Volume 24, Issue 19 p. 4916-4926
Full Paper

Crystal Nucleation of Tolbutamide in Solution: Relationship to Solvent, Solute Conformation, and Solution Structure

Dr. Jacek Zeglinski

Dr. Jacek Zeglinski

Materials and Surface Science Institute, Chemical and Environmental Science, University of Limerick, Limerick, Ireland

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Dr. Manuel Kuhs

Corresponding Author

Dr. Manuel Kuhs

Materials and Surface Science Institute, Chemical and Environmental Science, University of Limerick, Limerick, Ireland

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Dr. Dikshitkumar Khamar

Dr. Dikshitkumar Khamar

Materials and Surface Science Institute, Chemical and Environmental Science, University of Limerick, Limerick, Ireland

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Dr. Avril C. Hegarty

Dr. Avril C. Hegarty

MACSI, Department of Mathematics and Statistics, University of Limerick, Limerick, Ireland

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Dr. Renuka K. Devi

Dr. Renuka K. Devi

Materials and Surface Science Institute, Chemical and Environmental Science, University of Limerick, Limerick, Ireland

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Prof. Dr. Åke C. Rasmuson

Corresponding Author

Prof. Dr. Åke C. Rasmuson

Materials and Surface Science Institute, Chemical and Environmental Science, University of Limerick, Limerick, Ireland

Department of Chemical Engineering and Technology, KTH Royal Institute of Technology, Stockholm, Sweden

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First published: 12 February 2018
Citations: 48

Graphical Abstract

The crystal nucleation of tolbutamide in propanol, ethyl acetate and acetonitrile is governed by solvent–solute interaction strength. In toluene, however, the deciding factor is not the solvent–solute interaction strength, which is the weakest, but the propensity for the existence of intra-molecularly H-bonded (“wrong”) conformers. The results overall suggest that in case of tolbutamide the previously observed influence of desolvation on the nucleation process needs to be complemented by a second mechanism, namely the formation of crystal-incompatible conformers in solution.

Abstract

The influence of the solvent in nucleation of tolbutamide, a medium-sized, flexible and polymorphic organic molecule, has been explored by measuring nucleation induction times, estimating solvent–solute interaction enthalpies using molecular modelling and calorimetric data, probing interactions and clustering with spectroscopy, and modelling solvent-dependence of molecular conformation in solution. The nucleation driving force required to reach the same induction time is strongly solvent-dependent, increasing in the order: acetonitrile<ethyl acetate<n-propanol<toluene. The combined DFT and MD modelling results show that in acetonitrile, ethyl acetate and n-propanol the nucleation difficulty is a function of the strength of solvent–solute interaction, with emphasis on the interaction with specific H-bonding polar sites of importance in the crystal structure. A clear exception from this rule is the most difficult nucleation in toluene despite the weakest solvent–solute interactions. However molecular dynamics modelling predicts that tolbutamide assumes an intramolecularly H-bonded conformation in toluene, substantially different from and more stable than the conformation in the crystal structure, and thus presenting an additional barrier to nucleation. This explains why nucleation in toluene is the most difficult and why the relatively higher propensity for aggregation of tolbutamide molecules in toluene solution, as observed with FTIR spectroscopy, does not translate into easier nucleation. Thus, our combined experimental and molecular modelling study suggests that the solvent can influence on the nucleation not only via differences in the desolvation but also through the influence on molecular conformation.

Conflict of interest

The authors declare no conflict of interest.