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(12) United States Patent (10) Patent No.: US 7.495,098 B2 Tomazi (45) Date of Patent: Feb

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(12) United States Patent (10) Patent No.: US 7.495,098 B2 Tomazi (45) Date of Patent: Feb USOO7495098B2 (12) United States Patent (10) Patent No.: US 7.495,098 B2 Tomazi (45) Date of Patent: Feb. 24, 2009 (54) EXTRACTION OF ALKALOIDS FROM 1,234,729 A 10, 1917 Gams OPUM 5,922,876 A 7/1999 Huang et al. 6,262,266 B1 7/2001 Chiu et al. (75) Inventor: Keith G. Tomazi, Florissant, MO (US) 6,376,221 B1 4/2002 Fist et al. 2002/0045755 A1 4/2002 Coop et al. (73) Assignee: Mallinckrodt Inc., Hazelwood, MO (US) 2002/0106761 A1 8, 2002 Fist et al. 2003/00873.06 A1 5/2003 Christensen et al. (*) Notice: Subject to any disclaimer, the term of this 2003/0124086 A1 7/2003 Bentley et al. patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 225 days. CA 5O4758 8, 1954 (21) Appl. No.: 111578,627 DE 3O8151 6, 1915 DE 205121 5, 1978 (22) PCT Filed:1-1. May 6, 2005 FRDE 272692512684O1 12/194712/1978 GB 27378 Of 1912 (86). PCT No.: PCT/US2OOS/O16512 GB 114190 3, 1917 WO WO95/O1984 1, 1995 S371 (c)(1), (2), (4) Date: Oct. 16, 2006 OTHER PUBLICATIONS (87) PCT Pub. No.: WO2005/123743 Heumann et al., “The manufacture of alkaloids from opium'. Bulle tin on Narcotics, 1957, vol. 9, No. 2, pp. 34-40, XP002345736. PCT Pub. Date: Dec. 29, 2005 Primary Examiner Janet L. Andres Assistant Examiner David E. Gallis (65) Prior Publication Data US 2007/O241065A1 Oct. 18, 2007 (57) ABSTRACT Related U.S. Application Data A method for extracting at least one alkaloid from opium that (60) Provisional application No. 60/577,801, filed on Jun includes dissolving opium in a solvent, heating the dissolved pp sy- w us opium solution, cooling the dissolved opium Solution, adjust 8, 2004. ing the pH of the dissolved opium solution with at least one (51) Int. Cl. first weak acid, filtering the dissolved opium solution to CO7D 489/02 (2006.01) recover a filtrate; and then separating and purifying at least (52) U.S. Cl. ......................................... 5644, 514,282 one alkaloid in the filtrate. Preferably, this includes an addi (58) Field of Classification Search s 546/44: tional step of chilling the opium Solution after adjusting the pH of the dissolved opium solution with at least one first acid. 514/282; 210/773 The preferred method for separating and purifying at least See application file for complete search history. one alkaloid in the filtrate includes utilizing preparative liquid (56) References Cited chromatography, however, solvent extraction and filtration can also be utilized. U.S. PATENT DOCUMENTS 1,048,712 A 12/1912 Lloyd 23 Claims, 2 Drawing Sheets U.S. Patent Feb. 24, 2009 Sheet 1 of 2 US 7.495,098 B2 Opium Filtration (HCI/HOAC 100/50/15 C) 0.008 y E00000151X + 0.0006 ea R = 0.9903655 0.006 t/V mini?m 5134-166 is 0.004 3 hr 50/15 5 -Linear (t/V min/mL 0.002 5134-1663 hr 50/15) O O 100 200 300 400 500 Filtrate Volume, V (ml) F.G. 1 Alkaloid Extraction 25 vm-wave ------ • Morphine HCL & Morphine HOAC A Codeine HCL Codeine HOAC Thebaine HC othebaine HOAC O 2O 40 60 80 100 120 Time (hrs) FIG 2 U.S. Patent Feb. 24, 2009 Sheet 2 of 2 US 7.495,098 B2 Alkaloid Extraction, Butanol, pH = 9.0 14.00 12. OO 10.00 0 Morphine gll 8. OO 6, OO as Codeine g/L 4.00 Athebaine gll 2, OO O,OO Time (hrs) FG, 3 Cake Resistance of Opium 8 a te E. E v. X 9 O. 1 (D O 2O 40 60 Digest Temperature (C) FIG. 4 US 7,495,098 B2 1. 2 EXTRACTION OF ALKALOIDS FROM by extraction with toluene, then the aqueous morphine stream OPUM is extracted with fusel oil. The remaining alkaloids are sepa rated from the chloroform by acid extraction and evaporation. CROSS REFERENCE TO RELATED The narcotine, papaverine and thebaine are then obtained by APPLICATIONS fractional crystallization. The preferred method for separating the principal alkaloids This application is a national stage application of PCT/ is by using preparative liquid chromatography. This method US2005/016512, filed May 6, 2005, which claims the benefit includes loading a stationary phase media into a chromato of U.S. Provisional Application No. 60/577.801 filed Jun. 8, graphic column, feeding a crude narcotic alkaloid solution 2004. 