Salicylic Acid

SALICYLIC ACID, Acidum salicylicum, Acidum orthooxybenzoicum (Ph. VII) (from the Latin salix—willow, most species of which contain the glycoside salicin in their bark, a compound of the salicylic alcohol saligenin and glucose) (syn. Acidum spiricum). It represents ortho-hydroxybenzoic acid, C₆H₄(OH)COOH [1, 2], mol. wt. 138.05; it exists in the form of needle-like crystals or in the form of a light crystalline powder, with a scratching taste, odorless. When inhaled in atomized form, it causes sneezing. It dissolves in 460 parts of cold and 15 parts of boiling water, 2.7 parts of alcohol, 30 parts of ether, and easily in boiling chloroform. Solutions have an acidic reaction to litmus. Salicylic acid melts at 156–157° and, upon careful heating, sublimes without decomposition; upon rapid heating, it partially decomposes with the release of phenol (odor). A solution of salicylic acid (1:500) turns blue-violet from a drop of ferric chloride solution. In the past, salicylic acid and its salts were obtained from wintergreen oil (Ol. Gaultheriae), obtained from plants and consisting mainly of the methyl ester of salicylic acid, as well as from saligenin by its oxidation. Since 1874, the method of synthetic production of salicylic acid discovered by Kolbe has been used exclusively: sodium phenolate is treated with CO₂ in an autoclave under pressure, first in the cold and then upon heating to 120–130°; as a result of the reaction C₆H₅ONa + CO₂ -> C₆H₄OHCOONa, sodium salicylate is obtained. Another method of production is heating phenol to 130–160° with an excess of potassium carbonate and CO₂ in a closed vessel, whereby the potassium salt of salicylic acid is obtained. Salicylic acid and its salts are easily absorbed by all mucous membranes. Its esters are also rapidly absorbed by the intestines, which, when taken per os, are partially subjected to saponification; salicylic acid, as well as its esters (for example, methyl ester), are also absorbed by intact skin when applied in the form of ointments. Sodium salicylate is absorbed with more difficulty during such application, since, according to Schwenkenbecher, the decomposition of the salt under the influence of carbonic acid must precede absorption. In the blood, salicylic acid is converted into sodium salicylate. Salicylates pass from the blood into tissues and into various fluids, secretions, and excretions of the body (synovial fluid, cerebrospinal fluid, sweat, bile, milk, etc.), and upon excretion into the stomach, they partially convert into salicylic acid. The excretion of salicylates from the body occurs mainly in the urine, in humans predominantly in an unchanged form (Sollmann) and only partially in combination with sulfuric and glucuronic acid; part of the salicylic acid is oxidized to dihydroxybenzoic acid and hydroquinone. According to more recent studies (Hanzlik, 1916; Angelico, 1921), the excretion of salicylic acid in combination with glycocoll in the form of salicyluric acid, as was assumed on the basis of previous studies, does not occur. Excretion of salicylic acid in feces does not occur (Sollmann). A certain part of it is excreted in sweat. The excretion of salicylic acid begins 10–15 minutes after ingestion, and the main mass of it is excreted between 6 and 48 hours. The amount excreted in the urine is normally greater than during fever, even in those cases where kidney function is not impaired (Hanzlik, 1917). Both outside the body and within it, salicylic acid exhibits an antiseptic effect, apparently depending on its acidic properties, since its salts and esters exhibit a much weaker bactericidal effect. Previous authors equated the antiseptic effect of salicylic acid to phenol (Kolbe), however, more recent studies have shown that its effect is significantly stronger. Due to its antiseptic properties and relatively low toxicity, salicylic acid was used, and in part is still used, as a preservative for food products (for example, caviar) and beverages. Such use, with prolonged consumption, can cause damage to the digestive tract. Local action. Salicylic acid, applied in solution, dissolves the horny layer of the skin; it acts on mucous membranes in an irritating manner, with strong solutions exerting a sort of weak cauterizing effect; at the same time, its antiseptic effect is also manifested. Its salts do not possess an irritating property. General action. The main resorptive action of salicylic acid and its preparations is expressed in antipyretic, analgesic, and especially anti-rheumatic action (in acute articular rheumatism). The antipyretic action is close in character to the same action of typical antipyretics (antipyrine, phenacetin), although it is less pronounced than in the latter, and depends on increased heat dissipation, caused firstly by the dilation of surface vessels and the rush of blood to the surface of the body, and secondly by increased perspiration. Heat loss by the latter method with salicylic preparations is especially pronounced. As with antipyretics, a drop in temperature is difficult to achieve in healthy individuals and relatively easy in those with fever, and a decrease in temperature can also be observed in the post-febrile period, but only when central thermoregulation has not yet returned to a normal state (Barbour). According to Barbour, increased heat dissipation with antipyretics depends on an increase in blood volume, which affects the state of the thermoregulatory center. The analgesic action of salicylates is generally less pronounced than with typical antipyretics, with the exception of cases of acute