Recovery, separation and purification of narcotine and papaverine from Indian opium

Sections

ABSTRACT
Introduction
Experimental
Results and discussion
Conclusion
Acknowledgements

Details

Author: V. S. RAMANATHAN , P. CHANDRA
Pages: 55 to 63
Creation Date: 1981/01/01

Recovery, separation and purification of narcotine and papaverine from Indian opium

V. S. RAMANATHAN *
Central Revenues Control Laboratory, New Delhi, India P, CHANDRA
Government Opium and Alkaloid Works. Neemuch. Madhya Pradesh, India

ABSTRACT

This paper describes a chemical method for the recovery and separation of narcotine and papaverine on an industrial scale from a crude mixture of these alkaloids as well as their individual purification to meet pharma copoeial standards. A process for the removal of traces of cryptopine from papaverine using aluminium oxide is also discussed.

Introduction

Narcotine is the second most abundant alkaloid in opium [ 1] [ 2] [ 3] [ 4] . Opium from Madhya Pradesh, India, contains, on average, 7 per cent narcotine [ 5] . Narcotine is a non-narcotic and non-toxic alkaloid with no ill effects on blood pressure and respiration. It is used as an antitussive drug, particularly in wet cough, and is included in the British pharmacopoeia (BP), British Pharmaceutical Codex (B.P.C.) and Japanese Pharmacopoeia (J.P.) under the name of noscapine [ 6] [ 7] [ 8] [ 9] [ 10] [ 11] [ 12] . Cotarnine chloride B.P.C. 1934, State Pharmacopoeia of the Union of Soviet Socialist Republics (USSph), a styptic, and tritoqualine, an antihistamine, are synthetically prepared from narcotine [ 13] [ 14] [ 15] . Narcotine has no analgesic action and does not induce sleep or produce constipation. It is further used in the treatment of bronchial asthma and pulmonary emphysema. Noscapine B.P. and noscapine hydrochloride, United States National Formulary (U.S.N.F. XII) and J.P. are administered in the form of lozenges, linctus, syrup, tablets and resin-bound products.

Papaverine and papaverine hydrochloride and sulphate are described in the pharmacopoeiae of many countries. Papaverine occurs in opium collected in Madhya Pradesh, India [ 16] . Papaverine is a smooth-muscle relaxant. It is used as an antispasmodic in the treatment of intestinal, ureteric and biliary colic and of dysmenorrhoea. Being also a vasodilator, it is used to relieve pain in coronary and cerebral thrombosis; as a bronchodilator spray to relieve asthma and for the prevention of post-operative pulmonary collapse. Papaverine and narcotine hydrochloride are required in the production of Papaveretum B.P.C. [ 17] (pantopon and omnopon), which is used to relieve severe or prolonged labour pain. Papaverine from natural sources is supplemented by synthetic papaverine [ 18] [ 19] . India requires 1,350 kg per year of this alkaloid for medical purposes. The entire amount is presently imported.

*Present address: 25/27 East Patel Nagar. New Delhi-110008. lndia.

Narcotine and papaverine are therefore important opium alkaloids, used for the alleviation of human suffering.

In the Government Opium and Alkaloid Works, Neemuch, India, where opium collected from Madhya Pradesh (Malwa Opium) is used for the production of opium alkaloids, narcotine and papaverine are extracted as a crude mixture from the opium broth. No processes were available in the factory for the separation of narcotine and papaverine from this crude mixture or for their individual purification to meet pharmacopoeial specifications.

The purpose of the work described in this paper was to develop these processes. The literature mentions that narcotine is soluble in hot alkali [ 1] . Therefore, using a sodium hydroxide solution, the optimum conditions required for the formation of sodium narcotinate were investigated. The parameters of the reaction were studied in the laboratory and scaled up in the plant for industrial production of narcotine B.P.

papaverine, insoluble in alkaline solution, was filtered off and purified first as the oxalate. Technical grade papaverine of natural origin can contain up to 4 per cent of cryptopine [ 20] , which when present even at a 0.2 per cent level gives a purple colour with cold sulphuric acid [ 21] . The literature on opium alkaloids mentions the use of aluminium oxide [22-26]. Details of the experiments carried out in this study in order to remove traces of cryptopine in papaverine, using aluminium oxide, are described below.

