Microchemical identification of some modern analgesics

Sections

PRACTICAL PROCEDURE
DISCUSSION
SUMMARY

Details

Author: E. G. C. Clarke
Pages: 27 to 44
Creation Date: 1959/01/01

Microchemical identification of some modern analgesics

M.A., Ph.D E. G. C. Clarke Chemistry Division, Department of Physiology, Royal Veterinary College, London, N.W.1

Although the quest for a substance that will relieve pain is nearly as old as civilization, for centuries opium remained the only analgesic of importance, the part played by such substances as alcohol, hemp, henbane and mandragora being relatively slight. The first significant advance was the isolation of morphine by Serturner in 1803. With the discovery of this powerful analgesic of constant and reproducible properties the search might, indeed, have ended. However, the introduction of morphine had the additional effect of emphasizing the less desirable properties of narcotic drugs. Consequently, subsequent research was directed towards the production of a substance which, while possessing the analgesic action of morphine, was neither toxic nor liable to cause addiction. Initially, experiments designed to modify the morphine molecule resulted in the production of such substances as diacetylmorphine (heroin, 1900), dihydromorphinone (dilaudid, 1923) and methyl-dihydromorphine (metopon, 1937). The introduction of pethidine, the first entirely synthetic analgesic, in 1939, marked the next important advance. This discovery was soon followed by the introduction of a large number of similar substances. In spite of this, none of the compounds so far produced has been judged sufficiently free from habit-forming properties to merit exemption from international narcotic control. Some idea of the numbers involved can be obtained from the following figures. In 1928, 11 drugs were controlled; in 1938, 18; in 1948, 19; and in 1958, no fewer than 65.

Once a drug has been brought under international control, its absolute identification becomes a matter of prime importance. Owing to the penalties attached to its illegal possession or use, this identification must be a matter of complete certainty. This fact has long been realized, and many tests for the older analgesics have been described. In the last few years, however, the spate of new compounds flooding on to the market has made this identification extremely laborious. Not only has the number of analgesics increased, but hundreds of other alkaloidal substances such as antihistamines and local anaesthetics have become available. As there is no way, short of absolute identification, in which an analgesic can be differentiated from any other basic drug, the forensic analyst is nowadays faced with an almost impossible task, and must carry out a multiplicity of tests before he can make his diagnosis.

Although it is essential to have some method by which any analgesic (or, ideally, any alkaloidal substance) can be identified, with few exceptions tests have been described only for the better-known analgesics. It is not proposed to review these tests in detail, although mention may be made of x-ray diffraction patterns (Barnes, [1] ; Barnes & Sheppard, [2] ), ultra-violet spectra (Oestreicher, Farmilo & Levi, [3] ; Breinlich, [4] ), infra-red spectra (Levi, Hubley & Hinge, [5] ), paper chromatography (Curry & Powell, [6] ; Vidic, [7] ; Goldbaum & Kazyak, [8] ) and crystal and colour tests (Farmilo, Levi, Oestreicher & Ross, [9] ; Levi, [10] ; Farmilo & Levi, [11] ; Brandstratter, [12] ; Vidic, [13] ; and Lampe, [14] ). It is the purpose of this paper to describe crystal and colour tests for microgram quantities of 51 analgesic drugs.

As some confusion exists in the literature as to the nomenclature of these substances, they are listed in table 1. From the analytical point of view, these compounds may be divided into five groups as follows:

  1. The morphine group. This may be further subdivided into two sections: ( a) those substances in which the phenolic group is free as in morphine; ( b) those in which it is masked, as in codeine and heroin.

  2. The morphinan group.

  3. The pethidine group. This may be subdivided into ( a) the esters and ( b) the reversed esters, although such division does not include ketobemidone. A third sub-group, 3 ( c), contains substances in which a hexamethyleneimine ring replaces the pyridine ring.

  4. The methadone group. This may be subdivided into ( a) the alcohols and ( b) the ketones.

  5. Miscellaneous compounds, mainly butane derivatives. This group includes the dialkylthiambutenes.

For the sake of completeness, the narcotic antagonists nalorphine and levallorphan have been included in their respective groups.

PRACTICAL PROCEDURE

Microcrystalline tests. The hanging microdrop technique developed by Clarke & Williams ([15] , [16] ) is used. This method has now been applied successfully to various groups of nitrogenous bases, including, in addition to plant alkaloids, local anaesthetic, antihistamine, antimalarial, and sympathomimetic drugs (Clarke, [17] , [18] , [19] , [20] , [21] ; Williams, [22] ). Briefly, this technique consists in transferring a microdrop (volume approximately 0.1µl) of the test solution to a cover slip by means of a glass rod 1 mm in diameter. A similar drop of reagent is now added, and the two mixed, the glass being scratched with the rod to encourage crystallization. A cavity slide is ringed with 25% gum arabic solution, inverted and pressed down on the cover slip, and reinverted. The hanging drop is examined under low magnification, and any precipitate, crystalline or otherwise, recorded. The drop is re-examined at intervals during the next forty-eight hours.

2. The morphinan group. Members of this group give a blue colour, turning to green, with the sulphuric acid-molybdate reagent. A similar colour is seen with certain morphine derivatives, but the fact that the morphinans give no colour with the Marquis reagent distinguishes them from the latter group. The phenols give a yellow colour with nitric acid, while the methoxy derivatives do not. The diazo test described above also shows the phenolic group.

TABLE 1

Substances tested

Approved name

Common name

Chemical name

Approved name

Common name

Chemical name

Group 1 a
 
 
Group 3 b
 
 
Deso-morphine
Permonid
Dihydro-deso-xymorphine
Morpheridine
Morpholinoethyl- norpethidine
l-(2-morpholinoethyl)-4-phenyl-piperidine-4- carboxylic acid ethyl ester
Methyl-desorphine
 
6-methyl- Δ 6-desoxymorphine
Pethidine
Meperidine Dolantin
1-methyl-4-phenylpiperidine-4-carboxylic acid ethyl ester
Methyl-dihydro-morphine
 
6-methyl-dihydro-morphine
Properidine
Spasmodolisine
1 -methyl-4-phenyl-piperidine-4-carboxylic acid isopropyl ester
Metopon
 
Methyl-dihydro-morphinone
Trimeperidine
Promedol
1-2-5-trimethyl-4-phenyl-4-propionoxy piperidine
Morphine-N-oxide
Genomorphine
Morphine-N-oxide
Group 3 c
 
 
Nalorphine
Lethidrone
N-allyl-nor-morphine
Ethoheptazine
W401 Zactane
1-methyl-4-carbethoxy-4-phenyl-hexamethyl-cneimine
Normorphine
 
De-N-methyl-morphine
Proheptazine
W757
1,3-dimethyl-4-phenyl-4-propionoxy-hexamethyl-cneimine
Oxy-morphone
Numorphan
Dihydro-hydroxy-morphinone
 
 
 
Group 1 b
 
 
Group 4
 
 
Acethyl-dihydro-codeine
Acetylcodone
Acetyldihydrocodeine
Alphacetylmethadol
Methadyl acetate
α-4,4-diphenyl-6-dimethyl-amino-3-acet oxyheptane
Myrophine
Myricodine
Myristyl ester of Benzyl-rnorphine
Alphamethadol
Amidol
α-4,4-diphenyl-6-dimethyl-aminoheptanol-3
Norcodeine
 
De-N-methylcodeine
Dipipanone
Pipadone
4,4-diphenyl-6-piperidino-3-heptanone
Pholcodine
Ethnine
β-4-morpho-linylethyl-morphine
Isomethadone
Isoamidone
4,4-diphenyl-5-methyl-6-4imethyla minohexanone-3
Thebacon
 
Acetyl-dihydro-codeinone
Methadone
Amidone Physeptone
4,4-diphenyl-6-dimethyl-aminoheptanone-3
Group 2
 
 
 
 
 
Dextro-methorphan
Romilar
(+)-3-methoxy-N-methyl-morphinan
Normethadone
Ticarda
4,4-diphenyl-6-dimethyl-amino-3-hexanone
Dextrorphan
 
(+)-3-hydroxy-N-methyl-morphinan
Phenadoxone
Heptalgin
4,4-diphenyl-6-morpholinoheptanone-3
Levallorphan
Lorfan
(-)-3-hydroxy-N-allyl morphinan
 
 
 
Levo-methorphan
 
(-)-3-methoxy-N-methyl-morphinan
Group 5
 
 
Levo-rphanol
Dromoran
(-)-3-hydroxy-N-methyl-morphinan
Dextromoramide
R875
(+)-3-methyl-2,2-dipheny1-4-morpholino-butyryl-
Pheno-morphan
 
