction step (Eq. 2), the formed hydrochloride is unstable. However, it is converted to produce the diazo product instantaneously as it comes in contact with nitrous acid. Yield of the diazo product is almost 100%. For conservation “Instantaneous reaction” is the key and is manageable. Addition sequence, capitalizing on heat of reaction and equipment scheme are the key for the success. Figure 1 is an illustration of the process. 

 

Theoretically one mole of hydrochloric acid is needed to convert the amine to its hydrochloride and an additional mole of acid is needed to react with sodium nitrite to produce nitrous acid which produces the diazo. As illustrated in Figure 1 by adding slightly excess than two moles of acid, excess of acid assures the hydrochloride formation, assures mixing and formation of nitrous acid to produce the desired diazo compound. Reaction is carried out in a circulating pipe with an inline heat exchanger of proper material of construction. Slight excess of sodium nitrite is needed. They are considerably less than the stoichiometry mentioned in many patents, too many to cite. 

 

Reaction exotherm is controlled by in-line cooling, place and way the chemicals are added to the reaction system and the residence time. 

Again, nature of chemicals, how they react and act is the key. Similar addition schemes can be used by the chemists and chemical engineers to create other excellent processes. They can produce active pharmaceutical ingredients, a subset of fine/specialty chemicals and many other organic products. Every chemist and chemical engineer who has mastered their chemistry and process development traits well will totally understand value of such addition methods and processes.

 

Chemicals share/tell their mutual behavior with us. We have the opportunity to take advantage of them. However, due to tradition we are afraid to step out of the PLAY box to be different. 

 

There are many other situations, where exploiting mutual behavior of chemicals especially as liquids, can be used to simplify organic syntheses. Reaction mass of most syntheses are liquid or a slurry. Liquid/solution are the preferred phase over slurries. Ways and methods to capitalize on social behavior of chemicals have been reviewed ^{(3, 4, 5, 6, 11,12,13, 14, 15, 16,17)} and in many other publications. Again, it is up to chemists and chemical engineers to be creative. Many might not believe but such processes based on capitalizing physical and mutual behavior of chemicals used and produced are possible. Unless they are explored, we would not know their value. They are economic and have the highest financial return, a basic premise of great business.

 

Girish Malhotra, PE

 

EPCOT International 

 

1.     Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry https://pubs.rsc.org/en/content/articlelanding/2017/gc/c6gc02157c/unauth#!divAbstract , 2017, 19, 18-43 Accessed February 17, 2021

2.     Burke, J. What does net zero mean? https://www.greenbiz.com/article/what-does-net-zero-mean, May 2, 2019 Accessed April 27, 2021

3.     Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022 Accessed May 24, 2023

4.     Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability, John Wiley & Sons, February 2011 Accessed May 24, 2022

5.     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 Accessed May 24, 2022

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

7.     Malhotra, Girish: Sociochemicology May 30, 2013 Accessed January 13, 2023

8.     Diazonium Compound https://en.wikipedia.org/wiki/Diazonium_compound

9.     Continuous Process https://bit.ly/2Rp3Xlu

10.  L. F. Fieser & M. Fieser: Organic Chemistry, Third Edition, Reinhold Publishing Company 1956

11.  Malhotra, Girish: Improving APIs & Formulation: Are You Harnessing the Power of Liquids?  https://www.linkedin.com/pulse/improving-apis-formulation-you-harnessing-power-liquids-malhotra   April 23, 2023 Accessed May 24, 2023

12.  Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs. 63-66 Accessed May 24, 2023

13.  Malhotra, Girish: Process Simplification and The Art of Exploiting Physical Properties, Profitability through Simplicity, March 10, 2017

14.  Malhotra, Girish: Art and Science of Chemical Process Development & Manufacturing Simplification, AIChE May 17, 2023 Accessed May 24, 2023

15.  Blog Profitability through Simplicity Accessed May 20, 2023

16.  Malhotra, Girish: Review of Continuous Process for Modafinil, Continuous Processing in the Chemical and Pharmaceutical Industry II, 2009 AIChE Annual Meeting, November 10, 2009, Accessed May 20, 2023

17.  Malhotra, Girish: Analysis of API (Omeprazole): My perspective, Poster Session: Pharmaceutical Engineering, 2009 AIChE Annual Meeting, November 11, 2009 Accessed May 20, 2023

Process Simplification and The Art of Exploiting Physical Properties

Chemical additives, petrochemicals, plastics and pharmaceuticals are different reacted forms and formulations of organic (fine/specialty) and inorganic chemicals. We have mastered their use and continue to develop new uses to make our lives easier.

