Considerations to have an excellent environmentally friendly and economic chemical process?

We are taught chemistry and chemical engineering fundamentals and learn many of the tools through education and experience . We use our creativity and experience to string them together to create and commercialize good chemical synthesis processes. It is a never ending task and that is why it is called “process of continuous improvement”. This has been enumerated ^{(1, 2, 3, 4, 5)} and other references (too many to cite). With time we augment our experiences and continue to develop better processes. This is the Law of Nature.  

All of the views presented are mine and not influenced by any regulatory body or any profit/non-profit entity. Readers are more than welcome to add to the discussion and improve the process as they see fit. 

Synthesis of manufacture of pantoprazole outlined in Figure 1 USP 8,691,995 ⁽⁶⁾ is used as an example. 

                        

                                  Figure 1: Pantoprazole synthesis USP 8,691,995 ⁽⁶⁾

 

For creating and commercializing processes that are economical and have the lowest “E-Factor ⁽⁷⁾” we have to include and capitalize on mutual behavior of every chemical used and produced in every reaction step. Such review process begins as soon as we pen a viable chemical reaction. Village ⁽⁴⁾ has to be involved from inception of the process. Discussion and review is necessary for every chemical synthesis and formulation process ^{(1, 2, 3, 4, 8)}. They reduce commercialization time. 

 

First and the foremost thing necessary for the process is to write a mass balance of the process and identify physical and chemical properties of each reactant used and product/byproduct produced. Solubility of each chemical in different solvents is extremely helpful as it tells us how we can use solvents to have an excellent process. It is well documented that every reaction is best carried out in liquid phase ^{(4, 5, 8)}. This information can be used to incorporate value of physical properties ^{(1, 2, 3, 4, 5, 8)} i.e. relative solubility and insolubility, density differences, corrosivity, melting and boiling point etc. These might be considered valueless and/or mundane by many but are the guiding force and facilitator behind every good process design ^(4,8). They make the basis of equipment and process design.  

 

Most of the reactants are solid at room temperature. Their melting points can be high. Thus, they will have to be dissolved in a solvent. Solvent selection is critical. It should be such that they can dissolve or have a concentrated pumpable slurry. Uniform and well dispersed slurry can be easily metered for stoichiometric control. Since bleach and NaOH are used in the process ⁽⁶⁾ under discussion, their solubility/insolubility in water and other components has to be a consideration for this synthesis.   

 

In Step 1 sulfur dioxide is generated. In absence of water it is not corrosive but has to be handled safely. Proper material of construction for equipment is necessary. In step #3 bleach is used. Corrosion resistant equipment like glass will have to be used. If acids are used in the reaction and/or generated in the reaction, attention needs to be paid to material of constriction for the equipment used. 

 

Methylene chloride is acceptable and widely used for laboratory synthesis. However, consideration of alternate solvent/s for every commercial process alternate solvent/s that will simplify and improve the process is extremely important. Can the reaction be carried at higher temperature to speed the reaction ^{(1, 2, 4, 9)} has to be a consideration? Most likely it can be and that would require a different solvent of higher boiling point. Such options cannot be readily tested in laboratory development. Their water solubility and reuse will have to be a consideration. Use of higher boiling point solvent could allow the first reaction step ⁽⁶⁾ to carried out at a higher temperature. This can improve the reaction rate. We know that every ten degrees rise in temperature doubles the reaction rate ⁽⁹⁾.  

 

In the production of pantoprazole sulfide, step 2 ⁽⁶⁾, to facilitate the reaction patent calls for use of phase transfer catalyst. If the immiscibility of the reactants can be improved by alternate means such as feeding the reactants in confined space e.g. a miniature/confined space or use of in-line static mixer, it may be possible to eliminate the use of phase transfer catalyst and process simplified. In-line static mixers have been available for over fifty years. Such devises are not available to the chemists in the labs at majority of companies. In addition, most of the chemists and chemical engineers generally due to limited production volume per year do not consider such options as they would be considered too adventurous for any fine/specialty chemical or active pharmaceutical ingredient (API) producer.

 

In the conversion of pantoprazole sulfide to pantoprazole base bleach is used. This is a significant improvement over the use of m-chloroperoxybenzoic acid that was used in the preparation of Omeprazole ⁽¹⁰⁾. M-chloroperoxybenzoic acid is expensive and a challenge to handle compared to common bleach used in ⁽⁶⁾. Use of bleach in similar reactions ⁽¹¹⁾ has been practiced in the production since 1967. This suggests that literature and patent search from the inception of process development is critical as it can simplify and speedup process development.  

 

Pantoprazole like Omeprazole is a high volume API drug and can be produced using a continuous process. Based on my review both are still produced using batch processes ^{(12, 13)}. 

