INTRODUCTION:

Liquid chromatography time-of-flight mass spectrometry (LC–TOF-MS) analysis provides a superior technique for identifying many identified and non-identified analytes or chemical substances. This study evolves a screening method that utilizes automated solid-phase extraction to purify a wide array of analytes involving stimulants, benzodiazepines, muscle relaxants, antihistamines, hypnotics, antidepressants, opiates and newer synthetic “Spice/K2” cannabinoids and cathinone “bath salt” designer drugs. The extract was introduced to LC–TOF-MS analysis and by implementing a 13 min chromatography gradient with mobile phases of ammonium formate and methanol using positive mode electrospray.

Several other drugs and metabolites can split up the portion of same mass and chemical formula among unrelated compounds, but they are structurally different. In this method, the LC–TOF-MS was allowing us to resolve many isobaric compounds by accurate mass co-relation within 15ppm mass units and a narrow retention time interval of less than 10 s of the separation. Drug recovery yields miscellaneous spiked compounds, but resulted in overall sturdy area counts to deliver an average match score of 86 when compared to the retention time and mass of authentic standards. This method portrays a quick enhanced screen for blood and urine specimens in post-mortem, driving under the influence and drug facilitated sexual assault forensic toxicology casework.^1-2

Liquid Chromatography:

It is an analytical technique which is use to separate a sample into its individual parts. This separation occurs based on the interactions of the sample with the mobile and stationary phases. Because there are many stationary phases and mobile phases combination that can employed when separating a mixture, there are several different types of chromatography that are classified based on the physical states of those phases.

Types of Liquid Chromatography:

It is of two type that is liquid- solid chromatography and liquid-liquid chromatography.

Principle:

Liquid-solid chromatography is based on the principle of adsorption.

Liquid-liquid chromatography is based on the principle of partition.

Instrumentation:

The basic instrumentation of liquid chromatography consists of A solvent inlet filters, Pump, Inline solvent filter, Injector, Column, Detector, Recorder, Waist reservoir.

Diagram -1 liquid chromatography

Mass Spectroscopy:

Mass spectroscopyis an analytical technique that is used to determine the mass-to-charge ratio of ions. The results are represented as a mass spectrum, a plot of intensity as a function advantage of the mass-to-charge ratio. Mass spectrometry is used in many different fields and it is applied to pure samples as well as complex mixtures.

A mass spectrum is a type of plot of ion signal as a function of the mass-to-charge ratio. These spectra are used to determine the elemental or isotopic signature of a sample, the masses of particles and of molecules, and to demonstrate the chemical identity or structure of molecules and other chemical compounds.³

In a typical MS procedure, a sample which could be solid, liquid, gaseous or ionized, for example by bombarding it with a beam of electrons. This may cause some of the sample's molecules to split up into positively charged fragments or simply become positively charged without dispersing. These ions (fragments) are then differentiated according to their mass-to-charge ratio, (by accelerating them and subjecting them to an electric or magnetic field) these ions of the same mass-to-charge ratio will undergo the same amount of deflection. The ions are detected by a mechanism, which is capable of detecting charged particles, such as an electron multiplier. Results are displayed as spectra of the signal intensity shown to be ions as a function of the mass-to-charge ratio. The atoms or molecules in the sample can be identified by co-relating known masses (e.g., an entire molecule) to the identified masses or through a characteristic fragmentation pattern.^4-5

Principle:

The basic principle of mass spectroscopy is to produce ions from either inorganic or organic compounds by any suitable methods, to differentiate these ions by their mass-to-charge ratio and to determine them qualitatively and quantitatively by their respective to mass-to-charge ratio.

Instrumentation:

Diagram - 2 Mass spectroscopy

Basic main parts of mass spectrometry are discussed below:

Ionizer – The emitting of the sample is done by the electrons. These electrons move between cathode and anode. When the sample passes through the electron stream between the cathode and anode, electrons with high intensity strike electrons out of the sample and form ions.

· Accelerator – The ions placed between a set of charged parallel plates get attracted to one plate and repel from the other plate. The acceleration speed can be regulated by adjusting the charge on the plates.

· Deflector – Magnetic field deflects ions based on its charge and mass. ion is supposed to be heavy or has two or more positive charges, then it is least deflected. If an ion is light or has one positive charge, then it is deflected the most.

