• Penicillin G and Penicillin V

  • Penicillin V: Structure and Acid Stability

    • Penicillin V, or phenoxymethylpenicillin, has the chemical formula C₁₆H₁₈N₂O₅S and is very nearly identical to Penicillin G structurally.^1,2

      • Penicillin V (2D)

        Phenoxymethyl. PubChem. National Libraryof Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/Phenoxymethyl  (Reference 7).

       

      • The main difference is in the side chain: a phenoxymethyl group, which is different from Penicillin G's benzyl group due to the presence of an oxygen atom linking the phenyl ring to the acetyl moiety.^1,3,4

        • History:

          • The discovery of penicillin V stemmed from good fortune.

            • In 1951, at the Austrian company Biochemie, biologist Ernst Brandl was attempting to solve a bacterial contamination problem in penicillin fermentation tanks by adding phenoxyethanol as a disinfectant.

              • This approach resulted not only in increased penicillin production but in the creation of a new type of penicillin.

                • The fungus had metabolized the phenoxyethanol into phenoxyacetic acid and incorporated it into the penicillin structure, creating phenoxymethylpenicillin.

                • Brandl astutely recognized that this new compound was stable in the presence of stomach acid, a property that penicillin G lacked.³

      • This acid stability is the single most important feature distinguishing penicillin V from penicillin G.

        • The electron-withdrawing nature of the ether oxygen in the phenoxymethyl side chain stabilizes the amide bond of the β-lactam ring against acid-catalyzed hydrolysis.⁴

          •  Because penicillin G lacks this feature, it is rapidly destroyed by gastric acid and is therefore ineffective when taken orally.⁴

            •  In contrast, penicillin V, typically administered as its potassium salt (penicillin VK), resists acid degradation and is reliably absorbed from the gastrointestinal tract, making it suitable for oral administration.⁶

              • This fundamental difference, born from a single oxygen atom and a historical accident, determined the clinical distinction between these two drugs:

                • (1) penicillin G is reserved for parenteral therapy, typically for more severe or inpatient cases.

                • (2) penicillin V became a staple of outpatient primary care for oral treatment of common infections.

August, 2025