Experimental

Crude narcotine and papaverine mixture

The organic solution obtained from the opium broth and containing narcotine and papaverine together with other weakly basic alkaloids was stirred three times with 5% sulphuric acid. The combined acid extracts were made alkaline to pH 10 with 50% sodium hydroxide, under agitation, when the crude mixture of narcotine and papaverine precipitated out. The precipitate was filtered, washed with water and dried, to yield a brown crystalline product melting in the range 147- 169°C. An amount of 220 kg of opium at vat consistency yielded, on average, 13 kg of the dry crude mixture of narcotine and papaverine.

The narcotine and papaverine content in the crude alkaloid mixture was estimated following the method given for Papaveretum B.P.C. [ 17] . The narcotine percentage was also determined by another published method [5, 30]. The results are reported in table I.

Table 1

Narcotine and papaverine content in five batches of crude alkaloid

Batch

Weight of crude alkaloid mixture (kg)

Residue on ignition(%)

Narcotine on dry matter(%)

Papaverine on dry matter(%)

1 58.20 3.84 57.24 37.84
2 44.10 3.80 56.95 38.15
3 30.80 3.22 70.10 22.45
4 32.95 3.45 62.33 33.13
5 40.15 2.30 89.39 7.30

Technical grade mixture of narcotine and papaverine

An amount of 200 g of the crude narcotine and papaverine mixture was dissolved in hot toluene, decolourized over activated carbon and filtered. The volume of the filtrate was reduced to one third by distillation and the alkaloids were allowed to crystallize. They were then filtered, washed with cold toluene and dried, yielding 170 g of an off-white crystalline product melting between 162 and 169°C.

Using the same procedure on an industrial scale, 50 kg of the dry crude narcotine and papaverine mixture yielded, upon crystallization from toluene, 35 kg of technical grade off-white crystalline material. The content of the two alkaloids in the mixture thus obtained are indicated in table 2.

Table 2

Narcotine and papaverine content in several batches of technical grade alkaloid

Batch

Weight of alkaloid mixture (kg)

Melting range (°)

Residue on ignition(%)

Narcotine on dry matter(%)

Papaverine on dry matter(%)

1 14.90 165-168 0.64 90.10 9.00
2 23.55 165-167 0.85 89.13 10.06
3 18.65 162-164 0.75 81.29 18.00
4 44.15 160-163 0.95 79.08 20.00

Separation of narcotine from papaverine

The separation of narcotine from papaverine in the technical grade mixture of the two alkaloids was extensively investigated. However, on the basis of the results obtained with many of the methods studied, they could not be recommended for industrial application.

The use of sodium hydroxide for the separation of narcotine from papaverine was therefore thoroughly investigated. In a series of experiments, such parameters as the strength of the aqueous sodium hydroxide solution, the temperature at which it was to be heated with the alkaloid mixture, the heating time required to make the narcotine go into solution, and the degree of dilution of the reaction mixture with water were studied. Also investigated were the optimum conditions for the opening and closing of the lactone ring and precipitation of narcotine using sodium hydroxide or ammonium salt. The aqueous sodium hydroxide solutions used were at concentrations of 50, 40, 30, 20 and 15 g per 100 ml and the temperatures studied were 95, 90, 85, 80 and 75°C. Heating of the mixed alkaline-alkaloid solution was carried out for 2, 1.5, 1 and 0.5 h. In addition, consideration was given to the simplicity of the process and economy in respect of use of chemicals and energy. Thus the optimum conditions required for the recovery of the two alkaloids in high yield were arrived at in the laboratory experiment described below.

A mixture of 500 g of technical grade narcotine-papaverine in l.5 l of sodium hydroxide solution (15 g per 100 ml) was heated at 85°C for I h under vigorous mechanical stirring. The reaction mixture was then diluted with l.5 l of water, heated twice to 85°C and stirred each time for 10 min. Cooled to 40°C, the insoluble papaverine was filtered and washed twice with 100 ml of water each time. The clear filtrate was acidified with 50% sulphuric acid to pH 3, heated to 90°C for 10 min and allowed to cool. Sodium hydroxide solution (10 g-per 100 ml) was added slowly under stirring to raise the pH to 10 when narcotine precipitated out. The yield was 315 g of white, crystalline narcotine, m.p. 170-171°C, and 165 g of papaverine, m.p. 140-141°C. The filtrate, deep yellow in colour, was discarded.

