Studies on the Identification of Narcotics, III Microcrystal and Colour Tests for the New Synthetic Narcotics

Sections

INTRODUCTION
A. EXPERIMENTAL PROCEDURES FOR MICROCRYSTAL REACTIONS
B. RESULTS OF TESTS
C. DISCUSSION
D. TABULATION OF PREVIOUS WORK ON IDENTIFICATION OF METHADONE AND PETHIDINE
E. RECOMMENDATIONS FOR THE CRYSTAL IDENTIFICA-TION OF PETHIDINE AND METHADONE
F. SOME COLOUR REACTIONS FOR IDENTIFYING SYNTHETIC NARCOTICS
ACKNOWLEDGMENTS
GENERAL NOTE CONCERNING THE PHOTOGRAPHS
LIST OF CHARTS
Micro photographs of Synthetic Narcotics
LIST OF TABLES

Details

Author: Charles G. Farmilo,, Leo Levi,, P.M. L. Oestreicher,, R. J. Ross
Pages: 16 to 42
Creation Date: 1952/01/01

TECHNICAL

Studies on the Identification of Narcotics, III Microcrystal and Colour Tests for the New Synthetic Narcotics *

Ph.D., Charles G. Farmilo,
Ph.D., Leo Levi,
B.A., P.M. L. Oestreicher,
R. J. Ross

This article is a continuation of the one that appeared in the Bulletin (vol. II, No 2, April 1950) It was prepared by Drs. Charles G. Farmilo and L. Levi and Mrs P. M. L. Oestreicher, B.A., chemists of the Organic Chemistry and Narcotic Section, Food and Drug Laboratories, Department of National Health and Welfare, Ottawa (Canada), and Mr. R J. Ross, supervisor of the Special Effects Division, National Film Board of Canada, also at Ottawa These studies will be of great value to narcotics enforcement chemists in identifying the new synthetics

INTRODUCTION

A number of synthetic narcotics have recently been added to the schedule of the Canadian Opium and Narcotic Drug Act, 1929, by the Division of Narcotic Control, acting under the international treaty known as the 1948 Protocol. These synthetic drugs had been found to possess addiction liability similar to that of morphine by the Expert Committee on Drugs Liable to Produce Addiction of the World Health Organization. It is essential that drug analysts be prepared to identify these drugs now that they are covered by the Opium and Narcotic Drugs Laws, and research into the chemistry of their identification has been carried on in this laboratory to obtain and provide microchemical tests for this purpose.

The synthetics which may be encountered as illicit seizures are: methadone, pipidone, phenadoxone; pethidine, hydroxypethidine, ketobemidone, alphaprodine; methorphinan and metopon. The last-mentioned substance, metopon, is manufactured from natural thebaine, while the others are completely synthetic. Methadone, pethidine, methorphinan and metopon are commercially available in Canada; phenadoxone and pipidone are made in England; and ketobemidone is being sold in Denmark and Switzerland, under at least one trade name that we know of--Cliradon. Ketobemidone has been banned from production and sale in the United States and Canada because of its extremely dangerous addiction properties. Ketobemidone is poten-tially the most dangerous narcotic which has been synthesized up to the present time. Withdrawal symptoms from this material are so intense that they are liable to cause death, according to results found by Dr. Harris Isbell at the Lexington Drug Addiction Research Centre.[23] *

Superior figures refer to the references at the end of the article. See references 9 and 10 in article in the Bulletin, vol. II, no. 2, April 1950.

The purpose of this study was to discover satisfactory tests - and, so far as possible, the best tests--for microcrystal identification of a number of the new synthetic narcotics. Many reagents were tried out on a 0.1 per cent solution of each of the nine narcotics studied, and the more sensitive reagents were also tried at 0.05 per cent concentration of the narcotic. Whenever crystals were obtained in the survey, the reaction was studied further, as hereafter described. The investigation lasted several months and at least one good test was found for each of these narcotics.

Another purpose of this paper is to compare some common colour reactions of a number of narcotics with those of the new synthetics. The following spotplate reactions have been studied and results with thirty-four narcotics are reported: Marquis',[31] Mecke’s,[32] Wassicky's,[41] Froehde's,[12] Zernik's[45] and Flueckiger’s.[11] A few special colour reactions for metopon, pethidine and methadone have been previously described 9, 5, 7 and are briefly reviewed in the present paper.

As far as the authors have been able to learn, for four of these nine narcotics there has been no previous publication of any article dealing particularly with their identification as it may have to be made by narcotic or drug chemists. These four are: hydroxypethidine, alphaprodine, ketobemidone and methorphinan. For metopon, colour tests were previously given, in the first article of this series[9] and the crystal reactions given here are the first reported crystal tests. For phenadoxone (under its trade name of Heptalgin), and for pipidone, one microcrystal test for each was given in the second article of this series.[10] Recently another reaction of phenadoxone has been mentioned.[7] The remaining two substances, methadone (amidone, polamidon) and pethidine (dolantin, demerol, etc.) have been previously studied by a number of investigators, including two of the present authors. [5] , [7] , [8] , [9] , [10] , [27] , [24] , [21] , [18] , [37] , [28] , [29] , [22] , [39] , [44] The yarious recommendations are discussed below. Two more tests for pethidine which are new, though obtained with previously known reagents, are illustrated here; and for methadone one test which has been highly recommended before, but not previously photographed, and one test which employs a new reagent.

A. EXPERIMENTAL PROCEDURES FOR MICROCRYSTAL REACTIONS

Before beginning a study of identification reactions of the various new synthetics it wil1 be valuable to place them in chemical relationship with each other. The additional classification, shown in table I, of synonyms is intended to help organize in future innumerable potentially dangerous drugs and collect their proper chemical names which may be required to be shown on the certificate of analysis. Chart I shows the chemical structures and three classes to which these drugs belong. Table I shows the chemical names of the substances named from their formulas in chart I according to the Rules of the International Union of Chemistry as given in Patterson's Ring Index.[33]

Materials

The narcotics investigated in this study were obtained from the following sources of supply: physeptone hydrochloride brand of amidone hydrochloride (methadone hydrochloride) and also pipidone hydrochloride: Burroughs Wellcome and Co., 183-193 Euston Road, London, N.W.1, England; heptalgin hydrochloride brand of meperidine hydrochloride Glaxo Laboratories, Ltd., Greenford, Middlesex, England; demerol hydrochloride brand of meperidine hydrochloride (pethidine hydrochloride): Winthrop-Stearns Inc., Windsor, Ontario; metopon hydrochloride: Parke, Davis and Co., Walkerville, Ontario; dromoran hydrobromide brand of methorphinan (dl-3-hydroxy-N-methyl-morphinan) hydrobromide and also nisentil hydrochloride brand of prisilidene hydrochloride (alphaprodine hydrochloride): Hoffman-LaRoche, Nutley, New Jersey; cliradon hydrochloride brand of ketobemidone hydrochloride, and bemidone hydrochloride (hydroxypethidine hydrochloride): Ciba, Ltd., Basle, Switzerland.

Preparation of narcotic solutions

Solutions of the narcotic salts were prepared by dissolving the salt (0.25 g.) in a minimum amount of water and made up to volume in a volumetric flask (25 ml.). Each stock solution was then diluted as follows: to each of ten soft glass bottles (25 ml. capacity), fitted with plastic screw caps, rubber bulb and dropping pipette, Was added 5 ml. of water, then 5 ml. stock solution was pipetted into the first bottle, capped and shaken. Some of this solution (5 ml.) was then pipetted into a second bottle containing water (5 ml.) capped and shaken. The process was repeated until ten such serial dilutions had been made. The bottles were then labelled showing the narcotic name, concentration and date of preparation.

Chart I

DIARYLALKANONEAMINES

ARYLPIPERIDINES

HYDROPHENANTHRENES

Table I

LIST OF SYNTHETIC NARCOTICS WITH CHEMICAL NAMES, SYNONYMS AND TRADE NAMES

(See "Estimated World Requirements of Narcotic Drugs in 1952", E/DSB/9 Geneva 1951)

DIARYLALKANONEAMINES

1. Methadonea

dl-4;4-diphenyl-6-dimethylamino-heptanone-3; adanon, amidone, amidosan, AN-148, butalgin, depridol, draminon, dia- none, dolafin, dolamid, dolophine, dorexol, heptadon, heptanal, heptanol, Hoechst 10820, ketalgin(e), mecodin(e), mephenon(e), miadone, moheptan, physeptone, physopeptone, polamidon, symoron, turanone.

2. Pipidone

4,4-diphenyl-6-piperidino-5-methylhexanone-3; G.B. (poison list) P.1.S.1.

3. Phenadoxoneaa

4,4-diphenyl-6-morpholino-heptanone-3; C.B.-11, hepagin, heptalgin, heptalin, heptazone.

ARYLPIPERIDINES

1. Pethidineaa

Ethyl-1-methyl-4-phenylpiperidine-4-carboxylate; antiduol, avlon, centralgin, D-140, demerol, dispadol, dodonal, dolantal, dolantin, dolantol, dolaren, dolarin, dolatol, dolental, dolinal, dolopethin, dolosal, dolvanol, endolat, felidin, gratidina, isonipecaine, meperidin(e), mephedine, pantalgine, piridosal, precedyl, sauteralgyl.

2. Alphaprodine

?-l,3-dimethyl-4-phenyl-4-propionoxypiperidine; nisentil, Nu1196, prisilidene.

3. Hydroxypethidine

Ethyl-1-methyl-4-(m-hydroxyphenyl) piperidine-4-carboxylate; bemidone, Hoechst 10446. win. 771.

4. Ketobemidoneaa

1-Methyl-4-(m-hydroxyphenyl)-4-piperidyl ethyl ketone; cliradon, ceto-bemidone, Hoechst 10720, win 1539.

HYDROPHENANTHRENES

1. Morphinan

N-methyl-9,13-iminoethano-octahydrophenanthrene.

2. Methorphinan

N-methyl-9,13-iminoethano-3-hydroxyoctahydrophenanthrene;3-hydroxy-N-methylmorphinan, dromoran, NU-2206.

3. Metopon

N-methyl-9,13-iminoethano-7-methylhexahydro-6-ketophenanthro (4, 5, 12, 13) furan. ^b

International non-proprietary name adopted by the World Health Organization.

Metopon has not been completely determined structurally.

The position of the methyl group (C-7 or C-5) is still in doubt. Formula in chart I based on structure suggested by Small[32] uses the Cahn-Robinson numbering system.

Preparation of reagents particularly mentioned hereafter

(1) Basic reagents

Trisodium phosphate and ammonium carbonate were prepared by dissolving reagent grade chemicals in water. A 5 per cent weight by volume solution was used in each case. Ammonium hydroxide was diluted to a 5 per cent solution. Disodium monomethyl arsonate, Na ₂CH ₃AsO _2.5H ₂O (arrhenal), purchased from Mann Fine Chemical Inc., 136 Liberty St., N.Y. 6, N.Y., was used as a 5 per cent aqueous solution. This reagent was recommended by Denoel and Soulet[6] for morphine, dicodid, dilaudid and eucodal.

(2) Halogen reagents

Iodine in HBr: iodine - 1 g. HBr (40 per cent) - 25 ml. Let stand, with occasional shaking, until the iodine has all dissolved. (This takes several days). Then add 75 ml. water.15, 18.

(3) Acidic or metathetic reagents

Chromium sulfate chloride, CrSO ₄C1: chromic sulfate, Cr ₂(SO ₄) ₃.XH ₂O (7 g.) was placed in water in a mortar (50 ml.) and triturated thoroughly, then chromic chloride, CrC1 ₃.6H ₂O (3 g.) was added to the mortar with stirring. Concentrated hydrochloric acid (7 ml.) was then added. The solution and undissolved crystals were then rinsed into an Erlenmeyer flask (500 ml.) with an additional 35 ml. of water and heated on a steam bath for about ten minutes. Sulfuric acid (1 vol. H ₂O:1 vol. conc. H ₂SO ₄) (8 ml.) was then added to the chromic salts in solution and refluxed about forty minutes. The solution was cooled and transferred to a glass-stoppered bottle for storage. It was found impossible to make this reagent with another brand of chromium sulfate, Cr ₂(SO ₄) ₃.15H ₂O. Its properties seem to depend on particular characteristics of the chromium sulfate used, which was "Baker's Analysed". Originally prepared by Fulton and Williams.[18]

Mercuric bromide and HCl: 5 g. HgBr ₂ in 22 ml. concentrated HCl and 78 ml. water.[18]

Chlorauric acid in acetic acid:[18] this reagent wad prepared by dissolving 1 part of HAuCl ₄.4H ₂O crystals in sixty parts of dilute acetic acid (2 acid: 1 water).

Chloroplatinic acid with HCl: chloroplatinic acid crystals (2 g.) were dissolved in hydrochloric acid (15 ml. of 20. vol. per cent HCl).15,18

Bromauric acid, HAuBr ₄: chlorauric acid crystals (5 g.) and sodium bromide (5 g.) were dissolved in water (100 ml.). The reagent is a deep red colour.[14]

Bromauric acid in concentrated HCl; chlorauric acid crystals (5 g.) were added to hydrobromic acid (7.5 ml. 40 per cent) and hydrochloric acid (92.5 ml. 37 per cent).[15]

Potassium lead iodide: Martini's reagent[30] was prepared by adding enough saturated solution of potassium iodide to a lead nitrate (1 per cent) solution to dissolve the yellow precipitate that first forms. The solution is then clear and slightly yellow.

