A comprehensive assessment of the biological attributes of and analytical quantification methods for monosodium glutamate

Atyurmila Chakraborty; Kavitha Jayaseelan

doi:10.1556/1326.2023.01171

Acta Chromatographica

Volume/Issue:: Volume 36: Issue 4

A comprehensive assessment of the biological attributes of and analytical quantification methods for monosodium glutamate

Authors:

Atyurmila Chakraborty

Atyurmila Chakraborty Department of Pharmaceutical Analysis, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur - 603 203, Chengalpattu (Dt), Tamil Nadu, India

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ac5602@srmist.edu.in https://orcid.org/0000-0002-1770-5491

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Kavitha Jayaseelan

Kavitha Jayaseelan Department of Pharmaceutical Analysis, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur - 603 203, Chengalpattu (Dt), Tamil Nadu, India

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kavithaj@srmist.edu.in https://orcid.org/0000-0002-3037-6178

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Pages:: 287–306

Online Publication Date:: 11 Jan 2024

Publication Date:: 28 Oct 2024

Article Category:: Review Article

DOI:: https://doi.org/10.1556/1326.2023.01171

Keywords:: monosodium glutamate; umami flavour; analytical methods; determination with HPLC; chemometric analysis

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Abstract

This review focuses on monosodium glutamate which proclaims the fifth taste as “Umami”. Monosodium glutamate imparts a deep, meaty, umami flavour to foods. Asian cuisine frequently uses this flavouring, just as in the processed items produced across the United States and Europe. This article dealt with a detailed discussion of physicochemical features, pharmacological actions, and different reported analytical methodologies for the estimation of monosodium glutamate. Monosodium glutamate is analyzed using a variety of techniques, including spectroscopy, chromatography, electrochemistry, electrophoresis, chemometrics, flow injection analysis, and biosensors. According to results of comparative research of analytical methodologies, high performance liquid chromatography (HPLC) is most widely used method for analyzing monosodium glutamate which surpasses the gas chromatographic (GC) approach. All of the reported methods are accurate, precise, cost-effective, and sensitive. The European Union defined monosodium glutamate as a food additive that is permitted in some foods, but is subject to quantitative limits. Consequently, this study provides the analyst with an accessible path to quantifying monosodium glutamate's content for use in the food and pharmaceutical industries.

Abstract

1 Introduction

Glutamate is one of the twenty amino acids that can be found in meals that contain protein, including meat, poultry, and seafood. It is a product of mammalian metabolism and can be ingested in the form of dietary supplements. Glutamate is a key component of mammalian metabolism since it is found in the brain. It serves as a chemical messenger in the central nervous system, and it is also used as a transmitter during the transmission of electrical impulses. Additionally, glutamate is required for a variety of metabolic functions. Glutamate uses water for the deamination process, which helps with effective removal of excess nitrogen during nitrogen metabolism. Glutamate is generated as a result of the transamination of alpha-ketoglutarate in the tricarboxylic acid cycle.

Glutamate is a flavour enhancer that is widely found in soups, sauces, and a wide variety of processed foods and beverages. Glutamate sodium salts are used as food additives in a variety of products. Monosodium glutamate (MSG), often known as E-621, is a flavour enhancer that is commonly found in processed foods [1]. MSG is derived from nature's most plentiful amino acid, glutamate, or glutamic acid. In humans, the most acceptable dose of MSG is around 60 mg kg⁻¹ body weight per day [2]. MSG is responsible for the umami flavour, which gives a pleasant taste sensation. Its determination is crucial since the degree of its concentration is a good predictor of food quality [3].

At first, glutamic acid was isolated as a component of wheat gluten, which was obtained by the acidic hydrolysis of gliadin by the German chemist, Ritthausen, in the year 1866. But it wasn't discovered as a flavouring agent at that time. Later, in 1908, Ikeda, a Japanese scientist, brought to light that kelp, such as rockweed “konbu” or Laminaria Japonica, has the same flavour-enhancing characteristics as glutamic acid, which has been used in the preparation of soup stocks in Japan for generations [4]. Ikeda acquired glutamic acid by extracting rockweed with hot water, and he patented a method for separating MSG from wheat flour in 1909, which was sold under the brand name AJI-NO-MOTO (Aji no moto; “at the source of flavour”) [4].

Glutamate and MSG are glutamic acid's monosodium salts. The umami sensation is only present in the completely dissociated form of L-(+)-glutamic acid. It is clear that glutamic acid has its best umami effect when the pH is between 6 and 8 [4]. Glutamate receptors are only activated by free glutamates. When linked to other amino acids in a protein, it does not provoke the glutamate receptors. During processing, they are partially freed, emphasising their unique flavour traits. There are two isomers of MSG namely L-glutamate enantiomer and d-glutamate enantiomer but only the L-glutamate enantiomer has flavour-enhancing properties. Manufactured MSG has more than 99.6% of the naturally occurring L-glutamate form, which has a greater percentage of L-glutamate than reported in naturally occurring free glutamate ions [5]. The primary reason for using such an additive in most foods is that it has a higher and faster dissolution performance [6]. Fig. 1 depicts the chemical structure of MSG, and its physicochemical properties has been listed in Table 1 [6].

Fig. 1.

Chemical structure of MSG

Citation: Acta Chromatographica 36, 4; 10.1556/1326.2023.01171

Table 1.

Physicochemical properties of MSG

Chemical formula	C₅H₈NO_4.Na
IUPAC –ID	Sodium-2-aminopentanedioate
In Food Business	E621
Colour	White
Odour	Odourless
Texture	Crystalline powder
Molecular mass	169.11 g mol⁻¹
Melting point	232 °C
Taste	Umami
In aqueous solution	Easily dissolves and dissolutes to form sodium and free glutamate
In alcohol	Sparingly soluble
In water	Solubility is 385,000 mg L⁻¹ at 25 °C
In oil and other organic solvents	Soluble

2 Biological attributes of MSG

2.1 MSG as supplement

Glutamate is a kind of amino acid that the body produces and is involved in a number of bodily functions. It has been discovered in many peptides and proteins. A superior source of energy is provided to the liver and intestinal mucosa by glutamate and its metabolites. Humans can metabolise rather high amounts of glutamate, which is naturally created in the stomach by exopeptidase enzymes during protein breakdown, under normal conditions [7].

Glutamate is considered as an essential amino acid to sustain the metabolic needs of intestinal mucosa, especially when the depletion of glucose is severe. However, it is endogenously produced by the body and so is classified as a non-essential amino acid. It is understood that 1.3% of glutamic acid in the diet is needed for growth, so that glutamic acid is considered as a semi-essential amino acid [8].

2.2 Isolation of glutamic acid

MSG is inextricably appetising to the world of flavour and taste in the food business. Julius Maggi, a food industry pioneer, developed rapid-cooking dehydrated soups in the second half of the nineteenth century, which grew into a significant economic segment in many nations. Hydrolysed plant protein is one of the major elements. The meaty flavourings required for the production of these fast-cooking soups were created by hydrolysates. MSG, a key component of these vegetable hydrolysates, was unknown at the earlier times. Ikeda recognised glutamic acid as the quintessence of tastiness in konbu (kelp) rockweed and dubbed this well-defined taste “Umami” from dried skipjack and dry shiitake mushrooms, and 59 ribonucleotides were recovered from this. As a result, the Umami flavour note has been enhanced by this distinctive savoury taste [9].

2.3 Source of glutamate in nature

Glutamate is one of the nature's most well-known amino acids, found in a wide spectrum of peptides, tissues, and proteins. It is naturally synthesized in the human body and combines with relative amino acids to make structural proteins. As glutamate is tasteless; when coupled with protein molecules, it does not add umami flavour to food. Nonetheless, protein breakdown liberates tasty free glutamate during the fermentation, maturation, ripening, and heat cooking processes. Glutamate is an important flavour component in foods, including seafood, pork, cheese, and broths [2, 10].

2.4 Physicochemical properties

MSG does not degrade in quality or appearance when stored at room temperature for long period of time and it is determined to be stable. With the exception of acidic conditions at pH 2.2–2.4 and extreme heat, MSG does not break down during routine food preparation or cooking. At such pH values and temperatures, water is removed from MSG and it is transformed into 5-pyrrolidone-2-carboxylate. Furthermore, at extremely high temperatures, particularly in alkaline environments, glutamate tends to racemize to D and L-glutamineb [2].

