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The Determination of Acetophenetidin in Tablet Mixtures: A Potentiometric Method*
3 18
JOURNAL OF THE
AMERICANPHARMACEUTICAL ASSOCIATION Vol. XLVIII, No. 6
POLYMER l%WIVI
Fig. 6.-Ratio of the concentration of methylparaben inside the dialysis membrane to the concentration outside the membrane, in the presence of varying concentrations of tragacanth and carboxymethylcellulose at 30". Methylparaben concentration 6.60 X t o 9.88 X M. Table I presents a comparison of the degree of binding of parabens in the presence of 2% dispersions of the macromolecules studied. Although data are not presented for propylparaben in CMC and tragacanth dispersions, the results would be expected to parallel those obtained with the methyl ester. TABLE~.-COMPARATIVE BINDING OF PARABENS BY 2y0 POLYMER SOLUTIONS Total Methyl paraben Free, % '
Macromolecule 2% w/v
Polyvinylpyrrolidone Polyethylene glycol 4000 hfethylcellulose Gelatin Carboxymethylcellulose Tragacanth
78 84 91 92
100 100
Total Propylparaben Free, %
64
81 87 89 .. ..
ethylene glycol, methylcellulose, polyvinylpyrrolidone, and gelatin. The magnitude of the association is considerably less than that observed previously with several nonionic surfactants. 2. There was no evidence for a significant degree of interaction of methylparaben with car boxymethylcellulose or tragacanth. Any increased quantity of paraben required to preserve tragacanth dispersions cannot be attributed to adsorption of the preservative by the gum, and thus should not be a phenomenon restricted to any specific preservative. 3. It would appear that for concentrations in which the polymers under investigation are usually employed, binding of the parabens would not be sufficient to prohibit their efficient application as preservatives. REFERENCES H. B., THIS JOUR47, 289(1958). (2) Pisano, F. D., and Kostenbauder, H. B., ibid.. 48.310 (1959). (3) Eisman, P . C., Cooper, J.. and Jaconia, D., ibid., 46, 141( 1957). (4) Taub, A,, Meer, W. A , , and Clausen, L. W., ibid., 47, 235( 1959). ( 5 ) Tillman. W. J . , and Kuramoto, R., ibid., 46, 211 (1957). J. L., Ravel, K.. and Blaug, S. M., ibid., 46, ... (6) .- . I.ach, (1) Patel, N. K . , and Kostenbauder,
NAL,
1115(1Y57).
(7) Klotz, I. M . , Walker, M. F . , and Pivan, R. B., J . A m . Chem. Soc., 68 1486(1916). (8) Karush, F., Lnd Sonenberg. M . . ibid.. 71, 1369(1949). ?ax (9) R4iliiac.d) Higuchi, T., and Kuramoto, R., THISJOURNAL, 43, ?ax~,R4iliiac.d) -,-I_,. (10) Kennon, L.. and Higuchi T . ibid. 45 157(1956). (11) Guttman, D.. and Higucij, 3.,i b i i , , 45, 659(1956). (12) deNavarre, M . G . . and Balley, H. E., J . Soc. Cosmefic Chemisfs, 7, 427(1956). (13) Kostenbauder, H. B., and Higuchi. T., THISJOURNAL, 45. 518(1956). I"
SUMMARY 1. Methyl and propyl p-hydroxybenzoate were found to interact to some extent with poly-
The Determination of Acetophenetidin in Tablet Mixtures: A Potentiometric Method* By JOSEPH G. BALDINUS and IRVIN ROTHBERG When acetophenetidin is hydrolyzed with acid, the resulting p-phenetidin can be tiuated potentiometrically with sodium nitrite if potassium bromide is used as a catalyst to speed the diazotization reaction. This provides the basis for a simple, rapid, and accurate procedure for determining acetophenetidin. Aspirin, caffeine, salicylic acid, codeine, amphetamine, and amobarbital do not interfere with the titration.
