Recovery of thebaine and cryptopine from Indian opium

Sections

Introduction
Experimental
Conclusion

Details

Author: V. S. RAMANATHAN, P. CHANDRA
Pages: 49 to 63
Creation Date: 1980/01/01

Recovery of thebaine and cryptopine from Indian opium

V. S. RAMANATHAN Chief Chemist (Retired), Central Revenues Control Laboratory, New Delhi, India
P. CHANDRA Senior Chemist, Government Opium and Alkaloid Works, Neemuch, Madhya Pradesh, India

Introduction

Thebaine occurs in opium and in certain of its preparations, but thebaine has no direct medical use [ 1] [ 2] [ 3] [ 4] . During recent years, considerable interest has been shown in this alkaloid and there has been an increase in the demand for thebaine for the production of semi-synthetic drugs having analgesic, antitussive and sedative properties. It serves as the raw material in industry for increasing the production of codeine, which has as yet no adequate substitute in medicine [ 5] [ 6] [ 7] [ 8] [ 9] [ 10] [ 11] [ 12] [ 13] . At present, to meet the increasing demand for medical purposes, about 90 per cent of the morphine legally produced from opium poppy in the world is converted into codeine. A search for other sources of codeine has also been carried out. Dihydrocodeine, hydrocodone, oxycodone, thebacon and drotebanol [ 4] are other useful drugs that may be derived from thebaine. Naloxone [ 4] made from thebaine is used as an antagonist in the treatment of morphine and heroin addicts. Etorphine and some of its analogues known as Bentley compounds prepared from thebaine have a much greater activity than morphine and are used in veterinary medicine and in capturing wild animals [ 14] [ 15] . The Diels-Adler adducts of thebaine are easily prepared in high yields and are of great interest.

The United Nations Narcotics Laboratory has given attention to international scientific research designed to maximize the output of phenanthrene alkaloids, particularly thebaine, to meet the world shortage of codeine and for production of the other drugs mentioned above [ 16] [ 17] [ 18] .

Direct use of cryptopine as a drug has not been mentioned in the literature. However, it is a rare alkaloid [ 4] , and, on request, it was manufactured by the senior author and supplied from the Government Opium and Alkaloid Works at Ghazipur to a firm in the United Kingdom for research purposes [ 19] . Since it is a non-narcotic alkaloid like narcotine, there may be a demand for cryptopine if research should indicate possible uses in certain fields.

In the Government Opium and Alkaloid Works at Neemuch and Ghazipur, thebaine and cryptopine remain in the tarry waste mother liquors that are left behind after the removal of morphine and codeine from opium. In addition to thebaine and cryptopine, these contain gums, amphoteric resins, decomposed organic compounds, residual natural codeine and other alkaloids in traces. The methods described in the literature for the isolation of thebaine [ 20] [ 21] [ 22] [ 23] [ 24] could not be applied to these mother liquors with satisfactory results; hence, a new process was developed in the laboratory and scaled up in the factory to recover thebaine and cryptopine from the waste products. The developmental technological work carried out at the Central Revenues Control Laboratory in New Delhi, as well as in the factories at Neemuch and Ghazipur, and the results achieved are reported in this paper.

Experimental

Estimation of thebaine in opium

Opium collected from the fields of Madhya Pradesh (Neemuch, Mandsaur, Jaora, Manasa, Shamgarh and Ratlam districts) and received in the opium factory at Neemuch is issued by batches of 220 kg to the Alkaloid Works, Neemuch, for manufacture of alkaloids. Five samples drawn, one from each of the five batches of opium charged, were dried at 70°C to constant weight, powdered and sieved to make homogeneous samples. The thebaine content in each sample was estimated by a unified method of analysis [ 25] . The results, obtained in the year 1976/77, for opium taken for the manufacture of alkaloids in Neemuch, are given in table 1.

