Physico-chemical methods for the identification of narcotics (contd.)

Sections

I. - Introduction
II. - Materials
III. - Names and nomenclature
IV. - Methods of analysis
V. - Results
VI. - Discussion
VII. - Acknowledgements

Details

Author: L. MARTIN, K. GENEST, J. A. R. CLOUTIER, Charles G. FARMILO
Pages: 17 to 38
Creation Date: 1963/01/01

Physico-chemical methods for the identification of narcotics (contd.)

Part VI Common physical constants, UV, IR and X-Ray data for 12 narcotics and related compounds

L. MARTIN Government Narcotic Research Fellow in Canada, 1959-1960. Present address: Senior Analyst Research, Commonwealth Laboratory, Flinders Lane, Melbourne, Australia.
K. GENEST Chemist, Organic Chemistry and Narcotic Section, Food and Drug Directorate, Dept. of National Health and Welfare, Ottawa, Canada
J. A. R. CLOUTIER Head, Biophysics Section, Food and Drug Directorate, Dept. of National Health and Welfare, Ottawa, Canada.
Charles G. FARMILO Head, Organic Chemistry and Narcotic Section, Food and Drug Directorate, Dept. of National Health and Welfare, Ottawa, Canada.

The Bulletin on Narcotics presents in this issue the continuation of the Canadian series of articles on the "Physico-chemical methods for identification of narcotics" which appeared in volumes V (1953), VI (1954), VII (1955), XI (1959) and XII (1960) of this journal.

I. - Introduction

Seven years have passed since the first article in this series was printed in the Bulletin on Narcotics (1-10). The demand for these publications and for further data for narcotic identification has continued. The need was clearly stated by Dr. Jolanda Schmidlin-Meszaros (11) as follows:" Ihre Artikel-Serie umfasst ein Arbeitsgebiet, wo bisher ein Mangel an ahnlich wegleitenden Methoden bestand. Anlasslich eines Cliradon [ketobemidone]-Falles konnten wir auf Grund Ihrer Veroffentlich-ungen die chemisch-toxikologischen Untersuchungen systematisch ausführen (12)." The problem of obtaining the necessary physical-chemical data on which to base identification methods is at the heart of this statement. The number of identification tests required for narcotic analysis has to increase to cope with the new families of drugs.

In its broadest sense, narcotic identification is part of the area of qualitative and quantitative drug analysis which serves as a scientific basis for control and law enforcement. The history and methodology of drug identification has been reviewed by Farmilo & Genest (13).

The object of this paper is to report analytical data on some of the most recently developed important narcotics. The common physical constants, X-ray powder diffraction data, ultraviolet, infrared and titration data for twelve narcotics are given and discussed in relation to previous data in this series.

II. - Materials

The twelve narcotics were originally obtained from various commercial sources, as shown in Table I. They were used without further purification. Their purity was checked chromatographically (I0), which method will detect basic impurities present in amounts higher than 2-3%.

III. - Names and nomenclature

International non-proprietary names * and Chemical Abstracts nomenclature have been used wherever possible in tables and indexes. Otherwise, the rules given previously (2) for selecting names for the narcotics have been followed.

* The valuable United Nations list: E/CN7/436, "Narcotic Drugs under International Control ", was used.

IV. - Methods of analysis

A. Water analysis: The Karl Fischer titration method (14) was used. The electrometric titrimeter was equipped with a miniature electron ray tube visual indicator. An opening for l0 seconds of the visual indicator was taken as the end point. Pholcodine was dried in an Abderhalden pistol (15) under reduced pressure to a constant weight for determination of water.

B. Melting points: A Fisher Johns microfusion apparatus was used to determine the melting points according to the procedure given for class I compounds (16).

C. Dissociation constants(17): The acid coefficients (pK Avalues) of the twelve compounds were determined by fractional neutralization. Titration curves of the salts of the narcotics were obtained in aqueous ethanol (50%) whenever possible, but aqueous propanol (75%) was used when solubility in the former solvent was low. The salts were titrated electrometrically with 0.01 N NaOH and the free bases with 0.01 N HC1. Saunders & Srivastava (17) describe the method of calculation which was applied to the simple halide salts. Levallorphan tartrate, ethoheptazine citrate and pholcodine results require more complex calculations, which are discussed in section VI. A.

D. Non-aqueous titrations: The details of the method have been previously described (18) using perchloric acid in glacial acetic acid as a titrant, and crystal violet as the end point indicator. Some determinations were confirmed potentiometrically in glacial acetic acid using a pH meter equipped with glass and calomel electrodes.

E. Ultraviolet spectrophotometry: Absorbance curves were obtained over the range 205 to 360 millimicrons using a Beckman DK-2 automatic ratio recording spectrophotometer equipped with 1-cm silica absorption cells, a hydrogen lamp source and photomultiplier detector. The following instrument settings were used: sensitivity 30, time 5, time constant 0.1, initial absorbance range 0-1. The solvent was placed in cuvets in both the reference and sample beams and the wavelength set at 360 mμ, the instrument set at zero calibration, and the baseline scanned over the range with solvent only.

Approximately 25 mg of the samples were weighed accurately and dissolved in 0.1 N sodium hydroxide, 0.1 N hydrochloric acid, and ethanol, respectively. Each determination was carried out in replicate. The solutions were transferred to 50-ml volumetric flasks and made up to volume. All of the compounds were soluble in alcohol. The narcotics which were insoluble in aqueous sodium hydroxide were dissolved in ethanol (25 ml), to which was then added 0.1 N sodium hydroxide (25 ml). A similar procedure was used for the hydrochloric acid solutions of insoluble compounds. Dilutions were carried out when required to bring the absorbance into a suitable range.

For purposes of plotting, the individual absorbances were obtained from the sample spectrum by subtraction of the baseline absorbance and the recorded absorbances. From these data the molecular extinction coefficients ( ε) were calculated using the molecular weights corrected for water content. (Table I, column 7). The ε values were plotted as ordinates on semilogarithmic paper against wave lengths in millimicrons along the abscissae.

F. X-ray powder diffraction: 1 The samples were ground (250-mesh sieve) and loaded into a glass capillary tube (0.2 mm ID, 0.01 mm 2). Myrophine was put into a capillary at 40 °F in a cold room since it tended to melt at normal temperatures. The uniformity of packing and absence of foreign particles was checked microscopically. Diffraction patterns were obtained using Philips Debye-Scherrer powder cameras (diameter 114.83 mm) and cobalt 1Kα radiation. The film exposure times varied from l0 to 18 hours at 28 Kvp and l0 ma. The centre of each line on the negatives was determined using a standard powder-film measuring device and the position of the line calculated from it. When variations greater than 0.1 mm in the position of the centres of successive lines on a film were observed, the centres were remeasured. Line positions were corrected for film shrinkage, and converted into d-values using a table of values (19), λ = 1.78890. Relative intensities were estimated visually on a scale of 100.

At least four X-ray diffraction powder photographs of each compound were used as a basis of the measurements reported here. One photograph of each substance in its original state was taken to determine the effect of grinding on the pattern.

G. Infra-red spectrophotometry: Two types of IR spectra were obtained:

  1. Potassium bromide pressed disc spectra: The compound (5 mg) and potassium bromide (495 mg) were weighed separately, mixed in a dental amalgamator. 3The mixture (203 mg) was transferred to a die and pressed at 15,000 psi for 2 minutes to yield a pellet (200 mg) using a Carver press. A similar pure potassium bromide disc was made for use as a reference.

  2. Spectra in carbon tetrachloride: The narcotic myrophine gave opaque potassium bromide discs, and was dissolved in carbon tetrachloride (1%), in which the spectrum was obtained. Measurements were made in a sodium chloride cell (1 mm path length) using "spec-pure" carbon tetrachloride in the reference beam.

1 The X-ray powder diffraction results were obtained by Dr. J. A. R. Cloutier, Head, Biophysics Section, Food and Drug Directorate.

