Optimization of an Enantioselective Crystallization

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The Problem

A candidate progressing rapidly in Phase I needed process improvements to enable delivery for expanded clinical trials, but a low yield enantioselective crystallization was putting the timeline at risk.  

The Breakthrough

By building a ternary phase diagram to understand the eutectic composition and using PAT to navigate the kinetic landscape the necessary process understanding was obtained to conduct ultra-rapid process development.  

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The Impact

​In 18 weeks crystallization processes were designed and scaled up to the CMO. The new process reduced the number of steps required, delivered consistent particle size, ensured heavy metal impurities stayed within specification, and ultimately increased yield from 87% to 98%.  

Ternary Diagrams as a Tool for Process Definition

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Enantiomeric crystallization processes are challenging to develop with many thermodynamic and kinetics considerations to account for. From the rate of addition of the resolving agent to the collection of eutectic composition information, these processes contain inherent design challenges which often result in an output with low purity and yield. Frequently yield and purity are only increased at the expense of longer processes that become challenging to scale up and run in manufacturing.

With this challenge in mind, APC scientists developed an approach to enantiomeric crystallization process development that combines building a ternary phase diagram with PAT enabled kinetic profiling to unlock the thermodynamic and kinetics insights needed to support ultra-fast process development for these challenging crystallization processes.

This breakthrough enabled a medium-sized pharmaceutical company to increase the enantiomeric excess from 92% to >99% for a product that was moving rapidly through Phase 1. This was accomplished while also navigating a highly challenging impurity landscape caused by variability in heavy metal content in the final product.

With enhanced process understanding delivered via a data-rich approach to experimentation, the correct process parameters were chosen. This enabled a process that delivered the yield and purity improvements required while ensuring the heavy metal content was within specification. A significantly shorter process also made scale-up and productivity improvements possible at the CMO ensuring early phase clinical supply was met for a promising oncology candidate.