Problems connected with the production of opium alkaloids in Poland
An outline of the methods of poppy alkaloids manufacture in Poland
The problems of poppy cultivation and the organization of poppy-heads purchases in Poland
The problem of determination of morphine in the raw material and the problem of morphine balance
Sale of narcotic drugs
Export and import of narcotic drugs
Barbiturates, amphetamines and tranquillizers
Administration of narcotic drugs control
Author: Irena EGIERSZDORFF, Tadeusz DELONG
Pages: 1 to 6
Creation Date: 1967/01/01
It was 160 years ago that F. Serturner obtained morphine from opium, and 20 years later, Tilloy and Winkler found that morphine could be obtained not only from opium but also from mature, empty poppy-heads. The recognition of the medicinal properties of morphine and its derivatives caused a rapid increase of the demand for pharmaceutical preparations containing these substances. However, the increase of the production was based on the readily available and low-priced opium, whose properties had been much earlier recognized and used. The favourable climate in the Asian producing countries, the long tradition of opium cultivation and cheap labour, made it possible to utilize Asian opium as the raw material for the rapidly developing alkaloids manufacturing industry in Europe.
In the last century, in central Europe and in Russia antiquated social and economic systems prevailed, and the area was torn by national strifes. These conditions were not suitable for the industrialization, and a chemical industry did not come into being. The possibility of developing alkaloids production was not even considered. Only in Bulgaria and what is now Yugoslavia, opium production was carried on, due to the favourable climate.
It was only after 1927 that a Hungarian pharmacist, J. Kabay, rediscovered Tilloy's and Winkler's work and developed the first industrial method for the extraction of morphine from poppy-heads. This made it possible for the temperate-climate countries with a poppy-growing tradition to become potential manufacturers of opium alkaloids. Among these countries was Poland, where poppy had been grown for several hundreds of years. On the basis of Polish raw material and Kabay's patent licence, a Polish-Hungarian company "Motor-Alkaloida" started in 1934 the production of morphine and its derivatives: codeine, ethylmorphine and dihydrocodeine. The extraction of alkaloids from poppy-heads was localized in a factory built in Kutno, and the production of morphine and its derivatives was carried out in Warsaw. The scale of this work did not exceed 400 tons of poppy-heads a year.
The introduction of alkaloid manufacture to Poland is undoubtedly a considerable achievement of the "Motor-Alkaloida" company. During the war years 1939-1944, both factories were used by the Germans, and after the destruction of the Warsaw factory during the uprising, the alkaloid extracts obtained in the Kutno factory were sent to Germany for further processing.
After the liberation of Poland in 1945, the Plenipotentiary of the Polish Government, A. Zielinski, organized a team for rebuilding the alkaloids manufacturing industry. The factory in Kutno was reorganized and re-equipped with machinery that was salvaged from the Warsaw factory and elsewhere. Production started in April 1946, and in 1947 its volume reached 700 tons of processed poppy-heads. The credit for this work is due to a team of new people, since out of the prewar staff only five people had remained - four labourers and one technician. In spite of these difficulties, production grew rapidly. In 1953, the processing of poppy-heads reached 1 050.5 tons. In that year 1 090 kg of codeine and 141 kg of morphine hydrochloride were produced, and the production of dihydrocodeine tartrate was started.
Today, Kutno Pharmaceutical Works "Polfa" is a modem factory with a numerous scientific and technical staff. It produces a wide assortment of alkaloids, such as technical morphine, morphine hydrochloride, codeine base, codeine phosphate, codeine sulphate, codeine hydrochloride, ethylmorphine, dihydrocodeine tartrate. Since 1953, it exports a considerable part of its products.
Since 1955, the manufacture of morphine in Poland is based on Polish patent No. 39546 cl. 12 p. 14.
Finely divided poppy-heads are extracted in a series of ten concrete tanks at variable pH, the medium is acid (pH = 5-6) at the beginning of the series, and alkaline (pH = 11-12) at the end. The medium is made alkaline by adding calcium hydroxide or sodium hydroxide. Sodium bisulfite is added to the acid medium in order to prevent the oxidation of morphine. Morphine that is not extracted in the acid medium is extracted in the alkaline medium. The slightly acid extract from the first part of the series of tanks is evaporated in vacuum evaporators until its consistency becomes that of a thick paste. From this concentrate morphine is extracted with ethanol-benzene mixture at pH 11-12. The organic extract is acidified, evaporated, and made alkaline to pH 9. From the mixture thus obtained, morphine is removed by crystallization. The process is continuous, the extraction time is about 24 hours, the density of the aqueous extract d = 1035, the evaporation is carried out at 55-60 °C. The efficiency of the extraction is about 90 %. It is represented and compared with Kabay's and La Roche's methods on the following graph.
