Citric Acid: Emerging Applications of Key Biotechnology Industrial Product Rosaria Ciriminna1, Francesco Meneguzzo2, Riccardo Delisi1 and Mario Pagliaro1*
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Ciriminna et al. Chemistry Central Journal (2017) 11:22 DOI 10.1186/s13065-017-0251-y REVIEW Open Access Citric acid: emerging applications of key biotechnology industrial product Rosaria Ciriminna1, Francesco Meneguzzo2, Riccardo Delisi1 and Mario Pagliaro1* Abstract Owing to new biotechnological production units mostly located in China, global supply of citric acid in the course of the last two decades rose from less than 0.5 to more than 2 million tonnes becoming the single largest chemical obtained via biomass fermentation and the most widely employed organic acid. Critically reviewing selected research achievements and production trends, we identify the reasons for which this polycarboxylic acid will become a key chemical in the emerging bioeconomy. Keywords: Citric acid, Fermentation, White biotechnology, Bioeconomy Background to decline due to the introduction of the commercial Citric acid (2-hydroxy-1,2,3-propanetricarboxylic acid, production by sugar fermentation: first in 1919 by Cytro- C6H8O7) is an acidulant, preservative, emulsifier, fla- mices (now known as Penicillium) mold in Belgium fol- vorant, sequestrant and buffering agent widely used lowing the researches of Cappuyns; and then, in 1923, across many industries especially in food, beverage, phar- in New York following Currie’s discovery that strains of maceutical, nutraceutical and cosmetic products [1]. First Aspergillus niger (the black mold, a common contaminant crystallized from lemon juice and named accordingly by of foods belonging to the same family as the penicillins) Scheele in Sweden in 1784 [2], citric acid is a tricarboxylic in acidified solution containing small amounts of inor- acid whose central role in the metabolism of all aerobic ganic salts afforded unprecedented high yields of the acid organisms was undisclosed by Krebs in the late 1930s [3]. (today, 60% on dry matter basis) [6]. Rapidly adopted by Owing to its remarkable physico-chemical proper- numerous other manufacturers, the fermentation process ties and environmentally benign nature, the use of citric is still used nowadays across the world, and particularly acid across several industrial sectors increased rapidly in China, to meet the global demand for the acid, mainly throughout the 19th century when the acid was directly using low cost molasses as raw materials. Interestingly, as extracted from concentrated lemon juice, mainly in Sic- recounted by Connor [7], a global citric acid cartel fixed ily (Palermo in 1930 hosted the largest citric acid plant prices for decades. In this study, referring to production, in Europe, Palermo’s Fabbrica Chimica Italiana Golden- market and recent research achievements, we provide berg), by adding lime to precipitate calcium citrate, and arguments supporting our viewpoint that citric acid will then recovering the acid using diluted sulfuric acid. become a key chemical in the emerging bioeconomy [8], Along with its elegant chemistry in aqueous and with applications beyond conventional usage in the food, organic solutions, the history of citric acid utilization has pharmaceutical and cosmetic industries. been thoroughly recounted by Apelblat in 2014 [4]. In brief, production of citric acid from lemon juice peaked Structure, properties and biochemical function in 1915–1916 at 17,500 tonnes [5], after which it started The crystalline structure of anhydrous citric acid, obtained by cooling hot concentrated solution of the monohydrate form, was first elucidated by Yuill and *Correspondence: [email protected] Bennett in 1934 by X-ray diffraction [9]. In 1960 Nord- 1 Istituto per lo Studio dei Materiali Nanostrutturati, CNR, via Ugo La Malfa 153, 90146 Palermo, PA, Italy man and co-workers further suggested that in the anhy- Full list of author information is available at the end of the article drous form two molecules of the acid are linked through © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ciriminna et al. Chemistry Central Journal (2017) 11:22 Page 2 of 9 hydrogen bonds between two –COOH groups of each Remarkably, the X-ray analyses of Nordman [10], monomer (Fig. 1) [10]. Glusker and co-workers [13] were undertaken in the con- In 1994, Tarakeshwar and Manogaran published the text of biochemistry studies. Citric acid, indeed, plays a results of the ab initio quantum chemical calculations of central role in the biochemical cycle discovered by Krebs electron rich citric acid (and citrate trianion) approxi- in 1937. mated at the Hartree–Fock level [11]. The team found The citric acid cycle, as lately suggested by Estrada, that citric acid and the citrate trianion have unique fea- performs “a kind of concentration” in a