USP 11,267,798 B2: Manufacture of Piperine (1) An Excellent Teaching Tool

US patents that relate to fine/specialty chemicals are an excellent platform where their synthesis details are shared. Their manufacturing methods and details are left to the imagination of chemists and chemical engineers who take the synthesis route using unit processes ⁽²⁾ and appropriate unit operations ^(3,4) from the lab to the manufacturing floor. This tradition has been ingrained for the manufacture of fine/specialty chemicals that are used to enhance lifestyle as well as the chemicals that extend life. These are called active pharmaceutical ingredients (API) which are formulated to appropriate dispensable dose. However, there is a significant difference about the quality rigor each product has to follow. 

Fine/specialty chemicals that enhance life style have to meet their quality standards. API manufacturing methods have to meet stringent quality standards that are approved by regulatory bodies. This is necessary as they are used to cure diseases. Altering their manufacturing process can require companies to prove product efficacy and that can be an expensive time and money process. As a result API manufacturing process improvements are stalled and or even might not happen. How the API manufacturing processes are scaled up depends on individual company. Most of the API manufacturing patents detail the synthesis route and share clues and if capitalized on can lead to a very economic and environmentally friendly process that has low emissions ^{(5, 6)}.

Reviewing in-process patent filings and granted patents teach ways to review/learn chemical process synthesis and their manufacturing practices ⁽⁷⁾. 
 
The exercise here is not questioning the knowledge and skills of the people and/or the reaction scheme/process but how the information can be used to create simpler processes. Questioning and exploring what we do in the laboratory is and has been an excellent learning and gratifying process simplification tool, at least for me. I am sure others have similar experiences and come up with better and easier ways to simplify chemical synthesis and manufacturing. 
 
Generally majority of the chemical synthesis processes are fitted in the existing equipment. This is due to speed to market especially after API regulatory approval. Chemistries outlined in the patents give us the reaction mechanism for every reactive process. We can capitalize on that knowledge to commercialize using most appropriate unit operations ^(3,4) an economic and environmentally friendly process ^{(5, 6)} and move away from the traditions of the last SIXTY PLUS years. Modular plants or equipment of the size used in pilot plants might be the answer as only select number of APIs have the volume to have dedicated plants. This requires re-evaluation of fine/specialty chemical and API business model. Due to profitability and constantly changing API landscape and regulatory hurdles only an outlier company would be willing to step up to the challenge. Perspective presented is my own and not influenced by any for profit and/or nonprofit organization. 
 
Every reaction chemistry and synthesis process tells us how the product can be produced. Laboratory is its proving ground. Synthesis is demonstrated in the laboratory and commercialized by generally fitting it in the available existing equipment. This entails using excessive amounts of reactants and solvents. This is necessary for adequate mixing and heat transfer. Solvents, when feasible, are recovered and reused. As discussed later, creativity and imagination of the village ^{(8, 9, 10, 11)} for process simplification, reduced solvent use and the ensuing benefits need to be incorporated from the onset. 
 
Chemistries outlined in the patents give us the reaction mechanism for every/most reactive process. We can capitalize on that knowledge to commercialize using most appropriate unit operations ^(3,4) an achieve our environmental obligations ^{(5, 6)}.
 
USP 11,267,798 B2 ⁽¹⁾, luck of the draw, perfectly outlines the reaction chemistry and steps for the production of Piperine. Writing the reaction steps (Figure 1) is necessary as it familiarizes everyone with the reaction chemistry and the process. Reaction intermediates and byproducts are identified. Based on their chemical nature, methods for safe handling and disposal can be selected. Stoichiometry shared in the patent is just an example of what has been used to create a product and generally are not optimum.  
 
With creative application and combination of unit processes ⁽²⁾, unit operations ^{(3, 4)} and reaction kinetics ⁽¹²⁾ manufacturing process of piperine can be simplified. It is possible that the practitioner might have to move away from the tradition of moving away of fitting new reaction chemistries in the existing equipment. Such a move might necessitate deviating from tradition.  
 
