(3) F. D. Rossini. "Chemical Thermodynamics, "University of Notre Dame, Notre Dame, IN, 1949, pp 89-1 11. (4) R. Reubke and J. A. Mollica, Jr., J. Pharm. Sci., 56, 822 (1967). (5) N. J. DeAngelis and G. J. Papariello, J. Pharm. Sci., 51, 1868 (1968). (6) C. Plato and A. R. Glasgow, Jr., Anal. Chem.. 41, 330 (1969). (7) G. L. Driscoll, I. N. Duling. and F. Magnotta in "Analytical Calorimetry". Vol. I, R. S. Porter and J. F. Johnson, Ed.. Plenum Press, New York, 1968, pp 271-278. (8) G. J. Davis and R. S . Porter, J. Therm. Anal., 1, 449 (1969). (9) E. M. Barrall II and R. D. Diller, Thermochim. Acta, 1, 509 (1970). (IO) E. F. Joy, J. D. Bonn and A. J. Barnard, Jr., Thermochim. Acta, 2, 57 (1971). (1 1) D. L. Sondack, Anal. Chem., 44, 888 (1972)
(12) E. E. Marti, Thermochim. Acta, 4, 173 (1972). (13) R. Schumacher and B. Felder, Fresenius' 2. Anal. Chem., 254, 265 (1971). (14) H. Staub and W. Perron, Anal. Chem., 46, 128 (1974). (15) Perkin-Elmer Corp. Thermal Analysis Application Study, No. 3 and No. 10. (16) H. M. Heuvel and K . C. J. B. Lind, Anal. Chem., 42, 1044 (1970). (17) H. A. Laitinen, "Chemical Analysis," McGraw-Hill, New York, 1960, pp 537-578.
RECEIVEDfor review December 13, 1974. Accepted March 25, 1975.
Determination of Sulfonamides of Pharmaceutical Importance by Catalytic Thermometric Titration Edward J. Greenhow and Leslie E. Spencer Depafiment
of Chemistry, University of London, Manresa Road, London, S W3 6LX, England
Tetra-n-butylammonium hydroxide, sodium methoxide, potassium methoxide, and potassium hydroxide, in nonaqueous solution, and pyridine, dimethylformamide dimethylsulfoxide, 1,1,3,34etramethylurea, and N,N,N',N'-tetramethyll,2-dlaminoethane, have been evaluated as titrants and sample solvents, respectively, in the determination of the acidic functions of sulfanilamide derivatives and sulfonamide formulations of pharmaceutical importance by catalytic thermometric tltration. When acrylonltrlle Is used as the thermometric indicator, both the end-point sharpness and the reaction stoichiometry corresponding to this end point are influenced by the nature of the titrant and the sample solvent, particularly in determinations of sulfanilamide and sulfaguanidine. Satisfactory assay values are obtained with potassium hydroxide in propan-2-01 as the titrant, acrylonitrile as the solvent for sulfanilamide, dimethylsulfoxide as the solvent for sulfaguanidine, and dimethylformamlde or dlmethylsulfoxlde as the solvent for other sulfonamides. Preclslons of better than 1 and 2 % have been obtained with 0.01 and 0.001 mequlv samples, respectively.
