Manufacture of alkaloids from the poppy plant in Hungary

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Author: Dr. Istvan Bayer
Pages: 21 to 28
Creation Date: 1961/01/01

Manufacture of alkaloids from the poppy plant in Hungary

Dr. Istvan Bayer
Secretary, Hungarian Pharmacopoeia Commission

Since Sertürner's discovery, many research workers have attempted to produce morphine from poppy capsules - i.e., without going through the opium stage. A large number of failures were registered before Tilloy [ 1] in France and F. L. Winckler [ 2] in Germany succeeded in preparing morphine from poppy capsules. Their methods are of purely historical interest; those methods could not compete with the production of morphine from opium, so that opium remained the raw material in morphine manufacture. In the majority of European countries, attempts were made to produce opium itself from poppy capsules - in Hungary, for example, E. Deer [ 3] produced 4 cg of opium with a morphine content of 15-16% per capsule at Aszod - but these experiments are only of scientific interest; there was no actual production of opium, as this would have been uneconomical in view of European salary rates.

FIGURE 1 Statue of János Kabay at Tiszavasvári

Full size image: 42 kB, FIGURE 1 Statue of János Kabay at Tiszavasvári

The manufacture of morphine direct from poppy straw was only achieved one century after the first experiments. In 1925, a young Hungarian, J. Kabay, devised a method [ 4] for the production of morphine from green poppy plants; in 1927, he founded in his native country a small chemical factory under the name of "Alkaloida". On 14 March 1930 [ 5] , Kabay reported as follows to the Hungarian Pharmaceutical Society:

"The poppies are cut shortly after flowering. The usual method of harvesting is for the plants to be mown down and sheaved. The extracting machine is carried wherever the harvesters go, so as not to have to move the whole crop. The plants are weighed, then finely chopped and crushed. After a preliminary pressing these are fed into the extracting machine, where they are continually mixed with the extracting liquids.

"The extract and the juice emerging from the press are carried in barrels to the factory, where the liquid is concentrated into a soft extract and is stored in barrels. This pasty substance has a morphine content of 0.4% to 0.8%; there is no risk of deterioration, because it contains preservatives in sufficient quantity, and it can therefore be stored without loss.

"This phase of the manufacturing process is seasonal; the season varies in duration, and occurs between 15 May and 15 July.

"The second phase of the manufacturing process is the conversion of this concentrated extract into raw chlorophyll and a complex mixture of alkaloids."

This process is very costly and also technically complicated. The most serious difficulties involved are due to the presence of poppy-seed oil and chlorophyll. Other difficulties are described by Kabay [ 6] , [ 7] in his patent specification of 30 November 1931, in which he made known the principle of the extraction of morphine from poppy straw:

"Although the yield with this process is high and the opium alkaloids obtained are pure, the process has the disadvantage that it can be employed only at the season when the poppy plant is between the stages of blooming and maturity. This period is very short, so that it is difficult to manufacture with profit. Moreover, the cost of transporting the green plants is high, owing to the space required and to their weight, and the seed product is lost.

"The invention depends upon the surprising discovery that the opium alkaloids can be obtained from the poppy plant even when the plant is already ripe and dry. According to the invention, the ripe and dried plant portions are, for this purpose, suitably cut up, then treated with an extracting fluid, and the extract obtained by means of the extracting fluid is treated for opium alkaloids."

The Kabay family commenced production of alkaloids on a very small scale, but the importance of the above process became apparent within a few years (see table 1).

TABLE 1 (3)

Year

Morphine imports into Hungary (kg)

Morphine exports from Hungary (kg)

1927 991
-
1928 145
-
1930 49.7 12.6
1933 19.2 63.2
1934 2.6 79.6

In the beginning, J. Kabay not only had to struggle against technical and financial difficulties, but also the accusation that the manufacture of morphine in Hungary would facilitate the spread of addiction. The technical difficulties were surmounted; the financial problems were solved with state assistance, and the accusation regarding the spread of addiction was refuted in Hungary and abroad by publishing the manufacturing process. In 1934, a League of Nations committee visited Hungary [ 8] ; this visit represented a great honour, and a well-deserved one for Kabay. As a result, expert opinion realized not only that the Kabay process for the production of morphine is of great economic importance (because it makes use of waste material), but that it plays an even more signifi- cant role in public health; the omission of the "opium" stage has made it possible to produce, under complete control, morphine and other alkaloids from the poppy plant by using a raw material which is not itself a narcotic.

