Some Modern Aspects of Heroin Analysis
INFRA-RED SPECTRA (concluded)
INFRA-RED SPECTRA (concluded)
Author: Melvin LERNER, Albert MILLS
Pages: 37 to 42
Creation Date: 1963/01/01
U. S. Customs Laboratory, Baltimore, Maryland
The Bulletin on Narcotics devoted its June 1953 issue to heroin. The history of heroin, its pharmacology, and methods of analysis were described at length. In the ensuing nine years the history of heroin has not changed much: it is still, as the Bulletin stated, "by far the most important drug of addiction, at least in the Western world." If anything, its domain has been extended. Recent reports [ (1)] indicate that heroin has largely replaced opium among addicts in Hong Kong. In the United States, with the passage of the Narcotic Control Act of 1956 (Public Law 728, 84th Congress, 2nd Session), heroin has come to occupy a unique position: in certain circumstances, the government of the United States has provided a possible death penalty for those who sell heroin to minors; the law recognizes a special danger from heroin that does not apply to other narcotics.
In the field of pharmacology, recent studies [ (2)] confirm the earlier work of Eddy & Howes [ (3)] that the distinctive pharmacological properties of heroin are largely due to 6-monoacetylmorphine. Heroin is rapidly hydrolysed in the body to 6-monoacetylmorphine and, in time, to morphine. It is of interest that 6-monoacetylmorphine, which is both stable and easy to prepare, has never been deliberately manufactured for use in either legal or illegal medicine.
The analysis of heroin seizures has always been a difficult matter; small percentages of heroin must often be separated from very complex mixtures. The analysis has been complicated by the knowledge that two monoacetylmorphines existed and were of common occurrence, but that only one (in 1953) had been prepared in pure form and characterized; lack of consistency in the literary nomenclature of the two monoacetylmorphines served to complicate the problem. The accepted formula for morphine is shown in figure 1.
To serve as a frame of reference in the following discussion, the two monoacetylmorphines may be differentiated as follows. The 6-monoacetylmorphine hydrochloride crystallizes from water solution; the 3-monoacetylmorphine hydrochloride is amorphous. Both monoacetylmorphines have at various times been called alpha or beta. It would seem only proper that the wishes of the men who originally discovered heroin and the monoacetylmorphines should be respected; C. R. A. Wright & G. H. Beckett [ (4)] [ (5)] called the material which crystallized from water solution (6-monoacetylmorphine hydrochloride) "alpha" and that which they could not crystallize (3-monoacetylmorphine hydrochloride) "beta ". Wright and Beckett considered morphine a double molecule; heroin was tetra-acetylmorphine to them, but it is quite easy to unravel their work once it is conceded that morphine has but two replaceable hydroxyls. It is true that the gamma-monoacetylmorphine, which Wright and Beckett thought they had found, was found by no other investigator and would seem to be theoretically impossible; but their errors were minor compared to the fact that theirs was the first recorded synthesis of both heroin and the two monoacetylmorphines; their nomenclature, in the absence of any overriding theoretical considerations, should prevail.
The method of preparation of pure 6-monoacetylmorphine hydrochloride has long been known (6). C. I. Wright [ (7)] improved on earlier procedures by adding a concentrated aqueous solution of hydroxylamine hydrochloride to an alcoholic solution of heroin base. In this laboratory we have found that Wright's procedure can be made quantitative by eliminating all water and adding an alcoholic solution of hydroxylamine hydrochloride to an alcoholic solution of heroin base. We have also followed C. R. A. Wright's [ (4) ] procedure for producing alpha-monoacetylmorphine by reacting morphine alkaloid with glacial acetic acid; the alphamonoacetylmorphine so prepared had an infra-red spectrum identical to the spectrum of the 6-monoacetylmorphine prepared by the reaction of heroin and hydroxylamine hydrochloride.
6-monoacetylmorphine alkaloid (alpha)
6-monoacetylmorphine hydrochloride (alpha)
3-monoacetylmorphine alkaloid (beta)
3-monoacetylmorphine hydrochloride (beta)
The preparation of pure 3-monoacetylmorphine is a relatively recent development. L. H. Welsh in 1954 (8) synthesized it by reacting morphine base with acetic acid anhydride in the presence of sodium bicarbonate. Welsh also prepared two crystalline derivatives of the 3-monoacetylmorphine-the benzoate and the sulfamate- and confirmed the amorphous nature of the 3-monoacetylmorphine base and the 3-monoacetylmorphine hydrochloride. Welsh proved that his 3-monoacetylmorphine was identical with the beta of Wright and Beckett by incompletely acetylating morphine using Wright & Beckett's procedure; the crude material thus obtained gave, on purification, the same in infrared spectrum as 3-monoacetylmorphine. Our laboratory has confirmed Welsh's findings.
Our interest in the two monoacetylmorphines was aroused by certain difficulties that kept arising repeatedly in our analysis of heroin seizures. The samples would not "behave properly" on extraction, and would not give characteristic heroin crystals with platinic chloride or mercuric iodide; the infra-red spectra, although having a family resemblance to the spectrum of heroin, were distinctly different. We could prove the presence of a morphine derivative, and we suspected that one or both monoacetylmorphines were involved, but without pure known specimens complete identification was difficult.
Having prepared the two monoacetylmorphines by the methods of C. I. Wright (7) and L. H. Welsh (8), we found the following characteristics of analytical interest:
Some modern aspects of heroin analysis 41
Appended are the infra-red spectra (from potassium bromide pellets) of the base and hydrochloride of both monoacetylmorphines and, for comparison purposes, similar spectra for heroin and morphine. Of particular interest are the bands at approximately 5.75 microns. We have found it difficult or impossible to identify by means of the infra-red spectra alone the components of mixtures of morphine derivatives in which one or more of the components were present in minor amounts.