articular rheumatism. It depends on the effect on the corresponding parts of the brain. The action of salicylic preparations is especially sharp in acute articular rheumatism; the therapeutic effect in this case is manifested on all painful symptoms: temperature, soreness, and the inflamed state of the joints, the swelling of which subsides, and the redness disappears. With proper doses, the full effect is achieved in 1–5 days and lasts as long as the patient takes salicylic preparations. The total duration of the disease, however, as statistical data show (Sollmann), is not shortened. The question of whether salicylic acid prevents complications from the heart and whether it favorably affects their course still cannot be considered definitively resolved: while the majority of authors believe that with the use of salicylic acid these complications occur less frequently and proceed more easily, others claim that the probability of complications actually increases with it (Cushny). Observations by Levy and Turner indicate the favorable effect of salicylic acid on the heart in rheumatism, according to which the conductivity of the bundle of His, which decreases during rheumatism, returns to normal under the influence of salicylic acid. The action of salicylic acid in articular rheumatism is explained by some authors as an etiotropic action. Binz suggested that sodium salicylate, circulating in the blood and possessing a much weaker bactericidal action than salicylic acid, decomposes in inflamed joints under the influence of carbonic acid, which is under high tension, with the release of salicylic acid. Such an action of salicylic acid is supposedly facilitated by its accumulation in large quantities in the synovial fluid of the joints, especially during inflammation of the latter. Later studies, however, did not confirm this assumption (Scott, Thorburn, Hanzlik; 1917). At the same time, other authors (Hanzlik, Sollmann), in view of the fact that other analgesics (e.g., atophan or morphine + quinine) also act anti-rheumatically, explain the favorable effect of salicylic acid in rheumatism by its analgesic and antipyretic properties. Salicylic acid has some effect on nitrogen metabolism, especially increasing the excretion of uric acid, the content of which in the blood falls (Sollmann). The increase in uric acid excretion depends partly on the greater permeability of the kidneys and partly on less destruction of uric acid by the body. The effect on the kidneys, depending on the dose, can be of a different nature. Small and moderate doses can slightly increase urination, which can be explained by the action of salicylic acid on the renal epithelium, as well as by the increased formation of urea, which, as is known, has a pronounced diuretic effect. Large doses have the opposite effect on diuresis, partly due to increased water excretion through sweat and partly due to some damage to the kidneys. The latter is indicated by the sometimes observed albuminuria and reduced permeability of the kidneys, which can be determined by the phthalein test (Sollmann). Body weight increases due to water retention, although obvious edema is not noted (Hanzlik, Scott). Salicylic acid exerts an effect on the urinary organs, bladder, and tracts due to its antiseptic action (for details, see Salol). Salicylates also possess a pronounced choleretic effect. Steinmetzer, using the Stransky method, gives the following numerical assessment of this effect: if the effect of Carlsbad salt = 20, then that of sodium salicylate = 10, Ol. Menthae piperitae = 9, atophan = 4 1/2 (Handovsky). Gastric secretion is slightly reduced under the influence of salicylates. Previous authors pointed to the unfavorable effect of salicylic acid on the heart. Some confirmation of this can be seen from experiments on an isolated heart.

However, such an effect can be observed at ordinary doses only with a very weakened heart or with excessively large doses. Unlike other antipyretics (antipyrine) and caffeine, which cause dilation of cerebral vessels, salicylates, according to some authors (Handovsky), affect these vessels in a constricting manner, although the experiments of Berezin testify to the opposite effect. The effect on the central nervous system is weakly expressed, less than with other aromatics (Keshni). Salicylates have a stimulating effect on the uterus. An increase in menstruation is also noted. When using large doses of salicylates (full therapeutic dose), a number of side effects are usually observed. These include nausea, and sometimes vomiting, tinnitus, deafness, dizziness, headache, some confusion of thought, sweating, rapid pulse, and deepened breathing; skin rashes, albuminuria, visual disturbances are rarely observed, and delirium in alcoholics. All these symptoms usually pass immediately upon cessation of the administration of the drug. According to Hanzlik, they occur with doses of 1.0 every 1–2 hours after the administration of sodium salicylate in a total amount of 7 to 13 g. In women, side symptoms appear after taking 4/5 of the indicated total dose. Children show relatively high resistance. Dangerous poisoning is rarely observed; it occurs only after taking excessive doses—from 5 to 12 g—and is manifested by vomiting, loss of consciousness, delirium, dyspnea, deepening of breathing, arrhythmia, albuminuria, paresis, collapse, and asphyctic convulsions. Even severe cases usually end in recovery. During an autopsy of a poisoned person, Quincke found hyperemia of the brain and its membranes, kidneys, lungs, and pericardial ecchymoses (Sollmann).

Therapeutic use. For oral administration, salicylic acid, which irritates the gastric mucosa, is usually replaced by sodium salicylate or esters of salicylic acid. The use of sodium salicylate in acute articular rheumatism is of the greatest importance. Its effect in this disease is considered by many authors to be so specific that the absence of a favorable effect casts doubt on the diagnosis. However, to obtain the proper effect, it is necessary to use the drug in doses of 1.0–1.5 every two hours, and from 5 to 10 g per day, i.e., until the appearance of the first symptoms of poisoning. To avoid the release in the stomach of salicylic acid from the salt, which possesses irritating properties, some authors recommend administering sodium bicarbonate simultaneously with sodium salicylate (in equal amounts). Keshni, however, denies the benefit of such a combination. When used in the indicated doses, the full therapeutic effect is usually obtained after 48 hours. However, taking the medicine, even in smaller doses, must be continued. For patients with a particularly sensitive stomach, Natr. salicylicum can be prescribed in the form of enemas or suppositories (2.0 three times a day). Some also recommend the intravenous administration of sodium salicylate. Replacing sodium salicylate with complex esters of salicylic acid for use in articular rheumatism is hardly rational, since these esters (aspirin, salol), although they possess a lesser irritating effect on the stomach and generally less side effects, nevertheless exert a weaker effect on the course of rheumatism, because, according to Clark, the effect of various salicylic preparations is proportional to their toxic effect. Salicylic preparations exert the same effect on rheumatic tonsillitis as on acute articular rheumatism (Zolman). In subacute rheumatic diseases, the effect is far from as reliable and, according to Clark, is positive only in half of the cases. In neuralgias and gouty diseases, other agents are now usually used; salicylates are prescribed here in smaller doses—Natr. salicyl. 2.0–3.0 per day. As antipyretics and analgesics, salicylic preparations, with the exception of aspirin, are significantly inferior to the true antipyretics of the antipyrine-phenacetin group. Salicylates (especially sodium salicylate) are further used in pleurisy, pericarditis, peritonitis, and meningitis, then in large doses in diabetes, whereby the amount of sugar in the urine decreases. The symptomatic action of salicylic acid (against neuralgias, collapse) probably also plays a significant role in this. As a cholagogue—in catarrhal jaundice and gallstones. In amenorrhea—1.0 of Natr. salicyl. three times a day. As disinfectants for the intestine and urinary tract, esters of salicylic acid are used primarily (see Salol). For the penetration of salicylic acid into affected joints, iontophoresis with a bath of sodium salicylate solution can be used. Externally, salicylic acid, as possessing a much stronger antiseptic effect than its salts or esters, is used in preference to the latter; its antiseptic effect exceeds that of phenol. As an agent that destroys the epidermis (for corns, pityriasis versicolor), salicylic acid is used in ointments and a solution in collodion. Preparations. Acidum salicylicum—internally in capsules, 0.1–0.3 several times a day, as an anti-fermentative. As an anti-rheumatic (rarely) 0.5–1.0 several times a day. Externally as an antiseptic, in the form of dusting powders and powders mixed with boric acid, starch, or talc (4–10%) for foot sweat, in dressing material, as an anti-rheumatic in the form of ointments (10–50%); in alcoholic solution 1:10 against skin itching; in collodion (1:10) for corns, etc.—Pulv. salicylicus cum talco with 3% salicylic acid content (for foot sweat).—Natrium salicylicum—sodium salicylate (Ph. VII), white crystals or small flakes, odorless, sweetish-salty taste, soluble in an equal volume of water and in 6 parts of alcohol. When the salt is heated in a test tube, the smell of phenol develops and a carbonaceous residue remains. A 1:10 solution with a drop of diluted ferric chloride solution gives a violet coloration. Doses: 0.5–1.0 several times a day, up to 10.0 per day; for children 6 years old up to 5.0, for two-year-olds up to 2.0 per day. Prescribed in powders, capsules, solution, usually after meals.—Acidum acetylsalicylicum, s. aspirinum, acetylsalicylic acid—see Aspirin.—Kalmopyrin—calcium salt of acetylsalicylic acid, easily soluble in water. Used as a substitute for aspirin in the same doses and for the same purposes as the latter.—Hydropyrin—lithium salt of acetylsalicylic acid; readily soluble in water, possesses a weak acidic taste. Taken internally in tablets (0.5 each) or in solution at 0.5–1.0 several times a day.—Phenylum salicylicum, s. Salolum—see Salol.