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The Stability of Solutions of Urea Peroxide in Glycerol, Isopropanol, and Ethylene Glycol*
304
JOURNAL OF THE
AMERICAN PHARMACEUTICAL ASSOCIATION
When administered intraperitoneally, free fumaric acid (587 mg. per Kg.) produced corrosion of the viscera and death, and sodium fumarate a t a dose of 2.42 Gm. per Kg. produced “Shock,” changes in fluid distribution, and death. Sodium tartrate appeared less toxic than s o d i m fumarate when administered intraperitoneally.
These studies reaffirm the low toxicity of fumaric acid and of sodium fumarate. REFERENCES Straub, (1) Annau B.. ind’srent-Gy6rgyi. E Banga I. GoszyA.,B. Huszak p h y s i d .St. ckcm., Lakii 3K. a:
i.
l . 152 453(1944). 1(1iT5barker S. B. J . ~ i ~chcm. 3 1 ~ 0.: $Gold, H.. ~ and~ ~W., THISJOURNAL, (4) Locke, A,. Locke, R. B., Schlesinger, H., and Cam, H., ibid., p. 12.
The Stability of Solutions of Urea Peroxide in Glycerol, Isopropanol, and Ethylene Glycol* By ETHAN ALLAN BROWN, HAROLD A. ABRAMSON, MANUEL H. GORIN, HANS 0. KAUFFMANN, and EDWARD S. SHANLEY Data are presented which indicate that solutions of urea peroxide in glycerin, in ethylene glycol, and in isopropyl alcohol are stable under ordinary storage conditions for relatively long periods of time.
peroxide as a solute (and a source of hydrogen peroxide), and substantially anhydrous glycerol and similar liquids as solvents, it might be possible, first, to obtain a liquid peroxide system of enhanced storage stability; and second, to control the rate INCE their discovery 150 years ago, many attempts have been made to of decomposition by catalase systems thus stabilize peroxide compounds. Machu (1) prolonging the action of hydrogen peroxide lists almost 100 methods concerned with the a t the surface of the wounds. Although it addition of stabilizing substances to aqueous is well known that urea peroxide deteriorates peroxide solutions in order to prevent their rapidly in the presence of water, and aldecomposition and yet not interfere with the though glycerol has been added to aqueous use of peroxide solutions in true peroxidase hydrogen peroxide as a stabilizing agent systems. The decomposition of peroxide (l),no studies have been reported on solusolutions is always due to the presence of tions of hydrogen peroxide in glycerol or so-called “catalysts, the rate being deter- the use of urea peroxide to prepare such mined by the physical and chemical charac- solutions in solvents of high viscosity. The present communication deals with teristics of these “catalysts” and of the preliminary observations of the stability temperature. The control of the rate of such of urea peroxide in glycerol, isopropanol, decomposition has therefore been the suband ethylene glycol in the absence of subject of intense study. Studies of this type stantial amounts of water. Subsequent have been especially important not only in papers, in press and in preparation, deal the subject of peroxide chemistry but also with other properties and especially with in the fields of wound antisepsis and bacthe antiseptic effects of solutions of this teriology. type. Since little is known of the stability of hydrogen peroxide in organic solvents, it EXPERIMENTAL occurred to us that with the use of urea *Received Oct 1 1945 from the laboratories of the Asthma Research ‘Fohndatidn, Inc., Boston, Mass., and the Buffalo Electro-Chemical Co., Inc., Buffalo, N. Y.
The first observation on the stability of such solutions was made when it was noted that a 10% solution of urea peroxide in glycerol, kept in a clear
SCIENTIFIC EDITION
305
TABLE I.-TITRATION VALUESFOR UREAPEROXIDE IN GLYCEROL, ISOPROPANOL, ETHYLENE GLYCOL, AND PROPYLENE GLYCOL AT ROOMTEMPERATURE FOR PERIODS OF 1 TO 300 DAYS Weight % , Urea Peroxide, Gm.
