A simple strategy for d/l-carnitine analysis in food samples using ion mobility spectrometry and theoretical calculations.

This work presents a straightforward approach to the separation d/l-carnitine (d/l-Carn) using ion mobility-mass spectrometry (IM-MS) and theoretical calculations. Natamycin (Nat) was used as separation reagent to interact with the Carn, metal ions (G) were employed as ligand, the resultant ternary complexes [d/l-Carn + Nat + G]+ were observed experimentally. IM-MS results revealed that d/l-Carn could be baseline separated via complex formation using Li+, Na+, K+, Rb+, and Cs+, with a maximum peak separation resolution (Rp-p) of 2.91; Theoretical calculations were performed to determine the optimal conformations of [d/l-Carn + Nat + Li/K]+, and the predicted collisional cross section values were consistent with the experimental values. Conformational analysis was used to elucidate the enantiomeric separation of d/l-Carn at the molecular level via the formation of ternary complexes. Furthermore, quantitative analyses for the determination of the enantiomers were established with effective linearity and acceptable sensitivity. Finally, the proposed method was successfully applied in the determination of d/l-Carn in food samples.

Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis.

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.

Drug adulteration analysis based on complexation with cyclodextrin and metal ions using ion mobility spectrometry.

Drug adulteration and contamination are serious threats to human health therefore, their accurate monitoring is very important. Allopurinol (Alp) and theophylline (Thp) are commonly used drugs for the treatment of gout and bronchitis, while their isomers hypoxanthine (Hyt) and theobromine (Thm) have no effect and affect the efficacy of the drug. In this work, the drug isomers of Alp/Hyt and Thp/Thm are simply mixed with α-, ß-, γ-cyclodextrin (CD) and metal ions and separated using trapped ion mobility spectrometry-mass spectrometry (TIMS-MS). TIMS-MS results showed that Alp/Hyt and Thp/Thm isomers could interact with CD and metal ions and form corresponding binary or ternary complexes to achieve their TIMS separation. Different metal ions and CDs showed different separation effect for the isomers, among which Alp and Hyt could be successfully distinguished from the complexes of [Alp/Hyt+γ-CD + Cu-H]+ with separation resolution (R P-P) of 1.51; whereas Thp and Thm could be baseline separated by [Thp/Thm+γ-CD + Ca-H]+ with R P-P of 1.96. Besides, chemical calculations revealed that the complexes were in the inclusion forms, and microscopic interactions were somewhat different, making their mobility separation. Moreover, relative and absolute quantification was investigated with an internal standard to determine the precise isomers content, and good linearity (R 2 > 0.99) was obtained. Finally, the method was applied for the adulteration detection where different drugs and urine were analyzed. In addition, due to the advantages of fast speed, simple operation, high sensitivity, and no chromatographic separation required, the proposed method provides an effective strategy for the drug adulteration detection of isomers.

Nanoarchitecture factors of solid electrolyte interphase formation via 3D nano-rheology microscopy and surface force-distance spectroscopy.

The solid electrolyte interphase in rechargeable Li-ion batteries, its dynamics and, significantly, its nanoscale structure and composition, hold clues to high-performing and safe energy storage. Unfortunately, knowledge of solid electrolyte interphase formation is limited due to the lack of in situ nano-characterization tools for probing solid-liquid interfaces. Here, we link electrochemical atomic force microscopy, three-dimensional nano-rheology microscopy and surface force-distance spectroscopy, to study, in situ and operando, the dynamic formation of the solid electrolyte interphase starting from a few 0.1 nm thick electrical double layer to the full three-dimensional nanostructured solid electrolyte interphase on the typical graphite basal and edge planes in a Li-ion battery negative electrode. By probing the arrangement of solvent molecules and ions within the electric double layer and quantifying the three-dimensional mechanical property distribution of organic and inorganic components in the as-formed solid electrolyte interphase layer, we reveal the nanoarchitecture factors and atomistic picture of initial solid electrolyte interphase formation on graphite-based negative electrodes in strongly and weakly solvating electrolytes.

