Poor water solubility of active pharmaceutical ingredients (APIs) is a common challenge for drug product developers. Many marketed APIs are classified as BCS II/IV compounds, meaning they suffer from poor water solubility and/or low tissue permeability. For decades, scientists have relied on formulation techniques to enhance the bioavailability of APIs, and estimates predict that as many as 90% of APIs in the development pipeline suffer from solubility or bioavailability challenges (many of which are complex APIs and biologics). We will review common methods for increasing solubility and bioavailability of BCS Class II/IV APIs, including physical modification, chemical modification, encapsulation, and inclusion complexes. We will also explore the benefits of high energy media milling (AKA nanomilling)—a commercially-validated solubility enhancement technique.
Common Solubility-Enhancing Methods
Overcoming poor water solubility of active pharmaceutical ingredients (APIs) is an ongoing challenge for drug manufacturers. The issue affects an estimated 90% of new APIs, presenting a major hurdle in drug product development.
A common model for describing solubility and permeability of APIs is the Biopharmaceutical Classification System (BCS), which divides molecules into four quadrants based on their behavior in a pre-defined aqueous environment (Figure 1).
APIs that fall under a BCS Class II designation suffer from low solubility but exhibit high tissue permeability—meaning they are ideal candidates for solubility enhancement. BCS Class IV molecules—which exhibit low solubility and low permeability—require a combination of solubility enhancement and permeation enhancement to achieve a therapeutic effect.
Drug manufacturers can choose from several methods to increase the solubility and bioavailability of BCS Class II and IV APIs. These are commonly divided into four categories:
- API Physical Modification
- API Chemical Modification
- Inclusion Complexes