The polar surface area (PSA) or topological polar surface area (TPSA) of a molecule is defined as the surface sum over all polar atoms or molecules, primarily oxygen and nitrogen, also including their attached hydrogen atoms.
PSA is a commonly used medicinal chemistry metric for the optimization of a drug's ability to permeate cells.  Molecules with a polar surface area of greater than 140 angstroms squared (Å) tend to be poor at permeating cell membranes.  For molecules to penetrate the blood–brain barrier (and thus act on receptors in the central nervous system), a PSA less than 90 Å is usually needed.
TPSA is a valuable tool in drug discovery and development. By analyzing a drug candidates TPSA, scientists can predict its potential for oral bioavailability and ability to reach target sites within the body. This prediction hinges on a drugs ability to permeate biological barriers.
Permeating these barriers, such as the Blood-Brain Barrier (BBB), the Placental Barrier (PB), and the Blood-Mammary Barrier (BM), is crucial for many drugs to reach their intended targets.
The BBB, for example, protects the brain from harmful substances. Drugs with a lower TPSA (generally below 90 Å²) tend to permeate the BBB more easily, allowing them to reach the brain and exert their therapeutic effects (Shityakov et al., 2013).
Similarly, for drugs intended to treat the fetus, a lower TPSA (below 60 Å²) is preferred to ensure they can pass through the placenta (Augustiño-Roubina et al., 2019).
Breastfeeding mothers also need consideration. Here, an optimal TPSA for a drug is around 60-80 Å² to allow it to reach the breast tissue for milk production, while drugs exceeding 90 Å² are less likely to permeate the Blood-Mammary Barrier.