Surface enhanced Raman scattering microtips for microenvironment pH determination of semi-solid preparations

Semi-solid preparations such as ointments, creams, gels, and pastes are common topical dosage forms with complex compositions and microstructures. pH is a critical quality attribute for semi-solid preparations, affecting properties such as particle size distribution, drug dissociation state, and rheological behavior. Currently, traditional pH electrode methods only provide an "average" pH for large-volume matrices, with low spatial resolution and accuracy. Microenvironment pH detection is crucial for accurately assessing semi-solid preparations. Herein, we developed pH-sensitive surface enhanced Raman scattering (SERS) microtips to achieve localized pH detection in semi-solid preparations. SERS microtips were prepared from glass needles with a tip size of around 1 μm and gold nanoparticles (Au NPs) grown on glass surfaces for SERS enhancement. 4-Mercaptopyridine was selected as a pH sensitive Raman reporter and immobilized on the Au NPs, exhibiting characteristic Raman peak shifts within the pH range of 3-10. The SERS microtips were employed to conduct highly sensitive pH measurements in localized areas of 15 commercial ointments, 8 gels, and 1 laboratory-made ointment, providing higher spatial resolution and microenvironment differentiation compared to pH meters. The SERS microtips were used to monitor pH changes over time in ointment applied to localized wounds on live mice. This work introduces a new tool for pH detection in semi-solid preparations, offering a new method to enhance the prescription process and quality assessment of complex preparations like topical semi-solid preparations.