QUININE, the most important of the active principles contained in cinchona bark (see CINCHONA, vol. v. p. 780). Although the value of this bark in the treatment of intermittent fevers became widely known in 1638 through the cure of the countess of Chinchon, it was not until 1810 that any attempt was made to determine definitely the active principles to which its properties were due. In that year Gomez of Lisbon obtained a mixture of alkaloids by treating an alcoholic extract of the bark with water and then adding a solution of caustic potash. To this he gave the name of cinchonino. In 1820 two French chemists, Pelletier and Caventou, proved that the cin-chonino of Gomez contained two alkaloids which they named quinine and cinchonine. Some years afterwards quinidine and cinchonidine were discovered, and subse-quently several other alkaloids, but in smaller quantity, in different varieties of the bark.
Chemistry.—The alkaloids appear to exist in cinchona bark chiefly in combination with cinchotannic and quinic acids, since solvents of the alkaloids in the free state do not dissolve out any from the powdered bark. The cinchotannic acid apparently becomes altered by atmo-spheric oxidation into a red-colouring matter, known as cinchono-fulvic acid or cinchona red, which is very abundant in some species, as in C. succirubra. For this reason those barks which, like C. Calisaya, C. officinalis, and C. Ledgeriana, contain but little colouring matter are preferred by manufacturers, the quinine being more easily extracted from them in a colourless form. The value of cinchona bark for the manufacture of quinine depends on the amount of quinine sulphate that can be prepared from it in the crystalline form. The exact mode of extraction adopted by manufacturers is kept a profound secret. That hitherto adopted by the Indian Government for the preparation of the cinchona febrifuge (see below) has the merit of simplicity, but the whole of the alkaloid present in the bark is not obtained by it. This method is to exhaust the powdered bark as far as possible by means of water acidulated with hydrochloric acid and then to pre-cipitate the mixed alkaloids by caustic soda. Another method which is said to give better results consists in mixing the powdered bark with milk of lime, drying the mass slowly with frequent stirring, exhausting the powder with boiling alcohol, removing the excess of alcohol by distillation, adding sufficient dilute sulphuric acid to dis-solve the alkaloid and throw down colouring matter and traces of lime, &c, filtering, and allowing the neutralized liquid to deposit crystals. The sulphates of the alkaloids thus obtained are not equally soluble in water, and the sulphate of quinine can consequently be separated by fractional crystallization, since, being less soluble in water than the other sulphates, it crystallizes out first.
The quinine of commerce is the neutral sulphate, containing 7-| molecules of water of crystallization, and having the formula (C20H24N2O2)2. H2S04 + V H20. When crystallized from alcohol, or when dried over sulphuric acid, it contains only 2 molecules. Cownley has shown that the salt containing 2 molecules of water is the most per-manent one, for when the commercial sulphate containing 7J molecules is dried at 100° C. it becomes anhydrous, and when subsequently exposed freely to the air it rapidly absorbs 2 molecules of water; and that the commercial salt, if exposed to the air, effloresces until only 2 mole-cules of water are retained.
Two other sulphates are known. The one contains a single equivalent of acid, and in commerce bears the name of acid sulphate or soluble sulphate of quinine; it is soluble in 11 parts of water, but with considerable diffi-culty in absolute alcohol. The other sulphate contains 2 equivalents of sulphuric acid, is very soluble in cold water, but quite insoluble in ether; it is not an article of commerce. Both these sulphates crystallize with 7 molecules of water.
The neutral sulphate of quinine occurs in commerce in the form of slender white acicular crystals, which are very light and bulky. It is soluble in about 740 parts of cold water, but in 30 of boiling water, 60 of rectified spirits of wine (sp. gr. 0'85), and 40 of glycerin. Its solubility in water is lessened by the presence of sodium or magnesium sulphate, but is increased by nitrate of potassium, chloride of ammonium, and most acids. It is not soluble in fixed oils or in ether, although the pure alkaloid is soluble in both. It becomes phosphorescent on trituration. When prescribed it is generally rendered more soluble in water by the addition of dilute sulphuric acid or of citric acid, one drop of the former or f ths of a grain of the latter being used for each grain of the sulphate of quinine.