Rapid discrimination of enantiomers by ion mobility mass spectrometry and chemical theoretical calculation: Chiral mandelic acid and its derivatives.

Because R/S-mandelic acids (MA) and their derivatives are critical starting materials or intermediates in the synthesis of chiral drugs, their chirality discrimination is important. In this study, R/S-MA and its derivatives, including R/S-2-phenylpropionic acid (2-PPA), R/S-methoxyphenylaceticacid (MPA), and R/S-2-hydroxy-4-phenylbutyric acid (HPBA), were accurate simultaneous mobility-discriminated by forming diastereomer complexes for the first time, which were obtained by simply mixing with cyclodextrins (α, ß, γ-CD) and transition-metal ions (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and Zn2+). The mass spectra revealed non-covalent diastereomer complexes formed by CD, enantiomers, and metal ions, and ion-mobility spectrometry (IMS) was performed for 109 pairs of complexes. Significant chiral discrimination was observed in the formed diastereomeric complexes, and their separation peak-to-peak resolution (Rp-p) for the enantiomers depended on the transition metal ion type. In most cases, the Rp-p value gradually increases with CD size, with quaternary complexes having the largest Rp-p value. The greatest chiral distinctions of 2-PPA, MA, MPA, and HPBA were obtained by the diastereomeric complex ions of [(2-PPA)(α)2+Zn2+-H]+, [(MA)(α)2+Zn2+-H]+, [(MPA)2(ß)+Co2+-H]+, and [(HPBA)(α)2+Fe2+-H]+, with Rp-p values of 1.35, 1.57, 1.70, and 0.71, respectively. Furthermore, the favorable conformation and collisional cross section (CCS) value of the different [CD + R/S-MA + Cu-H]+ complexes were measured using chemical theoretical calculations to detail their intermolecular interaction, revealing that [α-CD + R/S-MA + Cu-H]+ has two favored gas complexes, and the CCS calculated were consistent with the TIMS observed. In addition, R2 > 0.99 was obtained for the relative quantification of the chiral enantiomers. Overall, the proposed method provides a promising strategy for distinguishing the enantiomers of MA and their derivatives, with the advantages of simplicity, speed, and accuracy, without the need for complex chemical derivatization or chromatographic separation.

A cyclodextrin-based reagent for cis/trans-geometrical isomers separation by mobility measurements and chemical calculations.

Identification of cis/trans-carbon-carbon double-bond (CC) isomers remain challenging. Herein, a simple and rapid method for the separation and analysis of cis/trans-maleic acid (MA) and aconitic acid (AA) using Trapped Ion Mobility Spectrometry (TIMS) was developed. α-, ß-, γ-cyclodextrin (CD) were served as the separation reagent, slight difference in mobility separation was obtained by [CD-MA/AA-H]-. Specially, with the addition of divalent metal ion (G2+) as coordination metal ion, the separation effect was much increased by [CD-MA/AA + G-H]+, and α-CD has better mobility separation effect than ß-/γ-CD. Moreover, chemical calculations revealed the binary and ternary complexes are in the inclusion forms, and microscopic interactions between cis/trans-MA/AA, CDs, and G2+ are somewhat different that making their mobility separation. Finally, quantifications of cis/trans-isomers were analyzed in food samples, with good linearity (R2 > 0.99) and recoveries obtained from 87.25 % to 100.73 %.

Genetic algorithm parallel optimization of a new high mass resolution planar electrostatic ion trap mass analyzer.

