Proceedings of the American Pharmaceutical Association at the Annual Meeting

The crude product is purified by agitation with strong brine, which dissolves the ordinary ethyl alcohol, together with a great portion of propyl and butyl alcohol, furfurol and other aldehydes and the soluble acids. An oily liquid remains undissolved and is distilled off, and the fraction passing over between 125° C. and 140° C. is separated and sold as "purified amyl alcohol." From this material the amyl nitrite of pharmacy is generally prepared.

It is evident that fractional distillation can only separate those ingredients whose boiling points are materially higher or lower than that of the fraction preserved. So we find, as a matter of course, in the purified amyl alcohol a number of the admixtures which were originally present in the crude product. Fusel oil from potato spirit [which is much produced in Germany] contains principally iso amyl alcohol and ethyl alcohol, and therefore furnishes, by the above-described treatment, a very pure and uniform product. Fusel oil from maize whiskey [which forms the principal part of that produced in the United States] contains besides the iso-amyl alcohol, small amounts of its several isomeric varieties, (normal amyl alcohol, lævo-rotary methyl-ethyl-carbin-carbinol, etc.) also iso-butyl and propyl alcohols.*

With a difference in the amyl alcohol from which the nitrite is prepared, we have to expect a difference in the final product, and hence we find that while imported amyl nitrite, derived from the potato, consists almost entirely of the nitrite of iso-amyl, the American product contains the nitrites of the other isomeric varieties, etc. Whether these have different physiological or medicinal effects, remains to be investigated.

But besides these differences arising from the mixed nature of the amylic alcohol used, and which can hardly be considered in the light of real impurities, there are liable to be present a number of other substances in amyl nitrite, principally due to imperfections in the manufacture. Among these is an amount of unchanged amyl alcohol and amyl valerianate, which however can be removed by careful redistillation at 100° C., when the amyl nitrite will boil and distil over, while the unchanged alcohol and the valerianate require a much higher temperature.

If nitric acid be used in the preparation, larger amounts of amyl nitrate, as well as valerianic aldehyde and acid are liable to form, but as its use has recently been almost entirely superseded by that of nitrous acid (potassium nitrite and sulphuric acid), these products occur in less quantity than in the product manufactured by the older process.

* Among the isomeric amyl alcohols, found in grain fusel oils, are the following:
Iso-amyl alcohol, boiling point 131.6° C., sp. grav. 0.8248.

Active methyl-ethyl-carbin-carbinol, boiling point 128° C.
Methyl-propyl-carbinol, boiling point 118.5° C., sp. grav. 0.8239.
Methyl-iso-propyl-carbinol, boiling point 112.5° C., sp. grav. 0.819.
Tertiary amyl alcohol, boiling point 102.5° C., sp. grav. 0.812.

Nitropentane, an isomeric modification of amyl nitrite, is also less frequently found now, since the use of nitric acid has been abandoned.

If ethylic alcohol has not been entirely removed from the amyl alcohol, ethyl nitrite will also be present, and occasionally butyl nitrite can be found in some quantity, and materially modifies the odor.

Some of the impurities are not originally present in the freshly distilled product, but result from decomposition, especially by light, as the habit of preserving in colorless bottles still prevails to a great extent. Among these are valeric and other aldehydes. Nearly all of the above-named impurities can be readily removed by careful fractional distillation, excepting valeric aldehyde, butyl nitrite, and water.

The tests for purity prescribed by the U. S. P. (1880) are:

The boiling point at about 96° C., which makes allowance for the peculiar composition of American fusel oil, for the amyl nitrite made from pure iso-amyl alcohol boils at 99° C.

The specific gravity is given at 0.874, which makes a similar allowance, for the pure iso-amyl nitrite has a specific gravity of 0.905 (Flückiger, Bunge, etc.). Then a test for water is given, demanding that, when refrigerated to o C., the product shall remain clear.

Finally, as a limit of acid, it is directed that 10 c.c. of amyl nitrite, after agitation with 2 c.c. cf a mixture of 1 part ammonia water and 9 parts of water, should yield a liquid which does not redden litmus paper.

The German Arzneibuch directs a boiling point of from 97° C. to 99° C., corresponding to the product from purified potato fusel oil, and a specific gravity from 0.870 to 0.880, which still permits the presence of some lighter material (such as unchanged iso-amyl alcohol, ethyl nitrite, etc.).

The tests for absence of water and the limitation of acid are the same as in the U. S. P. To these is added a test for absence of aldehydes with ammoniacal silver nitrate.

