THE STABILITY OF IODINE OINTMENTS

Paraffin175(M. P. by U. S. P. method 47.2 C.)97.5gm.Asphaltfrom 3to 5 dropsOlive oil1.5c.c.

Paraffin175(M. P. by U. S. P. method 47.2 C.)

Asphalt

Olive oil

Photographic reproduction from a booklet on “Thermozine” showing that it is identical with “Ambrine.”

About 10 c.c. of “asphalt varnish” (B. Asphaltum)176is placed in a beaker and heated on the steam bath for one-half hour. From 3 to 5 drops, delivered from a 1 c.c. pipet, are then placed in a casserole, and 1.5 c.c. of olive oil added. The mixture is heated and stirred for a few minutes until perfect solution is effected. To this is then added, with stirring, the paraffin, which has been previously melted. When it is cooled, a brown solid is obtained.177The physical factors of this paraffin mixture are, melting point 45.4 C. (U. S. P. method); plasticity, 28.5; ductility, 29; it is very pliable and strong at 38 C., and adheres exceedingly well to the skin, although it detaches easily. This mixture, which is easy to prepare, is inexpensive, the cost of the materials being approximately 10 cents a pound.

Both Hull and Sollmann noticed that tarlike substances and melted paraffin do not mix well. This is noticeable in “Ambrine,” which cannot be called an “elegant” preparation. The difficulty may be overcome by first mixing hot olive oil and asphalt; the asphalt will then go into solution. It is interesting to note that the suggested formula (as well as others which were also prepared)is not as plastic as the paraffin itself.178This is also true of “Ambrine.” On the other hand, the melting point of the paraffin is higher.The important point, however, in compounding all paraffin preparations, is to select a proper grade of paraffin as elaborated below.

Photographic reproduction (greatly reduced) of a full page magazine advertisement of “Thermozine,” the name under which “Ambrine” was sold to the public.

The name “paraffin” generally applies to a colorless and tasteless waxlike substance that is solid at ordinary temperature. It is composed of saturated hydrocarbons, that is, they are unable to take up any more hydrogen, andthereby are quite stable; the hydrocarbons in paraffin have the general formula of CnH2n+2, ranging as high as C24H50to C27H56. Paraffin may be found in crude form in coal, from which source the first paraffin candles were made. It may be produced from the distillation of brown coal, as in Germany, or from bituminous shale. In America, it is obtained chiefly from the distillation of crude petroleum, being in the residue after the distillation of such products as naphtha (gasoline), kerosene and the lubricating oils. The residue is treated by one of a number of processes causing the unpurified solid paraffin to be made available. The crude paraffin is either sold as such, or is refined. Paraffin or “paraffin waxes”179are designated in the trade by their melting points (which in the “American standard” is expressed in Fahrenheit degrees), and as to their state of refinement as “crude,” “semirefined” and “fully refined” paraffin. There are certain chemical and physical differences so that two refined waxes having the same melting point would not have the same plasticity. The higher melting point varieties of paraffin are hard and tough at room temperature: when melted, paraffin expands and forms a thin mobile liquid.

Photographic reproduction from a booklet on “Thermozine” giving the conditions in which the stuff was alleged to be “very useful.”

The significant requirements of paraffin for surgical dressings are that it should be solid at body temperature, at the same time having flexibility and adhesiveness, together with a certain amount of strength. A number of brands of paraffin are sold in the United States, so that it seemed advisable to examine some of them and compare them with certain paraffin-film preparations. They were tested as to their melting points, plasticity, ductility, strength of film, etc.

Melting Point Determination.—The melting point was determined by the method of the U. S. Pharmacopeia IX, p. 596. The melting point as obtained by this method is lower than the melting point used by manufacturers of paraffin (after conversion to Fahrenheit).

Pliability and Ductility, Limit Temperature.180—A little of the melted wax was poured from a teaspoon on the surface of the water at about 40 C., in a tin pan (bread mold). This formed a fairly thin film. The temperature ofthe water was then lowered by the addition of cold water. At each temperature the pliability and ductility were tested thus:

Pliability Test.—The film, immersed in water, was doubled on itself, note being taken whether or not it broke.

Ductility Test.—The film was pulled under water, note being taken whether it stretched on being pulled and broke with a ragged fracture; or whether it broke sharp without stretching. It is desirable that the pliability and ductility be preserved at as low a temperature as possible.

