FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention – An improved process for the preparation of amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino [4,5-c] pyrrole compound of formula I (asenapine maleate)
2. Applicant(s)
(a) NAME : ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which is to be
performed:

FIELD OF THE INVENTION
The invention relates to an improved process for the preparation of amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate)

BACKGROUND OF THE INVENTION
Asenapine is a compound for use in the treatment of central nervous system disorders, in particular schizophrenia. The chemical name of asenapine is trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole and the preparation thereof is disclosed in USP No. 4,145,434 and is represented by structure of formula II.

The pharmacological profile of asenapine, its kinetics and metabolism, and the first safety and efficacy studies in human volunteers are reviewed in De Boer et al., Drugs of the Future, 18(12):1117-1123 (1993). Asenapine is a broad-spectrum, high potency serotonin, noradrenaline and dopamine antagonist. As described in published patent application WO 99/32108, asenapine exhibits potential antipsychotic activity and may be useful for treating depression.

The maleate salt of asenapine is currently undergoing clinical evaluation. As described in Funke et al., Arzneim.-Forsch./Drug Res., 40:536-539 (1999), the earliest known form of asenapine maleate (Form H) is a monoclinic crystalline form having a melting point in the range of 141° C. to 145° C. Patent application PCT/EP2006/061480 describes the discovery of a new form of asenapine maleate (Form L), which is an orthorhombic crystalline form having a melting point in the range of 138° C to 142° C.
US patent application Pub. No. 20080090892A1 discloses asenapine and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein the compound is at least 50% amorphous based on total weight of the compound.
Amorphous asenapine may be used to treat CNS disorders, including schizophrenia and other psychotic disorders, mood disorders, and combinations thereof. The standards for diagnosis of these disorders may be found in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (4th ed., 2000), which is commonly referred to as the DSM Manual.
Amorphous asenapine may be prepared from crystalline asenapine (or suitable precursor) by spray drying, spray coating, lyophilization, and other methods. Spray drying and spray coating both involve dissolving asenapine in a compatible solvent, atomizing the resulting solution, and evaporating the solvent to form drug substance comprised of amorphous asenapine. Lyophilization or freeze drying also involves dissolving asenapine in a compatible solvent (usually water), and includes rapidly freezing the solution to form amorphous asenapine and removing the solvent via sublimation (typically under vacuum) and desorption. For more detailed description of lyophilization, see Georg-Wilhelm Oetjen, “Freeze-Drying,” Ullmann's Encyclopedia of Industrial Chemistry (2004).
The discovery of stable polymorphic form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product.
The present invention provides an amorphous form of asenapine maleate, which through the use of a special crystallization technique, can be prepared in a highly pure form.

Object of the invention
Therefore, it is an object of the invention to provide an improved process for the preparation of amorphous form of asenapine maleate and process for preparation thereof.
In another object of the present invention provides a process for the preparation of the amorphous form of asenapine maleate. The process comprises
a) Reacting trans-5-chloro-2-methyl-2,3,3a,12b- tetrahydro-1H- dibenz[2,3:6,7] oxepino[4,5-c] pyrrole maleate compound of formula II (asenapine) and maleic acid in isopropyl alcohol at 60°C to 65°C.
b) Stirred the reaction mixture for about 1 hr to 2 hr at room temperature and then for overnight at -15°C to 10°C.
c) Isolating the trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c] pyrrole maleate compound of formula I (asenapine maleate)
d) Dissolving trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate) in dichloromethane and sirred for 10 min. at room temperature.
e) Filtered off any undissolved solid and filtrate was concentrated on rota evaporator to dryness yielded amorphous form of asenapine maleate.
In another object of the invention provides a process for the preparation of the amorphous form of asenapine maleate. The process comprises
a) Dissolved trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole compound of formula I (asenapine maleate) in dichloromethane and sirred for 10 min. at room temperature.
b) Filtered off any undissolved solid and filtrate was concentrated on rota evaporator to dryness yielded amorphous form of asenapine maleate.

In a another object of the present invention relates to the amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole compound of formula I (asenapine maleate) is characterised by XRD.
Summary of the invention
This invention provides amorphous asenapine and pharmaceutically acceptable salts, which may be used to treat a variety of CNS disorders or conditions, including schizophrenia and other psychotic disorders, mood disorders, and combinations of these disorders or conditions.
The one aspect of the present invention relates to the amorphous form of trans-5-chloro-
2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate
compound of formula I (asenapine maleate).
In another aspect of the present invention provides a process for the preparation of the amorphous form of asenapine maleate. The process comprises
a) Reacting trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c]pyrrole compound of formula II (asenapine) and maleic acid in isopropyl alcohol at 60°C to 65°C.
b) Stirred the reaction mixture for about 1 hr to 2 hr at room temperature and then for overnight at -15°C to 10°C.
c) Isolating the trans-5-chloro-2-methyl- 2,3,3a,12b- tetrahydro-1H- dibenz [2,3:6,7] oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate)
d) Dissolving trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz [2,3:6,7] oxepino [4,5-c] pyrrole maleate compound of formula I (asenapine maleate) in dichloromethane and sirred for 10 min. at room temperature.
e) Filtered and concentrated to dryness yielded amorphous form of asenapine maleate.
In another aspect of the invention provides a process for the preparation of the amorphous form of asenapine maleate. The process comprises