FIGURE 2 [ 12] Production of crude morphine in Hungary, 1927-1958 (vertically tons, horizontally years).

Full size image: 22 kB, FIGURE 2 12Production of crude morphine in Hungary, 1927-1958 (vertically tons, horizontally years).

Worn out by over-work and disappointment at public misunderstanding, Kabay died at the early age of forty. Before he died, he was able to devise a chemical method of determining the morphine content of poppy straw, a task which was entrusted to him by the League of Nations [ 9] [ 10] , but he was unable to give a lecture at Geneva on his work.

The great importance of the process was also recognized abroad. In Switzerland, Hoffmann-La Roche was the first to produce morphine from poppy capsules [ 11] ; Poland and Czechoslovakia began producing morphine, making use of the Kabay patent.

Figure 2 shows the development of crude morphine in Hungary, and illustrates the very rapid growth of that production.

In 1958, the Hungarian People's Republic was the sixth producer of crude morphine in the world, being outstripped only by a few more densely inhabited and more highly industrialized countries (see table 2).

In the manufacture of morphine from poppy straw, the Hungarian People's Republic held the first place in 1958 with 34%; it produced 50% more than the quantity produced by the Netherlands, which held second place (see table 3).

One can have the assurance that the whole production of alkaloids manufactured from poppy plants in the Hungarian People's Republic serves to meet, in part, world morphine needs, because the perfect control system ensures that none of the production is diverted into the illicit traffic.

TABLE 2

World manufacture of crude morphine in 1958 [ 13]

 

Morphine manufacture

Country

Quantity (kg)

Percentage of world total

Total world manufacture
111,854 100
including:
   
United States of America
17,477 15.6
United Kingdom
17,393 15.6
Union of Soviet Socialist Republics .
15,826 14.2
Federal Republic of Germany
13,271 11.9
France
9,300 8.3
Hungarian People's Republic
7,479 6.7
Netherlands
5,594 5.0
Japan
3,566 3.2
Belgium
3,376 3.0
Polish People's Republic
2,743 2.5
Italy
2,354 2.1
Czechoslovak Republic
1,470 1.3
Argentina
1,437 1.3

The quantity of morphine produced depends on a number of factors, the chief one being raw-material supplies; the second is the process of manufacture.

The poppy plant ( Papaver somniferum L.) has been grown for centuries in Hungary and in other central European countries, where the poppy seed is an article of general consumption.

In Hungary, the species of poppy plant more generally grown has a dark-coloured seed, whereas the capsule from the Far Eastern plant contains a light-coloured seed.

The oil content of the seed is 40 to 50%. Poppy-seed oil (known in the trade in French as huile d'œillette) is used for human consumption, but is also much sought as a solvent for pigments in painting because of its quick-drying properties. The extensive use made in Hungary of the poppy seed has rendered necessary the cultivation of the poppy plant on a large scale.

TABLE 3

World manufacture in 1958 of crude morphine from poppy straw [ 13]

 

Manufacture of raw morphine from poppy straw

Country

Quantity (kg)

Percentage of world total

Percentage of national manufacture

Total world manufacture*
22,003 100  
including:
     
Hungarian People's Republic
7,479 34.0 100
Netherlands
5,590 25.4 99.9
Polish People's Republic
2,749 12.35 100
Czechoslovak Republic
1,470 6.7 100
Union of Soviet Socialist Republics
1,016 4.6 6.4
Federal Republic of Germany
26 0.001 0.2

This quantity represents 19.7% of the total world manufacture of crude morphine (mainly from opium and poppy straw).

Until about 1930, poppy straw, a waste product of the cultivation of the poppy plant, was used as all inferior-quality fuel; wherever possible, some use was made of it for cattle bedding.

J. Kabay was the first to draw attention to the possibility of using poppy straw as a raw material for the extraction of alkaloids; until then, as we have seen, this straw was used for purposes of minor importance.

