Methadon Hydrochloride Optical Properties, Microchemical Reactions, and X-Ray Difraction Data CLIFFORD E. HUBACH, Alcohol Tax Unit Laboratory, San Francisco, Calif., FRANCIS T . JONES, Western Regional Research Laboratories, rllbany, Calif.
AND
Physical and chemical properties of methadon hydrochloride are presented. Seven reagents are listed which produce characteristic microscopic crystals from dilute solutions. Single crystals grown from aqueous solutions can be used for measurement of the optic axial angle, extinction angles, and refractive indexes and for observation of interference figures. X-ray diffraction data are useful in identifying the powdered material, and the ultraviolet absorption spectra of methadon base and hydrochloride may be relied upon for identifying small quantities in solution.
M"'
1 to 500, 1 to 200, and 1 to 50, and a saturated solutioii ere mixed with approximately equal drops of reagent on a microscope slide and allowed to stand until crystals developed or all liquid evaporated. The drops were not stirred in the test described, although in some cases stirring hastens crystallization. The progress of crystallization was observed under a microscope a t a magnification of 100. Of the 25 reagents listed by Stephenson ( 6 ) , six produced satisfactory crystals. Good crystals were also obtained with uranium nitrate 20% and lanthanum nitrate 20'70. Results of the tests are shown in Table I.
1HBDON hydrorhloride (4,4-diphen~l-6-dimet hylamino-3-heptanone hydrochloride) has iecently been placed on the market under the names dolophine, amidone, etc., as a substitute for morphine. Because of its habit-forming characteristics, it is classified by law as a narcotic and its sale is restricted. 4 report on its physiological effects and the history of its development has been published ( 2 ) . It is a white crystalline compound, soluble in water and e t h j l alcohol and insoluble in ether. I t s melting point has been found by various investigators to be 230" to 232"C.(3),236"to236.5" C. ,)'it( and 241" to 242" C. corrected ( 7 ) . The solubility in water has been reported to be about 5% ( 2 ) ; however, solutions of 10% or more a t room temperature (20" to 25" C.) can be prepared nithout difficulty. From aqueous solutions of the hydrochloride, animonium hydroxide and other alkalies precipitate the free base as an oily substance which can be extracted with chloroform, ethyl ether, or petroleum ether. Levo- and dextrorotatory isomers of methadon have been prepared ( 2 ) ; however, the hydrochloride sal1 (manufactured by Eli Lilly & Company) used in the follotving experiments was proved by crystallographic and polaiiscopic observations to be the optically neutral raremate. 5
Table 11. Cr3-stallizationfrom Solution Reagent Potassium iodide, 5 % Potassium ferrocyanide, 5 % (fresh wlution) Potassium ferricyanide, 5VG (fresh soliltion) Marme's reagent (fresh solution) hlayer's reagent Wagner's reagent Lanthanum nitrate, 20%
In making these tests, the methods and reagents described by Stephenson ( 6 ) were used. Aqueous methadon hydrochloride solutions of roncentrations 1 to 10,000, 1 to 5000, 1 to 1000,
21 3 4 5
6 7 8
9 IO 11
12 13 14 15 16 17 18
19 20 21 22 23 24 25 26 27 28
Jlicrochemical Reactions
Reagents r s e d
Reaction
Sodium Sodium carbonate, nitroprusside, 57, Dinodium phosphate, 5 % Potassium hydroxide, 5 % Potassium acetate, 5 % Potassium 5% 5 % Potassium iodide. chromate, Potassium ferrocyanide, 5 % Potassium ferricyanide 5 % Potassium permangana'te, 5% Fold chloride, c570 Silver nitrate, 5 % Ammonium molybdate, 570 Platinum chloride, Ferric chloride, 5Yo5 % Zinc chloride, 5 % Picric acid, saturated solution Marme's reagent hIayer's reagent Millon's reagent Wagner's reagent Phosphomolybdic acid reagent Phosphotungstic acid reagent Kraut's reagent Sodium bisulfite Cranium nitrate, 5 % Cranium nitrate, 20% Lathanum nitrate, 20%
Oil droplets Oil droplets Oil droplets Oil droplets Oil droplets Colorless crystals Oil droplets Colorless crystals Yell ow crystals Amorphous precipitate .4morphous precipitate .4morphous precipitate Amorphous precipitate Amorphous precipitate pi0 reaction Oil droplets Amorphous preripitate Colorless crystals Colorless crystals Amorphous precipitate Pale brown crystals Amorphous precipitate Amorphous precipitate Amorphous precipitate No reaction No reaction Colorless crystals Colorless crystals
1:500 1 : 10,000 1 : 20,000 1: 1000