Cotton Films, Adhesives and Detachability.180—The melted wax was applied as it would be for burns; namely, a thin layer was painted on the inner surface of the forearm with a camel’s hair brush,181a transverse strip about an inch wide being made. This was covered with a very thin layer of absorbent cotton, and over this another layer of melted wax was painted. As soon as this had cooled a little, it was covered by a few layers of bandage and left on for at least an hour. At the end of that time, the bandage was removed. The cotton film should be found at the place at which it was applied, showing that it is sufficiently adherent. It should detach without “pulling” the skin.

Photographic reproduction (greatly reduced) of the carton in which “Ambrine” is now sold.

The results of these tests are given in the accompanying table. It can be seen that nearly all the paraffins examined have properties which would make them useful, the notable exceptions being Nos. 8, 15 and 16. The more satisfactory products would be those having a melting point about 47 C., ductility of 30 or below, and plasticity of 28 or below. The paraffin described in the U. S. Pharmacopeia is not so satisfactory, the required melting point being between 50 and 57 C.

The use of paraffin bandages has been suggested byFisher182and Sollmann.183In such cases, it may very likely be that a paraffin of higher melting point would be more satisfactory, owing to its greater resistance and tougher fiber.

1. “Ambrine” is essentially paraffin in which a small amount of fatty and asphalt-like body is incorporated; like most secret mixtures, its composition varies.

2. A simple formula for a paraffin film, similar in chemical composition but superior in physical properties to “Ambrine,” is that described as Formula 21. The superiority is due to using a grade of paraffin that is better adapted to the purpose. The cost of materials is about 10 cents a pound.

3. The properties of the paraffin used for a surgical dressing are important. A number of different grades have been examined, in order to determine the ones that appear most promising. Paraffins Nos. 3, 4, 10, 11 and 25 are the best in the table, and surpass “Ambrine” itself.

4. It is exceedingly probable that further experience will show that for most purposes simple paraffin will serve just as well as the mixtures—if, indeed, not better.

(Reprinted from the Annual Report of the Chemical Laboratory of The American Medical Association, Vol. 10 (1917), p. 32)

Since the foregoing was published, two other products—“Cerelene” and “Stanolind Surgical Wax”—were submitted to the Council on Pharmacy and Chemistry for investigation as to their acceptability for inclusion in New and Nonofficial Remedies. In this connection the Laboratory was requested to examine them.

“Cerelene” is manufactured by the Holliday Laboratories, Pittsburgh. According to the manufacturers, “Cerelene” is a compound composed of 84 per cent. paraffin, 15 per cent. myricyl palmitate and 1 per cent. elemi gum. As ordinarily marketed, “Cerelene” contains the following materials: To the beeswax is added Oil of Eucalyptus, U. S. P., 2 per cent., and Betanaphthol, U. S. P., 0.25 per cent. The manufacturer further states that the myricyl palmitate is a purified form of beeswax, free from all impurities, acids, etc., which is solely manufactured by this company and for which patents are pending. The properties described for “Cerelene” were as follows:

When cold, Cerelene is a solid wax-like cake of a fine yellow brown color. On exposure to air for long periods, the amber color darkens to some extent. It is entirely free from solids, odorless and tasteless; does not separate or change when melted repeatedly, and cannot in the melted state be separated by fractional crystallization. It is entirely neutral to indicators being perfectly free from both acids and bases.Tests:Melting Point, U. S. P. method, 126 F.Density, U. S. P. method, 0.907.Iodin value, 0.5.Saponification number, 0.9.

“Stanolind Surgical Wax” is manufactured by the Standard Oil Company of Indiana. In the submission of the product to the Council on Pharmacy and Chemistry, it was stated that the product was a specially prepared paraffin “free from dirt or other deleterious matter.... It has been steamed and resteamed to drive out any free oil and repeatedly filtered.”

The examination of the foregoing products yielded the figures described in Table “B.”—(From The Journal A. M. A., May 19, 1917.)

L. E. Warren, Ph.C., B.S.

In general, the literature on the keeping qualities of iodine ointment, and on the stability of iodine if mixed with ointment bases, is confusing. The recorded evidence is often contradictory. The attention of the writer was brought to thiscondition by studies of several proprietary preparations, Iodex,184Iod-Izd-Oil,185Iocamfen, and Iocamfen Ointment.186

Iodex was sold under the claim that it is

“... an embodiment of vaporized iodine, in an organic base, reduced and standardized at 5 per cent. by incorporation with a refined petroleum product.”