The poppy-seed needs of the Hungarian People's Republic amount to some 5,000 tons annually. About 70% to 80% of this quantity is grown on large holdings, the remainder being grown in vegetable plots, or as a catch crop in intercrop.

For the last thirty years, the area under poppy cultivation has varied in direct relation with price fluctuations of the poppy seed in the world market. The area under cultivation and the volume of poppy straw reached a maximum during the years 1950-1954; they decerased steadily during the subsequent years. During the latter period, there have been years during which the quantity of poppy straw produced, including that from catch crops and vegetable plots, did not even yield the quantity of raw material needed by the alkaloid industry.

TABLE 4

Area under poppy cultivation [ 12]

Period
Area under poppy cultivation *
1930-1934
20,760
1935-1939
13,815
1940-1944
15,255
1950-1949
13,538
1945-1954
19,355
1955-1958
15,101

The "hold" is a Hungarian unit of surface measurement equivalent to 0.57 hectares.

At present, the area under poppy cultivation in individual holdings is greater than that in state undertakings and agricultural co-operatives, but that in state undertakings is growing from year to year, which is a good sign.

TABLE 5

Area under poppy cultivation in state agricultural undertakings

Year
Holds
1955 285
1956 988
1957 1,376
1958 2,470
1959 2,621

In view of the increase in the designed capacity for production of the Alkaloida factory, the increase in the area under cultivation seems justified, particularly since it is desirable to stock poppy straw in years when there is a good harvest, to meet the deficit from bad harvest years. This would ensure the smooth production and export of alkaloids.

Our country has so far exported alkaloids produced from the poppy plant to some thirty different States. In order to meet our export commitments, we have been obliged, from time to time, to import raw material to remedy shortages of poppy straw. We imported poppy straw from Romania in 1952-1954, from Bulgaria in 1954, from Yugoslavia in 1956 and from the USSR in 1959; we have even been obliged, on occasion, to make certain imports of opium from Turkey, thus raising unduly production costs.

If we maintain an adequate area under poppy cultivation, and select for the purpose suitable varieties of the poppy plant, poppy straw supplies to suit the capacity of the Alkaloida chemical factory would seem to be assured.

Since 1951, several experiments have been made for the purpose of selecting an improved variety of poppy plant with a morphine content higher than the 1951 average; among others, the results obtained by Professor S. Särkaùy [ 14] , [ 15] may be mentioned.

In the production of alkaloids from the poppy plant, the question of the process of extraction is second in importance only to that of the poppy-straw supply.

Kabay's original process [ 3] - [ 7] has been improved in the last twenty-five years, but the method used in the production of alkaloids from poppy straw remains basically the same.

The Kabay process is as follows: The poppy capsules (with stalks not more than 10 cm in length) are thrashed, dried and then treated with an extracting liquid which consists of a solution of sodium bisulphite in water. The resultant aqueous extract is concentrated in vacuo using the "counter-current principle" method until it attains a syrupy consistency. The pasty substance thus obtained, which has a morphine content of 1% to 1.2%, is then treated with alcohol or other organic solvent. The solution-which, besides morphine, contains a lesser amount of other extractable material than the aqueous extract-is then distilled, yielding an extract having a morphine content of 2% to 4%. From this mixture of alkaloids in alkaline medium the morphine base can be precipitated by treating the mixture with ammonium sulphate in the presence of benzene. The product will have a morphine content of over 50%, and, by means of repeated precipitation or crystallization, it is possible to obtain from it the pure morphine base and morphine salts or semi-synthetic derivatives.

The process has the serious disadvantage of a very low yield, a disadvantage of Kabay's original method, which has not yet been eliminated; with this process, only part of the morphine in the plant is extracted.

Between 1951 and 1958, the yield at the Alkaloida factory at Tiszavasvári was at the rate of 49% to 54%. There are three possible ways of increasing the yield, and it is proposed to try all three in the factory. One method of raising the coefficient Of extraction is to work at higher temperatures, while continuing to use sodium bisulphite solution as the extracting fluid. The second method of increasing the quantity of morphine extracted is the process involving the use of chalk. In certain countries, these two methods are combined. The third method is to use organic solvents instead of water for the extracting fluid. The most frequently used organic solvent is 2-butanol.

