Tranquillizing and related drugs:

Sections

Instrumental methods of identification

Details

Author: Ponnusamy Rajeswaran, Paul L. Kirk
Pages: 19 to 33
Creation Date: 1962/01/01

Tranquillizing and related drugs:

Properties for their identification (part III)

Ponnusamy Rajeswaran
Paul L. Kirk [ 1]
School of Criminology, University of California, Berkeley, Cal.

Note by the editor: This is the concluding part of the article, of which parts I and II were included in volume XIII, Nos. 3 and 4, respectively, of the Bulletin on Narcotics.

Instrumental methods of identification

X-ray Diffraction Powder Analysis

In recent years, X-ray diffraction data have come into prominence for the characterization of drugs by revealing data on crystal structure and molecular composition. The crystalline structure in different polymorphic forms may be studied, and permanent records of the photographed powder patterns may be used for comparison purposes.

The method has been successfully utilized for the study and identification of alkaloids, barbiturates, analgesics, sedatives, and anticonvulsants (1-5). A few of the tranquillizing compounds reported in this work have also been investigated previously (6).

A total of forty-six compounds were examined, most of them obtained in their pure commercial forms. A few of them were extracted from the common dosage forms. For convenience, the three innermost strong lines out of ten are indicated for comparison and indexing purposes.

Experimental

Powdered samples were sprinkled on a glass slide which had been lightly smeared with Corning stop-cock grease. They were subjected to copper-K alpha radiation in a Norelco (North American Phillips Co.) Geiger counter X-ray spectrometer, type No. 42322, after mounting on a rotating specimen holder. The instrument was equipped with a recording potentiometer (Brown Electronik strip chart, paper speed 18 inches per hour), and the characteristic diffraction patterns obtained over a 45°arc in duplicate.

The instrument was calibrated over this range, using powdered quartz crystals, and mean readings were used to compute the "d" values. The position of the slide was changed in obtaining the duplicate recordings, and variations of 0-20 minutes resulted.

Results

The "d" values for the six groups of drugs investigated are shown in table 4. The values for the alkaloid reserpine from three different sources are reported and will be found to tally closely.

TABLE 4

The "d" distances using Cu K-alpha radiation

Group A. Phenothiazine derivatives

Promazine
Promethazine
Ethopropazine
Trimeprazine
Pyrathiazine
11.1 7.91 9.40 7.72 10.5
8.54
7.18 [ a]
7.57 [ a]
7.18
7.70 [ a]
5.56 6.71
5.69 [ a]
6.42 [ a]
7.24
5.28 [ a]
5.60 4.69
6.14 [ a]
6.88
5.06
5.23 [ a]
4.22
4.92 [ a]
5.00 [ a]
4.19 [ a]
4.95 [ a]
4.08 4.76 4.70
3.89 4.45 3.90 4.26 4.48
3.69 [ a]
3.90 3.78 3.85
4.36 [ a]
3.39 3.70
3.53 [ a]
3.72 3.68
3.17 3.30 3.26 3.33 3.26
Chlorpromazine
Proclor-perazine
Proclor-perazine ethane disulfonate
Proclor-perazine dimaleate
Perphenazine
10.6 8.49 10.3 6.17 7.30
7.86 7.36
6.87 [ a]
5.43
6.15 [ a]
5.69 [ a]
5.62 [ a]
5.73 [ a]
5.05 5.53
4.77 [ a]
5.46 5.13
4.69 [ a]
4.87
4.42 4.55 4.86 4.43 4.54
4.29 4.37
4.60 [ a]
4.11 [ a]
3.86
3.93 [ a]
4.22 [ a]
4.30
3.51 [ a]
3.74
3.63 3.92 3.84 3.07 3.67
3.49
3.63 [ a]
3.54 2.62
3.48 [ a]
3.23 3.38 3.39  
2.83 [ a]
        1.66
Triflu-promazine
Trifluo-perazine
Fluphenazine
Methoxy-promazine
Mepazine
14.5 7.79 18.2 8.83 7.64
7.98
5.84 [ a]
9.07 [ a]
6.94 [ a]
6.17 [ a]
7.23 5.10
8.71 [ a]
5.39 5.64
5.28 [ a]
4.55 6.07 5.09
4.78 [ a]
4.80 [ a]
4.35 [ a]
5.63
4.74 [ a]
4.24
4.54 [ a]
4.06 [ a]
4.85 4.50 4.02
4.44 3.79
4.54 [ a]
4.39 3.78
4.08 3.59 4.32
3.76 [ a]
3.68
3.84 3.46 4.02 3.63 3.59
3.60 3.24 3.75 3.20
3.09 [ a]

