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"Coca Alkaloids"

from "Commercial Organic Analysis" (Volume 3, Part 2)
Alfred Henry Allen (1907)

Coca Aklaloids

The leaves of Erythroxylon coca and other allied species contain a number of closely-allied alkaloids, all of which appear to be derivatives of ecgonine, C9H15NO3, a base which Einhorn and Hesse regard as a derivative of tetrahydropyridine, and to which they assign a constitution expressed by the following formula:

        { CH2.CH[CH(OH)CH2.COOH] }
    CH2 {                        } N.CH3
        { CH:CH                  }

According to this formula, ecgonine is methyltetrahydropyridl-β-hydroxypropionic acid. When heated with baryta [note: barium compounds], it splits into carbon dioxide and isotropine, and hence may be regarded as isotropyl-carboxylic acid

    Me.C5H7N.CH(OH).COOH == CO2 + Me.C5H7N.CH(OH).CH2.H
        Ecgonine            CO2 +      Isotropine

The relation between ecgonine and isotropine (and therefore between cocaine and atropine [the latter related to belladona]) is equally evident from a comparison of the formula of their respective anhydrides:

MeN { .CH.(CH:CH.COOH).CH2 }      MeN { .CH.(CH:CH.COOH).CH2 }
    { .CHCH2               }          { .CH:CH.CH2           }
        Anhydro-ecgonine                     Tropidine

The hydrogen of the hydroxyl-group of ecgonine can be substituted by acetyl, benzoyl, cinnamyl, and other acid-radicals. Thus:

Benzoyl-ecgonine      Me.C5H7N.CH(O.C7H5O).CH2.COOH
Cinnamyl-ecgonine     Me.C5H7N.CH(O.C9H7O).CH2.COOH
                                     ^ ^

(Note: .COOH - carboxylic acid, a family: H.COOH is formic acid, CH3.COOH is vinegar.)

By heating those compounds with alkyl iodides, the corresponding esters may be obtained:

Methyl  benzoyl-ecgonine (cocaine)   Me.C5H7N.CH(O.C7H5O).CH2.CO.OCH3
 Ethyl  benzoyl-ecgonine             Me.C5H7N.CH(O.C7H5O).CH2.CO.OC2H5
Methyl cinnamyl-ecgonine             Me.C5H7N.CH(O.C9H7O).CH2.CO.OCH3

Methyl benzoyl-ecgonine or cocaine (also as benzoylmethylecgonine) is the most important and characteristic of the bases of coca. Methyl cinnamyl-ecgonine occurs occasionally, in small quantity, in the broad-leaved South American coca, and regularly, and sometimes in considerable quantity, in Truxillo coca.

When dibasic acids react on ecgonine, bodies of more complex constitution result. One of these (the methyl-ester of a substance polymeric with cinnamic acid, called by Hesse cocaic acid, C18H16O4, and by Liebermann as γ-isatropic or truxillic acid), is the cocamine, C38H46N2O8, of Hesse, and the isatropyl-cocaine, or α-truxilline of Liebermann. The next higher homologue of cocayl-ecgonine methyl-ester also appears to exist in coca, as also the corresponding derivatives of iso-cocaic (β-truxillic) and homo-isococaic acids.

The following is a list of the bases hitherto detected in coca leaves. The amorphous base to which Hesse gave the name of cocaidine has been proved to be a mixture; and the volatile base called hygrine by Lossen has not since been obtained.

 C9H17NO2    Anhydro-ecgonine
 C9H15NO3    Ecgonine
C16H19NO4    Benzoyl-ecgonine
C17H21NO4    Benzoyl-ecgonine  methyl-ester (cocaine)
C18H21NO4    Cinnamyl-ecgonine
C19H23NO4    Cinnamyl-ecgonine methyl-ester
C17H19NO2    Benzoyl-pseudotropine
C38H46N2O8   Cocayl-ecgonine methyl-ester (cocamine/truxilline)
C40H50N2O8   Homococaine
C18H23NO4    Benzoyl-ecgonine   ethyl-ester (cocaethylene)

Isomerides of cocamine and homococaine probably exist in coca, as Hesse has isolated from the products of hydrolysis isococaine and homo-isococaic acids. Similarly, Liebermann has isolated two isomers of cinnamic acid, isocinnamic and allocinnamic acids, from the products of the decomposition of coca bases.

With the exception of ecgonine and anhydro-ecgonine, all the bodies in the foregoing list are saponifiable (hydrolyzed under basic conditions), splitting up when heated to 80 °C - 100 °C with hydrochloric acid, or when boiled with alcoholic potash, according to the following equations:

Cocaine           + Water =   Benzoyl-ecgonine + Methyl Alcohol

Benzoyl-ecgonine  + Water =           Ecgonine + Benzoic Acid

Cinnamyl-ecgonine + Water =  Cinnamyl-ecgonine + Methyl Alcohol

Cinnamyl-ecgonine + Water =           Ecgonine + Cinnamic Acid

Cocamine         + 3Water =           Ecgonine + Ecgonyl-cocaic acid
                                               + 2 Methyl Alcohol

Ecgonyl-cocaic acid   + Water =       Ecgonine + Cocaic Acid

Benzoyl-pseudotropine + Water =  Pseudotropine + Benzoic Acid

From these equations it is evident that the simpler bases of coca are decomposition products of the natural alkaloids cocaine, cocamine, homococaine and cinnamyl-ecgonine methyl-ester (cinnamyl-cocaine), all of which readily undergo hydrolysis with formation of ecgonine, methyl alcohol, and an aromatic acid. Benzoyl-pseudotropine differs from the other bases of coca by yielding no methyl alcohol on hydrolysis.

It is evident that the mixed alkaloids of coca will consist of the various natural bases in indefinite proportion, contaminated by the products of their decomposition. Hence the separation of pure cocaine from the co-existing bases is very troublesome. The difficulty has been overcome by Liebermann and Giesel in an interesting and ingenious manner, which allows of the utilization of the valueless and troublesome amorphous by-products, which are to be had in considerable quantity. The process consists in boiling the mixed bases with hydrochloric acid, whereby they all suffer hydrolysis, with formation of ecgonine; and this base forms the starting-point for the subsequent synthesis of cocaine by Einhorn's method. Thus by passing dry hydrochloric acid gas into a solution of ecgonine hydrochloride in methyl alcohol until the solution has become cold, and then boiling the liquid for an hour under an inverted condenser, the hydrochloride of ecgonine methyl-ester is formed, which on concentrating the alcoholic solution crystallizes in prisms, melting with decomposition at 212 °C. Cocaine is formed when this compound is heated on the water-bath with an equal weight of benzoyl chloride until the mixture becomes homogeneous and the evolution of hydrochloric acid ceases. The hot melted mass is poured into water, separated from the precipitated benzoic acid, and the cocaine precipitated by ammonia or an aklaline carbonate, and recrystalized from alcohol. An alternative method is to convert the ecgonine into the benzoyl-derivative, and treat a solution of the latter body in methyl alcohol with hydrochloric acid gas. The artificial cocaine prepared by either of these methods possesses all the characters of the natural alkaloid.