Preparation of (2E)-1(1-piperridinyl)-2-buten-1-one (Example 1):
 
To a well stirred mixture of crotonic acid (100 gms, 1.16 moles) DMF (1.0 ml) in dichloromethane 500 ml was added thionyl chloride (100 ml, 1.34 moles) dropwise under N₂ atmosphere at 25-30° C. and stirred for 14 hours at 30-35° C. After completion, reaction mass was concentrated and diluted with MDC (1000 ml) and cooled to 0° C. Piperidine (310.0 ml, 3.15 moles) was added drop wise over a period of 3 hours below 10° C. The reaction mixture was then agitated at 25-30° C. for 7 hrs. After completion, the reaction mixture was filtered and filtrate was sequentially washed with water (2×500 ml), 5% dil. HCl 500 ml, 5% sodium bicarbonate (500 ml) and finally with brine solution (500 ml). Organic layer was evaporated to obtain title compound as dark brown colored oil.
 
Yield: 110.0 grams     HPLC Purity: 95%  Yield of Example 1 step: 61.9%

                                

Figure 1: Scheme 2: Synthesis of Piperine from Crotonic Acid USP 11,267,798 B2 ⁽¹⁾

 

Preparation of (2E)-1(1-piperridinyl)-2-buten-1-one (Example 2):

 

To a well stirred mixture of crotonic acid (50 gms, 0.580 moles) DMF (1.0 ml) in toluene (500 ml) was added thionyl chloride (50 ml, 0.670 moles) dropwise under N₂ atmosphere at 25-30° C. and stirred for 10 hours at 35-40° C. After completion of the reaction additional 250 ml toluene is added to reaction mass. Piperidine (150.0 ml, 0.500 moles) was added drop wise over a period of 3 hours below 10° C. The reaction mixture was then agitated at 25-30° C. for 7 hrs. The progress of the reaction was monitored by HPLC. After completion, the reaction mixture was filtered and filtrate was sequentially washed with water (2×250 ml), 5% dil. HCl (250 ml), 5% Sodium bicarbonate (250 ml) and finally with brine solution (250 ml). Organic layer was evaporated to obtain title compound as dark brown colored oil.

Yield: 65.0 gms     HPLC Purity: 95%.  Yield of Example 1 step: 73.2%

Preparation of Piperine (Example 3):

To a well stirred mixture of (E)-1-(Piperidin-1-yl) but-2-en-1-one (100.0 gm, 0.653 moles), benzyl triethyl ammonium chloride (27.0 gm, 0.118 moles) in DMSO (1000 ml) was added piperonyl aldehyde (88.0 gm, 0.586 moles) at 25-30° C. Aq. NaOH (4.7 gm 0.118 moles in 100 ml water) was added drop wise over a period of 45 min. The reaction mixture was then stirred at 25-30° C. for 12-15 hours. After completion of reaction it was quenched in water (5000 ml) and further stirred at 25° C. for 2.0 hrs. The precipitated solid was isolated by filtration, washed with water and dried under vacuum at 55-60° C. to yield title compound piperine as yellow solid.

The crude piperine was purified by crystallization from 500 ml toluene to obtain crystalline solid.

Yield: 89.0 gm.             HPLC Purity: 99.95% Yield of this step: 47.8%

 

Preparation of Piperine Example 8: 

 

To a well stirred mixture of (E)-1-(Piperidin-1-yl) but-2-en-1-one (225.0 gm, 1.468 moles), benzyl triethyl ammonium chloride (67.0 gm, 0.294 moles) in DMSO (2250 ml) was added piperonyl aldehyde (198.5 gm, 1.322 moles) at 25-30° C. The reaction mixture was stirred for 15-20 mins and aq. NaOH (24.0 gm 0.6 moles in 225 ml water) was added drop wise over a period of 45 min. The reaction mixture was then stirred at 25-30° C. for 5 hours. After completion of reaction it was quenched in water (6750 ml) and further stirred at 25° C. for 1.0 hr. The precipitated solid was isolated by filtration, washed with water and dried under vacuum at 55-60° C. to obtain title compound piperine as yellow solid.