Solvent
Wt., % Distilled Water
Start
50 Davs
100 Davs
150 Davs
8 8 8 8 8 8 4
C. p. glycerol C. p. glycerol C. p. glycerol c. p. glycerol C. p. isopropanol C . p. ethylene glycol Propylene glycol
0 0 4.5 9.0 0 0 0
1.20 1.35 1.25 1.14 0.83 1.30 0.71
l.i8 1.35 1.24 1.14 0.80 1.30 0.71
1.27 1.34 1.23 1.13 0.78 1.29 0.70
1.26 1.32 1.22 1.12 0.75 1.28 0.69
TABLE II.-TITRATION VALUESFOR UREAPEROXIDE ALONEAND O F 1 TO 70 DAYS
Urea peroxide (10%) in distilled water
200
Days
Days
250
300 Days
1.25 1.30 1.20 1.11
1.24 1.26 1.18 1.10
1.21 1.23 1.14 1.08
i:is
.. ..
.. ..
0.67
..
DISTILLEDWATERAT 40’
FOR
..
PERIOD
Start
10 Days
Weight % Active Oxygen30 40 50 Days Days Days Days
Days
Days
17.0
17.0
16.8
16.4
14.1
14.4
0
Start
2
Days
7 Days
12 Days
15 Days
14.4
14.3
14.2
14.1
r
Urea peroxide (no solvent)
IN
-~
glass-stoppered bottle at room temperature, in and out of sunlight, for two years, retained a considerable amount of its biological activity. It was decided t o carry out laboratory studies on solutions of urea peroxide in glycerol, isopropanol. and ethylene glycol. A number of solutions were prepared and samples were stored in closed glass bottles at room temperature (in daylight but not in direct sunshine). The active oxygen content of the samples was determined a t intervals by an iodimetric method. Samples of approximately 1 Gm. were weighed into dry flasks, t o which were then added 25 ml. of 25q;b H m , , 2 Gm. of potassium iodide and a drop of ammonium molybdate solution. The liberated iodine was then titrated with standard N/10 thiosulfate. The data obtained in this fashion were plotted on coordinate paper. Values taken from the resulting curves are listed in Table I. Crystalline urea peroxide exhibits some significant contrasts as compared with the solutions noted. The urea peroxide of commerce is a stable material which can be stored without loss for extended periods of time if it is kept dry and reasonably cool. The decomposition of crystalline urea peroxide is, however, strongly self-accelerating and, once i t begins, goes to completion rapidly. Spontaneous decomposition will occur following prolonged. storage a t elevated temperatures and more quickly if the material becomes moist. The data listed in Table I1 is typical of such decomposition at 40’. This behavior is in marked contrast t o that of the various urea peroxide solutions. As shown above, the solutions decompose slowly and regularly. The
20
16.0
60
70
0
glycerol solutions also tolerate some moisture content without marked effect upon their stability.
SUMMARY
It has been shown that solutions of urea peroxide in glycerol, ethylene glycol, and isopropanol are relatively stable under ordinary storage conditions. The stability of these solutions is superior in some respect to that of crystalline urea peroxide. The glycerol solution exhibits a particularly desirable combination of properties. Concomitant studies in the field of bacteriology have shown this solution to possess bactericidal properties against both Grampositive and Gram-negative bacteria (2, 3). Clinical studies have proved it useful in the treatment of chronic middle ear infections (4). Papers recently published are concerned with lack of irritant properties as shown by patch test techniques and by results achieved in infections of the skin (5). REFERENCES (1) Macbu, Willy, “Wasserstoffperoxyd und die Perverbindungen.” Julius Springer, Wien, 1937; feprinted by Edwards Brothers. Ann Arbor, Mich. 1944. (2) Brown, E. A,. Krabek, W., an6 Skiffington, R., New England J . Med.. 234, 468(1946). (3) Brown. E. A,. and Slanetz. L. W.. DcnfaI Research. (iq4jreg.). . rown, E. A.. and Owen, W. E., Arch. Ofolaryngol. 43 605(1946). i5) Brown, E. A., A n n . Allergy, 4.33(1946).