Various titrimetric methods are, or have been, recommended for the routine assay of the sulfonamides of pharmaceutical importance and the sulfonamide content of pharmaceutical formulations. Titration with sodium nitrite solution, to determine the aromatic amine function, is now the most widely used assay procedure (1-3), but titration of acidic hydrogen in the sulfonamide group is an acceptable alternative method (4-6). According to Garratt (7), sulfisoxazole (sulfafurazole) cannot be determined satisfactorily by the nitrite method, and this compound and the related sulfamethoxazole are currently assayed (1, 2 ) by nonaqueous acid-base titration using a visual indicator to locate the end point. The latter procedure was previously recommended for the determination of sulfamethoxypyridazine ( 2 ) . Conventional thermometric titration has been used for the determination of sulfonamides in aqueous solution. The reactions employed include diazotization with 0.1M sodium nitrite ( 8 ) , oxidation with 0.5M sodium hypochlorite ( 9 ) , and the formation of silver derivatives with 0.3M 1384
ANALYTICAL CHEMISTRY, VOL. 47, NO. 8, JULY 1975
silver nitrate (10). Catalytic thermometric titrimetry, in which the heat evolved during the alkali-catalyzed anionic polymerization of acrylonitrile is used to establish the end point, has been shown to be suitable for the determination of carboxylic acids, phenols, and other weak acids in nonaqueous solution (11).The polymerization is initiated by a small excess of the alkali titrant, after the acid sample has been neutralized:
+ CH2=CHCN HOCH2CH-CN HOCH2CH-CN + nCHz=CHCN OH-
+
+
HO(CHzCHCN),CH&H-CN AHp = -18.3 kcal mol-1 (of monomer)
An evaluation of the use of this technique for the assay of sulfonamides, the subject of the present study is, in addition to its practical relevance, of theoretical interest because the sulfonamides represent a convenient series of weak acids suitable for a systematic investigation of the factors influencing the titrimetric process. In the earlier investigation, it was observed that, with some compounds, the end points corresponded to sub-stoichiometric neutralization reactions. For example, the titrant:acid molar ratios a t the thermometric end point were 0.17 and 0.69 when solutions of succinimide in dimethylformamide were titrated with 0.1M tetra-n-butylammonium hydroxide in toluenemethanol and 0.1M potassium hydroxide in propan-2-01, respectively. In the titration of 4-methyl-2,6-di-tert -butylphenol, in which the acidic function is sterically hindered, the corresponding reaction stoichiometries were 0.5 and 0.73. In the present study, pyridine, dimethylformamide, dimethylsulfoxide, 1,1,3,3-tetramethylurea and N,N,N',N'tetramethyl-1,2-diaminoethanehave been evaluated as solvents in combination with four titrants, namely, tetran-butylammonium hydroxide, sodium methoxide, potassium methoxide, and potassium hydroxide. The first three solvents are widely used in nonaqueous potentiometric and indicator titrations of weak acids, while 1,1,3,3-tetramethylurea has been evaluated (12) as a solvent in the determination of sulfonamides by these techniques. N,N,N',N'-tetramethyl-1,2-diaminoethanewas investigated as a repre-
Table I. Titration of Sulfanilamide Derivatives AcryloCompound
pKaU3)
mg
nitrile, ml
Titrant, Wb
Reaction ratio C
2 1.80 40.4 B, 0.1 (acid) 1. P h t haly sulfat hiaz ole 2 1.97 B, 0 . 0 1 4.3 (acid) 2 . Phthalysulfathiazole 4 2.05 K, 0 . 1 41.0 (acid) 3 . Pht haly sulfathiazole 2 B, 0 . 1 1.80 37.4 (acid) 4. Succinylsulfathiazole 2 1.96 B, 0.01 3.7 (acid) 5. Succinylsulfathiazole 1 B , 0.001 1.96 0.37 (acid) 6 . Succinylsulfathiazole 2 1.98 K, 0.1 36.2 (acid) 7 . Succinylsulfathiazole 2 B, 0.1 1.oo 25.1 6.52 8 . Sulfadiazine 1 B, 0.001 1.oo 0.25 6.52 9. Sulfadiazine 2 0.99 27.9 B, 0.1 7.37 1 0 . Sulfadi m idi ne 1 B, 0.001 1.oo 0.28 7.37 11. Sulfadimidine 2 0.99 B, 0.1 26.4 6.98 12. S u l f a m e r a z i n e 2 B, 0.01 0.98 .2.6 6.98 13. Sulfamerazine 2 B, 0 . 