The Physical Methods for the Identification of Narcotics

Sections

PART IB1

Details

Author: Charles G. Farmilo, Leo Levi
Pages: 7 to 19
Creation Date: 1954/01/01

TECHNICAL

The Physical Methods for the Identification of Narcotics

A series of articles, written under the direction of Charles G. Farmilo and Leo Levi

Charles G. Farmilo
Leo Levi
Organic Chemistry and Narcotic Section, Food and Drug Laboratories Department of National Health and Welfare, Ottawa, Canada

PART IB1

THE COMMON PHYSICAL CONSTANTS FOR IDENTIFICATION OF NINETY-FIVE NARCOTICS AND RELATED COMPOUNDS

By Charles G. Farmilo, P. M. Oestreicher and Leo Levi, Organic Chemistry and Narcotic Section, Food and Drug Laboratories, Department of National Health and Welfare, Ottawa

The usual schemes of organic analysis referred to in part IA, table I ([1] ),2 include the determination of the common physical constants, boiling point, melting point, empirical formula, molecular weight, optical rotation, refractive index, etc. In order to authenticate narcotics for X-ray, ultra-violet, and infra-red examination, the melting or boiling points and water of crystallization were determined and the "wet" molecular weights caclulated. Elemental analysis and calculation of empirical formulas from C, H, N, and O values were not undertaken at this time. Most substances which were studied were commercial preparations and met official requirements.

The object of this paper is to review common physical constants of narcotics, to present methods of preparation of narcotic free bases, the results of water analyses, melting or boiling points, and acidity coefficients of ninety-five narcotics and related compounds. Empirical formulas, molecular weights and specific optical rotations obtained from the chemical literature were tabulated along with other data useful in identification.

MATERIALS

The various narcotics and related compounds were originally obtained from the various sources, mainly commercial, shown in table I, column 2, at the end of this article. A number of free bases were prepared from the commercial salts and are indicated in table I, column 2, by a footnote. Commercial samples were otherwise used without further purification for the ultra-violet and infra-red studies, and for most of the X-ray work. Single crystals were grown in some cases for special X-ray studies by Dr. W. Barnes and details of these experiments are given in part IIB ([2] ).

1

For part IA, see Bulletin on Narcotics, vol. V, No. 4.

2

Figures in parentheses throughout the text refer to the numbered publications listed at the end of this article.

NAMES AND NOMENCLATURE

The problem of selecting a name for each substance from the multiplicity of chemical, common, official, and trade names is one which had to be faced to simplify tabulation and discussion. Recently Kautz ([3] ) and Miller ([4] ) outlined the same problem in relation to views of various national and international organizations and reviewed some general rules arrived at by WHO for setting up non-proprietary names ([5] ).

By no means all of the substances regarded as narcotics by the United Nations and the Canadian Narcotic Control Division, Department of National Health and Welfare, have been given official non-proprietary names. A comprehensive list of names for narcotics used in various manufacturing countries has been prepared by the Narcotic Division of the United Nations ([33] ). The selection of one name is often difficult since as many as twenty names in the English language occur for some compounds. It is obvious that one name has to be given primacy in each case.

It was decided that since this work would be mostly used by chemists, expanded chemical and common chemical names would be employed in the main tables and for labelling the spectra of the narcotics.

The following rules for selecting names for narcotics were adhered to as far as possible.

  1. The name was, if possible, selected from the following sources, so far as their decisions were known to us in the order of preference given:

  1. International Pharmacopoeia and international non-proprietary names selected by the WHO Expert Committee on the International Pharmacopoeia;

  2. British Pharmacopoeia and approved non-proprietary names selected by the Pharmacopoeia Commission of the General Medical Council;

  3. United States Pharmacopeia and approved nonproprietary names selected by the Council on Pharmacy and Chemistry of the American Medical Association (these names are used in New and Non-Official Remedies);

  4. The Merck Index of Chemicals and Drugs.

  1. The name was devised according to the rules of nomenclature for the international non-proprietary names ([5] ).

  2. Expanded chemical names were based on International Chemical Union rules of nomenclature given in Chemical Abstracts and The Ring Index ([6] ). These names are also given in the Merck index ([7] ).

One-trade name, Acedicon ® ([7] ) has been used as the only available brief name of the compound dihydrocodeinone enol acetate hydrochloride.

Common names and some trade names are listed in table II. The common or non-proprietary names are used for photographs, tables of data, and in discussion in the text. Following the common name in brackets, in table II, a chemical name is given, for example, dl-alphaprodine hydrochloride; (piperidine -1,3-dimethyl-4-phenyl-4-propionoxy hydrochloride ( dl-&alpha-(cis)) The name in parentheses is the form of the name used in table I. Normally, the chemical name would read ( dl-&alpha-(cis))-l,3-dimethyl-4-phenyl-4-propionoxypiperidine, as used in indexing spectra. However, it is desirable to bring out chemical relationships in tables and the index style of Chemical Abstracts is preferred for this reason.