Sodium lead iodide: sodium iodide (100 g.) and lead acetate (3 g.) were added to water (60 ml.).[13] For test purposes, if the reagent and narcotic solution are added in equal proportions, lead tetraiodide may precipitate, but another drop of the reagent will redissolve this type of precipitate.

Sodium silver iodide: silver nitrate (5 g.) and sodium iodide (75 g.) were dissolved in water (100 ml.).[13] With much dilution, silver iodide may be precipitated from this solution, therefore equal portions of the alkaloid and reagent should be used. Precipitated AgI should redissolve.

Potassium thorium iodide: thorium nitrate(1 g.) and potassium iodide (10 g.) were dissolved in water.

This reagent for methadone is new and is of special interest in that thorium is apparently outside the group of metals indicated by Fulton as forming double halides effective as alkaloidal precipitants.[15]

Reinecke's salt, ammonium diammine chromium tetrathiocyanate, NH ₄ (NH ₃) ₂Cr(SCN) ₄: the salt was dissolved in water (15 ml.) until a saturated solution (about 1.5 per cent) was obtained. Reinecke's salt can be obtained commercially. The solution has to be fairly fresh. The reagent is used extensively by Rosenthaler.[34]

Sodium mercuric nitrite, Na ₂Hg(NO ₂) ₄: mercuric nitrate (5 g.) and sodium nitrite (4 g.) were added to water (100 ml.). A few drops of nitric acid were added to make a clear solution. It is necessary to use 3 to 7 g. of sodium nitrite in the reagent for optimum sensitivity.[13]

(4) Organic reagents

Picric acid, 2,4,6-(NO ₃) ₃C ₆H ₂OH: picric acid (1 g.) in water (100 ml.) was used as a reagent.

Picric acid (alcoholic) - 2 per cent.

Picrolonic acid, NO ₂C ₆H ₄NN :C(CH ₃)C(NO ₂) :COH a saturated aqueous solution was used.[34] ,[39]

Methods for performing and assessing microchemical reactions

The microchemical reactions between the alkaloia and reagent were carried out as follows:

Microscope slides were set out on a black background to facilitate observation of the precipitate. One or more drops of narcotic solution were placed on the slide and the reagent added on top of the narcotic solution. The slide was left undisturbed for about ten minutes or until crystallization had occurred.

The crystalline products were examined under the microscope. Eight criteria, shown in table III, similar to those given by Fulton,[18] were used for comparing and judging the crystal reactions obtained and examined under the microscope. These criteria concern the complete microchemical reaction, reactants, conditions and products. The products may be either crystalline or amorphous, and the criteria apply to crystalline products.

Since analysts identify the reactants (A) or narcotic in a microchemical reaction on the basis of microscopic physical appearance of the product, it is obvious that this microcrystal product must fulfil the requirements of criteria (1) and (2) in table III. The crystal forma and habita must be easily obtained, reproducible and characteristic, and these terms can be defined exactly as follows: crystal faces which are alike constitute a forma(geometrical), several such forms may be combined (in one face), though ordinarily only a few are represented in one product, or microscopic crystal. When a crystal grows freely in all directions the forms which it exhibits represented by faces of different shapes and sizes constitute a habit.a Ideal crystal forms are usually obtained under conditions of very slow and uniform growth. Crystals developing under meta-stable conditions (supersaturation) tend to grow fastest at their angles, maintaining a few faces and a simple habit. Distortion of crystals may be avoided by growth of crystals suspended in a liquid drop, as in the case of material precipitated by metathetical reactions between reactant solutions. If the growth of the crystal upward is restricted by covers the crystals are flattened and distorted. It is thus necessary to specify the reaction conditions under which the crystals grow (criteria 4 and 5).

Another criterion which was used in assessing the value of the reagent was the sensitivity of the reagent. In order to compare the sensitivity of the reagents a comparison of the precipitating power of the reagent with that of phosphomolybdic acid was made according to the method described by Fulton.[14] This method enabled the relative sensitivity of reagents to be compared one with another.

Sensitivity measurements of the reagents were performed as follows: the microscope slides were arranged in front of the bottles containing narcotic solutions to maintain the correct concentration order. Phosphomolybdic acid solution was used as a reagent for determining the sensitivity and solution number. The reagent was prepared by dissolving P ₂O ₅.2OMoO ₅.51H ₂O (10 g.) in water (100 ml.) to which had been added concentrated nitric acid (1 ml.) A drop of this reagent was then mixed with a drop of the narcotic solution for each concentration. An instantaneous reaction, except at the limiting narcotic concentration, occurred producing an amorphous precipitate. This concentration varied with the type of narcotic, and the amount of precipitate varied directly with the concentration of the narcotic. The slides were observed and the one showing the least amount of the precipitate was selected and the bottle from which the solution came was labelled "solution 1". The bottles on the left and the right of solution 1 were then labelled 32, 16, 8, 4, 2, (1), 1/2, 1/4, 1/8, 1/16, 1/32. These numbers are referred to as solution numbers and are indicative of the general alkaloidal precipitation power of phosphomolybdic acid. Table II lists the concentration corresponding to solution 1 for the narcotic solutions.

Table II

SENSITIVITY OF NARCOTIC SOLUTIONS TO PRECIPITATION BY PHOSPHOMOLYBDIC ACID

Name of narcoticfree-base	Chemical classof narcotic	Concentration of narcotic corresponding to solution 1 in per cent
Methadone	---------	0.03
Pipidone	Diarylalkanoneamines	0.03
Phenadoxone	---------	0.03
Pethidine	---------	0.03
Hydroxypethidine	---------	0.08
Alphaprodine	Arylpiperidines	0.13
Ketobemidone	---------	0.02
Methorphinan	Hydrophenanthrenes	0.01

Table III

CRITERIA FOR BEST CRYSTAL TESTS

Products	(1) Highly characteristic crystal habita	Reactants (B)	(7) The reagent should be permanent
---------	(2) Easily recognizable geometrical forma	---------	(8) The reagent should be general alkaloidal
---------	(3) Crystals should develop readily (within 15 minutes)	---------	precipitant (provided that the crystal habits
---------	(4) Crystallization over a wide range of narcotic	---------	are easily distinguished from others given
---------	concentrations	---------	by the same reagent) or a reagent which
Reactants (A)	(5) Crystals should have same geometric form over a	---------	does not precipitate at all with most other
---------	wide concentration range	---------	alkaloids or amines
---------	(6) The reagent should be sensitive	aSee definition in text.

Criterion (8) in table III states that a reagent should be general. In order to illustrate the generality of the reagents mentioned earlier, a brief review of the reactions with other narcotics was made. The results of this work are shown in table IV.

Table IV

OTHER AMINES YIELDING CRYSTALLINE PRODUCTS WITH REAGENTS RECOMMENDED FOR SYNTHETIC NARCOTICS

Chemical class of reagent	Narcotic yielding characteristic crystals	Alkaloid or narcotic previously found to yield crystalline precipitates
Basic reagents	---------	---------
1. Sodium phosphate Na ₃ PO ₄	Metopon	Heroin, narcotine, papaverine, strychnine, cinchonidine38
2. Disodium methyl-arsonate Na ₂CH ₃AsO ₂5H ₂O	Metopon	Dicodid, dilaudid, eucodal, methadone6
3. Ammonium carbonate (NH ₄) ₂CO ₃	Metopon	Methadone,42 dicodide, dilaudid, eucodal6
4. Ammonium hydroxide NH ₄OH	Metopon	Methadone,42 thebaine, cinchonine,38 mor- phine, dicodide, eucodal,6 thebaine, bru-cine, cinchonidine17
Complex oxygen acids	---------	---------
5. Phosphomolybdic acid P ₂O ₅.20MoO ₂.51H ₂O	Amorphous precipitates with all synthetic narcotics	General alkaloidal-precipitant, used for de- termination of relative sensitivities of other alkaloidal reagents, i.e., determination of solution number13, 14, 15
Halogen reagents	---------	---------
6. Iodine in hydrobromic acid, I ₂+HBr	Methadone	Methadone18
Simple alkalihalides	---------	---------
7. Potassium iodide, KI	Pethidine	Apomorphine, codeine, morphine, narceine; dilaudid, brucine, strychnine, dicodid, eu-codal38
Double or complex salts or acids of central metals		---------
(a) Chlorides and chloroacids	---------	---------
8. Chlorauric acid HAuCI4	Metopon	Cocaine,16 apomorphine, benzoylecgonine,3heroin, narceine, thebaine, strychnine, caf-feine, theobromine, eucodal, benzedrine, homatropine,34, 35, 38
9. Chlorauric acid in acetic acid	Pipidone	Cocaine16
10. Chloroplatinic acid H ₂PtCl ₆	Pethidine, ketobemidone	Apomorphine, benzoylecgonine, cocaine, heroin, narceine, thebaine, ?-eucaine,17 brucine, cinchonidine, cotarnine38
11. Chromium sulfate chloride CrSO ₄Cl	Methadone	Strychnine18
(b) Bromides and bromauric acids	---------	---------
12. Bromauric acid HAuBr ₄	Pethidine	Methadone, cocaine, ecgonine, ?-eucaine, hyoscine38, 17
13. Bromauric acid in hydrochloric acid (HAuBr4+HCl)	Pethidine	Heroin, morphine, hyoscine, hyoscamine17,
14. Mercuric bromide in hydrochloric acid (HgBr ₂+HCl)	Methadone	Brucine17
(c) Iodides	---------	---------
15. Sodium silver iodide	Alphaprodine	Cocaine
16. Potassium lead iodide	Alphaprodine, hydroxypethidine	Codeine, arecoline, cocaine30
17. Sodium lead iodide	Alphaprodine, hydroxypethidine	Codeine, procaine
18. Potassium thorium iodide	Methadone	None

Chemical class of reagent	Narcotic yielding characteristic crystals	Alkaloid or narcotic previously found to yield crystalline precipitates
(d) Thiocyanates	---------	---------
19. Reinecke's salt, ammonium-diammine- chromium-tetrathiocyanate NH ₄(NH ₃) ₂Cr(SCN) ₄	Hydroxypethidine, methorphinan, ketobemidone	Narcotine, cocaine, papaverine, codeine cin-chonine, nicotine, brucine, stovaine, ephed- rine, betaine, carnitine, choline, morphine34, 26
20. Sodium mercuric nitrite Na ₂Hg(NO ₂) ₄	Ketobemidone	13
21. Picric acid, 2,4,6,- (NO ₂) ₃C ₆H ₂OH)	Phenadoxone, alphaprodine	Berberine, brucine, cinchonine, cotarnine, he- roin, strychnine, cocaine, cinchonidine38
22. Picrolonic acid NO ₂C ₆H ₄NN C(CH ₃)C(NO ₂) :COH	Metopon	Codein, morphine, eucodal6

B. RESULTS OF TESTS

The following descriptions of the characteristic crystal reactions are given to illustrate the results obtained with the various reagents. The narcotics are grouped according to the chemical family to which they belong. It must be remembered that in actual identification one should not rely on a word description of the product, but should make comparison with a sample of the known narcotic in all cases. A summary of sensitivities of the reagents is given in table V.

Descriptions of crystal tests

Diarylalkoneamines

(1) Methadone with chromium sulfate chloride: the precipitating reagent is apparently CrSO ₄Cl with an unknown proportion of acid associated with the molecule. Applied to the methadone or amidone solution it soon yields rather large, pale, yellow, feathered plates very characteristic especially in solutions 16 to 1 (see table V). In more dilute solutions they, form gradually down to solution 1/8 (1:25,600). The reagent does not appear to be general. Strychnine also gives some light yellow plates, but not similar to those of amidone. We have been able to prepare the reagent using chemicals obtained from one of the inventors (Fulton). However, the reagent could not be prepared using chromic sulfate and chloride obtained from two other sources. The reagent should be prepared by other workers and subjected to further field testing. Fulton's article should be consulted.[18]

(2) Methadone with iodine in hydrobromic acid: the precipitate after crystallization is often trimorphous and tricolour. The most easily obtained crystals are the feathered elongate plates in groups, white (entirely colourless) and transparent. Crystals occur in all solutions from 64 to 1/8 by allowing the test drop to stand. There are two other characteristic forms, these are red grains and pale yellow squarecut plates. The red grains and white plates in the same field present a unique and unmistakable appearance. They are obtained together in solutions 32 to 1/8 (1:200 to 1:25,600). This is the best test for amidone, Fulton.[18] Pictures of the three types of characteristic crystals were given by Farmilo et.al.[10]

(3) Methadone with platinum cyanide: rosettes of curving hairs or fine threads. Easily obtained down to solution 1/8, slowly even in solution 1/16, Fulton.[18]

(4) Methadone with mercuric bromide in hydrochloric acid: the crystals are colourless white feathered plates and splinter crystals often in groups. They are usually the same in all solutions. The plates are the characteristic habit. An, illustration of the characteristic habit was given by Farmilo et. al.[10] The test was described by Fulton.[18]

(5) Methadone with thorium nitrate potassiumiodide: this is an entirely new reagent invented for methadone in our laboratory. Amidone with KI alone forms a characteristic "book-like" crystal habit. The plates are rectangular and attached to a central line. This is entirely different from the habit for potassium thorium iodide reagent. The fine double-pointed thin rods are joined in pairs at their centre in the test solutions. This is the characteristic crystal habit with potassium thorium iodide and cannot be confused with the crystals obtained with potassium iodide alone. Solutions 8 to 1 yield the characteristic crystal habits with potassium thorium iodide.

