Application of ¹⁹F quantitative NMR to pharmaceutical analysis

Abstract

The presence of fluorine in an active pharmaceutical ingredient (API) can impart important pharmacological attributes with regards to metabolism, stability, and selectivity. As such, nearly one‐third of newly approved small molecule drugs contain at least one fluorine atom. 19F is 100% naturally abundant lending to virtually unimpeded detection of fluorine‐containing molecules, even in complex mixtures. Despite these promising characteristics, the thorough evaluation of a method for 19F qNMR (quantitative NMR) has been lacking. Herein we present experimental methodology and optimized parameters for uniform quantitative sampling of fluorine‐containing drugs and we compare results obtained using both gravimetric and absolute concentration methods for data reduction.

Improving the accuracy of 1H–19F internuclear distance measurement using 2D 1H–19F HOESY

“…By analogy with our previous 1 H- 1 H internuclear distance measurements, assuming that the initial rate approximation is true, and that the molecule is tumbling isotropically in solution, the internuclear 1 H- 19 F distances should be measurable by comparing the PANICcorrected HOESY intensities (η), via Equation (1)…”

“…The development of new 19 F NMR-based methods is being driven by the growth in newly approved small molecule drugs containing at least one fluorine atom [1] arising from the beneficial pharmaceutical effects when a hydrogen is replaced with a fluorine including improvements to conformation, potency, and metabolic stability. [2] 19 F NMR is also highly attractive as a tool for these systems with 100% natural abundance, I = ½, high gyromagnetic ratio, and minimal spectral overlap (spectral width of 19 F is >400 ppm, with typically only a handful of 19 F environments in a given molecule).…”

“…[15,16] PANIC corrects the experimental NOE intensities by standardization against the irradiated or diagonal peak in the onedimensional or two-dimensional NOESY experiments, respectively-effectively assuming that the external relaxation rates that perturb the NOE signal are dominated by the external relaxation of the irradiated/diagonal peak. Using PANIC, 1 [17] but did not apply PANIC-presumably for the simple reason that the irradiated 19 F signal does not appear in the measured 1 H spectrum. Consequently, heteronuclear NOE build-up curves were required to identify the region in which the initial rate approximation holds true.…”

Comprehensive and High‐Throughput Exploration of Chemical Space Using Broadband 19F NMR‐Based Screening

“…[14] The 19 Fc hemical diversity space represented by NMR signals of drug-like motifs covers alarge range of % 200 ppm (approximately À40 to À240 ppm; % 113 kHz on a6 00 MHz NMR). [15,16] Them ost commonly used NMR experiment to screen fluorinated compound libraries consists of a 19 F9 0 8 8 excitation pulse,asingle echo (SE) or aC arr-Purcell-Meiboom-Gill (CPMG) T 2 relaxation filter employing apulse train of fluorine 1808 8 refocusing pulses,a nd a 19 Fs ignal acquisition period with optional proton-fluorine decoupling (Figure 1a). [17] However,c ommonly used fluorine 908 8 hard excitation and, in particular, 1808 8 refocusing pulses have only al imited bandwidth where au niform manipulation of spins can be achieved (as described below).…”

Comprehensive and High‐Throughput Exploration of Chemical Space Using Broadband 19F NMR‐Based Screening

“…The 19 F chemical diversity space represented by NMR signals of drug‐like motifs covers a large range of ≈200 ppm (approximately −40 to −240 ppm; ≈113 kHz on a 600 MHz NMR) . The most commonly used NMR experiment to screen fluorinated compound libraries consists of a 19 F 90° excitation pulse, a single echo (SE) or a Carr–Purcell–Meiboom–Gill (CPMG) T 2 relaxation filter employing a pulse train of fluorine 180° refocusing pulses, and a 19 F signal acquisition period with optional proton‐fluorine decoupling (Figure a) .…”