In table II, trade names that are registered in the United States Patent Office have a small letter ® to designate this fact. Others may be registered as trade names in other countries but, in the latter cases, no letter ® follows the name. In both cases the name is begun with a capital letter, when used in the ordinary text of subsequent articles, while the common names and the chemical names are uncapitalized.

PREPARATION OF FREE BASES OF THE NARCOTICS

Samples (300 mg.) of the commercial hydrochlorides of ketobemidone, methylketobemidone, oxycodone, cocaine, hydromorphone, pethidine, and d-, l-, and dl-methadones, and racemorphan hydrobromide and dihydrocodeinone bitartrate were dissolved in a minimum volume of water (about 1 cc. in most cases) and the free bases precipitated with concentrated ammonium hydroxide; aqueous solutions of metopon, pipidone, ethylmorphine, isomethadone, and phenadoxone hydrochlorides were treated with 2N ammonium hydroxide; hydroxypethidine, alphaprodine, benzylmorphine, and diamorphine free bases were prepared from aqueous solutions of hydrochlorides by reaction with dilute sodium hydroxide. All the bases were obtained as solids except alphaprodine, pipidone, isomethadone, and pethidine, which separated from aqueous solutions as viscous oils. The mother liquors were removed from the solids by decanting and were filtered; the solids washed with cold water and recrystallized twice from 95 or 100 per cent ethanol, then dried in the presence of phosphorous anyhydride in a vacuum desiccator at reduced pressures. The solids were stored in the dark in small glass vials with plastic screw tops. In the case of the oils mentioned above, the base was dissolved in ether and the aqueous mother liquor extracted with ether. The combined ether extracts were dried in contact with Na 2SO 4 (anhydrous), then the volume of ether was partially reduced and the remaining ether solution poured into a Späth bulb, washed down with a small volume of clean, dry ether. The ether was completely removed at reduced pressure from the Späth bulb, carefully, by means of a water aspirator pump, and the oily residue distilled in an all-glass system at greatly reduced pressure (0.01 - 0.1 mm. Hg) by means of a mercury diffusion pump backed by a mechanical pump. The boiling point of the base was determined at this time; and the oil then removed from the distillation bulbs and run into vials which were sealed and stored in a refrigerator. The sample of pethidine oil, after refrigeration for about two weeks, solidified into a mass of needle-like crystals.

METHODS OF ANALYSIS

  1. Melting points of the pure crystalline narcotic bases were determined, using a Fisher-Johns melting-point block. The rate of heating of the compound was noted.

    Melting and boiling points of all the substances, salts and free bases, compared with values obtained from the chemical literature, are collected in table I for easy reference. Commercially available samples obtained from various drug companies were found to meet the required pharmacopoeial specifications of purity by quantitative analysis ([9] ), ([10] ), and were used without further treatment. Certain samples used without purification showed results which were different from the literature or expected values. The anomalies have been indicated by special notes on individual compounds in the experimental parts of the papers dealing with the individual methods, i.e., the X-ray, U.V., I.R., etc. This information will be useful in practical identification work.

  2. Water of crystallization and free or adherent water were together determined by means of a modified Karl Fischer titration technique ([11] ). The remaining compounds were dried in an Aberhalden pistol under reduced pressure to a constant weight. The weight difference was taken as loss of water. In some cases sublimation occurred at the pressure and temperatures used, and these cases are also noted.

  3. The pK A values of the substances ([9] ) were determined by the fractional neutralization of salts according to the method given by Saunders and Srivastava ([12] ).

  4. Optical rotation values were not experimentally determined for this study but values given in the literature and references are given in table I.

RESULTS

Physical data for the identification of narcotics and related compounds are listed in table I. The chemical name of the compound is listed in column 1. The source of the material is shown in column 2. Empirical formulas based on the generally accepted formula of the compound and the corresponding molecular weight are given in columns 3 and 4 respectively. The water content of the compounds as per cent and mole of water is shown in columns 5 and 6, along with the calculated molecular weight (computed by adding the found molecular weight of water to the anhydrous weight) is shown in column 7. Found and given melting points or boiling points are shown in columns 8 and 9 along with the literature reference in column 10. The specific optical rotation, and the concentration, solvent, and temperature used, and literature reference, are tabulated in columns 11 and 12. The acidic dissociation exponents, pK A, determined previously ([9] ) are tabulated in column 13.

Some notes on individual compounds are given in the following section. In table I, attention is called to them by a footnote.

NOTES ON INDIVIDUAL COMPOUNDS Codeine (free base)

The sample described in table I must have contained a large number of prismatic crystals of the monohydrate. Over a period of time much of the sample appeared to have lost water of crystallization as shown by Karl Fischer determinations. The anhydrous material was used for both ultra-violet and infra-red studies. It should be noted for purposes of analysis that codeine monohydrate is efflorescent.