In the presence of reducing sugars, MSG, like other amino acids, is capable of undergoing Maillard-type reactions. Due to its taste and active chemical properties, MSG is known to provide a distinct flavour. The stereochemical structure of MSG has a peculiar flavour, except for the D-isomer, which does not have any distinguishing flavour. The conversion of MSG upon heating is depicted in Fig. 2. MSG's best possible appetising concentration is between 0.2 and 0.8%, and its usage should be self-contained because excessive use diminishes palatability [2]. The composition of MSG is represented in Table 2 [9, 10].

Fig. 2.

Conversion process of MSG upon heating

Citation: Acta Chromatographica 36, 4; 10.1556/1326.2023.01171

Table 2.

Composition of MSG

S. No.	Parameters	Description
1.	Monosodium glutamate	Generally recognized as safe by FDA
2.	Monosodium glutamate contains	12% sodium + 88% glutamic acid
3.	L-glutamic acid	15% of total amino acid content in human body
4.	L-glutamic acid intake is high	3.5–10.6 g per day from food, 1.3 g from food additives
5.	L-glutamic acid generated in the body by total protein breakdown	48–50 g
6.	Total bound L-glutamic acid	1.4–2.0 g
7.	Average daily intake of glutamic acid	10–20 g

2.5 Pharmacology

2.5.1 Into bloodstream

Only about 12% of glutamate enters the bloodstream after being digested in the digestive tract. Glutamate is an enzyme's active site, a protein synthesis substrate, a precursor of N-acetyl glutamate/glutamine, and a neurotransmitter, specifically gamma-aminobutyric acid (GABA). Glutamate, in addition to protein synthesis, serves many important roles in the body, making it essential for maintaining and functioning of a healthy body [9].

2.5.2 MSG metabolism in human body

Glutamate enters the human body through two distinct routes. It enters through the food as hydrolysed protein or is added in the form of MSG. The active transport system, which was developed specifically for amino acids, absorbs glutamate in the intestines. This procedure depends on the sodium ion concentration and is both saturable and competitively block able. When consumed orally, MSG gets split into glutamate or sodium ions in the digestive tract. Active transport absorbs glutamate in the stomach and intestine. Excitatory amino acid carrier 1 (EAAC-1) and sodium dependent dicarboxylate-1 (NaDC-1) are glutamate transporters that move some of the glutamate from the stomach to the lumen via the apical membrane. Glutamate is transported into the bloodstream and is circulated throughout the body via these transporters. Glutamate catabolism begins in the cytosol and mitochondria of the intestinal enterocyte with transamination in the presence of aspartate aminotransferase, alanine aminotransferase, branched-chain aminotransferase, and glutamate dehydrogenase (GDH) enzymes, resulting in the formation of ketoglutarate. With the emission of carbon dioxide, ketoglutarate enters the tricarboxylic acid (TCA) cycle.

The metabolism of MSG yields nine urine metabolites which are glutamate, alpha-ketoglutarate, malonate, citrate, 5-amino valerate, 5-hydroxymethyl-4-methyluracil, dimethylamine methylamine, and beta-hydroxy isovalerate. As a result, MSG is excreted in the urine as these metabolites. Glutamic acid in dietary protein is assimilated to let out amino acids and tiny peptides, which are then absorbed into the mucosal cells where the peptides are hydrolysed to release free amino acids and some of the glutamate is metabolised.

The concentration of glutamate is greater in the portal circulation, where it is metabolised by the liver. The gastrointestinal system is responsible for majority of glutamate metabolism. However, just a small quantity of dietary glutamate penetrates the systemic or portal blood supply, indicating that the digestive tract uses it entirely [2, 10].

2.5.3 Sensory outlook of umami substances

The sensory information associated with the umami flavour has been explored and recorded, as it originates at the effector level and travels to the cerebral cortex. In 1987, Kurihara described the fundamental process through which all taste sensations are perceived [7].

The taste bud's receptor membranes absorb a fillip, such as an umami compound. A receptor potential is elicited in receptor cells, leading to the release of a neurotransmitter, which causes a gustatory sensitive nerve drive. The message is carried to the superior and inferior cortices, where it is processed and identified by subsequent brain relays [6]. The sensory path of umami substances from taste buds to brain is depicted in Fig. 3 [6].

Fig. 3.

Sensory outlook of umami substances from taste buds to brain

Citation: Acta Chromatographica 36, 4; 10.1556/1326.2023.01171

2.5.4 In-vivo production of glutamate in brain

In the brain, glutamate acts as a neurotransmitter, which has no relation with the glutamates found in other parts of the body. In the mammalian brain, glutamate is widely acknowledged as the primary excitatory neurotransmitter. Aminobutyric acid is the precursor biomolecule to the chemical messenger GABA. Most of the neurons in the brain get excited when glutamate is administered [6]. Certain taste receptors in taste buds, such as the amino acid receptor, are activated when glutamate is present. To produce the umami flavour, T1R1/T1R3 or other glutamate receptors, such as metabotropic receptors need to be activated. The flavour-enhancing effects are only found in the L-glutamate enantiomer. A substantial proportion of nerve cells activate glutamate effectors. There are two types of glutamate effectors, namely, metabotropic and ionotropic receptors. The N-methyl-D-aspartic acid (NMDA) receptor, the kainate receptor, and D, L-amino-3-hydroxy-5-methyl-isoxole propionic acid (AMPA) receptor, which selectively work with acids like NMDA, kainic acid, and AMPA, have been identified based on the usage of distinct agonists. The NMDA receptors play a role in both learning and development. Glutamate works as a feeding-stimulatory neurotransmitter in the lateral diencephalon [6].

2.6 Pharmacokinetics

In India, the Prevention of Food Adulteration Act limits MSG content in foods to 1% [11]. Glutamate is a prevalent amino acid present in high concentrations in the cerebral fluid. It was discovered in higher concentrations in regions of the brain that play a key role in mediating consciousness, such as the striatum, the hippocampus's dentate gyrus, and the cerebral cortex. Intake of very high levels of MSG on a daily basis raises glutamate levels in the blood. Glutamate levels in the blood are affected by a number of factors, including dose, concentration, and age [7]. The adsorption, distribution, metabolism and elimination pathway of MSG is depicted in Fig. 4 [2, 10].

Fig. 4.

Absorption, distribution, metabolism and elimination paths for MSG

Citation: Acta Chromatographica 36, 4; 10.1556/1326.2023.01171

2.7 Toxicity

MSG's fast absorption through the gastrointestinal tract may result in an increase in glutamate levels in the plasma. MSG is a chemical that belongs to the excitotoxins group. In animal studies, high doses of MSG was found to damage areas of the brain that were not protected by the blood–brain barrier, and its neurotoxicity can lead to a variety of chronic disorders [14].

MSG symptoms can also be caused by consuming a high concentration of glutamate. Headaches, numbness, and palpitation are the possible adverse effects of the same. It is readily absorbed through the gastrointestinal tract, increasing the levels in the blood plasma. Overstimulation of glutamate can harm neurons and has been related to neurodegenerative disorders such as Alzheimer's disease [14].

This excessive quantity of a neurotransmitter, however, can cause it to become an excitotoxin, a substance that over-excites cells to the point of damage, when the balance of glutamate is upset this substance can become neurotoxic, leading to enzymatic cascades resulting in cell death [5]. Moreover, the utilization of MSG has been associated with an elevated risk to cancer and neurodegenerative disorders [2, 10, 83]. Its metabolization product glutamine is one of the two fundamental nutrients (along with glucose) used by cancer cells. Glutamine has the capacity to serve as a source of both carbon and nitrogen for anabolic processes within neoplastic cells. Additionally, it is worth noting that tumor cells heavily depend on citrate as a precursor for the synthesis of fatty acids, which is essential for their growth. This reliance is facilitated by the tricarboxylic acid (TCA) cycle, where citrate plays a crucial role in coordinating both energy production and biosynthetic processes. The conversion of α-ketoglutarate produced from glutamine in neoplastic cells to isocitrate results in an imbalance between α-ketoglutarate and citrate. This imbalance disrupts the TCA cycle, leading to the production of acids and promoting tumor growth. L-2-hydroxyglutarate and R-2-hydroxyglutarate have been found to be linked with distinct forms of cancer. Despite the fact that the anticancer effects of α -ketoglutarate have garnered attention, there remains a lack of comprehensive understanding on the underlying mechanisms.

