Formulation-Driven Strategies for Overcoming Solubility Barriers in Drug Development: A Review

Low water solubility is one of the most critical hurdles in pharmaceutical development, as nearly 40-50% of the newly discovered drug molecules are poorly water-soluble. This low solubility often leads to inadequate dissolution, poor absorption, and reduced bioavailability, which limit the therapeutic potential of many promising drug candidates. Consequently, enhancing solubility has become a key area of focus in formulation science to improve the clinical efficacy and commercial viability of modern pharmaceuticals. This review provides a overview of the various strategies developed to improve the solubility and dissolution rate of low water-soluble drug candidates. Based on their solubility, drugs are categorized into four classes according to the Biopharmaceutics Classification System (BCS). Solubility issues are primarily encountered in Class II and Class IV drugs. Various approaches and techniques are employed to enhance the solubility and bioavailability of these poorly soluble drugs. Conventional methods such as particle size reduction, salt formation, solid dispersion, and use of co-solvents are discussed alongside novel and emerging techniques, including nanocrystals, inclusion complexation with cyclodextrin, solid lipid nanoparticles, and amorphous solid dispersions.