Compendium of the most significant studies with reference to properties, intake, effects.

Roosterman D, Cottrell GS. Rethinking the Citric Acid Cycle: Connecting Pyruvate Carboxylase and Citrate Synthase to the Flow of Energy and Material. Int J Mol Sci. 2021 Jan 9;22(2):604. doi: 10.3390/ijms22020604. 

Abstract. In 1937, Sir H. A Krebs first published the Citric Acid Cycle, a unidirectional cycle with carboxylic acids. The original concept of the Citric Acid Cycle from Krebs' 1953 Nobel Prize lecture illustrates the unidirectional degradation of lactic acid to water, carbon dioxide and hydrogen. Here, we add the heart lactate dehydrogenase•proton-linked monocarboxylate transporter 1 complex, connecting the original Citric Acid Cycle to the flow of energy and material. 

Berovic M, Legisa M. Citric acid production. Biotechnol Annu Rev. 2007;13:303-43. doi: 10.1016/S1387-2656(07)13011-8.

Abstract. Biochemistry of citric acid fermentation, various microbial strains, as well as various substrates, technological processes and product recovery are presented. World production and economics aspects of this strategically product of bulk biotechnology are discussed.

Zazgornik J, Mittermayer H. Citric acid inhibits growth of Helicobacter pylori in vitro: a new strategy for eradication. Wien Klin Wochenschr. 2011 Jan;123(1-2):38-40. doi: 10.1007/s00508-010-1524-9.

Abstract.  Citric acid is a cheap substance present in many fruits and produced by food industry, and it demonstrated powerful inhibitory effect on the growth of Helicobacter pylori strains. On the basis of our findings citric acid should be further evaluated for the eradication of Helicobacter pylori.

Huang WC, Li B, Qi X, Mao X. New type of green extractant for oil production: Citric acid/citric acid sodium extraction system. Food Chem. 2020 Apr 25;310:125815. doi: 10.1016/j.foodchem.2019.125815.

Abstract. The extraction of edible oils was achieved without the use of toxic chemicals or energy-intensive equipment. This study provided a green and efficient method, and showed the potential of the proposed citric acid/citric acid sodium extraction system for production of edible oils from natural sources.

Tandon S, Singh B, Kapoor S, Mangal S. Comparison of Effect of pH Modulation on Wound Healing with Topical Application of Citric Acid Versus Superoxide Ions. Niger J Surg. 2020 Jul-Dec;26(2):122-126. doi: 10.4103/njs.NJS_14_19.

Abstract. The objective of the study is compare the effect of pH modulation on wound healing with topical application of citric acid versus superoxide ions. The aim is to study the efficacy and safety of citric acid versus superoxide ions in the prevention and control of infection and their effect on wound healing in similar wound types.

Xie G, West TP. Citric acid production by Aspergillus niger on wet corn distillers grains. Lett Appl Microbiol. 2006 Sep;43(3):269-73. doi: 10.1111/j.1472-765X.2006.01958.x.

Abstract. To determine which citric acid-producing strain of Aspergillus niger utilized wet corn distillers grains most effectively to produce citric acid.

Toxicological evaluation of certain food additives with a review of general principles and of specifications. Seventeenth report of the joint FAO-WHO Expert Committee on Food Additives. World Health Organ Tech Rep Ser. 1974;539:1-40.

Thompson AA, Baillie JK, Bates MG, Schnopp MF, Simpson A, Partridge RW, Drummond GB, Mason NP. The citric acid cough threshold and the ventilatory response to carbon dioxide on ascent to high altitude. Respir Med. 2009 Aug;103(8):1182-8. doi: 10.1016/j.rmed.2009.02.007.

Abstract. We conclude that the change in citric acid cough threshold seen on exposure to hypobaric hypoxia is unlikely to be mediated by changes in the central control of cough. Sensitivity to citric acid may be due to early subclinical pulmonary edema stimulating airway sensory nerve endings.

 Max B, Salgado JM, Rodríguez N, Cortés S, Converti A, Domínguez JM. Biotechnological production of citric acid. Braz J Microbiol. 2010 Oct;41(4):862-75. doi: 10.1590/S1517-83822010000400005.

Abstract. This work provides a review about the biotechnological production of citric acid starting from the physicochemical properties and industrial applications, mainly in the food and pharmaceutical sectors.