The exact composition of Iodex is a trade secret. Analysis showed that it contains petrolatum-like substances and combined iodine, the latter probably in combination with oleic acid. Tests for free iodine were made in five specimens of Iodex. In one of these no free iodine was present; in the others the merest traces were found.

Two years ago a preparation called “Iod-Izd-Oil” was examined. This was claimed to contain 2 per cent. of free iodine in liquid petrolatum. At the time of the examination the age of the preparation was not known, but it had been obtained just prior to the analysis, and was thought not to be very old. The analysis showed that it contained but about 0.43 per cent. of iodine, all of which was in a free state. The fact that all of the iodine present was in the free state appeared to indicate that iodine is relatively stable in liquid petrolatum solutions.

Iocamfen is a liquid composed of iodine, camphor and phenol. It was claimed to contain 10 per cent. of free iodine. Analysis showed that it contained 9.3 per cent. of total iodine (of which 7.5 per cent. was present in an uncombined state), 66.1 per cent. of camphor and 19.7 per cent. of phenol. After storing for several months a second assay of Iocamfen showed no appreciable loss in iodine content. This would indicate that iodine is relatively stable in presence of phenol and camphor, although immediately after mixing there is some loss of free iodine. The Iocamfen Ointment was supposed to contain 50 per cent. of Iocamfen (equivalent to 5 per cent. of free iodine) in a lard-wax-cacaobutter base. The analysis showed that the ointment contained but 0.4 per cent. of free iodine, the balance being in combination. From the results of the examination, and from correspondence with the manufacturers (Schering and Glatz), it became evident that the only plausible explanation for the loss of free iodine in the preparation of Iocamfen Ointment from Iocamfen lay in the combination of the free iodine with the ingredients of the ointment base. It seems likely that the free iodine originally present in Iocamfen for the most part had gradually gone into combination with the fatty substances after the ointment had been prepared.

The literature was then examined to determine the consensus of opinion concerning the stability of iodine in iodine ointment. In the older literature the belief that iodine ointment is unstable appears to be quite general. Such statements as the following are typical:

The ointment should be prepared only when wanted for use, for it undergoes change if kept, losing its deep, orange-brown color, and becoming pale upon its surface.187It is better to prepare it only as it is required for use.188This ointment must not be dispensed unless it has recently been prepared.189

The ointment should be prepared only when wanted for use, for it undergoes change if kept, losing its deep, orange-brown color, and becoming pale upon its surface.187

It is better to prepare it only as it is required for use.188

This ointment must not be dispensed unless it has recently been prepared.189

In 1909 Lythgoe,190of the Massachusetts Board of Health laboratory, reported an examination of four samples of iodine ointment. Three were found to be pure, the fourth was low in iodine. Experiments showed that iodine ointment deteriorates rapidly; consequently, no further collections of samples were made.

In 1912 Pullen191reported that he had prepared two specimens of iodine ointment according to the British Pharmacopeia, one being from new lard and the other from a specimen of lard at least 2 years old. Assays for free iodine were carried out immediately after the preparations were made, and at intervals afterward up to four months. The following values were found:

Sample ISample IIOintment from newlard, per cent.Ointment from oldlard, per cent.Iodine introduced4.04.0Iodine found immediately after making3.953.38Iodine found after twenty-four hours3.303.15Iodine found on the third day3.182.62Iodine found on the seventh day3.152.46Iodine found on the fourteenth day3.002.45Iodine found after one month3.002.39Iodine found after two months2.902.31Iodine found after four months2.922.26

Iodine introduced

Iodine found immediately after making

Iodine found after twenty-four hours

Iodine found on the third day

Iodine found on the seventh day

Iodine found on the fourteenth day

Iodine found after one month

Iodine found after two months

Iodine found after four months

Pullen found that the loss in free iodine could be accounted for by the iodine which had gone into combination with the fats of the ointment base.

Pullen also found that if the potassium iodide and glycerin were omitted in the preparation of the ointment, the loss in free iodine was very rapid, the preparation containing practically no free iodine (only1⁄20) after a few hours. He concludes that the use of potassium iodide and glycerin is necessary for the preservation of the ointment. He obtained specimens of iodine ointment in drug stores, and assayed them for free iodine. It is to be presumed that the ages of the several specimens were not known. The results are found in the following table:

Specimen No. 12.74 per cent.Specimen No. 22.85 per cent.Specimen No. 32.62 per cent.Specimen No. 42.48 per cent.Specimen No. 52.53 per cent.Specimen No. 62.79 per cent.

