This article, with insights from Hong Li, Ph.D., Vice President of Formulation, BioDuro, was originally published in the Drug Development & Delivery, March/April 2026, pages 37-38. Visit the website: Drug Development & Delivery

Enhancement strategies for improving solubility and bioavailability can be grouped into chemical approaches and physical approaches. Chemical ap­proaches modify the drug molecule to im­prove solubility and absorption through salt formation, whereby, for ionizable drugs, an appropriate counterion is se­lected to form salts that can substantially increase dissolution rates; or through the use of prodrugs, used to covalently attach hydrophilic moieties that enhance solubil­ity. The prodrug is enzymatically converted to the active parent drug in vivo, preserv­ing pharmacological activity while over­coming delivery barriers.

Physical approaches are used to opti­mize a formulation without altering its mo­lecular structure, yet directly driving bioavailability gains. Dr. Hong Li, Vice President of Drug Product, BioDuro, says this can be achieved in several ways:

• Crystal engineering: tailor poly­morphs, cocrystals, or crystal habits or modulate lattice energy to balance sol­ubility and stability and enhance disso­lution and absorption.

• Particle size reduction: use microniza­tion or nanomilling technology to in­crease the surface area, thereby accelerating dissolution and improving the rate and extent of absorption.

• pH modification: adjust formulation or biological pH and maximize the ionized fraction of ionizable drugs, boosting solubility and membrane permeability.

• Solubilizers: surfactants form micelles to encapsulate hydrophobic drugs, in­creasing apparent solubility and facili­tating intestinal absorption.

• Lipid-based formulations: lipid matrices (e.g., self-emulsifying drug delivery sys­tems or SEDDS) exploit lipid solubility, bypassing aqueous dissolution limitations and improving oral bioavail­ability via lymphatic transport.

• Complexation: cyclodextrin inclusion can encapsulate drugs within their hy­drophobic cavity, increasing apparent solubility.

• Amorphous solid dispersions (ASDs): dispersing drugs in polymers as high-energy amorphous forms eliminates crystalline lattice energy, drastically im­proving dissolution rate and bioavail­ability.

"There is no one-size-fits-all solution," says Dr. Li. "Success lies in matching the molecule's properties with the most suit­able manufacturing approach. If the API is ionizable, salt screening is recommended, as stable, highly soluble salts can offer both cost-effectiveness and scalability. For non-ionizable crystalline APIs, ASD or lipid-based formulations are viable. The selection must also align with the develop­ment phase, dose requirements (especially for high-dose candidates), and process simplicity. Ultimately, the optimal ap­proach balances strong solubilization per­formance with cost control and scalability, ensuring a robust and practical path from IND filing and beyond."