Solubility of phytochemicals and challenges in in vitro studies: a literature review

Abstract

Poor solubility remains a critical barrier in the in vitro evaluation of phytochemicals, many of which are hydrophobic and difficult to dissolve in aqueous media. This review explores the physicochemical factors influencing phytochemical solubility, emphasizing the role of solvent properties such as polarity, proximity, and cytotoxicity. Commonly used solvents—including polar protic, polar aprotic, and non-polar solvents —are discussed concerning their solubilizing capacity and compatibility with biological systems. Solvent-induced changes in membrane dynamics and cytotoxic profiles are also examined, highlighting the need for cautious selection and optimization. Several advanced strategies to enhance solubility, such as co-solvent systems, pH modulation, nanocarrier encapsulation, surfactants, and deep eutectic solvents (DESs), are reviewed. A focused case study on curcumin illustrates how different solubilization methods can significantly improve in vitro performance. The review underscores the importance of standardized solvent reporting to ensure reproducibility and reliability in phytochemical research.