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New Polymorph of Febuxostat Crystallized from Aqueous Solution with an Investigation of the Incidence of Pre-nucleation Clusters (PNCs) as Solute Precursors

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2024

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Crystal Growth & Design. ACS Publications. 2024, 24(17), S. 7104-7113. ISSN 1528-7483. eISSN 1528-7505. Verfügbar unter: doi: 10.1021/acs.cgd.4c00725

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A novel reproducible process for the preparation of Febuxostat (FX) using a double dosing titration method is achieved by titrating 80 mL of 3 mM Febuxostat sodium salt solution with 15 mM HCl and 6 mM Febuxostat sodium salt solution at a dosing rate of 0.2 mL/min. A new crystalline form (polymorph AQ) is prepared, which is characterized by being the exceptional form produced directly in an aqueous medium, in contrast to the known and registered forms that were produced only in organic solvent systems. The same crystal form is reproduced when crystallized at different temperatures ranging from 10 to 50 °C. However, the pH value at which the onset of nucleation occurs is affected due to its effect on nucleation kinetics. The key parameters affecting the metastable zone are studied. Decreasing the dosing rate can lead to narrowing of the metastable zone and delay in the onset of nucleation. Increasing the temperature can lead to widening of the metastable zone and delay in the onset of nucleation. Analytical ultracentrifugation (AUC) analysis was conducted on supersaturated solutions to investigate the incidence of prenucleation clusters (PNCs) as solute precursors to phase separation. The AUC analysis indicated that nucleation of Febuxostat relies on PNCs as solute precursors and may include liquid–liquid phase separation as an intermediate step.

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ISO 690OMAR, Waid, Rose ROSENBERG, Helmut CÖLFEN, 2024. New Polymorph of Febuxostat Crystallized from Aqueous Solution with an Investigation of the Incidence of Pre-nucleation Clusters (PNCs) as Solute Precursors. In: Crystal Growth & Design. ACS Publications. 2024, 24(17), S. 7104-7113. ISSN 1528-7483. eISSN 1528-7505. Verfügbar unter: doi: 10.1021/acs.cgd.4c00725
BibTex
@article{Omar2024-09-04Polym-70659,
  year={2024},
  doi={10.1021/acs.cgd.4c00725},
  title={New Polymorph of Febuxostat Crystallized from Aqueous Solution with an Investigation of the Incidence of Pre-nucleation Clusters (PNCs) as Solute Precursors},
  number={17},
  volume={24},
  issn={1528-7483},
  journal={Crystal Growth & Design},
  pages={7104--7113},
  author={Omar, Waid and Rosenberg, Rose and Cölfen, Helmut}
}
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