Opium and its alkaloids

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

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History. In 1803, the Parisian Derosne describe the isolation of a "salt of opium" as the first crystalline compound to have been isolated from opium. Although the identity of the compound is not known with certainty, it is believed to have been morphine meconate or narcotine, or possibly an admixture of the two. Seguin described the isolation of this compound in detail in 1804, but it is a young German pharmacist, Friedrich Wilhem Adam Sertrner, who is rightfully credited with the isolation of morphine in 1806. He began his experiments with opium in 1803 in a back room of the Hof-Apotheke in Paderborn, Germany, and reported the results of his first experiments, which dealt principally with the isolation of meconic acid, in 1805. In 1806, he published a more detailed paper describing the results of some fifty-seven experiments in which he reported the isolation of "principium somniferum," the narcotic principle of opium. Furthermore, he reported that the new substance was alkaline in nature, and was the first representative of a new class of organic bases called "vegetable alkalis" that were "salifyable," that is, bases that formed salts with both organic and inorganic acids. Although Sertimer's reports were not widely accepted, he persisted and in 1817 published a review and conclusive re-evaluation of his earlier work, in addition to further new experiments. It is in this paper that Serturner first used the name "morphine" (Morpheus - Greek god of dreams) for the new compound, and stipulated that in addition to the usual carbon, hydrogen, and oxygen, morphine also contained nitrogen. He also described the results of experiments in which he and three of his colleagues each orally consumed three half-grain doses of morphine within approximately 30 minutes. Serturner became alarmed at the response of his friends, and had them drink vinegar, causing a violent emesis. In 1818, another German pharmacist, Karl Friedrich Wilhelm Meissner, assigned the name "alkaloid" ("alkali-like") to these new salifyable bases, a name that persists in history to this day(6,14,16-18).

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).