Table 1

Percentages of thebaine in Madhya Pradesh opium

Sample No.

thebaine on dry matter (%)

1235 1.57
1246 1.48
249 2.04
250 2.04
449
2.07

Production of crude thebaine

The mother liquor left behind after processing the solvent extract of opium broth and removal of natural codeine as sulphate is stored in vessels. This is a highly tarry acidic, viscous liquid with a pH of 2 and containing free sulphuric acid. The quantity of tarry liquid taken for processing was diluted with three times its volume of water, caustic soda solution (100 g/l) was added under stirring, and the pH was raised to 10. On leaving for 48 hours, with occasional stirring, a thick, bulky, blackish-brown resinous precipitate came down. This was filtered, washed six times with water and air-dried. The thebaine content in this crude thebaine was estimated by the method indicated above [ 25] ; the results obtained for the first six lots are reported in table 2.

Table 2

Thebaine content of crude thebaine

Amount of crude thebaine produced, wet weight (kg)

Loss on drying at 100°C(%)

Residue on ignition on dry matter (%)

Thebaine on dry matter (%)

Potential thebaine on dry matter (%)

36.79 36.53 0.36 13.39 3.13
18.24 38.05 0.44 27.82 3.14
22.90 49.15 0.30 13.43 1.56
24.50 23.93 0.51 11.53 2.15
82.57 33.09 0.48 23.78 13.14
69.80 1.91 0.32 16.85 11.54

Each batch (220 kg) of opium processed at Neemuch yielded about 20 1 of final tarry liquor which, on treatment with caustic soda, gave about 4 kg of crude thebaine. The quality and quantity of crude thebaine obtained depended upon the period of storage of the mother liquor and the extent of dilution before precipitation. Fresh mother liquor diluted with five times its volume of water gave a much better quality of crude thebaine which could be filtered the same day.

Recovery of thebaine and cryptopine from crude thebaine

Thirteen preliminary laboratory extraction experiments were carried out on the crude thebaine for the isolation of thebaine and cryptopine, the details of which are given below.

  1. 100g of crude thebaine was extracted in a glass percolator with cold benzene, 10 times, each time with 200 ml. The volume of the benzene extract, almost black in colour, was reduced by distillation to 500 ml. This was washed three times .with 100 ml of caustic soda solution (10 g/l) to remove resins and colouring matter. Then it was washed with water and extracted with dilute acetic acid. The thebaine was precipitated with caustic soda and purified as acid tartrate. Yield of thebaine: 28 g; m.p. 189°C. The tartrate mother liquor yielded 6.5 g of alkaloid, m.p. 184°C.s

  2. 100 g of crude thebaine was percolated 11 times with cold benzene using 200 ml each time. The volume of benzene was not reduced by distillation. No tartaric acid was used for the purification of the alkaloid. The benzene extract was washed with caustic soda solution (10 g/l) and finally with water. Thereafter it was extracted with acetic acid (1%) and the total alkaloids precipitated. The total alkaloids were fractionally crystallized from benzene. The first yield was 22 g, almost white, m.p. 172°-176°C. Second fraction 19.5 g, almost a white powder, m.p. 160°-165°C. This indicates that the crude thebaine also contains other alkaloids.

  3. 100 g crude thebaine was percolated, as in the earlier experiments with cold toluene, 10 times, using 150 ml of solvent each time. Toluene extracts less resin than benzene. The volume of extract was not reduced by distillation. The extract was processed using caustic soda solution, water, acetic acid and tartaric acid. Yield of thebaine: 34 g; white powder, m.p. 190°C.

  4. 100 g of crude thebaine was percolated with trichloroethylene, five times, each time with 150 ml. The solvent extracts were combined and the thebaine rose to the surface of the solvent on adding tartaric acid aqueous solution. The thebaine acid tartrate, brown in colour, was removed with a hand strainer and purified by crystallization. Yield of thebaine: 16.5 g; m.p. 191°C. This experiment was repeated with dichloroethane (ethylene dichloride) with almost the same results. This method of purification would have worked well had the crude thebaine been of a better quality with less gums and resins present.