The study and design of high-resolution mass analyzers is a very important task in mass spectrometry. A planar electrostatic ion trap (PEIT) mass analyzer with image charge detection and FT-based data processing has been developed, theoretically simulated, and experimentally validated. However, the 10 ring electrode configuration (PEIT-10) is difficult for mechanical construction and voltage tuning; moreover, few methods have been reported for optimizing the performance of multi-electrode mass analyzers. In this article, a simplified PEIT-7 mass analyzer was designed, and a genetic algorithm parallel optimization (GAPO) method was developed for optimizing multiple voltage settings of the new PEIT-7 mass analyzer to achieve spatial and energy isochronicity as well as iso-coordinate property. The automatic voltage optimization processes for the reduction of time aberration and spatial aberration showed that the developed GAPO method can significantly improve the optimization efficiency (the optimal voltage set being found within 5 hours with a maximum time aberration of 15 ps and a maximum z aberration of 0.10 µm). Based on the results obtained from the GAPO method, the resolving power of the PEIT-7 mass analyzer for six groups of ions with closely packed masses (m/z = 117.000 Th to 117.010 Th) was demonstrated, and a mass resolution of 171k was achieved at an acquisition time of 200 ms. The established GAPO method facilitates the design and optimization of high-resolution mass analyzers and may be useful for the design of other multi-electrode ion optical devices.

Simultaneous chirality separation of amino acids and their derivative by natamycin based on mobility measurements.

The separation of chiral amino acids (AAs) and their derivatives has always been a research difficulty in the field of biochemistry due to the high similarity of enantiomeric structures. In this work, a simple and quick method using natamycin (Nat) as chiral selector has been developed to simultaneously separate chiral AAs and their derivatives of carbobenzoxy/benzyl-AAs (Cbz/Bzl-AAs) by trapped ion mobility spectrometry-mass spectrometry (TIMS-MS). Specifically, 12 groups of the Cbz-AAs and Bzl-AAs can get baseline mobility separation by simple mixing with Nat to form binary diastereomeric complex ions [Nat+(Cbz-D/L-AA)+H]+ and [Nat+(Bzl-D/L-AA)+H]+. While for the remained 5 groups of Bzl-D/L-AAs and 16 groups of D/L-AAs with unsatisfying separation, by further adding P-toluenesulfonic acid (PTS), the formed ternary complexes can allow their baseline chiral separation. Specifically, Bzl-D-AAs and Bzl-L-AAs get much improved separation effect by the formed diastereomeric complexes of [Nat+(Bzl-AA)2+PTS2+H]+, which the Rp-p was improved from 0 to 2.40; while the D/L-AAs can get baseline separation by the formed diastereomeric complexes of [Nat + AA + PTS + H]+, [Nat + AA+(PTS)2+H]+, and [Nat+(AA)2+(PTS)2+H]+, with the Rp-p ranged from 0.44 to 3.53. Definitely, PTS is the first time reported as the ligand to improve the separation effect for the enantiomers, and with the higher assembly of chiral analyte, Nat, and PTS might enable better chiral separation for the chiral amino acid and their derivatives. Moreover, method validation of relative quantification and accuracy for the D/L-AA and their derivatives were measured in a mixture, yielding R2 greater than 0.99 and RSD% ≤ 2.68%. Overall, Nat and PTS as chiral selector and ligand can be widely used for chiral AAs and their derivatives mobility separation, and potentially for the separation of other AA-related chiral molecules.

Ultrasound Comparative Analysis of Coronary Arteries before and after Immune Blocking Therapy with Gamma Globulin in Children with Kawasaki Disease.

Objective: To investigate the ultrasound characteristics and clinical efficacy of coronary arteries before and after immune blocking therapy with gamma globulin in children with Kawasaki disease. Methods: A total of 64 children with Kawasaki disease who were treated in our hospital from January 2018 to October 2021 were selected. All the children were given immune blocking therapy with gamma globulin on the basis of conventional treatment. The disappearance time of related symptoms and signs (fever, mucosal congestion, cervical lymphadenopathy, and swelling of the hands and feet) in children were counted. The white blood cell count (WBC), platelet count (PLT), C-reactive protein (CRP), and procalcitonin (PCT) levels of the children before and after treatment were compared, and the characteristics of coronary echocardiography before and after treatment were observed for analysis and discussion, to carefully observe whether the coronary artery involvement of the children was improved. Results: The inner diameter of the left and right coronary arteries significantly decreased (P < 0.05), and the levels of leukocytes, platelets, CRP, erythrocyte sedimentation rate, vascular endothelial growth factor (VEGF), and endostatin were significantly decreased compared with those before treatment, with a statistical difference (P < 0.05). Conclusion: The effect of gamma globulin in the treatment of Kawasaki disease is remarkable, which can improve the blood indexes, VEGF, and endostatin levels in children, significantly reduce coronary dilatation, and reduce the incidence of coronary artery disease. Echocardiography is of high value in the examination of children with Kawasaki disease, which can accurately detect the size, location, and inner diameter of coronary artery lesions, and can effectively evaluate the treatment effect on children.

