Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-04
2001-07-17
Aulakh, Charanjit S. (Department: 1025)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S133000
Reexamination Certificate
active
06262067
ABSTRACT:
This invention is directed to certain polymorphs and forms of crystalline (2-Benshydryl-1-azo-bicyclo 2,2,2 oct-3yl)-(5isopropyl-2-methoxybenzyl)-amine dihydrochloride (hereafter the dihydrochloride salt) and their pharmaceutical compositions. The dihydrochloride salt is a CNS active NK-1 receptor antagonist and this invention is directed to methods of treating conditions effected or facilitated by a decrease in substance P mediated neuro-transmission. This invention is also directed to a substance P antagonist which is evaluated for acute and delayed anti-emetic efficacy in a mammal including humans receiving chemotherapy. Treating is defined here as preventing and treating.
U.S. Pat. No. 5,393,762 and U.S. Ser. No. 08/816,016 both incorporated by reference, describe pharmaceutical compositions and treatment of emesis using NK-1 receptor antagonists. The crystalline anhydrous dihydrochloride is hygroscopic at humidities of about 52% or greater and forms dihydrates. The dihydrates do not readily dehydrate when exposed to low relative humidity of about 33% or less.
SUMMARY OF THE INVENTION
The present invention relates to the anhydrous dihydrochloride of (2-Benzhydryl-1-azo-bicyclo 2,2,2oct-3-yl)-(5-isoproyl-2-methoxybenzyl)-amine, the dihydrochloride dihydrate and its two polymorphs.
In one embodiment of the invention, the anhydrous dihydrochloride is a crystalline hygroscopic single form. The morphology of the anhydrous dihydrochloride is rods with particle size of about 5 to 30 &mgr;m yielding birefringence. A differential scanning calorimetry (DSC) thermogram gave a sharp endotherm with an onset at 224° C., Tmax at 236° C. and a &Dgr;Hf of 32.8 cal/gram.
In two other embodiments, the dihydrochloride dihydrate is in Form I or Form II. Form I is characterized by the X-ray diffraction pattern below:
Dihydrochloride Dihydrate Form I
Peak No.
1
2
3
4
5
6
7
8
d space
17.2
9.5
8.4
6.9
4.9
4.4
3.9
3.5
Form I of the dihydrochloride dihydrate is a nonhydroscopic single form and discloses a Differential Scanning Calorimetry thermogram with onsets at about 150° C. and 230° C. Form I has a solubility of about 110 to 120 milligrams per milliliter. The crystalline habit of Form I is flakes with a size range of about 30 &mgr;m to 60 &mgr;m.
Form II is characterized by the X-ray diffraction pattern below:
Dihydrochloride Dihydrate Form II
Peak No.
1
2
3
4
5
6
7
8
9
d space
11.3
8.8
7.5
6.4
4.9
4.5
3.8
3.7
3.0
Form II is a lower energy, more stable form than Form I. Form It has a solubility of about 390-400 milligrams per milliliter. Form II's crystalline habit is flakes of about 15 to 25 &mgr;m.
The method of making the polymorphic Form I of the dihydrochloride dihydrate comprises stirring at ambient temperature the anhydrous dihydrochloride in an organic solvent containing about 0.5 to 2.5% water for about 15 to 25 hours to effect crystallization. The organic solvents are selected from ethyl or isopropyl alcohol, ethyl acetate, acetonitrile, tetrahydrofuran and acetone all containing about 0.5% to 2.5% water.
The method of making the polymorphic Form II of the dihydrochloride dihydrate comprises stirring Form I or the anhydrous dihydrochloride at ambient temperature in an organic solvent containing about 3 to 5% water for about 15 to 25 hours to effect crystallization. The solvents are chosen from ethyl acetate with about 5% water, tetrahydrofuran with about 5% water, acetone with about 5% water and acetonitrile with about 5% water.