Curve A characterizes the extraction of morphine by Kabay's method. The extraction is relatively slow, and the amount of unextracted morphine is about 40-45 % of the total. The extension of the extraction time by increasing the number of tanks in the series has no effect.
Curve B characterizes the extraction of morphine by La Roche's method. The extraction from the strongly alkaline medium is rapid, and the amount of unextracted morphine does not exceed 10% of the total.
Curve C characterizes the extraction of morphine by the acid-alkaline media method. It gives results similar to those obtained by La Roche's method. The extraction takes place in two steps; the upper part of the curve represents the extraction in the acid medium (pH 5-6), and the remaining part in the alkaline medium.
The above data indicate that in the extraction by Kabay's method, in the weakly acid medium only the part of morphine that is readily removed from poppy- heads is extracted, while the part of morphine that is probably present as compounds sparingly soluble in acids is left behind. The change of pH causes the decomposition of these compounds and facilitates the extraction of the remaining part of morphine.
The synthesis of codeine is carried out in xylene by the known method. The methylating agent is trimethylphenylammonium chloride. Codeine thus obtained is extracted with dilute sulfuric acid and then it is purified.
Since various pharmacopoeiae give different requirements regarding codeine, the methods of purification and standardization of this drug are the measure of the standard of its manufacturer. Kutno Pharmaceutical Works "Polfa" manufacture codeine, to the standards of the following pharmacopoeiae: Pharmacopea Polonica IV, Pharmacopea Nordica, Pharmacopea Internationalis, Pharmacopea Danica 48, Dutsche Arzenaibuch 7, Pharmacopoeia of the United States XVII, Pharmacopoeia Gallica VIII, and British Pharmacopoeia 63.
Poland is situated in Central Europe, and hence it has a moderate climate influenced by the North Atlantic. The climate is very changeable. It is characterized by relatively mild winters and fairly cool summers, westerly (moist) winds of moderate strength, and a high level of rainfall.
It is an agricultural country with rapidly developing industry. Although it has a long agricultural tradition, until recent years the agricultural methods used were backward, and it is only now that a rapid modernization is taking place. Poppy has been grown in Poland for a long time, the most important varieties being: Pulawy white, Pulawy blue, and KM blue. They are characterized by a high fat and protein content, uniformity of grain and satisfactory colour. For this reason Poland is one of the most important poppy-seed exporters. However, owing to the climatic conditions the morphine content of poppy-heads is not high, and largely depends on weather and the region in which the poppies are grown. For example in the year 1961-2 the mean morphine content of poppy-heads was 0.15-0.16%, and varied from 0.12 to 0.2%, while in the year 1963/4 the average was 0.2-0.24%, and the lowest content was 0.16 %
The principal poppy-growing provinces of Poland are Bydgoszcz, Poznań, Gdańsk, Rzeszów and Łódź, which during the period 1961-1966 provided 73 % of the total supply of poppy-heads. The provinces of Bydgoszez and Poznań provided 49 % of the total supply. There is a possibility of a considerable increase of the supply of the raw material for alkaloids production, but the extension of poppy cultivation and the increase of the supply of poppy-heads depend largely on the demand for poppy-seeds. For this reason the supply of poppyheads is different in different years.
The purchase of poppy-seeds and poppy-heads in Poland is organized by the Corporation of Agricultural Co-operatives "Samopomoc Chlopska", a powerful trading corporation, which has its agencies in every Polish country district. There are over 3 500 such agencies, which send poppy-heads directly to Kutno Pharmaceutical Works "Polfa ".
In the factory a special office controls the purchase of poppy-heads, which starts in September and ends in May. Immediately after delivery the poppy-heads, which consist of the capsule and a piece of stem 7 cm long, are tested for the presence of mechanical impurities and moisture content. If the moisture content exceeds 15% and mechanical impurities content 5%, the material is purchased at a lower price. The morphine content, which is determined in the factory's laboratory, does not affect the price, since the grower cannot be responsible for the morphine content, and the supply of poppy-heads is lower than the demand.
From the factory's point of view the raising of morphine content in poppy-heads is the most important problem, and in spite of the climatic conditions this can be done. The results of recently conducted statistical investigation of rationalization of poppy growing should make it possible to select regions with optimal climatic and soil conditions. Professor Moldenhawer developed KM-blue poppy, having a high morphine content, ranging from 0.30 to 0.40%. Although this variety was not accepted by a large number of growers because of such undesirable properties as a small capsule and ramified stem, the results of the experiment are encouraging. It is probable that a rapid solution of this problem will result from the selection of seeds of commonly used poppy varieties, suitable choice of soil, fertilizers and cultivation methods. These studies are time-consuming, and their organization is difficult, but we are convinced that they will help to improve the quality of our raw material.
