Analysis of chloride in amine hydrochlorides and quaternary ammonium chlorides by atomic absorption spectroscopy

MICROCHEMICAL

JOURNAL

17, 638-642 (1972)

Analysis of Chloride in Amine Hydrochlorides Ammonium Chlorides by Atomic Absorption ROBERT

and Quaternary Spectroscopy

V. SMITH AND MARK A. NESSEN

Division of Medicinal Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52240 Received July 13, 1972

INTRODUCTION Numerous amine hydrochlorides and quaternary ammonium chlorides are used as drugs. The United States (6, 15) and European (3) compendia require analyses for chloride content while certain drugs are indirectly determined by assaying chloride. Titrimetric methods are most commonly employed in analyzing chloride in pharmaceuticals (13,17). These procedures, though not usually very sensitive, can be improved in accuracy and precision by use of chloride-selective electrodes (2, 5, 7, 8).

Atomic absorption spectroscopy (AAS) has been utilized for the indirect determination of chloride in a variety of materials (I, 4, 9, 16). These methods are based on precipitation of chloride by silver nitrate and are attractive because of their accuracy, precision, and sensitivity (4,9, 1’6). An investigation was proposed to determine the applicability of the AAS technique to the analysis of chloride in amine salts. Results obtained with eleven quaternary amine chlorides possessing diverse structures, are described in this report along with comparison titrimetric analyses. MATERIALS AND METHODS Equipment A Jarrell-Ash 82-270 Atomsorb atomic absorption spectrophotometer, equipped with a single-slot burner head (10 cm pathlength) and silver hollow-cathode lamp, was used throughout. Silver was measured at 3281 A with instrumental parameters previously described (12). Reagents Quaternary amine chlorides. The following test compounds (USP or NF grade) were used as obtained (supplier) : apomorphine hydrochloride (Penick) , betazole hydrochloride (Lilly), bethanechol chloride (Merck), ephedrine hydrochloride (Merck), isoproterenol hydrochloride (Sigma), methamphetamine hydrochloride (Abbott), nalorphine 638 Copyright 0 1972 by Academic Press, Inc. All rights of reproduction in any form reserved.

cl

ANALYSIS

IN

AMINE

SALTS

BY

AAS

639

hydrochloride (Merck), phenylephrine hydrochloride (Winthrop), pralidoxime chloride (Aye&), procaine hydrochloride (Mallinckrodt ) , and tetracycline hydrochloride (Lederle). All other chemicals were of analytical reagent grade. Solutions. Chloride-free water was obtained by distillation from 0.1% sodium hydroxide (9). Solutions were stored in glass no longer than 24 hr. Silver nitrate solutions were prepared and maintained in redtinted volumetric flasks. Silver working standards, method 1. One and 2 ml aliquots of AgN03 stock solution (47 mg Ad100 ml) are added to 100 ml volumetric flasks containing 5 ml of HNO,. Dilute to 100 ml with water; final solutions equivalent to 3 and 6 ppm Ag. Silver working standards, method ZZ.A stock solution of Ag(NH,)‘,Cl is prepared by dissolving 53 mg of AgCl in 10 ml of cone NH,OH and diluting to 100 ml with water. One and 2 ml aliquots of this solution are diluted to 100 ml with 2.8% NH,OH; final solutions equivalent to 4 and 8 ppm Ag. Chloride precipitating solution. AgNO, (700 mg) is placed in a 100 ml volumetric flask; 5 ml of HNO, are added and the solution is made up to 100 ml with water. Procedures Method I. A solution containing 600 to 700 lug Cl/ml is prepared and 1 ml is reacted with 1 ml of AgN03 solution (7 mg/ml) in a 10 ml centrifuge tube. After standing in an ice bath for 10 min, the mixture is centrifuged at 2000g for 10 min. Supematant (1 ml) is pipetted into 250 ml volumetric flask containing 12.5 ml HNO,. Following dilution with water, the amount of Ag is determined by AAS. Method ZZ. The Cl-containing sample solution is reacted as in method I. The AgCl formed is collected on a sintered glass funnel, rinsed with water, and dissolved in 30 ml of cone NH,OH. The solution is made up to 300 ml with water and the amount of Ag is measured by AAS. Mercurimetric titration. Samples equivalent to 600 to 700 pg of Cl are titrated with mercuric nitrate according to the method of Schales and Schales (I 0) using reagents available from Sigma (II ) . Fujun’s titration. Samples containing 40 to 120 mg of Cl were titrated according to the official method (15). RESULTS AND DISCUSSION

Comparison of Methods Z and ZZ

Two procedures have generally been employed for atomic absorption analysis of chloride (I, 4, 9, 14, 16). One involves determination of silver remaining in a silver nitrate solution following precipitation of

640

SMITH

AND

NESSEN

TABLE I COMPARISON

OF

AA

METHODS

FOR CHWRIDE

a

$!&Recovered Method

Range

Mean

RSD

I

98.6-102.4

100.26

1.2

II

93.5- 98.2

95.5 c

1.2

a 600 to 700 fig Cl as NaCI. b Ten determinations. c Thirteen determinations.