Cocaine (benzoyl methyl-ecgonine, methyl benzoyl-ecgonine)

                         { O.CO.C6H6   }
C17H21NO4   C5H7(CH3)N.CH {             }
                         { CH2.CO.OCH3 }

Cocaine (also as benzoylmethylecgonine) is the characteristic alkaloid of coca leaves, and has recently acquired a place in the first rank of alkaloids of medicinal value. It may be extracted from the plant by the usual processes, avoiding as much as possible treatment with acids and alkalies, as it undergoes hydrolysis with great facility with formation of objectionable decomposition-products.

The synthesis of cocaine was effected by Merck by treating together ecgonine, benzoic anhydride and methyl iodide to 100 °C for ten hours in a sealed tube. The industrial reproduction of cocaine from ecgonine has been effected and patented by Liebermann (page 272).

Cocaine crystallises from a strong alcoholic solution in colorless monoclinic prisms, melting at 97 °C to 98 °C, and subliming with partial decomposition at a higher temperature.

Cocaine is very slightly soluble in water (solubility of cocaine in cold water is probably near to 1 in 1300, but is commonly greatly over-estimated, owing to the ease with which cocaine is decomposed by hot water with formation of soluble products). Cocaine dissolves readily in alcohol, ether, chloroform, benzene, petroleum spirit, carbon disulphide and volatile and fixed oils. It is readily removed from its solutions by adding ammonia and agitating with ether or other immiscible solvent.

An aqueous solution of cocaine has a strong alkaline reaction to litmus and methyl-orange, but does not affect phenolphthalein. The free base may be titrated with the aid of either of the former indicators. An aqueous solution of cocaine, if not very carefully prepared and secluded from air, or preserved by an antiseptic, rapidly decomposes with formation of vegetable growths.

Cocaine produces on the tongue a sudden and characteristic cessation of feeling, which lasts only a few minutes. One drop of a 4 percent solution (of the hydrochloride), if placed on the tongue, soon produces a decided numbness, the effect being evanescent unless the application be repeated. Cocaine also produces an intense local anesthetic and blanching effect on the mucous membrane. A single drop of 4 percent solution suffices to blanch the conjunctiva of the eye. Anesthesia of the eye, of much value in ophthalmic operations, can be produced by a somewhat larger dose. Dilation of the pupil is generally produced by cocaine, whether applied locally to the eye or otherwise introduced into the system; but the mydriasis produced by cocaine is not so invariable and is far less intense than that characteristic of atropine and its isomers.

In large doses, cocaine has marked poisonous properties. The fatal dose for dogs is from 2 to 5 grains (130 to 325 milligrams). The hypodermic injection of 1/20 grain (about 3 milligrams) has caused dangerous symptoms in a girl twelve years of ago (see Pharm. Jour. [3]. xvi. 721).

Cocaine is levorotatory, the specific rotation in chloroform solution being about -15.8 degrees for the sodium ray; while the rotation of the hydrochloride in dilute alcohol is -52.2 degrees.


Cocaine is precipitated from its solution by caustic alkalies, alkaline carbonates and ammonia. It is almost insoluble in excess of ammonia, which is to be preferred as a precipitant (If a solution of cocaine salt be precipitated with caustic soda or sodium carbonate, the filtrate will be found to contain a distinct trace of benzoic acid resulting from decomposition of the alkaloid; but this is not the case if ammonia be substituted). Precipitated cocaine is amorphous when thrown down from strong solutions, but rapidly becomes crystalline.

Mayer's solution precipitates cocaine from extremely dilute solutions, and A.B. Lyons has attempted to employ the reaction for the determination of cocaine, but with results which are wanting in exactness.

Iodised iodide of potassium gives a rose-colored precipitate with a solution of 1 part of cocaine hydrochloride in 7,500 of water; in stronger solutions the precipitate appears brown, and under the microscope assumes the form of black globules.

from U.S. Patent 4,956,429 (1990): "... cocaine detectable by the Bohm's test, a standard wet chemical test for detection of cocaine and ecgonine. Bohm's test employs a reagent known as Mayer's reagent. Mayer's reagent is made by dissolving 0.68 grams of mercury chloride and 2.5 grams of potassium iodide in water sufficient to make 100 ml of the reagent solution. In the Bohm's test as referred to in this disclosure, 2 to 4 drops of Mayer's reagent and 2 to 3 drops of concentrated sulfuric acid are added to 2-5 ml of a liquid extract or solution to be tested. If the solution turns cloudy, cocaine, ecgonine or both are present."

Tannin produces a distinct cloud in neutral solutions of cocaine containing 1:25,000, and a distinct precipitate with twice that proportion. Picric acid produces in strong solutions a yellow precipitate, rapidly becoming crystalline, and appearing under the microscope in sheaf-like forms. Phosphomolybdic acid produces a faint turbidity in solutions of 1:50,000, and a distinct precipitate with 1:12,500. Phosphotungstic acid gives a gelatinous white precipitate, soluble in ammonia.

Platinic chloride produces at once, in solutions of cocaine hydrochloride containing 1:400, a yellow precipitate consisting of plumose needles, mostly of stellate pattern. In solutions of 1:600 most of the crystals resemble carpet-tacks, consisting of short, well-formed prisms, with a single branch from the centre, joined at an oblique angle and tapering to a point. The characters of the chloroplatinate distinguish cocaine from the amorphous base associated with it in coca-leaves, the platinum salt of which is far less soluble inwater, and crystallizes in rosette-like forms, contrasting strongly with the feathery appearance of the cocaine salt.

Cocaine aurochloride is precipitated on adding auric chloride to a solution of cocaine hydrochloride. In solutions containing 1:3000 an immediate precipitate is produced, which appears under the microscope in forms resembling fern-fronds, generally with a stellate arrangement. In solutions of 1:12,000 similar crystals form after a short time. "Cocaidine" aurochloride forms minute prismatic crystals, having a microscopic appearance quite different from that of the cocaine salt.

According to Lerch and Scharges, if a drop of ferric chloride be added to a solution of cocaine and the liquid boiled, an intense red color will be developed "owing to the formation of benzoic acid". Benzoyl-ecgonine also gives the reaction.