0 1 0.98 2.7 5.45 14. Sulfamethizole 3 1.oo 24.6 K, 0.1 8.43 15. Sulfapyridine 3 1.oo 25.0 N , 0.1 8.43 16. Sulfapyridine 3 N , 0.1 0.99 24.6 8.43 17. Sulfapyridine 3 1.oo P , 0.1 24.9 8.43 18. Sulfapy r idine 3 0.99 K, 0 . 1 25.0 8.43 19. Sulfapyridine 4 1.01 3 0 .O B, 0 . 1 8.43 20. Sulfaquinoxaline 3 24.5 1.oo B, 0 . 1 7.25 21. Sulfathiazole 3 1.oo 24.5 K, 0 . 1 2 2 . Sulfathiazole 7.25 3 B, 0 . 1 1.02 25.5 7.25 2 3 . Sulfathiazole 3 0.95 25.5 N, 0 . 1 7.25 2 4 . Sulfathiazole 0.96 3 N, 0.1 25.7 7.25 25. Sulfathiazole 3 N, 0.1 0.95 25.5 7.25 26. Sulfathiazole 3 24.5 P, 0 . 1 1.01 2 7 . Sulfathiazole 7.25 3 K,0 . 1 0.97 25.5 7.25 2 8 . Sulfathiazole 2 20.05 B , 0.1 1.01 2 9 . Sulfaur ea 5.42 1 100.2 K, 1.0 1.02 3 0 . Sulfaur ea 5.42 a d = dimethylformamide; m = dimethylsufoxide; p = pyridine; t = 1,1,3,3-tetramethylurea. * B = tetra-n-butylammonium hydroxide; K = potassium hydroxide; N = sodium methoxide; P = potassium methoxide (molarities are nominal value). Equivalents of titrant combining with one molecule of compound.
sentative aliphatic a m i n e solvent instead of the more usual 1,2-diaminoethane, because the latter compound undergoes exothermic addition with acrylonitrile, the thermometric indicator. In all, some twelve pharmaceutical-grade sulfanilamides and seven sulfonamide formulations have been examined. T h e reported pK, values of these sulfonamides (13) lie i n the range 5.00 to 10.08 while sulfaguanidine is described merely as “basic” (the pKbl and PKb2 values are 11.25 and 13.52, respectively ( 1 4 ) ) , and phthalyl- and succinyl-sulfathiazole are described as “acidic”. A p a r t f r o m t h e last t w o sulfonamides, i n which the aromatic a m i n e group is also substituted, t h e c o m p o u n d s differ only i n the n a t u r e of the s u b s t i t u e n t on the sulfonamide group. EXPERIMENTAL Reagents. Acrylonitrile and the sample and titrant solvents were dried over molecular sieve type 4A before use. The 0.1M tetra-n-butylammonium hydroxide, sodium methoxide, and potassium methoxide were in methanol-toluene solution, 1:3. 1:6 and l : l 5 , respectively, and the 0.01 and 0.001M tetra-nbutylammonium hydroxide solutions were prepared by diluting the 0.1M reagent with a 1:3 mixture of propan-2-01 and toluene. Potassium hydroxide titrant, 1.0 and 0.1M was prepared by dissolving the solid (analytical-reagent grade) in propan-2-01, All the titrants were standardized vs. solutions of benzoic acid in dimethylformamide, using the thermometric procedure. All the sulfanilamide derivatives and sulfonamide formulations
except sulfaurea (1-sulfanilylurea) were of B.P., B.P.C., or B.Vet.C grade and were gifts. Apparatus. The automatic titration apparatus, comprising a motor-driven micrometer syringe, a thermistor coupled to a potentiometric chart recorder through a bridge circuit, and a stirred, insulated, reaction vessel (10-ml capacity), has been described earlier ( 1 5 ) . Procedure. The titrant was added a t a constant rate of 0.12 ml min-’ to a stirred mixture of the sample, solvent, and monomer (thermometric indicator) in the titration flask. Sample sizes were chosen to obtain titration volumes of about 1 ml above the blank titration value. Thus, the 1.OM titrant was used for the determination of sample sizes of about 1 mequiv and the 0.1, 0.01, and 0.001M titrants were used with correspondingly smaller samples. Temperatures and titrant volumes were recorded a t a chart speed of 600 mm hr-’ with the potentiometric recorder operating at 100 mV full scale. Details of the sample, solvent, monomer, and titrant are given in Tables I and I1 and Figures 2 and 3. The end point of the titration is taken to be the point where the tangent to the main heat rise leaves the curve a t its lower temperature end (16) (See Figures 1 (Zl),2 (K,a) and 3 (K(l.O)a). The assay methods given in the British Pharmacopeia ( 3 ) were used in the comparison of the thermometric method with the currently-recommended procedures for the determination of the sulfonamide content of the formulations.