10 into the chromatographic column, applying at least one mobile phase to the chromatographic column, and recovering BACKGROUND OF THE INVENTION at least one narcotic alkaloid eluate from the chromatographic column. This method is disclosed in International Patent Opium is a key material that is used in the production of Application No. WO03074526 that was published on Sep. 12, morphine, codeine, thebaine and narcotine. Moreover, it is 15 2003, which is incorporated herein by reference in its entirety. the only source for narcotine. Opium is obtained by cutting The present invention is directed to overcoming one or the unripe pods of Papaver Sonniferum, then collecting the more of the problems set forth above. resulting fluid and drying the fluid under ambient conditions. Opium is typically obtained in loaves that are individually SUMMARY OF INVENTION wrapped in paper and is a black, tarry material with a char acteristic odor. In one aspect of this invention, a method for extracting at A major problem is the ability to efficiently and effectively least one alkaloid from opium is disclosed. This method separate the principal alkaloids as well as separate the prin includes dissolving opium in a solvent, heating the dissolved cipal alkaloids from the opium residue. There are a number of opium solution, cooling the dissolved opium Solution, adjust methods for separating opium into the principal alkaloids, 25 ing the pH of the dissolved opium solution with one or more i.e., morphine, codeine, oripavine, thebaine, papaverine and somewhat strong to weak acids to improve the filterability of narcotine. However, all of these techniques are vastly the opium, and to extract the useful alkaloids, cooling to a improved by starting with material that is rich in the principal lower temperature to further improve the filterability, filtering alkaloids with minimal opium residue and other alkaloids. the dissolved opium solution to form a filter cake, and then The most common process to separate narcotic alkaloids, 30 washing the filter cake to recover more dissolved alkaloids. which includes morphine, codeine, oripavine, thebaine, The spent filter cake may be discarded. The filtrate and wash papaverine and narcotine (noscapine), is by solvent extrac liquors are then further processed to recover purified mor tion. Separation includes both purification as well as color phine, codeine, thebaine, and narcotine. The pH of the acid removal. The separated narcotic alkaloids are then purified by can vary greatly, however, the use of strong acids (for carbon adsorption and precipitation. 35 example, hydrochloric acid) is typically avoided in order to One specific example of this type of modified solvent improve yields. extraction is found in U.S. Pat. No. 6,054,584 issued to Ma, et These are merely some of the innumerable aspects of the al. on Apr. 25, 2000, which discloses a process for extracting present invention and should not be deemed an all-inclusive only morphine from opium wherein the opium is dissolved in listing of the innumerable aspects associated with the present a basic alcoholic solution. The basic alcoholic solution is then 40 invention. These and other aspects will become apparent to filtered and the alcohol is removed from the filtrate to leave a those skilled in the artin light of the following disclosure and residue. The residue is then extracted with a basic aqueous accompanying drawings. Solution having a pH of at least 11. The basic aqueous solution may be filtered to remove any solid matter remaining after the BRIEF DESCRIPTION OF THE DRAWINGS aqueous extraction step, and then is stirred with a sufficient 45 amount of salt to avoid the formation of an emulsion. The For a better understanding of the present invention, refer basic aqueous solution or filtrate is then extracted with ben ence may be made to the accompanying drawings in which: Zene or toluene. Next, the pH of the basic aqueous filtrate is FIG. 1 is a graphical plot of a constant pressure batch adjusted to a pH of between 8.5 to 9.5 that allows the mor filtration experiment, a plot oft/V versus volume: phine to precipitate for recovery. 50 FIG. 2 is a graphical plot of the concentration of alkaloids There are a number of different ways to achieve adsorption in the Supernatant liquor during the acid digest step compar besides the use of carbon. One way to achieve adsorption is ing hydrochloric acid and acetic acid; through ion exchange. Yet another way to achieve adsorption FIG. 3 is a graphical plot of alkaloid extraction with is through polar interaction or normal phase adsorption. Still, butanol at a pH of 9.0 of the assay (g/L) versus time in hours: yet another way to achieve adsorption is through separating 55 and alkaloids from other components based on molecular size by FIG. 4 is a graphical plot of the affect of acid digest tem utilizing a membrane. perature upon opium cake resistance. Another major method for processing opium to separate the principal alkaloids is based on dispersion of opium in DETAILED DESCRIPTION OF THE INVENTION water, which is then followed by extraction with hydrochloric 60 acid. This then is followed by separation of the insoluble In the following detailed description, numerous specific material with plate-and-frame filtration.
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