· Detector – The ions with correct charge and mass move to the detector. the ratio of mass to charge is analyzed through the ion that hits the detector. ^(6-9)

Hifinite Technique of Liquid Chromatography-Mass Spectroscopy [LC-TOF-MS]:

Liquid chromatography–mass spectrometry (LC–MS) is an analytical technique that amalgamate the physical separation capability of liquid chromatography with the mass analysis capability of mass-spectrometry (MS). Coupled chromatography - MS systems are well liked chemical analysis because the individual capability of each technique is enhanced synergistically. While liquid chromatography separates mixtures with multiple components, mass spectrometry provides spectral information that may help to identify the suspected identity of each disassociated component. MS is not only sensitive, but also provides selective detection, relieving the need for complete chromatographic separation. LC-MS is also appropriate for metabolomics because of its good coverage of a wide range of chemicals. This tandem technique can be used to analyse organic, and inorganic, biochemical compounds commonly found in complex samples of environmental and biological origin. Therefore, LC-MS may be applied in a wide range of fields including agrochemical, food processing, environment monitoring and pharmaceutical, biotechnology, and cosmetic industries.

In addition of liquid chromatography and mass spectrometry devices, an LC-MS system contains an interface that easily transfers the disassociated components from the LC column into the MS ion source. The interface is necessary because the LC and MS devices are basic incompatible. While the mobile phase in a LC system is a pressurised liquid, the MS analysers commonly operate under high vacuum. Thus, it is impossible to directly pump the eluate from the LC column into the MS source. Overall, the interface is a mechanically simple part of the LC-MS system that moves the maximum amount of analyte, removes a portion of the mobile phase used in LC and tends to preserves the chemical identity of the chromatography products (chemically inert).⁽¹⁰⁾ As a requirement, the interface should not mediate with the ionizing efficiency and vacuum conditions of the MS system. In present time, most extensively applied LC-MS interfaces are based on atmospheric pressure ionization (API) strategies like electrospray ionization (ESI), atmospheric-pressure chemical ionization (APCI), and atmospheric pressure photoionization (APPI).^11-13

Instrumentation:

Diagram -3 LC- TOF - MS

Applications in Various Fields:

-The joining of MS with LC systems is attractive because liquid chromatography can separate the delicate and complex natural mixtures, which chemical composition needs to be well established (e.g., biological fluids, environmental samples, and drugs). Further, LC-MS has be applicable to volatile explosive residue analysis. In present time LC-MS has become one of the most favourable chemical analysis techniques because more than 85% of natural chemical compounds are polar and thermally labile, whereas GC-MS cannot process these samples. As an example, HPLC-MS is valued as the leading analytical technique for proteomics and pharmaceutical laboratories. Other important measures of LC-MS include the analysis of food, pesticides, and plant phenols.^14-18

Pharmacokinetics

This system is widely used in the field of bioanalysis and is specially involved in pharmacokinetic studies of chemical substances and pharmaceuticals. Pharmacokinetic studies are needed to recognise how immediate a drug will excrete out from the body organs and the hepatic blood flow.^19-21 MS observer could be useful in these studies because of their short analysis time, and higher sensitivity and specificity as compared to UV detectors commonly attached to HPLC systems.^21-24 One major merit is the use of tandem MS-MS, where the detector may be programmed to select certain ions to fragment. The measured quantity is the sum of molecule fragments selected by the operator. As long as there are no involvement or ion suppression in LC-MS, the LC separation can be quite quick.^25-28

Proteomics/Metabolomics:

LC-MS technique is used in proteomics as a method to detect and identify the components of a complex mixture. The bottom-up proteomics LC-MS approach generally involves protease digestion and denaturation or changes using trypsin as a protease, urea to denature the tertiary structure, and iodoacetamide to modify or alter the cysteine residues. After digestion LC-MS is used for peptide mass fingerprinting, or LC-MS/MS is used to derive the sequences of single peptides. LC-MS/MS is the most common system used for proteomic analysis of complex samples where peptide masses may overlap even with a high-resolution mass spectrometry. Samples of complex biological (e.g., human serum) may be analyse in modified LC-MS/MS systems, which can identify over 1000 proteins. However, this high level of protein analyse is possible only after separating the sample by means of SDS-PAGE gel or HPLC-SCX. Recently, LC-MS/MS has been appearing to be applied to search peptide biomarkers.^29-30 An example is the recent discovered and validated of peptide biomarkers for four major bacterial respiratory tract pathogens (Staphylococcus aureus, Moraxella catarrhalis; Haemophilus influenzae and Streptococcus pneumoniae).^31-33

