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Discussion of Results “Available lime” means nothing until it is known for what purpose it is available. In the ammonia industry available lime is determined by boiling the sample with an excess of ammonium chloride and titrating the liberated ammonia. A sample of Portland cement, which may be considered an impure overburned lime, gave by this method 58.0 per cent, by the iodine method 16.5, by zinc chloride method 12.5, and by the sucrose method 9.8 per cent. The writer believes that the method is yet to be devised that will give the calcium oxide in lime without giving some of the silicates and other compounds present. Even pure water breaks down some silicates and the amount broken down depends upon the amount of water, the time of con; tact, and the temperature. It is possible that a method might be devised by using an-
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hydrous reagents. The writer did some work along this line with promising results, but the methods are not suited to factory work. There is always difficulty in getting, and keeping, anhydrous reagents. Of the three methods given in this paper the iodine and zinc chloride are quicker than the sucrose. The sucrose method requires one filtration; the others do not. The sucrose method requires standard flasks and pipets, and it is necessary to cool it to room temperature before making up to volume. The other methods require no standard flasks or pipets and should be run hot, as soon as the lime is hydrated. Standard flasks and pipets give possibilities of error which are avoided in the other methods. Which of these methods gives the lime available in the sugar industry has not yet been determined. The writer believes that one of these, probably the zinc chloride method, will give satisfaction.
The Choice of Indicators for Alkaloidal Titrations’ By H. Wales DRUGCOXTROL LABOUTORY, BUREAUOB CHEXISTRU,WASHINGTON, D. C.
H E customary procedure in the determination of alkaloids is to dissolve the base in an excess of standard acid and titrate this excess with standard alkali, usually with methyl red as an indicator. The accuracy of this method has not been extensively investigated. Keblerllx and later Kippenberger2 titrated a number of alkaloids with various indicators and chose the ones that gave the best results. On account of their broad range these have been largely discarded for the newer and more sensitive indicators. ever^,^ who investigated the hydrogen-ion concentrations of a few alkaloidal salts by colorimetric methods, recommended certain of the newer indicators for their titrations. The hydrogen-ion concentrations of some alkaloidal salts have been determined by M ~ G i l l ,Masucci ~ and MoffatJ6 and Krantz’ by potentiometer methods, using the hydrogen electrode. As the hydrogen electrode is known to reduce alkaloids,* Rasmussen and Schou,I1 and Wagener and McGil15have used the quinhydrone electrode for determining hydrogen-ion concentrations. Kolthoff ,9.t Treadwell and Janett,12 and Dutoit and Meyer-Levy13 have investigated the titration of alkaloids by conductivity methods, and Popoff and McHenry14 have used a platinum electrode in titrating alkaloids. The discrepancies in the results obtained by many of these investigators are too great to be explained on the basis of the reduction of the alkaloid by-the hydrogen electrode. Masucci and MoffatG found a wide variation in the hydrogenion concentrations of commercial samples used with no preliminary treatment. Some explanation may be afforded by the work of Tutin,lb who showed-that quinine sulfate crystallized from slightly acid or alkaline solutions required several recrystallizations to make it neutral again. Rasmussen and Schoull dissolved alkaloids in an excess of acid and titrated back, electrolytically, with alkali. The hydrogen-ion values computed from their titration curves
T
1 Received
February 6, 1926.
* Numbers in text refer to bibliography at end of article.
t During the course of this investigation Kolthoff [Pharm. Wcckblad, 61, 1287 (1925)l published the pH values of a large number of alkaloidal salts, computed from the dissociation constants, and recommended indicators in several cases. The fallacies arising by choosing indicators from the pH of the salt are discussed in this paper.
