Determination of sulfa drugs with chloramine-T - Analytical Chemistry

Two simple methods for the estimation of albendazole and its dosage forms ... the Quantitative Determination of Albendazole with Chloramine-T and Acid...
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Anal. Chem. 1982, 54, 249-253

in Table IV to illustrate the application of this method. The sampling sites are either harbours, marinas, or heavily industralized areas. The results obtained are higher than- data previously obtained for natural waters (5, 6).

Table IV. Analysis of Methyltin and Sn(1V) Species in Lake Watersa ( p g L-') location Port Maitland Mitchell Bay 1 Mitchell Bay 2 Toronto Harbour Port Dover Kingston Harbour

Me,Sn+ Me@'+

MeSn3+ Sn(1V)

nd

0.14

0.37

0.13

nd

0.10

0.35

0.98

nd

0.22

0.53

0.18

nd

0.29

0.96

0.54

nd nd

0.16 0.40

0.61 1.22

0.14 0.49

249

LITERATURE C I T E D Huey, C.; Brlnckman, F. E.; Grim, S.; Iverson, W. P. Proc. Int. Conf. Transp Persistent Chem. Aquat. Ecosyst. 1974, 73-78. Chau, Y. K.; Wong, P. T. S.; Kramar, 0.; Bengert, G. A. Proc. Int. Conf. Heavy Met. Environ. 1981, 641-644. Guard, H. E.; Cobet, A. B.; Coleman, W. M., I11 Science 1981, 213, 770-771. Brlnckman, F. E.; Jackson, J. A.; Blair, W. R.; Olson, G. J.; Iverson, W. P. Ultratrace speciation and biogenesis of methyltin transport species In estuarine waters. Trace Met. Seawater, NATO AUv. Res. Inst., In press. Braman, R. S.; Tompklns, M. A. Anal. Chem. 1979, 51, 12-19. Hodge, V. F.; Seidel, S. L.; Goldberg, E. D. Anal. Chem. 1979, 51, 1256-1259. Meinema. H. A.; Burger-Wiersma, T.; Versiuisde Haan, G.; Gevers, E. Ch. Environ. Scl. Techno/. 1978, 12, 288-293. Maguire, R. J.; Hunealt, H. J . chfOm8tOgr. 1981, 209, 288-293. Chau, Y. K.; Wong, P. T. S.; Goulden, P. D. Anal. Chlm. Acta 1976, 85. - - , 421-424. .- . .- .. Trachman, H. L.; Tyberg, A. J.; Branlgan, P. D. Anal. Chem. 1977, 49, 1090-1093. Vlckrey, T. M.; Howell, H. E.; Harrison, G. V.; Ramelow, G. J. Anal. Chem. 1980, 52, 1743-1746.

.

a Surface water taken from locations in Ontario, Sample size, 5-8. L; nd, not detected.

temperature used was isothermal at 30 OC. The trapping and desorbing of the analytes were similar to the procedure described for the analysis of volatile lead alkyls (9). Environmental Analysis of Methyltin Species. Several environmental samples (5-10 L) were collected in glass containers containing appropriate amounts of NaCl and brought back to the laboratory for analysis. Some resulta are tabulated

RECEIVED for review July 23,1981. Accepted October 8,1981.

Determination of Sulfa Drugs with Chloramine-T Krlshna K. Verma" and An11 K. Gupta Department of Chemlstry, Unlverslfy of Jabalpur, Jabalpur 48200 1, India

Sulfonamldes are tltrated In pharmaceutlcalPreparations by chloramlne-T In the presence of acldlled potassium bromide. Determlnatlons are made elther potentlometrlcally or vlsually uslng methyl red as lndlcator. SIX or four atoms of bromine are consumed dependlng on the substltuent attached to the sulfonamlde group. Acylatlon or dlarotlratlon of aromatlc amlno group prevents ortho substltutlon; thls addltlonal prereactlon has been used to analyze binary and ternary mlxtures of certaln sulfonamldes.

