A Brief Review on Liquid Chromatography-

Mass Spectrometry/LCMS and its Application

 

Amit Kumar J. Vyas, Sonali B. Mishra, A. B. Patel, N. K. Patel, S. R. Shah, D. B. Sheth

¹B. K. Mody Government Pharmacy College, Rajkot, Gujrat (India).

²L. M. College of Pharmacy, Ahmedabad, Gujarat (India).

 

ABSTRACT:

Liquid Chromatography- Mass Spectrometry is a powerful analytical technique having high Sensitivity and Specificity. LC-MS combines the separation capabilities of Liquid Chromatography with the mass analysis capabilities of Mass Spectrometry. Liquid Chromatography separates the mixture, which is having multiple components, and then Mass Spectrometry provides the Spectral information which is used to identify each separated component. Interfaces are used in LC-MS system to transfer the maximum amount of analyte, remove a significant portion of the mobile phase, and preserves the chemical identity. Different types of Interfaces are used which include Atmospheric-Pressure Ionization, Electrospray Ionization, Atmospheric Pressure Chemical Ionization, Thermospray and Plasma Spray Ionization, Particle Beam Ionization, Continuous Flow Fast Atom Bombardment. LC-MS having a wide range of application in various field which include Pharmaceutical, Drug Development, Forensic Science, Cosmetic, Petrochemistry, Environment, Food Analysis, Biochemical Application. In this article Principle, Instrument and Application are discussed briefly.

 

 

 

1. INTRODUCTION:

1.1. Introduction to Liquid Chromatography-Mass Spectrometry

The hyphenated analytical technique Liquid Chromatography-Mass Spectrometry (LC-MS) is a combination of Liquid Chromatography (LC) and Mass Spectrometry (MS). By passing mixtures over a chromatographic column, HPLC (LC) separates the components. In most cases, LC alone will not be able to positively identify the separated components.¹

 

Interfaces are used in LC-MS system to transfer the maximum amount of analyte, remove a significant portion of the mobile phase, and preserves the chemical identity. LC-MS having a wide range of application in various field which include Pharmaceutical, Drug Development, Forensic Science, Cosmetic, Petrochemistry, Environment, Food Analysis, Biochemical Application. In this article Principle, Instrument and Application are discussed briefly.²

 

1.2. Instrumentation:

The Liquid Chromatography-Mass Spectrometry (LC-MS) is combination of Liquid Chromatography and Mass Spectrometry in which HPLC has a separation power and MS having a detection power.⁴

·       The Liquid Chromatography (LC) is a high-performance liquid chromatography in which separation of components of mixture can be carried out by using liquid mobile and solid stationary phase. By using different packing of columns with high efficiency small amount of complex mixture can be separated. The components of HPLC include Pump, Sample Injector, Columns, Detectors, and recorder. Mass spectrometry is an analytical technique that measures the mass to charge ratio of ionic species^5,6,7. The ionization source and interfaces are the two most important components in LC-MS^8-12

 

2. APPLICATION:

2.1 Pharmaceutical application:

The main applications of LCMS in pharmaceutical analysis are in the study of drug metabolism, in the analysis and identification of impurities and degradation products in pharmaceutical products, and in the isolation and characterization of potential medicinal substances from natural or synthetic sources.^13,14

e.g. benzodiazepines were run by using UV and mass detectors.¹⁵

 

·       Detection of degradation product:

LCMS used to separate, identify, and characterize the degradation products under certain condition like oxidation, hydrolysis, photolytic and thermal stress.^{16,17,18,19,20}

 

Table 1: Summary of experimental procedure of LC/MS applications on bioanalysis in support of ADME