1. Dissolved trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7] oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate) in dichloromethane and stirred for 10 min. at room temperature.
2. Filtered and concentrated to dryness yielded amorphous form of asenapine maleate.
In a another aspect of the present invention relates to the amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate) is characterised by XRD.
Brief description of the drawing
Fig. 1 shows the X-ray powder diffraction pattern of amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7] oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate).
Detailed description of the invention
Surprisingly it has now been found that the amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate) meet these requirements and have advantageous properties.
The first embodiment, of the present invention relates to the amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole compound of formula I (asenapine maleate).
In another embodiment of the present invention provides a process for the preparation of the amorphous form of asenapine maleate. The process comprises
a) Reacting trans-5-chloro-2-methyl-2,3,3a,12b- tetrahydro-1H- dibenz[2,3:6,7]
oxepino[4,5-c]pyrrole compound of formula II (asenapine) and maleic acid in
isopropyl alcohol at 60°C to 65°C.

b) Stirred the reaction mixture for 1 hr at room temperature and then for 12 hr at -15°C to 10°C.
c) Isolating the trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz [2,3:6,7] oxepino [4,5-c]pyrrole compound of formula I (asenapine maleate)
d) Dissolving trans-5-chloro-2-methyl-2,3,3a,12b- tetrahydro-1H-dibenz[2,3:6,7] oxepino [4,5-c] pyrrole compound of formula I (asenapine maleate) in dichloromethane and sirred for 10 min. at room temperature.
e) Filtered and concentrated to dryness yielded amorphous form of asenapine maleate.
In another embodiment of the invention provides a process for the preparation of the amorphous form of asenapine maleate. The process comprises
a) Dissolving trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7] oxepino[4,5-c] pyrrole maleate compound of formula I (asenapine maleate) in dichloromethane and sirred for 10 min. at room temperature.
b) Filtered and concentrated to dryness yielded amorphous form of asenapine maleate.
In a another embodiment of the present invention relates to the amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b -tetrahydro-1H-dibenz[2,3:6,7] oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate) is characterised by XRD.
Suitable organic solvents are water, alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyi acetate, hydrocarbons like toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, and the like, nitriles like acetonitrile, and polar aprotic solvents like Ν,Ν-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine,

dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and the like; and mixtures thereof.
Isolation and concentration of an amorphous form of asenapine maleate from the solution may be affected by removing solvent. Suitable concentration techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi rotavapor, spray drying, agitated thin film dyring ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique.
Alternatively, isolation can be effected by addition of suitable antisolvent to the solution optionally by concentrating the solution. Suitable anti-solvents that may be used can be selected from hydrocarbons like hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane and the like; aromatic hydrocarbons like toluene, xylene, chlorobenzene, ethylbenzene and the like; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol and the like.
The process for preparing amorphous asenapine maleate may further comprise a recovery process. The recovery of amorphous asenapine maleate may be done by a method that doesn't include a drying step. Such method includes, but is not limited to, filtering the suspension.
Alternatively, asenapine salt can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of asenapine salt. Similarly, an amorphous solid form of the asenapine salt compound can be recovered by spray drying or freeze drying or agitated thin film drying a solution containing the asenapine salt compound.

Examples Example -1
Preparation of amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate)
Asenapine maleate dissolved in dichloromethane at room termperature and stirred for 10 min. Filtered off any undissolved solid. The filtrate was concentrated on rota evaporator to dryness yielded amorphous form of asenapine maleate.
Example -2
Preparation of amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate)
To a stirred solution of asenapine was added maleic acid in isopropyl alcohol dropwise at 60°C to 65°C during 30min and allowed the reaction mixture to stirred for 15 min. at the same temperature and then stirred for 1h at room temperature. Isopropyl alcohol was added to the above reaction mixture and allowed to stirred for 12h at -15°C to 10°C. The obtained solid was filtered, washed with isopropyl alcohol and dried. Asenapine maleate dissolved in dichloromethane at room termperature and stirred for 10 min. Filtered off any undissolved solid. The filtrate was concentrated on rota evaporator to dryness yielded amorphous form of asenapine maleate.

We Claim,
1. A amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate).
2. A process for the preparation of the amorphous form of asenapine maleate comprises:

a) Reacting trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7] oxepino[4,5-c]pyrrole compound of formula II (asenapine) and maleic acid in isopropyl alcohol at 60°C to 65°C.
b) Stirred the reaction mixture for about 1 hr to 2 hr at room temperature and then for overnight at -15°C to 10°C.
c) Isolating the trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate)
d) Dissolving trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7] oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate) in dichloromethane and sirred for 10 min. at room temperature. f) Filtered and concentrated to dryness yielded amorphous form of asenapine maleate.
3. A process for the preparation of the amorphous form of asenapine maleate
comprises:
a) dissolved trans-5-chloro-2-methyl -2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7] oxepino [4,5-c]pyrrole maleate compound of formula I (asenapine maleate) in dichloromethane and sirred for 10 min. at room temperature.
b) Filtered and concentrated to dryness yielded amorphous form of asenapine maleate.

4. The amorphous form of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate compound of formula I (asenapine maleate) is characterised by XRD Figure 1.