Group B. Reserpine and related alkaloids

Reserpine Serpasil (Ciba)
Reserpine (Panray)
Reserpine (Lilly)
Deserpidine
Rescinnamine
13.16 13.0 13.0 13.0 6.06
12.3 12.3 12.2
12.1 [ a]
4.68 [ a]
7.51 [ a]
7.46 [ a]
7.48 [ a]
7.42 [ a]
3.84 [ a]
5.79 7.26 5.77 6.92
3.42 [ a]
5.39 5.76
5.04 [ a]
5.39 3.33
5.07 [ a]
5.05 [ a]
4.80 [ a]
5.02 2.90
4.81 [ a]
4.80 [ a]
4.50
4.75 [ a]
2.49
4.53 4.50 4.26 4.49 2.29
4.28 4.26 3.73 4.24  
3.74 3.74 3.45 3.59  

Group C. Diphenyl methane derivatives

Adiphenine
Diphenyl-pyraline
Captodiamine
Chlorcyclizine
Benactyzine
8.29 9.46 6.34 7.66
8.23 [ a]
7.22
8.49 [ a]
5.91 5.99
6.96 [ a]
6.03 7.88 5.06
4.97 [ a]
5.99
5.25 [ a]
6.03 4.89 4.40 5.44
4.51 [ a]
4.74 [ a]
4.71
4.21 [ a]
4.86
4.44
4.47 [ a]
4.39 [ a]
4.07
4.52 [ a]
4.10 [ a]
4.08 [ a]
3.81
3.85 [ a]
4.22
3.96 3.70
3.74 [ a]
3.66 3.79
3.79 3.16 3.67a 3.24 3.59
3.39   3.44 3.11  
a

Strong.

Group C. Diphenyl methane derivatives (continued)

Pipradol
Azacyclonol
Hydroxyzine
Meclizine
Buclizine
11.0 7.51
14.2 [ a]
13.9 13.4
8.41 [ a]
7.03 [ a]
6.58
12.l [ a]
7.57 [ a]
7.34 [ a]
5.30 6.03
7.50 [ a]
6.75
6.27
4.44 [ a]
5.85 [ a]
6.37 6.26
4.65 4.32 5.12 6.06
4.77 [ a]
4.50 [ a]
4.08 4.24 5.56 4.47
3.64
3.79 [ a]
4.01 5.17 4.24
3.52 3.67 3.73 4.69 4.03
3.29 3.29 3.53 4.14
3.79 [ a]
3.05 2.83
3.27 [ a]
3.84 3.11

Group D. Substituted butanediols, propanediols

Phenaglycodol
Mephenesin
Meprobamate
9.37 15.6 14.0
8.20 7.81 8.10
6.42 [ a]
6.54 [ a]
6.87 [ a]
5.99
5.85 [ a]
4.72 [ a]
5.73 [ a]
5.46 [ a]
3.95 [ a]
4.96 5.19 3.69
4.79 4.82 3.51
4.50 4.20 3.13
4.14 [ a]
4.13 2.74
3.05 3.90 2.36

Group E. Ureides, amides, hydrazines and related compounds

Phenelzine
β-phenyl-isopropyl-hydrazine
Isocarboxazide
Iproniazid
Nialamide
18.9 10.8 9.73 9.04 15.3
9.85 [ a]
7.55 5.97
7.98 [ a]
9.63
6.51 5.99 4.92 5.79
7.68 [ a]
5.42 [ a]
5.38 [ a]
4.84 4.64
5.16 [ a]
4.89 [ a]
5.05 [ a]
4.67
4.49 [ a]
4.79 [ a]
3.90 [ a]
4.49 [ a]
4.30 [ a]
4.31 [ a]
4.44
3.24 4.29
4.08 [ a]
4.19 [ a]
4.18
2.79 3.60
3.73 [ a]
3.87
3.54 [ a]
2.44 3.53 3.55 3.37 3.18
 
