Exploring the salt-cocrystal continuum with solid-state NMR using natural-abundance samples: implications for crystal...

Area of Science:

• Solid-state chemistry
• Materials science
• Pharmaceutical sciences

Background:

• Differentiating multicomponent solid forms like salts and cocrystals is critical.
• Proton positioning in X-H⋯A-Y/X⁻⋯H-A⁺-Y systems impacts active pharmaceutical ingredient (API) requirements.
• Understanding these solid forms is vital for clinical, regulatory, and legal aspects of APIs.

Purpose of the Study:

• To investigate simple salt/cocrystal/continuum systems using high-field solid-state NMR (ssNMR).
• To determine proton positions in hydrogen bonds within these solid forms.
• To assess the sensitivity of ssNMR in distinguishing between salt, cocrystal, and continuum states.

Main Methods:

• Utilized high-field (700 MHz) ssNMR on samples with naturally abundant 15N.
• Employed two-dimensional inversely proton-detected cross-polarization with variable contact-time (invCP-VC) 1H→15N→1H experiments.
• Conducted experiments at ultrafast magic angle spinning (MAS) frequencies (≥ 60-70 kHz) to measure 15N-1H distances via dipolar interactions.
• Determined crystal structures using X-ray diffraction at low and room temperatures.

Main Results:

• Successfully determined H-atom positions by measuring 15N-1H distances.
• The ssNMR method demonstrated sensitivity to proton positioning, even in continuum systems.
• Observed {PyN⋯H-O-}/{PyN⁺-H⋯O⁻} hydrogen bonding in four model pyridine-containing compounds.
• Distinguished between salt, cocrystal, and continuum forms based on proton location.

Conclusions:

• High-field ssNMR with ultrafast MAS is effective for determining proton positions in pharmaceutical solid forms.
• This technique can resolve ambiguities in classifying solid forms like salts, cocrystals, and continuum systems.
• The findings have significant implications for the pharmaceutical industry regarding API characterization and regulatory standards.