Salicylic acid

Toxicity

Oral rat LD50: 891 mg/kg. Inhalation rat LC50: > 900 mg/m3/1hr. Irritation: skin rabbit: 500 mg/24H mild. Eye rabbit: 100 mg severe. Investigated a mutagen and reproductive effector.

Description

Salicylic acid (2-hydroxybenzoic acid) is a white solid first isolated from the bark of willow trees (Salix spp.), from which it gets its name. It also occurs as the free acid or its esters in many plant species.
In an early (1966) biosynthetic process, researchers at Kerr-McGee Oil Industries (now part of Andarko Petroleum) prepared salicylic acid via the microbial degradation of naphthalene. It is now commercially biosynthesized from phenylalanine.
Acetylsalicylic acid (aspirin), a prodrug to salicylic acid, is made by an entirely different process. Curiously, salicylic acid is also a metabolite of aspirin.
Salicylic acid and its esters are used as food preservatives, in skin-care products and other cosmetics, and in topical medicines. In 2015, J. L. Dangl, S. L. Lebeis, and co-workers at the University of North Carolina, Chapel Hill, discovered that native salicylic acid plays a role in determining which microbes are in the root microbiome of Arabidopsis thaliana, a weed that grows in Europe and Asia.

Description

Salicylic acid (from Latin salix, willow tree, from the bark of which the substance used to be obtained) is a mono hydroxy benzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin. In addition to being an important active metabolite of aspirin (acetylsalicylic acid), which acts in part as a prod rug to salicylic acid, it is probably best known for its use in anti-acne treatments. The salts and esters of salicylic acid are known as salicylates.

Chemical properties

Salicylic acid has the formula C₆H₄(OH) COOH, where the OH group is ortho to the carboxyl group. It is also known as 2- hydroxybenzoic acid. It is poorly soluble in water (2 g / L at 20 °C). Aspirin (acetyl salicylic acid or ASA) can be prepared by the esterification of the phenolic hydroxyl group of salicylic acid with the acetyl group from acetic anhydride or acetyl chloride.

Physical properties

Salicylic acid. Appearance: white crystalline powder. Solubility: Absolutely soluble in ethanol, soluble in ether and chloroform, slightly soluble in water and anhydrous ether. Stability: Stable at room temperature, discomposes into phenol and carbon dioxide after rapidly heated. It’s partially acidic.
Aspirin. Appearance: white crystal and decomposes at 136–140? °C. Melting point: 136?°C.?Aspirin is the acetyl derivative of salicylic acid with weak acidity. Its acidity coefficient is 3.5 at 25?°C. Stability: Aspirin decomposes rapidly in ammonium acetate, alkali metal of acetate, carbonate, citrate or hydroxide solutions. There are two crystal forms of aspirin including crystal form I and II.

Occurrence

Unripe fruits and vegetables are natural sources of salicylic acid, particularly blackberries, blueberries, cantaloupes, dates, raisins, kiwi fruits, guavas, apricots, green pepper, olives, tomatoes, radish and chicory; also mushrooms. Some herbs and spices contain quite high amounts, although meat, poultry, fish, eggs and dairy products all have little to no salicylates. Of the legumes, seeds, nuts, and cereals, only almonds, water chestnuts and peanuts have significant amounts.

History

The Greek physician Hippocrates wrote in the 5th century BC about a bitter powder extracted from willow bark that could ease aches and pains and reduce fevers . This remedy was also mentioned in texts from ancient Sumer , Lebanon , and As syria .
The active extract of the bark, called salicin, after the Latin name for the white willow (Salix alba), was isolated and named by the German chemist Johann Andreas Buchner in 1826. Raffaele Piria, an Italian chemist was able to convert the substance into a sugar and a second component, which on oxidation becomes salicylic acid.
Salicylic acid was also isolated from the herb meadowsweet (Filipendula ulmaria, formerly classified as Spiraea ulmaria) by German researchers in 1839. While their extract was somewhat effective, it also caused digestive problems such as gastric irritation, bleeding, diarrhea, and even death when consumed in high doses.