agreed very closely, while those obtained by “direct measurement” often showed appreciable variations. These authors, however, do not state how their direct measurement values were obtained. The quinhydrone electrode has been investigated by Granger and NelsonI1GBiilmann,’’ Kolthoff,Bl10 La Mer and Parsons,l* and others. It has been used for titrations by Harris,lg Wagener and M ~ G i l land , ~ Rasmussen and Schou.ll Procedure The procedure followed in the investigation here reported was essentially that of Rasmussen and Schou.ll The alkaloids used were commercial products obtained from wellknown manufacturers. One hundred milligrams of the alkaloid were dissolved in a slight excess of acid and the volume diluted to 50 cc. This excess of acid was then titrated with alkali, using quinhydrone and saturated calomel electrodes, and the voltages a t definite intervals were recorded. The variation in voltage per cubic centimeter of alkali was plotted against the volume of alkali used and the end point (center of break) of the titration determined. The hydrogen-ion values were computed from the formulazo pH =
-
-
0.4661 0.00014t 0.0541 0.0002c
+
T
where ?r is equivalent to the observed voltage plus a correction for the calomel cell, obtained by determining the voltage of known buffer solutions, and t is the temperature in degrees Centigrade. This formula is applicable between 15” and 30’ C . Wagener and McGillS have shown that the small quantity of neutral salt produced during the titration has a negligible effect on the hydrogen-ion values as determined by the quinhydrone electrode. Sulfuric and hydrochloric acid have been used in several cases. No differences greater than those due to experimental errors were obtained. Both 0.1 N and 0.02 N sodium hydroxide (carbonate-free) have been used with identical results. When an acid is titrated with an alkali the hydrogen-ion value of the solution changes slowly until all but a very small part is neutralized. With the neutralization of
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this last small portion comes a sharp break in the curve, which is indicated by a rapid change in voltage. Further addition of alkali produces only small changes in the hydrogen-ion value. In order that any particular indicator shall be used best for a particular titration the mid point of its color range must lie in this region of rapid change in hydrogen-ion value. It is, therefore, obvious that the pH value for the end point of the titration alone is not sufficient to determine the proper indicator. The range in which the color change of the indicator must take place for each alkaloid is, therefore, indicated in the table. The pH values are in each case an average of about six determinations. The deviation from the mean was in no case greater than *0.05 and in most cases did not exceed *0.02. Discussion of Results
AI ORPHINE-EVerS by colorimetric determinations found the pH value for morphine hydrochloride to be 3.65. Using the hydrogen electrode McGill obtained values from 3.98 to 4.00 and Masucci and Moffat found values of 3.67 to 4.28 with commercial samples of the sulfate. The quinhydrone electrode was used by Wagener and McGill, who found 4.66 to 5.1 for the sulfate, and by Rasmussen and Schou, who found 4.48 to 6.15 by “direct measurement” and 4.77 to 4.90 from the titration curve for the hydrochloride. Evers and McGill recommend bromophenol blue as the proper indicator. McGill states that methyl red or cochineal gives results that are too low. Later Wagener and RlcGill obtained excellent results with methyl red but report no end point with bromophenol blue. hsmussen and Schou recommend methyl red which is confirmed by work in this laboratory on both the sulfate and hydrochloride. MORPHIKB Used
Found
blue { Bromophenol Methyl red
Gram 0.06351 0.06423 0.0632
Per cent
...
101.1 100.2
