PHYSOSTIGMATIS SEMINA, B.P.
CALABAR BEAN.

Calabar beans, or Ordeal Beans (Physostigma, U.S.P.), are the ripe seeds of Physostigma venenosum, Balfour (N.O. Leguminosae), a climbing plant indigenous to the West Coast of Africa. The beans are dark chocolate brown in colour, and reniform. in shape, about 25 millimetres long, 18 millimetres broad, and 12 millimetres thick, with a deep groove (the hilum) extending almost the length of the arched side. The surface is somewhat rough, but with a slight polish. Cut transversely the beans exhibit a thick, brown shell, surrounding two large, firm, white, starchy cotyledons, which enclose a large cavity, the air in which causes the entire seeds to float upon water. The odour and taste are not specially characteristic. The seeds of Entada scandens (Garbee beans), of Mucuna urens (horse-eye beans), and of Pentaclethra macrophylla have been offered as Calabar beans; they bear scarcely any resemblance to the genuine. A seed very similar in appearance to Calabar beans, but nearly cylindrical in shape and with a shorter hilum, has also been imported; the plant yielding it, which is unknown, has been named Physostigma cylindrospermum, Holmes;it is said to contain eserine.

Constituents.—The chief constituent of Calabar beans is the alkaloid physostigmine (eserine), with which are associated small quantities of eseridine and eseramine. Physostigmine forms large crystals melting at 105° to 106°; it is tasteless, laevorotatory, sparingly soluble in water, readily in alcohol, ether, chloroform, benzene, or carbon bisulphide. Its characteristic reactions are described under Physostigminae Sulphas. Eseridine is crystalline, and changes, on heating with a mineral acid, into physostigmine; it has but little action on the pupil of the eye, and is not employed medicinally. Eseramine crystallises in needles, melting at 238° to 240°. The presence of calabarine, which was formerly considered to be a constituent of the seeds, has not been confirmed. The total alkaloid varies from 0.15 to 0.3 per cent. (U.S.P., not less than 0.15). The seeds also contain the phytosterol stigmasterol, and abundance of starch; and yield about 4 per cent. of ash.

Action and Uses.—The properties of Calabar beans are virtually those of the alkaloid physostigmine (see Physostigminae Sulphas). An extract and a tincture are prepared from the crude drug. They are employed in tetanus, in hemiplegia and paraplegia, in locomotor ataxy, and in strychnine poisoning. The extract may be administered in pills or cachets, or as a solution prepared for hypodermic use by dissolving it in water and filtering. In cases of poisoning by Calabar beans, the stomach should be evacuated, and atropine injected until the pulse quickens or the symptoms pass off.

Dose.—3 to 10 centigrams to 1 1/2 grains).

PREPARATIONS.

Extractum Physostigmatis, B.P.—EXTRACT OF CALABAR BEAN.

Calabar bean, in No. 40 powder, 100; alcohol (90 per cent.), 500; milk sugar, in fine powder, a sufficient quantity. Macerate the drug for forty-eight hours, with 125 of the alcohol, then percolate with the remainder of the alcohol, press the marc, filter, recover most of the alcohol by distillation, evaporate to a very soft extract, and add three times its weight of milk sugar. Dose.—15 to 60 milligrams (1/4 to 1 grain).

Extractum Physostigmatis, U.S.P.—EXTRACT OF PHYSOSTIGMA.

Physostigma, in No. 80 powder, 100; alcohol (95 per cent.), and peeled Russian glycyrrhiza, in No. 80 powder, a sufficient quantity. The physostigma is exhausted with the alcohol, the product evaporated to dryness, and sufficient glycyrrhiza added to make the extract contain 2 per cent. of ether-soluble alkaloids. Average dose.—8 milligrams (4 grain).

Tinctura Physostigmatis, B.P.C.—TINCTURE OF CALABAR BEAN. Syn.—Tincture of Physostigma. 1 in 5.

Used in paralysis and other nervous diseases, apparently for the exciting action of the drug on motor nerve-endings. Dose.—3 to 10 decimils (0.3 to 1.0 milliliters) (5 to 15 minims).

Tinctura Physostigmatis, U.S.P.—TINCTURE OF PHYSOSTIGMA.

Prepared by extracting 10 of Calabar bean with sufficient 95 per cent. alcohol to produce 100, and should contain 0.014 per cent. w/v of alkaloids. Average dose.—1 mil (15 minims).