3.41 [ a]
3.43 2.96 3.00
Acetyl-
Ectylurea
Oxonamide
carbromal
Glutethimide
  6.45 10.2 6.42 10.3
 
4.72 [ a]
9.23 [ a]
5.62 7.24
  4.00
7.98 [ a]
4.87
6.22 [ a] [ a]
 
3.76 [ a]
5.04 [ a]
4.69 6.04
 
3.18 [ a]
4.60
4.41 [ a]
5.13 [ a]
  2.78 4.42
4.25 [ a]
4.56
  2.75 4.03 3.62
3.79 [ a]
    3.48 3.36 3.60
    3.38 3.18 3.26
    3.14
2.41 [ a] [ a] [ a]
3.21

Group F. Miscellaneous compounds

Methyl-phenidate
Thonzyl-amine
Pyrro-butamine
Chlor-methazanone
Imipramine
Betazole
10.8 8.52 16.6 7.95 10.4 4.95
8.62 [ a]
5.86 [ a]
7.12
6.61 [ a]
8.74
3.76 [ a]
7.03 5.45 5.74
5.48 [ a]
7.36 [ a]
3.57
6.18
4.69 [ a]
4.53 4.81 6.98
3.32 [ a]
5.86 [ a]
4.52
4.24 [ a]
4.53 5.59 3.11
4.56
4.30 [ a]
4.16 [ a]
4.27 [ a]
4.97 [ a]
2.92 [ a]
4.28 [ a]
4.22
3.98 [ a]
4.08
4.26 [ a]
2.84
3.87 3.97 3.86 3.90
4.16 [ a]
2.77
3.77 3.60 3.60 3.40 3.78 2.65
3.56 3.14 3.32 3.28 2.65 2.14
  2.64        

Ultraviolet Absorption Spectrophotometric Identification

Spectrophotometric procedures are invaluable for the identification and assay of compounds of toxicological interest. Selective absorption in some portion of the spectrum, depending only on chemical structure, is useful for nearly all compounds.

The ultraviolet absorption is useful for most, but not all, compounds of interest, but will not distinguish between many closely related compounds.

Ultraviolet absorption data have been reported by several workers in the narcotics field: Bradford & Brackett (6); Ebstein & Van Meter (7); Farmilo (8); Goldbaum (9, 10); Grant & Jones (11); Ketelaar & Helingman (12); Ostreicher, Farmilo & Levi (13); Rotandaro (14); Smith & MacDougal (15); Hill, Castano & Lightburn (16); Williams (17). Table 5 of this paper includes the useful absorption data for 32 of the tranquillizer and related drugs; curves for 42 are shown in plates 7 to 15. Measurements were made on the available commercial forms in most cases. In a few instances, extraction from prescription forms was employed.

Experimental Procedure

Stock solutions of each of the drugs in 50% alcohol were diluted to prepare a test solution of 10 ppm. In one of those reported (Nialamide-Nardil) the test solution was 50 ppm.

For the Rauwolfia group of alkaloids, stock solutions of three preparations of reserpine, Rauwolfia whole root powder, deserpidine, rescinnamine, and the alseroxylon fraction were prepared in 95% alcohol. These were diluted to give test solutions of 10 ppm. The concentration of the phenothiazine derivative thioridazine was not determined, as all available extracted material was used (less than 100 mg).

Manual plots in the ultraviolet range 200 mμ to 400 mμ were made with a Beckman model DU spectrophotometer. The same quartz cells of 1 cm light path were used for the preparation of all curves. A blank solution of 50% alcohol in the same cell was used throughout in all tests. Absorption was measured at intervals ranging from 10 mμ, 5 mμ, and 1 mμ at points of inflection.

All the plots were made on special paper [ 2] (log log 1/T log λ) as reported in the study of Bradford & Brackett (6). This type of plotting gives curves which are reasonably independent of concentration. The curves obtained for the phenothiazine class of derivatives were compared with those obtained on a Cary Automatic Recording Spectrophotometer, model 14.