Falex (1) reported that p-phenetidin could be titrated with sodium nitrite using starch-iodide paper as an indicator. This would be an attractive procedure for acetophenetidin, except for a number of disadvantages: the starch-iodide paper is insensitive to dilute solutions of sodium nitrite, the temperature must be controlled, colored solutions give trouble, the reECENTLY,
R
* Received October 7, 1958, from the Smith Kline and French Laboratories, Philadelphia 1 , Pa.
action with starch-iodide paper requires considerable time, and, finally, the use of an external indicator is simply not conducive to accuracy and precision. In the work presented below, the diazotization reaction was speeded so that the titration of the P-phenetidin could be followed potentiometrically. The resulting procedure has proved considerably less troublesome than the existing methods for determining acetophenetidin (2-10).
June 1959
SCIENTIFIC EDITION
319
EXPERIMENTAL
bromide, the end point could be detected; however, it was not nearly so pronounced or so reproducible, Reagents.-A 0.05 N sodium nitrite solution as was the potentiometric end point. which was prepared by dissolving approximately 3.5 Caffeine, aspirin, salicylic acid, and the common Gm. sodium nitrite in one liter of distilled water; sulf- tablet excipients, such as starch, talc, magnesium anilamide, U. S. P. reference standard, which was stearate, calcium sulfate, and guar gum were checked used t o standardize the nitrite solution; potassium for possible interference in the titration; however, bromide crystals; and a 10% aqueous solution of no interference was found. Codeine, amphetamine, HCl. and amobarbital, also, did not affect the titration. Apparatus.-Either a Photovolt model 110 or a I n the blank titration, the acetophenetidin comes Beckman model G pH meter; a platinum electrode in contact with a 10% acid solution and might be which was used versus a calomel electrode; a timer, expected t o hydrolyze slightly. Pure acetophenetipreferably one with a second hand; and a 25-1111.din, however, gave a negligible blank even after buret. thirty minutes stirring in the acidic solution. Procedure.-The tablets were ground to a fine powder and an amount of sample that contained RESULTS about 160-180 mg. of acetophenetidin was refluxed for one to one and one-half hours with 50 ml. of 10% When pure acetophenetidin was analyzed by the aqueous HC1. The resulting solution was transfer- above procedure, theoretical recoveries were obred quantitatively to a 250-ml.beaker with the aid tained. Results obtained on various tablet mixtures of 50 ml. 10% aqueous HCI, 5 Gm. of potassium are reported in Table I. bromide was added, and the solution was then titrated potentiometrically with sodium nitrite, using TABLE ANALYSIS OF ACETOPHENETIDIN IN a magnetic stirrer for agitation. At the beginning VARIOUS TABLETS of the titration, the titrant was added rapidly, but Labe! near the end point, increments of 0.1 ml. were added. Declaration, Found, Since the potential drifted during the titration, the Sample gr./tablet gr./tablet readings were recorded exactly one minute after each 1" 5.00 4.94 addition of titrant. The idection point was cal2 5.00 5.02 3 5.00 5.00 culated by the method of Kolthoff and Laitinen
(11).
4 5
5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 2.50 2.50 2.50 2.50
4.95 4.97 4.94 5.00 4.96 4.95 4.98 5.02 5.02 2.50 2.52 2.48 2.50
A blank titration was also run on the sample prior to hydrolysis with acid. On all our samples, the blanks were negligible. Ordinarily, the blank would be nil unless p-phenetidin had somehow formed in the tablets. This conceivably could happen with age or under unusual storage conditions. For control work, the blank determination could probably be omitted altogether. After subtraction of the blank, each ml. of 0.05N sodium nitrite consumed was equivalent to 8.955mg. acetophenetidin. In standardizing the sodium nitrite with sulfanilamide, it was not necessary to use potassium bromide. However, the potentials were still recorded as above, one minute after the addition of each increment of titrant.
Samples 1-12 inclusive are APC tablets. b These tablets contain codeine sulfate, amphetamine sulfate, and aspirin in addition to the acetophenetidin. c Amphetamine sulfate, amobarbital, and aspirin are present in these samples.
DISCUSSION AND RESULTS
REFERENCES
Without the use of potassium bromide, a potentiometric end point could not be obtained when pphenetidin was titrated with sodium nitrite. Concentrations of potassium bromide ranging from 110% were tried, and the optimum concentration was found to be about 5%. Below concentrations of 4y0, the size of the end point seemed to diminish; above 5y0no improvement was noted. Iodide has been reported (12)to be a n even more effective catalyst for the diazotization of aromatic amines than bromide. While this may be true a t very low acidities, in our titrations the iodide was simply oxidized by the sodium nitrite. The dead stop method (13)using polarized platinum electrodes was also tried. With potassium
6
7 8 9 10 11 12 13* 14b 15" 16c
(1) Falex, O.,Australasian J . Pharm., 37, 7(1956). (2) Washburn, W. H., and Krueger, E. 0.. THISJOURNAL, 38, 623(1949). (3) Parke, T. V., Ribley, A. M., Kennedy, E. E., and Hilty W. W. Anal. Chcm. 23, 953(1951). (4j Holt, K. E., THIS~ O U R N A L 35 71(1946). (5) Jones, M.,and Thatcher, 'R. 'L., Anal. Chcm., 23, nr..,.n=.\ Vi), l D I ) l , .
16) Mattocks, A. M . , and Hernandez, H. R. , Bull. N a f ' l . Formulary Comm., 18, 113(1950). (7) Banes, D. THISJOURNAL 43 580(1954). ( 8 ) Levine, J.: i b i d . , 46, 687(i95?). (9) Wollish, E. G.,Colarusso. R. J . , Pifer, c. w'., and Schmall M. Anal. Chem. 26 1753(1954). (10) "*05'cial Methods' 0; Analvsis." Assoc. offic . AKr. . Chemists 8th ed. 1955 p. 619. (11) Kb!thoff, i. M., knd Laitinen, H. A., "pH and Electro Titrations, 2nd ed., John Wiley & Sons, Inc.. New York, 1944 p. 110. (15) Hughes, E. D . , and Ridd, J. H., J . Chem. SOC.,1958, 82. (13) Foulk. C. W., and Bawden, A. T . , J . A m . Chem. Sac., 48, 2045(1926).
JOURNAL OF THE
AMERICANPHARMACEUTICAL ASSOCIATION Vol. XLVIII, No. 6
POLYMER l%WIVI
Fig. 6.-Ratio of the concentration of methylparaben inside the dialysis membrane to the concentration outside the membrane, in the presence of varying concentrations of tragacanth and carboxymethylcellulose at 30". Methylparaben concentration 6.60 X t o 9.88 X M. Table I presents a comparison of the degree of binding of parabens in the presence of 2% dispersions of the macromolecules studied. Although data are not presented for propylparaben in CMC and tragacanth dispersions, the results would be expected to parallel those obtained with the methyl ester. TABLE~.-COMPARATIVE BINDING OF PARABENS BY 2y0 POLYMER SOLUTIONS Total Methyl paraben Free, % '
Macromolecule 2% w/v
Polyvinylpyrrolidone Polyethylene glycol 4000 hfethylcellulose Gelatin Carboxymethylcellulose Tragacanth
78 84 91 92
100 100
Total Propylparaben Free, %
64
81 87 89 .. ..
ethylene glycol, methylcellulose, polyvinylpyrrolidone, and gelatin. The magnitude of the association is considerably less than that observed previously with several nonionic surfactants. 2. There was no evidence for a significant degree of interaction of methylparaben with car boxymethylcellulose or tragacanth. Any increased quantity of paraben required to preserve tragacanth dispersions cannot be attributed to adsorption of the preservative by the gum, and thus should not be a phenomenon restricted to any specific preservative. 3. It would appear that for concentrations in which the polymers under investigation are usually employed, binding of the parabens would not be sufficient to prohibit their efficient application as preservatives. REFERENCES H. B., THIS JOUR47, 289(1958). (2) Pisano, F. D., and Kostenbauder, H. B., ibid.. 48.310 (1959). (3) Eisman, P . C., Cooper, J.. and Jaconia, D., ibid., 46, 141( 1957). (4) Taub, A,, Meer, W. A , , and Clausen, L. W., ibid., 47, 235( 1959). ( 5 ) Tillman. W. J . , and Kuramoto, R., ibid., 46, 211 (1957). J. L., Ravel, K.. and Blaug, S. M., ibid., 46, ... (6) .- . I.ach, (1) Patel, N. K . , and Kostenbauder,
NAL,
1115(1Y57).
