Crystallisation research could enhance API drug production

Controlled solvent activity liquid-assisted grinding (CSA-LAG), a mechanochemistry-based method, has potential to significantly influence crystallisation workflows, according to research by a joint team at Durham University, UK, and Pfizer.

Theodosiou et al. anticipate that their thermodynamic-based framework could support robust development of CSA-LAG in drug manufacturing by providing a scalable, robust, efficient and adaptive mechanochemistry approach for mapping the thermodynamic landscapes of solvates and hydrates.

When applied to solid form manufacturing, phase diagrams are intended to aid the design and optimisation of processes and prevent unwanted conversions. However experimental elucidation “can be tedious and time consuming with ‘slurry experiments’ providing the gold-standard methodology”, the authors noted.

Notably, Theodosiou et al. found that CSA-LAG enabled accurate and rapid exploration of these diagrams for four pharmaceutical compounds forming hydrates and solvates with a variety of solvents.

“CSA-LAG reproduces slurry boundaries and quantifies activity thresholds for single, stepwise and competitive solvations”. Defining these boundaries helps to turn “a month-scale empirical screening into a rapid, thermodynamically guided workflow”.

Beneficially, it “requires far less material and time than traditional slurries and affords high reproducibility”.

This is notable because exposure to solvents during active pharmaceutical ingredient (API) manufacturing can result in undesired solid form transformations, explained Theodosiou et al.

They cited that their research offers potential given that “crystalline solvates are becoming more common in drug delivery”.

As such, it is appropriate that the sector has an adequate understanding of the thermodynamic and kinetic stabilities of pharmaceutical solvates and hydrates to support in their production, packaging and storage.

Overall, the study established that for small API amounts, CSA-LAG is a “robust method for probing crystallisation thermodynamics via mechanochemistry within minutes, setting a benchmark for the rapid, resource-efficient mapping of solvate landscapes”.

This research was published in Nature Communications.