3-hydroxy-N-phenethyhl-morphinan
Diethylthiambutene
Themalon
3-diethylamino-1,1-di-(2'-thienyl)-1-butene
Race-methorphan
 
(±)-3-methoxy-N-methyl-morphinan
Dimethylthiambutene
 
3-dimethylamino-1,1-di-(2-thienyl)-1-butene
Race-morphan
Citarin
(±)-3-hydroxy-N-methyhl-morphinan
Dioxaphetyl butyrate
Amidalgon
4-morpholino-2,2-diphenylethyl butyrate
Group 3 a
 
 
Ethyhnethylthiambutene
 
3-ethylmethylamino-1,1-(2'-thienyl)-l-butene
Alpha-meprodine
 
α-l-methyl-3-ethyl-4-phenyl-4-propionoxy piperidine
Levomoramide
 
(-)-3-methyl-2,2-diphenyl-4-morpholino-butyryl- pyrrolidone
Alphaprodine
Nisentil
α-1,3-dimethyl-4-phenyl-4-propionoxy-piperidine
Propoxyphene
Doloxene
4-dimethylamlno-1,2-diphenyl-3-methyl-2-propio noxy butane
Anileridine
 
1 -[2-(p-aminophenyl)-ethyl ]-4-phenyl-piperidine-4- carboxylic acid ethyl ester
Racemoranaide
 
(±)-3-methyl-2,2-diphenyl-4-morpholino-butyryl-pyrrolidone
Beta-meprodine
 
a-l-methyl-3-ethyl-4-phenyl-4-propionoxy-piperidine
Tolpronine
Proponesin
α- Δ 3 -piperideino-B-hydroxy-y-ortho-toloxy-pro pane
Betaprodine
 
β-1,3-dimethyl-4-phenyl-4-propionoxy-piperidine
-
3570CT
Piperidino methyl-2-benzoyl-7-benzodioxan
Etoxeridine
 
1-[2-(2-hydroxyethoxy)-ethyl]-4-phenyl-piperidine-4--carboxylic acid ethyl ester
-
3638CT
Piperidinomethyl-2-p-met hoxybensoyl-7-benzo dioxan
Hydro-xypethidine
Bemidone
1-methyl-4-(3-hydroxyphenyl)-piperidine -4-carboxylic acid ethyl ester
-
3633CT
Morpholinomethyl-2-benzoyl-7-benzodioxan
Keto-bemidone
Cliradon
4-(3-hydroxyphenyl)-l-methyl-4-piperidyl ethyl ketone
-
3639CT
Morpholinomethyl-2-p-methoxybenzoyl-7-benzo dioxan

The substances tested were dissolved in 1% acetic acid, with the following exceptions. Levorphanol, levomethorphan, racemorphan, racemethorphan, levallorphan, phenomorphan, nalorphine, levomoramide, dextromoramide, and racemoramide were dissolved in 1% hydrochloric acid; myrophine was dissolved in 90% methanol and ketobemidone in both 1% acetic acid and syrupy phosphoric acid. Details of the reagents employed are given in appendix A.

The results are recorded in tables 2 and 3. Table 2 gives the type of precipitate obtained when a drop of a 1% solution of the substance is mixed with a similar drop of reagent, giving in effect a 1 in 200 solution. This table will often enable a tentative identification to be made, but too rigid an adherence to it must be avoided. Traces of organic matter will often inhibit crystallization, while, on the other hand, exceptionally favourable circumstances will sometimes cause crystallization of precipitates that are normally amorphous.

Table 3 gives descriptions of the various crystals obtained, those most suitable for the purpose of identification being printed in small capitals. In selecting these tests, various points have been considered; not only the sensitivity, but the speed and certainty with which the crystals form, as well as their dissimilarity to crystals produced by closely related compounds with the same reagent, have been taken into account. These results are discussed in more detail later.

Some of the crystals obtained are illustrated in plates 1-24.

2. Colour tests. These are carried out with microdrops on opal glass as described previously. In the case of the Marquis test, a microdrop of the test solution is evaporated to dryness and the residue moistened with a microdrop of a solution of 1 part of 40% formaldehyde in 20 parts of concentrated sulphuric acid. For Mandelin's, Frohde's, Mecke's and Reichard's tests, a microdrop of the test solution is mixed with a microdrop of an aqueous solution of the oxidizing agent (0.5% ammonium vanadate (Mandelin), 0.5% ammonium molybdate (Frohde), 0.5 % selenium dioxide (Mecke) and 1% sodium tungstate (Reichard)). After evaporating to dryness, the residue is moistened with a microdrop of concentrated sulphuric acid, and the colour changes noted.

Vitali's test is carried out by evaporating a microdrop of the test solution to dryness, and adding a microdrop of fuming nitric acid. The colour is noted and the acid evaporated to dryness. The colour is again noted, and yet again after moistening with an ethanolic solution of potassium hydroxide.

Another colour test that is sometimes of value in differentiating between free and masked phenolic groups (e.g., morphine and codeine, levorphanol and levomethorphan) is the microdiazo test. A microdrop of a saturated solution of p-nitro-aniline is placed on opal glass, and microdrops of 1% sodium nitrite solution, the test solution, and 2N sodium hydroxide solution added in that order. Phenols give red or purple colours. The same test may be used to identify substances containing a primary arylamino group. Thus if to a microdrop of a solution of anileridine in 2N hydrochloric acid is added a similar drop of 1% sodium nitrite solution, followed by one of an alkaline solution of β-naphthol, a red colour will be produced. The sensitivity of the microdiazo test is about 0.25μg.

The results obtained are shown in tables 4 and 5, and discussed below.

DISCUSSION

The identification of a narcotic drug presents special difficulties for the analyst. In the case of an ordinary alkaloidal substance, a provisional identification may be confirmed by comparison of crystals formed from the test material with those formed from a known sample of the suspected drug and the same reagent. In the case of a narcotic drug this may not always be possible, owing to the difficulty of obtaining specimens of these compounds. Thus while most laboratories engaged in this type of work will have morphine and pethidine available for use as controls, few are likely to possess such substances as properidine or dimethylthiambutene. And while it may be argued that these compounds are so uncommon that the question of their identification is unlikely to arise the fact remains, none the less, that they are controlled narcotic drugs, and that the clandestine manufacture and use of any synthetic chemical is possible, however improbable.

It is therefore essential that the final identification should be based on as many types of test as possible. X-ray diffraction patterns and ultra-violet and infra-red spectra should be obtained if the necessary apparatus is available. Rf values, and, if sufficient material is available, the ordinary physical constants such as melting point should be ascertained. Finally, crystal and colour tests should be carried out, and the results compared with those given in the tables.

In order to help in the application of these tables, they are now discussed group by group in greater detail.

1. The morphine group. All members of this group give varying shades of purple or violet with the Marquis reagent, but it is not usually practicable to pinpoint any particular derivative by the exact shade given. A transient yellow colour is sometimes seen before the purple develops. It must be realized that this purple colour with the Marquis reagent is in no way confined to members of the morphine group, since some of the pethidine group give a similar colour, as also do numerous phenothiazine derivatives such as chloropromazine (Clarke, [20] ). The colours given with the other reagents will in some cases help in identification. In particular, the microdiazo test serves to pick out those compounds with a free phenolic group.

With regard to the crystal tests shown in table 3, most of these compounds give a number of crystalline precipitates that will serve as tests. Desomorphine, however, gives crystals with only one of the ordinary reagents (plates with mercuric.chloride) although it will also give fans of needles with the chloromercuric acid reagent described by Fulton ([23] ).