  5. 200g of crude thebaine was suspended in 250 ml water. Tartaric acid solution was added under stirring until pH 5 was reached. After warming to 50°C, it was filtered in a Buchner. The pH of the filtrate was raised to 6.5-6.8 and filtered to remove the gums and resins which had separated. To the filtrate, more tartaric acid was added until pH 2. The acid tartrate was filtered and crystallized, and the thebaine was precipitated with alcoholic ammonia. Yield of thebaine: 43 g; m.p. 192°C. In view of the poor quality of the crude thebaine, it was found difficult to follow this procedure on an industrial scale.

  6. 100 g of crude thebaine was percolated with cold toluene 10 times, 150 ml each time. Instead of the acetic acid used in (2), hydrochloric acid (0.5%) was used. Being a solvent, acetic acid extracts much of the resin present in the toluene extract. The purification of thebaine extracted by hydrochloric acid could be done more easily. Yield of thebaine: 20 g; m.p. 192°C.

  7. 100 g of crude thebaine was percolated in the cold with 0.75% hydrochloric acid, six times with 150 ml each time. The combined acid extract was purified through acid tartrate. Yield of thebaine: 17 g; m.p. 192°C.

  8. 100 g of crude thebaine was percolated with 0.5% hydrochloric acid, six times, with 150 ml each time. The combined acid extract was allowed to stand for two weeks to study whether the storage of this dilute acid extract would cause the decomposition of all the thebaine. The extraction was started on 18 May 1977 and the thebaine isolated on 2 June 1977. Yield of thebaine: 13 g; white powder, m.p. 192°C.

  9. 150 g of crude thebaine was percolated with toluene in the cold 10 times as in (3) above. The toluene was distilled to a small volume in the hope that the thebaine would crystallize. The amount of resinous substance extracted was so large that the reduced toluene extract became a semi-solid. This was then extracted with 0.5% sulphuric acid and the thebaine recovered through acid tartrate. Yield of thebaine: 21.7 g; m.p. 193°C.

  10. 100g of crude thebaine was steeped in 1 1 of water and agitated mechanically with the addition of dilute sulphuric acid so that the percentage of the acid in the extract was kept below 1. Extraction in this manner was done twice under mechanical stirring. The slurry was filtered in a Buchner. The pH of the filtrate was raised to 6.8-7.0 and the precipitated gums and resins filtered. Thebaine was recovered through acid tartrate. Yield of thebaine: 18.6 g; m.p. 193°C. Sulphuric acid was used, as this would take up less gum and resin as compared to hydrochloric acid.

  11. 100 g of crude thebaine was extracted with 0.75% sulphuric acid, 11 each time as in (10) above. In two extractions, 30 min each, the whole thebaine was taken into solution. The pH of the filtrate was adjusted to 6.8-7.0 to remove gums and resins. Thebaine was purified as acid tartrate. Yield: 17.4 g; white powder, m.p. 193°C.

  12. 100 g of crude thebaine (buff-coloured, Lot No. 12 with 53.6% thebaine) was dissolved in toluene, 500ml under stirring. The solution was then filtered to remove insoluble impurities. The filtered toluene solution, yellow in colour, was extracted three times using 100ml, 50ml and 50ml of tartaric acid solution (200 g/l), keeping the pH at 6. The acid extracts were combined and more tartaric' acid saturated solution added until pH 2 was reached, when white thebaine acid tartrate separated. This was filtered and crystallized and thebaine precipitated. Yield: 45 g; m.p. 192°-193°C. This procedure can be adopted for the extraction of thebaine from crude thebaine with high thebaine content and comparatively low in resins and gums.

  13. After the separation of thebaine, the acid tartrate mother liquors from all the above experiments were combined and treated with caustic soda to pH 10. The precipitated alkaloid was purified as oxalate. Finally it was crystallized from the chloroform/alcohol mixture. Yield of white crystalline cryptopine: 11.5 g; m.p. 220°-221°C.

The results obtained in the above experiments are collected in table 3.