 

As suggested earlier, it is important that the village ⁽⁴⁾ be involved from process inception. Patents and literature are a treasure trove of knowledge and experience. They need to be exploited and used for creating better manufacturing processes. Use of equipment that is commercial and being used in other applications can be exploited ⁽⁴⁾. Scale up and to the market time will be reduced. Commercialized processes not only will be economic but will have significantly lower emission (E) factor ⁽⁷⁾. 

 

Girish Malhotra, PE

 

President,

 

EPCOT International

1. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011 
2. 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
3. Malhotra, Girish: Research Report: Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredient (API) Manufacturing Processes, March 2017; AVAILABLE FREE
4. Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April
5. Malhotra, Girish: Profitability through Simplicity
6. Kankan, R. N. et.al. USP 8,691,995 B2  2014, Process, Cipla Limited 
7. 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
8. Malhotra, Girish: Sociochemicology May 30, 2013 
9. Chemical reaction rate and temperature relationship https://chem.libretexts.org/Bookshelves/Physical_and_Theoretical_Chemistry_Textbook_Maps/Map%3A_Physical_Chemistry_for_the_Biosciences_(Chang)/09%3A_Chemical_Kinetics/9.05%3A_The_Effect_of_Temperature_on_Reaction_Rates
10.  Brändström, Arne: USP 5,386,032, 1995, Method of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sufinyl-1-H benzimidazole (omeprazole), Aktiebolaget Astra, Sodertalje, Sweden
11. Hill, D. R. et. al. USP 3,324,119, 1967, Production of Isatoic anhydride and Certain Halo Derivatives Thereof, Maumee Chemical Company, Toledo, Ohio 
12. Malhotra, Girish: Alphabet Shuffle – Moving from QbA to QbD, Pharmaceutical Processing world, February 2009 Accessed August 20, 023
13.  Malhotra, Girish: Analysis of API (Omeprazole) AIChE Nashville National Meeting 2009 

Chemicals tell us how to exploit their behavior for better processes. Clues are ignored. Should we?

  Every chemical that reacts or is soluble or insoluble with another chemical is based on its mutual behavior. My conjecture is that this statement will make most of chemists and chemical engineers ponder “what is the point of this statement/discussion?”. We, humans, are social people who exploit mutual relationships to create excellent affiliations in business, sports and personal adventures. Reality is that chemicals have a mutual behavior and generally it is least understood/exploited in process development. We generally do not exploit and take advantage of their relationships. Having an understanding leads to better economic process and higher quality products ⁽¹⁾. In the following I am sharing opportunities I see for excellent processes. Anyone can explore similar opportunities. Perspective presented is my own and not influenced by any external for profit and nonprofit organization.  

 

Due to lack of understanding/exploitation of the relationships quality of the resulting products is assured by repeated in-process and final products analysis i.e. QbA (Quality by Analysis). This is time consuming and expensive effort and lowers profits. It is manifestation of lack of command of the manufacturing process. If the processes were designed such process designers have total command of everything that happens and produces quality product no repeated analysis would be necessary i.e. it will be a QbD(Quality by Design) process. Even with this understanding readers who are more experienced and knowledgeable may be stymied by two alphabets that stand between “A” and “D”. They are “B” bureaucracy (regulators) and “C” concern for not following tradition ⁽²⁾.  

 

Value of taming of interaction and mutual behavior of chemical is incalculable as it has extremely high impact on manufacturing process, product quality and company profitability. Volumes have been written on the subject. Effort can significantly lower solvent emissions per kilo of active pharmaceutical ingredient (API) ^{(3, 4)}.Through publications attempt has been made share similar perspective ^{(5,6,7,8, 9)}. 

 

In order to capitalize on mutual behavior of chemicals one has to know and understand chemical and physical properties of every chemical used and produced in each reaction ^{(5,6,7,8, 9)}. Costs of raw materials and process have to be understood as they dictate the product economics. Familiarity with process equipment used is critical.

 

Process developers at the laboratory stage do not think and/or exploit chemical and physical properties in the laboratory. Purpose is to develop a laboratory process. Thought of scale-up and commercialization does not enter in the picture at this stage. Conservation regarding a manufacturing process which should begin at inception of the process development but generally is not a consideration ^{(5, 6, 7)}. Mass balance and mutual behavior of physical properties has to be understood. It is important as they lead to process optimization. Many developers are generally not familiar with manufacturing processes and product costs. 

