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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. |
