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Thursday, March 3, 2022

Pharma’s Active Pharmaceutical Ingredient Manufacturing: Their Environmental Impact and Opportunities

Chemists and chemical engineers have their own perspectives when it comes to developing a process and commercializing it. It is interesting to note that same family fine/specialty chemicals and active pharmaceutical ingredients (API, a subset of fine/specialty family) have different techniques and strategies. Their development methodologies could be parallel but the pathways and results can be very different. Each could be quite simple and equally complex in their efforts to commercialize an economic process. 

Every company has to chart its own course, they feel comfortable with, for their profitability. However, with the recent limelight on “climate change” pharma companies will have to think and act differently from their practices when it comes to developing and commercializing a product. 

Purpose of this review is not to be critical or pick or choose what is the right product/process development strategy but to identify the opportunities that pharma could adopt and include to be proactive toward “climate change”. It well known that pharma has the highest emission factor among the chemical and related industries (1, 2)


Process Development:


Through analysis of a product’s chemistry existing landscape of an API is reviewed. Observations might not apply across the landscape but can be used as an example to improve the development of APIs. It is expected that this analysis will plant the seeds for the needed change that could lower pharma’s environmental impact (2). Change process and theri impact is not going to be instant. Considerable and ongoing effort will be needed. There is no financial relationship with any profit making and non-profit organization. 

I randomly selected molecule patented in US 10,669,279 B2 (3) and US 10,077,269 (4) for review. This molecule reduces the side effects (nausea, emesis, headaches and diarrhea) caused by COPD treatment using Roflumilat (Daliresp ®) and by Apremilast (Otzela ®) used for psoriatic arthritis (PA). Daily recommended dosage of this drug is 500 micrograms (COPD) and 60 milligrams (PA) respectively per day per year. COPD drug usage is in micrograms and that suggests that a separate tablet would have to be taken to counter the side effects. Same most likely would be true for Otezla. Since the invented drug will be new, based on pharma’s tradition of high pricing of any new drug, it is going to be multi folds expensive (5) compared to any existing drug that could be used to curb similar side effects. My expectation is that the company will do its best to expand market usage beyond these two diseases but the selling price can intervene wide spread usage.  


In the following example 1 of [USP ‘269 (3) and USP ‘279 (4) every chemist and chemical engineer will see that the process described is a laboratory synthesis and its translation to a commercial operation will be a challenge. Execution or scale up details are not discussed. Observations are made on solvent use and yield as they have environmental impact.

Fig. 1: Synthesis of Azetidin-1-yl[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone (3) (3, 4)


Step 1. Synthesis of ethyl imidazo[1,2-b]pyridazine-2-carboxylate (C1) 

A mixture of pyridazin-3-amine (20 g, 210 mmol) and ethyl 3-bromo-2-oxopropanoate (82 g, 420 mmol) in ethanol (300 mL) was heated at reflux for 16 hours. After removal of solvent via distillation, the residue was taken up in 2 M hydrochloric acid (100 mL) and washed with ethyl acetate. The aqueous layer was basified to a pH of approximately 8 via addition of aqueous sodium bicarbonate solution and then extracted with chloroform; this organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Eluent: 20% ethyl acetate in petroleum ether) afforded the product as a brown solid. Yield: 8.0 g, 42 mmol, 20%. LCMS m/z 192.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl3) .delta. 8.53 (s, 1H), 8.39 (dd, J=4.4, 1.6 Hz, 1H), 8.01-8.04 (m, 1H), 7.12 (dd, J=9.3, 4.4 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H). 

Step 2. Synthesis of ethyl 3-iodoimidazo[1,2-b]pyridazine-2-carboxylate (C2) 

N-Iodosuccinimide (24.6 g, 109 mmol) was added to a solution of C1 (19 g, 99 mmol) in acetonitrile (250 mL), and the reaction mixture was stirred at room temperature for 24 hours. Additional N-iodosuccinimide (1 equivalent after every 24 hours) was introduced and stirring continued for a further 48 hours (72 hours overall), until complete consumption of starting material was indicated via thin layer chromatographic analysis. After removal of solvent in vacuo, the residue was taken up in dichloromethane and washed with 1 M hydrochloric acid and with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure; silica gel chromatography (Eluent: 20% ethyl acetate in petroleum ether) provided the product as an off-white solid. Yield: 14.5 g, 45.7 mmol, 46%. LCMS m/z 318.0 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d6) .delta. 8.74 (dd, J=4.3, 1.3 Hz, 1H), 8.18 (dd, J=9.2, 1.4 Hz, 1H), 7.41 (dd, J=9.3, 4.4 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H). 

