Determination of Volatile Amines in 2-Hydroxyethyltrimethylammonium (Choline) Salts ROBERT H. CUNDIFF
AND
JOHN A. RIDDICK, Commercial Solvents Corp., Terre Haute, Znd. Crystal Violet Indicator. Dissolvr 1 gram of crystal violet in 100 ml. of glacial acetic acid.
HOLINE usually is synthesized commercially by one of C general reactions. Wurts (6) prepared choline chloride from trimethylamine and ethylene chlorohydrin. The folloiving year
tn.o
PROCEDURE
he (6) obtained the free base from trimethylamine and ethylene oxide. The free base may be converted to any salt desired by the addition of the appropriate acid. Because trimethylamine is a fitarting material for both Ilasic processes, it is possible that trimethylammonium salts could he an impurity in choline salts and trimethylammonium hydroxide would be an impurity in choline base. Choline salts apparently are fairly stable even at slightly elevated temperatures. Their solutions are more stable than the corresponding concentrations of the free base. Kothnagle ( 4 ) found little detectable decomposition in solution of choline base u p t,o 470,but appreciable decomposition occurred in stronger solutions. Gulewitsch ( 1 ) found only negligible decompoPition of choline in relatively weak alkali solutions. Kauffman ( 2 ) observed that trimethylamine was given off when choline was heated with a concentrated solution of sodium or potassium hydroxide. .4ny test for volatile amines, and especially trimethylamine, in the presence of choline should he made under conditions that do not lead to the decompoition of choline itself. This work mas undertaken for two related reasons: to develop a method for determining volatile amine impurities in choline salts used for compounding pharmaceuticals, and to offer a means of correcting the choline assay made by titration in glacial acetic acid ( 3 ) for the prrsence of volatilr amines.
Add 50 nil. of choline salt solution to 50 ml. of sodium hydroxide solution in the reaction flask, and wash down the sides of the flask with a small amount of water. Add 50 ml. of glacial acetic acid to the Erlenmeyer flask and 10 ml. to the test tube trap. Connect the system, placing the delivery tube in the Erlenmeyer flask below the surface of the acetic acid. Pass washed air through the system for 75 minutes, adjusting the air flow so that bubhles rise continuously through the choline-caustic solution. At the conclusion of the aeration, combine the two acetic acid solutions in the Erlenmeyer flask, add 15 ml. of acetic anhydride, and boil gently for 5 minutes. Cool, then titrate to a blue-green end point with 0.1 Y perchloric acid, using 1 drop of crystal violet indicator, Calculation. nil. of HCIOa X N X 0.05911 ': trimethylamine = weight of sample
Table 111. Trimethylamine Impurity in Some Choline Salts Choline Salt Choline chloride (70% solution) Choline gluconate (60% solution) Choline dihydrogen citrate (60% solution) Choline hicarbonate Cloyo solution)
Trimethylamine Found, yo 1 2 AY. 0.46 0.47 0.465 0.21 0.22 0.215 0.017 0.017 0,017 0.011 0.010 0.0105 0.024 0.023 0.0235 0.037 0.037 0.037
APPARATUS AND REAGENTS
EXPERIMENTAL
Aeration Apparatus. The details of the construction are shown in Figure 1. The reaction vessel, A , is a 24/40 standard-taper one-necked flask. The male standard-taper joint, B, is lightly packed with glass wool. The exit tube is connected by glass tubing, D, to a 250-ml. Erlenmeyer flask: E, which contains the absorbing solution. This flask is connected t o a bulbed test tube which serves as a trap. An acid scruhbing tower, C', i p usrd to wash the incoming air.
