VII.—Chloral.
§ 195. Chloral Hydrate (C2H3Cl3O2) is made by mixing equivalent quantities of anhydrous chloral[181] and water. The purest chloral is in the form of small, granular, sugar-like crystals. When less pure, the crystals are larger. These melt into a clear fluid at from 48° to 49°, and the melted mass solidifies again at 48·9°. Chloral boils at 97·5°; it is not very soluble in cold chloroform, requiring four times its weight. The only substance with which chloral hydrate may well be confused is chloral alcoholate (C4H7Cl3O2), but chloral alcoholate melts at a lower temperature (45°), and boils at a higher (113·5°); it is easily soluble in cold chloroform, and inflames readily, whereas chloral scarcely burns.
[181] Anhydrous chloral (C2HCl3O) is an oily liquid, of specific gravity 1·502 at 18°; it boils at 97·7°. It is obtained by the prolonged action of chlorine on absolute alcohol.
Chloral hydrate completely volatilises, and can be distilled in a vacuum without change. If, however, boiled in air, it undergoes slow decomposition, the first portions of the distillate being overhydrated, the last underhydrated; the boiling-point, therefore, undergoes a continuous rise. The amount of hydration of a commercial sample is of practical importance; if too much water is present, the chloral deliquesces, especially in warm weather; if too little, it may become acid, and in part insoluble from the formation of meta-chloral (C6H3Cl9O3). Chloral hydrate, by the action of the volatile or fixed alkalies, is decomposed, an alkaline formiate and chloroform resulting thus—
C2HCl3O,H2O + NaHO = NaCHO2 + H2O + CHCl3.
Trichlor-acetic acid is decomposed in a similar manner.
Statistics.—Chloral caused, during the ten years 1883-1892 in England and Wales, 127 deaths—viz., 111 (89 males, 22 females) accidentally, 15 (14 males, 1 female) from suicide, and a case in which chloral was the agent of murder.
§ 196. Detection.—It is, of course, obvious that after splitting up chloral into chloroform, the latter can be detected by distillation and applying the tests given at [p. 152] and seq. Chloral hydrate is soluble in one and a half times its weight of water; the solution should be perfectly neutral to litmus. It is also soluble in ether, in alcohol, and in carbon disulphide. It may be extracted from its solution by shaking out with ether. There should be no cloudiness when a solution is tested with silver nitrate in the cold; if, however, to a boiling solution nitrate of silver and a little ammonia are added, there is a mirror of reduced silver.
§ 197. The assay of chloral hydrate in solutions is best effected by distilling the solution with slaked lime; the distillate is received in water contained in a graduated tube kept at a low temperature. The chloroform sinks to the bottom, and is directly read off; the number of c.c. multiplied by 2·064 equals the weight of the chloral hydrate present.
Another method, accurate but only applicable to the fairly pure substance, is to dissolve 1 to 2 grms. in water, remove any free acid by baric carbonate, and then treat the liquid thus purified by a known volume of standard soda. The soda is now titrated back, using litmus as an indicator, each c.c. of normal alkali neutralised by the sample corresponds to 0·1655 grm. of chloral hydrate. Small quantities of chloral hydrate may be conveniently recovered from complex liquids by shaking them up with ether, and removing the ethereal layer, in the tube represented in the [figure].[182] The ether must be allowed to evaporate spontaneously; but there is in this way much loss of chloral. The best method of estimating minute quantities is to alkalise the liquid, and slowly distil the vapour through a red-hot combustion-tube charged with pure lime, as in the process described at [p. 153]. A dilute solution of chloral may also be treated with a zinc-copper couple, the nascent hydrogen breaks the molecule up, and the resulting chloride may be titrated, as in water analyses, by silver nitrate and potassic chromate.