Rywińska A, Juszczyk P, Wojtatowicz M, Rymowicz W. Chemostat study of citric acid production from glycerol by Yarrowia lipolytica. J Biotechnol. 2011 Mar 10;152(1-2):54-7. doi: 10.1016/j.jbiotec.2011.01.007. 

Abstract. The aim of the study was to examine how the dilution rate and the chemical composition of the production medium impacts on the synthesis of citric acid by the Yarrowia lipolytica strain Wratislavia AWG7 from glycerol in a chemostat culture.

Citric acid (2-hydroxy-1,2,3-propane-tricarboxylic acid) is a primary metabolic product, odorless organic tricarboxylic acid and is obtained from lemon juice (from which the Latin name citrus derives the name of citric acid), other fruits, beet juice and other vegetables.

It is a commercial chemical compound born in England around 1826 from imported Italian lemons, commonly produced by microbial fermentation, with low toxicity and high solubility. For its production are used a large number of microorganisms, including bacteria and fungi such as A. wentii, Aspergillus niger (used industrially since 1919 supplanting the lemon) whose strains are able to produce citric acid, using the fermentation in a solid state, from grape pomace, pineapple waste, apple pomace, cassava etc.. 

The first industrial production of citric acid did not occur until 1890, when German chemist Carl Wehmer discovered that it could be produced by the fermentation of sugar by the mould Aspergillus niger. Even today, this is still the main method of producing citric acid. Here are the steps:

• Fermentation: the process starts with the fermentation of a carbohydrate source. The mould Aspergillus niger is used to ferment a sugar solution. The mould metabolises the sugar and, as a by-product, produces citric acid.
• Filtration and precipitation: after the fermentation process, the solution is filtered to remove mould and other solids. Calcium hydroxide is then added to the filtered solution to precipitate the calcium citrate.
• Conversion to citric acid: calcium citrate is reacted with sulphuric acid to produce citric acid and calcium sulphate, which precipitates from the solution.
• Purification: the resulting solution is purified through a combination of filtration, evaporation and crystallisation processes to produce pure citric acid.
• Drying and packaging: the purified citric acid is then dried and packaged for use.

In nature, citric acid is produced in the metabolism of almost all living things through the citric acid cycle, an important sequence of biochemical reactions that enables cells to extract energy from carbohydrates, fats and proteins.

Citric acid can also be produced from various yeast species (e.g., synthesized by the unconventional yeast Yarrowia lipolytica (1) from a widely available and renewable polysaccharide, inulin), glycerol, and symmetric dichloroacetone, 

It is the most widely used organic acid and the most widely produced chemical on an industrial scale.

What it is used for and where

Food

Ingredient included in the list of European food additives as the antioxidant E300.

Medical

It is generally used as an antioxidant :

• acidity (pH) regulator in the food and pharmaceutical industries.  In particular, it is used in pharmacological formulations such as "gummy" formulations and to suppress the bitter taste of certain ingredients. This provides the effect of a "flavor enhancer". "Acidity regulators" are substances that modify or control the acidity or alkalinity of a food product.
• excipient in pharmaceutical products with functions of anticoagulant, antioxidant, preservative
• anticoagulant, wound healing with reference to wound pH, important indicator of biochemical healing processes, transfusions (2)
• preparation of effervescent powders
• preservative in the food industry. Labeled as E330 in the list of European food additives, approved by FAO/WHO, is considered a safe additive.
• antioxidant in wine in oenology to prevent oxidative deterioration of flavor or color
• sanitizer in household detergents
• arsenic removal in drinking water (3) 
• plant nutritional element (4)

Its relationships in disorders of energy metabolism have also been studied (5).

In the human body, citric acid plays an important role of the tricarboxylic acid cycle in the mechanism of energy production during cellular metabolism. This study by Japanese researchers examined the effects, on physical fatigue, of two anti-fatigue substances involved in cellular metabolism, citric acid and l-carnitine. The results showed that citric acid reduced physiological stress, whereas carnitine did not achieve the same positive results (6).

Cosmetics

Acidity regulator (pH), preservative, antioxidant.

Buffering agent. An ingredient that can bring an alkaline or acid solution to a certain pH level and prevent it from changing. in practice a pH stabiliser.