The Uses of Salicylic acid

Although toxic in large quantities, salicylic acid is used as a food preservative and as bactericidal and an antiseptic . For some people with salicylate sensitivity even these small doses can be harmful .
Sodium salicylate is a useful phosphor in the vacuum ultraviolet with nearly flat quantum efficiency for wavelengths between 10 to 100 nm . It fluoresces in the blue at 420 nm. It is easily prepared on a clean surface by spraying a saturated solution of the salt in methanol followed by evaporation.

The Uses of Salicylic acid

Salicylic Acid is an Impurity of Acetylsalicylic Acid (A187780). Acetylsalicylic acid Impurity B.

The Uses of Salicylic acid

non-steroidal anti-inflammatory drugs

The Uses of Salicylic acid

salicylic acid is a beta-hydroxy acid with keratolytic and antiinflammatory activity. It helps dissolve the top layer of stratum corneum cells, improving the look and feel of the skin. Salicylic acid is an effective ingredient in acne products and as such is widely used in acne soaps and lotions. Because it is lipid soluble, it can more easily reduce sebaceous follicle blockage by penetrating the pores and exfoliating the cellular buildup. It is antimicrobial, anti-septic, enhances the activity of preservatives, and can be used to adjust the pH of products. For the treatment of aging skin, it appears to help improve skin wrinkles, roughness, and tone. In addition, it is a useful ingredient for products formulated to treat psoriasis, callouses, corns, and warts-cases where there is a buildup of dead skin cells. When applied topically, it is reported to penetrate 3 to 4 mm into the epidermis. A small amount of salicylic acid can convert to copper salicylate, a powerful anti-inflammatory. used at high concentrations, salicylic acid may cause skin redness and rashes. This is a naturally occurring organic acid, related to aspirin. It is found in some plants, particularly the leaves of wintergreen, willow bark, and the bark of sweet birch. Salicylic acid is also synthetically manufactured.

The Uses of Salicylic acid

Salicylic acid is known for its ability to ease aches and pains and reduce fevers. These medicinal properties, particularly fever relief, have been known since ancient times, and it is used as an antiinflammatory drug.
In modern medicine, salicylic acid and its derivatives are used as constituents of some rubefacient products. For example, methyl salicylate is used as a liniment to soothe joint and muscle pain, and choline salicylate is used topically to relieve the pain of mouth ulcers. As with other beta hydroxy acids, salicylic acid is a key ingredient in many skin-care products for the treatment of seborrhoeic dermatitis, acne, psoriasis, calluses, corns, keratosis pilaris, and warts.

Indications

Key additive in many skin-care products for the treatment of acne, psoriasis, callouses, corns, keratosis pilaris and warts.

Background

A compound obtained from the bark of the white willow and wintergreen leaves, and also prepared synthetically. It has bacteriostatic, fungicidal, and keratolytic actions. Its salts, the salicylates, are used as analgesics.

Definition

ChEBI: A monohydroxybenzoic acid that is benzoic acid with a hydroxy group at the ortho position. It is obtained from the bark of the white willow and wintergreen leaves.

Definition

A crystalline aromatic carboxylic acid. It is used in medicines, as an antiseptic, and in the manufacture of azo dyes. Its ethanoyl (acetyl) ester is aspirin. See aspirin; methyl salicylate.

Production Methods

Salicylic acid is biosynthesized from the amino acid phenylalanine. In Arabidopsis thaliana it can also be synthesized via a phenylalanine - independent pathway.
Sodium salicylate is commercially prepared by treating sodium phenolate ( the sodium salt of phenol ) with carbon dioxide at high pressure (100 atm ) and high temperature (390K) -a method known as the Kolbe-Schmitt reaction. Acidification of the product with sulfuric acid gives salicylic acid :
It can also be prepared by the hydrolysis of aspirin (acetylsalicylic acid) or methyl salicylate (oil of winter green) with a strong acid or base.

