Ball mills make kilograms of ibuprofen, a record for a pioneering and greener technique

For the first time, researchers used drum mills to make kilograms of ibuprofen-nicotinamide, a formulation that improves therapeutic efficacy and stability. This is part of European project IMPACTIVE, focused on studying mechanochemical methods to make pharma manufacturing more sustainable, reducing both carbon emissions and chemical waste. Now, the team have produced over 3 kilograms of racemic ibuprofen-nicotinamide co-crystals, pioneering the use of this green technique for large-scale synthesis.

Ibuprofen is a ubiquitous pain-relieving medication, listed in the essential medicines list by the World Health Organization (WHO). However, it faces challenges due to its limited water solubility, low bioavailability, and sensitivity to heat.

“The ibuprofen-nicotinamide co-crystal has been extensively studied for its improved physicochemical properties and therapeutic efficacy. Consequently, we need more sustainable synthetic methods for this promising pharmaceutical formulation,” explains Jan-Hendrik Schöbel, the first author of the study and a researcher at IMPACTIVE partner the Max Planck Institute für Kohlenforschung (Germany).

This further builds on recent results by IMPACTIVE researchers, who recently reported the first kilogram-scale batch synthesis of ibuprofen nicotinamide co-crystals using an industrial eccentric vibratory mill. This device, along with drum mills, is common in mechanochemical synthesis, which, compared to traditional solution-based synthesis, avoids the use of solvents and reduces the ecological impact.

Drum mills consist of a rotating drum with metallic balls inside, which grind dry compounds through 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 study demonstrates the possibilities of drum mills for the large-scale synthesis of pharmaceutical co-crystals, a previously unexplored application, bringing mechanochemistry closer to the industrial-scale production of these co-crystals.

“In comparison to industrial eccentric vibratory mills, drum mills offer several noteworthy advantages,” explains Schöbel. “For example, industrial drum mills provide an increased capacity to handle much larger volumes of material. Additionally, they offer better energy efficiency, especially at larger scales.”

In this study, the IMPACTIVE team used a minimal amount of solvent inside the mill, which is known as liquid-assisted grinding (LAG). LAG significantly improved the outcome and optimal conversion of a dry mixture milling, leading to excellent results with record-breaking efficiency. The reaction was completed within 90 minutes with a yield of 99%.

“This outcome is particularly impressive when compared to traditional solution-based methods, which often require large volumes of solvents, as well as energy- and time-intensive processes,” says Schöbel.

In addition, the co-crystals produced with mechanochemistry are of higher quality and stability. They also exhibit minimal metal contamination from the abrasion of the milling media during synthesis, with levels well within acceptable regulatory standards for daily intake. This is highly relevant towards commercialisation, due to the restrictive regulations on residual trace metal impurities in pharmaceuticals, created to ensure consumer safety.

In conclusion, the present 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 a relevant ibuprofen formulation, overall highlighting a promising potential applicability to larger industrial-scale operations. This pioneering work, co-ordinated by IMPACTIVE represents a greener approach to producing co-crystals. In contrast to conventional solution-based methods, which consume substantial amounts of solvents and energy, mechanochemistry offers an eco-friendly and efficient alternative.

About IMPACTIVE

IMPACTIVE is a European project funded by the European Commission, aimed at reinventing and strengthening the pharmaceutical supply chain through mechanochemistry. The consortium comprises 17 partners spanning 11 countries, led by the University of Montpellier in France.

Mechanochemistry is a technique that involves grinding and mashing molecules together. The mechanical force induces chemical reactions with high efficiency and low cost. The primary advantage of mechanochemistry is its independence from solvents, which are typically the foundation of traditional reactions and are often associated with high quantities of toxic waste. Eliminating solvents from synthesis and purification processes could significantly reduce the ecological impact of industrial chemistry.

More info: www.mechanochemistry.eu

About mechanochemistry

In recent decades, mechanochemistry has made a resurgence in academic laboratories. Mechanochemistry makes reactions happen by mechanical force and, although it's probably one of the oldest forms of chemistry, it's often overlooked by the industry. It's all about grinding compounds, literally mashing molecules together, which avoids high temperatures and solvents, and offers more environmentally friendly alternatives to traditional routes. Additionally, sometimes mechanochemistry methods give access to new transformations, inaccessible and unfeasible via conventional chemistry. Transferring mechanochemistry to the pharmaceutical industry could streamline processes, reducing the environmental impact of reactions and maximising atom-economy and efficiency.

How does mechanochemistry work? Molecules react when they impact on each other. Usually, this happens in solution, and molecules make contact aided by agitation, temperature, pressure, or a combination of these. In mechanochemistry, molecules are mashed together using tools like ball mills or extruders. In this case, the main driver of chemical reactions is mechanical force. Some sectors in the chemical industry already used this approach in their day-to-day to manufacture pigments, dyes, agrochemicals, and other substances. However, the pharmaceutical industry is still far behind, despite many successful examples published in papers.

While traditional chemistry happens in big reactors that contain solvents and reagents, mechanochemistry uses devices like ball mills or extruders. These have been widely developed by other industries, including the producers of plastics and polymers and even bakers and bread-makers. Mills and extruders excel at grinding, mashing, and pressing things together. Additionally, extruders offer advantages like the possibility to work in continuous mode and excellent temperature control. Other experimental techniques in mechanochemistry include using soundwaves, shockwaves, and others.

More info about mechanochemistry: https://mechanochemistry.eu/wp-content/uploads/2025/01/IMPACTIVE-in-a-nutshell.pdf

References

“Mechanochemical kilogram-scale synthesis of rac-ibuprofen:nicotinamide co-crystals using a drum mill.” RSC Mechanochemistry, 2025, DOI: 10.1039/D4MR00096J

“Scalability of Pharmaceutical Co-Crystal Formation by Mechanochemistry in Batch.” ChemSusChem, 2024, 17, 6, e202301220, DOI: 10.1002/cssc.202301220