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

Should Pharmaceutical Product Quality EVEN be discussed in a public forum? Shouldn’t it be EXPECTED?

Every so often topic of Quality in pharmaceuticals rears its “ugly” head in conversation or print. It should not as products are for human use. There is conversation about quality culture and its existence. It is known that pharma’s quality levels are much lower than Six Sigma ⁽¹⁾. Lack of pharma achieving six sigma for active pharmaceutical ingredient (API) and their formulators has been discussed for quite some time ⁽²⁾. Repeated discussion of less than quality products and out of specification excursions is manifestation of shortcomings of company’s  process development, commercialization, manufacturing and resulting record keeping practices. Perspective presented is my own and not influenced by and profit making company or regulatory body. 

There could be a simple explanation for pharma company’s quality level being stuck around 2-3 sigma. My conjecture that it is a case of seventy plus year old tradition and speed to market where every “t” is not crossed and every “i” in not dotted or lack of understanding of chemistry or chemical engineering practices and their application to produce quality products from the onset. Since in English alphabets “P” comes before “Q”, it seems that the companies are getting stuck at “P” = profit and not going to “Q” = quality. Once “P” is achieved there could be laxity in achieving “Q”. It could also be a case of every expense to achieve “Q” is paid for by the patient through higher prices.  

We all know that competitive market leads to quality perfection. If we look at the Brand and Generic pharma, brand drugs during their patent life have no competition. These companies cannot afford to offer less due to public relation they cannot have less than quality product. They have to maintain an image. Their sell prices are high as patient also pays for quality so why worry.  

Generic drugs are a different story. Multiple companies have their ANDA (abbreviated new drug application) approved. Some become the supplier to the developed countries. FDA approved drugs are placed on formulary lists. My conjecture is that “formulary lists” are an artificial barrier established by the Pharmacy Benefit Managers (PBMs) and associates along with US legislators to ration drugs to patients and maximize their profits through mutually subsidized healthcare systems. 

Placement of a drugs on formulary list are most likely being used by the intermediaries to maximize their rebates, i.e. profits. Manufacturing companies may be cutting corners if they have not perfected their process from the onset and rely on “quality by analysis ⁽³⁾ (aggravation)” process. 

All of the quality issues that keep popping their ugly head can be solved but will require a landscape change. There are too many players with vested interests and they would not let the change which is of benefit to US population happen. Pharma distribution landscape will have to change. Three distinct routes are reviewed.  

Route ONE:  ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability ⁽⁴⁾ can be used. 
 
If the current healthcare system is going to stay, steps stiffer than the current 483 issuances and correction have to be incorporated. PBMs and allies who acquire drugs from the manufacturers and distribute them should also be held accountable and responsible for any product that does not meet FDA approved and company agreed specifications.

 

Route TWO: Direct drug sales to customers: This route is being used across every sale item and supply chain members are held accountable except for in pharmaceuticals. These methods assure product quality and manufacturing technology innovation. It is time this route be considered for pharmaceuticals in parallel to the current method used by PBMs and their allies involved in distribution and sale of drugs. Direct sales to consumers i.e., competition will assure quality and lower prices.  

Either of the proposed route if promulgated will change the drug distribution and sales in USA. However, there will be resistance from Legislators, USFDA, Pharmaceutical Research and Manufacturers of America (PhMRA), PBMs, their allies and anybody and everybody who can intervene. 

 

Pharma companies for their manufacturing practices are stuck in practices from inception of drug manufacturing ^(5,6) and attempt to use better methods have been stifled by the companies due to speed to market and US FDA’s current approval processes. FDA needs to improve its approval practices. It talks about industry improving its practices but if FDA’s approval processes were labeled as a manufacturing process, FDA will completely fail. It’s practices are QbA (quality by analysis) vs. QbD (quality by design) and are an impediment to pharma manufacturing coming back to USA. 

