pH ADJUSTMENT
CRUDE MORPHINE LIQUOR TARRY SOLIDS
Figure 1.
Ion-exchange method.
Morphine adsorption from the extract liquor averaged about
98%
0.L. BREKKE, H. G. UAISTER, G. C. MUSTAKAS, L. VAN ERMENl, M. C. RAETHER, and C. T. LANGFORD2 Northern Utilization Research and Development Division, U. S. Department of Agriculture, Peoria, 111.
Morphine Recovery from a 2-Butanol Extract of Opium Poppy Meal Morphine can be recovered from domestically grown poppy, should' opium imports be interrupted by another war
T w o MmHoDs-ion exchange and distillation-were developed on a pilotplant scale to recover morphine and other opium alkaloids from a 2-butanol extract of opium poppy meal ( 7 , 4 ) . Recovery by Ion Exchange Two ion-exchange columns were used in this pilot-plant recovery study. The cation column, 1 1 8 / 4 inches in inside 1 Present address, 281 1 Houston Drive North, La Marque, Tex. 2 Present address, 5646 Chelsea Avenue, La Jolla, Calif.
diameter by 10 feet, contained 4.0 cubic feet of the synthetic sulfonated resin, Duolite C-10, in a bed 66.5 inches deep. This cation exchanger of low cross linkage adsorbs large organic molecules, and can be used to recover morphine quantitatively from a 2-butanol extract (6, 7). For the anion column (6 inches inside diameter by 10 feet) 0.57 cubic foot of Duolite A-7 in a bed 35 inches deep was used. Volume measurements were based on the regenelated, backwashed, settled, and drained resin. About 100 gallons of filtered 2-butanol extract, with a morphine concentration
of 0.20 to 0.22% and containing 21 to 25 ounces of morphine by the Matchett and Levine method of analysis (5, 9 ) , were pumped by downflow through the two columns in series (Figure 1). The rate through the cation column was 1.57 gallons per minute per square foot. This rate was maintained, as bed resistance increased near the end of the adsorption period, by using nitrogen a t 0.5 to 1.5 p s i . in the head space. After 20 minutes of drainage, the cation exchanger was washed with 88.5 .pounds of 91 volume yo of 2-propanol. The bed was aerated vigorously for 10 VOL. 50, NO. 12
DECEMBER 1958
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0.024
$ 0.016
E 8
Numbers Adjocenl To Points Indicate Test Numbers.
'
2 0.004 t o
0
-282 CUMULATIVE VOLUME OFoCATION EFFLUENT, GALLONS
m
.23* 60
100
80
120
140
'
160
"
180
TOTAL QUANTITY OF ELUATE, GALLONS
Figure 2. Little morphine leaked into the cation effluent until after 50 gallons of effluent
minutes with compressed air before the alcohol was drained. Alkaloids were eluted from the bed with 21.8 gallons of a 4% sodium hydroxide solution; the bed was again aerated for 10 minutes, rinsed with 75 gallons of tap water at a rate of 1.57 gallons per minute per square foot and drained. The eluate fractions were immediately acidified to p H 6.5 to 7.0 with concentrated sulfuric acid. The exchanger was regenerated with 21.8 gallons of 5% sulfuric acid solution, aerated, and rinsed with deionized water to an effluent p H of about 3.5. The anion column was regenerated by a similar procedure with 1S1/4 gallons of 1% sodium hydroxide solution and rinsing continued to a pH of about 9.0. Deionized water was used for all aqueous solutions put through the anion column, as well as for the cation regenerant and rinse solutions. After suitable conditions were established, an average of 98.7% of the morphine in the extract liquor was adsorbed by the cation exchanger. After passage through the anion column the 2-butanol effluent was saturated with water and had a morphine concentration of less than 0.005%. I t could be re-used without further treatment. Concentration of morphine in the cation effluent remained low until over 50 gallons were collected with 99.9% of the morphine being adsorbed u p to this point, then the concentration rose rapidly (Figure 2). These data are indicative of the typical break-through curve, which is sigmoidal in shape. According to Samuelson (8) plotting such a break-through curve on arithmetic probability paper transforms it into a straight line, and the total capacity of an exchanger can be estimated from the volume throughput when the concentration in the effluent has reached 50YG of that in the influent. Such a plot determined that 53/4 volumes of feed liquor per volume of resin corresponded to c/co = 50%. The total capacity of the Duolite '2-10 exchanger was thus esti-
1734
Figure 3. Elution approaching 100% could be obtained with 95 or more gallons of eluate