Codeine phosphate

The sample described in table I, employed for ultra-violet and infra-red examinations, was probably a mixture of hydrates. Codeine phosphate hydrates with 1, 1.5 and 2 moles of water have been reported ([13] ) and the higher ones are said to be efflorescent ([14] ). Variations in the water content of the samples submitted for X-ray diffraction have been noted by Barnes and Sheppard ([2] ). The sample reported in table I was found to contain 1.22 moles water.

Codeinone, diFhydro (free base) and codeinone, dihydrohydroxy (free base)

Water of crystallization was determined in both of these samples described in table I, using small amounts (5 mg.) of the free bases. Both were found to be anhydrous when dried at 55oC and 0.1 mm. Hg pressure using an Aberhalden drying pistol. Both also sublimed at 100oC and 0.1 mm. Hg.

Cotarnine (free base)

Two samples of cotarnine were available for study, the first (described in table I) was a dull brick red in color. The second, having similar common physical constants, was faint yellow in color. The color change is apparently a result of ageing. A careful study of the thermal and hydration reactions of cotarnine is required. dl-3-Heptanone, 6-dimethylamino-4,4-diphenyl, HBr

Two samples of the methadone hydrobromide were available for analysis. The original commercial sample (B) was found to contain 0.048 moles of water, indicating the lack of water of crystallization. Subsequent analysis showed the commercial sample to contain some methadone HCl as an impurity. A sample of methadone hydrobromide (A) (free of hydrochloride) was prepared, which was used for further studies. X-ray diffraction showed the methadone hydrobromide portion of the sample (B) to be identical with the laboratory preparation (A). Both compounds B and A are described in table I. dl-3-Hexanone, 6-diamethylamino-4,4-diphenyl-5-methyl (free base) and dl-3-hexanone, 6-piperidine-4,4-diphenyl-5-methyl (free base)

Both compounds were obtained as liquids and purified by distillation in a high vacuum. They were essentially anhydrous when prepared and were stored under anhydrous conditions.

Isoquinoline, 6,7-dimethoxy-1-veratryl, HCl

This sample of papaverine hydrochloride was dried in an Aberhalden drying pistol at 100oC and 0.1 mm. Hg for several days. No loss in weight was found. The sample was found to be anhydrous. Sublimation occurred at 140oC and 0.1 mm. Hg. dl-Morphinan, 3-methoxy-N-methyl, HBr, monohydrate

The different melting ranges were observed when conditions of heating were altered. If a sample was placed on the block at 50oC (or lower) the melting range was observed to be 112o-115oC. When the sample was placed on the melting block which was heated to 75o-80oC, then complete melting of the sample was observed between 82o and 85oC. It was assumed that dehydration (loss of 1 mole of water) occurred when the sample was heated at a rate of 5o/min. from a temperature of 50o to 112o-115oC. No difficulties were encountered in determination of water of crystallization.

Morphine, HI, dihydrate

Three melting point ranges for morphine hydrogen iodide dihydrate were observed:

Block temp. oC
Observed m.p. oC
80-120
( a) 180-185
120-138
( b) 250-253
139
( c) 140-141

The sample melted in range (a) when the block temperature was initially between 80o-120oC. The true melt- ing point of the dihydrate of morphine HI appears to be ( c), 140o-141oC. The melt ( a) recrystallizes at about 200oC and then melts again at 250o-253oC with decomposition.

Two samples of morphine HI were available for study. The first, sample A, was a commercial sample, the second, B, was prepared in our laboratory. They were identical in properties.

Morphine, H2SO4, dihydrate and pentahydrate

Three commercial preparations of morphine sulfate were titrated with Karl Fischer reagent and the averages of five titrations were obtained. The moles of water per mole of narcotic were 4.98, 5.14 and 5.14 respectively. It was observed by Barnes and Sheppard ([2] ) that morphine sulfate pentahydrate was readily changed to a dihydrate on exposure to high temperatures and low humidity, conditions which sometimes exist in the laboratory.

Morphine, diacetyl, (free base) anhydrous

Water of crystallization was obtained by drying under reduced pressure in an Aberhalden drying pistol. The sample was anhydrous at 56oC and 1.0 mm. Hg and sublimed at 100oC and 1.0 mm. Hg.

Morphine, ethyl, HCl dihydrate

Two melting points were observed:

Block temp. oC
Observed m.p. oC
123
( a) 123
125 or less
( b) 150-160

No recrystallization phenomenon was observed.

Morphinone, dihydro (free base), anhydrous

A sample of dihydromorphinone free base was dried in the Aberhalden drying pistol over P 2O 5 and showed no weight loss after 12 hours at 70oC and 10 mm. Hg. The sample was assumed to be anhydrous.

