WO2012038975A2

WO2012038975A2 - Process for the preparation of (3ars,12brs)-5-chloro-2-methyl-2,3,3a12b-tetrahydro-1hdibenzo[2,3:6,7] oxepino [4,5-c]pyrrole maleate and it's pharmaceutical composition thereof

Info

Publication number: WO2012038975A2
Application number: PCT/IN2011/000648
Authority: WO
Inventors: Manne Satyanarayana Reddy; Srinivasan Thirumalai Rajan; Sajja Eswaraiah; Elevathingal Nicholas Madhu; Komati Satyanarayana; Peri Seetha Rama Sarma
Original assignee: Msn Laboratories Limited
Priority date: 2010-09-22
Filing date: 2011-09-21
Publication date: 2012-03-29
Also published as: WO2012038975A3

Abstract

Improved processes for preparation of asenapine by using specific intermediates and reaction conditions are provided. The intermediates for preparation of asenapine and the pharmaceutical composition comprising asenapine are also provided.

Description

Process for the preparation of (3ai?tS.12bl?.SV5-Chloro-2-methyl- I aJlb-tetrahvdro-l dibenzom^Jl oxepino

[4,5-cl yrrole and its pharmaceutical composition thereof

Related Application:

This application claims the benefit of priority of our Indian patent application numbers 2766/CHE/2010 filed on 22^nd Sept. 2010, 3313/CHE/2010 filed on 8^th Nov 2010 and 1719/CHE/201 1 filed on 20^th May 201 1 which is incorporated herein by reference.

Field of invention:

The present invention relates to an improved process for the preparation of (3a tS^,,12b/?-S)-5-Chloro-2-methyl-2,3,3a, 12b-tetrahydro-lHdibenzo[2,3:6,7]oxepino

[4,5-c]pyrrole (commonly known as asenapine) compound of formula- 1 and its pharmaceutically acceptable salt. Asenapine maleate is represented by structural formula- la.

i ¹

Formula- 1 Formula- la Asenapine is an antipsychotic drug used for the treatment of schizophrenia and acute mania associated with bipolar disorder. It has an antagonistic activity for dopamine (D₂ receptor) as well as serotonin receptor.

The present invention also relates to an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5c]pyrrol- 1-one compound of formula- 10. Further, the present invention relates to a novel and orally disintegrating sublingual pharmaceutical composition comprising asenapine and its pharmaceutically acceptable salts thereof, and methods of preparing the same. In particular, the invention relates to granulated pharmaceutical composition of asenapine and its salts thereof.

Background of the Invention:

Asenapine and its pharmaceutically acceptable salts, specifically asenapine maleate and process for its preparation were disclosed in US 4145434. The disclosed process comprises of reducing 1 l-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one with magnesium in methanol/toluene to provide a mixture of desired trans-l l-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino [4,5-c]pyrrol-l-one and unwanted cis-1 l-chloro-2,3,3a,12b-tetra1iydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one in 1:4 ratio. The ratio of wanted trans isomer was improved by repeated isomerization of unwanted cis isomer, followed by chromatographic separation with the yield of 38%. The obtained product was reacted with lithium aluminium hydride and aluminium chloride to provide asenapine, which on further reaction with maleic acid provides asenapine maleate. The said process involves chromatographic separation and repeated racemisation and hence not suitable for commercial scale up. The yield and purity of the intermediates and final compounds were also not satisfactory.

EP 1710241 Bl also disclosed a process for the preparation of asenapine, which comprises of hydrolyzing a mixture of lactams i.e. trans-1 l-chloro-2,3,3a,12b- tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one and cis-11-chloro- 2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one or pure cis isomer with strong alkali in alcohol which resulted in formation of a mixture of trans-8-chloro- 10, 11 -dihydro- 11 -[(methylamino)methyl]-dibenz[b,f]oxepin- 10- carboxylic acid and cis-8-chloro- 10, 11 -dihydro- l l-[(methylamino)methyl]-dibenz [b,f| oxepin-10-carboxylic acid in a ratio of 10: 1. The trans isomer was subsequently isolated using methanol-water, which on further cyclization followed by reduction with lithium aluminium hydride provided trans isomer of asenapine with an yield of 62%. It also disclosed the preparation of asenapine from a mixture of cis and trans-5-chloro- 2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c] pyrrole-l-one or from cis isomer alone using the same above said process. Eventhough yields are high the said process involves more steps to get the desired compound and hence increases the production time and overall cost.

An Orally Disintegrating Tablet (ODT) was defined as 'solid-dosage form containing medicinal substances which disintegrates rapidly, usually in less than a minute when placed on the tongue. Orally disintegrating pharmaceutical compositions including granules, tablets are convenient oral delivery systems, designed to disintegrate rapidly upon contact with aqueous fluids like water, saliva to form a dispersion which can be swallowed easily. Orally disintegrating pharmaceutical compositions are particularly advantageous for pediatric or geriatric patients, who have difficulty in swallowing conventional tablets or capsules, and for individuals who may not have difficulty in swallowing, but may have an aversion to swallowing conventional tablets or capsules. Orally disintegrating pharmaceutical compositions can be administered without water, they are also convenient oral dosage forms while traveling.

Various methods have been used to manufacture orally disintegrating tablets. Many of these methods use speciality equipment and complicated processing techniques such as lyophilization (freeze-drying). Asenapine maleate are manufactured by using Lyophilization (freeze-drying) technique are marketed by Organon USA Inc. under the brand name of SAPHRIS in 5mg and 10 mg strenths in USA.

US5763476 patent discloses sublingual or buccal pharmaceutical composition of asenapine maleate and a water soluble carrier material like hydrolysed gelatin, mannitol and distill water comprising quickly freeze-drying (Lyophilization) soluble composition. Pharmaceutical compositions disclosed in this patent are produced by using freeze-drying (Lyophilization) process which can disintegrate within 10 seconds in water at 37 0C. Manufacturing process involved in the preparation of sublingual or buccal pharmaceutical composition requires expensive and speciality equipment (Lyophilizer) with increased processing times. As the final dosage form manufactured by using the disclosed process are fragile and hence requires speciality packaging. Increased manufacturing time, requirement of speciality equipment increases the cost of the final product and hence it is not affordable for common needy people.

Based on the above disadvantages involved with the manufacturing process, which was disclosed in innovators patent, there exists a need for the development of cost effective orally disintegrating pharmaceutical compositions of asenapine maleate which can be manufactured by using conventional equipment.

Hence there is a need in the art to prepare asenapine maleate which can reliably carried out in an industrial scale with high yield and purity in a convenient and cost efficient manner and avoids problems mentioned in the prior art.

Advantages of the Present Invention:

• Provides an improved process for the preparation of asenapine with high yield and purity. Use of 2-chlorophenyl aceticacid in place of 2-bromophenyl acetic acid reduces the total cost of production.

• Provides an improved process for the preparation of trans-5-chloro-2,3,3a,12b- tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one with a high yield and purity by avoiding the additional steps for purification.

· Avoids chromatographic separation, hence conducive to be carried out in large scale process.

• Avoids the usage of Lypholization technology in the preparation of pharmaceutical composition.