(7) Klotz, I. M . , Walker, M. F . , and Pivan, R. B., J . A m . Chem. Soc., 68 1486(1916). (8) Karush, F., Lnd Sonenberg. M . . ibid.. 71, 1369(1949). ?ax (9) R4iliiac.d) Higuchi, T., and Kuramoto, R., THISJOURNAL, 43, ?ax~,R4iliiac.d) -,-I_,. (10) Kennon, L.. and Higuchi T . ibid. 45 157(1956). (11) Guttman, D.. and Higucij, 3.,i b i i , , 45, 659(1956). (12) deNavarre, M . G . . and Balley, H. E., J . Soc. Cosmefic Chemisfs, 7, 427(1956). (13) Kostenbauder, H. B., and Higuchi. T., THISJOURNAL, 45. 518(1956). I"
SUMMARY 1. Methyl and propyl p-hydroxybenzoate were found to interact to some extent with poly-
The Determination of Acetophenetidin in Tablet Mixtures: A Potentiometric Method* By JOSEPH G. BALDINUS and IRVIN ROTHBERG When acetophenetidin is hydrolyzed with acid, the resulting p-phenetidin can be tiuated potentiometrically with sodium nitrite if potassium bromide is used as a catalyst to speed the diazotization reaction. This provides the basis for a simple, rapid, and accurate procedure for determining acetophenetidin. Aspirin, caffeine, salicylic acid, codeine, amphetamine, and amobarbital do not interfere with the titration.
Falex (1) reported that p-phenetidin could be titrated with sodium nitrite using starch-iodide paper as an indicator. This would be an attractive procedure for acetophenetidin, except for a number of disadvantages: the starch-iodide paper is insensitive to dilute solutions of sodium nitrite, the temperature must be controlled, colored solutions give trouble, the reECENTLY,
R
* Received October 7, 1958, from the Smith Kline and French Laboratories, Philadelphia 1 , Pa.
action with starch-iodide paper requires considerable time, and, finally, the use of an external indicator is simply not conducive to accuracy and precision. In the work presented below, the diazotization reaction was speeded so that the titration of the P-phenetidin could be followed potentiometrically. The resulting procedure has proved considerably less troublesome than the existing methods for determining acetophenetidin (2-10).
June 1959
SCIENTIFIC EDITION
319
EXPERIMENTAL
bromide, the end point could be detected; however, it was not nearly so pronounced or so reproducible, Reagents.-A 0.05 N sodium nitrite solution as was the potentiometric end point. which was prepared by dissolving approximately 3.5 Caffeine, aspirin, salicylic acid, and the common Gm. sodium nitrite in one liter of distilled water; sulf- tablet excipients, such as starch, talc, magnesium anilamide, U. S. P. reference standard, which was stearate, calcium sulfate, and guar gum were checked used t o standardize the nitrite solution; potassium for possible interference in the titration; however, bromide crystals; and a 10% aqueous solution of no interference was found. Codeine, amphetamine, HCl. and amobarbital, also, did not affect the titration. Apparatus.-Either a Photovolt model 110 or a I n the blank titration, the acetophenetidin comes Beckman model G pH meter; a platinum electrode in contact with a 10% acid solution and might be which was used versus a calomel electrode; a timer, expected t o hydrolyze slightly. Pure acetophenetipreferably one with a second hand; and a 25-1111.din, however, gave a negligible blank even after buret. thirty minutes stirring in the acidic solution. Procedure.-The tablets were ground to a fine powder and an amount of sample that contained RESULTS about 160-180 mg. of acetophenetidin was refluxed for one to one and one-half hours with 50 ml. of 10% When pure acetophenetidin was analyzed by the aqueous HC1. The resulting solution was transfer- above procedure, theoretical recoveries were obred quantitatively to a 250-ml.beaker with the aid tained. Results obtained on various tablet mixtures of 50 ml. 10% aqueous HCI, 5 Gm. of potassium are reported in Table I. bromide was added, and the solution was then titrated potentiometrically with sodium nitrite, using TABLE ANALYSIS OF ACETOPHENETIDIN IN a magnetic stirrer for agitation. At the beginning VARIOUS TABLETS of the titration, the titrant was added rapidly, but Labe! near the end point, increments of 0.1 ml. were added. Declaration, Found, Since the potential drifted during the titration, the Sample gr./tablet gr./tablet readings were recorded exactly one minute after each 1" 5.00 4.94 addition of titrant. The idection point was cal2 5.00 5.02 3 5.00 5.00 culated by the method of Kolthoff and Laitinen
(11).