Specimen No. 1

Specimen No. 2

Specimen No. 3

Specimen No. 4

Specimen No. 5

Specimen No. 6

Fried192prepared iodine ointment according to the U. S. P. VIII formula, and assayed it at intervals. His results are tabulated herewith:

Per cent.Iodine introduced4.00Iodine found immediately after making3.89Iodine found one hour after making3.51Iodine found one day after making3.48Iodine found five days after making3.06Iodine found ten days after making2.84Iodine found thirty days after making2.81Iodine found ninety days after making2.81Iodine found eight months after making2.81

Iodine introduced

Iodine found immediately after making

Iodine found one hour after making

Iodine found one day after making

Iodine found five days after making

Iodine found ten days after making

Iodine found thirty days after making

Iodine found ninety days after making

Iodine found eight months after making

Iodine ointment has been official in the U. S. Pharmacopeia since 1870. Briefly, the method now used for making the preparation is as follows:

Four gm. of iodine, 4 gm. of potassium iodide and 12 gm. of glycerin are weighed into a tared mortar and the mixture triturated until the iodine and potassium iodide are dissolved and a dark, reddish-brown, syrupy liquid is produced. Eighty gm. of benzoinated lard are then added in small portions and with trituration after each addition. The mass is then triturated until of uniform consistence.193

PARAFFINS AND PARAFFIN PREPARATIONS—TABLE A

FormulaSubstanceMeltingPoint,U. S. P.DuctilityLimitPlasticityLimit(a) Adhesivenessand Detachability(b) Strength of Film at 38 C.1“Parowax,” Stand. Oil Co. of Ind.50.832.529.0(a) Adheres and detaches well; rather hard(b) Pliable and strong3“Paraffin 118–120 F.,” Stand. Oil Co. of Ind.46.828.524.5(a) Does not adhere well; detaches easily(b) Pliable but not strong4“Paraffin 120–122 F.,” Stand. Oil Co. of Ind.47.229.024.5(a) Adheres well; detaches well(b) Pliable and fairly strong5“Paraffin 123–125 F.,” Stand. Oil Co. of Ind.48.831.528.5Same as 46“Paraffin 128–130 F.,” Stand. Oil Co. of Ind.52.033.030.0(a) Adheres well; detaches not so easily(b) Pliable and strong7“Texwax,” Texas Co., Port Arthur, Texas51.232.529.8Same as 68“Paraffin Wax 122–124 F.,” Warren Refining Co., Warren, Pa.50.636.034–35(a) Unsatisfactory; does not adhere(b) Only slightly pliable; too tough9“Paraffin No. 910,” Waverly Oil Works, Pittsburgh47.030.526–27(a) Adheres well; detaches well(b) Pliable and strong10“Paraffin No. 920,” Waverly Oil Works, Pittsburgh44.427.525.0(a) Adheres well; detaches well(b) Pliable and fairly strong11“Hard Paraffin,” Rob’t Stevenson & Co., Chicago48.028.524.5–⁠25.5(a) Adheres well; detaches well(b) Pliable and strong12“Paraffin,” Island Petroleum Co., Chicago47.233.032.5Not quite as good as 1113“Paraffin 122 F.,” Gulf Refining Co., Pittsburgh46.830.527.5–28(a) Does not adhere so well; detaches well(b) Very pliable14“Paraffin 125 F.,” Gulf Refining Co., Pittsburgh50.032.031.0About as 1315“Paraffin 132 F.,” Gulf Refining Co., Pittsburgh54.835.534.0(a) Does not adhere well(b) Not very pliable, but strong16“Paraffin No. 301,” National Refining Co., Cleveland50.233.032–32.5(a) Does not adhere well(b) Not very pliable18Paraffin recovered from “Ambrine”48.630.528–28.5(a) Adheres well; detaches well(b) Pliable but not strong19“Hyperthermine”49.433.530.5–31(a) Does not adhere well; detaches well(b) Very pliable and strong20“Ambrine”48.430.527.0(a) Adheres well; detaches well(b) Very pliable and strong21Paraffin 120–122 F. (see 3), 97.5; olive oil, 1.5; asphalt, 4 drops45.429.028.5(a) Adheres excellently; detaches well(b) Very pliable and strong22“Parowax” (see 1), 97.5; olive oil, 1.5; asphalt, 4 drops49.232.030.5(a) Adheres well; detaches well(b) Pliable and strong23“Mulene”51.036.028.0(a) Adheres but detaches with difficulty(b) Pliable but not strong24“Parresine,” Abbott Laboratories, Chicago46.029.526.0(a) Adheres well; detaches easily(b) Pliable and fairly strong25“Paraffin 118–121 F.,” The Atlantic Refining Co., Philadelphia45.826.423.2(a) Adheres well; detaches easily(b) Pliable and fairly strongTABLE B26“Cerelene,” Holliday Lab.,* Pittsburgh50.030.526.5(a) Adheres well; detaches with pulling(b) Not strong at 38 C.27“Stanolind” Surgical Wax,† Standard Oil Co. of Ind.47.028.825.0(a) Adheres well; detaches easily(b) Fairly strong at 38 C.

