Crystallization is of prime importance in the pharmaceutical industry as more than 80% of the active pharmaceutical ingredients are produced in crystalline form. The crystallization step has a strong effect on the desired polymorphic form, crystal size distribution and shape of crystals. These critical properties then affect the downstream processing as well as the therapeutic response of the drug. Nucleation and crystal growth are the governing phenomena characterising most of the crystallization processes. To control a desired balance between nucleation and growth in industry normally an open loop control strategy is employed when the system follows a preset cooling profile [1]. The quality of product obtained as a result of this is often not satisfactory and is characterised by large batch-to-batch variability as the control does not account for any dynamic changes in the system due to disturbances or scale-up. A key objective in the design of crystallization operating recipes is to obtain consistent product quality and avoid excessive secondary nucleation. The industrial practice to achieve this objective is to use seeded operation. However, the production of seed with consistent properties, such as size distribution or polymorphic form is difficult. In the case of unseeded operation when the “seed” is generated in situ the initial size distribution at the onset of nucleation is uncertain, which will lead to variability in the product quality. Due to the advent of process analytical technology and increased availability of sophisticated equipment which can be used in situ, the control of crystallization processes has improved significantly in recent years [2, 3].

Supersaturation control (SSC) is more and more commonly used today for improved consistency in the final crystalline product quality for cooling and antisolvent crystallization systems [1,2,4]. The idea of supersaturation control is to control the process within the metastable zone so that secondary nucleation or the formation of undesired polymorphs is avoided. The design of the SSC requires the choice of a supersaturation setpoint or profile within the metastable zone. The performance of the SSC depends on the correct determination of the MSZW. However the boundaries of the MSZW can change significantly due to changing mixing conditions during scale-up. Therefore a supersaturation operating profile designed on smaller scale may not be effective on the industrial scale. The cloud point (nucleation) can be detected by modern process analytical equipment. However the nucleation boundary of the MSZW is the combined result of the actual nucleation (formation of critical cluster) and growth to the detectable size. This contribution evaluates the use of different PAT for the detection of the MSZW at two different scale reactors. Focused beam reflectance measurement (FBRM), attenuated total reflectance (ATR) Fourier Transform Infrared (FTIR) and UV spectroscopy, together with calorimetric measurements and image analysis will be corroborated for the detection of MSZW. The advantages and caveats of each method will be presented. For the determination of the robust operating zone in the phase diagram a series of experiments with all the aforementioned PAT tools are conducted under different operating conditions to estimate the uncertainties on the boundaries of the MSZW. The small scale experiments are performed in a 50 mL patented calorimetric reactor [5]. The reactor temperature is controlled using the principle of power compensation. In order to compensate changes of the heat transfer through the reactor wall, Peltier elements are incorporated between the jacket and the surrounding heat exchanger. Combining the principles of power compensation and heat balance calorimetry, the reactor allows the direct measurement of the heat release without any additional calibration.

According to our knowledge this is the first time when crystallization experiments are conducted with simultaneous monitoring of five different in situ signals from the system (FBRM, ATR-UV, ATR-FTIR, in situ image analysis, and calorimetric measurement).

Larger scale MSZW experiments are also performed on a 100L scale reactor and the effect of the scale up on the MSZW is evaluated. A systematic methodology is proposed based on PAT based MSZW experiments to determine a robust operating zone which can be used as the operating envelop for supersaturation controlled crystallization systems, to design the operating curves which are robust against scale-up and minimize variability in the final product quality.

References

[1] Nagy, Z. K. , J.W. Chew, M. Fujiwara, and R. D. Braatz, Comparative performance of concentration and temperature controlled crystallizations, Journal of Process Control, 18 (3-4), 399-407, 2008.

[2] M. Fujiwara, Z. K. Nagy, J. W. Chew, R. D. Braatz, First-principles and direct design approaches for the control of pharmaceutical crystallization, Journal of Process Control, 15, 493-504, 2005.

[3] Doki, N., Seki, H., Takano, K., Asatani, H., Yokota, M. and Kubota, N., Process Control of Seeded Batch Cooling Crystallization of the Metastable -Form Glycine Using an In-Situ ATR-FTIR Spectrometer and an In-Situ FBRM Particle Counter, Crystal Growth & Design, 4 (5), 949-953, 2004.

[4] Zhou, G. X., M. Fujiwara, X. Y. Woo, E. Rusli, H.-H. Tung, C. Starbuck, O. Davidson, Z. Ge, and R. D. Braatz, Direct design of pharmaceutical antisolvent crystallization through concentration control, Crystal Growth & Design, 6 (4), 892 -898, 2006.

[5] Zogg A., Fischer U., Hungerbühler K. A new small scale reaction calorimeter that combines the principles of power compensation and heat balance. Industrial and Engineering Chemistry Research (2003) 42: 767-776