Extraction and Determination of Salts of Organic Bases and Acids RZORTON SCHMALL, C. W. PIFER, AND E. G. WOLLISH Products Control Laboratory, Hoffmann-LaRocheInc., Nutley, N . J .
to prevent any creeping of solvent, and the two are connected with each other. The ball joint is attached and the desired solvent is placed in the reservoir. Water is added through the funnel so as to bring the volume to 10 to 25 ml., and the magnetic stirrer is set in motion. The desired quantity of alkali or mineral acid is added through the funnel in order t o liberate the corresponding free organic base or acid. For optimum efficiency, the total volume of the aqueous phase should not exceed 30 ml. Solvent is now added slowly from the reservoir, and after the extracting flask is filled with a mixture of solvent and aqueous phase, the speed of the stirring mechanism is regulated so that the vortex of the aqueous phase does not rise higher than the ground-glass joint. The usual rate of solvent delivery is 5 ml. per minute The solvent is collected in an Erlenmeyer flaqk.
The usual method for the assay of salts of organic bases and acids involves extraction of the liberated base or acid with an immiscible solvent, using separators, followed by titration in aqueous medium. Two new and simple designs of automatic liquidliquid extractors greatly reduce the working time required for the extraction. When used in conjunction with titrations in nonaqueous solvents, it is possible to eliminate transfers and to obtain sharper end points. Results obtained with the proposed method show good agreement with those obtained by the U. S. Pharmacopeia or conventional procedures. The method may be applied to bulk products as well as to pharmaceutical preparations and the apparatus may be used for direct saponification and extraction without transfer. Among the advantages of this new procedure are easier preparation of sample, automatic extraction, elimination of washings, and reduction of labor cost of analysis.
C
OblPARATIVELY few new designs of apparatus for analytical extractions have been reported in the literature. The more recent field of such extractions has been comprehensively surveyed by Craig in his annual review papers ( I ) , while Golumbic ( 7 ) discussed the theoretical aspects of liquid-liquid extractions. However, up to the present time, the Squibb separator has been considered the standard equipment for analytical extractions with immiscible solvents. The U. S. Pharmacopeia assay procedure for many salts of organic bases and acids requires a number of individual extractions of the liberated base or acid n-ith immiscible solvents using separators. This is usually followed by mashing of the eutract, reextraction of the washings, evaporation of the solvent, and either weighing of the dried residue or titration in aqueous medium. In order t o simplify the extraction technique and eliminate many hand operations, two new types of liquid-liquid extractors were designed, one for use with solvents lighter than water and the other for those heavier than water. When these eutractors are used in conjunction with titration of the extract in a nonaqueous solution, the procedure offers many advantages over the present method.
YER ANHYDROU NnZSO4
EXTRACTOR FOR SOLVENTS LIGHTER THAN WATER
The apparatus as shown in Figures 1 to 4 consists of an Erlenmeyer-type flask with a side arm, extending from the bottom of the flask up to a female ball joint. A Y-tube, fitted with a male ball joint, is connected with a separator, acting as a solvent reservoir, and to a small funnel, The extraction flask is fitted with a round joint to the separator column, into which a glass baffle pyate is fused The separator column is bent a t a sharp angle to form the soivent delivery tube, which has a male ground joint a t its end. A drying tube with female joint may be connected to the delivery tube, if necessary. For hydrolysis reactions, a condenser with standard-taper joint can be attached in place of the separator column. Operation. A sample or aliquot of a solution is weighed or measured into the extracting flask. A magnetic bar (Teflon coated) is carefully placed in the flask, preferably with a magnetized ickup rod, and the assembly is brought into position on top o r a magnetic stirrer. The ground-glass joint between the extracting flask and separator column is wetted with water BO as
Figure 1. Apparatus for Solvents Lighter than Water
For samples requiring approximately 30 ml. of 0.1 N titrant, about 150 ml. of solvent are usually sufficient for quantitative extraction. The solvent remaining in the apparatus is eluted by continuous slow addition of water through the side arm until all of the solvent has been forced over into the receiving flask. Care should be taken that none of the aqueous phase is permitted to flow over. For normal extraction of acids or bases, the special drying tube, charged with anhydrous sodium sulfate, is not necessary: however, it may serve a useful purpose in specific cases, where a completely anhydrous extract is desired. EXTRACTOR FOR SOLVENTS HEAVIER THAN WATER
The apparatus as shown in Figures 5 and 6 is used for extractions with solvents heavier than water.