When a solution of quinine is exposed to sunlight it assumes a yellowish or brown colour due to the formation of " quiniretin," a body which is isomeric with quinine but has not an alkaline reaction, is not precipitated by tannin, and has an aromatic as well as a bitter taste. Quinine is precipitated from its solution by alkalies and their carbonates. It is very soluble in solution of ammonia, and also slightly soluble in lime water.
The acid solution of sulphate of quinine is fluorescent, especially when dilute ; it is levogyrate ; and when a solution of chlorine is first added and then ammonia an emerald green colour, due to the formation of thalleoquin, is developed. This test answers with a solution contain-ing only 1 part of quinine in 5000, or in a solution containing not more than oJ-JT^OTJ Par* ^ bromine be used instead of chlorine. The fluorescence is visible in an acid solution containing one part in 200,000 of water.
Quinine forms with sulphuric acid and iodine a com-pound known as herapathite, 4C20H24N2O2.3S04H2.61 + 3H90, which possesses optical properties similar to those _of tourmaline; it is soluble in 1000 parts of boiling water; and its sparing solubility in cold alcohol has been utilized for estimating quinine quantitatively. The other alkaloids are distinguished from quinine thus :—quinidine resembles quinine, but is dextrogyrate, and the iodide is very in-soluble in water ; the solution of cinchonidine, which is levogyrate, does not give the thalleoquin test, nor fluor-escence ; cinchonine resembles cinchonidine in these respects, but is dextrogyrate.
Commercial sulphate of quinine frequently contains from 1 to 10 per cent, of the sulphate of cinchonidine owing to the use of barks containing it. The sulphate of _cinchonidine is more soluble than that of quinine ; and, when 1 part of quinine sulphate suspected to contain it is nearly dissolved in 24 parts of boiling water, the sulphate of quinine crystallizes out on cooling, and the cinchonidine is found in the clear mother liquor, from which it can be precipitated by a solution of tartrate of potassium and sodium. Samples of quinine in which cinchonidine is present usually contain, according to Hesse, a smaller per-centage of water than the pure sulphate, the cinchonidine salt exercising a reducing influence on the quinine salt in this respect. Traces of quinidine are also sometimes, though rarely, found in commercial quinine, but, since quinidine is even more valuable as a medicine than quinine, its presence does not detract in a medicinal point of view from the value of the latter.
Owing to its voluminous character, as much as 18 per cent, of water may remain present in apparently dry samples of sulphate of quinine. If it loses more than 14-6 per cent, of water when dried at 100° C. it contains an excessive amount of moisture. Owing to its variability in this respect the hydrochlorate of quinine has been recommended as a more constant salt ; it also possesses advantages from a therapeutical point of view.
Sulphate of quinine manufactured from cuprea bark {Remijia pedunculate/) is liable to contain from "10 to o90 per cent, of sulphate of homoquinine, which almost coincides in solubility with sulphate of quinine. Homo-quinine has been shown by Paul and Cownley to be decomposed on treatment with caustic soda into quinine and a new alkaloid, cupreine, in the proportion of 2 to 3.
They have also shown that cupreine is soluble in a solu-tion of caustic soda (differing in this respect from quinine), and that therefore it is easy to prepare sulphate of quinine perfectly free from either homoquinine or cupreine. So far as the medicinal properties of cupreine and homo-quinine are at present known they appear to be of no practical importance.1
In consequence of the high price of the alkaloid an attempt was made a few years since by the Government of India to manufacture from cinchona bark a cheap febrifuge which should represent the alkaloids contained in the bark and form a substitute for quinine. This enterprise met with such success that in 1884 as much as 8714 tt> of the febrifuge were prepared; and during the previous year 9144 lb were distributed, of which 4880 lb were supplied to the Government institutions at a cost of little more than a rupee per ounce.
This mixture is known as cinchona febrifuge, and is prepared chiefly from C. succirubra, which succeeds better in India than the other species in cultivation, and grows at a lower elevation, being consequently procurable in large quantities at a comparatively low price. A mixture of the cinchona alkaloids, consisting principally of cinchoni-dine sulphate, with smaller quantities of the sulphates of quinine and cinchonine, is sold under the name of " quine-tum" at a cheaper rate than quinine.
In 1870 the Indian Government purchased no less than 81,600 ounces of sulphate of quinine, besides 8832 ounces of the sulphates of cinchonine, cinchonidine, and quinidine ; but at the present date it is able to meet the require-ments of its establishments almost entirely by the cinchona febrifuge prepared at the Government plantations in India.