Preparation

Prepared by heating sodium phenolate with carbon dioxide under pressure

Production Methods

Salicylic acid may be obtained (1) from oil of wintergreen, which contains methyl salicylate, or (2) by heating dry sodium phenate C6H5ONa plus carbon dioxide under pressure at 130 °C (266 °F) and recovering from the resulting sodium salicylate by adding dilute sulfuric acid.

Indications

Salicylic acid is a β-hydroxy acid that penetrates into the sebaceous gland and has comedolytic and anti-inflammatory properties. It can be used as an adjunctive therapy and is found in cleansers, toners, masks, and peels.
Salicylic acid is keratolytic and at concentrations between 3% and 6% causes softening of the horny layers and shedding of scales. It produces this desquamation by solubilizing the intercellular cement and enhances the shedding of corneocytes by decreasing cell-to-cell cohesion. In concentrations >6%, it can be destructive to tissue. Application of large amounts of the higher concentration of salicylic acid can also result in systemic toxicity. Salicylic acid is used in the treatment of superficial fungal infections, acne, psoriasis, seborrheic dermatitis, warts, and other scaling dermatoses. When it is combined with sulfur, some believe that a synergistic keratolytic effect is produced. Common preparations include a 3% and 6% ointment with equal concentration of sulfur; 6% propylene glycol solution (Keralyt); 5% to 20% with equal parts of lactic acid in flexible collodion for warts (Duofilm, Occlusal); in a cream base at any concentration for keratolytic effects; as a 60% ointment for plantar warts; and in a 40% plaster on velvet cloth for the treatment of calluses and warts (40% salicylic acid plaster).

brand name

Advanced Pain Relief Callus Removers (Schering-Plough HealthCare); Advanced Pain Relief Corn Removers (Schering-Plough HealthCare); Clear Away Wart Remover (Schering-Plough HealthCare); Compound W (Whitehall-Robins); Dr. Scholl’s Callus Removers (Schering-Plough HealthCare); Dr. Scholl’s Corn Removers (Schering-Plough HealthCare); Dr. Scholl’s Wart Remover Kit (Schering-Plough HealthCare); Duofilm Wart Remover (Schering-Plough HealthCare); Duoplant (Stiefel); Freezone (Whitehall-Robins); Ionil (Galderma); Ionil-Plus (Galderma); Salicylic Acid Soap (Stiefel); Saligel (Stiefel); Stri-Dex (Sterling Health U.S.A.).

Synthesis Reference(s)

The Journal of Organic Chemistry, 27, p. 3551, 1962 DOI: 10.1021/jo01057a035
Tetrahedron Letters, 37, p. 153, 1996 DOI: 10.1016/0040-4039(95)02120-5

General Description

Odorless white to light tan solid. Sinks and mixes slowly with water.

Air & Water Reactions

Sublimes and forms vapor or dust that may explode [USCG, 1999].

Reactivity Profile

Salicylic acid is a carboxylic acid. Carboxylic acids donate hydrogen ions if a base is present to accept them. They react in this way with all bases, both organic (for example, the amines) and inorganic. Their reactions with bases, called "neutralizations", are accompanied by the evolution of substantial amounts of heat. Neutralization between an acid and a base produces water plus a salt. Carboxylic acids with six or fewer carbon atoms are freely or moderately soluble in water; those with more than six carbons are slightly soluble in water. Soluble carboxylic acid dissociate to an extent in water to yield hydrogen ions. The pH of solutions of carboxylic acids is therefore less than 7.0. Many insoluble carboxylic acids react rapidly with aqueous solutions containing a chemical base and dissolve as the neutralization generates a soluble salt. Carboxylic acids in aqueous solution and liquid or molten carboxylic acids can react with active metals to form gaseous hydrogen and a metal salt. Such reactions occur in principle for solid carboxylic acids as well, but are slow if the solid acid remains dry. Even "insoluble" carboxylic acids may absorb enough water from the air and dissolve sufficiently in Salicylic acid to corrode or dissolve iron, steel, and aluminum parts and containers. Carboxylic acids, like other acids, react with cyanide salts to generate gaseous hydrogen cyanide. The reaction is slower for dry, solid carboxylic acids. Insoluble carboxylic acids react with solutions of cyanides to cause the release of gaseous hydrogen cyanide. Flammable and/or toxic gases and heat are generated by the reaction of carboxylic acids with diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, and sulfides. Carboxylic acids, especially in aqueous solution, also react with sulfites, nitrites, thiosulfates (to give H2S and SO3), dithionites (SO2), to generate flammable and/or toxic gases and heat. Their reaction with carbonates and bicarbonates generates a harmless gas (carbon dioxide) but still heat. Like other organic compounds, carboxylic acids can be oxidized by strong oxidizing agents and reduced by strong reducing agents. These reactions generate heat. A wide variety of products is possible. Like other acids, carboxylic acids may initiate polymerization reactions; like other acids, they often catalyze (increase the rate of) chemical reactions.

