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A TEXTBOOK OF PHARMACOGNOSY
By T.C. Denston. B.Pharm (London) F.R.I.C., F.P.S.
Compiled and Edited by Ivor Hughes

In Two Parts.

LATICES, DRIED JUICES, AND EXTRACTS

OPIUM
Synonym: Raw Opium.
Fam.: Papaveracece.

Official Source
The latex obtained by incision from the unripe capsules of Papaver somniferum Linn., dried or partly dried by heat or spontaneous evaporation, and worked into somewhat irregularly-shaped masses ("natural opium") or moulded into masses of more uniform size and shape ("manipulated opium"); known in commerce as Turkish, Persian, Indian and European Opium. It contains, in its moist conditions, as imported, not less than 9.5 per cent of morphine, calculated as anhydrous morphine.

Geographical Source
Turkish Opium
Turkey, to some extent in European Turkey principally in Asiatic Turkey (in Anatolia, a large district south of the Black Sea); exported from Smyrna (Izmir) and Istanbul (Constantinople). 

Macedonian (Salonika) Opium
Yugo-Slavia, chiefly in the South ; exported from Salonica.Also produced in Bulgaria (in the area known as Eastern Rumelia bordering the Black Sea) and in Greece (in the north-east, on the plains of Thrace contiguous with European Turkey). 

Persian
Around Ispahan, Shiraz, and Yend. 

Indian
Restricted to the central portion of the valley of the Ganges chiefly around Benares, the opium being prepared for home use and export at a factory at Ghazipur, 44 miles north-east of Benares.

China (not exported).

Plant Habit
The opium poppy is an herbaceous annual attaining a height of about 1 metre, bearing 5 to 8 capsules. Several varieties occur, of which P. somniferum, var. glabrum, is the one grown principally in the Near East; its capsule is subglobular with 10 or 12 stigmata (Fig. 120), and the petals are purple. Laticiferous vessels, though distributed throughout the plant, are most numerous in the wall of the capsule, this alone being used as the source of opium.

Cultivation
The plant is grown from seed, sown in porous, well-manured soil in a sunny position. The seedlings are planted out and commence to flower in May or June.

TURKISH OPIUM

Collection and Preparation
1. Time of Incision. The highest yield of latex is obtained by incision of the capsule about 14 days after the petals have dropped, the best time for incision being indicated by the presence on the surface of a light-green, wax-like bloom, easily removed by rubbing with the fingers. At this stage the capsules are about 5 cm. in diameter, and are soft, yielding to pressure by hand. The incisions are made in the afternoon and evening, being the coolest parts of the day, in weather which consists of clear hot days and warm dewless nights so that the exuded latex is not washed away.

2. Method of Incision (Figs. 121 and 122). With the left hand holding the capsule, a knife is drawn lightly across the surface to make an incision extending either about two-thirds round in a transverse direction, or completely round in a spiral. These incisions must be carefully made, and must be quite shallow (usually about 1 mm. deep); if the cuts are too deep the inner wall of the capsule will be pierced, and the latex will flow inwards.


Fig. 120
(a) Poppy capsule cut vertically. (b) Entire Poppy Capsule (c) Poppy Seeds.

3. Collection of Latex. The exuded latex, which is white, turns brown and coagulates to form a pasty mass around the incisions, and next morning it is removed by scraping. The


Fig. 121

UNRIPE CAPSULE  OF PAPAVER SOMNIFERUM, INCISED, SHOWING EXUDATION OF LATEX; 

3. Collection of Latex. The exuded latex, which is white, turns brown and coagulates to form a pasty mass around the incisions, and next morning it is removed by scraping. The collector transfers the soft material to a poppy leaf cupped in the hand, and when this is full another leaf is placed above, and the whole is then set aside in the shade to thicken and harden. In former years these cakes of opium were allowed to become sufficiently firm and then placed in bags along with dock fruits to prevent agglomeration of the cakes. The sealed bags were then enclosed in baskets and transported by mules, chiefly to Smyrna. Here the bags were opened, the cakes inspected, graded, sorted, and re-packed in hermetically-sealed boxes lined with tin, called opium chests. The product, known as "Druggists' Opium," was the variety common in English commerce. A similar but softer variety, termed "Soft Shipping Opium," was imported into this country for transhipment or the manufacture of alkaloids.

Following the imposition of a monopoly in Opium products by the Turkish Government, a new form of opium ("manipulated opium") has been produced since 1935 and the old varieties ("natural opium") are no longer imported. The inspissated latex is sent to a factory, bulked, passed through a mill to render the mass uniform and then pressed into moulds to give regular cakes, weighing 2 kilogrm. The cakes are coated with coarsely-powdered poppy leaf and then packed, forty in a tin-lined case. The product is known as Turkish Government Monopoly Opium.

