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Crystal nucleation of tolbutamide in solution: relationship to solvent, solute conformation, and solution structure

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Show simple item record Zeglinski, Jacek Kuhs, Manuel Khamar, Dikshitkumar Hegarty, Avril C. Devi, Renuka K. Rasmuson, Åke C. 2018-08-21T14:21:30Z 2018
dc.description peer-reviewed en_US
dc.description.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. en_US
dc.language.iso eng en_US
dc.publisher Wiley and Sons Ltd en_US
dc.relation.ispartofseries Chemistry: A European Journal;24 (19), pp. 4916-3926
dc.rights This is the peer reviewed version of the following article: Crystal Nucleation of Tolbutamide in Solution: Relationship to Solvent, Solute Conformation, and Solution Structure Dr. Jacek Zeglinski,Dr. Manuel Kuhs,Dr. Dikshitkumar Khamar,Dr. Avril C. Hegarty,Dr. Renuka K. Devi, Prof. Dr. Åke C. Rasmuson Chemistry: A European Journal 2018, 24 (19), pp 4916-4926 which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
dc.subject crystallization processes en_US
dc.subject product crystal structure en_US
dc.title Crystal nucleation of tolbutamide in solution: relationship to solvent, solute conformation, and solution structure en_US
dc.type info:eu-repo/semantics/article en_US
dc.type.supercollection all_ul_research en_US
dc.type.supercollection ul_published_reviewed en_US
dc.identifier.doi 10.1002/chem.201705954
dc.contributor.sponsor SFI en_US
dc.contributor.sponsor HEA en_US
dc.contributor.sponsor Swedish Research Council en_US
dc.relation.projectid 10/IN.1/B3038 en_US
dc.relation.projectid 621-2010-5391 en_US
dc.relation.projectid 12/IA/1683 en_US 2019-02-12
dc.embargo.terms 2019-02-12 en_US
dc.rights.accessrights info:eu-repo/semantics/embargoedAccess en_US
dc.internal.rssid 2868433

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