Morphothebaine, HCl anhydrous

No loss of weight was observed when a sample of morphothebaine hydrochloride was heated at 155oC and 0.1 mm. Hg for 5 days in an Aberhalden drying pistol containing P 2O 5. The sample was assumed to be anhydrous.

Narceine (free base) and narceine hydrochloride

Narceine free base and narceine hydrochloride hydrates have been reported ([7] ), ([13] ) with 1 or 3, and 1, 3 or 5? moles water per mole anhydrous free base and anhydrous salt respectively. Karl Fischer titration of commercial samples of the free base and salt indicated an average value of 1.72 mole and 0.26 mole water respectively. The melting points for narceine free base mono- and trihydrates are given as 138oC and 176oC respectively and the melting point found for the intermediate hydrate 152o-155oC. Melting point ranges of 188o-192oC and 192o-193oC have been reported by Merck (7) and Small (13) for anhydrous narceine hydrochloride. The observed melting point for the intermediate narceine hydrochloride hydrate (0.26 mole H 2O) was dependent upon the temperature of the block at the beginning of the melting point determination. If the material was placed on the block at 120oC, the observed melting point range was 148o-157oC, and if placed on the block before 120oC, the melting occurred at 190oC.

dl-&alpha- (cis)-Piperidine, 1,3-dimethyl-4-phenyl-4-propionoxy

A sample was prepared from the anhydrous alphaprodine hydrochloride. It gave a boiling point of 70o-175oC at 0.02 mm. Hg and did not crystallize on further purification. Ziering ([26] ) obtained a crystalline material melting 130oC.

dl-&alpha-(cis)- and, dl-&alpha-(trans),-Piperidine, 1,3-dimethyl-4-phenyl-4-propionoxy HCl

The samples of dl-alphaprodine and dl-betaprodine hydrochlorides were examined by Barnes and Sheppard ([2] ) who separated crystals of two different habits from the anhedral fragments composing a large part of dl-betaprodine hydrochloride. Both crystal types were monoclinic but those of alphaprodine hydrochloride were pseudo-rectangular plates while those of betaprodine hydrochloride were pseudo-hexagonal plates. The alphaprodine hydrochloride sample was homogeneous and the betaprodine hydrochloride was non-homogeneous with respect to crystal type. Melting points given by Ziering ([26] ) are 214o-215oC and 218o-220oC for alphaprodine hydrochloride, and 190o-192oC for betaprodine hydrochloride. The observed melting points were 223o-225oC using a heating rate of lo/min, and 193o-194oC using a heating rate of 5o/min. for the alpha and beta compounds respectively. The samples of alpha and betaprodine hydrochloride were used for ultra-violet and infrared studies without further purification.

Piperidine, ethyl-l-methyl-4-phenyl-4-carboxylate (free base)

Two samples of pethidine (free base) were available, one-laboratory preparation (A) and one commercial sample (B). Sample A, prepared from commercial pethidine hydrochloride was an oil which distilled at 80o-100oC at 0.025 mm. Hg. It yielded crystals on standing which, like those of sample B, melted at 31o-34oC using a heating rate of 2o/mm. Bergel (27) reported pethidine (free base) to be a liquid boiling at 115oC at 0.2 mm. Hg.

Protopine (free base)

Three samples of protopine (free base) were available for examination. The original sample A contained two crystalline phases, one comprised of clear crystal fragments, the other a mass of fine powder. A water analysis on sample A indicated the material to be anhydrous. Sample B was obtained from the same commercial source as sample A, while sample C is an authentic sample of protopine supplied by Dr. Leo Marion. Samples B and C were found by Barnes and Sheppard ([2] ) to be homogeneous and identical. Sample A melted at 206°-208°C; samples B and C melted at 208°C and 209°C, respectively. Samples A and C were studied by means of ultraviolet and X-ray methods, and findings are discussed by Barnes and Sheppard ([2] ) and by the present authors ([8] ).

Samples A and C are described in table I. There appears to be a second component in sample A which is unidentified.

Pseudomorphine (free base)

Only a small amount of the pseudomorphine (free base) was available for experiments.

Karl Fischer titration indicated 3 moles of water were present; duplicate analyses were not made. The trihydrate form was assumed to be present.

Tropane, 3-hydroxy, carboxylic acid (ecgonine)

The sample of ecgonine was a commercial grade obtained from Merck and Co. It was a thick viscous liquid.