L-Glutamate is an ergonomic product found in a variety of meals that contributes to their taste. Excessive consumption of L-glutamate from food can result in brain illnesses such as migraines, seizures, autism, attention deficit disorder, hyperactivity, Alzheimer's disease, Lou Gehrig's disease, multiple sclerosis, Alzheimer's and Parkinson's disease. Hence, monitoring its level becomes critical during food processing and fermentation management [5, 15].

2.7.1 Idiosyncratic intolerance (Chinese Restaurant Syndrome)

Glutamate is a copious amino acid in dietary protein. Free glutamate in the diet improves flavour and palatability. Glutamate when attached to a protein becomes free only when it reaches the small bowel, glutamate attached to protein will no longer have effect on flavour of food at this level. Taste and palatability are mediated by glutamate receptors on taste buds and in the stomach and the stimulation of the gastric vagus nerve has physiologic benefits for gut function. Despite the fact that glutamate receptors and physiologic function have been discovered, most people identify MSG with the so-called “Chinese Restaurant Syndrome” (CRS).

Several symptoms have been proposed as part of MSG illness. MSG can trigger three sorts of symptoms, according to our observations: burning, face pressure, and chest pain. A small percentage of people suffer from headaches on a regular basis. Only if a susceptible person consumes the meal on an empty stomach, the symptoms may arise [5, 11–13].

3 Analytical methods

Several analytical approaches for identifying glutamate have been refined recently. As a result, low-cost monitoring technologies to detect and quantify MSG in food and biological samples are required [16].

3.1 Spectrophotometric methods

3.1.1 Ultra violet-Visible (UV-Vis) spectrophotometry

Afraa Alnokkari et al. proposed a Vis spectrophotometric method for estimating the concentration of MSG in food samples. 4-Aminoantipyrine and phenol were employed in the colour development to yield the coloured chromogen which exhibited absorption maximum at 502 nm. A total of 20 min was necessary for the complete colour development and the calibration curve was linear up to 125 mmol L⁻¹ with a detection limit of 2 mmol L⁻¹. The concentration of MSG in different samples ranged from 0.93 to 4.9 g kg⁻¹. This method is relatively sensitive and specific and does not require any sample pre-treatment especially those using flame ionization and test strip [17].

Marlina et al. developed a Vis spectrophotometric method for the investigation of MSG in meat ball soup. The method was based on the coordination of MSG to Cu²⁺ ions with to form a complex ([Cu(C₅H₈NO₄)₂]²⁺), which was identified by the change in the colour of Cu²⁺ ion in solution from light blue to dark blue and the absorbance of the formed coloured complex was measured at a wavelength of 621 nm. The highest absorbance of the complex [Cu(C₅H₈NO₄)₂]²⁺ was determined at pH 10, the Cu²⁺ concentration was 0.01 M, and the optimum time for complex formation was 30 min and the colour of the complex remained stable for 170 min. Cu²⁺-MSG complex had a linear response between the MSG concentration range of 0.0005–0.025 M (r² = 0.994) and the detection limit for MSG was 0.0003 M. The method had a good repeatability (% RSD = 0.89) and recovery value of 93% [18].

3.1.2 Infrared spectrophotometry

As infrared spectrophotometry (IR) is a non-destructive technique, it is ideal for analysing the secondary structure of complex substances such as biological molecules, proteins, DNA, and membranes. In the last decade, IR has been employed in medical sciences to characterise healthy and unhealthy human tissues [19].

The use of IR for detecting MSG are more beneficial as the technique is capable of categorising more than 99% of samples from diverse MSG brands. Use of multivariate calibration approaches like Partial Least Squares (PLS) adds more advantage to the technique. According to Zhengjun Qiu et al. [20] Vis and near infrared reflectance spectroscopy (NIRS) were used to identify and authenticate distinct MSG species. Partial least squares (PLS) models were developed to identify distinct MSG species like Xihu, Linhua, Taitaile, and Foshou; where these samples were homogenised and the reflectance was scanned in the Vis and near infrared [17] areas of 325–1,075 nm.

3.1.3 Microplate based fluorimetry

In terms of sensitivity and specificity, fluorimetry outperforms other analytical techniques. In comparison to absorbance measurements, fluorescence has 10–1,000 fold greater sensitivity [21].

Analytical methods such as HPLC, spectrophotometry, and enzyme biosensors for determining L-glutamate have limitations such as low sensitivity or procedures that are difficult to conduct in a high-throughput format, which is overcome by employing fluorimetry in analysis. Justin Chapman et al. used enzymatic recycling and extremely sensitive indicators like resazarin and Amplex Red to estimate glutamate in dietary samples. The new microplate-based fluorimetric approach was reported to be 500 times more sensitive, with low Limit of detection (LOD) and Limit of quantification (LOQ) values [22].

3.2 Chromatographic methods

In order to utilize the power of chromatography to obtain acceptable separation in a reasonable amount of time [23], many chromatographic techniques including High-Performance Liquid Chromatography (HPLC), High performance thin layer chromatography (HPTLC), Gas chromatography (GC), thin layer chromatography (TLC), Paper chromatography (PC) were employed to estimate MSG. Amongst them, GC is the least utilized due to the absence of amino acids with sufficient volatility for direct GC analysis. Additionally, the polar characteristics of amino acids necessitate the employment of hazardous volatile chemicals for derivatization prior to GC analysis [84].

3.2.1 High-Performance Liquid Chromatography

HPLC allows for both structural and functional analysis, as well as purgation [23]. As buffer is pushed fast through columns under pressure in HPLC, this approach increases the separation power of HPLC by employing small particles and increasing the velocity of solvent flow. As a result, the analysis can be performed in a fairly short period of time [23].

As glutamic acid lacks functional groups with strong enough UV absorptivity or fluorescence, traditional technologies such as liquid chromatographic detection were employed using an amino acid analyser, which required post-column or pre-column derivatization, which istime-consuming [24].

Shu Kaneko et al.performed the separation of umami enhancing compounds employing preparative HPLC and the separated fractions were analysed by Liquid chromatography, time of flight-Mass spectrophotometer (TOF-MS) and Nuclear magnetic resonance (NMR) spectrophotometric techniques[25].

Analytical methods for MSG estimation utilising HPLC were reported and are tabulated in Table 3 [24–41].

Table 3.