mated to be 9.6 ounces of morphine per cubic foot of resin. A plot of morphine actually adsorbed us. that in the feed liquor, both based on a cubic foot of the exchanger, gave a substantially straight line relationship. The amount adsoi-bed varied from 5.2 to 7.3 ounces, and averaged 5.6 ounces per cubic foot of exchanger, or 98.7% of that in the influent. By using two or more columns in series, essentially all of the morphine can be adsorbed. Because cations other than alkaloids are adsorbed, both organic and inorganic acids are liberated; their concentration in the effluent varies as the adsorption proceeds, thus p H and conductance should change accordingly. Data from several tests indicated that the pH readings either remained constant or declined for the first effluent fractions and then rose for succeeding portions. If the adsorption step is carried sufficiently far, the p H approaches that of the influent. The first rise in p H value correlates approximately with the appearance of morphine in the effluent. A pH system possibly can be used in commercial operations to ascertain when the cation exchanger no longer adsorbs mofphine to an adequate degree. In the initial pilot-plant tests, a decline in the percentage of morphine adsorbed was attributed to fouling of the exchanger bed with tars and other alcohol-soluble materials that were not removed in the elution step. The use of 91 volume % of 2-propanol as a wash prior to elution of the ,alkaloids overcame this difficulty. Solids content of the spent wash varied from 1.2 to 1.4% with almost one half of these solids being soluble in petroleum ether. Tests made with methanol rather than 2propanol resulted in considerable foaming when the eluate solution was aerated. Anhydrous 2-propanol was also tried in one test, but it removed essentially no more solids than the 91% solution. Analyses indicated that the 2-propanol washes contained about 39?0 of the morphine retained by the cation exchanger.
INDUSTRIAL AND ENGINEERING CHEMISTRY
However, these values are subject to considerable question-the samples were difficult to analyze as a result of the tars present and because these tars are phenolic in nature and thus cause high morphine values. The first 30 gallons of eluate contained a very large fraction of the total morphine eluted. To obtain elution approaching loo%, about 95 gallons of eluate were collected (Figure 3), but even then, the percentage of morphine eluted varied considerably; this cannot be explained definitely. In one test the elution was as low as 96%, as high as 109% in another. In three out of the last four tests made elution was over lOOYG,suggesting a possible buildu p of morphine in the earlier tests. The average elution for all 12 tests was 96%. The first eluate fraction obtained from the cation exchanger was dark in color. As rinsing continued, the eluate became progressively lighter in color, and near the final stages it was light amber. The first fraction usually became covered with a thin tarlike floating layer upon standing, and when the fraction was neutralized with sulfuric acid, a flocculent precipitate was formed. The second fraction formed a brown scum upon acidification, but generally nothing appeared on the third. The tarlike material in the first and second fractions was small in quantity, but it did gather and cling to the walls of the tank. After the alcohol-wash procedure was adopted, the quantity of tars and precipitated solids appeared, a t least visually, to decrease. The eluates contained significant quantities of alcohol. Operation of the anion column was satisfactory and reasonably good deacidification of the 2-butanol influent was accomplished. The p H of the anion effluent tested between 6.0 and 6.7, and that of the cation influent varied between 7.7 and 8.4. In several tests made before the alcohol-wash procedure was adopted for the cation exchanger, the anion column had to be backwashed with water prior to regeneration to re-
MORPHINE RECOVERY move a small quantity of slimelike solids deposited on top of the bed. Negligible quantities of morphine were lost in the spent regenerant solutions from both the anion and cation beds. Using as the datum point the volume of resin in the backwashed, settled, and drained state after regeneration, data were obtained on volume change for both the cation and anion 'exchangers during a complete cycle. For the cation resin, the volume decreased 13% in the exhaustion step and in the elution step increased to 12% above the datum point after aeration. The volu q e of the anion exchanger decreased 7% during the exhaustion step and increased 7y0in regeneration. The unfiltered eluates were concentrated batchwise under 28- to 29-inch vacuum in a 50-gallon jacketed kettle constructed of Type 317 stainless steel and equipped with a turbine-type agitator, condenser, receiver, and steamjet ejector. Temperature of the boiling solution was maintained between 92' and 100' F., and steam at a pressure of 2 to 3 p s i . was used in the jacket. Average compositioh