Table 3

Table 3

Isolation of thebaine alkaloid from crude thebaine in the laboratory experiments

 

Experiment

Thebaine alkaloid recovered

Cryptopine recovered

No.

Method

Amount of crude thebaine taken for extraction (g)

Amount (g)

Melting point (°C)

Amount (g)

melting point (°C)

1
Percolated with cold benzene, extracted with acetic acid and purified as acid tartrate
100.00 28.00 189    
2
Percolated with benzene and crystallized in two fractions
100.00
First fraction: 22
172-176
   
     
Second fraction: 19.5
160-165
   
3
Percolated with cold toluene, extracted with acetic acid and purified as acid tartrate
100.00 34.00 190    
4
Percolated with cold trichloroethylene and dichloroethane, prilled with aqeous tartaric acid solution and purified
100.00 16.5 191    
5
Extracted with tartaric acid solution, gums and resins removed at pH 6.5-6.8 and purified as acid tartrate
200.00 43.00 192    
6
Percolated with cold toluene, extracted with 0.5% HCI and purified as acid tartrate
100.00 20.00 192    
7
Percolated with 0.75% HCI and purified as acid tartrate
100.00 17.00 192    
8
Percolated with 0.5% HCI, solution kept for two weeks and purified
100.00 13.00 192    
9
Percolated with toluene, distilled, extracted with 0.5% H 2 SO 4 and purified as acid tartrate
50.00 21.7 193    
10
Extracted with 1% Ha SO 4 by mechanical stirring, gums and resins removed at pH 6.8-7.0 and purified as acid tartrate
100.00 18.6 193    
11
Extracted twice with 0.75% H 280 4,gums and resins removed and purified as acid tartrate
100.00 17.4 193    
12
High content crude dissolved in toluene, filtered, extracted with tartaric acid solution at pH 6 and purified as acid tartrate
100.00 45.00 192    
13
Acid tartrate mother liquors combined, alkaloid precipitated and purified as oxalate
      11.5
220-22

Industrial-scale production of thebaine

From Lots'l-6 of crude thebaine prepared in the Government Opium and Alkaloid Works, Neemuch, 160 kg was taken to the Government Opium and Alkaloid Works, Ghazipur, for recovery of thebaine, as suitable operational vessels were not readily available at Neemuch. An amount of 50 kg of crude thebaine per batch taken for extraction represents a scaling up of 500 times of the process used in the experiments in the Central Revenues Control Laboratory, New Delhi. The results of processing the 160 kg of crude thebaine are shown in table 4.

Table 4

Results of processing 160 kg crude thebaine (Weighted averages)

Loss on drying at 100 °C (%)

Reside on ignition (%)

Thebaine alkaloid content of the crude thebaine, on dry matter (%)

Potential thebaine in 160 kg (kg)

35.35 0.44 18.5 19.13

Extraction of crude thebaine with dilute sulphuric acid

A glass-lined digester of 500-1 capacity was charged with 50 kg of crude thebaine. Water (350 1) was added and the mixture was stirred mechanically. Sulphuric acid (commercial) diluted to 50 per cent was added slowly and the pH of the extraction solution was adjusted to 5-6. The slurry was stirred for two hours at 30°C and allowed to settle for 15 min. The supernatant liquid had a pH of 6 and was siphoned into a centrifugal machine (915 mm diameter, 1000 rev/min) and purged, using cotton filter cloth. The solid at the bottom of the digester was also later transferred to the machine and centrifuged. The black insoluble solid in the filter net in the machine was transferred back into the digester for a second extraction at pH 6 using water and sulphuric acid. The acid extraction was done three times in this way. The third acid extract contained practically no alkaloid and hence in subsequent batches crude thebaine was extracted twice only to make the extraction process economical.