1446
V O L U M E 24, NO. 9, S E P T E M B E R 1 9 5 2 I t consists of an extracting cylinder which is flared a t the top.
A U-shaped capillary delivery tube is fused to the bottom of the extracting cylinder. At the upper bend of the delivery tube a
stopcock permits regulation of the solvent flow. The end of the delivery tube has a ground-glass joint, onto which a stopcock attachment can be fitted. A solid glass plug is carefully inserted into the extracting cylinder, on top of which a glass ring and subsequently a wiremesh screen, or perforated stainless steel disk, are brought into place. A mechanical stirrer with small blades is centered within the extraction cylinder, and the blades are allowed to revolve about 1 inch above the wire screen. A solvent reservoir (separatory funnel) extends into the flared top of the extraction cylinder. Operation. The extraction cylinder is filled with solvent heavier than water to a level equal to the height of the delivery tube. An aqueous solution or a suspension of a weighed sample is transferred quantitatively on top of the solvent layer and the stirrer is immediately set in operation. The desired quantity of alkali or mineral acid is added in order to liberate the corresponding free base or acid. The total aqueous phase should not exceed 25 ml. and the solvent interphase should not extend below the wire screen, when the stirrer is not in motion. The usual rate of solvent delivery is 5 ml. per minute. The solvent is collected in an Erlenmeyer flask. For samples requiring approximately 30 ml. of 0.1 N titrant, about 150 ml. of solvent should be added from the reservoir. When the extraction is completed, the remaining solvent in the extracting cylinder is uantitatively removed as follows: The stopcock attaclment is fitted to the end of the delivery tube and its stopcock is opened. The stopcock on the top of the delivery tube is closed. Water is added to the extracting cylinder so as t o start siphoning of the solvent. All of the solvent is siphoned from the extracting cylinder into the Erlenmeyer flask and its flow is regulated with the stopcock attached to the end of the delivery tube until the solvent is completely separated from the aqueous phase.
1442 same solvents and indicators. Details concerning such titrations are available from the literature ($,SI8). Acids may be titrated directly in solvents such as chloroform, benzene, or carbon tetrachloride; in case of an ether extraction the solvent should be evaporated to dryness and the residue dissolved in about 80 ml. of one of the above-mentioned solvents. About 10 ml. of dimethylformamide (technical) are added, followed by 5 to 10 drops of 1% thymol blue in dimethyl formamide. The solution is titrated with a standard solution of lithium or sodium methoxide in benzene-methanol (4-6, I O ) .
TITRATION OF BASES AND ACIDS
Bases may be titrated directly in the extracting solvent, with the exception of ether, which should be evaporated almost to dryness. The residue from an ether extraction is dissolved in chloroform, benzene, p-dioxane, etc. The sample is titrated with a standard solution of perchloric acid in dioxane, using 3 to 5 drops of a 1% solution of methyl red in absolute ethyl alcohol as indicator. The perchloric acid solution is standardized against recrystallized diphenylguanidine, melting point 150' (corrected), using the
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APPLICATIONS
Salts of organic bases and acids can be determined by the procedure described. While salts of organic bases can usually be directly titrated (S), salts of organic acids require extraction prior t o their titration. In mixtures and in many pharmaceutical preparations, such as tablets, capsules, ointments, and ampoule solutions, the extraction procedure is usually necessary, Mthough this paper deals primarily with the extraction of acids and bases, it is believed that the apparatus described can be used for the extraction of phenols, epoxy compounds, esters, etc. Compounds that can be saponified or hydrolyzed prior to extraction include esters and primary and secondary amides. RESULTS
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Figure 2.
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L I O r n .
Extraction Flask and Delivery Tube
Pure compounds as well as pharmaceutical preparations were assayed by the method described, and the results compared with those obtained by U.S.P. (9) procedures (Tables I and 11).