• Uses simple, milder reagents which are easier to handle and use in large scale. · Provides stable asenapine maleate form-H.

• Eco-friendly and cost effective process.

Brief Description of Drawings:

Figure- 1 is a graph showing the result of dissolution test of asenapine in pH 1.2 (0.1N HCl) medium of sublingual tablet in Example-(ii) of the present invention and Saphris [the reference drug]. Figure-2 is a graph showing the result of dissolution test of asenapine in pH 4.5 medium of sublingual tablet in Example-(ii) of the present invention and Saphris [the reference drug].

Figure-3 is a graph showing the result of dissolution test of asenapine in pH 6.5 medium of sublingual tablet in Example-(ii) of the present invention and Saphris [the reference drug].

Figure-4 is a graph showing the result of dissolution test of asenapine in pH 7.4 medium of sublingual tablet in Example-(ii) of the present invention and Saphris [the reference drug].

Figure-5 is the PXRD pattern of crystalline form-H of Asenapine maleate compound of formula- la.

Brief description of the invention:

The first aspect of the present invention is to provide an improved process for the preparation of asenapine compound of formula- 1, which comprising of reducing trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl- lH-dibenz[2,3 :6,7]oxepino[4,5- c]pyrrol-l-one, compound of formula- 10 with a suitable reducing agent in a suitable solvent to provide compound of formula- 1.

The second aspect of the present invention is to provide an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula- 10, which comprising of reducing 5-chloro-2,3-dihydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-9 with a suitable reducing agent in a suitable solvent followed by recrystallization from a suitable solvent to provide compound of formula- 10.

The third aspect of the present invention is to provide an improved process for the preparation of asenapine maleate salt compound of formula- la, which comprising of the following steps;

a) Esterification of 2-chlorophenyl acetic acid, compound of formula-2 to provide alkyl 2-chlorophenyl acetate compound of general formula-3, b) condensation of compound of general formula-3 with 4-chloro phenol compound of formula-4 to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid ester, which is hydrolyzed in-situ and further reacted with a suitable amine in a suitable solvent to provide the corresponding amine salt of 2-(2-(4-chlorophenoxy)phenyl)acetic acid compound of general formula-5,

c) converting the compound of general formula-5 into free acid and condensing it with 2-(methylamino)acetic acid ester compound of general formula-6 in presence of suitable reagent to provide alkyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methyl acetamido) acetate compound of general formula-7,

d) reacting the compound of general formula-7 with a suitable base in a suitable solvent to provide 3-(2-(4-chlorophenoxy)phenyl)-l-methylpyrrolidine-2,4-dione compound of formula-8,

e) cyclization of compound of formula-8 using polyphosphoric acid, followed by purification with a suitable solvent to provide 5-chloro-2,3-dihydro-2-methyl-lH- dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-9,

f) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent, followed by recrysallization with a suitable solvent to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l- one compound of formula- 10,

g) reducing compound of formula- 10 with a suitable reducing agent in a suitable solvent to provide asenapine compound of formula- 1,

h) reacting the asenapine compound of formula- 1 with maleic acid in a suitable solvent, followed by purification with a suitable solvent provides asenapine maleate compound of formula- la.

The fourth aspect of the present invention is to provide an improved process for the preparation of asenapine maleate salt compound of formula- la, which comprising of the following steps;

a) Condensation of compound of 2-chlorophenyl acetic acid compound of formula-2 with 4-chloro phenol compound of formula-4 in presence of suitable base, Cu (I) catalyst and a ligand in a suitable solvent to provide 2-(2-(4- chlorophenoxy)phenyl)acetic acid compound of formula- 15,

b) reacting the compound of formula- 15 with 2-(methylamino)acetic acid ester compound of general formula-6 in presence of suitable reagent in a suitable solvent to provide alkyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methylacetamido) acetate compound of general formula-7,

c) reacting the compound of general formula-7 with a suitable base in a suitable solvent to provide 3-(2-(4-chlorophenoxy)phenyl)-l-methylpyrrolidine-2,4- dione compound of formula-8,

d) cyclization of compound of formula-8 in presence of polyphosphoric acid or P₂0₅/ phosphoric acid, followed by purification of the obtained compound in methanol to provide pure 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino [4,5-c]pyrrol-l-one compound of formula-9,

e) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent, followed by recrysallization with a suitable solvent to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula-10,

f) reducing compound of formula-10 with a suitable reducing agent in a suitable solvent to provide asenapine compound of formula- 1,

g) reacting the asenapine compound of formula- 1 with maleic acid in a suitable solvent provides asenapine maleate compound of formula- la.

The fifth aspect of the present invention is to provide stable crystalline form-H of asenapine maleate.

The sixth aspect of the present invention is to provide novel amine salts of 2-(2- (4-chlorophenoxy)phenyl)acetic acid and process for their preparation.

The seventh aspect of the present invention is to provide an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-10, which comprising of, a) Suspending a mixture of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula- 11 and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable inert solvent, and heating the reaction mixture at a suitable temperature for a suitable period of time, b) distilling off the solvent to provide a residue,

c) adding isopropyl alcohol to the residue obtained in step-b) and heating the suspension to high temperature to get a clear solution,

d) lowering the temperature of the solution, preferably to about 50°-60°C, more preferably to 50°- 55°C to precipitate a solid,

e) filtering off the solid obtained and collecting the filtrate,

f) distilling off the solvent from the filtrate obtained in step-e), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10.

The eighth aspect of the present invention is to provide an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula- 10, which comprising of,

a) Suspending a mixture of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula- 11 and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable inert solvent, and heating the reaction mixture at a suitable temperature for a suitable period of time, b) distilling off the solvent to provide a residue,

c) adding a suitable solvent selected from methyl tertiarybutyl ether, hexane, heptane, cyclohexane, diethyl ether, diisopropyl ether, petroleum ether to the residue obtained in step-b) and heating the suspension to high temperature to get a clear solution,

d) cooling the reaction mixture at room temperature to precipitate a solid, e) filtering off the solid obtained and collecting the filtrate,

f) distilling off the solvent from the filtrate obtained in step-e), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10. The ninth aspect of the present invention is to provide a process for the preparation of trans-5-chloro-2,3 ,3 a, 12b-tetrahydro-2 -methyl- 1 H-dibenz[2,3,6,7] oxepino[4,5-c] pyrrol- 1 -one compound of formula- 10, which comprising of,

a) Suspending a mixture of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula- 11 and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable inert solvent, and heating the mixture to higher temperature for a period of time,

b) distilling off the solvent to provide a residue,

c) adding isopropyl alcohol to the residue obtained in step-b) and heating the suspension to higher temperature,

d) filtering the suspension and collecting the filtrate,

e) distilling off the solvent from the filtrate obtained in step-d), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10.

The tenth aspect of the present invention is to provide a process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7] oxepino[4,5-c] pyrrol- 1 -one compound of formula- 10, which comprising of;

a) Suspending a mixture of cis and trans isomers of 5-chloro-2,3,3a,12b- tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one in a suitable solvent,

b) heating the suspension to higher temperature,

c) filtering the suspension and collecting the filtrate,

d) distilling off the solvent from the filtrate obtained in step-c) to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10.

