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Tale of Two Polymorphs: Investigating the Structural Differences and Dynamic Relationship between Nirmatrelvir Solid

Maryam Sadat Sadeghi1, Rui Guo2, Michael A Bellucci3

  • 1Pfizer Worldwide R&D, Groton, Connecticut 06340, United States.

Molecular Pharmaceutics
|July 25, 2024
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Summary

Researchers identified two anhydrous polymorphs of nirmatrelvir, the antiviral in Paxlovid. Form 1 is the stable form above 17°C, crucial for Covid-19 treatment development.

Keywords:
computational chemistrymolecular dynamicspolymorphismsolid-state chemistrytransition dynamics

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Area of Science:

  • Solid-state chemistry
  • Crystallography
  • Pharmaceutical development

Background:

  • Nirmatrelvir is a key antiviral component of Paxlovid, an oral treatment for Covid-19.
  • Polymorphism, the existence of different solid-state forms, can significantly impact drug efficacy and stability.
  • Distinguishing closely related polymorphs requires sophisticated analytical techniques.

Purpose of the Study:

  • To identify and characterize two anhydrous polymorphs of nirmatrelvir (Forms 1 and 4).
  • To determine the enantiotropic relationship and thermodynamic stability of these nirmatrelvir polymorphs.
  • To establish the nominated crystalline form for pharmaceutical development.

Main Methods:

  • Powder X-ray diffraction (PXRD) and single-crystal X-ray diffraction (SCXRD).
  • Solid-state characterization: thermal analysis, solid-state NMR, and Raman spectroscopy.
  • Computational methods: crystal structure prediction, Gibbs free energy calculations, and molecular dynamics simulations.

Main Results:

  • Two anhydrous polymorphs, Forms 1 and 4, were successfully distinguished.
  • Forms 1 and 4 were identified as enantiotropically related.
  • Form 1 was determined to be the stable polymorph above a transition temperature of approximately 17°C.

Conclusions:

  • Form 1 is the thermodynamically stable and nominated form for nirmatrelvir drug development.
  • The study highlights the necessity of orthogonal experimental and computational approaches for polymorph elucidation.
  • This research facilitated the rapid development and patient delivery of Paxlovid during the Covid-19 pandemic.