“Parowax,” Stand. Oil Co. of Ind.

“Paraffin 118–120 F.,” Stand. Oil Co. of Ind.

“Paraffin 120–122 F.,” Stand. Oil Co. of Ind.

“Paraffin 123–125 F.,” Stand. Oil Co. of Ind.

“Paraffin 128–130 F.,” Stand. Oil Co. of Ind.

“Texwax,” Texas Co., Port Arthur, Texas

“Paraffin Wax 122–124 F.,” Warren Refining Co., Warren, Pa.

“Paraffin No. 910,” Waverly Oil Works, Pittsburgh

“Paraffin No. 920,” Waverly Oil Works, Pittsburgh

“Hard Paraffin,” Rob’t Stevenson & Co., Chicago

“Paraffin,” Island Petroleum Co., Chicago

“Paraffin 122 F.,” Gulf Refining Co., Pittsburgh

“Paraffin 125 F.,” Gulf Refining Co., Pittsburgh

“Paraffin 132 F.,” Gulf Refining Co., Pittsburgh

“Paraffin No. 301,” National Refining Co., Cleveland

Paraffin recovered from “Ambrine”

“Hyperthermine”

“Ambrine”

Paraffin 120–122 F. (see 3), 97.5; olive oil, 1.5; asphalt, 4 drops

“Parowax” (see 1), 97.5; olive oil, 1.5; asphalt, 4 drops

“Mulene”

“Parresine,” Abbott Laboratories, Chicago

“Paraffin 118–121 F.,” The Atlantic Refining Co., Philadelphia

“Cerelene,” Holliday Lab.,* Pittsburgh

“Stanolind” Surgical Wax,† Standard Oil Co. of Ind.

* On being heated, it readily loses eucalyptol, and a small amount of resinous substance forms in the bottom of the beaker. If “Cerelene” is heated to 145 C. and cooled, the resulting product no longer has the properties of the original “Cerelene.”

† Accepted by the Council on Pharmacy and Chemistry for inclusion in New and Nonofficial Remedies.

Iodine ointment is officialized also in several foreign pharmacopeias, although the iodine strength of the several preparations is not uniform. The formula in the British Pharmacopeia is exactly like that in the U. S. Pharmacopeia except that pure lard is directed to be used instead of benzoinated lard. Some of the foreign pharmacopeias also specify that the preparation must be freshly prepared when wanted. In the earlier editions the U. S. Pharmacopeia directed the ointment to be prepared by using water as the solvent for the potassium iodide. In the U. S. Pharmacopeia VIII the formula was changed so as to employ glycerin, and that solvent is now official. Water is still prescribed as the potassium iodide solvent by the Pharmacopeias of the Netherlands and of France.

From the examination of the literature it seems probable that iodine ointments which contain petrolatum products only as the ointment bases are apt to be relatively stable, so far as the content of free iodine is concerned. On the other hand, ointments the bases of which contain fats of the unsaturated fatty acid series, such as oleic acid, do not satisfactorily preserve the iodine in the free state. In the latter class it seems likely that the iodine enters into combination with the unsaturated fatty acids. Accordingly, on theoretical grounds, an ointment base composed of pure stearin (if such substance were available) but softened by an admixture of liquid petrolatum would preserve the iodine satisfactorily. Cocoanut oil (iodine No. 8) ought to be suitable also if mixed with hard paraffin.