The eleventh aspect of the present invention is to provide a process for the preparation of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7] oxepino [4,5-c]pyrrol-l-one compound of formula- 11, which comprising of, a) Reacting 5-Chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c] pyrrol- 1 -one compound of formula-9 with magnesium in presence of catalytic amount of iodine in methanol,

b) concentrating the solvent from the mixture obtained in step-a) and adding appropriate amount of isopropyl alcohol to the concentrate to precipitate cis-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 11 as a solid,

c) filtering the mixture to isolate the solid and optionally recrystallizing it using isopropyl alcohol to provide pure cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl- 1 H-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1 -one compound of formula- 11.

The twelfth aspect of the present invention is to provide an orally disintegrating pharmaceutical composition comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate compound of formula- la as an active ingredient in an amount from about 1% to 30%, preferably 2% to 25% by total weight of the composition.

The thirteenth aspect of the present invention is to provide an orally disintegrating pharmaceutical composition comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate, wherein orally disintegrating pharmaceutical composition is an uncoated or coated tablet and the diameter of the tablet ranging from 5 mm to 7 mm.

The fourteenth aspect of the present invention is to provide an orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate having hardness not less than 20 N (~2 kgs).

The fifteenth aspect of the present invention is to provide an orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof having low friability not more than 0.5%. The sixteenth aspect of the present invention is to provide an orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof and having dispersion time in the range of 35-60 seconds.

The seventeenth aspect of the present invention is to provide orally disintegrating pharmaceutical composition comprising asenapine or its paharmaceutically acceptable salts thereof, wherein orally disintegrating pharmaceutical composition is in the form of granules.

The eighteenth aspect of the present invention is to provide a method for producing orally disintegrating pharmaceutical compositions of asenapine maleate by conventional methods known in the art. The method of producing orally disintegrating pharmaceutical compositions comprises direct compression, dry granulation or wet granulation.

The nineteenth aspect of the present invention relates to an orally disintegrating pharmaceutical composition having dissolution time from 5 minutes (80% to 90%) to 10 minutes (90% to 100%).

Detailed description of the Invention:

The suitable solvents, wherever necessary, used in the present invention are selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, pet. ether; "hydrocarbon solvents" like toluene, xylene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutaol; "chloro solvents" like dichloromethane, dichloroethane, carbon tetrachloride, chloroform and ethylene chloride; polar solvents like water; and also mixtures there of.

The term "orally disintegrating pharmaceutical compositions " as used herein refers to the ability of a pharmaceutical composition (e.g., granules, a tablet for oral administration) to disintegrate rapidly when contacted with a fluid, particularly an aqueous fluid (e.g.,water, bodily fluids (e.g., saliva), and the like), to form a suspension, slurry or dispersion, which facilitates administration of the contents of the composition (e.g., by forming a suspension, slurry or dispersion, which is easily swallowed). According to the present invention, oral granular formulations such as granules, powders and fine granules can also be prepared.

The term "orally" includes the region within the interior of the mouth, including, but not limited to, the buccal cavity (e.g., anterior to the teeth and gums) as well as the sublingual and supralingual spaces, and the like.

According to the tenth aspect of the present invention, the diluents are selected from but are not limited to various cellulose derivatives such as microcrystalline cellulose(MCC) and the like, mannitol, lactose, dextrose, sorbitol, starch, xylitol, pearlitol flash, F-Melt, maltose, dicalcium phosphate and their derivatives thereof, and the preferred diluents are microcrystalline cellulose, pearlitol flash and F-Melt.

The binders are selected from but are not limited to various cellulose derivatives such as low molecularweight hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like, methacrylate copolymers, amino alkyl methacrylate copolymers and the like, povidone and the like, sodium alginate and the like, and the preferred binders are hydroxypropylmethyl cellulose , hydroxypropylcellulose and povidone K 30.

The dintegrants are selected from but are not limited to starch or its derivative like pregelatinised starch, sodium carboxymethyl starch, sodium starch glycolate and the like, various cellulose derivatives like crosslinked sodiumcarboxymethyl cellulose, low substituted hydroxypropylcellulose, croscarmellose calcium and the like, crosspovidone and the like, alginic acid and various ion exchange resins, and the preferred disintegrants are cross linked sodium carboxymethyl cellulose (Ac-di- sol),croscarmellose calcium and crospovidone.

The lubricants may be selected from but are not limited to talc, magnesium stearate, calcium stearate, stearic acid,sodium stearyl fumarate and the like, and the preferred lubricants are magnesium stearate, calcium stearate, stearic acid,sodium stearyl fumarate.

The sweeteners may be selected form but are not limited to aspartame, acesulfam potassium, sucralose, xylitol, saccharine, saccharine potassium, sugars and the like, and the preferred sweetners are aspartame, sucralose, acesulfam potassium and sugars. The flavors may be for example mint flavors, orange flavor, lemon flavor, banana flavor, strawberry flavor, magnasweet, grape flavor and the like, and the preferred flavouring agents are peppermint flavour, strawberry flavor, magnasweet, grape flavor and black cherry flavor. The suitable coloring agent is selected from brilliant blue, iron oxide red, iron oxide blue, FD&C, D&C lakes, Ti0₂₎ Talc, Pyrogenic silica, channel black and natural colorants, preferably brilliant blue.

The binder fluids or solvents are selected from but are not limited to aqueous or non-aqueous or their mixtures thereof, for example may be isopropyl alcohol, acetone and ethanol.

Throughout this disclosure, compounds represented by structural formulae having a pair of bold and hashed wedged bonds as shown, e.g., in compound of formula- 1 or a pair of bold wedged bonds as shown, e.g., in compound of formula-2, refer to "trans" or "cis" diastereoisomers respectively. Each of the compounds may exist as a single enantiomer having the absolute stereo chemical configuration indicated by the wedged bonds, or having the opposite absolute configuration or as a mixture of enantiomers having the relative stereo chemical configuration indicated by the wedged bonds.

The first aspect of the present invention is to provide an improved process for the preparation of asenapine co

Formula- 1 which comprises of reducing trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula- 10

Formula- 10

with a suitable reducing agent in a suitable solvent to provide compound of formula- 1 , characterized in that the reducing agent is selected from BF3-etherate/sodium borohydride, lithium aluminium hydride (LAH), vitride, sodium borohydride/ aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9- BBN.

The second aspect of the present invention provides an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-10, which comprises of reducing 5- chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-9

Formula-9

with a suitable reducing agent in the presence of an activator in a suitable solvent to provide compound of formula-10, characterized in that the reduction is carried-out in the presence of proton donor like formic acid or acetic acid.

Wherein the suitable reducing agent is selected from magnesium, zinc or iron and the activator is iodine or dibromoethane. The usage of proton donor such as formic acid or acetic acid in the above reduction provides the desired trans-isomer in high ratio compared to the prior art process and hence the present process is more advantageous over the prior art.