Reported HPLC method for the estimation of MSG

Column (length × internal diameter × particle size)	Matrix/Extraction technique	Solvent used	Mobile phase	Wave length (nm)	Flow rate (mL min⁻¹)	CT (°C)	Linearity	LOD	LOQ	Ref
Econosil CN column (250 mm × 4.6 mm × 5-µm)	Food products	LC grade Solvents	H₂O: ACN: THF (77:20:3) containing 1 mM HClO₄, H₂O: ACN: THF (77:20:3) containing 1 mM TCAA	Conductometric Detection (detector zero suppression, 2; detector range, 1 or 10; and chart speed, 0.5 cm min⁻¹)	1.0	30	0–500 μg mL⁻¹	N/A	N/A	[24]
ODS R18 Column (250 × 20 mm × 10-µm)	Fractions obtained B -II -19	H₂O	100% distilled H₂O containing aqueous FA (0.1%)	214	1.0	N/A	N/A	N/A	N/A	[25]
Whatman Partisil SAX column (25 cm × 4.6 mm)	Food sample is diluted with water	HPLC H₂O	pH 4.0, 0.175M NH₄CH₃CO₂ +GAA + NH₄OH	N/A	1.5	20	N/A	N/A	0.15 mg mL⁻¹	[26]
ODC Hypersil column (20 cm × 4.6 mm × 5-µm)	Chicken and beef stock cube samples were homogenised with PBS	100 mL PBS	Ethanol PBS (pH 5.35)-(25:75, v/v)	336	0.8	N/A	N/A	0.1 g kg⁻¹	0.5 g kg⁻¹	[27]
Waters Spherisor C₁₈ column, (150 mm × 4.6 mm × 5-µm)	Food sample was grounded and condiments were diluted in water, to which buffer solution is added	Deionized water	Isocratic solution of 1% v/v GAA in 45% MeOH	Fluorescence detection 328 530	1.2	N/A	N/A	0.21 μg mL⁻¹	0.71 μg mL⁻¹	[28]
RP C₁₈ column (125 mm × 4.6 mm × 5-µm)	Soup, meat product and Chinese foods were homogenised and extracted with hot water	MeOH	ACN: PBS:H₂O (80 + 180 + 740, v/v)	340, 389/440	1.0	N/A	N/A	N/A	N/A	[29]
Waters AccQ-Tag C₁₈ column (150 mm × 3.9 mm × 4-µm)	Mushroom, tomato and yeast extract	MeOH	2% MeOH 98%: 0.05% H₃PO₄	N/A	0.7	N/A	N/A	1.99 mg mL⁻¹	6.02 mg mL⁻¹	[30]
C₁₈ column (150 mm × 4.6 mm × 2.7-µm)	Soups, Chicken and beef bouillon, vegetable seasoning, potato and corn chips.	PBS	10 mM PBS (pH -5.90): MeOH (75:25, v/v)	DAD (336 nm)	0.6	N/A	1–50 μg mL⁻¹	0.015 µg mL⁻¹	0.050 µg mL⁻¹	[31]
Column Thermostat L-7360 DAD detector*	Meat products, soup bases, vegetable concentrates homogenised with phosphate buffer and extracted with petrol ether	MeOH	0–50% MeOH gradient in a pH 3 phosphate buffer	196–400 nm	1.0–1.2	N/A	0–25 µg mL⁻¹	Less than 50 mg kg⁻¹	Less than 50 mg kg⁻¹	[32]
C₁₈ column (150 mm × 4.6 mm × 3-µm)	N/A	H₂O	95% H₂O +5% CH₃CN	N/A	0.5	N/A	N/A	Less than 100 ng	N/A	[33]
PICO TAG column (Waters) (3.9 × 30 cm)	blood sample from rats and serum separated	N/A	PITC, N(CH₂CH₃)₃, Amino acid standard	254	1	46	N/A	N/A	N/A	[34]
Luna RP C₁₈ column (250 × 4.6 mm × 5-µm)	Food, serum and tissue sample	MeOH as Solvent for Food Sample	Mixture of ACN: 30 mM phosphate buffer 50:50, v/v	470 and 530	1	N/A	N/A	N/A	N/A	[35]
CLC-OD RP C₁₈ column (83 mm × 4.6 mm × 3-µm)	Traditional Meat dishes were taken as sample, extracted using diethyl ether	MeOH	70% MeOH: 30% H₂O	254	0.5	N/A	N/A	N/A	N/A	[36]
Kromasil column (250 mm × 4.6 mm × 5-µm)	10 samples of prepared spices extracted with (C₂H₅)₂O	MeOH H₂O	50% MeOH: 50% H₂O (1:1 v/v)	254	1.2	25	N/A	N/A	N/A	[37]
Kromasil column (250 mm × 4.6 mm × 5-µm)	Broths, soups, sauces and salad dressings extracted with 0.1N HCl	Distilled H₂O	370 ml of water plus 90 ml of phosphate buffer at pH 7.0, solvent A, solvent B is acetonitrile. gradient programming	Spectroflourimetric detection330 nm (γ excitation) and 440 nm (γ emission)	0.8	N/A	N/A	N/A	N/A	[38]
C₁₈ column (125 mm × 4.6 mm × 5-µm)	Soup extracted with H₂O	MeOH	Pump A, 1% V/V glacial acetic acid in methanol; and pump B, 1% water. VjV glacial acetic acid in 45% methanol + 55% water.	Spectroflourimetric detection328 nm (γ excitation) and 530 nm (γ emission)	3	N/A	0–10 $μ g μ L$ -l)	N/A	N/A	[39]
RP C₁₈ column (250 mm × 4.6 mm × 5-µm)	Hibiscus sabdariffa L. Aqueous Extract	Ultrapure H₂O	aqueous solution of 0.1% by volume trifluoroacetic acid (eluent A) and acetonitrile (eluent B)	UV detection at 254 and 360 nm.	0.8	N/A	N/A	N/A	N/A	[40]
C₁₈ ODS column (80 mm × 4.6 mm × 3-µm)	Plasma samples	MeOH	0.1 M sodium dibasic phosphate buffer, 25% (v/v) methanol and 5% (v/v) acetonitrile, pH 6.4 with phosphoric acid	N/A	1.2	N/A	N/A	N/A	N/A	[41]

NH₄CH₃CO₂ – Ammonium acetate, H₂O – Water, THF – tetrahydrofuran HPLC – High Performance Liquid Chromatography, NH₄OH – Ammonium hydroxide, GAA – glacial acetic acid, PBS – phosphate-buffered saline, TCAA – Trichloroacetic acid, NaHCO₃ – sodium hydrogen carbonate, MeOH – Methanol, DODC Test – degree of difference from control, ELSD – Evaporative light scattering detector, UV – ultra violet, CH₃CN – Acetonitrile, DAD – Diode array detection, PITC – Phenyl isothiocyanate, phosphate buffer - Potassium di-hydrogen phosphate and di-potassium hydrogen phosphate, TFA – Trifluoroacetic acid C₂H₃NaO₂ – Sodium acetate, N(CH₂CH₃)₃ – Triethylamine, HCCOH/FA – formic acid, OPA – O-phthalaldehyde, (C₂H₅)₂O –Diethyl ether, N/A – Not available.

*Column details not provided in the literature.

3.2.2 High performance thin layer chromatography (HPTLC) and thin layer chromatography (TLC)

HPTLC enables faster separations with less zone diffusion and greater sensitivity, which entails employing adsorbent with a smaller average particle size in the manufacturing of TLC plates. HPTLC is a quantitative analysis technique based on TLC with enhancements targeted at improving separation and allowing quantitative analysis of the compounds. The use of higher-quality TLC plates as the stationary phase with smaller particle sizes, allows for greater resolution [14].

Krishna Veni N, et al. reported a HPTLC technique for the measurement of MSG in food items following post-chromatographic derivatization with 1% ninhydrin solution, and the developed spots were scanned by using a densitometer in absorbance mode at 485 nM. MSG had a retardation factor value of 0.64. The results of the analysis have been validated statistically. Linearity was observed in the concentration range of 400–1,000 nG. The LOD and LOQ for MSG was reported to be 0.7 and 2.3 ng. The proposed HPTLC method for determining MSG in various food products proved to be fast, precise, accurate, and sensitive. It can therefore be conveniently adopted for the routine analysis of MSG in food products [42].

Mohammed M. S. K. A, et al. used a mobile phase to perform TLC separation and quantification of MSG on a silica gel pre-coated plate. The current investigation focused solely on MSG detection, and ANOVA statistical analysis was used to analyse the data. The samples were weighed (equal to 1 g) and HPLC water was used to dilute them to 100 mL. Methanol (CH₃OH): chloroform (CHCL₃): formic acid (FA) (5:5:1) was used as the mobile phase for all of the samples. In the TLC plate, 10 µL were used to spot the samples and standard. 1% ninhydrin in acetone solution was used as detection agent. TLC samples with a high Rf value were validated by LC-MS. TLC results revealed the presence of MSG in the majority of the foods [43].

3.2.3 Gas chromatography

Glutamate in the form of Glutamic acid is subjected to GC which requires derivatization before measurement, since MSG lacks volatility which is a basic necessary criterion for GC analysis. GC is a forensic method used in drug analysis, arson investigations, and toxicity studies of various organic substances [44].

Hiroshi N developed an improved clean-up and derivatization method employing GC equipped with flame ionization detector (FID) for the estimation of MSG in food samples. Acetone-water (1 + 1) is used to extract the sample. After removing the acetone, an aliquot of the extract is buffered with 1M ammonium hydroxide (NH₄OH) - 1M ammonium chloride (NH₄Cl) pH 9 solution and chromatographed on a QAE Sephadex A-25 column that has been prepared with the same buffer. MSG is eluted with 0.1N hydrochloric acid (HCl), and a part of the extract is evaporated to dryness before being treated with dimethyl formamide (DMF)-dimethylacetal to produce the glutamic acid derivative, which is then injected into a gas chromatograph and quantified using flame ionisation detection. Average recovery was 95.8% with a range of 92.8–100% and a coefficient of variation of 2.7% [45].

MSG estimation in soups and soup bases were carried out employing Gas -Liquid Chromatography (GLC) by Henry B.S. Conacher et al. The developed GLC technique provides more significant results over other reported methods, including greater specificity and simultaneous detection of several amino acids in a stretch [46].

3.2.4 Paper chromatography

Separation and identification of components depending on the concept of partition coefficient of the solute between stationary and mobile phases is the concept of work [47].