The quartz 1 cm path cells were calibrated using the same solvent, and corrections ranging from 0.025 at 210 mμ to 0.005 at 250 mμ and 0.001 at 300 mμ were applied at the maximum and minimum absorbance points. Inasmuch as the absorbances were all measured under a single standardized set of conditions, it is apparent that deviations of pH, solvent, and other factors will have an influence on the values listed. Such differences must not be neglected when other conditions are utilized.

Results

Absorbance = log I o
I

I o - Intensity of light transmitted by solution blank.

I - Intensity of light transmitted by test solution plus blank.

Absorptivity = D

1c

D - Absorbance.

1- light path of cell 1 cm.

c- concentration in ppm.

The specific absorbance E = Absorptivity at a concentration of 1 ppm for a light path of 1 cm.

Values reported in table 5 are: λmax.
E max.
λmin.
E min.

Spectral absorbance data are presented in table 5 for the following compounds:

Group A
Group B (Continued)
Promazine hydrochloride
Reserpine (Panray)
Promethazine hydrochloride
Deserpidine
Ethopropazine hydrochloride
Group C
Trimeprazine tartrate
Chlorcyclizine hydrochloride
Pyrathiazine hydrochloride
Hydroxyzine hydrochloride
Chlorpromazine hydrochloride
Meclizine hydrochloride
Proclorperazine dihydrochloride
Group D
Proclorperazine ethane disulfonate
Phenaglycodol
Proclorperazine dimaleate
Mephenesin
Perphenazine
Group E
Thiopropazate dihydrochloride
Phenelzine dihydrogen sulphate
Triflupromazine hydrochloride
Iproniazid phosphate
Trifluoperazine dihydrochloride
Nialamide
Fluphenazine dihydrochloride
Acetylcarbromal
Methoxypromazine maleate
Group F
Mepazine hydrochloride
Thonzylamine hydrochloride
Thioridazine hydrochloride
Pyrrobutamine phosphate
Group B
Chlormethazanone
Reserpine (Lilly)
Imipramine hydrochloride
Reserpine (Ciba)
 

Spectral absorbance curves are reproduced, in plates 7 to 15, for all of the above compounds and the following additional ones, under the same experimental conditions:

Group B
Group C (continued)
Reserpine whole root powder
Azacyclonol hydrochloride
(Squibb)
Buclizine hydrochloride
Group C
Group E
Adiphenine
β-Phenyl isopropyl hydrazine
Diphenylpyraline
Isocarboxazide
Banactyzine hydrochloride
Ectylurea
Pipradol hydrochloride
Glutethimide

A number of other compounds, examined in a similar manner, are not reported because experimental conditions were not found to be satisfactory, or because the compounds showed no characteristic ultraviolet absorbance. In many instances concentrations ranging from 500 to 1,000 ppm were required. Methods have been reported in the literature for some of these compounds (18-25). These compounds include:

Group B
Group E
Rescinnamine
Oxonamide
Alseroxylon
Group F
Group C
Methylphenidate hydrochloride
Captodiamine hydrochloride
Ethchlorvynol
Group D
Betazole
Meprobamate
 

TABLE 5

Ultra-violet spectral absorbance data

Compound
Conc ppm
λmax mμ.
E 1 ppm 1 cm
λmin cmμ
E 1 ppm 1 cm
Compound
Conc ppm
λmax mμ.
E 1 ppm 1 cm
λmin cmμ
E 1 ppm 1 cm
Group A. Phenothiazine derivatives
         
Group B. Reserpine and related alkaloids
         
Promazine hydrochloride
10 253
.093
221
.023
Reserpine (Lilly)
10 218
.064
245
.008
    303
.013
275
.005
    270
.019
   
Promethazine hydrochloride
10 251
.089
221
.025
Reserpine (Ciba)
10 218
.062
246
.008
    300
.011
274
.004
    569
.018
   
Ethopropazine hydrochloride
10 251
.079
220
.021
Reserpine (Panray)
10 219
.066
245
.009
    299
.010
275
.004
    269
.019
   
Trimeprazine tartrate
10 253
.075
222
.020
Deserpidine
10 220
.099
243
.010
    302
.010
277
.004
    272
.030
   