Improvements in the Kabay process are being directed towards simplification and the attainment of the highest possible degree of perfection in the preparation of alkaloids other than morphine, and in the conversion of natural alkaloids into semi-synthetic derivatives.

The Alkaloida factory also produces large quantities of the following natural alkaloids: codeine, noscapine (narcotine), narceine and thebaine.

The following methods have been devised and developed in the Hungarian People's Republic by Prof. R. Bognár, who has published the following processes [ 16] :

Raw morphine is precipitated in the presence of benzene.

Morphine is not very soluble in benzene, which readily dissolves the secondary alkaloids. From this solution in benzene, it is possible to extract codeine, noscapine (narcotine), and thebaine. These three alkaloids can be obtained or separated in two ways.

  1. The alkaloids may be extracted by treating the benzene solution with 0.02N sulphuric acid, the amount used being calculated by titration. If the sulphuric acid solution thus obtained is left in a cool place, the codeine sulphate will crystallize (this process for obtaining natural codeine has been known for a long time in the factory). The remaining benzene solution is treated with an excess of acid, and the acid solution is then combined with the acid mother-liquor of the codeine sulphate; an alkali treatment of the resulting solution will liberate all the alkaloids in an amorphous raw mixture. The mixture is treated with alcohol, and the noscapine base, which is not very soluble in alcohol, will crystallize. Tartaric acid, the amount used being determined by titration, is then added to the mother liquor. The solution is allowed to stand for one or two days, which results in the separation of crystals of thebaine bitartrate; these can be purified by re-crystallization in water, yielding a product from which the pure base can be obtained.

  2. Another method which is used to extract all the alkaloids present in the benzene solution is that of treatment with acid; the acid solution is then washed with caustic soda, thus freeing the alkaloids. From the amorphous mixture of alkaloids thus obtained, the noscapine is then extracted by crystallization from alcohol; the thebaine is then extracted in the form of the bitartrate and, after extraction from the mother liquor, the codeine sulphate, which is not very soluble, is precipitated from the aqueous solution.

The bulk of the natural narceine remains in the aqueous solution of morphine compounds thus obtained. The solution is allowed to rest for a comparatively long time - one or two months - with, as a result, the separation, together with various other substances, of narceine, which can be purified by repeated crystallization. Of course, narceine can be prepared by the well-known method of using noscapine chlor-methylate.

FIGURE 3 The Alkaloida factory in Tiszavasvári

Full size image: 80 kB, FIGURE 3 The Alkaloida factory in Tiszavasvári

It is not economical to extract natural papaverine, as this alkaloid is present only in small quantities and its price is comparatively low; the fact should, however, be mentioned that 50% of the total world needs of papaverine are synthesized in the Hungarian People's Republic (Chinoin chemical and pharmaceutical laboratory, Ujpest). Our country is the world's greatest exporter of papaverine.

The Alkaloida factory is manufacturing increasingly large quantities of hydrogenated derivatives of morphine and codeine [ 16] , but codeine and ethylmorphine remain to this day the most important semisynthetic alkaloids. Table 6 shows the development of the production of these alkaloids.

TABLE 6

Production of codeine and ethylmorphine in Hungary [ 12]

 

Quantity in kg

Year
Codeine pure base
Codeine hydrochloride
Codeine phosphate
Ethylmorphine hydrochloride
1943...
163 879 718 371
1949...
836 898 1,775 1,076
1950...
1,039 775 2,678 356
1951...
967 1,471 3,044 424
1952...
1,759 1,705 3,564 921
1953...
1,284 905 3,591 482
1954...
1,259 1,120 2,121 538
1955...
1,431 1,422 2,296 762
1956...
955 776 1,494 527
1957...
1,347 1,445 4,954 924
1958...
1,193 1,680 4,117 1,017