(6) Pipidone with chlorauric acid in acetic acid: the precipitate is a characteristic massive crystal growth made up of blade-like forms growing in clusters. The clusters gather in groups and are weed-like in general appearance. The crystal habit is very characteristic and forms readily in all solutions from, 2 to 1/2. The reagent is sensitive. The test fulfils all the criteria in table III.

(7) Phehadoxone with picric, acid: the characteristic crystal habit formed by this microchemical reaction between phenadoxone and picric acid is a mass of fragile, irregular, corrugated, wafer-like transparent plates. The plates overlie one another and the upper layers are shaded by the lower plates, which cast sharply defined, triangular shadows which give the field a very striking characteristic appearance. The crystal habit was obtained from solutions 4 and 1 (1:800 to 1:3,200). The reagent is only medium sensitive.

Arylpiperidines

(8) Pethidine with bromauric acid and with bromauric acid in hydrochloric acid: these reagents were designed for application to the dry narcotic. Direct application to a few grains of the pethidine hydrochloride powder yields the highly characteristic crystal habits. The crystal forms are transparent rectangles and plates with tooth-like indentations in the narrow end. The forms are grouped together and grow out of the regions of narcotic grains which may remain undissolved. The bromauric acid reagents are very sensitive and have been used[17] to give characteristic crystals with cocaine, ecgonine, eucaine, heroin, morphine, as well as with non-narcotics hyoscine and hyoscyamine and nicotine. The reagent prepared with hydrochloric acid is most sensitive for direct application.[19]

(9) Hydroxypethidine with potassium lead iodide: the precipitate formed in the reaction between hydroxypethidine (bemidone) and potassium lead iodide is a characteristic crystal habit made up of long, fine rods, criss-crossed throughout the solution. The reagent was first used by Martini for the identification of cocaine.[30] Solutions of bemidone containing 0.13 to 0.03 per cent produce the same crystal form. The reagent in the present formula is medium to sensitive, on the sensitivity scale (table VI).

(10) Hydroxypethidine with Reinecke's salt: the characteristic crystal habit formed in the identification reaction between bemidone and Reinecke's salt is dimorphous. The forms are needles and plates. The needles are found in sheaf-like masses and two or more sheaves may be found joined together; the plates have irregular curved edges and are transparent and may be grouped in the outline of a rosette. The sheaves of needles grow most frequently on the edge of the drop. Crystals are obtained from solutions 4 to 1/2 using a freshly prepared saturated solution of ammonium reineckate. The reagent is not very stable in aqueous solution and only a small amount of solution should be prepared at the time of testing. The reagent is extremely general and gives precipitates with most amines.[26]

(11) Hydroxypethidine with sodium lead iodide: clusters of rectangular transparent short plates make up the characteristic crystal habit formed in this reaction. The reagent is only medium-sensitive, crystalline precipitates being obtained with solution 8 and 4.

(12) Alphaprodine with sodium lead iodide: the characteristic crystal habit formed in the reaction of nisentil with sodium lead iodide is dimorphous. The two forms present are spheroids and clusters of transparent plates. The plates grow out of the mass of spheres. The spheres appear to be clusters of very minute needles. The crystal habit is formed in solutions 1 or higher. The solution concentration is 1:800 and hence the reagent is of low sensitivity.

(13) Alphaprodine with picric acid (aqueous): the characteristic crystal habit is a thread-like mass of crystals in no definite pattern. The threads may be joined together in a tree-like structure. A second coarser type of crystal is found. These are in dense rosettes which grow from the amorphous precipitate. The test has only low sensitivity and is given by solutions 1 to 4 (1:200 - 1:800). The reagent has been applied very widely in alkaloidal identification and characterization (see under discussion).

(14) Alphaprodine with sodium silver iodide: a highly characteristic crystal habit and easily formed crystalline product is obtained with nisentil and sodium silver iodide. The crystals are in the forms of rectangular blocks in clusters and spear-shaped plates in groups of four. The latter have a butterfly-like appearance. The reagent is sensitive and yields crystals with solutions 1 and 2.

(15) Alphaprodine with potassium lead iodide: the results of sodium lead iodide and potassium lead iodide reagents with nisentil are related. The crystals formed with potassium lead iodide are long, narrow, rectangular, thin plates which gather in tufts, or are scattered in finer groups in solution 1 (1:800). There are also some of the tufts which viewed from the end appear to be heavy balls made up of thin plates. The reagent produces crystals down to solution 1/4 and is therefore quite sensitive to alphaprodine. The habit is quite characteristic. The reagent gives crystals with cocaine and hydroxypethidine, which are closely related to alphaprodine in structure as well as having about the same basic strength. The crystal habits of these three narcotics with potassium lead iodide are sufficiently different for purposes of identification.

(16) Ketobemidone with sodium mercuric nitrite: the precipitate is made up of highly characteristic four-pointed stars which have an internal structure and are extremely fine grained. The reagent has medium sensitivity. The best crystal habit was obtained from solution 16 (1:400).

(17) Ketobemidone with Reinecke's salt: the crystal forms are transparent plates with round ends arranged as rosettes. The crystal habit changes somewhat on standing and the plates may show dendritic growths along their sides; the rosettes are somewhat simpler in these cases. The characteristic habit is obtained in concentrations from 0.5 to 0.06 per cent. The reagent is only moderately sensitive and must be used as a freshly prepared solution.

(18) Ketobemidone with chloroplatinic acid: this reagent is used in direct application to the powdered narcotic. A few grains of ketobemidone are sufficient to perform the identification. The crystals may be quadrilateral plates or parallelograms and the habit is characteristically clusters of groups of two or three floating in the drop. When viewed on end the plates may appear to be fine rods. The reagent is generally applicable and sensitive. The test fulfils all the criteria in table III.

Hydrophenanthrenes

(19) Methorphinan with Reinecke's salt: Methorphinan has been recently introduced into Canada as a narcotic. It is quite strongly basic and has a high sensitivity to phosphomolybdic acid. It can be readily identified as the reineckate, Solution 1 is 1:25,600. The characteristic crystals produced by dromoran and ammonium reineckate are rosettes of elliptical, transparent, fine plates. These occur almost specifically in solution 8 (1:600) and down to solution 4 (1:3,200).In more dilute solutions the plates become elongated and connected in thread-like masses. The test is very good and the only microcrystal test developed so far for the identification of methorphinan.*

(20) Metopon with disodium methylarsonate: the characteristic crystals produced in the reaction of disodium methylarsonate (arrhenal) and metopon are clusters of very dense short rods (rhombohedrons). The forms are easily recognized and specific. The test is not very sensitive since it is not given below a concentration of 1:200. Other ketones of the hydro-phenanthrene series of narcotic bases such as dicodide, dilaudide, eucodal give somewhat similar reactions. The test is probably most useful in a diagnostic sense; it is definitely not the best crystal test.

(21) Metopon with picrolonic acid: the crystals from the reaction between metopon and picrolonic acid are pointed blades which soon show secondary growths at the interfacial angles. The characteristic crystal habits in dilute solutions (less than 0.5 per cent) are clusters of saw-like pointed blades. The reagent is the best one for metopon.

Table V shows the reagents considered most characteristic for these narcotics. The sensitivity is stated in terms of solution number (i.e., in comparison to phosphomolybdic acid), and the range of concentration for optimum crystallization is also stated, in terms of per cent. The order of sensitivity of the reagents is also described in words in table V, e.g., medium sensitive (Med. sens.), which brackets the precipitating power in relation to phosphomolybdic acid which is a sensitive reagent. The full scale of sensitivities is described in table VI.

Another test for methorphinan has recently come to our attention. The reagent platinic chloride in 1N HCl is prepared as follows: 5 ml., 0.5 per cent platinic in 1N HCl diluted with 45 ml. 0.1 per cent KI solution and subsequently diluted to 100 ml. with H ₂O. The characteristic precipitate is formed with the dry powdered narcotic, rosettes and needles. [The formula of this reagent was supplied by Dr. C. J. Umberger, Bellevue Hospital, N.Y. City]

Table V

MICROCHEMICAL REAGENTS FOR SYNTHETIC NARCOTIC IDENTIFICATION

---------	---------	---------	SOLUTION SENSITIVITY	---------
---------	Reagent name	Limit of precipi- tation	Rrange of concentration for optimum crystallization	Order of sensit- vity
1. Amidone	Chromium sulfate chloride	1/8	050-0:0301:200-1:3,200	Med. sens.
---------	Iodine in hydrobromic acid	1/16	0.13-0.0031:850-1:25,600	Med. high
---------	Platinum cyanide	1/8	0.03-0.0031:3,200-1:25,600	Sens. High
---------	Mercuric bromide and hydro-chloric acid	1/16	0.06-0.0301:1,600-1:3,200	Med. sens.
---------	Potassium thorium iodide	8	0.50-0.0301:200-1:3,200	Low sens.
2. Pipidone	Chlorauric acid in acetic acid	1	0.06-0.0151:1,600-1:6,400	Med. sens.
3. Phenadoxone	Picric acid (alcoholic)	2(1)	0.13-0.031:800-1:3,200	Med. sens.
4. Pethidine	Brumauric acid	On solid	On solid	---------
---------	Bromauric acid in hydro- chloric acid	On solid	On solid	---------
5. Hydroxypethidine	Potassium lead acetate	4	1.13-0.031:800-1:3,200	Med. sens.
---------	Reinecke's salt	4	0.13-0.061:800-1:6,400	Med. sens.
---------	Sodium lead iodide	4	0.25-0.131:400-1:800	Med. med.
6. Ketobemidone	Sodium mercuric nitrite	32	0.50-0.131:200-1:800	Low med.
---------	Reinecke's salt	8	0.5-0.061:200-1:6,400	Low sens.
---------	Chlorplatinic acid	On solid	On solid	---------
7. Alphaprodine	Sodium lead iodide	?	Solution (2) 1:600	Med.
---------	Picric acid (aqueous)	?	0.5-0.251:200-1:400	Low low
---------	Sodium silver iodide	1	0.25-0.131:200-1:800	Low med.
---------	Potassium lead iodide	?	0.13-0.061:800-1:600	Med med.
8. Methorphinan	Reinecke's salt	2(1/8)	0.13-0.021:800-1:5,000	Med. sens.
9. Metopon	Disodium methyl arsonate	---------	1.0-0.51:100-1:200	Low low
---------	Picrolonic acid	---------	1.0-0.51:100-1:200	Low Iow

C. DISCUSSION

At present most narcotic identification is based on derivative formation of a special kind. Precipitates are obtained which have reproducible and readily recognizable crystal habits; characteristic of the particular narcotic. Experience has shown[25] that when the product resulting from the reaction of narcotic and reagent is distinctive and readily formed the microscopic method leaves little to be desired.[14] Usually, in fact, mere inspection under the ordinary microscope is quite satisfactory - when the crystals are truly characteristic - but the polarizing microscope is often useful, and data of optical crystallography can be used, not only on crystalline derivatives, but also on the original salt.[22] ,[24] ,[25] ,[44] X-ray diffraction is also a powerful means of identifying crystalline material, and is coming into use more and more. [20] , [22 ]

One of the difficulties of the narcotic analyst is to choose between the large number of precipitating reagents available to him. To facilitate a systematic survey of the many reagents, listed in the literature [1] , [2] , [4] , [8] , [13] , [15] , [34] , [38] , [43] it was convenient to organize them according to their obvious chemical properties. This logical method helped to avoid duplication, evident in empirical formulae listed under a variety of inventors’ names, and enabled choice of the most sensitive reagent formula to be made. Fulton[13] to [19] has made the most detailed study of this problem of multiplicity of reagents. Whitmore and Wood[43] have used his classification in their study of toxicologically important alkaloids. Fulton’s classification of reagents into certain chemical groups is used in most of the following tables.

In our view, while the subdivided groups are extremely useful, the reagents may be classified primarily into two major chemical groups: basic, and acidic or metathetic. The basic reagents liberate the organic free-base, and the acidic reagents undergo a metathetical reaction with the amine or salt to produce a new molecule. In the present study it was found, with the exception of metopon, that most of the synthetic narcotics of the diarylpiperidine, alkanoneamine and hydrophenanthrene groups undergo the metathetical type of reaction. However, as table IV shows, the basic reagents are quite useful for identification and give characteristic crystals with eighteen other amines. Perhaps the most widely applied reagents are the complexes of gold and platinum such as chlorauric, chloroplatinic and bromauric acids. These reagents have been used not only in chemical characterizations familiar to classical organic chemists, but primarily by drug analysts. Picric acid is one of the popular organic reagents and is almost equal to chloroplatinic acid in its ability to produce crystalline precipitates. Of forty-one opium alkaloids and derivatives described by Small and Lutz,[35] eighteen are recorded as giving crystalline precipitates with chloroplatinic acid, nine with chlorauric acid, and fourteen with picric acid. In Stephenson’s studies on fifty-four alkaloids, twenty-two crystalline precipi- tates were obtained with chlorauric acid, nineteen with chloroplatinic acid and thirteen with picric acid.[38] The best other reagents in Stephenson’s studies were Kraut’s (potassium bismuth iodide), Wagner’s (iodine in potassium iodide), mercuric chloride (yields many crystals, but they are usually not as characteristic as those with gold and platinum chlorides), potassium iodide, Marme’s (potassium cadmium iodide), Mayer’s (potassium mercuric iodide), palladous chloride, and basic reagents of three widely different strengths, potassium hydroxide, sodium carbonate and potassium chromate.

