Profile of Ascorbic Acid

Profile of Ascorbic Acid

August 1, 2013 | Contact Author | By: Michael J. Fevola, PhD, Johnson & Johnson
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Title: Profile of Ascorbic Acid
ascorbic acidx vitamin Cx antioxidantx pH adjusterx skin conditionerx
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Keywords: ascorbic acid | vitamin C | antioxidant | pH adjuster | skin conditioner

Abstract: L-Ascorbic acid (AscA), more commonly referred to as vitamin C, is best known for its vital role in human health and nutrition, where it functions as a cofactor in enzymatic reactions, such as collagen synthesis, and as an antioxidant.

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M Fevola, Profile of Ascorbic Acid, Cosm & Toil 126(9) 622 (2011)

L-Ascorbic acid (AscA), more commonly referred to as vitamin C, is best known for its vital role in human health and nutrition, where it functions as a cofactor in enzymatic reactions, such as collagen synthesis, and as an antioxidant. This compound earned its notoriety in the mid-1930s, when Nobel laureate Albert Szent-Györgyi established the link between AscA and the prevention of scurvy, a debilitating disease caused by vitamin C deficiency. As the importance of antioxidants in health and nutrition has become more widely publicized, the addition of AscA and its derivatives to products ranging from food and beverages to nutritional supplements and cosmetics has become increasingly common.

Chemistry and Manufacture

AscA (INCI: Ascorbic Acid) is a six-carbon organic acid with molecular formula C6H8O6, corresponding to a molecular weight of 176.13 g/mol.1, 2 The predominant structure of AscA is shown in Figure 1; however, AscA can exist as a variety of keto-enol tautomers, i.e., isomers resulting from the migration of a proton accompanied by inter- conversion of a C=C or C=O double bond with an adjacent C–O or C–C bond, respectively (Figure 2).

The ability of AscA to undergo intramolecular rearrangements and to delocalize electron density over its structure render AscA an acidic molecule (pKa = 4.17, even though it lacks a carboxylic acid group), a strong reducing agent and a potent free-radical scavenger (antioxidant).2 AscA is a chiral (optically active) molecule with stereocenters at C4 (D-configuration) and C5 (L-configuration). The stereochemistry of AscA is critical to its activity as vitamin C. For example, erythorbic acid, the stereoisomer of AscA with a D-configuration at C5, exhibits only 5% of the vitamin C activity of AscA.3

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L-Ascorbic acid (AscA), more commonly referred to as vitamin C, is best known for its vital role in human health and nutrition, where it functions as a cofactor in enzymatic reactions, such as collagen synthesis, and as an antioxidant. This compound earned its notoriety in the mid-1930s, when Nobel laureate Albert Szent-Györgyi established the link between AscA and the prevention of scurvy, a debilitating disease caused by vitamin C deficiency. As the importance of antioxidants in health and nutrition has become more widely publicized, the addition of AscA and its derivatives to products ranging from food and beverages to nutritional supplements and cosmetics has become increasingly common.

Chemistry and Manufacture

AscA (INCI: Ascorbic Acid) is a six-carbon organic acid with molecular formula C6H8O6, corresponding to a molecular weight of 176.13 g/mol.1, 2 The predominant structure of AscA is shown in Figure 1; however, AscA can exist as a variety of keto-enol tautomers, i.e., isomers resulting from the migration of a proton accompanied by inter- conversion of a C=C or C=O double bond with an adjacent C–O or C–C bond, respectively (Figure 2).

The ability of AscA to undergo intramolecular rearrangements and to delocalize electron density over its structure render AscA an acidic molecule (pKa = 4.17, even though it lacks a carboxylic acid group), a strong reducing agent and a potent free-radical scavenger (antioxidant).2 AscA is a chiral (optically active) molecule with stereocenters at C4 (D-configuration) and C5 (L-configuration). The stereochemistry of AscA is critical to its activity as vitamin C. For example, erythorbic acid, the stereoisomer of AscA with a D-configuration at C5, exhibits only 5% of the vitamin C activity of AscA.3

Most plants and animals are able to biosynthezise their own supply of AscA; however, a small number of animals, including humans, are unable to produce AscA because they lack the enzyme L-glucuronolactone oxidase; therefore, they must obtain it via consumption of foods rich in vitamin C and/or nutritional supplements.2, 4 AscA has been extracted in small amounts from a variety of fruits and vegetables, such as rose hips, lemons, cabbage, and peppers, but this method is not commercially feasible for obtaining pure AscA in large quantities. Instead, AscA is synthesized starting from D-glucose through a combination of various chemical and biochemical reaction processes.2, 5 The principal commercial route for AscA production, known as the Reichstein and Grüssner synthesis, was introduced in 1934. Figure 3 depicts a representative synthesis of AscA via this route. It should be noted that during the past seven decades, many alternative reaction conditions have been developed to improve the yield of this synthesis and to even eliminate certain reaction steps, yet the basic synthetic strategy remains the same.2, 5 Additionally, a great deal of effort has been focused on developing fermentation-based routes to AscA to eliminate one or more of the chemical synthesis steps.