Since the literature was not sufficiently concordant to warrant positive conclusions concerning the stability of ointments containing free iodine, it seemed worth while to conduct experiments with preparations of known origin. Accordingly, a number of preparations containing free iodine were made under varying conditions and each was assayed for its free iodine content immediately after its manufacture and from time to time later.

Leaf lard of the best quality obtainable was purchased from a butcher. This was rendered in an open dish on the steam bath. The preparation was of a fine color, and uniform consistence and had a faint but not unpleasant odor. Two specimens of lard were furnished by the research department of Armour and Company. An effort was made to procure specimens of lard having iodine absorption numbers as far apart as possible,i. e., one with a low and the other with a high iodine value. This was done in order to determine whether the keeping qualities of the ointments prepared from the two would be alike.

One of the specimens (a) was described as

“Natural lard; iodine value, 57.1. Leaf lard used exclusively for butterine and benzoinated lard.”

The other specimen was described as

“Prime steam lard. Good, commercial grade of lard for general use; iodine value, 69.0.”

The iodine absorption numbers of the three specimens were determined by the U. S. P. process to be as follows:

Laboratory rendered specimen57.1Armour specimen (a)57.65Armour specimen (b)67.55

Laboratory rendered specimen

Armour specimen (a)

Armour specimen (b)

Each specimen was benzoinated according to the process described in the U. S. P. IX and 100 gm. of iodine ointment were prepared from each according to the U. S. P. process. Another specimen was made from benzoinated lardand iodineonly194without the addition of either glycerin or potassium iodide. This was made to contain 4 per cent. of iodine.

Immediately after preparation each of these iodine ointments was assayed for free iodine, and each was reassayed at intervals later. The method for the determination of iodine in the ointment was that employed in this laboratory for the determination of iodine in Iocamfen Ointment.195It is essentially the same as was employed by Pullen for the determination of uncombined iodine in iodine ointment.196As carried out in this laboratory for iodine ointment it is as follows:

From 5 to 8 gm. of the ointment were weighed in a small porcelain capsule, the capsule and contents placed in a 16 oz. salt mouth bottle together with 20 c.c. of chloroform, 10 c.c. of potassium iodide solution and 40 c.c. of water. Tenth-normal sodium thiosulphate was slowly added with agitation until the pink color of the chloroform layer had nearly disappeared. A little soluble starch was then added and the titration continued until a blue color in the aqueous layer could no longer be obtained by repeated shaking.

The findings for the several assays are tabulated herewith:

Age at time of assayU. S. P.Ointment fromlaboratoryrendered lardU. S. P.Ointment fromcommercial lardGrade IU. S. P.Ointment fromcommercial lardGrade IIOintment fromlard and iodineonly (laboratoryrendered lard)(% I)(% I)(% I)(% I)Freshly made3.323.263.300.32After 3 days3.25............0.23After 7 days2.993.173.15......After 3 weeks3.013.193.07......After 7 weeks3.12*3.103.02......After 3 months2.982.882.88......

Freshly made

After 3 days

After 7 days

After 3 weeks

After 7 weeks

After 3 months

* This slight rise in iodine content followed by a fall could not be accounted for. The specimen was believed to have been very thoroughly mixed at the time of manufacture.

That the fatty constituents of the ointment contained iodine after the preparation had been made for some time was demonstrated. Some of the material was examined as follows:

A portion of the ointment which had been made for nearly three months was shaken in a separator with chloroform and a dilute mixture of potassium iodide and sodium thiosulphate solutions. After all of the free iodine had been removed the chloroformic solution of the fats was washed several times with a very dilute solution of sodium thiosulphate. The chloroformic solution was filtered, evaporated and the residue dried over sulphuric acid.197

The separated fat was then tested for iodine by Kendall’s method.198It was found to contain iodine in considerable amounts, but quantitative determinations were not made.