Sr. No.	Sample matrix	Method description	Ref. No.
1	Vildagliptin (API)	Column:C18(250mm × 4.6mm, 5µm) Mobile phase: Ammonium Acetate Buffer: Methanol (80:20 %v/v) Flow rate: 1ml/min Ionization method: Electrospray	21
2	Sitagliptin and ertugliflozin (Rat Plasma)	Column:C18(150mm × 4.6mm, 2µm) Mobile phase: Acetonitrile: OPA Buffer (50:50 %v/v) Flow rate: 1ml/min Ionization method: Electrospray	22
3	Tryptophan metabolites    (Culture Medium)	Column:C18(2.1mm × 12.5mm, 5µm) Mobile phase: Acetonitrile: Ammonium format. Flow rate: 0.15ml/min Ionization method: API	23
5	RGH-1756 (Rat Plasma)	Column:C18(150mm × 4.6mm, 5µm) Mobile phase: Water: Ammonium acetate Flow rate: 1ml/min Ionization method: APCI	24
6	Cefadroxil and Clavulanic acid (Human Plasma)	Column:C18(150mm × 4.6mm, 5µm) Mobile phase: Methanol: Acetonitrile: 2mM Ammonium acetate. Flow rate: 0.8ml/min Ionization method: APCI	25
7	Hydroxyzine Hydrochloride (Human plasma)	Column:C18(150mm × 2.1mm, 5µm) Mobile phase: 5mM Ammonium acetate: methanol: Acetonitrile (45:36:19 %v/v) Flow rate: 0.8ml/min Ionization method: Electrospray	26
8	Cefpodoxime proxetil and clavulanic acid (Human Plasma)	Column:C18(150mm × 4mm, 5µm) Mobile phase: Methanol: Acetonitrile: 2mM Ammonium acetate (25:25:50 %v/v) Flow rate: 0.8ml/min Ionization method: APCI	27
9	Lisinopril (Human plasma)	Column:C18(150mm × 2.1mm, 5µm) Mobile phase: formic acid solution (ph 2.9): methanol: acetonitrile (58: 25:17 %v/v) Flow rate: 1ml/min Ionization method: Electrospray	28
10	Haloperidol (Human Plasma)	Column:C18(100mm × 2.1mm, 5µm) Mobile phase: 1mM Ammonium acetate (ph 3): Acetonitrile (70:30 %v/v) Flow rate: 0.2ml/min Ionization method: Electrospray	29
11	Enalapril and enalaprilat (Human Plasma)	Column:C18(150mm × 4.6mm, 2µm) Mobile phase: methanol: ammonium acetate (53:47%v/v) Flow rate: 0.1ml/min Ionization method: Electrospray	30
12	Topiramate (tablet)	Column:C18(150mm × 4.6mm, 5µm) Mobile phase: Acetonitrile: Water (85:15 %v/v) with 0.1% formic acid Flow rate: 0.5ml/min Ionization method: Electrospray	31
13	Tamsulosin (Human Plasma)	Column:C18(125mm × 4mm, 5µm) Mobile phase: Methanol: 0.05M Ammonium acetate Flow rate: 0.5µl/min Ionization method: Electrospray	32
14	Maraviroc (Human Plasma)	Column:C18(3.5mm × 2.1mm, 5µm) Mobile phase: 0.1Mm EDTA: Acetonitrile: methanol (15:80:5 %v/v) Flow rate: 0.2ml/min Ionization method: Electrospray	33
15	Ezetimibe (Human Plasma)	Column:C18(100mm × 2.1mm, 3.5µm) Mobile phase: Acetonitrile: Ammonium acetate (75:25 %v/v) Flow rate: 0.5µl/min Ionization method: APCI	34
16	Clopidogrel metabolite (Human Plasma)	Column:C18(75mm × 4.6mm, 3µm) Mobile phase: Acetonitrile: water (75:25 %v/v) 0.1%formic acid Flow rate: 0.2ml/min Ionization method: Electrospray	35
17	Triethylenetetramine (Human Plasma)	Column:C18(100mm × 4.6mm, 5µm) Mobile phase: Acetonitrile: methanol (15:85 %v/v) 0.1%heptaflurobutyric acid Flow rate: 0.5ml/min Ionization method: Electrospray	36
18	Methotrexate (Human Plasma)	Column:C8(50mm × 1mm, 5µm) Mobile phase: Acetonitrile: 0.1% formic acid (20:80 %v/v) Flow rate: 0.15ml/min Ionization method: Electrospray	37
19	Lapatinib (Human Plasma)	Column:C18(150mm × 3mm, 3.5µm) Mobile phase: Acetonitrile: methanol (75:25 %v/v) 0.1%formic acid Flow rate: 0.45ml/min Ionization method: Electrospray	38
