Smaller drugs have better skin penetration/absorption. Which statement is true?

• A. False
• B. True
• C. Sometimes
• D. Not related

Answer: (B)

Smaller molecules generally penetrate the skin better because the rate of diffusion through the stratum corneum—the outer skin barrier—depends strongly on how easily a molecule can move through the lipid matrix. Diffusion is faster for smaller molecules because their diffusion coefficient is higher, so they flow through the barrier more readily and reach deeper layers or systemic circulation more easily. In practice, compounds with smaller molecular size often show higher permeation flux than larger ones, all else being equal.

That said, other properties matter a lot too. Lipophilicity needs to be balanced: too lipophilic molecules may stay trapped in the outer skin layers, while too hydrophilic ones may struggle to partition into the lipid-rich barrier. Ionization, hydrogen bonding, and formulation factors also influence absorption. For example, small, moderately lipophilic molecules tend to diffuse through the barrier efficiently, whereas large peptides and proteins typically penetrate poorly unless special delivery methods are used. Overall, the tendency for smaller drugs to have better skin penetration makes the statement true.