Is Your Crystallization Development Workflow Ready For 2018?

Since 2004, Crystallization Systems is helping scientists around the world with process analytical technology (PAT) based small scale equipment providing solutions in crystallization development. Both the Crystal16 and Crystalline instruments can be used as a strategy for the development of a crystallization process. PAT implemented at scales as small as milliliters in medium-throughput equipment, enables the early acquisition of key data to select the best crystallization approach.

The development of crystallization processes based on the Crystal16 and Crystalline as PAT is a strategy for: 

  • Identification of best solvent media through high throughput solubility screens;
  • Identification of best approach to crystallization via small scale PAT; 
  • Understanding the properties of the solid/solvent system through PAT. 

The Crystalline instrument with integrated cameras offers a window into process kinetics and the weakness of a process arising from the potential formation of different solid state forms:

  • labile solvate/hydrate;
  • meta-stable polymorphic forms. 






Crystallization process optimization of a compound using the PV module of the Crystalline instrument



A recent study performed by CMAC and presented this year at ISIC in Dublin, shows that solubility and particle size data collected with the Crystalline instrument offers:

  • Initial estimates of crystallisation kinetics parameters as part of typical solubility measurement experiments;
  • Identification of most dominant crystallization phenomena by making use of the PV module;
  • ~57 % reduction in compound usage when compared with estimating parameters solely at lab scale (1 L).

The Crystal16 combines automation with integrated turbidity measurement to determine clear and cloud points resulting in solubility data and nucleation curves. In order to understand the observed crystallization behavior of a compound, one needs to assess polymorphism, hydration, and solvation properties of the solid throughout the process development. Using the solubility curves and metastable zone width (MSZW), one is able to significantly improve a crystallization process.

As previously shown in a study performed by Pfizer and published in 2005, the solubility data collected with the Crystal16 helped to understand the crystallization behavior of one of their compounds. Pfizer managed in this way to identify a new solvent system preventing solvate formation. Additionally, they also identified a working temperature for the crystallization process which helped avoiding solvation.






Solubility and metastable zone edge curves for anhydrous and solvate forms of a Pfizer compound




The use of the particle view and Raman on the Crystalline instrument enables one to visualize the complete crystallization process and have real time particle size and shape information. Moreover, PAT enables the rapid identification of a crystallization protocol and its possible downfalls. 

Following the development of a crystallization process, further insight into process kinetics and robustness is highly needed for scale-up. The scale-up of the process enables formulation studies and helps understand whether material obtained via a specific route is viable.

As shown in various studies, the Crystal16 and Crystalline instruments offer a strategy for the rapid, material-efficient development of crystallization processes centered on the use of process analytical technology (PAT).

Cameron J. Brown, Niall Mitchell, Micro-scale process development and optimization for crystallization processes, Poster at ISIC Dublin 2017.
Melissa Birch, Steven J. Fussell, Paul D. Higginson, Neil McDowall, and Ivan Marziano, Towards a PAT-Based Strategy for Crystallization Development, Organic Process Research & Development, Vol. 9, No. 3, 2005, 360-364.