The conditions for quantitative volatilization of trimethylamine were established with standard trimethylammonium chloride in aqueous and 70% choline chloride solutions. 0 h
Table I. Recovery of Trimethylamine from Trimethylammonium Chloride Solution Milliequivalents of Trimethylamine Added Recovered
ST
Recovery, % 98.5 100.8 99.2 100.8
101.3
Table 11. Recovery of Trimethylamine from Trimethylammonium Chloride in 70Yo Choline Chloride Solution Milliequivalents of Trimethylamine Added Recovered
Recovery, % 99.0 98.0 97.7 97.6 100.5
Figure 1. Diagram of Apparatus The choline chloride was purified by crystallization from watersaturated butanol, and four successive recrystallizations from specially denatured 2B ethanol. The aeration time of 75 minutes was established by determining the recovery of trimethylamine from standard trimethylammonium chloride in 70% choline chloride solution for several different time periods. The original reaction vessel was a 2-necked 250-ml. round-bottomed flask, but it was found that the air volume of this flask was too large for the aspirated air to remove all of the trimethylamine in a reasonable time. The apparatus was modified t o that illustrated in Figure I, in order to obtain more efficient aspiration. Some of the pre-
Sodium Hydroxide Solution. Dissolve 300 grams of sodium hydroxide in water t o make 1 liter of solution. Acetic Acid, Glacial, ACS reagent grade. Acetic Anhydride, B C S reagent grade. Perchloric Acid Solution, 0.1 -V. Dissolve 14.5 grams of perchloric acid (70 t o 727,) in 960 ml. of glacial acetic acid contained in a 1-liter borosilicate glass bottle and mix well. S l o ~ l yadd 24.2 grams of acetic anhydride while constantly swirling the bottle. 910
V O L U M E 2 4 , NO. S, M A Y 1 9 5 2
911
liminarv determinations rere made a t 30" C..but subsecluent de-
Tables I and I1 show tho ierover.y of trimethylamine from known tlimethylammonium chloride solutions. The amount of trimethylamine impurity was determined i n several choline salts using the above procedure. Data OIL duplicate analyses are given in Table 111. It was observed during the course of this investigation that the trimethylamine value was greater if itii aeration period of OVOI' 75 minutes was used, This increase in trimethylaminc content ivm observed in all the choline salts tePted. Tcsts made on recrystdliaed choline chloride and choline dihydrugen citrate in&
c a t d that they did not contain more than 0.01% tiimethylamine, or that decomposition into tiimet,hyIamine did not exceed 0.01% in the i5-minute aeration period. This amount of trimethylrtmine, whether from occlusion or deeorrrpmdion, was considered negligible and no correction for nonnqurous titration was deemed necessary. LITER.&TURE CITED
Gulewitsch. V-.,2. physiol. Ciirm., 24, 513 (1898). ( 2 ) Krsuffrnan, M.. Ibid.. 66, 343 (1910). (3) Markunas, P. C.. and Riddiek, J. A., A Y . ~ LCHEM., . 24, 312
(1)
(1952). (4)Nothnagle, G., Arch. Phann., 232, 261 (1894). ( 5 ) Wurts, A., Gmnpt. r e d . . 65, 1015 (1867). (6) Ibid.. 66,772 (1868). RECEIYDD for review October 12. 1951. lcoevted Janvary 25, 1952.
56. Phthalic Anhydride Contributed by MAX B. WILLIAMS AND W. P. VAN METER, Oregon State College, Cowallis, Ore., AND W. C. McCRONE, Armour Research Foundation of Illinois Institute of Technology, Chicago, Ill.
HTHALIC anhydride can bo crystallized from a!cohol. Pacetone, chloroform, and bensene, or sublimed to give needles elongated parallel to e. Sloa cooling or evaporation of an acetone solution or crystallization from turpentine an % microscope slide will produce granular orystals. Crjktallbation from the molt will often show the presence of a highly unstable polymorphic form. There is no difficulty in obtaining the stable form described below from all laboratory recrystallizations. CRYST*L ~fIIORPHOLO(iY
Crystal System. Orthorhomhic. Form and Habit. Slow cooling of an acetone solution will produce granular crystals showing prism (110), brachydome ( a l l ) , and pyramid (111). Rapid evaporation from benzene, alcohol, and iLcet,oneyields needle crystals, as does sublimation.
morph of Yhthalic Anhydride I W m
Turpentine Asia1 Ratio. a:bx = 0.558:1:0.4_19. 0.5549:1:0.4173 (8). Interfacial Angles (Polar). 110 A 110 = 58" 18'; 58" 3' (8). n..i.l ~ n i =i 45O30': 45"IS'ib). . . Clemage. i l 0 . X-RATD ~ s ~ n n c ~DATA rox Cell Dimensions. a = 7.90 A; b = 14.16 A.; c = 5.94 A. a = 7 . i 4 A . : b=lR.66A.: e=5.SGA.i1). lated from x-ray drtts). ~~
-0.
~~~
Dens d
d
7.0 5.5
b-
I 2 '
Figure 1. Orthographic Projection of Typical Crystal of Phthalic Anhydride
5.3 4.50 3.9.5 3.80 3.69 3.54 3.43 3.31 3.28 3.19 3.03 2.97 2.84 2.73 2.63
0.29 0.73 0.67 0.68 0.41 0.16 0.43 0.13 very weak
0.17 1.00 0.75 0.35 0.16 0.14 0.19 0.13
2.55 2.43 2.31 2.30 2.27 2.18 2.11 1.98 1.96 1.89 1.86 1.81 1.71 1.71 1.61 1.63 1.60
1/11
0.43 0.08 0.56 0.22 0.22 0.11 0.13 0.11 0.06 0.25 0.10 0.03 0.02 0.10 0.02 0.03 0.03