A PC method for the determination of MSG in food samples was reported by Brian W. B, et al. and effective separation was achieved on Whatman No. 40 filter paper employing n-Butanol: glacial acetic acid (GAA): distilled water (H₂O) as mobile phase in the ratio of 12: 3: 5. It is performed in a Glass jar (18″ high x 12″) in diameter, with glass plate for cover, with Ninhydrin [0.25% in acetone containing 1% pyridine (C₅H₅N)] as the detecting agent. In a variety of Chinese foods, free glutamate was measured by PC method. Glutamate concentrations of 0.4–1.5% by weight as the monosodium salt are reported. The approach outlined is a simple, quick process that could be suggested and should be explored when a more advanced treatment is not possible due to a lack of apparatus [48].

3.2.5 Hyphenated techniques

Hyphenated procedures are the result of technical linkage between two analytical techniques, such as separation (typically chromatography) and detection (usually spectroscopy). Hyphenated methods are those that integrate two or three techniques. The combination of chromatographic and spectroscopic methods makes hyphenated approaches more appealing and extensively applicable in almost all sectors of science, biology, geography, engineering, agriculture, and so on. While chromatographic procedures yield pure or almost pure chemical ingredients in combinations, spectroscopic techniques yield selective information for identifying components using library spectra or standards [49, 50].

The TLC separation coupled with LC -MS for the estimation of MSG was carried out by Mohammed M. S. K. A, et al. [43] on a pre-coated silica gel plate using MeOH: CHCl₃: FA (5: 5: 1), the separated samples were confirmed by LC-MS. For this research, ANOVA statistical analysis was employed. Due to its excellent detectability, reliability, and adaptability, the elution head-based TLC-MS Interface is quickly gaining popularity [44].

A separation strategy was combined with on-line spectroscopic detection technology to develop the hyphenated technique. A technique based on ultra-high pressure liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the detection of GABA and glutamic acid in human plasma to put an end for further research into their health effects merits, accurate and sensitive methods. Protein precipitation and SPE with acetonitrile were used to produce the samples. Gradient elution was used to produce chromatographic separation on an Acquity UPLC HSS reversed phase C18 column. Electrospray ionisation and selective reaction monitoring (SRM) were used to identify analytes. Mobile phases used were Eluent A (Milli Q H₂O with 0.1% v/v FA) Eluent B (consisted of 100% CH₃OH). CH₃OH is used as solvent. Column temperature is 30 °C. Glutamic acid standard curve values range from 30.9 ng mL⁻¹ to 22,500 ng mL⁻¹. In quality control samples of GABA and glutamic acid at low, medium, and high concentrations, within- and between-day accuracy and precision were less than 10% at low, medium, and high concentrations. After freeze–thaw cycles and up to 12 months of storage, GABA and glutamic acid were shown to be stable in plasma. Human plasma from 17 donors was tested using the established technique. The glutamic acid concentrations reported varied from 2,269 to 7,625 ng ml⁻¹. The system presented here is ideally suited for measuring plasma GABA and glutamic acid in pre-clinical and clinical research. The LOD and LOQ for glutamate was reported to be 4.43 ng mL⁻¹ and 30.9 ng mL⁻¹ [51].

LC coupled with MS has been considered as a method of “gold standard” for quantitative food testing. When compared to traditional liquid chromatography, LC-MS/MS methods give greater mass measurement accuracy, better peak separation, and high accuracy and resolution. It also has higher sensitivity due to lower noise, and it can gather chemical information about the analytes and can be employed efficiently in complicated sample matrices. Nur Cebi et al. described an effective and simultaneous LC-MS/MS method for determining MSG levels in food samples such as chips, flavour cubes, sauces, and soups. Hyphenated techniques reported for the estimation of MSG. The LOD and LOQ values were very low, 1.0 g kg⁻¹ and 5.0 g kg⁻¹, respectively, and the results were linear (R² = 1). Excellent repeatability and reproducibility were also achieved. MSG content in food samples ranged from 0.01 g/100–15.39 g/100 g. Importantly, determining the amount of free glutamic acid in one's daily diet may help to prevent a variety of side effects linked with excessive free glutamic acid consumption [52].

3.3 Flow injection analysis and enzymatic method of analysis

The Flow Injection Analysis (FIA) combines the use of micro dialysis sample system with enzyme reactors. Similar methods have been employed to detect a variety of substrates, including glucose, nicotinamide adenine dinucleotide (NAD) coenzymes, l-glutamate, phosphate, and L-lactate, among others [53].

Glutamate in food is often tested using spectrophotometric, chromatographic, and fluorimetric techniques. The introduction of automation techniques resulted in the development of more efficient, lower-cost analytical methods with sample preparation steps. As a result, several literature-based solutions rely on flow methods with enzymatic reactions. The majority of them employ L-glutamate oxidase (GO) enzymes, glutamate dehydrogenase, or glutamate decarboxylase immobilised in columns or on electrode surfaces [16].

Using a flow injection system, Nobutoshi et al. [54] published a chemiluminometric flow-through sensor for simultaneous detection of L-Glutamate (Glu) and L-lysine (Lys) in blood employing immobilised oxidases in a single sample. Glutamate dehydrogenase catalyses the deamination of L-glutamate in the presence of NAD⁺ using the concept of the following reaction:

L - glutamate + {NAD}^{+} + H_{2} O \Rightarrow α - ketoglutamate + {NH}_{4}^{+} + NADH

The peak activity was observing at pH 9.0. At the desired pH, the enzyme was covalently bonded to controlled-porosity glass beads and was analysed by the flow-injection device [54].

Constantine d. Stalika et al. developed an enzymatic method to identify glutamic acid in food samples and pharmaceuticals. L-glutamate dehydrogenase (GLDH) from beef liver was immobilised on isothiocyanate-modified controlled pore glass for the creation of a packed bed reactor. The enzymic process generates nicotinamide adenine dinucleotide hydrogen (NADH), which was measured fluorimetrically [3].

Nicacio J. M. Arruda et al. devised a method based on the detection of carbon dioxide (CO₂) generated by the decarboxylation of L-glutamate catalysed by Cucurbita maxima (pumpkin) L-glutamate decarboxylase. In this research, the determination of L-glutamate was carried out using a flow injection technique with potentiometric detection [16].

FIA combined with enzyme immobilisation techniques for the analysis of MSG are detailed in Table 4 [3, 16, 54–59].

Table 4.

Reported FIA method for the estimation of MSG

Column	Matrix/Extraction technique	Buffer	Injection volume (µl)	Flow rate (ml/min)	Wave length (nm)	Linearity	Precision	LOD	LOQ	Ref
Isothiocyanate -CPG glass columns (4 cm × 1.7 mm)	GLDH from beef liver was immobilised on column bed	Phosphate buffer	58	0.29 0.32	340 460	200 µmol L⁻¹	1	0.3 μmol L⁻¹	N/A	[3].
Enzymatic column (8 × 0.5 cm)	Glutamate carboxylase immobilised in columns	Phosphate buffer (0.1 mol L⁻¹, pH 5.5)	50	1.4	494	10–100 m mol⁻¹	N/A	N/A	N/A	[16].
Piston pump 6-way valve polymerised over beads	Immobilised enzymes	0.05 M Na₂CO₃: 0.1 M NaHCO₃	6	0.1	CIM	40–1,000 nM	N/A	20 nM	N/A	[54].
Enzyme-glass beads were packed the beads in glass tubes (1.7 mm × 7.5 cm)	Cheese samples prepared by pasteurization	0.1M Phosphate Buffer, 1 mM EDTA, 1.5 mM NAD⁺	88	1.2	360 450	0.01–0.50 mM	Better than 1.2%	0.005 mM	N/A	[55].
Stainless steel column (3 cm × 4 mm)	GLDH serum immobilised on PVA beads	5 mM NAD⁺ Glycine Buffer	30	0.3 to 0.7	340 465	0.5 to 500 µM	N/A	0.2 µM	N/A	[56].
LC-4C equipped With thermostat	Biological and food sample	Potassium Phosphate buffer	N/A	0.5	Ampero metric Enzyme detector	0.5 to 3 mM	N/A	3 µM	10 µM	[57].
Plastic columns immobilised with protein (7 × 19 mm) Glass beads	Enzymes immobilised onto CPG packed into columns	100 mM imidazole/HCl	25	2	345	0–3 mM	N/A	N/A	N/A	[58].
Column (0.5 cm × 3.5 mm) CPG immobilised	l-glutamate in food sample based on bi-enzymatic amplification	Phosphate buffer, Tris-HCl buffer	N/A	0.2	Fluoresence and UV 340,460	2.5–50 µM	N/A	0.4 µM	N/A	[59].

