(203l) PAT on Oscillatory Systems: Monitor and Control Continuous Crystallization with Fourier Transform Infrared (FTIR) Spectrometer

Most pharmaceutical manufacturing processes include a crystallization step to purify active pharmaceutical ingredients (APIs). Despite its long history, difficulties associated with crystallization control prevail due to its complex kinetics.¹ However, process analytical technologies (PAT) have improved swiftly allowing for crystallization monitoring and control.² Traditionally, crystallization is carried out in batch which often results in batch-to-batch variation.³ Continuous crystallization, on the other hand, is promising for its enhanced reproducibility and narrower property distributions amongst other improvements.⁴ Continuous crystallization has become a key step in the current trend to reform the pharmaceutical industry from batch to continuous manufacturing. A well-studied system for continuous crystallization is the Mixed-Suspension-Mixed-Product-Removal (MSMPR) crystallizer in which the hydrodynamics are controlled with an agitator. There are many challenges associated with stirred tank systems such as poor local mixing, low heat and mass transfer, and varying shear rate.⁵ To address these challenges, a novel commercial oscillatory baffled reactor (OBR) has been studied. It consists of a reactor tank and oscillating ‘donut’ shaped baffles to provide more uniform mixing.⁶ Such systems have been well studied for API synthesis and are gaining interest for crystallization given their enhanced mass and heat transfer characteristics while imposing less shear rate, ideal for crystallization.⁷ However, control strategies for continuous crystallization in such oscillatory systems have yet to be studied in the literature. The difficulty controlling continuous crystallization in an OBR stems from inadequate measurement of key factors. Vibrations caused by the oscillating motion often interfere with the signals of the PAT tools which consequently result in inconsistent readings.

A model-free control strategy for continuous cooling crystallization of paracetamol in the OBR is implemented in this study. Supersaturation control (SSC) is a model-free technique where concentration is monitored and supersaturation level is controlled by adjusting operating conditions such as temperature for the case of cooling crystallization. SSC has been well studied in MSMPR systems.^8,9 An SSC implementation was carried out for continuous crystallization in the OBR via CryMOCO, a commercially available integrated control software, a Huber thermo-regulator with a temperature sensor and a FTIR spectrometer. The FTIR is equipped with the Interferogram correcting the signal interference from oscillations. It provides online measurements of solute concentration in solution used by CryMOCO to control supersaturation. This study serves as a proof-of-concept for continuous crystallization SSC control in oscillatory systems.

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