Structure Elucidation of Poly-Faldaprevir: Polymer Backbone Solved Using Solid-State and Solution Nuclear Magnetic...

Area of Science:

• Pharmaceutical Chemistry
• Polymer Science
• Analytical Chemistry

Background:

• Large-scale synthesis of Faldaprevir, a hepatitis C virus drug, led to the unexpected precipitation of an insoluble solid.
• This impurity posed a challenge to the drug manufacturing process and required thorough characterization.

Purpose of the Study:

• To identify and characterize the unknown insoluble solid impurity formed during Faldaprevir synthesis.
• To elucidate the structure and polymerization mechanism of the impurity.
• To confirm the polymer structure through independent synthesis and analysis.

Main Methods:

• Size exclusion chromatography coupled with electrospray ionization mass spectrometry (SEC-ESI-MS)
• Solution and solid-state Nuclear Magnetic Resonance (NMR) spectroscopy, including CP/MAS, cross polarization-polarization inversion, and HETCOR experiments
• Ultracentrifugation, elemental analysis, and atom absorption spectroscopy for sodium quantitation

Main Results:

• The unknown solid was identified as a polymer of Faldaprevir.
• The polymerization occurred at the vinyl cyclopropane moiety, likely initiated by a free radical mechanism.
• The polymer's backbone structure was elucidated using advanced solid-state NMR techniques.
• Full proton and carbon chemical shift assignments for the polymer were obtained via solution NMR.

Conclusions:

• The formation of Faldaprevir polymer is a critical impurity during synthesis.
• The study successfully characterized the polymer's structure and proposed a polymerization mechanism.
• Chemical synthesis and NMR analysis confirmed the elucidated polymer structure, aiding in process control and drug quality assurance.