OBSERVATIONS ON THE VOLATILITY AND SOLUBILITY OF CANTHARDIN IN VIEW OF THE MOST ELEGIBLE PHARMACEUTICAL TREATMENT OF SPANISH FLIES. BY WILLIAM PROCTER, JR.
Cantharides have been used in Pharmacy since the days of Hippocrates. It was not till 1810, however, that the principle giving them activity was isolated by Robiquet (Annal. de Chimie lxxvi. 302,) and subsequently named Cantharidin by Dr. Thomas Thompson. Since then various experimenters have been engaged in the chemical investigation of these flies, and in the more recent treatises they are stated to consist of cantharidin, yellow fixed oil, green fixed oil, a yellow viscous substance, a black matter, ozmazome, uric acid, acetic acid, phosphoric acid, and the phosphate of lime and magnesia. It is proverbial among apothecaries and physicians, that the pharmaceutical preparations designed to produce vesication, vary very much in their power as prepared by different individuals, and from different samples of cantharides by the same recipes. Is this variableness of power due to the inequality of strength of the commercial drug? or, are we to attribute it to the treatment employed by the apothecary? The real importance of these queries demands an answer. To proceed {356} properly, the investigator should examine cantharidin in a pure state, ascertain how far the statements of writers are correct, then by a series of analyses, quantitative as regards that principle, determine whether its proportion varies, and to what extent, in different specimens of cantharides of fair quality; and finally to test the preparations derived from the same samples and see how far they correspond with the inferences drawn from the ascertained properties and proportion of the active principle. I have at present undertaken to resolve but a part of these queries—yet by far the most important ones—as will be seen.
Cantharidin is a white, neutral substance, of which the formula according to Regnault is C10 H O4. Gmelin considers it of the nature of a solid volatile oil. As usually seen it has the form of minute flatted four-sided prisms (c,) much broken up, so as to appear like scales. When deposited from an ethereal solution of cantharides by slow evaporation, or from its solution in hot acetic acid by cooling, it assumes the form of flattened oblique four-sided prisms with dihedral summits, derived from the rectangular prism by the bevelment of its edges (see fig. a and b from c.) The crystals by slow sublimation are four-sided rectangular prisms of great brilliance and sometimes iridescent, c and d.
SOLUBILITY.—Pure cantharidin is insoluble in water, hot or cold. It is slightly soluble in cold alcohol, readily so when hot. Ether dissolves it to a greater extent, yet much more easily hot than cold. Chloroform is its best solvent, cold or hot, as shown in a former essay (Am. Jour. Pharm. vol. xxiii. 124,) and will remove it from the aqueous infusion of the flies. Acetic ether dissolves cantharidin, especially when hot, but does not retain much on cooling. When one part of cantharides is mixed with 20 parts of olive oil and heated to 250° Fahr. it is completely dissolved. As the solution cools, the cantharidin rapidly separates in shining needles in such quantity as {357} at first to give the oil a pulpy consistence. The clear cold oil retains sufficient to act as an efficient rubefacient but not as an epispastic. One part of cantharidin requires 70 parts of oil of turpentine to dissolve it at the boiling temperature, the greater part separating, as the solution cools, in long asbestos-like needles. A piece of paper saturated with the cold solution and applied to the skin under adhesive plaster did not vesicate. Acetone (from the distillation of acetate of lime) dissolves cantharidin with great readiness and ranks next to chloroform in this regard. The solution deposits the substance in crystals by evaporation. The commercial methylic alcohol or wood naphtha also dissolves cantharidin, but to a much less extent than acetone. When acetic acid sp. gr. 1.41 (U. S. P.,) is added to cantharidin, it but slightly acts on it in the cold; heat much increases its solvent power, which is lost on cooling and the substance deposited by standing, though not immediately. One part of cantharidin was mixed with 40 parts of crystallizable acetic acid and agitated together during five hours, but a small percentage was dissolved; but on applying heat the crystals were dissolved quickly. On standing, nearly all of the cantharidin was slowly deposited in regular crystals. To ascertain whether, as has been asserted,[30] a combination was effected, and an acetate of cantharidin produced, an acetic solution of cantharidin was evaporated to dryness and the crystals mixed with strong sulphuric acid and heated till dissolved, while the nose was held near, without the slightest evidence of acetic odor; one twentieth of a grain of acetate of potassa was then added, which instantly evolved the well marked smell of acetic acid. Formic acid dissolves but a trace of cantharidin, cold or hot; and muriatic acid sp. gr. 1.18 hardly can be said to act on it in the cold, but when boiling a minute portion is taken up. The same is true of phosphoric acid dissolved in five parts water. Sulphuric acid sp. gr. 1.840, when heated readily dissolves pure cantharidin without being discolored, {358} and deposits it in crystals unchanged by cooling. Hot nitric acid sp. gr. 1.38, dissolves cantharidin readily, and deposits the greater part of it on cooling in brilliant crystals, unchanged. A concentrated solution of ammonia slowly dissolves cantharidin to a small extent, and yields it up on evaporation in crystals. Solutions of pottassa and of soda also dissolve this principle.
[30] New York Jour. Pharm. vol. 1. p. 72.
ITS VOLATILITY.—About ten grains of pure and perfectly dry cantharidin was spread on the pan of an Oertling’s balance, (sensitive to 1-150th of a grain,) and the equilibrium carefully adjusted with platina weights. After exposure for a week to the action of the air, a vessel of lime being present to keep the air dry, no change in the adjustment had occurred. To further test the volatility of cantharidin, a portion of it was put at the bottom of a dry test tube, through a paper funnel so as not to soil the sides, which was then fixed so as to dip half an inch in a mercurial bath having a thermometer suspended in it. It lost nothing appreciable after being kept at 212° F. for half an hour, no sublimate being visible with a lens. At 220° F. no visible effect was produced. Kept at 250° F. for twenty minutes, a very slow sublimation commenced. At 300° F. the vaporization was but slightly increased. The heat was then raised to 360° F., when the sublimation became more decided, yet still slow. Between 402° F. and 410° F. it fused, and rapidly sublimed at a few degrees higher. Cantharidin at this temperature volatilizes with great ease and condenses in beautiful well defined crystals like salicylic acid.
The specific gravity of cantharidin is considerable, as it sinks in nitric acid sp. gr. 1.38; it is exceedingly acrid; its powder applied to the skin with a little oil, produces speedy vesication, and taken internally it is an irritant poison of the most virulent kind.
Such are some of the more prominent characters of this remarkable substance, which exhibits a permanence and want of affinity extraordinary in an animal principle. Let us now see how far experiments with cantharidin as it exists in the flies in substance, correspond with its behaviour in an isolated state. {359}
1st. Is cantharidin, as it exists in Spanish flies, volatile at common temperatures, or at the temperature usually employed in making the cerate; and if so to what extent?