Discover more sustainable alternatives in the synthesis and API landscape.
In recent years, there has been a significant surge in efforts to explore greener, more sustainable solvents in pharmaceutical manufacturing. The primary factors driving this interest include legislative regulations aimed at increasing industrial sustainability and the need to reduce the global carbon footprint. Many of these objectives align with the United Nations Sustainable Development Goals (SDGs). However, solvents are just one component of a product’s lifecycle. Energy, water, production time, and disposal of the solvent must be considered as well.
Synthesising active pharmaceutical ingredients (APIs) requires a series of complex chemical reactions and large quantities of solvents. Major pharmaceutical companies can each produce anywhere from 3,000 to 6,000 metric tonnes of hazardous waste per year, with solvents accounting for most of this waste by volume. Several companies have developed methods for solvent recycling and recovery. However, what would happen if greener solvents were used at the very first synthesis step? What if the process started with a solvent that has better biodegradability, lower volatility, and less toxicity, while still providing the same, if not better, yield?
Industry insights: A dialogue on sustainable API manufacturing
To delve into the challenges and opportunities within sustainable API manufacturing, we spoke with Dr Hashim Javaid, IMCD International Technical Manager for Synthesis, and Dr Cristina Martí, Director of API Sales and Strategy at IMCD Group.
HJ: Industry experts agree that API manufacturing could become significantly greener if environmental considerations were integrated from the very start of the process, rather than focusing on solvent recovery later in the game. Solvent selection is often a key consideration. Emerging neoteric solvents that are more environmentally friendly compared to commonly used dipolar aprotic solvents such as DMF, DMAc, and NMP have become of increasing interest to researchers.
CM: Many originators and an increasing number of generic companies have a green, sustainable agenda. Some have already achieved notable breakthroughs, though most are still in the early stages. For instance, Pfizer has developed a green route for the synthesis of pregabalin, reducing the use of almost 38 million litres of alcoholic organic solvents and nearly 2,000 metrics tonnes of raw materials on an annual basis. Similarly, GSK has announced a new reaction for paroxetine, leading to a process that is not only greener but also more cost-efficient, with nearly double the yield compared to conventional methods. Additionally, when sertraline hydrochloride (also known as Zoloft) was synthesised using a greener route, the removal of metal salts and the use of a Pd/C catalyst resulted in a more selective and environmentally friendly process.
IMCD Greener Solutions
HJ: Sustainable APIs start with sustainable reactions. Through IMCD’s Greener Solvents Seminar, we offer alternatives to some of the potentially toxic or environmentally harmful solvents commonly used in chemical synthesis today. For example, as replacements to DMAc, DMF, or NMP, emerging neoteric dipolar aprotic solvents such as GVL and NBP could be considered, or the more established DMSO, which is now gaining new interest as a sustainable alternative, particularly for solid-phase peptide synthesis.
Similarly, in place of THF, there is growing interest in CPME, MeTHF, and MTHP, which have the potential to beneficially impact lithiation chemistry. Here, reactions can be conducted at -20oC versus the traditional -70oC in THF with little loss in yield, thereby reducing energy consumption and solvent wastage.
The first step towards green API manufacturing could be as simple as reducing the number of reactions and isolations required to produce a given molecule. Fewer steps mean less solvent to recover and dispose of. The second step could be to replace volatile harmful solvents and dangerous reagents with those that are better for the environment. It is recognised that making a process greener is seldom enough to persuade a manufacturer to alter an established production process. The time, expense, and regulatory filings needed to change an established manufacturing process can be daunting. However, bringing greener solutions into the API manufacturing process from the outset can drive the development of the more sustainable APIs of the future.
Get in touch with us today to start a conversation about how we can help you advance innovation in sustainable pharmaceutical manufacturing.
References:
Replacement of Less-Preferred Dipolar Aprotic and Ethereal Solvents in Synthetic Organic Chemistry with More Sustainable Alternatives
Andrew Jordan, Callum G. J. Hall, Lee R. Thorp, and Helen F. Sneddon
Chemical Reviews 2022 122 (6), 6749-6794
DOI: 10.1021/acs.chemrev.1c00672