CODEINE-MaSUCCi and Moffat found the pH values for codeine sulfate to be 4.53 to 5.15. Rasmussen and Schou found 4.13 to 4.40 by “direct measurement” and 4.93 to 4.94 from the curve for the hydrochloride. They recommend methyl red as the proper indicator. This choice is confirmed by the present investigations, NARCOTINE-Rasmussen and Schou report that the pH values for narcotine hydrochloride are 4.48 and 4.35 by “direct measurement” and 4.32 and 4.29 from the curves. They recommend for the titration standard a methyl orange buffer mixture having a pH value of 4.2. The writer’s measurements on narcotine hydrochloride shorn that an indicator having the range of bromophenol blue should be used. COTARNINE-The color changes of propyl red (o-carboxybenzene azodipropylaniline) and bromocresol purple lie in the range for cotarnine hydrochloride and either may be used, although the color change of the latter may be dhsked by the yellow color of the alkaloid. Methyl red will give results slightly too high. PAPAVERINE-The smaU and illdefined break in the titration curve shows that papaverine is a very weak base. Although the color change of bromophenol blue occurs a t this point, the rate of change in hydrogen-ion concentration is too small to give a pronounced change with any indicator. NARCEINE-Narceine hydrochloride is apparently completely dissociated in aqueous solution, as no indication of a break in the titration curve was observed until the total acid content had been neutralized. HYDRAsTIm-Rasmussen and Schou report hydrogen-ion values of 4.92 and 5.01 for hydrastine hydrochloride as computed from the titration CUN~S, and 5.10 and 5.15 by “di-
391
rect measurement.” They recommend methyl red as the indicator. The titration curve showed a poorly defined break between 3.8 and 5.0 in the bromophenol blue range. It has been stated that salts of hydrastine are unstable in mater and that chloroform will completely extract the alkaloid from acid solutions. Titrations with various indicators failed to give satisfactory end points, confirming the hydrolysis of hydrastine salts QUININE-TWO investigations have been made on quinine dihydrochloride. Evers reports a pH value of 3.40 and Masucci and Moffat report values ranging from 2.45 to 2.79. Evers recommends bromophenol blue for the titration. The neutral salts have been studied by Evers, who found a pH value of 5.15; by Krantz, who found values of 6.15 and 6.19; by McGill, who found values from 5.96 to 6.01; and by hlasucci and Moffat, who found values from 5.60 to 5.93. Rasmussen and Schou found 6.29 to 6.52 by “direct measurement” and 6.39 to 6.42 from the titration curve. For the titration of quinine hydrochloride Evers recommends methyl red. McGill suggests bromocresol purple, saying that the results obtained with methyl orange or methyl red will be too high. He states, however, that bromocresol purple did not give a more definitely marked end point than that given by methyl red. Rasmussen and Schou recommend p-nitrophenol and titration to the color given by this indicator in a buffer mixture of pH 6.2. Rupp and Seegers21 recommend p-nitrophenol for colorless solutions and tetrachlorotetrabromophenolphthalein for colored solutions. They say that quinine may be titrated directly in alcoholic solutions with these indicators, or indirectly from solutions containing enough alcohol to prevent precipitation. The curve obtained for quinine hydrochloride is identical with that obtained with quinidine and the proper indicators will be considered under that heading. QUINIDINE-The indicators that give their characteristic color changes a t the point of the break in the curves for quinine and quinidine hydrochloride are bromocresol purple and propyl red, The color change for methyl red occurs a t too high a hydrogen-ion concentration to be suitable for these alkaloids, and should give too high results. INDICATOR Methyl red Propyl red Bromocresol purple
Quinidine used Gram 0.05970 0.05970 0.0.5970
-Quinidine foundGram Per cent 0.06042 102.9 0.05993 100.4 0.05974 100.0
ENDPOINT Poor Fair Good
Direct titrations of quinidine with 0.02 N hydrochloric acid in alcoholic solution were attempted, using as indicators p-nitrophenol, propyl red, and bromocresol purple. No definite end points could be obtained. I n all cases the indicator changed color before enough acid had been added to neutralize the alkaloid. Addition of water would then cause the indicator to return to its alkaline color. The effect on the end point caused by adding alcohol to prevent precipitation was studied. INDICATOR Methyl red Propyl red Bromocresol purple
-Quinidine 25% alcohol Per cent 102.9 100.6 100.4
found in:50% alcohol Per cent 99.4 98.9 98.4
Similar results were obtained in the titrations of cinchonine and cinchonidine with the same indicators. These show that bromocresol purple will give the best results. Propyl red may be used, however, and it is perhaps preferable for slightly colored solutions. Methyl red gave too high values in all cases. As much as 25 per cent alcohol may be added to prevent precipitation without affecting the results.
