Pharmaceutical co-crystallization is an innovative method to improve the chemical properties, such as solubility and stability of active pharmaceutical ingredients. This approach is particularly valuable for enhancing the performance of poorly soluble drugs.
In a recent study published in RSC Mechanochemistry, researchers from the Max Planck Institute for Coal Research in Germany investigated the synthesis of racemic ibuprofen:nicotinamide (rac-IBU:NIC) co-crystals through a mechanochemical process using an industrial drum mill.
By employing liquid-assisted grinding, the researchers demonstrated the feasibility of large-scale production with minimal solvent use and highlighted the potential for sustainable, greener alternatives in pharmaceutical manufacturing.
Study: Mechanochemical kilogram-scale synthesis of rac-ibuprofen:nicotinamide co-crystals using a drum mill. Image Credit: Doucefleur/Shutterstock.com
Background
Co-crystals are becoming increasingly important in the pharmaceutical industry due to their ability to modify the mechanical and physicochemical properties of active pharmaceutical ingredients and address challenges such as poor solubility, fragility, and polymorphism. These crystalline structures consist of an active pharmaceutical ingredient and a coformer linked by supramolecular interactions.
For example, the co-crystallization of ibuprofen, a widely used pain-relief medication, with nicotinamide improves its solubility and bioavailability without compromising its therapeutic efficacy. However, traditional synthesis methods rely heavily on energy-intensive processes and use organic solvents, raising concerns about safety, cost, and environmental impact.
Mechanochemistry, which drives chemical reactions using mechanical forces, offers a promising alternative by enabling solvent-free or solvent-minimized synthesis. Although mechanochemical methods have been explored at smaller scales, industrial-scale applications remain underdeveloped.
Given the pharmaceutical industry's increasing emphasis on sustainability, there is a pressing need to explore scalable, eco-friendly mechanochemical processes that reduce solvent consumption and energy requirements and provide greener drug manufacturing technologies.
About the Study
The present study utilized a drum mill to synthesize rac-IBU:NIC co-crystals at a kilogram scale. The scientists combined a 1:1 mixture of racemic ibuprofen and nicotinamide with stainless steel grinding media in a drum mill of approximately 14-liter capacity.
They began with performing neat grinding at 60 revolutions per minute, a speed that was calculated to be 78% of the critical speed for effective milling. The process was monitored using differential scanning calorimetry (DSC), which indicated co-crystal formation within 30 minutes.
To address challenges such as substrate adhesion to the drum walls, they then employed liquid-assisted grinding. Ethanol was introduced as an additive, which was found to improve the reaction efficiency dramatically. The co-crystals were then separated from the grinding media through sieving.
The study also included the characterization of the synthesized co-crystals using powder X-ray diffraction and DSC. Additionally, the researchers employed inductively coupled plasma optical emission spectrometry to carry out trace metal analysis to assess the contamination from the grinding media.
They aimed to demonstrate that the drum mill was a cost-effective and sustainable alternative for producing pharmaceutical co-crystals with potential applications in large-scale industrial settings.
Key Findings
The study showed that rac-IBU:NIC co-crystals can be efficiently synthesized using a drum mill, achieving high purity and yield.
Liquid-assisted grinding using ethanol was shown to significantly improve reaction efficiency, reducing processing time from 540 minutes to 90 minutes. The final product yielded 99% pure co-crystals, which were easily recovered by sieving.
Furthermore, DSC and powder X-ray diffraction analyses confirmed the complete conversion of the starting materials into co-crystals, with no residual components or additional crystalline phases.
The researchers also performed stability tests, which showed that the co-crystals retained their integrity and crystallinity after six months of storage under ambient conditions, demonstrating their robustness for potential pharmaceutical applications.
Additionally, trace metal analysis revealed minimal contamination from the grinding media. The levels of aluminum, iron, and other metals were significantly lower than those observed in previous mechanochemical processes and remained well below the regulatory limits for pharmaceuticals. The researchers attributed the lower metal abrasion levels to the reduced mechanical energy input of the drum mill.
The study also highlighted the scalability of this method, with a process that is operationally simple and environmentally sustainable. The addition of ethanol as a grinding aid not only accelerated the reaction but also minimized energy requirements, aligning with greener pharmaceutical production goals.
The findings also demonstrated the feasibility of using readily available industrial equipment for pharmaceutical co-crystallization and offered a practical pathway for large-scale production.
Conclusions
To summarize, the study demonstrated the effectiveness of drum mills for large-scale mechanochemical synthesis of pharmaceutical co-crystals.
By optimizing process parameters and employing liquid-assisted grinding, the researchers showed that the process could achieve high purity, reduce processing time, and minimize environmental impact.
The researchers highlighted the potential for integrating sustainable practices into pharmaceutical manufacturing and adapting eco-friendly production methods that meet industrial-scale demands while adhering to strict regulatory standards for product quality.
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