A quantitative test is not given in either Pharmacopoeia, and yet it would be easy enough to base one on the percentage of nitrous acid in combination. This would not guard against the presence of other nitrites (ethyl, propyl and butyl nitrites would count for full, and even more than full, on account of their lower molecular weight); but it would serve, in connection with the tests for identity and those for limit of impurities already prescribed, to exercise a greater control over the article. That such a control is necessary, the great diversity of percentage found in the commercial product will amply prove. Several methods are suitable for ascertaining the percentage of nitrite in any sample, and all of those practiced for the analysis of the spiritus ætheris nitrosi may be so modified as to apply to amyl nitrite. In a series of papers read before the Missouri State Pharmaceutical Association a few weeks ago, I have discussed these methods somewhat in extenso, and beg leave to refer to those papers, recently published, for a detailed description of a variety of volumetric and nitrometric processes of analysis.

For the examination of a number of specimens of amyl nitrite, collected from various sources, and for many of which I am indebted to the kindness of friends, I have adopted the method devised by Allen for spirit of nitrous ether, which gives prompt and accurate results. The instrument used for the purpose is a modification of the nitrometer of Lunge, who first devised this useful apparatus. Fig. 1 of the accompanying plate shows the original instrument of Lunge, designed for general use with nitrates. Fig. 2 shows his later arrangement for the analysis of saltpetre. Fig. 3 represents Allen's instrument, and Fig. 4 a modification of this, made by myself, having bulbs at the bottom of the tubes for the reception of the reagents so as to avoid their passing into the open tube and thus occasioning loss of gas.

Each instrument consists of a graduated measuring tube with stopcock and cup on top, and an open equilibrium tube, connected with the measuring tube by stout rubber tubing. Figs. 1 and 2 have the so-called 3-way stopcock, permitting the attachment of apparatus to the side tube. Figs. 3 and 4 have the ordinary stopcock with single bore. They are fastened by screw clamps to the upright rod of the common iron support used in laboratories.

The chemical reaction upon which the nitrometric method is based, is the conversion of amyl nitrite by the addition of potassium iodide and sulphuric acid into amyl alcohol, potassium bisulphate, free iodine, and nitric oxide. The latter-also called nitrogen dioxide, NO, or N,O,-is measured in the graduated tube of the nitrometer, and from it the amount of amyl nitrite is readily calculated. The equation reduced to the simplest proportions would read:

CH1NO+KI + H2SO

CH1OH + KHSO, + I + NO.

From this it follows that each molecule of amyl nitrite yields one molecule of nitric oxide, or that 116.78 grams of amyl nitrite yield 29.97 grams (measuring 22321.2052 c.c.) of the gas. Hence it will require 0.5231797 grams of amyl nitrite to yield 100 c.c. of NO gas, and if such amount be used in the nitrometer, each c.c. of gas will correspond to one per cent. of amyl nitrite. The volume of the gas must however be first reduced, so as to correspond to the normal conditions adopted by physicists for measuring gases, i. e., to the volume the gas would occuy at 760 mm. of barometric pressure and at o' C.

The analysis is made as follows: The measuring tube of the nitrometer is filled up to the stopcock, including its bore, with a saturated solution of sodium chloride in water, the stopcock is closed and the equilibrium tube emptied, so that only a few cubic centimetres of the solution are allowed to remain in its bulb. The tubes are so adjusted to their support that the measuring tube stands as high, the equilibrium tube as low, as the fastenings will conveniently permit. Next, 0.523 gm. of the amyl nitrite, diluted

with about 5 c.c. of alcohol, are introduced into the cup, and by careful opening of the stopcock are transferred into the graduated part of the tube, without admitting air. To secure this, few drops are left in the cup and washed down by, the repeated addition of a few c.c. of the salt solution which is used for filling the instrument. The reagents for decomposition are best used in the strength of normal volumetric solutions, and in the quantity of 10 c.c. each, so that uniformity may prevail in the difference of specific gravity in the two tubes.

The solution of potassium iodide is therefore made to contain 165.59 gm. of KI per litre; the normal sulphuric acid contains 48.91 gm. of H SO, in 1 litre.

After the introduction of the sample of amyl nitrite 10 c.c. of normal KI solution are next introduced, followed by 10 c.c. of normal sulphuric acid, using the same precautions as before against the admission of air. A strong effervescence now ensues, and while the gas fills the upper portion of the graduated tube, the reagents are pressed down, but still, on account of their mixture being specifically lighter than the salt solution, they mix but little with it and float on top. Some agitation is necessary to favor the rapid and complete evolution of the gas. The reaction is generally finished inside of five minutes. The two tubes are now so adjusted that the liquid in the equilibrium tube stands about 3.3 c.c. lower than that in the measuring tube, and the number of c.c. of NO gas evolved is then read off and noted. The correction for temperature is now made by dividing the number of c.c. by the number of c.c. to which one cubic centimetre of gas, measured at o° C., will expand when raised to the temperature prevailing at the time of making the experiment. This number is found on the following table:

CORRECTION OF GAS VOLUME FOR TEMPERATURE.