538 THE JOURNAL OF INDUSTRIAL AND ENGINEERING ’CHEMISTRY Vol. 13, No. 6

co~cLusIo~s uents of the oils from the fresh herb over a period of 1-The yield of oil from the fresh herb during its years appear to be in closer conformity than the al- flowering stage varies greatly from year to year, coholic constituents. owing entirely to varying climatic conditions. Low 3-The highest yield of oil is obtained during the precipitation, coupled with high temperature and much flowering period of the plants. of the oil in sunshine, affects the yield of oil favorably, while apparently is a criterion of the percentage of converse conditions cause a lower yield. esters present. Likewise, specific gravity bears a close 2-Drying of the plants before distillation invariably relationship to the ester content of the oils. The causes a reduction in the yield of oil, but apparently alcoholic constituents decrease as the plant approaches promotes esterification in the oils. The ester constit- maturity.

Studies in Synthetic Drug Analysis. VIII-Estimation of Salicylates and Phenol‘ By W. 0. Emery SYNTHETICPRODUCTS LABORATORY,BUREAU OR CHEMISTRY,WASHINGTON, D. C. The estimation of salicylates in general, and of salol, ~C.SHSOH+ 612 + 4NazC03 = phenol, , , etc., in particular, are 2CsH2120 + 8NaI + 4co2 + 4Hz0 2CeHd(OH)C02H + 612 + 4NanC03 = constantly recurring problems, the satisfactory solu- 2CeH2120 + 8NaI + 6CO2 + 4Hz0 tion of which depends in large measure upon the nature from which it appears that every molecule of salol is of the preparations in which such medicaments occur, capable of yielding two molecules of the iodine deriv- whether alone or in simple admixture with inert ma- ative, expressed in its simplest form. Irrespective of terials susceptible of easy separation, or again in more the chemical constitution-whether an oxide or quinone complicated mixtures containing, besides vehicular in character-the physical properties are such as to matter, combinations of several therapeutic agents. warrant its analytical application not only in cases In a former paper,2 one of the two procedures outlined involving salol, but also as a check on the various involved the alkaline hydrolysis of salol preliminary methods hitherto employed to determine salicylic acid to its separation from by the aid of im- and phenol. miscible solvents, the subsequent steps constituting in EXPERIMENTAL principle, in so far as they related to salol, the well- The tabulated data are representative of several known Koppeschaar method. While a similar or hundred determinations carried out on both control slightly modified procedure can undoubtedly be ap- and commercial mixtures. The individual products plied also to mixtures in which the phenacetin is re- required for these controls were checked as to purity, placed in whole or part by acetanilide, it not in- being selected from both domestic and foreign brands. frequently happens that knowledge of the salol con- In general, the treatment consisted, in the case of pills tent appears desirable without the necessity of first and compressed tablets, in triturating with or without eliminating the accompanying medicaments, particu- sand, exhausting the finely powdered sample with chlo- larly in preparations which involve not only acet- roform, then, after dissipation of the solvent, hydro- anilide but phenacetin and caffeine as well. With this lyzing the residue (in the case of salol) with aqueous object in view, and in the belief also that most cases of sodium hydroxide, heating with iodine in the presence drug analysis are facilitated in proportion to the num- of sodium carbonate, and finally filtering, drying, and ber and accuracy of alternative methods available for weighing the precipitate. the solution of any given problem, advantage has been RESULTSOBTAINED ON CONTROLS taken of the characteristic behavior of salol, or rather Salol Acetanilide Phenacetin Caffeine CRHZIZO Salol No. Gram Gram Gram Gram Gram Per cent its constituent elements, phenol and salicylic acid, 1 0.10 “R” .. .. 