THE STABILITY OF IODINE OINTMENTS
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 this condition by studies of several proprietary preparations, Iodex,[184] Iod-Izd-Oil,[185] Iocamfen, 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.[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,[190] of 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 Pullen[191] reported 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 I | Sample II | |
| Ointment from new lard, per cent. | Ointment from old lard, per cent. | |
| Iodine introduced | 4.0 | 4.0 |
| Iodine found immediately after making | 3.95 | 3.38 |
| Iodine found after twenty-four hours | 3.30 | 3.15 |
| Iodine found on the third day | 3.18 | 2.62 |
| Iodine found on the seventh day | 3.15 | 2.46 |
| Iodine found on the fourteenth day | 3.00 | 2.45 |
| Iodine found after one month | 3.00 | 2.39 |
| Iodine found after two months | 2.90 | 2.31 |
| Iodine found after four months | 2.92 | 2.26 |
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 (only 1⁄20) 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. 1 | 2.74 per cent. |
| Specimen No. 2 | 2.85 per cent. |
| Specimen No. 3 | 2.62 per cent. |
| Specimen No. 4 | 2.48 per cent. |
| Specimen No. 5 | 2.53 per cent. |
| Specimen No. 6 | 2.79 per cent. |
Fried[192] prepared iodine ointment according to the U. S. P. VIII formula, and assayed it at intervals. His results are tabulated herewith:
| Per cent. | |
| Iodine introduced | 4.00 |
| Iodine found immediately after making | 3.89 |
| Iodine found one hour after making | 3.51 |
| Iodine found one day after making | 3.48 |
| Iodine found five days after making | 3.06 |
| Iodine found ten days after making | 2.84 |
| Iodine found thirty days after making | 2.81 |
| Iodine found ninety days after making | 2.81 |
| Iodine found eight months after making | 2.81 |
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
| Formula | Substance | Melting Point, U. S. P. | Ductility Limit | Plasticity Limit | (a) Adhesiveness and Detachability (b) Strength of Film at 38 C. |
| 1 | “Parowax,” Stand. Oil Co. of Ind. | 50.8 | 32.5 | 29.0 | (a) Adheres and detaches well; rather hard (b) Pliable and strong |
| 3 | “Paraffin 118–120 F.,” Stand. Oil Co. of Ind. | 46.8 | 28.5 | 24.5 | (a) Does not adhere well; detaches easily (b) Pliable but not strong |
| 4 | “Paraffin 120–122 F.,” Stand. Oil Co. of Ind. | 47.2 | 29.0 | 24.5 | (a) Adheres well; detaches well (b) Pliable and fairly strong |
| 5 | “Paraffin 123–125 F.,” Stand. Oil Co. of Ind. | 48.8 | 31.5 | 28.5 | Same as 4 |
| 6 | “Paraffin 128–130 F.,” Stand. Oil Co. of Ind. | 52.0 | 33.0 | 30.0 | (a) Adheres well; detaches not so easily (b) Pliable and strong |
| 7 | “Texwax,” Texas Co., Port Arthur, Texas | 51.2 | 32.5 | 29.8 | Same as 6 |
| 8 | “Paraffin Wax 122–124 F.,” Warren Refining Co., Warren, Pa. | 50.6 | 36.0 | 34–35 | (a) Unsatisfactory; does not adhere (b) Only slightly pliable; too tough |
| 9 | “Paraffin No. 910,” Waverly Oil Works, Pittsburgh | 47.0 | 30.5 | 26–27 | (a) Adheres well; detaches well (b) Pliable and strong |
| 10 | “Paraffin No. 920,” Waverly Oil Works, Pittsburgh | 44.4 | 27.5 | 25.0 | (a) Adheres well; detaches well (b) Pliable and fairly strong |
| 11 | “Hard Paraffin,” Rob’t Stevenson & Co., Chicago | 48.0 | 28.5 | 24.5–25.5 | (a) Adheres well; detaches well (b) Pliable and strong |
