Using Raman spectroscopy to analyse in situ a precipitate appearing in a catheter line after drug co-administration

To use the Raman scattering technique to identify precipitating drug substance(s) in situ.

The case originated when a combination of midazolam hydrochloride, clonidine hydrochloride and fentanyl citrate with Numeta G16E was administered in a central venous catheter line. Following an alarm from the syringe pump, a precipitate in the catheter line was visually observed.

The actual catheter line, with the precipitate still inside, was removed from the clinic and brought to the laboratory. Raman spectra of the precipitate, both when still inside the catheter line (in situ) and after removal, were recorded and analysed for similarity using our in-house database. Additionally, to validate the method, dry powders of midazolam, clonidine and fentanyl were mixed in the ratio of ~300:1:1. This tailor-made mixture was subjected to Raman analysis with the aim of validating the ability of the method to identify all components in a mixture, even if some of the components were present only in small amounts.

The precipitate was successfully identified as midazolam. Measuring in situ caused some additional peaks in the Raman spectra, attributed to the plastic of the catheter line. The influence of these additional peaks was eliminated by a two-component search or by demixing the spectra. The spectra of the precipitate indicated no traces of either clonidine or fentanyl. The experimental results were in line with the results from the theoretical calculations. The ability of Raman spectroscopy to identify both midazolam and small amounts of clonidine and fentanyl in a powder mixture was successfully demonstrated by scanning the tailor-made mixture.

Raman spectroscopy in combination with a database was used for rapid and non-invasive bulk identification in situ. However, to confirm or refute small amounts of a second drug substance in the precipitate, a large area scan of the particle on a flat surface is recommended.