In table 1 are shown the absorbances in half normal hydrochloric acid that we obtained.
Max. Wavelength my;
Max. Absorbance (log E)
Minimum log E
The acid solutions of 3-monoacetylmorphine and heroin showed rather large shifts in their minima on standing for four hours; the 3-monoacetylmorphine minimum became 256 mµ and the heroin minimum became 254 mµ.
Heroin and 3-monoacetylmorphine both give a green-blue with concentrated nitric acid; morphine and 6-monoacetylmorphine give an orange-red.
The U.S. Customs Heroin Field Test (9) is positive for heroin and negative for morphine and both monoacetylmorphines.
Ferric chloride solution gives a green colour with morphine and 6-monoacetylmorphine; no colour is given with heroin and 3-monoacetylmorphine.
3-monoacetylmorphine hydrochloride- no crystals with mercuric iodide or platinic chloride; dense feathers with gold hydrobromide; yellow sheaves or rosettes of branches with Wagner's reagent.
6-monoacetylmorphine hydrochloride- rods with mercuric iodide; brown puff-balls with platinic chloride; red rosettes with gold hydrobromide; yellow needles and rods with Wagner's reagent.
Qualitative. -The two monoacetylmorphines, morphine and heroin, can be qualitatively separated by paper chromatography (10); a solvent mixture of iso-amyl alcohol, water, and glacial acetic acid gives four distinct spots with iodoplatinate reagent.
Gas chromatography is potentially applicable to this separation; alkaloids such as codeine, morphine, caffeine and quinine have been separated by Lloyd et al (11), and it is our intention to try various silicone gums and oils as liquid phases for the effective separation of the two monoacetylmorphines.
Quantitative. - Fulton's original scheme for the analysis of heroin mixtures (12) was substantially modified by us to give quantitative separations for the four narcotics we have usually found in "heroin" seizures. The sample is first extracted with chloroform from a cold (> 20°C) 10% (by volume) hydrochloric acid solution. This extracts the heroin and the 3-monoacetylmorphine; these hydrochlorides are then converted to bases by adjusting the pH to 8.4 with dilute ammonia, and water-soluble materials such as the barbiturates removed in the aqueous phase. The material remaining after evaporating the chloroform solution is dissolved in ethanol and an alcoholic solution of hydroxylamine hydrochloride added; after standing two hours at room temperature the alcohol is evaporated, at room temperature, with the aid of a gentle stream of air. At this point any heroin present has been quantitatively converted to 6-monoacetyhnorphine hydrochloride and any 3-monoacetylmorphine present has been quantitatively converted to morphine. Extraction now with chloroform from a cold 10 % (by volume) hydrochloric acid solution will take into the chloroform such materials as narcotine, acetylcodine, papaverine, methadone, and caffeine, which were originally extracted with the heroin and the 3-monoacetylmorphine. The heroin (now converted to 6-monoacetylmorphine hydrochloride) is determined by filtering off from the aqueous layer the bulk of the slightly soluble 6-monoacetylmorphine hydrochloride and extracting the remainder with carbon tetrachloride from a slightly ammoniacal (pH 8.4) water solution. The 3-monoacetylmorphine (now converted to morphine) is determined by extraction of the morphine from ammoniacal solution with 3 : 1 chloroformisopropanol.
6-monoacetylmorphine hydrochloride present in the original sample is separated, after the original acid chloroform extraction, by ammoniacal carbon tetrachloride extraction, and any morphine hydrochloride present in the original sample is determined, after removing the 6-monoacetylmorphine, by extraction from the ammoniacal solution with 3 : 1 chloroform-isopropanol.
Most illicit "heroin" has been found by this procedure to contain significant amounts of 6-monoacetylmorphine hydrochloride; some seizures contain mixtures of morphine and 3-monoacetylmorphine. 3-monoacetylmorphine is primarily the result of the incomplete acetylation of morphine; two mechanisms are responsible for the presence of 6-monoacetylmorphine in clandestine heroin production - the presence of some moisture in the acetic anhydride used, or the subsequent partial hydrolysis of the heroin by moist air, or both.
Sealed vials of heroin hydrochloride manufactured prior to 1930 by Malinkcrodt & Merck were found to contain approximately 5 % 6-monoacetylmorphine hydrochloride and 95% heroin hydrochloride; a sample of heroin alkaloid manufactured by Bayer in 1926 was found to contain 2% 6-monoacetylmorphine and 98% heroin; we believe these figures show the stability of heroin which has been properly manufactured; recent seizures we have examined rarely approximate the purity of these thirty-year-old samples; in fact, the origin of the heroin seizure can often be correlated with the degree of purity of the heroin and the proportions of the two monoacetylmorphines present.
Large shipments can be traced from the illicit manufacturer to the wholesaler to the retailer to the peddler by taking advantage of the fact that dilution with lactose or quinine does not affect the original ratios of heroin to the two monoacetylmorphines and morphine, if present.
It is our belief that the use of new tools of analysis such as infra-red and gas chromatography, coupled with a knowledge of the chemistry of morphine and its acetyl derivatives, will result in a closer co-operation between the analytical chemist and the enforcement agencies of the world so that scientific aid can be given to tracking down and eliminating the clandestine factories that manufacture heroin and encourage and profit by its use.
The authors acknowledge their indebtedness to the following members of the Baltimore Customs Laboratory for their assistance: Mr. Jerome V. Hopson for his preparation and interpretation of the infra-red spectra; Mr. Robert M. Lerner for his preparation and purification of the two monoacetylmorphines.
Acknowledgement is also made to Commissioner of Narcotics H. J. Anslinger for his kindness in furnishing us with the authentic samples of legally manufactured heroin.
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