2 Wall thickness of capillary tube.

3 Wiglbug, Amalgamator-Model 5A, Crescent Dental Mfg., Chicago, Ill., U.S.A.

V. - Results

Table I lists in alphabetical order the international non-proprietary names of the twelve narcotics, their sources, empirical formulae, molecular weights, the water content (%) and mole water content melting points, acidic dissociation exponents pK Aand recovery data.

TABLE I

Physical data for authentication of twelve narcotics

 

Water analysis

International name

Source and other Identification numbers

Empirical formula

Formula weight calculated

Per cent

Moles

Formula weight, + H 2O found

Melting point, found (°C)

Acid coefficient, found (pK A)

Non-aqueous, titrations, % recovery

Dipipanone hydrochloride monohydrate
Burroughs Wellcome Co. Ltd., 78828
C 24H 34ClNO 2
403.98 4.87 1.09 405.69
112-116
8.7 102.1
Ethoheptazine citrate a
John Wyeth, Bros. Co. Ltd., Walkerville, Ont., RR18746
C 22H 31NO 9
453.46 0.24 0.06 454.56 138.5
8.45 b
100.4
Levallorphan tartrate
Roche Ltd., London, England, RO-1-7700
C 23H 31NO 7
433.49
0.35
0.08
435.01
178-179
8.3
98.5
Levomoramide (free base)
Smith, Kline, French, Phil., U.S.A., 15157, NIH 7579
C 25H 33N 2O 2
392.52 0.09 0.02 392.87 190 6.6 99
Myrophine (free base)
NIH 5986 A, USPHS
C 38H 51NO 4
585.81 1.55 0.51 595.18
33-34
6.8 c
100
Nicomorphine hydrochloride dihydrate
Lannacker, Heilmittel, Vienna, Austria
C 29H 30C1N 3O 7
567.5 5.9 1.86 567.5
172-177
7.0 100.3
Normethadone hydrochloride
Hoechst, Germany, NIH 2820
C 20H 26ClNO
331.88 1.21 0.22 335.92
175-177
6.0 101
Phenazocine hydrobromide
Mallinckrodt, St. Louis, Miss., J259, NIH 7519
C 22H 28BrNO
402.37 1.04 0.235 406.60 164.5 8.5 103.5
Phenomorphan hydrobromide
Roche Ltd., London, England, RO-1-1955
C 24H 30BrNO
428.40 1.09 0.262 433.16
289-292
7.3
- d
Pholcodine monohydrate
Alien & Handbury Co. Ltd., Toronto, Canada
C 23H 32N 20 5
416.53
4.77 e
1.10 418.45 69.70
5.3 b 6.9 c
99
Piminodine ethane sulfonate
Winthrop, Can., Ltd., 14-098-2, NIH 7590
C 25H 36N 2O 5S
476.6.3 0.59 0.157 479.46 135.5 6.9 101
Propoxyphene hydrochloridea
Eli Lilly & Co., Indianapolis, U.S.A.
C 22H 30ClNO 2
375.93 0.504 0.105 377.83
169-170
6.3 102.9

a Not under international narcotic control.

b pK A of ethoheptazine free base in 50% aqueous ethanol.

c pK A, determined in 75% n-propanol.

d Phenomorphan did not dissolve in glacial acetic acid.

e Moisture content confirmed by determination in Abderhalden apparatus.

Table II shows the acid coefficients (pK A's), endpoint pH-values, and solution pH-values of twelve narcotics. Some typical titration curves are illustrated in Plate I. Table III shows an index of ultraviolet spectral data arranged according to Goldbaum (20). Ultraviolet spectral curves in which the logarithm of the molar extinction co-efficients (log ) are plotted against the corresponding wave-length (mμ) are shown in Plates II to IV. Charts of infrared spectra of the twelve substances are shown in Plates V, VI and VII. Functional group characteristics of molecules related to those of their IR-spectra are shown in Table IV. The UV and IR-spectra are arranged in an order based on chemical structure similar to that used in previous publications in this series (1-6). Table V shows the interplanar spacings (d-values) and relative intensities (I/I 1-values) of the X-ray powder diffraction photographs of these compounds. Plate VIII shows typical examples of photographs similar to those on which the measurements in table V were based. Table VI lists the innermost lines in increasing order of d-values. Table VII is a numerical index according to Hanawalt (21).

TABLE II

Acid coefficients, end point pHs, and solution pHs of twelve narcotics

 

pH of salt solutions

 

Compound

pK A

Theoretical pH at end point

Actual pH at end point

Calc.

Found

Dipipanone HCl a
8.7 10.3 10.15 5.8 6.1
Levallorphan tartrate
8.3 10.0 10.1

5.6 b (5.1)

4.8
Levomoramide c
6.6 9.2 8.5 4.45 4.5
Myrophine c
6.8 9.5 8.8 4.9 4.4
Nicomorphine HCl a
7.0 9.4 9.5 4.65 4.8
Normethadone HCl a
8.1 9.95 10.15 5.2 5.4
Phenazocine HBr a
8.5 10.15 10.2 5.4 5.7
Phenomorphan HBr
7.3 9.6 9.5 4.65 4.85
Piminodine ethane sulfonate
7.2 9.35 9.0
-
-
Propoxyphene HCl a
7.8 9.8 10 5.1 5.6

a Salt of strong acid and weak base.

b When Calculating pH of salt solution using formula for salt of weak acid and weak base, the value (5.6) differs appreciably from that found. This expression does not include a term for concentration, and is valid only at concentrations 0.01 N where pK A = pK B. This is clearly not the case here (cf. Glasstone). Considering the compound as a salt of a strong acid and a weak base, a value of 5.1 is calculated.

c Free bases. Positive is reversed here: "end point " is pH of 0.01 N solution of compound in solvent, pH of salt solution is at point of inflection obtained. Differences between found and calculated initial pH may be due to carbon-dioxide absorption or trace impurities.

VI. - Discussion

A. Dissociation Constants

Saunders & Srivistava (17) make use of the fact that in sufficiently dilute solutions (weak electrolytes) of acids or bases pH equals pk A, at the half-neutralization point - i.e.,when the ratio[acid]/[base] equals 1.This relationship holds when a monobasic acid or a monoacidic base is titrated with a similarly simple base or acid. Not all of the twelve compounds fall into this category; in fact, they can be discussed under four headings as follows:

(a) Salts of the type [RNH]+X-. - In this class one basic function is combined with a monobasic acid.

For practical purposes it includes compounds having more than one nitrogen atom of which only one can be titrated in aqueous solution. Examples are the hydrochloride salts of dipipanone, normethadone, propoxyphene, and nicomorphine; phenazocine hydrobromide, and piminodine ethane sulfonate.

(b) Free bases with one titratable basic function. - Myrophine and levomoramide 4 are the two narcotics in this class

(c) Free bases with two titratable basic functions. - Pholcodine is the only example in this set of twelve.

(d) Salts in which a monoacidic base is combined with a polybasic acid. - Ethoheptazine citrate and leval-lorphan tartrate are examples of compounds of this type.

(e) Individual compounds. - Two equivalents of acid were required to neutralize 1 mole of pholcodine free base, but the titration curve showed only one point of inflexion at the end point, indicating the equal strength of the nitrogens. When a polyacidic base, or polybasic acid is titrated, distinct inflexions are obtained at each stage, if the difference between successive pK's is greater than 3 - i.e., Kn / (Kn + 1) > 10 3. If the Kn and Kn + 1 are closer together, then the neutralization of the (n + 1)th step will have commenced before the n th end point has been reached. The curve for variation of pH with ml of titrant will become a straight line through the equivalence (n th) point. However, the influence of the (n + 1)th stage on the n th stage is small at points sufficiently removed from the n th equivalence point, so that, as a first approximation, pK n 2 = pH ?.

Similarly, pK n 2 + 1 = pH?. This is illustrated in Plate I, figure 1, by the titration curve of pholcodine.

Levallorphan tartrate shows two clearcut end points, one of which results from the second stage of tartaric acid ionization and the other from the base. Since pK >3, this experiment illustrates the statement mentioned above. Confirmation was obtained by titrating tartaric acid under exactly similar conditions, and it was found that the second stage of tartaric acid neutralization coincided with the first inflexion point of the titration curve obtained from neutralization of levorphanol tartrate with base.

