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A Note on the Crystallography of l-Isomethadone Hydrochloride Hydrate
September 193.3
SCIENTIFIC EDITION
their glycosides having hydroxy groups in positions 2, 3, 6, or 7. The aloe-like action results in larger, shinier, more pasty stools which will adhere t o the filter paper but will not produce distinct stains. Because of this fact, it is difficult in low concentrations to differentiate between the stools obtained from normal as against those obtained from treated animals. Anthraquinone derivative aglycones such as aloe emodin, frangula emodin. alizarin and hydroxychrysazin, as well as preparations of cascara, frangula, and rhubarb, produce a n aloe-like laxative action in mice. It can be seen from the data reported in Table I, that standard senna powder is 50% active in doses of 6.25 mg. whereas powdered extract of aloe must be given in doses of 23 mg. t o produce the same activity. I t is further seen, that aloin in doses of 20 mg. produces laxation in only 40% of the mice treated. The aglycones such as chrysazin, rhein, chrysophanic acid, aloe emodin, and frangula emodin, are either inactive or only slightly active under the same conditions. The glycosides prepared from the aglycones mentioned above show increased activity over the corresponding aglycones when given in water. When suspended in sodium carbonate solution, these glycosides show a marked increase in activity due probably to increased solubility and uniformity of dosage. The use of the magnesium hydroxide-potassium hydroxide dosing solution had no effect on the activity of the aglycones such as chrysazin, rhein, or chrysophanic acid over that produced when these compounds were administered in water. This was not the case with the glycosides, however. It can be seen from Table I, that potassium chrysazin glucoside given in doses of 2.56 mg. in aqueous solution gave a positive response of 75%. The Same effect, however, was produced by only 0.064 mg. of this glucosidal salt when administered in the magnesium hydroxide-potassium hydroxide solution showing that this solution produced a definite increase in activity. Similarly, potassium rhein glucoside in doses of 0.070 mg. is inactive when administered in aqueous solution but produces 60% positive responses in the magnesium hydroxidepotassium hydroxide medium.
6.53
Potassium chrysophanic acid anthranol-9-glucoside was also prepared and tested since it has been suggested that the active constituents of aloe as well as those of senna might be anthranol glycosidcs. I t is seen that this compound is moderately active iii the magnesium hydro-cide-potassium hydroxide dosing solution. The effect of changing the potassium hydroxide as well as the magnesium hydroxide concentrations are shown in Table 11. Here it is seen that the optimum concen;ration for potassium hydroxide is of the order of 23.30 X moles per dose of 0.128 mg. (1.45 X moles) of potassium chrysazin glucoside. The optimum concentration for magnesium hydroxide under the same conditions is 14.20 X 10-7moles. Substituting an equal amount of calcium hydroside or aluminum hydroxide for magnesium hydroside resulted in a decrease in the activity of potassium chrysazin glucoside. These data are presented in Table 111.
REFERENCES
'HIS
11, (8) Fairbairn. J . W., J . Pharm. and Pharinacol., 1, 683(1949) (9) Faubairn, J. W., and Lou, T. C., ibid., 3,93(1951). (10) Stoll. A., Becker, B.. and Kassmaul, W . . Hrlu. Chirrt. Acla.. 32, 1892(1949). (11) Stoll. A., Becker. B . . and Helfenstein. A , , ibid., 33, 313(1950). (12) McDonnell, T.F., and Gardner, J . H . , J . Arrr. Chrm. Soc., 56, 1246(1934). (13) Gardner, J. H., McDonnell, T. F.. and Wiegand. C . J . W . . i b i d . . 5 7 , 1071(1935). (14) Gardner, J. H., and Demaree. W . H . , ibid., 58, 75711986l .-..~ ._., (15) Foster H. and Gardner J. H. ibid. 58 597(1936). (16) GardnLr, H., and McDonkell. %. 'F., ibid.. 59, S57( 1937). (17) Ferguson. N. M., and Gardner. J . H.. ibid.. 7 2 , 2877(1960). (18) Takahashi, R . , J . Pharm. SOC.Japatr., 525,968(1925). (19) See references 17 and 18. (20) Hazelton, I,. W., Talbert. K. D., THISJOURNAL, 33. 170( 1944). (21) Lou, T.C . , J . Pharnz. and Pharmacol.. 1, 673(1949).
.
i.
A Note on the Crystallography of I-Isomethadone Hydrochloride Hydrate* By
HARRY A. ROSE and ANN V A N CAMP
I-ISOMETHADONE is referred to in the literature as a narcotic and analgetic (1). Data are presented here which permit the identification of this compound by crystallographic methods. The structural formula of I-isomethadone hydrochloride hydrate is as follows:
* Received April 14, 1956, from the Lilly Research Labora-
tories. Eli Lilly and Co., Indianapolis 6. Ind.