The extensive use of sulfa drugs in the treatment of various bacterial infections necessitates having accurate methods for determining these substances alone or in mixtures with other sulfa drugs in pharmaceutical preparations. A number of methods have been reported that employ bromination. Four atoms of bromine need be consumed per mole of sulfa drug (2-4); however, there are recorded cases of more bromine being consumed when the substituent attached to the sulfonamide group (5-12) is changed. For this reason, bromimetry could not enjoy wide popularity despite the availability of a variety of brominating agents, their good stability, and their applicability under various experimental conditions. The present investigations was undertaken to establish the stoichiometry of bromination reactions of sulfa drugs with respect to changing substituents and to work out the conditions suitable for their determination. It was also prompted by the lack of methods for analyzing mixtures of sulfonamides 0003-2700/82/0354-0249$01.25/0

commonly encountered in drug formulations. Sulfonamides have been titrated with chloramine-T (CAT) in the presence of acidified potassium bromide, the end point being detected potentiometrically or visually using methyl red as indicator. The equivalents of bromine consumed as a function of substituents present in sulfonamide are given in Table I. The free aromatic amino group of sulfonamides can be diazotized with nitrous acid and the diazonium group prevents bromine substitution in the two ortho positions. The atoms of bromine consumed by nitrous acid prereacted sulfonamides are also given in Table I. These two titration methods have been utilized to analyze certain mixtures of sulfa drugs. EXPERIMENTAL SECTION Reagents. CAT, 0.02 M solution, was made by dissolving 5.62 g of sodium N-chloro-4-toluenesulfonamide trihydrate in 1L of water and standardizing the solution iodometrically (13). A 0.02% solution of methyl red in 95% ethanol was used as indicator. Methods. Determination of Individual Sulfa Drugs. A known number of tablets are weighed and fiiely ground. A weight of powder equivalent to one tablet is treated with 10 mL of 10% sulfuric acid, ground to effect salt formation, and diluted to about 50 mL with continuous stirring. Any insoluble matter is filtered off on Whatman no. 41 paper and washed with 10 mL of 1% sulfuric acid. The combined filtrate and washings are diluted to a known volume with water. Succinyl and phthalylsulfathiazole are extracted by shaking with 20 mL of 10% sodium carbonate solution. The following methods of titrations are used: ' Method A. A known aliquot of drug solution is mixed with 5 mL of 3% sulfuric acid, 100 mg of potassium bromide, and 15 0 1982 American Chemlcal Society

250

ANALYTICAL CHEMISTRY, VOL. 54, NO. 2, FEBRUARY 1982

Table I. Stoichiometry of Sulfonamides as a Function of Substituents

sulfonamide

mol wt

equiv of Br method A method B

no. 1 2

sulfanilamide sulfacetamide

172 214

4 4

0 0

3

sulfaguanidine

214

4

0

4

sulfapyridine

24 9

4

0

5

sulfadiazine

250

6

2

6

sulfamerazine

264

6

2

7

sulfamethoxy diazine

280

4

0

8

sulfamethazine

27 8

4

0

9

sulfisomidine

27 8

4

0

10

sulfadimethoxine

310

6

2

11

sulfamethoxypyridazine

280

4

0

12

sulfathiazole

255

6

2

13 14

phthalylsulfathiazole succinylsulfathiazole

403 355

2" 2"

2 2

15

sulfamethiazole

270

4

0

16

sulfaphenazole

314

6

0

267

6

0

M e-& N-N

-0 N-N

1

Ph

17

sulfafurazole

pMe Me

a

18

sulfamoxole

26 7

6

0

19

sulfamethoxazole

253

4

0

20

sulfaproxyline

334

4

0

Six after hydrolysis.

mL of water and the contents are titrated with 0.02 M CAT either visually by using 3 drops of methyl red indicator taking the sharp bleaching of red color as the end point or potentiometrically by using a saturated calomel and platinum electrode pair. Sufficient methanol (10-15 mL) should be added to dissolve the precipitated

bromosulfonamides and to obtain a perceptable visual end point. In case the color of indicator fades gradually, 2 drops more of the indicator are added when the red color has almost faded and the titration is continued to the sharp bleaching of color. An indicator blank correction on the same number of drops of indicator is also

ANALYTICAL CHEMISTRY, VOL. 54, NO. 2, FEBRUARY 1982

251

Table 11. Determination of Sulfa Drugs by Method A

sulfa drug

sulfonamide

Diastrep Sulfaguanidine M&B 693 FuroquinolC SDM LAS Trimexold Sulfuno Lasibon Nebasulf e Orisul Cibazol Thalazole Urolucosil Elkosin

sulfadiazine sulfaguanidine sulfapyridine sulfafurazole sulfadimidine sulfame thoxypyridazine sulfame thoxazole sulfamoxole sulfadimethoxine sulfacetamide sulfaphenazole sulfathiazole phthalylsulfathiazole sulfame thiazole sulfisomidine

amt of sulfonamide,a mg present comparison mnfrs specifn method method 100 500 500 350 500 500 400 500 500