World production of morphine varies in direct ratio with codeine consumption. Eighty-seven per cent of raw morphine is converted into codeine, and 7% or 8% into ethylmorphine, so that only approximately 5% or 6% is used in the form of morphine. The estimated total world consumption of morphine has steadily decreased; it stood at about 9 tons in 1934, but fell to approximately 5 tons for 1959. On the other hand, the estimated requirements of morphine for conversion have constantly increased; for 1934, the figure was approximately 33 tons, rising to approximately 106 tons for 1959. The increased consumption of codeine and ethylmorphine clearly stems from the increase in world population and the rise in levels of living, combined with the extension of medical and welfare services in many countries where these services did not exist in 1934. However, the quantity of opium available was not sufficient to produce the estimated 111 tons of raw morphine required for 1959 [ 17] . Thus, in 1955, instead of the estimated 105 tons, only about 88 tons of morphine were produced.

It must be remembered that world opium production, which was of the order of 1,295 tons in 1953, fell to 939 tons in 1958, a decrease of 32% [ 13] . Accordingly, there could be no question of decreasing the quantity of 22 tons of morphine produced from poppy straw in 1958 throughout the world (corresponding to the morphine which would be produced by approximately 140 to 160 tons of opium), but on the contrary, to increase it by every legitimate means.

Now it is obvious that the restrictions contemplated in the third draft of the Single Convention on Narcotic Drugs [ 18] would certainly lead to a decrease in this type of production.

Moreover, the decrease in world opium production has led to a reduced level of reserve stocks. Total reserve stocks throughout the world were of the order of 1,744 tons at the end of 1953, but, at the end of 1958, these stocks had dwindled to approximately 840 tons, representing a little less than the total licit world consumption for one year.

For this reason, the Hungarian People's Republic considers that it should make every effort to increase the production and export of alkaloids prepared from poppy straw.

Hungarian exports of alkaloids from the poppy plant started to develop in 1942; in recent years they have varied between 6 and 8 tons annually. In 1958, the Hungarian People's Republic exported 24.6% of the morphine exported throughout the world, being in this respect second only to the Netherlands, which exported 50.8% of the world total. With regard to codeine, our country held third place, with 15.5% of the total exports, the United Kingdom being first with 34%. As to ethylmorphine, our country held second place with 29%, being led by the United Kingdom [ 13] .

Any provisions which might interfere with the freedom to grow the poppy plant for the purpose of producing the edible poppy seed would have the counter-effect of spreading drug addiction. Such provisions would reduce the quantity of alkaloids extracted from the poppy straw; in order to replace the missing quantity, other countries would soon increase their production of opium, which is more difficult to control than poppy straw.

This fact was stressed by the Hungarian delegation at the thirteenth and fourteenth sessions of the United Nations Commission on Narcotic Drugs, when the Commission discussed the third draft of the Single Convention on Narcotic Drugs [ 18] . Noting the objection by several States to the provisions of the draft Single Convention relating to poppy straw and cannabis, the Commission agreed to insert the following general observation as a footnote, after article 30 of the draft Single Convention:

"The countries mentioned below wish to have recorded objections or reservations with respect to all the provisions of the Convention, in so far as they related to poppy straw and to the production of cannabis: Austria, Canada, Czechoslovakia, Federal Republic of Germany, France, Hungary, Italy, Switzerland, the United Kingdom and Yugoslavia."

Throughout the world, great hopes are being placed on the entry into force of the draft convention, which would constitute a great step forward in the struggle against the abuse of narcotic drugs. In this spirit, all governments support the aspirations of those countries which wish to produce alkaloids from the poppy straw, a raw material which, unlike others, cannot be used as a narcotic drug. However, a rigid application of the convention, which would leave no scope for reservations, would prevent the extraction of alkaloids from poppy straw in the event of a shortage of opium. That shortage would, in its turn, lead to that of alkaloids, and result in a great increase in the price of alkaloids in the world market. Therefore, encouragement of the production of morphine from poppy capsules is fully consistent with the spirit of a single convention. A more strict control is possible of that production than of the extraction of morphine from opium.