We are also familiar with or can find chemical and physical properties of the chemicals that are used in these applications. However, many of us have not totally understood or mastered their mutual behavior and/or how their mutual behavior can be used/manipulated/modified/exploited to simplify processes, especially the reactive processes. To some extent it is an art that can significantly improve profitability.  

Simpler processes streamline manufacturing. They are sustainable and assist in many other ways e.g. lower costs, higher profit, improve supply chain, give competitive edge through better product quality.

We have to ask ourselves a question “are we exploiting physical and chemical properties to their fullest extent?” If we are not, then the question is why not? Answer is very simple, at least to me. Values and virtues of physical and chemical are taught. However, we generally are not taught how to exploit them. I learnt from my mentors and colleagues. Shortcomings have been discussed in the past ^(1,2,3,4) and in many other publications. If we can understand and manipulate their mutual social behavior “sociochemicology” we should be able to create, design and simplify many of the reactive or formulation processes.

Collectively fault lies with us. Why? When developing a new process we don’t have the time to exploit these properties.

Opportunities are tremendous, however, getting from studying to practicing may not be the simplest. We do practice what we are taught, but not to the extent we could. Traditions also come in the way of exploitation. Most of the time textbook methods and laboratory practices are followed.

Everything has to be done yesterday and the pressure to have the process ready to be scaled up day before yesterday is omnipresent. With such constraints even the best, creative and imaginative chemists and chemical engineers can falter. Processes are commercialized and they may not be the most optimum. Generally such processes are accepted in the chemical industry. Continuous improvement opportunities allow us to better these processes. However, there are applications where commercializing a perfect process that has very stringent tolerances and meet certain regulatory needs are a must. Electronic chemicals and pharmaceuticals fit the higher tolerance regimen with pharmaceuticals due to regulations being even more demanding. Second chances in these areas can cost significant time and money.

Process Development Opportunities:

Process development is done in the laboratory and at times circumstances are not helpful to think BIG. By BIG, I mean how we will deal with commercial quantities of raw materials and intermediates. Our “Imagineering” falters somewhere when we are scaling up from the lab to a commercial process. We pay a price via higher product cost and at times with lack of first time product quality because we have not spent the time needed to create an efficient economic process.

Exploitation and imagineering of physical and chemical properties of the chemicals to create an economic process can be an art which depends on “eye of the designer”. Individual imprints come from our experiences and understanding of unit processes and unit operations.

I have used one of the physical properties as an example to illustrate how we can master/exploit sociochemicalogy to create and commercialize excellent and sustainable processes.

Liquids are Developer’s Best Friend: 

Every chemical comes in its natural state in one of the three forms: gas, solid and liquid.

At room temperature gas cannot be held in hand where as solid and liquid can be handled. When it comes to handling gases in the lab they are a challenge. Liquefied gas handling has use constraints in the lab. They can be a challenge in plants also. Special equipment would be needed if liquefied gas were to be handled. Since many labs are not equipped, gases are dissolved in a liquid and used in process development. Use of ammonia as ammonium hydroxide is an example. Process productivity can be lost when dilute gas solutions are used. Commercial handling of liquefied gases requires special attention and is product volume dependent.

In laboratory, solids are generally dissolved in appropriate solvent and used as a dissolved solution. Depending on solubility at room temperature process productivity can be significantly impacted. On commercial scale if the solid raw material can be used as a melt, it would be ideal, as the process will have high productivity. Again process economics and product demand come into play.

Raw materials, reaction intermediates and products as liquid are easiest to handle. Our ability to recognize the differences in density, mutual solubility, boiling point differences and other physical properties and exploit them to our advantage generally results in an economic and sustainable process ^(4,5,6). Exploitation of physical and chemical properties is not a cookie cutter exercise but is more like a precision surgery for each process, especially for the reactive processes.