FIA – Flow Injection Analysis, EDTA – Ethylene Diamine tetraacetic acid, NAD⁺ – Nicotinamide adenine dinucleotide, HCl – Hydrochloric acid, Na₂CO₃ – Sodium Carbonate, GLDH – glutamate dehydrogenase, NaHCO₃ – Sodium bicarbonate, CPG – Controlled Pore Glass, PVA – Polyvinyl alcohol, CIM – Chemiluminescence, N/A – not available.

3.4 Electrochemical methods

Electrochemical analysis is the study of a reaction on an electrode surface. Working electrode substrate properties are crucial for successful electrochemical analysis since they can have a substantial impact on the efficiency of reactions [60].

3.4.1 Potentiometric method

Potentiometry is a method of measuring potential between the electrodes using a high-impedance voltmeter. The application area of potentiometry has been expanded continuously by merging potentiometry with corrosion monitoring, clinical diagnostics, in situ environmental analysis, and bioassays. Paper-based potentiometric sensors have aroused a lot of attention since they can be made cheaply, scalable, and disposable for point-of-care and in-field applications [61].

The Kinetic-Potentiometric determination of Monosodium Glutamate in soups and soup bases of Glutamate Dehydrogenase was proposed by Dimiitrios P. Nikolelis. The AOAC's technique was used as the method of analysis. Water or water/acetone was used to remove MSG from food [12].

Joan Rhodes et al., performed a survey on the level of MSG in foods and estimated the daily consumption of MSG. The glutamic acid is eluted with 170 ml of 1.0 N HCl after filtering and concentration. The formal potentiometric titration technique is used to measure glutamic acid. Glass wool was used for filtering instead of asbestos as described, which was a minor change [62].

Demet Yilmaz et al. proposed the construction of a potentiometric glutamate biosensor for the determination of glutamate in certain real samples. A potentiometric glutamate biosensor based on an ammonium-selective poly vinyl chloride (PVC) membrane electrode was produced by chemically immobilising glutamate oxidase [63].

Alonge et al. proposed a first derivative potentiometric titration method to perform direct assay of MSG in Multi–sourced Bouillon Cubes. It was stipulated finally in the method that the findings can be adopted by regulatory organisations such as the National Agency for Food, Drugs, and Administration Control (NAFDAC) and the International Standard Organization [4] must implement the findings [64].

Thayyath .S Anirudhan et al. proposed the use of a surface modified multi-walled carbon nanotube based molecularly imprinted polymer (MWCNT-MIP) for the specific detection of MSG in food samples. The MWCNT-MIP sensor membrane was used as an effective tool in this procedure [65].

3.4.2 Amperometric method

Amperometric method employs the principle of applying a steady reducing or oxidising potential to an indicator (working) electrode and the resulting faradaic current is measured. The use of Amperometric detection in conjunction with flowing solutions is increasing in regular analysis. When electrochemical detectors are combined with improved separation processes, highly complex samples may be processed for simultaneous analysis [66].

Toshio Yao et al. developed an Amperometric assay for measuring a trace amount of l-Glutamate. The development of an on-line Amperometric micro flow analysis was based on substrate recycling. The authors performed an in - vivo microflow measurement of l-Glutamate in rat brain cells with an on-line enzyme amplifier based on a substrate recycling and amphoteric detection. The sensitivity of the devised approach is demonstrated by an unamplified responses obtained [67].

Sulesimsek et al. developed an Amperometric l-Glutamate biosensor, which was prepared from GO, which was further immobilised in polypyrrole-polyvinyl sulphonate film. The authors have also studied the stability properties of the enzyme electrode employed in the method [1].

3.4.3 Cyclic voltammetry

Cyclic voltammetry (CV) is an electroanalytical method for analysing electroactive compounds that are versatile. The discovery of polarography paved the way for the creation of voltammetry, a branch of electrochemistry [68].

Dora Domnica Baciu et al. proposed a voltammetry assay and an extraction procedure for the detection of MSG from different processed food sources. The electrochemical behaviour of MSG was investigated in this article [69].

3.5 Chemometrics

The study of mathematical and statistical designs in order to create the most pertinent chemical information by analysing chemical data and getting data about chemical systems is the study of Chemometrics [70]. Carolina. C used the concept of PLS 1 model assisted MVC and Spectrophotometric technique for the determination of MSG in stock cube samples. The sole reagent used in the analysis was buffer solution. As a result, the method can be claimed as a green method [71].

3.6 Titrimetric method

In 1996, E. Fernandez Florez proposed a titration method, namely, Sorenson formaldehyde Titration, which is less sensitive with modification of titrimetricestimation of Glutamate. After Glutamateis calculated as an aliquot of concentrated extract, it is chromatographed on a Dowex 50W—X8 (H⁺ form) Column. The glutamic acid is kept on the column, and 1 N HC1 is used to elute it [72].

In the same year, E. Fernandez Florez et al. reported a collaborative study of Glutamate in food products [73].

3.7 Capillary electrophoresis

Capillary Electrophoresis (CE) is a method that utilises electrophoretic mobility to get speedier results. It also has a high separation resolution. Capillary zone electrophoresis (CZE) is the most extensively used method [74].

Perez Ruiz et al. [75] devised a capillary electrophoresis technique for determining glutamate content in soft drinks and other meals. Laser-induced fluorescence [1] was employed as the detection method to allow the approach to be used at low concentration levels. Fluorescein isothiocyanate (FITC) was used to label glutamate because of its high quantum efficiency and excitation wavelength that matched the argon laser's 488 nm light.

Swetha Kaul et al. [76] developed a CE with LIF method based on napthalene-2, 3-dicarboxyaldehyde derivatization for simultaneously identifying neurotransmitter amino acids and carbamathione in brain microdialysis samples. On a 75 cm × 50 mm id fused-silica capillary, Glutamate, GABA, and carbamathione were separated using a 50 mmol L⁻¹ boric acid buffer (pH 9.6). Glutamate, GABA, and carbamathione had detection limits of 6, 10, and 15 nmol L⁻¹, respectively.

Hnin Pwint Aung et al. [77] suggested a capillary derivatization of MSG in the presence of 3-mercaptopropionic acid (3- MPA) with o-phthalaldehyde (OPA) and detected the resultant OPA-MSG derivative, as well as non-derivatized Benzoic acid and Sorbic acid, at 230 nm.

CE methods for the estimation of MSG are reported in Table 5.

Table 5.

Reported CE-LIF method estimating MSG

Apparatus	Matrix/Extraction technique	Derivatisation	Wave length (nm)	Detector	Linearity	LOD	LOQ	REF
P/ACE model 5,500 instrument	MSG in soft drinks and food products which is dissolved in deionised H₂O	Sample + carbonate buffer (pH 9, 0.2 M, 990 µL), FITC (5 × 10⁻⁴ M, 1,000 µL) incubated for 12 h in dark and then diluted to 100 folds	448 520	LIF	10⁻⁷ to 10⁻⁴ M	5.4 × 10⁻⁷ M	N/A	[75].
Automatic P/ACE MDQ system	Micro dialysis of brain is used as sample	50 mmol L⁻¹ boric acid buffer (pH 9.6) on a 75 cm × 50 mm id fused-silica capillary (60 cm effective) at +27.5 kV voltage with a run time of 11 min	442	LIF	N/A	6 nmol L⁻¹	3 × 10⁻⁹	[76].
Hewlett Packard 3D CE-System equipped with a DAD detector and an uncoated fused silica capillary	Canned and other processed food samples	Rapid derivatization of MSG with OPA in the presence of 3- MPA	230	UV	N/A	0.46 mg L⁻¹	1.4 mg L⁻¹	[77]

CE – Capillary Electrophoresis, H₂O – water, FITC – Fluorescein isothiocyanate, LIF – laser induced fluorescence, N/A – Not available, DAD – Diode array detection, UV – Ultraviolet, OPA – o-phthalaldehyde, 3- MPA – mercaptopropionic acid.

3.8 Biosensor method

Anjan Kumar Basu et al. introduced a Biosensor based on co-immobilized L-glutamate oxidase and L-glutamate dehydrogenase for measuring MSG in food. The detection of MSG using an L-glutamate oxidase (L-GLOD) and L-Glutamate dehydrogenase (L-GLDH) linked with enzymatic sensor based on an oxygen electrode has been investigated [78].

For detection of MSG, Anjan Kumar Basu et al. also presented a polarographic biosensor method made by immobilising L-GLOD on a polycarbonate membrane and then using a push cap mechanism to link it to a DO probe [79].

