PEER REVIEWED – Scaling Mechanochemistry via Continuous Bead Milling Technology

638

Introduction

Mechanochemistry offers a powerful and sustainable alternative to conventional solution-based chemistry, with the potential to fundamentally reshape chemical synthesis. By eliminating or drastically reducing the need for solvents, mechanochemical processes inherently minimize waste generation, simplify downstream purification, and align closely with the principles of green chemistry (1-5). Over the past decade, mechanochemistry has matured into an influential field at the interface of chemistry and materials science. As global priorities increasingly focus on sustainability and energy efficiency, mechanochemistry stands out as one of the most promising routes toward greener and more resource-efficient chemical manufacturing. Despite significant advances, the adoption of mechanochemistry in the pharmaceutical industry remains limited (6). Key barriers include challenges related to scalability, process robustness, economic viability, and compatibility with existing regulatory frameworks. Translating mechanochemical reactions from laboratory-scale experiments to industrial production introduces significant complexities (7,8). Maintaining reaction efficiency, managing heat dissipation, and ensuring uniform energy transfer across larger reaction volumes demand advanced and carefully engineered solutions.

Currently, exploratory mechanochemical transformations are conducted using small-scale milling devices, such as mixer or planetary ball mills, which apply mechanical force through the motion of grinding media (Figure 1). These systems generally operate at the gram scale, while larger-scale implementations, particularly for synthetic chemistry, remain scarce (7,8). In contrast, reactive extrusion enables continuous processing and offers flexible production capacities extending to manufacturing scale (Figure 1) (9-11). However, industrial experience with reactive extrusion in chemical synthesis remains limited, and direct translation of reaction conditions from ball mills to extruders is often challenging due to fundamentally different operating principles, energy inputs, and process parameters (7-11).

 

 

To unlock the full industrial potential of mechanochemistry, continued innovation in scalable instrumentation and process design is essential. In this context, bead milling emerges as a highly promising yet underexplored platform for mechanochemical activation. Agitator bead mills employ large numbers of grinding beads agitated within a confined chamber, delivering high and controllable energy input. Compared with conventional ball mills, agitator bead mills offer clear advantages in scalability, operational flexibility, and the ability to operate in both batch and continuous modes. While traditionally applied to particle size reduction in a variety of different areas (12-14), agitator bead mills share key technical similarities with small-scale mechanochemical systems while offering well-established industrial scalability.

 

Agitator bead milling technology

Most of the published bead milling work in the field of synthetic organic mechanochemistry has relied on the use of commercially available agitator bead mills (15). These systems typically comprise of a cylindrical grinding chamber packed with miniature grinding beads (∅ 0.05–1.0 mm beads) and equipped with a specialized agitation mechanism enabled by a rotating shaft (Figure 2). High rotational speeds set the beads in motion, generating a large number of collisions that provide the mechanical energy required for mechanochemical activation. The rapid rotation simultaneously propels the reaction mixture toward the outlet, where a sieve plate retains the beads, enabling continuous flow operation. By replacing the sieve with a screen plate, the mill can alternatively be operated in batch mode, in which the reactants are confined within the grinding chamber. A major advantage of these platforms is that industrial-scale versions of the same technology are commercially available for decades, facilitating straightforward scale-up without substantial changes to the underlying process characteristics (see below) (15).

 

 

Literature examples

Traditionally, bead milling has been applied to particle size reduction in sectors such as pigment dispersion, pharmaceuticals, nutrition, mineral processing, and nanomaterial fabrication (12-14). Despite these well-established applications, and in contrast to their apparent technical resemblance to small-scale ball mills, the potential of agitator bead mills to promote mechanochemical transformations has only recently begun to be explored (17-28). Reported applications in batch mode include, N-arylations (18), nitrations (19), and the two-step synthesis of paracetamol via a Beckmann rearrangement (20,21) (Figure 3, left column). A significantly higher throughput can be achieved by operating the agitator bead mill in single-pass continuous flow (or in recirculation) mode. Published examples related to the use of renewable resources are shown in Figure 3 (right column) and include the synthesis of solketal (22) and triactin (23) from glycerol, and the preparation of deep eutectic solvents (24), including their esterification (25). Additional reported examples describe the generation of vanillin from the biomass-derived feedstocks isoeugenol and vanillyl alcohol (26), the isomerization of glucose to fructose using a layered double hydroxide hydrocalumite catalyst (27) and the manufacturing of biodiesel employing a calcium diglyceroxide catalyst (28).