Simultaneous Differentiation of C═C Position Isomerism in Fatty Acids through Ion Mobility and Theoretical Calculations.

Fatty acids play a pivotal role in biological processes and have many isomers, particularly at the C═C position, that influence their biological function. Distinguishing between isomers is crucial to investigating their role in health and disease. However, separating the isomers poses a significant analytical challenge. In this study, we developed a simple and rapid strategy combining ion mobility spectrometry and theoretical chemical calculations to differentiate and quantify the C═C positional isomers in 2-/3-butenoic acid (BA), 2-/3-/4-pentenoic acid (PA), and 2-/3-/5-hexenoic acid (HA). C═C positional isomerism was mobility-differentiated by simple complexation with crown ethers (12C4, 15C5, and 18C6) and divalent metal ions (Mg2+, Ca2+, Mn2+, Fe2+, Co2+, Ni2+, Zn2+, Sr2+, and Ba2+), that is, converting C═C positional isomers with small structural differences into complexes with large structural differences through the interaction with metal ions and crown ethers. Metallized isomers were formed but could not be differentiated due to their complex and overlapping extracted ion mobiliograms (EIMs). Binary crown ether-isomer complexes were not observed, indicating that C═C positional isomers could not be separated by simple mixing with crown ethers. However, significant EIM differences were obtained for the formed ternary complexes, allowing baseline separation for the isomers. Notably, all crown ethers and metal ions have a separation effect with the isomers, with a calculated separation resolution (Rp-p) of 0.07-2.44. Theoretical chemical calculations were performed to provide in-depth structural information for the complexes and explain the separation principle. Theoretical conformational space showed that the divalent metal ions act as a bridge connecting the crown ether and the isomer. Additionally, the ternary complex becomes more compact as the distance between C═C and -COOH increases. Theoretical results can reflect the features of mobility experiments, with relative errors between the experiment collision cross-section (CCS) and theoretical CCS of no more than ±8.06%. This method was also evaluated in terms of quantification, accuracy, and precision repeatability. Overall, this study establishes that the crown ether-metal ion pair can function as a robust unit for differentiating C═C positional isomerism.

The chirality determination of amino acids by forming complexes with cyclodextrins and metal ions using ion mobility spectrometry, and a DFT calculation.

Chiral recognition is of highly interest in the areas of chemistry, pharmaceuticals, and bioscience. An effective strategy of enantiomeric determination of amino acids (AAs) was developed in this work. All 19 natural AAs enantiomers can be easily distinguished by ion mobility-mass spectrometry of the non-covalent complexes of AAs with cyclodextrins (α-CD, ß-CD and γ-CD) and Mg2+ without any chemical derivatization. Differences of the mobilities between the enantiomers' complexes is from 0.006 to 0.058 V s/cm2. In addition, the complex of [ß-CD + Phe + Mg]2+ was selected as an example to study the relative quantification by measuring L/D-Phe at different molar ratio of 10:1 to 1:10 in the µM range, resulting in a good linearity (R2 > 0.99) and high sensitivity at 2 µM. A DFT calculation was also performed to illustrate the detailed molecular structure of the complexes of CDs, Mg2+ and D- or L-Phe. Both experiment and theoretical calculation showed that Mg2+ plays an important role in host/guest interactions, which changed the molecular conformations by non-covalent interaction between Mg2+ and CDs, and resulted in the different collision cross-sections of the complex ions of CDs, Mg2+ and D- or L-AAs in the gas phase. This effective and convenient strategy could potentially be utilized in scientific research and industry for routine enantiomeric determination of natural AAs, peptides and some other small chiral biomolecules such as non-natural AAs and carboxylic acid-containing drugs.

