896
INDUSTRIAL AWD ENGINEERING CHEMISTRY
.Val, 16, N O , 9.
T h e More Common Impurities of Anesthetic Ether' By A. W.Rowe EVANS MEMORIAL, BOSTON, MASS.
H E deleterious effects different temperatures, and Simple tests for the examination of the purity of anesthetic ether was found to be 0.0008 per of storage on the puhave been selected. One hundred ethers have been subjected to these degree. (Corrections for ritJyof anesthetic ethtests and thirty-four of these have been found to be seriously contamitemperature a t no time exer have received comment nated. ceeded ~ 0 . 0 0 2 . ) On this by several writers. Warden2 Peroxide and aldehyde are the chief contaminanfs, the former nearly forty years ago found basis of temperature comsharply predominating. aldehyde and peroxide but parison, the density of pure The probability of oxidative changes subsequent to preparation as did not identify the latter, ether approximates 0.711, the causative factor has been suggested, and evidence is oflered that and about twelve years ago and as water and alcohol the time of storage is a factor in determining oxidation. an exhaustive study of the represent the two common The deleterious influence of water and alcohol and the catalytic various contaminants found impurities, an upper limit action of the metal of the container are briefly discussed. of 0.714 was set to embrace in the more commonly used anesthetics was undertaken allowable amounts of these two substances. The hygroscopicity of anhydrous ether is by Baskerville and HamorU3 A certain number of high-grade anesthetic ethers were a complicating factor and determines this somewhat liberal examined by them and were found, in several instances, to specific gravity range. The boiling point and distillation tests are usually considcontain appreciable amounts of deleterious contaminants. More recently the writer has had occasion to reinvestigate ered together. The former test is nearly valueless, as water this problem and certain preliminary results have already and alcohol exercise opposite effects on the boiling point. a ~ p e a r e d . The ~ present paper deals with a summary of the The difficulty of carrying out the distillation test in such earlier work as an introduction to the presentation of the manner as to exclude error makes it time-consuming if properly results of studies suggested by it and now in process of com- performed, and worthless if carelessly carried out. In many of the later determinations the test was omitted. pletion. I n the earlier samples acidity was titrated by the modified PHARMACOPEIAL REQUIREMENTS Vulpius5 technic, but the amounts found were so small that An analysis of the pharmacopeias of the United States, the standard qualitative litmus paper test was substituted. The odor test is easily performed and is surprisingly in(1916), England (1914), Belgium (1912), France (19201, Germany (19101, Switzerland (1907), Norway (1913), Italy (1892), Sweden formative concerning the possible presence of the higher (1901), Japan (1901), Russia (19021, and Spain (1915) shows a alcohols and their products, free acids and peroxides. very definite unanimity in the specifications for anesthetic The aldehyde test is one of the two fundamental exclusion ethers in relation to contaminants. True, specific gravities as listed show material variation among themselves and in several tests. The test selected was the standard potassium hydroxide method, the time being G hours. A white turbidity instances lack a specificity as to the temperatures of observation. Further, the boiling points and distillation tests, when included, may be caused by alcohol; brown or yellow coloration inare not in strict mutual conformity, The odor, acid, aldehyde, dicates the formation of aldehyde resin. and peroxide tests, however, are practically universal and uniThe peroxide test is the second one for basic exclusion and form. Of the two latter a positive aldehyde test is one of exclusion in all the countries except Japan, while the peroxide test is is the test for the most commonly found deleterious contamiomitted only by Japan and Spain. Germany, Norway, Sweden, nant. Following the recommendation of Baskerville and Japan, and Russia specify glass containers. Hamor, cadmium and potassium iodide in 10 per cent aqueous solution are used aB the reagent and the requirement is placed TESTSFOR PURITY a t freedom from liberation of iodine within 1hour. Note.