(125g) Achieving Particle Size and Impurity Control for a Continuous Crystallization Process Using a Digital Design Approach

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 and
wet milling process, and explore the impact of varying process parameters and
process configurations (namely the position of the wet mill unit in the
continuous crystallization process – in recycle with the first or the third crystallization
stages) on the attainable processing regions for particle size and purity, subject
to various process constraints.

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. Refinement of the crystallization kinetic parameters for the pure API solid phase, utilising targeted data sets suggested by the model fitted in 1 using batch data sets.
4. Optimisation of the continuous crystallization process without wet milling to determine its feasibility.
5. 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.
6. Optimisation of the combined crystallization and wet milling process for pure API to achieve a target product PSD. The configuration of the process, in terms of the position of the wet mill unit, in a recycle with the first or third crystallization stages, was also probed.
7. Model validation of crystallization kinetics for an API dimer solid phase from batch de-supersaturation experimental runs. The API dimer forms as a separate solid phase that can crystallize during the process and is considered to be a process impurity.
8. Optimisation of the combined crystallization and wet milling process for the pure API and API dimer solid phases (impurity) to achieve target product PSD and desired level of 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.
• In terms of configurations for the continuous process, it was found that having the wet mill placed in a recycle with the first crystallization stage was more effective at reducing product PSD and at decreasing the impurity level of the material produced, compared to having the wet mill placed in a recycle with the third stage.
• Mechanistic modelling approaches can be utilised to significantly reduce the development timelines, material consumption and efficiency of continuous API crystallization production processes.

Figure 1:
Simulation flowsheet used model for optimisation of continuous crystallization
and wet milling process.