TABLE 2

Type of precipitate obtained

1 Gold bromide
2 Gold bromide / hydrochloric acid
3 Gold chloride
4 Lead iodide
5 Mercuric chloride
6 Pciric acid
7 Platinum chloride
8 Platinum iodide
9 Potassium bismuth iodide
10 Potassium cadimum iodide
11 Potassium chromate
12 Potassium iodide
13 Potassium mercury iodide
14 Potassium permanganate
15 Potassium tri-iodide (1)
16 Potassium tri-iodide (2)
17 Potassium tri-iodide (3)
18 Sodium carbonate
19 Sodium phosphate
20 Zinc chloride
21 Trinitrobenezoic acid
22 Patinum bromide
23 Picrolonic acid
24 Styphnic acid
25 Di-sodium methylarsonate
26 Potassium cyanide
27 Ammonium thiocyanate

ALKALOID/Reagent

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

Group 1a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Desomorphine
a
a
a
a
x
a
a
a
a
a
a
-
a
a
o
-
o
-
-
-
-
a
a
a
-
-
-
Methyldesorphine
a
a
o/a
a
x
x
a
a
x
a
x
-
a
a
o
a
o
a
x
-
a
a
a
a
x
a
-
Methyl-dihydro-morphine
a
x
o/a
-
o
x
x
x
x
x
-
-
x
a
o
-
o
-
-
-
-
x
-
x
-
-
-
Metopon
a
a
a
-
o
a
a
a
x
a
-
-
a
a
o
o
x
x
-
-
-
a
x
a
x
-
-
Morphine-N-oxide
o
o
a
-
-
x
x
a
a
a
-
-
a
a
o
-
x
-
-
-
-
a
-
a
-
-
-
Nalorphine
a
a
o
-
a
a
a
a
a
a
x
-
x
a
x
-
x
-
-
-
-
a
a
a
-
-
-
Normorphine
x
x
a
-
-
x
a
a
x
x
a
-
x
a
o
-
o
-
-
-
-
-
-
-
-
-
-
Oxymorphone
x
x
a
-
x
a
-
a
a
-
-
-
o/a
a
o
-
-
-
-
-
-
-
-
-
-
-
-
Group 1b
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acteyl-hydro-codeine
a
x
x
x
a
x
x
a
a
a
-
-
a
-
a
-
a
-
-
-
-
o/a
x
a
-
-
-
Myrophine
a
a
a
a
a
a
a
a
a
a
o
a
a
a
o
x
o/a
o
o
-
x
a
x
a
o
o/a
o/a
Norcodeine
x
x
x
-
-
o/a
a
a
a
x
x
x
x
a
o
-
o
-
-
x
-
a
a
a
-
-
x
Pholcodeine
a
a
a
a
-
a
x
a
x
a
-
-
a
a
o
-
o
-
-
-
-
a
a
x
-
-
-
Thebacodeinme
x
x
x
a
x
x
a
a
a
x
x
-
x
a
x
x
x
x
-
-
-
a
a
a
x
-
-
Group 2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Levallorphan
x
o
o
-
o
a
a
a
o
a
a
x
a
a
o
-
o
x
-
o/a
o/a
a
a
a
x
x
x
Levo-methorphan (Dextro-methorphan)
a
a
o/a
x
x
a
x
a
a
a
x
x
a
a
o
-
o
o
-
-
a
x
a
x
-
o
x
Levorphanol (Dextrorphan)
a
a
o/a
a
o
a
x
a
o/a
a
o/a
-
a
a
o
-
o
a
-
-
-
x
a
a
 
-
a
Phenomorphan
a
a
a
a
a
a
a
a
o/a
a
a
x
a
a
o/a
-
a
x
a
a
a
a
a
a
x
a
a
Racemethorphan
a
a
a
x
x
a
a
a
a
a
x
x
a
a
o
-
o
o
-
-
x
x
a
x
o
o
o
Racemorphan
a
a
o
a
o
a
x
a
a
a
a
-
a
a
o
-
o
x
-
-
o/a
x
o/a
a
x
a
o
Group 3a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anileridine
a
o
a
x
o/a
a
a
a
a
a
a
x
a
a
o
a
o
o
-
x
a
a
a
a
x
o
x
Etoxeridine
o
o
o
x
o
o
-
x
o
o
-
-
o
a
o
o
o
-
-
-
-
o
-
o
-
-
-

x = crystals. a = amorphous. o = oil. o/a = oily amorphous. - = no precipitate.

table 2 (cont.)

Morpheridine
a
x
a
a
x
x
a
a
x
x
x
-
x
a
o
-
x
-
-
x
a
a
a
x
-
-
-
Pethideine
x
o
o
x
o
x
x
a
a
o
-
-
o
-
o
-
o
o
-
-
-
x
x
x
-
o
-
Properidine
x
o
o
x
o
x
x
a
o
o
-
x
o
x
o
-
o
o
-
-
o
a
x
x
o
o
-
Hydroxy-pethidine
x
x
o
-
-
x
o
a
o
o
-
-
o
a
o
-
o
o
-
-
-
a
a
x
-
-
-
Ketobemidone1
o
o
o
-
-
o
a
a
o/a
a
-
-
-
a
o
-
o
-
-
-
-
a
a
o/a
-
-
-
Group 3 b
 
Alphameprodine
x
x
o/a
x
o
x
x
a
o
o/a
x
-
a
a
o
-
o
o
-
-
x
x
x
x
-
o
-
Alphaprodine
a
a
o
x
o
x
a
a
a
a
-
-
a
a
o
-
o
o
-
-
x
a
x
x
-
o
-
Betameprodine
x
x
x
x
o
x
a
a
a
a
-
-
a
o
o
-
o
o
-
-
-
a
a
x
o
o
-
Betaprodine
x
x
x
x
o
x
a
a
a
a
-
-
a
o
x
-
o
o
-
-
-
a
x
x
o/a
o
-
Trimeperidine
a
a
a
x
o
x
-
a
o/a
a
-
-
a
a
o
-
o
o
-
-
-
a
a
x
-
o
-
Group 3 c
 
Ethoheptazine
o
o
o
-
-
x
a
a
o
o
-
-
o
a
o
-
o
a
-
-
-
a
a
x
-
o
-
Proheptazine
a
a
o
a
o
a
a
a
o/a
a
x
x
a
a
o
-
o
o
-
-
a
a
a
a
-
o
-
Group 4
 
Alpha-acetyl-methadol
x
x
x
x
x
x
a
x
a
x
x
x
x
a
o
x
o/a
o
x
x
x
a
x
x
o
o
x
Alphamethadol
a
x
x
a
x
a
a
a
o
a
x
-
a
a
o
-
o
o
-
x
x
a
a
x
o
o
o
Dipipanone
a
a
a
a
o/a
a
x
a
o
a
a
o
a
a
o
-
a
o
-
o/a
a
x
a
a
a
o
o
Isomethadone
x
x
o
a
x
x
x
a
o
a
x
x
x
a
o
-
o
o
-
-
x
x
a
a
o
o
o
Methadone
x
a
x
x
x
a
o/a
x
a
a
o
-
x
o/a
x
-
x
o
-
-
a
x
a
a
x
o
x
Normethadone
o
x
x
x
o
o/a
a
o/a
o
o
x
o
x
a
-
o
o
-
-
o/a
a
o/a
o/a
o/a
o/a
o
o
Phenadoxone
a
a
a
a
o
a
a
a
a
a
a
o
a
a
x
-
o
o
o
a
x
a
x
a
o
o
o
Group 5
 
Dextro-moramide
x
x
x
a
a
a
a
a
a
a
o/a
-
a
a
x
a
x
x
a
-
x
a
x
a
x
a
o
Diethyl-thiambutene
o
o
o
x
o
x
a
a
o
o
o
x
o
a
o
-
o
o
-
o
x
a
o
o
o
o
x
Dimethyl-thiambutene
o
o
o
x
o
x
a
a
o
o
x
o
x
a
o
-
o
o
-
o
x
a
x
x
o
o
x
Dioxyphetyl butyrate
x
x
x
a
x
a
a
x
o
a
x
x
a
x
o
x
o
o
o
o
a
a
x
a
o
o
x
Ethylmethyl-thiambutene
o
o
o
x
o
a
a
a
o
a
x
a
o
a
o
-
o
o
-
o
x
a
x
x
o
o
o
Levo-moramide
x
x
x
a
a
a
a
a
a
a
o/a
-
a
a
x
a
x
x
a
-
x
a
x
a
x
a
o
Propoxy-phene
a
x
a
a
o
a
a
a
o
a
o
x
a
a
x
-
x
o
-
o
a
a
a
a
o
o
o
Race-moramide
a
x
x
a
a
a
a
a
a
a
a
a
a
a
a
-
x
x
a
x
x
x
x
a
x
x
x
Tolpronine
o
o
o
x
o
x
o
a
o
o
-
-
o
a
x
-
x
o
-
-
-
a
a
x
o
o
-
3570CT
a
a
a
a
a
a
a
a
a
a
a
o
a
a
x
o
x
o
o
a
a
a
a
a
a
a
a
3638CT
a
a
a
a
o
a
a
a
a
a
a
x
a
a
a
a
a
o
o
a
a
a
a
a
o
o
a
3633CT
a
a
a
a
o
a
a
a
a
a
a
x
a
a
o
x
o
o
o
o
a
a
a
a
o
o
o
3639CT
a
a
a
a
o
a
a
a
a
a
a
o
a
a
o
o
o
o
o
o
a
a
a
a
o
o
o