The third aspect of the present invention is to provide an improved process for the preparation of asenapine maleate compound of formula- la, which comprising of the following steps;

a) Esterification of 2-chlorophenyl acetic acid, compound of formula-2

Formula-2

with an alcohoHn presence of an acid to provide alkyl 2-chlorophenylacetate compound of general formula-3,

Formula-3

wherein R is Q-C₄ alkyl,

b) condensation of alkyl 2-chlorophenylacetate compound of general formula-3 with 4-chloro phenol compound of formula-4

Formula-4

in presence of suitable base, Cu (I) catalyst and a ligand in a suitable solvent to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid ester, which is hydrolyzed in- situ in presence of a base like KOH or NaOH in a suitable solvent to provide 2- (2-(4-chlorophenoxy)phenyl) acetic acid, which is further reacted with a suitable amine in a suitable solvent to provide corresponding amine salt of 2-(2- (4-chlorophenoxy) phenyl)acetic acid compound of general formula-5, Amine

Formula-5

c) converting the compound of general formula-5 into free acid by treating with a suitable acid in a suitable solvent and in-situ treating of the obtained free acid with 2-(methylamino)acetic acid ester compound of general formula-6

Formula-6

in presence of a suitable reagent ift a suitable solvent to provide alkyl 2-(2-(2- (4-chlorophenoxy)phenyl)-N-methylacetamido) acetate compound of general formula-7,

wherein R is as defined above

d) reacting the compound of general formula-7 with a suitable base in a suitable solvent to provide 3-(2-(4-chlorophenoxy)phenyl)-l-methylpyrrolidine-2,4- dione compound of formula-8,

Formula-8

e) cyclization of compound of formula-8 with a suitable reagent in a suitable solvent, followed by purification from a suitable solvent provides 5-chloro-2,3- dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-9,

Formula-9

f) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent, followed by recrystallization with a suitable solvent to provide the desired trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c] pyrrol- 1 -one compound of formula- 10,

Formula- 10

g) reducing the compound of formula- 10 with a suitable reducing agent in a

suitable solvent to provide asenapine compound of formula- 1,

h) reacting the asenapine compound of formula- 1 with maleic acid in a suitable solvent, followed recrystallization from a suitable solvent to provide asenapine maleate compound of formula- la.

wherein, in step a) alcohol refers to methanol, ethanol, propanol, isopropanol, butanol, isobutanol, secondary butanol, tertiary butanol, preferably methanol; acid is selected from sulfuric acid, para toluene sulfonic acid, methane sulfonic acid and trifluoro aetic acid, preferably sulfuric acid;

In step b) the suitable base is selected from K₂C0₃, Cs₂C0₃, preferably Cs₂C0₃; Cu (I) catalyst selected from Cu₂0, CuX, CuXPPh₃, CuX(PPh₃)₃, Copper bi pyridyl complexes, (wherein X refers to halogens i.e. CI, Br and I, preferably CI) preferably CuCl and a ligand selected from Me₄Phen, l,l,l-tris(hydroxymethyl)ethane, diphenyl glycine, dimethyl glycine, Chxn-Py-Al, 1,10-phenonthroline, preferably dimethylglycine; and amine is selected from mono, di and trialkyl amine, preferably tributylamine;

In step c) the suitable reagents is selected from dehydrating agents, like carbodiimides optionally in combination with N-hydroxy benzotriazole or N-hydroxy succinamide, N^'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethyl amino propyl)carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HO At), N-hydroxy succinamide (HOSu), 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin- 4-one, diethyl phosphoraro cyanidate- triethylamine, di phenylphosphoroazidate (DPPA), 3-(diethoxyphosphoryloxy)-l,2,3-benzotriazine-4(3H)-one (DEPBT), 1- hydroxy- lH-1, 2,3 -triazole-4-carboxylate(HOCt), P₂0₅, (2-(lH-benzotriazol-l-yl)- 1,1,3 ,3 -terra methyluronium tetrafluoroborate (TBTU), NjN'-dicyclohexyl carbodiimide (DCC)-dimethyl amino pyridine (DMAP), preferably DCC in combination with DMAP; the suitable acid used for deprotection of amine salt is selected from organic acid selected from acetic acid, oxalic acid and formic acid and inorganic acid is selected from hydrochloric acid, sulphuric acid and the like, preferably hydrochloric acid.

In step d) the suitable base is selected from sodium tertiary butoxide, potassium tertiary butoxide, sodium methoxide, preferably potassium tertiary butoxide;

In step e) the suitable reagent is selected from polyphosphoric acid or P₂0₅ and phosphoric acid. The usage of a solvent in the cyclisation reaction improves the yield and purity when compared to the prior art;

In step f) the suitable reducing agent is magnesium in presence of an activator, i.e. I₂ or dibromoethane and in the presence of proton donor like formic acid or acetic acid;

In step g) the suitable reducing agent is selected from BF₃-etherate and sodium borohydride, vitride, sodium borohydride and aluminium chloride or borane and aluminium chloride, 9-BBN.

In step h) the suitable solvent is selected from alcoholic solvents like methanol, ethanol, propyl alcohol and isopropyl alcohol, preferably isopropyl alcohol. In a preferred embodiment of the present invention, improved process for the preparation of asenapine maleate compound of formula- la comprising of the following steps:

a) Esterification of 2-chlorophenyl acetic acid, compound of formula-2

Formula-2

with methanol in presence of sulfuric acid to provide methyl 2- chlorophenylacetate compound of formula-3a,

Formula-3a

b) condensation of methyl 2-chlorophenylacetate compound of formula-3a with 4- chloro phenol compound of formula-4 in the presence of CS2CO3, CuCl and dimethyl glycine in dioxane provides 2-(2-(4-chlorophenoxy)phenyl)acetic acid ester which is insitu hydrolyzed in the presence of KOH in methanol to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid, which on in-situ reaction with tributyl amine in pet.ether to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid tributyl amine salt compound of formula-5a,

Formula-5a

c) treating the compound of formula-5a with hydrochloric acid in ethyl acetate and water to provide its free acid, which on in-situ reaction with methyl 2- (methylamino)acetate compound of formula-6a in presence of DCC in combination with DMAP in methylene chloride provides methyl 2-(2-(2-(4- chlorophenoxy)phenyl)-N-methylacetamido) acetate compound of formula-7a, d) reacting the compound of formula-7a with potassium tertiary butoxide in toluene provides 3-(2-(4-chlorophenoxy)phenyl)- 1 -methylpyrrolidine-2,4-dione compound of formula-8,

e) cyclization of the compound of formula-8 with polyphosphoric acid or P₂0₅ and phosphoric acid in xylene, followed by purification of the obtained compound in methanol to provide pure 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-9,

f) reducing the compound of formula-9 with Mg in presence of I₂ in methanol and formic acid in toluene and methanol mixture, followed by recrystallization of the obtained compound from methanol provides the desired compound trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-

1-one compound of formula- 10,

g) reducing the compound of formula- 10 with BF₃-etherate and sodium boro

hydride in THF to provide asenapine compound of formula- 1.

h) reacting the asenapine compound of formula- 1 with maleic acid in isopropyl alcohol, followed by recrystallization of the obtained compound from ethanol to provide asenapine maleate compound of formula- la.

a) Condensation of compound of 2-chlorophenyl acetic acid compound of formula-2 with 4-chloro phenol compound of formula-4 in presence of a suitable base, Cu (I) catalyst and a ligand in a suitable solvent to provide 2-(2- (4-chlorophenoxy)phenyl)acetic acid compound of formula- 15,