The most general reagent for characterization that we have discovered for synthetic narcotics is ammonium-diammine-chromium-tetrathiocyanate or Reinecke’s salt, which yielded crystalline precipitates with methadone, pipidone, phenadoxone, pethidine, alphaprodine, ketobemidone, methylmorphinan and metopon.

These precipitates were crystalline, when prepared under the proper conditions, and they may be used for chemical characterization. Three of the reineckates are included in table V, and a further and more detailed report on the results with this reagent will be made elsewhere.[26]

D. TABULATION OF PREVIOUS WORK ON IDENTIFICATION OF METHADONE AND PETHIDINE

Table VI illustrates four different methods used by workers to express the concentrations of the narcotic or reactant A (see table III) of a microchemical reaction for identification of amidone. The concentration range of narcotic solutions has been divided into four regions of sensitivity. The best crystal tests are those given with reagents below solution 1 (least concentration which gives precipitates with phosphomolybdic acid). Solution I is identical in concentration for pethidine and amidone. The initials in the body of table VI indicate the concentrations studied by the various workers in this field.

Tables VII and VIII summarize the names and show the chemical classes of the reagents which give crystals with amidone and pethidine hydrochlorides. Tables VII and VIII also show how well the reagents fit the requirements of a best crystal test given in table III, numbers 4, 5 and 6.

Table IX shows the most promising microchemical reactions which have been recommended to date by various authors for the detection of amidone and pethidine. These reagents were selected as the most promising by the various workers shown in the column entitled "References". The authors, except in two cases, did not indicate what criteria were used in selecting the recommended tests. Fulton[18] listed eight criteria which are essentially the same as those given above, table III, Watson and Bowman[42] used four criteria, of which two were negative ones, i.e., were used for discarding all but three of forty-three crystals that they found as tests for amidone. It may be pointed our that at least fifteen of Watson and Bowman’s tests are basic reagents and would give the free-base amidone which crystallizes readily from basic solutions.

Tables IX and X summarize the "best" crystal tests for amidone and pethidine as recommended by ana- lytical chemists for the detection of narcotics. Table X shows the tests listed in order of their decrease in sensitivity (criterion (6), table III). Illustrations of the crystals obtained with these reagents can be found in the original papers.

Table VI

COMPARISION OF CONCENTRATIONS USED BY VARIOUS AUTHORS IN STUDY OF MICROCHEMICAL REACTIONS OF AMIDONE AND PETHIDINE

SENSITIVITY SCALE				REFERENCES
				Amidone HCl									Pethidine HCl
		Solution parts	Concentration per cent	Solution no.									Solution no.
Low	-	1:50	2.0	64	F	W and B	H and J	-	B and F	L and F	-	-	64	B and F	L and F	D	-	H	-	W
	-	1:100	1.0	32	F	-	-	S	B and F	L and F	-	-	32	B and F	L and F		L		-
	-	1:200	0.5	16	F	W and B	H and J	-	B and F	L and F	-	-	16	B and F	L and F		-		-
	-	1:300	0.33		-	-	-	-	-	-	-	-	-	-	-		-		-
	-	1:400	0.25	8	F	-	-	-	B and F	L and F	-	-	8	B and F	L and F		-		-
Med.	-	1:500	0.20		-	-	H and J	-	-	-	-	-	-	-	-		L		-
	-	1:600	0.165		-	-	-	-	-	-	-	-	-	-	-		-		-
	-	1:700	0.143		-	-	-	-	-	-	-	-	-	-	-		-		-
	-	1:800	0.125	4	F	-	-	-	-	L and F	-	-	4	-	L and F	Data not available	-		-
	-	1:900	0.111		-	-	-	-	-	-	-	-	-	-	-		-	None given	-	None given
	1000	1:1,000	0.100		-	W and B	H and J	S	B and F	-	-	Lu	-	B and F	-		-		-
	-	1:1,600	0.0625	2	F	-	-	-	-	L and F	-	-	2		-		L		-
Sens.	-	1:2,000	0.05		-	-	-	-	B and F	-	-	-	-	B and F	-		-		-
	-	1:3,200	0.03125	1	F	-	-	-	-	L and F	-	-	1	-	L and F		-		-
	-	1:4,000	0.025		-	-	-	-	-	-	-	-	-	-	-		-		-
	-	1:5,000	0.02		-	-	H and J	-	-	-	-	-	-	-	-		-		-
	-	1:6,400	0.015625	1/2	F	-	-	-	-	L and F	-	-	1/2	-	L and F		-		-
	100	1:10,000	0.01		-	-	H and J	-	B and F	-	V	-	-	B and F	-		-		-
High	-	1:12,800	0.007125	1/4	F	-	-	-	-	L and F	-	-	1/4	-	L and F		-		-
	50	1:20,000	0.005		-	-	-	-	-	-	-	-	-	-	-		-		-
	-	1:25,600	0.00356	1/8	F	-	-	-	-	L and F	-	-	1/8	-	L and F		-		-
	20	1:50,000	0.00200		-	-	-	-	-	-	-	-	-	-	-		-		-
	-	1:51,200	0.00128	1/16	F	-	-	-	-	L and F	-	-	1/16	-	L and F		-		-


Key to references
F	Fulton ¹⁸	D	Ducloux ⁸
W and B	Watson and Bowman ⁴²	L	Levine ²⁷
H and J	Hubach and Jones ²²	Lu	Lucas ²⁸
S	Schuldiner ³⁷	V	Vidic ³⁹
B and F	Berry and Farmilo ¹⁰	K	Keenan ²⁴
L and F	Levi and Farmilo	H	Hanson ²¹
		W	Wickström ⁴⁴

Table VII

MICROCHEMICAL REAGENTS WHICH GIVE CRYSTALS WITH AMIDONEHYDROCHLORIDE

--------	--------	--------	Limits of immediate precipitation and of crystallization		--------	--------	Reference
Group		Chemical classification of reagents	Solution no.	Percent	Parts		(see table VI)
A	I.	Basic reagents	16	0.500	1:200	F,	W and B
--------	------	Potassium acetate	1/2	0.016	1:6,400	F,	W and B
--------	------	Potassium hydroxide	1/2	0.016	1:6,400	F,	W and B
--------	------	Sodium carbonate	4	0.125	1:800	F,	W and B
--------	------	Sodium phosphate (Na ₂HPO ₄)	--------	--------	--------	--------	--------
B	------	Oxygen acids	--------	--------	--------	--------	--------
--------	II.	Simple oxygen acids	--------	--------	--------	--------	--------
--------	------	Chlorochromic acid	1	0.030	1:3,200	--------	--------
--------	------	--------	(1/16)	0.0013	1:51,200	F,	--------
--------	III.	Complex oxygen acids	--------	--------	--------	--------	--------
--------	------	(None used for crystals)	--------	--------	--------	--------	--------
C	IV.	Halogen reagents	--------	--------	--------	--------	--------
--------	------	Bromine water	1/8	0.0036	1:25,600	F,	W and B
--------	------	Iodine in 10 per cent hydrochloric acid	1/16	0.001	1:25,600		--------
--------	------	--------	(1/8)	0.0036	1:51,200	F	--------
--------	------	Iodine in sodium bromide	1/16	0.001	1:12,800	F,	S
--------	------	--------	(1/4)	1.007	1:12,800	F	--------
--------	------	Iodine in potassium iodide (1:1)	1/8	0.0036	1:25,600	--------	--------
--------	------	Iodine in potassium iodide (1:133)	(1/16)	0.0036	1:25,600	--------	--------
--------	------	--------	--------	0.001	1:56,000	F	--------
--------	------	Bromine in potassium bromide	--------	No definite conc. Given		S	--------
--------	------	Iodine zinc chloride	4	0.1	1:1,000	S	--------
D	V.	Simple alkali halides and pseudohalides	--------	--------	--------	--------	--------
--------	------	Potassium iodide (1:2)	16	0.5	1:200	--------	--------
--------	------	--------	(1)	0.03	1:3,200	F,	H and J


------	------	Limits of immediate precipitation and of crystallization	------
------	------	Reference


Group		Chemical classification of reagents	Solution no.	Per cent	Parts	(see table VI)
E		Double or complex salts and acids of central metals	------	------	------	------
VI.		Chlorides	------	------	------	------
------		Chlorpalladous acid	2	06	1:1,600	------
------		------	(1/4)	0007	1:12,800	F, W and B
------		Chlorpalladous and hydrochloric acids	8	025	1:400	------
------		------	(1)	00313	1:3,200	F
------		Chlorplatinic acid	4	0.125	1:800	------
------		------	(1/4)	0007	1:12,800	F
------		Chlorplatinic and hydrochloric acids	8	0.25	1:400	------
------		------	(1/2)	1.016	1.6,400	F
------		Ferric chloride and concentrated hydrochloric	4	025	1:800	------
------		------	(1/16)	0013	1:51,200	F
------		Stannic chloride and hydrochloric acid	8	025	1:400	F
------		Chromium sulfate chloride	16	05	1:200	------
------		------	(1/8)	00036	1:25,600	F
------		Uranylchloride in concentrated hydrochloric	32	1.0	1:100	------
------		------	(2)	0.063	1:1,600	F
VII.		Bromides	------	------	------	------
------		Bromopalladous and hydrochloric acids	1/4	0007	1:6,400	------
------		------	(1/2)	0.0157	1:12,800	F
------		Bromoplatinic acid	1	00313	1:3,200	------
------		Bromoplatinic and hydrobromic acids	2	0.063	1:1,600	------
------		------	(1)	0031	1:3,200	F
------		Bromopentachlorplatinic and hydrochloric acids	4	025	1:800	------
------		------	(2)	00625	1:1,600	F
------		Stannic hydrobromic acid	2	006	1:600	------
------		------	(1)	00313	1:3,200	F
------		Zinc hydrobromic acid	8	025	1:400	------
------		------	(2)	00625	1:600	F
VIII.		Iodides	------	------	------	------
------		Mercuric iodide in potassium iodide (1.1)	1/2	00156	1:6,400	------
------		------	(1/16)	0.0013	1:57,200	F, H and J
------		Goldchloride in hydrogeniodide	?	0.0062	1:1,600	L
------		------	4	0.1	1:1,000	S
------		Cadmium iodide	None given	------	------	------
IX.		Cyanides	------	------	------	------
------		Platinum cyanide	1	0.3125	1:25,600	------
------		------	(1/8)	0.0035	1:3,200	F
------		Gold cyanide	1	0.312	1:3,200	------
------		------	(1/8)	0.00356	1:25,600	F
------		Potassium ferricyanide	32	1.0	1:100	------
------		------	------	0.20	1:500	F, H and J
------		Potassium ferrocyanide	16	0.20	1:500	H and J, W and B
X.		Thiocyanates	------	------	------	------
------		Cobalt thiocyanate	0.1	1:1,000	S	------
------		(yields non-crystalline blue precipitate)			------	------
XI.		Nitrites (Nitrates)	------	------	------	------
------		Mercuric sodium chloronitrite	(4)	0.125	1:800	F
------		Lanthanum and uranium nitrates	-	5.0	1:20	H and J
XII.		Double halides and pseudohalides	------	------	------	------
------		Mercuric iodide in hydrochloric acid	?	0.0156	1:6,400	F
------		Mercuric cyanide and sodium iodide	?	0.007	1.12,800	F
------		------	(1/8)	00036	1:25,600	F
------		Mercuric sodium bromide	1/8	00036	1:25,600	------
------		Mercuric sodium chloride	1	003	1:3,200	------
------		------	(1/16)	0.0013	1:51,200	F
------		Chloromercuric acid	1	0.03	1:3,200	------
------		------	(1/16)	0.0013	1:51,200	F
------		Mercuric chloride with hydrochloric	2	1.06	1:1,600	------
------		------	(1/4)	0.007	1.12,800	F, V
------		Mercuric bromide with hydrochloric acid	1	0.03	1:3,200	------
------		------	(1/16)	0.013	1:51,200	------
------		Mercuric chloride (5 per cent)	1	0.025	1:400	L
------		Mercuric bromide	------	None given	S	------
F.	XIII	Organic reagents	------	------	------	------
------		Picric acid	?	0.015	1:6,400	------
------		------	?	0.007	1:12,800	B and F, V.
------		Saccharin	------	None given	W and B	------

The solution number is given in parentheses where it stands for the limit of crystallization, i.e., the limit for a reliable crystal test.