ANALYTICAL CHEMISTRY
1448 Table I.
Sodium Sodium Sodium Sodium
Sample benzoate saccharin diphenylhydantoin pentobarbital
Sodium phenobarbital tablets
Salts of Organic Acids Assay, % U.S.P. Proposed method method 99.8 98.8 96.2 97.3 98.0 97.4 98.0 98.6 M d t a b . Mg./tab. 98.4 97.1
Solvent Used in Proposed hlethod Ether Ether Ether Ether
7 Deviatfon from U.S.P. Method
Ether
-1 3
Ether
-0
Table 11.
-0.6 +O.6
DISCUSSION
h f d c a p . Mg./cap. 50.0 49.8
Sodium pentobarbital rapsules
-1.0
+1.1
average deviation from the theory was &0.6'% with a maximum of 1.1%, and the average reproducibility was f0.5'%. Where the extractor for solvents heavier than water wm used (solution of 3-pyridyl carbinol), the average deviation from the theory wap f0.3% with an average reproducibility of f0.2%. 3-Pyridyl carbinol is very soluble in aqueous solution, yet could be completely extracted.
2
For the extraction of compounds that are very soIuble in water, such as ephedrine base, it was necessary to saturate the aqueous layer with sodium chloride and extract a t a slow rate (approximately 2 ml per minute).
Salts of Organic Bases
U.S.P. Method, Sam& &Ze./CaD. . Ephedrine sulfate capsules 25.9 Quinine sulfate capsules 186.7 Mg./tab. .4mphetamine sulfate tab10.1 lek Codeine sulfate tablets 33.1 Chloroguanide tablets 100.2 hIg./ml. Ephedrine sulfate ampoules 50 9 Papaverine HC1 ampoules 32.0
Proposed Method, hle./CaD. . 26.3 187.3 186.2 Mg./tab. 9.9 33.8 101.3 hfg,/ml. 50.3 32.0
Solvent Used in Proposed Method Benzene Ether Benzene
Deviaifon from U.S P. Method 1-1.7 +0.2
~7
-0
1
Benzene
-1.1
Chloroforni Benzene
+1 +l
Benzene Chloroform
+O
3
1
-1.2 0
The results indicate good agreement with those obtained by procedures used heretofore. The accuracy and precision obtainable by the proposed procedure are exemplified in Table 111. Tablets containing 27.5 mg of 2-methy1-9-phenyl-2,3,4,9-tetrahydro-1-pyridindene (Thephorin) tartrate, and a solution containing 50 mg. of 3-pyridpl carbinol (Roniacol), were assayed five times each, using the extractors for solvents lighter and heavier than water, respectively. In the case of the tablets, the
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Apparatus for Solvents Heavier than Water
Connecting Y Tube
Table 111. Hecoverv and Precision "c Deviation 70Deviation
As?ay, froin Theory from Mean hIg./Tab. (Recorwy) (Reproducibility) Extractor for solvents lighter than water (benzene) Sample, Thephorin tartrate tablets containing 27.5 ms./tablet -0.7
.issay
zko.0 +0.7
-0.7
Table IV. Comparison of Proposed Extractor and U.S.P. Proced-ure (U.S.P. assay of amphetamine sulfate tab1 ets) Steps U.S.P. Extractor X X 1. Grinding of tablet mass X X 2. Weighing of sample X 3. Solution in measured volume x 4. Filtration X 5 . Removal of aliquot X X 6. Addition of alkali (Automatic) (Minimum 7. Extraction of 6 hand extractions) X 8. Water wash x 9. Extraction of wash water Addition of excess titrant X 10. X 11. Evaporation of solvent x x 12 Fina. titration
+0.4 50 5
Alean 2 7 . 6 .IT. + 0 . 6 Extractor for solvents heavier than water (chloroform) Sample, solution of 3-pyridyl carbinol containing 50 mg./4 cc. hIP../4 cc. 49.9 -0 2 +0.2 I
4
50.0 49 7
49 8 49.8 Mean 4 9 . 8
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I
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Av. A 0 . 3
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10.0 fO.0 10.2
In cases where an emulsion was formed, it was found advantageous to place some glass wool loosely around the upper part of the baffle plate of the extractor for liquids lighter than water. When the extractor for liquds heavier than water is used for the extraction of a tablet mass or an emulsion, glass wool should be placed around and within the glass ring between the screen and the glass plug.