1:20
These reagents were selected for trial because their reactions n i t h most of the common alkaloids have been reported (6). Uranium and lanthanum nitrates are exceptions. However, when these two reagents n.ere mixed, as described above, with solutions of morphine, codeine, heroin, novocaine, strychnine, brucine, pilocarpine, quinine, caffeine, dilaudid, dionine, peronine, stovaine, urotropine, and ethanolamine, no similar crystals were formed. Seven of the eight crystalline compounds observed were examined microscopic:ally. Photomicrographs of typical crystals are reproduced in Figures 1and 2. Some of these are undoubtedly sufficiently distinctive to be used for identification. Marme's reagent has been recommended by Schuldiner ( 4 ) and potassium ferrocyanide by Watson and Bowman (9) for this purpose. Table I1 shoas the lowest concentrations of methadon hydrochloride solutions from nhich crystals were obtained.
MICROCHE,MICAL REACTIONS
Table 1.
Concentration of Methadon HC1 1 : 1000 1 : 500
PREPARATION
OF METHADON HYDROCHLORIDE CRYSTALS FOR OPTICAL EXAMINATIONS
Methadon hydrochloride can be recrystallized from water, in n-hich it is much more soluble hot than cold. This fact is useful in the preparation of cryst'als for optical examination and identification. A saturated solution can be made by crushing fragmerits of methadon hydrochloride in a drop of distilled water on a microscope slide until many small pieces remain in excess; a few large fragments may be left to hold up the cover glass, which should be large enough to prevent the solution from bulging out around the edges. A seal of paraffin oil or other similar oil should be run around the edge of the cover glass to prevent evaporation of the solvent,. The sealed preparation can be warmed 595
596
ANALYTICAL CHEMISTRY A
U
C
8
n Figure 1. Photomicrographs of Typical Crystals (X80)
I .1
~siumiodide isium ferrooyanide isium lunowanida "...sium ferricyanide yanidc
cautiously over a microflame or hot plate to muse most of the small fragments to dissolve; the remilining fragments will grow slowly upon cooling the prepitration. The crystals which result will look like those in Figure 2,F. An uncovered drop of solntuion evaporates too rapidly, forming a vitreous film without satisfactory orystals. Larger quantities of crystals can be grown by cooling a warm saturated solution in a covered weighing bottle or similar container. It is important to have a few particles of methadon hydrochloride present as seed in order to obtain good crystallization. Rapid evaporation must be avoided. INDEX DETERMINATION
Single crystals grown as described above were immersed in various refractive-index liquids for determination of the refractive indexes ( 1 ) . It was necessary to mount crystals on a stage goniometer in order to measure the principal refractive indexes, because the peculiar shape of the crystals causes them to lie with their principal optical directions oblique to the anis of the microscope in most cases. All angles of Figure 3 were measured by means of the rotating stage. Diamond-shaped
concsntra*iooof Methadon HCI Saturstd aoll 1-200 1-50
Saturated sol, 1-50
1-50
crystals which are resting on an end face can be seen in Figures 2,F, and 3. Suoh crystals show symmetrical extinction, They give a n interference figure showing the obtuse biseotrix a t one edge of the field. From such crystals the refractive index, 8, can he obtained and also an index, a' (Figure 3), intermediate between CI and y . The acute angle of 62" is a reliable diagnostic charact.eristic. ,Crystals of the elongated type in Figure 2,F, show extinction within 1' or 2" of parallelism relative to the long edge. The maximum extinction angle found by measuring six different, crystals was 1.5"; the average was 0.75". The setting error was ahout 0.5". The refractive index, y, is obtainable for vibrations parallel to the long edge, RS can be seen by reference to Figure 3. The elongated crystals with the broad dark borders shown in Figure 2,P, give an interference figure intermediate between the optic normal and the acute bisectrix, rr-hereas the nearly corresponding drawing in Figure 3 is the optic normal view. The striated sides of the goniometer-mounted crystals caused by many narrow vicinal faces made accurate measurements of angles impossible; therefore, the angles shown on the optic
V O L U M E 22, NO. 4, A P R I L 1950 :~ ,
r,.;)., .