20	Clonidine hydrochloride (Human Plasma)	Column:C18(30mm × 2.1mm, 3.5µm) Mobile phase: Acetonitrile: water (60:40 %v/v) 0.2%formic acid Flow rate: 0.2ml/min Ionization method: Electrospray	39
21	Tenofovir (Human Plasma)	Column:C18(50mm × 2.1mm, 3.5µm) Mobile phase: trifluoroacetic acid: acetonitrile Flow rate: 0.2ml/min Ionization method: Electrospray	40
22	Sunitinib (Human Plasma)	Column:C18(150mm × 3mm, 3.5µm) Mobile phase: 0.1%formic acid: acetonitrile (80:20 %v/v) Flow rate: 0.35ml/min Ionization method: Electrospray	41
23	Artesunate and dihydroartemisinim (Human plasma)	Column:C18(75mm × 4.6mm, 4µm) Mobile phase: 0.1%Acetic acid: methanol: acetonitrile (38:46.5;15.5 %v/v) Flow rate: 0.5ml/min Ionization method: APCI	42
24	Amlodipine atorvastatin (Human Plasma)	Column:C18(75mm × 4.6mm, 3µm) Mobile phase: Acetonitrile: water (70:30 %v/v) Flow rate: 0.15ml/min Ionization method: Electrospray	43
25	Flupentixol (Human Plasma)	Column:C18(100mm × 2.1mm, 3.5µm) Mobile phase: 10mM ammonium acetate: acetonitrile: methanol (26:62:12 %v/v) Flow rate: 0.5ml/min Ionization method: electrospray	44
26	Metoclopramide (Human Plasma)	Column:C18(150mm × 2.1mm, 5µm) Mobile phase: 40Mm Ammonium acetate: methanol: acetonitrile (75:5:20 %v/v) Flow rate: 0.24µl/min Ionization method: electrospray	45
27	Candesartan and hydrochlorothiazide (Human Plasma)	Column:C18(250mm × 3mm, 5µm) Mobile phase: Acetonitrile: 0.3%formic acid (70:30 %v/v) Flow rate: 0.5ml/min Ionization method: APCI and electrospray	46
28	Metformin and miglitol (Human Plasma)	Column:C18(100mm × 2.1mm, 3.5µm) Mobile phase: Ammonium acetate: methanol (95:5 %v/v) Flow rate: 0.5ml/min Ionization method: electrospray	47
29	Febuxostat (Human Plasma)	Column:C8(100mm × 4.6mm, 3.5µm) Mobile phase: Acetonitrile: 5mMAmmonium a format (75:25 %v/v) Flow rate: 0.5µl/min Ionization method: API	48
30	Atorvastatin and telmisartan (Human Plasma)	Column:C18(150mm × 4.6mm, 5µm) Mobile phase: 10mMAmmonium acetate: methanol (20:80 %v/v) Flow rate: 1ml/min Ionization method: electrospray	49
31	Telmisartan (Human Plasma)	Column:C18(150mm × 2.1mm, 5µm) Mobile phase: Acetonitrile: Ammonium acetate (42:58 %v/v) 0.2% acetic acid Flow rate: 0.2ml/min Ionization method: electrospray	50
32	Eplerenone (Human Plasma)	Column:C18(150mm × 3mm, 3µm) Mobile phase: Methanol: Ammonium acetate (60:40 %v/v) Flow rate: 0.3ml/min Ionization method: Electrospray	51
33	Ursodiol (Human Plasma)	Column:C18(100mm × 2.1mm, 3.5µm) Mobile phase: 1mM Ammonium acetate: acetonitrile (65:35 %v/v) Flow rate: 0.2ml/min Ionization method: Electrospray	52
34	Azithromycin (Human Plasma)	Column:C18(150mm × 3mm, 5µm) Mobile phase: 20mMAmmonium acetate: acetonitrile: water (50:40:10 %v/v) Flow rate: 0.2ml/min Ionization method: Electrospray	53
35	Erythromycin ethyl succinate	Column:C18(250mm × 2mm, 5µm) Mobile phase: Acetonitrile: 1.67Mm acetic acid (70:30 %v/v) Flow rate: 0.2ml/min Ionization method: Electrospray	54
36	Amlodipine (Human Plasma)	Column:C18(150mm × 3mm, 3µm) Mobile phase: Methanol: 10mM Ammonium acetate (70:30 %v/v) Flow rate: 0.2ml/min Ionization method: Electrospray	55
37	Felodipine (Human Plasma)	Column:C18(150mm × 4.6mm, 5µm) Mobile phase: Acetonitrile: 2mM Ammonium acetate (80:20 %v/v) Flow rate: 0.8ml/min Ionization method: Electrospray	546
38	Amantadine (Human Plasma)	Column:C18(150mm × 2.1mm, 5µm) Mobile phase: Methanol: acetonitrile:  20mM Ammonium acetate (45:10:45 %v/v) Flow rate: 0.25ml/min Ionization method: Electrospray	57