Ethoheptazine citrate, more correctly named ethoheptazine dihydrogen citrate, is a more complicated substance, being a salt of a tribasic acid and a monoacidic base. The following titratable ionic species are present in solution: second stage and third stage ionization of citric acid, and ethoheptazinium acid. In the titration, 2 moles of base were used before an inflexion point was observed, but no indication of the third species was obtained. The pKs of citric acid are known, and it appeared that the point of inflexion obtained corresponds to that of neutralized cistric acid - i.e., the titration curve provides no information regarding ethoheptazine, except to show that it belongs to the group of stronger bases in comparison to the other narcotics studied. Preparation of the free base, ethoheptazine and subsequent titration in 50% ethanol yielded a pK A = 8.45.

4 Demoen, P. J. A. W., J.Pharm. Sci 50, 79 (1961) pK A = 7.05 in 50% MeOH for dextromoramide.

TABLE III

Ultraviolet spectral data of twelve narcotics in acidic, basic and ethanolic solvents

 

Solvent 0.1 N HCl

Solvent 0.1 N NaOH

Solvent ethanol (50%)

 

Wave-length, mμ

Com-pound max-imum

Molar extinc-tion

Com-pound mini-mum

Molar extinc-tion

Com-pound max-imum

Molar extinc-tion

Com-pound mini-mum

Molar extinc-tion

Com-pound maxi-mum

Molar extinc-tion

Com-pound mini-mum

Molar extinc-tion

Wave-length, mμ

204
-
-
-
-
-
-
-
-
-
-
Myro-phine
33 000 204
210
-
-
-
-
-
-
-
-
Myro-phine
35 400
-
-
210
223
-
-
-
-
-
-
Pimino-dine
1 735
-
-
Phena-zocine
6 600 223
-
-
-
-
-
-
-
-
-
-
-
Pimino-dine
7 130
-
226
-
-
-
-
-
-
Levall-orphan
1 317
-
-
-
-
226
-
-
-
-
-
-
-
Phena-zocine
1 645
-
-
-
-
-
227
-
-
-
-
-
-
Pheno-morphan
1 800
-
-
Phena-zocine
6 860 227
232
-
-
Propoxy-phene
129
-
-
-
-
-
-
-
-
232
234
-
-
-
-
-
-
-
-
-
-
Propoxy-phene
111 234
238
-
-
-
-
-
-
Propoxy-phene
153
-
-
-
-
238
240
-
-
-
-
-
-
-
-
-
-
Etho-hepta-zine
156 240
241
-
-
Nico-mor-phine
5 360
-
-
-
-
-
-
-
-
241
243
-
-
Levall-orphan
78
Phena-zocine
9 590
Nico-mor-phine
8 600
-
-
-
-
243
-
-
-
Pheno-morphan
202
-
-
-
-
-
-
-
-
-
244
-
-
-
-
-
-
-
-
-
-
Pheno-morphan
221 244
245
-
-
Pimino-dine
340
-
-
-
-
Pimino-dine
13 320
Nor-metha-done
313 245
246
-
-
-
-
-
-
-
-
-
-
Phena-zocine
230 246
247
Pimino-dine
348
-
-
-
-
-
-
-
-
Levall-orphan
144 247
-
-
-
-
-
-
-
-
-
-
-
Nico-mor-phine
5 960
-
248
-
-
Etho-hepta-zine
153
-
-
-
-
-
-
-
-
248
249
-
-
Levo-mora-mide
340
-
-
Etho-hepta-zine
160
-
-
Dipipa-none
360 249
-
-
-
Pimino-dine
346
-
-
-
-
-
-
-
-
-
250
-
-
Dipipa-none
491
-
-
-
-
-
-
-
-
250
251
Etho-hepta-zine
179
Nor-metha-done
503
-
-
Nor-metha-done
486
-
-
-
-
251
-
Propoxy-phene
331
-
-
-
-
-
-
-
-
-
-
-
252
-
-
Pimino-dine
260
-
-
Etho-hepta-zine
188
-
-
Etho-hepta-zine
178 252
-
-
-
-
-
Propoxy-phene
319
-
-
Propoxy-phene
315
Phol-codine
494
-
253
Dipipa-none
495
-
-
-
-
-
-
-
-
-
-
253
-
Levo-mora-mide
358
-
-
-
-
-
-
-
-
-
-
-
-
Nor-metha-done
522
-
-
-
-
-
-
-
-
-
-
-
-
Pimino-dine
392
-
-
-
-
-
-
-
-
-
-
-
254
-
-
Etho-hepta-zine
168
Nor-metha-done
515
-
-
Dipipa-none
410
-
-
254
-
-
-
Propoxy-phene
312
-
-
Propoxy-phene
294
Nor-metha-done
427
-
-
-
255
-
-
Dipipa-none
486
-
-
Etho-hepta-zine
168
-
-
Etho-hepta-zine
153 255
-
-
-
Levo-mora-mide
353
-
-
-
-
-
-
Propoxy-phene
287
-
-
-
-
Nor-metha-done
526
-
-
-
-
-
-
-
-
-
-
-
-
Pimino-dine
364
-
-
-
-
-
-
-
-
-
256
-
-
-
-
Nico-mor-phine
10 410
-
-
-
-
Dipipa-none
402 256
257
Etho-hepta-zine
216
-
-
-
-
Levo-mora-mide
361
-
-
Levo-mora-mide
377 257
258
Dipipa-none
533
-
-
Etho-hepta-zine
219
-
-
Etho-hepta-zine
210
-
-
258
-
Levo-mora-mide
399
-
-
Propoxy-phene
400
-
-
Levo-mora-mide
401
-
-
-
259
Nor-metha-done
580
-
-
Dipipa-none
883
-
-
Dipipa-none
478
-
-
259
-
-
-
-
-
Levo-mora-mide
400
-
-
Levo-mora-mide
400
-
-
-
-
-
-
-
-
-
-
-
-
Nor-metha-done
510
-
-
-
260
-
-
Phol-codine
1 000
Nor-metha-done
566
-
-
-
-
-
-
260
261
Nico-mor-phine
11 760
Etho-hepta-zine
153
-
-
Pholco-dine
527
-
-
-
-
261
-
-
-
Myro-phine
797
-
-
-
-
-
-
-
-
-
-
-
-
Propoxy-phene
294
-
-
-
-
-
-
-
-
-
262
-
-
Levo-mora-mide
327
-
-
Etho-hepta-zine
143
-
-
Etho-hepta-zine
127 262
-
-
-
Propoxy-phene
269
-
-
-
-
-
-
Myro-phine
865
-
-
-
-
-
-
-
-
-
-
-
-
Propoxy-phene
266
-
263
Etho-hepta-zine
163
Dipipa-none
502
-
-
-
-
Etho-hepta-zine
154
Dipipa-none
425 263
-
Propoxy-phene
324
Nor-metha-done
551
-
-
-
-
Nico-mor-phine
7 610
Nor-metha-done
456
-
-
Pimino-dine
264
-
-
-
-
-
-
-
-
-
-
-
264
Levo-mora-mide
336
-
-
Etho-hepta-zine
160
Levo-mora-mide
304
Propoxy-phene
321
Levo-mora-mide
306 264
-
-
-
-
-
Propoxy-phene
315
Nor-metha-done
523
-
-
-
-
-
265
Dipipa-none
511
-
-
Levo-mora-mide
306
-
-
Dipipa-none
460
-
-
265
-
Nor-metha-done
482
-
-
Nor-metha-done
427
-
-
Levo-mora-mide
308
-
-
-
-
-
-
-
-
-
-
-
-
Nor-metha-done
530
-
-
-
268
-
-
-
-
-
-
Levall-orphan
668
-
-
-
-
268
270
-
-
-
-
-
-
Pheno-morphan
695
Pimino-dine
823
-
-
270
271
-
-
-
-
-
-
Pimino-dine
1 014
-
-
-
-
271
272
-
-
-
-
-
-
Phena-zocine
788
-
-
-
-
272
274
-
-
Dipipa-none
390
-
-
-
-
Phol-codine
1 579
-
-
274
-
-
-
Nor-metha-done
418
-
-
-
-
-
-
-
-
-
275
-
-
-
-
-
-
-
-
Dipipa-none
293
Nor-metha-done
303 275
276
-
-
-
-
-
-
Nor-metha-done
366
-
-
-
-
276
277
Phena-zocine
1 982
-
-
-
-
-
-
-
-
-
-
277
278
Levall-orphan
2 452
-
-
-
-
-
-
-
-
-
-
278
279
-
-
-
-
-
-
Dipipa-none
515
-
-
-
-
279
281
-
-
-
-
-
-
-
-
Phena-zocine
2 253
-
-
281
282
-
-
-
-
-
-
-
-
Levall-orphan
2 413
-
-
282
-
-
-
-
-
-
-
-
-
Myro-phine
1 630
-
-
-
283
Myro-phine
1 690
-
-
-
-
Nico-mor-phine
1 990
-
-
-
-
283
284
Phol-codine
3 270
-
-
Myro-phine
1 736
-
-
-
-
-
-
284
-
-
-
-
-
Phol-codine
1 602
-
-
-
-
-
-
-
289
-
-
-
-
Pimino-dine
1 523
-
-
-
-
-
-
289
292
Dipipa-none
594
-
-
Dipipa-none
556
-
-
-
-
-
-
292
-
Nor-metha-done
598
-
-
-
-
-
-
-
-
-
-
-
293
-
-
-
-
-
-
-
-
Pimino-dine
1 909
-
-
293
294
-
-
-
-
-
-
-
-
Dipipa-none
448
-
-
294
295
-
-
-
-
Nor-metha-done
569
-
-
Nor-metha-done
479
-
-
295
298
-
-
-
-
Nico-mor-phine
2 640
-
-
-
-
-
-
298
299
-
-
-
-
Phena-zocine
3 035
-
-
-
-
-
-
299
300
-
-
-
-
Levall-orphan
3 236
-
-
-
-
-
-
300

