SALICYLIC

ACID (ortho-hydroxybenzoic acid)  , an aromatic acid, C6H4(OH)(CO2H), found in the free state in the buds of Spiraea Ulmaria and, as its methyl ester, in gaultheria oil and in the essential oil of Andromeda Leschenaultii . It was discovered in 1838 by Piria as a decomposition product of salicin . It may be obtained by the oxidation of saligenin and of salicylic aldehyde; by the distillation of copper benzoate; by the decomposition of anthranilic acid with nitrous acid; by fusion of ortho-chlor or ortho-brom benzoic acid with potash; by heating orthocyanphenol with alcoholic potash; by heating a mixture of phenol, carbon tetrachloride and alcoholic potash to zoo° C . (F . Tiemann and K Reimer, Ber., 1876, 9, p . 1285); and by the action of sodium on a mixture of phenol and chlorcarbenic ester (T . Wilm and G . Wischin, Zeit. f . Chemie, 1868, 6) . It is manufactured by Kolbe's process or by some modification of the same . Sodium phenolate is heated in a stream of carbon dioxide in an iron retort at a temperature of 18o-22o° C., when half the phenol distils over and a basic sodium salicylate is left . The sodium salt is dissolved in water and the free acid precipitated by hydrochloric acid (H .

Kolbe,

Ann., 186o, 115, p . 201) . R . Schmitt (Jour. peak . Chem., 1885 (2), 31, p . 407) modified the process by saturating sodium phenolate at 13o C. with carbon dioxide, in an autoclave, sodium phenyl carbonate C6H6O•CO2Na being thus formed; by continuing the heating under pressure this carbonate gradually changes into mono-sodium salicylate . S . Manasse (German patent 73,279) prepared an intimate mixture of phenol and potassium carbonate, which is then heated in a closed vessel with carbon dioxide, best at 130-16o° C . The Chemische Fabrik vorm . Hofmann and Schotensack decompose a mixture of phenol (3 molecules) and sodium carbonate (4 moll.) with carbonyl chloride at 140-200° C . When 90 % of the phenol has distilled over, the residue is dissolved and hydrochloric acid added, any phenol remaining is blown over in a current of steam, and the salicylic acid finally precipitated by hydrochloric acid . The acid may also be obtained by passing carbon monoxide over a mixture of sodium phenolate and sodium carbonate at 200° C .

: Na2COa+ C6H2ONa+CO = C7H4O2Na2 + HCO2Na;and by heating sodium phenolate with

ethyl phenyl carbonate to 200° C.: C6HSO•CO2C2H +CsH5ONa = HO•C6H4COiNa+CiHs•C2Hs . It is to be noted in the Kolbe method of synthesis that potassium phenolate may be used in place of the sodium salt, provided that the temperature be kept low (about 15o° C.), for at the higher temperature (220° C.) the isomeric para-oxybenzoic acid is produced . Salicylic acid crystallizes in small colourless needles which melt at 155° C . It is sparingly soluble in cold water, but readily dissolves in hot . It sublimes, but on rapid heating decomposes into carbon dioxide and phenol . It is volatile in steam . Ferric chloride colours its aqueous solution violet . Potassium bichromate and sulphuric acid oxidize it to carbon dioxide and water; and potassium chlorate and hydrochloric acid to chloranil . On boiling with concentrated nitric acid it yields picric acid . When heated with resorcin to zoo° C. it gives trioxybenzophenone . Bromine water in dilute aqueous solution gives a white precipitate of tribromophenol-bromide C6H2Br3.OBr . Sodium reduces salicylic acid in boiling amyl alcohol solution to n-pimelic acid (A .

Einhorn and R . Willstatter, Ber., 1893, 26, pp . 2, 913; 1894, 27 p . 331) . Potassium persulphate oxidizes it in alkaline solution, the product on boiling with acids giving hydroquinone carboxylic acid (German Patent 81,297) . When boiled with calcium chloride and ammonia, salicylic acid gives a precipitate of insoluble basic calcium salicylate, C6114 <C82> Ca, a reaction which serves to distinguish it from the isomeric meta-and para-hydroxybenzoic acids . It yields both esters and ethers since it is an acid and also a phenol . Methyl Salicylate, C6H4(OH)•CO2CH6, found in oil of wintergreen, in the oil of Viola tricolor and in the root of varieties of Polygala, is a pleasant-smelling liquid which boils at 222° C . On passing dry ammonia into the boiling ester, it gives salicylamide and dimethylamine . When boiled with aniline it gives methylaniline and phenol . Ethyl salicylate, C6H4(OH)•CO2C2H6, is obtained by boiling salicylic acid with alcohol and a little sulphuric acid, or by dropping an alcoholic solution of salicylic acid into 13-naphthalene sulphonic acid at a temperature of 140-150° C . (German Patent 76,574) .

It is a pleasant-smelling liquid which boils at 233° C . It is practically unchanged when boiled with aniline . Phenyl salicylate, C6H4(OH)•C•02C6H6, or salol, is obtained by heating salicylic acid, phenol and

phosphorus oxychloride to 120-125° C.; by heating salicylic acid to 220° C.; or by heating salicyl metaphosphoric acid and phenol to 140-150° C . (German Patent 85,565) . It crystallizes in rhombic plates which melt at 42° C. and boil at 172° C . (12 mm.) . Its sodium salt is transformed into the isomeric C6H4(OC6H5) CO2Na when heated to 300° . When heated in air for many hours it decomposes, yielding carbon dioxide, phenol and xanthone . Acetyl-salicylic acid (salacetic acid), C5H4(O•000H3)•CO2H, is obtained by the action of acetyl chloride on the acid or its sodium salt (K . Kraut, Ann., 1869, 15o, p . 9) . It crystallizes in needles and melts at 132° C .