 

It is time USA adopts policies so that its population is not held hostage for lack drug supplies and shortages. Issues and remediation methods have been discussed over the years. They are: 

 

1.     Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity March 16, 2020

2.     Long Term Drug Quality Supplies for US, FDA and A New Reality, Profitability through Simplicity April 3, 2020

3.     Health and National Security Issues for the USA and Is The United States of America Prepared, Profitability through Simplicity May 8, 2020

4.     Euphoria to Bring Pharma Manufacturing Home to United States its Reality and Challenges, Profitability through Simplicity May 23, 2020

5.     Bring Pharmaceutical Manufacturing Back to USA: Additional Thoughts and Recap, Profitability through Simplicity May 29, 2020

6.     US’s Self Sufficiency for Generic Drugs: A Supply Dilemma and Potential Solutions, Profitability through Simplicity March 31, 2022

7.     Has US lost its Business Acumen, Creativity and Imagination for its Healthcare Needs? Profitability through Simplicity June 6, 2022

 

Route Three: Issues of product quality could easily and very quickly disappear if the process developers and designers operate the manufacturing processes in the plants they have commercialized for a designated time. This will get everyone firsthand information of the deficiencies of their commercialized processes. They will correct all of the issues and produce quality products first time and all the time. This proposal is bold and works as I have lived it. This route also protects intellectual property. 

 

Combination of the above routes should be considered. Inclusion of bringing pharmaceutical manufacturing back to USA and eliminate the pervasive drug quality and shortages are the PRIME objectives. It is time US take bold and necessary steps to curtail drug quality discussion and at the same time bring manufacturing home. Quality should be expected and not discussed. 

 

Girish Malhotra, PE

President

EPCOT International 

 

References:

 

1.     What is Six Sigma https://asq.org/quality-resources/six-sigma Accessed March 31, 2023

2.     Shanley, Agnes: Will the Pharmaceutical Industry Ever Get to Six Sigma? Pharmtech.com July 12, 2017 Accessed March 31, 2023

3.     Malhotra, Girish: “Quality by Analysis” cannot compete against “Quality by Design” Profitability through Simplicity March 15, 2008 Accessed April 10, 2023

4.     Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability (4) was proposed in December 2019. Profitability through Simplicity , December 6, 2019

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

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

Artificial intelligence in Chemical Process Development, Manufacturing & Net Zero

Artificial Intelligence (AI) ⁽¹⁾ is becoming the latest go to technology/methodology for almost every application. Numerous articles have been published in the areas of chemical properties, discoveries, process design and development and manufacturing areas ^{(2,3,4,5,6,7)}. If the machine language can be used to simplify conventional chemical process development and design, it is my speculation that commercialization of products can be sped up multifold. Chemical manufacturing landscape could change dramatically. This will lead to improved profits through faster availability and reduced shortages of products in every segment of the chemical industry that includes fine/specialty chemicals, additives, cosmetics, flavors and fragrances and pharmaceuticals. In addition, every chemical related business can make significant progress towards “net zero” ^(8,9) emissions.   

 

I am presenting my perspective on how AI could be used to develop, simplify, speed up development, commercialization and manufacturing of the products. Perspective presented here is my own. There is no financial relationship with any “for profit” and nonprofit organization.

 

AI and Process Development:

 

For most of the product categories mentioned above development and commercialization take their own course. This is due to availability of data such as properties and mutual behavior of the chemicals needed and used in product evaluation, formulation and process design. Development moves from the laboratory to commercial scale following their established paths that have been taught and practiced over the last 70+ years. 

 

For product development physical and chemical properties of chemicals are needed. Much of the data about chemicals (physical and chemical properties, safety and health value of the chemicals) used and produced might be available from Chemical Abstract Services ⁽¹⁰⁾ NIST Chemistry Web Book ⁽¹¹⁾, product suppliers and can be generated internally at the companies. AI should accelerate and facilitate availability of solubility and safety data. Safety data and solubilities of solvents identified by AI would have to be verified in the laboratory. It could also be used to define process conditions for chemical processing. Process development and commercialization will be accelerated.

