Opium and its alkaloids

American Journal of Pharmaceutical Education, Summer 2002 by Schiff, Paul L Jr

Morphine became generally used as an analgesic in the 1830s, but it use for rapid analgesia did not occur until the perfection of the hypodermic needle in 1853. The alkaloid was used extensively during the Franco-Prussian war and the American Civil War, but since hypodermic needles were not readily available in those years, opium tincture and opium pills were far more commonly encountered. Morphine was commonly placed directly on flesh wounds. The Union Army used 2.8 million ounces of opium tincture and powder and about 500,000 opium pills. It is even reported that an officer would sometimes sit on his horse while men licked opium off of his glove. At the termination of the Civil War, many wounded veterans had become addicted to morphine and their continued dependence on the drug was dubbed the "soldiers' disease"(4,6,7).

Isolation. The isolation of morphine from opium takes advantage of the amphoteric nature of the alkaloid, since morphine is a phenolic amine. Opium is mixed with water, followed by the addition of lime (calcium hydroxide), in order to convert the opium alkaloids from their ionized, water soluble meconate or other plant acid salts into their unionized, water-insoluble free bases. The phenolic alkaloid morphine is soluble in the alkaline lime solution (pH 12) due to the formation of a water soluble phenolate salt. The suspension is filtered and ammonium chloride is added to the filtrate, resulting in the conversion of calcium hydroxide into calcium chloride and ammonia. As a consequence, morphine precipitates at this lower pH (pH 8-9) because its phenolate salt has been converted back to the unionized phenol, which is not capable of remaining ionized in the weakly basic environment of ammonium hydroxide. The crude morphine precipitate is mixed with charcoal and either hydrochloric or sulfuric acid, filtered, and the filtrate alkalinized with ammonium hydroxide, resulting in reprecipitation of morphine. This precipitate is collected via filtration and appropriately dried. It may be subsequently be converted to its sulfate salt for commercial purposes using conventional methods(40).

Chemistry. The elucidation of the structure of morphine, the major alkaloid of the morphinan group, proceeded slowly in the infancy of organic chemistry that prevailed in the early 19th century. The initial elemental analysis of C^sub 34^H^sub 36^O^sub 6^N^sub 2^ proposed by Liebig in 1831 was corrected to C^sub 17^H^sub 19^O^sub 3^N by Laurent in 1847. These experiments were followed by simple chemical transformations of the alkaloid, such as its acetylation to heroin (diacetylmorphine) by Wright in 1874 and its methylation to codeine (monomethylmorphine) by Grimaux in 1881. Herculean efforts directed at the degradation of the alkaloid by Hesse, Knorr, Pschorr, and Vongerichten established the bridged phenanthrene nature of the compound, with the research of Robinson, Schopf and others leading to the accepted structure(18-20). Various oxazine formulae were proposed during initial studies and this is origin of the term "morpholine," which is the common name for tetrahydro-1,4oxazine(19). Finally, in 1925, a series of key degradations and rearrangements led Gulland and Robinson to propose the correct structures for morphine and codeine, the validity of which remained for many years based totally on the ability of the authors to rationalize numerous key rearrangements. The synthesis of morphine proceeded through numerous innovative approaches, with the contributions of Gates and Tschudi, Grewe, and Ginsburg being significant. The complete synthesis of natural morphine and codeine was reported in 1952 by Gates and Tschudi (18-20), with the relative stereochemistry being determined chemically by Holmes in 1952 and confirmed by X-ray cyrstallographic analysis in 1955. The absolute stereochemistry was also determined in 1955 via chemical degradation of dihydrocodeinone (18).