 

As stated earlier thought of scale-up and commercialization does not enter in the picture at the laboratory stage. Imagination and experience in scaleup of a process can contribute. Involvement of Village ^{(5, 6, 7)} from process inception accelerates process development and commercialization. It is an opportunity that is generally ignored but needs to be considered. Following examples illustrate value of physical properties and their mutual behavior. They can be capitalized on to create excellent QbD processes. They have been reviewed ^{(5,6,7,8, 9)} and in other publications, too many to cite.    

Gabapentin:

 

Preparation of Gabapentin is an example of exploiting mutual behavior and physical properties. Its synthesis is illustrated in Figure 1 where mutual behavior of chemicals can be exploited. Review of the filed patent  US20080103334A1⁽¹⁰⁾ and other patents suggest solvent use. This is normal for every laboratory process development. 

 

Figure 1: Synthesis of  Gabapentin ⁽¹⁰⁾

Physical properties of the raw materials (Table 1) suggest that the solvent use can be minimized and/or eliminated. This proposition is based on a process that was commercial about seventy years ago, still in use, to produce a product of similar chemistry at an approximate rate of 1,600 kilos per hour operating about 7,140 hours per year (i.e. about 11,000 MT per year), a continuous process ^(5,11). Except for water no organic solvent was used.

 

Global demand for Gabapentin is about 3,135 MT per year ⁽¹²⁾. One or two plants can produce the product at about 220 kg/hour rate operating bout 7,140 hours per year. However, currently about 70 produce the global demand ⁽¹³⁾ operating limited hours per year. In their effort they most likely use and generate significant amounts of solvents per kilo of product and even after recovery and re-use have significant impact on our environment. Due to cGMP and cleaning practices asset utilization estimated at 50% on high side ⁽¹⁴⁾.

 

Chemical name	1,1-Cyclohexanediacetic Anhydride	1,1 Cyclohexane diacetic mono amide	1-(aminomethyl) cyclo hexaneacetic acid (Gabapentin)
CAS number	1010-26-0	99189-60-3	60142-96-3
Chemical Formula	C10H14O3	C10H17NO3	C9H17NO2
Molecular Weight	182.22	199.25	171.24
Melting Point, °C	70	145 -148	162-166
Boiling Point °C	126	443.6±18.0 predicted

 

Table 1: Properties of chemicals used and produced in Gabapentin

 

Process that is similar to the chemistry in Figure 1 had the anhydride fed as a melt with stoichiometrically controlled addition of liquid ammonia. Use of liquid ammonia eliminated water as a solvent. Melt acted as a solvent for the next step ⁽⁵⁾. Resulting amide was reacted with in-situ produced chlorine and feed stoichiometrically. Intermediate produced was converted to the product by stoichiometrically controlled acidification. Details are not discussed. 

 

Continuous conversion of 1,1-Cyclohexanediacetic Anhydride  to 1,1 Cyclohexane diacetic mono amide to produce Gabapentin would be an excellent and simple process. Its processing conditions will have to be optimized and can result in an excellent continuous process. Figure 2 is conceptual manufacturing process scheme for Gabapentin. Similar chemistries have been commercial. As stated earlier details are not discussed. 

Figure 2: Continuous Gabapentin Manufacturing Process

 

In the proposed continuous process 1,1-Cyclohexanediacetic Anhydride would be metered as a liquid along with liquid ammonia in required stoichiometric ratio. Formed amide would be converted to Gabapentin using chlorine based bleach that will be produced inline and fed to the reaction system. Chlorine based bleach is significantly cheaper than bromine based reactant. Bleach will have enough water to slurry the product for subsequent processing. The proposed process would need necessary development work to have an optimum process. Pfizer did attempt to green its batch process ⁽¹⁵⁾. 

 

Process for Piperine Intermediate:

Discussed below is an example two steps for the process to produce Piperine ⁽¹⁶⁾ intermediate, Figure 3. Chemistry and physical properties suggest that the first two steps could be a solventless process. Any astute chemist and chemical engineer should consider all liquid process to produce (2E)-1(piperidinyl)-2-buten-1-one which is a liquid.  

Figure 3: First two steps of USP 11,267,798 B2 ⁽¹⁶⁾

 

Chemical  Name	Crotonic acid	Thionyl Chloride	Crotonyl chloride	Piperidine	(2E)-1(1-piperidinyl)-2-buten-1-one
CAS Number	107-93-7	7719-09-7	10487-71-5	110-89-4	3626-69-5
Chemical Formula	C4H6O2	SOCl2	C4H5ClO	C5H11N	C9H15NO
Molecular Wt.	86	119	104.5	85	153
Melting Point, °C	70-73			-7	(-ve) 3-5
Boiling Point, °C	185	76	121-123	107	~295

 

      Table 2: Properties of chemicals used and produced in USP 11,267,798 B2 ⁽¹⁵⁾

 

Once the chemical physical and chemical properties of the reactants and intermediates are understood, it is very feasible to create a safe and simple commercial process. In every reaction step solubility and insolubility of chemicals used matters and attention has to be paid as it can lead to significant process optimization and reduction of solvent use leading to “Net Zero ^{(3, 4)}”. 