 

Many of the chemicals are raw materials are solid at ambient temperatures. To facilitate processing and ease of handling, they are solubilized or slurried in inert solvent/s. These are recovered and reused. This has been the tradition for the last century. Even though the solvents are recovered and reused, they still leave a large environmental footprint than a process which is all liquid process i.e. solids do not have to be slurried to facilitate processing. 

 

Sociochemicology ^{(12, 13)} i.e. mutual behavior of chemicals plays a significant part in development and commercialization of chemical synthesis processes. Some of the methods that can be used to facilitate incorporation of physical properties of the chemicals are reviewed ^(14,15). However, the methods should not be limited to what has been discussed in literature. 

 

Some of the methods that value use of liquids in chemical processing are reviewed ⁽¹⁶⁾. Between AI and “collaborative creativity” ⁽¹⁷⁾ of the village ⁽¹⁶⁾ excellent processes can be developed. I believe that with the help of artificial intelligence it can and will become possible, if it is not already being tried. Having knowledge that all liquid processes could minimize solvent use would be giant leap to “Net Zero” processes. Developers can take advantage of point of addition and heat of reaction to control the reaction kinetics to speed up the processes. 

 

Having an all liquid process could lead to use of smaller size reactors or alternate reaction systems ⁽¹⁶⁾ that could eliminate or significantly reduce the amount of solvent use. It would be a significant step to achieving “Net Zero”. 

 

I believe that AI could scour the processing equipment world and propose equipment that is commercially used in chemical and other industries and would be suitable for the chemical synthesis and blended product applications. It will be interesting to see how AI will change chemical engineering practices. My conjecture is that it could propose processing methods and sequences that would simplify chemical process manufacturing and further augment “collaborative creativity” ⁽¹⁶⁾ of the “village” ⁽¹⁵⁾. Business models should improve.  

 

For the AI proposed designs my expectation is that the unit processes and unit operations might not change much from traditional ways but not having seen any such design it would enlightening to see the results of what will change. Proposed process designs would be readily accepted in the companies after they have been tested internally and product quality meets or exceeds expectations. Adoption in most companies will come quickly. However, companies that are regulated e.g. pharmaceuticals will be skeptical and apprehensive. This will be due major regulatory acceptance challenges as most of the regulatory folks have essentially no or very little chemical process development, design, commercialization and manufacturing experience. Lack of the knowledge and experience at regulators could be a major expenditures and time delays as the regulators will have to be taught value of better technologies. There will be cost implications to the companies and they might not or be slow to venture out in using AI based designs for their product development and manufacturing.  

 

Brand pharma companies could adopt the AI based technologies quickly as they are single product focused. However, generics since they are fragmented and do not have dedicated equipment could be reluctant to accept better technologies that could be AI generated. If AI based manufacturing is accepted overall equipment running time in pharmaceuticals could be lower than the current times. This might deter adoption of AI based technologies. Regulations would have to re-written. 

 

With the progress that is being made in AI it is expected that process development and manufacturing technologies will be of great benefit to humanity ^{(18, 19)}. With the changing landscape regulators will have change their posturing especially when it comes to pharmaceutical product approvals. If they don’t and will not keep up with time, stone age will be a burden on space age needs. 

 

Tomorrow is here:

 

Some might say AI will arrive tomorrow. However, we all know that TOMORROW never comes. AI’s TOMORROW is HERE. We have to learn and capitalize on what we do especially when it comes to chemical products and processes. Listening to the linked ^{(20, 21, 22, 23)} my conjecture is that it will have a powerful impact on chemical process synthesis and could deliver us pathways and processes that we think are or thought to be impossible. Acceptance in chemical process development, design and commercialization could be fast in non-FDA approved products. Incorporation of AI in drug development could be fast. However, as suggested earlier, incorporation of AI in manufacturing could lag “quite” some time due to regulator’s lack of hands on knowledge and experience in product, process development, design and manufacturing practices. My conjecture is that combination of “Creative Destruction” ^{(24, 25)} and “Nondestructive Creation” ^{(16, 26)} will come in play. Business Models, Regulatory policies and procedures will require a monumental change. 