Step 3. Synthesis of ethyl 3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (C3) 

Aqueous sodium carbonate solution (3 M, 8.4 mL, 25 mmol) was added to a mixture of C2 (2.00 g, 6.31 mmol), (4-chlorophenyl)boronic acid (1.48 g, 9.46 mmol), and [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (382 mg, 0.505 mmol) in 1,4-dioxane (32 mL). The reaction mixture was heated at 90º C. overnight, whereupon it was partitioned between ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (3.times.150 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product. Yield: 1.25 g, 4.14 mmol, 66%. LCMS m/z 302.0, 304.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl3) .delta. 8.39 (dd, J=4.3, 1.5 Hz, 1H), 8.09 (dd, J=9.3, 1.5 Hz, 1H), 7.65 (br d, J=8.5 Hz, 2H), 7.50 (br d, J=8.5 Hz, 2H), 7.17 (dd, J=9.3, 4.3 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H). 

Step 4. Synthesis of 3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylic Acid, Sodium Salt (C4) 

A solution of C3 (1.75 g, 5.80 mmol) in methanol (25 mL) and tetrahydrofuran (25 mL) was added to an aqueous solution of sodium hydroxide (2 M, 25 mL), and the reaction mixture was stirred at room temperature for 4 hours. The resulting solid was collected via filtration and washed with cold water (2.times.25 mL) to provide the product as a solid. Yield: 1.50 g, 5.07 mmol, 87%. LCMS m/z 274.0, 276.0 [M+H].sup.+. 

Step 5. Synthesis of azetidin-1-yl[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone (3) 

Compound C4 (1.40 g, 4.74 mmol) was combined with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 2.92 g, 7.70 mmol) and N,N-diisopropylethylamine (3.56 mL, 20.4 mmol) in N,N-dimethylformamide (75 mL). After 2 minutes, azetidine hydrochloride (957 mg, 10.2 mmol) was added, and the reaction mixture was stirred at 50º C. overnight. After removal of solvent in vacuo, the residue was subjected to chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in heptane) followed by trituration with ethyl acetate (30 mL) at 50º C.; this mixture was cooled to 0º C. and filtered. The collected solid was washed with diethyl ether (50 mL) and with cold ethyl acetate (15 mL). Subsequent recrystallization from ethyl acetate provided the product as an off-white solid. Yield: 980 mg, 3.13 mmol, 66%. LCMS m/z 313.2, 315.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl3) .delta. 8.41 (dd, J=4.4, 1.6 Hz, 1H), 8.10 (br d, J=9.2 Hz, 1H), 7.75 (br d, J=8.6 Hz, 2H), 7.48 (br d, J=8.6 Hz, 2H), 7.19 (dd, J=9.2, 4.3 Hz, 1H), 4.46-4.57 (m, 2H), 4.17-4.28 (m, 2H), 2.28-2.39 (m, 2H). 


On review of the five process steps few things are very obvious. Excessive volumes and multiple solvents are being used at every step of each reaction along with low overall yield of Example 1 [about 3.48% = 0.2X0.46x0.66x0.87x0.66]. Such a low yield processes would be considered economically unviable process in fine/specialty chemical market. To every astute chemist and chemical engineer such yield numbers tell LOUD AND CLEAR that “the chemistry and the process needs help”. 


However, based on pharma’s practices of the last 70+ years, one can easily conjecture that the process chemistry developed in these patents has no consideration for their impact on climate change (1, 2), yield  (2), cost or pricing (5). Since the invented drug will be new, based on pharma’s tradition of high pricing of any new drug, it is going to be multi folds expensive compared to any existing drug that could be used to curb similar side effects. Drug based on this API might have features above and beyond what is currently on the market but unless the drug is acquired through a mutually subsidized healthcare system, it will be prohibitively expensive (5, 6) and on the verge of being unaffordable to large population. Actually selling prices of API and their formulations are a small percentage of the drug selling prices. 


In addition, for a pharmaceutical product, cGMP practices will have to be followed and that means extensive cleaning will be required for each step/batch. Volume of solvent used in most processes can make the process simplification and their reduction a challenge. High solvent use also results in poor asset utilization (7)


Patents USP ‘269 (3) and USP ‘279 (4) and every other API patent (brand or generic) present the following distinct opportunities. They can be considered and applied for every API synthesis. However, based on pharma’s tradition any such effort could be a challenge as process optimization is not an industry norm especially when the drug already has regulatory approval. 


1.     Yield improvement

2.     Solvent reduction

3.     Efficient asset utilization


If the average yield of each processing step in Example 1 of USP ‘269 (3) and USP ‘279 (4) is raised to 95% for each step, the overall process yield will be about 77.4% [0.95*0.95*0.95*0.95*0.95*= 0.774]. This will be about ~22 times higher than the overall yield from Example 1 of the reviewed patents. This would translate to significantly lower waste and reduction in number of solvents and their volume used in each step. All this will significantly improve the asset utilization and batch cycle times. Thus, there are opportunities for a green and economic process. Still, significant effort would be needed. 