			Sensitivity values
Group	------	Chemical classification of reagents	Solution no	Per cent	Parts	Reference (see table VI)

Table VIII

MICROCHEMICAL REAGENTS WHICH GIVE CRYSTALS WITH PETHIDINE HYDROCHLORIDE


A	I.	Basic reagents	------	------	------	------
------	------	None gave crystals	------	------	------	------
B	------	Oxygen acids	------	------	------	------
------	II	Simple oxygen acids	------	------	------	------
------	------	Perchloric acid	------	------	------	D
------	------	Potassium dichromate in hydrochloric	8	0.2(?)	1:500-?	L
------	------	Potassium chromate in hydrochloric	8	0.2(?)	1:500-?	L
------	------	Chromic anhydride in hydrochloric	8	02(?)	1.500-?	L
------	------	Nitric acid	-	5-10	1 200-1/10	W
------	III.	Complex oxygen acids	------	------	------	------
------	------	(None used for crystals with pethidine)	------	------	------	------
C	IV.	Halogen reagents	------	------	------	------
------	------	Hydrobromic acid	------	None given		D
------	------	Iodine in potassium iodide (1:1)	------	------	------	D
D	V.	Simple alkali halides and pseudohalides	------	------	------	------
------	------	Potassium iodide (5 per cent)	1	02	1:2,000	L, K
------	------	------	8	0.5	------	------
E	------	Halide and pseudohalide salts and acids of central metals	------	------	------	------
------	VI.	Chlorides	------	------	------	------
------	------	Platinic chloride	8	0.2(?)	1:500(?)	L, D
------	------	Mercuric chloride	8	0.2(?)	1:500(?)	L, D
------	------	Palladium chloride	8	02(?)	1:500(?)	L
------	------	Cobaltic chloride	------	------	------	D
------	------	Chlorauric acid in conc. HCl.	------	------	------	------
------	------	Chlorauric acid in phosphoric and acetic acids	------	------	------	------
------	------	(2:1)	------	------	------	------
------	------	Chlorauric acid in (1?1)	On solid only		------	F
------	VII.	Bromides	------	------	------	------
------	------	Sulfuric acid	------	------	------	------
------	------	Bromoplatinic acid in (2?3) sulfuric	------	------	------	------
------	VIII.	Iodides	------	------	------	------
------	------	Bismuth potassium iodide, acid	2.0(?)	------	------	D
------	IX.	Cyanides	------	------	------	------
------	------	Potassium ferricyanide	------	------	------	F, B and F, D
------	------	Potassium ferricyanide	64	2.0(?)	------	L
------	------		------	None given	------	------
------	------	Sodium nitroferricyanide	8	02	1:400	L, K
------	------	------	32	10	1 400	------
------	------	------	16	0.4	1:300	D, B and F, L and F
------	X.	Thiocyanates	------	------	------	------
------	------	Reinecke's salt	1	003	1:3,200	------
------	XI.	Nitrites (Nitrates)	------	------	------	------
------	XII.	Double halides and pseudohalides	------	------	------	------
------	------	(None used for crystals with pethidine)	------	------	------	------
F	XIII.	Organic reagents	------	------	------	------
------	------	Picric acid	4	0.1	1 100	H, L, V, K
------	------	------	1/2	0.02	1 500	------
------	------	Picrolonic acid	1/2	002	1.5,000	H, V, K
------	------	Styphnic acid	1/2	0.02	1:5,000	------


------	Chemical class		Crystallization range for test or lowest Concentration	Author Reference	No
------	(References 13, 14 and 15)
------	------	------.

Table IX

MICROCHEMICAL REAGENTS RECOMMENDED BY VARIOUS AUTHORS FOR DETECTION OF AMIDONE AND PETHIDINE HYDROCHLORIDES


Amidone hydrochloride:	------	------	------		------	------
------	------	------	------		------	------
Reagent name	------	------	------		------	------
------	------	------	------	------	------	------
Chromium sulfate chloride	E	VI	1:200	- 1:25,600	Fulton	18
Iodine in 10 per cent hydrobromic acid	C	IV	1:100	- 1:25,600	Fulton	18
Platinum cyanide	E	IX	1:100	- 1:25,600	Fulton	18
Mercuric bromide with HCI	E	XII	1:100	- 1:51,200	Fulton	18
Iodine zinc chloride	C	IV	1:1,000	------	Schuldiner	37
------	------	------	------		Fulton	18
Iodine potassium iodide (1:1)	C	IV	None given		Schuldiner	37
Potassium bromobromide (1:1)	C	IV	None given		Schuldiner	37
Mercuric bromide	E	XII	None given		Schuldiner	37
Cadmium iodide in KI (1:2)	E	VIII	None given		Schuldiner	37
------	E	VIII	None given		Schuldiner	37
Palladium chloride	E	VI	1:400 - 1:3,200		Fulton	18
------	------	------	------		Watson and Bowman	42
------	------	------	------		Hubach and Jones	22
Potassium ferrocyanide	E	IX	1:50		Watson and Bowman	42
Bromine water	C	IV	1:200 - 1:1,000		Watson and Bowman	42
Chlorauric acid in HI (1:0.5)	E	VIII	1:16,000		Lucas	28
Mercuric chloride (5 per cent)	E	XII	1:4,000		Lucas	28
Mercuric bromide	E	XII	None given		Lucas	29
Potassium iodide (5 per cent)	D	V	1:1,000		Hubach and Jones	22
Potassium ferrocyanide (5 per cent)	E	IX	1:500		Hubach and Jones	22
Cadmium iodide in potassium iodide (1:2)	E	VIII	1:10,000		Hubach and Jones	22
Mercuric iodide in potassium iodide (1:2)	E	VIII	1:20,000		Hubach and Jones	22
Iodine in potassium iodide (1:1)	C	IV	1:1,000		Hubach and Jones	22
Lanthanum nitrate, 20 per cent	E	XI	1:20		Hubach and Jones	22
Uranium nitrate, 20 per cent	E	XI	None given		Hubach and Jones	22
Mercuric chloride in HCl(dil)	E	XII	1:50,000		Vidic	39
------	------	------	------		------	------
Pethidine hydrochloride:	------	------	------		------	------
------	------	------	------		------	------
Reagent name	------	------	------		------	------
------	------	------	------		------	------
Picric acid (aq.)	F	XIII	1:1,000 or less		Levine	27
Potassium iodide (20 per cent)	D	V	1:500 - 1:2,000 or less		Levine	27
Sodium nitroferricyanide	E	IX	1:100 - 1:500		Levine	27
Lead iodide in NaOAc	B	II	1:1,000 or less		Levine	27
Potassium dichromate	------	------	1:500 or less		Levine	27
Picric acid (aq.)	F	XIII	None given		Hanson	21
Picrolonic acid (aq.)	F	XIII	None given		Hanson	21
Bismuth potassium iodide	E	VIII	None given		Ducloux	8
Iodine in potassium iodide (1:1)	C	IV	None given		Ducloux	8
Chloroplatinic acid	E	VI	None given		Ducloux	8
Picrolonic acid	E	VIII	None given		Ducloux	8
Perchloric acid	B	II	None given		Ducloux	8
Mercuric chloride	F	VI(c)	None given		Ducloux	8
Cobaltic chloride	E	VI(c)	None given		Ducloux	8
Potassium ferrocyanide	E	IX	None given		Ducloux	8
Reinecke's salt	E	X	None given		Ducloux	8
Chromium tetrathiocyanate
Chlorauric acid in HCl	E	VI	On solid (10 ?)		Fulton	19
Chlorauric acid in H3PO4-HOAc (2:1)	E	VI	On solid (10 ?)		Fulton	19
Chlorauric acid in (l+1)H2SO4	E	VI	On solid (5 ?)		Fulton	19
Bromoplatinic acid in (2+3)H2SO4	E	VII	On solid (5 ?)		Fulton	19
Picric acid	F	XIII	1:1,000 - 1:5,000		Vidic	39
Picrolonic acid	F	XIII	1:5,000		Vidic	39
Styphnic acid	F	XIII	1:5,000		Vidic	39
Bismuth iodide potassium iodide	E	VIII	1.50		Farmilo	10
Reinecke's salt	E	X	1:3,200		Farmilo	10
Chloroplatinic acid	E	VI	1:10,000		Farmilo	10
Nitric acid	B	II	1:20		Wickström	44
Potassium iodide	D	V	None given		Keenan	24
Picrolonic acid	F	XIII	None given		Keenan	24
Sodium nitroprusside	E	IX	None given		Keenan	24


---------	Lowest concentration	------	Reference
Reagent name	------	------	------	------
Amidone :	------	------	------	------
Mercuric bromide in HCl	1:51,200	------	Fulton	18
Mercuric chloride in HCl	1:12,800	------	Fulton	18
Platinum cyanide	1:50,000	------	Vidic	39
Iodine in 10 per cent HBr	1:51,200	------	Fulton	18
Chromium sulfate chloride	1:25,600	------	Fulton	18
Cadmium iodide in KI (1:2)	1:25,600	------	Fulton	18
------	1:25,600	------	Schuldiner	37
Mercuric iodide in KI (1:2)	1:20,000	------	Hubach and Jones	22
Chlorauric acid in HI (1:05)	1:16,000	------	Lucas	28
Mercuric chloride (5 per cent)	1:4,000	------	Lucas	28
Zinc-chloriodide	1:1,000	------	Schuldiner	37
Potassium iodide (5 per cent)	1:100	------	Hubach and Jones	22
Bromine water (fresh)	1:200 - 1:1,000	------	Watson and Bowman	42
Iodine in KI (1:1) Wagners	1:1,000	------	Hubach and Jones	25
Potassium ferrocyanide	1:500	------	Hubach and Jones	22
Potassium ferrocyanide	1:500	------	Hubach and Jones	22
Chlorpalladous acid	1:50 - 1:200	------	Watson and Bowman	42
Pethidine :	------	------	------	------
Chlorplatinic acid	1:10,000	------	Farmilo	10
Picric acid	1:5,000	------	Levine	27
------	------	------	Vidic	39
Ammonium reineckate	1:3,200	------	Farmilo	10
Potassium iodide (5 per cent)	1:2,000	------	Levine	27
Chlorauric acid in HCl	10 ? (solid)	------	Fulton	19
Chlorauric acid in H ₃PO ₄	10 ? (solid)	------	Fulton	19
Bismuth, potassium iodide	1:50	------	Ducloux	8
Picrolonic acid	None given	------	Ducloux	8

Table X

COMPARISON OF REAGENTS FOR AMIDONE AND PETHIDINE Most sensitive tests in decreasing order for amidone and pethidine hydrochloride recommended by authors, not necessarily "best" tests

E. RECOMMENDATIONS FOR THE CRYSTAL IDENTIFICA-TION OF PETHIDINE AND METHADONE

Pethidine

Ducloux (1943) did not give any specific recommendations as to the best reagents for dolantine (pethidine), but illustrated crystals with eleven reagents and mentioned one other as yielding crystals. These reagents included picric acid (0.25 per cent), picrolonic acid (in water and alcohol), chloroplatinic acid, mercuric chloride, and Reinecke's salt.[8] Levine (1944) particularly recommended saturated aqueous picric acid, and Wagenaar's lead iodide reagent.[40] He pointed out that picric acid under the proper conditions gives two very distinct types of crystals, depending not upon concentration but upon whether or not the drop is stirred.[27]

Keenan (1946) described crystal tests, but of a different kind, using data for identifying the hydrochloride or the crystals obtained with potassium iodide or sodium nitroprusside by optical crystallography.[24] These crystals had been previously mentioned by Levine as secondary tests, without reference to the optical properties.[27] Wickström (1950) also used optical crystallography on the crystals formed with nitric acid.[44]

Hanson (1946) recommended saturated aqueous picric and picrolonic acids.[21]

Vidic (1951) used saturated aqueous picric, styphnic and picrolonic acids.[39]

Notice might also be taken of Fulton's mention (1948) of crystals with dilute permanganic acid (0.2 per cent KMnO ₄ in 1 normal H ₂SO ₄), applied directly to a little of the dry substance.[18]

Our article in 1950[10] illustrated crystals with Dragendorff's reagent, Reinecke's salt, potassium ferricyanide and chloroplatinic acid, all reagents previously used by Ducloux.[8] In the present article we also recommend, for direct addition to the dry substance, bromauric acid in water, and bromauric acid in concentrated hydrochloric acid. The latter was originally suggested to us by Fulton[19] in an unpublished communication.

Our recommendations are particularly platinic chloride for the aqueous solution, and either or both of the bromauric acid reagents mentioned for application directly to the solid narcotic.

Methadone

Methadone yields a wealth of crystals, and some very unusual reagents have been proposed for it.

There is a certain amount of agreement as to good tests with some of the more common reagents.

Fulton,[18] Lucas,[28] ,[29] and Vidic[39] have recommended mercuric chloride or mercuric chloride with hydrochloric acid; and Fulton, Schuldiner,[37] Lucas, and Vidic have recommended mercuric bromide or mercuric bromide with hydrochloric acid. We also illustrated these reactions in our previous article,[10] Demonceau[7] re- commended mercuric chloride (5 per cent aqueous) alone and mixed with potassium bromide (40 per cent aqueous) in equal volumes, as a most sensitive reagent ( 1:30,000) .

Watson and Bowman,[42] and Hubach and Jones,[22] recommended potassium ferrocyanide, Schuldiner37 and Vidic39 both used bromine in potassium bromide solution.

Crystals with Marme's reagent were illustrated by Schuldiner and also by Hubach and Jones; both also illustrated crystals with potassium iodide. Marme's reagent was included by Fulton in a list of what he considered the twelve best crystal tests for methadone; for iodine in potassium iodide he recommended a form of the reagent with little iodine and considerable potassium iodide (0.15 g. iodine, 20 g. KI in 100 ml. water, designated as Bouchardat reagent no. 10, which was also included in his twelve best crystal tests. Vidic also recommended iodine in potassium iodide.

We now turn to consideration of the separate articles.