RESULTS A N D DISCUSSION Details of some titrations that are representative of those obtained in the determination of ten of the twelve sulfonamides, using the different t i t r a n t s and solvents, a r e given ANALYTICALCHEMISTRY, VOL. 47, NO. 8, JULY 1975
1385
T,rnW/,n
Figure 1.
1 ,,“,,,m * 1 T I
,
Catalytic thermometric tltratlon curves for sulfonamides
2, Phthalylsulfathiazole: 4, succlnylaulfathiazole; 8 and 9, suifadlarine; 13, sulfamerazine: 14, sulfamethizole: 15, 17, and 19, aulfapyridlne: 20, suifaquinoxaiine: 2 1-26, 28, sulfathiazole; 29, sulfaurea. Numbers correspond to those in Table I: titration detalls are given In the table. end polnt, curve 21
r
IdW,,Dr:‘*I
~
Catalytic thermometric titration of sulfanilamide
Curve symbols refer to the titrant and sample solvent, respectively. B = 0.1 M tetra-n-butylammonium hydroxide: N = 0.1M sodium rnethoxide; P = 0.1M potassium methoxide: K = 0 . l M (K(l.O) = 1.Onn) potassium hydroxide. e = N,N,N’,N’-tetramethyl-1,2-diaminoethane: p = pyridine; d = dlmethylformamide; t = 1,1,3,3-tetramethylurea: m = dimethylsulfoxide: a = acrylonitrile. Titrant/sample reaction stoichiometry: B,e: 0.18; B,p: 0.17; B,d: 0.16: B,t: 0.30;B,m: 0.19: B,a: 0.18; N.e: 0.56:N.p: 0.67; N,d: 0.20: N,t: 0.22: N,m: 0.19; N,a: 0.85:P,e: 0.53;P,p: 0.59:P,d: 0.16; P.t: 0.22; P,m: 0.17: P,a: 0.70; K.e: 0.71; K.p: 0.64; K,d: 0.37;K,t: 0.38: K,m: 0.52; K,a: 0.63:K(l.O).a: 1.00. Titration details: 0.1-mequiv sample (1.0 mequiv with the 1.OM titrant): 1 mi solvent: 3 ml acrylonitrile. ? end point, curve K,a
in Table I, and Figure 1 shows some typical titration curves. The details for the titrations of the very weakly acidic sulfanilamide and the “basic” sulfaguanidine, together with the titration curves, are given in Figures 2 and 3, respectively. Apart from the last two sulfonamides, the compounds examined can be determined satisfactorily as their solutions in any of the six solvents with any of the four titrants with precisions of better than 1%with sample sizes down to about 0.01 mequiv, and 2% with samples down to 0.001 mequiv by using titrants of the appropriate molarity. Precision values are given in Table 11. The end-point inflections obtained in the titrations of the more acidic sulfonamides (pK, values up to 8.43) listed in Table I, differ in shape to a small extent when different titrant-solvent combinations are used. Thus, with sulfapyridine and sulfathiazole, the sharpest end points are ob1386
3. Catalytic thermometrlc titration of sulfaguanidine
Curve symbols (for tltrant and solvent) are explained in Figure 2. Tltratlon,details are as In Figure 2. Tltrant/sample reaction stolchlometry: B,p: 1.OO;B,d: 1.00: B,t: 1.02: B,m: 1.02; B,a: 0.95: N,p: 0.95: N,d: 0.95; N,t: 0.96: N,m: 0.99; N,a: 0.45; P,p: 0.99: P,d: 1.03: P,t: 1.00; P,m: 1.08: P,a: 0.54: K,p: 1.01: K,d: 1.00: K,t: 1.01: K,m: 0.94; K,a: 0.96; K(l.O),a: 1.18. t end polnt, curve K(l.O),a
83
hd/”.