1 In 1% acetic acid

TABLE 3

Types of crystals obtained

Alkaloid

Reagent

Type of crystal

Sensitivity (µg)

Group 1
 
 
 
Acetyl-dihydro-codeine
Gold bromide / hydrochloric acid
Very small rosettes (o/n)
0.25
 
Gold chloride
Dense rosettes (o/n)
0.25
 
Lead iodode
ROSETTES OF LONG PLATES (O/n)
0.5
 
Picric acid
GELATINOUS ROSETTES (o/n)
0.1
 
Platinum chloride
Smudge rosettes
1.0
 
Picrolonic acid
BUNCHES OF SERRATED NEEDLES
0.25
Desomorphine
Mercuric chloride
PLATES
0.5
Methyl-desorphine
Mercuric chloride
Rosettes of plates (o/n)
0.1
 
Picric acid
Oily rosettes (o/n)
0.25
 
Potassium bismuth iodide
SMALL BLADES
0.1
 
Potassium chromate
Small oily crystals (o/n)
0.1
 
Sodium phosphate
LONG NEEDLES
0.1
 
Di-sodium methyl arsonate
Long needles
1.0
Methyl-dihydro-morphine
Gold bromide / hydrochloric acid
Oily rosettes1
0.1
 
Picric acid
Branching needles
0.25
 
Platinum chloride
Gelatinous rosettes
0.25
 
Platinum iodide
Bunches of fibres (o/n)
0.5
 
Potassium bismuth iodide
Small rosettes of plates
0.025
 
Potassium cadmium iodide
PLATES, SOME SERRATED
0.25
 
Potassium mercury iodide
FEATHERY ROSETTES
0.1
 
Platinum bromide
Bunches of oily needles (o/n)
1.0
 
Styphnic acid
Fans of oily needles (o/n)
0.5
Metopon
Potassium bismuth iodide
VERY SMALL RODS
0.1
 
Potassium tri-iodide (3)
Rosettes of rods (o/n)
0.5
 
Sodium carbonate
Bundles of rods
1.0
 
Picrolonic acid
SERRATED NEEDLES
0.5
 
Di-sodium methyl arsonate
Bundles of rods
1.0
Morphine-N-oxide
Picric acid
Dense golden rosettes (o/n)
0.5
 
Platinum chloride
SMALL OILY ROSETTES (O/n)
0.5
 
Potassium tri-iodide (3)
DENSE ROSETTES
0.5
Myrophine
Potassium tri-iodide (2)
OILY NEEDLES
0.25
 
Trinitro benzoic acid
Smudge rosettes
1.0
 
Picrolonic acid
BUNCHES OF NEEDLES
0.25
Nalorphine
Potassium chromate
FOUR-POINTED STARS
0.5
 
Potassium mercury iodide
SMUDGE ROSETTES OR FIBRES
0.25
 
Potassium tri-iodide (1)
Fuzzy rosettes of needles (o/n)
0.25
 
Potassium tri-iodide (3)
Dense rosettes of rods (o/n)
0.25
Oxymorphone
Gold bromide
DENSE ROSETTES
0.1
 
Gold bromide / hydrochloric acid
Irregular crystals (2 days)
1.0
 
Mercuric chloride
FANS OF NEEDLES (O/n)
0. 1
Pholcodine
Platinum chloride
FEATHERY ROSETTES
0.25
 
Potassium bismuth iodide
Dendrites (2 days)
1.0
 
Styphnic acid
ROSETTES OF PLATES (o/n)
0.1
Thebacon
Gold bromide
Small curved needles
0.025
 
Gold bromide/hydrochloric acid
Small curved needles
0.025,
 
Gold chloride
Small curved needles
0.025,
 
Mercuric chloride
Rosettes of rods
1.0
 
Picric acid
Hedgehogs
0.25
 
Potassium cadmium iodide
FINE DENDRITES
0.05
 
Potassium chromate
Feathery needles
1.0
 
Potassium mercury iodide
FEATHERY ROSETTES
0.025
 
Potassium tri-iodide (1)
Branching needles
0.025
 
Potassium tri-iodide (2)
Rosettes of needles (2 days)
1.0
 
Potassium tri-iodide (3)
Branching needles (2 days)
0.25
 
Sodium carbonate
Rosettes of needles
0.5
 
Di-sodium methyl arsonate
Rosettes of rods
1.0
Normorphine
Gold bromide
Rosettes (2 days)
1.0
 
Gold bromide / hydrochloric acid
Gelatinous rosettes
0.25
 
Picric acid
Branching needles (2 days)
0.25
 
Potassium bismuth iodide
ROSETTES OF PLATES
0.1

See notes at end of table.

TABLE 3

Types of crystals obtained (continued)

Alkaloid

Reagent

Type of crystal

Sensitivity (µg)

Normorphine (contd.)
Potassium cadmium iodide
PLATES, OFTEN HEXAGONAL
0.1
 
Potassium mercury iodide
Plates, often hexagonal
0.1
Norcodeine7
Gold bromide / hydrochloric acid
Smudge rosettes
0.5
 
Gold chloride
Needles
0.25
 
Potassium cadmium iodide
Bunches of irregular needles
0.05
 
Potassium chromate
NEEDLES
0.25
 
Potassium iodide
Needles (2 days)
0.5
 
Potassium mercury iodide
Bunches of irregular needles
0.05
 
Potassium tri-iodide (2)
Needles (2 days)
0.5
 
Zinc chloride
NEEDLES
0.1
 
Ammonium thiocyanate
Fine rods
0.25
Group 2
 
 
 
Levallorphan
Gold bromide
Irregular needles
0.25
 
Potassium iodide
NEEDLES AND PLATES (o/n)
0.5
 
Sodium carbonate
Dense rosettes (o/n)
0.5
 
Di-sodium methyl arsonate
Dense rosettes (o/n)
0.5
 
Potassium cyanide
Dense rosettes
0.25
 
Ammonium thiocyanate
BUNCHES OF RODS
1.0
Levomethorphan
Lead iodide
BUNCHES OF SERRATED PLATES
0.25
(Dextro-methorphan)
Mercuric chloride
Irregular rods
0.25
 
Platinum chloride
FEATHERY ROSETTES
0.25
 
Potassium chromate
Oily rosettes (o/n)
1.0
 
Potassium iodide
Curved plates (o/n)
1.0
 
Platinum bromide
Feathery rosettes
1.0
 
Styphnic acid
Dense rosettes
0.25
 
Ammonium thiocyanate
Curved plates
1.0
Levorphanol (Dextrorphan)
Platinum chloride
MASSES OF SMALL IRREGULAR CRYSTALS
0.25
 
Platinum bromide
BUNCHES OF SMALL IRREGULAR PLATES
0.25
Phenomorphan2
Potassium iodide
Dense rosettes
0.25
 
Sodium carbonate
SMALL IRREGULAR PLATES
0.1
 
Di-sodium methyl arsonate
NEEDLES, SOME SERRATED
0.1
Race-methorphan
Lead iodide
Dense rosettes (2 days)
0.25
 
Mercuric chloride
Irregular blades
0.25
 
Potassium chromate
Rosettes of plates
1.0
 
Potassium iodide
Plates
1.0
 
Trinitrobenzoic acid
ROSSETTES OF SMALL PLATES
0.25
 
Platinum bromide
Small plates
0.25
 
Styphnic acid
ROSETTES OF PLATES AND NEEDLES (O/n)
0.25
Racemorphan
Platinum chloride
Dense rosettes (o/n)
1.0
 
Sodium carbonate
PLATES OR RODS IN BUNCHES
0.25
 
Platinum bromide
Rosettes of plates
0.1
 
Disodium methyl arsonate
ROSSETTES OF PRISMS
0.25
Group 3
 
 
 
Alphameprodine
Gold bromide
Irregular needles (o/n)
0.25
 
Gold bromide / hydrochloric acid
Rosettes of plates and needles
0.05
 
Lead iodide
Dense rosettes
0.1
 
Picric acid
Minute curved needles
0.025
 
Platinum chloride
PLATES, OFTEN IN BUNCHES
0 1
 
Potassium chromate
Plates (o/n)
1.0
 
Trinitrobenzoic acid
Masses of small rods (o/n)
0.25
 
Platinum bromide
BUNCHES OF RODS OR PLATES
0.1
 
Picrolonic acid
Dense rosettes of plates (o/n)
0.25
 
Styphnic acid
Small irregular crystals
0.25
Alphaprodine
Lead iodide
Dense rosettes
0.25
 
Picric acid
SMALL SERRATED PLATES, OFTEN IN BUNCHES
0.025
 
Trinitrobenzoic acid
Plates(o/n)
1.0
 
Picrolonic acid
Rosettes of plates (o/n)
1 .0
 
Styphnic acid
VERY SMALL CRYSTALS3
0.1
Anileridine
Lead iodide
BRANCHING RODS
0.25

See notes at end of table.