There are many chemical reactions that can be commercially done in all liquid phase when the raw materials are solid or gas at room temperature. With sufficient residence time and using fundamental of chemistry and chemical engineering the produced product can be purified to produce global needs from a single plant. Latent advantages of such processes are very high productivity with minimal use of diluting solvents that are necessary in conventional processes. One has to imagine, explore and look. As explained earlier reason and rational for not looking in the lab is that we do not have the necessary equipment to explore such reactions. Many times such opportunities are never explored even after commercial success of such products.

Many books can be written about how sociochemicology of the chemicals can be used and improved to commercial advantage. It is best that such methods be left to the imagination of chemists and chemical engineers. Given a chance they are extremely creative, imaginative and resourceful and the results would magnificent.

Girish Malhotra, PE

EPCOT International

1. Malhotra, Girish: A Radical Approach to Fine/Specialty API Manufacturing, Profitability Through Simplicity January 20, 2010
2. Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs 63-66
3.  Malhotra, Girish: Industry 4.0 (Digitization): Its Benefits to Pharma and Other Chemical Industries, Profitability through Simplicity, November 11, 2016
4.  Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability, ISBN: 978-0-470-48754-9, January 2011, John Wiley & Sons Inc.
5.  US patents: 3,928,457; 4,945,184; 5,004,839; 3,564,001; 4,363,914
6. McCabe, W. L. and Smith, J.C. Unit Operations of Chemical Engineering, McGraw-Hill, Inc. 1956; 40

Is McLaren Going to be Pharma’s “Creative Destructionist”?

Since 2011 ^{(1, 2, 3)} I have postulated that pharma needs a “creative destructionist” for its manufacturing technology innovations to get out from its archaic “quality by analysis” methods to “quality from the get go methods”. Current practices have cost patients billions in excessive costs.

Generally most of the “creative destructionists” are from outside the industry, McLaren could be the one for the pharma and the chemical industry.  

“What Can the McLaren Racing Team Teach the Rest of Us?⁽⁴⁾” is an interesting read. McLaren Applied Technologies (MAT) is analyzing generated/available information and creating scenarios that are changing the current operating models in some industries. Their analysis and methods along with human creativity take an acceptable 2+2=2.5 or 3 to a higher number, closer to 4 and are the key. Such improvements are game changers.

Methods and technologies of MAT besides winning car races have been used to train Olympic athletes, in oil drilling and improving airport operations. These are just few examples. GSK, the pharma company, is using them to improve its toothpaste production and drug discovery processes. In these applications there is complex interaction of humans and machines. Since MAT methods and technologies are being successfully applied to these complex situations, I believe that they could be very effectively used in less complex manufacturing situations e.g. reactive chemical manufacturing and their formulations.

Total revenue for these markets would soon be approaching FOUR Trillion dollars, one trillion dollar for the global pharma ⁽⁵⁾ and about three trillion dollars for the chemicals ⁽⁶⁾. Combined savings of 10% for pharma and chemicals could be about $400+ billion dollars and that would be a wonderful achievement. Savings will come from improvements in supply chain, process yields, business practices and product quality.

Significant information about the reactive processes used to produce chemicals including active pharmaceutical ingredients that are chemicals with disease curing value and their formulation is readily available. Proficient chemists/chemical engineers can combine chemistry and chemical engineering principles, creativity ⁽⁷⁾ along with “what if” scenarios to create processes that are efficient, cost effective and significantly sustainable compared to the current processes. Their application would be extremely helpful for pharma molecules before they get in to clinical trials. QbD in pharma could become a reality. We all know that once the selected molecule gets in clinical trials, process changes are difficult. “Process centricity” will overtake “regulation centricity” and for the first time quality from the get go will become way of life for pharmaceuticals.

Girish Malhotra, PE

President

EPCOT International

1.     Malhotra, Girish: Does the Pharmaceutical Industry Need A Steve Jobs? November 8, 2011

2.     Malhotra, Girish: Can the Combination of Creative Destruction and “Steve Jobs’ Traits” Lead to Pharma QbD Spring? April 15, 2012  

3.     Malhotra, Girish: Landscape Disrupters Are Becoming Part of the Pharma’s Playing Field, August 17, 2014

4.     Bennett, Drake: What Can the McLaren Racing Team Teach the Rest of Us? Business Week, October 2, 2014 accessed October 7, 2014

5.     Pharma Report Predicts Trillion Dollar Global Industry by 2020 Accessed October 13, 2014

6.     Chemical Industry Profile Accessed October 10, 2014

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

Is the New Terminology Going to Make the Pharmaceutical Processes Environmentally Friendly and Economic?

