A Full Evaporation Static Headspace Gas Chromatography Method with Nitrogen Phosphorous Detection for Ultrasensitive Analysis of Semi-volatile Nitrosamines in Pharmaceutical Products.

The recent detection of potent carcinogenic nitrosamine impurities in several human medicines has triggered product recalls and interrupted the supply of critical medications for hundreds of millions of patients, illuminating the need for increased testing of nitrosamines in pharmaceutical products. However, the development of analytical methods for nitrosamine detection is challenging due to high sensitivity requirements, complex matrices, and the large number and variety of samples requiring testing. Herein, we report an analytical method for the analysis of a common nitrosamine, N-nitrosodimethylamine (NDMA), in pharmaceutical products using full evaporation static headspace gas chromatography with nitrogen phosphorous detection (FE-SHSGC-NPD). This method is sensitive, specific, accurate, and precise and has the potential to serve as a universal method for testing all semi-volatile nitrosamines across different drug products. Through elimination of the detrimental headspace-liquid partition, a quantitation limit of 0.25 ppb is achieved for NDMA, a significant improvement upon traditional LC-MS methods. The extraction of nitrosamines directly from solid sample not only simplifies the sample preparation procedure but also enables the method to be used for different products as is or with minor modifications, as demonstrated by the analysis of NDMA in 10+ pharmaceutical products. The in situ nitrosation that is commonly observed in GC methods for nitrosamine analysis was completely inhibited by the addition of a small volume solvent containing pyrogallol, phosphoric acid, and isopropanol. Employing simple procedures and low-cost instrumentation, this method can be implemented in any analytical laboratory for routine nitrosamine analysis, ensuring patient safety and uninterrupted supply of critical medications. Graphical Abstract.

Kipukasins, nucleoside derivatives from Aspergillus versicolor.

Seven new aroyl uridine derivatives (kipukasins A-G; 1-7) were isolated from solid-substrate fermentation cultures of two different Hawaiian isolates of Aspergillus versicolor. The structures of compounds 1-7 were determined by analysis of NMR and MS data. The nucleoside portion of lead compound 1 was assigned as uracil-1-beta-D-ribofuranoside by spectral comparison with an authentic standard. The bioactivity of the original A. versicolor extracts was accounted for mainly by the presence of the known metabolite sterigmatocystin, but kipukasins A and B showed modest activity in assays against Gram-positive bacteria.

Sporminarins A and B: antifungal metabolites from a fungicolous isolate of Sporormiella minimoides.

Cultures of a fungicolous isolate of Sporormiella minimoides afforded two new polyketide metabolites which we have named sporminarins A (1) and B (2). The planar structures of 1 and 2 were elucidated by analysis of NMR and MS data, and by chemical methods. 1 exhibited significant antifungal activity against Aspergillus flavus.

Heliconols A-C: antimicrobial hemiketals from the freshwater aquatic fungus Helicodendron giganteum.

[Structure: see text] Cultures of the freshwater aquatic fungus Helicodendron giganteum afforded three new compounds, heliconols A-C (1-3), that contain an unusual reduced furanocyclopentane unit. The structures of these metabolites were assigned by analysis of 1D and 2D NMR data. The absolute configuration of heliconol A (1) was assigned by single-crystal X-ray crystallographic analysis of its dibromobenzoate derivative. Heliconol A showed antifungal and antibacterial activities in disk diffusion assays.