Solid Modification Strategies for Active Pharmaceutical Ingredients (APIs): A Systematic Review on Approaches, Improvements, and Limitations.

Poor aqueous solubility remains a major barrier in drug development, affecting approximately 40% of marketed drugs, up to 75% of drugs under development, and nearly 90% of new chemical entities. To overcome this limitation, solid modification of active pharmaceutical ingredients (APIs) emerged as a strategy to enhance drug physicochemical properties, particularly for Biopharmaceutics Classification System (BCS) II and IV drugs. This review systematically analyzes recent advancements in solid modification techniques, including salt formation, cocrystallization, polymorphs, solvate and hydrate forms, amorphous and co-amorphous systems, inclusion complexes, and nanocrystallization. A systematic literature search spanning 2020-2025 was conducted using PubMed and ScienceDirect databases, focusing on studies that improve the physicochemical properties of the APIs. By categorizing APIs, matrices, and methods of each study, this review shows the most frequently used techniques and their matrices, advantages, and limitations of each modification, providing insights for optimizing drug performance and future research in pharmaceutical development. Among the various approaches reviewed, cocrystals, amorphous systems, nanocrystals, and inclusion complexes emerged as the most frequently used techniques. Amorphous systems and inclusion complexes offer the highest median solubility enhancements by maximizing kinetic supersaturation or equilibrium solubility, respectively, while nanocrystals efficiently improve equilibrium solubility via particle size reduction, and cocrystals provide reliable, moderate gains with superior long-term thermodynamic stability.