Visualization of Primary Particles in a Tablet Based on Raman Crystal Orientation Mapping

Abstract

Objective: The morphology of the primary particles in the active pharmaceutical ingredient (API) is one of the most important determinants for formulation function. However, it has not been possible to visualize primary particles in a tablet using various imaging methods, including spectroscopic mappings, because these particles usually exist as aggregated clusters in tablets. We revealed that the Raman spectrum of crystalline particles is determined depending upon the angle between the crystallographic axis and the polarization direction of the excitation laser. In this paper, we report a method to visualize primary particles within the aggregated cluster based on the Raman spectral change on the boundary of primary particles. Method: Metformin hydrochloride was chosen as a model API for this study. The crystal structure of metformin hydrochloride was solved using X-ray crystal structure analysis. The Raman spectra of metformin hydrochloride crystal along the xyz axes were recorded and resolved into components along the abc axes. Using the abc components, Raman mapping of metformin hydrochloride in tablets was performed to visualize the crystal orientation at each data point. Results: Metformin hydrochloride crystals recrystallized from water/ethanol formed a primitive monoclinic cell. Datasets of five distinct peak areas from the metformin hydrochloride Raman spectrum were used for analyses. Raman crystal orientation mapping (RCOM) from the tablet cross-section provided an image of primary particles within the aggregation cluster of metformin hydrochloride in the tablet. Conclusion: Based on the RCOM, we developed a visualization method for primary API particles in tablets. Because the morphology of primary particles is the key factor of formulation function, this method would contribute to better formulation development and quality control.

Fast and quantitative 2D and 3D orientation mapping using Raman microscopy

“…Raman microscopy is often used for chemical mapping of pharmaceutical and biological materials 56 . It has been shown that PRM can be used to visualize particles on the surface of tablet formulations 57 , however so far no quantitative information on the orientation of single particles has been provided. Here, we performed a content uniformity Raman measurement on a tablet containing carbamazepine dihydrate (CBZD) and polyvinylpyrrolidone (PVP).…”

General Method for the Identification of Crystal Faces Using Raman Spectroscopy Combined with Machine Learning and Application to the Epitaxial Growth of Acetaminophen

“…For example, in the PXRD method, Rietveld refinement, , Le Bail fit , or a comparison of angles and faces with a known isotypic compound is required. On the other hand, optical goniometry requires one to obtain interfacial angles from crystals , and the SEM method requires to extract angular measurements from photographs. ,, Analysis of crystal morphology is also possible using Raman spectroscopy. − Moriyama et al have used Raman microscopy to determine the crystal habit of the organic crystal phenytoin . However, to the best of our knowledge in all reported examples Raman spectroscopy was only used to characterize well-grown single crystals and the possibility of using Raman spectroscopy as an alternative method for face indexing in complex multicrystalline systems has not been investigated thus far.…”