**1. Introduction**

Ascorbic acid (L-enantiomer, Figure 1), commonly known as vitamin C, is composed of six carbons and related to the C6 sugars. It is the aldono-1,4-lactone of a hexonic acid with an enediol group on carbons 2 and 3. As an essential micronutrient, ascorbic acid plays a vital role in maintaining normal metabolic processes and homeostasis within the human body. Although D-isoascorbic acid is the stereoisomer of ascorbic acid (Figure 1), such analogues hardly express the activity of ascorbic acid. Mammalian cells cannot synthesize ascorbic acid de novo due to the lack of L-gulono-1,4 lactone oxidase, which is an essential enzyme for the production of ascorbic acid [1]. Vegetables and fruits serve as natural sources of vitamin C intake, but only a limited number of plants are rich in vitamin C. Nowadays, ascorbic acid is industrially produced from D-glucose, and the procedure involves several complex chemical and biotechnological stages [2].

An ordinary diet of natural and synthetic ascorbic acid is the only way to maintain the physiological requirements. The well-known symptom of ascorbic acid deficiency is associated with connective tissue damage, such as scurvy, which is characterized by fragile tissues and poor wound healing [3]. The currently recommended dietary allowances (RDA) for ascorbic acid are 90 mg/day and 75 mg/day for men and women, respectively [4]. Researchers have found that the steady-state concentration of ascorbic acid in plasma is about 80 μmol/L, when sufficient fruits and vegetables are consumed every day. Oral dosing of ascorbic acid (1.25 g) can improve the concentration of ascorbic acid in plasma to 134.8 ± 20.6 μmol/L [5]. In order to maintain the ascorbic acid concentration required by

**Citation:** Yin, X.; Chen, K.; Cheng, H.; Chen, X.; Feng, S.; Song, Y.; Liang, L. Chemical Stability of Ascorbic Acid Integrated into Commercial Products: A Review on Bioactivity and Delivery Technology. *Antioxidants* **2022**, *11*, 153. https://doi.org/10.3390/ antiox11010153

Academic Editor: Stanley Omaye

Received: 23 December 2021 Accepted: 12 January 2022 Published: 13 January 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

the body, ascorbic acid-fortified dietary supplements or foods have attracted interest from consumers, in addition to fruits and vegetables found in nature.

**Figure 1.** Structures of L-ascorbic acid and its stereoisomer.

The main challenge in the development of ascorbic acid products is its high instability and reactivity. Ascorbic acid is reversibly oxidized into dehydroascorbic acid (DHA) upon exposure to light, heat, transition metal ions and pH (alkaline condition), then DHA further irreversibly hydrolyzes to form 2,3-diketogulonic acid (Figure 2A). In recent decades, the strategy of shielding ascorbic acid from sensitive environments by encapsulating ascorbic acid within a layer of wall material has attracted much interest among researchers. A series of innovation delivery technologies have emerged, including microfluidic [6], melt extrusion [7], spray drying and chilling [8,9]. The particles prepared by these methods are usually on the microscale. Under certain conditions, nano-encapsulation of ascorbic acid can be realized through ion gelation of chitosan or complex coacervation with anionic polymers [10,11]. On the other hand, some bioactive compounds with low molecular weight can protect ascorbic acid by scavenging the pro-degradation factors of ascorbic acid in the solution [12].

**Figure 2.** Degradation of L-ascorbic acid to dehydroascorbic acid and 2,3-diketogulonic acid (**A**) and pro-oxidant effects of ascorbic acid (**B**).

Stable ascorbic acid needs to be accurately delivered to the desired site, and released from the carrier at a desired rate and time. This is the basis for obtaining excellent bioavailability of ascorbic acid. For oral products, the expected release site of ascorbic acid is the small intestine rather than the stomach, since the absorption and metabolization of

bioactive compounds mainly occur in the small intestine [13]. This is a challenge for the selection of suitable carrier and wall materials, which is related to the dissolution of the coating polymer in the gastrointestinal environment and its molecular weight. There is a hypothesis that the molecular weight of the used polymers is negatively related to the release of the encapsulated compounds [14]. The encapsulation efficiency of ascorbic acid in gelatin-coated microcapsules reached up to about 94%, but the release of ascorbic acid in the stomach was faster than that in the intestine [15]. However, only 30% of ascorbic acid in chitosan nanoparticles was released in a simulated gastric solution, while the release in simulated intestinal condition exceeded 75% [16].

Figure 3 shows the number of patents related to ascorbic acid from 1992 to 2021; there have been a stable and relatively high number of applications since 1997. From 2010 to 2013, the patents were even more than 1200 per year. It can be found that the importance of ascorbic acid has aroused widespread interest in the consumer market. Ascorbic acid itself or in conjunction with co-existing ingredients in the food matrix can express various physiological activities beneficial to health. This review mainly aims to provide a comprehensive summary about the strategies for stabilizing and controlling release of ascorbic acid in the past 20 years. The commercial products fortified with ascorbic acid are also summarized.