IndustriaI-scale separation of narcotine from papaverine

An amount of 75 kg of technical grade narcotine-papaverine was placed in a digester of about 700 l capacity, and 350 l of sodium hydroxide solution (15 g per 100 ml) were added under vigorous stirring. The reaction mixture was heated at 80-85°C for 1.5 h, filtered under a vacuum and washed with 50 l of water. The clear filtrate was returned to the digester, mixed with 300 l water and after its pH was adjusted to 3 with the addition of 40% sulphuric acid, the solution was heated to 90°C. It was then cooled, made alkaline with sodium hydroxide (40 g per 100 ml), when narcotine separated as a white solid. This was filtered, washed with water till free from alkali and dried to yield 60 kg of narcotine, almost white in colour, and 10 kg of crude papaverine. The analytical results are reported in table 3.

Table 3

Narcotine content in several batches of narcotine separated from papaverine m the technical grade mixture

Batch

Weight of narcotine separated (kg)

Loss on drying at 105°(%)

Melting range(°C)

Residue on ignition(%)

Narcotine on dry matter(%)

1 90.20 0.48 171-173 0.20 98.00
2 50.00 0.18 172-174 0.18 98.50
3 91.65 0.52 172-173 0.19 98.20

Noscapine B.P.

An amount of 40 kg of papaverine-free narcotine was dissolved in 200 l of hot toluene. This was gently agitated with 50 l of a 2% sodium hydroxide solution for 15 min, allowed to stand for 30 min, after which the aqueous layer was drawn out. The toluene fraction was then washed with l00 l of water to remove the adhering sodium hydroxide. This procedure helped to remove the phenolic alkaloids, resins and colouring matter present in the toluene solution. This solution was then heated in the presence of 500 g activated carbon and filtered. The filtrate was distilled to less than half the volume. The crystallized narcotine was centrifuged, using a terylene filter cloth in the basket. The material was then washed in the machine with 4l each of cold toluene and cold 95% alcohol. Narcotine thus obtained was a white crystalline powder which satisfied the specifications in the pharmacopoeia. Yield: 32.0 kg (first crop).

Crude papaverine

The insoluble residue recovered from 5 batches of technical grade narcotine treated with sodium hydroxide solution was combined and digested once again with 15% sodium hydroxide to remove the narcotine present in it. The crude papaverine thus purified and recovered was a grey solid. Analyses of this product are given in table 4.

Table 4

Analytical data on several batches of crude papaverine

Batch

Weight of crude papaverine(kg)

Melting range(°C)

Loss on drying at 105°(%)

Residue on ignition on dry matter(%)

Papaverine on dry matter(%)

Narcotine on dry matter(%)

1 18.0 138-142 49.92 0.90 65.61 9.08
2 5.2 138-143 12.19 0.95 76.69 6.33
3 7.6 140-142 8.09 0.72 76.02 0.50

Removal of last traces of narcotine from crude papaverine

To remove residual narcotine from the crude papaverine, 350 g sodium hydroxide were added to 600 g of grey coloured papaverine in 1.51 of water, and the mixture was digested for 2 h at 80-85°C under mechanical stirring, after which it was filtered. The alkaline filtrate, however, yielded no narcotine. The insoluble residue was steeped for 30 min under stirring in 1.51 of water to which 10% sulphuric acid was added to pH 4 and filtered. The acid-insoluble wet residue weighed 250 g (34 per cent moisture and 0.6 per cent ash). The filtrate was diluted with 500 ml water, 25 g sodium chloride was added to the solution under stirring and the pH was raised to near 5. This procedure caused resins, gums and impurities to precipitate out. Filtered, washed and dried, the precipitate weighed 21 g. The filtrate was made alkaline to pH 10 and the papaverine obtained therefrom was filtered, washed with water and dried to yield 342. l g of a dull white powder, m.p. 142-144°C. With cold sulphuric acid at 15°C, this powder gave a brilliant purple colour, indicating the presence of cryptopine. By thin-layer chromatography (TLC), the powder was found to consist mainly of papaverine with traces of cryptopine.

Purification of papaverine as oxalate

A saturated aqueous solution of oxalic acid was added to 260 g papaverine in 500 ml water under stirring and the mixture was heated to 90°C. Papaverine first dissolved in the acid solution, but at pH 2 separated out as the acid oxalate. This was heated on a steam bath for an hour, allowed to stand overnight, filtered and washed with 200 ml of cold water and 50 ml of cold alcohol (95%). The oxalate, a white crystalline solid, m.p. 198-199°C, was once again steeped in 500 ml water, heated to 96°C on a steam bath for an hour and allowed to cool. The acid oxalate, whose solubility in water is approximately l in 400, was filtered and suspended in 500 ml water. The mixture was made alkaline with sodium hydroxide, when papaverine precipitated out. The precipitate was filtered, washed with water and dried to yield 245 g of a white crystalline solid, m.p. 143- 145°C. The papaverine passed all the tests laid down in the Indian Pharmacopoeia (I.P.) except the limit test for cryptopine. The filtrate and washings yielded 5 g of a brown-coloured product.

