Molecular Strategies to Enhance Drug Solubility

Dear Colleagues,

Poor aqueous solubility remains a critical barrier in the development of many active pharmaceutical ingredients, limiting bioavailability and, ultimately, therapeutic success. In recent years, the field of pharmaceutics has witnessed a remarkable evolution in molecular-level strategies to overcome these challenges, moving beyond empirical formulation approaches to more rational, design-driven solutions.

At the heart of this progress is our deeper understanding of how the molecular and solid-state properties of drugs dictate solubility. By modulating crystal lattice energy, molecular mobility, and interactions with solvents and excipients, researchers have devised sophisticated techniques that improve dissolution without compromising stability or efficacy.

Salt formation remains one of the most established strategies, leveraging the ionizable nature of many drug molecules to enhance solubility and dissolution rates. However, as many new chemical entities are non-ionizable, alternative approaches have become increasingly important. The development of pharmaceutical co-crystals, where the active molecule is combined in the solid state with a neutral co-former through non-covalent interactions, exemplifies this shift. Co-crystals can offer substantial improvements in solubility and mechanical properties, guided by crystal engineering and molecular modelling.

Amorphization, through the production of amorphous solid dispersions, directly addresses the barrier posed by high lattice energy, converting drugs into thermodynamically metastable yet kinetically stabilized forms. Advances in polymer science and processing have enabled better stabilization against recrystallization. Within this context, co-amorphization has emerged as a promising extension, where two or more low-molecular-weight compounds are converted into a single-phase amorphous system. This approach can further diminish their recrystallization tendencies through complementary molecular interactions, offering an attractive option for non-polymeric stabilization.

Other molecular strategies include the design of prodrugs, where chemical modification of the drug molecule increases hydrophilicity or leverages transport mechanisms, with subsequent in vivo conversion to the active form. Molecular complexation, using carriers such as cyclodextrins, also improves apparent solubility by forming inclusion complexes that shield hydrophobic regions of the drug. Complementing these approaches, advances in particle engineering and nanotechnology now enable the precise control of particle size, morphology, and surface chemistry, further enhancing dissolution performance.

A defining feature of these modern strategies is their rational foundation. Computational chemistry, molecular dynamics, and machine learning models now inform the selection of co-formers, predict amorphous stability, and guide prodrug design. This integration of molecular science and data-driven tools has accelerated development and reduced empirical trial-and-error, although experimental validation remains essential.

Despite these advances, challenges persist. Achieving robust physical stability, ensuring the scalability of manufacturing processes, and complying with regulatory requirements all demand a delicate balance between molecular innovation and practical considerations. Moreover, the trend toward more complex, high-molecular-weight, and hydrophobic drug candidates will likely intensify the demand for novel solubility-enhancing strategies.

Looking towards the future, the field will benefit from continued interdisciplinary collaboration, bridging pharmaceutical sciences, materials chemistry, and computational modelling. Tailored polymers, new classes of co-formers, hybrid nanostructures, and predictive algorithms all hold the potential to further expand the toolkit available to formulation scientists.

In this context, this Special Issue of Pharmaceutics aims to capture the latest scientific and technological developments in molecular approaches to improving drug solubility. We warmly invite researchers to contribute original research articles, reviews, and perspectives that deepen our understanding of solubility at the molecular level and help translate these insights into better medicines for patients worldwide.

Dr. Ana Isabel Fernandes
Dr. João F. Pinto
Guest Editors

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• drug solubility
• molecular strategies
• co-crystals
• amorphous solid dispersions
• co-amorphous systems
• salt formation
• prodrugs
• molecular complexation
• solubility enhancement
• pharmaceutical formulation