PHYSOSTIGMINAE SALICYLAS.
PHYSOSTIGMINE SALICYLATE.

C22H27N₃O₅.= 413.246.

Synonym.—Eserine Salicylate.

Physostigmine salicylate, C₆H4(OH)COOHC₁₅H₂₁N₃O₂, a salt of the alkaloid physostigmine, may be prepared by neutralising a solution of 10 of physostigmine in warm ether with a solution of 10 of salicylic acid in ether until a drop of the liquid on moistened blue litmus paper produces a faint reddening. After the crystals have separated, they are collected, and dried at a very gentle heat. Physostigmine salicylate is official in the U.S.P. It occurs in the form of colourless or slightly yellow, glistening needles, or short, columnar, odourless crystals, having a faintly bitter taste. Solutions should only be tasted cautiously. The diluted aqueous solution is neutral; the concentrated alcoholic solution reddens blue litmus paper slightly. The aqueous solution becomes pink on standing for some time, owing to formation of rubreserine. Physostigmine salicylate softens on heating, and becomes slightly yellow at 160°, melting at 179°. On ignition it leaves no residue. The aqueous solution gives with ferric chloride a deep violet colouration (due to the salicylic acid); with calcium hypochlorite a red colouration; with a drop of caustic alkali solution a cherry-red, changing to darker red, and, finally, to a green colour. On evaporating an aqueous solution to dryness with a few drops of ammonia water, a blue residue is produced which is soluble in alcohol, this solution yielding a red fluorescence on the addition of excess of acetic acid. A few milligrams dissolved in nitric acid gives a yellow solution, which on heating changes to orange and then blood-red, and on evaporation to dryness yields a green residue. This on exposure to the fumes of nitric acid becomes violet-blue, and when a drop of nitric acid is added it forms a reddish-violet solution, which soon changes to blood-red, and finally, on standing or on dilution, becomes greenish-yellow. Sulphuric acid produces a colourless solution, becoming yellow after a time. Sulphuric acid, containing one drop of solution of formaldehyde in each mil, gives a bright pink colour when added to the salt; if sulphuric acid and a few grains of cane sugar be added, a yellow colour is produced, turning to brown, then to purple, and lastly to greenish-black. It is more stable than the other salts of the alkaloid, and is similarly employed, but its sparing solubility in water stands in the way of its more general use.

Soluble in water (1 in 130); alcohol (1 in 12).

Action and Uses.—The action of physostigmine and its salts is described under Physostigminae Sulphas. The salicylate is preferred to the sulphate for the preparation of eye-drops, as its solutions do not so readily become pink in colour. The colouration of solutions of physostigmine salts, due to oxidation, can be prevented by the addition of a trace of boric, hypophosphorous, or sulphurous acid (see Physostigminae Sulphas).

Dose.—1 to 3 milligrams (1/60 to 1/20 grain)

PHYSOSTIGMINAE SULPHAS, B.P.
PHYSOSTIGMINE SULPHATE.

C₃₀H₄₄N₆O₈S = 648.482.

Synonym.—Eserine Sulphate.

Physostigmine sulphate, (C₁₅H₂₁N₃O₂)2, H₂SO₄, a salt of the alkaloid physostigmine, may be prepared by adding sulphuric acid (10 per cent.) to a solution of physostigmine in ether, drop by drop, until separation of the crystalline sulphate ceases. The salt is collected and carefully dried at a temperature of about 40°. It is also official in the U.S.P. It occurs as a yellowish-white micro- crystalline, very deliquescent, odourless powder, having a bitter taste, gradually becoming reddened on exposure to air and light, owing to formation of rubreserine, a product of oxidation, which is insoluble in ether, but soluble in chloroform and in carbon bisulphide. The aqueous solution, which is colourless at first, becomes pink on keeping, like the salt, and is neutral to litmus, or only very faintly acid. Heated to 130°, it becomes soft, and at 140° melts without decomposition. With gold chloride it produces a purple colour. With sulphuric acid alone the salt gives only a faint yellow colour, but with sulphuric acid containing a crystal of potassium iodate a light purple colour is produced, changing at once to yellowish-red.

Soluble in water (4 in 1), alcohol (2.5 in 1), soluble in chloroform, but not very soluble in ether.