of the feed was morphine concentration, 0.175y0, specific gravity, 30'/15' c.,0.994, and total solids, 1.64%. Foaming of the boiling solution was controlled but not eliminated by occasionally adding about 5 ml. of octyl alcohol per gallon of feed. However, some entrainment always occurredthe condensates were colored and contained small amounts of morphine. However, no entrainment was encountered in similar evaporations conducted in an all-glass. long-tube, natural-circulation evaporator used in the laboratory. Tarry solids became encrusted on the walls of the kettle, especially at the liquid surface level. These tais were removed by a hot-water rinse followed by scrubbing with a 5% sodium hydroxide solution and then with either water or a 1% sodium hydroxide solution, If concentration of the eluates was carried sufficiently far, excessive quantities of tarry solids appeared in the concentrate or remained in the kettle, sodium sulfate came out of solution, and a greater loss of morphine was incurred. A material balance made over eight tests showed that 98.8% of the morphine fed to the evaporator was present in the concentrated liquor, the filtrates and filter cakes from the kettle rinses, and the condensate. If the solids, mostly tars, that were removed upan filtration of the first caustic rinse are not included. the morphine recovery was 94.670. The crude morphine liquors obtained by evaporation were brown and dark in color. After standing for several
weeks they solidified partially or entirely depending upon their solids content. Thick sirups were obtained when the solids content was 20% or more, and thinner sirups that readily drained frorrl the evaporator were obtained with a solids content of about 15%. Recovery by Distillation Distillations were conducted in a copper column, 8*/, inches in inside diameter, containing 20 plates with a 6-inch plate spacing and 3 bubble caps per plate. Heat at the bottom of the column was provided by indirect steam in the shell of a tube-and-shell type calandria and by the admission of open steam through a perforated pipe. Vapors leaving the top of the column passed first through a partial condenser, which preheated the feed, and then into a total condenser from which the condensate flowed into a 10-gallon decanter. A bottoms stream was withdrawn continuously from the column through an overflow leg that was used to maintain a constant liquid level above the calandria. This stream was collected in an open 100-gallon jacketed kettle equipped with a top-mounted, propeller-type agitator where it was cooled and the tars separated and extracted. A stainless steel 5-gallon Buchner filter was used for filtering the decanted bottoms stream. All evaporations were conducted in the same 55-gallon jacketed kettle used to concentrate the cation-exchanger eluates (Figure 4). I Prior to distillation, the slightly alkaline extract liquor was adjusted to a
p H of about 6.5 with dilute sulfuric acid. Extract liquor was pumped onto the fifth plate of the distillation column a t a rate of 17 to 18l/2 gallons per hour after being preheated to 150' to 162' F. in the partial conqenser. 2-Butanol in the extract liquor was distilled overhead at atmospheric pressure as the 2-butanolwater azeotrope. The two layers formed when the vapors condensed were separated in the decanter, and the water layer was pumped directly back onto the fifth plate of the column. This water layer provided the water required to form the azeotrope and also created some reflux within the column. The alcohol layer, which was cloudy because of finely dispersed water droplets, was collected in 55-gallon drums. These droplets separated from the alcohol upon standing. Steam a t 45 p s i . was used in the calandria and dilution of the bottoms stream was controlled by adjusting the ratio of direct to indirect steam. Alkaloids and other solubles present in the extract liquor were transferred to this bottoms stream, which was collected in the 100-gallon receiving kettle under constant cooling. When distillation was completed, liquor remaining in the column was drained and combined with that in the kettle. To obtain a high morphine recovery in the distillation step,, the calandria section was boiled out twice with 1% sodium hydroxide solution to remove accumulated tars, then drained ; after being adjusted in a separate container to a p H of 6.5 with 3ooj, sulfuric acid, the solution was then added to the bottoms stream in the kettle. By
-
P~EHEATEDEXTRACT LIQUOR
DISTILLATION
DIRECT S T E A M SINDIRECT STEAM I B A L A Y E R TO KENNEDY EXTRACTOR BOTTOMS EXTRACT LIQUOR
i
I
Ked
O !DECANTED ! @ J i H ; iBOTTOMS : ; T M E N T
Qeconlotion totlornr liquor foildwd by of Iw6 wolvr c x t r o c l l o n ~ of f&duol tor in m e YWI.