Pyrathiazine hydrochloride
10 251
.096
221
.028
           
    300
.012
274
.005
Group C. Diphenyl methane derivatives
         
Chlorpromazine hydrochloride .
10 255
.090
225
.029
Chlorcyclizine hydrochloride
10 230
.042.
219
.024
    310
.011
277
.003
Hydroxyzine hydrochloride
10 230
.030
218
.017
Proclorperazine dihydrochloride
10 257
.076
225
.023
Meclizine hydrochloride
10 231
.029
223
.024
    312
.010
280
.003
           
Proclorperazine ethane disul
                     
Fonate
10 257
.060
226
.018
Group D. Substituted butanediols, propanediols
         
    311
.008
280
.002
Phenaglycodol
10 221
.048
   
Proclorperazine dimaleate
10 257
.059
235
.028
Mephenesin 10 271
.009
   
    309
.007
281
.003
           
Perphenazine
10 257
.053
225
.016
           
    310
.007
280
.003
Group E. Ureides, amides, hydrazines and related compounds
         
Thiopropazate dihydrochloride .
10 256
.033
227
.013
Phenelzine dihydrogen sulphate.
50 258
.008
228
.001
    307
.006
280
.003
Iproniazid phosphate
10 264
.016
229
.008
Triflupromazine hydrochloride .
10 258
.077
224
.022
Nialamide 10 265
.015
232
.009
    306
.009
280
.003
Acetylcarbromal 10 210
.048
-
-
Trifluoperazine dihydrochloride .
10 259
.063
225
.015
           
    312
.007
281
.002
           
Fluphenazine dihydrochloride
10 259
.052
224
.013
Group F. Miscellaneous compounds
         
    305
.006
280
.002
           
Methoxypromazine maleate
10 252
.061
230
.044
Thonzylamine hydrochloride
10 242
.072
   
    305
.011
279
.004
    276
.007
266
.005
Mepazine hydrochloride
10 254
.083
222
.020
    308
.008
290
.006
    307
.011
275
.004
Pyrrobutamine phosphate
10 247
.016
283
.014
Thioridazine hydrochloride
<10
262
-
220
-
Chlormethazanone
10 228
.072
-
-
    315
-
290
-
Imipramine hydrochloride
10 251
.023
231
.007

ULTRA-VIOLET SPECTRAL ABSORBANCE CURVES

Group A. Phenothiazine derivatives

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PLATE 7 a PLATE 7 b

BULLETIN ON NARCOTICS l JANUARY-MARCH 1962 25

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PLATE 8 a PLATE 8 b

26 BULLETIN ON NARCOTICS l JANUARY-MARCH 1962

Group A. Phenothiazine derivatives (continued)

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PLATE 9 A PLATE 9 b

BULLETIN ON NARCOTICS l JANUARY-MARCH 1962 27

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Group B. Reserpine and related alkaloids

PLATE 10 a PLATE 10 b

28 BULLETIN ON NARCOTICS l JANUARY-MARCH 1962

Group C. Diphenyl methane derivatives

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PLATE 11 a PLATE 11 b

BULLETIN ON NARCOTICS l JANUARY-MARCH 1962 29

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PLATE 12 a PLATE 12 b

Group D. Substituted butanediols, propanediols
Group F. Miscellaneous compounds
Full size image: 436 kB
PLATE 13 a
PLATE 13 b
MephenesinPhenaglycodol
Thonzylamine hydrochloride Imipramine hydrochloride Pyrrobutamine phosphate Chlormethazanone

Group E. Ureides, amides, hydrazines and related compounds

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PLATE14 a
PLATE14 b
β-phenylisopropyl hydrazine Phenelzine dihydrogen sulfate
AcetylcarbromalIproniazid phosphate
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Group E. Ureides, amides, hydrazines and related componds (continued)

PLATE 15 a
PLATE15 b
EctylureaNialamide
GlutethimideIsocarboxazide
1

This work was supported by grants from the National Institutes of Health, Public Health Service, Department of Health, Education and Welfare (RG-4372) ,and the Research Committee of the University of California. Acknowledgment is made to thirty manufacturers of tranquillizing drugs for supplying samples of their products.

a

Strong.

2

Available from Globe Printing Co.,P.O. Box 968, San José, California.