Recognition of Cis-Trans and Chiral Proline and Its Derivatives by Ion Mobility Measurement of Their Complexes with Natamycin and Metal Ion.

Discrimination of isomers is an important and valuable feature in many analytical applications, and the identification of chiral isomers and cis-trans isomers is the current research focus. In this work, a simple method for direct, simultaneous recognition of d-/l-proline (P), d-/l-/cis-/trans-4-hydroxyproline (4-HP), and d-/l-/cis-/trans-N-tert-butoxycarbony (N-Boc-4-HP) was investigated by means of trapped ion mobility spectrometry-mass spectrometry (TIMS-MS). The isomers with cis-/trans-/d-/l-configuration can be directly recognized based on their mobility upon reaction with natamycin (Nat) and metal ions through noncovalent interactions. The results indicate that the recognition of the enantiomers has certain specificity, and the structural difference of the enantiomers was increased in a complex with Nat and metal ions. Herein, d-/l-P can be recognized through the ternary complexes [P + Nat + Mg - H]+, [P + 2Nat + Ca - H]+, [P + 2Nat + Mn - H]+, and [P + Nat + Cu - H]+. Similarly, c-4-HPL, c-4-HPD, t-4-HPL, and t-4-HPD can be recognized by [4-HP + Nat + Ca - H]+, [4-HP + 2Nat + Ca - H]+, and [4-HP + Nat + Cu - H]+, while N-Boc-c-4-HPL, N-Boc-c-4-HPD, N-Boc-t-4-HPL, and N-Boc-t-4-HPD were recognized through the enantiomer complexes [N-Boc-4-HP + Nat + Li]+, [N-Boc-4-HP + Nat + 2Na - H]+, [N-Boc-4-HP + Nat + K]+, [N-Boc-4-HP + Nat + Mn - H]+, and [N-Boc-4-HP + Nat + Ba - H]+. Moreover, tandem mass spectrometry (MS/MS) results indicated that different collision energies were obtained for the same fragment ions, which implied that the enantiomer complexes that contributed to their mobility separation shared identical interaction mode but had different gas-phase rigid geometries. Furthermore, the relative quantification for the enantiomers was performed, and the results were supported by a satisfactory coefficient (R2 > 0.99). The developed method can provide a promising and powerful strategy for the separation of chiral proline and its d-/l-/cis-/trans derivatives, bearing the advantages of higher speed, better accuracy, high selectivity, and no need for chemical derivatization and chromatographic separation.

Application of the poly (POSS-octavinyl-co-N-methylacetamide-co-divinylbenzene) solid extraction column in analyzing preservatives.

In this study, a special poly solid-phase extraction (in-tube SPE) column consisting of poly (POSS-octavinyl-co-N-methylacetamide-co-divinylbenzene) [poly (POSS-OS-co-DVB-co-NMA)] was prepared based on the chemical structure of the preservatives, and was used as medium for extraction analysis in combination with UPLC. The composition of polymer SPE was optimized and characterized; good scanning electron microscopy (SEM) properties and satisfactory porosity were obtained with 30% monomer (POSS-OS:DVB:NMA = 2 wt%:13 wt%:15 wt%) and 70 wt% porogenic solvent (PEG20000:DMSO:ACN = 10 wt%:50 wt%:10 wt%). The experimental parameters of the in-tube SPE-UPLC analysis were optimized systematically. Then, the in-tube SPE-UPLC method was applied for analyzing the beverage sample, and correlation coefficients (R2) > 0.99 were obtained for the linear relationship within limits of 0.1~5.0 µg mL-1. Excellent extraction efficiency, good precision, and satisfactory limit of detection sensitivity between 0.03 and 0.10 µg mL-1 were obtained. The recovery ranged from 71.5 to 88.0%, with RSD ≤ 6.1%. Furthermore, the proposed method has the features of simple sample pretreatment, high throughput, rapid analysis, cost-effectiveness, and satisfactory sensitivity. Hence, the developed in-tube SPE-UPLC method based on the poly (POSS-OS-co-DVB-co-NMA) SPE column can be potentially used for simple and sensitive detection of preservatives.