597
A
,
B
.
Figure 2. A. H.
,.~ I
.I.
._ .r
._
C
, .
.
~ . Y . ~ - ~. .~ ,
P h o t o m i c r o g r a p h s or Typical Crystal* Concentration Of Methadon HCI 1-200 (X104)
Reagent* Marme's reagent Meyer's reagent
I-low(X80)
wa.ne.'s
1-200 ( X80) 1-50 (X120)
C. Wagner's reagent D. E.
.
reagent Lanthenum nitrate
F. Mofhadon HCI aryaiallimd
s a t " r a t d ao1ution ( X M ) from solution
3:.._/ _. ..> ..
41.5. -*.
/-
&E*
I6.
7.1.634
L.1.571
eo
Figure 3. O r t h o g r a p h i c Projection for Typical Crystal of ~
M e t h a d o n IIydroehloride
~
normal and acute bisectrix views in Figure 3 are only approximate. The y vibration direat,ion was within 0.5" of parallelism with the. long base edge on the crystal measured, but the edge was imperfect; consequently, slight obliquity may be observed on other crystals, a s would be expected for a. monoclinic substance. Solutions of this preparation cannot beoptically active because the crystals are monoclinic a n d belong to Class 3 (Schaenflies, C . ) which h a s only a plane of symmetry. Polariscopic eramination of a 10% aqueous solution showed n o opticalmtation. Table 111 and Figure 3 summarize the optical and crystallographic data. Standard procedures for identifying crystalline compounds by the use of x-rays are applicable to methadon hydrochloride, Weissenberg x-ray diffraction photographs c o n h the Class 3 ~symmetry The e of this ~ substance. i ~ photographs show that ( h k 1 ) reflections occur only
ANALYTICAL CHEMISTRY
598 Table 111. Optical and Crystallographic Properties of Racemic >\lethadon Hydrochloride hlonoclinic, Class 3, only a plane Crystal system of symmetry; acute angle 0 = 740 p vibration direction is parallel to crystallographic axis b. Plane of
Optic orientation
symmetry contains axial plane. a direction is acute bisectrix which is nearly perpendicular to crystallographic axis c. Refrttctive indexes, 5593 A.; 250
c.
(Y
1.5713 * 0.0005, p = 1.6232 0.0005, y = 1.6360 * 0.0005, a = 1.5760 * 0.0005 from crystals resting on an end face =
*
Optic axial angle Observed Calcd. from sin V Observed
2E = 90’ + 1’ by calibrated micrometer eyepiece =
sin E 1.623
2” = 520
trum of the free Ixrse, methadon, in :tleohol or hexane is essentially the same in the region of the 294 nip band but is uniquely ultered a t w ~ v vlengths below 250 nip oiring to the appearance of a new strong absorption band; on the long wave-length wing of this band the phenyl 259 mp maximum has an apparently erihanerd v:iIu~of = 760 iii :rl(whol. c,,,,,~ = 880 in hrxnrir
‘lo0l _I
1000
900
800
u
2V = 52’ by rotating from one
optic axis to the other on goniometer
700
Calcd. from indexes. 2T’ = 520
c.