For a low solvent use and higher overall yield process, every step of these patents will have to be redeveloped and optimized. These patents might be an extreme case but the thought can be extended to every brand and generic product API. Review of global patents could show many similar cases.  


Unless drastic changes are made to the USP ‘269 (3) and USP ‘279 (4) processes, my conjecture is that the process outlined if commercialized as is would exceed emission factor of 100 kg/kg (1, 2) for the product. Emission factor of 10 kg/kg of API could be set as a target across the board for API processes and formulations. Many camps could say that such a goal is impossible but unless we try it everything is impossible. Yoda has said it right “Do or do not, There is no try” (8). If pharma does not make an effort to do its part for climate change, its legacy for human health improvement would be irreparably tarnished. 


Effort has to be made from the onset of process development (9, 10, 11)  and has to be applied to every brand and generic API process development, their manufacture and formulations. If pharma does not include solvent reduction and yield improvement from inception of the process development, it is extremely difficult for the API manufacturer to do anything especially if the formulated API has been approved by regulatory bodies. No company wants to go through the expense and the time needed for re-approval. 


Analysis of patents of the most pharmaceutical companies suggest use of multiple solvents and recommend isolating intermediates for reuse. Isolation of solids adds to processing time and use of multiple solvents adds to what I call “separation complexity and anxiety”. Solvents have to be separated for re-use. Most process and product developers (chemists and chemical engineers) understand these scenarios but live with traditions. They have to challenge the current practices. They have to think that product being developed is their product and they have to manage the process in the plant. They would opt for simpler processes for manufacturing ease. Principles of chemistry and chemical engineering have to be applied for every process step. Unless the developers understand the operating challenges created by their processes not much progress will be made in the pharma product development. They have to adopt and rely on “nondestructive creation” practices (9)


API processes related to brand drugs are the most complex. Generics do simplify them but still not enough to minimize the environmental footprint. Pharma has to minimize its footprint and Emission Factor (1, 2). A total overhaul of its product development practices (9, 10, 11) is needed. Pharma will have to be mindfulness to its contribution to global warming which it has grossly neglected (1, 2). With emphasis being placed on “global warming”, it is time for the pharmaceutical industry to do its part and take on the responsibility lower its impact on climate change. Pharma will have also have to be mindful of the ecotoxicity of its effluent (12, 13). It has not paid much attention to it. It is time. There will be significant internal resistance. Regulators will be in a tizzy as they will lose the current stranglehold they have. 


Girish Malhotra, PE


EPCOT International 


1.   Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing (API) and Formulation Drive to NET ZERO (Carbon Neutral)? Profitability through Simplicity, April 29, 2021 Accessed January 24, 2022 

2.     Malhotra, Girish: Climate Change and Greening of Pharmaceutical Manufacturing, Profitability through Simplicity, January 24, 2022 accessed February 22, 2022

3.     Chapple et. al. US 10,669,279 B2 Pfizer Inc., Imidazopyridazine Compounds, Sept. 18, 2018 accessed Feb 22, 2022  

4.     Chapple et. al. US 10,077,269 B2 Pfizer Inc., Imidazopyridazine Compounds, June 2, 2020 accessed Feb 22, 2022

5.     Malhotra, Girish: Systematic Demystification of Drug Price Mystique and the Needed Creative Destruction, Profitability through Simplicity, October 2, 2019 Accessed February 25, 2022

6.     Malhotra, Girish: Opportunities to Lower Drug Prices and Improve Affordability: From Creation (Manufacturing) to Consumption (Patient), Profitability through Simplicity, March 9, 2018 Accessed February 28, 2022

7.     Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharma Manufacturing, Sep 20, 2007 Accessed January 18, 2022

8.     Yoda:  https://www.starwars.com/video/do-or-do-not Accessed February 27, 2022

9.     Malhotra, Girish K.: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation, https://www.degruyter.com/document/isbn/9783110702842/html April 2022

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

11. 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

12.   Larsson, D.G. Joakim et al. Effluent from drug manufactures contains extremely high levels of pharmaceuticals; Journal of Hazardous Materials, Volume 148, Issue 3, 30 September 2007,Pages 751-755 Accessed November 2007

13.  Malhotra, Girish: Pharmaceuticals, Their Manufacturing Methods, Ecotoxicology, and Human Life Relationship, Pharmaceutical Processing, November 2007, pgs. 24-26, Accessed August 10, 2009

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