The collection of Macedonian Opium is similar to that of Turkish Druggists' Opium; the partly-dry juice is usually transferred from the capsules to a tin can and later made into balls of 0.5 to 1.0 kilogram., wrapped in poppy leaves, and stored until dry.

INDIAN OPIUM

1. Time of Incision.
The time of incision (April to June) is carefully selected as for Turkish Opium.

2. Method of Incision.
In India, several vertical incisions extending almost from base to apex of the capsule are made with a sharp four-pronged instrument called a " nushtur." Early next morning the coagulated latex is scraped off with a small trowel-like instrument called a " seetooar " and transferred to an earthenware pot carried by the gatherer. These are emptied at the factory into a tilted vessel which allows a deleterious dark fluid called " pusse-wah" to separate and drain away. The material is then matured by exposing to the air and after reaching a " standard " consistence, it is made into cakes or balls which are encased in poppy leaves rendered adherent by an adhesive (" Provision" Opium imported for the manufacture of Alkaloids), or into cakes or square blocks wrapped in oiled paper ("Medical" Opium for Indian Medical Department supplies or for export).

The production of Opium in India for export to China was reduced annually from 1907 by agreement with the Chinese Government, and ceased entirely in 1913. The exports from India are chiefly to this country for use in the manufacture of morphine and codeine. Indian Opium is not suitable for the preparation of official extracts, particularly Dry Extract of Opium, on account of its low morphine content, low moisture content and high water-soluble extractive

PERSIAN OPIUM

Collection resembles that described for Turkey Opium. The latex is then usually mixed with gummy matter (probably sarcocolia, a gummy exudation from species of Pendea or inferior qualities of tragacanth) and sometimes with grape juice (indicated by the high proportion of glucose frequently present to which the vitreous fraction of some specimens is attributed). This admixture is then beaten to form a homogeneous paste, and afterwards made into brick-shaped pieces which are separately wrapped in red paper.

Persian Opium is not regularly brought into this country, but quantities are exported to the Far East. Some Persian Opium is prepared in a form similar to the old Turkish '' Druggists' " Opium.

Constituents
All varieties of opium contain a large number of alkaloids, but evaluation is normally based on the principal alkaloid, namely 'Morphine'.
12-13 per cent in Turkish Government Monopoly Opium. 
12-17 per cent in Macedonian Opium. 
9-13 per cent in Persian Opium. 
7-12 per cent, generally about 9 per cent, in Indian Opium.

The above figures refer to anhydrous morphine in opium as imported (raw opium). The proportion of moisture present varies and was formerly greatest in Turkish Soft Shipping (about 30 per cent) which contained 15 to 18 per cent morphine on drying. Turkish Druggists' Opium contained about 20 per cent moisture and yielded 12 to 16 per cent morphine on drying.

The Pharmacopoeia requires opium to contain not less than 9-5 per cent anhydrous morphine and this requirement is met by most consignments of the above varieties except Indian Opium, which frequently fails to reach this figure.

It has been demonstrated on a number of occasions that a hot climate is not required for the production of opium of high morphine content. Experimental cultivation in Denmark yielded opium containing 23.8 per cent morphine. Commercial cultivation, however, is not likely to develop in western European countries due to the heavier labour costs.

There is stated to be some decline in morphine content on long storage of raw opium but, according to Henry, powdered opium does not deteriorate in this way when stored in well-closed containers.  The alkaloids next in importance are

Codeine.
1-1-5 per cent in good-quality Turkish Monopoly Opium.
2-5 to 3 per cent in good quality Persian Opium. 3 per cent in Indian Opium.

Narcotine.
2 to 8 per cent, most in Indian and least in Turkish Opium, partly free and partly as meconate and sulphate.

Papaverine.
About 0-8 per cent; after extraction of morphine and codeine from opium, the residues are worked to extract this alkaloid. Papaverine is also prepared synthetically on a commercial scale.

The large scale on which morphine is extracted has provided considerable amounts of residues for the investigation of the minor alkaloids, of which more than 20 are known. These include Thebaine 0-4 per cent, Narceine 0-2 per cent, and the following, each of known chemical constitution but each present to the extent of less than 0-1 per cent�

Xanthaline (an oxidation product of papaverine), laudanine, laudanidine (also known as tritopine), laudanoaino, oodamine, narootoline, oxynarcotine, hydrocotamino, protopine, cryptopine, noopine (isomeric with codeine) and porphyroxine.

Non-alkaloidal constituents of opium include;

Meconic Acid: a dibasic acid peculiar to opium and with which the morphine is combined as a water-soluble salt; the proportion ranges from 3-5 per cent, being greater in opiums of high morphine content.