The determination of a pharmacologically active substance in a vegetable material always presents many difficulties. Although we have now modern physical and chemical methods, such as chromatography, polarography, spectrophotometry, etc., the problem can always be reduced to the development of a simple but quantitative method of isolation of the active substance from such complex mixture as a vegetable organism.
The determination of morphine in poppy-heads can be carried out by a number of methods, such as the Hungarian alkalimetric method, Pfeifer's combination of chromatography and colorimetry, or the "calcium" method described in USP XVII. The scatter of results obtained by these methods is relatively large, since the principal problem lies in the quantitative extraction of morphine and accompanying alkaloids, which is by no means a simple matter. After many years of experience, we have found that the most suitable is the Pfeifer method, which is rapid and more easily reproducible than the other methods.
During the period 1964-1965, a team of analysts from Kutno Pharmaceutical Works, directed by Mrs. Lucja Pilch, M.Sc., elaborated a variant of the Pfeifer's method, by adapting it to polarographic determinations. In this method the scatter of results does not exceed 0.5%. It can be used in all stages of morphine production, such as aqueous extracts, condensed extracts, organic extracts, and mother liquors after the crystallization. The principal advantage of this method is the possibility of carrying out a series of determinations in a short time. In this method one analysis takes on the average 1 hour, while in Pfeifer's method it takes 2-2 hours. In our method morphine is quantitatively extracted from the sample by means of acidified alumina, which makes it possible to prepare solutions sufficiently pure and free from ballast substances for direct polarographic determinations. The amount of morphine in the sample by percentage is calculated from the difference of heights of the polarographic waves of the examined solution and standard solution. Polish analysts have thus developed a valuable method for the determination of morphine in production conditions.
From the point of view of the manufacturer and the narcotic drugs controller the principal problem is the residue of morphine unextracted during the technological processing from raw material to final product. The attempts to solve this problem have been unsuccessful so far for the following reasons:
it is nearly impossible to take a representative sample from the large mass of raw material;
the morphine content of batches of the raw material supplied by individual growers varies according to the type of soil, fertilizer, sowing and harvesting time, method of cultivation, etc.;
the standard analytical errors;
the changes in the technological process resulting from the non-uniform character of the raw material.
4 Bulletin on Narcotics, Vol. XIX, No. 3, July-September 1967It is very difficult to safeguard narcotic drugs in a factory, and for this reason Kutno Pharmaceutical Works use various security measures. Statistical data on the production and utilization of the drugs are used for checking and preventing any unjustified losses. The data are collected over a number of years, and are used for both technological control and drug safety control. For these purposes the following average amounts are calculated:
the amount of the raw material used in the preparation of 1 kg of poppy straw concentrate;
the amount of the concentrate used in the preparation of 1 kg of codeine and ethylmorphine;
the amount of codeine used in the preparation of 1 kg of codeine phosphate and dihydrocodeine.
In addition, the whole production process, from the poppy straw through the intermediate substances until the finished drugs, is shown in special control books. In these books each production batch is entered under its number, which makes it possible to check the calculations for every batch separately. The books are numbered, tied with string and sealed by the Department of Health and Social Welfare of the Provincial National Council, which supervises the factory. The entries in the books are made during the production.
Another form of safeguarding the narcotic drugs is isolation and guarding the premises in which morphine and other alkaloids are produced. The entry to the factory grounds is reserved for bearers of passes that must be shown to the guards at the gate. The poppy straw is kept on the factory grounds in two separate stores. The production of narcotic drugs is carried out in an isolated building, where only authorized staff may enter.
Unlike the manufacture of morphine from opium, during its extraction from poppy straw, the raw material and the first intermediate products do not require a strict control, since the volume of the material is very large, and the morphine content is very low. Extraction of morphine from such material requires apparatus that cannot be assembled even in a chemical laboratory. Therefore not all the stages of production require the same degree of control. Special precautions are taken in the premises where the alkaloids complex is precipitated, dried and weighed. These premises can be safely locked, and after the working hours they are officially locked and sealed. The right of being present in these premises is reserved to workers directly employed in morphine production, certain members of the staff, and technical control employees. The stores are situated on the first floor and have reinforced doors and windows, which are locked before nightfall.
The narcotic drugs are packed in double plastic sacks. The inner sack bears a seal and a label stating the name and the batch number of the preparation, its weight, alkaloids content by percentage, and moisture content. The outer sack is heat sealed. If the narcotic is not to be further processed, the sacks are placed in metal containers.