It should be noted that in mechanochemical transformations, small amounts of liquid additives, typically organic solvents, are often employed to enhance or control both reactivity and processability (1-5). This approach, known as liquid-assisted grinding (denoted as LAG in Figure 3), can improve mixing, facilitate mass transfer, and accelerate reaction rates through complex interactions (29).

 

 

Scaling amide bond formations from gram to kilogram scale

Amide bonds are vital structural motifs due to their exceptional stability and bioavailability, making them essential in both natural and synthetic biologically active molecules, particularly in pharmaceuticals. Given the critical importance of scalable, solvent-minimized approaches to amide bond formation, mechanochemical approaches that translate readily from gram scale to kilogram scale with little or no re-optimization are therefore of significant interest. As a model reaction we have chosen the amidation of 4-hydroxyphenylacetic acid with 3,5-dimethylaniline employing 1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride (EDC·HCl) as coupling agent, as its water solubility allows for easy removal of the urea byproduct, thus facilitating product isolation without any organic solvent needed (Figure 4a). The carboxylic acid, the aniline derivative, and the coupling agent were used in equimolar amounts to maximize atom economy and simplify work-up and purification. A small amount of EtOAc as a LAG additive was used (16).

The agitator bead mill employed for lab-scale experiments (DYNO-MILL Research Lab, Figure 4a) (15,16) featured a cylindrical silicon carbide grinding chamber and a specialized rotational grinding system (accelerator), mounted on a rotating shaft. The reaction mixture is continuously fed into the chamber via a feed screw, where it combines with a large number of miniature grinding beads (∅ 0.05–1.0 mm beads). The high rotational speed of the accelerator imparts motion to the grinding beads and creates a multitude of impacts, providing mechanochemical activation via shock, pressure, shear, friction, impact, and torsion, while constantly renewing the surface of the reactants. Additionally, strong turbulence further promotes excellent mixing and effective mass transfer within the reactor zone. The fast rotational movement continuously drives the reaction mixture toward the reactor outlet, where a sieve plate retains the grinding beads. The system was operated either in continuous single-pass mode or in recirculation mode, the latter achieved by redirecting the outlet flow back to the inlet funnel (Figure 2). Owing to their excellent mechanical properties and exceptional hardness (Mohs scale 9), yttria-stabilized zirconia beads (ZrO2/Y2O3; ∅ 0.8 mm) were selected as the grinding medium.

After initial optimization experiments on 1 mmol scale using a conventional mixer ball mill, the most suitable conditions were than translated to the DYNO-MILL Research Lab agitator bead mill (80 mL internal volume), employing single-pass experiments on 50 mmol scale, and finally recirculation experiments on a 1 mol scale (Figure 4b). Within just 5 min of recirculation, the experiments furnished 240.5 g (94%) of the amide product following a straightforward work-up involving precipitation with cold water, filtration, washing with water, and drying (16).

 

 

After careful consideration of safety aspects (10) and to achieve even higher throughput, the protocol was subsequently scaled to the kilogram level using an industrial-scale agitator bead mill. The scale-up campaign was conducted in two stages. First, a sixfold increase (5.7 mol) was accomplished on a pilot-scale instrument (DYNO-MILL UniLab, 0.5 L grinding chamber volume; Figure 4c). This was followed by a further fourfold scale-up (22 mol) using an industrial bead mill equipped with a 5 L grinding chamber (DYNO-MILL UBM5; Figure 4d). Notably, the pilot-scale system (0.5 L) was successfully operated in both recirculation and fully continuous single-pass modes, highlighting the flexibility and potential for further expansion of production capacity. Taking material consumption for these trails into account, the industrial-scale mill (5 L) was operated exclusively in recirculation mode; nevertheless, it delivered a productivity of ca. 65 kg/h. The reactions reached completion in the large-scale agitator bead mills without the need for reagent excess, added bases, or large volumes of organic solvents, thereby minimizing waste generation. This was reflected in E-factors below 2 and process mass intensities (PMIs) below 3 (30).