Formula- 15

b) reacting the the compound of formula- 15 with 2-(methylamino)acetic acid ester compound of general formula-6 in presence of suitable reagent in a suitable solvent to provide alkyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N- methylacetamido)acetate co a-7,

Formula-7

wherein R is defined above

e) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent, followed by recrysallization with a suitable solvent to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10,

f) reducing compound of formula- 10 with a suitable reducing agent in a suitable solvent to provide asenapine compound of formula- 1,

In a preferred embodiment of the present invention, improved process for the preparation of asenapine maleate compound of formula- la comprising of the following steps:

a) Condensation of 2-chlorophenyl acetic acid compound of formula-2 with 4- chloro phenol compound of formula-4 in the presence of K₂CC>3, CuCl in toluene provides 2-(2-(4-chlorophenoxy)phenyl)acetic acid compound of formula- 15, b) treating the compound of formula- 15 with methyl 2-(methylamino)acetate compound of formula-6a in presence of DCC in combination with DMAP in methylene chloride provides methyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N- methylacetamido) acetate compound of formula-7a,

c) reacting the compound of formula-7a with potassium tertiary butoxide in toluene provides 3-(2-(4-chlorophenoxy)phenyl)- 1 -methylpyrrolidine-2,4-dione compound of formula-8,

d) cyclization of the compound of formula-8 in presence of polyphosphoric acid or P₂0₅/ phosphoric acid, followed by purification of the obtained compound in methanol to provide pure 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-9,

e) reducing the compound of formula-9 with Mg in presence of I₂ in methanol and formic acid in toluene and methanol mixture, followed by recrystallization of the obtained compound from methanol provides the desired compound trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10,

f) reducing the compound of formula- 10 with lithium aluminium hydride (LAH) in THF to provide asenapine compound of formula- 1.

g) reacting the asenapine compound of formula- 1 with maleic acid in ethanol to provide asenapine maleate compound of formula- la.

The fifth aspect of the present invention is to provide stable asenapine maleate crystalline form-H. Asenapine maleate compound of formula- la prepared as per the present invention is stable and the crystalline characteristics are well matches with the known crystalline form H of asenapine maleate.

According to WO 2006/106135 Al the crystalline form H of asenapine maleate is not stable during micronisation and converted into crystalline form-L or mixture of form-L and form-H. However asenapine maleate prepared as per the present invention is stable even after micronisation and does not converted in to crystalline form-L during micronisation or its storage after micronisation. The following table shows the stability of asenapine maleate of the present invention before micronisation, after micronisation and during storage of the same. And the stability data generated for 10 kg scale-up batch is given below:

The present invention further provides a process for the preparation of stable form-H of asenapine maleate, which comprises of the following steps:

a) Stirring asenapine maleate of form-H in ethanol for 15 minutes at 60-65 °C, b) subjecting the reaction mixture to carbon treatment,

c) stirring for 10 minutes at 60-65 °C,

d) cooled to - 15°C to - 10°C over a period of 2 hours,

e) filtered, washed with ethanol and dried to get the stable asenapine maleate

form-H.

The sixth aspect of the present invention is to provide novel amine salts of 2-(2 (4-chlorophenoxy)phenyl)acetic acid represented by the following structural formula,

Formula-5

Wherein, amine is selected from mono, di and trialkyl amine, preferably methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, isobutyl amine, sec-butyl amine, tertiarybutyl amine, dimethyl amine, diethyl amine, di(n-propyl)amine, di(isopropyl)amine, di(n-butyl)amine, di(isobutyl)amine, di(sec-butyl)amine, di(tertiarybutyl)amine, trimethyl amine, triethyl amine, tri(n-propyl)amine, tri(isopropyl)amine, tri(n-butyl)amine, tri(isobutyl)amine, tri(sec-butyl)amine, tri(tertiarybutyl)amine, most preferably tri(n-butyl) amine. Further the present invention provides a process for the preparation of novel amine salts of 2-(2-(4-chlorophenoxy)phenyl)acetic acid salt compound of general formula-5, which comprises of reacting the 2-(2-(4-chlorophenoxy)phenyl)acetic acid with a suitable amine as discussed above in a suitable solvent and isolating the corresponding salt compound of formula-5 in a convenient manner.

The seventh aspect of the present invention is to provide an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7]oxepino [4,5-c]pyrrol-l-one compound of formula- 10, which comprises of,

Formula- 10

a) Suspending a mixture of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7]oxepino[4, -c]pyrrol-l-one compound of formula-11,

Formula- 11 and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable inert solvent, and heating the reaction mixture at a suitable temperature for a suitable period of time,

b) distilling off the solvent to provide a residue,

e) filtering off the solid obtained and collecting the filtrate, f) distilling off the solvent from the filtrate obtained in step-e), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10.

a) Suspending a mixture of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-11 and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable inert solvent, and heating the reaction mixture at a suitable temperature for a suitable period of time, b) distilling off the solvent to provide a residue,

The cis-5-chloro-2,3,3a,12b-tetrahydro-2 -methyl- lH-dibenz[2,3,6,7]oxepino [4,5-c]pyrrol-l-one compound of formula-11, used as the input in the present invention and the process for the preparation of said compound is similar to the process disclosed in US 4145434.

The ninth aspect of the present invention is to provide a process for the preparation of trans-5-chloro-2,3,3a, 12b-tetrahydro-2 -methyl- 1 H-dibenz[2,3,6,7] oxepino [4,5-c]pyrrol-l-one compound of formula- 10, which comprising of,

a) Suspending a mixture of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-11 and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable inert solvent, and heating the mixture to higher temperature for a period of time,

b) distilling off the solvent to provide a residue,

d) filtering the suspension and collecting the filtrate,

The tenth aspect of the present invention is to provide a process for the preparation of trans-5-chloro-2,3 ,3 a, 12b-tetrahydro-2 -methyl- 1 H-dibenz[2,3 ,6,7] oxepino [4,5-c] pyrrol- 1 -one compound of formula- 10, which comprises of;

b) heating the suspension to higher temperature,

c) filtering the suspension and collecting the filtrate,

d) distilling off the solvent from the filtrate obtained in step-c), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-

1-one compound of formula- 10.

Wherein, the solvent used in step-a) is isopropyl alcohol, methyl tertiary butyl ether, hexane, heptane, diethyl ether, di isopropyl ether, cyclohexane and pet. ether.

The eleventh aspect of the present invention is to provide a process for the preparation of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7] oxepino [4,5-c]pyrrol-l-one compound of formula- 11, which comprising of,

a) Reacting the 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]

- 1 -one compound of formula-9

Formula-9 with magnesium in presence of catalytic amount of iodine in methanol, b) heating the reaction mixture to reflux temperature and stirring the reaction mixture,

c) cooling the reaction mixture and quenching the reaction mixture with water, d) adding ethyl acetate to the reaction mixture and stirred.

e) concentrating the organic layer obtained in step-c) and adding an appropriate amount of isopropyl alcohol and concentrate to obtain cis-5-chloro-2,3,3a,12b- tetrahydro-2 -methyl- 1 H-dibenz[2,3,6,7] oxepino[4,5-c]pyrrol- 1 -one compound of formula- 11 as a solid,

f) filtering the mixture to isolate the solid and optionally recrystallizing it using isopropyl alcohol to provide pure cis-5-chloro-2,3,3a,12b-tetrahydro-2methyl- v v

lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula- 11.

