Assessing the Detection Limit of a Minority Solid-State Form of a Pharmaceutical by 1H Double-Quantum Magic-Angle Spinning Nuclear Magnetic Resonance Spectroscopy.

The lower detection limit for 2 distinct crystalline phases by 1H magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) is investigated for a minority amount of cimetidine (anhydrous polymorph A) in a physical mixture with the anhydrous HCl salt of cimetidine. Specifically, 2-dimensional 1H double-quantum (DQ) MAS NMR spectra of polymorph A and the anhydrous HCl salt constitute fingerprints for the presence of each of these solid forms. For solid-state NMR data recorded at a 1H Larmor frequency of 850 MHz and a MAS frequency of 30 kHz on ∼10 mg of sample, it is shown that, by following the pair of cross-peaks at a 1H DQ frequency of 7.4 + 11.6 = 19.0 ppm that are unique to polymorph A, the level of detection for polymorph A in a physical mixture with the anhydrous HCl salt is a concentration of 1% w/w.

Identifying the intermolecular hydrogen-bonding supramolecular synthons in an indomethacin-nicotinamide cocrystal by solid-state NMR.

Two-dimensional (1)H double-quantum and (14)N-(1)H & (1)H-(13)C heteronuclear magic-angle spinning (MAS) NMR spectra recorded at natural isotopic abundance identify specific intermolecular COOH···N(arom) and CH(arom)···O=C hydrogen-bonding interactions in the solid-state structure of an indomethacin-nicotinamide cocrystal, thus additionally proving cocrystal formation.

Conformations of spermine in adenosine triphosphate complex: the structural basis for weak bimolecular interactions of major cellular electrolytes.

Selectively (2)H- and (13)C-labeled spermines (SPM) were efficiently synthesized and analyzed by NMR spectroscopy to determine the spin-spin coupling constants for six conformationally relevant bonds. SPM that is composed of three alkyl moieties, a butanylene, and two propanylene chains undergoes a conformational change when interacting with multivalent anions (e.g., adenosine triphosphate (ATP), ATP-Mg(2+) , and tripolyphosphate). Upon interaction with ATP, the C-C bonds, which affect the distance between the neighboring pairs of ammonium groups (i.e., N1/N5 and N5/N5'), increase the population of gauche rotamers by 17-20% relative to those in the 4 HCl salt of SPM. However, the trend in increments of the gauche conformers for the SPM-ATP complex profoundly differs from that of the spermidine (SPD)-ATP complex. This implies that SPM may preferentially recognize the adenyl group of ATP rather than the tripolyphosphate moiety. This may account for the higher affinity of SPM to ATP-Mg(2+) than with that of SPD, which chiefly interacts with ß- and γ-phosphates and is easily replaced by Mg(2+) . These results may provide a clue for the further understanding of the structural basis of polyamine biological functions.

Conformational change of spermidine upon interaction with adenosine triphosphate in aqueous solution.

Endogenous polyamines, represented by putrescine, spermidine, and spermine, are known to exert their physiological functions by interacting with polyanionic biomolecules such as DNA, RNA, adenosine triphosphate (ATP), and phospholipids. Very few examples of conformation analysis have been reported for these highly flexible polymethylene compounds, mainly due to the lack of appropriate methodologies. To understand the molecular basis of the weak interaction between polyamines and polyanions that underlies their physiological functions, we aimed to elucidate the solution conformation of spermidine by using diastereospecifically deuterated and (13)C-labeled derivatives (1-7), which were designed to diagnose the orientation of seven conformationally relevant bonds in spermidine. (1)H-(1)H and (13)C-(1)H NMR coupling constants ((3)J(H,H) and (3)J(C,H)) were successfully determined for a spermidine-ATP complex. The relevant coupling constants markedly decreased upon complexation. The results reveal that spermidine, when interacting with ATP, undergoes changes that make the conformation more bent and forms the complex with the triphosphate part of ATP in an orientation-sensitive manner.