The control of this process is quite different from that of the manufacture of morphine from opium. This fact was noted as early as 1934 in document O.C.1546 [ 1] reproduced as annex 3 to document O.C.1562 [ 1] of the League of Nations (memorandum submitted by the Secretariat following the visit to Hungary of a member of the Opium Section), which contains the following passage [ 8] :

"From the administrative point of view, the control of poppy straw as such must be regarded as superfluous; it is not dangerous in itself and is unlikely to pass into the illicit traffic. Moreover, its control as raw material actually utilized for manufacture is greatly facilitated for the reasons mentioned above-namely, the impossibility of concealing the raw material, or of clandestine manufacture (see paragraph 11)."

Paragraph 11 of the memorandum states:

"As large quantities of poppy straw are required for manufacture, it is impossible, in practice, to conceal the raw material. As, moreover, manufacture cannot take place in small laboratories, but only in large factory premises, secret manufacture is practically impossible."

It would be in keeping with the whole tenor of the convention to encourage this type of production, which makes possible a much more effective control than the manufacture of morphine from opium. When the poppy seed has been removed by thrashing, the poppy capsules, with their stalks, constitute agricultural waste products; these products become a raw material for the production of alkaloids only if they are gathered and delivered to state purchasing agencies. It is only at the subsequent stage, within the framework of the manufacture of morphine, that rigorous control must be exercised.

Moreover, the designation of the areas in which cultivation of the opium poppy, for the purpose of producing poppy straw, should be permitted, presents insurmountable difficulties. In Hungary, the poppy seed is part of the people's diet, and hundreds of thousands of cultivators grow the poppy plant not only on large plots, but also as a catch crop and even in vegetable plots, making it impossible to introduce a control system like that contemplated in the convention. In practice, it is impossible to require the delivery of the total crop of poppy straw, because cultivators burn part of it and use part as bedding for cattle. Besides, the stalk, apart from the capsule and the 10 cm immediately below it, is not suitable for manufacturing purposes.

As we shall explain, however, an automatic control exists in connexion with the delivery of the poppy.

Well before the commencement of the agricultural year, the purchasing agencies enter into contracts with the state agricultural undertakings, the co-operatives and the cultivators of individual plots, to guarantee the production and delivery of a certain quantity of poppy seed; the delivery of the quantity of poppy seed purchased entails that of a corresponding quantity of straw.

Large purchases are made by the Alkaloida chemical products factory itself, or by the Federation of Medicinal Plant and Silk Cocoon Co-operatives. The Federation of Market Agricultural Products Co-operatives also purchases smaller quantities.

The weight of the poppy straw is approximately equal to that of the poppy seed harvested, although the relationship varies (very slightly in any case) with meteorological conditions, the fertility of the soil and certain other factors. As a general rule, a harvest of approximately 2 quintals of poppy seed is obtained from a cultivated area of 1 Hungarian hold (0.578 ha); on that basis, the quantity of poppy straw obtained is smaller by a few tenths of 1%. For example, in 1960, in Hungary, the quantity of poppy seed harvested per hold in a certain plot of land was of the order of 2.46 quintals (each capsule containing 3.53 g of seed), and the quantity of poppy straw harvested on the same land was 2.24 quintals per hold.

Control operates automatically in the following manner. At the time of the harvest, the purchasing agencies take samples of about 100 poppy capsules, with approximately 10 cm of straw attached, at various points in a given field; the ratio of the weight of seed to that of straw is calculated so as to determine the deliveries of poppy straw, which should correspond to a given quantity of seed. If the quantity of poppy straw delivered is less, the cultivator is required to replace the missing straw. It should also be added that, in Hungary, the poppy plant is grown exclusively for the purpose of obtaining the poppy seed and its oil, and that the sale of the poppy seed is becoming year by year more remunerative under the contracts entered into with the purchasing agencies. It is obvious that, in view of these advantageous conditions, practically the whole of the poppy seed and straw produced reaches the purchasing agencies, allowing for certain quantities of straw, which, as we have already stated, are used by cultivators as cattle bedding, or merely as fuel.

The foregoing procedure provides the equivalent of an absolutely safe control.

As soon as the poppy straw reaches the stores of the above mentioned factory, the average morphine content of the various lots is determined, according to their origin and species. This method makes it possible to determine the yield in alkaloids of the various species of poppy selected.

