Microchemical identification of modern analgesic drugs (part II)

Sections

Introduction
Results
Discussion
Acknowledgements

Details

Author: E. G. C. Clarke
Pages: 17 to 20
Creation Date: 1961/01/01

Microchemical identification of modern analgesic drugs (part II)

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

Introduction

Since the publication of a previous paper on the identification of analgesic drugs (Clarke, 1959 a), additional substances have been brought under international control, or recommended for such restriction. It is the purpose of this paper to describe tests for seventeen of these new compounds.

It must be realized that the ever-increasing number of alkaloidal substances available makes their identification progressively more difficult. Although crystal tests are excellent for final confirmation when the compound has already been tentatively identified, they do not lend themselves to the "pinpointing" of one unknown substance out of the hundreds now in use for one purpose or another. Colour tests are more useful for this purpose, but are in many cases not available. To overcome this difficulty use may be made of paper chromatography, the system used by the writer being that described by Curry & Powell (1954). It is not proposed to consider here the details of paper chromatography, for which the reader is referred to the excellent paper by Genest & Farmilo (1959); but it must be emphasized that Rf values are not strictly reproducible, and no attempt should be made to effect an identification on the Rf value alone. Paper chromatography does, however, serve a most useful purpose in narrowing the field for identification by crystal and colour tests. Should it be necessary, these tests may be carried out on material eluted from the paper chromatogram (Clarke, 1960 a; Clarke & Hawkins, 1960).

Results

Table 1 gives the approved name for the compound, its chemical name and the Rf value on the Curry & Powell system. Table 2 shows the type of precipitate obtained when a micro-drop of a 1% solution of the compound is added to a similar drop of the reagent. Table 3 shows the type of crystal obtained, those most suitable for identification purposes being printed in capitals. Table 4 shows the results of various colour tests. The composition of the reagents and the technique for carrying out the tests are as described previously (Clarke & Williams, 1955; Clarke, 1959 a).

Phenazocine and dimenoxadol have been included in the tables, although tests for these substances have already been described (Clarke, 1959b; Clarke, 1960b). R.951 (1-(3-oxo-3-phenylpropyl)-4-phenylpiperidine-4-carboxylic acid ethyl ester) has also been included, because it appears to have Outstanding analgesic properties (janssen, Jageneau, Van Proosdij-Hartzema & de Jongh, 1958). This compound is the ketone corresponding to the secondary alcohol phenoperidine.

Discussion

It will be noted that while this group of new analgesic drugs includes derivatives of morphine, morphinan and pethidine, it also shows the introduction of fresh types of compound.

Some of these substances are not easy to identify; for example, hydromorphinol gives colour reactions similar to those of morphine, but even from concentrated solution forms few precipitates, only one of which is crystalline. Diampromide and phenamprornide give no satisfactory colour reactions and few crystals. Levophenacylmorphan gives colour reactions that are not particularly characteristic; while the test with picrolonic acid is of little value, as the crystals form only from dilute solutions, and often fail to appear. Furethidine forms no crystals and gives only a single non-specific colour reaction. This substance is noteworthy on account of the number of precipitates which form as oily droplets.

Acknowledgements

My thanks are due to Dr. Nathan B. Eddy; Dr Harris Isbell; Dr. Paul Janssen; Dr. E. L. May; British Drug Housses Ltd.; Ciba (Basle) Ltd.; J. F. Macfarlan & Co. Ltd. and G. D. Searle & Co. Ltd. for supplying me with compounds used for this work. I am also greatly indebted to Miss Ann Cooper and Miss Sandra Gavin for technical assistance.