0
a\
/ C! I C H I C H ~ CHa
a/c\HcHt,
I
CH3
.x
i . H?o
664
JOURNAL OF THE
AMERICAN PHARMACEUTICAL ASSOCIATION
TABLEI.-X-KAY DIFFRACTION DATAFOR ~-XSOMETHADONE HYDROCHLORIDE HYDRATE -
a. = 13.05A, b. = 13.3CIA, Ynit cell dimensions co = 11.754 4 Formula weights per cell Formula weight 363.92 1.193Gm./cc. (flotation), 1.187 Gm./cc. Density (X-ray) 0:6:c = 0.9812: 1:0.8835 -\xial ratio P22121 Space group
TABLEII.-oPTICAL CRYSTALLOGRAPHIC DATAFOR l-ISOMETHADONEHYDROCHLORIDE HYDRATE ~~
Refractive Indexes (5893 A , 25’). a = 1.590, j3 = 1.602. y = 1.638 Optic axial angle (+) 2V = 59’2’ (calcd. from a,B and Y) Optic axial plane 001 . Acute bisectrix y = b
TABLE111.---X KAY POWDERDIFFRACTION DATA FOR I-ISOMETHADONE HYDROCHLORIDE HYDRATE -~~ d
13.38 9.40 8.58 7.30 6.65 5.84 5.32 4.97 4.66 4.34 4.16 3.91 3.64 3.51 3.35 3.22 3.09 3.00 2.86 2.80 2.66 2.60 2.49 2.40 2.35 2.28 2.17 2.07 1.959 1.877 1,769
I/II
0.08 0.16 0.08 1.oo 0.20 1.oo 0.60 0.04 0.08 0.40 0.40 0.12 0.40 0.12 0.32 0.08 0.20 0.08 0.16 0.04 0.08 0.08 0.04 0.08 0.08 0.08 0.04 0.04 0.08 0.04 0.04
d (calcd.)
h k l
100 110 101 111 020 002,210 102 112 220 202,300,221 212.310 3i 1 222,320,113 302 312,023,040 140 141,330,322 331 313 114 323 ~~
500
.. ..
13.05 9.32 8.73 7.30 6.65 5.87, 5.86 5.36 4.97 4.66 4.36,4.35,4.33 4.15, 4.13 3.90 3.65,3.64,3.61 3.50 3.38,3.37,3.33 3.22 . 3.11,3.11,3.09 3.00 2.84 2.80 2.67 2.61
..
..
..
.. ..
EXPERIMENTAL
The crystals are orthorhombic prisms elongated parallel to the c axis and lying on the 100 face.
Vol. XLV, No. 9
The X-ray powder diffraction data were obtained using copper radiation and nickel filter with a camera 114.6 mm. in diameter. A wave-length value of 1.54054 was used in the calculations. The indexing of the powder pattern was done on the basis of single crystal rotation patterns around both the h and c axes.
TABLEIV.-X-RAY POWDER DIFFRACTION DATA FOR ANHYDROUSI-ISOMETHADONE HYDROCHLORIDE ~
-
~
_
_
d
l/Il
9.20 7.96 . 7. I8 6.53 5.84 5.00 4.73 4.43 4.28 3.87 3.60 3.47 3.35 3.23 3.17 3.00 2.85 2.68 2.62 2.48 2.24 2.20 2.16 2.08
0.03
_
-
0.53
1.00 0.67 0.13 1.00 0.53 0.07 0.07
0.H 0.03 0.20 0.20 0.20 0.20 0.33 0.03 0.07 0.03 0.03 0.07 0.07 0.07 0.07
The space group determination as P22121 is uniquely determined by Weissenberg photographs in combination with the rotation photographs. These patterns show no systematic absences for (h k I) reflections or (h o o) reflections and that (o k o ) is present only with k = 2n and ( 0 o 1 ) is present only with 1 = 2n. The compound does show a positive piezoelectric effect. On heating, l-isomethadone hydrochloride hydrate starts melting a t 137”. However, as the temperature rises new crystals which have been identified as the anhydrous material, appear in the melt and the final melting point is 229-232’. The melt does not crystallize on cooling. The sample of anhydrous crystals used for the Dowder diffraction Dattern was obtained by heating the hydrate to d&e off the-water. REPERENCE (1) “Merck Index.” 6th ed.. M u c k and Co.. Rahway, N. J . , 1952, p. 544
SCIENTIFIC EDITION
their glycosides having hydroxy groups in positions 2, 3, 6, or 7. The aloe-like action results in larger, shinier, more pasty stools which will adhere t o the filter paper but will not produce distinct stains. Because of this fact, it is difficult in low concentrations to differentiate between the stools obtained from normal as against those obtained from treated animals. Anthraquinone derivative aglycones such as aloe emodin, frangula emodin. alizarin and hydroxychrysazin, as well as preparations of cascara, frangula, and rhubarb, produce a n aloe-like laxative action in mice. It can be seen from the data reported in Table I, that standard senna powder is 50% active in doses of 6.25 mg. whereas powdered extract of aloe must be given in doses of 