Removal of gums and resins

The filtrate (450 1) from the centrifugal machine was brownish black with suspended particles. It was transferred to a glass-lined digester (500-1 capacity), sodium chloride (7 kg dissolved in 251 water) added and the mixture stirred mechanically. Sodium hydroxide solution (50 g/l) was added carefully in a thin stream and the pH of the solution raised to 6.8-7.0. Blackish-brown resins and gums separated in lumps that floated on the surface of the liquid. A filtering aid (2.5 kg) was then added and the mixture stirred for a further 15 min. The whole operation took not more than 45 min. The solution was allowed to stand for 15 min and centrifuged.

Table 5

Technical -grade thebaine recovered form crude thebaine on industrial scale

Crude thebaine taken for extraction

Amount of chemicals used

Acid-insoluble black solid a

Brownish-black resins and gums separated at pH 6.8-7.0 aa

Technical-grade thebaine recovered (straw-yellow) a

Amount (kg)

Weighted average moisture content

Amount calculated on dry basis

Sulphuric acid (kg)

sodium chloride (kg)

Filter aid (kg)

Caustic soda (kg)

Wet weight (kg)

Loss on drying at 100°C (%)

Amount calculated on dry basis (kg)

Wet weight (kg)

Loss on drying at 100°C (%)

Amount calculated on dry basis (kg)

Wet weight (kg)

Loss on drying at 100°C (%)

Amount calculated on dry basis (kg)

50 36.95 31.52 3.6 7.0 2.5 4.0 23.5 33.2 15.7 19.0 38.92 11.61 13.00 54.63 5.98
50 36.91 31.54 3.8 7.0 2.5 4.0 49.0 34.1 32.3 16.0 27.34 11.63 9.50 54.75 4.30
60 32.72 40.37 4.0 9.0 2.7 5.0 22.0 34.1 14.50 17.00 54.13 7.80      
160   103.43 11.4 23.0 7.7 13.0 72.5   48.0 57.0  
37.74 b
39.50 c
 
18.08

a Tested and found to be free from thebaine.

b Including 7.7 kg of filter aid added.

cAbout 1,4001 of deep-brown alkaline filtrate discarded.

Precipitation of technical-grade thebaine

The filtrate, free from resin, was treated with sodium hydroxide (100 g/l) under stirring; a straw-yellow precipitate came down, which was filtered and washed with water. Finally the solid was centrifuged (66 mm diameter, 1400 rev/rain). The wet weight of thebaine obtained was 13 kg. The alkaline filtrate, which was deep brown in colour because of the dissolved coloured organic compounds, was discarded. The above procedure in recovering the technical-grade thebaine from the second batch of 50 kg and third batch of 60 kg of crude thebaine was carried out. Data and results are summarized in table 5.

Purification of technical-grade thebaine through acid tartrate

An amount of 10 kg of wet technical-grade thebaine was taken in a glass-lined steam-jacketed tilting pan (100-1 capacity), and water (20 1) was added under stirring. Glacial acetic acid was added till pH 5 was reached, when all the thebaine went into solution. This solution was gently heated to 50°-60°C. Tartaric acid (5 kg in 10 1 of water) was added until pH 2 was reached, when thebaine acid tartrate separated as a creamy yellow crystalline solid. This was allowed to stand for two hours for complete separation of the acid tartrate. The acid tartrate was centrifuged and washed in the machine with 1 1 of recovered rectified spirit. The acid filtrate was deep brown and preserved for recovery of dissolved thebaine and cryptopine.

Precipitation of thebaine

The creamy white acid tartrate was transferred from the machine to a steam-jacketed pan (100-1 capacity), and water (20 1) was added under stirring. Sodium hydroxide (10% solution) was added and pH adjusted to 6, when the solution became clear. The solution was heated to 50°-60°C, decolourizing carbon added, and the mixture stirred and filtered. The filtrate (25 1) was yellow in colour. Recovered rectified spirit (8 1) was added and mixed. Sodium hydroxide (10% solution) was added slowly under stirring till pH 10 was reached. After allowing the solution to stand for some time, thebaine was filtered, washed with water and dried at 40°C. The dried thebaine was cream coloured. Yield: 4.5 kg; m.p. 189°-190°C.