Potassium bichromate does not precipitate cocaine except from neutral solutions, unless they are very concentrated (1:25); but Metzer states that from a solution containing hydrochloride acid, chromic acid precipitates the chromate, C17H21NO4,H2CrO4, in silky, lustrous plates. If 0.05 grams of cocaine hydrochloride be dissolved in 5 cubic centimeters of water, and five drops of a 5 percent, aqueous solution of chromic acid added, each drop produces a distinct precipitate, which immediately redissolves; but if 1 cubic centimeter of strong hydrochloric acid be now added, a heavy yellow precipitate of cocaine chromate is produced. If cocamine be present, reduction of the chromic acid will ensue. Ecgonine, sparteine, atropine, caffeine, pilocarpine, codeine and morphine do not form yellow precipitates with chromic acid or potassium chromate. Quinine, quinidine, cinchonine, cinchonidine, hydroquinine, apomorphine, brucine, strychnine and veratrine form precipitates with 5 percent chromic acid if the solutions are neutral; but, according to K. Metzer, cocaine is singular in being precipitated only after addition of hydrochloric acid.

F. Giesel has observed that cocaine permanganate is very stable compared with the corresponding salts of the majority of alkaloids. Hence, if 10 milligrams of cocaine hydrochloride be dissolved in one or two drops of water, and about 1 cubic centimeter of a 3 percent solution of potassium permanganate (KMnO4) be added, a purple-violet crystalline precipitate of cocaine permanganate is produced, the supernatant liquid acquiring a purple-violet tint. A.B. Lyons recommends that a strong solution of the cocaine salt should be used, and the permanganate employed in decinormal solution (3.162 grams per liter). The precipitate is unstable, and decomposes in a few hours even at the ordinary temperature, leaving a brown hydrated manganese dioxide. If the liquid containing the precipitate be heated to boiling, decomposition occurs at once, but without the production of any peculiar odor. But if examined under the microscope when first thrown down, the precipitate is found to consist, wholly or in part, according to the strength of the cocaine solution, of translucent, violet-red, rhombic (nearly rectangular) plates of great beauty, often grouped together to form rosettes. A 5 percent solution of cocaine gives a copious precipitate at once, and a 2 percent solution after a short time; but with a 1 percent solution the crystals only form as evaporation takes place.

The behavior with potassium permanganate serves to detect an admixture of methyly cinnamyl-ecgonine and certain other impurities in cocaine hydrochloride. The presence of these causes an immediate reduction of the permanganate in the cold. The first drop or two of the reagent produces a brown discoloration, while the precipitate thrown down by a further addition is more or less brown, instead of a distinct violet-purple or red. If a limited quantity of the reagent by employed, and the liquid heated to boiling, in presence of impurities, a distinct odor will be developed in some cases resembling that of bitter-almond oil, and in others, like that of crude cocaine. The behavior of other alkaloids with potassium permanganate is described on page 144.

According to F. da Silva, when treated by Vitali's test for atropine, (evaporate with fuming nitric acid, add a drop of potassium hydroxide) even a minute quantity of cocaine (0.0005 grams) develops a distinct and peculiar odor, recalling that of peppermint or citronella. No other alkaloid extracted by benzene from an ammoniacal solution behaves at all similarly, though atropine, hyoscyamine, strychnine, codeine and eserine give color reactions, and the last-name alkaloid develops a disagreeable smell resembling phenyl-carbamine (page 46). Delphinine, brucine, and veratrine develop slight odors which cannot be mistaken for that produced by cocaine. A.C. Stark has confirmed Da Silva's statements, but considers the odor scarcely distinctive enough to render the test completely reliable.


Cocaine Hydrochloride - C17H21NO4.HCl
This salt, which is readily prepared by neutralizing cocaine by hydrochloric acid, crystallizes from alcohol in short prisms melting at 181.5 °C. The crystals from the aqueous solution contain, according to A.B. Lyons, 9.6 percent of water, while those from the alcoholic solution are anhydrous. The salt is not hygroscopic, but is soluble in less than its own weight of water, forming a thick syrupy liquid. It is readily soluble in spirit, but with less facility in absolute alcohol, chloroform, and amylic alcohol; and is practically insoluble in ether, petroleum spirit, and fixed and volatile oils. Ether precipitates cocaine hydrochloride from its solutions in absolute alcohol and chloroform.

Cocaine Hydrobromide - crystallizes readily from its aqueous solution in transparent prisms, stable in the air.

Cocaine Acetate - is readily soluble in water. It is difficult to obtain it in a crystalline condition, as acetic acid is given off during the evaporation of its solution.

Cocaine oleate - readily crystallizes, and is soluble in oleic acid and fixed oils. Cocaine gives crystalline salts with sulphuric, boric and oxalic acids. The citrate is hygroscopic, and crystallizes with difficulty.

Cocaine Benzoate - C17H21NO4, C7H6O2
May be prepared by mixing molecular proportions of cocaine and benzoic acid (C6H5.COOH - often used as a food preservative). It is a very soluble salt, obtainable with difficulty in acicular crystals, the solution usually drying up to a gummy mass, which gradually acquires a crystalline structure. A sample of commercial cocaine benzoate of French origin was found by B.H. Paul to give no precipitate with ammonia, and no benzoic acid with hydrochloric acid. It consisted of benzoyl-ecgonine. According to A. Bignon, the anesthesia produced by a 5 percent solution of cocaine benzoate lasts during four consecutive hours, and is not preceded by the sensation of pain produced by the hydrochloride.


The absolute purity of cocaine and cocaine salts intended for medicinal use is essential, as various undesirable and even dangerous symptoms are produced by certain impurities liable to be present. The characters and tests for cocaine hydrochloride given in the British Pharmacopeia of 1885 are inadequate, and in several respects grossly inadequate. In the first issue, it was incorrectly described as readily soluble in ether, whereas in fact it is practically, if not absolutely, insoluble. This mistake is corrected in the reprint, but the aqueous solution is still described as having a bitter taste, which is not a characteristic of the pure salt, and is said to yield a white precipitate with carbonate of ammonium, soluble in excess of the reagent, which is not the fact. "The aqueous solution dilates the pupil of the eye. It (?the aqueous solution?) dissolves without color in cold concentrated acids, but chars with hot sulphuric acid."

Crude Cocaine has for some time been manufactured in South America for export to European markets in place of coca leaves, which have been found liable to deterioration in transit. B.H. Paul describes it as a white or yellowish pulverant substance compressed into thin cakes. It contains not only earthly substances, e.g., sodium carbonate and lime salts, but also a waxy substance and traces of petroleum. Its manufacture has probably been effected by extracting the coca acid, and then precipitating it with lime or sodium carbonate. It is represented as containing from 80 to upwards 90 percent of alkaloid, but the proportion of crystallisable cocaine present varies considerably, in one instance not exceeding one-half of the total alkaloid present (85 percent). The remaining portion was precipitated on adding ammonia to its solution in hydrochloric acid in oily globules, which after a time collected at the bottom of the liquid as a viscid semi-transparent layer, which ultimately because more or less crystalline. In all cases, the liquid remained milky for a considerable time, in this respect presenting a marked contrast to the rapid clearing of the liquid, which takes place when pure cocaine is precipitated from the solution of its hydrochloride.

