obtained from cevadilla seed. The mixture of alkaloids in the seed being very complex, no attempt is made at separation in the process of extraction. The seed, having been crushed, are exhausted by repeated boiling with acidulated water and the mixed decoctions evaporated to a syrupy consistence and treated with milk of lime. The precipitate thus obtained by decomposition of the natural salts of the alkaloids with veratric acid, and consisting of crude alkaloids and extractive matter, is extracted with alcohol and the latter recovered from the resulting solution, after which the residue is digested with acetic acid in order to bring the alkaloids into solution as acetates. The last-named solution is decomposed with ammonia water in excess and the precipitate, having been washed with water, is dissolved in diluted hydrochloric or sulphuric acid, the solution decolorized with animal charcoal and again precipitated with an alkali. Finally, the precipitate of mixed alkaloids is washed with water and dried at a moderate temperature. This process has the advantage over others in avoiding the extraction of fatty and resinous matter.

The most abundant and most important alkaloid in veratrine is cevadine, CHNO,, which may be crystallized from alcohol in the form of anhydrous needles. It is exceedingly toxic and very irritating to the nasal mucous membrane. A solution of cevadine in nitric acid assumes a violet color upon being warmed, which changes to scarlet-red on boiling. With cold sulphuric acid cevadine yields a yellow solution, the color, however, changing to blood-red on warming. According to Allen, the facility with which cevadine undergoes hydrolysis is the cause of the formation of much amorphous alkaloid and other products in the extraction of cevadilla seed.

Besides cevadine, veratridine, CHNO, named veratrine by its discoverers, Luff and Wright, is present in the official veratrine, and also cevadilline or sabadilline, C,HNO, both of which are amorphous. Sabadine, CH,,NO, and sabadinine, CHNO, both crystallizable alkaloids, have also been found.

Owing to its intensely irritating effect upon the mucous membranes, care is necessary in handling veratrine, and dampening with alcohol or expresed oil of almond will be found desirable when mixing it with other substances. Veratrine is rarely used internally, but mostly as oleate or ointment.

Veratrine is not found in white or green hellebore, but other alkaloids, jervine, CHNO, and veratroidine, CH,N,O16, have been isolated from these plants.

Besides the foregoing there are a number of alkaloids and alkaloidal salts not recognized in the Pharmacopoeia which are of more or less interest to pharmacists, and will, therefore, be briefly considered.

13

Arecoline Hydrobromide. CH12NO,HBг.-This salt, which is official in the German Pharmacopoeia, may be obtained by dissolving

the pure alkaloid in diluted hydrobromic acid and crystallizing from an alcoholic solution. The alkaloid arecoline occurs in the areca or betel nut to the extent of 0.1 per cent., and its extraction involves a tedious and somewhat complicated process; it is the only one of the four alkaloids found in the areca nut which is highly poisonous, and, while an oily liquid of strongly basic reaction, it is soluble in water in all proportions.

20 17

Berberine. C2H,,NO,.-The chief interest attached to this alkaloid arises from the fact that, while the alkaloid is soluble in water, its salts are difficultly soluble, and are deposited in a crystalline form from acid liquids. Berberine occurs in several plants-in hydrastis to the extent of 3 or 4 per cent., from which it may be obtained by adding to a concentrated aqueous infusion of the drug hydrochloric or sulphuric acid in excess, when the corresponding berberine salt will be deposited in crystals, which, after purification by recrystallization from boiling water, may be decomposed by means of freshly prepared lead hydroxide. After filtration and concentration of the filtrate, berberine will separate as a yellow, crystalline powder.

Coniine. CH,,N.-Conium owes its medicinal virtues entirely to the volatile alkaloid, which is present in the unripe fruit (probably combined with malic acid), to the extent of 0.5 or 0.8 per cent. It can be extracted by exhausting the drug with water acidulated with acetic acid, evaporating the infusion down to an extract, in a vacuum apparatus, adding an alkali carbonate, and distilling. By collecting the distillate in diluted sulphuric acid, coniine sulphate is at once formed, which may be freed from the accompanying ammonium salt by treatment with alcohol and ether, in which the latter is insoluble; by addition of an alkali to the alcohol and ether solution and distillation, coniine will be isolated, and may be dissolved in ether, from which it can be obtained as hydrochloride, by passing dry hydrochloric acid gas into the solution, the salt being insoluble in ether. Coniine hydrochloride occurs in white crystals, which are non-deliquescent, may be dried at 100° C. (212° F.) without decomposition, and are soluble in water and alcohol.

Coniine belongs to the amines, and has been prepared synthetically by Ladenburg; it has a strong alkaline reaction and a penetrating, suffocating odor. When pure it is a colorless, oily liquid, lighter than water, and boiling at 169° C. (336.2° F.).

23

7

Narcotine. CHNO,.-This substance occurs in opium, sometimes to the extent of 10 per cent. and over. Being readily soluble in chloroform and ether, it is easily extracted from powdered opium by maceration or percolation with either of these solvents, but, not being soluble in petroleum benzin, it is not removed in the present official processes for Deodorized Opium and Tincture of Deodorized Opium. Narcotine is a very weak base and does not neutralize

acids; it exists in opium in a free state, and, although it forms crystallizable compounds with hydrochloric and sulphuric acids, these are readily decomposed by an excess of water, and yield narcotine to both ether and chloroform when shaken with these liquids. A solution of narcotine in sulphuric acid soon becomes yellow, and, upon heating, turns red, and finally purple.