Although quinine is manufactured in the United States, a large quantity has been imported from Europe since the high duty levied on its manufacture has been removed. There is considerable difficulty in obtaining trustworthy statistics as to the extent of the manufacture of quinine. The largest sale that has taken place in America appears to have been in 1883, when li tons were put up to auction, and in the same year 16,000 ounces were sold in London and a similar quantity at Berlin.
Physiological Action.—Quinine arrests the movements of the white corpuscles of the blood, rendering them round and darkly granulate, and, by preventing them from making their exit from the blood-vessels, diminishes or arrests the formation of pus in inflammation and causes contrac-tion of the spleen when that organ is enlarged. It acts upon the cerebro-spinal nervous system, giving rise to headache and a sense of tension in the brain ; these symptoms may be removed by the addition of hydrobromic acid or prevented by the use of the hydrobromide of quinine. It acts through the sympathetic nervous system on the heart, and is thus capable of restraining all the animal processes which develop heat, organic changes, or muscular action. It is antagonistic to atropine in its physiological action.
The use of quinine in medicine dates from its discovery in 1820. Its chief value is as an antiperiodic, especially in intermittent fevers, but also in other diseases when they assume a periodic character, such as neuralgia, asthma, hooping cough, &c. In blood poisoning, whether arising from natural or traumatic causes, it has been found of great utility. Its curative powers in sunstroke have been repeatedly proved in the East Indies, and a dose of quinine will often cut short an attack of catarrh if taken in the early stage. In malarial districts persons have been exposed to miasmatic influence without danger after taking a dose or two of five grains of quinine once or twice a day. In the smallest medicinal doses it is purely tonic, in larger ones stimulant; but it differs from other medicines of the same class in the stimulant action being longer sus-tained. In large doses it acts as a sedative, and in exces-sive doses it is poisonous. In some individuals it pro-duces an erythematous eruption, and it is also known to act as an oxytocic. Large doses also sometimes produce deafness, and act injuriously in all inflammatory states of the mucous membrane.
The other alkaloids of cinchona bark—quinidine, cincho-nidine, and cinchonine—also possess similar properties, quinidine being even more effectual than quinine; but cinchonine appears to produce nausea and gastric disturb-ance. This is also the case with the cinchona febrifuge prepared from C. succirubra.
Until the year 1867 English manufacturers of quinine were entirely dependent upon South America for their supplies of cinchona bark, which were obtained exclusively from uncultivated trees, growing chiefly in Bolivia, Peru, and Ecuador, the prin-cipal species which were used for the purpose being Cinchona Calisaya, Wedd. ; C. officinalis, Hook. ; C. macrocalyx, var. Palton, How. ; C. Pitayensis, Wedd. ; C. micrantha, R. and P. ; and C. lancifolia, Mutis. Since the cultivation of cinchona trees was com-menced in Java, India, Ceylon, and Jamaica, several other species, as well as varieties and hybrids cultivated in those countries, have been used. Recently C. lancifolia, var. Calisaya, Wedd., known as the calisaya of Santa Ee, has been strongly recommended for cultivation, because the shoots of felled trees afford bark containing a considerable amount of quinine ; C. Pitayensis has also been lately introduced into the Indian plantations on account of yielding the valuable alkaloid quinidine, as well as quinine, but the last two species have not as yet been grown in sufficient quantities to afford marketable bark.
The first importation from India took place in 1867, since which time the cultivated bark has arrived in Europe in constantly increasing quantities, London being the chief market for the Indian barks and Amsterdam for those of Java. The principal sales take place in May. In 1876, when Indian calisaya bark first came into the European market, the imports into London were the following :—Cinchona succirubra, 45,000 lb ; C. officinalis, 20,000 lb ; C. Calisaya, 1000 lb. During the last few years Cinchona Cali-saya has also been cultivated extensively in Bolivia and in Tolima, United States of Colombia, and this bark, which had almost dis-appeared from commerce, is likely in a few years to again become an available source of quinine.
