Hydrotropy and co-solvency: Sustainable strategies for enhancing solubility of poorly soluble pharmaceutical active ingredients

• Sustainable Alternatives : Hydrotropy and co-solvency offer eco-friendly methods for enhancing the solubility of poorly soluble PAIs. • Green Chemistry Alignment : Techniques align with Green and White Analytical Chemistry, minimizing environmental impact. • Interpreted Mechanisms : Provides new insights into how hydrotropes and cosolvents improve solubility. • Wide Applicability : Effective in pharmaceutical, industrial, and environmental applications. • Research Opportunities : Highlights gaps for future research in sustainable solubility enhancement. This review explores sustainable strategies for enhancing the solubility of poorly water-soluble pharmaceutical active ingredients (PAIs), focusing on hydrotropy and co-solvency, while comparing their effectiveness, sustainability, and applicability in analytical chemistry, particularly within the frameworks of green and white analytical chemistry (GAC and WAC). Methods like hydrotropy, co-solvency, solid dispersions, and pH modification are discussed, each with distinct advantages and limitations. Hydrotropy, introduced by Carl A. Neuberg in 1916, enhances solubility without altering a drug's UV measurement range and is known for its eco-friendliness, stability, and scalability. Co-solvency modifies the solvent environment using solvents like ethanol but poses environmental concerns. Hydrotropy is safer and more scalable, though it requires more additives, while co-solvency is cost-effective but presents toxicity and precipitation risks. The environmental and safety benefits of hydrotropic solvents align with global sustainability initiatives like the UN SDGs. A case study comparing two UV methods (one with organic solvents and another with hydrotropic solvents) showed hydrotropy's superiority in sensitivity, stability, and sustainability, achieving a sustainability score of 71% versus 29% for methanol. The review also highlights the synergistic effects of multiple hydrotropic agents in improving solubility and drug stability. Overall, hydrotropy, particularly when combined with other solubility-enhancing techniques, represents a promising, sustainable approach for improving PAI solubility, offering significant safety, environmental, and economic benefits over traditional organic solvents.