[182] The figure is from “Foods”; the description may be here repeated:—A is a tube of any dimensions most convenient to the analyst. Ordinary burette size will perhaps be the most suitable for routine work; the tube is furnished with a stopcock and is bent at B, the tube at K having a very small but not quite capillary bore. The lower end is attached to a length of pressure-tubing, and is connected with a small reservoir of mercury, moving up and down by means of a pulley. To use the apparatus: Fill the tube with mercury by opening the clamp at H, and the stopcock at B, and raising the reservoir until the mercury, if allowed, would flow out of the beak. Now, the beak is dipped into the liquid to be extracted with the solvent, and by lowering the reservoir, a strong vacuum is created, which draws the liquid into the tube; in the same way the ether is made to follow. Should the liquid be so thick that it is not possible to get it in by means of suction, the lower end of the tube is disconnected, and the syrupy mass worked in through the wide end. When the ether has been sucked into the apparatus, it is emptied of mercury by lowering the reservoir, and then firmly clamped at H, and the stopcock also closed. The tube may now be shaken, and then allowed to stand for the liquids to separate. When there is a good line of demarcation, by raising the reservoir after opening the clamp and stopcock, the whole of the light solvent can be run out of the tube into a flask or beaker, and recovered by distillation. For heavy solvents (such as chloroform), which sink to the bottom, a simple burette, with a fine exit tube is preferable; but for petroleum ether, ordinary ether, &c., the apparatus figured is extremely useful.
§ 198. Effects of Chloral Hydrate on Animals.—Experiments on animals have taught us all that is known of the physiological action of chloral. It has been shown that the drug influences very considerably the circulation, at first exciting the heart’s action, and then paralysing the automatic centre. The heart, as in animals poisoned by atropine, stops in diastole, and the blood-pressure sinks in proportion to the progressive paralysis of the cardiac centre. At the same time, the respiration is slowed and finally ceases, while the heart continues to beat. The body temperature of the warm-blooded animals is very remarkably depressed, according to Falck, even to 7·6°. Vomiting has been rather frequently observed with dogs and cats, even when the drug has been taken into the system by subcutaneous injection.
The secretion of milk, according to Röhrig, is also diminished. Reflex actions through small doses are intensified; through large, much diminished. ·025-·05 grm. (·4-·7 grain), injected subcutaneously into frogs, causes a slowing of the respiration, a diminution of reflex excitability, and lastly, its complete cessation; this condition lasts several hours; at length the animal returns to its normal state. If the dose is raised to ·1 grm. (1·5 grain) after the cessation of reflex movements, the heart is paralysed—and a paralysis not due to any central action of the vagus, but to a direct action on the cardiac ganglia. Rabbits of the ordinary weight of 2 kilos. are fully narcotised by the subcutaneous injection of 1 grm.; the sleep is very profound, and lasts several hours; the animal wakes up spontaneously, and is apparently none the worse. If 2 grms. are administered, the narcotic effects, rapidly developed, are much prolonged. There is a remarkable diminution of temperature, and the animal dies, the respiration ceasing without convulsion or other sign. Moderate-sized dogs require 6 grms. for a full narcosis, and the symptoms are similar; they also wake after many hours, in apparent good health.[183]
[183] C. Ph. Falck has divided the symptoms into (1) Preliminary hypnotic; (2) an adynamic state; and (3) a comatose condition.
§ 199. Liebreich considered that the action of chloral was due to its being broken up by the alkali of the blood, and the system being thus brought into a state precisely similar to its condition when anæsthetised by chloroform vapour. This view has, however, been proved to be erroneous. Chloral hydrate can, it is true, be decomposed in some degree by the blood at 40°; but the action must be prolonged for several hours. A 1 per cent. solution of alkali does not decompose chloral at a blood-heat in the time within which chloral acts in the body; and since narcotic effects are commonly observed when, in the fatty group, hydrogen has been displaced by chlorine, it is more probable that chloral hydrate is absorbed and circulates in the blood as such, and is not broken up into chloroform and an alkaline formiate.
§ 200. Effects of Chloral Hydrate on Man.—Since the year 1869, in which chloral was first introduced to medicine, it has been the cause of a number of accidental and other cases of poisoning. I find, up to the year 1884, recorded in medical literature, thirty-one cases of poisoning by chloral hydrate. This number is a small proportion only of the actual number dying from this cause. In nearly all the cases the poison was taken by the mouth, but in one instance the patient died in three hours, after having injected into the rectum 5·86 grms. of chloral hydrate. There is also on record a case in which, for the purpose of producing surgical anæsthesia, 6 grms. of chloral were injected into the veins; the man died in as many minutes.[184]
[184] This dangerous practice was introduced by M. Ore. In a case of traumatic tetanus, in which M. Ore injected into the veins 9 grms. of chloral in 10 grms. of water, there was profound insensibility, lasting eleven hours, during which time a painful operation on the thumb was performed. The next day 10 grms. were injected, when the insensibility lasted eight hours; and 9 grms. were injected on each of the two following days. The man recovered. In another case, Ore anæsthetised immediately a patient by plunging the subcutaneous needle of his syringe into the radial vein, and injected 10 grms. of chloral hydrate with 30 of water. The patient became insensible before the whole quantity was injected with “une immobilité rappellant celle du cadavre.” On finishing the operation, the patient was roused immediately by the application of an electric current, one pole on the left side of the neck, the other on the epigastrium. Journ. de Pharm. et de Chimie., t. 19, p. 314.