0.3209 99.9 2 0.10“M” ...... 0.3201 99.6 toward iodine. The final product of such action in 3 0.10 “C” .. .. 0.3211 100.0 the presence of alkali or alkaline carbonates is a pur- 4 0.10 “C” o:io .. .. 0,3203 99.7 5 0.10 “C” 0.20 .. .. 0.3204 99.7 plish red amorphous compound3 having the composition 6 0.10 “C” 0.50 .. 0.3220 100.2 7 0.1O“C” 0.10 o:io .. 0.3220 100.2 CsH2120,and variously termed diiodophenylene oxide, 8 0.10 “C” 0.10 0.30 .. 0.3217 100.1 9 0.10 “C” 0.20 0.20 0.3207 99.8 tetraiodophenylene oxide, and tetraiodophenylene qui- 10 0.10 “C” 0.25 0.20 0:05 0.3214 100.1 11 0.10 “C” 0.25 0.20 0.10 0.3215 100.1 none, the derivation of which may be represented in the 12 0.10 “C” .. 0.10 .. 0.3216 100.1 13 0.10 ‘“2” .. 0.30 .. 0.3219 100.2 following manner: 14 0.10 “C” .. 0.50 .. 0.3225 100.3 Phenol cryst. 1 Received February 11, 1921. 15 0.10 “K” ...... 0.3627 99.1 Emery, Spencer and LeFebvre, “Estimation of Phenacetin and Salol 16 0.10 “M” ...... 0.3648 99.8 in Admixture,” THISJOURNAL, 7 (1915), 681. Salicylic acid 17 0.10 “K” .. *. 0.2471 99.2 8 The formation of this substance, first reported by Lautemann, Ann., 18 0.10 “Mt” .. .. 0,2474 99.3 120 (l86l), 309, and later corroborated by Kekul6, Ibid., IS1 (1864). 221, 19 0.10 “Mk” .. .. 0.2464 98.9 was observed in studying the iodine substitution products of salicylic, acid. Acetylsalicylic acid 20 0.10 “D” ...... 0.1897 99.3 The same compound was more fully described by Kammerer and Benzinger, 21 0.10 “B” ...... 0.1894 99.2 Bcr., 11 (1878), 557, who operated with iodized potassium iodide on phenol 22 0.10“H” ...... 0.1899 99.4 hot aqueous soda. Bougault, J. pharm. chim., 16128,147, was apparently 23 0.10 “E’.’ ...... 0.1905 99.9 in the Erst to suggest its use in a gravimetric way, employing it successfully in 24 0.10 “Mk” ...... 0.2115 98.4 estimating salicylic acid admixed with either benzoic or cinnamic acid. 25 0.10 “K” ...... 0.2136 99.4 June, 1921 THE JOURNAL OF INDUSTRIAL AND ENGINEERING BEEMISTRY 539

R&SULTSOBTAINED ON COMMERCIAL SAaaPLsS the expulsion of carbonic acid gas liberated in the final Amount of Salol and Salicylic phase of the reaction. In the case of salol and phen- Acid, Respectively, per Tablet acetin, or of salol, acetanilide, and phenacetin mixtures, Declared Found No. Tablets Grains Grains the quantity of iodine solution added should be in- 26 Salol 2.5 2.46 creased over that above specified by 5 cc. for every 27 Salol 5.0 4.82 28 Salol 2.5 2.49 100 mg. phenacetin known or believed to be present 29 Salol 2.5 2.49 in the sample taken for analysis. Allow the precipitate Acetanilide 2.5 .. 30 Salol 2.5 2.47 to settle, then decant the supernatant liquid on to a Acetanilide 2.5 .. Gooch crucible, add hot water to the flask, mix 31 Salol 2.5 2.51 Phenacetin 2.5 .. thoroughly, and gradually transfer the entire pre- 32 Salol 2.5 2.02 Phenacetin 2.5 .. cipitate quantitatively to the filter, washing with not 33 Salol 0.5 0.51 less than 200 cc. of hot water. Dry in an air bath Acetanilide 1.25 .. Phenacetin 1.0 .. at 100' to constant weight; finally, multiply the weight Caff. citr. 0.5 .. Acid tartar. 0.25 .. of the precipitate obtained by 0.3113. This product Sodium bicarb. 1.5 .. gives the quantity of salol in the aliquot taken. 34 Salicylic acid 5.0 4.94 35 Sodium salicylate 3.0 2.98 36 Sodium salicylate 5.0 4.96 COMMENTS AND SUGGESTIONS 37 Sodium salicylate 5.0 5.01 38 Strontium salicylate 5.0 4.99 With salol and acetanilide mixtures, the filtrate from 39 Ammonium salicylate 2.5 2.49 Acetanilide 2.5 .. the diiodophenylene oxide should be nearly or quite Caffeine 0.5 .. 40 Ammonium salicylate 3.0 2.97 colorless, while with phenacetin present light to deep Caffeine 0.5 .. 