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TABLE II

LIST OF THE COMMON OR NON-PROPRIETARY NAMES USED, AND SOME OF THE BEST-KNOWN TRADE NAMES, WITH THE CORRESPONDING CHEMICAL NAMES

Acedicon® hydrochloride (codeinone, dihydro enol acetate, HC1)

Acetoxyketobemidone hydrochloride (4-piperidyl ethyl ketone,-4-(m-acetoxyphenyl) -1-methyl, HCl)

d-&alpha-Acetyl methadol hydrochloride (see d-&alpha-methadyl acetate hydrochloride)

dl-&alpha-Acetyl methadol hydrochloride (see dl-&alpha-methadyl acetate hydrochloride)

l-&alpha-Acetyl methadol hydrochloride (see l-&alpha-methadyl acetate hydrochloride)

dl-Alphaprodine (free base) (piperidine, 1,3-dimethyl-4-phenyl-4-propionoxy) ( dl-&alpha- (cis)

dl-Alphaprodine hydrochloride piperidine, 1,3-dimethyl-4-phenyl-4-propionoxy, HCl) ( dl-&alpha-(cis))

d-Amidone (free base) (see d-methadone (free base) )

dl-Amidone (free base) (see dl-methadone (free base) )

l-Amidone (free base) (see l-methadone (free base) )

dl-Amidone hydrobromide (see dl-methadone hydrobromide)

d-Amidone hydrochloride (see d-methadone hydrochloride)

dl-Amidone hydrochloride (see dl-methadone hydrochloride) l-Amidone hydrochloride (see l-methadone hydrochloride)

Apomorphine hydrochloride

Bemidone (free base) (see hydroxypethidine (free base))

Bemidone hydrochloride (see hydroxypethidine hydrochloride)

Benzylmorphine (free base) (morphine, benzyl)

Benzylmorphine hydrochloride (morphine, benzyl, HCl)

dl-Betaprodine hydrochloride (piperidine, 1,3-dimethyl-4-phenyl-4-propionoxy, HCl) ( dl- &beta-(trans))

Cliradon® (free base) (see ketobemidone (free base))

Cliradon® hydrochloride (see ketobemidone hydrochloride)

Cocaine (free base) (ecgonine, benzoyl, methyl)

Cocaine hydrochloride (ecgonine, benzoyl, methyl, HCl)

Codeine (anhydrous free base)

Codeine monohydrate (free base)

Codeine phosphate (anhydrous)

Codeine phosphate dihydrate

Cotarnine (free base)

Cryptopine (free base)

Demerol® (free base) (see pethidine (free base) )

Demerol® hydrochloride (see pethidine hydrochloride)

Dextromethorphan hydrobromide monohydrate ( d-morphinan, 3- methoxy-N-methyl, HBr)

Diamorphine (free base) (morphine, diacetyl)

Diamorphine hydrochloride monohydrate (morphine, diacetyl, HCl)

Dicodid® (free base) (see dihydrocodeinone (free base))

Dicodid® bitartrate (see dihydrocodeinone bitartrate (dihydrate))

Dihydrocodeine (free base) (codeine, dihydro)

Dihydrocodeinone (free base) (see hydrocodone (free base)

Dihydrocodeinone bitartrate (see hydrocodone bitartrate (dihydrate) )

Dihydromorphine monohydrate (free base) (morphine, dihydro)

Dihydromorphinone (free base) (see hydromorphone (free base) )

Dihydromorphinone hydrochloride (see hydromorphone hydrochloride)

Dilaudid® (free base) (see hydromorphone (free base))

Dilaudid® (free base) hydrochloride (see hydromorphone hydrochloride)

Dionin (free base) (see ethylmorphine (free base) )

Dionin hydrochloride (see ethylmorphine hydrochloride)

Dioxyline phosphate (isoquinoline, 6,7-dimethoxy-1-(4'-ethoxy-3&rsquo methoxybenzyl)-3-methyl, 1-1/2 H 3PO 4)

Dolantin (free base) (see pethidine (free base) )

Dolantin hydrochloride (see pethidine hydrochloride)

Dolophine® (free base) (see dl-methadone (free base) )

Dolophine® hydrochloride (see dl-methadone hydrochloride)

Dromoran® (free base) (see racemorphan (free base))

Dromoran® hydrobromide (see racemorphan hydrobromide) l-Dromoran® tartrate (see levorphan tartrate dihydrate)

Ecgonine (free base) (2-tropane, 3 hydroxy, carboxylic acid)

Ethylmorphine (free base) (morphine, ethyl)

Ethylmorphine hydrochloride (morphine, ethyl, HCl)

Ethylnarceine hydrochloride (narceine, ethyl, HCl)

Ethylpethidine hydrochloride ( dl-piperidine, ethyl-l-methyl-3-ethyl- 4-phenyl-4-carboxylate, HCl)

Eukodal® (free base) (see oxycodone (free base) )

Eukodal® hydrochloride (oxycodone hydrochloride)

Genomorphine (see morphine-N-oxide)

Heptalgine® (free base) (see phenadoxone (free base) )

Heptalgin® hydrochloride (see phenadoxone hydrochloride)

Heroin (free base) (see diamorphine (free base) )

Heroin hydrochloride (see diamorphine hydrochloride monohydrate)

Hycodan® (free base) (see dihydrocodeinone (free base) )

