(223c) Monitoring Co-Crystal Purity with on-Line Raman Spectrascopy

Pharmaceutical co-crystals are defined as stoichiometric molecular complexes that contain an active pharmaceutical ingredient (API) and a coformer in crystal lattice via noncovalent interactions, predominantly hydrogen bonds. Compared with APIs themselves, pharmaceutical co-crystals have advantages in solid state properties, such as solubility, melting point, chemical interaction, stability and bioavailability. Solution crystallization is an important method to produce co-crystals. However, crystals of constituent components, either API or co-former, may crystallize out concomitantly due to operational fluctuations in starting composition or temperature, compromising the purity of co-crystals. Therefore, it is desirable to detect crystals of single components when they appear during co-crystallization, whereby corrective operation can be taken to ensure co-crystal purity. In this study, a methodology is developed to monitor co-crystal purity using Raman spectroscopy with caffeine-glutaric acid-acetonitrile as the model system. Caffeine and glutaric acid can form co-crystal from solution in acetonitrile at the appropriate conditions. Raman spectra were collected in three classes of suspensions with a solid mixture of caffeine crystals and co-crystals, pure co-crystals, and a mixture of glutaric acid crystals and co-crystals, respectively at different temperatures. Principal component analysis (PCA) was performed for these spectra and the resulting first few principal components were put to discriminant analysis. It was found that Raman spectroscopy is able to distinguish the three classes of suspensions clearly.

Key Words, co-crystal, PAT, Raman spectroscopy, crystallization, principal component analysis