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The Effects of Humidity on Spontaneous Cocrystallization: A Survey of Diacid Cocrystals with Caffeine, Theophylline, and Nicotinamide

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Abstract

Pharmaceutical cocrystals comprise one active pharmaceutical ingredient (API) and at least one small molecule excipient coformer. While solvent evaporation and mechanochemistry are the preferred methods for their synthesis, some cocrystals are known to form spontaneously at ambient conditions when powders of input materials are mixed—a process not yet fully understood. Aqueous humidity is also known to accelerate spontaneous cocrystal formation. We report here the extent of spontaneous cocrystallization for 14 cocrystal systems, at four levels of humidity. The binary cocrystals in our study consist of a model API (caffeine, theophylline, nicotinamide) and a small chain diacid coformer (oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, glutaric acid). The spontaneous cocrystal formation was monitored ex situ by powder X-ray diffraction over several weeks. Our results show cocrystal formation in all 14 systems to varying extent and are consistent with literature reports that higher humidity correlates with more rapid cocrystal formation. We find that cocrystals containing smaller coformers often form faster. Based on our findings, we identify several cocrystals as candidates for future study.

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Abbreviations

CA:

Caffeine

TH:

Theophylline

NA:

Nicotinamide

OA:

Oxalic acid

MA:

Malonic acid

ME:

Maleic acid

FU:

Fumaric acid

SU:

Succinic acid

GA:

Glutaric acid

PXRD:

Powder X-ray diffraction

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Acknowledgements

We thank Mr. William Mohler and Mr. Michael Miller of Oberlin College for their assistance at various stages of this project.

Funding

Funding for this research was provided by National Science Foundation, RUI (Awards CHE-1464948 and CHE-2100582); National Science Foundation, MRI (Award DMR-0922588). Support is also acknowledged from Oberlin College.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Oberlin College, 119 Woodland Street, Oberlin, OH, 44074, USA

    Riley D. Davies, Nicolas J. Vigilante, Aaron D. Frederick, Venkata S. Mandala & Manish A. Mehta

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  1. Riley D. Davies
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  2. Nicolas J. Vigilante
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  3. Aaron D. Frederick
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Correspondence to Manish A. Mehta.

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Davies, R.D., Vigilante, N.J., Frederick, A.D. et al. The Effects of Humidity on Spontaneous Cocrystallization: A Survey of Diacid Cocrystals with Caffeine, Theophylline, and Nicotinamide. J Chem Crystallogr 52, 479–484 (2022). https://doi.org/10.1007/s10870-022-00922-8

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  • DOI: https://doi.org/10.1007/s10870-022-00922-8

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