Another aspect of the invention relates to a pharmaceutical composition having pharmaceutical activity which comprises at least one of polymorphic Forms I and II of the dihydrochloride dihydrate and the anhydrous dihydrochloride in the treatment of emesis. A method of treating emesis comprises administering to a subject in need of treatment, an antiemetic effective amount of Form I or II or the anhydrous dichloride.
DETAILED DESCRIPTION OF THE INVENTION
Polymorphic Form I of the dihydrochloride dihydrate may be formed by stirring the anhydrous form of the compound in an appropriate organic solvent containing 0.5% to 2.5% water for a suitable time to effect the crystallizaton. Appropriate solvents may include the following: ethyl or isopropyl alcohol, ethyl acetate, acetonitrile, tetrahydrofuran, and acetone, all containing between 0.5% to 2.5.% water.
Polymorphic Form II may be formed by stirring either Form I or the anhydrous form of the dihydrochloride in an appropriate organic solvent containing 3% to 5% water for a suitable time to effect the crystallization. Appropriate solvents may include the following; Ethyl acetate containing 3.5% water, tetrahydrofuran (THF) containing 5% water, acetone containing 5% water and water.
The “wet” THF bridge resulted in complete conversion to Form II. When Form I is slurried in THF with less than 2% H
2
O there is no conversion to Form II. When Form I is slurried in THF with about 3% to 5% H
2
O, the conversion is to Form II. When Form I is slurried in THF with >5% H
2
O, solubility increases dramatically due to the high aqueous solubility.
Table I below shows an ambient polymorph screen with wet solvents:
Table I
Polymorph
Starting
Isolation
Isolation
Isolated
Form
Solvent
Temperature
Method
Form I
Form I
IPO/5% H
2
O
ambient
Slurry
Form II
Form I
Ethyl Acetate/3.5%
ambient
Slurry
H
2
O
Form I
Form I
Acetonitrile/5%
ambient
Slurry
H
2
O
Form II
Form I
Tetrahydrofuran/5%
ambient
Slurry
H
2
O
Form II
Form I
Acetone/5% H
2
O
ambient
Slurry
Form II
Form I
H
2
O
ambient
solutions
seeded
with Form II
Table II below gives a polymorph characterization of Form I and Form II:
TABLE II
Assay
Form I
Form II
Combination Analysis
dihydrochloride,
dihydrochloride,
dihydrate
dihydrate
Karl Fisher
7.08%
7.10%
Powder X-ray
Form I
Form II
Fusion Microscopy
Slow water loss
Sharp water loss
(50° C.-75° C.)
~100° C.
VTI (% H
2
O absorbed)
0.8% wt.
0.4% wt.
Aqueous Intrinsic
>648 mg/ml.
<329 mg. ml
Solubility
Aqueous Equilibrium
>1155 mg/ml.
395 mg/ml.
Crystal Habit
flake, ~30 × 60 &mgr;m
flake, ~15 × 25 &mgr;m
TGA/DTA
Water loss 30° C.-
Water loss 30° C.-
110° C., two events
100° C. with
prior to degradation @
apparent
194° C.
degradation @
178° C.
Differential Scanning
Event @ ~175° C.
Hydrates Off @
Calorimetry (DSC)
then degradation @
~130° C. and
~230° C.
~155° C., possible
Water loss is
re-cryst @ ~170° C.,
undetected,
possible anhydrous
melt @ 240° C., then
degradation
REFERENCES:
patent: 5939433 (1999-08-01), Ito et al.
Hesketh, P.J. et al.: Randomized phase II study of the Neurokinin 1 receptor antagonist CJ-11,974 in the control of Cisplatin-induced emesis. J. Clin. Oncol. vol. 17, pp. 338-343, Jan. 1999.*
Biles, J.A.: Crystallography. Part II. J. Pharm. Sci. vol. 51, pp. 601-617, Jul. 1962.
Allen Douglas J. M.
Appleton Troy Anthony
Gumkowski Michael Jon
Muehlbauer David Joseph
Norris Timothy
Appleman Jolene W.
Aulakh Charanjit S.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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