EP 1710241 discloses a process which involves the reduction of double bond in 1 l-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one by treating with magnesium/I₂ in methanol toluene solvent to provide a mixture of required 'trans' isomer and the unwanted 'cis' isomer of 1 l-chloro-2,3,3a,12b- tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one in a ratio of 1:4 respectively. The trans and cis isomers are separated from the racemic mixture using chromatography over silica gel.

In the present invention the reduction of 5-chloro-2,3-dihydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-9 is carried out using 5-8 equivalents of magnesium/I₂ in methanol providing a mixture 'trans' and 'cis' isomers of 5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7] oxepino [4,5- c]pyrrol-l-one in a ratio of around 2:8. The present invention provides a process in which the pure cis isomer is isolated as pure solid without the use of column chromatography. The above aspects of 6,7,8 and 9 of the present invention can be practiced using the l l-chloro-2,3-dihydro-2 -methyl- lH-dibenz[2,3:6,7] oxepino [4,5-c] pyrrol- 1 -one compound of formula- 12, as an input material to prepare 'cis' isomer of 11-chloro- 2,3 ,3 a, 12b-tetrahydro-2-methyl- 1 H-dibenz[2,3 ,6,7]oxepino[4,5-c]pyrrol- 1 -one compound of formula-13 and 'trans' isomer of 1 l-chloro-2,3,3a,12b-tetrahydro-2- methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c] pyrrol- 1 -one compound of formula- 14.

Formula- 12 Formula-13 Formula- 14

The twelfth aspect of the present invention relates to an orally disintegrating pharmaceutical composition comprising of, asenapine or its salts in combination with one or more of,

a) Diluent(s),

b) binding agent(s),

c) solvents or binding fluids,

d) disintegrating agent(s),

e) lubricant(s),

f) sweetener(s),

g) flavoring agents and optionally coloring agents.

In a preferred embodiment of the above aspect of the present invention relates to an orally disintegrating pharmaceutical composition comprising of, asenapine maleate in an amount from 2% to 25% by total weight of the composition in combination with one or more of,

a) Microcrystalline cellulose,

b) F-melt,

c) povidone,

d) crosspovidone,

e) magnesium stearate,

f) aspartime,

g) pipperment flavor and optionally coloring agents. The thirteenth aspect of the present invention provides orally disintegrating pharmaceutical compositions comprising asenapine and pharmaceutically acceptable salts thereof, particularly asenapine maleate, wherein the orally disintegrating pharmaceutical composition (e.g., granules, a tablet for oral administration), particularly in an uncoated or coated tablet form and the diameter of the tablet preferably ranging from 5 mm to 7 mm preferably 6 mm of diameter.

The fourteenth aspect of the present invention refers to hardness of orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate. Hardness refers to the diametral breaking strength as measured by conventional pharmaceutical tablet hardness determination "methods, which are well known in the art. A higher hardness value, sometimes measured in Newtons (N) and kilograms (kg), the hardness of the tablet of the present invention preferably ranges from about 20 N (~2 kg) to about 50 N (~5 kg), and more preferably from about 35 N (~3.5 kg) to about 45 N (~ 4.5 kg), and most preferably from about 20 N (~2 kg) to about 40 N (~4 kg).

The fifteenth aspect of the present invention provides orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof having low friability not more than 1%, preferably 0.8%, more preferably 0.5%.

The sixteenth aspect of the present invention provides orally disintegrating sublingual tablet comprising asenapine or its pharmaceutically acceptable salts thereof and having dispersion time of about 35-60 seconds, when contacted with an aqueous fluid (e.g., water, saliva, or a buffered solution), to form a slurry, a dispersion or a suspension, which can be administered (e.g., swallowed) easily. The dispersion time of the pharmaceutical compositions of the present invention can range from within about 35 seconds to 60 seconds, more preferably from within about 40 seconds to 50 seconds.

The seventeenth aspect of the present invention provides orally disintegrating pharmaceutical compositions comprising asenapine or its pharmaceutically acceptable salts thereof, wherein orally disintegrating pharmaceutical composition is in form of granules.

The eighteenth aspect of the present invention provides a process for preparation of an oral disintegrating sublingual pharmaceutical composition by wet granulation method comprising;

a) Mixing asenapine maleate and diluent,

b) dissolving the binder in a suitable binder fluid or solvent,

c) adding the above formed binder solution to the mixture obtained in step-a), d) drying the above obtained granules,

e) adding the mixture of second diluent, disintegrant, sweetening agent and flavouring^vagent to the granules obtained in step-d,

f) adding the lubricant to the above mixture,

g) compressing the above blend into tablets. The nineteenth aspect of the present invention relates to orally disintegrating pharmaceutical composition having dissolution time from 5 minutes (80% to 90%) to 10 minutes (90% to 100%).

The present invention relates to orally disintegrating pharmaceutical composition comprising asenapine and its pharmaceutically acceptable salts thereof, particularly asenapine maleate is in either crystalline or in amorphous form.

The following are the impurities which are formed during the preparation of asenapine and its salts. These impurities are identified, synthesized and characterized: (Sa^S.nb -^^-methyl^^.S^^b-tetrahydro-^'lHdibenzo^^^,?] oxepino[4,5- c]pyrrole herein designated as "deschloroimpurity"; (3a-¾S^,,12b/¾S)-5-chloro-2,3,3a,12b- tetrahydro-lHdibenzo[2,3:6,7] oxepino[4,5-c]pyrrole, herein designated as "desmethylimpurity"; (3a&S, 12b_J¾S)-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro- lHdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole-N-oxide, herein designated as "N-oxide impurity"; 2-chloro-phenyl acetic acid, herein designated as "Impurity-A".

Asenap ne ma eate prepare as per t e present nvent on s av ng pur ty than 99% by HPLC and the impurities which are mentioned above are well controlled with in the limits as per the ICH guidelines.

HPLC Analysis Method:

Asenapine and its related compounds were analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector and integrator; Column: Inertsil C8-3, 250 x 4.6 mm, 5 μπι or equivalent; Flow rate: 1.0 ml/min; Wavelength: 220 nm; Temperature: 40°C; injection volume : 10 μL; Run time: 40 minutes; Diluent: Acetonitrile:water (50:50 v/v); Elution: Isocratic; Buffer: 3.48 grams of Dipotassium hydrogen ortho phosphate in 1000 ml of water and added triethylamine, adjust pH to 6.8 with diluted orthophosphoric acid. Filtered this solution through 0.45 um Nylon membrane filter paper and sonicate to degas it.

PSD Analysis Method:

A dispersion liquid has made consisting of (0.7 mg/mL) lecithin (used as surfactant) in iso-octane saturated with asenapine maleate. This solution is stirred over night. Subsequently the solution is filtered over a 0.22/0.45 μηι filter. The samples were prepared by weighing approximately 30mg of asenapine maleate in a 25 ml measurable tube and adding 2 ml of the dispersion liquid. Ultrasonic treatment of the samples was performed for 2 minutes in an ultrasonic bath (Hydro2000S). Subsequently, the particle size distribution of the sample was analyzed using laser diffraction (Malvrn Mastersizer2000). The particle sized distribution has been calculated using the Fraunhofer algorithm.

The present invention is schematically represented as follows:

S

Fotmula-4 Formula-₅

Formula- la Scheme-II:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:

Example-1: Preparation of methyl 2-chlorophenyl acetate (formula-3a)

A mixture of 2-chlorophenyl acetic acid (100 g), sulfuric acid (2 g) and methanol (1 lit) was stirred for 1 hour at reflux temperature. Distilled off the solvent completely and then added water followed by ethyl acetate. The reaction mixture was neutralized with 10% sodium bicarbonate. Both the organic and aqueous layers were separated; the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined and distilled off the solvent completely to get the title compound.

Yield: 100 g

ExampIe-2: Preparation of tributylamine salt of 2-(2-(4-chlorophenoxy) phenyl)acetic acid (formula-5a): ^*

To a mixture of methyl 2-chlorophenyl acetate (100 g), 4-chloro phenol (69.6 g) in dioxane, cesium carbonate (352.9 g) and cuprous chloride (21.5 g) were added, followed by Ν,Ν-dimethyl glycine (11.2 g) and stirred upto the completion of reaction at 110-115°C. After completion of the reaction, the reaction mass was cooled to RT and filtered, the solvent was distilled off completely under reduced pressure. Ethyl acetate (250 ml) was added to obtained residue and stirred for 15 minutes at RT and acidified with 1M HC1. The layers were separated and extracted the aqueous layer with ethyl acetate. Washed with sat.sodium chloride and dried with sodium sulfate then distilled off the solvent under reduced pressure. Methanol (500 ml), potasium hydroxide (32.4 g) was added to the obtained residue at 25-35°C, heated to 60-65°C and stirred for 5 hrs. The reaction mass was cooled to 45°C and solvent was distilled under reduced pressure. Water was added to the residue and acidified with hydrochloric acid. Ethyl acetate was added to the reaction mass and stirred for 15 minutes at RT. Both the layers were separated and the organic layer was dried with sodium sulphite and then distilled off the solvent under reduced pressure. Pet. Ether (300 ml) was added to the reaction mass and stirred for 20 minutes and then cooled to 5-10°C. Tributyl amine (300 ml) was added to the reaction mass and stirred for lhr. The solid obtained was filtered, washed with pet.ether and then dried to get the title compound. Yield: 65 g Example-3: Preparation of 2-(2-(4-chlorophenoxy)phenyl)acetic acid (formula- 15):

Potassium carbonate (109 gm) was charged into a clean and dry RBF at below 20°C under N₂ atmosphere. To this toluene (400 ml) and 4-chloro phenol (56.5 gm) were added at the same temperature. To the resulting mixture 0.5 gm of CuCl was added at 20°C and the temperature of the reaction mixture was slowly raised to 100°C. To this 2-chloro phenyl acetic acid (50 gm) was added at 100°C and the obtained mixture was stirred for 1 hr at the same temperature. The reaction mixture was refluxed for 8 hrs at 110°C. K₂C0₃ (80 gm) was added to the resulting mixture and stirred for 12 hrs at the same temperature. Then the reaction mixture was cooled to room temperature and water (250 ml) was added. The resulting mixture was acidified with HC1 and again

v

water (100 ml) was added. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both the organic layers were combined and washed with 10% NaCl solution. The resulting organic layer was dried over Na₂S0₄ and the solvent was completely distilled off under vacuum at below 60°C. n-Heptane (50 ml) was added to the obtained residue and stirred for 30-45 min at 25-35°C. The obtained solid was filtered, washed with n-heptane and then dried at 50-60°C to get the title compound. Yield: 79%. Example-4: Preparation of methyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N-methyl acetamido)acetate (formula-7a):

To the compound of formula-5a obtained in example-2 (62 g), water (300 ml) and methylene chloride (250 ml) were added and P^H was adjusted to 1.5 with aqueous hydrochloric acid. Both the aqueous and organic layer were separated. Distilled off the solvent from the organic layer under reduced pressure. Methylene chloride (300 ml), dicyclohexylcarbodiimide (48.7 gm) in methylene chloride (300 ml), 4-dimethyl amino pyridine (0.5 gms) and followed by methyl 2-(methylamino)acetate solution (prepared from methyl 2-(methylamino)acetate.HCl (32.9 g) in methylene chloride (62 ml) by adding triethyl amine (28.6 gms)) was added to the above obtained residue at 0-5°C. The reaction mass was stirred for 45 minutes at 10-15°C. After completion of the reaction, the reaction mass was filtered and washed with methylene chloride. To the filtrate water was added and stirred for 15 minutes at RT. Both the layers were separated; the organic layer was washed with sodium chloride solution and dried with sodium sulfate followed by distilled off the solvent to get the title compound.

Yield: 80 grams

Example-5: Preparation of 3-(2-(4-chlorophenoxy)phenyl)-l-methylpyrrolidine- 2,4-dione (formula-8):

Potassium tertiary butoxide (21.7 gm) in toluene (40 ml) was added to the compound of formula-7a of example-4 (80 g) in toluene (650 ml) and stirred for 3 hrs at RT. Quenched the reaction mixture with water and washed thrice with ethyl acetate. Acidified the aqueous layer with concentrated hydrochloric acid and stirred for 3 hours at RT. The solid obtained was filtered, washed with water and then dried to get the title compound. Yield: 8.5 grams Example-6: Preparation of 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino [4,5-c]pyrrol-l-one (formula-9) :

Phosphorous pentoxide (90 g) was added to ortho phosphoric acid (90 g) slowly at 140°C and then stirred for 90 minutes at 1 15-120°C. Added compound of formula-8 of example-5 (30 g) and xylene (300 ml) to the above reaction mass over a period of 15 minutes and then stirred for 4 days at the 1 15-130°C. Decanted the solvent, quenched the reaction with water and methylene chloride was added to the reaction mass. Both the aqueous and organic layers were separated; the organic layer was distilledoff completely. Acetonitrile was added to the reaction mass and stirred for 2 hours at 0- 5°C. The reaction mass was filtered; the obtained filtrate was distilled off to get the title compound as a solid.

Yield: 9.8 grams

Example-7: Preparation of 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino [4,5-c] pyrrol-l-one (formula-9) :

Phosphorous pentoxide (90 g) was added to ortho phosphoric acid (90 g) slowly at 140°C and then stirred for 90 minutes at 115-120°C. Added compound of formula-8 of example-5 (30 g) to the above reaction mass over a period of 15 minutes and then stirred for 4 days at the 1 15-120°C. For every 24 hours, add Phosphorous pentoxide ( 15 g) and ortho phosphoric acid (7.5 g) to the reaction mixture for 3 times. Decanted the solvent, quenched the reaction with water and methylene chloride was added to the reaction mass. Both the aqueous and organic layers were separated; the organic layer was distilledoff completely. Methanol was added to the reaction mass and stirred for 2 hours at 0-5 °C. Filtered the obtained solid and dried the compound to get the title compound. Yield: 12.8 grams

Example-8: Purification process for 5-chIoro-2,3-dihydro-2-methyl-lH-dibenz

[2,3:6,7]oxepino[4,5-c]pyrrol-l-one (formula-9):

Compound of formula-9 obtained in example-7 (9.8 g) was in methanol (520 ml) was stirred for 15 minutes at reflux temperature. Distilled off the solvent half of the amount and then stirred for 14 hours at -10 to -12°C. Filtered the solid, washed with chilled methanol and dried to get highly pure title compound.