In the typical Reichstein and Grüssner synthesis, D-glucose is first reduced via catalytic hydrogenation to D-sorbitol, which is then oxidized to L-sorbose through fermentation with the microorganism Acetobacter suboxydans. This biochemical reaction step is critical in the overall synthesis of AscA, as it yields only the desired L-isomer of sorbose. In the third step, the hydroxyl groups at the 2, 3, 4, and 6 positions are protected by acid-catalyzed acetal formation with two equivalents of acetone to yield a compound called 2,3:4,6 diacetone-L-sorbose (DAS). The unprotected hydroxyl group of DAS is then oxidized to the corresponding carboxylic acid, resulting in the formation of 2,3:4,6 diacetone-2-keto-L-gulonic acid (DAG). In the final stage of the synthesis, DAG is treated with aqueous hydrochloric acid and ethanol in an inert solvent system to deprotect the molecule via hydrolysis of the acetal groups to liberate acetone, which is recovered and recycled. These reaction conditions allow for rearrangement of the deprotected molecule to AscA through subsequent lactonization and enolization steps. During this final stage, crude AscA typically precipitates from the solvent system as it is formed. Crude AscA is then isolated and purified via recrystallization from water, followed by filtration, washing with ethanol and drying.

Properties

AscA is a white, odorless, crystalline solid with a sharp acidic taste.2, 4 It is typically supplied as a fine powder or in granular form. Whereas the granular form is more desirable in large scale compounding operations where dusting is an issue, fine powders are easier to compress in tablets. AscA is freely soluble in water and is sparingly soluble in polar solvents such as propylene glycol and ethanol; it is insoluble in nonpolar organic solvents and oils. The United States Pharmacopeia (USP) specifies that pharmaceutical grade AscA must contain 99.0–100.5% C6H8O6 as determined via iodine titration, have a residue on ignition (sulfated ash content) of no more than 0.1%, and may not contain more than 0.002% heavy metal impurities.6 To ensure purity of this optically active compound, a freshly prepared solution of USP-grade AscA (100 mg/mL in carbon dioxide-free water) must exhibit a specific rotation between +20.5 and +21.5 degrees.

Dry, solid AscA is stable in air but can darken gradually upon exposure to light. In aqueous solutions, AscA is highly susceptible to oxidation upon exposure to air, light and/or elevated temperatures; this oxidative degradation leads to formation of multiple degradation products that cause solutions of AscA to develop a yellowish to tan color over time.2 Factors that can influence the rate of AscA degradation include solution pH, temperature, dissolved oxygen concentration and the presence of metals. Many metal ions, especially those of copper, readily catalyze the oxidation of AscA and its derivatives. Thus, it is usually advisable to formulate AscA with a chelating agent, e.g., ethylenediaminetetraacetic acid (EDTA), to inhibit such degradation and to avoid processing or storing formulations containing AscA above 40° C for prolonged periods.

Technology and Applications

The leading uses of AscA are as a nutritional supplement and as an antioxidant in the large scale manufacture of food and beverage products. In the formulation of cosmetics and personal care products, AscA is reported to function as an antioxidant, pH adjuster and a skin conditioning agent.1 Unlike other organic acids, AscA does not pose any significant irriation risks. According to the Cosmetic Ingredient Review (CIR), it has even been applied to compromised skin (burn patients) with no adverse effects. AscA is also used in the form of sodium or calcium salts, which offer improved solubility and pH buffering capacity. AscA usage is especially prevalent in the formulation of permanent hair coloring products, where it functions as an antioxidant and a reducing agent to improve the stability and performance of the dye product.4, 7 The concentration of AscA in these formulations may range from 0.1–0.6% w/w. Compositions comprising higher concentrations (up to 10% w/w) of AscA formulated at low pH values (pH = 2–5) have been developed to function as decolorants that can reduce or eliminate the color of hair treated with permanent oxidative dyes.8

The functionality of AscA is readily improved by synthesizing simple derivatives of the molecule (see Figure 4 for examples) to enhance its stability, delivery, and/or compatibility with nonpolar media, e.g., oil phases and lipid bilayers.2–4, 9–10 Upon uptake into the body, such derivatives are readily converted back to AscA and biocompatible by-products, such as fatty acids or salts of phosphoric acid, i.e., phosphates. Fatty acid esters of AscA, such as ascorbyl palmitate, are lipophilic derivatives of AscA that offer the antioxidant activity of AscA with the benefits of oil phase solubility and enhanced skin barrier penetration. The phosphate ester salts of AscA, such as sodium ascorbyl phosphate and magnesium ascorbyl phosphate (MA2P), are water-soluble derivatives of AscA that offer significantly improved stability compared to AscA.