In another purification experiment, 10kg of wet technical-grade thebaine yielded 5 kg of dry thebaine alkaloid, m.p. 190°-192°C.

Analytical data on the thebaine recovered in the two experiments above are shown in table 6.

Thebaine alkaloid (pure)

A 50-g sample of the thebaine prepared above was suspended in 200 ml of water. Tartaric acid (30% aqueous solution) was slowly added and at pH 6 the thebaine went into solution. More tartaric acid solution was added until pH 3 was reached, when the acid tartrate separated. Water (100 ml) and the slurry stirred well. This was heated to boiling, when the acid tartrate went into solution, and left for three hours for the acid tartrate to crystallize. The acid tartrate was filtered in a Buchner, washed with ice-cold water (50 ml) and then steeped in water (300 ml). Sodium hydroxide solution (10 g/l) was added until pH 6 was reached. The solution was heated to 50°C, treated with activated carbon and filtered. To the filtrate, rectified spirit (50 ml) was added and the pH raised to 10, when the thebaine separated as white plates/leaflets. Filtered and dried at 40°C. Yield: 40 g; m.p. 193°C. The results of an analysis of the thebaine alkaloid obtained were as follows:

Table 6

Analytical data on the thebaine alkaloid obtained from two 10-kg batches of technical-grade thebaine

Amount of thebaine alkaloid recovered (kg)

Solubity

Loss on drying at 105°C (%)

Reside on ignition (%)

melting point (°C)

Thebaine by K/34 method (%)

4.5
Benzene 1 in 15; alcohol (99.9% hot) 1 in 15; chloroform 1 in 5
0.08 0.08
189-190
95.0
5
All clear, faint yellow
0.04 0.03
190-192
98.0
4.5
Benzene 1 in 15; alcohol (99.9% hot) 1 in 15; chloroform 1 in 5
0.08 0.08
189-190
95.0
5
All clear, faint yellow
0.04 0.03
190-192
98.0
Colour
White
Form
Plates/leaflets
Solubility
Benzene, 1 in 15 Alcohol (99.9%, hot), 1 in 15 Chloroform, 1 in 5 (All solutions clear and colourless)
Loss on drying at 800C
0.10%
Residue on ignition
0.02%
Melting point
193°-1940°C
TLC result
Less than 0.5% other compounds
Thebaine content
 
By non-aqueous titration (BP 1973)
99.5%
By K/34. method
99.9%
Ultraviolet scan
250-267 nm
Infrared peaks
907, 1,029, 1,143, 1,233, 1,252, 1,276, 1,443, 1,603 cm -l

Cryptopine

The acid tartrate mother liquor (60 1) left behind after the purification of 20 kg of wet technical-grade thebaine was diluted with 10 1 water and allowed to stand for four hours under stirring. The creamish white precipitate that separated was filtered. Thebaine from this thebaine acid tartrate (2 kg wet weight) was recovered. Sodium hydroxide solution (10%) was added to the filtrate slowly under stirring and the pH raised to 7; the resins and impurities which separated were filtered. The pH of the filtrates was raised to 10, when an off-white precipitate came down. Yield: 1.5 kg wet weight; m.p. 190°-200°C. This alkaloid gave colour reactions for cryptopine.

A portion of this alkaloid on purification through oxalate and crystallization from a mixture of alcohol and chloroform gave white crystalline cryptopine, m.p. 220°-221°C.

Experiments on the extraction of thebaine from opium broth

  1. An amount of 1 g of pure thebaine was suspended in water (150 ml) and acetic acid (10%) added to pH 3, when all the thebaine went into solution. The pH of the solution was raised to 6.0-6.2. Thebaine was extracted with trichloroethylene four times, each time using 20 ml. The combined extracts were distilled off in a tared flask, dried and weighed. The weight of recovered thebaine was 0.955g. The experiments were repeated with carbon tetrachloride, dichloroethane and chloroform. All the chlorohydrocarbons were effective in extracting the thebaine at pH 6.0 to 6.2.

