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A note on a simple assay method for certain mercurial diuretics*
A Note on a Simple Assay Method for Certain Mercurial Diuretics* By EDGAR E. THEIMER and PETER ARNOW The mercury-carbon bond i n many mercurial diuretics is rather weak, and the mercury may be converted t o titratable form by relatively mild treatment. A simple assay method based o n such a titration i s described.
T
HOSE DIURETICS, such as mersalyl, which are formed by the addition of alkyl mercuric salts to compounds containing an ally1 group, when dissolved in 50 per cent sulfuric acid, react instantaneously with two moles of potassium thiocyanate, arid thus may be titrated just like inorganic mercuric compounds, using ferric alum indicator. Halide ions must be absent. This assay procedure is applicable to injectable solutions of thesc diuretics, as well as t o their organic mercurial components alone. I t is a special case of a well-known reaction:
1
1
I
I
RO-C-C-HgX
+ HXl+ I
I
I
I
HgXX,
+
ROH f C=C (X,XI = acid radicals) discovered in 1900 ( l ) , and recently used as the basis of a method of determination of unsaturated compounds (2).
TABLEI.-MERCURY ASSAYSOF CERTAIN DIURETICS" ~
Mercurial
Mersalyl acid Mersalyl-theophylline inj. U. S. P. Acid of mercuri component of mercurop hylline Mercurophylline inj. U. S. P. Merethoxylline MerethoxyllineDrocaine w. iheophylline inj. N.N. R. Mercumallylic acid Mercumatilin sod. inj. N. N. R. Meralluride ini. N. N.R.
Hg Found by Proposed Method, Per Cent
Hg Found by U . S. P. or N . N. R. Method, Per Cent
41.1 3.95
41.3 4.02
41.5 3.9
42.4
42.1
41.1
Hg Calculated=, Per Cent
3.92
3.92
3.9
39.7 4.18
39.0 4.20
39.3
40.2b 3.936
40.3 3.93
-41.8 3.9
3.87
3.86
3.9
__
3.93
~~~~
We wish t o thank Eli Lilly and Co.. Endo Products C O . . and Campbell Pharmaceutical Cu. for the compounds supplied by them. b Determined by modified method. See text. c As staled on the lal:el or calculated lrom the formula.
METHOD N'cigh or measure accurately a sample containing about 200 mg. of mercury; add 10 ml. distilled water and chill in an ice-bath. Add 10 ml. of sulfuric acid dropwise, with good agitation keeping in an ice-bath ten minutes more. Add 2 ml. of 89: ferric ammonium sulfate and titrate with 0.1 N potassium thiocyanate. (Each ml. of 0.1 N thiocyanate is equivalent to 10.03 mg. of mercury.) EXPERIMENTAL Many assays of various diuretics were run, by the various methods, and typical results are presented in Table I. Mercumallylic acid and Mercumatilin sodium may give dark decomposition products during titration if treatcd as directcd above. This trouble may bc avoided by adding 30 ml. of water irtstcad of 10 nil. Also, in the case of Mercumallylic acid, this powder is bcst dissolved in about 6 ml. 0.1 N sodium hytlroxide before addition of the water a ~ l dsulfuric arid; otlicrwise it may not dissolve con~plctcly. DISCUSSION kIalidc ions interfere in the titration. sinccb they compete with thiocyanate for mcrcury. A preliin-
*
Receiyed October 10, 1954, from the Metropolitan Laboratories, Inc., Oyster Bay, N. Y.
inary test for halide should therefore be madc. Wc have found that commercial injectable mercurial diuretics are usually free of halide ions. Oneto and Cataldi (3) have described a dcterminative method likewise involving a relatively mild treatment, namely, heating with HCl, HNOI, and water until colorless. The mercury thus brought into titratable form is treated with standard KCN, and the excess KCN is back-titrated with standard AgNOs in the presence of ammonia, using K I as indicator. They claim t o have obtained precise results for a variety of mercurial diuretics, including mercaptomerin, which cannot be assayed by our method, but they do not mention how long the heating takes. CONCLUSIONS
I ti applicablc cases, thc mcthotl proyowl licreiii for assaying nicrcurial diuretics is fully its rcprotlucible and accurate as the co~iitnoit methods i i i use herctoforc, mid has thc advantagc of bciiig much shortcr. REFERENCES ( I ) H,,lrnann K . A.. and Sand, J., Rev., 33, 1310(1!IlJO). (2) Marquardt, R. P., and Luce. E. N., Anal. Chem. 20, 781 (1948). (3) Oneto, E. I., and Cataldi, M . E., Anales asoc. qaim. y farm., Uruguay. 51.36(1951).