In order to obtain the cultivated bark as economically as possible, experiments were made some years ago by M'lvor and others which resulted in the discovery that, if the bark were removed from the trunks in alternate strips so as not to injure the cambium, or actively growing zone, a new layer of bark was formed in one year which was richer in quinine than the original bark and equal in thickness to that of two or three years' ordinary growth. This is known in commerce as renewed bark. The process has been found to be most conveniently practised when the trees are eight years old, at which age the bark separates most easily. The yield of quinine has been ascertained to increase annually until the eleventh year, at which it seems to reach its maximum. The portion of the trunk from which the bark has been removed is sometimes pro-tected by moss, and the new bark which forms is then distinguished by the name of mossed bark. The species which yield the largest amount of quinine are by no means the easiest to cultivate, and experiments have consequently been made in cross-fertilization and grafting with the view of giving vigour of growth to delicate trees yielding a large amount of alkaloid or of increasing the yield in strong growing trees affording hut little quinine. Grafting, how-ever, has not been found to answer the purpose, since the stock and the graft have been found to retain their respective alkaloids in the natural proportion just as if growing separately. Hybridization also is very uncertain, and is very difficult to carry out effectually ; hence the method of propagating the best varieties by cuttings hai been adopted except in the case of those which do not strike readily, as in C. Ledgeriana, in which the plants are grown from the shoots of felled trees.
A few years ago it was discovered that a bark imported from the United States of Colombia under the name of cuprea bark, and derived from Remijia pedunculata, Triana, and other species, con-tained quinine to the extent of \ to 2i¿ per cent., and in 1881 this bark was exported in enormous quantities from Santander, exceed, ing in amount the united importations of all the other cinchona, barks ; and by reason of its cheapness this has since that date been largely used for the manufacture of quinine.
The imports of cinchona bark into London in 1884, including cuprea bark, are stated to have been 59,287 bales, into France 9271 bales, and into New York 8150 bales.
Cinchona bark as imported is never uniform in quality. The South-American kinds contain a variable admixture of inferior barks, and the cultivated Indian barks comprise, under the respec-tive names of yellow, pale, and red barks, a number of varieties of unequal value. For this reason a sample from every bale is analysed before the importations are offered for sale.
The alkaloids are contained, according to Howard, chiefly in the cellular tissue next to the liber. No definite knowledge has as yet been attained of the exact steps by which quinine is formed in nature in the tissues of the bark, nor have the numerous endeavours that have been made to build up quinine artificially or to obtain some idea of its constitution by splitting it up into its component parts been more successful. Nearly all that is known at present has resulted from analyses of the leaves, bark, and root. From these it appears that quinine is present only in small quantities in the leaves, in larger quantity in the stem bark, and increasing in. proportion as it approaches the root, where quinine appears to decrease and cinchonine to increase in amount, although the root bark is generally richer in alkaloids than that of the stem. The altitude at which the trees are grown seems to affect the production of quinine, since it has been proved that the yield of quinine in C. officinalis is less when the trees are grown below 6000 feet than above that elevation, and that cinchonidine, quinidine, and resin are at the same time increased in amount. It has also been shown by Broughton that C. peruviana, which yields cinchonine but no quinine at a height of 6000 feet, when grown at 7800 feet gives nearly as much crystallized sulphate of quinine, and almost as readily, as C. officinalis. Karsten also ascertained by experiments, made at Bogota on C. lancifolia that the barks of one district were sometimes devoid of quinine, while those of the same species from a neighbouring locality yielded 3J to i!¿ per cent, of the sulphate ;. moreover, Dr De Vrij found that the bark of C. officinalis cultivated at Utakamand varied in the yield of quinine from 1 to 9 per cent. In these cases the variation may have been due to altitude. Free access of air to the tissues also seems to increase the yield of quinine, for the renewed bark is found to contain more quinine than the original bark.
See Pharmacographia, 2d ed., pp. 359-370; Howard, Quinology of the East Indian Plantations ; Hesse in Pharm. Jour. and Trans., ser. 3, vol. iv. pp. 649-750, 795; Bartholow, Materia Medica and Therapeutics ; King, Manual of Cinchona Cultivation. (E. M. H.)
Footnotes
Pharm. Jour., [3], vol. vii. p, 189.
1 Pharm. Jour, and Trans., [3], vol. xii. p. 497, and vol. xv. p. 729.
The above article was written by: E. M. Holmes, Curator of Museum, Pharmaceutical Society, London.