102 468 51 9 334 528 5 26 413 514 492

60 500 500 500 500 500

63 506 502 5 24 505 518

452,‘ 513f 51 Og 520g 51 Og 4882 501g 508g 52gf 513g 522g

The drug excipients a Average of six determinations; coefficient of variation ranges0.6-1.2 in the present method. were chloramphenicol (125 mg) and streptomycin sulfate ( 1 2 5 mg). CThe drug excipients were diiodohydroxyquinoline The drug excipient was trimethoprim (200 mg), chloroquine phosphate ( 5 0 mg), and oxyphenonium bromide ( 2 mg). (80 mg). e The drug excipients were necomycin sulfate ( 5 mg) and bacitracin ( 2 5 0 units). f Nitrite titration (22). Nonaqueous alkalimetry (23). Table 111. Determination of Sulfa Drugs by Method B amt of sulfonamide: present mnfrs specifn method

sulfa drug

sulfonamide

Diastrep Cibazol Lasibon ProxymerC Thalazole Cremomycin

sulfadiazine sulfathiazole sulfadimethoxine sulfamerazine phthalylsulfathiazole succinylsulfathiazole

100 500 500 375 500 500

mg comparison method

104 521 492 382 519 510

525d 503 e ~508~ 515d

Average of six determinations; coefficient of variation.ranges 0.4-0.8 in the present method. The drug excipients were chromamphenicol ( 1 25 mg) and streptomycin sulfate (1 25 mg). C The drug excipient was sulfaproxyline (375 mg). Nitrite titration (22). e Nonaqueous alkalimetry (23). applied; for 0.5 mL of methyl red solution the blank titer is 0.10 mL of 0.02 M CAT. Method B. A known portion of drug solution is mixed with 5 mL of 2% sodium nitrite and 2 mL of 3% sulfuric acid, and the mixture is allowed to stand for 2 min. Then, 1 g of urea is added to decompose the residual nitrous acid, the mixture being shaken well and kept for 2 min more. About 100 mg of potassium bromide, 5 mL of 3% sulfuric acid, and 15 mL of water are added and the sulfonamide is titrated with 0.02 M CAT potentiometrically or visually as before. Determination of Mixtures of Sulfa Drugs. Mixture No. 1-4,6,and 7. For the determination of compound I (Tables IV and V) an aliquot of mixture is analyzed by method B, the following equation being used: compound I (mg) = (mol wt)MVA (1) where VA is volume (mL) for “alone” titration using CAT of molarity M. Thereafter, an equal but separate aliquot of mixture is analyzed by method A to yield a total of two sulfonamides. The second substance is found by difference compound I1 (mg) of mol w t mixt no. 1-3, 6, and 7 = -[(MVT) - 3(MVA)1 2

(2)

hydrolyzed by mixing with 10 mL of 10%sulfuric acid and heating in a boiling water bath for 15 min. After cooling, the solution is determined by method A (titer VII). A third equal aliquot is again hydrolyzed and titrated by method B (titer VIII)

[

phthalylsulfathiazole (mg) = (mol wt) M-

(V11;

VI’]

(4)

sulfathiazole (mg) = (mol wt)M mol w t sulfamethazole (mg) = -M V I I - 3v111)l 2

(6)

Mixture No. 8 and 9. The mixture is titrated first by method A to yield titer VI; thereafter, an equal but second aliquot is hydrolyzed by mixing with 10 mL of 10%sulfuric acid and heating in a boiling water bath for 15 min and titrated after cooling by method A (titer VII). Equation 4 is used to determine phthalylsulfathiazole while the other compound is calculated by following sulfamerazine or sulfadiazine (mg) =

sulfafurazole (mg) of (3)

where VT is volume (mL) for “total”sulfonamide determination. Mixture No. 5. An aliquot of mixture is determined by method A to yield titer Vp A separate but equal portion of mixture is

RESULTS AND DISCUSSION A number of reagents can be employed to liberate bromine from acidified potassium bromide (1,12,14-17).CAT, however, excells in its ready availability, stability, and easy applicability (18-20).

252

ANALYTICAL CHEMISTRY, VOL. 54, NO. 2, FEBRUARY 1982

Table IV. Determination of Synthetic Mixtures of Sulfonamides amt taken, mg mixt. no.