TABLE 3

Types of crystals obtained (continued)

Alkaloid

Reagent

Type of crystal

Sensitivity (µg)

Anileridine (contd.)
Potassium iodide
LARGE PLATES AND SMALL NEEDLES FROM EDGE
0.25
 
Zinc chloride
Long needles (2 days)
1.0
 
Di-sodium methyl arsonate
Long plates (o/n)
0.5
 
Ammonium thiocyanate
Plates
1.0
Beta-meprodine
Gold bromide
Serrated blades (o/n)
0.025
 
Gold bromide / hydrochloric acid
Rosettes of needles and plates
0.25
 
Gold chloride
Rosettes of needles
0.25
 
Lead iodide
SMALL BLADES, SOMETIMES IN ROSETTES
0.1
 
Picric acid
BUNCHES OF STOUT RODS
0.1
 
Styphnic acid
Small rosettes
0.1
Betaprodine
Gold bromide
Branching rods and plates (o/n)
0.025
 
Gold bromide / hydrochloric acid
Serrated rods (o/n)
0.25
 
Gold chloride
Serrated plates and needles, sometimes in bunches
0.05
 
Lead iodide
ROSETTES OR BUNCHES OF IRREGULAR RODS
0.1
 
Picric acid
Irregular plates and rods
0.25
 
Potassium tri-iodide (1)
Plates (o/n)
0.1
 
Picrolonic acid
Dense rosettes (2 days)
1.0
 
Styphnic acide
PLATES, OFTEN IN ROSETTES
0.1
Etoxeridine
Lead iodide
BURRS OF FINE NEEDLES
1.0
 
Platinum iodide
PLATES (o/n)
1.0
Hydroxy-pethidine
Gold bromide
SMALL PLATES AND PRISMS
0.1
 
Gold bromide / hydrochloric acid
Plates, some serrated
0.5
 
Picric acid
Rosettes of plates
1.0
 
Styphnic acid
BLADES, SOMETIMES IN ROSETTES
0.5
Ketobemidone4
Gold bromide
Rods, some segmented
0. 025
 
Gold bromide / hydrochloric acid
Plates, some serrated
0.05
 
Gold chloride
Serrated needles and plates
0.5
 
Potassium cadmium iodide
Irregular crystals
1.0
Morpheridine
Gold bromide / hydrochloric acid
Masses of very small crystals (o/n)
0.25
 
Mercuric chloride
Serrated plates, often in rosettes
0.25
 
Picric acid
Small rods and needles
0.25
 
Potassium bismuth iodide
SMALL ROSETTES AND FANS OF NEEDLES (o/n)
0. 1
 
Potassium cadmium iodide
PLATES, OFTEN IN BUNCHES (o/n)
0.1
 
Potassium chromate
Irregular crystals
0.25
 
Potassium mercury iodide
Small plates (o/n)
0.25
 
Potassium tri-iodide (3)
Rosettes of needles (o/n)
1.0
 
Zinc chloride
Plates
1.0
 
Styphnic acid
Minute crystals3
0.25
Pethide
Gold bromide
Plates, some serrated (o/n)
0.25
 
Lead iodide
Bunches of branching rods
0.25
 
Picric acid
FEATHERY ROSETTES
0.1
 
Platinum chloride
Plates and feathery rosettes (o/n)
0.25
 
Platinum bromide
Feathery rosettes (o/n)
0.25
 
Picrolonic acid
FEATHERY ROSETTES
0.1
 
Styphnic acid
Bunches of small plates
0. 1
Propene
Gold bromide
Plates (2 days)
1.0
 
Lead iodide
MASSES OF BLADES, SOME SERRATED
0.05
 
Picric acid
Bunches of plates, often curved
0.05
 
Platinum chloride
Oily dendrites (o/n)
0.25
 
Potassium iodide
Long plates (2 days)
1.0
 
Potassium permanganate
PLATES, OFTEN LARGE AND SERRATED
0. 1
 
Picrolonic acid
Rosettes of plates (o/n)
1.0
 
Styphnic acid
Masses of transparent plates
0.05
Trimepe
Lead iodide
ROSETTES OF NEEDLES
0.25
Picric acid
Dense rosettes
1.0
 
Styphnic acid
FANS OR BUNCHES OF RODS, OFTEN SERRATED (o/n)
0. 1
Ethohe
Picric acid
BUNCHES OF IRREGULAR RODS (o/n)
0.5
 
Styphnic acid
DENSE ROSETTES (o/n)
0.25
Proher
Potassium chromate
BUNCHES OF PLATES
1.0
 
Potassium iodide
STOUT RODS OR PRISMS, OFTEN IN ROSETTES
0.5

See notes at end of table.

TABLE 3

Types of crystals obtained (continued)

Alkaloid

Reagent

Type of crystal

Sensitivity (µg)

Group 4
 
 
 
Acetyl-methadol
Gold bromide
Branching rods (o/n)
0.25
 
Gold bromide / hydrochloric acid
Fans of irregular rods (o/n)
0.25
 
Gold chloride
Irregular rods
0.25
 
Lead iodide
Smudge rosettes
0.05
 
Mercuric chloride
Dense rosettes
0.1
 
Picric acid
Rosettes of blades
0.05
 
Platinum iodide
Dense rosettes
0.25
 
Potassium cadmium iodide
Hairlike rosettes (2 days)
1.0
 
Potassium chromate
SMALL ROSETTES OF PLATES
0.1
 
Potassium iodide
IRREGULAR RODS AND PLATES
0.25
 
Potassium mercury iodide
Bundles of small needles
0.25
 
Potassium tri-iodide (2)
Small rods or plates (o/n)
1.0
 
Sodium phosphate
Bunches of small needles (o/n)
0.25
 
Zinc chloride
Small oily needles
0.25
 
Trinitrobenzoic acid
Dense rosettes
0.25
 
Picrolonic acid
Dense rosettes (o/n)
0.25
 
Styphnic acid
Rosettes of small needles
0.25
 
Ammonium thiocyanate
Small rods and plates
0.25
Methadol
Gold bromide / hydrochloric acid
Rosettes of plates (2 days)
1.0
 
Gold chloride
Irregular rods
1.0
 
Mercuric chloride
Dense rosettes (o/n)
1.0
 
Potassium chromate
FANS OF SMALL NEEDLES
0.5
 
Zinc chloride
RODS OR PLATES
0.5
 
Trinitrobenzoic acid
Dense rosettes
1.0
 
Styphnic acid
Dense rosettes of plates (o/n)
0.1
Dipipanone
Platinum chloride
BUNCHES OF SERRATED BLADES
0.1
 
Platinum bromide
CURVING BLADES, MOSTLY SERRATED
0.25
Isomethadone
Gold bromide
Bunches of plates
0.25
 
Gold bromide / hydrochloric acid
Oily needles and blades
0.1
 
Mercuric chloride
Rosettes of plates (2 days)
1.0
 
Picric acid
DENSE ROSETTES OF RODS
0.25
 
Platinum chloride
DENSE ROSETTES OF SMALL PLATES
0.1
 
Potassium chromate
Plates (o/n)
0.25
 
Potassium iodide
Bunches of prisms
1.0
 
Potassium mercury iodide
Plates or blades, some serrated
0.25
 
Trinitrobenzoic acid
Dense rosettes
1.0
 
Platinum bromide
Dense rosettes and rods
0.1
Methadone
Gold bromide
Needles (o/n)
0.25
 
Gold chloride
Rods and plates (o/n)
0.025
 
Lead iodide
Dense rosettes of rods (o/n)
0.25
 
Mercuric chloride
ROSETTES OF BRANCHING RODS
0.05
 
Platinum iodide
Plates and needles (2 days)
0.25
 
Potassium mercury iodide
Needles
0.025
 
Potassium tri-iodide (1)
Splinters or needles
0.025
 
Potassium tri-iodide (3)
Splinters
0.1
 
Platinum bromide
BUNCHES OF PRISMS
0.25
 
Di-sodium methyl arsonate
Prisms (o/n)
1.0
 
Ammonium thiocyanate
Plates (o/n)
1.0
Normethadone
Gold bromide / hydrochloric acid
SMALL PLATES, OFTEN CRUCIFORM
0.1
 
Gold chloride
Small blades and plates
0.1
 
Lead iodide
MASSES OF BLADES, SOME SERRATED
0.1
 
Potassium chromate
Prisms
1.0
 
Potassium mercury iodide
Rods and prisms (o/n)
0.25
Phenadoxone
Potassium tri-iodide (1)
RODS AND PLATES (o/n)
0.1
 
Trinitrobenzoic acid
Smudge rosettes
0.5
 
Picrolonic acid
DENSE OILY ROSETTES
0.1
Group 5
 
 
 
Diethyl-thlambutene
Lead iodide
Dense rosettes (o/n)
0.25
 
Picric acid
IRREGULAR BLADES (o/n)
0.25
 
Potassium iodide
ROSETTES OF PLATES
0.5

See notes at end of table.

