Selective detection of active pharmaceutical ingredients in tablet formulations using solid-state NMR spectroscopy

Area of Science:

• Solid-state Nuclear Magnetic Resonance (ssNMR) Spectroscopy
• Pharmaceutical Analysis
• Materials Science

Background:

• Atomic-level characterization of Active Pharmaceutical Ingredients (APIs) is vital for drug formulation development.
• Analyzing APIs in intact tablets is challenging due to excipient interference and low API concentrations.
• Standard ssNMR methods often suffer from signal overlap in complex pharmaceutical mixtures, hindering analysis.

Purpose of the Study:

• To develop a selective ssNMR experiment for detecting APIs in complex tablet formulations.
• To overcome spectral overlap issues in ¹H ssNMR spectra of pharmaceutical mixtures.
• To enable accurate determination of chemical shifts and proximities of APIs within dosage forms.

Main Methods:

• A fast magic-angle spinning (MAS) NMR experiment combining symmetry-based dipolar recoupling (SR4₁²) rotational-echo saturation-pulse double-resonance (RESPDOR) with phase-modulate (PM) saturation pulses.
• Integration of radio frequency-driven recoupling (RFDR) for spin diffusion within API regions.
• Utilization of double-quantum excitation using Back-to-Back (BaBa) pulse sequence elements for structural elucidation.

Main Results:

• The proposed PM-S-RESPDOR-RFDR-BaBa experiment successfully achieved selective detection of ¹H ssNMR signals for l-cysteine in a commercial tablet formulation.
• The 2D ¹H double-quantum-single-quantum (DQ-SQ) spectrum of the API in the tablet closely matched that of pure l-cysteine.
• The method demonstrated sensitivity and robustness, validated by selective detection of ¹H{¹⁴N} signals in l-histidine·H₂O·HCl.

Conclusions:

• The developed ssNMR technique effectively simplifies complex spectra, enabling selective API detection in pharmaceutical formulations.
• This method provides a powerful tool for detailed structural analysis and quality control of drug products.
• The approach offers enhanced sensitivity and robustness for characterizing APIs at low concentrations.