TABLE 1. - SUBSTANCES TESTED

Approved name or INN

Chemical designation

Rf value

Approved name or INN

Chemical designation

Rf value

Allylprodine
3-allyl-1-methyl-4-phenyl-4-propion-oxypiperidine
0.69
Levo-phenacylmorphan
(-)-3-hydroxy-N-phenacylmorphinan
0.77
Benzethidine
1-(2-benzyloxyethyl)-4-phenylpiperi-dine-4-carboxylic acid ethyl ester
0.82
Metazocine
2'hydroxy-2,5,9-trimethyl-6,7-benzomorphan
0.48
Clonitazene
2-( para-chlorbenzyl)-1-diethylami-noethyl-5-nitrobenzimidazole
0.66
Norlevorphanol
(-)-3-hydroxymorphinan
0.58
Diampromide
N-[2-(N-methylphenethylamino) propyl] propionanilide
0.76
Phenampromide
N-(1-methyl-2-piperidinoethyl) propionanilide
0.68
Dimenoxadol
2-dimethylaminoethyl - 1-ethoxy-1,1- diphenylacetate
0.60
Phenazocine
(±) 2'-hydroxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan
0.80
Diphenoxylate
1-(3-cyano-3, 3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid ethyl ester
0.90
l-Phenazocine
(-) 2h-ydroxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan
0.80
Etonitazene
1-diethylaminoethyl-2- para-ethoxy-benzyl-5-nitrobenzimidazole
0.70
Phenoperidine
1-(3 - hydroxy - 3 - phenylpropyl)-4-phenylpiperidine-4-carboxylic acid ethyl ester
0.84
Furethidine
1-(2-tetrahydrofurfuryloxyethyl)-4-phenylpiperidine-4-carboxylic acid ethyl ester
0.64
Piminodine
4-phenyl-1-(3-phenylaminopropyl)-piperidine-4-carboxylic acid ethyl ester
0.72
Hydromorphinol
14-hydroxydihydromorphine
0.11
R.951
1-(3-oxo-3-phenylpropyl)-4-phenylpiperidine-4-carboxylic acid ethyl ester
0.86

TABLE 3. - TYPES OF CRYSTAL OBTAINED

Alkaloid and reagent

Type of crystal

Sensitivity (μg)

Alkaloid and reagent

Type of crystal

Sensitivity (μg)

Allylprodine
   
Hydromorphinol
   
Lead iodide
Dense rosettes
0.1
Gold bromide/hydrochloric acid
VERY SMALL PLATES
1.0
Platinum chloride
Dense rosettes o/n
1.0
Levophenacylmorphan
   
Picric acid
SMALL PLATES
0.25
Picrolonic acid
Small oily needles
0.25 a
Trinitrobenzoic acid
Dense rosettes
1.0
Metazocine
   
Picrolonic acid
Rosettes of rods
0.1
Platinum chloride
Bunches of small plates
0.25
Styphnic acid
SMALL IRREGULAR PLATES
0.25
Sodium carbonate
DENSE ROSETTES OR PRISMS
0.25
Benzethidine
   
Trinitrobenzoic acid
Segmented plates
1.0
Gold chloride
SMALL PLATES o/n
0.1
Platinum bromide
Dense rosettes
1.0
Potassium iodide
Branching needles
1.0
Picrolonic acid.
CURVING NEEDLES
0.25
Potassium permanganate
FEATHERY ROSETTES o/n
0.1
Di-sodium methyl arsonate
Dense rosettes
1.0
Picrolonic acid
Smudge rosettes o/n
1.0
Potassium cyanide
Dense rosettes
1.0
Styphnic acid
Masses of blades o/n
0.25
Norlevorphanol
   
Clonitazene
   
Gold bromide
Rosettes of needles
0.25
Gold bromide/hydrochloric acid
Rosettes of curved needles
0.25
Gold bromide/hydrochloric acid
ROSETTES OF RODS
0.1
Mercuric chloride
Rosettes of rods
1.0
Gold chloride
Rosettes of rods
1.0
Potassium chromate
Bunches of blades
0.25
Mercuric chloride
Dense rosettes o/n
1.0
Potassium iodide
Bunches of plates
0.5
Picric acid
Dense rosettes o/n
1.0
Potassium tri-iodide (1)
SMALL PLATES OR NEEDLES o/n
0.25
Platinum chloride
IRREGULAR BLADES
0.5
Potassium tri-iodide (2)
Bunches of plates o/n
0.25
Platinum bromide
Rectangular plates
0.5
Zinc chloride
VERY SMALL ROSETTES
0.1
Phenampromide
   
Picrolonic acid
Small rosettes o/n
0.25
Gold bromide
SERRATED BLADES
0.25
Ammonium thiocyanate
Bunches of plates
0.25
Gold bromide/hydrochloric acid
PLATES OR PRISMS o/n
0.25
Diampromide
   
dl-Phenazocine
   
Lead iodide
Dense rosettes and tablets o/n
1.0
Potassium iodide
ROSETTES OF OILY NEEDLES
1.0
Dimenoxadol
   