TABLE 3

Types of crystals obtained (continued)

Alkaloid

Reagent

Type of crystal

Sensitivity (µg)

Dimethylthiambutene
Trinitrobenzoic acid
Rosettes of needles (o/n)
1.0
 
Ammonium thiocyanate
Large rods (o/n)
0.5
 
Lead iodide
ROSETTES OF BRANCHING RODS
0.1
 
Picric acid
Small plates (o/n)
0.5
 
Potassium chromate
Prisms, usually rhomboidal
0.5
 
Potassium mercury iodide
LONG PLATES (o/n)
0.1
 
Trinitrobenzoic acid
Rosettes of branching needles
0.25
 
Picrolonic acid
Small feathery rosettes
0.1
 
Styphnic acid
Leaflike plates
0.1
 
Ammonium thiocyanate
Plates and needles
1.0
Ethyl-methyl-thiambutene
Lead iodide
Oily rods (2 days)
1.0
 
Potassium chromate
TABLETS, USUALLY HEXAGONAL
0.5
 
Trinitrobenzoic acid
Rosettes of needles
0.25
 
Picrolonic acid
Rosettes of rods (2 days)
0.25
 
Styphnic acid
SERRATED NEEDLES
0.25
Dextro-moramide
Gold bromide
Oily needles (o/n)
1.0
(Levomoramide)
Gold bromide / hydrochloric acid
Oily needles (o/n)
1.0
 
Gold chloride
OILY NEEDLES, SOME SERRATED (o/n)
0.25
 
Potassium tri-iodide (1)
Oily needles
1.0
 
Potassium tri-iodide (3)
Blades
1.0
 
Sodium carbonate
Rosettes or masses of irregular crystals (o/n)
0.25
 
Trinitrobenzoic acid
Dense rosettes
0.25
 
Picrolonic acid
ROSETTES OF BRANCHING RODS, SOMETIMES DENSE
0.25
 
Di-sodium methyl arsonate
Bunches of prisms
0.25
Dioxaphetyl-butyrate
Gold bromide
Transparent plates and needles (o/n)
0.025
 
Gold bromide / hydrochloric acid
Small irregular rods and plates
0.25
 
Gold chloride
Bunches of splinters
0.25
 
Mercuric chloride
Rosettes of needles
1.0
 
Platinum iodide
Small plates
1.0
 
Potassium chromate
FANS OF FINE NEEDLES
0.5
 
Potassium iodide
Plates
0.5
 
Potassium permanganate
Hairlike needles
0.5
 
Potassium tri-iodide (2)
Plates (2 days)
0.25
 
Picrolonic acid
Masses of needles, often curved
0.25
 
Ammonium thiocyanate
FINE DENDRITES
0.25
Propoxyphene
Gold bromide / hydrochloric acid
CURVING BLADES (o/n)
0.25
 
Potassium iodide
Irregular crystals
1.0
 
Potassium tri-iodide (1)
SMALL PLATES IN FERNLIKE PATTERNS
0.025
 
Potassium tri-iodide (3)
Small plates in fernlike patterns
0.025
Racemoramide
Gold bromide / hydrochloric acid
Branching needles (2 days)
1.0
 
Gold chloride
OILY NEEDLES, SOME SERRATED (o/n)
0.1
 
Potassium tri-iodide (3)5
Plates and needles, often in rosettes
1.0
 
Sodium carbonate
Rosettes or masses of irregular crystals (o/n) 6
0.25
 
Trinitrobenzoic acid
Dense rosettes
0.25
 
Picrolonic acid
ROSETTES OF BRANCHING RODS, SOMETIMES DENSE
0.1
 
Di-sodium methyl arsonate
Dense rosettes
0.25
 
Potassium cyanide
Irregular dense rosettes
1.0
 
Ammonium thiocyanate
LARGE PLATES
1.0
Tolpronine
Lead iodide
Very small rosettes
0.5
 
Picric acid
ROSETTES OF FINE NEEDLES OR TABLES, SOMETIMES HEXAGONAL
0.1
 
Potassium tri-iodide (1)
PLATES, USUALLY RECTANGULAR
0.1
 
Potassium tri-iodide (3)
Rhomboids
0.025
 
Styphnic acid
Hedgehogs
0.05
3570CT7
Potassium tri-iodide (1)
SMALL PLATES (2 days)
0.5
 
Potassium tri-iodide (3)
SMALL PLATES (o/n)
0.25
3638CT
Potassium iodide
DENSE ROSETTES (o/n)
0.5
3633CT
Potassium iodide
ROSETTES OF RODS (o/n)
0.5
 
Potassium tri-iodide (2)
ROSETTES OF RODS (o/n)
1.0
3639CT
No crystals were obtained
 
 

O/N (overnight). Crystals do not usually form till the following day.

1Crystals not stable.

2Saturated solution (about 1 in 400).

3Best seen under polarised light.

4In phosphoric acid.

5Excess alkaloid.

6 Sometimes bunches of prisms.

7Saturated solution (about 1 in 200).

TABLE 4

Result of Marquis, Mandelin and Frohde colour tests

Alkaloid

Formaldehyde (Marquis)

in μg

Ammonium vanadate (Mandelin)

in μg

Ammonium molybdate (Frohde)

in μg

Group 1 a
 
 
 
 
 
 
Desmorphine
Purple
0.1
Grey-purple
1.0
Deep violet - green - blue - yellow
0.1
Methyl-desorphine
Purple
0.1
Brown
0.25
Black-violet - greenish-brown
0.1
Methyl-dihydro-morphine
Purple
0.1
Grey-purple - yellow
0.5
Violet-blue - green
0.1
Metopon
Purple
0.5
Dull violet
0.25
Black-violet - blue-green
0.1
Morphine-N-oxide
Purple
0.25
Dull purple - brown
0.1
Deep violet - blue - green
0.25
Nalorphine
Purple
0.25
-
 
Deep blue - green
0.25
Normorphine
Purple
0.1
Grey - green
0.5
Purple - blue
0.1
Oxymorphone
Purple
0.5
Brown
1.0
Bright blue - green
0.25
Group 1 b
 
 
 
 
 
 
Acethyl-dihydro-codeine
Purple
0.25
-
 
Green - blue
0.25
Myrophine
Red-purple
0.25
-
 
Blue-violet
0.25
Norcodeine
Purple
0.1
-
 
Blue-green - blue - green
0.1
Pholcodeine
Purple
0.25
-
 
Green - blue
0.25
Thebacon
Purple
0.25
-
 
Green - blue
0.25
Group 2
 
 
 
 
 
 
Levallorphan
-
 
-
 
Blue-green
0.25
Levo-methorphan (Dextro-methorphan)
-
 
-
 
Blue-green
0.25
Levorphanol (Dextrophan)
-
 
-
 
Blue-green
0.25
Phenomorphan
-
 
-
 
Blue-green
0.25
Race-methorphan
-
 
-
 
Blue-green
0.25
Racemorphan
-
 
-
 
Blue-green
0.25
Group 3a
 
 
 
 
 
 
Anileridine
Dull orange
1.0
-
 
-
 
Etoxeridine
Dull orange
1.0
-
 
-
 
Morpheridine
Dull orange
1.0
-
 
-
 
Pethidine
Dull orange
1.0
-
 
-
 
Properidine
Dull orange
1.0
-
 
-
 
Hydroxy-pethidine
Dull orange
1.0
Dull green
0.5
Bright blue, fading
0.25
Ketobemidone
Dull orange
1.0
Blue-green
0.5
Bright blue, fading
0.25
Group 3b
 
 
 
 
 
 
Alpha-meprodine
Brownish-red
0.5
Blue-grey
0.5
Blue-grey - green with blue rim
0.5
Alphaprodine
Brownish-red
0.5
Blue-grey
0.5
Blue-grey - green with blue rim
0.5
Beta-meprodine
Red-purple
0.5
Blue-grey
0.5
Blue-grey - green with blue rim
0.5
Betaprodine
Red-purple
0.5
Blue-grey
0.5
Blue-grey - green with blue rim
0.5
Trimeperidine
Red-purple
0.25
-
 
