Quantitative Monitoring of Cocrystal Polymorphisms in Model Tablets Using Transmission Low-Frequency Raman Spectroscopy.

Cocrystallization is a technique for improving the physical properties of active pharmaceutical ingredients. However, cocrystals can transform into more stable polymorphs as well as dissociate to original materials. Therefore, an analytical technique is required to determine the polymorphic transformation quickly and accurately in tablets. The purpose of this study is to develop a method to monitor cocrystal polymorphs in model tablets using transmission low-frequency Raman spectroscopy. The tablets, consisting of only metastable polymorphs of caffeine-glutaric acid cocrystals, were stored under various relative humidity levels. The composition of the cocrystal polymorphs were calculated from a calibration curve relating the actual composition to the predicted values calculated by partial least squares regression processing of low-frequency Raman spectra. The metastable form gradually converted to a stable form, and polymorphic phase transformation occurred with increasing relative humidity. Ninety-six percent of the metastable form converted into a stable form stored at 25 °C after 3 h at 95% RH. In conclusion, transmission low-frequency Raman spectroscopy can be used to quantitatively monitor cocrystal polymorphs. This technique is one of the candidate techniques to quantifiably evaluate the physico-chemical stability of cocrystal polymorphs in tablets.

Solid-State Quantification of Cocrystals in Pharmaceutical Tablets Using Transmission Low-Frequency Raman Spectroscopy.

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.