Solubility properties of a compound are one of the most important considerations in drug design and development. A chemical’s solubility or lack thereof has far reaching implications throughout the development process, potentially impacting dosing route, formulation strategies, bioavailability and the design of in vitro assays. Therefore, the earlier solubility issues can be identified and rectified, the better.
Oral bioavailability is largely dependent on a drug’s permeability and solubility. This is defined by the Biopharmaceutical Classification System which categorises drugs into 4 classes based on these key ADME properties:
Class 1: High permeability, high solubility
Class 2: High permeability, low solubility
Class 3: Low permeability, high solubility
Class 4: Low permeability, low solubility
Generally, Class 1 drugs have the optimal permeability and solubility properties for good oral bioavailability, Class 2 drugs can potentially be improved by suitable formulation strategies but most Class 3 and 4 drugs may require improvement through structural modification.
Ideally, compounds that could face solubility issues would be identified before in vitro ADME testing is initiated. Virtual screening using QSAR models is a valuable approach prior to compound synthesis. However, confirming the solubility using a turbidimetric (kinetic) or thermodynamic method is advisable once the compound is synthesised as poor solubility can invalidate some of the later in vitro efficacy, ADME or toxicology data if not taken into consideration.
Read our free ADME Guide to learn more about solubility.