The Pharmacopeia of the Netherlands directs that iodine ointment shall contain 3 per cent. of potassium iodide and 2 per cent. of iodine instead of equal proportions (4 per cent. of each) as prescribed by the U. S. Pharmacopeia. Likewise the French Pharmacopeia directs that 10 per cent. of potassium iodide and only 2 per cent. of iodine shall be used. Both of these pharmacopeias use water instead of glycerin as the solvent. Loose combinations of iodine and potassium iodide, such as are represented by the compound having the formula KI3, have been described. The quantity of potassium iodide prescribed by the U. S. Pharmacopeia for the preparation of iodine ointment is not sufficient to form such a compound as KI3with all of the iodine directed to be used. Since some of the pharmacopeias use larger proportions of potassium iodide (more than sufficient to form the compound, KI3), it seemed worth while to determine whether an ointment containing a greater proportion of potassium iodide than that required by the U. S. Pharmacopeia would be more stable than the official article. Accordingly a specimen was prepared to contain 4 per cent. of iodine, 8 per cent. of potassium iodide (twice the U. S. P. requirement), 12 per cent. of glycerin and 76 per cent. of lard. This was assayed for its free iodine content immediately after preparation, and found to contain 3.68 per cent. Nine days later it contained 3.70 per cent. Another specimen of the same iodine strength prepared from grade No. 2 of commercial lard assayed 3.69 per cent. at the initial assay, and seven days later 3.40 per cent. From these experiments it seems likely that the free iodine content of the U. S. Pharmacopeia iodine ointment could be raised somewhat by increasing the proportion of potassium iodide.

The results of these studies confirm the findings of Pullen and of Fried in all essential particulars. It appears that during the process of manufacture of iodine ointment about 20 per cent. of the free iodine goes into combination with the fatty constituents of the ointment. On standing for a month approximately an additional 5 per cent. goes into combination, after which there is practically no loss in free iodine content. In other words iodine ointment which is a month old is a relatively stable preparation. It appears to make no noticeable difference upon the rate and amount of iodine absorption whether the lard from which the ointment is made has a high or a low iodine absorption value. The composition of iodine ointment, which has been made sufficiently long to have reached equilibrium, is approximately as follows:

Free iodine3per cent.Iodine combined with fat1per cent.Potassium iodide4per cent.Benzoinated lard (containing iodine)80per cent.

Free iodine

Iodine combined with fat

Potassium iodide

Benzoinated lard (containing iodine)

The U. S. Pharmacopeia requirement that iodine ointment shall be freshly prepared when wanted appears to be unnecessary. Probably most pharmaceutical manufacturers are aware of this, for many of them include the preparation in their trade lists. The presence of an iodide appears to be necessary, to prevent practically all of the iodine from entering into combination with the fat.199—(From the American Journal of Pharmacy, August, 1917.)

The Council on Pharmacy and Chemistry was asked to examine a preparation submitted with the statement that it was “iodin crystals incorporated in a petroleum product.” The name “Iodolene” was proposed by the promoters, providing the product was found eligible for New and Nonofficial Remedies.

Iodolene was stated to have been prepared by treating a liquid petrolatum, obtained from Gulf Coast petroleum, with an excess of iodin; the mixture was subsequently “placed in an oven for three hours.” The claim was made that this method of procedure produced a preparation containing more iodin than market specimens which had been examined, namely: “over 1.50 per cent. free iodine.”

Two specimens of the product were submitted, one stated to have been unfiltered, and the other filtered. Both of the specimens emitted a strong odor of hydrogen sulphide upon removing the stopper from the respective containers.

Iodin Content of Iodolene.—The iodin content of the filtered specimen was determined thus: A weighed amount—3 to 5 gm.—was transferred to a separator by means of 20 c.c. of ligroin, used in portions. Twenty c.c. of 10 per cent. potassium iodid solution was added and the free iodin titrated with tenth-normal sodium thiosulphate solution (with agitation), the end point being the absence of a yellow color in theaqueouslayer. The amount of free iodin was found to be 1.32 per cent.

The Solubility of Iodin in Liquid Petrolatum.—To determine the solubility of iodin in Liquid Petrolatum, 200 c.c. of Liquid Petrolatum-Squibb (said to be composed of hydrocarbons of the naphthene series) and 200 c.c. of Stanolind Liquid Paraffin (said to be composed chiefly of marsh gas hydrocarbons) were each treated with 5 gm. of iodin crystals. The two mixtures were maintained for a week at a temperature somewhat above that of the room and agitated occasionally. Each was then cooled to room temperature (about 22 C.), agitated for a day and then filtered. The amount of iodin in the preparation made with Liquid Petrolatum-Squibb was found to be 1.42 per cent. The iodin content of the preparation made with Stanolind Liquid Paraffin was 1.30 per cent.

