CrystalBreeder: the perfect tool to investigate inhibition or promotion of crystallization

The CrystalBreeder takes the guesswork out of solid-state screening.

The crystallization space can be systematically explored with the ability to control temperature profiles, stirring speed and crystallization mode. Whether you are searching for new polymorphs, or doing salt or co-crystal screens, the turbidity signal gives you a clear indication of a hit. The compatible software makes it effortless to scale up to a millilitre scale for solubility studies or MSZW determination by using the Crystal16® or Crystalline.

The solubility of a compound in organic solvents or water is equally important for screen design and later for process development.  For designing a screen, for instance around cooling crystallization, you need to select solvents that have enough solubility and that have a high dependency of solubility on temperature. In addition, a selection of solvents and mixtures that spans the range of possible chemical functionalities will maximize the chances of finding new, interesting and developable solid forms.

The CrystalBreeder, Crystal16 and Crystalline provide the ideal tools to efficiently gather and analyse solubility data.

Polymers are known to play an important role in crystallization processes of active ingredients either as adjuvant or inhibitor. Matzger et al published in 2019 a study showing the solubility of polymers can either speed up or slow down a crystallization process. With the use of a CrystalBreeder or Crystal16, one can easily determine the solubility of a compound in water or organic solvent.

Further Matzger et all used the CrystalBreeder to monitor the crystallization by the changes in solution turbidity. The authors have performed 80 induction times for each crystallization condition in order to assess the effects of the different polymers. The CrystalBreeder offered Matzger et al an easy, effective and automatic way to perform multiple experiments in the same time.  Additionally, the CrystalBreeder with the feedback control functionality enables you to easily detect when the compound is completely dissolved (clear point) and controls crystallization by triggering the next temperature-controlled step (cloud point).

Matzger et al tested if insoluble polymers accelerate crystallization and soluble polymers inhibit crystallization. The authors have found that the same functional groups that promote heteronucleation on an insoluble polymer also promote crystallization inhibition by using a soluble polymer. Nevertheless, the authors further mention that the ability of water-soluble polymers to inhibit crystallization is more sensitive to the functional group chemistry than the ability of insoluble polymers to accelerate crystallization.

References

Technobis Crystallization Systems is grateful to Prof Adam Matzger et al for their support with this case study.

• Derek S. Frank, Qingyuan Zhu, Adam J. Matzger, Mol. Pharmaceutics 2019, 16, 8, 3720-3725