Yield: 301.0 gm Yield of this step: 71.87% 

Depending on the route selected Piperine yield based on the above examples could be between 29.6 to 52.6% 

                        

Table 1: Physical Properties of chemicals used in the preparation of Piperine 

 

Analysis of Process Stoichiometry:

 

Information about the process similar to what is illustrated in Figure 1, Table 1 and Table 2 should be compiled for every process step and reaction chemistry. Figure 1 illustrates the reaction chemistry and is of utmost value. Using the information similar to figure 1 the developers can collect every physical and chemical property ^{(8, 9, 10, 13, 14, 15)} of the chemicals used and produced in each reaction step e.g. molecular weight, density, mutual solubilities, boiling/melting point, azeotropic behavior and viscosity etc. Compiled information facilitates every chemist and chemical engineer in creating an optimum process. They can also be considered and used to modify the process. 

 

Information is of utmost importance in the process design, handling, safety, storage and use. They teach us how the chemicals can and need to be handled at every process step. More we know about the chemicals used, intermediates and the final product produced, the task of scale up, design and commercialization becomes easier and is facilitated. Compilation of such information might be considered redundant but is of value and a treasure as long as the product is being produced by the company. Every chemist and chemical engineer can use the information. Using their creativity and imagination can optimize and economize the process. 

 

This information is also necessary for process simplification, design and improvement. It is very possible that some or many of the physical and chemical properties of the chemicals ^{(8, 9, 10, 13, 14, 15)} used and produced might not be readily available from the databases and/or vendors. They might have to be generated internally. A word of caution. Physical and chemical properties ^{(8, 9, 10, 13, 14, 15)} provided by the vendors need to be verified for accuracy. 

 

Table 2 is compilation of theoretical and actual amounts of key chemicals used to produce (2E)-1(1-piperridinyl)-2-buten-1-one and piperine. It lists mole ratios and yields relative to the crotonic acid, selected as the KEY component, in Example 1 and Example 2. Solvents are excluded. Example 2 has less than theoretical amount of piperidine per mole of crotonic acid but has higher yield. Yield variation between the two routes is significant and it suggests a review of the reported information and its validity. Molar ratios for the preparation of Piperine as also illustrated. 

 

Active reactants concentration in the total reaction mass is about 20% in each reaction. What can be done to conduct the reaction at higher concentration and what would be the result? Generally active concentration of key raw materials is low and that is based on tradition. Based on the chemistry and chemical engineering fundamentals and creativity alternates to do the reaction at higher concentrations ^{(8, 9, 10)} need to be explored and tested.  

 

Another word of caution when acquiring chemicals from different vendors. They generally want to know how and where their product will be used. General answer should be “chemical synthesis” rather than pharmaceutical. Some vendors even go to the extent of signing confidentiality agreements before Moment they know use of chemical is for a pharmaceutical synthesis, prices go up. Their rationale is pure chemical will produce higher purity product. This is not true as the product developer/producer will produce and process the product to meet their own specification. Supplier has to meet buyer needs to produce a product that meets their quality standards. Commercially available raw materials are competitively priced and generally suppliers make every effort to make a deal.  

 

USP 11,267,798 B2 ⁽¹⁾ suggests Piperine can be purified using toluene or isopropyl alcohol with yields ranging from 79.2-80.5%. This suggests that an optimum process can be developed. Every astute chemical engineer and chemist for the subject patent using unit operations ^{(3, 4)} can figure out how to handle evolved SO₂ and hydrochloric acid gas. Use of eductors and inline scrubbing is a possibility. Creativity and imagination is needed ⁽¹⁰⁾. 