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Cr?icHoNINE--McGi11 reports pH values of 5.71 and 5.77 for cinchonine hydrochloride. Rasmussen and Schou found 5.71 to 5.82 by “direct measurement” and 5.93 to 5.96 from the titration curves. Rasmussen and Schou recommend titration to the color given by methyl red in a buffer mixture having a pH value of 5.9. As this is the point of change to a full yellow for methyl red, it is believed better to titrate to the first trace of color with bromocresol purple as recommended by lIcGil1 or to the change in color of propyl red. STRYcHNINE-McGill reports pH values of 5.42 to 5.45 for strychnine hydrochloride; and Krantz one of approximately 6.1. Rasmussen and Schou found values of 4.17 to 5.11 by “direct measurement’’ and values of 4.96 to 5.09 from the curve. For the sulfate Masucci and Moffat report pH values from 4.48 to 5.07 and Wagener and McGill obtained 4.89 and 5.38. McGill and Rasmussen and Schou recommend methyl red as the proper indicator. The writer’s results confirm this recommendation. BRucINE-Rasmussen and Schou found pH values of 3.94 and 4.42 for brucine hydrochloride by “direct measurement” and of 4.65 and 4.83 from the curve. Their choice of methyl red as an indicator is confirmed by the writers results, the curve being very similar to that obtained from strychnine. ATROPINE-Previous work on the hydrogen-ion concentrations of atropine salts shows little agreement. Evers reports 3.75; Krantz, approximately 5.8; McGill, 3.8 to 3.84; Masucci and Moffat, 4.39 to 6.67; Wagener and hIcGill, 4.03 to 4.19; Rasmussen and Schou, 4.50 to 4.70 by “direct measurement” and 4.75 to 4.90 from the curves. Evers and McGill recommend bromophenol blue, McGill stating that the results from using methyl red or bromocresol purple are too low. Rasmussen and Schou favor methyl red. Titrations on both the hydrochloride and the sulfate gave a very sharp break in the curve between pH 3.8 and 7.2. Some indicators falling in this range which have been found to give good results are methyl red, propyl red, and bromocresol purple. Bromophenol blue gives values too high for atropine. HYOSCINE-The break in the titration curve (3.6 to 5.6) is much smaller than that given by atropine, homatropine, and hyoscyamine. Bromophenol blue should give closer results than methyl red, although both indicators give sharp end points. SPARTEINE-TitrBtiOnS of sparteine dissolved in a slight excess of sulfuric acid failed to show any break in the curve until all of the acid present, both free and combined, had been neutralized. The pH values a t this point were 6.99, 7.05, and 7.03, with an average of 7.02. Evidently sparteine sulfate is completely hydrolyzed in aqueous solution, and a titratiori with alkali will be of value only to show the total amount of acid radical present. The titration in this case is to the neutral point (pH 7.0), and bromothymol blue should be used. Sparteine is said to be a strongly alkaline base, monoacidic to litmus or phenolphthalein but diacidic to methyl orangelZ2 Jewel123 reports that sparteine sulfate is monoacidic to methyl red and may be titrated, using either this indicator or phenolphthalein. 0.2169 gram of sparteine sulfate u. s. P. was dissolved in 100 cc. of distilled water and 30-CC.aliquots were taken for titrations. The total sulfuric acid in this volume is calculated as 0.01510 gram. Using methyl red as the indicator, an exceedingly poor end point was reached with 6.88 cc. of 0.02 N sodium hydroxide which is equivalent to 0.01350 gram of sulfuric acid, or 89.4 per cent of the theoretical amount. With phenolphthalein 8.57 cc. of alkali