Potassium tri-iodide (2)
ROSETTES OF CURVING NEEDLES
1.0
Gold chloride
Bunches of needles o/n
1.0
Sodium carbonate
Bunches of prisms
1.0
Lead iodide
Rectangular plates
0.25
Sodium phosphate
Rosettes o/n
1.0
Platinum chloride
Small dense rosettes
0.25
Di-sodium methyl arsonate
Bunches of prisms
1.0
Trinitrobenzoic acid
Small rosettes
1.0
Potassium cyanide
Bunches of prisms
1.0
Platinum bromide
ROSETTES OF BRANCHING RODS
0.25
l-Phenazocine
   
Picrolonic acid
Small rosettes of rods
0.25
Sodium carbonate
FANS OF OILY NEEDLES o/n
1.0
Styphnic acid
BUNCHES OF IRREGULAR PLATES
0.25
Picrolonic acid
SHELL - LIKE CRYSTALS
1.0
Mercuric chloride
Rhomboids
1.0
Styphnic acid
Shell-like crystals
1.0
Diphenoxylate
   
Di-sodium methyl arsonate
Fans of oily needles o/n
1.0
Potassium iodide
SMUDGE ROSETTES
0.25
Potassium cyanide
Smudge rosettes o/n
1.0
Potassium tri-iodide (1)
Bunches of needles o/n
1.0
Phenoperidine
   
Potassium tri-iodide (2)
BUNCHES OF PLATES
0.25
Platinum chloride
Dense rosettes o/n
0.25
Ammonium thiocyanate
Branching needles o/n
0.5
Potassium chromate
Rosettes of rods
0.25
Etonitazene
   
Potassium iodide
ROSETTERS OF RODS
0.5
Gold bromide/hydrochloric acid
Curved oily needles o/n
0.25
Potassium permanganate
PLATES OR B LADES
0.1
Picric acid
Needles
1.0
Potassium tri-iodide (2)
Dense rosettes o/n
1.0
Potassium cadmium iodide
Rosettes or feathery crystals
0.25
Platinum bromide
Gelatinous or smudge rosettes o/n
0.25
Potassium chromate
BUNCHES OF RECTANGULAR PLATES
0.25
Piminodine
   
Potassium iodide
Needles or blades
1.0
Lead iodide
Masses of needles
0.5
Potassium tri-iodide (1)
Dense rosettes o/n
1.0
Picric acid
Curved branching needles
0.1
Potassium tri-iodide (2)
Bunches of plates or prisms
1.0
Platinum chloride
Sheaves of oily needles
1.0
Potassium tri-iodide (3)
Prisms or rosettes
1.0
Potassium chromate
BUNCHES OF BLADES
0.25
Picrolonic acid
Bunches of prisms
0.25
Potassium iodide
SMALL ROSETTES OF ELIDES
0.25
Ammonium thiocyanate
BUNCHES OF RODS OR PRISMS
0.25
Potassium tri-iodide (1)
Small irregular rosettes
1.0
Furethidine
   
Potassium tri-iodide (2)
Small irregular crystals
0.25
-
-
-
Potassium tri-iodide (3)
Small irregular crystals
1.0
Piminodine (contd.)
   
Lead iodide
Oily blades o/n
0.25
Platinum bromide
Masses of oily needles o/n
0.25
Platinum chloride
Curved needles
1.0
Styphnic acid
Branching needles o/n
1.0
Potassium chromate
Rosettes of needles
0.1
Ammonium thiocyanate
Large needles o/n
1.0
Potassium iodide
Very small needles
0.25
Trinitrobenzoic acid
Dense rosettes o/n
1.0
Potassium mercury iodide
Curved needles o/n
1.0
R. 951
   
Potassium permanganate
Small plates or needles
0.25
Gold bromide
Oily needles
1.0
Potassium tri-iodide (1)
Rosettes of needles
1.0
Gold bromide/hydrochloric
   
Potassium tri-iodide (2)
ROSETTES OF NEEDLES
0.25
acid
Oily needles o/n
1.0
Potassium tri-iodide (3)
Bunches of oily needles
1.0
Gold chloride
Oily needles o/n
0.25
Ammonium thiocyanate
BUNCHES OF PLATES OR NEEDLES
0.1

o/n (overnight = Crystals do not form until the following day.

a Crystals form from dilute solutions only.