Hycodan® bitartrate (see dihydrocodeinone bitartrate (dihydrate))

Hydrastinine (hydro) chloride monohydrate

Hydrocodone (free base) (see codeinone, dihydro)

Hydrocodone bitartrate (codeinone, dihydro, C 4H 6O 6)

Hydromorphone (free base) (morphinone, dihydro)

Hydromorphone hydrochloride (morphinone, dihydro, HCl)

Hydroxypethidine (free base) (piperidine, ethyl-1-methyl-4-(m-hydroxyphenyl) -4-carboxylate)

Hydroxypethidine hydrochloride (piperidine, ethyl-l-methyl-4-(m-hydroxyphenyl) - 4-carboxylate, HCl)

dl-Isoamidone (free base) (see dl-isomethadone (free base))

dl-Isoamidone hydrochloride (see dl-isomethadone hydrochloride monohydrate)

dl-Isomethadone (free base) ( dl-3-hexanone, 6-dimethylamino-4,4- diphenyl-5-methyl)

dl-Isomethadone hydrochloride monohydrate ( dl-3-hexanone-6-di-methylamino-4,4-diphenyl-5-methyl, HCl)

Ketobemidone (free base) (4-piperidyl ethyl ketone, 4-(m-hydroxy- phenyl) -1-methyl)

Ketobemidone hydrochloride (4-piperidyl ethyl ketone, 4-(m-hy- droxyphenyl)-1-methyl, HCl)

Levomethorphan hydrobromide monohydrate ( l-morphinan, 3-meth- oxy-N-methyl, HBr)

Levorphan tartrate dihydrate ( l-morphinan, 3-hydroxy-N-methyl, C 4H 6O 6) dl-Laudanine (free base)

Meconic acid trihydrate (1,4-pyran, 3-hydroxy-4-oxo-2,6-dicarboxylic acid)

Meperidine (free base) (see pethidine (free base) )

Meperidine hydrochloride (see pethidine hydrochloride)

Mescaline sulphate dihydrate ( &beta-phenethylamine, 3,4,5-trimethoxy, H 2SO 4)

d-Methadone (free base) ( d-3-heptanone, 6-dimethylamino-4,4-di- phenyl)

dl-Methadone (free base) ( dl-3-heptanone, 6-dimethylamino-4,4-di- phenyl)

l-Methadone (free base) ( l-3-heptanone, 6-dimethylamino-4,4- diphenyl)

dl-Methadone hydrobromide ( dl-3-heptanone, 6-dimethylamino-4,4- diphenyl, HBr)

d-Methadone hydrochloride ( d-3-heptanone, 6-dimethylamino-4,4- diphenyl, HCl)

dl-Methadone hydrochloride ( dl-3-heptanone, 6-dimethylamino-4,4- diphenyl, HCl.

l-Methadone hydrochloride ( l-3-heptanone, 6-dimethylamino-4,4- diphenyl, HCl)

d-&alpha-Methadyl acetate hydrochloride ( d-&alpha-3-heptanyl acetate, 6-di-methylamino-4,4-diphenyl, HCl)

dl-&alpha-Methadyl acetate hydrochloride ( dl-&alpha-3-heptanyl acetate, 6-di-methylamino-4,4-diphenyl, HCl)

l-&alpha-Methadyl acetate hydrochloride ( l-&alpha-3-heptanyl acetate, 6-di- methylamino-4,4-diphenyl, HCl)

dl-Methorphan (free base) (see racemethorphan (free base))

d-Methorphan hydrobromide (see dextromethorphan hydrobromide monohydrate)

l-Methorphan hydrobromide (see levomethorphan hydrobromide monohydrate)

dl-Methorphan hydrobromide (see racemethorphan hydrobromide dihydrate)

dl-Methorphinan (free base) (see racemorphan (free base))

dl-Methorphinan hydrobromide (see racemorphan hydrobromide)

l-Methorphinan tartrate (see levorphan tartrate dihydrate)

Methylketobemidone (free base) (4-piperidyl methyl ketone-4-(m-hydroxyphenyl)-l-methyl)

Methylketobemidone hydrochloride (4-piperidyl methyl ketone-4- (m-hydroxyphenyl) -1-methyl, HCl)

Metopon (dihydrate) (free base) (morphinone, methyl, dihydro)

Metopon hydrochloride (morphinone, methyl, dihydro, HC1)

&alpha-Monoacetylmorphine (free base) (morphine, &alpha-monoacetyl)

Morphine hydriodide dihydrate

Morphine hydrochloride (anhydrous)

Morphine hydrochloride trihydrate

Morphine monohydrate (free base)

Morphine-N-oxide

Morphine sulphate dihydrate

Morphine sulphate pentahydrate

Morphine tartrate monohydrate

Morphothebaine hydrochloride

Nalorphine hydrochloride (normorphine, N-allyl, HCl)