The analysis of a sample of crude cocaine by E.R. Squibb showed: moisture, 3.25 percent; residue insoluble in ether, 5.25; impurity soluble in ether, 0.50; pure alkaloid, 89.94; and loss, 1.06 percent.

A convenient method of purifying cocaine is to recrystallize it several times from strong alcohol, and, when a certain degree of purity has been obtained, percipitate the base from its solution in 10 parts of strong alcohol by addition of 5 measures of water.

Paul and Cownley have pointed out that the solubility of a sample of cocaine in petroleum spirit (petroleum ether, a solvent) cannot be relied on as a proof of its purity, since cinnamylcocaine behaves similarly.

John Williams (Year-Book Pharm., 1887, page 502) proposed to purify and assay commercial cocaine hydrochloride by dissolving it in the smallest possible quantity of absolute alcohol (sp. gr. 0.795), and adding to this solution six times its measure of dry ether, when the cocaine hydrochloride is precipitated in a finely-divided but perfectly crystalline condition. Unfortunately, as pointed out by B.H. Paul, the hydrochlorides of the amorphous bases and of benzoylecgonine are precipitated under the same conditions; and hence the method is useless for the assay of crude cocaine hydrochloride or for the elimination of impurities, though serviceable for improving the appearance of a pure salt and converting it into a convenient form for use.

Paul adds that it is a mistake to attempt the purification of cocaine hydrochloride at all. The free alkaloid is much more susceptible of purification, and may be obtained in very fine crystals either from ether or alcohol. From pure cocaine the hydrochloride can be readily prepared, as the neutral solution may be evaporated to dryness without decomposition, and the resultant dry salt can be readily converted into a good-looking crystalline condition by Williams' method.

Cocaine hydrochloride should be perfectly colorless, and soluble in water to a perfectly colorless solution, which ought to be absolutely neutral to litmus paper. The solution of the pure salt keeps fairly well, but in presence of common impurities is decomposed with great facility. In the dry solid state, cocaine hydrochloride undergoes no change by keeping. It ought to be perfectly free from odor; but as sold it not unfrequently retains the odor of a solvent used in its preparation, or has a peculiar butyric or mousy smell, or even a distinct benzoic odor. In any case, a sample having a distinct odor must be regarded with suspicion.

Pure cocaine hydrochloride is always distinctly crystalline, though much of the commercial article presents an amorphous or granular appearance. The tendency to crystallize is so marked that B.H. Paul regards an amorphous condition, or even difficult crystallizability, as an indication of the presence of an impurity. Paul states that on dissolving 5 to 10 grains of a pure sample in 1 drachm of water (1 dram is 1/8th of an ounce) and rapidly evaporating the solution (in a glass basin) on a water-bath, the dry residue obtained will be white and opaque, presenting a radiating crystalline structure, while in the case of an impure mixed salt the residue will be more or less yellow, translucent, and of a gummy or resinoid character.

The most definite test for the purity of cocaine hydrochloride is said by Antrich (Ber., xx 310) to be the optical activity. In dilute alcoholic solution, at 20 °C, the specific rotatory power is SD = - ( 52.18° + 0.1588 q ), and SD = - ( 67.982° - 0.15828 c ); where q is the weight of dilute alcohol of .9353 specific gravity at 20°/4° (which corresponds to a mixture of 6 parts by weight of absolute alcohol with 9 parts of water) in 100 parts by weight of the solution, and c is the weight of hydrochloride in 100 volumes of the solution. Whe q=0, or, in other words, the solution is aqueous, SD - -52.2° and when q is 100, SD - -68.06°

The characteristics of cocaine hydrochloride should be, according to Beckurts, that it should give a clear and colorless solution in water; leave no residue on ignition; give a colorless solution in concentrated sulphuric acid, when dissolved in the proportion of 0.02 gram to 1 cubic centimeter; that a concentrated aqueous solution should be absolutely neutral (to litmus); not immediately reduce potassium permangante; and when heated with the latter reagent give off no odor of bitter-almond.

The German Pharmacopeia (1890) prescribes the following tests for cocaine hydrochloride: 0.1 gram is dissolved in 5 cubic centimeters of water, and 3 drops of diluted sulphuric acid added. This solution should be colored violet by 1 drop of a 1 percent solution of potassium permangante, and if kept in a closed vessel the coloration should but slightly decrease in half an hour. One cubic centimeter of sulphuric or nitric acid should dissolve 0.1 gram of a cocaine salt without coloration.

The following test is due to H. Maclagan (Amer. Drug., 1887, page 22; Pharm. Jour. [3], xvii 686): - one grain of cocaine hydrochloride is dissolved in 2 ounces of water, 2 drops of strong ammonia are added, and the walls of the containing vessel rubbed from time to time with a glass rod; in a quarter of an hour a good crop of glistening crystals separate. When the cocaine is not very pure, the solution remains clear, or else deposits only a small crop. With a good sample, a dense precipitate is produced either at once or on stirring, and soon acquires a crystalline condition, the liquid rapidly clearing. When the cocaine contains more than 4 percent of amorphous alkaloid, the solution becomes milky.

B.H Paul (Pharm. Jour. [3], xviii 783) has pointed out that the precipitate of cocaine produced in Maclagan's test redissolves if left for a long time in the ammoniacal solution, owing to its conversion into the soluble base benzoyl-ecgonine. He describes a quantitative application of the ammonia test (using a 2 percent solution of the salt) which, in the case of good samples free from odor and color, will fairly indicate the purity and value; but, in the case of bad samples, regard must also be paid to the character of the precipitated alkaloid. This is done by adding the ammonia gradually, with constant stirring, as long as crystalline precipitate forms and the liquid clears promptly. When the precipitate begins to form clots which adhere to the sides of the beaker, and the liquid remains milky, the precipitate already formed is separated, and the amorphous precipitate produced on further addition of ammonia collected separately (the amorphous alkaloid when freed from coloring matter is a clear yellowish transparent substance, resembling thick canada-balsam, and the hydrochloride forms a varnish-like mass that cannot be reduced to powder).

The following results were obtained by B.H. Paul by the examination of commercial cocaine hydrochloride by the above process: - [TABLE APPEARS]. The ammonia precipitates from the first eight of these samples were perfectly crystalline, without any trace of stickiness; they deposited rapidly, and left the supernatant liquid quite clear and bright. In the case of samples 9, 10 and 11, a considerable proportion of the alkaloid was of an amorphous sticky nature, quite different from that obtained froma pure salt.

Paul states that the principal impurity in the last four samples was undoubtedly the hydrochloride of the amorphous alkaloid associated with cocaine in coca leaves (see page 287), the salts having been probably produced by evaporating the solution of the mixed bases in hydrochloric acid; and it is questionable whether the presence of this amorphous base should be tolerated in a product with purports to be "cocaine hydrochloride".