23 mg. t o produce the same activity. I t is further seen, that aloin in doses of 20 mg. produces laxation in only 40% of the mice treated. The aglycones such as chrysazin, rhein, chrysophanic acid, aloe emodin, and frangula emodin, are either inactive or only slightly active under the same conditions. The glycosides prepared from the aglycones mentioned above show increased activity over the corresponding aglycones when given in water. When suspended in sodium carbonate solution, these glycosides show a marked increase in activity due probably to increased solubility and uniformity of dosage. The use of the magnesium hydroxide-potassium hydroxide dosing solution had no effect on the activity of the aglycones such as chrysazin, rhein, or chrysophanic acid over that produced when these compounds were administered in water. This was not the case with the glycosides, however. It can be seen from Table I, that potassium chrysazin glucoside given in doses of 2.56 mg. in aqueous solution gave a positive response of 75%. The Same effect, however, was produced by only 0.064 mg. of this glucosidal salt when administered in the magnesium hydroxide-potassium hydroxide solution showing that this solution produced a definite increase in activity. Similarly, potassium rhein glucoside in doses of 0.070 mg. is inactive when administered in aqueous solution but produces 60% positive responses in the magnesium hydroxidepotassium hydroxide medium.
6.53
Potassium chrysophanic acid anthranol-9-glucoside was also prepared and tested since it has been suggested that the active constituents of aloe as well as those of senna might be anthranol glycosidcs. I t is seen that this compound is moderately active iii the magnesium hydro-cide-potassium hydroxide dosing solution. The effect of changing the potassium hydroxide as well as the magnesium hydroxide concentrations are shown in Table 11. Here it is seen that the optimum concen;ration for potassium hydroxide is of the order of 23.30 X moles per dose of 0.128 mg. (1.45 X moles) of potassium chrysazin glucoside. The optimum concentration for magnesium hydroxide under the same conditions is 14.20 X 10-7moles. Substituting an equal amount of calcium hydroside or aluminum hydroxide for magnesium hydroside resulted in a decrease in the activity of potassium chrysazin glucoside. These data are presented in Table 111.
REFERENCES
'HIS
11, (8) Fairbairn. J . W., J . Pharm. and Pharinacol., 1, 683(1949) (9) Faubairn, J. W., and Lou, T. C., ibid., 3,93(1951). (10) Stoll. A., Becker, B.. and Kassmaul, W . . Hrlu. Chirrt. Acla.. 32, 1892(1949). (11) Stoll. A., Becker. B . . and Helfenstein. A , , ibid., 33, 313(1950). (12) McDonnell, T.F., and Gardner, J . H . , J . Arrr. Chrm. Soc., 56, 1246(1934). (13) Gardner, J. H., McDonnell, T. F.. and Wiegand. C . J . W . . i b i d . . 5 7 , 1071(1935). (14) Gardner, J. H., and Demaree. W . H . , ibid., 58, 75711986l .-..~ ._., (15) Foster H. and Gardner J. H. ibid. 58 597(1936). (16) GardnLr, H., and McDonkell. %. 'F., ibid.. 59, S57( 1937). (17) Ferguson. N. M., and Gardner. J . H.. ibid.. 7 2 , 2877(1960). (18) Takahashi, R . , J . Pharm. SOC.Japatr., 525,968(1925). (19) See references 17 and 18. (20) Hazelton, I,. W., Talbert. K. D., THISJOURNAL, 33. 170( 1944). (21) Lou, T.C . , J . Pharnz. and Pharmacol.. 1, 673(1949).
.
i.
A Note on the Crystallography of I-Isomethadone Hydrochloride Hydrate* By
HARRY A. ROSE and ANN V A N CAMP
I-ISOMETHADONE is referred to in the literature as a narcotic and analgetic (1). Data are presented here which permit the identification of this compound by crystallographic methods. The structural formula of I-isomethadone hydrochloride hydrate is as follows:
* Received April 14, 1956, from the Lilly Research Labora-
tories. Eli Lilly and Co., Indianapolis 6. Ind.
