Rapid Quantification of Pharmaceuticals via ¹H Solid-State NMR Spectroscopy

Abstract

The physicochemical properties of active pharmaceutical ingredients (APIs) can depend on their solid-state forms. Therefore, characterization of API forms is crucial for upholding the performance of pharmaceutical products. Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is a powerful technique for API quantification due to its selectivity. However, quantitative SSNMR experiments can be time consuming, sometimes requiring days to perform. Sensitivity can be considerably improved using 1H SSNMR spectroscopy. Nonetheless, quantification via 1H can be a challenging task due to low spectral resolution. Here, we offer a novel 1H SSNMR method for rapid API quantification, termed CRAMPS–MAR. The technique is based on combined rotation and multiple-pulse spectroscopy (CRAMPS) and mixture analysis using references (MAR). CRAMPS–MAR can provide high 1H spectral resolution with standard equipment, and data analysis can be accomplished with ease, even for structurally complex APIs. Using several API species as model systems, we show that CRAMPS–MAR can provide a lower quantitation limit than standard approaches such as fast MAS with peak integration. Furthermore, CRAMPS–MAR was found to be robust for cases that are inapproachable by conventional ultra-fast (i.e., 100 kHz) MAS methods even when state-of-the-art SSNMR equipment was employed. Our results demonstrate CRAMPS–MAR as an alternative quantification technique that can generate new opportunities for analytical research.

Exploiting solid-state dynamic nuclear polarization NMR spectroscopy to establish the spatial distribution of polymorphic phases in a solid material

“…6–16 Unfortunately, the intrinsically low sensitivity of NMR may limit the opportunity to detect a minor polymorphic phase in a mixture with a major polymorphic phase. 17–19…”

“…[6][7][8][9][10][11][12][13][14][15][16] Unfortunately, the intrinsically low sensitivity of NMR may limit the opportunity to detect a minor polymorphic phase in a mixture with a major polymorphic phase. [17][18][19] Interestingly, recent advances in dynamic nuclear polarization (DNP) NMR, [20][21][22][23][24][25][26][27] in which polarization from the electron spin of an exogenous polarizing agent [28][29][30][31][32] is transferred to nuclear spins through microwave irradiation, can signicantly enhance the ability of NMR to detect small amounts of solid phases in heterogenous materials by enhancing the sensitivity of solid-state NMR measurements by several orders of magnitude. Furthermore, DNP NMR may also generate large polarization gradients, allowing domain sizes between ca.…”

Efficient analysis of pharmaceutical drug substances and products using a solid-state NMR CryoProbe

“…[26][27][28] Emerging studies have demonstrated the advantages of fast and ultrafast MAS for the characterization of pharmaceutical materials. 17,20,26,[29][30][31][32][33][34][35] For instance, Lu et al investigated the molecular packing of POSA crystals using 1 H ssNMR at a MAS rate of 110 kHz. 17 Polenova and coworkers studied the structure of a fluorine-containing drug, mefloquine, using 19 F methods under fast MAS.…”

Residual proton line width under refocused frequency-switched Lee-Goldburg decoupling in MAS NMR

“…1,2 Further reduction in the line width by imporoved homonuclear decoupling schemes would allow a broader use of proton solid-state NMR to applications especially in small molecules and pharmaceuticals. [3][4][5] The total observed line width in experimental NMR spectra is determined by several different contributions. Following the convention introduced by Maricq and Waugh 6 , one usually distinguishes the inhomogeneous and the homogeneous broadening.…”

“…1,2 Further reduction in the line width by imporoved homonuclear decoupling schemes would allow a broader use of proton solid-state NMR in applications especially for small molecules and pharmaceuticals. 3–5…”