Full size image: 36 kB

In some similar cases of a salt of this type the pK Aof the BH+ ion lies between the two end points of the acid with which it is combined. To demonstrate this case, codeine phosphate was titrated: the second and third dissociation constants of phosphoric acid are 7.2 and 12.3. Values for the base dissociation constant of codeine from 6.1 (Kolthoff, titration of codeine hydrochloride with aqueous sodium hydroxide) to 6.7-6.9 (Baggesgard-Rasmussen & Reimers, from titration of the free base with sodium hydroxide in 50% aqueous ethanol). The range of pK Avalues corresponding to these are 8.2 to 7.5 (where pK A = pK W - pK B), which value may be seen to lie between the second and third dissociation constant exponents of phosphoric acid. It was found that 2 moles of sodium hydroxide were required to reach the point of inflexion for codeine phosphate, and applying the procedure outlined above the pKs for the two species titrated were found to be 7.0 and 8.2 respectively. According to these experiments, therefore, the pK A of codeine is 8.2, while the value 7.0 corresponds to the second pK of phosphoric acid.

From the experimentally determined pK-values, the theoretical end-point pH-value and the salt solution pH-value (prior to titration) were calculated, and compared with the values found experimentally. These data are listed in table II, and it can be seen that reasonable agreement was obtained, which confirms the pK A values determined.

(f) Summary. - Summarizing the discussion of the dissociation constant it may be stated that in using the Henderson-Hasselbach equation to approximate the acid dissociation constant (pK A), and applying it as an identification constant especially where salts of polybasic acids are concerned, their full titration curve should be obtained along with that of the free acid with which the base is combined. The weakness of the method and variability of this factor lie in the lack of control of temperature which affects the value of pK W; the use of an insensitive pH meter, and the difficulty of obtaining exactly reproducible laboratory conditions, under ordinary circumstances.

B. Ultraviolet Spectra

The spectra of narcotics grouped according to chemical structure show clearly the influence of the major and minor chromophores. The comparisons mentioned below refer to those compounds and spectra which Farmilo et al. (5) dealt with.

1. Aryl Spectra

( a) Arylpiperidines. - The piminodine spectrum (Plate II, fig. 1) does not compare with those of its relatives in the pethidine family. However, the spectrum of aniline (22) shows two maxima at 287 and 235 mµ in isooctane, while pimidodine has maxima at 245 and 293 mµ as shown in Table III. The phenylamino chromophore dominates the piminodine spectrum. The effect of hydrochloric acid on the spectrum should be noted. (For special discussion of pH effect, see section VI.B.3.) In the latter spectra the modified phenyl fine structure reappears in the piminodine spectrum in acidic media.

( b)Arylazepines. - Ethoheptazine citrate, whose spectra are shown in Plate II, fig. 2, is a non-narcotic analgesic, which is closely related in chemical structure to proheptazine, which is a narcotic drug. Structurally, these compounds are related to pethidine having a hexamethyleneimine instead of a piperidine ring. Spectral characteristics reflect this close structural relationship; both pethidine and ethoheptazine have virtually identical spectra.

( c) Phenalkoxams. - The spectrum of propoxyphene shown in Plate II, fig. 3, shows the typical fine structure of the aryl chromophore, quite similar to that which is manifested by methadyl acetate. The presence of two phenyl-chromophores approximately doubles the ε-values of the maxima compared with the absorbance of the monophenyl compounds.

( d)Moramides. - The narcotic levomoramide 5 (Plate II, fig. 4) also contains two phenyl groups and its spectrum shows two maxima of the phenyl triplet at 259 and 265 with ε-values similar to those of the propoxyphene spectrum. On the lower wavelength side of the graph the swamping effect of the ring nitrogens is observed. The maximum around 290 mµ which is observed in spectra of other members of this general family - e.g., dipipanone and methadone - is absent in levomoramide. Since the carbonyl of levomoramide, which is an amide, -dine is linked to a nitrogen of the pyrrolidine group it does not show ketonic properties.

( e) Arylalkoneamines. - The spectra of normethadone and dipipanone in Plate III, figs. 5 and 6 respectively are quite similar to those of methadone and pipidone reported previously in part III.B of this series.

Demoen, loc. cit., U.V. max. 256, 261.5, 266.5 mµ and min. 253, 258.5. 266.0 mµ in 0.01N HCl in 90% Iso-PrOH.

TABLE V

Interplanar spacings (d) and relative intensities (I/I 1 ) of X-ray diffraction patterns of twelve narcotics

d(A)

I/I 1

d(A)

I/I 1

d(A)

I/I 1

d(A)

I/I 1

1. Piminodine ethanesulfonate
             
16.4 5 4.36 70 2.89 20 2.19 1
12.2 5 4.24 2 2.83 1 2.16 3
11.1 55 4.20 5 2.76 15 W 2.13 3
8.91 10 4.09 45 2.68 5 W 2.10 1
8.23 55 4.02 3 d 2.62 5 W 2.07 5
7.71 2 3.91 30 2.55 10 2.01 2
6.17 10 3.83 30 2.50 1 1.97 3
5.91 1 3.69 80 2.45 10 1.93 5 d
5.53 60 3.46 25 2.41 5 1.87
2
5.34 100 3.38 35 2.38 5 1.85 1
5.08 35 3.29 35 2.36 5 1.83 5
4.91 30 3.22 3 2.32 10 1.79 1
4.73 30 3.15 10 2.27 4 W 1.78 2
4.65 20 3.04 20 2.24 15 1.76 2
4.49 3 2.96 20 2.23
2 d
   
