High-Resolution Elemental Mass Spectrometry Using LC-ICP-Nanospray-Orbitrap for Simultaneous and Species-Independent Quantitation of Fluorinated and Chlorinated Compounds

Abstract

Simultaneous elemental detection of F and Cl offers quantitation of fluorinated and chlorinated compounds and their transformation products without compound-specific standards. Despite wide-ranging applications, this capability has been hindered by fundamental and technical shortcomings of current inductively coupled plasma (ICP)-MS methods in ion formation and isobaric interference elimination. These hurdles are alleviated here via a chemical ionization method. Fluorine and chlorine in analytes are first converted to HF and HCl by an ICP with post-plasma recombination and subsequently react with barium-containing ions supplied by a nanospray, yielding BaF + and BaCl + as elemental reporter ions. Notably, the method is readily interfaced to an Orbitrap MS which eliminates isobaric interferences at resolving powers as low as 35,000, far greater than that of current ICP−MS instruments. Moreover, the instrument is easily reverted to the ESI-MS mode for complementary molecular characterization. To demonstrate analytical capabilities, a workflow for rapid quantitation of compounds separated by reversed-phase liquid chromatography is developed using a species-independent calibration. The independent F and Cl measurements agree with each other, providing recoveries of >90% and LODs of 8−12 pmol Cl and 5− 12 pmol F on the column. The workflow along with LC-ESI-MS on the same instrument is then applied to identify and quantify invitro drug metabolites, yielding total drug-related material recoveries of >80% and quantitation of minor metabolites summing to 8% of the total drug-related compounds. These results highlight the strengths of simultaneous F and Cl speciation for rapid quantitation with applications in early drug development.

Fluorine-selective post-plasma chemical ionization for enhanced elemental detection of fluorochemicals

“…Elemental methods coupled with chromatography are attractive approaches for such analyses since the uorine atom acts as a quantitative tag without regard to the compounds' chemical structure. 5 Inductively coupled plasma mass spectrometry (ICPMS) is oen used for elemental speciation but F determination using this technique is hindered by the high ionization potential of uorine (17.42 eV), 6 resulting in low ionization yield of F to F + (9 × 10 −4 % at 7500 K). 7 This limitation along with susceptibility of F + to the space charge effect and reduced ion transmission efficiency lead to a signicantly lower sensitivity for F + (0.03 cps per (ng mL −1 )) 8 compared to that of metals such as In + with a sensitivity >1 × 10 6 cps per (ng mL −1 ).…”

“…16 The potential of this approach was further demonstrated by coupling it to reversed phase liquid chromatography (LC), 5 resulting in on-column detection limits of 5-12 pmol F compared to in-plasma BaF + methods with on-column limits of detection (LODs) > 100 pmol F. 14,17 Moreover, quantitation of drug metabolites without a species-specic standard was demonstrated by this method, enabling the application of F speciation in drug development. 5 On the other hand, post-plasma chemical ionization is susceptible to chemical interferences. For example, the BaF + signal detected from organouorines via post-ICP nanosprayinduced chemical ionization was suppressed by 32% in the presence of 246 mM Cl as organochlorines in the sample.…”

“…Moreover, our recent studies have shown that the amount of oxygen introduced into the plasma significantly affects F detection sensitivity in post-plasma BaF + formation. 5 Notably, introduction of oxygen into the ICP is necessary to prevent the deposition of carbon onto surfaces downstream of the plasma when organic solvents are used. Therefore, a synchronized tuning of the oxygen flow rate with the solvent gradient was necessary for coupling this technique to gradient LC.…”

“…Therefore, a synchronized tuning of the oxygen flow rate with the solvent gradient was necessary for coupling this technique to gradient LC. 5…”

“…To improve F detection sensitivity with ICP, we have developed a new approach where the plasma is sampled in a cool atmospheric-pressure recombination zone for the formation of F-specic neutral species, which subsequently undergo chemical ionization. 5,15,16 Consequently, in-plasma ion formation constraints are alleviated, resulting in substantially improved sensitivities. For example, a sensitivity of 180 cps per (ng mL −1 ) F was observed by post-plasma formation of Na 2 F + upon cointroduction of sodium and uorochemicals into the plasma.…”