Liquid-liquid extraction (LLE) is a widely employed technique for the isolation of bioactive heterocyclic compounds from natural products, fermentation broths, and synthetic mixtures. The efficiency of LLE depends on several factors, including solvent selection, pH manipulation, salting-out effects, and temperature control. Conventional solvent systems, such as water-organic solvent pairs, are commonly used, while advanced strategies, including ionic liquids (ILs), deep eutectic solvents (DESs), ultrasound-assisted extraction (UAE), and microwave-assisted extraction (MAE), have been developed to enhance selectivity and yield. Sequential and countercurrent LLE methods further improve the fractionation of complex mixtures. This review highlights key LLE strategies, emphasizing their optimization for the selective extraction of bioactive heterocyclic compounds, with a focus on green and sustainable approaches. Liquid-liquid extraction (LLE) is a crucial technique for isolating bioactive heterocyclic compounds from natural products, fermentation broths, and synthetic mixtures. Its efficiency depends on solvent selection, pH manipulation, and extraction optimization. Traditional water-organic solvent systems remain widely used, while green alternatives like ionic liquids (ILs) and deep eutectic solvents (DESs) enhance sustainability. Advanced techniques, including ultrasound-assisted (UAE) and microwave-assisted extraction (MAE), improve selectivity and yield. LLE applications span pharmaceuticals, nutraceuticals, food, and environmental industries. Future research aims to optimize LLE conditions, integrate advanced purification methods, and expand eco-friendly solvent use for sustainable bioactive compound isolation.

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1. Discovery of a Secalonic Acid Derivative from Aspergillus aculeatus , an Endophyte of Rosa damascena Mill., Triggers Apoptosis in MDA-MB-231 Triple Negative Breast Cancer Cells Sep 2020
2. Biosynthesis of oxygenated brasilane terpene glycosides involves a promiscuous N-acetylglucosamine transferase Sep 2020
3. Application of Optimized and Validated Agar Overlay TLC–Bioautography Assay for Detecting the Antimicrobial Metabolites of Pharmaceutical Interest Aug 2020 CHROMATOGR SCI
4. Hessel V, Tran NN, Asrami MR, Tran QD, Long NVD, Escribà-Gelonch M, Tejada JO, Linke S, Sundmacher K. Sustainability of green solvents–review and perspective. Green Chem. 2022;24(2):410–37.
5. Mišan A, Nađpal J, Stupar A, Pojić M, Mandić A, Verpoorte R, Choi YH. The perspectives of natural deep eutectic solvents in agri-food sector. Crit Rev Food Sci Nutr. 2020;60(15):2564–92.
6. Osorio-Tobón JF. Recent advances and comparisons of conventional and alternative extraction techniques of phenolic compounds. J Food Sci Technol. 2020;57(12):4299–315.
7. Fratelli C, Burck M, Amarante MCA, Braga ARC. Antioxidant potential of nature’s “something blue”: something new in the marriage of biological activity and extraction methods applied to C-phycocyanin. Trends Food Sci Technol. 2021;107:309–23.

8. Chugh NA, Bali S, Koul A. Integration of botanicals in contemporary medicine: road blocks, checkpoints and go-ahead signals. Integr Med Res. 2018;7:109–25.
9. Cvjetko Bubalo M, Vidović S, Radojčić Redovniković I, Jokić S. Green solvents for green technologies. J Chem Technol Biotechnol. 2015;90:1631–39.
10. Kaufmann B, Christen P. Recent extraction techniques for natural products: microwave-assisted extraction and pressurized solvent extraction. Phytochem Anal. 2002;13:105–13.
11. Zhang QW, Lin LG, Ye WC. Techniques for extraction and isolation of natural products: a comprehensive review. Chin Med. 2018;13:20.
12. Bora K.S., Sharma A. The Genus Artemisia: A Comprehensive Review. Pharm. Biol. 2011;49:101–109. doi: 10.3109/13880209.2010.497815.
13. Abad M.J., Bedoya L.M., Apaza L., Bermejo P. The Artemisia L. Genus: A Review of Bioactive Essential Oils. Molecules. 2012;17:2542–2566. doi: 10.3390/molecules17032542.
14. Ivanescu B., Lungu C., Vlase L., Gheldiu A.M., Grigorescu C., Corciova A. Bioactive Compounds from Artemisia campestris L. Subsp. Campestris. Rev. Chim. 2018;69:3076–3081. doi: 10.37358/RC.18.11.6686.
15. Setzer W.N., Vogler B., Schmidt J.M., Leahy J.G., Rives R. Antimicrobial Activity of Artemisia Douglasiana Leaf Essential Oil. Fitoterapia. 2004;75:192–200. doi: 10.1016/j.fitote.2003.12.019.
16. Abdiaj I, Cañellas S, Dieguez A, Linares ML, Pijper B, Fontana A, Rodriguez R, Trabanco A, Palao E, Alcázar J. End-to-end automated synthesis of C (sp3)-enriched drug-like molecules via Negishi coupling and novel, automated liquid–liquid extraction. Journal of medicinal chemistry. 2022 Dec 15;66(1):716-32.
17. Parys W, Dołowy M, Pyka-Pająk A. Current strategies for studying the natural and synthetic bioactive compounds in food by chromatographic separation techniques. Processes. 2021 Jun 24;9(7):1100.
18. Almohasin JA, Balag J, Miral VG, Moreno RV, Tongco LJ, Lopez EC. Green Solvents for Liquid–Liquid Extraction: Recent Advances and Future Trends. Engineering Proceedings. 2023 Nov 15;56(1):174.
19. Almohasin JA, Balag J, Miral VG, Moreno RV, Tongco LJ, Lopez EC. Green Solvents for Liquid–Liquid Extraction: Recent Advances and Future Trends. Engineering Proceedings. 2023 Nov 15;56(1):174.
20. Yu L, Li Z, Huang W, Ali A, Chen Y, Zhao G, Yao S. Recovery and post-treatment processes for ionic liquids and deep eutectic solvents. Journal of Molecular Liquids. 2024 Apr 16:124767.

Liquid-liquid extraction (LLE) is a widely employed technique for the isolation of bioactive heterocyclic compounds from natural products, fermentation broths, and synthetic mixtures. The efficiency of LLE depends on several factors, including solvent selection, pH manipulation, salting-out effects, and temperature control. Conventional solvent systems, such as water-organic solvent pairs, are commonly used, while advanced strategies, including ionic liquids (ILs), deep eutectic solvents (DESs), ultrasound-assisted extraction (UAE), and microwave-assisted extraction (MAE), have been developed to enhance selectivity and yield. Sequential and countercurrent LLE methods further improve the fractionation of complex mixtures. This review highlights key LLE strategies, emphasizing their optimization for the selective extraction of bioactive heterocyclic compounds, with a focus on green and sustainable approaches. Liquid-liquid extraction (LLE) is a crucial technique for isolating bioactive heterocyclic compounds from natural products, fermentation broths, and synthetic mixtures. Its efficiency depends on solvent selection, pH manipulation, and extraction optimization. Traditional water-organic solvent systems remain widely used, while green alternatives like ionic liquids (ILs) and deep eutectic solvents (DESs) enhance sustainability. Advanced techniques, including ultrasound-assisted (UAE) and microwave-assisted extraction (MAE), improve selectivity and yield. LLE applications span pharmaceuticals, nutraceuticals, food, and environmental industries. Future research aims to optimize LLE conditions, integrate advanced purification methods, and expand eco-friendly solvent use for sustainable bioactive compound isolation.

🔒 This is a subscription article

Full text is available to subscribers and institutional members. Please choose an option below to access it.

