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Crystal Nucleation of Tolbutamide in Solution: Relationship to Solvent, Solute Conformation, and Solution Structure
Univ Limerick, Mat & Surface Sci Inst, Chem & Environm Sci, Limerick, Ireland..
Univ Limerick, Mat & Surface Sci Inst, Chem & Environm Sci, Limerick, Ireland..
Univ Limerick, Mat & Surface Sci Inst, Chem & Environm Sci, Limerick, Ireland..
Univ Limerick, MACSI, Dept Math & Stat, Limerick, Ireland..
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2018 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 19, p. 4916-4926Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018. Vol. 24, no 19, p. 4916-4926
Keywords [en]
crystal nucleation, density functional theory, FTIR spectroscopy, molecular dynamics, tolbutamide
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-226769DOI: 10.1002/chem.201705954ISI: 000429414100027PubMedID: 29431236Scopus ID: 2-s2.0-85043240171OAI: oai:DiVA.org:kth-226769DiVA, id: diva2:1203523
Funder
Swedish Research Council, 621-2010-5391
Note

QC 20180503

Available from: 2018-05-03 Created: 2018-05-03 Last updated: 2018-05-03Bibliographically approved

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