Hazard

Respiratory alkalosis, hyperkalemia, hyperthermia, dehydration, convulsions, shock, res- piratory paralysis, respiratory acidosis, lesions and death from respiratory collapse; fetotoxic.

Health Hazard

Inhalation of dust irritates nose and throat. Vomiting may occur spontaneously if large amounts are swallowed. Contact with eyes causes irritation, marked pain, and corneal injury which should heal. Prolonged or repeated skin contact may cause marked irritation or even a mild burn.

Biochem/physiol Actions

Salicylic acid (SA) plays a major role in the growth and development of plants. It also plays a role in endogenous signaling for plant disease resistance. SA is also involved in mediating thermogenesis and symptom development.

Mechanism of action

Salicylic acid has been shown to work through several different pathways. It produces its anti - inflammatory effects via suppressing the activity of cyclo oxygenase (COX), an enzyme which is responsible for the production of pro - inflammatory mediators such as the prostaglandins. Notably, it does this not by direct inhibition of COX, unlike most other non-steroidal anti-inflammatory drugs (NSAIDs), but instead by suppression of the expression of the enzyme (via a yet-un elucidated mechanism) . Salicylic acid has also been shown to activate adenosine monophosphate-activated protein kinase (AMPK), and it is thought that this action may play a role in the anticancer effects of the compound and its prod rugs aspirin and salsalate. In addition, the anti diabetic effects of salicylic acid are likely mediated by AMPK activation primarily through allosteric conformational change that increases levels of phosphorylation. Salicylic acid also uncouples oxidative phosphorylation which leads to increased ADP:ATP and AMP:ATP ratios in the cell. Consequently, salicylic acid may alter AMPK activity and subsequently exert its anti-diabetic properties through altered energy status of the cell. Even in AMPK knock - out mice, however, there is an anti-diabetic effect demonstrating that there is at least one additional, yet - unidentified action of the compound.

Pharmacokinetics

Salicylic acid treats acne by causing skin cells to slough off more readily, preventing pores from clogging up. This effect on skin cells also makes salicylic acid an active ingredient in several shampoos meant to treat dandruff. Use of straight salicylic solution may cause hyperpigmentation on unpretreated skin for those with darker skin types (Fitzpatrick phototypes IV, V, VI), as well as with the lack of use of a broad spectrum sunblock. Subsalicylate in combination with bismuth form the popular stomach relief aid known commonly as Pepto-Bismol. When combined the two key ingredients help control diarrhea, nausea, heartburn, and even gas. It is also very mildly anti-biotic.

Pharmacology

Aspirin is a nonsteroidal anti-inflammatory drug (NSAID). The main pharmacological effect is to inhibit prostaglandin metabolism and thromboxane synthesis by inhibiting prostaglandin metabolism-required cyclooxygenase, via irreversible acetylation of 530 serine residues in the hydroxyl of COX-1 polypeptide chain, which results in COX-1 inactivation, blocks the conversion of arachidonic acid into thromboxane A2 pathway and then inhibits the platelet aggregation.
Prostaglandin is a hormone produced locally in the body. It can pass the pain to the brain, regulate body temperature in the hypothalamus and cause inflammation. Inhibition of prostaglandin synthesis can have antipyretic, analgesic, antiinflammatory and antirheumatic effects. The adverse effects of aspirin are mainly gastrointestinal symptoms such as nausea, vomiting, upper abdominal discomfort or pain. It can also cause allergic reactions, cardiotoxicity, liver and kidney damage and Wright’s syndrome. In addition, high doses of aspirin can cause salicylic acid reactions such as headache, dizziness, tinnitus, hearing loss and other central nervous system symptoms.

