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.

Magnesium stearate (Mg-St), which is currently available on the market, has a wide variety of properties, including pseudopolymorphism, relative content of stearic acid in fatty acid, and particle size. These properties of Mg-St influence manufacturing processes of pharmaceutical products, and therefore, it is necessary to control the quality of Mg-St from suppliers. The purpose of this study was to evaluate the low-frequency region of Raman spectroscopy for identification of pseudopolymorphism in Mg-St. Ten samples of Mg-St obtained from different suppliers were measured by powder X-ray diffraction (PXRD) and thermogravimetry and differential thermal analysis (TG-DTA) to identify the pseudopolymorphism of Mg-St. Then we investigated the relationship between their Raman spectra, including the low-frequency region, and pseudopolymorphism. The results were categorized as four types of Mg-St, namely, mono-, di-, and trihydrate and their mixture. The conventional region of the Raman spectrum (greater than 200 cm −1 ) was able to identify pseudopolymorphism to a certain degree, but it was not easy to completely distinguish pseudopolymorphism for the mixture of Mg-St. In contrast, the lowfrequency region of the Raman spectrum (less than 200 cm −1 ) was able to clearly distinguish them. These data suggest that Raman spectroscopy, especially in the low-frequency region, is an effective method for rapid identification of pseudopolymorphism in Mg-St.

To enable the continuous production of cocrystal-containing pharmaceutical tablets, guaranteeing the cocrystal content of the final pharmaceutical tablets in the solid state is critical. This study demonstrates the quantification of caffeine-glutaric acid cocrystals in model tablets using transmission low-frequency Raman spectroscopy. Although distinguishing between cocrystals and raw materials using conventional Raman spectroscopy is difficult, the use of low-frequency Raman spectroscopy enables the discrimination of cocrystals and raw materials. Low-frequency Raman spectra were analyzed by the partial least-squares method (PLS) to obtain the predicted contents in the model tablets. To evaluate the quantitative ability of this method, the root means square error of cross-validation (RMSECV) was determined by comparing the actual concentration and predicted content with a calibration curve. For cocrystal-containing tablets, the quantitative ability of the transmission mode (RMSECV = 2.06- 3.17) was 13.4–31.4% higher than that of the backscattering mode (RMSECV= 2.37- 3.91). The coexistence of raw crystalline materials did not affect the quantitative ability for cocrystals.