2. Ethoheptazine citrate
             
20.8 50 4.41 35 2.94 3W 2.20 2
11.5 25 4.26 35 2.86 20 2.19 2
8.51 80 4.17 55 2.84 5 2.15
1
7.12 70 W 4.07 30 2.76 2 W 2.09 3
6.71 40 3.96 35 2.69 1 2.04 2 d
6.35 1d 3.81 5 2.63 35 d 2.00 2 d
6.08 5 3.71 5 2.55 15 2.00 2d
5.89 40 3.68 10 2.50 2 1.98 2 d
5.71 35 3.59 10 2.49 2 1.93 3
5.37 30 3.47 10 2.43 2 1.91 1
5.29 100 3.38 65 2.40 1 1.88 2 W
5.11 10 3.28 2 2.36 2 1.84 1
5.03 15 3.23 20 2.32 1 1.82 1
4.87 40 3.14 2 2.29 2 1.79 2
4.71 5 3.08 1 2.27 2    
4.59 40 3.03 15 2.23
3
   
3. d-Propoxyphene hydrochloride
             
9.40 10 4.17 25 2.85 20 2.06 1
8.75 45 4.07 100 2.82 5 2.03 10
8.13 1 4.02 15 2.77 5 2.00 3 W
7.84 1 3.87 25 2.71 15 d 1.97 3
7.38 40 3.82 2 2.62 15 1.95 3
6.89 1 3.74 40 2.56 1 1.93 2 W
6.57 1 3.66 5 2.52 30 1.90 1
6.40 10 3.63 10 2.46 15 d 1.88 2
6.07 45 3.57 1 2.41 10 1.85 2
5.97 100 3.50 10 2.36 5 1.83 1
5.81 2 3.47 30 2.33 5 1.81 5
5.66 10 3.39 10 2.30 2 1.79 5
5.42 10 3.33 10 2.26 3 W 1.77 1
5.22 3 W 3.28 10 2.23 15 1.75 2
5.05 40 3.21 30 2.19 1 1.71 2
4.85 1 3.17 10 2.16 5 1.70 1
4.69 3 3.10 15 W 2.14 10 1.68 2
4.52 35 3.02 10 2.12 1 1.66
l
4.37 35 3.00 10 2.10 2 1.64 2
4.26 15 2.91 30 2.08
2
   
4. Levomoramide (free bases)
             
10.2 35 4.37 45 2.78 1 1.99
l
9.23 15 4.31 45 2.73 5 1.97 8
8.57 80 4.17 5 2.64 35 1.95 1
8.07 1 4.05 70 2.58 3 1.92 1
7.67 30 3.93 65 2.53 2 1.90 5
7.33 50 3.81 40 2.48 2 1.88 1
7.04 65 3.72 40 2.43 20 1.86 4
6.66 60 3.64 15 2.38 3 1.85 3 d
6.42 1 3.52 15 2.34 20 1.81 4
6.12 65 3.43 65 2.30 1 1.80 1
5.85 60 3.31 3 2.28 1 1.75 2
5.52 2 3.22 10 2.26 5 1.72 2
5.43 1 3.19 10 2.24 3 1.71 1
5.17 40 3.13 20 2.21 1 1.65 2
4.97 70 3.06 15 W 2.19 15 1.64 1
4.83 1 2.99 1 2.16 5 1.61 2
4.69 40 2.92 5 2.11 15 1.58 2
4.59 100 2.91 5 2.08 5 1.56 1
4.50 45 2.85 20 2.04 5 d 1.54 1
    2.82 15 2.02 1    
5. Normethadone hydrochloride
             
12.3 20 4.11 25 2.65 10 1.98 2
8.40 2 4.01 25 2.58 10 1.95 1
8.04 60 3.89 20 2.54 10 1.93 2
7.69 50 3.76 20 2.50 4 1.91 2
7.24 85 3.66 20 2.46 4 1.88 5
6.77 2 3.63 3 2.39 8 1.85 2
6.62 2 3.45 10 2.36 1 1.84 2
6.26 10 3.34 10 2.32 5 1.80 5
6.05 20 3.21 25 2.28 10 1.79 1
5.68 5 3.15 2 2.26 8 1.75 2
5.47 2 3.12 45 2.21 3 1.72 5
5.27 5 3.04 45 2.17 8 1.70 1
5.03 2 2.97 20 2.13 5 1.67 1
4.79 10 2.89 5 2.09 3 1.66 3 W
4.70 80 2.87 25 2.08 3 1.61 1
4.55 20 2.75 1 2.05 5 1.60 2
4.36 100 2.73 5 2.03 3 1.59 1
4.21 20 2.69 10 1.99 2 1.56 2
6. dl-Dipipanone hydrochloride monohydrate
             
15.0 2 3.52 20 2.40 15 1.83 2
8.93 1 3.46 15 2.35 1 1.81 3
8.09 80 3.34 15 W 2.32 3 1.79 2
7.32 20 3.25 55 2.29 15W 1.78 2
6.99 1 3.16 25 2.25 1 1.75 2
6.70 2 3.11 25 2.22 3 1.72 2
6.48 65 3.05 5 2.21 1 1.70 2
6.25 55 2.98 35 2.16 10 1.66 2
5.30 60 2.90 55 2.14 2 1.63 1 d
5.17 30 2.82 2 d 2.11 10 1.60 2
5.02 75 2.80 20 2.07 8 1.58 1
4.79 60 2.76 5 2.05 5 1.57 1
4.34 60 2.71 20 2.02 8 1.53 2
4.24 35 2.64 10 2.01 3 1.52 1
4.14 35 2.60 10 1.97 10 1.480 1
4.02 100 2.56 10 1.95 2 1.461 1
3.90 5 2.52 2 1.93 4 1.449 2
3.80 20 2.50 10 1.90 10 1.422 1
3.68 55 W 2.47 5 1.88 2 d 1.410 2
3.58 5 2.44 10 1.85 5 1.373 2
7. Phenazocine hydrobromide
             
15.2 100 4.93 30 3.31 10 2.46 1
13.5 2 4.78 30 3.23 5 2.44 2
10.6 2 4.60 3 3.20 30 2.39 2 W
9.38 1 4.44 3 3.13 3 2.34 2
8.85 50 4.39 35 3.06 1 2.29 2
8.23 1 4.30 5 3.00 2 2.24 2
7.75 3 4.21 3 2.94 30 2.19 1
7.31 5 4.13 60 2.87 1 2.17 3
7.08 3 4.02 10 2.83 3 2.14 1
6.75 1 3.94 5 2.81 3 2.12 2
6.50 4 3.81 5 2.75 5 2.08 2
6.23 20 3.78 5 2.72 2 2.07 2
6.02 15 3.69 2 2.66 4 2.02 2
5.78 1 3.62 10 2.61 2 2.01 2
5.51 25 3.51 8 2.59 2 1.96 2
5.31 1 3.44 1 2.53 5 1.95 2
5.13 35 3.38 5     1.92 1
8. d-Phenomorphan hydrobromide
             
10.3 10 3.96 10 2.62 15 1.94 2
9.38 75 3.88 5 2.56 3 1.92 10
8.93 1 3.77 65 2.53 5 1.90 1
8.22 5 3.67 55 2.49 3 1.88 3
7.77 1 3.60 5 2.46 2 d 1.85 3 d
7.31 40 3.53 20 2.41 1 1.82 4
6.82 5 3.47 3 2.37 8 d 1.80 1
6.52 40 3.41 3 2.31 8 1.78 3
6.18 1 W 3.34 2 2.27 2 1.76 3
5.90 5 3.27 5 2.23 5 1.74 2
5.81 5 3.21 10 2.20 3 1.72 2
5.58 5 3.16 10 2.18 5 1.70 1 W
5.41 1 3.09 5 2.13 5 1.67 2 W
5.16 100 3.03 2 2.11 2 1.65 1
4.93 60 3.01 2 2.08 3 1.64 1
4.74 1 W 2.94 20 2.06 3 1.62 2
4.55 50 2.89 20 2.05 2 1.60 2
4.40 70 2.79 5 2.02 2 1.58 1
4.28 1 2.74 5 2.01 3 1.55 2
4.17 35 2.68 1 1.98 2 1.54 1
4.05 3 2.67 3 1.97 1 1.52 2
9. Levallorphan tartrate
             
9.50 50 3.81 25 2.53 40 1.93 1
7.34 35 3.69 30 W 2.49 8 1.92 2
7.14 40 3.55 70 2.46 8 1.90 5
6.70 75 3.46 1 2.42 2 1.86 3
6.36 1 3.38 35 2.38 1 1.84 2
6.30 15 3.35 35 2.35 5 1.82
1
5.93 1 3.25 2 d 2.30 45 1.81 1
5.72 100 3.21 3 2.27 2 d 1.79 25
5.51 80 3.16 3 2.23 25 1.76 5
5.29 2 W 3.09 2 2.18 15 1.74 1 W
5.08 20 3.04 10 2.14 2 1.72 1
4.92 1 2.99 5 2.10 1 1.71 1
4.74 40 2.93 5 2.09 1 1.69 3
4.58 15 2.85 30 2.04 20 1.67 2
4.43 30 2.79 35 2.01 1 d 1.65 1
4.35 40 2.72 2 2.00 10 1.62 2
4.20 50 2.64 1 1.98 8 1.60 1
4.04 70 2.60 5 1.96 8 1.58 3
3.92 2        
-
-
10. Pholcodine (free base) (monohydrate ?)
             