Identification of Bi-2-naphthol and Its Phosphate Derivatives Complexed with Cyclodextrin and Metal Ions Using Trapped Ion Mobility Spectrometry.

The separation of chiral enantiomers has gained increasing importance in many research fields, becoming a major research hotspot. 1,1'-Bi (2-naphthol) (BINOL) and 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (BNP) are referred to as atropisomer chiral molecules, which are essential chiral catalysts and intermediates in several reactions. In this work, BINOL and BNP atropisomers are separated and identified using trapped ion mobility spectrometry (TIMS) to monitor the different mobilities of their derivative complexes. The latter are obtained by the simple mixing of BINOL/BNP, cyclodextrin (CD), and the metal ions through noncovalent interactions. The results indicate that the enantiomer complexes of BINOL/BNP can be separated with a certain specificity, showing that R-, S-BINOL can be separated by the ternary complexes of [BINOL+γ-CD + Rb]+, [BINOL+γ-CD + Cu-H]+, and [BINOL+ß-CD + Cu-H]+ based on the difference in their mobility; similarly, the R-, S-BNP enantiomer can be isolated by the formed ternary complexes of [BNP+α-CD + Ba-H]+, [BNP+ß-CD + Co-H]+, [BNP+ß-CD + Ca-H]+, [BNP+ß-CD + Cu-H]+, [BNP+ß-CD + Fe-H]+, [BNP+ß-CD + Li]+, and [BNP+ß-CD + Sr-H]+. Furthermore, the peak separation rate (Rp-p) of the complexes was calculated, with the Rp-p of the three enantiomers of BINOL being 1.130 and the Rp-p of the seven complexes of BNP reaching 2.089. At last, the different survival yields for the collision energies were found for the enantiomer complexes, revealing the rigid structural differences in the stereospecificity of the enantiomer complexes that result in the separation by the TIMS. Additionally, due to the advantages of simple operation, fast speed, and high sensitivity and because chemical derivatization and chromatographic separation are not required, the developed method can provide a promising and powerful strategy for the separation and identification of binaphthyl derivatives or even other enantiomers of the reaction intermediates.

Distinction of chiral penicillamine using metal-ion coupled cyclodextrin complex as chiral selector by trapped ion mobility-mass spectrometry and a structure investigation of the complexes.

Penicillamine (Pen) is a common chiral drug that is obtained from penicillin. Between the two enantiomers of Pen, only D-Pen can be used to treat cystinuria and rheumatoid arthritis while L-Pen is toxic. Therefore, it requires great efforts for the research of the rigorous analysis and distinction of the two enantiomers. The non-covalent combination of chiral molecules and chiral selectors (CSs) has been proved as a unique strategy for chiral distinction by ion mobility spectrometry in coupling with -mss spectrometry (IM-MS). Here, we developed a simple method to distinguish D, L-Pen by using special CSs for IM-MS separation. The CSs utilized here include cyclodextrins (CD) and linear chain oligosaccharides plus metal ions. We found that non-covalent complexes [Pen+ß-CD + Li]+ could be easily formed by electrospray ionization of the mixture of the solution, and the chirality of Pen could be effectively recognized by measuring their mobilities due to the different collision cross collision sections of [D-Pen+ß-CD + Li]+ and [L-Pen+ß-CD + Li]+. A detailed analysis of [Pen+ß-CD + Li]+ was then conducted by the optical rotation measurements and NMR experiments to reveal their structural differences. Furthermore, DFT calculation showed the differences of molecular conformation between the complexes. The results provide a new powerful method for fast analysis and recognition of chirality of Pen compounds by IM-MS.