Figure 2.
Figure
ANALYTiCAL CHEMISTRY, VOL. 47, NO. 8, JULY 1975
tained with the sodium methoxide titrant and pyridine and 1,1,3,3-tetramethylurea as the sample solvents (curves 17 and 25, Figure 1). In general, however, these variations have little influence on the precision of measurement, and the choice of titrant and sample solvent for the determination of the ten sulfonamides will depend on the availability or convenience of preparation of the reagents. When 0.1-mequiv samples of the difunctional phthalyland succinyl-sulfathiazoles are titrated with the 0.1M tetra-n-butylammonium hydroxide titrant, the end-point inflection occurs before neutralization is complete. Precipitation of the acid salt is the probable cause. The correct stoichiometry was achieved by using 0.01-mequiv samples or 0.1-mequiv samples in conjunction with 0.1M potassium hydroxide as the titrant (Table I). Calibration graphs have been constructed for four of the sulfonamides, namely, succinylsulfathiazole, sulfadiazine, sulfadimidine, and sulfamerazine, using the 0.1, 0.01, and 0.001M tetra-n-butylammonium hydroxide titrants. In the range 0 to 1ml of titrant, the calibration graphs were linear for the 0.1 and 0.01M titrants and almost linear for the 0.001M titrant. The blank titration was negligible with the first two titrants but was about 0.3 ml with the 0.001M one. The lower practicable limit of determination was the amount of sample corresponding to 0.1 ml of titrant, Le., 60001 mequiv when the 0.001M titrant is used. The low titration values obtained in the determination of sulfanilamide with most of the titrant-solvent combinations (Figure 2) might be related to its high pK, value (10.08), Le., its low acidity in aqueous solution, although phenols of similar pK, value can be titrated accurately. A satisfactory titration curve, with an end point corresponding to the required 1:l stoichiometry is obtained by using acrylonitrile as both the solvent and thermometric indicator and 1.OM potassium hydroxide as the titrant. The highest value for the stoichiometric ratio when 0.1M potassium hydroxide was used as the titrant was 0.71:1, with an amine, N,N,N!,N’-tetramethyl-1,2-diaminoethane, as the solvent. These results follow a pattern similar to those obtained by Fritz and his coworkers using visual end-point indicators and potentiometric methods. They found that sulfanilamide could not be titrated as an acid in dimethylformamide solution, but was titrated satisfactorily in rz-butylamine ( 5 )and also in acetone solution (6).
Table 11. Results for Precision from the Catalytic Thermometric Titration of Sulfonamides and Sulfonamide Tablets AcryloAmount,
mg
Solvent,
Per cent
Relative
Recovery,
nitrile,
Titrant,
N o . of
Mean
Std
Std dev,
thermometric
ml
molarity5
dems
titerlml
dev
05
titration
assay ( 3 )
1 .oo
4 1 3.5
0.006 0.006 0.003 0.025 0.001 0.003 0.001
0.56 0.62 0.30 2.00 0.23 0.50 0.17
...
0.99 1.05 1.27 0.50 0.50 0.75
. .. .. .
B, 0.01 B, 0.001 K, 0 . 1 K, 1.0 B, 0 . 1
3 3 3 3 3 3 3
. ..