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were required to produce the first trace of color. This is equivalent to 0.01681 gram of sulfuric acid, or 111.3 per cent. Almost 1 cc. of alkali additional was required to produce full color. Titration with bromothymol blue gave a very sharp end point at 7.68 cc. of alkali, equivalent to 0.01507 gram of sulfuric acid, or 99.8 per cent of the theoretical amount. ~IcoTINE-Rasmussen and Schou report pH values of 6.54 and 6.63 for nicotine hydrochloride by “direct measurement” and 6.41 and 6.58 from the curves. In each case the 6 is obviously a misprint. It should be 5, as the authors recommend methyl red as the indicator. This choice of indicator is confirmed by the writer’s results. DELcosrm-This alkaloid was obtained from larkspur seed (Delphinium consolida) by Markwoodlz4who very kindly furnished a sample for this investigation. It proved to be a monoacidic alkaloid, the hydrochloride of which may be titrated with bromophenol blue. I n d i c a t o r s for Alkaloidal Titrations p H range Average for INDICATOR pH indicator SALTOP: 5.04 4 . 2 5.8 Methyl red Aconitine Methyl red 4.81 3.8 5.8 Arecoline Methyl red, propyl red, bromo3 . 8 7.2 Atropine 5.56 cresol purple 4.85 3 . 9 6.0 Methyl red Brucine 4 . 2 5.4 Methyl red 4.81 Cephaeline Bromocresol DUrDk 5 . 5 6.5 Cinchonine 6.02 Bromocresol purple 5.90 5.4 6.4 Cinchonidine Methyl red 4.0 6 . 5 Cocaine 5.20 Methyl red 3.6 6 . 3 4.86 Codeine Bromocresol purple 5.97 4 . 9 7.0 Cotarnine Bromophenol blue 4.42 3.6 5.2 Delcosine Methyl red 4.89 4 . 2 5.7 Diacetyl morphine Methyl red 4 . 2 .5.6 4.90 Emetine Bromocresol purple 6.33 5.6 7 . 0 Ethyl hydrocupreine Methyl red 4 . 2 5.8 4.99 Ethyl morphine Methyl red. propyl red, bromo3.9 7 . 6 5.74 Homatropine cresol purple 3.8 5 . 0 No end point with methyl red 4.45 Hydrastine or bromophenol blue Bromophenol blue 3 . 6 5.6 4.83 Hyoscine Methyl red, propyl red, bromo5.83 3.8 7 . 6 Hyoscyamine cresol purple Methyl red 4.68 4.0 5.2 Morphine h‘arreine (a) Bromoohenol blue 4.43 3.9 4 . 9 NatGtine Methyi red 4.4 6 . 1 5.26 Nicotine Indistinct, cannot be titrated 3.8 4 . 6 4.23 Papaverine Methyl red 3.8 6 . 0 4.85 Physostigmine Bromophenol blue 3.6 5 . 0 4.31 Pilocarpine Bromocresol purple 6.12 5.5 6.5 Quinine Bromocresol purple 5.5 6 . 5 6.10 Ouinidine Sparteine (a) Methyl red 6.0 4.81 3.8 Strychnine Methyl red 5.08 4.0 6 . 2 Thebaine Methyl red 5 . 3 4.72 4.0 Yohimbine ((2) Salt is completely dissociated.
Bibliography I-Kebler, J. A m Chem. Soc.. 17, 822 (1895). 2-Kippenberger, 2. ami. Chem., S9, 201 (1900). 3--Evers, Pharm. J . , 106, 470 (1921). 4-McGill, J. A m . Chem. Soc., 44, 3156 (1922). 5-Wagener and McGill, J . A m , PFarm. Assoc., 14, 288 (1925). 6-Masucci and Moffat, Ibid., 12, 609 (1923). 7-Krantz. Ibid., 14, 294 (1925). 8-Kolthoff, Rec. lrau. chim., 42,188 (1923). [See also discussion fob IowingBrticle by Rrante 0 . 1 9-Kolthoff, 2.anorg. allgem. Chem., 112, 196 (1920). 10-Kolthoff, Z . physiol. Chcna., 114, 259 (1925). 11-Rasmussen and Schou, Pherm. Zenlralhalle, 65, 729 (1924). 12-Treadwell and Janett, Weloclica Chim. Acta, 6, 734 (1923). 13-Dutoit and Meyer-Levy, J. chim. phys., 14, 355 (1916). 14-Popoff and McHenry, J. A m . Pharm. Assoc., 14,473 (1925). 15--Tutin, Pharm. J . , [4J 29, 600 11909). 16-Granger and Nelson, J. A m . Chem. Soc., 43, 1401 (1921). 17--Biilmann, Trans. Faraday Soc., 19, 676 (1924). 18-I,a Mer and Parsons, J. Bioi. Chem., 67, 613 (1923). Ig-Harris, J. Chem. SOC.(London), 123, 3294 (1923). Z@-Dawson. “Measurement of the p H of Sugar House Products with the Quinhydrone Electrode,” t o be published soon. 21-Rupp and Seegers, Apoth. Z.,22, 748 (1907). 22-Henry, “The Plant Alkaloids,” 1924, p. 120. P. Blakiston’s Son & Company. 23-Jewell, J . A m . Pharm. Assoc., 12, 107 (1923). Z.l-Markwood, lbid., 13, 696 (1924).