 

Based on my experiences I would expect a reasonable excess of piperidine used per mole of crotonic acid for both examples. Molar ratios of piperidine to crotonic acid in examples 1 and 2 in Table 2 need scrutiny. Using different process schemes piperine overall yield varies between 29.6% to 52.6%. Village team members ^{(8, 9, 10, 11)} should review so much variation. My conjecture is that if they were involved from the onset the overall process yield higher than ~75% could be achieved. Even if the process is not going to be commercialized each chemical process development becomes a fertile training ground for excellence. 

Table 2: Relative ratio of key reactants

 

With the start of development process product cost analysis ^{(8, 9, 10)} of the wet chemistry is a very important exercise that needs to be done. Such exercise allows selection of the most profitable process. Again expertise of the village ^{(8, 9, 10, 11)}can be of great benefit for the process development chemists and chemical engineers as they select the most profitable process. Prices of each ingredient used in the illustrated examples are readily available. My crudest factory manufacturing cost ^{(8, 9, 10)}, without putting lot of effort, piperine factory should be less than $40 per kilo. If the conversion cost of any product is equal to or exceeds the raw material cost, it suggests that the commercialized process needs a rigorous review and redesign. Overall yield of less than 75% also suggests that the chemistry needs to be reviewed.   

Information similar to what is compiled in Table 2 can be used to understand what the patentee is citing in their granted or in-process patent. Compared to theoretical yield of a process chemistry, shortfalls of the process are highlighted right away. I am not a patent expert but based on the variations validity of the patent could be questioned. 

Generally when a process is experimented in the laboratory many overlook the fact that someday the process, if the product has high economic value, will be commercialized and the lab developed processes could pose commercialization challenges. Fundamentals of chemistry and chemical engineering have to be applied from the onset of process development to reduce/minimize process development time. To me laboratory is an important cog in the whole scheme. 

 

Expect for benzyl triethyl ammonium chloride (phase transfer catalyst) all of the organic chemicals used and produced are liquid at 40 ºC or above. Since the reactants and the reaction products are liquid at above 40 ºC, They present an opportunity to minimize solvent use in the reaction and present an opportunity to review the reaction stoichiometry to optimize the yield of each reaction step. 

 

Example 1 & 2 for the preparation of (2E)-1(1-piperridinyl)-2-buten-1-one give us clues. Boiling points of dichloromethane (~ 40 °C) and toluene (110 °C) can be used to advantage by raising the reaction temperature (taking advantage of doubling the reaction rate with every 10 °C rise in temperature ⁽¹²⁾. Every chemist and chemical engineer knows and practices associated value. Generally these considerations come in play only when village ^{(8, 9, 10, 11)} is involved from beginning of product and process development. Reduced reaction time impacts type of equipment used and its investment.  

 

Dichloromethane and toluene reactions are being conducted at room temperatures or near room temperatures for 10-15 hours suggest that value of reaction rate ⁽¹²⁾ is not part of the laboratory experiments. They present an opportunity. Are the low yields due to side reaction products being produced when the reactions are being carried out for prolonged time period? Potential of sequential reactions i.e. crotonic acid  crotonyl chloride (2E)-1(1-piperridinyl)-2-buten-1-one  piperine does exist and needs to be considered. At certain annual production volume a continuous manufacturing ⁽¹⁶⁾ is very possible.  

 

Some could easily say that when developing a laboratory synthesis process all of the information discussed above is not necessary. Some could say lab experiments just illustrate feasibility. Unless an outlier attempt is made from the onset, especially in the synthesis of active pharmaceutical ingredients no process simplification effort is made when a molecule enters regulatory filings. Village’s ^{(8, 9, 10, 11)} involvement is necessary and of great value. Low yield suggests many opportunities. Chemicals that enhance lifestyle have different quality needs and their processes can be continually improved. 

 

My conjecture is that if the laboratory syntheses can be simplified and commercialized the time and investment needed to improve the commercial processes can be significantly reduced. 