§ 201. Fatal Dose.—It is impossible to state with any exactness the precise quantity of chloral which may cause death. Children bear it better, in proportion, than adults, while old persons (especially those with weak hearts, and those inclined to apoplexy) are likely to be strongly affected by very small doses. A dose of ·19 grm. (3 grains) has been fatal to a child a year old in ten hours. On the other hand, according to Bouchut’s observations on 10,000 children, he considers that the full therapeutic effect of chloral can be obtained safely with them in the following ratio:—
| Children of | 1 | to | 3 | years, | dose | 1 | to | 1 | ·5 | grm. | ( | 15·4 | to | 23·1 | grains | ) | |
| „ | 3 | „ | 5 | „ | „ | 2 | „ | 3 | „ | ( | 30·8 | „ | 46·3 | „ | ) | ||
| „ | 5 | „ | 7 | „ | „ | 3 | „ | 4 | „ | ( | 46·3 | „ | 61·7 | „ | ) | ||
| These quantities being dissolved in 100 c.c. of water. | |||||||||||||||||
These doses are certainly too high, and it would be dangerous to take them as a guide, since death has occurred in a child, aged 5, from a dose of 3 grms. (46·3 grains). Medical men in England consider 20 grains a very full dose for a child of four years old, and 50 for an adult, while a case is recorded in which a dose of 1·9 grm. (30 grains) proved fatal in thirty-five hours to a young lady aged 20. On the other hand, we find a case[185] in which, to a patient suffering from epileptic mania, a dose of 31·1 grms. (1·1 oz.) of chloral hydrate was administered; she sank into a deep sleep in five minutes. Subcutaneous injections of strychnine were applied, and after sleeping for forty-eight hours, there was recovery. On the third day a vivid scarlatinal rash appeared, followed by desquamation. The examples quoted—the fatal dose of 1·9 grm., and recovery from 31 grms.—are the two extremes for adults. From other cases, it appears tolerably plain that most people would recover, especially with appropriate treatment, from a single dose under 8 grms., but anything above that quantity taken at one time would be very dangerous, and doses of 10 grms. and above, almost always fatal. If, however, 8 grms. were taken in divided doses during the twenty-four hours, it could (according to Sir B. W. Richardson) be done with safety. The time from the taking of the poison till death varies considerably, and is in part dependent on the dose.
[185] Chicago Medical Review, 1882.
In seven cases of lethal poisoning, three persons who took the small doses of 1·25, 2·5, and 1·95 grms. respectively, lived from eight to ten hours; two, taking 4 and 5 grms. respectively, died very shortly after the administration of the chloral. In a sixth case, related by Brown, in which 3·12 grms. had been taken, the patient lived an hour; and in another, after a dose of 5 grms., recorded by Jolly, death took place within a quarter of an hour.
§ 202. Symptoms.—With moderate doses there are practically no symptoms, save a drowsiness coming on imperceptibly, and followed by heavy sleep. With doses up to 2 grms. (30·8 grains), the hypnotic state is perfectly under the command of the will, and if the person chooses to walk about or engage in any occupation, he can ward off sleep; but with those doses which lead to danger, the narcosis is completely uncontrollable, the appearance of the sleeper is often strikingly like that of a drunken person. There is great diminution of temperature commencing in from five to twenty minutes after taking the dose—occasionally sleep is preceded by a delirious state. During the deep slumber the face is much flushed, and in a few cases the sleep passes directly into death without any marked change. In others, symptoms of collapse appear, and the patient sinks through exhaustion.
§ 203. With some persons doses, which, in themselves, are insufficient to cause death, yet have a peculiar effect on the mental faculties. A case of great medico-legal interest is described by the patient himself, Dr. Manjot.[186] He took in three doses, hourly, 12 grms. of chloral hydrate. After the first dose the pain, for which he had recourse to chloral, vanished; but Manjot, although he had all the appearance of being perfectly conscious, yet had not the slightest knowledge of what he was doing or speaking. He took the other two doses, and sank into a deep sleep which lasted twelve hours. He then awoke and answered questions with difficulty, but could not move; he lay for the next twelve hours in a half slumber, and the following night slept soundly—to wake up recovered.
