Dynamic Nuclear Polarization Enhanced NMR Spectroscopy for Pharmaceutical Formulations

Abstract

Dynamic nuclear polarization (DNP) enhanced solid-state NMR spectroscopy at 9.4 T is demonstrated for the detailed atomic-level characterization of commercial pharmaceutical formulations. To enable DNP experiments without major modifications of the formulations, the gently ground tablets are impregnated with solutions of biradical polarizing agents. The organic liquid used for impregnation (here 1,1,2,2-tetrachloroethane) is chosen so that the active pharmaceutical ingredient (API) is minimally perturbed. DNP enhancements (ε) of between 40 and 90 at 105 K were obtained for the microparticulate API within four different commercial formulations of the over-the-counter antihistamine drug cetirizine dihydrochloride. The different formulations contain between 4.8 and 8.7 wt % API. DNP enables the rapid acquisition with natural isotopic abundances of one- and two-dimensional (13)C and (15)N solid-state NMR spectra of the formulations while preserving the microstructure of the API particles. Here this allowed immediate identification of the amorphous form of the API in the tablet. API-excipient interactions were observed in high-sensitivity (1)H-(15)N correlation spectra, revealing direct contacts between povidone and the API. The API domain sizes within the formulations were determined by measuring the variation of ε as a function of the polarization time and numerically modeling nuclear spin diffusion. Here we measure an API particle radius of 0.3 μm with a single particle model, while modeling with a Weibull distribution of particle sizes suggests most particles possess radii of around 0.07 μm.

35Cl solid-state NMR spectroscopy of HCl pharmaceuticals and their polymorphs in bulk and dosage forms

“…as an alternative method for the structural analysis of APIs. 11,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] Our research group and others have demonstrated that 35 Cl SSNMR can function as a non-destructive structural probe and a technique for polymorph identification and screening of hydrochloride (HCl) APIs. [36][37][38][39] Given that more than 50% of APIs are produced as HCl salts, 40 the widespread use of 35 Cl SSNMR in quality assurance, and research and development departments of pharmaceutical companies is promising.…”

Materials Characterization by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy

“…Subsequently, relayed DNP was shown to be a general method to polarize microcrystalline organic solids, including pharmaceuticals. [46][47][48] Alternatively, DNP NMR was performed on amorphous solid dispersions (ASD) of pharmaceuticals and polymers by directly incorporating the PA during synthesis. 49 Relayed DNP has enabled a number of challenging solid-state NMR experiments on organic solids including natural isotopic abundance 2D double-quantum 13 C-13 C correlation ( Figure 5C Sn solid-state NMR spectra of Sn-β catalysts prepared by different synthetic procedures illustrate that the sample preparation greatly affects the distribution of tin-sites within the zeolite framework ( Figure 5D).…”

Recent Advances in Solid-State Analysis of Pharmaceuticals

“…In another more extensive study, the crystalline and amorphous forms of cetirizine, povidone (excipient), as well as four brands of cetirizine tablet formulations (Life, CVS, Reactine and Wal-Zyr) were analysed by both 13 C and 15 N CP/MAS NMR under DNP (Fig. 2) [9].…”