Crystal nucleation of tolbutamide in solution: relationship to solvent, solute conformation, and solution structure
journal contributionposted on 2023-01-17, 10:14 authored by Jacek Zeglinski, Manuel KuhsManuel Kuhs, Dikshitkumar Khamar, Avril C. Hegarty, Renuka K. Devi, AKE RASMUSONAKE RASMUSON
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.
PHILIP KAARET / UNIVERSITY OF IOWA FOSSIL JETS FROM BLACK HOLE TRANSIENTS RECENT XMM-NEWTON OBSERVATIONS HAVE LED TO THE DISCOVERY OF A LARGE SCALE X-RAY JET FROM THE LONG-TERM X-RAY TRANSIENT AND BLACK HOLE CANDIDATE 4U 175533. WE OBTAINED A FOLLOW-UP OB
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PublicationChemistry: A European Journal;24 (19), pp. 4916-3926
PublisherWiley and Sons Ltd
Other Funding informationSFI, HEA, Swedish Research Council
RightsThis 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 https://doi.org/10.1002/chem.201705954 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. http://olabout.wiley.com/WileyCDA/Section/id-828039.html#terms
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