A mass spectrometric method has been developed for the identification of the carboxylic acid functional group in analytes evaporated and ionized by electrospray ionization (ESI). This method is based on gas-phase ion-molecule reactions of ammoniated ([M + NH4]+) and sodiated ([M + Na]+) analyte molecules with trimethyl borate (TMB) in a modified linear quadrupole ion trap mass spectrometer. The diagnostic reaction involves addition of the deprotonated analyte to TMB followed by the elimination of methanol. A variety of analytes with different func-tionalities were examined, and this reaction was only observed for molecules containing the carboxylic acid functionality. The selectivity of the reaction is attributed to the acidic hydrogen present in the carboxylic acid group, which provides the proton necessary for the elimination of methanol. The diagnostic products are easily identified based on the m/z value of the product ion, which is 72 Th (thomson) greater than the m/z value of the charged analyte, and also by the character-istic isotope pattern of boron. The applicability of this method for pharmaceutical analysis was demonstrated for three nonsteroidal anti-inflammatory drugs: ibuprofen, naproxen, and ketoprofen.
"   The choice of using negative ionization mode in mass spectrometric methods is appropriate for the direct analysis of carboxylic acids due to their acidic nature.   However, high-performance liquid chromatography/electrospray ionization mass spectrometry (HPLC/ESI-MS) methods are typically used in positive ion mode to analyze carboxylic acids after their covalent derivatization,     because the ionization efficiencies of carboxylic acids in negative ion mode are rather low,   and, in addition, the acidic mobile phase additives which are routinely used to improve chromatographic resolution in reversed-phase HPLC separations tend to suppress the negative ionization in ESI- MS.   Despite the significant improvement in sensitivity for positive MS detection of carboxylic acids after their derivatization, the covalent derivatization reactions are nonetheless time-consuming and may result in the formation of unwanted side products,  which is not good for the rapid detection of samples. Cyclodextrins (CDs) are cyclic oligosaccharides consisting of α-1,4-linked glucose residues. "
[Show abstract][Hide abstract] ABSTRACT: A liquid chromatography/tandem mass spectrometry (LC/MS(3)) method based on ion-molecule reactions and collision-activated dissociation (CAD) is presented for the identification of analytes with the N-oxide functional group directly in mixtures. Tri(dimethylamino)borane (TDMAB) rapidly and selectively derivatizes protonated N-oxides in a modified commercial linear quadrupole ion trap (LQIT) mass spectrometer to yield a distinct product ion (adduct-(CH(3))(2)NH). The LQIT was outfitted with an external reagent-mixing manifold that allows TDMAB to be mixed with the helium buffer gas used in the trap. The derivatized analytes are readily identified on the basis of a shift of 98 Th (Thomson) relative to the m/z value of the protonated analyte. Further probing of the derivatized analytes via isolation followed by CAD can be used to confirm the presence of an N-oxide, and distinguish between aliphatic and aromatic tertiary N-oxides. Since the ion-molecule reaction is fast, these experiments can be accomplished on the same time scale as typical CAD-based MS(n) experiments, thus maintaining the duty cycle of the instrument for this type of experiment. To demonstrate real world applicability, the method was tested on real active pharmaceutical ingredients and their derivatives.
Journal of pharmaceutical and biomedical analysis 10/2009; 51(4):805-11. DOI:10.1016/j.jpba.2009.09.047 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) approach to the characterization of dialkyl tertiary amine-N-oxides is presented. The methodology is based upon forming reconstructed ion current chromatograms (RICCs) of m/z values of product ions known to form through diagnostic losses from dialkyl tertiary amine-N-oxides. The diagnostic losses of N,N-dimethylhydroxylamine and N,N-diethylhydroxylamine were identified through the analysis of a structurally diverse library of compounds by ESI-low-energy collision-induced dissociation (CID)-MS/MS using quadrupole ion trap-mass spectrometry (QIT-MS) and quadrupole time-of-flight-mass spectrometry (QqTOF-MS). The library consisted of dialkyl tertiary amine-containing commercially available pharmaceuticals, along with a number of model, synthetic N-oxides. The loss of the nitrogen-containing group was observed in 89% of the low-energy CID product ion spectra acquired using various collision energies. Further, the resultant product ions, formed through the loss of the nitrogen-containing group, were shown to be unstable because of the observation of second-generation dissociation. These observations regarding gas-phase ion chemistry could be useful to developers of in silico programs for fragmentation prediction by allowing the creation of improved algorithms and models for predicting dissociation. Using the information derived from the library analysis, the characterization methodology was developed and demonstrated using tetracaine. The approach is rapid, MS/MS platform independent, utilizes existing technology, and could be automated. Further, it is definitive and overcomes the limitations of other tools for N-oxide identification by localizing the site of oxidation. Thus, it provides a useful addition to the existing approaches for metabolite identification.
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