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Novel polymorphs of azabicyclohexane

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Title: Novel polymorphs of azabicyclohexane.
Abstract: The invention provides polymorphic crystalline forms of acid addition salts of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane designated as polymorph form A, polymorph form B and polymorph form C, where polymorph form A is more thermodynamically stable than the other forms, methods for preparing and using such polymorph forms and pharmaceutical compositions containing such polymorph forms. ...


USPTO Applicaton #: #20090326245 - Class: 548515 (USPTO) - 12/31/09 - Class 548 
Organic Compounds -- Part Of The Class 532-570 Series > Azo Compounds Containing Formaldehyde Reaction Product As The Coupling Component >Carbohydrates Or Derivatives >Hetero Ring Is Five-membered Consisting Of One Nitrogen And Four Carbons (e.g., Halopyrrolidines, Etc.) >Polycyclo Ring System Having The Five-membered Hetero Ring As One Of The Cyclos >Bicyclo Ring System Having The Five-membered Hetero Ring As One Of The Cyclos (e.g., Octahydroindoles, Etc.) >The Ring Nitrogen Is Bonded Directly To Two Ring Carbons Of The Same Cyclo Which Carbons Are Members Of One Cyclo Only (e.g., Cyclopenta(c)pyrroles, Etc.)

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The Patent Description & Claims data below is from USPTO Patent Application 20090326245, Novel polymorphs of azabicyclohexane.

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This application claims priority to U.S. patent application Ser. No. 10/920,748, filed Aug. 18, 2004, which is converted to a provisional application.

Salts of the (−) isomer of phenyl azabicyclohexane having the formula

are known for use in treating depression. As set forth in Lippa et al., U.S. Pat. No. 6,372,919, the compound of formula I whose chemical name is (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in its (+) isomeric form has been found to have potent anti-depressive activity.

While the azabicyclohexanes of formula I have been prepared as described in various U.S. patents such as U.S. Pat. Nos. 4,231,935, 4,131,611, 4,435,419, 4,118,417 and 4,196,120, these compounds were prepared in racemic form. In the procedure of Lippa et al., U.S. Pat. No. 6,372,919, the (+) optical antipode was produced as a mixture of various isomeric polymorphic forms which heretofore have been unrecognized. A pure crystalline form of the (+) isomer of the compound of formula I is of particular importance since it could be formulated into various pharmaceutical dosage forms such as for example tablets or capsules for treatment of patients. Variations in crystal structure of a pharmaceutical drug substance are known to affect the dissolution, manufacture, stability and bioavailability of a pharmaceutical drug product, particularly in solid oral dosage forms. Therefore it is important to produce the (+) isomer of the compound of formula I in a pure form comprising a single thermodynamically stable crystal structure.

SUMMARY

OF INVENTION

In accordance with this invention, it has been discovered that the (+) optical antipode of the compound of formula I as prepared in Lippa et al., U.S. Pat. No. 6,372,919 exists as a mixture of two crystalline polymorphic structures, one being the hemi-hydrate form, which is designated as polymorph form A, and the other being the anhydrous form, which is designated as polymorph form B. A dehydrated form designated as polymorph form C has also been found. When the (+) optical antipode of the compound of formula I is produced by prior art procedures, it has been found that it was produced as a mixture of polymorph form A and polymorph form B which do not readily separate into their pure polymorphic crystalline forms.

In accordance with this invention, a method of forming these polymorphs as pure independent polymorph forms has been discovered. In addition we have found that the polymorph form A of the (+) optical antipode of the compound of formula I in its pure crystalline structure produced in accordance with this invention is a thermodynamically stable polymorph form. Therefore, form A is the preferred crystalline form of the (+) optical antipode of the acid addition salt of the compound of formula I for formulation into pharmaceutical drug products.

DETAILED DESCRIPTION

OF THE INVENTION

In accordance with this invention, it has been discovered that the (+) optical antipode of acid addition salts of the compound of formula I exists in three different crystalline polymorphic forms designated as polymorph form A, polymorph form B and polymorph form C and that polymorph form A, which is the hemi-hydrate form, is a thermodynamically stable form.

Polymorph form A may be characterized as the hemi-hydrate of acid addition salts of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. It is the hemi-hydrate crystalline form, which uniquely characterizes polymorph form A from polymorph form B and polymorph form C of acid addition salts of the compound of formula I. Polymorph form B and polymorph form C of acid addition salts of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane do not exist as hemi-hydrates.

The polymorphs of acid addition salts of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane may also be characterized by their X-ray powder diffraction patterns (XRPD) and/or their Raman spectroscopy peaks. With respect to X-ray powder diffraction, the relative intensities of the X-ray powder diffraction peaks of a given polymorph may vary depending upon the crystal size of the polymorph used to determine the pattern. This is a phenomenon of preferred orientation. Preferred orientation is caused by the morphology of crystals. In this case, the XRPD analysis should be carried out with the sample spinning in the sample holder during XRPD analysis to reduce the preferred orientation effects. Samples for XPRD analysis for determination of the presence and nature of their polymorph status in accordance with this invention should be lightly ground and/or sieved to a crystal size of from about 10 to 40 microns for XPRD analysis.

A Bragg-Brentano instrument, which includes the Shimadzu system, used for the X-ray powder diffraction pattern measurements reported herein, gives a systematic peak shift (all peaks can be shifted at a given “°2θ” angle) which result from sample preparation errors as described in Chen et al.; J Pharmaceutical and Biomedical Analysis, 2001; 26, 63. Therefore, any “°2θ” angle reading of a peak value is subject to an error of about (±) 0.2°.

The X-ray powder diffraction pattern (XRPD) analyses of polymorph forms A, B and C were performed with a Shimadzu XRD-6000 X-ray powder diffractometer using Cu Ka radiation. In this procedure the compound as a hydrochloride salt was loaded onto the machine as a crystalline powder. The instrument was equipped with a long fine focus X-ray tube. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A theta-two theta continuous scan at 3°/min (0.4 sec/0.02° step) from 2.5 to 40° 20 was used. A silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6000 v. 4.1.

The following Table 1 shows the peaks of the X-ray powder diffraction pattern of purified polymorph form A of the hydrochloride salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystal size of from about 10 to 40 microns. This pattern is given in terms of the “°2θ” angles of the peaks subject to the angle error set forth above. With respect to the percent value of relative intensity (I/lo) given in Table 1, Io represents the value of the maximum peak determined by XRPD for the sample for all “°2θ” angles and I represents the value for the intensity of a peak measured at a given “°2θ” angle”. The angle “°2θ” is a diffraction angle which is the angle between the incident X-rays and the diffracted X-rays. The values for the relative intensities for a given peak set forth in percent and the “°2θ” angles where said peaks occur are given in Table 1 below.

TABLE 1 XRPD Peaks (°2θ) and Relative Intensities (I/lo) for Polymorph Form A Form A °2θ I/lo

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stats Patent Info
Application #
US 20090326245 A1
Publish Date
12/31/2009
Document #
12428399
File Date
04/22/2009
USPTO Class
548515
Other USPTO Classes
International Class
07D209/52
Drawings
0


Crystal
Paring
Pharmaceutical Compositions
Polymorphic
Thermodynamic


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