-The various requirements outside of the United States usually The preliminary studies already cited dealt primarily with the establishment of a few simple, dependable tests covering specify potassium iodide alone, b u t as this is notably subject to the influence atmospheric oxygen when in acid solution, the foregoing technic seems the points mentioned, and these may be briefly reviewed as an of t o offer the greater accuracy and to be the fairer criterion. introduction to the body of the paper. The specific gravity was determined by the Westphal RESULTS balance, the earlier determinations being checked by pycnometric measurements. The ether was contained in a silvered, The present report comprises results obtained from the cylindrical Dewar flask and the density determined by a care- examination of 100 samples of anesthetic ether, gathered fully standardized Westphal balance. Temperatures were from widely divergent sources over a period of nearly three carefully recorded. Owing to the prevailing laboratory tem- years, and representing quantities of material well in excess of perature, all measurements were referred to a basis of spe- 10 tons. cific gravity a t 25"/25' c. To avoid delay in the measureThe tabulated results are divided into three series: The ment-a thermally homogeneous ether is essential-the tem- first of 25 samples was tested prior to the first report, the perature coefficient of the specific gravity was determined second of 50 samples contained many lots sent direct from the by a series of careful pycnometric measurements, a t factory; and the third comprised a series of 25 samples the majority of which were obtained direct aed so not subject 1 Received April 19, 1924. Presented in part before the National to the vicissitudes of storage. In all, 66 ethers complied with Anesthesia Research Society Congress, Columbus, Ohio, October 31, 1922. 2 A m . J . Pharm., 57: 148 (1895). the standards of the Pharmaoopeia and 34 did not. An * THISJOURNAL, 8, 301, 378 (1911). analysis of the rejections is compiled in Table I. 4 The Modern Hospital, 17 (1922). Current Res. anaes. analg., 2,
T
104 (1923).
8
Chem. Ztg., 11, 1248 (1887); J . SOC.Chem. Ind., 6 , 750 (1887).
I N D U S T R I A L A N D ENGINEERING CHEiVIXTRY
September, 1924 TABLE I-ANALYSIS
CONTAMINANT Aldehyde and peroxide Aldehvde Perox;de Acid Odor Totals ~ ‘
]
REJECTION OF ETHER SAMPLES ---NUMBER REJECTED--Series 1 Series 2 Series 3 Total 1 3 0 4
O F CAlJSsS OF
3 8 la
0
0
10 2
5 0 25
0
1
12b ~ $48
16 ~ 32
~246 b
3 23 3a 35 34b 34
a A150 contained peroxide. b
Correcting for samples counted twice.
The first inference to be drawn from the results is that onethird of a series of 100 ether samples have been rejected because of failure to comply with the U. S. P. specifications. The second lies in the relative results of the three series, in which there is apparently an inverse proportion between the number of rejected lots and the presumptive period of storage. I n other words, there seems to be a clear indication that the ether, after being placed in the container, undergoes certain deleterious changes. Further analysis of the table shows that aldehyde and peroxide are the dominant contaminants, with the latter a factor in over two-thirds of the samples. An interesting confirmation of this conclusion is found in the results of a series of analyses made a t the Royal Victoria Hospital of Montreal. Of 14 fsamples drawn from three different sources, 3, or 21 per cent, were rejected because of the presence of peroxide. Odor and acid tests were uniformly negative. Five of the sample13 showed turbidity and a white separate referable to alcohol, but in none of them was there the brown discoloration of aldehyde resin. Two samples showed high specific gravities but were otherwise satisfactory. In the writer’s opinion the presence of aldehyde alone indicates an ether contaminated a t the time of placing in the containers; those containing peroxide alone, ethers which have probably undergone deterloration during storage. Where both are present the aldehyde probably represents a second phase in the oxidation of the ether or the alcohol, although it may conceivably be due to an initial contamination. The term “peroxide” is used for its nonspecificity, although the recent work of Clovera has done much to clear up the question of ether oxidation. Clover regards the first oxidative step as the formation of an ether peroxide and to this latter body assigns what seems to be a probable formula. This by decomposition could go t o form aldehyde directly, while alcohol and water might be among the other products. In the presence of acid, hydrogen peroxide would be formed, and in the opinion of Clover the presence of hydrogen peroxide is to be regarded as indicative of secondary rather than primary oxidation.