chloride. The second is based on dissolution of precipitated silver chloride in ammonium hydroxide and measurement of the silver content of the resulting silver diamine chloride solution. These techniques are described in the Procedures section as methods I and II, respectively. A side-by-side comparison of the accuracy and precision of these methods was made with sodium chloride prior to analysis of amine salts. Results of this experiment appear in Table 1. Method II inexplicably gave low recoveries of chloride while method I showed good accuracy and precision. In terms of convenience, method I is also the superior procedure. TABLE 2 ANALYSIS

OF CHLORIDE

IN AMINE

SALTS

‘% Recovery f RSD a Compound

AAS, method I b

Mercurimetric titr. b

Apomorphine HCI Betazole HCI Bethanechol chloride Ephedrine HCI Isoproterenol HCl Methamphetamine HCI Nalorphine HCI Phenylephrine HCl Pralidoxime chloride Procaine HCI Tetracycline HCI

103.7 * 1.8 102.0 f 1.3 98.6 z!z 1.1 100.6 & 1.3 100.3 f 2.7 100.6 f 1.3 102.4 f 1.8 99.0 f 3.1 99.7 f 1.8 99.6f2.1 98.9 f 1.3

98.8 f 1.1 91.8 f 1.7 lOl.Of 1.1 99.9 f 0.9 98.1 f 0.9 lOl.Of0.7 101.0 f 1.0 98.2 f 2.5 98.3 f 1.8 97.9 f 0.5 100.8 f 1.8

0 Eight to ten determinations. bAmine salts equivalent to 600 to 700 pg of Cl. eAmine salts equivalent to 40 to 120 mg of Cl.

Fajan’s titr. c 94.5 f 1.5 96.5 f 1.0 102.7 f 1.1 102.5 f 1.7 103.1 f 0.3 97.1 f 1.6 102.6f0.5 96.0 i 1.2 97.8 f 1.2

cl

An&y&

ANALYSIS

of Chloride

IN AMINE

SALTS

BY AAS

641

in Amine Salts

Method I was used to determine chloride content of 11 amine salts. The results of these analyses are indicated in Table 2 along with comparison titrimetric assays. The atomic absorption method compares favorably in accuracy and precision to the mercurimetric titrimetric procedure. The Fajan’s titrimetric method, on the other hand, yields consistently poorer results than the mercurimetric or atomic absorption procedures. It is noteworthy that the different functional groups in the drugs used, do not appear to adversely affect the results achieved with either the atomic absorption or mercurimetric methods. SUMMARY

The atomic absorption analysis of chloride in amine salts has been studied. The method employed is based on measurement of excess silver following precipitation of chloride with silver nitrate. Eleven quaternary amine chlorides, possessing diverse structures, have been successfully analyzed. The accuracy and precision of the atomic absorption method compares favorably with results obtained with mercurimetric and Fajan’s titrimetric procedures. ACKNOWLEDGMENT This investigation was supported in part by a Mead Johnson Laboratories grant for undergraduate research in pharmacy. REFERENCES 1. Bartels, H., An indirect determination of serum chloride by atomic absorption methods. At. Absorption Newslett. 6, 132 (1967). 2. Dessouky, Y. M., Toth, K., and Pungor, E., The application of anion-selective membrane electrodes in pharmaceutical analysis. Analyst (London) 95, 1027-1031 (1970). 3. “European Pharmacopeia,” Vol. 1, Maisonneuve, Saite-Ruffine, France, 1969. 4. Ezell, J. B., Jr., Atomic absorption analysis of chloride in plant liquors. At. Absorption New&t. 6, 84-85 (1967). 5. Katz, D. A., and Mukherji, A. K., Determination of halides with ion-selective electrodes. Microchem. .I. 13, 604-615 (1968). 6. “National Formulary,” 13th ed., Mack, Easton, PA, 1970. 7. Papp, E., and Pungor, E., Determination of chloride content of biological fluids using a chloride-selective electrode. Fresenius’ Z. Anal. Chem. 246, 26-28

(1969).

8. Papp, E., and Pungor, E., Determination of chloride in chloride salts of some drugs using the chloride-selective membrane electrode. Fresenius’ Z. Anal. Chem. 250, 31-34 (1970). 9. Reichel, W., and Acs, L., Determination of chlorine in selenium by a distillation-atomic absorption procedure. Anal. Chem. 41, 1886-1888 (1969). 10. Schales, O., and Schales, S. S., A simple and accurate method for the determination of chloride in biological fluids. J. Biol. Chem. 140, 879-884 (1941). 11. Sigma Bull. No. 830, Mar. 1965.

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12. Smith, R. V., and Nessen, M. A., Atomic absorption anaIysis of sodium, potassium, and calcium in Ringer’s solution. J. Pharm. Sci. 60, 907-908 (1971). 13. Sutherland, J. W., Williamson, D. E., and Theivagt, J. G., Pharmaceuticals and related drugs. And. Chem. 43, 216R (1971). 14. Truscott, E. D., Determination of chlorine in a polyvinyl chloride matrix using the Schoniger oxygen flask and atomic absorption spectrometry. Anal. Chem. 42, 1657 (1970). 15. “United States Pharmacopeia,” 18th Rev., Mack, Easton, PA, 1970. 16. Westerlund-Helmerson, U., The determination of chloride as silver chloride by atomic absorption spectroscopy. At. Absorption Newslett. 5, 97 (1966). 17. Zapotocky, J. A., In “Pharmaceutical Chemistry” (L. G. Chatten, Rd.), Vol. 1, pp. 129-140. Dekker, New York, 1966.