Particle Size Control in Batch Crystallisation of Pyrazinamide on Different Scales

In the past, the particle size of finished APIs was mostly controlled by processes such as milling and micronization, but this often creates fines and can lead to formulation issues for some compounds. More recently companies are trying to control the particle size of the product as part of the crystallisation process (not forgetting that the filtration and drying can change the PSD by processes such as agglomeration). While there is a lot of good academic research on the factors that control the growth of crystals and the particle size distribution (PSD), often the scale up of chemical processes can lead to variations in PSD from batch to batch, leading to the conclusion that some unknown factors are having an effect. Even with controlled seeding variations in PSD can occur.

The group of Reginald Tan in Singapore ( OPRD DOI10.1021 acs.oprd.6b00327) has now studied the effects of seed size and loading, and the effect of stirrer speed on the scale up of a seeded batch crystallisation of a model compound pyrazinamide. The criterion of equivalent impeller tip speed on scale up produced crystals with D50 values that agreed with the empirical process model, whereas the criterion of equivalent input energy per unit volume produced smaller D50 values. The study provided a feasible experimental and modelling strategy to ensure consistent PSD from laboratory process development to small production scale.