39	Simvastatin	Column:C18(150mm × 4.6mm, 5µm) Mobile phase: Methanol: water (90:10 %v/v) Flow rate: 0.8ml/min Ionization method: API	58
40	Tamsulosin (Human Plasma)	Column:C18(125mm × 4mm, 5µm) Mobile phase: Methanol: 0.05mM Ammonium acetate (60:40 %v/v) Flow rate: 0.5ml/min Ionization method: Electrospray	59
41	Doxycycline	Column:C18(100mm × 4.6mm, 5µm) Mobile phase: acetonitrile: 5mM Ammonium acetate (80:20 %v/v) Flow rate: 0.3ml/min Ionization method: Electrospray	60
42	Manidipine (Human Plasma)	Column:C18(200mm × 4.6mm, 5µm) Mobile phase: Methanol: 5mM Ammonium acetate (85:15 %v/v) Flow rate: 0.7ml/min Ionization method: Electrospray	61
43	Phosphatidylcholine hydroperoxide (Human Plasma)	Column:C18(100mm × 2.1mm, 5µm) Mobile phase: acetonitrile: 5mM Ammonium acetate: 2-propanol Flow rate: 0.2ml/min Ionization method: Electrospray	62
44	Artemether (Human Plasma)	Column:C18(150mm × 4.6mm, 5µm) Mobile phase: Acetonitrile: 0.1% glacial acetic acid (66:34 %v/v) Flow rate: 1ml/min Ionization method: APCI	63
45	Sodium ferulate (Human Plasma)	Column:C18(100mm × 3mm, 3.5µm) Mobile phase: Methanol: 0.05% acetic acid (40:60 %v/v) Flow rate: 0.4ml/min Ionization method: Electrospray	64
46	Silodosin and silodosin β-D-Glucuronide (Human Plasma)	Column:C18(100mm × 4.6mm, 3.5µm) Mobile phase: 5mM Ammonium acetate: Acetonitrile (20:80 %v/v) Flow rate: 0.8ml/min Ionization method: Electrospray	65
47	Lafutidine (Human Plasma)	Column:C18(150mm × 2mm, 5µm) Mobile phase: Methanol: 1mMAmmonium acetate (55:45 %v/v) 0.04%Triethylamine Flow rate: 0.3ml/min Ionization method: Electrospray	66
48	Phenytoin	Column:C18(150mm × 4.6mm, 5µm) Mobile phase: 2Mm Ammonium Acetate in water(pH 6.3): Methanol (30:70%v/v) Flow rate: 1ml/min Ionization method: Electrospray	67
49	Levetiracetam	Column:C18 Mobile phase: Methanol: Acetonitrile: 10mMAmmonium acetate (45:45:10 %v/v) 0.04%Triethylamine Flow rate: 1 ml/min Ionization method: Electrospray	68
50	Glicelazide	Column:C18 Mobile phase: MAmmonium acetate: Methanol (55:45 %v/v) Flow rate: 1 ml/min Ionization method: Atmospheric pressure Ionization	69
51	2-acetoxy ethyl Acetoxy methy ether	Column:C18(150mm × 4.6mm, 3 µm) Mobile phase: Methanol: 1mMAmmonium acetate (25: 75%v/v) Flow rate: 0.3ml/min Ionization method: Electrospray	70
52	Teneligliptin hydrobromide	Column:C18 Mobile phase: Methanol: 1mMAmmonium formate (80: 20%v/v) Flow rate: 0.5ml/min Ionization method: Electrospray	71
53	Emetricitabine and Tenofovir	Column:C18(100mm × 4.6mm, 5 µm) Mobile phase: Methanol: Formic acid  (80: 20%v/v) Flow rate: 0.3ml/min Ionization method: Electrospray	72
54	Moxonidine	Column:C18(100mm × 4.6mm) Mobile phase: Acetonitrile: 10Mm Ammonium acetate (85: 15%v/v) Flow rate: 1 ml/min Ionization method: Electrospray	73
55	Emtricitabine	Column:C18(50mm × 2.1mm, 5 µm) Mobile phase: 5mMAmmonium acetate: Acetonitrile (30: 70%v/v) Flow rate: 0.3ml/min Ionization method: Electrospray	74
56	Drotaverine	Column:C18(150mm × 4.6mm, 3 µm) Mobile phase: Actonitrile: Ammonium formate (50: 50%v/v) Flow rate: 1 ml/min Ionization method: Electrospray	75
57	Budesomide	Column:C18 Mobile phase: Acetonitrile: 5mM Ammonium formate (60: 40%v/v) Flow rate: 2.5ml/min Ionization method: Electrospray	76
58	Ciprofloxacin	Column:C8 Mobile phase: Acetonitrile: water: formic acid (80: 20: 20%v/v) Flow rate: 0.3ml/min Ionization method: Electrospray	77