The factory employs a controller, whose duty is to ensure that the narcotic drugs control regulations and the related orders of the factory management are observed by employees. The controller is present during the weighing of the poppy straw concentrate, he checks the entries in the narcotic drugs control books, checks the stores, and is responsible for the tally of production figures with the average drug yields.
The determinations of morphine and other alkaloids are carried out in a separate analytical laboratory, employing a highly qualified staff. The laboratory keeps detailed records of the analyses.
In addition to the factory manufacturing narcotic drugs there are 7 other factories in Poland where drugs are used for making ampoules and tablets, and for the preparation of mixtures containing narcotics, such as morphine, oxycodone, codeine, and opium. The amounts of codeine and opium in these drugs are such that they are listed in Schedule III, and therefore their turnover is less severely supervised than that of other narcotic drugs. Opium is also used in galenic preparations, such as tinctures and extracts. All the above factories keep control books where the supply and the expenditure of narcotic drugs are recorded. For each factory and for each manufactured drug, the permissible limits of natural waste, occurring during the production processes, have been determined.
The sale of narcotic drugs is strictly controlled. The wholesale trade is reserved to drug stores which have obtained a licence from the competent authorities. The conditions of the licence state that the store must employ a qualified pharmacist, who is responsible for the narcotic drugs. The drugs must be kept in separate premises having barred windows and iron-covered doors with very strong locks. The stores are State owned, and are technically a part of the provincial drug stores administration, or provincial veterinary suppliers organisation "Centrowet ". The concentration of narcotic drugs wholesale trade in the hands of the State is a vital element of the security system. The wholesalers can sell narcotic drugs only to chemist's shops, hospitals, and Health Service establishments that have the permission of the Department of Health and Social Welfare of the Provincial National Council. Each drug store keeps records of purchase and sale of narcotic drugs. The right of sale over the counter is reserved to chemist's shops, (which in Poland are a part of the Social Health Service, and are governed by the provincial chemist's shops organisation), or to hospitals and sanatoria. Retail distribution is only allowed against a proper prescription
Physicians issuing prescriptions for narcotic drugs must enter their name and address, as well as the name and address of the patient. The right to sign such prescriptions is reserved to physicians, dentists and veterinary surgeons. The chemist's shops keep strict records of purchase and sale of narcotic drugs. The prescriptions and the purchase certificates must be kept for three years.
According to statistical data for 1965, about 71 % of the population of Poland is entitled to the benefit of free medical care. Consequently, the network of social health service establishments is very dense. According to the type of services some of the establishments must have a licence for possessing narcotic drugs from the Department of Health and Social Welfare of the Provincial National Council, whereas other establishments can possess these drugs on the basis of existing laws. The licence states the kinds of drugs that can be used in the licensed establishments. The stock of narcotic drugs in such establishments cannot exceed the amount estimated for one month, except in emergency stations, where the reserve stock can equal quantities required in three months. Maternity rooms and clinics in villages situated at a considerable distance from chemist's shops can possess two ampoules of pethidine, which can be administered by the midwife in strictly-defined cases. The midwives obtain prescriptions for pethidine from physicians responsible for maternity rooms and clinics. Since Social Health Service Establishments have no chemist's shops and do not employ pharmacists, the control of narcotic drugs and the right to use them in such establishments is the duty of a physician. All the establishments using narcotic drugs keep records of their purchase and use. The purchase, storing and use of narcotic drugs on ships are subject to special regulations. All the above security measures regarding the possession, purchase, sale, and registration do not apply to narcotic drugs classed in Schedule II and Schedule III.
Export and import of narcotic drugs are controlled by Polish laws, which are based on international conventions. The importers must obtain a certificate from competent authorities, and the exporters must obtain a special permission, which is given on the basis of an import certificate issued by the authorities of the importing country.
The Ministry of Foreign Trade has created a special organisation for the import and export of chemicals called "Ciech ". In "Ciech" there is the Pharmaceutical Products Office, which is responsible for international trade in narcotic drugs. The principal narcotic drugs imported are: pethidine, oxycodone, hydrocodone, cocaine, dextromoramide and levorphanol. The principal drugs exported are codeine and concentrate of poppy straw; export has reached considerable proportions since 1953. Codeine is exported as pure codeine, codeine phosphate, or codeine hydrochloride. Morphine hydrochloride is not exported. The morphine content of the concentrate of poppy straw is 48-50 %. The volume of the export depends on many factors, and therefore it varies in different years. The principal factors affecting the export trade are: the demand on the world's markets, fluctuation of prices, and Polish production possibilities, which depend on the harvest and morphine content of poppy straw.