LC-MS has emerged as one of the most commonly used techniques in worldwide metabolite of biological tissue (e.g., blood plasma, serum, urine). LC-MS system also used for the analysis of natural products and the profiling of secondary metabolites in plants. In this regard, MS-based systems are useful to acquire more detailed information about the wide spectrum of compounds from a complex biological sample.^34-37 LC-Nuclear magnetic resonance (NMR) is also used in plant metabolomics, but this technique can only detect and quantify the most abundant metabolites. LC-MS has been useful to advance the field of plant metabolomics, which aims to study the plant system at molecular level providing a non-biased characterization of the plant metabolome in response to its environment. The first application of LC-MS in plant metabolomics was the detection of a wide range of highly polar metabolites, oligosaccharides, amino acids, amino sugars, and sugar nucleotides from Cucurbita maxima phloem tissues. Another example of LC-MS in plant metabolomics is the efficient separation and identification of glucose, sucrose, raffinose, stachyose, and verbascose from leaf extracts of Arabidopsis thaliana.^37-39

Developmentdrug:

LC-MS is frequently used in drug development because it allows molecular weight confirmation and structure identification. These features boost up the process of generating, testing, evaluating and validating a discovery starting from a vast arrangement of products with potential application. LC-MS applications for drug development are highly motorised machine methods used for peptide mapping, glycoprotein mapping, lipidomic, natural products de-replication, bio affinity screening, in vivo drug screening impurity identification, metabolic stability screening, metabolite identification, quality control, and quantitative bio-analysis^40-41

Analysis of Pesticides in Vegetables:

A quantitative method comprehend of solvent extraction followed by Liquid Chromatography-Time Of Flight-Mass Spectroscopy analysis was evolved for the identification quantitation of three chloronicotinyl pesticides, commonly used on salad vegetables. Accurate mass measurements with in 3ppm error were obtained for all the pesticides studied in numerous vegetables matrixes. e.g. (Tomato, Pepper, Cucumber, Lettuce), which allowed an unequivocal identification of the target pesticides,^42-45 calibration curves covering to orders of magnitude were linear over the concentration range studied, thus showing the quantitative ability of TOF-MS as a observing tool for pesticides in vegetables.^46-48 Matrix effect were also estimated using matrix-matched standard showing no distinguished interferences between matrix and clean extracts. Intraday reproducibility was 2-3% relative standard deviation and intraday values were 5% relative standard deviation. The correctness of the mass measurements was estimated and it was less than 0.23mDa between days. Detection limits of the chloronicotinyl insecticides in salad vegetables ranged from 0.002-0.01mg/kg. These values are equal to or better than the EU directives for controlled pesticides in vegetables representing that LC-TOF-MS analysis is a potent tool for identification of pesticides in vegetables.^49-51

In terms of study, metabolite profiling of five medicinal Panax herbs consist Panaxginseng (Chinese ginseng), Panax notoginseng (Sanchi), Panax japonicus (Rhizoma Panacis Majors), Panax quinquefolium L. (American ginseng), and P. ginseng (Korean ginseng) were performed using ultra-performance LC-quadrupole TOF MS (UPLC-QTOFMS) and various statistical analysis technique. Principal component analysis (PCA) of the analytical data showed that the five Panax herbs could be separated into five distinguished groups of phytochemicals. The chemical makers such as ginsenoside Rf, 20(S)-pseudoginsenoside F11, malonyl gisenoside Rb1, and gisenoside Rb2 accountable for such variations were detected through the stuff plot of PCA, and were identified provisional by the accurate mass of TOF-MS and partially substantiate by the available reference standards. Result of this study represents the proposed method is reliable for the rapid analysis of a group of metabolites found to be in herbal medicines and some other natural products and applicable in the distinction of complex samples that share similar chemical constituents.^52-53

Investigation of Pesticides Metabolites in Food and Water

We represent the potential of liquid chromatography with (quadrupole) time-of-flight mass spectrometry [LC-(Q)TOF-MS] in examining the presence of pesticide metabolites in food and water samples. The mostly polarity of metabolites compared to their ancestors’ pesticides makes the amalgamation of LC [both high-performance (HPLC) and ultra-performance (UPLC)] with TOF-MS one of the most reasonable techniques for their analysis, from a qualitative view of point.

Both target analysis and non-target analysis have been traversed making use of this technique. Target analysis is typically applied in the scrutiny of maximum residue limits in food, when a relevant metabolite is carried in the residue definition for toxicological causes or its presence in significant amounts. Within this field, LC-TOF-MS, thanks to its intrinsic attribute of high sensitivity in full-scan acquisition mode and elevated mass accuracy, has great possible for qualitative purposes, and it allows reliable identification of a large number of metabolites in only one chromatographic trial without the need for re-analysis.