Negative (r < t ) distinct on both optic axes
Optical character Dispersion
+
when h k = 2%and ( h o 1 ) reflections only when h = 2n and 1 = 2n. From microscopic observations (Figure 3) it is evident, however, that the crystals do not possess a twofold axis of symmetry. The space group is therefore uniquely determined t o be C: - C,. An x-ray photograph of powdered racemic methadon hydrochloride has been taken in a General Electric XRD powder camera with nickel filtered CuK, ( A = 1.542 ‘4.) radiation. The sample was ground to a very fine powder in an agate mortar and then placed in a cellulose acetate capillary about 1 mm. in diameter. The capillary was rotated during exposure. The results obtained are recorded in Table IV.
Table IV.
X-Ray Powder Data of Kacemic Methadon Hydrochloride CuKa ( A = 1.542p
d, A.
Ib
12.33 8.27 7.46 6.45 5.91 5.65 5.38 3.04 .C . 7 0
ni s M vvs vs MS MW
vw vw MS
d, A. 4.55 4.33 4.13 4.00 3.86 3.70 3.48 3.32 3.19
Ib
d, A.
16
vvs
3.09 2.96 2.90 2.83 2.74 2.67 2.59 2.52
hls
S
Ji s >IS
LIS
niw JIs niw RI S
li
W nf w
RI ni
500
400 300
3bD 2$0 MILLIMICRONS
2O0’310
2AO
210
2k0
COURTESY L
Figure 4.
24)3
250 A
STRAIT
Ultraviolet .4bsorption Spectra of \lethadon 1. Methadon base in hexane 2. Methadon base in e t h j l alcohol 3. Methadon hydrochloride in ethyl alcohol
-4 10 mg. yosolution in a 1-cm. path length is adequate to reveal clearly the spectrum properties. ACKNOWLEDGMENT
T h e assistance given by G. E. Mallory of the Alcohol Tax Unit Laboratory in the study of the microchemical reactions is gratefully acknowledged.
w M
a Furnished by Merle Ballantyne, Western Regional Research LaboraWries. b Visually estimated intensities. S, strong: h l , medium: W , weak: V, very.
T h e ultraviolet absorption spectra (8) of methadon base and methadon hydrochloride can also serve for identification (Figure 4). Alcoholic solutions of the hydrochloride exhibit two characteristic electronic absorption bands at wave lengths and molecular extinctions as follows: Am,, = 294 mp, Emsx = 460; the phenyl band Am= = 259 mp, emax = 480. ( e = l/cd loglo I / I o . c = concentration in moles per liter. d = length of path in centimeters. loglo Ill0 = optical density.) T h e minimum between t h e two electronic bands occurs at h = 275 m p , emin = 300. I n water solutions, the long wave-length maximum shifts to 292 mp and the absorption rises, emax = 520. The absorption spec-
LITERATURE CITED
Chamot, E. M . , and Mason. C. W.,“Handbook of Chemical hlicroscopy,” 1‘01. 1, New York, John Wiley & Sons, 1938. Eddy, K.B., J . Am. Pharm. Assoc., Prac. Pharm. Ed., 8, 536-40 (1947). Office of Publication Board, Dept. Coninierce, Washington, D. C., “Pharmaceutical Activities of I . G. Farbeniridustrie P1ant:‘Hochst am Main,” Rept. 981 (July 1945). Schuldiner, J. A , ANAL.CHEM.,21, 295-300 (1949). Scott, C. C., and Chen, K. K., J . Pharmacol. Erptl. T h e r a p . , 87, 63-71 (1946). Stephenson, C. H., “hlicrochemical Tests for Alkaloids,” Philadelphia and London, J. B. Lippincott Co., 1921. Strait, L. A,, University of California Medical Center, Sari Francisco, Calif., private communication. Strait, L. 9., Kumler, W. D., et al., J . Optical SOC. Am., 38, 1098 (1948); abstracts, 115th Meeting, AMERICAX CHEMICAL SOCIETY,8K-10, Ran Francisco, March 1949. Watson, R. C., and Bowman, M. I., J . Ani. Pharm. A s s o c . . S c t . Ed., 38, 369-72 (1949). RECEIVED February 21, 1919