V O L U M E 2 4 , NO. 9, S E P T E M B E R 1 9 5 2
1449
a t least 12 separate steps are required by the U.S.P. method for amphetamine sulfate tablets, in addition t o the minimum six hand extractions necessary. The proposed method eliminates all but five of these steps and the extraction is performed automatically. A number of extractors can be set up siniultaneously and operated \)y one analyst. ACKNOWLEDGMENT
The authors wish t o express their appreciation t o E. G. E. Shafer for his helpful advice and t o Kelson 0. Klaner for suggesting the use of the baffle plate and modifications of the side arms. Frank J. Brandler constructed the eytract ors. LITER4TURE CITED
c.,
Figure 6 . Apparatus for Solvents Heavier than Water
(1) Craig, L. ASAL. CHEM.,22, 61 (1950); 23, 41 (1951); 24, 66 (1952). (2) Fritz, J. S., Ibid., 22, 578 (1950). (3) Ibid., p. 1028. (4) Ibid., 24, 306 (1952). (5) Fritz, J. S., and Keen, R. T., Zbid., 24, 808 (1952). (6) Fritz, J. S., and Lisicki, N.& Ibid., ‘I., 23, 589 (1951). ( 7 ) Golumbic, C., Zbid., 23, 1210 (1951). (8) Pifer, C. IT., and Wollish, E. G., ANAI.. CHEM.,24, 300 (1952). (9) U. S. Pharmacopoeia, XIVth rerision, 1950. (10) Vespe, V., and-Fritz, J. S., AWAL.CHEM.,in
press. ADV.ANT.4(; ES
~k~~ proposed has advantages Over conventional and U.S.1’. extraction methods for assay purposes. The labor savings are illustrated in Table IV. As can be seen,
RECEIVED for review April 4, 19.32. Accepted J u n e 9, 1952. Presentedat t h e Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy hlarch 6, 1952, and before the Division of Analytical Chemistry a t t h e 121st YIeetinp of t h e BIIERICAK C n ~ ~ r c a POCIP:TY, r, Buffalo, N. I-.
Photometric Determination of Zirconium in Magnesium Alloys GLENN B. WENGERT The Doic Chemiral Co.,Midland, Mich.
I
N T H E search for high t~enq~erature alloys for use in jet aircraft, it was found that the addition of small amounts of eirconium t,o magnesium allo? Ilowed higher operating tempc’ratures and grain refinement without adversely affecting creep resistance (6). A new syptem of alloys was developed for which a fast’er,more accurate method for the determination of eirconiuni in low concentrations was desired. The gravimetric determination of zirronium by precipitation as the phosphate ( 3 )is subject to error in the low concentration range and requires a number of hours to compIet,e. Since the alizarin red S color complex har bec,n used for a number of years ap a qualitative spot test for zirconium (1, 2, E ) , it was decided t o investigate the possihility of dweloping a quantitative method using this reagent (4). APPARATUS AND REAGENTS
Transmittance measurements were made with a Beckman spectrophotometer, Model B, modified t o hold a 40-mm. Klett cell.
Zirconium Standard Solution. Dissolve approximately 0.356 gram of zirconyl chloride (ZrOCI2.8Hz0) in about 100 ml. of water. Add 100 nil. of concentrated hydrochloric acid and dilute to 1000 ml. One milliliter contains approximately 0.1 mg. of zirconium. Standardize by analyzing 100 ml. gravimetrically by the phosphate method. Alizarin Red S, 0.05% water solution (Sational Aniline and Chemical Co., Inc.). Potaspiurn Pyrosulfate (Ii2S?O7), ( .P., potassium bisulfate (fused powder). Ferric Chloride Solution. Dissolve 2.5 grams of iron wire in a minimum amount of hrdrochloric acid and nitric acid and dilute to 100 nil. with water. COLOR REACTION
Effect of pH. The effert of pH is shown in Figure I . The optimum color development is k)etween pH 0.6 and 1.5. Between pH 1.5 and 3.0 the oxychlorides of zirconium depress the color intmqity, while above pH 2.5 the lake formation occurs. Below