 

Conclusions and Future outlook

The findings presented in this work have highlighted bead milling as a sustainable and industrially relevant platform for continuous amide bond formation, combining high efficiency, minimal waste generation, and straightforward scalability. It has been demonstrated that the utilization of different sized agitator bead mills allows a seamless scale-up from lab to manufacturing scale with minimal re-optimization of reaction conditions changing from one platform to another, performing transformations either in recirculation of single-pass continuous mode. We are confident that these principles can be extended to a large variety of different mechanochemical processes, and investigations along these lines are currently being investigated in our laboratories in close collaboration with industrial partners. At the moment, no direct comparisons between different technologies used for scaling mechanochemistry (i.e., bead milling, reactive extrusion or resonant acoustic mixing) with respect to energy efficiency, operational cost, or process safety can be made due to lack of data (5,8,10).

Regardless of the technology chosen, the development of scalable mechanochemical protocols will in the not too distant future enable more efficient manufacturing processes with reduced waste, shorter processing times, and lower costs.

 

References and notes

1. Do JL, Friščić T. Mechanochemistry: a force of synthesis. ACS Cent. Sci. 2017;3:1319. https://doi.org/10.1021/acscentsci.6b00277−
2. Howard JL, Caoa Q, Browne DL. Mechanochemistry as an emerging tool for molecular synthesis: what can it offer. Chem. Sci. 2018;9:3080–3094. https://doi.org/10.1039/C7SC05371A
3. Hwang S, Grätza S, Borchardt L. A guide to direct mechanocatalysis. Chem. Commun. 2022;58:1661−1671.
   https://doi.org/10.1039/D1CC05697B
4. Cuccu F et al. Mechanochemistry: new tools to navigate the uncharted territory of “impossible” reactions. ChemSusChem 2022;15:e202200362. https://doi.org/10.1039/D1CC05697B
5. Stolar T et al. Mechanochemistry: looking back and ahead. Chem 2026;12:102880. https://doi.org/10.1016/j.chempr.2025.102880
6. Haneef J, Ali S. Medicinal mechanochemistry: sustainable and efficient route towards synthesis of active pharmaceutical ingredients. Sustain. Chem. Pharm. 2025;45:102044. https://doi.org/10.1016/j.scp.2025.102044
7. Colacino E, Isoni V, Crawford D, García F. Upscaling mechanochemistry: challenges and opportunities for sustainable industry. Trends Chem. 2021;3:335−339. https://doi.org/10.1016/j.trechm.2021.02.008
8. Reynes, JF, Isoni V, García F. Tinkering with mechanochemical tools for scale up. Angew. Chem. Int. Ed. 2023;62:e202300819. https://doi.org/10.1002/anie.202300819
9. Bolt RRA, Leitch JA, Jones AC, Nicholson WI, Browne DL. Continuous flow mechanochemistry: reactive extrusion as an enabling technology in organic synthesis. Chem. Soc. Rev. 2022;51:4243−4260. https://doi.org/10.1039/D1CS00657F
10. Atapalkar RS, Kulkarni AA. Batch and continuous flow mechanochemical synthesis of organic compounds including APIs. React. Chem. Eng. 2024;9:10−25. https://doi.org/10.1039/D2RE00521B
11. Freisa P, Lattuada L, Barge A, Cravotto G. Flow-through mechanochemical synthesis by reactive extrusion. RSC Mechanochem. 2026;3:144-160. https://doi.org/10.1039/D5MR00097A
12. Knieke C. et al. Nanoparticle production with stirred-media mills: opportunities and limits. Chem. Eng. Technol. 2010;33:1401−1411. https://doi.org/10.1002/ceat.201000105
13. Tanaka H, Ochii Y, Moroto Y, Ibaraki T, Ogawara, K. Development of novel bead milling technology with less metal contamination by pH optimization of the suspension medium. Chem. Pharm. Bull. 2021;69:81–85. https://doi.org/10.1248/cpb.c20-00623
14. Guner G et al. Do mixtures of beads with different sizes improve wet stirred media milling of drug suspensions? Pharmaceutics 2023;15:2213. https://doi.org/10.3390/pharmaceutics15092213