1.5 .. amber-colored solutions will result, thus rendering it Phenacetin 1.0 *. not altogether easy to recognize the point which in- 41 Acetyl salicylic acid 5.0 4.95 42-~ Acetvl salicvlic acid 5.0 4.97 dicates that an excess of iodine has been added. The 43 Acerid salicylic acid 5.0 3.92 44 Acetyl salicylic acid 5.0 4.80 second gram of sodium carbonate is added partly to 45 Acetyl salicylic acid 5.0 4.90 effect the final elimination of such excess iodine, partly METHOD also to facilitate the complete conversion of all iodine substitution products of phenol and salicylic acid into On a small (5.5 cm.) tared filter, carefully fitted the completely insoluble diiodophenylene oxide. In while moist and subsequently dried in a suitable funnel, the absence of phenol, this method may be carried weigh out an amount of the uniformly triturated ma- out in an Erlenmeyer flask without a reflux condenser. terial equivalent to or containing about 100 mg. of salol, as calculated from the alleged content. Wash with successive small portions of chloroform, in quan- The Belgian Bureau of Chemical Standards tity from 25 to 30 cc.-sufficient at least to insure At the last meeting of the International Union of Pure and complete extraction of all therapeutic agents present Applied Chemistry, held in Rome in July 1920, the Belgian and soluble in this medium-receiving the solution in delegates reported on a plan to establish a collection of samples of a 3OD-cc. Erlenmeyer, and evaporating the solvent at pure chemicals at the University of Brussels. The Union there- the ordinary temperature by means of an air bbst to upon decided to establish such a Bureau, leaving the details of its apparent dryness. Add 10 cc. of a 1 per cesc solution development to Belgium. of sodium hydroxide, connect with a vertical reflux Inasmuch as a collection of pure organic liquids had already over a wire gauze, and apply gentle heat so that the been begun by Dr. J. Timmermans, this has been used as a contents of flask begin to boil in about 2 min. Now nucleus, and it is planned to devote attention to this group of substances for the present, though eventually the collection add more water in 30- and 50-cc. portions, SO ad- lo-, is to contain all types of chemical compounds. justing the heat that the liquid reaches the boiling It is hoped to make this Bureau an international center of temperature at the end of about 3-, 5- and 10-min. exchange, through which European chemists may obtain Amer- intervals, respectively. Just prior to the addition of ican standard chemicals, and vice versa. It is still further planned the 50-cc. portion, introduce into the top of condenser to make it a center of information for everything dealing with 1 g. of dry sodium carbonate, washing it down with pure products, including publications on the subject, etc. the water. To the absolutely clear boiling solution add, The Bureau is asking for financial support at home, in order to in the case of salol and acetanilide mixtures, 55 to establish research scholarships, and for the cooperation of manu- 60 cc. of approximately 0.2 N iodine (iodized potassium facturers in undertaking the production of the pure materials, iodide), sufficient at least to insure an excess of this after the Bureau has worked out the details of manufacture, and of laboratory heads, in furnishing pure samples which they reagent, then heat to boiling, disconnecting the flask have had occasion to prepare. at this juncture, and washing off the lower end of con- denser into the flask below. Add another gram of dry sodium carbonate, and boil very gently for a period Centennial of Philadelphia College of Pharmacy of 15 to 20 min., being careful to gage the heat so that During the week of June 12 to 15, 1921, the Philadelphia the liquid, and with it the precipitate, does not froth College of Pharmacy and Science will celebrate its centennial. over the rim of container and thus jeopardize the de- In addition to the usual Commencement festivities the program termination. Any undue tendency in this direction includes a centennial banquet and reception to Rear Admiral may be largely obviated by the addition of a few drops William C. Braisted, Surgeon General (retired) U. S. Navy, of water from time to time, or, better, by the timely and president of the College. This will occur on Tuesday, the 14th, vigorous rotation of the flask, thus greatly facilitating at the Bellevue-Stratford.