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

Atomic-level characterization of active pharmaceutical ingredients (API) is crucial in pharmaceutical industry because APIs play an important role in physicochemical properties of drug formulations. However, the analysis of targeted APIs in intact tablet formulations is less straightforward due to the coexistence of excipients as major components and different APIs at dilute concentrations (often below 10 ​wt% loading). Although solid-state (ss) NMR spectroscopy is widely used to investigate short-range order, polymorphism, and pseudo-polymorphism in neat pharmaceutical compounds, the analysis of complex drug formulations is often limited by overlapped signals that originate from structurally different APIs and excipients. In particular, such examples are frequently encountered in the analysis of H ssNMR spectra of pharmaceutical formulations. While the high-resolution in H ssNMR spectra can be attained by, for example, high magnetic fields accompanied by fast magic-angle spinning (MAS) approaches, the spectral complexity associated with the mixtures of compounds hinders the accurate determination of chemical shifts and through-space proximities. Here we propose a fast MAS (70 ​kHz) NMR experiment for the selective detection of H signals associated with an API from a severely overlapped NMR spectrum of a tablet formulation. Spectral simplification is achieved by combining (i) symmetry-based dipolar recoupling (SR4) rotational-echo saturation-pulse double-resonance (RESPDOR) with phase-modulate (PM) saturation pulses, (ii) radio frequency-driven recoupling (RFDR), and (iii) double-quantum excitation using Back-to-Back (BaBa) pulse sequence elements. First, H sites in close proximities to N nuclei of an API are excited using a PM-S-RESPDOR sequence, and simultaneously, the other unwanted H signals of excipients are suppressed. Then, H magnetization transfer to adjacent H sites in the API is achieved by spin diffusion process using a RFDR sequence, which polarizes to H sites within the crystalline API regions of the drug formulation. Next, a PM-S-RESPDOR-RFDR sequence is combined with a Back-to-Back (BaBa) sequence to elucidate local-structures and H-H proximities of the API in a dosage form. The PM-S-RESPDOR-RFDR-BaBa experiment is employed in one- (1D) and two-dimensional (2D) versions to selectively detect the H ssNMR spectrum of l-cysteine (10.6 ​wt% or 0.11 ​mg) in a commercial formulation, and compared with the spectra of neat l-cysteine recorded using a standard BaBa experiment. The 2D H double-quantum-single-quantum (DQ-SQ) spectrum of the API (l-cysteine)-detected pharmaceutical tablet is in good agreement with the 2D H DQ-SQ spectrum obtained from the pure API molecule. Furthermore, the sensitivity and robustness of the experiment is examined by selectively detecting H{N} signals in an amino acid salt, l-histidineHOHCl.