Solubility is one of the most important properties in drug discovery, which affects research such as bioactivity, in vivo efficacy, toxicity testing, pharmacokinetics and dosage forms. The potential adverse effects of low compound solubility on drug discovery and development are summarized in the figure below.
1. What is the required solubility of the compound?
The required level of solubility of a compound depends on two factors: permeability and dose. If expressed as the maximum absorbed dose (MAD) of a drug at a given dose, the following formula exists:
MAD=S×Ka×SIWV×SITT
In this formula, S represents solubility (mg/mL, pH=6.5). Ka denotes the intestinal absorption rate constant (min⁻¹), which corresponds to the permeability measured in rat intestinal perfusion experiments and is numerically similar to human Ka. SIWV indicates small intestinal water volume (approximately 250 mL), while SITT stands for small intestinal transport time (about 270 minutes). Therefore, solubility and permeability are the two primary factors determining maximum absorption.
2. Classification of solubility
The U.S. FDA's Biological Drug Administration (BCS) classification system guidelines (FDA Guidelines, 2000) define drug solubility as follows: A compound is classified as "highly soluble" when it is soluble in a water-based medium with a pH of 1.0 to 7.5 at a maximum dosage form volume of 250 mL or less. This volume is approximately equivalent to the amount of water consumed during a patient's empty-mouth oral administration. Since clinical doses are typically unknown during preclinical studies, the solubility category of NCEs can only be estimated during discovery and early development phases.
For drugs with moderate permeability, the effects of different solubilities can be roughly estimated as TABLE 4.2 when the predicted dose is approximately 1mg/kg.
In drug development, the Biopharmaceutical Classification System (BCS) is widely used to classify compounds into four categories based on solubility and permeability. This system aims to highlight similarities and differences in these properties. Compounds within the same BCS category exhibit comparable absorption behaviors and may follow identical regulatory approval procedures for both in vitro and in vivo studies.
Class 1 compounds: The most desirable category for easily absorbed and orally administered drugs.
Category 2 compounds: dissolution rate and solubility usually limit bioavailability, and formulations are often used to improve the solubility of these compounds.
Class 3 compounds: During the drug discovery phase, structural modification or prodrug strategies are often used to improve compound permeability.
Category 4 compounds: oral bioavailability is usually low, development is risky and expensive.
3. Strategies to improve solubility
In the drug discovery phase, the first strategy to improve solubility is structural modification. With the further advancement of candidate molecules, the formulation development strategies that can be used include pH adjustment, salting out, co-solvent, complexing, amorphous solid dispersion, etc.
Source: Drug Classification: Concepts, Structural Design and Methods (2nd Edition), by E.H. Koenes (American), translated by Renren Bai. Intractable Drug Delivery Technology (3rd Edition), edited by R. Liu, translated by Rong Liu. doi:10.1002/0471141755.ph0917s60.
Disclaimer: This article is only for the purpose of knowledge exchange and sharing, and does not involve commercial publicity, and does not serve as relevant medical guidance or medication advice. If there is any infringement, please contact us for deletion.
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