  2. A volume of 3 1 of acidic opium broth freed from narcotine and papaverine was treated with sodium hydroxide to raise pH to 6.0-6.2 and extracted with trichloroethylene three times. The solvent was distilled to a small volume, kept at 20°C, and thebaine separated as thebaine acid tartrate using 20% tartaric acid solution and later purified. Yield: 2.8 g; white crystalline solid, m.p. 192°-193°C.

  3. Opium (0.5 kg) was extracted three times with acetic acid (2%) and filtered. After removal of narcotine and papaverine, the pH was raised to 6.0-6.2 and the filtrate was extracted with chloroform, the volume of extract was reduced and thebaine separated as thebaine acid tartrate. Yield: 2 g; white crystalline powder, m.p. 192°-193°C.

    The yield of thebaine in (b) and (c) was on the low side. Either the extraction with solvent or the separation of the thebaine and tartrate appears incomplete. Further studies are to be made on this. However, the thebaine can be extracted separately.

  4. Amounts of 1 g of pure thebaine and 0.5 g of codeine B.P. were mixed, steeped in 200 ml of water and dissolved in acetic acid. The pH of solution was raised to 6.0-6.2. Thebaine was extracted with trichloroethylene, separated as thebaine acid tartrate and purified. The pH of the solution was thereafter raised to 10 and extracted with trichloroethylene three times with 25 ml. The codeine from the reduced solvent was separated as codeine sulphate and purified. Yield: white crystalline solid; thebaine 0.95 g and codeine 0.45 g.

Trichloroethylene has a density of 1.46 with b.p. 87°C and is insoluble in water, whereas chloroform has a density of 1.48 with b.p. 61°C and a solubility of 1 ml in 200 ml of water at 25°C. In view of this, trichloroethylene would be preferable for industrial use. The health hazard in using chlorohydrocarbons should also be kept in mind.

Extraction of thebaine from the waste slaked-lime residues

In the Gregory-Robertson process followed in the Government Opium and Alkaloid Works, Ghazipur, a tarry, mother liquor is left behind after the separation of the crude morphine-codeine alkaloid cake [ 19] . This mother liquor is diluted with five times its volume of water, treated with slaked-lime and filtered. This waste slaked-lime residue contains thebaine, papaverine, cryptopine, traces of narcotine, resins, gums and other organic impurities. It becomes the raw material for the extraction of thebaine and cryptopine.

An amount of 100 kg of blackish-brown lime residue was charged into a glass-lined digester of 500-1 capacity. Water (350 1) was added and the mixture stirred. The pH of this slurry was 10. Sulphuric acid (commercial 50%) was added slowly, checking the pH at close intervals and maintaining it at 5 to 6. The temperature of the slurry went up to 50°C due to the exothermic reaction. Stirring was contained for two hours and was followed by centrifuging. The solid in the machine was re-extracted with water (1501), keeping the pH at 5-6. This was centrifuged.

Removal of gums and resins from the filtrate

The combined filtrates from the first and second extractions were taken in a digester of 500-1 capacity. Sodium chloride (5 kg in 20 1 of water) was added and the mixture stirred. The pH of the solution was adjusted to 6.8-7.0 by adding sodium hydroxide. Filter aid (2 kg) was added, stirred and filtered.

Precipitation of crude thebaine

Caustic soda solution (100 g/l) was added to filtrate and the pH brought to 10, when a brown solid separated. This was filtered and centrifuged. Yield: 6 kg (wet weight). From a second batch of 100 kg of lime residues, 8 kg (wet weight) of crude thebaine was obtained.

Purification of crude thebaine

The 14kg of crude thebaine was purified as acid tartrate by the method described earlier in this paper. The tartrate solution was treated with activated carbon and finally the thebaine alkaloid was precipitated, washed with water and dried. Yield of thebaine: 1.5 kg; m.p. 190°-192°C.