[186] Gaz. des Hôp., 1875.
§ 204. The treatment of acute chloral poisoning which has been most successful is that by strychnine injections, and the application of warmth to counteract the loss of temperature which is so constant a phenomenon. As an illustration of the treatment by strychnine, an interesting case recorded by Levinstein[187] may be quoted.
[187] Vierteljahrsschr. f. ger. Med., Bd. xx., 1874.
A man, thirty-five years old, took at one dose, for the purpose of suicide, 24 grms. of chloral hydrate. In half an hour afterwards he was found in a deep sleep, with flushed face, swollen veins, and a pulse 160 in the minute. After a further half hour, the congestion of the head was still more striking; the temperature was 39·5°; the pulse hard and bounding 92; the breathing laboured, at times intermittent.
Artificial respiration was at once commenced, but in spite of this, in about another half hour, the face became deadly pale, the temperature sank to 32·9°. The pupils contracted, and the pulse was scarcely to be felt; 3 mgrms. (·04 grain) of strychnine were now injected subcutaneously; this caused tetanic convulsions in the upper part of the body and trismus. The heart’s action again became somewhat stronger, the temperature rose to 33·3°, and the pupils dilated; but soon followed, again, depression of the heart’s action, and the respiration could only be kept going by faradisation. Two mgrms. (·03 grain) of strychnine were once more injected, and the heart’s action improved. During the succeeding six hours the respiration had to be assisted by faradisation. The temperature gradually rose to 36·5°; ten hours after taking the dose the patient lay in a deep sleep, breathing spontaneously and reacting to external stimuli with a temperature of 38·5°. Eighteen hours from the commencement, the respiration again became irregular, and the galvanic current was anew applied. The last application aroused the sleeper, he took some milk and again slept; after twenty-seven hours he could be awakened by calling, &c., but had not full consciousness; he again took some milk and sank to sleep. It was not until thirty-two hours had elapsed from the ingestion of the poison that he awoke spontaneously; there were no after effects.
§ 205. Chronic Poisoning by Chloral Hydrate.—An enormous number of people habitually take chloral hydrate. The history of the habit is usually that some physician has given them a chloral prescription for neuralgia, for loss of sleep, or other cause, and finding that they can conjure sleep, oblivion, and loss (it may be) of suffering whenever they choose, they go on repeating it from day to day until it becomes a necessity of their existence. A dangerous facility to chloral-drinking is the existence of patent medicines, advertised as sleep-producers, and containing chloral as the active ingredient. A lady, aged 35, died in 1876, at Exeter, from an overdose of “Hunter’s solution of chloral, or sedative draught and sleep producer.” Its strength was stated at the inquest to be 25 grains to the drachm (41·6 per cent.).[188]
[188] Exeter and Plymouth Gazette, Jan. 12, 1876.
The evil results of this chloral-drinking are especially to be looked for in the mental faculties, and the alienists have had since 1869 a new insanity-producing factor. In the asylums may usually be found several cases of melancholia and mania referred rightly (or wrongly) to chloral-drinking. Symptoms other than cerebral are chilliness of the body, inclination to fainting, clonic convulsions, and a want of co-ordination of the muscles of the lower extremities. In a case recorded by Husband,[189] a lady, after twelve days’ treatment by chloral hydrate, in doses of from 1 to 2 grms. (15·4 to 30·8 grains), suffered from a scarlatina-like rash, which was followed by desquamation. Among the insane, it has also been noticed that its use has been followed by nettle-rash and petechiæ (Reimer and others).
[189] Lancet, 1871.
§ 206. Excretion of Chloral.—Chloral hydrate is separated in the urine partly as urochloral acid (C8H11Cl3O7). Butylchloral is separated as butyl urochloral acid (C10H15Cl2O7). Urochloral acid is crystalline, soluble in water, in alcohol, and in ether, reduces copper from Fehling’s solution, and rotates a ray of polarised light to the left. Urochloral acid, on boiling with either dilute sulphuric or hydrochloric acid, splits up into trichlorethyl alcohol and glycuronic acid—
C8H11Cl3O7 + H2O = C2H3Cl3O + C6H10O7.
Trichloralcohol is an oily fluid (boiling-point 150°-152°); it yields by oxidation trichloracetic acid.