Decomposition-Products of Cocaine

Benzoyl-ecgonine. C16H19NO4; or C8H13N(O.C7H5O).COOH.
This base may be prepared by the action of benzoic anhydride or benzoic chloride ecgonine, and is also a product of the action of acids or water or cocaine. Hence, it occurs as a by-product of the manufacture of cocaine. (It is also a metabolite of cocaine, produced in the liver).

Benzoyl-ecgonine is easily produced by heating cocaine with about 20 parts of water in a closed tube. The cocaine melts at about 90 °C, but gradually dissolves on maintaining the temperature at 100 °C. The change is facilitated by agitation, and in about twelve hours a clear solution is obtained, which is only faintly acidic if pure cocaine was employed.

On a large scale, benzoyl-ecgonine is prepared by gradually adding a little more than one molecule of benzoic anhydride to a hot saturated aqueous solution of one molecule of ecgonine, and heating the mixture on the water-bath for about an hour. After cooling, the product is shaken with ether to remove unchanged benzoic anhydride and acid, and the residual benzoyl-ecgonine washed with a little water to dissolve unaltered ecgonine. The yield is about 80 percent of the ecgonine employed, and an additional quantity can be obtained by concentrating the mother-liquor and again treating it with benzoic anhydride.

Benzoyl-ecgonine crystallizes with 4H2O in transparent, flat, trimetric prisms, resembling ammonium oxalate, which melt at a variable temperature ranging from 87 °C - 140 °C. When fusion occurs at the lower temperature (as happens when the heat is rapidly applied), the substance resolidifies on further heating, and melts again at 195 °C, turning brown at the same time.

Benzoyl-ecgonine is sparingly soluble in cold water, but readily in hot water, alcohol, and dilute alkalies and acids. It is almost insoluble in ether.

The acetate and sulphate of benzoyl-ecgonine crystallize in prisms. BHAuCl4 forms small, yellow, anhydrous scales, soluble in alcohol but only sparingly so in water.

When heated with alkalies or with hydrochloric acid to 100 °C in sealed tubes, the base is decomposed into benzoic acid and ecgonine. By treatment with methyl iodide, it yields cocaine.

Benzoyl-ecgonine does not appear to have much, if any, anesthetic effect when applied to the eye, and exerts only a moderate dilating action on the pupil. R. Stockman states that it is very irritating to the mucous membranes, and when injected subcutaneously produces tetanic spasms. In many respects its action resembles that of caffeine, but paralysis of the sensory nerves is quite absent (Pharm. Journ. [3], xvi. 898i).

Ecgonine. C9H15NO3; or C8H13N(OH).COOH
(see also page 270). Ecgonine is obtained, together with benzoic acid and methyl alcohol, by heating cocaine with concentrated hydrochloric acid to 100 °C in sealed tubes (page 272)(Liebermann and Giesel obtain ecgonine on a large scale by boiling the amorphous base obtained in the manufacture of cocaine for about an hour with hydrochloric acid. The filtered solution is evaporated to dryness, the residue treated with a little alcohol to remove impurities, and the residual ecgonine hydrochloride decomposed by sodium carbonate, the liberated base being recrystallized from alcohol.) Also, when cocaine or its hydrochloride is heated with 20 parts of water and 10 of baryta to 120 °C in sealed tubes, it is decomposed according to the equation:

C17H21NO4 + 2H2O = C7H6O2 + C9H15NO3 + CH4O

The actual products are methyl alcohol (methanol), barium benzoate, and a compound of barium benzoate with the barium compound of ecgonine, which forms slender prismatic needles, very soluble in water and alcohol, but only slightly soluble in ether. This compound is a convenient source of ecgonine. On subjecting it to dry distillation it yields an isatropine, the chloroplatinate of which forms bulky, orange-red, deliquescent (tending to liquify in air) crystals.

Ecgonine crystallizes from absolute alcohol in monoclinic prisms containing 1 aqua, which melt at 198 °C; or after drying at 140 °C to expel the water of crystallization, at 205 °C. Ecgonine is very soluble in water, sparingly in absolute alcohol, and insoluble in ether. It has a slight bitter-sweet taste.

When ecgonine is heated with moderately strong sulphuric acid, neither carbonic oxide nor formic acid is formed, but a base is produced which bears the same relation to ecgonine that ether bears to alcohol. It unites both with acids and bases.

C.E. Merck (Ber., xix. 3002) states that ecgonine, when distilled with nearly dry barium hydroxide, yields methylamine and not ethylamine as one of the products, thus agreeing with the behavior of tropine when similarly treated.

When ecgonine (or anhydro-ecgonine) is oxidized with potassium permanganate, or nitric acid, succinic acid is formed (Einhorn, Ber., xxi. 47), a fact that shows that the side-chain in the molecule of ecgonine must be either in the α- or β-position.

Ecgonine contains a carboxyl-group, and hence behaves at once as an acid and a base. It has a neutral reaction, but reacts with alkalies to form gummy compounds of faint alkaline reaction, which crystallizes with difficulty and are very soluble in water and alcohol. Ecgonine hydrochloride, C9H15NO3.HCl, forms triclinic tables, difficultily soluble in alcohol in alcohol and melting at 246 °C. B2H2PtCl6 (BH == cocaine HCl ??), after drying at 140 °C, melts at 226 °C. It is extremely soluble in water, and is deposited in orange-red prisms on adding excess of alcohol to its aqueous solution. BHAuCl4 is a greenish yellow, gummy substance, very soluble in water and alcohol.

Anhydro-ecgonine. C9H13NO2; or C5NH7Me.CH:CH.COOH. This base is formed by the action of phosphorous oxychloride or pentachloride on ecgonine, or by heating cocaine for eight hours to 140 °C with glacial acetic acid which has been saturated with hydrochloric acid gas. It forms colorless crystals melting at 235 °C, soluble in water and alcohol, but insoluble in ether, chloroform, benzene and petroleum spirit [1]. When anhydro-ecgonine is heated with water to 150 °C, methylamine is liberated. It combines directly with bromine to form a base containing C9H13Br2NO2, the hydrochloride of which melts at 184 °C. The salts of anhydro-ecgonine are crystallizable. BHCl crystallizes from absolute alcohol in white needles melting at 240-241 °C.


Dextro-cocaine. C17H21NO4. Einhorn and Marquardt (Ber., xxiii. 469,979) have found that by warming with aqueous potash for twenty-four hours, ecgonine is converted into a base which differs from ordinary ecgonine in being much less soluble in absolute alcohol, and having a much higher melting-point (254 °C); but especially in being dextro-rotatory.

From this dextro-ecgonine a symthetic dextro-cocaine may be prepared as a colorless oil, which solidifies on standing, and is readily soluble in ether, alcohol, benzene, and petroleum spirit.