I

I1

1

sulfadiazine 4.21 8.44 12.60 16.90 sulfamerazine 5.25 7.61 10.15 sulfadimethoxine 7.98 5.98 3.96 sulfathiazole 6.64 5.32 3.67 phthalylsulfathiazole 19.35 15.48 23.22 27.10 30.96 34.83

sulfaguanidine 14.80 11.10 7.40 3.68 sulfamethazine 8.88 13.32 4.44 sulfisomidine 4.02 5.03 6.60 sulfafurazole 3.12 7.80 10.92 sulfathiazole 6.64 5.32 7.97 5.32 3.97 7.94

2

3

4

5

a

amt found:

I

I1

4.42 8.45 12.67 16.87

14.38 10.93 7.66 3.70

5.40 7.81 10.40

9.08 13.73 4.73

8.06 5.97 4.00

4.04 5.08 6.53

6.60 5.28 3.72

3.16 7.75 10.70

I11

mg

I11

sulfamethiazole 9.13 19.06 7.00 8.94 7.31 15.65 5.56 6.65 10.96 23.90 7.90 11.41 12.78 27.89 5.38 12.93 14.61 31.57 3.95 15.40 16.44 35.29 8.08 17.17 Average of six determinations; coefficient of variation ranges 0.6-1.2 in binary mixtures and 1.1-2.1 in ternary mixture.

Table V. Determination of Mixtures of Sulfa Drugs amt, mg mnfrs present specifn methoda

sulfonamides present mixt no. 6

I

sulfa drug Streptriad

I1

sulfadiazine

150 150 375 375 150 50 200 150

sulfadimidine

7

Proxymer

sulfamerazine

8

Chlorosulf

phthalylsulfathiazole

9

Entromycetin sulfac

sulfadiazine

sulfaproxyline sulfamerazine phthalylsulfathiazole a Average of six determinations; coefficient of variation ranges 0.8-1.3. The drug excipient was chloramphenicol, 150 mg. 100 mg.

Sulfonamides on reaction with bromine undergo 3,5-dibromination, both positions being ortho to the amino group.

+

-

MeC6H4S02NNaC1 2HBr MeC6H4So2NH2

+ NaCl + Br2

142 154 382 366 14 5 59 21 0 156

The drug excipient was choramphenicol,

amides, viz., sulfadiazine and sulfathiazole, may be written as

+

tl,N*S02NH--(9

3Br2

-

Br

/

Br

On the acylation of amino group (as in succinyl and phthalylsulfathiazole), however, this characteristic ortho dibromination stops. The same effect results if the sulfa drugs are diazotized beforehand. The prevention of 3,5-dibromination in this way permitted determination of bromine consumption by R group in sulfonamides (Table I). The carbon p to nitrogen is active for electrophilic substitution in the side chain (21). Thus reactions with two typical sulfon-

Br

tl2N9SO2NH---(>Br

N

+

3HBr

Results are given in Table 11 for the determination of a number of sulfa drugs by direct titration with CAT. Nitrous

Anal. Chem. 1982, 5 4 ,

acid prereaction method could only be used when sulfonamide in question retains a two-electron change (Table 111). Chloramine-T is a general reagent which may react with a number of substances that happen to be present with sulfonamides in unknown samples and may vitiate the analysis (22). Therefore a study of interferences was warranted. Materials which do not interfere in method A when present up to 20-fold molar excess to the determinant include glucose, sucrose, starch, lactose, citric acid, tartaric acid, formic acid, urea, histidine, glycine, glutamic acid, thiamine hydrochloride, iron(I1) sulfate, folic acid, dibutylbarbituric acid, phenacetin, and acetylsalicylic acid; other examples are given in the footnote of Table 11. It appears from this freedom from a number of foreign materials that the bleaching of methyl red is faster than most secondary reactions. Method B can also tolerate p-aminobenzoic acid, vitamin C, isonicotinyl hydrazide, barbituric acid, and sulfonamides which change their bromine equivalents from four or six to nil (Table I). Tyrosine, tyrptophan, morphine, codeine, allylbarbituric acid, thymol, methionine, cystine, and penicillins vitiate the analysis in both the methods even when present in small amounts.