In view of these findings the prospective manufacturer was advised that the Council cannot countenance a proprietary name for an unofficial, simple solution of iodin in liquid petrolatum.—(From Reports A. M. A. Chemical Laboratory, 1917, p. 87.)

Paul Nicholas Leech, Ph.D.

At the request of the Council on Pharmacy and Chemistry, the A. M. A. Chemical Laboratory has undertaken examinations of American-made synthetic drugs. The most extensively used synthetic is acetylsalicylic acid and hence an investigation of this product was deemed expedient.

For seventeen years acetylsalicylic acid was protected by a United States Patent (the proprietors were not given a patent in other countries) and sold under the name “Aspirin.” In February, 1917, the patent expired, and since then a number of firms have engaged in the manufacture of acetylsalicylic acid,selling it either as such or as aspirin, modified, of course, by a distinctive firm designation. During this period the former manufacturers (The Bayer Co., New York, in past years called Farbenfabriken of Elberfeld Co., New York) have been extensively advertising, both to physicians and the public, the alleged superior qualities of their product. The chemical examination, therefore, was concerned chiefly with tests of purity, and the comparison of the American brands with the formerly patented product.

In European countries, acetylsalicylicacid200is described in the various pharmacopeias as a condensation product of acetic anhydride or acetyl chloride with salicylic acid (o-hydroxybenzoic acid). Generally the test of identification is hydrolysis of acetylsalicylic acid and qualitative tests for acetic acid and salicylic acid. For purposes of purity the requirements are essentially that the specimen should have a certain melting point, should show absence of salicylic acid by means of ferric chloride (the manipulations for the tests are variously described) and leave no appreciable ash. The two tests of purity most generally employed, however, are the melting point and the reaction with ferric chloride.

The melting point of acetylsalicylic acid has been given at various temperatures from 118 to 137 C.201; the British Pharmacopeia describes the melting point at 133 to 135 C.; the German Pharmacopeia “about 135 C.;” the French Pharmacopeia at 135 C.; New and Nonofficial Remedies, 1917, 134 to 136 C. The Bayer Company, in the patent trial at Chicago a number of years ago, gave among the “four infallible tests” a melting point of “about 135 C.” Several men have carefully determined the melting point in recent years. Emery andWright202in 1912 found that “Aspirin, Bayer” melted at 130.5 to 131 C. In France,François203has determined the melting point of pure acetylsalicylic acid, which, according to his method, is 132 C. When various samples of acetylsalicylic acid were examined in this laboratory, it was found that the melting point of none was as high as that described in New and Nonofficial Remedies or the British, French, or German pharmacopeias when taken according to the general method of the U. S. Pharmacopeia, Vol. 9, p. 596. On critical observation, it may be seen that the melting point of acetylsalicylic acid is preceded and accompanied by decomposition. If the sample in the melting tube is heated from the original room temperature of the bath to 120 C., the temperature of melting will be lower than if the bath is first heated to 120 C. and the melting-point tube then placed in the bath.204Thus the melting point of acetylsalicylic acid, like so many organic compounds which decompose and do not melt sharply, is unsatisfactory and cannot be taken as an “infallible test” of purity, especially when determined by different operators who do not give their method in detail. After making a large number of melting-point determinations of acetylsalicylic acid, alone and in parallelwith other operators, it was decided to use the method described in the U. S. Pharmacopeia modified by first heating the bath to 120 C. before attaching the melting-point tube to the thermometer.

The melting point of purified acetylsalicylic acid was found to be 131.5 to 132.5 C. (corr.).205With the exception of one specimen, which was obviously impure, the various specimens examined melted between 128 and 133 C. as may be seen in the accompanying table. It would appear that this range of melting points would be more acceptable and reliable than the melting points described in various standards.

It is generally conceded that the presence of salicylic acid in amounts more than traces is deleterious. Furthermore, the amount of salicylic acid is a good index of the purity of the acetylsalicylic acid, because the test is so delicate that, under favorable conditions, mere traces may be determined and, as a rule, the better the product, the less the amount of free salicylic acid.

The tests appearing in various pharmacopeias for salicylic acid as an impurity in acetylsalicylic acid do not give concordant results, different workers interpreting the results differently, nor are they detailed in such a manner as to yield maximum delicacy.

After experimentation, it was decided to establish a “limit” test of approximately 0.1 per cent. free salicylic acid, when carried out according to the following method:

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