Although the Hungarian People's Republic is a producer of poppy straw, addiction has not taken roots in the country, thus showing that the production of poppy straw does not of itself lead to any illicit use. Opium, on the other hand, is a narcotic drug par excellence; its morphine content can attain approximately 15% and opium can produce addiction by itself in the absence of any chemical conversion. Poppy straw cannot be considered as a narcotic drug, since it is a very bulky raw material with an average morphine content of barely 0.3% to 0.4%. From the foregoing it will be apparent that any attempt at clandestine manufacture of morphine from poppy straw would be much too dangerous for those wanting to engage in it, because the large volume of raw material to be processed would expose them to detection. No attempts to manufacture morphine illicitly in our country have come to our knowledge.

There is no extraction of alkaloids from the poppy straw outside the Alkaloida factory, the staff of which consists of trustworthy specialists.

The Alkaloida chemical products factory is required to register the following data on its factory journal: quantities of raw material processed; date and mode of transport to the factory; quantity of alkaloids produced; quantity delivered by the factory; date and mode of transport from the factory; losses in manufacture; and quantity of alkaloids used for pharmaceutical preparations.

The factory is required to prepare every three months a general table containing the above data and to submit it to the Hungarian control agency. In addition, the Public Health Office and the police authorities inspect the factory at least once every six months, and sometimes several times a year [ 19] .

In the Hungarian People's Republic, the manufacture of these alkaloids and the control relating to their manufacture are governed by the provisions of decree No. 2222/1934 issued by the Hungarian Prime Minister to implement the International Opium Convention, signed at Geneva on 19 February 1925 (incorporated into Hungarian legislation under No. XXXVII/1930) and the international Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs, signed at Geneva on 13 July 1931 (incorporated into Hungarian legislation under No. XXXVIII/1933).

In any event, there is no problem of addiction in Hungary. The few cases of addiction observed have resulted from prolonged medical treatment of patients in a grave condition.

* * *

The Kabay process of Hungarian origin has given a great impetus to the manufacture of morphine during the past thirty years, not only in our country but also throughout the world; this process is preferred everywhere because it is economical, and because poppy straw cannot give rise to any abuse.

The improvement of technical methods and the increase in the morphine percentage yield will contribute to spread this method, and at the same time bring about a fall in the quantities of morphine manufactured from opium.

The author wishes to express his deep gratitude to Dr. I. Viertes, representative of the Hungarian People's Republic to the United Nations Commission on Narcotic Drugs, for valuable advice kindly given by him in the preparation of this paper; he also thanks the management of the Alkaloida factory and, in particular, Dr. E. Alberovsky, for their kind assistance in preparing this paper. Lastly, the author wishes to thank Professor J. Halmai for supplying him with important information on the life of János Kabay.

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01

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02

WINCKLER, F. L.: Büchners Repertorium für die Pharmazie, 39, 473 (1831).

03

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04

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05

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06

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07

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08

Memorandum concerning the process employed by the Alkaloida Co. Ltd. factory at Büdszentmihaly (Hungary) to extract morphine and other opium alkaloids direct from the dry poppy plant (poppy straw) - Document O.C.1546(1) reproduced as annex 3 to League of Nations document O.C.1562(1), official No. C.256.M.105, 1934.XI.

09

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10

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12

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13

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14

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15

SÁRKÁNY, S., DÁNOS, B. & SÁRKÁNY-KISS, I.: Studien über Heterosiswirkung an Mohnhybriden, Annales Univers. Sci., Budapest. Rol. Eötvös, Sect. Biol., 2, 211 (1959).

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BOGNÁR, R.: A. Magyar Tudományos Akadémia Kémiai Tudományok Osztályának Közleményei, 5, 57 (1954).

17

Drug Supervisory Body. Estimated world requirements of narcotic drugs in 1959. First supplement. Document E/DSB/16/Add.1, p. 18.

18

Single Convention on Narcotic Drugs (third draft). Document E/CN.7/AC.3/9.

19

See GEBÖCZY, M.: Kábitószerek elöállitása, kezelése és forgalma, Budapest, Közgazdasági és Jogi Könyvkiadó, 1959.