Action and Uses.—The action of physostigmine on involuntary muscle and on secretory glands closely resembles that of pilocarpine. Applied to the eye, it causes great constriction of the pupil; the effect is local, and is due mainly to stimulation of the terminations of the third nerve; intra-ocular pressure is largely reduced as a result of the contraction. Other plain muscle is affected by physostigmine in much the same way; gastric movements are increased and vomiting may result, intestinal peristalsis is exaggerated with production of liquid motions, owing to the hurried passage of the intestinal contents; the bladder and uterine movements are augmented and the bronchioles constricted. All these effects are antagonised by atropine. A similar stimulation of the peripheral nerve-endings in glands, results in an increase of their secretions, especially in the case of the sudoriferous, salivary, mucous, and lachrymal glands. The action of physostigmine on the circulation is to slow the pulse and raise blood pressure. It depresses the central nervous system, causing muscular weakness and diminished reflexes. Very large doses excite motor nerve-endings, and so cause irregular twitchings. Physostigmine has been employed internally for its depressant action on the central nervous system in epilepsy, chorea, etc., but has not proved of much service. It is given hypodermically, 3/4 milligram (1/100 grain), every four hours, in acute tetanus, and in some abdominal conditions to obtain an action of the bowels, or to prevent the formation of adhesions after operation, by exciting peristalsis. In veterinary practice it is used as a hypodermic purgative. The chief use of physostigmine is for its action on the eye; under its influence the pupil commences to contract in five to fifteen minutes, reaches the maximum contraction in thirty minutes, and remains contracted for more than twelve hours. The muscles regulating accommodation are also affected, but they regain their normal condition in three to four hours. Physostigmine is employed to correct the dilatation caused by atropine, homatropine, or cocaine. It is used in glaucoma to decrease intra-ocular pressure, but whether this is brought about by lessening the secretion of fluid or by facilitating its escape is not yet clear. For ophthalmic use, Lamellae Physostigminae or 0.25 to 1 per cent. solutions in sterile distilled water are employed. Neutral solutions rapidly become pink in colour; this may be to a great extent avoided by dissolving the alkaloidal salt in a weak solution of boric acid (2 per cent.). The addition of sulphurous or hypophosphorous acid to solutions of physostigmine sulphate has been suggested in order to prevent this colouration; the use of such powerful deoxidising agents is unnecessary, and offers no advantage for the purpose over the weak acidity of the boric acid solution. For internal use the sulphate may be administered in pills, the salt being carefully triturated with milk sugar, and massed with glycerin, of tragacanth. In cases of poisoning by physostigmine the stomach, should be washed out with 0.2 per cent. solution of potassium permaganate, and atropine and strychnine administered hypodermically. The alkaloid physostigmine occurs in colourless or pale pink crystals, very slightly soluble in water, soluble in castor oil (1 in 100), and in melted soft paraffin (1 in 180). It is employed in the preparation of ointments and oily drops for application to the eye as myotics.

Dose.—1 to 3 milligrams (1/60 to 1/20 grain).

PREPARATIONS.

Guttae Physostigminae, B.P.C.—PHYSOSTIGMINE EYE DROPS. Syn.—Guttae Eserinae; Eserine Eye Drops. 1 per cent.

Physostigmine contracts the pupil and reduces intra-ocular tension. It is antagonistic to atropine. Solutions of physostigmine tend to become pink owing to slow oxidation of the salt. They should be preserved in amber bottles, and kept as much as possible from the air; the addition of boric acid largely prevents colouration, which also occurs less readily in the presence of cocaine.

Guttae Physostigminae et Cocainae, B.P.C.—PHYSOSTIGMINE AND COCAINE EYE DROPS. Syn.—Guttae Eserinae et Cocainae; Eserine and Cocaine Eye Drops.

Physostigmine sulphate, 0.25 per cent.; cocaine hydrochloride, 1 per cent.

Lamellae Physostigminae B.P.—PHYSOSTIGMINE DISCS. Syn.—Lamellae Eserinae; Eserine Discs.

Each disc weighs about 1 1/4 milligrams (1/50 grain) and contains 0.065 milligram (1/1000 grain) of physostigmine sulphate. These discs are used to diminish intra-ocular pressure, as in glaucoma, and to contract the pupil. Stronger discs, containing 1/250 or 1/500 grain, are also prepared.

Oculentum Physostigminae, B.P.C.—PHYSOSTIGMINE EYE OINTMENT. Syn.—Oculentum Eserinae; Eserine Eye Ointment. 1 (alkaloid) in 500.

The British Pharmaceutical Codex, 1911, was published by direction of the Council of the Pharmaceutical Society of Great Britain.