0
a\
/ C! I C H I C H ~ CHa
a/c\HcHt,
I
CH3
.x
i . H?o
664
JOURNAL OF THE
AMERICAN PHARMACEUTICAL ASSOCIATION
TABLEI.-X-KAY DIFFRACTION DATAFOR ~-XSOMETHADONE HYDROCHLORIDE HYDRATE -
a. = 13.05A, b. = 13.3CIA, Ynit cell dimensions co = 11.754 4 Formula weights per cell Formula weight 363.92 1.193Gm./cc. (flotation), 1.187 Gm./cc. Density (X-ray) 0:6:c = 0.9812: 1:0.8835 -\xial ratio P22121 Space group
TABLEII.-oPTICAL CRYSTALLOGRAPHIC DATAFOR l-ISOMETHADONEHYDROCHLORIDE HYDRATE ~~
Refractive Indexes (5893 A , 25’). a = 1.590, j3 = 1.602. y = 1.638 Optic axial angle (+) 2V = 59’2’ (calcd. from a,B and Y) Optic axial plane 001 . Acute bisectrix y = b
TABLE111.---X KAY POWDERDIFFRACTION DATA FOR I-ISOMETHADONE HYDROCHLORIDE HYDRATE -~~ d
13.38 9.40 8.58 7.30 6.65 5.84 5.32 4.97 4.66 4.34 4.16 3.91 3.64 3.51 3.35 3.22 3.09 3.00 2.86 2.80 2.66 2.60 2.49 2.40 2.35 2.28 2.17 2.07 1.959 1.877 1,769
I/II
0.08 0.16 0.08 1.oo 0.20 1.oo 0.60 0.04 0.08 0.40 0.40 0.12 0.40 0.12 0.32 0.08 0.20 0.08 0.16 0.04 0.08 0.08 0.04 0.08 0.08 0.08 0.04 0.04 0.08 0.04 0.04
d (calcd.)
h k l
100 110 101 111 020 002,210 102 112 220 202,300,221 212.310 3i 1 222,320,113 302 312,023,040 140 141,330,322 331 313 114 323 ~~
500
.. ..
13.05 9.32 8.73 7.30 6.65 5.87, 5.86 5.36 4.97 4.66 4.36,4.35,4.33 4.15, 4.13 3.90 3.65,3.64,3.61 3.50 3.38,3.37,3.33 3.22 . 3.11,3.11,3.09 3.00 2.84 2.80 2.67 2.61
..
..
..
.. ..
EXPERIMENTAL
The crystals are orthorhombic prisms elongated parallel to the c axis and lying on the 100 face.
Vol. XLV, No. 9
The X-ray powder diffraction data were obtained using copper radiation and nickel filter with a camera 114.6 mm. in diameter. A wave-length value of 1.54054 was used in the calculations. The indexing of the powder pattern was done on the basis of single crystal rotation patterns around both the h and c axes.
TABLEIV.-X-RAY POWDER DIFFRACTION DATA FOR ANHYDROUSI-ISOMETHADONE HYDROCHLORIDE ~
-
~
_
_
d
l/Il
9.20 7.96 . 7. I8 6.53 5.84 5.00 4.73 4.43 4.28 3.87 3.60 3.47 3.35 3.23 3.17 3.00 2.85 2.68 2.62 2.48 2.24 2.20 2.16 2.08
0.03
_
-
0.53
1.00 0.67 0.13 1.00 0.53 0.07 0.07
0.H 0.03 0.20 0.20 0.20 0.20 0.33 0.03 0.07 0.03 0.03 0.07 0.07 0.07 0.07
The space group determination as P22121 is uniquely determined by Weissenberg photographs in combination with the rotation photographs. These patterns show no systematic absences for (h k I) reflections or (h o o) reflections and that (o k o ) is present only with k = 2n and ( 0 o 1 ) is present only with 1 = 2n. The compound does show a positive piezoelectric effect. On heating, l-isomethadone hydrochloride hydrate starts melting a t 137”. However, as the temperature rises new crystals which have been identified as the anhydrous material, appear in the melt and the final melting point is 229-232’. The melt does not crystallize on cooling. The sample of anhydrous crystals used for the Dowder diffraction Dattern was obtained by heating the hydrate to d&e off the-water. REPERENCE (1) “Merck Index.” 6th ed.. M u c k and Co.. Rahway, N. J . , 1952, p. 544