... ... ...
73.3
72.8
3.5
B, 0 . 1
7
0.79
0.002
0.27
82.8
82.4
3
K, 0 . 1
6
0.67
0.003
0.37
79.1
78.3
4
K, 0.1
3
0.89
0.005
0.57
87.0
86.2
5
K, 1.0
3
0.60
0.004
0.65
83.6
83.7
3.5
B, 0.1
3
0.77
0.004
0.54
80.0
80.3
4
B, 0.1
3
0.89
0.004
0.41
87.9
88.4
mln
Sulfadiazine B. P. d, 1 25.07 Sulfadimidine B. P . d, 1 27.94 Sulfamethizole B. P . d, 1 2.71 d, 1 Sulfadiazine B. P . 0.25 Sulfaguanidine B . P . C. m, 1 10.09 Sulfaurea d, 1 100.20 Sulfadiazine d, 1 25.07 (tablets) B . P . 24.61 d, 1 Sulfisoxazole (tablets) B. P . 16.13 m, 2 Sulfaguanidine (tablets) B. P , C. 25.22 m, 1 Sulfathiazole (tablets) B. P. C . 201.6 ... Sulfamethoxypyridazine (tablets) B. P. C. 25.95 Sulfamethizole d, 1 (tablets) B . P . Sulfadimidine 28.09 d, 1 (tablets) B. P . a d = dimethylformamide: rn = dimethylsulfoxide. B nominal values).
B, 0 . 1 B, 0.1
2 2 2
1
=
B.
. ..
...
...
11.
...
...
tetra-n-butylammonium hydroxide; K = potassium hydroxide (molarities are
An alternative explanation for the low, but reproducible, titration values and the sharp end-point inflections in many of the thermometric determinations of sulfanilamide is that sulfanilamide undergoes addition to the acrylonitrile indicator to yield a non-acidic cyanoethylation product. This type of addition would be less likely to occur with the substituted sulfonamides, in which the reactive acidic hydrogen is sterically hindered. The titrants will catalyze the cyanoethylation reaction and their efficacies will depend on the extent to which they are dissociated in the solvent mixture. The results obtained with the sodium methoxide, potassium methoxide, and potassium hydroxide titrants support this requirement. Thus, the lowest titration values are obtained when the sample is dissolved in the strongly cation-solvating solvents, dimethylformamide, diwhile higher methylsulfoxide and 1,1,3,3-tetramethylurea, titration values result by using solvents which are not so effective in increasing the concentration of free hydroxyl ions, namely, the organic bases and acrylonitrile. Consistently low titration values are obtained with tetra-n-butylammonium hydroxide as the titrant, irrespective of the solvent used. This is to be expected because the quaternary ammonium ion is effectively “solvated” by its n-butyl radicals. In the determination of sulfaguanidine, titration values close to those required for the 1:l stoichiometry are obtained with 19 of the 21 titrant-solvent combinations evaluated. However, most of the titration curves are rounded and the end-point inflections are difficult to locate (Figure 3). The end points are acceptably sharp when 0.1M potassium hydroxide is used as the titrant and either dimethylsulfoxide or 1,1,3,3-tetramethylureais the solvent. Sulfaguanidine cannot be determined in the N,N,N’,N’- tetramethyl1,2-diaminoethane solvent, in which it is insoluble. The rounded titration curves suggest that, with most of the titrant-solvent combinations, the very weakly acidic sulfaguanidine is neutralized only very slowly and it retards, rather than inhibits, the anionic polymerization of the thermometric indicator. However, when potassium hydroxide is used as the titrant, this retardation is less noticeable
and the shape of the titration curves is more characteristic of polymerization inhibition, i.e., the process required for accurate catalytic thermometric titration. Tablets containing a sulfonamide as the active ingredient have been assayed by the catalytic thermometric method. Details of the titrations, including precision values, are shown in Table 11. The results are compared with those obtained by using the procedures recommended in the 1973 edition of the British Pharmacopoeia ( 3 ) . Dimethylformamide is a satisfactory solvent for the thermometric titration of the sulfadiazine, sulfadimidine, sulfaisoxazole, and sulfamethizole tablets, but when it is used as the solvent for the sulfamethoxypyridazine and sulfathiazole tablets, the