Penicilloic acid (PA) is a degraded byproduct of
penicillin and often causes fatal
allergies to humans, but its rapid detection in
penicillin drugs remains a challenge due to its similarity to the mother structure of
penicillin. Here, we reported a
ligand-replaced molecularly imprinted monolayer strategy on a surface-enhanced Raman scattering (SERS) substrate for the specific recognition and rapid detection of Raman-inactive PA in
penicillin. The bis(phenylenediamine)-Cu(2+)-PA complex was first synthesized and stabilized onto the surface of
silver nanoparticle film that was fabricated by a
bromide ion-added
silver mirror reaction. A molecularly imprinted monolayer was formed by the further modification of alkanethiol around the stabilized complex on the Ag film substrate, and the imprinted recognition site was then created by the replacement of the complex template with Raman-active probe molecule
p-aminothiophenol. When PA rebound into the imprinted site in the alkanethiol monolayer, the SERS signal of
p-aminothiophenol exhibited remarkable enhancement with a detection limit of 0.10 nM. The imprinted monolayer can efficiently exclude the interference of
penicillin and thus provides a selective determination of 0.10‰ (w/w) PA in
penicillin, which is about 1 order of magnitude lower than the prescribed residual amount of 1.0‰. The strategy reported here is simple, rapid and inexpensive compared to the traditional chromatography-based methods.