-
 
Group 3c
 
 
 
 
 
 
Ethoheptazine
Dull orange
0.5
-
 
-
 
Proheptazine
Dull purple
0.5
Grey-purple, fading
0.25
Blue-grey - green
0.25
Group 4
 
 
 
 
 
 
Alpha-acetyl-methadol
Purple-brown - grey-green
0.25
Grey-green
0.25
Brown-purple-green
0.25
Alphamethadol
Purple-brown - grey-green
0.25
Grey-green
0.25
Brown-purple-green
0.25
Dipipanone
-
 
Deep green-blue
0.25
-
 
Isomethadone
-
 
Brown-purple - violet-blue
0.1
-
 
Methadone
-
 
Faint green-blue
0.5
-
 
Normethadone
-
 
Yellow-green
1.0
-
 
Phenadoxone
-
 
Deep green-blue
0.25
-
 
Group 5
 
 
 
 
 
Dextro-moramide
-
 
-
 
-
 
Diethyl-thiambutene
Purple-brown
0.1
Green - green-blue
0.1
Orange-brown - pale green
0.1
Dimethyl-thiambutene
Purple-brown
0.1
Green - green-blue
0.1
Orange-brown - pale green
0.1
Dioxaphteyl-thiambutene
-
 
-
 
-
 
Ethylmethyl-thiambutene
Purple-brown
0.1
Green - green-blue
0.1
Orange-brown - pale green
0.1
Propxyphene
Black-violet - dull green
0.5
Grey
0.5
Black-green
0.5
Racemoramide
-
 
-
 
-
 
Tolpronine
Red
0.5
Green-grey - grey-violet
0.5
Grey-blue - green
0.5
3570CT
Yellow
0.1
Yellow
0.1
Yellow
0.1
3638CT
Yellow
0.1
Yellow
0.1
Yellow
0.1
3633CT
Yellow
0.1
Yellow
0.1
Yellow
0.1
3639CT
Yellow
0.1
Yellow
0.1
Yellow
0.1

TABLE 5

Result of Mecke’s, Reichard’s and Vitali’s colour tests

Alkaloid

Selenious acid (Mecke)

in μg

Sodium tungstate (Reichard)

in μg

Vitalis test

in μg

Group 1 a
 
 
 
 
 
 
Desomorphine
Black-violet - deep-green
0.1
Grey
0.25
Yellow / yellow / orange
0.5
Methyl-desorphine
Greenish-brown
0.25
Deep purple
0.25
Yellow / yellow / orange
0.25
Methyl-dihydro-morphine
Green
0.25
Grey
1.0
Yellow / yellow / orange
1.0
Metopon
Yellow-brown
0.5
-
 
Yellow / yellow / orange
0.25
Morphine-N-oxide
Green
0.25
Grey-purple
0.5
Yellow / yellow / orange
0.5
Nalorphine
Brown
0.25
Black-purple
0.5
Yellow / yellow / orange
0.5
Normorphine
Green
0.25
Grey
1.0
Yellow / yellow / orange
0.25
Oxymorphine
Yellow
1.0
Deep violet
1.0
Yellow / yellow / orange
0.5
Group 1 b
 
 
 
 
 
 
Acethyl-dihydro-codeine
Green
0.5
-
 
Faint yellow / - / pale orange
1.0
Myrophine
Greenish-brown
1.0
Faint purple
1.0
Yellow / yellow / orange
1.0
Norcodeine
Green
0.1
Grey
0.5
Yellow / yellow / orange
0.5
Pholcodeine
Grey-green
1.0
-
 
Faint yellow / - / pale orange
1.0
Thebacon
Green
0.5
-
 
Faint yellow / - / pale orange
1.0
Group 2
 
 
 
 
 
 
Levallorphan
Yellow-brown
0.5
Purple
0.25
Yellow / yellow / orange
0.25
Levo-methorphan (Dextro-methorphan)
Yellow-brown
0.5
Faint brown
1.0
-
 
Levorphanol (Dextrophan)
Yellow-brown
0.5
Purple
0.25
Yellow / yellow / orange
0.25
Phenomorphan
Yellow-brown
0.5
Purple
0.25
Yellow / yellow / orange
0.25
Racemethorphan
Yellow-brown
0.5
-
 
Yellow / yellow / orange
0.25
Racemorphan
Yellow-brown
0.5
Purple
0.25
Yellow / yellow / orange
0.25
Group 3a
 
 
 
 
 
 
Anileridine
-
 
-
 
 / pale yellow / light brown
1.0
Etoxeridine
-
 
-
 
-
 
Morpheridine
-
 
-
 
-
 
Pethidine
-
 
-
 
-
 
Properidine
-
 
-
 
-
 
Hydroxypethidine
Grey-blue - brown
0.5
Reddish-purple
0.5
--/--/ yellow
0.25
Ketobemidone
Blue-green
0.25
Reddish-purple
0.5
--/--/ yellow
0.25
Group 3b
 
 
 
 
 
 
Alphameprodine
Orange-brown
1.0
-
 
-
 
Alphaprdine
Orange-brown
1.0
-
 
-
 
Betameprodine
Orange-brown
1.0
-
 
-
 
Betaprodine
Orange-brown
1.0
-
 
-
 
Trimeperidine
Yellow
1.0
-
 
-
 
Group 3c
 
 
 
 
 
 
Ethoheptazine
-
 
-
 
-
 
Proheptazine
Yellow-brown - orange
0.5
Yellow-brown - green-grey
1.0
-
 
Group 4
 
 
 
 
 
 
Alpha-acetyl-methadol
Purple-brown - brown
0.25
Faint green-grey
1.0
-
 
Alphamethadol
Purple-brown - brown
0.25
Faint green-grey
1.0
-
 
Dipipanone
Light brown
0.5
-
 
-
 
Isomethadone
-
 
-
-
   
Methadone
-
 
-
-
   
Normethadone
-
 
-
-
   
Phenadoxone
-
 
-
-
   
Group 5
 
 
 
 
 
 
Dextro-moramide
-
 
-
 
-
 
Diethyl-thiambutene
Violet-blue
0.1
Orange
0.25
Red - green / brown / brown
0.5
Dimethyl-thiambutene
Violet-blue
0.1
Orange
0.25
Red - green / brown / brown
0.5
Dioxaphteyl-thiambutene
-
 
-
 
-
 
Ethylmethyl-thiambutene
Violet-blue
0.1
Orange
0.25
Red - green / brown / brown
0.5
Levomoramide
-
 
-
 
-
 
Propxyphene
Faint brown
0.5
Grey
1.0
-
 
Racemoramide
-
 
-
 
-
 
Tolpronine
Green
0.5
Grey - grey-violet
1.0
-
 
3570CT
Yellow
0.1
Yellow
0.1
Yellow /--/--
0.5
3638CT
Yellow
0.1
Yellow
0.1
Yellow /--/--
0.5
3633CT
Yellow
0.1
Yellow
0.1
Yellow /--/--
0.5
3639CT
Yellow
0.1
Yellow
0.1
Yellow /--/--
0.5

Several crystal tests may be used to identify the different members of the group. The bunches of small irregular plates which levorphanol gives with platinum bromide do not differ greatly in appearance from the rosettes given by racemorphan. Both levomethorphan and racemethorphan give crystals with styphnic acid, the former dense rosettes, the latter rosettes of plates and needles.

Neither crystal nor colour tests serve to distinguish levorphanol and levomethorphan from their dextro isomers, although, as the table shows, the former may be used to distinguish between the racemic and the optically active forms. This fact affords a simple method of differentiating between (+) and ( - ) isomers (Clarke, [24] ). A drop of a solution of one known isomer is added to a drop of the test solution, followed by a drop of a suitable reagent (5 per cent sodium carbonate in the case of levorphanol and dextrophan, saturated trinitro-benzoic acid in the case of their methyl ethers). If the isomer added is the same as the unknown, the precipitate formed will be due to that isomer only, but if it is the enantiomorph, crystals typical of the racemate will be formed.

