API Salt Solubility: Unresolved Problems and Innovative Solutions Beyond Conventional Approaches

Solubility is one of the most important factors that influences the bioavailability and therapeutic effectiveness of active pharmaceutical ingredients (APIs). Salt formation remains one of the most widely applied strategies to enhance the solubility and dissolution rates. However, many pharmaceutical salts still face persistent solubility challenges, which compromise clinical bioavailability and delay drug development timelines. These challenges are further complicated by the influence of excipients and the frequent discrepancies between in vitro dissolution data and in vivo performance. This review highlights the limitations of API salt forms with poor solubility and emphasizes the growing importance of advanced analytical and predictive tools. Modern approaches such as artificial intelligence (AI) and machine learning (ML) algorithms, along with high-throughput microfluidic screening methods, are increasingly being adopted to better understand and predict the solubility behavior of designed salts. In addition, the review explores innovative strategies to overcome solubility barriers, including the development of dynamic salt forms responsive to physiological conditions, hybrid solid forms such as salt–cocrystals, and counterion engineering with designer ions and ionic liquids. Promising formulation and processing innovations─such as additive manufacturing, microenvironmental pH modulation, and coprocessing with solubility-enhancing polymers─are also discussed as means to further improve solubility. Finally, to foster continued advancement in this field, this review underscores the need for integrated computational–experimental methodologies and cross-disciplinary collaboration. It also addresses regulatory and commercialization challenges associated with these emerging salt approaches while presenting future perspectives.