Fulton (1948) particularly recommended chromium sulfate chloride, iodine in l0 per cent hydrobromic acid, platinum cyanide reagent, and mercuric bromide with hydrochloric acid. Numerous other crystals were described but none were illustrated; a list of the twelve best tests for the aqueous solution was given, and the best reagents for direct application to the dry substance were also discussed. The recommendation of platinic chloride with hydrochloric acid for the aqueous solution of methadone, ferric chloride in concentrated hydrochloric acid for the aqueous solution or in 17 1/2 volume-per cent hydrochloric acid for direct application to the dry substance, chromium sulfate chloride for direct application as well as for use with the aqueous solution, and dilute permanganic acid (0.2 per cent KMnO ₄ in 1 normal H2SO4) for direct application, may also deserve mention here.[18]

Schuldiner (1949) illustrated crystals with six reagents, and though he did not give a choice among them, iodine zinc chloride (an iodine reagent which is generally given the misnomer "zinc chloriodide") may be mentioned in addition to Marme's reagent, mercuric bromide, potassium iodoiodide, and potassium bromobromide.[37]

Watson and Bowman (1949) recommended very dilute bromine water (3.5 ml. saturated bromine water diluted to 100 ml.), and palladium chloride with hydrochloric acid (1 g. in (35+ 65) HCI), as well as potassium ferrocyanide.42 Fulton mentioned palladium chloride with hydrochloric acid, though not of just the same formula, as giving "a peculiar mixed form of crystallization".[18]

Lucas (1949-1950) recommended a reagent obtained from gold chloride and hydrogen iodide and illustrated the crystals, as well as those with mercuric chloride and bromide.[28] ,[29]

Hubach and Jones (1950) mentioned eight crystals and illustrated seven, without specific recommendation among them. They give the sensitivity of Marme's, probably their best recommendation for the usual type of crystal test, as 1:10,000. They also gave optical properties and X-ray diffraction data for methadone hydrochloride. [22]

Vidic (1951) particularly recommended mercuric chloride with hydrochloric acid. He also recommended mercuric bromide, iodine in potassium iodide solution, and bromine in potassium bromide, as already mentioned .[39]

In our second article of this series (1950) crystals were illustrated with several reagents, including iodine in 10 per cent hydrobromic acid, mercuric bromide with hydrochloric acid, Bouchardat reagent no. 1, chloroplatinic acid with hydrochloric acid, and ferric chloride in concentrated hydrochloric acid.10 Demonceau (1952) recommended sodium perchlorate (5 per cent aqueous) for a sensitive reagent; our second article (1950) illustrates the same perchlorate formed by means of ammonium perchlorate (5 per cent aqueous). In the present article, the crystals with chromium sulfate chloride are illustrated. This is a fine test, but we have found that the composition of the reagent is not fully understood (see above). We also include crystals with a new reagent, potassium thorium iodide.

Our recommendations are particularly: iodine in 10 per cent hydrobromic acid (crystallization trimorphous and tricolour); mercuric bromide with hydrochloric acid (more sensitive and perhaps somewhat more characteristic than mercuric chloride with hydrochloric acid).; and Bouchardat no. 1 (iodine and KI each in 1 g. in 100 ml. water).

F. SOME COLOUR REACTIONS FOR IDENTIFYING SYNTHETIC NARCOTICS

Experimental procedure for colour reactions

Standard techniques were used in making the spot-plate colour reactions: a small amount (0.1 mg.) of the powdered narcotic was placed in the spot-plate and a full drop of the reagent was added. The immediate colour obtained was recorded and the reaction was then observed at two minutes and five-minute intervals. The spot was stirred with a glass rod after the initial observation had been made. The colours obtained at each interval were compared with a standard colour chart.

The following Marquis’, Wasicky's, Mecke's, Froehde's, Zernik’s and Flueckiger's colour reactions with acetyldehydrocodeinone (acedicon), methadone (iso) (isoamidone), methadone HBr (amidone HBr), codeine, cocaine dihydrocodeinone (dicodide), dihydromorphinone (dilaudid) pethidine (demerol), ethylmorphine (dionine), dihydroxycodeinone (eukodal), phenadoxone (heptalgin), diacetylmorphine (heroin), methorphinan (3-hydroxy-N-methylmorphinan), metopon, morphine, alphaprodine (nisentil), papaverine, pipidone, thebaine and a number of other substances which are sometimes called narcotics have been studied. In each of the following sections, the reagent preparation and common colour reaction with morphine as a standard of comparison is given.

Marquis' reagent.[31] Formaldehyde in concentrated sulfuric acid.

This is one of the best known, most characteristic and most sensitive reagents for morphine. The complete reaction is given (even under adverse condition) with 0.03 mg. morphine and often 0.01 to 0.02 mg. will give the final blue colour. The use of only one drop of the reagent with 0.005 mg. morphine shows the red-purple colour.

The reagent consists of one to three drops of formaldehyde solution (37-40 per cent) in concentrated sulfuric acid (3 ml.). We have used two drops to 3 cc. as the standard. The reagent will not keep indefinitely.

The purple-red colour is given with phenolic opiates, or etheric opiates such as: apomorphine, codeine, dicodide, heroin, narcotine and with the phenoltetrahydrocannabinol (pyrahexyl). It is interesting to note that methorphinan, also a phenol, gives an orange colour.

The comparison of colours for other narcotics is given in chart II entitled "Marquis' reagent".

Wasicky's reagent.[41] Para-aminobenzaldehyde in concentrated sulfuric acid.

This reagent is another aldehyde-sulfuric acid reagent, and is more sensitive than Marquis' reagent toward morphine as a standard. Under favourable conditions of purity the orange colour is quite distinct with a 0.001 mg. morphine using one drop of the reagent; and 0.01 mg. will colour a "spot" full of reagent a good orange. There is no real succession of colours.

The reagent has been recommended by a number of authors:according to Balls and Wolff3 it was first proposed by Wasicky.41 We made the reagent by dissolving p-aminobenzaldehyde (0.3 g.) in sulfuric acid (10 ml. (8 1/2+1 1/2) H2SO4). Small variations from this formula do not appear to change the colours obtained very much.

Various phenolic and etheric narcotics give strong yellow, orange or red colours. Other phenols such as thymol, phenol and resorcin pyrogallol will also give positive colours with the Wasicky reagent.

Wasicky's reagent does not give colours with narcotics belonging to the alkonamine, or non-phenolic arylpiperidines groups. It gives the orange colour with ketobemidone and bemidone. The colours of thirty-four substances are given in chart III entitled "Wasicky's reagent".

Froehde's reagent:[12] Molybdate in concentrated sulfuric acid.

Added to morphine an intense purple-red colour is obtained initially which fades within about three minutes to colourless, then develops to a bright green which, if the solution stands for about two hours in a test tube, become a pure, deep blue.

Froehde's reagent is very sensitive. A single drop, applied to a small dry deposit of morphine, strikes a noticeable purple red, with 0.001 mg. Under even most adverse conditions, and with stirring, the green colour develops within a few minutes of the time the red colour fades (with no more than 0.02 mg. morphine).

The reagent is prepared by dissolving 0.5 to 1 g. of sodium (or ammonium) molybdate in 100 ml of concentrated sulfuric acid. More than 1 g. per 100 ml should not be used except in the definite variation of Buckingham's reagent. As little as 0.1 g. (1 mg./ml.) is sometimes used. Solution of the salt is obtained by heating on the water bath.

The reagent is stable if kept stoppered and not exposed to air or moisture. The colour with morphine and other compounds is not due merely to lower oxides of molybdenum. The reagent has been tested with a large number of compounds.

The comparative colour reactions obtained with other narcotics than morphine are given in chart IV entitled "Froehde's reagent". Methorphinan may be distinguished from morphine by means of Froehde's reagent.

Mecke's reagent:[32] Selenious acid in concentrated sulfuric acid.

With morphine as a standard, Lafon's or Mecke's reagent strikes blue, changing to a stronger bluishgreen, changing to an olive green and finally to brown.

The reagent is fairly sensitive, only 0.05 mg. of morphine is necessary. An indication of morphine can be obtained with 0.004 mg. of morphine.

The reagent is made by dissolving 0.5 g. of selenious acid in 100 cc. of concentrated sulfuric acid. Solution takes place readily at room temperature. The reagent may also be made by dissolving sodium selenate (0.75 g.) in sulfuric acid (100 ml.) Lafon also used selenate (0.5- 10.0 g. sodium selenate in H ₂SO ₄,100 ml.) The colours with selenite, selenate and selenious acid reacting with the opiates are very similar.

The reaction of Mecke's reagent with codeine and dionine as with morphine are essentially as strong, unlike Froehde's reagent.

The reaction is evidently specific for the phenolic group but the colour obtained depends on the other functional groups adjacent to the phenol.


Narcotics		Initially	Within 1 - 3 min.	Within 5 min.
Acedicon	(1)	Yellow	Purple	Purple-blue
Amidone (Iso)	(2).	Colourless	Colourless	Pink
1-Amidone	(3)	Colourless	Colourless	Pink
d-Amidone	(4)	Colourless	Colourless	Pink
Amidone HBr	(5)	Colourless	Faint pink	Orange-red
Apomorphine HCl	(6)	Purple-red	Black	Black
Codeine phosphate	(7)	Purple-blue	Blue-purple	Blue-purple
Crytopine	(8)	Green	Blue	Blue
Cocaine HCl	(9)		No reaction
Cotarnine	(10)	Olive-green	Orange-green	Green-yellow
Dicodid	(11)	Purple-red	Purple	Purple-blue
Dilaudid HCl	(12)	Yellow	Orange-red	Purple-red
Demerol HCl	(13)	Colourless	Orange	Bright orange
Ethylmorphine HCl	(14)	Orange-red	Deep purple	Blue-purple
Ethyl narceine	(15)	Purple-orange	Orange-red	Orange-red
Eukodal	(16)	Bright yellow	Purple	Purple-blue
Heptalgin	(17)	Colourless	Faint pink	Faint orange
Heroin HCl	(18)	Purple-red	Purple	Purple-blue
Meconic acid	(19)	Colourless	Faint pink	Faint pink
Methorphinan HBr	(20)	Orange	Olive-green	Dark green
Metopon HCl	(21)	Yellow-orange	Red-purple	Purple
Morphine	(22)	Purple-red	Purple	Purple-blue
Narceine	(23)	Red-orange	Orange-red	Orange-red
Narceine HCl	(24)	Red-orange	Orange-red	Orange-red
Narcotine	(25)	Purple	Olive-green	Green-yellow
Narcotine HCl	(26)	Purple	Olive-green	Green-yellow
Nisentil	(27)	Orange	Red-orange	Red-orange
Opianic acid	(28)	Colourless	Light green	Colourless
Papaverine	(29)	Colourless	Purple	Purple
Papaverine HCl	(30)	Colourless	Purple	Purple
Pipidone	(31)	Colourless	Colourless	Faint pink
Pyrahexyl	(32)	Purple	Purple-blue	Purple-blue
Physeptone	(33)	Colourless	Faint pink	Orange
Thebaine	(34)	Red-orange	Red-orange	Red-orange

Chart II

MARQUIS' REAGENT


Narcotics		Initially	Within 1 - 3 min.	Within 5 min.
Acedicon	(1)	Orange-yellow	Orange-red	Orange-red
Amidone (Iso)	(2)	---------	No reaction	---------
1-Amidone	(3)	---------	No reaction	---------
d-Amidone	(4)	--------	No reaction	---------
Amidone HBr	(5)	--------	No reaction	---------
Apomorphine HCl	(6)	Red-orange	Red-orange	Orange-yellow
Codeine phosphate	(7)	Orange-yellow	Orange-red	Orange-red
Crytopine	(8)	Colourless	Pale red-orange	Purple
Cocaine HCl	(9)	---------	No reaction	---------
Cotarnine	(10)	Green	Yellow-green	Green-yellow
Dicodid	(11)	Colourless	Pale orange-yellow	Orange
Dilaudid HCl	(12)	Colourless	Pale orange-yellow	Orange
Demerol HCl	(13)	----------	No reaction	---------
Ethylmorphine HCl	(14)	Orange-red	Red-orange	Red-orange
Ethyl narceine	(15)	Yellow-green	Olive-green	Dark green
Eukodal	(16)	Colourless	Faint orange	Orange
Heptalgin	(17)	---------	No reaction	---------
Heroin HCl	(18)	Orange-yellow	Orange-red	Orange-red
Meconic acid	(19)	---------	No reaction	---------
Methorphinan HBr	(20)	Yellow	Orange-purple	Purple
Metopon HCl	(21)	Colourless	Pale orange-yellow	Orange-yellow
Morphine	(22)	Orange-yellow	Orange-red	Orange-red
Narceine	(23)	Bright yellow	Orange-yellow	Orange-yellow
Narceine HCl	(24)	Bright yellow	Orange-yellow	Orange-yellow
Narcotine	(25)	Bright green	Olive-green	Green-black
Narcotine HCl	(26)	Bright green	Olive-green	Green-black
Nisentil	(27)	---------	No reaction	---------
Opianic acid	(28)	---------	No reaction	---------
Papaverine	(29)	Red-orange	Red-orange	Red-orange
Papaverine HCl	(30)	Red-orange	Red-orange	Red-orange
Pipidone	(31)	-------------	No reaction	---------
Pyrahexyl	(32)	Red	Red	Red-purple
Physeptone	(33)	---------	No reaction	---------
Thebaine	(34)	Orange-yellow	Yellow-orange	Orange

Chart III

WASICKY'S REAGENT


Narcotics		Initially	Within 1- 3 min.	Within 5 min.
Acedicon	(1)	Green	Yellow-orange	Yellow-green
Amidone (Iso)	(2)	--------	No reaction	---------
1-Amidone	(3)	-------	No reaction	---------
d-Amidone	(4)	-------	No reaction	---------
Amidone HBr	(5)	Colourless	Faint yellow	Faint green
Apomorphine HC1	(6)	Dark green	Blue-green	Blue
Codeine phosphate	(7)	Light green	Green	Greenish-blue
Crytopine	(8)	Purple-red	Blue	Blue
Cocaine HC1	(9)	------	No reaction	---------
Cotarnine	(10)	Green	Green	Orange-red
Dicodid	(11)	Faint yellow-orange	Yellow-orange	Orange-red
Dilaudid HC1	(12)	Purple-blue	Orange-red	Orange-yellow
Demerol HC1	(13)	------	No reaction	---------
Ethylmorphine HC1	(14)	Yellow-orange	Green	Green-blue
Ethyl narceine	(15)	Green	Blue	Blue
Eukodal	(16)	Yellow-orange	Yellow-orange	Almost colourless
Heptalgin	(17)	Colourless	Faint yellow	Faint yellow
Heroin HC1	(18)	Purple-red	Orange-red	Green
Meconic acid	(19)	---------	No reaction	---------
Methorphinan HBr	(20)	Green	Blue	Almost colourless
Metopon HC1	(21)	Purple-blue	Faint purple	Green
Morphine	(22)	Purple-red	Almost colourless	Green
Narceine	(23)	Orange-yellow	Green	Darker green
Narceine HC1	(24)	Orange-red	Green	Orange-yellow
Narcotine	(25)	Green	Olive-green	Orange-red
Narcotine HC1	(26)	Green	Olive-green	Orange-red
Nisentil	(27)	--------	No reaction	---------
Opianic acid	(28)	Green	Greenish-yellow	Yellow-green
Papaverine	(29)	Faint green	Green-blue	Blue-green
Papaverine HC1	(30)	Gray	Green	Green-yellow
Pipidone	(31)	--------	No reaction	---------
Pyrahexyl	(32)	Deep red	Deep red	Deep red
Physeptone	(33)	Colourless	Faint greenish-yellow	Greenish-yellow
Thebaine	(34)	Orange-red	Orange-yellow	Orange-yellow

Chart IV

FROEHDE'S REAGENT

A comparison of colour reactions of narcotics with Mecke's reagent is shown in chart V entitled "Mecke's reagent".