determined sulfonamide contents are significantly lower than those measured by the B.P. assay procedure. However, good agreement with the B.P. assay values is obtained by using potassium hydroxide as the titrant with acrylonitrile and dimethylsulfoxide as the solvents in the determinations of sulfamethoxypyridazine and sulfathiazole, respectively. The sulfaguanidine tablets can be determined satisfactorily by using the potassium hydroxide titrant and dimethylsulfoxide or 1,1,3,3-tetramethylurea as the solvent. The titration curves for the formulations were very similar in shape to those obtained for the pure sulfonamides. The assay values from the thermometric and the recommended methods differ by 0.596, or less, with most of the samples but, with sulfaguanidine tablets, the values obtained by using dimethylsulfoxide and 1,1,3,3-tetramethylurea as solvents are high compared with the B.P. assay value. However, with the dimethylsulfoxide solvent, the coefficient of variation is small (0.37%), and it would be reasonable to apply a correction factor to allow for the difference (about 1%) between the assay values from the thermometric and B.P. methods. The excipients most commonly used in the formulation of sulfonamide tablets are magnesium stearate, lactose, and starch. According to Faber ( 4 ) , magnesium stearate, talc, and potato starch can give rise to titration values of up to 0.4% high when sulfonamide formulations are determined ANALYTICALCHEMISTRY, VOL. 47, NO. 8, JULY 1975
1387
by the nonaqueous titration of the acidic function, using a visual end-point indicator. We have shown ( 1 7 ) that the titration value is negligible when dispersions of magnesium stearate in dimethylformamide are determined by the catalytic thermometric procedure. The titration values of dispersions of 0.5-g amounts of lactose and starch in the same solvent are similarly low, and it may be assumed that all three excipients have no significant influence on the titration values of the formulations. The results obtained in this investigation suggest that catalytic thermometric titration is a suitable technique for the rapid quantitative analysis of sulfonamides, alone or in admixture with nonacidic excipients, provided that the appropriate solvent and titrant are used for each sulfonamide. They also show that 1,1,3,3-tetramethylurea offers no advantages over the more readily available dimethylsulfoxide as a titration solvent. Similarly, the tetra-n-butylammonium hydroxide reagent appears to offer no advantages over the more-easily-prepared potassium hydroxide solution. The problem of occlusion of titrant in a precipitated product does not arise when dimethylformamide, dimethylsulfoxide, or 1,1,3,3-tetramethylurea is used as the solvent because the potassium derivatives of the sulfonamides are then soluble. The method described for the determination of sulfaguanidine appears to be the only one a t present available for the titration of this compound as an acid. Catalytic thermometric titrimetry is not selective because the end point corresponds to the total acid content of the sulfonamide samples. However, the recommended procedures with which it is compared, i.e., diazotization with a visual or dead stop end-point detection and nonaqueous titration with a visual indicator, are also non-selective. Thus, the former method determines all diazotizable material in the sample while the latter method measures all the titratable acids. In contrast, both conventional thermometric and potentiometric titrimetry are selective in that, in theory a t least, the titration curves show inflections corresponding to the various titratable constituents of a mixture. In the conventional thermometric analyses of sulfonamides noted above (8-10), three different reactions were investigated. The reaction of choice would normally be the one most selective for the constituent to be determined. Thus, Bark and Grime (10) pointed