T
HOSE DIURETICS, such as mersalyl, which are formed by the addition of alkyl mercuric salts to compounds containing an ally1 group, when dissolved in 50 per cent sulfuric acid, react instantaneously with two moles of potassium thiocyanate, arid thus may be titrated just like inorganic mercuric compounds, using ferric alum indicator. Halide ions must be absent. This assay procedure is applicable to injectable solutions of thesc diuretics, as well as t o their organic mercurial components alone. I t is a special case of a well-known reaction:
1
1
I
I
RO-C-C-HgX
+ HXl+ I
I
I
I
HgXX,
+
ROH f C=C (X,XI = acid radicals) discovered in 1900 ( l ) , and recently used as the basis of a method of determination of unsaturated compounds (2).
TABLEI.-MERCURY ASSAYSOF CERTAIN DIURETICS" ~
Mercurial
Mersalyl acid Mersalyl-theophylline inj. U. S. P. Acid of mercuri component of mercurop hylline Mercurophylline inj. U. S. P. Merethoxylline MerethoxyllineDrocaine w. iheophylline inj. N.N. R. Mercumallylic acid Mercumatilin sod. inj. N. N. R. Meralluride ini. N. N.R.
Hg Found by Proposed Method, Per Cent
Hg Found by U . S. P. or N . N. R. Method, Per Cent
41.1 3.95
41.3 4.02
41.5 3.9
42.4
42.1
41.1
Hg Calculated=, Per Cent
3.92
3.92
3.9
39.7 4.18
39.0 4.20
39.3
40.2b 3.936
40.3 3.93
-41.8 3.9
3.87
3.86
3.9
__
3.93
~~~~
We wish t o thank Eli Lilly and Co.. Endo Products C O . . and Campbell Pharmaceutical Cu. for the compounds supplied by them. b Determined by modified method. See text. c As staled on the lal:el or calculated lrom the formula.
METHOD N'cigh or measure accurately a sample containing about 200 mg. of mercury; add 10 ml. distilled water and chill in an ice-bath. Add 10 ml. of sulfuric acid dropwise, with good agitation keeping in an ice-bath ten minutes more. Add 2 ml. of 89: ferric ammonium sulfate and titrate with 0.1 N potassium thiocyanate. (Each ml. of 0.1 N thiocyanate is equivalent to 10.03 mg. of mercury.) EXPERIMENTAL Many assays of various diuretics were run, by the various methods, and typical results are presented in Table I. Mercumallylic acid and Mercumatilin sodium may give dark decomposition products during titration if treatcd as directcd above. This trouble may bc avoided by adding 30 ml. of water irtstcad of 10 nil. Also, in the case of Mercumallylic acid, this powder is bcst dissolved in about 6 ml. 0.1 N sodium hytlroxide before addition of the water a ~ l dsulfuric arid; otlicrwise it may not dissolve con~plctcly. DISCUSSION kIalidc ions interfere in the titration. sinccb they compete with thiocyanate for mcrcury. A preliin-
*
Receiyed October 10, 1954, from the Metropolitan Laboratories, Inc., Oyster Bay, N. Y.
inary test for halide should therefore be madc. Wc have found that commercial injectable mercurial diuretics are usually free of halide ions. Oneto and Cataldi (3) have described a dcterminative method likewise involving a relatively mild treatment, namely, heating with HCl, HNOI, and water until colorless. The mercury thus brought into titratable form is treated with standard KCN, and the excess KCN is back-titrated with standard AgNOs in the presence of ammonia, using K I as indicator. They claim t o have obtained precise results for a variety of mercurial diuretics, including mercaptomerin, which cannot be assayed by our method, but they do not mention how long the heating takes. CONCLUSIONS
I ti applicablc cases, thc mcthotl proyowl licreiii for assaying nicrcurial diuretics is fully its rcprotlucible and accurate as the co~iitnoit methods i i i use herctoforc, mid has thc advantagc of bciiig much shortcr. REFERENCES ( I ) H,,lrnann K . A.. and Sand, J., Rev., 33, 1310(1!IlJO). (2) Marquardt, R. P., and Luce. E. N., Anal. Chem. 20, 781 (1948). (3) Oneto, E. I., and Cataldi, M . E., Anales asoc. qaim. y farm., Uruguay. 51.36(1951).