Chemistry

Drum Mill achieves kilogram-scale ibuprofen synthesis with environmentally friendly technology

Co-crystal powder (rac-ibuprofen nicotinamide) and milling ball IMPACTIVE. Credit: Jan-Hendrik Schöbel

For the first time, researchers have used a drum mill to produce kilograms of ibuprofen-nicotinamide, a formulation that improves therapeutic efficacy and stability. This is part of the European project IMPACTIVE, which focuses on researching mechanochemical methods to make pharmaceutical manufacturing more sustainable and reduce both carbon emissions and chemical waste. The team has now produced over 3 kilograms of racemic ibuprofen-nicotinamide co-crystals, pioneering the use of this environmentally friendly technology for large-scale synthesis.

Ibuprofen is a ubiquitous painkiller listed on the World Health Organization’s (WHO) list of essential medicines. However, they face challenges due to limited water solubility, low bioavailability, and heat sensitivity.

“Ibuprofen-nicotinamide cocrystals have been extensively studied for improved physicochemical properties and therapeutic efficacy. As a result, more sustainable synthetic methods are needed for this promising pharmaceutical formulation,” said RSC Machinery. explains Jan Hendrik Schobel, lead author of the chemical study. He is also a researcher at the IMPACTIVE partner, the Max Planck Institute Köhrenforschung Institute (Germany).

This further builds on recent results by researchers at IMPACTIVE, who recently reported the first kilogram-scale batch synthesis of ibuprofen nicotinamide cocrystals using an industrial eccentric vibration mill. This equipment, along with drum mills, is common in mechanochemical synthesis, avoiding the use of solvents and reducing environmental impact compared to traditional solution-based synthesis. Their research is published in ChemSusChem.

A drum mill consists of a rotating drum with metal balls inside, which crushes dry compounds by impact and friction. These devices are commonly used in industries such as mining, cement production, and other large-scale processes, making them readily available tools. This work demonstrates the potential of drum mills in the large-scale synthesis of pharmaceutical cocrystals, a previously unexplored application, and brings mechanochemistry closer to industrial-scale production of these cocrystals.

“Compared to industrial eccentric vibratory mills, drum mills have several notable advantages,” explains Schobel. “For example, industrial drum mills will have increased capacity to process much larger quantities of material. Additionally, they will be more energy efficient, especially at larger scale.”

In this study, the IMPACTIVE team used a minimal amount of solvent in the mill, known as liquid-assisted grinding (LAG). LAG has significantly improved dry mix milling results and optimal conversion, delivering superior results with record efficiency. The reaction was completed within 90 minutes with a yield of 99%.

“This result is especially impressive when compared to traditional solution-based methods, which often require large amounts of solvent and energy-intensive and time-consuming processes,” Schobel said.

A ball mill produces kilograms of ibuprofen, a record of pioneering and environmentally friendly technology

Drum mill (RETSCH TM 300) used by IMPACTIVE in this study. Credit: Jan-Hendrik Schöbel

Moreover, the cocrystals produced by mechanochemistry are of higher quality and stable. Metal contamination due to abrasion of the grinding media during synthesis is also minimal, with levels well within acceptable regulatory standards for daily intake. This is highly relevant for commercialization because of the restrictive regulations on residual trace metal impurities in pharmaceutical products that have been put in place to ensure consumer safety.

In conclusion, this study provides proof of concept for the use of drum mills in mechanochemical processes for the production of pharmaceutical co-crystals, demonstrating success at the kilogram scale with related ibuprofen formulations, and overall We highlight the promising potential applicability to industry. scale operation.

This pioneering work, coordinated by IMPACTIVE, represents a greener approach to producing cocrystals. In contrast to traditional solution-based methods that consume large amounts of solvent and energy, mechanochemistry offers an environmentally friendly and efficient alternative.

Further information: Jan-Hendrik Schöbel et al., Mechanochemical kilogram-scale synthesis of rac-ibuprofen:nicotinamide cocrystals using a drum mill, RSC Mechanochemistry (2024). DOI: 10.1039/D4MR00096J

Alexander Bodach et al, Scalability of mechanochemical pharmaceutical cocrystal formation in batches, ChemSusChem (2023). DOI: 10.1002/cssc.202301220

Source: Drum Mills Achieves Kilogram-Scale Ibuprofen Synthesis with Green Technology (January 16, 2025) from https://phys.org/news/2025-01-mills-kilogram-scale-ibuprofen-Synthetic.html 2025 Retrieved January 19th

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