Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry

Oral drug absorption depends on four key factors: effective membrane permeability, available surface area for absorption, apparent luminal drug concentration, and residence time in the lumen. These factors work together to determine how much drug reaches the systemic circulation through passive diffusion across intestinal membranes.

Drug permeability can be enhanced by adjusting the drug's lipophilicity, polarity, or molecular size. These modifications promote passive transport across intestinal membranes, increasing the amount of drug that diffuses through and enters systemic circulation. Enhanced permeability directly improves bioavailability and therapeutic effectiveness.

Drug stability significantly impacts bioavailability because degradation during shelf life or conversion by GI components renders drugs inactive or poorly soluble, diminishing absorption. For example, erythromycin rapidly degrades in acidic stomach conditions, reducing its therapeutic effectiveness unless protected by an enteric coating.

An enteric coating is a protective layer applied to oral drugs to shield them from the stomach's acidic environment. It stabilizes drugs like erythromycin that degrade in acidic conditions, allowing them to pass through the stomach intact and dissolve in the less acidic small intestine, enhancing bioavailability.

Enantiomers are mirror-image forms of chiral drugs that exhibit different physicochemical properties, such as melting points and solubilities, directly impacting dissolution rates. One enantiomer may form a more stable crystalline structure dissolving slowly, while the other dissolves more readily, affecting overall drug absorption.

Stereoselectivity does not impact passive absorption because passive biological processes rely solely on a molecule's physical and chemical characteristics without selectivity for one isomer over another. However, stereoselectivity does play a role in protein binding and carrier-mediated absorption processes requiring specific molecular interactions.

Evidence of stereoselective absorption indicates that a drug is absorbed through a carrier-mediated process rather than passive diffusion. Since most drugs are absorbed passively and do not display stereoselectivity, observing stereoselective absorption reveals that the drug requires specific carrier proteins for transport across intestinal membranes.