Development and application of a porous cage carrier method for detecting trace elements in soils by direct current glow discharge mass spectrometry

The accurate and reliable determination of trace elements in soil still remains a big challenge for glow discharge mass spectrometry due to the poor conductive nature of soils. In the present work, a porous cage carrier was developed and used in the analysis of soils. The investigation results suggested that the carrier with a circular cross-sectional area in the range from 20 to 38 mm2, length from 15 to 17 mm and diameter of hole size from 1.5 mm to 2.0 mm could obtain good signals. Then the porous cage carrier method was systematically evaluated by analysing three types of soil reference materials. The discharge process was kept stable for more than 100 minutes, which was much longer than the boric acid method and indium sheet method. The investigations suggested that the internal precision was obtained within 16%, the external precision was better than 20% and the relative error was in the range from 0.7% to 17%. The detection limit of Tb could reach 0.014 μg g−1, which indicated that the new method qualified for the analysis of trace elements in soils. Compared to traditional tablet-pressed methods, the porous cage carrier method was not only convenient for sample preparation, but also showed good stability, reproducibility and better detection limits for trace elements. Furthermore, this method was proved to promote the potential application of GD-MS in the environmental field

Red-fluorescent argininamide-type NPY Y(1) receptor antagonists as pharmacological tools

Fluorescently labelled NPY Y1 receptor (Y1R) ligands were synthesized by connecting pyrylium and cyanine dyes with the argininamide-type Y1R antagonist core structure by linkers, covering a wide variety in length and chemical nature, attached to the guanidine group. The most promising fluorescent probes had Y1R affinities (radioligand binding) and antagonistic activities (calcium assay) in the one- to two-digit nanomolar range. These compounds turned out to be stable under assay conditions and to be appropriate for the detection of Y1Rs by confocal microscopy in live cells. To improve the signal-to-noise ratio by shifting the emission into the near infrared, a new benzothiazolium-type fluorescent cyanine dye (UR-DE99) was synthesized and attached to the parent antagonist via a carbamoyl linker yielding UR-MK131, a highly potent fluorescent Y1R probe, which was also successfully applied in flow cytometry

Case-Based Thermal Safety Evaluation on a Pharmaceutical Process Using Dimethyl Sulfoxide as a Solvent

A rupture disc burst was recorded when conducting a calorimetric test by sensitive detection of exothermic reaction. The tested sample was a reaction mixture from a hydroamination process containing the solvent dimethyl sulfoxide (DMSO). Subsequent investigation indicated that the event was caused by the strong autocatalytic decomposition of DMSO. The hazardous decomposition of DMSO that could be initiated by an inadvertent contact with substances involved in the process was studied. Furthermore, risk evaluation on the process thermal runaway was carried out based on the cooling failure scenario. In this particular case, although Stoessel criticality class 2 was assigned, the boiling point of DMSO could not serve as the safety barrier. On the basis of the thermal safety evaluation, the hydroamination process was safely scaled up in the Novartis pilot plant and successfully launched in a commercial production unit. This investigation highlights that every scale-up process involving DMSO as a solvent should be carefully evaluated owing to the potential safety concern caused by its autocatalytic behavior

Toward a Scalable Synthesis and Process for EMA401. Part I: Late Stage Process Development, Route Scouting and ICH M7 Assessment

We present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies; an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative; and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl)ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes, with consequent improvements in the PMI factor. This sequence includes a Pictet-Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable, modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized-bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH2O in the Pictet-Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments