Fixing formulation problems through particle shape control

The Problem

• Low bulk density and poor flowability of needle-shaped crystals were making formulation of a clinical-stage asset troublesome.

The Breakthrough

• Computational and experimental screens helped select a new solvent system that made kinetic control of particle shape possible.

The Impact

• The new crystallization process flowed better, had a higher bulk density, and enabled the delivery of formulations with faster dissolution rates.

Project Summary

Poor physical particle properties of APIs can cause significant issues for drug product formulations. Subtle changes in particle size, shape, and distribution can have a major impact on pharmaceutical solubility and stability. And low bulk densities can cause flow and formulation challenges during processing. 

With these challenges in mind, APC scientists developed an approach to crystallization process development that focuses on selecting a solvent-antisolvent system that enables the kinetic control of particle morphologies. A combination of computational and experimental screens target 100s of solvent candidates, quickly, so that fit-for-purpose solvents can be selected in record time. With a perfect solvent system selected - fast and effective process design is possible enabling tight control of particle morphology and other physical properties. This first-principles approach dramatically shortens development time, eliminates future rework and process redesign and enables formulators to quickly design effective solid oral dosage forms.

Workflow (above) for computational and experimental solvent screening and selection.

This approach was used to redesign the final API crystallization step for a lead clinical asset that was experiencing formulation issues. 177 solvent systems were screened computationally before targeted experimentation, focused on identifying particle morphology options, identified a suitable solvent-antisolvent system. This solvent choice enabled a rapid crystallization process redesign that delivered enhanced particle morphology and improved bulk density. Throughput was improved through the same isolation equipment and the dissolution rate of the final solid oral dosage forms was increased by 83%.  

Before (left) and after (right) process redesign: Improved bulk density (above) and morphology adjustment shown by SEM (below).