 

2.2 Molecular weight determination:

API-electrospray LC/MS can be used to rapidly determine the molecular weight of a protein.¹⁵

 

2.3 Drug Development⁷⁸

2.4  Forensic Science:

·       Such as in drug analysis, toxicology, trace analysis, etc.^79,81

e.g Extracted ion chromatogram of orange juice using LCMS using ESI in negative mode

 

·       LCMS analysis of fingerprint, the amino acid profile of 20 donors⁸⁰

·       Morphine and metabolites:

LC-API-MS procedure for determination of morphine metabolites in biological fluid.⁸²

 

 

2.5  Cosmetics:

Pyridsoxamine is used in cosmetic to avoid proteins modification. By direct injection positive ESI LCMS.⁸³

 

2.6  Petrochemistry:

Analysis of oil derived molecule (hydrocarbon) and contaminants. Negative ion chemical ionization.1-nitropyrene and its isomers (environment contaminants) are well for its carcinogenic properties. Considerable amounts of these compounds have been detected in diesel engine exhausts.⁸³

 

2.7  Environment application:

A qualitative method using 2,4-dinitrophenylhydrazine (DNPH) derivatization followed by analysis with liquid chromatography (LC)/negative ion-electrospray mass spectrometry (MS) was developed for analyzing and identifying highly polar aldehydes and ketones in ozonated drinking water.^84,85,

2.8  Food analysis⁸⁷

Total ion chromatograms of cocoa procyanidins obtained after post column addition of 10mM ammonium acetate in both positive and negative electrospray ionization modes.⁸⁹ Identification of aflatoxins in food^[89]Determination of Vitamin D³ in poultry feed supplements. Determination of sterigmatocystin (STC) in grains^90,91,92.

 

2.9 Biochemical application:

Determination of endogenous structural biopolymers such a peptide, proteins, glycoproteins, and lower molecular mass compounds such as fatty acids, vitamins, steroids, and nucleic acids.^93,94

 

2.10 Clinical application:

Automated Immunoassay in Therapeutic Drug Monitoring^[95].  Steroid hormones, Assay for urine free cortisol, estrogens and multiplexed assays for various adrenal steroids have been developed^96,97,88. 

 

CONCLUSION:

The LC-MS is a hyphenated technique used in combination with separation power of HPLC with detection power of Mass spectrometry. MS using ESI and other ionization methods can be applied to a much wider range of biological molecules than GC-MS and will thus find greater application in clinical biochemistry. Direct injection methods can determine many analytes with high through-put when highly specific tandem MS is used for detection. LC-MS provides superior specificity and sensitivity compared to direct injection methods. When combined with stable isotope dilution, LC-MS can be used to develop highly accurate and reproducible assays. Modern mass spectrometers are highly sensitive and LC-MS assays are now viable replacements for many immunoassays. It is widely used in pharmaceutical, chemical, food, agrochemical industries, environmental and forensic applications. LC-MS is used for qualitative and quantitative determination of drug substances and biological samples. Also, it is commonly used in drug research and quality control.s

 

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Received on 16.02.2022       Modified on 27.04.2022

Accepted on 12.06.2022   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Ana. 2022; 12(3):203-210.