Dextro-cocaine may be obtained in crystals, melting at 43-45 °C, by treating its solution with a crystal of benzoyl-dextroecgonine ethyl-ester.

The salts of dextro-cocaine crystalize well. BHCl is much more difficultly soluble than the hydrochloride of ordinary cocaine, and melts at 205 °C instead of 181.5 °C. BHNO3 is especially characteristic. 100 parts of water at 20 °C dissolve 1.55 parts of the nitrate, which is precipitated in crystals on adding nitric acid to solutions of other salts of the base. This behavior distinguishes dextro-cocaine from ordinary cocaine. B2H2PtCl6 crystallizes from hot water in yellowish needles. BHAuCl4 crystallizes from dilute alcohol in needles melting at 148 °C. With chromic acid, potassium permangate, and auric chloride, dextro-cocaine behaves like cocaine.

Dextro-cocaine was found to resemble ordinary cocaine in its physiological effects, except that local anesthetic action commenced more rapidly, and disappeared in a shorter time. (Dextro-cocaine is the stereo-isomer of cocaine.)>

Cocethyline, Homococaine, or benzoyl-ecgonine ethyl-ester (now cocaethylene, ethyl-benzoylecgonine, formed in vivo by the liver when cocaine and ethanol coexist in the blood) - C18H23NO4, is the higher homologue of cocaine, which base it closely resembles. It is prepared by heating benzoyl-ecgonine with ethyl iodide and alcohol for eight hours at 100 °C. It crystallizes from alcohol in vitreous prisms melting at 108-109 °C, and is also soluble in ether but nearly insoluble in water. The chloroplatinate forms bright yellow, rhombic plates, resembling the cocaine salt but more crystalline. Physiologically, homococaine is similar in its effects to cocaine, but is weaker and less toxic, and does not appear to be mydriatic (pupil dilating).

The higher homologoues of cocethyline, containing propyl and isobutyl groups, have been prepared by similar means; and also by passing hydrochloric acid gas into a solution of benzoyl-ecgonine in the corresponding alcohol.

Cinnamyl-cocaine, Cinnamoylcocaine (or methylecgonine cinnamate, can dimerize to truxilline) - C19H23NO4; or C9H13(CH3)(C9H7O)NO3. This base has been obtained synthetically by passing dry hydrochloric gas into a solution of cinnamyl-ecgonine (prepared by heating ecgonine with cinnamic anhyride and water). It forms large colorless crystals melting at 121 °C, and is almost insoluble in water, but readily soluble in alcohol, ether, etc. When boiled with hydrochloric acid it is decomposed readily and quantitatively into cinnamic acid, ecgonine, and methyl alcohol. BHCl is precipitated as an oil which solidifies after a time on adding a large volume of ether to a strong acidulated solution of the salt in alcohol. B2H2PtCl6 crystallizes in microscopic needles melting at 217 °C. When treated with a cold solution of potassium permanganate, cinnamyl-cocaine and its salts immediately evolve a strong odor of benzaldehyde (bitter-almond oil) (which can be converted into cinnamaldehyde, which gives cinnamon its flavor and odor).

Cinnamyl-cocaine has been proved to occur naturally in coca leaves from various sources. Paul and Cownley (Pharm. Jour. [3], xx. 165) exmained a sample of leaves containing 1.75 percent of total alkaloid, nearly 0.5 percent being crystallizable from petroluem spirit, but which, nevertheless, contained very little real cocaine. On oxidation by permanganate, the crystallizable alkaloid yielded abundance of benzaldehyde, and in other respects corresponded with cinnamyl-cocaine (methyl cinnamyl-ecgonine).

Cocamine, α-Truxilline. C38H46NO8. This base is contained in notable quantity in Truxillo coca leaves. Hesse found 0.6 percent in leaves of a different kind, and states that East Indian coca leaves, and especially those from Java, contain cocamine in considerable amount. Lierbermann regards cocamine as identical with the base originally described by him as γ-isatropyl cocaine, and afterwards as α-truxilline; but Hesse contends that Liebermann's product was a mixture; of which cocamine was a leading constituent.

Cocamine has a bitter taste. Hesse and Stockman found its physiological effect to be similar to that of cocaine, but somewhat weaker, and its anæsthetic action especially weak. On the other hand, G. Falkson alludes to γ-isatropylcocaine (cocamine) as a "deadly alkaloid", and Liebermann describes it as a heart-poison which does not produce anæsthesia. To its presence as an impurity, the occasionally highly toxic effects of commercial cocaine are not improbably due.

Cocamine is precipitated by caustic alkalies and ammonia from solutions of its salts, and after exposure at the ordinary temperature in a desiccator retains one molecule of water. It is readily soluble in alcohol, ether, benzene and chloroform, but differs from cocaine in being very sparingly soluble in petroleum spirit. Neither the free base nor its salts have been obtained crystallised. Repeated solution in hydrochloric acid and reprecipitation by soda was the process employed by Liebermann to purify the cocamine from the co-occurring isococamine (β-truxilline), which is also bitter, and produces numbness of the tongue slowly by reason of its sparing solubility.

Both cocamine and its isomeride have been obtained synthetically. When hydrolysed by mineral acids they yield ecgonine, methyl alcohol, and cocaic and isococaic acids respectively.

Cocaic Acid, α-Truxillic acid. C9H8O2, also called by Liebermann as γ-isatropic acid, is produced by boiling cocamine with hydrochloric acid. The isomeric isococaic acid (β-truxillic acid) is the similar product from isococamine. Cocaic acid melts at 274 °C, is tasteless and odourless, insoluble in water, and nearly insoluble in ether, from which, however, it crystallizes in forms resembling benzoic acid. Isococaic (β-truxillic) acid melts at 206 °C. Both cocaic and isococaic acids yield cinnamic acid and other products on distillation.

Benzoyl-Pseudotropine. C8H14NO.C7H5O, is a base isolated by Giesel from a narrow-leaved coca plant cultivated in Java (Ber., xxiv, 2236). It somewhat resembles dextrococaine, but is optically inactive, and differs from other coca-bases in not yielding methyl alcohol on hydrolysis; for, when heated with hydrochloric acid under a reflex condenser for some hours, it is completely decomposed into benzoic acid and pseudotropine, C8H15NO (see page 247). In this respect, the base resembles atropine and the other tropines. Benzoyl-pseudotropine is obtained as a milky precipitate which does not become crystalline on adding sodium carbonate to the solution of one of its salts. The base may be extracted by ether, and on evaporating the solution is obtained as an oil which, when quite dry, solidifies in radiating crystals melting at 49 °C. It has a strong alkaline reaction, and is easily soluble in alcohol, ether, chloroform, benzene and petroleum spirit. BHCl, obtained by passing hydrochloric acid gas into an ethereal solution of the base, crystallizes in white needles melting at 271 °C. The solution gives a bulky crystalline precipitate with mercuric chloride. B2H2PtCl6 is a flesh-coloured precipitate, insoluble in hot water, alcohol and ether. BHAuCl4 crystallises from water in sparingly soluble yellow needles, melting at 208 °C. The picrate forms fine yellow needles, difficultly soluble in water. With potassium bichromate, benzoyl-pseudotropine yields a crystalline precipitate, instead of an oily one like cocaine and dextrococaine.