7.59 100 3.59 20 2.49 10 1.90 10 W
6.71 35 3.51 70 2.39 35 1.87 10
6.25 40 3.39 5 d 2.36 5 1.85 3
6.00 20 3.36 25 2.33 10 1.83
3
5.82 1 3.31 10 W 2.38 15 1.80 5
5.55 100 3.15 15 2.24 5 1.79 5 d
5.37 25 3.08 40 2.23 10 1.76 3
5.27 100 3.03 40 2.17 35 1.74 3 W
4.71 25 2.96 1 2.15 2 1.71 1
4.64 80 2.90 35 2.13 1 1.68 2
4.48 40 2.83 1 2.10 5 1.64 8
4.33 40 2.78 35 2.08 5 1.63 1
4.23 1 2.74 2 2.05 10 1.61 2
4.12 35 2.70 10 2.02 8 1.59 1
3.96 35 2.65 1 2.01 2 1.56 2
3.87 1 2.60 15 1.98 10 1.55 1
3.79 80 2.57 1 1.97 5 d 1.54 2
3.69 2 2.53 35 1.93 5 1.53 2
3.67 5            
11. Myrophine (free base)
             
14.4 65 4.44 20 2.88 5 2.15 3 W
9.61 60 4.30 3 2.83 1 2.11 2
8.96 1 4.16 35 W 2.79 2 2.09 2
8.82 1 4.02 30 2.72 1 d 2.06 3
8.30 85 3.92 30 2.66 1 d 2.01 4
7.69 15 3.83 3 2.61 4 W 1.99 2
7.22 15 3.74 10 2.55 4 W 1.96 5
6.83 1 3.70 5 2.50 3 1.92 2
6.57 35 3.58 20 2.46 1 1.90 1
6.27 3 3.49 10 2.44 4 1.87 2
5.97 40 3.43 3 2.39 5 1.84 1
5.74 3 3.36 2 2.34 3 1.80 2
5.65 2d 3.29 3 2.29 1 1.79 2
5.31 25 3.21 3 2.27 10 1.74 2 d
5.01 100 3.13 3 2.24 5 1.70 1
4.87 3 3.03 5 2.21 1 1.68 1
4.72 40 2.97 2 2.19
2
   
4.58 1 2.94 2        
12. Nicomorphine hydrochloride dihydrate
             
15.6 95 4.34 100 2.75 1 2.09 1
11.2 10 4.16 10 2.71 8 2.06 3 d
10.3 1 4.04 1 2.67 2 2.03 1
9.43 90 3.92 15 2.62 3 2.00 3
8.72 1 3.83 1 2.58 2 1.97 4
7.84 3 3.66 35 2.54 5 1.95 1
7.30 1 3.58 5 2.48 3 1.93 1
7.00 1 3.48 45 2.42 4 1.90 4
6.56 25 3.39 20 2.40 2 d 1.88 1
6.32 15 3.33 5 2.36 4 1.83 2 W
5.97 85 3.26 20 2.33 1 1.77 2 W
5.87 20 3.18 10 2.28 1 1.73 2
5.61 10 3.12 1 2.26 4 1.71 2
5.41 1 3.07 5 2.23 1 1.69 1
5.20 20 3.01 3 2.17 4 1.66 2
4.98 1 2.95 10 2.16 4 1.65 1
4.76 15 2.88 3 2.12 2 1.63 2
4.52 80 2.80 15        

In general, an examination of the spectra of aryls shows certain common features.

( i) Compounds containing phenyl groups linked C-C bond to a chain of carbon atoms to which no other chromatophore of comparable strength is attached have a spectrum characterized by a triple-peaked-benzoid band about 260 mμ. The presence of two such phenyl groups approximately doubles the ε-values at the maxima (23).

( ii) The influence of any additional chromophores in the narcotic molecules depends on their relative strength -e.g., weak chromophores, such as those with ketonic-carbonyls like diarylalkoneamines, may add another band to the triple-peaked-benzoid spectrum, but have little effect on this absorption. A strong chromatophore like a phenylamino substituent causes a complete change in the spectrum producing one like that of aniline.

2. Benzazocine Spectra

The only compound in this group to be investigated was phenazocine, Plate III, fig. 7, which spectrum is similar to those of the iminoethanophenanthrene compounds investigated previously (5) and described in section VI.B.3 below.

3. Phenanthrene Spectra

( a) Iminoethanophenanthrenes. - The spectra of levallorphan tartrate and phenomorphan shown in Plate III, fig. 8, and Plate IV, fig. 1, respectively, are closely similar in character to those of other "morphinans".

( b) Iminoethanophenanthrofurans. - Pholcodine has a spectrum (Plate IV, fig. 10) similar to that of codeine in ethanolic solution except for a shift of 12 mμ in the maximum. The spectrum of myrophine (Plate IV, fig. 11) closely resembles that of benzylmorphine to which it is chemically related. Nicomorphine has a spectrum shown in fig. 12 of Plate IV which, compared with that of morphine, shows a strong hypsochromic shift combined with a hyperchromic effect. The effect of changes in pH will be discussed in section VI.B.4 below.

4. Influence of pH Changes on Spectra

Ethoheptazine, propoxyphene spectra showed no significant change whether obtained in ethanolic, acidic or in basic solutions. Levomoramide, normethadone, dipipanone, and myrophine show minor changes in spectral features; the first and last compounds in this set have maxima at 253 and 260 mμ which are supressed in acid and base respectively. The second and third compounds show small increases in absorbances (ε-values) in acid and base compared with ethanolic solution. On the other hand substantial changes in the spectra of piminodine, phenomorphan, levallorphan, phenazocine, pholcodine, and nicomorphine are produced by changing the pH of the media. Piminodine shows complete suppression of the aniline-type spectrum in HCl solution, which phenomena has been discussed in terms of electronic theory by Farmilo (5). The reappearance in the spectrum of the fine structure owing to the presence of phenyl resonators and the sharp decrease in absorbances (ε-values) should be observed.

TABLE VI

Innermost line index

d(A)

I/I 1

Name

No.

20.8 50
Ethoheptazine citrate
2
16.4 5
Piminodine ethane sulfonate
1
15.6 95
Nicomorphine hydrochloride dihydrate
12
15.2 100
Phenazocine hydrobromide
7
14.4 65
Myrophine (free base)
11
12.3 20
Normethadone hydrochloride
5
10.3 10
d-Phenomorphan hydrobromide
8
10.2 35
Levomoramide (free base)
4
9.50 50
Levallorphan tartrate
9
9.40 10
d-Propoxyphene hydrochloride
3
[8.09 80
dl-Dipipanone hydrochloride monohydrate
6]
7.59 100
Pholcodine (free base) (monohydrate ?)
10

Phenomorphan, levallorphan and phenazocine (fig. 7, 8 and 9, Plates III and IV), which are phenols and have similar spectra in ethanol, show identical shifts of their spectra by approximately 20 mμ to higher wavelengths in alkaline solution. A hyperchromic effect from 2,000 to 3,000 ε-units was observed. These findings are characteristic of the behaviour of other spectra of phenols and phenolates (23).

