Real-time probe-type Raman spectroscopy of CBZ crystal transition in the low-frequency region.

As a result of performing principal component analysis using the low-frequency Raman spectrum, it became possible to quantitatively analyze and evaluate the crystal transition.

In the pharmaceutical industry, there are active pharmaceutical ingredients with multiple crystal structures, which are said to influence various physicochemical properties such as solubility, depending on the intellectual property rights of the drug and polymorphism. Furthermore, it is known to affect the bioavailability of drugs, making it one of the most important tasks for originator, generic, and pharmaceutical companies, with crystal forms and impurities often selected as Critical Quality Attributes (CQA). In industrial crystallization, the goal is to separate impurities and control the crystal structure and particle size distribution of the product crystals. However, many phenomena related to crystallization remain unclear, despite the use and investigation of inline analytical techniques such as FBRM, FT-IR, near-infrared, and Raman spectroscopy. Raman spectroscopy is known to have a clear advantage over other inline analytical techniques in that it can quantitatively operate crystal transitions. This paper presents the practical applicability and usefulness of low-frequency Raman spectroscopy by equipping a Raman spectrometer with a low-frequency Raman module, which has recently been commercialized and enables measurement of low-frequency Raman spectra, and conducting real-time observation of crystal transitions using CBZIII form as a model formulation.

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