Exploring molecular interactions of drugs in different biologically active solvents: A comprehensive review for safe and efficient drug delivery systems.

In this review, the interactions between drugs and biologically active solvents have been extensively investigated due to their importance in optimizing pharmaceutical formulation performance for effective therapeutic efficacy and safe drug delivery. These interactions determine the molecular stability, reactivity and solubility of drugs in different biocompatible solvents. The knowledge about their absorption, distribution, metabolism, transport and bioavailability can be enhanced from their molecular interactions data. There have been reports of improved solubility and stability of drugs like metformin hydrochloride and hydralazine hydrochloride in aqueous solutions of carbohydrates and amino acids, which has an immediate effect on their bioavailability and treatment efficacy. Moreover, the COVID-19 pandemic has reestablished the importance of this review, as some drugs were clinically approved after proving their activity and efficacy during this phase. The antivirals favipiravir, remdesivir and two repurposed drugs, antimalarial hydroxychloroquine and metabolic inhibitor 2-deoxy-d-glucose (2-DG) were approved during this phase based on their available physicochemical data. These results established the clinical efficacy and dependency of drugs on their solvation environment, highlighting the pharmacological importance of studying molecular interactions in addition to their theoretical significance. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) model was adopted to conduct this systematic review, covering scientific articles from 2000 to 2025 to ensure a careful evaluation of recent advancements. This review focuses on the molecular interactions of various drugs with different biological solvent systems, using physicochemical, spectroscopic, and computational methods. It critically examines drug-solvent interactions by specifying quantitative physicochemical (free energy changes), spectral (binding constant) and computational metrics (binding affinity). This integrated approach provides a novel molecular-level insight into the structural, solvation, and interaction behavior of drugs under physiological conditions. The integration of molecular dynamics, artificial intelligence/machine learning tools, and experimental validation represents a prospective approach for addressing current limitations, contributing to the development of precision in drug delivery strategies for personalized medications. This review could be substantial for biochemical and medicinal sectors with important implications in formulation, stability, bioavailability, and solubility of drugs in clinical pharmacology. The outcome may provide an important basis for advanced research in future, serving the scientific community in understanding pharmacokinetics and pharmacodynamics of drug interactions. This can further strengthen the advanced research in future, involving drug-solvent interactions, which ultimately improves the safety, treatment efficacy and delivery performance of the drugs.