(83d) Super-Saturation Control In API Crystallization for Optimal Impurity Rejection and Particle Size Distribution

Understanding and control of crystallization process plays an important role in pharmaceutical API manufacturing. Major API quality attributes such as impurity profile, crystal form, and particle size distribution (PSD) are usually controlled in the crystallization process.

We present an integrated platform for real time super-saturation detection and control to meet the target impurity profile and final crystal PSD under certain solvent systems. High sensitive Mid-IR ATR probe (Mettler Toledo ReacIR^TM 45) is used for quantitative measurement of API concentration in liquid phase. Crystal size is characterized using a Focused Beam Reflectance Measurement (FBRM) probe (Mettler Toledo Lasentec D600). The software package developed by Professor Richard Braatz and his group is capable of integrating the signals from both IR and FBRM probes to be used in the platform^1,2.

By controlling a heating/cooling system and a solvent charge pump, this platform is automated to realize the following objectives: 1) determining meta-stable limit of an API compound for a given solvent system; 2) building a robust chemometric IR model for concentration quantification; 3) determining the quasi-equilibrium solubility as a function of temperature and solvent composition; 4) imposing feed-back control to follow a pre-determined super-saturation profile during cooling/anti-solvent crystallization process.

The above-mentioned platform is applied to two case studies. In the first case study, small particle sizes are desired, however, the current crystallization protocol produces large crystals that require a harsh milling. The correlation between desuper-saturation rate and final crystal PSD is achieved using the platform, enable us to obtain the target PSD without the need for milling. The second case study is to relate nucleation and initial crystal growth with impurity rejection. Previously knowledge about the API crystallization from its crude solution indicates that one or two impurities tend to co-crystallize with the API under certain conditions. It is desired to establish the operating range where this phenomenon can be suppressed, and we successfully applied this crystallization platform to achieve the objective.

References:

1. P. Barrett and B. Glennon, Characterizing the metastable zone width and solubility curve using Lasentec FBRM and PVM.
2. T. Togkalidou, H.-H. Tung, Y. Sun, A. Andrews, and R. D. Braatz. Solution concentration prediction for pharmaceutical crystallization processes using robust chemometrics and ATR FTIR spectroscopy. Org. Process Res. Dev., 6:317-322, 2002.