Particle Size Control of a Drug Substance through Process Crystallization

The solid state characteristics of an Active Pharmaceutical Ingredient (API) have great impact on the Drug Product (DP) performances and its formulation development approach.

One Critical Quality Attribute (CQA) that has to be controlled in order to ensure the success of a given formulation strategy in terms of manufacturability is the API Particle Size Distribution (PSD). In this case study, the API (PSD) had to be controlled to produce a blend which was homogeneous and flowable once combined with the chosen excipients and, in parallel, to reduce the risk of segregation during the DP manufacturing process.

The initial drug substance batch available for the formulation prototype production and selection showed a D(v,0.9) around 350mm. A mechanical PSD reduction via FitzMill was required in order to tune the drug substance PSD to match the PSD of the chosen excipients to ensure proper blend flowability and homogeneity attributes as well as to mitigate the risk of segregation during the encapsulation. As the alternative, the control of the PSD via process crystallization was investigated. Ultimately an anti-solvent mediated seeded crystallization process was developed. This process was able to deliver drug substance in the desired PSD range and avoided the need for post isolation milling.