JOURNAL OF THE
AMERICAN PHARMACEUTICAL ASSOCIATION
When administered intraperitoneally, free fumaric acid (587 mg. per Kg.) produced corrosion of the viscera and death, and sodium fumarate a t a dose of 2.42 Gm. per Kg. produced “Shock,” changes in fluid distribution, and death. Sodium tartrate appeared less toxic than s o d i m fumarate when administered intraperitoneally.
These studies reaffirm the low toxicity of fumaric acid and of sodium fumarate. REFERENCES Straub, (1) Annau B.. ind’srent-Gy6rgyi. E Banga I. GoszyA.,B. Huszak p h y s i d .St. ckcm., Lakii 3K. a:
i.
l . 152 453(1944). 1(1iT5barker S. B. J . ~ i ~chcm. 3 1 ~ 0.: $Gold, H.. ~ and~ ~W., THISJOURNAL, (4) Locke, A,. Locke, R. B., Schlesinger, H., and Cam, H., ibid., p. 12.
The Stability of Solutions of Urea Peroxide in Glycerol, Isopropanol, and Ethylene Glycol* By ETHAN ALLAN BROWN, HAROLD A. ABRAMSON, MANUEL H. GORIN, HANS 0. KAUFFMANN, and EDWARD S. SHANLEY Data are presented which indicate that solutions of urea peroxide in glycerin, in ethylene glycol, and in isopropyl alcohol are stable under ordinary storage conditions for relatively long periods of time.
peroxide as a solute (and a source of hydrogen peroxide), and substantially anhydrous glycerol and similar liquids as solvents, it might be possible, first, to obtain a liquid peroxide system of enhanced storage stability; and second, to control the rate INCE their discovery 150 years ago, many attempts have been made to of decomposition by catalase systems thus stabilize peroxide compounds. Machu (1) prolonging the action of hydrogen peroxide lists almost 100 methods concerned with the a t the surface of the wounds. Although it addition of stabilizing substances to aqueous is well known that urea peroxide deteriorates peroxide solutions in order to prevent their rapidly in the presence of water, and aldecomposition and yet not interfere with the though glycerol has been added to aqueous use of peroxide solutions in true peroxidase hydrogen peroxide as a stabilizing agent systems. The decomposition of peroxide (l),no studies have been reported on solusolutions is always due to the presence of tions of hydrogen peroxide in glycerol or so-called “catalysts, the rate being deter- the use of urea peroxide to prepare such mined by the physical and chemical charac- solutions in solvents of high viscosity. The present communication deals with teristics of these “catalysts” and of the preliminary observations of the stability temperature. The control of the rate of such of urea peroxide in glycerol, isopropanol, decomposition has therefore been the suband ethylene glycol in the absence of subject of intense study. Studies of this type stantial amounts of water. Subsequent have been especially important not only in papers, in press and in preparation, deal the subject of peroxide chemistry but also with other properties and especially with in the fields of wound antisepsis and bacthe antiseptic effects of solutions of this teriology. type. Since little is known of the stability of hydrogen peroxide in organic solvents, it EXPERIMENTAL occurred to us that with the use of urea *Received Oct 1 1945 from the laboratories of the Asthma Research ‘Fohndatidn, Inc., Boston, Mass., and the Buffalo Electro-Chemical Co., Inc., Buffalo, N. Y.
The first observation on the stability of such solutions was made when it was noted that a 10% solution of urea peroxide in glycerol, kept in a clear
SCIENTIFIC EDITION
305
TABLE I.-TITRATION VALUESFOR UREAPEROXIDE IN GLYCEROL, ISOPROPANOL, ETHYLENE GLYCOL, AND PROPYLENE GLYCOL AT ROOMTEMPERATURE FOR PERIODS OF 1 TO 300 DAYS Weight % , Urea Peroxide, Gm.
