Moving towards fast characterization of polymorphic drugs by solid-state NMR spectroscopy

Area of Science:

• Solid-state chemistry
• Pharmaceutical analysis
• Spectroscopy

Background:

• Solid-state nuclear magnetic resonance (SS-NMR) spectroscopy is crucial for high-resolution analysis of pharmaceutical polymorphism.
• Long ¹H spin-lattice relaxation (T₁) times in solid compounds limit the throughput of SS-NMR.
• Efficient characterization of drug polymorphs is essential for pharmaceutical development.

Purpose of the Study:

• To investigate the use of paramagnetic relaxation reagents to accelerate SS-NMR data acquisition.
• To assess the impact of these reagents on pharmaceutical polymorphs.
• To enable high-throughput SS-NMR studies of drug solid forms.

Main Methods:

• Addition of paramagnetic reagents (Cr(acac)₃, Ni(acac)₂) to pharmaceutical polymorphs.
• Measurement of ¹H spin-lattice relaxation (T₁) times using high-resolution ¹³C cross-polarization magic angle spinning SS-NMR.
• Powder X-ray diffraction (PXRD) to confirm polymorphic stability.
• Inductively coupled plasma optical emission spectroscopy (ICP-OES) to quantify metal ion incorporation.

Main Results:

• Paramagnetic reagents significantly reduced T₁ values for carbamazepine, cimetidine, nabumetone, and acetaminophen polymorphs.
• PXRD confirmed no polymorphic transitions occurred during experiments.
• ICP-OES quantified chromium ion levels.
• NMR spectral quality was maintained, and polymorphic integrity was preserved.

Conclusions:

• Paramagnetic relaxation reagents effectively accelerate SS-NMR data acquisition for pharmaceutical polymorphs.
• This method preserves spectral quality and polymorphic form, enabling high-throughput analysis.
• The approach provides a foundation for advanced NMR crystallography studies of solid forms.