A detailed discussion of the oxidative changes is to be the subject of a shortly forthcoming paper. A few general considerations are pertinent to the present discussion, however. The three substances normally present in the majority of high-grade anesthetic ethers are alcohol, water, and air. The statement is usually made that alcohol is included to prevent the undue cooling effects obtained by the evaporation of an alcohol-free ether. Two problems-first, the possible prevention of contamination by the presence of alcohol; and second, the removal of contaminants by means of alcohol -were studied a number of years ago by Thoms.7 He concluded that alcohol neither prevented contamination nor removed contaminants. Susceptible as it is to oxidation, it forms a very evident potential source of aldehyde. Its exclusion should improve the keeping power of the ether, and the objection to an alcohol-free ether previously cited could be met by the addition of definite amounts of pure alcohol prior to use. Water is a powerful catalytic agent for certain types of reaction. Further, in the presence of oxygen and many of the metals it tends spontaneously to produce hydrogen peroxide, 8
7
J . A m . Chem. SOC.,44, 1107 (1922). Pharm. Gesell., Berlin, 1894.
897
a powerful midizing agent. Its boiling point is relatively high compared with that of ether and if its inclusion is for the purpose of moistening the ether vapor the end is hardly attained. The substitution of a water bottle through which the ether vapor is bubbled gives a far more efficient saturation and removes another source of potential contamination. Air cannot be entirely excluded, although the sealing of containers of ether a t the boiling point of the liquid and with the container practically full would cut down the concentration of the active agent. That this offers mechanical difficulties is obvious. The current practice in this country is to market ether in metal containers and with an appreciable air space. The number of chemical reactions catalyzed by metal is too great and the details are too well known to require comment. Glass, on the other hand, while possessing certain catalytic powers, is far less active in determining the velocity of oxidation reactions than is metal. Analyses made upon two samples of ether sustain this contention. The first lot was an anesthetic ether of foreign make, bearing the factory date of February 7, 1910. Not only had no precautions been observed in the storage of this ether, but for a number of years it had reposed on a laboratory shelf subject to all possible vicissitudes of light and temperature change. The ether was contained in small, dark amber, glass bottles of approximately 150cc. capacity. It showed a specific gravity of 0.711 indicating the absence of all but minimal traces of alcohol and water, and gave definitely negative response to all the tests applied. The second ether was contained in an ampul of white glass of about the same capacity as the bottle of the first sample. The glass ampul, however, was enclosed in a wooden case which effectually protected it from light. The specific gravity was 0.711, the entire sample distilled between 34” and 35” C., and all the tests as given were definitely negative. The exact age of the sample could not be ascertained, but it was known to be a t least several years old. While too sweeping a generaliza$ion should not be based upon the examination of two lots of ether, the results obtained are certainly suggestive. Of the three samples rejected because of odor, one contained a large amount of peroxide which could well have been the cause (the sharp irritating odor of peroxide has been commented on by others), while the other two were contaminated by appreciable amounts of higher alcohols (fusel oil) or their oxidation products. Of the three samples showing acid reaction, one contained free hydrochloric acid with appreciable amounts of a metallic chloride-in other words, soldering fluid. (The odor here was sharp and irritating, but as this came from so patently foreign a cause, it is not included in the tabulation.) Of the two remaining, one also had peroxide in liberal amount and presumably represented a later stadium in the oxidation, while no clue to origin was given by the analysis of the other. ACKNOWLEDGMENT The author takes pleasure in expressing his thanks to Marion D. Alcott and Endora Mortimer, for their assistance in making many of the analyses; to Drs. D. H. Arnott and R. C. Kingswood for the analyses made at the Royal Victoria Hospital of Montreal; and to Drs. F. L. Richardson, Samuel Johnston, and E. A. Tyler for their cooperation with regard to the samples of old ether contained in glass.
*
Celluloid films so thin that 254,000 of them could be packed into a space an inch thick have been produced by the Bureau of Standards. They were made by dissolving the celluloid in amyl acetate and dropping the solution on a clean water surface, allowing the acetate to evaporate. These films are intended for use in connection with some X-ray studies the Bureau of Standards is undertaking.