TABLE 4. - COLOUR TESTS

Alkaloid

Marquis

Sensitivity (μg)

Ammonium vanadate

Sensitivity (μg)

Ammonium molybdate

Sensitivity (μg)

Allylprodine
Blue-black
0.1
Grey-green
1.0
Grey → green
1.0
Benzethidine
Orange
1.0
Orange-brown
1.0
Orange-brown
1.0
Clonitazene
-
-
-
-
Grey-blue
1.0
Diampromide
Orange
1.0
-
-
-
-
Dimenoxadol
Orange → greenish blue
0.1
Orange → brown → purple
0.1
Orange → brown → dull purple
0.1
Diphenoxylate
-
-
-
-
-
-
Etonitazene
Faint orange
1.0
-
-
Pale green
1.0
Furethidine
Faint orange
1.0
-
-
-
-
Hydromorphinol
Purple
0.1
Grey
0.1
Purple → blue → yellow
0.1
Levo-phenacylmorphan
Faint purple → grey → green
1.0
Grey-blue
1.0
Bright blue
0.5
Metazocine
Brown
1.0
Greenish-brown
1.0
Bright blue → green
1.0
Norlevorphanol
Olive
1.0
-
-
Blue → yellow-green
0.1
Phenampromide
-
-
-
-
-
-
dl-Phenazocine
Brown
1.0
Greenish-brown
1.0
Bright blue → green
1.0
l-Phenazocine
Brown
1.0
Greenish-brown
1.0
Bright blue → green
1.0
Phenoperidine
-
-
-
-
Faint grey-purple
1.0
Piminodine
-
-
-
-
-
-
R.951
-
-
-
-
-
-

Alkaloid

Selenious acid

Sensitivity (μg)

Sodium tungstate

Sensitivity (μg)

Vitalis test

Sensitivity (μg)

Allylprodine
Pale olive
1.0
Blue-grey
1.0
Yellow/yellow/grey → purple-brown
0.5
Benzethidine
Orange-brown
1.0
Faint grey
1.0
-/-/-
-
Clonitazene
-
-
-
-
Faint brown/faint brown/yellow-brown
1.0
Diampromide
-
-
-
-
-/-/-
-
Dimenoxadol
Orange
0.1
Orange → purple
0.1
-/-grey
1.0
Diphenoxylate
-
-
-
-
-/-/-
-
Etonitazene
Yellow
1.0
Yellow-brown
1.0
Light brown/lt. brown/yellow-brown
1.0
Furethidine
-
-
-
-
-/-/-
-
Hydromorphinol
Green
0.1
Grey-purple
0.1
Yellow/yellow/orange
0.5
Levo-phenacylmorphan
Pale yellow
1.0
Black-purple
0.25
Yellow/yellow/orange
0.25
Metazocine
Brown
1.0
Grey-purple
1.0
Yellow/yellow/orange
1.0
Norlevorphanol
Yellow-brown
1.0
Black-purple
0.5
Yellow/yellow/orange
1.0
Phenampromide
-
-
-
-
-/-/-
-
dl-Phenazocine
Brown
1.0
Black-purple
0.1
Yellow/yellow/orange
1.0
l-Phenazocine
Brown
1.0
Black-purple
0.1
Yellow/yellow/orange
1.0
Phenoperidine
Faint brown
1.0
-
-
-/-/faint orange
1.0
Piminodine
-
-
-
-
Bright orange/yellow/orange
0.5
R.951
-
-
-
-
-/-/faint orange
1.0

REFERENCES

CLARKE, E. G. C., Bull. Narcotics, XI, (1) 27 (1959 a).

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

GENEST, K. & FARMILO, C. G., Bull. Narcotics, XI, (4) 20 (1959).

CLARKE, E. G. C., Nature, 188, 411 (1960 a).

CLARKE, E. G. C. & HAWKINS, A. E., J. Pharm. Pharmacol 12, 509 (1960).

CLARKE, E. G. C. & WILLIAMS, M., Bull. Narcotics, VII, (3-4), 33

CLARKE, E. G. C., Nature, 184, 451 (1959 b).

CLARKE, E. G. C., Bull. Narcotics, XII (1) 41 (1960 b).

JANSSEN, P. A. J., JAGENEAU, A. H., VAN PROOSDIJ-HARTZEMA, E. G. & DE JONGH, D. K., Act. Physiol. Pharmacol Needandica, 7, 373 (1958).