15. DYNO-MILL Research Lab (WAB-GROUP, Switzerland): https://www.wab-group.com/en/products/dyno-mill-research-lab/
16. Caboni P, Porcheddu, A, Ötvös, SB, Kappe CO. Scalable mechanochemical synthesis of amides using bead milling technology. Green Chem. 2026;28: 2049−2055. https://doi.org/10.1039/D5GC04764A
17. Martín-Perales AI, Balu AM, Malpartida I, Luque R. Prospects for the combination of mechanochemistry and flow applied to catalytic transformations. Curr. Opin. Green Sustain. Chem. 2022;38:100714. https://doi.org/10.1016/j.cogsc.2022.100714
18. Guha G, Mariaux R, Crochet A, Gremaud L Mechanochemically accelerated N‑arylation: a scalable and solvent-minimized approach bypassing friction sensitive reagents. ACS Sustainable Chem. Eng. 2026;14:437−449. https://doi.org/10.1021/acssuschemeng.5c10214
19. Valsamidou V et al. Mechanochemical nitration of arenes and alcohols using a bench-stable organic nitrating reagent. Green Chem. 2025;27:7122–7128. https://doi.org/10.1039/D5GC02232K
20. Geib R, Colacino E, Gremaud L. Sustainable Beckmann rearrangement using bead-milling technology: the route to paracetamol. ChemSusChem 2024;17:e202301921. https://doi.org/10.1002/cssc.202301921
21. A 3+2 cycloaddition example has also been reported: Singh S. et al. Metal- and base-free spirocyclization of alkylidene oxindoles via photo- and mechanochemicallygenerated nitrile ylides and nitrile imines as 1,3-dipoles. Org. Chem. Front. 2025;12: 4698–4707. https://doi.org/10.1039/D5QO00851D. For a recent example involving pyridine ylides, see: Bera S et al. Harnessing pyridinium ylides for ionic cascades provides a scalable mechanochemical route to azaindazoles and related heterocycles. Cell Rep. Phys. Sci. 2026;7: https://doi.org/10.1016/j.xcrp.2026.103098
22. Nguyen R, Haloumi S, Malpartida I, Len C. Impact in continuous flow heated mechanochemical technology: an improved solketal synthesis. J. Flow Chem. 2025;15:1–9. https://doi.org/10.1007/s41981-024-00339-8
23. Nguyen R, Halloumi S, Malpartida I, Len C. Solvent-free production of triacetin from glycerol through complementary mechanochemical, biphasic, and catalytic approaches using ICHeM technology. Org. Process Res. Dev. 2025;29:769−777. https://doi.org/10.1021/acs.oprd.4c00501
24. Nguyen R, Auvigne A, Pérez Merchán AM, Malpartida I, Len C. New high-throughput mechanochemical assisted continuous flow for the formation of deep eutectic solvents. Org. Process Res. Dev. 2024;28: 3560−3569. https://doi.org/10.1021/acs.oprd.4c00079
25. Liu Q et al. Biphasic continuous esterification of choline chloride-based deep eutectic solvents using ICHEM technology: a step toward new hydrotropes with potential anticorrosive properties. Chem. Eur. J. 2025;31:e01702. https://doi.org/10.1002/chem.202501702
26. Martín-Perales AI et al. Continuous flow catalyst-free mechanochemical conversion of isoeugenol and vanillyl alcohol for vanillin production: from lab experiments to scaled-up premises. Ind. Eng. Chem. Res. 2023;62:17545−17552. https://doi.org/10.1002/chem.202501702
27. Pérez‑Merchán AM et al. Flow semi‑continuous mechanochemistry as a versatile and efficient tool for the synthesis of hydrocalumite and the isomerization of glucose to fructose, Top. Catal. 2025;68:126–140. https://doi.org/10.1007/s11244-024-02001-y
28. Malpartida I et al. Semi-continuous mechanochemical process for biodiesel production under heterogeneous catalysis using calcium diglyceroxide. Renew. Energy 2020;159, 117-126. https://doi.org/10.1016/j.renene.2020.05.020
29. Breinsperger J, Podlesnik N, Mele M, Schnürch M. Silent partners in the mill: unveiling the role of additives in mechanochemical synthesis. https://doi.org/10.1002/chem.202503536
30. Banderob K, Roth P, Caboni P, Kappe CO, Ötvös SB, manuscript in preparation