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