Flueckiger's reagent:[11] titanic acid in concentrated sulfuric acid.

This reagent with morphine strikes a dull purple or maroon colour, dissolving maroon red, soon changing to plain red, gradually becoming scarlet.

The reagent is prepared by digesting titanic acid anhydride (0.2-0.5 g.) in sulfuric acid (100 cc. conc.) for several hours at 140-160o C. This treatment will dissolve the oxide although it dissolves with difficulty.

The reagent will produce colours with 0.001 mg. of morphine and is about as sensitive as Froehde's, but the colour does not appear as promptly. 0.01 mg. morphine will colour a "spot" full of reagent a good maroon red, 0.04 mg. morphine will give the complete reaction.

With phenolic compounds in general the titanic reagent is very reactive. The colours vary from orange to scarlet red.

The colour reactions obtained with narcotics are given in chart VI entitled "Flueckiger's reagent".

Zernik's reagent:[45] concentrated nitric acid.

Nitric acid (conc.) added to morphine or its salts gives strong red or orange red colour soon fading through orange to yellow. The salts give a stronger colour than the free base. A red-orange can be noticed with 0.5 mg. of morphine.

The reagent is used as a routine test for morphine. It is the test commonly relied on by narcotic analysts and police agents for tentative identification in the field. It is perhaps the only good colour reaction in which codeine resembles morphine more closely than does heroin. Codeine turns orange and heroin gradually becomes bright green. It is the latter reaction which has given the name Zernik to the reagent. Phenols appear to give the reactions similar to morphine * The reactions with other narcotics are shown in chart VII entitled "Zernik's reagent".

The colour reactions for morphine, studied above, were examined in great detail in a monograph by C. C. Fulton which is as yet unpublished, but would be of considerable benefit to narcotic analysts. This monograph was kindly lent to us by C. C. Fulton, United Nations Secretariat.


Narcotics	------	Initially	Within 1 - 3 min.	Within 5 min.
Acedicon	(1)	Bright yellow	Green	Blue-green
Amidone (Iso)	(2)	------	No reaction	------
l-Amidone	(3)	------	No reaction	------
d-Amidone	(4)	------	No reaction	------
Amidone HBr	(5)	Yellow	Orange-yellow	Orange-yellow
Apomorphine HCl	(6)	Black	Black	Black
Codeine phosphate	(7)	Green	Blue	Blue
Crytopine	(8)	Blue-green	Blue	Purple-blue
Cocaine HCl	(9)	------	No reaction	------
Cotarnine	(10)	Green	Olive-green	Orange-green
Dicodid	(11)	Blue-green	Blue	Blue
Dilaudid HCl	(12)	Yellow	Blue-green	Blue-green
Demerol HCl	(13)	------	No reaction	------
Ethylmorphine HCl	(14)	Green	Blue-green	Blue-green
Ethyl narceine	(15)	Green	Blue-black	Purple-blue
Eukodal	(16)	Bright yellow	Olive-green	Blue-green
Heptalgin	(17)	------	No reaction	------
Heroin HCl	(18)	Green-blue	Blue-green	Blue-green
Meconic acid	(19)	------	No reaction	------
Methorphinan HBr	(20)	Bright yellow	Purple	Purple
Metopon HCl	(21)	Orange-yellow	Green	Blue
Morphine	(22)	Blue	Blue-green	Blue-green
Narceine	(23)	Yellow-green	Orange-red	Purple-red
Narceine HCl	(24)	Green	Red-orange	Purple-red
Narcotine	(25)	Green	Blue-black	Purple
Narcotine HCl	(26)	Green	Purple-red	Red-orange
Nisentil	(27)	Green-yellow	Orange-red	Orange-yellow
Opianic acid	(28)	Green-yellow	Yellow-green	Green-yellow
Papaverine	(29)	Blue-green	Purple-black	Blue-black
Papaverine HCl	(30)	Olive-green	Purple-black	------
Pipidone	(31)	------	No reaction	------
Pyrahexyl	(32)	Orange-red	Orange-yellow	Dark orange-red
Physeptone	(33)	Colourless	Pale yellow-orange	Pale yellow-orange
Thebaine	(34)	Orange-yellow	Green	Orange-yellow

Chart V

MECKE’S REAGENT


Narcotics	------	Initially	Within 1- 3 min.	Within 5 min.
Acedicon	(1)	Colourless	Pale orange-red	Pale orange-red
Amidone (Iso)	(2)	------	No reaction	------
l-Amidone	(3)	------	No reaction	------
d-Amidone	(4)	------	No reaction	------
Amidone HBr	(5)	------	No reaction	------
Apomorphine HCl	(6)	Purple-red	Purple-red	Dark purple-red
Codeine phosphate	(7)	Colourless	Pale purple-blue	Purple-blue
Crytopine	(8)	Orange-purple	Purple-blue	Bluish-black
Cocaine HCl	(9)	------	No reaction	------
Cotarnine	(10)	Olive-green	Orange-red	Orange-red
Dicodid	(11)	------	No reaction	------
Dilandid HCl	(12)	Red-orange	Red-orange	Red-orange
Demerol HCl	(13)	------	No reaction	------
Ethylmorphine HCl	(14)	Colourless	Faint purple	Purple
Ethyl narceine	(15)	Orange-yellow	Orange-red	Orange-red
Eukodal	(16)	Colourless	Pale purple	Pale purple
Heptalgin	(17)	------	No reaction	------
Heroin HCl	(18)	Purple-red	Purple-red	Orange-red
Meconic acid	(19)	------	No reaction	------
Methorphinan HBr	(20)	Red-orange	Red-orange	Red-orange
Metopon HCl	(21)	Red-orange	Red-orange	Red-orange
Morphine	(22)	Purple-red	Purple-red	Red-orange
Narceine	(23)	Orange-yellow	Orange-yellow	Orange-red
Narceine HCl	(24)	Orange-red	Orange-red	Orange-red
Narcotine	(25)	Yellow	Orange-red	Orange-red
Narcotine HCl	(26)	Yellow-green	Orange-red	Orange-red
Nisentil	(27)	------	No reaction	------
Opianic acid	(28)	Yellow	------	Green
Papaverine	(29)	Colourless	Pale purple	Pale purple
Papaverine HCl	(30)	Bright purple	Purple	Purple-blue
Pipidone	(31)	------	No reaction	------
Pyrahexyl	(32)	Deep red	Red	Red
Physeptone	(33)	------	No reaction	------
Thebaine	(34)	Orange	Orange	Orange

Chart VI

FLUECKIGER’S REAGENT

Nitric acid has been the basis for developing colour reactions for demerol.[5] A mixture of sulfuric and nitric acids was used to nitrate the benzene ring, the nitro group was then reduced with Zn and the amine diazotized and phenolic group was then condensed with resorcinol or naphthol or phloroglucinol, all of which produced red or orange-red dyes. Condensation of the nitrated demerol with ketone (acetone) in basic solution produces a red-violet colour.

A similar series of reactions for the identification of the keto group in the ketone derivatives of the hydro-phenanthrene alkaloids, such as metopon, diocodide, dilaudide, eucodal, as well as the alkoneamines such as amidones, was studied by Farmilo and Lucas.[9] In their method dinitrobenzene with the keto-narcotic in alcoholic solution were condensed by means of alkali, violet coloured products were obtained. Demonceau[7] stated that the absorption maxima of the coloured product with methadone at a wave length equals 525 mµ. The reaction appears to be specific for the presence of a keto group. A similar reaction has recently appeared for the colorimetric quantitative analysis of amidone obtained from tissues. In this method the phenyl groups are nitrated and the nitro product of amidone is then condensed with methyl-ethyl ketone in alcoholic alkaline solution. The colour appeared to be relatively stable.


Narcotics	------	Initially	Within 1 - 3 min.	Within 5 min.
Acedicon	(1)	Yellow-green	Yellow-green	Pale green
Amidone (Iso)	(2)	------	No reaction	------
1-Amidone	(3)	------	No reaction	------
d-Amidone	(4)	------	No reaction	------
Amidone HBr	(5)	Pale orange-yellow	Pale orange-yellow	Colourless
Apomorphine HC1	(6)	Purple-red	Red-orange	Orange-red
Codeine phosphate	(7)	Yellow	Yellow-green	Green
Crytopine	(8)	Orange-yellow	Pale yellow	Yellow-green
Cocaine HC1	(9)	------	No reaction	------
Cotarnine	(10)	Orange-yellow	Orange-yellow	Orange-yellow
Dicodid	(11)	Colourless	Pale yellow	Pale yellow
Dilaudid HCl	(12)	Yellow	Yellow-orange	Yellow-orange
Demerol HCl	(13)	------	No reaction	------
Ethylmorphine HCl	(14)	Colourless	Yellow	Pale yellow
Ethyl narceine	(15).	Yellow	Red-orange	Orange yellow
Eukodal	(16)	Colourless	Pale yellow	Pale yellow
Heptalgin	(17)	------	No reaction	------
Heroin HC1	(18)	Pale yellow	Pale yellow	Light green
Meconic acid	(19)	------	No reaction	------
Methorphinan HBr	(20)	Yellow	Orange	Orange
Metopon HC1	(21)	Yellow	Faint yellow	Faint yellow
Morphine	(22)	Orange-red	Orange	Yellow
Narceine	(23)	Orange-yellow	Yellow-green	Yellow-green
Narceine HCl	(24)	Yellow	Pale yellow-green	Yellow-green
Narcotine	(25)	Orange	Yellow	Yellow
Narcotine HCl	(26)	Orange	Yellow	Yellow
Nisentil	(27)	------	No reaction	------
Opianic acid	(28)	------	No reaction	------
Papaverine	(29)	Yellow-green	Green	Green
Papaverine HCl	(30)	Yellow	Orange-yellow	Orange-yellow
Pipidone	(31)	------	No reaction	------
Pyrahexyl	(32)	Red-orange	Red-orange	Red-orange
Physeptone	(33)	------	No reaction	------
Thebaine	(34)	Yellow	Faint yellow	Faint yellow

Chart VII

ZERNIK’S REAGENT

Demonceau[7] described a nitration reaction with diarylalkanoneamines, such as methadone and phenadoxone, in which the narcotic salt was nitrated with HNO ₃, H ₂SO ₄. The hydrochloride was necessary for production of the rose colour. Powdered potassium nitrate could be used in place of HNO ₃ to give the same reaction. Demonceau also mentioned the condensation reaction of the nitrated products with acetone to give a rose-coloured product. This reaction was termed semi-quantitative. The similarity between the reaction product colours obtained after nitration and ketone condensation with arylpiperidines and diaralkoneamines should be noted.

It was observed also that ketobemidone and hydroxypethidine give the phenol type colour reactions with Marquis’, Froehde’s, Mecke’s, Wasicky’s and Flueckiger's reagents.

ACKNOWLEDGMENTS

The authors would like to express their thanks to Dr. L. I. Pugsley, Chief, Food and Drug Laboratories, for continued help and advice and permission to publish this work; and to Messrs. Hossick and Hammond, Division of Narcotic Control, for assistance in obtaining some of the drugs. Our thanks are also due to Mr. H. W. Holmes and Miss B. A. Anderson and Mr. Kerr of the Biological Photographic Laboratory for assistance in making the photographic prints and enlargements.

Acknowledgment of the loan of photographic equipment from Mr. J. Graham and Mr. Holmes is made.

Appreciation of the substantial help and information from Mr. Charles C. Fulton, Chemist, United Nations Secretariat, is acknowledged by the authors. We would also like to thank the pharmaceutical and chemical companies for their generous gifts of samples.

GENERAL NOTE CONCERNING THE PHOTOGRAPHS

PHOTOGRAPHIC METHODS

The photographs were taken using the same general procedure as described previously.[10] The method for determining correct photographic exposure for photomicrography is based on the comparative-image-evaluation principle.

