The rapid population growth and escalating spread of human diseases have given rise to an increase in both the usage of pharmaceuticals and in the level of pharmaceutical waste, necessitating proper management strategies to address this challenge effectively. Sources of pharmaceuticals wasted in the form of unused drugs can range from patients disposing of medicines that exceed their needs or have exceeded their shelf life to medicines past their shelf life occurring anywhere upstream in the supply chain, as well as the failed batches generated during drug product manufacture. Previous research has highlighted the undesirable presence of pharmaceutical pollutants in water, soil, and surface environments.^1,2 Further, antibiotics in water streams can contribute to the development of resistance in certain bacteria.³ Given the significant health and environmental impacts of active pharmaceutical ingredients (APIs) in unused medicines, prioritizing their separation from various excipients in their formulations is an effective approach to addressing this challenge.

This research proposes a framework for selectively recovering the active ingredient from drug formulations using dissolution, filtration, and crystallization stages to produce highly pure API crystals. Crystallization is a crucial purification and particle control process used extensively in the pharmaceutical industry.⁴ The critically important variable in crystallization is the choice of solvent used to affect the phase separation.

Accordingly, a key part of the framework we propose is a solvent selection workflow, which serves to identify the best solvent to effect the dissolution of the active ingredient, the filtration of excipients, and the crystallization of the API with the goal of achieving a high overall yield. The workflow is applied to determine the most appropriate solvent to recover paracetamol via cooling crystallization from a formulation of five of the most common excipients. The recovered API was characterized to determine the purity of the crystals and compared with the virgin API. Subsequently, the framework is tested on commercial paracetamol tablets from different manufacturers and found to be effective despite the wide variety of excipients used by the manufacturers. Azithromycin was selected as the second application to recover from its formulations due to its widespread use and global significance as a broad-spectrum antibiotic, particularly in respiratory infections. These case studies confirm that the proposed framework can be generalized to recover API from different high-volume pharmaceuticals, thus helping pharmaceutical supply chains to become circular and reducing the need for fresh API as feedstock to manufacture the drug product.

References

1. Glassmeyer, S. T. et al. Disposal practices for unwanted residential medications in the United States. Environ Int 35, 566–572 (2009).
2. Deo, R. P. Pharmaceuticals in the Surface Water of the USA: A Review. Curr Environ Health Rep 1, 113–122 (2014).
3. Kümmerer, K. Drugs in the environment: emission of drugs, diagnostic aids and disinfectants into wastewater by hospitals in relation to other sources – a review. Chemosphere 45, 957–969 (2001).
4. Barhate, Y., Kilari, H., Wu, W.-L. & Nagy, Z. K. Population balance model enabled digital design and uncertainty analysis framework for continuous crystallization of pharmaceuticals using an automated platform with full recycle and minimal material use. Chem Eng Sci 287, 119688 (2024).