Cryptopine-free papaverine

Experiments were carried out in which the effectiveness of different types of aluminium oxide (Al2O3) for the removal of traces of cryptopine from papaverine were evaluated. The types of Al2O3 evaluated included active neutral, active basic, active acidic, basic, anhydrous extra pure alumina (gamma), and acidic for TLC.

The results obtained from these experiments showed that only the active neutral (Glaxo and Sarabhai) and active acidic (pH 5.2 Sarabhai) types produced cryptopine-free papaverine passing the limit tests for cryptopine given in I.P. and U.S.N.F. XIV. Papaverine purified using the other types of Al2O3 did not pass these tests. The papaverine purification experiments involving the use of the active neutral and active acidic types are describedbelow.

  1. An amount of 50 g of active neutral Al2O3 (Glaxo, BDH) was heated in an air oven at 120°C for 2 h, cooled in a dessicator and transferred into a chromatographic column (glass, 800 mm long, 18 mm internal diameter) fitted with a porous sintered glass disc [ 31] . Reagent grade chloroform (50 ml) was added to the Al2O3 and allowed to percolate. It took 10 min for the chloroform to wet the entire column. More chloroform (25 ml) was then allowed to pass through the column until the liquid reached 1 cm above the surface of the Al2O3 in the column. A solution containing 5 g of papaverine in 80 ml chloroform was transferred into the Al2O3 column and eluted at the rate of 120 drops per minute. Four additional batches involving 5 g of papaverine in 80 ml chloroform each time were eluted through the same column at the same rate, for a total of 25 g of papaverine passing through the column. The column was then eluted three times with 10 ml, 10 ml and 15 ml chloroform. The chloroform was evaporated to dryness, yielding 24 g of purified papaverine. This was recrystallized from alcohol (95%) to yield 21.5 g of white crystalline powder, meeting all the specifications of Papaverine l.P. [ 32] . It also passed the limit test for cryptopine in U.S.N.F. XIV [ 27] and the Europea Pharmacopoeia [ 29]

  2. An amount of 50 g of active acidic Al2O3 (Sarabhai M. Chemicals), heated in an air oven at 120°C for 2 h, was transferred into a chromatographic column, and after chloroform was allowed to percolate a solution of 10 g of papaverine in 100 ml chloroform was eluted through the Al2O3 at the rate of 120 drops per minute. This was repeated twice with 10 g of papaverine each time for a total of 30 g papaverine passing through the column. The column removed the yellow colour in the chloroform solution. When the chloroform was evaporated to dryness, 29.2 g of a white crystalline solid were obtained. This solid passed the limit test for cryptopine in I.P., U.S.N.F. XIV and European Pharmacopoeia. Analysis by TLC showed the absence of cryptopine in the papaverine.

  3. An amount of 20 g of active acidic (pH 5.2) Al2O3 was added to a solution of 10 g papaverine in 100 ml chloroform in a conical flask and the mixture was shaken every 10 min by hand for 3 h. Following filtration and evaporation of the chloroform, 9.8 g of papaverine were recovered.

  4. Experiment 3 was repeated, except that instead of manual shaking a mechanical shaker was used to agitate the mixture for l h. In this way, 9.5 g of papaverine were recovered.

  5. A solution of 10 g of papaverine in 150 ml of benzene warmed to 45°C was mixed with 20 g active acidic (pH 5.2) Al2O3. The mixture was heated to 45°C and agitated for l h using a mechanical shaker. After filtration and distillation of benzene, 9.5 g of papaverine were recovered.

In experiments 3, 4 and 5, the active acidic (pH 5.2) Al2O3 removed all colouring matter from the chloroform and benzene solutions and the papaverine recovered was free from cryptopine, gave no colour with concentrated sulphuric acid and conformed to I.P. specifications.