**Figure 3.** The proportion of patents related to ascorbic acid search terms before 2021 (**a**) and the number of ascorbic acid patents in each of the past 30 years (**b**).

#### **2. Bioactivity of Ascorbic Acid**

#### *2.1. Antioxidant*

The by-products of normal cell metabolism are reactive oxygen species (ROS), including superoxide radicals (O2· <sup>−</sup>), singlet oxygen (1O2), hydrogen peroxide (H2O2) and highly reactive hydroxyl radicals (OH·). The adverse effect of ROS is that it can initiate a cascade of radicals, producing hydroxyl free radicals and other destructive species. These further induce protein and DNA damage, lipid peroxidation and finally lead to cell apoptosis [17]. The antioxidant defense system cannot fully eliminate the toxic ROS accumulated in the cells, that is, the so-called "oxidative stress" occurs [18]. In addition to enzymatic reactions, ROS can also be eliminated through non-enzymatic means such as antioxidants. Ascorbic acid is a free radical and other oxygen species scavenger, which can protect cells from oxidative damage caused by ROS. Antiradical capability commonly reflects the antioxidant ability, and ascorbic acid in foodstuff and bio-systems acts as antioxidant. As the most effective and natural antioxidant with the least side effects, ascorbic acid can inhibit various diseases caused by oxidative stress in the body, such as cancer, cardiovascular disease, aging and cataracts [15]. Studies have shown that the mortality from these diseases is inversely related to plasma concentration of ascorbic acid [19]. Ascorbic acid and its derivatives can reduce the level of lipid peroxidation in vivo due to aging [20]. In the absence of transition metals, ascorbic acid can reduce the frequency of mutations induced by H2O2 in human cells [21]. Compared with other polyphenols or flavonoid antioxidants, ascorbic acid terminates the free radical chain reaction through disproportionation

reaction, and the reaction products such as DHA and 2,3-diketogulonic acid (Figure 2A) are non-damaging and non-radical products [22]. Another manifestation of antioxidant property is that ascorbic acid can form relatively stable ascorbic acid free radicals to donate single electrons [23]. As reported, antioxidants can also repair tryptophan free radicals produced by the one-electron oxidation of free tryptophan in lysozyme to maintain protein integrity [24].

Ascorbic acid is also used as an antioxidant to protect the sensory and nutritional properties of foods. As an anti-browning agent, it can inhibit the browning of vegetables and fruits caused by oxidation. The formation of quinones mediated by polyphenol oxidase causes the accumulation of H2O2, which in turn causes the browning of polyphenols mediated by peroxidase [25]. Ascorbic acid inhibits browning by reducing the o-quinone produced by polyphenol oxidase to the original diphenol through a process called "deactivation reaction" [26]. In addition to the regeneration mechanism of polyphenols, the protective effect is also attributed to the competitive inhibition of polyphenol oxidase activity by ascorbic acid. Meanwhile, addition of ascorbic acid causes a decrease in pH and is not conducive to the expression of polyphenol oxidase activity [27]. In meat products, ascorbic acid is widely used as a natural agent for color retention, which can inhibit lipid oxidation and maintain color stability [28]. Compared with other organic acids such as malic acid, citric acid and tartaric acid, ascorbic acid had the best protective effect on the quality of cured meat and was a suitable ingredient for cured meat products [29]. The surface of the pork sprayed with ascorbic acid and a mix of that and rosemary extract maintained good stability in color, water content and pH after frozen storage [30]. It is worth noting that this dietary source of ascorbic acid added in meat products is often overlooked. Norwegian researchers found that the content of ascorbic acid in sausages is 11–40 mg/mL, but ascorbic acid is usually ignored in the table of food ingredients because the added ascorbic acid is used as a color retention agent rather than a nutrient component. As a result, the actual ascorbic acid intake of Norwegian residents increased by 3–10% [31]. The ascorbic acid added to the edible polysaccharide film can eliminate or quench the free radicals generated by radiation. As a radiation inhibitor, ascorbic acid can inhibit the decrease in the viscosity of carrageenan caused by radiation and protect its rheological properties [32]. Ascorbic acid can inhibit food-borne pathogens in the early stage of biofilm formation due to its anti-quorum sensing activity and inhibition of extracellular polymer production. The efficacy of ascorbic acid is related to its concentration and the strain. For *Escherichia coli* and *Staphylococcus aureus*, the inhibitory effect of ascorbic acid at 25 mg/mL is the greatest, and lower concentrations of ascorbic acid are ineffective. For *Listeria monocytogenes*, ascorbic acid at 0.25 mg/mL shows an inhibitory effect [33].
