Raman Spectroscopy for Monitoring the Continuous Crystallization of Carbamazepine

Crystallization has a significant impact on the properties of the active pharmaceutical ingredient (API) since it is the final step in the manufacturing of the drug substance and determines particle size distribution, purity, shape, and polymorphs. Many publications have focused on the implementation of Process Analytical Technology (PAT) tools for monitoring batch and continuous operation; however, a comprehensive method development and validation of Raman spectroscopy to monitor continuous crystallization has not been presented. This work demonstrates the development and validation of a method to monitor the solute concentration of Carbamazepine and quantifies the limit of detection for a metastable polymorphic form. The experiments were based on the cooling crystallization of Carbamazepine to produce the most stable form. The method was validated following the principles described in USP general chapter ⟨1225⟩ validation procedures for analytical methods. The results demonstrate the model can predict t...