LAYER
RECEIVER
I
POT NAPORATOR
I
FILTER FILTER A I D
CRUDE MORPHINE LIQUOR
Figure 4. Distillation method. Alkaloids and nonvolatile substances are transferred from the 2-butanol extract to an aqueous liquor VOL. SO, NO. 12
DECEMBER 1958
1735
Table 1.
The Crude Morphine Liquors Can Be Used for Commercial Production
-
N -.T T
Solids Content, %
Specific Gravity 3O0/15O C. 1.117
Recovery Method Ion exchange 18.0 1.104 Distillation 22.2 a Matchett and Levine method (4, 6).
Morphine“ Analysis, Refiner’s Analyses, % % Morphineb Codeine Thebaine 0.248 0.404
0.086 0.219
Modified U. S.Pharmacopoeia method ( 3 ) .
standing overnight in the kettle, most of the tars settled out, and a cloudy supernatant liquor with a pH of 5.0 to 6.0 could be siphoned off. The considerable amount of morphine (37,) in the tars remaining in the kettle was recovered by extraction. Based on preliminary laboratory tests, 6 pounds of distilled water per pound of tar were added to the kettle. Under vigorous agitation the temperature was raised to 185’ F. and the p H was adjusted to 9.0 with 30% sodium hydroxide, whereupon the color of the mixture turned black, indicating a uniform dispersion of the tars. The mixture was held at this temperature for 10 minutes and then acidified slowly with 30% sulfuric acid. Upon passing the neutral point, the color of the solution changed from black to a grayish brown and large globules formed. Acidification was stopped when the p H reached about 4.0. After the mixture cooled to room temperature and stood overnight, a clear supernatant liquor, p H 3.6, was siphoned off. The tars were subjected to a second extraction by the same procedure except that 10 pounds of water were used per pound of tar. The tar extracts and supernatant liquor from the still bottoms were combined, adjusted to a pH of 4, and filtered in a 5-gallon Buchner filter. Filtration is required to eliminate heavy incrustation in the evaporator and over. loading the final product with nonmorphine solids. The filtrate was adjusted to a p H of 6.5 because preliminary tests indicated that at this pH, the morphine loss would be lowest during the evaporation that followed. This evaporation was carried out in the 50-gallon jacketed kettle a t 90’ to 105’ F. and a 28-inch vacuum Upon completion, the crude morphine liquor was drained and the kettle rinsed twice with hot water. The distillation column operated smoothly after a start-up procedure was adopted whereby the calandria section was filled with condensed steam before the feed was introduced. Temperature readings indicated that only five plates and the reboiler were required for the desired separation. Column operation required about 0.90 pounds of steam per pound of 2-butanol extract, and the over-all loss of alcohol was held to 3%. Little morphine was lost or destroyed
1 736
1.62 2.28
2.16 3.64
in the distillation step, and an over-all loss of 1.5% was incurred for the distillation and tar extraction steps. A larger amount of morphine (5.3%) was lost in adjusting the p H and in filtering the liquor in preparation for the evaporation step. Recovery of morphine in the evaporation step was 9670, which is essentially the same as for the cation eluates, and the crude morphine liquor was concentrated to a solids content ranging from 22 to 35%. The extract liquors contained approximately 0.8% tar, based on the amount collected from the bottoms stream.
