Trends in sustainable extraction and purification techniques – Ionic liquids from a clinical and pharmacological point of view

Environmental pollution caused by industry has increased in last decades. The industrial chemical processes use mainly volatile and inflammable organic solvents and require high time and energy demands. In addition, currently, the techniques used have low extraction efficiencies and poor selectivity. The focus of scientists is now the development of more sustainable and environmental friendly chemical processes for the production, extraction and purification of biomolecules and bioactive compounds.

Ionic liquids have emerged as a promising alternative solvent since they are known by their non-flammable, non-volatile and recyclable character, being many times called green solvents. Since Paul Walden described the first ionic-liquid (ethylammonium nitrate) in 1914, the ionic liquids became one of the major scientific area of research and the number of papers addressing their outstanding properties has exponentially increased from a few to more than 5000 in the last 20 years.

In this piece I will describe ionic liquids from a clinical point of view; specifically, I will evidence how ionic liquids may be important in the diagnosis industry. In a further piece, I will describe the surprising applications that ionic liquids have on the food and drinks industry.

What are ionic liquids?

Ionic liquids are salts constituted by large unsymmetrical organic cations and organic or inorganic cations. Due to this asymmetry they not easily form a crystalline structure and they are liquid salts at low (<100ºC) temperatures. The ionic character associated to ionic liquids is responsible for their negligible vapor pressure, non-flammability and high chemical and thermal stabilities. In addition, ionic liquids are recognized by their excellent solvation ability for a wide range of compounds and as a good stabilization media for biological molecules such as proteins. Moreover, ionic liquids are recognized as tunable designer solvents, a result of the possibility of choose the cation and anion constituents offering a large number of ion combinations and the possibility of designing specific solvents allowing the development of more effective extraction and purification platforms.

Ionic liquids in clinical and pharmacological fields

Aqueous biphasic systems (ABS) are, in general, two aqueous solutions of structurally different compounds separated into two coexisting phases where, above a given concentration, one of the phases will be enriched in one of the solutes and other in the second one. Below this concentration both phases are miscible. The mono- and biphasic region of each ABS is usually depicted in a phase diagram with a binodal curve separating the miscible and immiscible region.

Phase diagram example of an IL-based ABS.

The partitioning behaviour of a protein among the coexisting phases of an ABS is a complex phenomenon but a lot of attention has been given to the extraction, purification and concentration of proteins and other biomolecules of clinical interest using ionic liquids as phase-forming components of aqueous biphasic systems, in particular, a specific type of ionic liquids.

Proteins stability is highly affected by the pH of the medium and this specific type of IL show self-buffering capacity at pHs among 6-8. Being aware of this property, researchers developed a patent pending single-step platform to extract and concentrate prostate specific antigen (PSA), a prostate cancer biomarker. However, the PSA measurement requires the use of blood in a laborious and expensive techniques. Using ABS composed of ionic liquids lead to the total extraction of PSA to the ionic liquid-rich phase and, by reducing this one, it was concentrated samples of urine with PSA up to a factor that allows their measurement in a less expensive and laborious approach such as a simple HPLC analysis. In addition, HPLC analysis have shown that different PSA isoforms could be measured allowing the use of urine for primary or complementary prostate cancer diagnosis and evaluation, what can be a revolution in methodologies of cancer for early detection. There are a lot of cancer biomarkers, and by using specific ionic liquids, it could be possible to achieve a platform where a mixture of ILs is employed in an ABS composed of ionic liquids and urine to, in a single step, measure all of biomarkers related to each type of cancer. This will thus lead to a cheaper, non-invasive, and much more reliable early detection of cancer.

Graphic representation of the use of IL’s for the purification and concentration of PSA.

Besides, attention have also been given to the use of ionic liquids in pharmaceutical industries in the production segment as a way of reducing the use of environmentally hazardous and toxic organic solvents, and as a way of reducing the pollution, recovering drugs from wastes valuing them.

ABS composed of ionic liquids were found to be a successfully platform to extract morphine and the vasodilator papaverine (extraction efficiency of 96%).

Antibiotics, such as tetracycline, penicillin G or ciprofloxacin were also studied. In one investigation, penicillin G was extracted from a filtered fermentation broth with extraction efficiencies of 90%.

Studies regarding the purification and valorization of pharmaceutical solid wastes proposes new strategies to reuse them as an alternative to incineration. An integrated platform for the recovery of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and ketoprofen was conceptualized and involves 3 steps: extraction and purification of NSAIDs using IL three phase partitioning systems; precipitation of the drug using antisolvents; recycle and reuse of solvents. The results shown extraction efficiencies of approximately 84% and isolation efficiencies higher than 75 %, what are promising results not only because of the possibility of reuse and recycle the components, but also because of their low cost.

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Sources

[1]      Z. Lei, B. Chen, Y.-M. Koo, and D. R. MacFarlane, “Introduction: Ionic Liquids,” Chem. Rev., vol. 117, no. 10, pp. 6633–6635, 2017.[2]      F. A. E Silva, M. Caban, M. Kholany, P. Stepnowski, J. A. P. Coutinho, and S. P. M. Ventura, “Recovery of Nonsteroidal Anti-Inflammatory Drugs from Wastes Using Ionic-Liquid-Based Three-Phase Partitioning Systems,” ACS Sustain. Chem. Eng., vol. 6, no. 4, pp. 4574–4585, 2018.
[3]      K. Ghandi, “A Review of Ionic Liquids, Their Limits and Applications,” Green Sustain. Chem., vol. 4, no. 1, pp. 44–53, 2014.
[4]      T. Summary, “PSA PURIFICATION AND CONCENTRATION FROM URINE SAMPLES FOR NON-INVASIVE EARLY STAGE DIAGNOSIS OF PROSTATE CANCER PSA PURIFICATION AND CONCENTRATION FROM URINE SAMPLES FOR NON-INVASIVE EARLY STAGE DIAGNOSIS OF,” pp. 1–2.
[5]      S. P. M. Ventura, F. A. E Silva, M. V. Quental, D. Mondal, M. G. Freire, and J. A. P. Coutinho, “Ionic-Liquid-Mediated Extraction and Separation Processes for Bioactive Compounds: Past, Present, and Future Trends,” Chem. Rev., vol. 117, no. 10, pp. 6984–7052, 2017.

 

Author: Joao Calixto

MSc in Biochemistry with interest in the clinical field, having worked with ionic liquids for diagnosis purposes. Joao has an advanced knowledge in beverages, and he is the head of production in Companhia de Cervejas de Leiria, ensuring the productive, industrial and laboratorial quality control of Xarlie beer brand. He has also been in charge of developing a new cider named Xina. He is currently responsible for the development of continuous improvement and cost saving strategies in an industrial scale of CCL. Joao is a CFER consultant and educator for the areas of food and drinks innovation.

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