4 5
5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 2.50 2.50 2.50 2.50
4.95 4.97 4.94 5.00 4.96 4.95 4.98 5.02 5.02 2.50 2.52 2.48 2.50
A blank titration was also run on the sample prior to hydrolysis with acid. On all our samples, the blanks were negligible. Ordinarily, the blank would be nil unless p-phenetidin had somehow formed in the tablets. This conceivably could happen with age or under unusual storage conditions. For control work, the blank determination could probably be omitted altogether. After subtraction of the blank, each ml. of 0.05N sodium nitrite consumed was equivalent to 8.955mg. acetophenetidin. In standardizing the sodium nitrite with sulfanilamide, it was not necessary to use potassium bromide. However, the potentials were still recorded as above, one minute after the addition of each increment of titrant.
Samples 1-12 inclusive are APC tablets. b These tablets contain codeine sulfate, amphetamine sulfate, and aspirin in addition to the acetophenetidin. c Amphetamine sulfate, amobarbital, and aspirin are present in these samples.
DISCUSSION AND RESULTS
REFERENCES
Without the use of potassium bromide, a potentiometric end point could not be obtained when pphenetidin was titrated with sodium nitrite. Concentrations of potassium bromide ranging from 110% were tried, and the optimum concentration was found to be about 5%. Below concentrations of 4y0, the size of the end point seemed to diminish; above 5y0no improvement was noted. Iodide has been reported (12)to be a n even more effective catalyst for the diazotization of aromatic amines than bromide. While this may be true a t very low acidities, in our titrations the iodide was simply oxidized by the sodium nitrite. The dead stop method (13)using polarized platinum electrodes was also tried. With potassium
6
7 8 9 10 11 12 13* 14b 15" 16c
(1) Falex, O.,Australasian J . Pharm., 37, 7(1956). (2) Washburn, W. H., and Krueger, E. 0.. THISJOURNAL, 38, 623(1949). (3) Parke, T. V., Ribley, A. M., Kennedy, E. E., and Hilty W. W. Anal. Chcm. 23, 953(1951). (4j Holt, K. E., THIS~ O U R N A L 35 71(1946). (5) Jones, M.,and Thatcher, 'R. 'L., Anal. Chcm., 23, nr..,.n=.\ Vi), l D I ) l , .
16) Mattocks, A. M . , and Hernandez, H. R. , Bull. N a f ' l . Formulary Comm., 18, 113(1950). (7) Banes, D. THISJOURNAL 43 580(1954). ( 8 ) Levine, J.: i b i d . , 46, 687(i95?). (9) Wollish, E. G.,Colarusso. R. J . , Pifer, c. w'., and Schmall M. Anal. Chem. 26 1753(1954). (10) "*05'cial Methods' 0; Analvsis." Assoc. offic . AKr. . Chemists 8th ed. 1955 p. 619. (11) Kb!thoff, i. M., knd Laitinen, H. A., "pH and Electro Titrations, 2nd ed., John Wiley & Sons, Inc.. New York, 1944 p. 110. (15) Hughes, E. D . , and Ridd, J. H., J . Chem. SOC.,1958, 82. (13) Foulk. C. W., and Bawden, A. T . , J . A m . Chem. Sac., 48, 2045(1926).