 

Girish Malhotra, PE

 

EPCOT International

 

1.     Artificial Intelligence, Wikipedia  https://en.wikipedia.org/wiki/Artificial_intelligence Accessed March 21, 2023

2.     Chemical Engineering And Artificial Intelligence https://aichatgpt.co.za/chemical-engineering-and-artificial-intelligence/ Accessed March 21, 2023

3.     Artificial Intelligence In Chemical https://aichatgpt.co.za/artificial-intelligence-in-chemical-engineering/#AI_For_Developing_Novel_Chemicals_and_Products Accessed March 22, 2023

4.     Stephanopoulos, G. Artificial Intelligence in Process Engineering, Chemical Engineering Education https://journals.flvc.org/cee/article/view/124525/123536 pg. 182-185, 192 Accessed March 21, 2023

5.     Lou, H. H., Gai, H. Lamar University, How AI can better serve the chemical process industry, July 2020 Accessed March 21, 2023

6.     Trinh, C.; Meimaroglou, D.; Hoppe, S. Machine Learning in Chemical Product Engineering: The State of the Art and a Guide for Newcomers. Processes 2021, 9, 1456. https://doi.org/10.3390/pr9081456 Accessed March 21, 2023

7.     Gasteiger J.: Chemistry in Times of Artificial Intelligence ChemPhysChem 2020, 21, 2233– 2242 Accessed March 21, 2023

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

9.     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

10.  Chemical Abstract Service https://www.cas.org/cas-data Accessed March 21, 2023

11.  NIST Chemistry Web Book SRD 69 https://webbook.nist.gov/chemistry/ Accessed March 21, 2023

12.  Malhotra, Girish: Process Simplification and The Art of Exploiting Physical Properties, Profitability through Simplicity March 10, 2017 Accessed March 21, 2023

13.  Malhotra, Girish: Sociochemicology, 2014 Accessed March 21, 2023

14.  AI for chemistry https://chemintelligence.com/ai-for-chemistry Accessed March 21, 2023

15.  Butler, Keith T. et.al Machine learning for molecular and materials science, Nature volume 559, pages 547–555 (2018) Accessed March 22, 2023

16.  Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation April 19, 2022 https://www.degruyter.com/document/doi/10.1515/9783110702842/html

17.  Malhotra, Girish: API Manufacturing and Environmental Sustainability Chemistry Today, September/October 2022 Vol. 40(5)

18.  Artificial Intelligence In Chemical Engineering https://aichatgpt.co.za/artificial-intelligence-in-chemical engineering/#AI_For_Developing_Novel_Chemicals_and_Products Accessed March 22, 2023

19.  Chemical Engineering And Artificial Intelligence https://aichatgpt.co.za/chemical-engineering-and-artificial-intelligence/ March 21, 2023

20.  A360 Day 1 Emad Mostaque https://www.youtube.com/watch?v=aEWHrqxniLM Accessed March 24, 2023

21.  Bubeck S. et.al. Sparks of Artificial General Intelligence: Early experiments with GPT-4, https://arxiv.org/pdf/2303.12712.pdf Accessed March 24, 2023

22.  Gates Bill: AI and the rapidly evolving future of computing https://www.youtube.com/watch?v=bHb_eG46v2cAccessed March 24, 2023

23.  Gates Bill, The Age of AI has begun https://www.gatesnotes.com/The-Age-of-AI-Has-Begun March 21, 2023 Accessed March 25, 2023 

24.  Malhotra, Girish: Is "Creative Destruction" the way to go for the Pharmaceuticals? Profitability through Simplicity, December 12, 2008 Accessed March 22, 2023

25.  Creative Destruction Schumpeter: Definition https://youmatter.world/en/definition/creativedestruction-schumpeter-definition/ April 20, 2020 Accessed August 15, 2022 

26. Kim, Chan W., Mauborgne: Nondisruptive Creation: Rethinking Innovation and Growth, MIT Sloan Review, February 21, 2019