out that reaction involving the formation of a silver derivative was preferable to that employing the less-selective reagent, sodium hypochlorite (9). In principal, thermometric titration methods, conventional and catalytic, are faster and more reliable than potentiometric titration because the measuring probe responds almost instantaneously, in aqueous and in nonaqueous solutions, and its sensitivity is unaffected by any of the constituents of the titration solution. When applied to acid-base titrimetry in nonaqueous solution, the chemistry employed in the present study, conventional thermometric methods may suffer from two dis-
1388
ANALYTICAL CHEMISTRY, VOL. 47, NO. 8, JULY 1975
advantages: (a) Inflections in the titration curve may be obscured by the considerable temperature changes caused by the mixing of the titrant and titrand solvents, e.g., propan2-01 and dimethylsulfoxide, respectively, and (b) the heat of precipitation of reaction products may give rise to spurious end-point inflections, e.g., when tetra-n-butylammonium salts of certain sulfonamides and the potassium salt of benzoic acid are formed in nonaqueous solvents. In catalytic thermometric titration, the endothermic heats of mixing are relatively insignificant, in terms of temperature change, when compared to the heat of polymerization at the end point; the formation of insoluble material also does not influence reproducibility of the end point, provided that the stirring is efficient. The catalytic method can, with certain compounds, be made selective by carrying out two determinations on each sample, using a different titrantholvent combination for each determination. This procedure has been used for the analysis of mixtures of phenol and resorcinol (18). The temperature rise at the end point usually exceeds 10 O C in catalytic thermometric titration, when a vinyl monomer is the thermal indicator, and it is then possible to use simpler apparatus than is normally required for the conventional thermometric method. For example, with 0.1M titrant, insulation of the titration vessel is not essential, a thermometer (0-50 O C ) may be used to measure the temperature and titrant can conveniently be added manually from a burette ( 1 5 ) .
ACKNOWLEDGMENT May and Baker Ltd., and A. J. Seward (U.A.C. International) (J. C. E. Hall) are thanked for providing the test compounds and formulations. LITERATURE CITED (1) The Pharmacopeia of the United States of America, 18th Revision, United States Pharmacopeia1 Convention, Washington, 1970. Ibid, 17th Revision, 1965. The British Pharmacopeia, H. M. Stationery Office, London, 1973. J. S. Faber, J. Pharm. Pharmacol., 8 , 187 (1954). J. S. Fritz and R . T. Keen, Anal. Chem., 24, 308 (1952). J. S. Fritz and S. S. Yamamura. Anal. Chem., 29, 1079 (1957). D. C. Garratt, "The Quantitative Analysis of Drugs", 3rd ed., Chapman and Hall, London, 1964, p 608. (8) J. Jordan, R. A. Henry, and J. C. Wasilewski, Microcbem. J., 10, 260 (1966). (9) H. Schafer and E. Wilde, Fresenius'Z. Anal. Chem., 130, 396 (1949). (10) L. S. Bark and J. K. Grime, Analyst(London), 98, 452 (1973). (1 1) E J. Greenhow and L. E. Spencer, Analyst(London). 98, 90 (1973). (12) M. S. Greenberg, B. J. Barker, and J. A. Caruso, Anal. Chim. Acta, 54, 159 (1971). (13) L. Doub. in "Kirk-Othmer Encyclopaedia of Chemical Technology", 2nd ed.. H. F. Mark, J. J. McKetta Jr., and D. F. Othmer, Ed., Vol. 19, Interscience, New York, 1969, p 262. (14) D. D. Perrin, "Dissociation Constants of Organic Bases in Aqueous Solution", Butterworths, London, 1965, p 81. (15) E. J. Greenhow and L. E. Spencer, Analyst(London), 98, 98 (1973). (16) G. A. Vaughan and J. J. Swithenbank, Analyst(London), 95,890 (1970). (17) E. J. Greenhow and L. E. Spencer, Analyst (London), 485 (1973). (18) E. J. Greenhow and R . Hargitt, Proc. Soc. Anal. Chem., 10, 276 (1973). (2) (3) (4) (5) (6) (7)
RECEIVEDfor review December 10, 1974. Accepted March 14, 1975.