Lactic acid, sulphates, meconin, gummy substances, fat, inorganic salts and caoutchouc-like material are also present.

Tannin, starch, fat and calcium oxalate are absent; they are present in a number of potential adulterants and suspected samples should therefore be tested for these substances.

Substitutes and Adulterants.
The substances occasionally used are fig pulp, apricot pulp, and extract of liquorice; artificial weighting is also practised by the addition of clay, and pieces of metal, commonly lead shot. Powdered poppy capsules have been reported as an adulterant and may be identified by the microscopical characters of the innor epidermis of the pericarp.

Smoking opium usually contains about 5 per cent of morphine and is prepared by partially extracting opium with water, concentrating and roasting the extract.

The evaluation of opium on its morphine content, and the care taken in sampling for this purpose, render most forms of adulteration almost useless; artificial weighting naturally causes serious loss, but the practice is now rare.

OPIUM PULVERATUM. Powdered Opium (Pulvis Opii).
This is Opium which has been dried, powdered, and adjusted to contain 10 per cent (limits 9-5-10-5) of anhydrous morphine by the addition of powdered lactose suitably coloured with burnt sugar, or powdered cocoa husk.

Morphine from Poppy Straw
All morphine produced in this country (Britain) is obtained by extraction from opium, but in a number of European countries work has proceeded since about 1930 on entirely different methods, based on direct extraction from the poppy plant. The first process was devised in Hungary and patent specifications have been published in Switzerland, France, Belgium, Poland, England, and elsewhere. A typical process, known as the "Dry Poppy Straw Method," uses the dried poppy straw and chaff remaining after the ripe plants have been threshed to obtain the seed. This "straw," which can be stored and processed throughout the year, contains about 0-08 per cent morphine and 0-008 per cent codeine. Details of the extraction methods vary considerably in different patented processes.

The Opium Alkaloids and Derivatives

Morphine has been mentioned as the principal alkaloid of opium, but codeine and narcotine are also important. The mixed alkaloids are also used as Papaveretum B.P.C., containing all the opium alkaloids, in soluble form as hydrochlorides, in the proportion normally found in the drug.

Morphine. The formula C17H17NO(OH)2 for this alkaloid shows that it contains two hydroxyl groups, one of which is phenolic. For this reason two types of morphine derivative are possible, esters and ethers.

Esters of Morphine. The esters are prepared by treating morphine with acids or acid anhydrides under conditions nuitublo for esterification, and are therefore called acyl doriva.tivoH,

Like other esters these derivatives are readily hydrolysed, whereby morphine is re-formed�this change occurs in the body. Hence, because morphine is readily recoverable from the esters, and because, like morphine, they are habit-forming, all these derivatives are regulated by the Dangerous Drugs Acts.

The more important esters are;

Diamorphine (Syn. Diacetyl-morphine, Acetomorphine, Heroin) is prepared by treating morphine with acetic anhydride, whereby both hydroxyl groups are replaced by the acetyl group (CH3CO-), as indicated by the chemical name, diacetyl-morphine.

Benzoyl-morphine. This is similarly prepared using benzoyl chloride or benzoic anhydride. This acyl derivative must be carefully distinguished from benzylmorphine (see below).

Ethers of Morphine. 
The ethers are formed by the condensation of one molecule each of morphine and an alcohol, with elimination of a molecule of water, analogous to the formation of the simple ethers, like ordinary (i.e. di-ethyl) ether. The ethers differ from the esters in not undergoing hydrolysis (compare the simple ethers in this respect). Hence morphine is not readily obtained from them, nor is it produced therefrom in the body; consequently most are not habit-forming. The ethers other than Codeine and Ethylmorphine are, however, now included in the Dangerous Drugs Acts.

Ethers may be prepared from aliphatic alcohols (to form alkyl derivatives), or aromatic alcohols (to form aryl derivatives), of which the following are the more important�

Codeine. This is methyl morphine, and has the formula C17H17NO(OH)(OCH3). In addition to natural codeine extracted from opium, synthetic codeine is prepared by the tnethylation of morphine.

Ethylmorphine (Syn. Dionine). As indicated by the name, this is the ethyl ether, its formula being C17H17NO(OH)OC2HS.

Benzylmorphine (Syn. Peronine). Similarly this is the benzyl ether, and is the only commonly used aryl derivative.

In addition to the esters and ethers, there is another important derivative of morphine, namely;

Apomorphine. This is prepared by heating morphine with hydrochloric acid in sealed tubes, whereupon part of the morphine loses two molecules of hydrogen and one of oxygen, to form apomorphine, which is separated and purified. The narcotic effect of this derivative is modified by its powerful emetic properties, for which it is exclusively used.

Part 2 Here.

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