Nicomorphine (fig. 12, Plate IV) is an ester, dinicotinyl-morphine, whose spectrum in ethanolic and acidic solution is essentially the same as the nicotinic acid spectrum. In alkaline medium, hydrolysis occurs to produce morphinate and nicotinate ions, which in solution yield an ultraviolet spectrum similar to that of a mixture of morphine and nicotinic acid. To prove that the change in spectral characteristics had been produced owing to hydrolysis in alkaline medium and not in ethanolic solution the solutions were chromatographed in iso-BuOH:AcOH:H 2O (10:1:2.4) on ammonium sulphate treated paper (10). The ethanolic solution showed one spot (R f = 0.68) which was detected by its absorbance of 2537 ? ultraviolet light, and as an orange spot with a modified König's reagent (24), which is used for the detection of pyridine derivatives in paper chromatography. On the other hand, the alkaline solution gave two spots. The first with the lowest R f = 0.13 was identified by UV-light, potassium iodoplatinate spray reagent (10) and Kieffer's (25) reagent as morphine.

TABLE VII

Numerical (Hanawalt) index

84. - 15.9 to 14.0
             
14.4 5.01 8.30 65 100 85
Myrophine (free base)
(11)
15.6 4.34 9.43 95 100 90
Nicomorphine hydrochloride dihydrate
(12)
15.2 4.13 8.85 100 60 50
Phenazocine hydrobromide
(7)
79. - 9.49 to 9.00
             
9.38 5.16 4.40 75 100 70
d-Phenomorphan hydrobromide
(8)
9.43 4.34 15.6 90 100 95
Nicomorphine hydrochloride dihydrate
(12)
78. - 8.99 to 8.50
             
8.85 15.2 4.13 50 100 60
Phenazocine hydrobromide
(7)
8.75 5.97 4.07 45 100 100
d-Propoxyphene hydrochloride
(3)
8.51 5.29 7.12 80 100 70
Ethoheptazine citrate
(2)
8.57 4.59 4.97 80 100 70
Levomoramide (free base)
(4)
77.- 8.49 to 8.00
             
8.30 5.01 14.4 85 100 65
Myrophine (free base)
(11)
8.09 4.02 5.02 80 100 75
dl-Dipipanone hydrochloride monohydrate
(6)
76. - 7.99 to 7.50
             
7.59 5.55 5.27 100 100 100
Pholcodine (free base) (monohydrate ?)
(10)
75.- 7.49 to 7.00
             
7.12 5.29 8.51 70 100 80
Ethoheptazine citrate
(2)
7.24 4.36 4.70 85 100 80
Normethadone hydrochloride
(5)
74. - 6.99 to 6.50
             
6.70 5.72 5.51 75 100 80
Levallorphan tartrate
(9)
72. - 5.99 to 5.75
             
5.97 4.07 8.75 100 100 45
d-Propoxyphene hydrochloride
(3)
71. - 5.74 to 5.50
             
5.55 7.59 5.27 100 100 100
Pholcodine (free base) (monohydrate ?)
(10)
5.51 5.72 6.70 80 100 75
Levallorphan tartrate
(9)
5.72 5.51 6.70 100 80 75
Levallorphan tartrate
(9)
70. - 5.49 to 5.25
             
5.29 8.51 7.12 100 80 70
Ethoheptazine citrate
(2)
5.27 7.59 5.55 100 100 100
Pholcodine (free base) (monohydrate ?)
(10)
5.34 3.69 4.36 100 80 70
Piminodine ethane sulfonate
(1)
69. - 5.24 to 5.00
             
5.16 9.38 4.40 100 75 70
d-Phenomorphan hydrobromide
(8)
5.01 8.30 14.4 100 85 65
Myrophine (free base)
(11)
5.02 4.02 8.09 75 100 80
dl-Dipipanone hydrochloride monohydrate
(6)
68. - 4.99 to 4.90
             
4.97 4.59 8.57 70 100 80
Levomoramide (free base)
(4)
66. - 4.79 to 4.70
             
4.70 4.36 7.24 80 100 85
Normethadone hydrochloride
(5)
64. - 4.59 to 4.50
             
4.59 8.57 4.97 100 80 70
Levomoramide (free base)
(4)
63. - 4.49 to 4.40
             
4.40 5.16 9.38 70 100 75
d-Phenomorphan hydrobromide
(8)
62. - 4.39 to 4.30
             
4.34 15.6 9.43 100 95 90
Nicomorphine hydrochloride dihydrate
(12)
4.36 7.24 4.70 100 85 80
Normethadone hydrochloride
(5)
4.36 5.34 3.69 70 100 80
Piminodine ethane sulfonate
(1)
60. - 4.19 to 4.10
             
4.13 15.2 8.85 60 100 50
Phenazocine hydrobromide
(7)
59.- 4.09 to 4.00
             
4.02 8.09 5.02 100 80 75
dl-Dipipanone hydrochloride monohydrate
(6)
4.07 5.97 8.75 100 100 45
d-Propoxyphene hydrochloride
(3)
55.- 3.69 to 3.60
             
3.69 5.34 4.36 80 100 70
Piminodine ethane sulfonate
(1)

The second spot gave a dark absorbance under UV-light (2537 ?,) and a red-purple color with König's reagent (24) and an R f value of 0.51, which had identical properties with that produced by a known nicotinic acid. Another hydrolysis product, probably O 6-mononicotinylmorphine R f=0.33, was found when the alcoholic solution of nicomorphine was spotted on the chromatogram, and a drop of aqueous sodium hydroxide (0.1 N) was superimposed on the same spot prior to development.

There are four main facts which emerge from a study of the spectral changes produced in the acidic, basic and neutral media: (i) phenyl groups which are dominant chromophores show little change; (ii) phenols undergo ionization to phenolates, which reaction produces appreciable bathochromic shifts; (iii) the aniline-anilinium tautomeric reaction in phenylamino-chromophores causes noticeable phenyl structure changes; (iv) hydrolysis of esters produces ionic species which absorb differently from the acidic, or neutral, molecule.

C. Infrared Spectra

(a) General features. - The useful infrared absorption bands given in wave numbers, cm -1 and ranges are shown in Table IV. All of the narcotics' infrared spectra show evidence of the CH bonds of the molecules. Aromatic rings are identified by the two bands in the 1,500 to 1,600 cm -1 region, which are of variable intensity, and sometimes show as shoulders on stronger bands. All of the spectra have characteristic bands at 700 and 750 cm -1 typical features of compounds containing monosubstituted aromatic rings. Pyridine, which is present in the nicotinic acid portion of nicomorphine, has a strong band in the 700 cm -1 region of its spectrum. The weak band at 3,000 cm -1 is characteristic of spectra of aromatic compounds. The methylene groups present in all narcotics show strong infrared spectral absorption at 1,450 and 2,900 cm -1 except in the citrate and tartrate salts. Methyl groups attached to carbon atoms are manifested by absorption in the same spectral region. They produce peaks at 1,370-1,380 cm -1,but they are of low intensity. With one exception (pimonodine) the narcotics contain only tertiary aliphatic basic groups. In general such compounds show weak absorption bands in spectral regions where other groups absorb strongly. On the other hand compounds examined in salt form shown in the fourth section of Table IV have typical broad spectral absorption bands in the 2,400-2,600 cm -1 region owing to the ≡ NH + stretching vibrations of the molecules. The citrate and tartrate anions obscure this absorption band owing to the presence of a number of hydroxyl groups, which give rise to strong hydrogen bonding and produce a dampening effect. It will be observed that the spectra of free bases like pholcodine, myrophine and levomoramide do not show this band.