Amorphous Bases of Coca

In isolating cocaine there is found in the mother-liquors a variable quantity of a basic substance commonly known as "amorphous cocaine", while the name cocaicine and cocainoidine have also been applied to it. Amorphous cocaine is described by R. Stockman (Pharm. Jour., [3], xvii, 861) as ranging in colour from dark yellow to dark brown, and consistence from that of treacle to a sticky tenacious solid, having a peculiar smell resembling that of nicotine, and a bitter and aromatic taste. Stockman concludes that "amorphous cocaine" is in reality a soluton of ordinary crystalline cocaine in hygrine, the liquid alkaloid said to have been found in coca leaves by Lossen. The amorphous alkaloid is extracted from the coca in greater or less amount by the processes now employed by manufacturers, and its presence is considered by Stockman to account for certain disagreeable effects resulting from the employment of cocaine containing the impurity. THus if the hydrochloride of the impure alkaloid be used to produce anæesthesia of the conjunctiva, then considerable irritation ensues.

W.C. Howard (Pharm. Jour. [3], xviii, 71) to a certain extent agrees with Stockman's view as to the nature of amorphous cocaine. He found that when the solution of the bases of coca in hydrochloric acid was completely precipitated with platinic chloride, and the liquid filtered after standing overnight, the mixed platinum salts obtained were amorphous or semi-crystalline, and somewhat light in colour. When the precipitate was washed with a large quantity of water at a temperature not exceeding 80 °C, the cocaine chloroplatinate dissolved, and the alkaloid could be obtained therefrom in a crystalline state. The fraction of the platinum salt insoluble in water when decomposed by sulphuretted hydrogen, and extracted with ammonia and ether, left on evaporating the ether a liquid based which thickened considerably on keeping, but in which no crystals appeared even after a week. It had an intensely bitter taste, formed an uncrystallisable hydrochloride, and a chloroplatinate containing 18.5 percent of platinum (against 19.3 percent in the cocaine salt) and not affected by hot water, all which characters distinguish the base from the description of hygrine given by Lossen (Annal. der Pharm., cxxi, 374).

O. Hesse states that when working on the bases from the broad-leaved coca, separating the cocaine as hydrochlorate "by a special process", and ascertaining the absence of cocamine, the residual mixture was dissolved in dilute hydrochloric acid and the solution treated with ammonia in excess, this process of solution and reprecipitation being repeated until the precipitate dissolved in hydrochloric acid gave a solution which showed no fluorescence on dilution with water, thus proving its freedom from hygrine. The precipitate, after being further washed with water at 80 °C, gave a melted mass which was spread on glass plates and dried at 60 °C, by which means it was obtained in transparent, brittle, hygrosopic laminæ which were nearly insoluble in water and alkaline liquids, but dissolved readily in alcohol, ether, chloroform, benzene and petroleum spirit. The solution was alkaline to litmus, but without effect on phenolphthalein (Pharm. Journ. [3], xviii, 71, 437). When boiled with alcoholic baryta, or heated in a sealed tube with hydrochloric acid, the amorphous base yields benzoic acid, and another product not yet identified.

From a later investigation (ibid, xix, 867), Hesse concludes that the amorphous bases from true coca consist chiefly of benzoyl compounds of an oily non-volatile base, together with some cocamine; while, on the contrary, those obtained from Truxillo leaves consist essentially of cocamine, and the cinnamyl compounds of the before-mentioned oily base; and the cocamine is in each case accompanied by a base containing H-H less than cocamine.

A specimen of the amorphous base from coca examined by B.H. Paul (Pharm. Jour., xviii, 784) is then described by him as being pale yello, and of the consistence of thick Canada balsam. It had a faint odour at once suggestive of benzoin and butyric acid, and a distinctly bitter taste, but produced no anæsthetic effect on the tongue until after the lapse of some minutes, and then very slight compared with that produced by cocaine.

HYGRINE. Under this name several bases have been described, which were either impure or actually dissimilar. The name was first applied by Lossen to a liquid volatile base which has not since been obtained. The hygrine of O. Hesse (Pharm. Journ. [3], xviii, 438i) is best prepared from the mother-liquor obtained in the preparation of "cocaidine" from amorphous cocaine. This is treated with caustic soda and ether, the ethereal solution separated and evaporated, and the residue distilled with water. The hygrine passes into the distillate, which is faintly acidified by hydrochloric acid, evaporated to dryness, and the residue treated with caustic soda and ether. The ether leaves on evaporation a brown oily residue, which, on treatment with dilute acetic acid, deposits a brown smeary mass, which is filtered off, the solution again treated with caustic soda and ether, and the ether evaporated.

Hygrine thus obtained is a yellowish oily substance having an odour suggestive of that of quinoline. It has a slight burning taste, and a strong alkaline reaction on litmus, but does not alter phenolphthalein. It is but little soluble in water or solution of caustic soda, but dissolves readily in alcohol, ether and chloroform. Hygrine volatilises with steam, and at a higher temperature may be distilled alone.

BHCl is crystallisable. Its dilute aqueous solution exhibits a marked fluorescence, not perceptible in a concentrated solution, and destroyed by sodium chloride and other substances. An aqueous solution of hygrine hydrochloride becomes milky on addition of caustic soda, owing to the separation of the free base in minute oily globules, which aggregate after a time. Hesse attributes to hygrine the formula C12H13N and the constitution of a trimethylquinoline, but Liebermann regards it as a mixture of oxygenated bases, which may be separated by fractional distillation. The most volatile boils at 193-195 °C, and has the formula C8H15NO, but is not identical with tropine (page 246). The less volatile portion of hygrine appears to contain CH24N2O, and cannot be distilled unchanged at the ordinary pressure. Neither of these bases is affected by heating to 120 °C with concentrated hydrochloric acid (Ber., xxii, 675).

Hesse points out that hygrine probably does not pre-exist in coca leaves, but is a product of decomposition. He states that when sound coca leaves are moistened with ammonia, shaken with ether, and the ether treated with dilute hydrochloric acid, the acid liquid on dilution at first shows no fluorescence, but after a time exhibits this character distinctly.