PHOTOGRAPHS

ALKANONEAMINES

Methadone (hydrochloride)

1. Solution 2 with potassium thorium iodide.

2. Solution 16 with chromium sulfate chloride.

3. Solution 16 with chromium sulfate chloride, typical crystals enlarged.

4. Solution 16 with chromium sulfate chloride, highly magnified crystals.

Pipidone (hydrochloride)

5. Solution 2 with chlorauric acid in acetic acid.

Phenadoxone (hydrochloride)

6. Solution 1 with picric acid (alcoholic).

Pethidine (hydrochloride)

7. Powdered pethidine (100 micrograms) with sodium bromaurate.

8. Powdered pethidine (100 micrograms) with bromauric acid in concentrated hydrochloric acid.

Crystallization of the pethidine bromaurate complex is well advanced and quite characteristic.

Hydroxypethidine (hydrochloride)

9. Solution 4 with lead sodium iodide.

10. Solution 4 with lead sodium iodide.

11. Solution 2 with lead potassium iodide.

12. Solution 2 with Reinecke's salt.

13. Solution 2 with Reinecke's salt, enlargement of characteristic crystal group.

Alphaprodine (hydrochloride)

14. Solution 1 with aqueous picric acid.

15. Solution 1/2 with aqueous picric acid. Both are characteristic crystals.

16. Solution 2 with silver sodium iodide.

17. Solution 1 with silver sodium iodide.

18. Solution 1 with lead potassium iodide.

19. Solution 1 with lead potassium iodide.

20. Solution 1 with lead sodium iodide.

21. Solution 2 with lead sodium iodide.

Ketobemidone (hydrochloride)

22. Solution 4 with Reinecke's salt, earliest forms and most characteristic.

23. Solution 4 with Reinecke's salt, later forms.

24. Solution 4 with Reinecke's salt, much later forms.

25. Solution 4 with Reinecke's salt, enlargement of characteristic crystal.

Pictures 22 to 25 inclusive illustrate three characteristic crystal habits and include an enlargement of a single most characteristic crystal.

26. Powdered solid narcotic (100 micrograms) with chloroplatinic acid.

27. Solution 16 with mercuric sodium nitrite. Shows a very characteristic starlike habit.

HYDROPHENANTHRENES

Methorphinan (hydrobromide)

28. Solution 8 with Reinecke's salt.

29. Solution 4 with Reinecke's salt.

Pictures show the two characteristic forms of crystals which depend on concentration of narcotic solution.

Metopon (hydrochloride)

30. Metopon 2 per cent solution with disodium methylarsonate. Shows characteristic crystals of what appears to be the free base.

31. Metopon 0.05 per cent with picrolonic acid.

LIST OF CHARTS

I. Structural formulae of synthetic narcotics.

II. Marquis' reagent.

III. Wasicky's reagent.

IV. Froehde's reagent.

V. Mecke's reagent.

VI. Flueckiger's reagent.

VII. Zernick's reagent.

Micro photographs of Synthetic Narcotics

LIST OF TABLES

I. List of synthetic narcotics, with chemical names, synonyms and trade names.

II. Sensitivity of narcotic solutions to phosphomolybdic acid.

III. Criteria for best crystal tests.

IV. Other amines yielding crystalline products with reagents recommended for synthetic narcotics.

V. Microchemical reagents for synthetic narcotic identification.

VI. Comparison of concentrations used by various authors in study of microchemical reactions of amidone and pethidine.

VII. Microchemical reagents which give crystals with amidone hydrochloride.

VIII. Microchemical reagents which give crystals with pethidine hydrochloride.

IX. Microchemical reagents recommended by various authors for detection of amidone and pethidine hydrochlorides.

X. Comparison of reagents for amidone and pethidine. Most sensitive tests in decreasing order for amidone and pethidine hydrochlorides recommended by authors, not necessarily "best" tests.

REFERENCES

⁰⁰¹

Association of Official Agricultural Chemists, Official Methods, 7th edition, 1950, chapt. 32; Drugs 32.151-32.156, Microchemical tests for alkaloids 32.151-32.154; pp. 601-605; for Synthetics 32.155-32.156, pp. 605-609.

⁰⁰²

Amelink, F., Amsterdam, 1934, "Schema zur mikrochemischen Identifikation von Alkaloiden" (Ubereetzt von marge haur), N.V.D.B. Centen's Uitgevers Maatschappij.

⁰⁰³

Balls, A. K., and Wolff, W. A., "Determination of Morphine" , Jour. Biol. Chemm., LXXX, 379 (1928).

⁰⁰⁴

Behrens, H., "Anleitung zur mikrochemischen Analyse", vol. iii, 1st edition, 1896.

⁰⁰⁵

D'Alessio de Carnevale Bonino, Rosa C., "Some reactions of ethyl 1-methyl-4-phenylpiperidine-4-carboxylate hydrochloride or dolantine, and methods of determination" (translated title) , La Semana Med. (Buenos Aires) 1, 289-293 (1943).

⁰⁰⁶

Denoel, A. and Soulet, U., "Study of some synthetic derivatives of morphine and codeine ", Journal de Pharmacie de Belgique, part I, p. 34, vol. 1 (March 1942); part II, pp. 50-55 (April 1942).

⁰⁰⁷

Demonceau, J., "Contribution à l'étude analytique de la Methadone ", Journal de Pharmacie de Belgique, septième année, nouvelle série, nos. 1-2, janvier-fevrier, pp. 36-45 (1952).

⁰⁰⁸

Ducloux, E. H., "Notas Microquímicas sobre 'Doping', Buenos Aires (1943)".

⁰⁰⁹

Farmilo, C. G., and Lucas, G. H. W., "Studies on the Identification of Narcotics, I, Microchemical (Color) Reactions for Identification of Metopon", Journal of the American Pharmaceutical Association, Scientific edition, vol. XXXVIII, no. 9, 491-495, September 1949.

⁰¹⁰

Farmilo, C. G., Ross, R. J. Berry and Kennett, P. M. L., "Microchemical Identification of Synthetic Narcotics; Amidone, Heptalgin, Demerol, Pipidone" (Studies on the Identification of Narcotics, II ), Bulletin on Narcotics, vol. II, no. 2, April 1950 (12 pp., 28 illus.).

⁰¹¹

Flueckiger, F. A., February 1880, cited in the Dispensatory of the United States of America, edited by Remington, J. P., Wood, H. C. and others, 20th edition, J. B. Lippincott & Co, Philadelphia.

⁰¹²

Froehde, A., Archiv der Pharm. 1866, 54.

⁰¹³

Fulton, Charles C., "The Precipitating Agents for Alkaloids", Am. Jour. Pharm. 104, 244-271 (1932).

⁰¹⁴

Fulton, C. C., "Alkaloids and Their Reagents" , American Journal of Pharmacy, III, no. 5, 183-191 (1939).

⁰¹⁵

Fulton, C. C., "New Precipitating Agents for Alkaloids and Amines" , Am. Jour. Pharm. 112, 1-35 (1940).

⁰¹⁶

Fulton, C. C., "Micro-Crystal Identification Tests for Morphine, Heroin, Dilaudid and Cocaine" , J. of Crim. Law and Criminology, XXXII, no. 3, 359-365 (1941).

⁰¹⁷

Fulton, C. C., "Notes on Micro-Crystal Tests for Alkaloids and Amines Chiefly in Aqueous Solution" (unpublished data), September 1942 (3rd edition).

⁰¹⁸

Fulton, C. C., "Identification of Methadone by Micro-crystals", United Nations document E/CN.7/117, pp. 17-31, 27 February 1948.

⁰¹⁹

Fulton, C. C., "Microcrystal Reagents for the Direct Application to the Dry Narcotic Demerol" (unpublished data), private communication, 11 December 1949.

⁰²⁰

Cross, S. T., and Oberst, F. W., "Micro Analysis of Opiates by X-ray diffraction" , Journal of Lab. and Clin. Med. 32, 94-101 (1947).

⁰²¹

Hanson, Arne, "The Identification of Opiates and Narcotics'', (in English) , Svensk Kemisk Tidschrift 58, 10-23 (1946).

⁰²²

Hubach, C. E., and Jones, F. T., "Methadon Hydrochloride, Optical Properties, Microchemical Reactions and X-ray Diffraction Data", Analytical Chemistry 22, 595-598 (1950).

⁰²³

Isbell, H., "The Addiction Liability of Some Derivatives of Meperidine" , The Jour. of Pharm. and Exper. Therap. 97, 182-189 (1949).

⁰²⁴

Keenan, G. L., "The Microscopic Identification of Demerol", Journal of the American Pharmaceutical Association, Scientific edition 35, 338-339 (1946).

⁰²⁵

Keenan, G. L., "Notes on the Microscopy of some Important Alkaloids" , The Chemist Analyst 39, 33, 52, 79 (1950), ibid., 40, 4, 28 (1951).

⁰²⁶

Levi, L., and Farmilo, C. G., "The Characterization of Narcotics as Reineckates" , Canadian Journal of Chemistry, 30: 783-792, October 1952.

⁰²⁷

Levine, J., "The Identification of Demerol Hydrochloride" , Industrial and Engineering Chemistry, Analytical edition 16, 408-410 (1944).

⁰²⁸

Lucas, G. H. W., "Detection of Amidone", Dept. of Pharmacology, University of Toronto, Toronto, Can. Report to the Dept. of National Health and Welfare, Food and Drug Laboratories, 22 July 1948.

⁰²⁹

Lucas, G. H. W., "Crystal Tests as a Means of Identifying Alkaloids" , Can. Jour. of Research 28, 37-42 (1950).

⁰³⁰

Martini Ardiono, "Uebereine neue empfindliche mikrochemische Reaktion des Kokains" , Microchemie 12, 111 (1932/ 33).

⁰³¹

Marquis. Ed. Magister Dissertation 1896, Surjew.; Arb. Der Pharm. Inst. zu Dorpat 15, 117 (1896); Pharmazeutische Zantralhalle fur Deutschland 1896, 814. (Cited in various sources; original references not available).

⁰³²

Mecke, "Ein Neues Reagens auf Alkaloide, Nachweis von Opium" , Zeitschr. offentl. Chem., 25, 351 (1899) (original reference not available to authors) cited i n Merck's Index, 5th edition, 1940, published by Merck and Co Inc., Rahway, N. J., p. 878, "Chemical, Clinico-Chemical Reactions, Tests and Reagents", no. 3325. See also Levine, V. E., "Studies in Toxicologic Chemistry, I. The Detection of the Opium Alkaloids by Selenious- Sulfuric Acid: The specificity of This Reagent for the Phenolic Group". J. of Lab. and Clin. Med. XI, no. 9, 809-816 (1926).

⁰³³

Patterson, A. M., and Capell, L. T., "A List of Ring Systems Used in Organic Chemistry", Ring Index, Reinhold Publishing Corporation, New York, 1940. Compound no. 3094. p. 425.

⁰³⁴

Rosenthaler, L., "Toxikologische Mikroanalyse-Qualitative Mikrochemie der Gifte im gerichtlich- chemikal wichtiger Stoffe", Verlag. von Gebrüder Borntraeger , Berlin, 1935, pp. 358-362.

⁰³⁵

Small, L. F., and Lutz, R. E., "Chemistry of the Opium Alkaloids", U. S. Govt. Printing Office, Washington, 1932. Supplement no. 103 to the Public Health Reports.

⁰³⁶

Small L. F., "Chemistry of Natural and Synthetic Analgesics'' , Annals of the New York Academy of Sciences 51, 12-20 (1948). Structure of Metopon, pp. 18, 19.

⁰³⁷

Schuldiner, J. A., "Identification of Amidone", Analytical Chemistry 21 , 298-300 (1949).

⁰³⁸

Stephenson, C. H., and Parker, C. E., "Microchemical Tests for Alkaloids", J. B. Lippincott Co., Phil., 1921.

⁰³⁹

Vidic, E., "Der Nachweis con Polamidon and Dolantin im Urin und Ihre Trennung von Morphin", Arch. exper. Path. u. Pharmakol, Bd. 212, S. 339-351 (1951).

⁰⁴⁰

Wagenaar, C. H., "Microchemical Alkaloid Reactions with a New Reagent Containing Lead Iodide" (translated title), Pharm. Weekblad 76 , 276 (1939) (see also Chemical Abstracts 33, 4375 (1939)).

⁰⁴¹

Wasicky, Zeit. fur. Anal. Chem. (1915), p. 394.

⁰⁴²

Watson, R. C. and Bowman, M. I., "Microchemical Identification of Amidone" , Journal of the American Pharmaceutical Association, Scientific edition 38, 369-373 (1949)

⁰⁴³

Whitmore, W. F., and Wood, C. A., "Chemical Microscopy of Some Toxicologically Important Alkaloids", Microchemie 27, 249-334 (1939).

⁰⁴⁴

Wickström, A., "The Optical Crystallographic Properties of Crystals Formed with Nitric Acid from Pethidine, Nicotinamide and Cincophen", Journal of Pharmacy and Pharmacology 2 , 444-445 (1950).

⁰⁴⁵

Zernik: Ber. deut. pharm. Geo. 1903, 67, cited in Merck's Index, p. 970. Test no. 4483. Many other chemists have recommended nitric acid, the name Zernik is used for convenience only. See also: Fulton, C. C., "The Principal Chemical Tests for Morphine" , Amer. Jour. of Pharm. 109, no. 5, 1-22 (1937).