Harvard University and the Chinese University of Hong Kong researchers have developed a technique that increases the solubility of drug molecules by up to three orders of magnitude. This could be a breakthrough in drug formulation and delivery.
Over 60% of pharmaceutical drug candidates suffer from poor water solubility, which limits their bioavailability and therapeutic viability. Conventional techniques such as particle-size reduction, solid dispersion, lipid-based systems, and mesoporous confinement often have drug-specific limitations, can be costly to implement, and are prone to stability issues.
The newly developed approach addresses these issues by leveraging the competitive adsorption mechanism of drug molecules and water on engineered silica surfaces. It avoids chemical modification of drug molecules or using additional solubilizing agents to achieve solubility, potentially replacing multiple drug delivery technologies.
In the study “Enhancing drug solubility through competitive adsorption on silica nanosurfaces with ultrahigh silanol densities,” published in the Proceedings of the National Academy of Sciences, investigators describe nanosurfaces that adsorb drug molecules in dry conditions and release them rapidly once introduced to water.
Silica nanoparticles ranging from 7 to 22 nm were used as raw materials. These nanoparticles, characterized by high-curvature convex surfaces, were agglomerated through controlled evaporation, forming a porous template capable of adsorbing drug molecules. Competitive adsorption between water and drug molecules on these engineered surfaces boosts drug dissolution by two to three orders of magnitude.
The U.S. Food and Drug Administration classifies silica as Generally Recognized as Safe. Conventional silica surfaces have a silanol density of 4 to 6 OH/nm², which is insufficient for strong interactions with drug molecules or water.
Researchers increased this density up to 20 OH/nm², creating an ultrahigh-affinity surface. This enhancement allowed the surface to adsorb drug molecules in an anhydrous state and, upon exposure to water, undergo a competitive adsorption process where water molecules replace drug molecules, facilitating rapid desorption and dissolution.
Ibuprofen was used as the model drug for in vitro and in vivo testing. Dissolution studies showed that 90% of the drug was released within one hour, compared to less than 20% from crystalline ibuprofen over six hours.
In vivo tests with mice demonstrated nearly double the peak plasma concentration and 1.5 times greater drug exposure compared to a commercially available product.
The team also tested the formulation method on 15 poorly soluble active pharmaceutical ingredients, including ketoprofen, docetaxel, and fenofibrate. Across all tested drugs, solubility was enhanced by 10-fold to 2,000-fold compared to crystalline forms.
Stability testing over two years demonstrated no significant degradation in solubility performance.
Computational analysis using density functional theory corroborated the experimental observations, showing that water molecules favorably displace adsorbed drugs due to higher binding affinity on densely populated silanol surfaces.
The researchers believe they have found a solution to the solubility problem in drug delivery that will apply to a broad range of drugs while remaining cost-effective and scalable for mass production. If the study results translate into real-world results in clinical studies, it could significantly impact drug development, manufacturing costs, required dosage amounts and drug availability.