Urobutyl chloral acid gives on treatment with mineral acids trichlorbutyl alcohol and glycuronic acid.
To separate urochloral acid from the urine the following process has been found successful:—
The urine is evaporated to a syrup at the heat of the water-bath, and then strongly acidulated with sulphuric acid and repeatedly shaken out in a separating tube with a mixture of 3 vols. of ether and 1 vol. of alcohol. The ether-alcohol is separated and distilled off, the acid residue is neutralised with KHO, or potassic carbonate, and evaporated; the dry mass is then taken up with 90 per cent. alcohol, the filtrate precipitated with ether, and the precipitate washed with ether and absolute alcohol.
Next the precipitate is boiled with absolute alcohol and filtered hot. On cooling, the potassium salt of urochloral acid separates out in tufts of silky needles. The crystals are dried over sulphuric acid and again washed several times with absolute alcohol and ether to remove impurities.
To obtain the free acid, the potassium salt is dissolved in a little water and acidulated with hydrochloric acid; the liquid is then shaken out in a separating tube, with a mixture of 8 vols. of ether and 1 of alcohol. The ether-alcohol is distilled off, the residue treated with moist silver oxide until no farther separation of silver chloride occurs, the silver chloride is separated by filtration, the soluble silver salt decomposed by SH2, and the filtrate carefully evaporated to a syrup; after a few hours, the acid crystallises in stars of needles.
Urobutylchloral acid can be obtained in quite a similar way.[190]
[190] V. Mering u. Musculus, Ber., viii. 662; v. Mering, ibid., xv. 1019; E. Kulz, Ber., xv., 1538.
§ 207. Separation of Chloral from Organic Matters.—It will be most convenient to place the organic fluid or pulped-up solid, mixed with water, in a retort, to acidify with tartaric acid, and to distil.
Chloral hydrate distils over from a liquid acidified with tartaric acid; to obtain the whole of the chloral requires distillation in a vacuum almost to dryness.
The distillation will, unless there is also some partly decomposed chloral, not smell of chloroform, and yet give chloroform reactions.
To identify it, to the distillate should be added a little burnt magnesia, and the distillate thus treated boiled for half an hour in a flask connected with an inverted condenser; in this way the chloral hydrate is changed into chloroform and magnesium formate—
2CCl3CH(OH)2 + MgO = 2CHCl3 + (HCOO)2Mg + H2O.
The fluid may now be tested for formic acid: it will give a black precipitate with solution of silver nitrate—
(HCOO)2Mg + 4AgNO3 = 4Ag + Mg(NO3)2 + 2CO2 + 2HNO3.
It will give a white precipitate of calomel when treated with mercuric chloride solution—
(HCOO)2Mg + 4HgCl2 = 2Hg2Cl2 + MgCl2 + 2HCl + 2CO2.
Chloral (or chloroform), when boiled with resorcinol and the liquid made strongly alkaline with NaHO, gives a red colour, which disappears on acidifying and is restored by alkalies. If, on the other hand, there is an excess of resorcinol and only a very small quantity of NaHO used, the product shows a yellowish-green fluorescence; 1⁄10 of a milligramme of chloral hydrate gives this reaction distinctly when boiled with 50 mgrms. of resorcinol and 5 drops of a normal solution of sodium hydrate.[191]
[191] C. Schwarz, Pharm. Zeit., xxxiii. 419.
Dr. Frank Ogston[192] has recommended sulphide of ammonium to be added to any liquid as a test for chloral. The contents of the stomach are filtered or submitted to dialysis, and the test applied direct. If chloral is present, there is first an orange-yellow colour; on standing, the fluid becomes more and more brown, then troubled, an amorphous precipitate falls to the bottom, and a peculiar odour is developed. With 10 mgrms. of chloral in 1 c.c. of water, there is an evident precipitate, and the odour can readily be perceived; with 1 mgrm. dissolved in 1 c.c. of water, there is an orange-yellow colour, and also the odour, but no precipitate; with ·1 mgrm. in 1 c.c. of water, there is a weak, pale, straw-yellow colour, which can scarcely be called characteristic. The only substance giving in neutral solutions the same reactions is antimony; but, on the addition of a few drops of acid, the antimony falls as an orange-yellow precipitate, while, if chloral alone is present, there is a light white precipitate of sulphur.
[192] Vierteljahrsschrift f. gerichtl. Medicin, 1879, Bd. xxx. Hft. 1, S. 268.