Reading two recent articles in Organic Process Research & Development magazine ^(1,2) had me wondering about my chemistry and chemical engineering education and practices. They created a doubt in my mind and raised a question “would the fundamentals that we had learnt and are the building blocks of the chemical industry where chemicals are either reacted or blended to produce useful products not work anymore?”

These articles also eluded that the pharmaceutical manufacturing is different and cut above the chemical industry. A new terminology rather than the fundamentals of chemical engineering and chemistry (simple heat/energy and mass balance, improving process productivity and having an economic process) are more important and necessary to design and create an economic and sustainable process. If that is the case then things have changed dramatically and many others and I could be oblivious to the change. The new terms are process mass intensity (PMI), reaction mass efficiency, E factor, Eutrophication Potential, atom economy and space-time yield etc.

During my undergraduate degree in chemical engineering, we were taught the fundamentals of heat/energy and mass balance, organic, physical and inorganic chemistry along with unit operations and unit processes, thermodynamics, chemical reaction kinetics and economics to develop processes that when commercialized using properly designed and appropriate equipment produced quality product, had minimal impact on environment and were economical. As the time progressed environmental laws encouraged us to improve processes to minimize the ecological impact.

Based on end application of the products, the manufacturing processes were labeled differently e.g. products covering surfaces were called coatings, chemicals that have disease curing value were called pharmaceuticals, chemicals that did not have disease curing value but were used as additives were classified as fine/specialty chemicals and products from crude oil were categorized as petrochemicals and so on. However, the fundamentals that were/are applied for the process design and development have not changed much.

I am not sure how many practicing chemical engineers or chemists understand what the new terminology discussed above means or are they just fancy expressions for the fundamentals that many will not understand. Due to diverse chemistries and processes of active pharmaceutical ingredients and formulations being produced in existing equipment that is not designed and/or optimized for their production, I am not sure if these factors truly on their own can deliver a green process.

There are ninety-nine references in these articles. One is from 1994 and two are from 1999. Does the lack of prior references suggest that the chemists and chemical engineers before 1990 were totally naïve and oblivious to good process development, design and engineering practices and did not use the fundamentals to develop, design and commercialize sustainable chemical processes? Or is there a latent message that the pharmaceutical development and manufacturing is elite, complex and chemistry and chemical engineering principles apply differently to them or some other principles apply?

I hope that is not the case. If it is, then it is suggests that the manufacturing will have occasional problems. This will be manifested by our lack of command of the processing steps forcing us to rely on QbA (Quality by Analysis) methods to ensure quality of active pharmaceutical ingredients and their formulations. Occasional recalls and increasing citations are suggestive of our lack of command and control of the manufacturing practices. 

To have robust, economic and sustainable processes I strongly believe that we need to have understanding and command of the processes. That can only happen by application of fundamentals that we learn in our chemistry and chemical engineering curricula along with our creativity and imagination ^(3,4). The products produced using such processes will produce the desired quality products. Quality by Design (QbD) will prevail and the environmental impact will be minimized. 

Girish Malhotra, PE

EPCOT International

1. Jimenez-Gonzales, C. etal, Using the Right Green Yardstick: Why Process Mass Intensity is Used in the Pharmaceutical Industry to Drive More Sustainable Processes, Organic Process Research and Development, Org. Process Res. Dev., 2011, 15, pgs. 912–917
2.  Jimenez-Gonzales, C. etal, Key Green Engineering Research Areas for Sustainable Manufacturing: A Perspective from Pharmaceutical and Fine Chemicals Manufacturers, Org. Process Res. Dev., 2011, 15, pgs. 900–911
3. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability, February 2011, John Wiley & Sons Inc.
4. Malhotra, Girish: Focus on Physical Properties To Improve Processes, Chemical Engineering, Vol. 119, No. 4, April 2012, pgs. 63-66