 

Most of the fine/specialty chemical and their subset API plants have sufficient idle equipment that can be assembled for batch or continuous processes. Creativity and imagination and Village’s ^{(5, 6, 7)} support would be needed. Yields of many products could be higher ^(9,17) and processes can be simplified. Effort will be necessary for innovation and better methods. 

If what all has been discussed ^{(5, 6, 7)} above is applied for product and process development any product that has an annual demand of about 50 to 100+ Metric Tonnes per year per site can be produced using a continuous process ^{(5, 11)}. A concerted effort would be needed. Solvent use could be reduced and overall productivity improved. Chemists and chemical engineers have to exploit and apply all of their knowledge and learning. Process design will require every bit of creativity, imagination to capitalize mutual behavior of chemicals used and produced ^{(5, 6, 18, 19, 20, 21)}. Using the methods reviewed above batch processes for new brand and generic products can be optimized along with lower commercialization time and will have lower “Net Zero” ^(3,4) impact than the current batch processes. Judicious ROI analysis will have to be done. Another benefit of such designs will be that product demands can be addressed very quickly resulting no or minimum shortages.

 As suggested earlier incorporation of the suggested/proposed methods is not going to easy. Traditions of the last seventy plus years used to manufacture API will come in the way. Desire to change has to come from within each company and has to be acceptable to the regulators who are not familiar with discussed chemical synthesis methods and manufacturing practices. My hope is that simplicity of processes and improved asset utilization will lead to consistently superior quality products and higher profits will be the driver for their adoption. Time will be the spokesperson.  

 

Girish Malhotra, PE

 

EPCOT International 

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

2.     Malhotra, Girish: Alphabet Shuffle: Moving From QbA to QbD - An Example of Continuous Processing, Pharmaceutical Processing, February 2009 pg. 12-13

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

4.     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

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

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

7.     Malhotra, Girish: Chapter 4 “Simplified Process Development and Commercialization”  Quality by Design-Putting Theory into Practice co-published by Parenteral Drug Association and DHI Publishing© February 2011 Accessed May 24, 2022

8.     Malhotra, Girish: Profitability through Simplicity June 15, 2023 Accessed May 24, 2023

9.     Malhotra, Girish: Considerations to Simplify Organic Molecule (API) Manufacturing Processes: My perspective, Profitability through Simplicity April 20, 2019 Accessed May 24, 2023

10.   Kumar, A. et. al. IPCA Laboratories Process for Synthesis of Gabapentin USP 20080103334A1, Published May 1, 2008 Accessed June 6, 2023 

11.   Continuous Production https://bit.ly/2Rp3Xlu Accessed June 5, 2023

12.   Kumar, S. Top Ten Most Produced API in India https://www.linkedin.com/posts/apibusinessanalyst_top-10-most-produced-apis-in-india-in-2022-activity-7068750309526781953-frPN?utm_source=share&utm_medium=member_desktop Accessed June 1, 2023

13.   Gabapentin Indian API Producers https://www.pharmacompass.com/active-pharmaceutical-ingredients/gabapentin, Accessed June 1, 2023  

14.   Benchmarking Shows Need to Improve Uptime, Capacity Utilization, https://www.pharmamanufacturing.com/articles/2007/144/ Sep 20, 2007, Accessed May 19, 2020

15.   Liam Tully, Green API Manufacturing, Pharmaceutical Technology, Volume 33, Issue 9, pp. 46-48 Accessed December 9, 2009

16.   Phull M.S. et. al. Process for the Preparation of Piperine US 11,267,798 B2 March 8, 2022 Accessed June 12, 2023

17.   Malhotra, Girish : Capitalizing on Mutual Behavior and Chemical Reactivity of Chemicals, Profitability through Simplicity, May 29, 2023 Accessed June 6, 2023

18.   Malhotra, Girish: Considerations to Simplify Organic Molecule (API) Manufacturing Processes: My perspective, Profitability through Simplicity, April 20, 2019 Accessed June 5, 2023 

19.   Malhotra, Girish: Review of Continuous Process for Modafinil, Continuous Processing in the Chemical and Pharmaceutical Industry II, 2009 AIChE Annual Meeting, November 10, 2009,Nashville, TN. 

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

21.   Malhotra, Girish: Art and Science of Chemical Process Development & Manufacturing Simplification, AIChE.org May 17, 2023 Accessed June 10, 2023