Noor Z.M.M et al. [15]developed an optical glutamate biosensor test strip based on layered membranes of nafion/sol–gel (bottom layer) and chitosan (top layer) on a sheet of paper as a substrate. The simultaneous immobilisation of several sensing agents, one indicator dye, 3,3′, 5,5′-tetramethylbenzidine (TMB) and two enzymes, GLOD and horseradish peroxidase (HRP) via a stacked membrane system with no covalent attachment of the sensing components is a unique feature of this optical biosensor design. Using simple approaches, a stacked membrane device may immobilise many sensing components without any covalent connection. The presence of L-glutamate in the uppermost membrane was recognised by the immobilised enzymes GLOD and HRP. The test strip's colour shifts from light green to dark green, which occurs when the quantity of L-glutamate rises and is used to quantitatively analyse L-glutamate. Quantitative research might be done using the reflectance intensity of the colour shift at 550 nm. With a detection limit of 5 µM, the glutamate biosensor test strip reacted linearly to L-glutamate in the range of 0.01–0.30 mM. Table 6 [1, 5, 78–81] tabulates the biosensor methods reported for MSG estimation.

Table 6.

Reported biosensor method estimating MSG

Apparatus	Matrix/Extraction technique	Buffer/Enzyme solution	Wave length (nm)	Response time	Linearity	LOD	LOQ	REF
Amperometric glutamate -sensitive biosensor, platinum disk electrode	Food sample	8% GluOx, 4% BSA, 10% glycerol in 100 mM Phosphate buffer	N/A	5–20 s	N/A	5.0 × 10⁻⁹ M	N/A	[1].
Optical glutamate biosensor strip	Food stocks were diluted (10–250 times)	Isocratic M.P Methanol: phosphate buffer (35:65,v/v)	FLD	N/A	0.01–0.30 mM	5 $µ$ M	N/A	[15].
Biosensor with a probe, DO meter, electrodes	Food products like soy sauce, Chinese food	PBS with 2 enzymes L-GLOD and L-GLDH	N/A	2 min	0.02–1.2 mg L⁻¹	0.1 mg L⁻¹	N/A	[78].
MSG Biosensor with immobilised L-GLOD,O₂ electrodes, silver and gold cathodes	Soups, sauces	PBS containing L-GLOD	260	2 min	20 mg dl⁻¹	1 mg dl⁻¹	N/A	[79].
PVA -Fe₃O₃ membrane receptor on chemical sensor with SPCE	MSG	PVA 5%w/v, C₅H₈O₂ %v/v, Citric acid 5%w.v suspension Fe₃O₄	N/A	180 s	N/A	N/A	N/A	[80].
Electrochemical Microfluidic paper based	MSG in food sample (voltammetry)	0.05 M Na₂B₄O₇, 0.05M KCl	N/A	N/A	N/A	0.82 g L⁻¹	N/A	[81].

DO meter – Dissolved oxygen meter, PBS – Phosphate buffer saline, L-GLOD – L-glutamate oxidase, L-GLDH – L-glutamate dehydrogenase, O₂ – Oxygen, M.P – Mobile phase, FLD – Fluorescence detection, PVA – Polyvinyl alcohol, Fe₃O₃ – Iron (III)oxide_, Glu Ox – Glutamate oxidase, BSA – Bovine serum albumin, C₅H₈O₂ – glutaraldehyde, Na₂B₄O₇ – Sodium tetraborate, KCl – Potassium chloride, N/A – Not available.

3.9 Miscellaneous method

Carolina C. Acebal. reported an automated flow batch methodology to explore the content of MSG in dehydrated broths [82]. The inclusion of nephelometric detection in the proposed approach gives a notable advantage owing to its inherent simplicity. The suggested methodology enables the automated generation of the calibration curve and eliminates the need for pre-treatment of the samples. Furthermore, there exists the potential to achieve substantial reductions in reagent use and waste generation, so making a valuable contribution to the field of green chemistry. The overall proportion of analytical methods reported for the estimation of MSG is represented in Fig. 5.

Fig. 5.

Proportion of analytical methods available for the estimation of MSG; Ultra Violet-Visible (UV-Vis); High performance liquid chromatography (HPLC); Ultra high performance liquid chromatography (UPLC), High performance thin layer chromatography (HPTLC), Thin layer chromatography (TLC), Gas chromatography (GC), Paper chromatography (PC), Flow injection analysis (FIA), Capillary electrophoresis (CE)

Citation: Acta Chromatographica 36, 4; 10.1556/1326.2023.01171

4 Discussion

The major purpose of this article was to review about the amino acid glutamate, popularly known as MSG in the industry. It is considered as a non-essential amino acid, but due to its flavouring effects, it has become a regular food component. It is an important component of the umami or savoury flavour found in a wide range of foods.

Glutamate's increased cellular activity, on the other hand, produces over-excitation of nerve cells at large dosages, leading to cell death, schizophrenia, and depression. Herbs including lemon balm, chamomile, and passion flower assist in offsetting glutamate's negative effects by restoring GABA balance.

MSG is still used in a number of culinary preparations as a flavour enhancer. Despite the fact that the FDA deems MSG safe for limited use, some studies have lately revealed unfavourable side effects from long-term use, raising questions about its safety and toxicity. American Academy of Paediatrics Committee stated that MSG has no effect on lactation and possesses no risk for the consuming infant.

Several articles have been studied for the estimation of MSG, which comprises of HPLC, UPLC, HPTLC, UV, IR, fluorimetry, electro-analytical, and biosensor techniques. HPLC has been utilised most effectively, while GC has been employed the least.

HPLC is commonly used in the health and food sectors for pharmaceutical research, evaluating the nutritional advantages of diverse foods, and enforcing food safety requirements. Although the literature contains numerous reports on HPLC methods; when considering various analytical approaches, it can be argued that LC-MS/MS is the most favourable method for analyzing MSG. This is due to its ability to combine the separation capabilities of LC with the identification and quantification capabilities of MS. Consequently, LC-MS/MS offers greater accuracy, sensitivity, and specificity compared to HPLC, which is limited to screening purposes only.

Introduction of automated techniques resulted in even more time savings, lower analytical costs, and easier sample preparation. As a result, some literature-based alternatives include flow methods with enzymatic reaction like FIA and biosensor CE have gained interest. Biosensors for glutamate determination have become an incredibly extensive technique, due to strong specifications such as high sensitivity, selectivity and quick response.

5 Conclusion

MSG, often known as Chinese salt, has been a dominant force in the food industry for decades. The study of MSG's effects on the human body has become more important in recent days because of its controversial nature. As a salt substitute and a flavouring agent, MSG can be used in small amounts. This reduces salt consumption, which lowers blood pressure and water retention, and also makes food taste better. Glutamate, whether present as an amino acid constituent of protein or in its unbound state, comprises around 8–10% of the total amino acid content in the human diet. In adults, the average daily intake of glutamate ranges from 10 to 20 g. The consumption of high quantities of monosodium glutamate (>10–12 g), which exceeds normal human dietary intake, leads to a transitory increase in systemic blood levels of glutamate. However, these levels return to normal within 2 h following the cessation of consumption. In relation to the metabolic processes occurring within a span of two hours, it has been observed that glutamine and alpha-ketoglutarate are produced, leading to the formation of isocitric acid. Additionally, an imbalance in the ratio of α-ketoglutarate to citrate has been identified within the TCA cycle. Maintaining a proper harmony in the daily consumption of glutamate is of utmost importance, as failure to do so may result in the manifestation of various symptoms associated with MSG including headaches, numbness, palpitation, cancer, neurodegenerative disorders etc.

MSG concentrations as low as one part per trillion can be accurately measured using HPLC, which can separate and identify MSG virtually in any sample. Identifying the loopholes in the current analytical assessment of MSG helps researchers to build more reliable, easy-to-cost-effective, greener ways of determining MSG, which is important in both the medicinal and food industries, as well as in the monitoring this compound and its metabolites in clinical and toxicological investigations.

Conflict of interest

Authors declare no conflict of interest.

Acknowledgements

Authors are grateful to the management of SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur for providing various reprographic sources for executing this review article successfully.