AscA and its derivatives are claimed to provide numerous skin health benefits, in particular anti-aging benefits, based on their ability as antioxidants to protect skin from reactive oxygen species (ROS) generated by exposure to environmental stresses and UV radiation.10–11 The phosphate ester salts of AscA, especially MA2P, have also been demonstrated to inhibit melanogenesis and therefore can provide skin lightening benefits.12–14

References
1. Ascorbic Acid, Monograph ID 213, in the International Cosmetic Ingredient Dictionary and Handbook, 13th ed, Personal Care Products Council, Washington, DC USA (2010)
2. V Kuellmer, Ascorbic Acid, in Kirk-Othmer Encyclopedia of Chemical Technology, John Wiley & Sons, Hoboken, NJ USA (Apr 16, 2001) pp 1–33
3. FA Andersen, Final report on the safety assessment of ascorbyl palmitate, ascorbyl dipalmitate, ascorbyl stearate, erythorbic acid and sodium erythorbate, Int J Toxicol 18 suppl 3 1–26 (1999)
4. FA Andersen, Final report on the safety assessment of L-ascorbic acid, calcium ascorbate, magnesium ascorbate, magnesium ascorbyl phosphate, sodium ascorbate, and sodium ascorbyl phosphate as used in cosmetics, Int J Toxicol 24 suppl 2 51–111 (2005)
5. TC Crawford, Synthesis of L-ascorbic acid, Chapter 1 in Ascorbic Acid: Chemistry, Metabolism, and Uses, Vol 200, Adv Chem Ser, PA Seib and BM Tolbert, eds American Chemical Society, Washington DC USA (1982) pp 1–36
6. Ascorbic Acid, Official Monograph, in the United States Pharmacopeia 34, United Book Press Inc., Baltimore, USA (2011) p 1929 7. GM Wis-Surel, Some challenges in modern hair colour formulations, Int J Cosmetic Sci 21(5) 327–340 (1999)
8. US 5782933, Ascorbic and isoascorbic acids to remove or adjust oxidative color in hair, G Wis-Surel, A Mayer and I Tsivkin, assigned to Bristol-Myers Squibb Co. (Jul 21, 1998)
9. R Austria, A Semenzato, A Bettero, Stability of vitamin C derivatives in solution and topical formulations, J Pharm Biomed Anal 15(6) 795–801 (1997)
10. Stay C-50–Exploring the untapped potential of vitamin C for skin, hair, and oral care, DSM Product Bulletin, DSM Nutritional Products Inc., Parsippany, NJ USA (2006)
11. S Kobayashi, M Takehana, S Itoh, E Ogata, Protective effect of magnesium L-ascorbyl-2-phosphate against skin damage induced by UVB irradiation, Photochem Photobio 64(1) 224–228 (1996)
12. S Parvez, M Kang, H-S Chung, C Cho, M-C Hong, M-K Shin, H Bae, Survey and mechanism of skin depigmenting and lightening agents, Phytother Res 20(11) 921–934 (2006)
13. JM Gillbro and MJ Olsson, The melanogenesis and mechanisms of skin-lightening agents – existing and new approaches, Int J Cosmetic Sci 33(3) 210–221 (2011)
14. K Kameyama, C Sakai, S Kondoh, KZ Yonemoto, S Nishiyama, M Tagawa, T Murata, T Ohnuma, J Quigley, A Dorsky, D Bucks, K Blanock, Inhibitory effect of magnesium L-ascorbyl-2-phosphate (VC-PMG) on melanogenesis in vitro and in vivo, J Am Acad Dermatol 34(1) 29–33 (1996)

 

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Figure 1. Chemical structure of L-Ascorbic acid (AscA)

Figure 1. Chemical structure of L-Ascorbic acid (AscA)

The predominant structure of AscA is shown in Figure 1; however, AscA can exist as a variety of keto-enol tautomers, i.e., isomers resulting from the migration of a proton accompanied by inter- conversion of a C=C or C=O double bond with an adjacent C–O or C–C bond, respectively (Figure 2).

Figure 2. Keto-enol tautomerization in L-Ascorbic acid

Figure 2. Keto-enol tautomerization in L-Ascorbic acid

The predominant structure of AscA is shown in Figure 1; however, AscA can exist as a variety of keto-enol tautomers, i.e., isomers resulting from the migration of a proton accompanied by inter- conversion of a C=C or C=O double bond with an adjacent C–O or C–C bond, respectively (Figure 2).

Figure 3. Synthesis of AscA via the Reichstein and Grüssner route

Figure 3. Synthesis of AscA via the Reichstein and Grüssner route

Figure 3 depicts a representative synthesis of AscA via this route.

Figure 4. Derivatives of AscA commonly employed in cosmetic and personal care products

Figure 4. Derivatives of AscA commonly employed in cosmetic and personal care products

The functionality of AscA is readily improved by synthesizing simple derivatives of the molecule (see Figure 4 for examples) to enhance its stability, delivery, and/or compatibility with nonpolar media, e.g., oil phases and lipid bilayers.

Biography: Michael J. Fevola, PhD, Johnson & Johnson

Michael J. Fevola, PhD, is a manager in the New Technologies group at Johnson & Johnson Consumer and Personal Products Worldwide in Skillman, NJ, where he leads R&D in polymer and surface chemistry. Fevola has authored 12 peer-reviewed articles and book chapters, is an inventor on six US patents, and is a member of the Personal Care Product Council’s International Nomenclature Committee and the Society of Cosmetic Chemists.

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