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Nuclear magnetic resonance (NMR) is potentially a very powerful process analytical technology (PAT) tool as it gives an atomic resolution picture of the reaction mixture without the need for chromatography. NMR is well suited for interrogating transient intermediates, providing kinetic information via NMR active nuclei, and most importantly provides universally quantitative information for all species in solution. This contrasts with commonly used PAT instruments, such as Raman or Flow-infrared (IR), which requires a separate calibration curve for every component of the reaction mixture. To date, the large footprint of high-field (≥400 MHz) NMR spectrometers and the immobility of superconducting magnets, coupled with strict requirements for the architecture for the room it is to be installed, have been a major obstacle to using this technology right next to fume hoods where chemists perform synthetic work. Here, we describe the use of a small, lightweight 60 MHz Benchtop NMR system (Nanalysis Pro-60) located on a mobile platform, that was used to monitor both small and intermediate scale Grignard formation and coupling reactions. We also show how low field NMR can provide a deceptively simple yes/no answer (for a system that would otherwise require laborious off-line testing) in the enrichment of one component versus another in a kilogram scale distillation. Benchtop NMR was also used to derive molecule specific information from Flow-IR, a technology found in most manufacturing sites, and compare the ease at which the concentrations of the reaction mixtures can be derived by NMR versus IR., (© 2020 John Wiley & Sons, Ltd.)

A thorough investigation into the mechanism of the reaction of 3-methylpentanoic acid and Meldrum's acid using online NMR spectroscopy is reported. This study is an expansion of a previous analysis of this chemical transformation in the synthesis of an active pharmaceutical ingredient imagabalin. The 3-methylpentanoic acid analogue reveals similar behavior under the reaction conditions. Online NMR spectroscopy and offline characterization experiments reveal new information about the mechanism, providing conclusive spectroscopic evidence for the previously hypothesized dimer anhydride intermediate species 3-methylpentanoic anhydride as a productive intermediate. The presence of an acyl chloride intermediate species, 3-methylpentanoyl chloride, is also revealed for the first time in this synthesis. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

We report findings from the qualitative evaluation of nuclear magnetic resonance (NMR) reaction monitoring techniques of how each relates to the kinetic profile of a reaction process. The study highlights key reaction rate differences observed between the various NMR reaction monitoring methods investigated: online NMR, static NMR tubes, and periodic inversion of NMR tubes. The analysis of three reaction processes reveals that rates derived from NMR analysis are highly dependent on monitoring method. These findings indicate that users must be aware of the effect of their monitoring method upon the kinetic rate data derived from NMR analysis. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

In this paper we describe the development of a 5 mm NMR flow tube that can be used in a standard 5 mm NMR probe, enabling the user to conduct experiments on flowing samples or, more specifically, on flowing reaction mixtures. This enables reaction monitoring or kinetic experiments to be conducted by flowing reaction mixtures from a reaction vessel to detection in the coil area of the NMR, without the need for a specialized flow NMR probe. One of the key benefits of this flow tube is that it provides flexibility to be used across a range of available spectrometers of varying magnetic field strengths with a standard 5 mm probe setup. The applicability of this flow tube to reaction monitoring is demonstrated using the reaction of p-phenylenediamine and isobutyraldehyde to form the diimine product.

Detector response is not always equivalent between detectors or instrument types. Factors that impact detector response include molecular structure and detection wavelength. In liquid chromatography (LC), ultraviolet (UV) is often the primary detector; however, without determination of UV response factors for each analyte, chromatographic results are reported on an area percent rather than a weight percent. In extreme cases, response factors can differ by several orders of magnitude for structurally dissimilar compounds, making the uncalibrated data useless for quantitative applications. While impurity reference standards are normally used to calculate UV relative response factors (RRFs), reference standards of reaction mixture components are typically not available during route scouting or in the early stages of process development. Here, we describe an approach to establish RRFs from a single experiment using both online nuclear magnetic resonance (NMR) and LC. NMR is used as a mass detector from which a UV response factor can be determined to correct the high performance liquid chromatography (HPLC) data. Online reaction monitoring using simultaneous NMR and HPLC provides a platform to expedite the development and understanding of pharmaceutical reaction processes. Ultimately, the knowledge provided by a structurally information rich technique such as NMR can be correlated with more prevalent and mobile instrumentation [e.g., LC, mid-infrared spectrometers (MIR)] for additional routine process understanding and optimization.

The calibration of a solid-state NMR spectrometer requires setting the magic angle, setting the reference and decoupler frequencies, ensuring that the magnetic field is homogeneous across the sample volume, optimizing the signal-to-noise ratio, determining the pi/2 pulse durations, and optimizing the Hartman-Hahn matching condition. Each task has one or more widely accepted standards, such as potassium bromide for setting the magic angle, adamantane for optimizing magnet homogeneity, and hexamethylbenzene or glycine for measuring the signal-to-noise ratio. We show that all of these tasks can be performed using 3-methylglutaric acid (MGA). In the case of high-powered decoupling, the CH(2) and CH carbon peaks of MGA provide an opportunity to evaluate the decoupling in a manner that is superior to any of the commonly used standard compounds. Thus, MGA can be used as a single solid-state NMR standard compound to perform all calibration steps except for magnet shimming.

