On our day to day, we’re all used to ibuprofen: an over-the-counter analgesic that solves our daily headaches. Ibuprofen is the Active Pharmaceutical Ingredient (API) within the pills we take, meaning that is the compound that has a therapeutical effect. However, stand-alone ibuprofen faces some challenges: it’s difficult to dissolve in water, which affect its bioavailability and efficacy in the body. Like many things in life, ibuprofen gets better with a partner. It’s what we call a co-crystal: combining the API with another compound, that enhances its effect. The good news is that we have managed to produce a co-crystal of ibuprofen, at kilogram scale, using mechanochemical methods. Keep reading to know all the details!
Specifically, we have produced over 3 kg of rac-ibuprofen:nicotinamide using a drum mill, pioneering the use of this technique for pharmaceutical co-crystal synthesis. This achievement was recently published in the journal RSC Mechanochemistry. The full paper is available here.
Ibuprofen is a ubiquitous pain-relieving medication—so much so that the World Health Organization (WHO) has listed it as an essential medicine. However, it faces challenges due to its limited water solubility, low bioavailability, and sensitivity to heat.

“Its co-crystal formulation with nicotinamide has been extensively studied for improved physicochemical properties and therapeutic efficacy. Consequently, there is a need for alternative and more sustainable synthesis methods for this promising pharmaceutical co-crystal,” explains the first author of the study, Jan-Hendrik Schöbel, researcher in the group of Michael Felderhoff at the Max Planck Institute für Kohlenforschung (Germany). The Felderhoff group has been active in the field of mechanochemistry for many years and has recently also focused on scaling up mechanochemical processes.
In fact, we recently reported the first kilogram-scale batch synthesis of rac-ibuprofen:nicotinamide using an industrial eccentric vibratory mill. The paper was published in the journal ChemSusChem. Building on this study, we aimed to explore whether the synthesis of rac-ibuprofen:nicotinamide could also be achieved using a drum mill.
In Schöbel’s words: “In comparison to industrial eccentric vibratory mills, drum mills offer several noteworthy differences. For example, drum mills provide increased capacity, as industrial drum mills can handle much larger volumes of material. Additionally, they offer better energy efficiency, typically requiring less energy per unit of material processed compared to vibratory mills, especially at larger scales.”

Drum mills resemble a washing machine, but with metallic balls instead of water and dry compounds instead of dirty clothes. These devices are commonly used in mining, cement production, and other large-scale industrial processes. This means they are readily available industrial tools. So, demonstrating their use in the synthesis of pharmaceutical co-crystals, something that had not yet been explored, brings us one step closer to the industrial-scale production of these co-crystals.
In our work, we utilised a minimal amount of solvent—a technique known as liquid-assisted grinding (LAG). While we did not achieve optimal conversion results using only the milling balls, the LAG technique significantly improved the outcome. For this reason, a second experiment was conducted using LAG from the beginning of the milling process, leading to excellent results. The reaction was completed within 90 minutes and yielded 99%.
“This outcome is particularly impressive when compared to traditional solution-based methods, which often require large volumes of solvents and energy- and time-intensive processes,” says Schöbel.
“Our outcome is particularly impressive when compared to traditional solution-based methods, which often require large volumes of solvents and energy- and time-intensive processes”
Jan-Hendrik Schöbel, researcher at the Max Planck Institute für Kohlenforschung (Germany)
To this excellent result, we must add the high quality and stability of the co-crystals. 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. Due to stringent quality regulations on residual trace metal impurities in pharmaceutical products, the resulting impurities from the mechanochemical processes must also undergo rigorous scrutiny.
And, needless to say, that this is a greener approach to producing co-crystals. In contrast to conventional solution-based methods, which typically consume substantial amounts of solvents and energy, we present a more eco-friendly and efficient process.
In conclusion, our 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 and highlighting their potential applicability to larger industrial-scale operations.