3. The pethidine group. With the Marquis reagent the reversed esters give varying shades of brownish or purplish red, while the other members give a dull orange. This latter test is not very delicate, and the colour may be missed altogether on the microgram scale. The sensitivity may be increased by adding the reagent to the residue heated to 100° C, but reagents containing sulphuric acid readily cause charring under these conditions, and cannot be used in this way with substances extracted from cadaveric material, which often char even in the cold. The other colour tests also serve chiefly to distinguish between esters and reversed esters, although the light blue colour given by the sulphuric acid-molybdate reagent with hydroxypethidine and ketobemidone helps to distinguish these two compounds, as does the reddish purple with the sulphuric acid-tungstate reagent.

Although most of these compounds form numerous crystalline derivatives, difficulty arises in two cases. With etoxeridine, the crystals formed with both lead iodide and platinum iodide form very slowly, and from concentrated solutions only. On occasions they may fail to appear at all, and thus cannot be regarded as providing a satisfactory test. With ketobemidone it was found impossible to obtain any crystals from solutions in dilute acids. Solutions in 90% phosphoric acid yielded excellent crystals with the gold halide reagents, but these are rather similar to those given by pethidine and hydroxypethidine under similar conditions. Differentiation may, however, be made by colour tests and by the fact that the latter substances readily form crystals from solutions in dilute acids.

The crystals formed by alphaprodine with styphnic acid are very small, and are best viewed under polarized light.

4. Methadone group. Only the alpha isomers of methadol and acetylmethadol were available. There is no single colour test by which members of this group may be identified, but several tests serve to distinguish methadol and acetylmethadol from methadone, normethadone, isomethadone, phenadoxone and dipipanone. The former give a purple-brown changing to grey-green with Marquis reagent, a brown-purple changing to green with the sulphuric acid-molybdate reagent, and a dull grey-green with the sulphuric acid-vanadate reagent. The ketone members of the group give colours with the last reagent only, normethadone giving a pale yellow-green, methadone, dipipanone and phenadoxone a green changing to blue, and isomethadone a transient brown-purple changing to violet-blue.

Numerous crystal tests serve to differentiate between members of the group. The crystals given by normethadone with the gold bromide/hydrochloric acid reagent are rather difficult to see, as they are usually mixed with amorphous material.

Alphamethadol and alpha-acetylmethadol may be distinguished from one another by the crystals they give with potassium chromate, the latter giving small rosettes of plates and the former rosettes and burrs of fine needles.

5. Miscellaneous group. The dialkylthiambutenes give brilliant colours with all the reagents used, the colour change with fuming nitric acid being particularly distinctive. In addition to the tests shown in table 4, these compounds give a red colour turning to green with the paraformaldehyde/ phosphoric acid reagent introduced for the detection of solanaine (Clarke, [18] ). The various members of the group may be distinguished from one another by crystal tests.

Both colour and crystal tests are available for the identification of propoxyphene and tolpronine. In the case of dioxyphetyl butyrate and moramide, however, no colour tests could be found, although there are several good crystal tests. The three isomers of the latter compound may be differentiated by the method described above for the N-methyl-morphinans, using a 5% solution of ammonium thiocyanate. Racemoramide gives large plates with this reagent, while the optically active forms give only oils. The latter are distinguished from one another by cross testing with a solution of one known enantiomorph. As the test is not particularly sensitive, concentrations should be in the range of 5%-1%.

The benzodioxans (Jacob, Blozovski, & Echinard-Garin, [25] ) give a bright yellow colour with all the sulphuric acid reagents. In this they resemble the benzhydryl ether derivatives (Clarke, [20] ). They form few crystalline derivatives, however, and differentiation between members of this group is not easy if only microgram quantities are available.

All the tests described in this paper were carried out with microgram quantities of the pure subtance. The sensitivities given refer to the actual quantity of the compound that may be detected in that particular test.

SUMMARY

Crystal and colour tests are described for 51 analgesic drugs.

Examples of crystals obtaine dwith the micro-crystalline tests (continued)

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Appendix A Reagents for microcrystalline tests

(Unless otherwise indicated, the quantities shown are dissolved in 100 ml of water)

  1. Gold bromide : 5 g gold chloride + 5 g sodium bromide.

  2. Gold bromide / hydrochloric acid : 5 g gold chloride + 5 g sodium bromide in 100 ml concentrated hydrochloric acid.

  3. Gold chloride : 5 g.

  4. Lead iodide : Dissolve 30 g potassium acetate in 100 ml of water, adjust to pH6 with acetic acid, and saturate with lead iodide.

  5. Mercuric chloride : 5 g.

  6. Picric acid : 5 g.

  7. Platinum chloride : 5 g.

  8. Platinum iodide : 5 g platinum chloride + 25 g sodium iodide.

  9. Potassium bismuth iodide : 5 g bismuth subnitrate + 25 g potassium iodide in 100 ml of 2% sulphuric acid.

  10. Potassium cadmium iodide : 1 g cadmium iodide + 2 g potassium iodide.

  11. Potassium chromate : 5 g.

  12. Potassium iodide : 5 g.

  13. Potassium mercury iodide : 1.5 g mercuric iodide + 5 g potassium iodide.

  14. Potassium permanganate : 2 g potassium permanganate + 5 drops syrupy phosphoric acid.

  15. Potassium tri-iodide (1) : 2 g iodine + 4 g potassium iodide.

  16. Potassium tri-iodide (2) : 0.1 g iodine + 0.2 g potassium iodide.

  17. Potassium tri-iodide (3) : 1 g iodine + 50 g potassium iodide.

  18. Sodium carbonate : 5 g.

  19. Sodium phosphate : 5 g Na 2HPO 4.

  20. Zinc chloride : 5 g.

  21. Trinitrobenzoic acid : Saturated solution.

  22. Platinum bromide : 5 g platinum chloride + 10 g sodium bromide.

  23. Picrolonic acid : Saturated solution.

  24. Styphnic acid : 5 g.

  25. Di-sodium methyl arsonate : 5 g.

  26. Potassium cyanide : 5 g.

  27. Ammonium thiocyanate : 5 g.

Acknowledgements

My thanks are due to Dr O. J. Braenden, Dr N. B. Eddy, Dr C. C. Fulton, Dr H. Isbell, Dr J. Jacob, Professor D. K. de Jongh, Dr D. Kharkevitch, Dr J. Marks, Mr P. Peterson, Dr J. M. Robins, Dr O. Schnider and Mr T. D. Whittet for help in obtaining material. I acknowledge most gratefully gifts of drugs from Messrs Allen & Hanbury, Ltd. ; British Drug Houses Ltd.; Burroughs Wellcome & Co.; Carlo Erba S.p.A.; Ciba (Basle) Ltd.; The Distillers Co., Ltd.; Farbwerke Hoechst AG.; Glaxo Laboratories, Ltd.; Laboratoire de recherches biologiques Laborec.; Eli Lilly & Co., Ltd.; H. Lundbeck & Co.; J. F. Macfarlan & Co., Ltd.; Merck Sharp & Dohme International; Mining and Chemical Products, Ltd.; Roche Products, Ltd.; S. A. Produits Bios; Sigurta Farmacutici; T. & H. Smith, Ltd.; Sojuzchimexport; and J. Wyeth & Brother, Ltd. I am also greatly indebted to Mr R. F. S. Creed and Mr H. Burgess for taking the photographs, and to Mrs Ann Williams for technical assistance.

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BARNES, W. H., Bull. Narcotics, VI, (1) 20 (1954).

002

BARNES, W.H., & SHEPPARD, H. M., ibid., VI (2), 27 (1954)

003

OESTREICHER, P. M., FARMILO, C. G., & LEVI, L., ibid., VI (3-4), 42 (1954).

004

BREINLICH, J., Arzneimitt-Forsch., 3, 93 (1953).

005

LEVI, L., HUBLEY, C. E., & HINGE, R. A., Bull. Narcotics, VII (1), 42 (1955).

006

CURRY, A. S., & POWELL, H. Nature, 173, 1143 (1954).

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VIDIC, E., Arznemitt.-Forch. 5, 291 (1955).

008

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009

FARMILO, C. G., LEVI, L., OESTREICHER, P. M., & ROSS, R. J., Bull Narcotics, VI (4), 52 (1952).

010

LEVI, L., ibid., VII, (3-4), 43 (1955).

011

FARMILO, C. G., & LEVI, L, Canad. J. Chem., 30, 782 (1952),

012

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013

VIDIC, E, ibid., 3, 34 (1953).

014

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015

CLARKE, E.G. C., & WILLIAMS, M., J. Pharm. Pharmcol., 7 255 (1955).

016

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017

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018

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019

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020

CLARKE, E.G. C., ibid., 9, 752 (1957).

021

CLARKE, E.G. C, ibid., 10, 194 (1958).

022

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023

FULTON, C.C., Am. J. Pharm., 104, 244 (1932).

024

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