A Monte Carlo Method for Analyzing Systematic and Random Uncertainty in Quantitative Nuclear Magnetic Resonance Measurements

Abstract

Quantitative nuclear magnetic resonance (qNMR) is a powerful analytical technology that is capable of quantifying the concentration of any analyte with exquisite accuracy and precision so long as it contains at least one nonlabile nuclear magnetic resonance (NMR)-active nucleus. Unlike with traditional analytical technologies, the concentrations of analytes do not directly influence the uncertainty in the quantification of NMR signals because an ideal NMR response depends only on the nature and amount of the nucleus being observed. Rather, in the absence of spectral artifacts and under favorable experimental conditions, the measurement uncertainty may be influenced by the following factors: (1) spectroscopic parameters such as the spectral width, number of time domain points, and acquisition time; (2) postacquisition data processing, such as apodization and zero-filling; (3) the signal-to-noise ratios (SNRs) and lineshapes of the two signals being used in a qNMR measurement; and (4) the method of signal quantification employed, such as numerical integration or lineshape fitting (LF). Here, a general Monte Carlo (MC) method that considers these factors is presented, with which the random and systematic contributions to qNMR measurement uncertainty may be calculated. Autocorrelation analysis of synthetic and experimental noise is used in a fingerprint-like approach to demonstrate the validity of the simulations. The MC method allows for a general quantitative assessment of measurement uncertainty without the need to acquire spectral replicates and without reference to the molecular structures and concentrations of analytes. Representative examples of qNMR measurement uncertainty simulations are provided in which the metrological performances of integration and LF are contrasted for signal pairs obtained using various acquisition and processing schemes in the low-SNR regimean area where application of the proposed MC method may prove to be particularly salient.

Quantification of Biopharmaceutically Relevant Nonionic Surfactant Excipients Using Benchtop qNMR

“…In contrast, modern high-field quantitative NMR − (qNMR) may provide nondestructive measurement without generating excessive solvent waste. Additionally, qNMR does not require the construction of calibration curves due to its inherently linear signal response over multiple orders of magnitude and its universal response for a given nucleus (i.e., hydrogen). ,− However, its routine application for the quantification of surfactants in formulated biologics is hindered by the technology’s high cost, its necessity for specialized facilities and cryogenic upkeep, and the high degree of expertise required for its proper operation. In contrast, these barriers may be removed by performing quantitative analysis of NISE at low-field (i.e., 60–100 MHz).…”

Nuclear magnetic resonance‐based solvent system selection for counter‐current chromatography separation of compounds present in the same high‐performance liquid chromatography peak: Flavonoids in barley seedlings as an example

“…The 1H (proton) NMR spectrum, the chemical shift and coupling constants provide the quantitative relationship between inter-molecular and intramolecular resonance [13]. NMR is especially powerful and useful for quantification in a special way since, metabolites cannot be physically separated, and the number of nuclei actually accountable for a resonance determines its intensity [14]. Besides the no physical separation, another advantage is that NMR-based quantitation could proceed precisely without any specific reference standard, which seriously restricts the precise quantitation in HPLC or LC-MS-based methods [15,16].…”

Quantitative nuclear magnetic resonance of chloride by an accurate internal standard approach

“…[13] Alternative to other analytical approaches, quantitative NMR (qNMR) is a robust technique that is widely and routinely used in the pharmaceutical industry for reaction monitoring, impurity and degradant measurements, residual solvent determinations, and assaying both drug substances and formulated drug products. [30][31][32][33] Additionally, counterion measurements are frequently performed, especially for those counterions such as maleate, mesylate, fumarate, acetate, and succinate that have non-labile protons that can be accurately integrated in a 1 H NMR spectrum. Less routine is the application of 19 F and 31 P qNMR for counterions such as trifluoroacetate (TFA) and phosphate (PO 4 3À ), respectively, but these are both relatively simple measurements using appropriate internal or external standards given that 19 F and 31 P are abundant spin 1/2 nuclei.…”