Chelating agent. It has the function of preventing unstable reactions and improving the bioavailability of chemical components within a product, and removes calcium and magnesium cations that can cause cloudiness in clear liquids.

pH adjuster. This ingredient tends to restore the pH of a cosmetic formulation to its optimal value. The correct pH value is an essential determinant for lipid synthesis in the stratum corneum. The average physiological pH value of the face ranges between 5.67 and 5.76. The hair fibre has a pH value of 3.67.

Fragrance. It plays a very important role in the formulation of cosmetic products as it allows perfume to be enhanced, masked or added to the final product, improving its commercial viability.  The consumer always expects to find a pleasant scent in a cosmetic product.

Safety

The SCCP Expert Committee Report on the safety of citric acid in cosmetic products concludes as follows:

"On the basis of the data submitted, the safety of citric acid (and) silver citrate cannot be assessed. Before a final conclusion can be reached, an in vitro mammalian gene mutation assay to exclude gene mutation potential is required."

The most relevant studies on this acid have been selected with a summary of their contents:

Citric acid studies

Industrially citric acid comes in the form of a white powder, or white crystals

Optimal typical characteristics of the commercial product Citric acid

• Molecular Formula : C₆H₈O₇
• Linear Formula : CH₂COOH-C(OH)COOH-CH₂COOH
• Molecular Weight : 192.123 g/mol
• CAS :  77-92-9  3458-72-8   6018-92-4 
• UNII PQ6CK8PD0R
• EC Number: 201-069-1    200-066-2
• DSSTox Substance ID: DTXSID5020106
• MDL number  MFCD00011669
• PubChem Substance ID 201-069-1
• InChI=1S/C6H8O6/c7-1-2(8)5-3(9)4(10)6(11)12-5/h2,5,7-10H,1H2/t2-,5+/m0/s1 
• InChl Key      CIWBSHSKHKDKBQ-JLAZNSOCSA-N
• SMILES    C(C(C1C(=C(C(=O)O1)O)O)O)O
• IUPAC   (2R)-2-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2H-furan-5-one
• ChEBI    29073
• Beilstein    782061
• FEMA 2109
• eCl@ss   39021801

Synonyms:

• E330
• Anhydrous citric acid
• 1,2,3-Propanetricarboxylic acid, 2-hydroxy-
• 2-hydroxy-1,2,3-propanetricarboxylic acid
• 2-Hydroxytricarballylic acid
• 2-hydroxypropane-1,2,3-tricarboxylic acid
• PubChem Substance ID: 329768287
• EC Number: 201-069-1
• MDL number: MFCD00011669 

References__________________________________________________________________

(1) Rakicka M, Wolniak J, Lazar Z, Rymowicz W. Production of high titer of citric acid from inulin. BMC Biotechnol. 2019 Feb 11;19(1):11. doi: 10.1186/s12896-019-0503-0.

(2) Aniort J, Petitclerc T, Créput C. Safe use of citric acid-based dialysate and heparin removal in postdilution online hemodiafiltration. Blood Purif. 2012;34(3-4):336-43. doi: 10.1159/000345342. . [Epub ahead of print]

(3) Majumder S, Nath B, Sarkar S, Islam SM, Bundschuh J, Chatterjee D, Hidalgo M. Application of natural citric acid sources and their role on arsenic removal from drinking water: a green chemistry approach. J Hazard Mater. 2013 Nov 15;262:1167-75. doi: 10.1016/j.jhazmat.2012.09.007.

(4) Tapia Y, Eymar E, Gárate A, Masaguer A. Effect of citric acid on metals mobility in pruning wastes and biosolids compost and metals uptake in Atriplex halimus and Rosmarinus officinalis. Environ Monit Assess. 2013 May;185(5):4221-9. doi: 10.1007/s10661-012-2863-y.

(5) Siekmeyer M, Petzold-Quinque S, Terpe F, Beblo S, Gebhardt R, Schlensog-Schuster F, Kiess W, Siekmeyer W. Citric acid as the last therapeutic approach in an acute life-threatening metabolic decompensation of propionic acidaemia. J Pediatr Endocrinol Metab. 2013;26(5-6):569-74. doi: 10.1515/jpem-2012-0148.

(6) Sugino T, Aoyagi S, Shirai T, Kajimoto Y, Kajimoto O. Effects of Citric Acid and l-Carnitine on Physical Fatigue. J Clin Biochem Nutr. 2007 Nov;41(3):224-30. doi: 10.3164/jcbn.2007032.