Crystallization is one of the most useful processes for the separation and purification of crystalline compounds. In crystallization processes, real-time monitoring is essential to obtain constant quality of crystalline compounds. This paper is the first to report in situ monitoring of crystalline transformations of active pharmaceutical ingredients by probe-type low-frequency Raman spectroscopy. In this study, carbamazepine was used as a model active pharmaceutical ingredient. We attempted to monitor the crystalline transformation of carbamazepine during heat treatment and the addition of solvent in a one-pot reaction. When carbamazepine form III was heated to 170 °C, the indicative spectrum of carbamazepine form I appeared over time. Subsequent addition of ethanol with heat treatment caused the carbamazepine form I spectrum to disappear. After cooling to room temperature, the spectrum of carbamazepine form III reappeared. To optimize the solvent ratio, we monitored carbamazepine form III as it dispersed into a mixture of ethanol/water with different compositions (75/ 25, 62.5/37.5, 50/50, 37.5/62.5, and 25/75 (v/v)). The spectra of carbamazepine dihydrate were observed in all solvent compositions. When the mixture of ethanol/water was 62.5/37.5 (v/v), the conversion time to carbamazepine dihydrate was fastest. Therefore, probe-type lowfrequency Raman spectroscopy can be used for the in situ monitoring of crystalline transformation and may become a useful process analytical technology technique.
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 4hydroxybenzoic acid using a Raman microscopy system equipped with a measurement module to access the lowfrequency 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.
The purpose of this study was to quantify polymorphs of active pharmaceutical ingredients in pharmaceutical tablets using a novel transmission low-frequency Raman spectroscopy method. We developed a novel transmission geometry for low-frequency Raman spectroscopy and compared quantitative ability in transmission mode versus backscattering mode using chemometrics. We prepared two series of tablets, (1) containing different weight-based contents of carbamazepine form III and (2) including different ratios of carbamazepine polymorphs (forms I/III). From the relationship between the contents of carbamazepine form III and partial least-squares (PLS) predictions in the tablets, correlation coefficients in transmission mode (R 2 = 0.98) were found to be higher than in backscattering mode (R 2 = 0.97). The root-mean-square error of cross-validation (RMSECV) of the transmission mode was 3.9 compared to 4.9 for the backscattering mode. The tablets containing a mixture of carbamazepine (I/III) polymorphs were measured by transmission low-frequency Raman spectroscopy, and it was found that the spectral shape changed according to the ratio of polymorphs: the relationship between the actual content and the prediction showed high correlation. These findings indicate that transmission low-frequency Raman spectroscopy possesses the potential to complement existing analytical methods for the quantification of polymorphs.
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