253-256

253

(3) Gopal, M. I.; Pande, U. C. 2.Anal. Chem. 1975, 277, 125. (4) Prasad, B. B.; Khandelwal, G. D.; Singh, T. B. Acta Pol. fharm. 1977, 34, 177. ( 5 ) Abdlne, H.; Abdel Sayed, W. S. Egypt. fharm. Bull. 1982, 44, 453. (6) Wermescher, B.; Murea, L.; Beral, H. Rev. Chlm. (Bucharest)1982, 13, 105. (7) Ahrarez Large, J. L.; Pla Delfin, J. M. Galenlca Acta 1983, 76, 209. (8) Ibrahlm, M. A.; Sadlk, A. E. J . Pharm. Scl. U.A.R. 1987, 8 , 133. (9) Aklra, E.; Jun, T.; Mumlo, I . YakugakuZasshl1987, 87, 769. (IO) Shukla, V. K. S.; Shukla, S.; Sharma, J. P. 2.Anal. Chem. 1973, 265, 352. (11) Shaker, M.; Yousset, 0. W. Microchem. J . 1974, 79, 339. (12) Verma, K. K.; Srivastava, A.; Ahmed, J.; Bose, S. Talanta 1978. 25, 469. (13) Berka, A.; Vulterin, J.; Zyka, J. “Newer Redox Titrant”; Pergamon Press: Oxford, 1965;p 37. (14) Barakat, M. 2.; Abou-ECMakarem, M.; Abd-El-Raoof, M. Anal. Chem. 1974, 46, 777. (15) Plllal, V. N. S.; Nair, C. G. R. Talanta 1975, 22, 57. (16) Nalr, C. 0. R.; Indrasenan, P. Talanta 1978, 23, 239. (17) Mahadevappa, D. S.;Gowda, B. T. Talanta 1977, 24, 325. (18) Srlvastava, A.; Bose, S. J . Indlan Chem. SOC.1975, 52, 214. (19) Gowda, N. M. M.; Mahadevappa, D. S. Talanta 1977, 24, 470. (20) Verma, K. K.; Gulatl, A. K. Anal. Chem. 1980, 52, 2336. (21) Joule, J. A.; Smith, G. F. “Heterocycllc Chemistry”; Van NostrandRelnhold: London, 1979;p 322. (22)Garratt, D. C. “The Quantitatlve Analysls of Drugs”; Chapman & Hall: London, 1964; p 608. (23) Fritz, J. S.;Keen, R. T. Anal. Chem. 1952, 24, 308.

LITERATURE CITED (1) Barakat, M. 2.; Shaker, M. Analyst (London) 1984, 89, 216. (2) Agrawal, S. P.; Walash, M. I.; Blake, M. I. J . Pharm. Scl. 1972, 67, 779.

RECEIVED for review April 7,1981. Resubmitted August 14, 1981. Accepted September 22, 1981.

Screening Procedure for Determination of Total N-Nitroso Content in Urine Robert D. Cox’ and Clyde W. Frank” Department of Chemistty, The University of Iowa, Iowa Clty, Iowa 52240

Lisa D. Nlkolalsen and Ruth

E. Caputo

Institute of Agricultural and Environmental Health, Environmental Chemlstry Sectlon, College of Medicine, The University of Iowa, Iowa City, Iowa 52240

The total N-nltroso content In urlne Is determlned by the acld-catalyzed denltrosatlon of N-nltroso compounds and determlnatlon of the NO produced via Its chemllumlnescence wlth ozone. The detectlon limit Is 3 X lo-’ M and preclslon Is approxlmately 10% on urlne samples. Nitrate and nltrlte Interfere and must be removed prlor to the denltrosatlon step. Detectable levels of N-nltroso content were found In the urlne of 10 lndlvlduals that were tested.

N-Nitroso compounds are a broad class of chemicals which pose serious health hazards to humans. The carcinogenicity, mutagenicity, and teratogenicity of these compounds are well documented (1-5). Humans may be exposed to N-nitroso compounds in a variety of ways, such as ingestion of food, water, or alcoholic beverages, from the consumption of smoking of tobacco, absorption from the air or consumer products, occupational exposure, and in vivo formation within the human digestive system. In vivo formation of N-nitroso compounds from nitrite and amine percursors has been dem‘Present address: Radian Corp., Austin, TX 78766.

onstrated (6-8). Although initial studies investigating this phenomenon used relatively large amounts of the precursors, in vivo formation from typical environmental levels has recently been demonstrated (9). In addition, a consistent detectable level of N-nitrosodimethylamine,apparently resulting from in vivo formation, has been demonstrated in human blood (9). Although acidity and low nitrite levels occurring in the urinary bladder are not favorable toward nitrosamine formation, bacterial infection and high nitrate consumption could present conditions favorable toward formation of these compounds (IO). Urine contains significant amounts of nitrogeneous compounds which can potentially undergo reactions to form N-nitroso compounds. The distribution of urine nitrogen consists of approximately 84% as urea, 4-5% each of amino acid, ammonia, and creatinine nitrogen, and 1-2% as uric acid and hippuric acid. The major amino acids normally found in urine are histidine, glycine, glutamic acid, aspartic acid, and cystine. The primary inorganic constituents in urine are sodium, potassium, and chloride, with lower concentrations of calcium and potassium. The primary analytical techniques used for determination of N-nitroso compounds are gas and liquid chromatography.

0003-2700/82/0354-025380 1.25/0 0 1982 Amerlcan Chemical Soclety