Narceine (free base)

Narceine hydrochloride

Narcotine (free base)

Narcotine hydrochloride

Neopine hydrobromide

Nisentil® (free base) (see dl-alphaprodine (free base) )

Nisentil® hydrochloride (see dl-alphaprodine hydrochloride)

&beta-Nisentil® hydrochloride (see dl-betaprodine hydrochloride)

Opianic acid (benzoic acid, 5,6-dimethoxy-2-formyl)

Oxycodone (free base) (codeinone, dihydrohydroxy)

Oxycodone hydrochloride (codeinone, dihydrohydroxy, HCl)

Papaverine (free base) (isoquinoline, 6,7-dimethoxy-l-veratryl)

Papaverine hydrochloride (isoquinoline, 6,7-dimethoxy-l-veratryl, HC1)

Paracodin® (free base) (see dihydrocodeine (free base))

Parahexyl (see pyrahexyl®)

Paveril® phosphate (see dioxyline phosphate)

Peronin (free base) (see benzylmorphine (free base) )

Peronin hydrochloride (see benzylmorphine hydrochloride)

Pethidine (free base) (piperidine, ethyl-l-methyl-4-phenyl-4-car- boxylate)

Pethidine hydrochloride (piperidine, ethyl-l-methyl-4-phenyl-4-car- boxylate, HCl)

Phenadoxone (free base) (3-heptanone, 6-(N-morpholino)-4,4- diphenyl)

Phenadoxone hydrochloride (3-heptanone, 6- (N-morpholino) -4,4-di- phenyl, HC1)?

Physeptone (free base) (see dl-methadone (free base) )

Physeptone hydrochloride (see dl-methadone hydrochloride)

Pipidone (free base) (3-hexanone,6-piperidino-4,4-diphenyl-5-me- thyl)

Pipidone hydrochloride (3-hexanone,6-piperidino-4,4-diphenyl-5-me- thyl, HCl)

dl-&alpha-Prodine (free base) (see dl-alphaprodine (free base) )

dl-&alpha-Prodine hydrochloride (see dl-alphaprodine hydrochloride)

dl- &beta-Prodine hydrochloride (see dl-betaprodine hydrochloride)

Propylketabemidone (free base) (4-piperidyl propylketone, 4-(m-hydroxyphenyl) -1-methyl)

Protopine (free base)

Pseudomorphine trihydrate (free base)

Pyrahexyl® ( pyran,l-hydroxy,3-n-hexyl,6,6,9-trimethyl, 7,8,9,10-tetra- hydro-6-dibenzo)

Racemethorphan (free base) ( dl-morphinan, 3-methoxy-N-methyl)

Racemethorphan hydrobromide dihydrate ( dl-morphinan, 3-methoxy-N-methyl, HBr)

Racemorphan (free base) dl-morphinan, 3-hydroxy-N-methyl)

Racemorphan hydrobromide ( dl-morphinan, 3-hydroxy-N-methyl, HBr)

Sinomenine hydrochloride dihydrate

Synhexyl (see pyrahexyl®)

Thebaine (free base)

Thebaine hydrochloride

Thebenine hydrochloride monohydrate

Trichocereine hydrochloride ( &beta-phenethylamine, 3,4,5-trimethoxy-N-dimethyl, HCl)

REFERENCES

001

FARMILO, C. G. AND LEVI, L.: Part IA: "Introduction to identification of narcotics by physical methods", Bulletin on Narcotics, vol. V, No. 4.

002

BARNES, W. H. AND SHEPPARD, HELEN M.: Part IIB: "X-ray diffraction powder data for eighty-three narcotics", Bulletin on Narcotics , vol. VI.

003

KAUTZ, H. D.: Generic and Brand Names for Drugs, Abstracts of papers, 124th Meeting American Chemical Society, Chicago, Ill., Sept. 6 to 11, 1953; Paper number 44, page 16G (abstract).

004

MILLER, L. C.: International Non-proprietary Names, ibid., paper No. 45, p. 16G (abstract).

005

World Health Organization, Technical Report Series No. 43, Expert Committee on the International Pharmacopoeia, Report on the Eighth Session, p. 27, p. 29 to 35. Appendix 1, General Principles for a System of International Non-proprietary Names.

006

PATTERSON, A.M. AND CAPELL, L. T.: The Ring Index, A List of Ring Systems used in Organic Chemistry, Reinhold Publishing Corporation, New York; 1940, compound No. 3094, p. 425.

007

The Merck Index of Chemicals and Drugs. An encyclopedia for the chemist, pharmacist, physician and allied professions, sixth edition, published by Merck and Co. Inc., Rahway, N.J., 1952.

008

FARMILO, C. G., OESTREICHER, P.M. AND LEVI, L.: Part IIIB: "Ultra-violet spectral data for ninety narcotics", Bulletin on Narcotics , vol. VI.

