(469a) Digital Design Via Mechanistic Modelling of a Continuous Crystallization Process with Periodic Wet Milling

The attainable regions for critical quality attributes, such as Particle Size Distribution (PSD) and impurity levels, in the manufacture of Solid Oral Dosage Forms (SODF) can be highly dependent upon the type and operation of the crystallization process. In this work, we outline a step-wise workflow consisting of model validation, model-based technology transfer and process optimisation employed for the digital design of a continuous cascade cooling crystallization and wet milling process for manufacturing an Active Pharmaceutical Ingredient (API). Following this workflow, the mechanistic model was first validated using batch crystallization data and subsequently applied to describe the continuous crystallization process and with continuous and periodic wet milling, and explore the impact of varying process parameters, including duration of milling, rotor speed and frequency of milling operation during the crystallization process.

The step-wise approach taken for model validation and its subsequent application was as follows:

1. Model validation of crystallization kinetics for the pure API solid phase from batch de-supersaturation experimental runs.
2. Application of the validated crystallization kinetics to describe the continuous crystallization of pure API in a three-stage cascade process, as shown in Figure 1 below (wet milling was not considered at this stage).
3. Model validation of breakage kinetic parameters using batch data from a wet milling unit operated in a recycle with a batch crystallizer. A rotor-stator wet mill was utilised for this process, with a range of rotor frequencies and milling head generator configurations probed to assess the impact on the PSD over time and to fit the breakage kinetic parameters. Subsequent refinement of the breakage kinetic parameters utilizing continuous crystallization experiments, where intermittent/periodic wet milling was employed using an immersion wet mill in the first stage crystallizer.
4. Scenario analysis of the continuous crystallization and periodic wet milling process for this API, looking at the impact of process parameters on the Critical Quality Attributes (CQAs) of the product, including product PSD and dimer phase formation (impurity).

Conclusions

The main conclusions of the work include the following:

• The continuous crystallization process was unable to achieve the desired product PSD without wet milling, due to very low levels of secondary nucleation in the system. Optimal PSD quantiles (d10, d50 and d90) predicted for the product were significantly higher than the target PSD quantiles required to achieve the desired product performance for this compound.
• Addition of a wet milling step in a recycle with the continuous crystallization significantly increased the lower end of the attainable region in terms of PSD quantiles and impurity level, allowing the process to comfortably achieve the desired range for product PSD quantiles.
• Mechanistic modelling approaches can be utilised to significantly reduce the development timelines, material consumption and efficiency of continuous API crystallization production processes, in particular cases where periodic operation of some units, in this case the wet mill, are employed.