Structural resolution of disaccharides through halogen anion complexation using negative trapped ion mobility spectrometry.

Carbohydrates are an indispensable part of early life evolution. The determination of their structures is a key step to analyze their critical roles in biological systems. A variation of composition, glycosidic linkage, and (or) configuration between carbohydrate isomers induces structure diversity and brings challenges for their structural determination. Ion mobility spectrometry (IMS), an emerging gas-phase ion separation technology, has been considered as a promising tool for performing carbohydrate structure elucidation. In this work, eight disaccharides were analyzed by trapped ion mobility spectrometry-mass spectrometry (TIMS-MS) in the negative ion mode as the complexed form of [M + X]-, where M = disaccharide, and X = Cl, Br, and I. As compared to the positive ion analysis of the selected disaccharide in a sodiated form, a reversal charge state provided the ability to eliminate or even reverse the collision cross section (CCS) difference between disaccharide isomers. By the combination of TIMS analysis and the calculation of density functional theory, the only observed two conformers of ions [lactulose + I]- may result from different adduction sites for an iodide anion. Based on the comparison of different halogen adducts, the [M + I]- ion form exhibited more powerful ability for isomeric disaccharide differentiation with an average resolution (RP-P) of 1.17, which results in a 34.5% improvement as compared to the corresponding chloride adducts. This result indicates that the use of negative charge states, especially the complexation of an iodide anion, could be a supplemental strategy to commonly used positive ion analysis for carbohydrate separation.

Direct distinction of ibuprofen and flurbiprofen enantiomers by ion mobility mass spectrometry of their ternary complexes with metal cations and cyclodextrins in the gas phase.

Enantiomeric drugs are widely used and play important roles in pharmaceuticals. Ion mobility spectrometry coupled with mass spectrometry technology provides a unique method for distinguishing the enantiomeric drugs, enantiomeric identification, and quantitation in the gas phase. In this study, enantiomeric molecules of ibuprofen and flurbiprofen were clearly recognized by forming host-guest complex ions using trapped ion mobility time-of-flight mass spectrometry. Ternary complex ions can be produced easily by electrospray ionization of the mixed solutions of ibuprofen, cyclodextrins, and CaCl2 , LiCl, or NaCl, as well as flurbiprofen, cyclodextrins, and CaCl2 . The relative contents of different chiral ibuprofens in a mixed solution were also quantitatively measured. This new method is a simple, effective, and a convenient enantioselective analysis method.

Direct and simultaneous recognition of the positional isomers of aminobenzenesulfonic acid by TIMS-TOF-MS.

Positional isomer recognition is a challenging scientific issue. Fast and accurate detection of isomers is required for understanding their chemical properties. Here, we describe a method for simultaneous recognition of three positional isomers of 2-aminobenzenesulfonic acid (2-ABSA), 3-ABSA, and 4-ABSA using trapped ion mobility spectroscopy-time-of-flight mass spectrometry (TIMS-TOF-MS). The three ABSA positional isomers were recognized by measuring the different ion mobility of the ternary complexes of [ß-cyclodextrin (CD)+ABSA + Li]+ or [λ-CD + ABSA + Na]+, because their different collision cross-sections or different spatial conformations. The collision-induced dissociation mechanism of the different complexes of [ß-CD + ABSA + Li]+ and [λ-CD + ABSA + Na]+ using tandem mass spectrometry exhibited the same dissociation process with slightly different dissociation energies, which the smaller cross-section requires higher collision energy that means the smaller complex with tighter and more stable conformation than a larger complex for the ABSA complexes. In addition, relative quantification of the ABSA isomers was studied by measuring any two of the three ABSA isomer complexes at different molar ratio of 10:1 to 1:10 in the µM range, good linearity (R2 > 0.99) with precision between 2.14% and 2.58%, and accuracy ≥ 97.1% were obtained. The method for fast determination and recognition of ABSA positional isomers by combination with CD and alkali metal ions possesses the advantages of being simple, direct, rapid, sensitive, cost-effective, and needs no chemical derivatives or chromatographic separation before analysis. Therefore, the proposed method would be a powerful tool for the analysis of ABSA isomers or even other positional isomers.