quantity of morphine obtained from 1 ton of the meal will be 190.6 ounces as determined by the method of Matchett and Levine. By the refiner’s assay, the expected recovery will be somewhat less-Le., 119.4 ounces of morphine [190.6 X 2.28/3.64] and 21.2 ounces of codeine [119.4 X 0.404/2.28], 01 a total of 140.6 ounces for the two alkaloids. Codeine recovery is comparable in the two processing methods, but the combined yield for both alkaloids by distillation is 26.7 ounces or 16.0% less than by ion exchange based on the refiner’s sssav. This difference in yield is considered sufficient to make the ion exchange recovery method more economical. Acknowledgment
The products from both methods were a liquid containing some solids. Two commercial refiners evaluated the crude liquors, and in an emergency, provided some process modifications were made, they considered both products equally suitable for producing pure morphine and codeine (2, 3 ) .
The authors wish to thank C. L. Mehltretter and F. B. Weakley for helpful suggestions regarding the ion exchange recovery method; T. A. McGuire, Helen Kiefer, E. H. Giehl, and F. R. Earle for the morphine determinations; and the Illinois Water Treatment Co. for technical information which proved useful in the design and operation of the ion exchange columns. The evaluations made of crude morphine liquors by the Mallinckrodt Chemical Works and by Merck & Co. and the former’s suggestions on precautions to prevent the loss of morphine are gratefully acknowledged.
Selection of Recovery Method
Literature Cited
Using the ion exchange method, a ton of meal containing 0.70% morphine should yield crude morphine liquor containing 193.5 ounces of morphine by the Matchett and Levine analysis, or 145.1 ounces of morphine [193.5 X 1.62/2.16] and 22.2 ounces of codeine [145.1 X 0.248/1.62] for a total of 167.3 ounces of the two alkaloids, based on an assay by one of the commercial refiners. Using the distillation method, the
(1) Brekke, 0. L., Mustakas, G. C., Hubbard, J. E., Maister, H. G., Van Ermen, L., Raether, M. C., Langford, C. ‘I.,J . Agr. Food Chem., in press. (2) Clapham, W.E., Merck & Co., Inc., personal communication, 1953. (3) Homeyer, A . H., De LaMater,-G., Mallinckrodt Chemical Works, personal communication, 1953. (4) Maister, H. G. (to U.S.A.), U. S. Patent 2,752,350 (June 26, 1956). (5) Matchett, J. R., Levine, J., IND.ENG. CHEM., ANAL.ED. 13,264-5 (1941). (6) Mehltretter, C. L., Weakley. F. B., J . Am. Pharm. Assoc. Sci. Ed. 46, 193-6
Product Evaluation
An Over-all Morphine Recovery of 86% Is Expected Ion Distilla- Extion, change,
%
%
Extraction (1) 95.0 95.0 Distillation,tar extraction; 98.5 98.5 or adsorption Filtration, pH adjustment; or elution 94.7 95.5 Concentration 96.0 96.V Over-all recovery 85.1 86.4 a Assuming 50% recovery from tars.
INDUSTRIAL AND ENGINEERING CHEMISTRY
119571.
(7(-Mehltretter, C. L., Weakley, F.TB. (to U.S.,4.), U. S. Patent 2,740,787 (-4pril 3, 1956). (8) Samuelson, O., “Ion Exchangers in Analvtical Chemistrv.” .u. 48, Wilev, Newkork, 1953. (9) Van Etten, C. H., Earle, E’. R., McGuire, T.A., Senti, F. R., Anal. Ciicm. 28, 867-.70(1956). RECEIVED for review October 7, 1957 ACCEPTEDAugust 13, 1958 Mention of firm names or commercial products does not constitute an endorsement of such firms or products by the U. S. Department of Agriculture. Presented at 17th Midwest Regional Meeting of Amcrican Chemical Society, Ames, Iowa, Xovember 8-10, 1936.