Solid-state nuclear magnetic resonance spectroscopy (SSNMR) line widths were measured for various ibuprofen preparations, including crystallization from different solvents (acetone, acetonitrile, methanol), melt-quenching, manual grinding, cryogrinding, compacting, and by blending with various excipients. Ibuprofen recrystallized from acetonitrile exhibited broader lines than ibuprofen recrystallized from either acetone or methanol. Manually ground ibuprofen had SSNMR line widths that were indistinguishable from the commercial sample, but cryoground ibuprofen had larger line widths than either. Physical mixtures with most excipients decreased the SSNMR line widths. Only dilution in talc led to line width increases, which is attributed to the magnetic susceptibility anisotropy of the talc excipient. Our results show that SSNMR line widths can be used to understand physical characteristics including particle size and morphology, degree of order in the materials, and physical environment.

Purpose: To show, using a model study, how electronic structure theory can be applied in combination with LC/UV/MS/MS for the prediction and identification of oxidative degradants., Methods: The benzyloxazole 1, was used to represent an active pharmaceutical ingredient for oxidative forced degradation studies. Bond dissociation energies (BDEs) calculated at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level with isodesmic corrections were used to predict sites of autoxidation. In addition, frontier molecular orbital (FMO) theory at the Hartree-Fock level was used to predict sites of peroxide oxidation and electron transfer. Compound 1 was then subjected to autoxidation and H2O2 forced degradation as well as formal stability conditions. Samples were analyzed by LC/UV/MS/MS and degradation products proposed., Results: The computational BDEs and FMO analysis of 1 was consistent with the LC/UV/MS/MS data and allowed for structural proposals, which were confirmed by LC/MS/NMR. The autoxidation conditions yielded a number of degradants not observed under peroxide degradation while formal stability conditions gave both peroxide and autoxidation degradants., Conclusions: Electronic structure methods were successfully applied in combination with LC/UV/MS/MS to predict degradation pathways and assist in spectral identification. The degradation and excipient stability studies highlight the importance of including both peroxide and autoxidation conditions in forced degradation studies.

The title compounds (both C(9)H(10)O(4)) have nearly planar structures, and the methyl and/or carboxylic acid groups lie out of the molecular plane, as dictated by steric interactions. 2,5-Dimethoxybenzoic acid (2,5-DMBA) forms an unusual intramolecular hydrogen bond between the carboxylic acid group and the O atom of the methoxy group in the 2-position [O.O = 2.547 (2) A and O-H.O = 154 (3) degrees ]. 2,4-DMBA forms a typical hydrogen-bond dimer with a neighboring molecule.

A bulk powder of sulfamerazine polymorph II in a narrow distribution of particle size was prepared for the first time. The two known sulfamerazine polymorphs, I and II, were physically characterized by optical microscopy, powder X-ray diffractometry, differential scanning calorimetry, carbon-13 solid-state nuclear magnetic resonance spectroscopy, and measurements of aqueous solubility and density. The thermodynamics and kinetics of the transition between the polymorphs was examined under various pharmaceutically relevant conditions, such as heating, cooling, milling, compaction, and contact with solvents. The two polymorphs were found to be enantiotropes with slow kinetics of interconversion. The thermodynamic transition temperature lies between 51 and 54 degrees C, with polymorph II stable at lower temperatures. Ostwald's Rule of Stages explains the crystallization of the polymorphs from various solvents and may account for the delay in the discovery of polymorph II., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1089-1100, 2002)

The identification of the racemic species, as a racemic compound, a racemic conglomerate, or a racemic solid solution (pseudoracemate), is crucial for rationalizing the potential for resolution of racemates by crystallization. The melting points and enthalpies of fusion of a number of chiral drugs and their salts were measured by differential scanning calorimetry. Based on a thermodynamic cycle involving the solid and liquid phases of the enantiomers and racemic species, the enthalpy, entropy and Gibbs free energy of the racemic species were derived from the thermal data. The Gibbs free energy of formation, is always negative for a racemic compound, if it can exist, and the contribution from the entropy of mixing in the liquid state to the free energy of formation is the driving force for the process. For a racemic conglomerate, the entropy of mixing in the liquid state is close to the ideal value of R ln 2 (1.38 cal.mol-1. K-1). Pseudoracemates behave differently from the other two types of racemic species. When the melting points of the racemic species is about 30 K below that of the homochiral species, is approximately zero, indicating that the racemic compound and racemic conglomerate possess similar relative stabilities. The powder X-ray diffraction patterns and 13C solid-state nuclear magnetic resonance spectra are valuable for revealing structural differences between a racemic compound and a racemic conglomerate. Thermodynamic prediction, thermal analysis, and structural study are in excellent agreement for identifying the nature of the racemic species.