Drug solubility is a multifaceted challenge with important trade-offs to consider. For such a pivotal issue, the intricacies are vital, yet they often go unnoticed or under-appreciated.
Approximately 70% of new compounds emerging from modern drug discovery pipelines display insufficient aqueous solubility. This means they cannot be adequately absorbed after oral intake without some form of enhancement to achieve the necessary bioavailability.
Solubilizing an Insoluble Molecule: "Aqueous solubility" is a general term, and understanding its individual components, as listed below, is beneficial. Together, they comprise what is termed "apparent solubility."
- Crystalline Solubility
This refers to the concentration of an Active Pharmaceutical Ingredient (API) that can be solubilized when the API is in its crystalline form (its lowest energy state).
- Amorphous Solubility
This relates to the concentration of an API that can be solubilized when the API is in its amorphous state (a higher energy form). Typically, it's approximately 5-10 times greater than the crystalline solubility.
- Colloidal Phase
When the concentration of an API surpasses its amorphous solubility, droplets rich in amorphous drug form, typically measuring between 100-500 nm in size.
It's crucial to break down the apparent solubility values we encounter into each of their individual contributing solubilities:
Crystalline, Amorphous, and Colloidal
When solubility exceeds the amorphous threshold, a phenomenon known as Liquid-Liquid Phase Separation (LLPS) takes place, leading to the formation of a colloidal phase.
In practical terms, this implies that the API will spontaneously separate from the aqueous phase to form API-rich colloids (typically 100-500nm in size).
It's worth noting that these formed colloids are not genuinely solubilised. While they usually don't contribute directly to absorption, they act as an amorphous reservoir. This reservoir is in equilibrium with the amorphous API, ensuring sustained high absorption rates.
The occurrence of LLPS is significant as it represents the peak of thermodynamic activity—a term denoting the API's propensity to permeate across epithelial cells for absorption.
As evident from these figures, the primary question isn't just 'how do I increase the solubility of the drug' since that tackles only about 1% of the challenge. The more pressing query is, 'given that up to 99% of the administered dose isn't immediately available for absorption, how can it be temporarily stabilized to facilitate absorption over time?'