009

LEVI, L., OESTREICHER, P.M. AND FARMILO, C. G.: "Nonaqueous titration of narcotics and alkaloids", Bulletin on Narcotics , vol. V, No. 1, pages 15-25.

010

LEVI, L. AND FARMILO, C. G.: "The quantitative determination of narcotics by ion exchange", Canadian Journal of Chemistry 30 , 793-799, October 1952.

011

The Pharmacopeia of the United States of America , fourteenth revision, 1950. "Water determination, Karl Fischer method", p. 795.

012

SAUNDERS, L., AND SRIVASTAVA, R. S.: "The potentiometric titration of alkaloidal salts", Journal of Pharmacy and Pharmacology, 3, 78-86, 1951.

013

SMALL, L. F., AND LUTZ, R. G.: Chemistry of the Opium Alkaloids, U.S. Government Printing Office, Washington, 1932. Supplement No. 103 to the Public Health Reports.

014

Handbook of Chemistry and Physics. C. D. Hodgman, M.S., editor, published by Chemical Rubber Publishing Co.

015

RAPOPORT, H.: "Degradation of dihydrocodeine", Journal of Organic Chemistry, 13, 714-721, 1948.

016

LARSEN, A. A., TULLAR, B. F., ELPERN, B. AND BUCK, J. S.: "The resolution of methadone and related compounds", Journal of the American Chemical Society, 70, 4194-4197, 1948.

017

THORPE, R. H., WALTON E., AND OFNER, P.: "Optical isomers of amidone, with a note on isoamidone", Nature, 160, No. 4070, 605-606, 1947.

018

BRODE, W. R. AND HILL, M. W.: "The optical resolution of amidone", . Journal of Organic Chemistry, 13, 191-193, 1948.

019

WALTON, E., OFNER, P., AND THORP, R. H.: "Search for new analgesics. Part III. Homologues of amidone, isoamidone, and some related compounds", Journal of the Chemical Society, London, part I, 648-655, 1949.

020

POHLAND, A., MARSHALL, F. J., AND CARNEY, T. P.: "Optically active compounds related to methadone", Journal of the American Chemical Society, 71, 460-462, 1949.

021

EASTON, N. R., GARDNER, J. H., EVANICK, M. L., AND STEVENS, J. R.: "Some isomers of amidone and related compounds", ibid., 70, 76-78, 1948.

022

ELI LILLY AND COMPANY : "Paveril phosphate (Dioxyline phosphate, Lilly), a full statement of the composition of the drug". Private communication to Food and Drug Laboratory, Ottawa, March 13, 1951.

023

SPAETH, E., AND POLGAR, N.: "Ueber Opium-Alkaloide, V: Pseudo-papaverin und Methylen-papaverin", Berichte, 59, 2780-2787, 1926.

024

RAPOPORT, H., NAUMANN, R., BISSELL, E. R., AND BONNER, R. M.: "The preparation of some dihydro ketones in the morphine series by Oppenauer oxidation". Journal of Organic Chemistry, 15, 1103-1107, 1950.

025

RETI, L. AND CASTRILLON, J. A.: "Cactus alkaloids, I. Trichocereus Terschekii (Parmentier) Britton and Rose", Journal of the American Chemical Society, 73, 1767-1769, 1950.

026

ZIERING, A., AND LEE, J.: "Piperdine derivatives. V. 1,3-dialkyl-4-aryl-4-acyloxypiperidines", Journal of Organic Chemistry, XII, 911-914, 1947.

027

BERGEL, F., MORRISON, A. L.: AND RINDEKNECHT, H.: "Synthetic analgesics. Part II. A new synthesis of pethidine and similar compounds", Journal of the Chemical Society (London), 265-267, 1944.

028

KAGI,H.,MIESCHER,K.: "Ueber eine neue Synthese morphinahnlich Wirkender 4-Phenylpiperidin-4-alkylketone und verwandter Verbindungen", Helvetica Chimica Acta, 32, No. 7, 2489-2507, 1949.

029

MARION, L.: Private communication from National Research Council, Ottawa.

030

MANSKE, R. H. F., AND HOLMES, H. L.: The Alkaloids; Chemistry and Physiology, Published by Academic Press, Inc., New York, 1950.

031

ADAMS, R., LOEWE, S., JELINEK, C., AND WOLFF, H.: "Tetrahydrocanabinol homologs with marihuana activity", IX. Journal of the American Chemical Society, 63, 1971-1973, 1941.

032

ATTENBURROW, J., ELKS, J., HEMS, B. A., SPEYER, K. N.: "Analgesics. Part II. The synthesis of amidone and some of its analogues". Journal of the Chemical Society, 114, 510-518, 1949.

033

UNITED NATIONS: List of the basic narcotic drugs coming under the international narcotics treaties. Document E/CN.7/ 247, 1953.