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 the solute concentration with a root-mean-square-error of prediction of 2.46 mg/mL. The repeatability and intermediate precision were evaluated, and the relative standard deviation is below 5%. The limit of detection for the metastable form was determined by monitoring the ratio of characteristic peaks when increasing the percentage of the metastable form in the total amount of crystals in the solution. A significant change in the peak ratio is observed when 22.9% of the crystals are of the metastable form. In addition, this PAT method was used to monitor a continuous run for 10 residence times, in which the system reached a controlled state of operation after six residence times.

• U.S. Food and Drug Administration (FDA)
• Purdue University

• API
• PAT

1. API
2. Continuous crystallization
3. Method development
4. Method validation
5. pat
6. Process analytical technology (PAT)
7. Raman microscopy
8. Research Article