—Novaspirin—methylene-citric acid ester of salicylic acid, white powder, slightly acidic taste, almost insoluble in water, easily soluble in alcohol. Used for rheumatism instead of sodium salicylate, causes fewer side effects than aspirin. Doses: 1.0 several times a day.—Diplosal (Boehringer)—salicylic ester of salicylic acid, C₆H₄(OH)COO.C₆H₄(OH)COOH, colorless, tasteless, and odorless powder, almost insoluble in water, does not irritate the stomach. Decomposes in the intestine into 2 molecules of salicylic acid. Doses: 0.5–1.0 three to six times a day.—Salophen, salophen (Bayer)—acetylparaamidosalol, crystalline leaflets; barely soluble in water, easily dissolved in alkalis. Devoid of smell and taste. In the intestine, it splits off about 50% of salicylic acid. Replaces sodium salicylate, for example in influenza, neuralgias, migraine, etc. Dose: 0.5–1.0, up to 6.0 pro die.—Rheumatin—rheumatin (Zimmer), quinine salicylate (Salochinin), white colorless powder, difficult to dissolve in water. Prescribed for rheumatism, gout, neuralgias. Dose: 1.0 three times a day with breaks every 3–4 days.—Pyrazolum phenyl dimethylicum salicylicum—Salipyrin (salipyrin)—ester of salicylic acid and antipyrine, white powder, difficult to dissolve in water, easily in alcohol. Internally 0.5–1.0 several times a day, as an anti-rheumatic and analgesic agent.—Methylum salicylicum—methyl salicylate, methyl ester of salicylic acid, C₆H₄(OH)COO.CH₃, synthetically prepared artificial wintergreen oil; colorless or slightly yellowish liquid with a pleasant smell. Easily absorbed by the skin. Irritates less than natural wintergreen oil. Externally 50–120 drops up to 12.0–25.0 per day, in the form of applications to diseased joints, which are then covered with oilcloth and cotton wool. Also good for pleurisy.—Mesotan (Bayer), mesotan—methoxymethyl ester of salicylic acid, oily liquid, miscible with alcohol and oils; possesses a weak smell. Easily absorbed by the skin, which it irritates more than the previous preparation, which is why in pure form and strong dilutions it can be used only in the form of applications, not rubbings. Externally—in pure form or mixed with vegetable oil in equal parts. Also in the form of ointments (10–30%) for acute and chronic rheumatism, gout, pleurisy, angina, etc. The area after application or rubbing in of the ointment remains uncovered.—Salit (Heyden)—salit, ester of borneol and salicylic acid, oily liquid, devoid of smell, insoluble in water, but easily soluble in alcohol, ether, and oils. Possesses a weak irritating effect. Used for rubbings.—Salen (Ciba)—salen, mixture of methyl and ethyl glycolic esters of salicylic acid, oily liquid, solidifying at -5°. Easily soluble in alcohol, ether, benzene, and castor oil, difficult in olive oil. Used externally in pure form or also in a mixture with equal parts of alcohol or Salen 10.0, Chloroformii + Ol. Oliv. ana 5.0.—Salenal—salenal, ointment containing 33 1/3% salen.—Rheumasan (R. Reiss)—rheumasan, soap ointment containing 10% easily absorbed salicylic acid. Externally for rubbings 5.0–20.0—one to two times a day into dry skin.—Bismutum subsalicylicum—basic bismuth salt of salicylic acid, white powder, devoid of taste and smell, insoluble in water and alcohol. Used like Bismutum subnitricum at 0.5–2.0 several times a day. As a salicylic preparation, it possesses a more pronounced antiseptic effect than the nitric acid salt.—Natrium dithiosalicylicum, s. Dithion, sodium salt of dithiosalicylic acid, which consists of two molecules of salicylic acid linked by one sulfur atom. Internally 0.2 pro dosi, up to 1.0 pro die. Externally—strongly antiseptic.

A. Likhachev. Detection in forensic cases. When examining viscera and other objects, Salicylic Acid is detected in the distillate during steam distillation (see Poisons, isolation) and enters the chloroform (or ether) extract from an acidic solution. The residue after evaporation of the extract is dissolved with the help of sodium carbonate. The solution is re-extracted with ether (purification), then acidified with sulfuric acid and extracted again with ether. The residue after evaporation of the ether extract is dissolved in a few drops of water (or cubic centimeters, depending on the size of the precipitate) and reactions for Salicylic Acid are performed: 1) ferric chloride gives a violet coloration that does not disappear upon the addition of ethyl alcohol; the reaction is conveniently performed using a piece of paper moistened with a ferric chloride solution, which takes on a violet coloration in the presence of Salicylic Acid in the solution; 2) bromine water gives a white precipitate; 3) heating the residue with methyl alcohol with the addition of concentrated sulfuric acid causes the characteristic odor of methyl salicylate.