Solvent
Wt., % Distilled Water
Start
50 Davs
100 Davs
150 Davs
8 8 8 8 8 8 4
C. p. glycerol C. p. glycerol C. p. glycerol c. p. glycerol C. p. isopropanol C . p. ethylene glycol Propylene glycol
0 0 4.5 9.0 0 0 0
1.20 1.35 1.25 1.14 0.83 1.30 0.71
l.i8 1.35 1.24 1.14 0.80 1.30 0.71
1.27 1.34 1.23 1.13 0.78 1.29 0.70
1.26 1.32 1.22 1.12 0.75 1.28 0.69
TABLE II.-TITRATION VALUESFOR UREAPEROXIDE ALONEAND O F 1 TO 70 DAYS
Urea peroxide (10%) in distilled water
200
Days
Days
250
300 Days
1.25 1.30 1.20 1.11
1.24 1.26 1.18 1.10
1.21 1.23 1.14 1.08
i:is
.. ..
.. ..
0.67
..
DISTILLEDWATERAT 40’
FOR
..
PERIOD
Start
10 Days
Weight % Active Oxygen30 40 50 Days Days Days Days
Days
Days
17.0
17.0
16.8
16.4
14.1
14.4
0
Start
2
Days
7 Days
12 Days
15 Days
14.4
14.3
14.2
14.1
r
Urea peroxide (no solvent)
IN
-~
glass-stoppered bottle at room temperature, in and out of sunlight, for two years, retained a considerable amount of its biological activity. It was decided t o carry out laboratory studies on solutions of urea peroxide in glycerol, isopropanol. and ethylene glycol. A number of solutions were prepared and samples were stored in closed glass bottles at room temperature (in daylight but not in direct sunshine). The active oxygen content of the samples was determined a t intervals by an iodimetric method. Samples of approximately 1 Gm. were weighed into dry flasks, t o which were then added 25 ml. of 25q;b H m , , 2 Gm. of potassium iodide and a drop of ammonium molybdate solution. The liberated iodine was then titrated with standard N/10 thiosulfate. The data obtained in this fashion were plotted on coordinate paper. Values taken from the resulting curves are listed in Table I. Crystalline urea peroxide exhibits some significant contrasts as compared with the solutions noted. The urea peroxide of commerce is a stable material which can be stored without loss for extended periods of time if it is kept dry and reasonably cool. The decomposition of crystalline urea peroxide is, however, strongly self-accelerating and, once i t begins, goes to completion rapidly. Spontaneous decomposition will occur following prolonged. storage a t elevated temperatures and more quickly if the material becomes moist. The data listed in Table I1 is typical of such decomposition at 40’. This behavior is in marked contrast t o that of the various urea peroxide solutions. As shown above, the solutions decompose slowly and regularly. The
20
16.0
60
70
0
glycerol solutions also tolerate some moisture content without marked effect upon their stability.
SUMMARY
It has been shown that solutions of urea peroxide in glycerol, ethylene glycol, and isopropanol are relatively stable under ordinary storage conditions. The stability of these solutions is superior in some respect to that of crystalline urea peroxide. The glycerol solution exhibits a particularly desirable combination of properties. Concomitant studies in the field of bacteriology have shown this solution to possess bactericidal properties against both Grampositive and Gram-negative bacteria (2, 3). Clinical studies have proved it useful in the treatment of chronic middle ear infections (4). Papers recently published are concerned with lack of irritant properties as shown by patch test techniques and by results achieved in infections of the skin (5). REFERENCES (1) Macbu, Willy, “Wasserstoffperoxyd und die Perverbindungen.” Julius Springer, Wien, 1937; feprinted by Edwards Brothers. Ann Arbor, Mich. 1944. (2) Brown, E. A,. Krabek, W., an6 Skiffington, R., New England J . Med.. 234, 468(1946). (3) Brown. E. A,. and Slanetz. L. W.. DcnfaI Research. (iq4jreg.). . rown, E. A.. and Owen, W. E., Arch. Ofolaryngol. 43 605(1946). i5) Brown, E. A., A n n . Allergy, 4.33(1946).