The latest generations of TOF instruments have also been fortunately successful, applied for quantitative purposes. By contrast with food analysis, for drinking water, most regulations of residues do not specify which pesticide metabolites must be included in analysis, and even less so for environmental waters. In such cases, analytical laboratories can focus analysis on a list of (normally) a few target metabolites, or on non-target analysis, where the objective is to recognise (pre-defined) metabolites in samples without previously selecting them.

We review the use of LC-TOF-MS and LC-(Q)TOF-MS in pesticide-metabolite analysis, considering different approaches:

● Multi-residue pesticide analysis, where several metabolites are specified within the list of target analytes.

● Investigation of pesticide metabolites in samples that were possibly selected pesticides in previous target analysis.

● Investigation of metabolites in pesticide-metabolism or degradation studies, typically in laboratory or field experiments under administered conditions; and non-target analysis, where there is no previous information or restrictions on the compounds to be justified in the samples.^54-58

Identification of Diphenhydramine in Segment Sample:

Diphenhydramine is approved over the opposing anti histaminic medication used for the treatment of allergies. After consumption, excretion from waste water treatment plants, it is possible that diphenhydramine will be found in environmental sediments due to its hydrophobicity. The work describes a methodology for the first unequivocal identification of diphenhydramine were disallowed to environmental sediments. The is removed from the sediments by boosting solvent extraction and then analysed by LC-TOF-MS and an ion trap mass spectrometer.^59-62 This combination of technique provided unequivocal identification and confirmation of diphenhydramine into sediment samples. The accurate mass measurements of the protonated molecules were compared to calculated mass, resulting in error of ppm. This mass accuracy was sufficient to verify the elemental configuration of diphenhydramine in each sample. Furthermore, accurate mass measurements of the primary fragment’s ion were obtained. This work is the first application of time of-flight mass spectroscopy for the estimation of diphenhydramine and shows the gathering of an over-the-counter medication in sediments at five different locations.^63-64

Identification and Quantification of Synthetic Cathinones in Blood and Urine:

Synthetic cathinone’s shows a formidable challenge to forensic toxicology laboratories despite the fact that they are variably encountered in impaired driving and death investigations. Due these limitations in immunoassay-based screening technologies, most of forensic toxicology laboratories must rely on more labor intensive chromatographic-based screening approaches as result to detect these drugs in biological evidence. Solid phase extraction (SPE) and liquid chromatography-quadrupole/time of flight (LC-Q/TOF) mass spectrometry was supposed to identify twenty-two synthetic cathinones in urine and blood. Target drugs included methcathinone, ethcathinone, pentedrone, buphedrone, 3-fluoromethcathinone (3-FMC), 4-fluoromethcathinone (4-FMC), 4-methylethcathinone (4-MEC), 3,4-dimethylmethcathinone (3,4-(DMMC), 4-ethylmethcathinone (4-EMC), mephedrone, methedrone, butylone, pentylone, eutylone, methylone, methylenedioxypyrovalerone (MDPV), 4-methylpyrrolidinobutiophenone (MPBP), 3,4-methylenedioxypyrrolidinobutiophenone (MDPBP), α-pyrrolidinopentiphenone (α-PVP), pyrovalerone, and naphyrone. Precision, bias and matrix hr effect were all within acceptable thresholds and the assay was free from more than fifty interferences. The validated method was used to identify cathinones in authentic urine case samples (n = 20) and these results highlight important considerations for cathinone stability and the subsequent interpretation of results.⁶⁵

CONCLUSION:

At the end conclusion of whole technique is used for quantitative and qualitative analysis. Combination of both techniques become more accurate results. LC-TOF-MS is used in various fields such as identification and quantification of synthetic cathinones in blood and urine, identification of diphenhydramine in segment sample, investigation of pesticides metabolites in the food and water, analysis of pesticides in vegetables, development drug, proteomics/metabolomics, pharmacokinetics. In this technique samples can be easily detected by using these significant techniques. These features boost up the process of generating, testing, evaluating and validating a discovery starting from a vast arrangement of products with potential application.

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Received on 11.05.2022 Modified on 05.08.2022

Asian J. Pharm. Ana. 2023; 13(1):35-41.

DOI: 10.52711/2231-5675.2023.00006