Co-administration of Intravenous Drugs: Rapidly Troubleshooting the Solid Form Composition of a Precipitate in a Multi-drug Mixture Using On-Site Raman Spectroscopy

Abstract

Intravenous drugs are often co-administrated in the same intravenous catheter line due to which compatibility issues, such as complex precipitation processes in the catheter line, may occur. A well-known example that led to several neonatal deaths is the precipitation due to coadministration of ceftriaxone-and calcium-containing solutions. The current study is exploring the applicability of Raman spectroscopy for testing intravenous drug compatibility in hospital settings. The precipitation of ceftriaxone calcium was used as a model system and explored in several multi-drug mixtures containing both structurally similar and clinically relevant drugs for co-infusion. Equal molar concentrations of solutions containing ceftriaxone and calcium chloride dihydrate were mixed with solutions of cefotaxime, ampicillin, paracetamol, and metoclopramide. The precipitate formed was collected as an "unknown" material, dried, and analyzed. Several solid-state analytical methods, including X-ray powder diffraction, Raman spectroscopy, and thermogravimetric analysis, were used to characterize the precipitate. Raman microscopy was used to investigate the identity of single sub-visual particles precipitated from a mixture of ceftriaxone, cefotaxime, and calcium chloride. X-ray powder diffraction suggested that the precipitate was partially crystalline; however, the identity of the solid form of the precipitate could not be confirmed with this standard method. Raman spectroscopy combined with multi-variate analyses (principal component analysis and soft independent modelling class analogy) enabled the correct detection and identification of the precipitate as ceftriaxone calcium. Raman microscopy enabled the identification of ceftriaxone calcium single particles of sub-visual size (around 25 μm), which is in the size range that may occlude capillaries. This study indicates that Raman spectroscopy is a promising approach for supporting clinical decisions and especially for compatibility assessments of drug infusions in hospital settings.

Innovative Approaches for Drug Discovery: Quantifying Drug Distribution and Response with Raman Imaging

“…Pharmaceutical formulations typically have well-defined APIs and excipients. Due to its inherent specificity, Raman imaging has shown to be useful in the analysis of solid pharmaceutical samples and the classification of different APIs and their structures. − Importantly, Raman can also be used to characterize chemically identical forms of an API that differ in their crystalline lattice structures or molecular conformations, known as polymorphs. Polymorphism plays an important role in drug dissolution, thermodynamic stability, and API bioavailability. , Grand et al developed a fast Raman imaging technique using compressive sensing for rapid characterization and mapping of clopidogrel polymorphs and three excipients in tablets with a pixel dwell time of 2.5 ms .…”