Raman Spectroscopy for Monitoring the Continuous Crystallization of Carbamazepine

Abstract

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.

Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review

“…Chord length and chord length distribution can be translated into crystal size and CSD, based on the offline determination (microscope) of crystal size, distribution, and crystal morphology. Spectroscopy technologies such as ATR-FTIR and ATR-UV/vis are mainly used to monitor the concentration of solutes based on the correlation between the peak heights in the associated absorption spectrum and the concentration. ,,,− These data can also be used for steady-state and kinetics determination. , On the other hand, Raman spectroscopy can be used for polymorphism determination ,, and, like the other two spectroscopic methods mentioned, also for concentration monitoring. ,, The output of the PVM method is an in-process image and is used for process characterization. The images obtained are usually used to enhance the CSD determined by an FBRM approach and also to assess crystal morphology. , For temperature monitoring are typically acquired thermocouples. ,, …”

Recent Progress in Continuous Crystallization of Pharmaceutical Products: Precise Preparation and Control

“…Thus, repetitive collection of data with long scanning times should be required to achieve stabilized test results. , Esmonde-White et al gave a general introduction about the application of continuous manufacturing in the biological and pharmaceutical industries. Acevedo et al developed a comprehensive method that could monitor the bulk concentration and quantified the metastable polymorphic form above the base detection line of carbamazepine in cooling continuous crystallization. Li et al established a Raman method during batch and continuous manufacturing processes of acetaminophen that could precisely quantify the content of the API powder during tablet compression.…”

In situ non-invasive Raman spectroscopic characterisation of succinic acid polymorphism during segmented flow crystallisation

“…the size of an immersion probe induces unwanted influence on the flow profile of the crystalliser and is prone to causing nucleation and growth on the probe. 6 This alters the crystallisation profile, has a deleterious effect on the ability of the probe to representatively sample the crystallisation environment and ultimately leads to blockage and failure of the crystalliser.…”

“…Due to the complications of integrating Raman into crystallisation environments, previously published examples of exploring crystallisation processes through Raman spectroscopy have either used microscopy in static environments [14][15][16] or immersion probes in batch, 6,[17][18][19] mixed suspension mixed product removal (MSMPR) 5 and hot melt extrusion (HME) 20 environments.…”