| 12 | “Paraffin,” Island Petroleum Co., Chicago | 47.2 | 33.0 | 32.5 | Not quite as good as 11 |
| 13 | “Paraffin 122 F.,” Gulf Refining Co., Pittsburgh | 46.8 | 30.5 | 27.5–28 | (a) Does not adhere so well; detaches well (b) Very pliable |
| 14 | “Paraffin 125 F.,” Gulf Refining Co., Pittsburgh | 50.0 | 32.0 | 31.0 | About as 13 |
| 15 | “Paraffin 132 F.,” Gulf Refining Co., Pittsburgh | 54.8 | 35.5 | 34.0 | (a) Does not adhere well (b) Not very pliable, but strong |
| 16 | “Paraffin No. 301,” National Refining Co., Cleveland | 50.2 | 33.0 | 32–32.5 | (a) Does not adhere well (b) Not very pliable |
| 18 | Paraffin recovered from “Ambrine” | 48.6 | 30.5 | 28–28.5 | (a) Adheres well; detaches well (b) Pliable but not strong |
| 19 | “Hyperthermine” | 49.4 | 33.5 | 30.5–31 | (a) Does not adhere well; detaches well (b) Very pliable and strong |
| 20 | “Ambrine” | 48.4 | 30.5 | 27.0 | (a) Adheres well; detaches well (b) Very pliable and strong |
| 21 | Paraffin 120–122 F. (see 3), 97.5; olive oil, 1.5; asphalt, 4 drops | 45.4 | 29.0 | 28.5 | (a) Adheres excellently; detaches well (b) Very pliable and strong |
| 22 | “Parowax” (see 1), 97.5; olive oil, 1.5; asphalt, 4 drops | 49.2 | 32.0 | 30.5 | (a) Adheres well; detaches well (b) Pliable and strong |
| 23 | “Mulene” | 51.0 | 36.0 | 28.0 | (a) Adheres but detaches with difficulty (b) Pliable but not strong |
| 24 | “Parresine,” Abbott Laboratories, Chicago | 46.0 | 29.5 | 26.0 | (a) Adheres well; detaches easily (b) Pliable and fairly strong |
| 25 | “Paraffin 118–121 F.,” The Atlantic Refining Co., Philadelphia | 45.8 | 26.4 | 23.2 | (a) Adheres well; detaches easily (b) Pliable and fairly strong |
| TABLE B | |||||
| 26 | “Cerelene,” Holliday Lab.,* Pittsburgh | 50.0 | 30.5 | 26.5 | (a) Adheres well; detaches with pulling (b) Not strong at 38 C. |
| 27 | “Stanolind” Surgical Wax,† Standard Oil Co. of Ind. | 47.0 | 28.8 | 25.0 | (a) Adheres well; detaches easily (b) Fairly strong at 38 C. |
* 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 specimen | 57.1 |
| Armour specimen (a) | 57.65 |
| Armour specimen (b) | 67.55 |
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 lard and iodine only[194] without 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.[195] It is essentially the same as was employed by Pullen for the determination of uncombined iodine in iodine ointment.[196] As 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 assay | U. S. P. Ointment from laboratory rendered lard | U. S. P. Ointment from commercial lard Grade I | U. S. P. Ointment from commercial lard Grade II | Ointment from lard and iodine only (laboratory rendered lard) |
| (% I) | (% I) | (% I) | (% I) | |
| Freshly made | 3.32 | 3.26 | 3.30 | 0.32 |
| After 3 days | 3.25 | ...... | ...... | 0.23 |
| After 7 days | 2.99 | 3.17 | 3.15 | ...... |
| After 3 weeks | 3.01 | 3.19 | 3.07 | ...... |
| After 7 weeks | 3.12* | 3.10 | 3.02 | ...... |
| After 3 months | 2.98 | 2.88 | 2.88 | ...... |
* 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.[198] It 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 KI3 with 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 iodine | 3 | per cent. |
| Iodine combined with fat | 1 | per cent. |
| Potassium iodide | 4 | per cent. |
| Benzoinated lard (containing iodine) | 80 | per cent. |
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.)