1. Discovery of a Secalonic Acid Derivative from Aspergillus aculeatus , an Endophyte of Rosa damascena Mill., Triggers Apoptosis in MDA-MB-231 Triple Negative Breast Cancer Cells Sep 2020
2. Biosynthesis of oxygenated brasilane terpene glycosides involves a promiscuous N-acetylglucosamine transferase Sep 2020
3. Application of Optimized and Validated Agar Overlay TLC–Bioautography Assay for Detecting the Antimicrobial Metabolites of Pharmaceutical Interest Aug 2020 CHROMATOGR SCI
4. Hessel V, Tran NN, Asrami MR, Tran QD, Long NVD, Escribà-Gelonch M, Tejada JO, Linke S, Sundmacher K. Sustainability of green solvents–review and perspective. Green Chem. 2022;24(2):410–37.
5. Mišan A, Nađpal J, Stupar A, Pojić M, Mandić A, Verpoorte R, Choi YH. The perspectives of natural deep eutectic solvents in agri-food sector. Crit Rev Food Sci Nutr. 2020;60(15):2564–92.
6. Osorio-Tobón JF. Recent advances and comparisons of conventional and alternative extraction techniques of phenolic compounds. J Food Sci Technol. 2020;57(12):4299–315.
7. Fratelli C, Burck M, Amarante MCA, Braga ARC. Antioxidant potential of nature’s “something blue”: something new in the marriage of biological activity and extraction methods applied to C-phycocyanin. Trends Food Sci Technol. 2021;107:309–23.

8. Chugh NA, Bali S, Koul A. Integration of botanicals in contemporary medicine: road blocks, checkpoints and go-ahead signals. Integr Med Res. 2018;7:109–25.
9. Cvjetko Bubalo M, Vidović S, Radojčić Redovniković I, Jokić S. Green solvents for green technologies. J Chem Technol Biotechnol. 2015;90:1631–39.
10. Kaufmann B, Christen P. Recent extraction techniques for natural products: microwave-assisted extraction and pressurized solvent extraction. Phytochem Anal. 2002;13:105–13.
11. Zhang QW, Lin LG, Ye WC. Techniques for extraction and isolation of natural products: a comprehensive review. Chin Med. 2018;13:20.
12. Bora K.S., Sharma A. The Genus Artemisia: A Comprehensive Review. Pharm. Biol. 2011;49:101–109. doi: 10.3109/13880209.2010.497815.
13. Abad M.J., Bedoya L.M., Apaza L., Bermejo P. The Artemisia L. Genus: A Review of Bioactive Essential Oils. Molecules. 2012;17:2542–2566. doi: 10.3390/molecules17032542.
14. Ivanescu B., Lungu C., Vlase L., Gheldiu A.M., Grigorescu C., Corciova A. Bioactive Compounds from Artemisia campestris L. Subsp. Campestris. Rev. Chim. 2018;69:3076–3081. doi: 10.37358/RC.18.11.6686.
15. Setzer W.N., Vogler B., Schmidt J.M., Leahy J.G., Rives R. Antimicrobial Activity of Artemisia Douglasiana Leaf Essential Oil. Fitoterapia. 2004;75:192–200. doi: 10.1016/j.fitote.2003.12.019.
16. Abdiaj I, Cañellas S, Dieguez A, Linares ML, Pijper B, Fontana A, Rodriguez R, Trabanco A, Palao E, Alcázar J. End-to-end automated synthesis of C (sp3)-enriched drug-like molecules via Negishi coupling and novel, automated liquid–liquid extraction. Journal of medicinal chemistry. 2022 Dec 15;66(1):716-32.
17. Parys W, Dołowy M, Pyka-Pająk A. Current strategies for studying the natural and synthetic bioactive compounds in food by chromatographic separation techniques. Processes. 2021 Jun 24;9(7):1100.
18. Almohasin JA, Balag J, Miral VG, Moreno RV, Tongco LJ, Lopez EC. Green Solvents for Liquid–Liquid Extraction: Recent Advances and Future Trends. Engineering Proceedings. 2023 Nov 15;56(1):174.
19. Almohasin JA, Balag J, Miral VG, Moreno RV, Tongco LJ, Lopez EC. Green Solvents for Liquid–Liquid Extraction: Recent Advances and Future Trends. Engineering Proceedings. 2023 Nov 15;56(1):174.
20. Yu L, Li Z, Huang W, Ali A, Chen Y, Zhao G, Yao S. Recovery and post-treatment processes for ionic liquids and deep eutectic solvents. Journal of Molecular Liquids. 2024 Apr 16:124767.