self-amplifying tures which differentiate them from other α-carboxylic cycle in which citrate “pulls in carbon and then it splits, acids. The main difference between the central carboxyl and both parts go back into the cycle, so where you had group and the terminal carboxyl groups, highlighted by one you now have two” [14]. Indeed, Fig. 2 reproduced the ν(C=O) frequencies, was ascribed to an intramo- from a 1972 article [15], neatly explains that the sequence lecular hydrogen bond between the central hydroxyl of reactions in the Krebs cycle consumes the load of hydrogen and one of the terminal carboxyl groups, with the “carrier” (the four-carbon skeleton of oxalacetate) the ν(C=O) stretch frequency appearing at a lower fre- by transforming it into two molecules of CO2, with the quency than the ν(C=O) stretch of the other terminal unloaded carrier left in oxalacetate form, ready to be carboxyl. loaded again with two-carbon acetyl group. In 2011, Bichara and co-workers published the out- comes of the structural and vibrational theoretical study Production, properties and applications for the citric acid dimer (Fig. 1) [12]. The values obtained Due its eminent biochemical role, it is perhaps not sur- through natural bond orbitals and atoms in molecules prising that citric acid is widely distributed in animal spe- calculations, clearly indicate formation of the dimer cies, plants and fruits (Table 1). through hydrogen-bond between two COOH groups of Since the late 1920s, however, the carbohydrate fer- each monomer. Numerous bands of different intensi- mentation route has replaced extraction from lemon ties observed in the vibrational spectra not previously juice. So efficient and affordable was the new process that assigned, could now be assigned to the citric acid dimer. as early as of 1934 the acid production cost, using today’s Fig. 1 Optimized structure of citric acid dimer from Hartree–Fock ab initio calculations (Adapted from Ref. [12], with kind permission) Ciriminna et al. Chemistry Central Journal (2017) 11:22 Page 3 of 9 comprised of anyhydrous or monohydrate form typically available in 25 kg paper bags or large (500–1000 kg) bags. In general, the fermentation process generates twice the volume amount of by-products originating both from the carbohydrate raw material and from the down- stream process in the form of a solid sludge (gypsum and organic impurities). All co-products are sold for techni- cal, agricultural and feed applications. The organic part of the molasses, after concentration, is sold as a binding agent for feed. The protein rich mycelium resulting is sold as animal feed, while gypsum is marketed as a filler in cement or in medical applications. In 2012 Ray and co-workers were noting that the increasing demand required “more efficient fermenta- tion process and genetically modified microorganisms for higher yield and purity” [17]. However, while it is true that numerous citric acid suppliers use molasses from genetically modified corn and genetically modified sugar Fig. 2 The citric acid cycle devised by Nafissy in 1972, in which the beet, other manufacturers produce only citrate products four-carbon skeleton of oxalacetate is a four-wheel carrier to be certified to originate from carbohydrates obtained from loaded with two carbon atoms of acetyl group to form the six carbon non-genetically modified crops and without any involve- citrate (Reproduced from Ref. [15], with kind permission) ment of microorganisms derived from recombinant DNA technology. Odourless and colourless citric acid is highly soluble Table 1 Citric acid in different fruits Reproduced from Ref. in water (62.07% at 25 °C) [18] and slightly hygroscopic. [17], with kind permission From an environmental viewpoint, the acid quickly Fruit Citric acid content (mg/100 mL) degrades in surface waters, and poses no hazards to the environment or to human health [19]. Once dissolved Lime 7000 in water, it shows weak acidity but a strongly acid taste Lemon 5630 which affects sweetness and provides a fruity tartness for Raspberry 2480 which it is widely used to complement fruit flavours in Tomato 1018 the food and beverage industry. In combination with cit- Pineapple, strawberry, cranberry 200–650 rate, the acid shows excellent buffering capacity, while its excellent metal ions chelating properties add to the phys- ico-chemical properties that make it ideally suited for currency values, was €0.2/kg vs. €1.0/kg of 1920 when the food, cosmetic, nutraceutical and pharmaceutical appli- acid was still obtained from lemon juice [16]. Today, cit- cations (Table 2), whose number testifies to its exquisite ric acid is produced at large chemical fermentation plants versatility. The acid has the E330 food ingredient code (Fig. 3) and eventually isolated in two forms, anhydrous in the European Union (E331 and E332, respectively, for and monohydrate.