Abbreviations

➢ 1	-Primary
➢ 2	-Secondary
➢ 3-MPA	-3-mercaptopropionic acid
➢ ACN/CH₃CN	-Acetonitrile
➢ AMPA	-D, L-amino -3- hydroxy -5 methyl-isoxole propionic acid
➢ AOAC	-Association of Official Analytical Collaboration
➢ BSA	-Bovine serum albumin
➢ C₅H₈O₂	-Glutaraldehyde
➢ CE	-Capillary electrophoresis
➢ CH₃OH	-Methanol
➢ CHCl₃	-Chloroform
➢ CHOH	-Formaldehyde
➢ CLM	-Chemiluminescence
➢ CNS	-Central nervous system
➢ CO₂	-Carbon dioxide
➢ CRS	-Chinese restaurant syndrome
➢ CV	-Cyclic voltammetry
➢ C₂H₃NaO₂	-Sodium acetate
➢ DAD	-Diode array detection
➢ DNA	-Deoxy ribonucleic acid
➢ DO meter	-Dissolved oxygen meter
➢ DODC Test	-Degree of difference from control test
➢ EAAT	-Excitatory amino acid transporters
➢ EDTA	-Ethylene diamine tetraacetic acid
➢ ELSD	-Evaporative light scattering detector
➢ FDA	-Food and drug administration
➢ Fe₃O₃	-Iron (III)oxide
➢ FIA	-Flow injection analysis
➢ FID	-Flame ionisation detector
➢ FITC	-Fluorescein isothiocyanate
➢ FLD	-Fluorescence detection
➢ FR	-Flow rate
➢ FTIR	-Fourier transform infrared spectroscopy
➢ GAA	-Glacial acetic acid
➢ GABA	-Gamma amino butyric acid
➢ GC	-Gas chromatography
➢ GLC	-Gas liquid chromatography
➢ GPT	-Glutamic–pyruvic transaminase
➢ GRAS	-Generally recognised as safe
➢ HCl	-Hydrochloric acid
➢ HCOOH/FA	-Formic acid
➢ HRP	-Horseradish peroxidase
➢ HPLC	-High performance liquid chromatography
➢ HPTLC	-High performance thin layer chromatography
➢ IR	-Infrared
➢ ISO	-International Standard Organization
➢ KCl	-Potassium chloride
➢ LC	-Liquid Chromatography
➢ LOD	-Limit of Detection
➢ LOQ	-Limit Of Quantification
➢ LIF	-Laser Induced Fluorescence
➢ LC-MS/MS	-Liquid chromatography - tandem mass spectrometry
➢ Lys	-L-lysine
➢ MP	-Mobile phase
➢ MQ	-Milli Q
➢ MS	-Mass spectroscopy
➢ MeOH	-Methanol
➢ MSG	-Monosodium Glutamate
➢ MWNT	-Multi-walled carbon nanotubes
➢ MVC	-MultiVariate Calibration
➢ N	-Normality
➢ NAD	-Nicotinamide Adenine dinucleotide
➢ N(CH₂CH₃)₃	-Triethylamine
➢ N/A	-Not available
➢ Na₂B₄O₇	-Sodium tetraborate
➢ Na₂CO₃	-Sodium carbonate
➢ NaCl	-Sodium chloride
➢ NAD⁺	-Nicotinamide adenine dinucleotide
➢ NaDC	-Sodium Dicarboxylate transporter
➢ NAFDAC	-National Agency for food, Drugs, and administration control
➢ NaHCO₃	-Sodium Bicarbonate
➢ NaOH	-Sodium hydroxide
➢ NH₄ CH₃CO₂	-Ammonium acetate
➢ NH₄OH	-Ammonium hydroxide
➢ NH₄Cl	-Ammonium Chloride
➢ NMDA	-N-methyl D-aspartic acid
➢ OPA	-O-phthalaldehyde
➢ PBS	-Phosphate-buffered saline
➢ PC	-Paper chromatography
➢ PVA	-Polyvinyl alcohol
➢ PVC	-Polyvinyl Chloride
➢ PITC	-Phenyl isothiocyanate
➢ RNA	-Ribonucleic acid
➢ RP	-Reverse phase
➢ SPE	-Solid phase extraction
➢ TCA	-Tricarboxylic acid cycle
➢ TCAA	-Trichloro acetic acid
➢ TFA	-Trifluoroacetic acid
➢ TLC	-Thin layer chromatography
➢ TMB	-3,3′, 5,5′-tetramethylbenzidine
➢ THF	-Tetrahydrofuran
➢ UPLC	-Ultra performance liquid chromatography
➢ UPLC-MS/MS	-Ultra performance Liquid chromatography tandem mass spectrometry

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Acta Chromatographica

Online ISSN:: 2083-5736

Senior editors

Editor(s)-in-Chief: Sajewicz, Mieczyslaw, University of Silesia, Katowice, Poland

Editors(s)

Danica Agbaba, University of Belgrade, Belgrade, Serbia
Łukasz Komsta, Medical University of Lublin, Lublin, Poland
Ivana Stanimirova-Daszykowska, University of Silesia, Katowice, Poland
Monika Waksmundzka-Hajnos, Medical University of Lublin, Lublin, Poland

Editorial Board

Ravi Bhushan, The Indian Institute of Technology, Roorkee, India
Jacek Bojarski, Jagiellonian University, Kraków, Poland
Bezhan Chankvetadze, State University of Tbilisi, Tbilisi, Georgia
Michał Daszykowski, University of Silesia, Katowice, Poland
Tadeusz H. Dzido, Medical University of Lublin, Lublin, Poland
Attila Felinger, University of Pécs, Pécs, Hungary
Kazimierz Glowniak, Medical University of Lublin, Lublin, Poland
Bronisław Glód, Siedlce University of Natural Sciences and Humanities, Siedlce, Poland
Anna Gumieniczek, Medical University of Lublin, Lublin, Poland
Urszula Hubicka, Jagiellonian University, Kraków, Poland
Krzysztof Kaczmarski, Rzeszow University of Technology, Rzeszów, Poland
Huba Kalász, Semmelweis University, Budapest, Hungary
Katarina Karljiković Rajić, University of Belgrade, Belgrade, Serbia
Imre Klebovich, Semmelweis University, Budapest, Hungary
Angelika Koch, Private Pharmacy, Hamburg, Germany
Piotr Kus, Univerity of Silesia, Katowice, Poland
Debby Mangelings, Free University of Brussels, Brussels, Belgium
Emil Mincsovics, Corvinus University of Budapest, Budapest, Hungary
Ágnes M. Móricz, Centre for Agricultural Research, Budapest, Hungary
Gertrud Morlock, Giessen University, Giessen, Germany
Anna Petruczynik, Medical University of Lublin, Lublin, Poland
Robert Skibiński, Medical University of Lublin, Lublin, Poland
Bernd Spangenberg, Offenburg University of Applied Sciences, Germany
Tomasz Tuzimski, Medical University of Lublin, Lublin, Poland
Adam Voelkel, Poznań University of Technology, Poznań, Poland
Beata Walczak, University of Silesia, Katowice, Poland
Wiesław Wasiak, Adam Mickiewicz University, Poznań, Poland
Igor G. Zenkevich, St. Petersburg State University, St. Petersburg, Russian Federation

SAJEWICZ, MIECZYSLAW
E-mail:mieczyslaw.sajewicz@us.edu.pl

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2023
Web of Science
Journal Impact Factor	1.7
Rank by Impact Factor	Q3 (Chemistry, Analytical)
Journal Citation Indicator	0.43
Scopus
CiteScore	4.0
CiteScore rank	Q2 (General Chemistry)
SNIP	0.706
Scimago
SJR index	0.344
SJR Q rank	Q3

Acta Chromatographica
Publication Model	Online only Gold Open Access
Submission Fee	none
Article Processing Charge	400 EUR/article Effective from 1st Feb 2025: 700 EUR/article
Regional discounts on country of the funding agency	World Bank Lower-middle-income economies: 50% World Bank Low-income economies: 100%
Further Discounts	Editorial Board / Advisory Board members: 50% Corresponding authors, affiliated to an EISZ member institution subscribing to the journal package of Akadémiai Kiadó: 100%
Subscription Information	Gold Open Access
Purchase per Title

Acta Chromatographica
Language	English
Size	A4
Year of Foundation	1988
Volumes per Year	1
Issues per Year	4
Founder	Institute of Chemistry, University of Silesia
Founder's Address	PL-40-007 Katowice, Poland, Bankowa 12
Publisher	Akadémiai Kiadó
Publisher's Address	H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible Publisher	Chief Executive Officer, Akadémiai Kiadó
ISSN	2083-5736 (Online)