20 24

4

Quinidine Sulphate. (CHN2O),H,SO, + 2H2O.—Quinidine usually remains in the mother-liquors from the crystallization of quinine sulphate, from which it may be obtained by adding a large excess of ammonia water, whereby cinchonine and cinchonidine are thrown down, while quinidine remains in solution; it can subsequently be precipitated by means of caustic soda and dissolved in diluted sulphuric acid, the resulting salt being purified by recrystallization. From the purified alkaloid, obtained by precipitation with sodium hydroxide, the sulphate can be readily prepared by solution in just sufficient warm diluted sulphuric acid to neutralize the same and crystallizing; if an excess of acid be used, a salt differing from the official salt will be formed.

Quinidine sulphate somewhat resembles official quinine sulphate in appearance, and has some chemical properties in common with it, but may be distinguished by its greater solubility in water and in alcohol and by being precipitated in concentrated aqueous solution by potassium iodide. Its solutions, like those of quinine sulphate, form thalleioquin and show a blue fluorescence when acidulated with sulphuric acid.

CHAPTER LXI.

ASSAY OF ALKALOIDAL DRUGS.

In view of the fact that the Pharmacopoeia demands a definite alkaloid content for seventeen crude drugs and thirty-three galenical preparations, a discussion of the subject appears desirable for the purpose of offering to students some explanation of the official and other methods in use for the quantitative determination of active principles. In the case of alkaloidal drugs the valuation may be made either gravimetrically or volumetrically, but with accuracy in the last-named case only if a single alkaloid is present, or if the exact proportion of the several alkaloids present be known.

The first step in assaying alkaloidal drugs is to extract them either with acidulated water, or with alcohol, ether, or chloroform, or a mixture of two or three of the latter-named liquids, in the presence of an alkali, usually ammonia water. In the first case the alkaloids are obtained in aqueous solution as salts of the particular acid used, while in either of the latter cases the alkaloids will be liberated by the alkali, and be dissolved as free bases in the respective solvents. If an acid solution is obtained it is transferred, either direct or after concentration to small bulk, to a glass separator, made alkaline with ammonia, or potassium or sodium hydroxide, and shaken out with chloroform or ether, or a mixture of the two solvents. If an alkaline solution, however, has been obtained, this is shaken out in a separator with successive portions of diluted acid (1, 3, or 5 per cent.), whereby the alkaloids are removed as salts in aqueous solution, which latter is then further treated as previously stated; or the alkaline solution may be evaporated to dryness and then treated with weak dilute acid, either in the cold or with aid of a gentle heat, for the purpose of getting rid of alcohol or chloroform and any fatty or resinous substances possibly held by them in solution. Some alkaloids, such as aconitine and those obtained from the mydriatic drugs, are very sensitive to heat, either alone or in the presence of strong alkalies, and hence a moderate temperature, not exceeding 50° C. (122° F.), must be employed, and sodium or potassium carbonate is to be preferred to the caustic alkalies.

As a rule, 10 or 20 Gm. of the drug in fine powder are treated with 100 or 200 Cc. of the solvent, and after due maceration (from one to six hours), with frequent agitation, an aliquot part of the fluid is withdrawn, representing a definite weight (5 or 10 Gm.) of the drug. As it is often very difficult to pour off an aliquot part of the lighter liquid entirely free from floating particles, water is added to the

mixture (from 10 to 40 Cc., as may be necessary) just before the liquid is to be poured off, and the mixture actively shaken for a few minutes, which causes the powdered drug to ball together and permits the separation of a perfectly clear upper layer, easily removed by decantation.

The final solution of the alkaloids in ether or chloroform, or both, is evaporated to dryness and weighed; the weight multiplied by 100 and divided by the weight of the drug represented in the final solution will express the percentage of alkaloids in the sample of drug operated upon. If a volumetric determination is to be made, the residue of crude alkaloid is dissolved in a measured quantity of tenth-normal acid, with the aid of a moderate heat if necessary, sufficient acid being used to insure an excess, which latter is then determined by titration with fiftieth-normal alkali in the presence of a suitable indicator, either hematoxylin, cochineal, or iodeosin solution, the latter being especially intended for colored alkaloidal residues. The object of using alkali solution so much weaker than the acid is to enable the operator to approach the end of the reaction. with greater precision, avoiding a large excess of alkali, and the quantity of such weaker alkali solutions used must be brought to the equivalent of the stronger acid solution by calculation. Thus, if fiftieth-normal alkali is used, 5 Cc. will be equivalent to 1 Cc. of tenth-normal acid, and hence the number of cubic centimeters necessary to neutralize the acid must be divided by 5 to find the exact number of cubic centimeters of tenth-normal acid in excess, and if this number be subtracted from the quantity of acid originally used the difference will indicate the quantity of acid neutralized by the alkaloids. Having ascertained the number of cubic centimeters of tenth-normal acid taken up by the alkaloids, the same is multiplied by the factor representing the weight of the respective pure alkaloids equivalent to one cubic centimeter to find the total quantity of alkaloid in the residue, from which the percentage of alkaloid present in the sample of drug is readily calculated as shown above.

The following list indicates the quantity of some of the leading alkaloids (anhydrous) necessary to neutralize one cubic centimeter of tenth-normal acid:

An annoying feature sometimes encountered in the shaking-out process of alkaloidal solutions is the formation of persistent emulsions, which is usually caused by too-active agitation of the contents