The sale of codeine and concentrate of poppy straw during the last six years, as well as the directions of export, are shown in tables 1, 2 and 3.
|
1960 |
1961 |
1962 |
1963 |
1964 |
1965 |
|
|---|---|---|---|---|---|---|
|
Codeine
|
1 021 | 964 | 2 680 | 1 267 | 2 473 | 2 665 |
|
Concentrate of poppy straw
|
-
|
-
|
-
|
-
|
1 800 | 3 240 |
|
1963 |
1964 |
1965 |
|
|---|---|---|---|
|
Europe
|
540 | 902 | 1 281 |
|
Australia
|
179 | 1 021 | 708 |
|
Africa
|
116 | 7 | 18 |
|
Asia
|
432 | 494 | 651 |
|
America
|
-
|
49 | 7 |
|
1964 |
1965 |
|
|---|---|---|
|
Australia
|
100 |
-
|
|
America
|
120 |
-
|
|
Europe
|
1 580 | 3 240 |
The official drugs list in Poland includes five pharmaceutical preparations from the barbiturates group, namely: phenobarbital, cyclobarbital, barbital, methylphenobarbital, and allobarbital. These substances are used either alone, or in a combination with other drugs.
The use of barbiturates is shown in Table 4.
|
1959 |
1960 |
1961 |
1962 |
1963 |
1964 |
|
|---|---|---|---|---|---|---|
|
Phenobarbital (Luminal)
|
2694 | 2447 | 2340 | 2254 | 2028 | 1944 |
|
Cyclobarbital (Phanodorm)
|
1586 | 1752 | 1938 | 2006 | 1926 | 2077 |
|
Barbital (Veronal) .
|
100 | 142 | 153 | 146 | 176 | 200 |
|
Methylphenobarbital (Prominal)
|
197 | 255 | 189 | 195 | 201 | 198 |
|
Allobarbital (Dial)
|
8 | 13 | 11 | 9 | 9 | 9 |
From 1959, when the use of tranquillizers reached considerable proportions, the use of phenobarbital decreased. The use of methylphenobarbital and allobarbital remained unchanged, whereas the demand for cyclobarbital and barbital has a tendency to increase, probably because of the sleep-inducing and pain-killing properties of these substances. The home demand for barbiturates is fully satisfied by Polish production which takes place in a single State-owned factory.
As regards substances from the amphetamine group, only amphetamine and phenmetrazine are to some extent used in Poland. Amphetamines are classed by Polish law as narcotic drugs, and therefore in the internal trade they are treated as such.
Of the tranquillizers, the most important in Poland are: hydroxyzine (Atarax), Chlorpromazine (Fenactil), Meprobamate, Reserpine, Thioridazine and Perezin. These substances are often used in combination with other drugs. Other substances of this type are used invery small amounts, for research purposes or in special clinics. The demand for these drugs is largely met by import, and it has shown a steady tendency to increase.
The use of these substances is indicated in Table 5.
Barbiturates and tranquillizers, and also composite drugs containing them, can be sold in chemists' shops on doctors' prescriptions only.
|
1959 |
1960 |
1961 |
1962 |
1963 |
1964 |
|
|---|---|---|---|---|---|---|
|
(Amphetamine Psychedrin)
|
2.5 | 1.8 | 1.9 | 1.7 | 1.3 | 1.2 |
|
Phenmetrazine
|
-
|
-
|
1.1 | 64 | 90 | 105 |
|
Chlorpromazine (Fenactil)
|
860 | 1 434 | 1 772 | 2 023 | 2 457 | 2 488 |
|
Hydroxyzine (Atarax)
|
1 | 5 | 99 | 290 | 348 | 387 |
|
Perazine (Pernazinum)
|
-
|
-
|
28.6 | 106.9 | 115.1 | 164.7 |
|
Thioridazine (Melleril)
|
-
|
16 | 35 | 40 | 100 | 153 |
|
Reserpine
|
5.9 | 9.2 | 9.5 | 10.4 | 10.5 | 12 |
The execution of regulations regarding narcotic drugs is entrusted to the Ministry of Health and Social Welfare. The direct control is carried out by the Department of Health of Provincial National Council, which appoints pharmaceutical inspectors. The inspectors must have a university degree in pharmacy. They carry out inspections in factories, stores, chemist's shops and Health Service establishments that have the right to possess narcotic drugs. They check the conditions of storing and safeguarding narcotic drugs, verify the agreement between the entries in the control books and documents regarding the purchase and utilization of these drugs, and compare the natural waste of narcotic drugs with the permissible limits.