Results and discussion

Madhya Pradesh opium contains 1.5-2.0 per cent thebaine on dry matter. Various methods for the estimation of thebaine have been published in the United Nations series of papers ST/SOA/SER.K/... and ST/SOA/SER.J/ .... The method described in ST/SOA/SER.K/34, indicated above as the K/34 method, was adopted for the estimation of thebaine in opium, crude thebaine and thebaine alkaloid, as it was found convenient.

The tarry mother liquor taken for precipitation of crude thebaine in Neemuch was in storage for more than 15 months. It was a strongly acidic solution containing sulphuric acid. Thebaine, being an enol ether, would have undergone partial decomposition by the mineral acid during this long storage, as well as by the heating of the solution to 80°C during the separation of natural codeine. The crude thebaine precipitated from the mother liquor in the first few lots was therefore of poor quality, containing a high percentage of resins, gums and other organic compounds as impurities. To avoid the decomposition of thebaine and the formation of other organic compounds during storage, crude thebaine should be recovered from the mother liquor as soon as it is formed.

The percentage of thebaine alkaloid in the crude thebaine was low, although the organic components in it were over 99 per cent. Hence, extraction of thebaine, using organic solvents, was difficult. The elimination of gums, resins and coloured organic matter from the crude thebaine is the important step in the process.

The methods for extraction and purification of thebaine and cryptopine are based on the adjustment of the pH at various stages. At pH 7 the precipitate contains not only the amphoteric resins, but also all the weakly basic alkaloids like narcotine and papaverine. Sodium chloride helps in coagulating the suspended matter and separating the resins from the solution. The two steps of extraction with sulphuric acid and removal of resins from the acid extract can be avoided if the quality of the crude thebaine can be improved. These steps cannot, however, be avoided when starting with the lime residues in Ghazipur. No organic solvents were used in the extraction and purification of thebaine. Although thebaine can be purified through thebaine salicylate, it was found that the acid tartrate method was easier and more efficient.

The potential yield of thebaine alkaloid from 160 kg of crude thebaine was 19.13 kg. An amount of 39.5 kg of wet technical-grade thebaine recovered from this crude would yield 18 kg of thebaine and 1 kg from the acid tartrate mother liquor. With 96.5 per cent thebaine in it and 16.5 kg of thebaine alkaloid (pure), the recovery of thebaine works out to 95.8 per cent and 86.0 per cent respectively, calculated on the crude thebaine.

The 4 kg of crude thebaine obtained from 220 kg of opium processed should contain at least 2.6 kg of thebaine. In other words, the crude thebaine should contain 65 per cent thebaine. The much lower percentage of thebaine in the crude thebaine indicates that it has undergone decomposition in the processing by the time the tarry mother liquor is formed. This can be avoided if the thebaine is extracted from the opium broth at pH 6.0-6.1 using a chlorohydrocarbon. The purification of thebaine and of natural codeine extracted separately at different stages would then become easier and the recovery of both these alkaloids could also be much improved. If crude thebaine with nearly 50 per cent thebaine is produced, then this product can be purified by dissolving in trichloroethylene or toluene, and the thebaine in solution separated or extracted with tartaric acid solution.

Good quality slaked-lime residues free from black resins should be kept separately for extraction of thebaine. The residues should also be stored in a dried condition so that extraction would yield more thebaine, reducing operational expenditure.

Conclusion

An industrial method for the manufacture of thebaine and cryptopine has been worked out. Only cheap and easily available chemicals such as commercial sulphuric acid, sodium hydroxide, sodium chloride, filtering aids, activated carbon and tartaric acid are required, using water as the solvent. The thebaine produced is pure enough to be used as a raw material for the production of codeine, dihydrocodeine and other semi-synthetic drugs for medical use.

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 in Central Revenues Control Laboratory, New Delhi, Neemuch and Ghazipur. The senior author sincerely appreciates the technical assistance of Rakesh Kumar, Senior Chemist, Central Revenues Control Laboratory, New Delhi.

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