 

It is again emphasized that every nuance of the reaction and that includes how and where the chemicals are added, their physical properties ^{(8, 9, 10, 13, 14, 15)} i.e. melting point, boiling point, reaction temperature/s mutual solubilities and/or insolubilities can be exploited and capitalized on to create an excellent process. In the reviewed patent higher temperature reactions are eluded. From these claims it becomes obvious that the process chemistry was tested but the results are not known. Testing reaction at higher temperatures has to become a habit from the start of process development. Village ^{(8, 9, 10, 11)} helps in such exploitations. 

 

It is possible to use crotonic acid as a melt or a solution at appropriate temperature and thionyl chloride can be metered in stoichiometrically controlled amount. Availability of appropriate equipment has to be explored for every chemical manufacturing applications. We are generally not taught or are familiar with many of the equipment that is available from other industries and can be used in the manufacture of fine/specialty chemicals. 

 

In the first reaction step hydrochloric acid and sulfur-di-oxide are the reaction byproducts and have to be removed in a way that they do not impede reaction progress. How they would be removed are different for a batch or continuous process. 

 

It would be ideal if piperidine which is liquid at room temperature can be added sequentially to the reaction mass to produce (2E)-1(1-piperridinyl)-2-buten-1-one. Reaction temperature will have to be maintained at an appropriate temperature to assure all of the liquid mass is liquid. Benzyl triethyl ammonium chloride can be introduced as a solution. Based on the discussion one can conjecture that reaction mass is all liquid and is easy to process and flow control. Piperine being a solid at room temperature can be crystallized using most suitable crystallization process, separated and dried. 

 

Equipment size and processing methodology ^{(4, 8, 9, 11)} will dictate the selected method. Again, companies have to evaluate alternate processes and methods and that includes process equipment design and size to suit their technologies. Strategies that are different from the current methods that have not been considered need to be evaluated. Once we see the benefits of what all has been discussed process development and simplification methodologies become second nature. 

 

Information discussed and reviewed is necessary for process design, equipment design and troubleshooting needs that arise during the life of product being produced by the company. All of the compiled/documented information which includes rationale for its process design and operating methods becomes part of the process design manual, the “Holy Book” for that product. Information complied is also helpful for every regulatory filing, compliance, training and trouble shooting. 

Again, purpose of the analysis of USP 11,267,798 B2 is not to find errors in methods used by others but present my perspective and consider opportunities to optimize, have an excellent environmentally friendly and economic process. Creativity and ingenious application along with combination of chemical and physical properties ^{(8, 9, 10, 13, 14, 15)} and unit operations ^{(3, 4)} lead to excellent manufacturing processes ^{(8, 9, 10)}. This has been proven many times over and can repeated for every active pharmaceutical ingredient synthesis.

 

Girish Malhotra, PE

EPCOT International

1. Phull M. S. et. al. USP 11,267,798 B2 “Process for the Preparation of Piperine”, CIPLA Limited
2. Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem. 1954, 46, 4, 672
3. Unit Operations https://bit.ly/2Rp3Xlu
4. Chemical Engineer’s Handbook, Fourth Edition, McGraw-Hill Chemical Engineering Series
5. Burke, J. What does net zero mean? https://www.greenbiz.com/article/what-does-net-zero-mean, May 2, 2019 Accessed April 27, 2021 
6. 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
7. Malhotra, Girish: Patents: Should We Change Our Intellectual Property Model/Strategies? Profitability through SimplicityOctober 5, 2012  
8. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011 
9. 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
10. Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022
11. Kalam, APJ Abdul, Wings of Fire: An Autobiography of APJ Abdul Kalam, Sangam Books Ltd, 1999 Accessed January 31, 2024
12. Levenspiel, O: Chemical Reaction Engineering, John Wiley & Sons 1999
13. Malhotra, Girish: Sociochemicology May 30, 2013   
14. Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs. 63-66
15. Malhotra, Girish: Process Simplification and The Art of Exploiting Physical Properties, Profitability through Simplicity, March 10, 2017
16. Continuous Production https://bit.ly/2Rp3Xlu