Discrimination of Aminobiphenyl Isomers in the Gas Phase and Investigation of Their Complex Conformations.

The analysis of positional isomers is of great significance because their different chemical properties but similar structures make separation difficult. In this work, a simple method for simultaneously discriminating three positional isomers of 2-aminobiphenyl (2-ABP), 3-ABP, and 4-ABP was studied by ion mobility spectrometry (IMS) and quantum mechanical calculations at the molecular level. In the experiments, three ABP isomers were mixed with α-, ß-, and γ-cyclodextrins (CD), and the IMS results show that the three ABP isomers were clearly recognized by the formed complex of [α-CD + ABP + H]+ via measuring their IMS, in which the different ion mobilities of 1.515, 1.544, 1.585 V·s·com-2 with the collision cross sections (CCS) of 307.3, 312.5, 320.8 Å2 were obtained for [α-CD + 2-ABP + H]+, [α-CD + 3-ABP + H]+, and [α-CD + 4-ABP + H]+, respectively. Collision induced dissociation analysis of the three [α-CD + ABP + H]+ isomer complexes were further studied, indicating that the same fragmentation process required different collisional energies, and the greater the CCS for the [α-CD + ABP + H]+ with looser structure and the smaller energy required. Besides, the favorable conformation and the CCS value of the different [CD + ABP + H]+ isomer complexes were measured via quantum mechanical calculations to detail their intermolecular interactions. It revealed that the intermolecular binding between 2-ABP and α-CD is different from that of 3- and 4-ABP, resulting in different molecular conformations and CCS, and the interaction modes of ABP with ß-CD are similar to that with γ-CD, which are very consistent with the experimental observations. Finally, relative quantification of the method was performed, and satisfactory linearity with correlation coefficients (R2) greater than 0.99 was obtained. This method for isomer discrimination and conformation analysis possesses the advantages of simplicity, sensitivity, cost-effectiveness, and as such it may be widely applied in chemistry and pharmaceutical sciences.

Enantio-separation of pregabalin by ternary complexation using trapped ion mobility spectrometry.

Rationale The rapid identification of small-molecule chiral drugs is challenging due to subtle structural differences. Different enantiomers of chiral drugs may produce inverse biological effects through their different pharmacokinetics. Therefore, it is highly desirable to distinguish the chirality of drug molecules. METHODS: The chirality of pregabalin was distinguished by studying the ion mobility spectra of the ternary non-covalent complexes formed with cyclodextrins (CDs), pregabalin, and alkali-earth cations using trapped ion mobility spectrometry (TIMS). The ternary non-covalent complex ions were determined by electrospray ionization of mixed solutions. The analyzed sample was simply mixed, without derivatization or sample pretreatment. The relative contents of pregabalin enantiomers were derived using a calibration curve method. RESULTS: The ion mobility spectra of several ternary non-covalent complexes formed with α-, ß-, and γ-CD, pregabalin, and alkali-earth cations were obtained. We compared their ability to distinguish the chirality of pregabalin. The best peak-to-peak resolution (Rp-p ) was estimated to be 2.20 for [2ß-CD + pregabalin + Sr]2+ , which can be ascribed as baseline separation. The derived relative contents for S-pregabalin were in agreement with the actual contents. CONCLUSIONS: A novel and convenient method for discriminating the chirality of the pregabalin molecule by TIMS was developed and optimized. The chirality of pregabalin was recognized by studying the ion mobility spectra of the ternary non-covalent complexes, such as [2ß-CD + pregabalin + Sr]2+ . This TIMS method could also be used to quantify the relative contents of pregabalin enantiomers.