(with decomposition) .

Hydrolysis with baryta water gives acetic and salicylic acids . It is used in medicine under the names aspirin, acetysal, aletodin, saletin, xaxa; &c . It has the same action as salicylic acid and salicylates, but is said to be much freer from objectionable secondary effects . Salicylo-salicylic acid O•(C6H4CO2H)2 Is obtained by continued heating of salicylic acid and acetyl chloride to 130-140° C . It is an amorphous yellow mass which is easily soluble in alcohol . Applications.—The addition of a little of the acid to glue renders it more tenacious; skins to be used for making leather do not undergo decomposition if steeped in a dilute solution; butter containing a small quantity of it may be kept sweet for months even in the hottest weather . It also prevents the mouldiness of preserved fruits and has been found useful in the manufacture of vinegar . The use of salicylic acid as a food preservative, was, however, condemned in the findings of the commission appointed by the government of the United States of America, in 1904 . Medicine.—The pharmacopeial dose of the acid is 5-2o grains, but it is so unrelated to experience and practice that it may be ignored . The British Pharmacopeia contains only one preparation, an ointment containing one part of acid to 49 of white paraffin ointment . Salicylic acid is now never given internally, being replaced by its sodium salt, which is much cheaper, more soluble and less irritating to mucous membranes .

The salt has a sweet, mawkish

taste . Salicylic acid and salicin (q.v.) share the properties common to the group of aromatic acids, which, as a group, are antiseptic without being toxic to man—a property practically unique; are unstable in the body; are antipyretic and analgesic. and diminish the excretion of urea by the kidneys . As an antiseptic salicylic acid is somewhat less powerful than carbolic acid, but its insolubility renders it unsuitable for general use . It is much more powerful than carbolic acid in its inhibitory action upon unorganized ferments such as pepsin or ptyalin . Salicyclic acid is not absorbed by the skin, but it rapidly kills the cells of the epidermis, without affecting the immediately subjacent cells of the dermis (" true skin ") . It has a very useful local anhidrotic action . Salicylic acid is a powerful irritant when inhaled or swallowed in a concentrated form, and even when much diluted it causes pain, nausea and vomiting . When salicin is taken internally no irritant action occurs, nor is there any antisepsis . Whatever drug of this group be taken, the product absorbed by the blood is almost entirely sodium salicylate . When the salt is taken by the mouth, absorption is extremely rapid, the salt being present in the peripheral blood within ten minutes . Sodium salicylate circulates in the blood unchanged, decomposition occurring in the kidney, and probably in tissues suffering from the Diplococcus rheumaticus of Poynton and Paine . It used to be stated that these drugs are marked cardiac depressants; and the heart being invariably implicated in rheumatic fever, it is supposed that these drugs must be given with great caution .

It has now been established that, provided the kidneys be healthy, natural salicylic acid, sodium salicylate prepared from the natural acid, and salicin, are not cardiac depressants . Of the two latter, 300 grains may begiven in a dose and 1y oz. in twenty-four hours, without any toxic symptoms . The artificial acid and its salt contain ortho-, para- and meta-cresotic acids, which are cardiac depressants . The

vegetable product—which is extremely expensive—must be prescribed or the synthetic product guaranteed " physiologically pure," i.e. tested upon animals and found to have no toxic properties . Salicylates are the next safest to quinine of all antipyretics, whilst being much more powerful in all febrile states except malaria . Sodium salicylate escapes from the blood mainly by the kidneys, in the secretion of which sodium salicylate and salicyluric acid can be detected within fifteen minutes of its administration . After large doses haematuria has been observed in a few cases . The rapid excretion by the kidneys is one of the cardinal conditions of safety, and also necessitates the very frequent administration of the drug . Therapeutics.—Salicylic acid is used externally for the removal of corns and similar epidermic thickenings . It causes some pain, so that a sedative should be added . A common formula has II parts of the acid, 3 of extract of Indian hemp, and 86 of collodion . There is probably no better remedy for corns .

Perspiration of the feet cannot be attacked locally with more success than by a powder consisting of salicylic acid, starch and chalk . These drugs are specific for acute rheumatism (rheumatic fever) . The drug is not a true specific, as quinine is for malaria, since it rarely, if ever, prevents the cardiac damage usually done by rheumatic fever; but it entirely removes the agonizing pain, shortly after its administration, and, an hour or two later, brings down the temperature to normal . In thirty-six hours no symptoms are left . If the drug be now discontinued, they will return in over 9o% of cases . In acute gonorrhoeal arthritis, simulating rheumatic fever, salicylates are useless . They may thus afford a means of diagnosis . In rheumatic hyperpyrexia, where the poison has attacked the central nervous system, salicylates almost always fail . The mode of their administration in rheumatic fever is of the utmost importance . At first 20 grains of sodium salicylate should be given every hour: the interval being doubled as soon as the pain disappears, and extended to three hours when the temperature becomes normal . The patient should continue to take about loo grains a day for at least a fortnight after he is apparently convalescent, otherwise a recrudescence is very probable . Sahcylate of soda may occasionally be of use in cases of'gallstone, owing to its action on the bile .

It often relieves

neuralgia, especially when combined with caffeine and quinine . Salicylism, or salicylic poisoning, occurs in a good many cases of the use of these drugs . Provided the kidneys be healthy, the symptoms may be ignored . If nephritis be present, it may be seriously aggravated, and the drug must therefore be withheld . The headache, deafness, ringing in the ears and even delirium of salicylism, are practically identical with the symptoms of cinchonism . The drug must be at once withheld if haemorrhages (subcutaneous, retinal, &c.) are observed . As in the case of quinine, the administration of small doses of hydrobromic acid often relieve the milder symptoms .