The effect of structural QSAR parameters on skin penetration

Area of Science:

• Pharmacokinetics and Drug Delivery
• Computational Chemistry
• Dermal Science

Background:

• Solute permeability through the stratum corneum (log kp) is crucial for dermal drug delivery.
• Previous models relied on octanol-water partition coefficients (log Poct) and solvatochromic parameters.

Purpose of the Study:

• To investigate the utility of theoretical chemistry-derived structural parameters, molecular connectivity, and shape indices in predicting skin permeability.
• To compare the predictive power of these novel parameters with established solvatochromic parameters and log Poct.

Main Methods:

• Correlation analysis of permeation coefficient data (log kp) with theoretical chemistry-derived structural parameters.
• Evaluation of molecular connectivity and molecular shape indices.
• Analysis of equilibrium distribution (log Km) and diffusion (log D/h) using these parameters.

Main Results:

• Theoretical structural parameters showed comparable correlations with log kp as solvatochromic parameters.
• Log Poct could be effectively corrected using theoretical parameters to explain permeation and equilibrium distribution (log Km).
• Diffusion coefficients (D) and path length (h) were successfully analyzed using the structural parameters.

Conclusions:

• Theoretical chemistry-derived parameters provide a robust alternative for predicting solute permeability across the stratum corneum.
• These parameters enhance the understanding of compound distribution and diffusion within the skin.
• The findings offer valuable insights for optimizing topical and transdermal drug formulation.