Manipulating cocrystal size and morphology using a combination of temperature cycling and additives

Civati, Francesco and Svoboda, Vaclav and Urwin, Stephanie Jane and McArdle, Patrick and Erxleben, Andrea and Croker, D. and Ter Horst, Joop (2021) Manipulating cocrystal size and morphology using a combination of temperature cycling and additives. Crystal Growth and Design, 21 (3). pp. 1496-1506. ISSN 1528-7483 (

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A cooling crystallization of benzoic acid and isonicotinamide in ethanol yields the 1:1 cocrystal with an extreme needle-like morphology with an initial mean aspect ratio of ∼10 and a size of ∼64 μm. We demonstrate that the use of suspension temperature cycling in combination with tailor-made additives alleviates such extreme needle-like morphologies and increases the average particle size of this cocrystal material. Temperature cycling of the cocrystal suspensions in ethanol alone reduces the mean aspect ratio from 10 to 3.3 while it increases the average crystal size from 64 to 450 μm. The further addition of low concentrations of benzamide or nicotinamide suppresses the growth rate at the tip of the needle even more, resulting in a more favorable equant morphology. An iterative mechanism in which additives are incorporated in the lattice structure and released during the temperature increase in each cycle is proposed. Thus, the incorporation of an additive at the normally fast growing and potential needle tips and its release during the temperature increase part of the cycle effectively makes an additive action catalytic. The simultaneous use of temperature cycling and tailor-made additives offers a new and effective approach for the elimination of unsatisfactory needle-like crystal morphologies and a small crystal size during the production of a pharmaceutical cocrystal material.


Civati, Francesco, Svoboda, Vaclav ORCID logoORCID:, Urwin, Stephanie Jane, McArdle, Patrick, Erxleben, Andrea, Croker, D. and Ter Horst, Joop ORCID logoORCID:;