PLATE I. - Titration curves of narcotics

Full size image: 28 kB, PLATE I. - Titration curves of narcotics

PLATE II. - Ultraviolet curves of narcotics in 3 solvents

Full size image: 116 kB, PLATE II. - Ultraviolet curves of narcotics in 3 solvents

PLATE III. - Ultraviolet curves of narcotics in 3 solvents

Full size image: 117 kB, PLATE III. - Ultraviolet curves of narcotics in 3 solvents

PLATE IV. - Ultraviolet curves of narcotics in 3 solvents

Full size image: 122 kB, PLATE IV. - Ultraviolet curves of narcotics in 3 solvents

PLATE V. - Infrared spectra of narcotics

Full size image: 135 kB, PLATE V. - Infrared spectra of narcotics

PLATE VI. - Infrared spectra of narcotics

Full size image: 132 kB, PLATE VI. - Infrared spectra of narcotics

PLATE VII. - Infrared spectra of narcotics

Full size image: 146 kB, PLATE VII. - Infrared spectra of narcotics

PLATE VIII. - X-Ray powder diffraction patterns of narcotics

Full size image: 210 kB, PLATE VIII. - X-Ray powder diffraction patterns of narcotics
Fig. 1. Piminodine ethane sulfonate
Fig. 7. Phenazocine hydrobromide
Fig. 2. Ethoheptazine citrate
Fig. 8. d-Phenomorphan hydrobromide
Fig. 3. d-Propoxyphene hydrochloride
Fig. 9. Levallorphan tartrate
Fig. 4. Levomoramide (free base)
Fig. 10. Pholcodine monohydrate (free base)
Fig. 5. Normethadone hydrochloride
Fig. 11. Myrophine (free base)
Fig. 6. dl-Dipipanone hydrochloride monohydrate
Fig. 12. Nicomorphine hydrochloride dihydrate

(b) Functional groups - Most of the narcotics containing characteristic functional groups - e.g., ketones, esters, amides, phenols - have spectra which reflect this. The carbonyl group has a strong absorbance 1,700-1,750 cm -1,which is the C = O stretching region. These types of compound are listed in Table IV, insection 2 of the table. The compounds with phenolic hydroxyl group show absorption bands in their spectra in the 3,200-3,400 cm -1 region, which indicates polymeric association through hydrogen bonding. Bellamy (26) points out that spectra prepared from material in the solid state have the molecules oriented to produce maximum hydrogen bonding. Phenomorphan, levallorphan and phenazocine spectra show absorption in the 1,230 and 1,310 cm -1 region which reinforces the above evidence. The morphine derivatives are phenanthrofurans, and thus contain the ether linkage, C-O-C. Their spectra show bands in the 1,070-1,150 cm -1region.

D. X-ray Diffraction

Most of the weak lines (I/I 1 ≤ 3) in the diffraction data in Table V were included because they are useful for checking on the purity of the specimen. However, such weak lines do not appear on a negative exposed in the X-ray camera for shorter times. In the table, the letters following the relative intensities of some of the lines are used to denote the reflection of sample condition in the crystallographic sense. The letter "d" refers to lines which were diffuse. These were probably caused by imperfections in the crystal lattice. Wide lines were marked "w ". Lines whose relative intensities are between brackets are closely spaced, which were resolved by careful technique and use of the cobalt Kα source. A change in experimental conditions would probably result in the broadening of these lines into a single wide line with intermediate d-value.

The X-ray powder diffraction patterns in the photographs in Plate VIII are arranged in the following order:

X-ray pattern

Compound name

1.
Piminodine ethanesulfonate
2.
Ethoheptazine citrate
3.
d-Propoxyphene hydrochloride
4.
Levomoramide (free base)
5.
Normethadone hydrochloride
6.
dl-Dipipanone hydrochloride monohydrate
7.
Phenazocine hydrobromide
8.
d-Phenomorphan hydrobromide
9.
Levallorphan tartrate
10.
Pholcodine (free base) monohydrate
11.
Myrophine (free base)
12.
Nicomorphine hydrochloride monohydrate

The same order was used in the arrangement of the interplanar spacings and relative intensities of the twelve narcotics in Table V. No significant variations were observed in the patterns described in Table V or shown in Plate I during the course of investigation.

Conventions regarding the two indexes Table VI and VII, which are the numerical and innermost line indexes, were discussed by Barnes (3) and Barnes & Sheppard (4) in previous articles of this series. In Table VI the relative intensity of the innermost line of dl-dipipanone hydro-chloride monohydrate is less than 5, and therefore the d-value of the third line was listed. This entry is enclosed in square brackets.

VII. - Acknowledgements

The authors wish to acknowledge the help of Jean-Charles Meranger for obtaining the X-ray powder diffraction photographs. The drawings were made by G. Morris, and the photographs were produced by the biological photographic laboratory of this department, with the exception of plate VIII, which was made in the biophysics section.

The authors wish to acknowledge the help of the various drug companies who supplied the compounds through the good offices of Mr. R. C. Hammond, Chief, Narcotic Control Division.

VIII. - References

FARMILO, C. G. & LEVI, L.: Bull. on Narcotics, 5, No. 4, 20-27 (1953), part 1 A.

FARMILO, C. G. et. al.: ibid., 6, No. 1, 7-19 (1954), part 1 B.

BARNES, W. H.: ibid., 6, No. 1, 20-31 (1954), part II A.

BARNES, W. H. & SHEPPARD, H.: ibid., 6, No. 2, 27-68 (1954), part II B.

FARMILO, C. G.: ibid., 6, No. 3, 18-41 (1954), part III A.

OESTREICHER, P. M. et. al.: ibid., 6, No. 3, 42-70 (1954), part III B.

HUBLEY, C. E. & LEVI, L.: ibid., 7, No. 1, 20-41 (1955), part IV A.

LEVI, L. et. al.: ibid., 7, No. 1, 42-84 (1955), part IV B.

GENEST, K. & FARMILO, C. G.: ibid., 11, No. 4, 20-37 (1959), part V A.

GENEST, K. & FARMILO, C. G.: ibid., 12, No. 1, 15-24 (1960), part V B.

SCHMIDLIN, Jolanda, Gerichlich-Medizinisches Institut der Universität, Zürich, Switzerland: Private communication to C. Farmilo, 27 June 1960.

SCHMIDLIN-MESZAROS, J. & HARTMANN, H.: Archiv für Toxikologie, 18, 259-268 (1960).

FARMILO, C. G. & GENEST, K.: Chap. 7 in Toxicology Mechanisms and Analytical Methods, volume II, edited by Stewart, C. P. and Stolman, A., Academic Press, New York, 1961.

The Pharmacopoeia of the United States of America, fourteenth revision, Mack Publishing Co., Easton, Pa., p. 795. 1 Nov. 1950.

CHERONIS, N. D. & ENTRIKIN, J. B.: Semimicro Qualitative Organic Analysis. 2nd edition, Interscience Publishers, Inc., New York, 1957.

Same reference as 14, p. 734.

SAUNDERS, L. & SRIVASTAVA, R. S.: Journal of Pharmacy and Pharmacology, 3, 78 (1951).

LEVI, L., OESTREICHER, P. M. & FARMILO, C. G.: Bull. on Narcotics, 5, No. 1, 15 (1953).

SWANSON, H. E.: "Table for Conversion of X-ray Diffraction Angles to Interplanar Spacings ", App. Math. Ser. 10, National Bureau of Standards, Washington, D.C. (1950).

KAYE, S. & GOLDBAUM, L. R.: "Toxicology ". Chap. 24 in the text Legal Medicine, edited by Gradwohl, R. B. H., The C. V. Mosby Co., St. Louis, Mo., 1954.

HANAWALT, J. D., RINN, H. W. & FREVEL, L. K.: Ind. Eng. Chem. Anal. ed., 10, 457-512 (1938).

FRIEDEL, R. A. & ORCHIN, M.: UV-Spectra of Aromatic Compounds, Wiley, N.Y., 1951. Spectrum No. 140.

GILLAM, A. E. & STERN, E. S.: Introduction to Electronic Absorption Spectroscopy, p. 9, 134. Second ed. 1959. Edward Arnold, Ltd., London.

HUEBNER, I.: Nature, 167, 119 (1951).

MIRAM, R. & PFEIFER, S.: Scientia Pharmaceutica, 26, 22-40 (1958).

BELLAMY, L. J.: Infrared Spectra of Complex Molecules, Methuen and Co. Ltd., New York, second edition, p. 102, 1958.