Direct High-Resolution Imaging of Crystalline Components in Pharmaceutical Dosage Forms Using Low-Frequency Raman Spectroscopy

Abstract

Crystalline forms of active pharmaceutical ingredients need to be clearly understood and characterized by the pharmaceutical industry to ensure the correct dosage is produced. In this study, we evaluated the crystalline form of two different pharmaceutical cocrystals and a physical mixture consisting of caffeine and 4-hydroxybenzoic acid using a Raman microscopy system equipped with a measurement module to access the low-frequency region. We also demonstrated the differences between a low-frequency Raman spectroscopy image of a cocrystal and its physical mixture in a pharmaceutical dosage form. The measured pharmaceutical dosage forms were: a prepared pharmaceutical cocrystal, a physical mixture, and microcrystalline cellulose. The spectral patterns of the cocrystal and physical mixture were easily distinguished in the low-frequency region of the Raman spectrum. Based on the spectrum of the cocrystal and physical mixture, two different crystalline forms in the pharmaceutical dosage form were visualized using Raman microscopy. We concluded that low-frequency Raman spectroscopy is able to directly visualize the crystalline form of active pharmaceutical ingredients in pharmaceutical dosage forms without any pretreatment.