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Dudek MK, Wielgus E, Paluch P, et al. Understanding the formation of apremilast cocrystals. Acta Crystallogr B Struct Sci Cryst Eng Mater. 2019;75:803-814doi: 10.1107/S205252061900917X.
Dudek, M. K., Wielgus, E., Paluch, P., Śniechowska, J., Kostrzewa, M., Day, G. M., Bujacz, G. D., & Potrzebowski, M. J. (2019). Understanding the formation of apremilast cocrystals. Acta crystallographica Section B, Structural science, crystal engineering and materials, 75803-814. https://doi.org/10.1107/S205252061900917X
Dudek, Marta K, et al. "Understanding the formation of apremilast cocrystals." Acta crystallographica Section B, Structural science, crystal engineering and materials vol. 75 (2019): 803-814. doi: https://doi.org/10.1107/S205252061900917X
Dudek MK, Wielgus E, Paluch P, Śniechowska J, Kostrzewa M, Day GM, Bujacz GD, Potrzebowski MJ. Understanding the formation of apremilast cocrystals. Acta Crystallogr B Struct Sci Cryst Eng Mater. 2019 Oct 01;75:803-814. doi: 10.1107/S205252061900917X. Epub 2019 Sep 07. PMID: 32830759.
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Acta Crystallogr B Struct Sci Cryst Eng Mater. 2019 Oct 01;75:803-814. doi: 10.1107/S205252061900917X. Epub 2019 Sep 07.

Understanding the formation of apremilast cocrystals.

Acta crystallographica Section B, Structural science, crystal engineering and materials

Marta K Dudek, Ewelina Wielgus, Piotr Paluch, Justyna Śniechowska, Maciej Kostrzewa, Graeme M Day, Grzegorz D Bujacz, Marek J Potrzebowski

Affiliations

  1. Centre of Molecular and Macromolecular Studies PAS, Sienkiewicza 112, Lodz, 90363, Poland.
  2. Computational Systems Chemistry, School of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK.
  3. Institute of Technical Biochemistry, Technical University of Lodz, Stefanowskiego 4/10, Lodz, 90-924, Poland.

PMID: 32830759 DOI: 10.1107/S205252061900917X

Abstract

Apremilast (APR), an anti-psoriatic agent, easily forms isostructural cocrystals and solvates with aromatic entities, often disobeying at the same time Kitaigorodsky's rule as to the saturation of possible hydrogen-bonding sites. In this paper the reasons for this peculiar behavior are investigated, employing a joint experimental and theoretical approach. This includes the design of cocrystals with coformers having a high propensity towards the formation of both aromatic-aromatic and hydrogen-bonding interactions, determination of their structure, using solid-state NMR spectroscopy and X-ray crystallography, as well as calculations of stabilization energies of formation of the obtained cocrystals, followed by crystal structure prediction calculations and solubility measurements. The findings indicate that the stabilization energies of cocrystal formation are positive in all cases, which results from strain in the APR conformation in these crystal forms. On the other hand, solubility measurements show that the Gibbs free energy of formation of the apremilast:picolinamide cocrystal is negative, suggesting that the formation of the studied cocrystals is entropy driven. This entropic stabilization is associated with the disorder observed in almost all known cocrystals and solvates of APR.

Keywords: apremilast; aromatic–aromatic interactions; cocrystal formation; periodic DFT (density functional theory); solid-state NMR

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