Switching nitrofurantoin polymorphic outcome in solvent mediated phase transformation and crystallization using solvent and additives

19 May 2023, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


We demonstrate that several additives and solvents allow switching the polymorphic outcome of solvent mediated phase transformation experiments and crystallization of the antibacterial drug nitrofurantoin. Polymorph β is obtained from most of the solvents, whereas selection of alcohols as solvents or use of crystallization additives provides formation of polymorph α. We also demonstrate that this can be linked to reversed apparent relative solubility of nitrofurantoin polymorphs in these solvents or in presence of the respective additives. We propose that this could be caused by different surface-additive and surface-solvent interactions formed by each of the nitrofurantoin polymorphs, which would change the relative surface energy of polymorphs.


Pharmaceutical polymorphism
solvent mediated phase transformations
thermodynamic stability

Supplementary materials

Switching nitrofurantoin polymorphic outcome SI
Experimental details, Evaluation of relative stability of nitrofurantoin polymorphs, Crystal form outcome of crystallization, Nucleation induction times, Speciation in solution, Analysis of crystal structures and morphology of nitrofurantoin polymorphs, Characterization of α obtained in the crystallization from acetonitrile in presence of BIS-TRIS


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