Results and discussion

A crude narcotine-papaverine mixture produced in the factory from opium broth was found to contain about 90 per cent by weight of the alkaloids, the rest consisting of gums, resins, colouring matter and other impurities. The mixture was crystallized once from benzene/toluene to remove the non-alkaloidal impurities. The technical grade narcotine thus obtained was found to be a mixture of papaverine and narcotine. Since both are weakly basic alkaloids, they go together during the extraction. Malwa opium contains, on a dry matter basis, about 7 and 0.8 per cent, respectively, narcotine and papaverine [ 5] [ 16] . Several methods to separate these two alkaloids from their mixture using a variety of solvents and chemicals were tried but were not considered suitable for use on a commercial basis. Narcotine, being a phthalide isoquinoline alkaloid, has a lactone ring. Parameters affecting the opening of this lactone ring with sodium hydroxide to form sodium narcotinate were worked out. Also the fact that sodium narcotinate is soluble in water helped in making the separation of the two alkaloids convenient, easy and economical. Since papaverine is insoluble in sodium hydroxide solution, it was filtered out along with other alkali-insoluble impurities. The closing of the lactone ring in the sodium narcotinate was achieved easily using sulphuric acid and the narcotine precipitated with sodium hydroxide. precipitation of narcotine from the alkaline sodium narcotinate solution using ammonium chloride and sulphate was also attempted. However, the separation of narcotine in this way proved to be time-consuming and the ammonia liberated in the process caused air pollution. Hence use of sodium hydroxide was preferred.

In order to purify the crude papaverine, it had first to be made free from narcotine. Thereafter the traces of cryptopine in the papaverine had to be removed. Crystallization of papaverine oxalate from water removed other impurities but the cryptopine oxalate, which is sparingly soluble in water (1 in 300), remained with the papaverine oxalate. Removal of cryptopine from papaverine was achieved using aluminium oxide.

Cryptopine is strongly basic, whereas papaverine is a weakly basic alkaloid and amongst the various grades of aluminium oxide available in India, the active neutral type (pH 6.5, 5% aqueous suspension) and the active acidic type (pH 5.2) were found to be very effective in removing the cryptopine in the papaverine. Percolation of a solution of papaverine in chloroform not exceeding 10 g per 100 ml worked well for the removal of cryptopine. In addition, not only did active acidic Al2O3 with pH close to 5 effect complete removal of cryptopine, but its use also presented two advantages, namely: (a) colour, if any, present in the chloroform solution was removed by Al2O3 and a clear, colourless eluate was collected at a high rate of percolation; (b) the yield of papaverine from the eluted chloroform solution was quite high. On an industrial scale, using benzene as the solvent, with active acidic Al2O3 (pH 5.2) and agitating the slurry in a shaker, it was possible to effect the complete removal of cryptopine from papaverine.

The colour developed by treating 50 mg of the purified papaverine with 2 ml of cold (15°C) concentrated sulphuric acid was lighter than the pink colour obtained with an equal volume of 3.0 ml of N/10 potassium permanganate diluted to 11 [ 27] . Many investigators recommend the use of "cold'' concentrated sulphuric acid in testing the presence of cryptopine in papaverine [ 2] [ 3] [ 20] [ 21] [ 28] . According to the European Pharmacopoeia [ 29] , 6- I 5°C is considered as "cold or cool?". Hence the cryptopine limit test was carried out at 15°C (the laboratory temperature was 25-30°C. The European Pharmacopoeia, which is followed by B.P. and B.P.C., recommends the addition of 5 ml of sulphuric acid for the limit test of cryptopine as against 2 ml in I.P. and U.S.N.F).

Papaverine of natural origin is a by-product in the manufacture of morphine, codeine and narcotine. The cost of its purification to the stage of papaverine I.P. would compare well with that of papaverine produced synthetically. Based on the method described above, papaverine I.P. on an industrial scale can be produced economically in India.

Conclusion

A chemical method for the separation of narcotine and papaverine from a mixture of the two alkaloids has been developed. The purification of narcotine and papaverine to pharmacopoeial standards has been worked out. Only inexpensive and readily available chemicals and solvents like sulphuric acid, sodium hydroxide, oxalic acid, aluminium oxide, chloroform, benzene and alcohol are required in the process.

Acknowledgements

The authors thank the Chief Controller, Government Opium and Alkaloid Works Undertaking, New Delhi, and the Government of India, Ministry of Finance, New Delhi, for granting permission and for affording the necessary facilities to carry out this work at the Central Revenues Control Laboratory, New Delhi, and at Neemuch. The senior author sincerely appreciates the help and co-operation extended to him by M/s Sarabhai M. Chemicals, Baroda, and M/s Glaxo Laboratories, B.D.H. Chemicals Division, Bombay, in supplying some of the grades of aluminium oxide used in the study free of cost.

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