Clinical Use

The clinical application of aspirin varies with the therapeutic dose. Low-dose aspirin (75–300?mg/day) has antiplatelet aggregation effect and can be used to prevent and treat the coronary and cerebrovascular thrombosis and other postoperative thrombosis. The middle dose of aspirin (0.5–3? g/day) has antipyretic analgesic effects, so it is commonly used in the treatment of fever, headache, toothache, neuralgia, muscle pain and menstrual pain. High doses of aspirin (more than 4?g/day) have anti-inflammatory and antirheumatic effects for the treatment of acute rheumatic fever and rheumatoid arthritis. In addition, aspirin is used for the treatment of skin and mucous membrane lymphadenopathy (Kawasaki disease) in paediatric.

Side Effects

Salicylic acid's side effects include erythema and scaling.

Safety Profile

Poison by ingestion, intravenous, and intraperitoneal routes. Moderately toxic by subcutaneous route. An experimental teratogen. Human systemic effects by skin contact: ear tinnitus. Mutation data reported. A skin and severe eye irritant. Experimental reproductive effects. Incompatible with iron salts, spirit nitrous ether, lead acetate, iodine. Used in the manufacture of aspirin. When heated to decomposition it emits acrid smoke and irritating fumes.

Potential Exposure

Used as a topical keratolytic agent; in manufacture of aspirin, salicylates, resins, as a dyestuff intermediate; prevulcanization inhibitor; analytical reagent; fungicide, antiseptic, and food preservative.

Veterinary Drugs and Treatments

Often combined with sulfur, salicylic acid shampoos are often employed to treat patients with seborrheic disorders (seborrhea sicca and oleosa) exhibiting mild to moderate scaling, with mild waxy and keratinous debris. In higher concentrations, topicals such as Kerasolv? Gel (6.6% salicylic acid) can be used to remove localized excessive tissues associated with hyperkeratotic disorders, such as calluses and idiopathic thickening of the planum nasale and footpads.
Salicylic acid has mildly antipruritic, antibacterial (bacteriostatic), keratoplastic and keratolytic actions. Lower concentrations are primarily keratoplastic and higher concentrations, keratolytic. Salicylic acid lowers skin pH, increases corneocyte hydration and dissolves the intercellular binder between corneocytes. Salicylic acid and sulfur are thought to be synergistic in their keratolytic actions.

Purification Methods

It has been purified by steam distillation, by recrystallisation from H2O (solubility is 0.22% at room temperature and 6.7% at 100o), absolute MeOH, or cyclohexane and by sublimation in a vacuum at 76o. The acid chloride (needles) has m 19-19.5o, b 92o/15mm, the amide has m 133o (yellow needles from H2O), the O-acetyl derivative has m 135o (rapid heating and the liquid resolidifies at 118o), and the O-benzoyl derivative has m 132o (aqueous EtOH). [IR: Hales et al. J Chem Soc 3145 1954, Bergmann et al. J Chem Soc 2351 1950]. [Beilstein 10 IV 125.]

Plant hormone

Salicylic acid (SA) is a phenolic phytohormone and is found in plants with roles in plant growth and development, photosynthesis, transpiration, ion uptake and transport. SA also induces specific changes in leaf anatomy and chloroplast structure. SA is involved in endogenous signaling, mediating in plant defense against pathogens. It plays a role in the resistance to pathogens by inducing the production of pathogenesis-related proteins . It is involved in the systemic acquired resistance (SAR) in which a pathogenic attack on one part of the plant induces resistance in other parts. The signal can also move to nearby plants by salicylic acid being converted to the volatile ester, methyl salicylate.

Incompatibilities

iron salts; lead acetate; iodine. Forms an explosive mixture in air.