R. Stockman (Pharm. Journ. [3], xviii, 701) states that hygrine exists in coca leaves in very minute quantity only, and some manufacturers never meet with it. He found it in cocaine mother-liquors given to him by Messrs. Howard & Sons, and notably in the alcoholic tincture of fresh coca leaves. Stockman finds hygrine to distil very imperfectly with steam in presence of cocaine (the treatment is stated to have decomposed the cocaine present, some bezoic acid passing over with the hygrine - it seems probable that a difficultly volatile or non-volatile benzoate of hygrine was formed). The whole of the statements respecting hygrine require confirmation.

Stockman describes hygrine as a brown oily liquid with a characteristic smell. A drop placed on the tongue causes a burning sensation. Frogs were killed by the subcutaneous injection of hygrine mixed with water. There was considerable irritation at the place of injection, while the muscles all over the body, the bowels, and the serous membranes were studded with numerous minute hemorrhages.

Coca Leaves

The coca leaves occurring in commerce are chiefly of two kinds, the one being obtained from Erythroxylon coca, which was the original trade product, and the other, which is of more recent importation, derived from Jamaica and St. Lucia. Coca leaves, in addition to the ordinary plant constituents and the characteristic alkaloids, contain cocatannic acid. The coca plant is a small shrub from 4 to 6 feet in height, growing and largely cultivated in Peru and Bolivia, and to some extent, in Brazil and the Argentine Republic.

Cocatannic acid (C.J.H. Warden, Pharm. Jour. [3], xviii, 985, May 1888) has the probable composition C14H18O8. It melts at 189-191 °C to a deep red liquid, and is only slightly soluble in cold water, cold absolute alcohol, ether and chloroform. In hot water it dissolves more readily, and rather freely in boiling absolute alcohol. A hot aqueous solution of cocatannic acid has an acid reaction. It yields no reaction with ferrous salts (according to some observers, green), but with ferric acid gives a dark green coloration, and reduces silver nitrate slowly in the cold and immediately on heating, but not Fehling's solution. It does not precipitate gelatin. The alcoholic solution gives, with alcoholic lead acetate, a precipitate varying from yellow to orange-red. When heated with hydrochloric acid to 100 °C, cocatannic acid yields a glucose and a phlobaphene (a phenolic substance). The products of potash-fusion do not appear to be characteristic. They are said to include butyric and traces of benzoic acid.

C.J.H. Warden (Pharm. Jour. [3], xviii, 1010, 1027) has observed that coca leaves which are rich in cocatannic acid also contain much alkaloid, and suggests, with much probability, that the cocaine and allied alkaloids of coca leave exist in combination with cocatannic acid. Warden, in nine specimens of the dry leaves from plants grown in different parts of India, found from 6.36 to 12.64 percent of ash (average of 8.85 percent), and from 0.358 to 1.671 percent of "crude alkaloid" (average 0.982 percent). Warden did not succeed in obtaining a crystalline alkaloid from Indian coca, but does not consider the non-crystalline character detracts from its physiological activity.

A.G. Howard (Pharm. Jour. [3], xix, 569) has published analyses of a large number of coca leaves from different sources. His results show that while Erythroxylon coca yields about 0.75 percent of alkaloid, the proportion obtainable from most other species of Erythroxylon is extremely insignificant, and in some cases the alkaloid is wholly absent. In Brazil along there are upwards of eighty species of Erythroxylon.

H.T. Pfeiffer (Chem. Zeit., xi, 783, 818; Jour. Soc. Chem. Ind., vi, 561) has described the following process of manufacturing crude cocaine hydrochloride direct from coca leaves :-- The disintegrated leaves are digested in closed vessels at 70 °C, for two hours, with a very weak solution of caustic soda and petroleum boiling between 200-250 °C. The mass is filtered, pressed while still tepid, and the filtrate allowed to stand until the petroleum has completely separated from the aqueous liquid. The former is then drawn off and carefully neutralised with very weak hydrochloric acid, when a bulky, white precipitate of cocaine hydrochloride is obtained, together with an aqueous liquid from which a further quantity of the salt can be recovered by evaporation.

The dried product contains about 75 percent of real alkaloid, besides traces of "hygrine", gum, and other matters. A repetition of the process proved that the whole of the alkaloid was removed by a single treatment. The soda cannot be substituted by lime, nor the hydrochloric acid by other acid.

Assay of Coca Leaves. Pfeiffer employs a similar process for the assay of coca leaves, 100 grammes of which should be digested in a flask with 400 c.c. of water, 50 c.c. of 10 percent soda solution, and 250 c.c. of petroleum. The mixture is kept warm for some hours and shaken occasionally, then strained, the residue pressed, and the filtrate allowed to separate. The aqueous liquid is tapped off, and the oily layer titrated with N/100 hydrochloric acid. The number of c.c. required, multiplied by 0.042, gives the percentage of cocaine in the sample. The fresh leaves contain from 0.3 to 0.6 percent, but this proportion decreases considerably if the leaves have been stored for any length of time before being worked up.

For the assay of coca, v.d. March (Jour. Pharm. [5], xx, 500; Analyst, xiv, 115), after a trial of various processes, recommends that 50 grammes of the leaves should be mixed with 20 grammes of calcined magnesia and moistened with a little water, dried at 60 °C, and the mixture exhausted with ether. The ether is distilled off, and the residue treated with 30 c.c. of 2 percent hydrochloric acid. The solution is filtered, and repeatedly shaken with ether to remove colouring-matters. Ammonia is then added, and the cocaine extracted by shaking three times with 25 c.c. of ether. After standing for a short time over some fragments of calcium chloride, the ether is evaporated, and the residual alkaloid weighed.

For the estimation of the cocaine in coca leaves, A.B. Lyons (Jour. Pharm. [5], xiii, 197) recommends that the finely-powdered leaves should be macerated for twenty-four hours with eight times their weight of a mixture of 95 volumes of ether with 5 of ammonia. From an aliquot part of this liquid the alkaloid is extracted by agitation with acidulated water, the ether separated, and the alkaloid liberated from the aqueous liquid by means of ammonia and then again extracted with ether, which is then evaporated to dryness and the cocaine weighed. The associated bases, being soluble in water and insoluble in ether, remain in the ammoniacal liquid. Lyons states that coca leaves do not contain more more than 0.8 percent of cocaine, and sometimes the proportion is as low as 0.15 percent. The leaves rapidly deteriorate in value, so that in six months they are practically worthless. The product from deteriorated leaves is always more or less coloured, and very little of it is crystallisable; while that from good leaves is almost colourless, and easily crystallises.

M. Bignon in Lima (Pharm. Jour. [3], xvi, 267; xvii, 506) states that coca leaves dried in damp weather, with frequent turning, and sheltered from dew and moisture, yield easily 0.8 percent of alkaloid, and the finer sorts can give 1.0 percent and upwards under exceptional circumstances. Coca leaves dried in damp weather, or pressed into sacks before being completely dried, undergo a gradual ferment which ends in the complete destruction of the cocaine.

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