Identification and enrichment of a UV-induced degradant of Anagrelide drug substance.

Anagrelide (ANG) is a widely used drug for the treatment of essential thrombocytosis and myeloproliferative neoplasms. Recently, a new oxidative degradant was identified when the drug product capsule underwent stress testing. Full structural characterization of this previously unidentified degradant was conducted.

NMR spectroscopy goes mobile: Using NMR as process analytical technology at the fume hood.

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.

A detailed mechanistic investigation into the reaction of 3-methylpentanoic acid with Meldrum's acid utilizing online NMR spectroscopy.

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.

Reaction monitoring using online vs tube NMR spectroscopy: seriously different results.

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.

NMR flow tube for online NMR reaction monitoring.

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.

Online NMR and HPLC as a reaction monitoring platform for pharmaceutical process development.

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.

An orthomolecular approach to the prevention and treatment of psychiatric disorders.

Orthomolecular medicine is based on the use of endogenous and naturally occurring substances to supplement deficiencies in vitamins, minerals, and other essential substances in the human body. Although the medical community has long regarded it as a nonscientific approach to healing, scientific and clinical evidence is emerging for the supplemental use of orthomolecular medicine in the treatment of schizophrenia, depression, bipolar disorder, generalized anxiety disorder, and attention deficit hyperactivity disorder. Psychiatrists currently treat these common psychiatric disorders using a wide range of pharmacological approaches that often have significant side effects, resulting in patients' noncompliance.

3-Methylglutaric acid as a 13C solid-state NMR standard.

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).

Investigation of solid-state NMR line widths of ibuprofen in drug formulations.

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.

Long-range carbon-carbon connectivity via unsymmetrical indirect covariance processing of HSQC and HMBC NMR data.

It was recently demonstrated that an IDR- (Inverted Direct Response) HSQC-TOCSY data set could be decomposed into a negatively phased direct response spectrum and a positively phased relayed response spectrum that could then be subjected to unsymmetrical indirect covariance processing for the removal of artifacts due to response overlap in the proton NMR spectrum of the molecule. Using experimentally discrete HSQC and HMBC data sets, it is shown that unsymmetrical indirect covariance processing of the pair of NMR spectra affords a presentation containing long-range carbon-carbon connectivity information. The method is demonstrated using strychnine as a model compound.

Early prediction of pharmaceutical oxidation pathways by computational chemistry and forced degradation.

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.

2,4-dimethoxybenzoic acid and 2,5-dimethoxybenzoic acid.

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.

Crystallization and transitions of sulfamerazine polymorphs.

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.