Example-9: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one (formula-10):

Iodine (2.13 g) followed by formic acid (25 g) was added to a mixture of magnesium (0.4 g) and toluene (25 ml) at room temperature. Compound of formula-9 obtained from example-8 (5 g) and a mixture of toluene and methanol (1: 1 ratio) was added to the above reaction mass slowly over a period of 45 minutes and stirred for 5 hours at 40°C. The reaction was quenched with water and acidified with conc.HCl at 5- 10°C (i.e. P^H~1). The reaction mass was extracted with toluene and the organic and aqueous layers were separated. All the organic layers were combined and concentrated to yield the crude trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3:6,7] oxepino[4,5-c]pyrrol-l-one (10). Recrystallization from methanol provides the pure title compound of formula-10. Yield: 0.1 grams

Example-10: Preparation of asenapine (forniula-1):

Method-I:

Sodium borohydride (0.63 gm) was added to the compound of formula-10 obtained from Example-9 (0.5 gm) in THF (20 ml) at RT and stirred for 15 minutes at the same temperature. To the above reaction mass I₂ solution (4.2 gm of I₂ in 15 ml THF) was added slowly at reflux temperature for 6 hours. After the reaction completed, cooled to 10-15°C and acidified with 10% HC1 solution (1.5 ml HC1 in 13.5 ml water), followed by treatment with dilute.sodium hydroxide. The reaction mass was extracted with toluene twice, combined both the organic layers and washed with water followed by sat.brine solution and dried and distilled to yield the title compound. Yield: 0.5 gm. Method-II:

Sodium borohydride (3.2 gm) was added to the compound of formula- 10 obtained from Example-9 (5 gm) in THF (100 ml) at RT. BF₃ etherate (23.6 gm) was added to the above reaction mass over a period of 1 hour at reflux temperature and stirred for 12 hours at the same temperature. The reaction was quenched with 2.5% sodium

v

hydroxide solution and both the organic and aqueous layers were separated. The aqueous layer was extracted twice with toluene. All the organic layers were combined, washed with water followed by sat. sodium chloride solution, dried and distilled to yield the title compound. Yield: 3.4 gm

Method-Ill:

The compound of formula- 10 obtained from Example-9 (5 gm) was dissolved in THF (30 ml) and Lithium aluminium hydride (2.5 gm) suspension (LAH in 30 ml THF) at 0°C and stirred for 15 minutes. Water was added to the reaction mixture and filtered the obtained reaction mixture. Seperated the layers from the filtrate and dried the organic layer. Distill-off the organic layer to get the title compound. Yield: 3.8 gm

Example-11: Preparation of asenapine maleate (formula- la)

Maleic acid (41.1 grams) in isopropyl alcohol (300 ml) was added to asenapine (92 grams) in isopropyl alcohol (500 ml) at 60-65°C over a period of 30 minutes and stirred for 15 minutes at the same temperature and then stirred for 1 hour at RT. Isopropyl alcohol (184 ml) was added to the above reaction mass and stirred for 12 hours at -10 to -5°C. Filtered, washed with isopropyl alcohol and dried to yield the title compound. Yield: 108 grams

Example-12: Purification of asenapine maleate (formula-la): Stirred the crude asenapine maleate (45 grams) in ethanol (225 ml) for 15 minutes at 65-70°C and followed by 3 hours at RT. The reaction mass was filtered, washed thrice with ethanol and dried to yield pure asenapine maleate compound of formula- la. Yield: 25.7 gms

Example-13: Preparation of asenapine maleate form-H:

Stirred asenapine maleate (90 grams) in ethanol (225 ml) for 15 minutes at 60- 65°C. The reaction mass was treated with carbon and stirred for 10 minutes at 60-65°C. Filtered the reaction mass, filtered mi's were stirred for 10 minutes at 60-65°C and slowly cooled to 18-22°C over a period of 2 hours. The reaction mass was stirred for 4 hours at -15 to -10°C. Filtered, washed with ethanol and dried to yield asenapine maleate form-H. Yield: 78 gm; PSD: D₁₀= 0.918 μιη, D₅₀ = 2.635 μπι, D₉₀ = 6.832 um, Dioo ⁼ 47.95 μπι; Specific surface area: 3.13 m²/g Exmaple-14: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-lH-dibenz

[2,3:6,7] oxepino[4,5-c] pyrrole oxalate:

A mixture asenapine maleate (5 gm), water (50 ml) and methylene chloride (25 ml) was stirred for 15 minutes at RT at pH 9.3 (adjusted with 10% sodium hydroxide). Both the organic and aqueous layers were separated; the aqueous layer was again extracted with methylene chloride. Both the organic layers were combined, dried with sodium sulfate and distilled off the solvent under reduced pressure. Methylene chloride (50 ml) was added to the above reaction mass followed by ethyl chloro formate (2.8 gm) and stirred for 45 minutes at RT. After the reaction completed, distilled off the solvent completely. Toluene (10 ml) followed by poly ethylene glycol (20 ml) and sodium hydroxide (2 gm) were added to the above reaction mass at RT and stirred for 14 hours at 125-130°C. After the reaction completed, the reaction mass was cooled to RT and the reaction mass was quenched with water. Ethyl acetate was added to the reaction mass and both the organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate. Combined both the organic layers, washed with water followed by sat.brine solution and then dried and distilled to remove the solvent completely under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel. Elution with cyclohexane/ethylacetate (1: 1) followed by methanol/ethylacetate gave the trans-5-chloro-2,3,3a,12b-tetrahydro-lH-dibenz [2,3:6,7]oxepino[4,5-c]pyrrole compound.

The obtained pure residue in ethanol (25 ml) was added oxalic acid (1.2 gm) and heated to 60-65°C to obtain a clear solution and then cooled to RT. The reaction mass was stirred for 2 hours at 5-10°C. The reaction mass was filtered, washed with ethanol and dried to yield oxalate salt of title compound.

Yield: 0.7 gms; FT-IR (KBr) 769.39, 1445.73, 1480.17 cm^"1; 1H NMR (CDC1₃) 3.470- 3.506 (d, 2H), 3.682 (d, 2H), 3.696-3.746 (q, 2H), 7.01-7.32 (m, 7H) δ; MS (LCMS) 272 (M⁺+1).

Example-15: Preparation of (3aRS,12bRS)-2-methyl-2,3,3a,12b-tetrahydro-lH dibenz [2,3:6,7]oxepino[4,5-c] pyrrole oxalate:

Stage-a: Preparation of trans-2,3,3a,12b-tetrahydro-2-methyI-lH-dibenz[2,3:6,7] oxepino [4,5-c] py rrol-1 -one

A solution of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz

[2,3:6,7]oxepino[4,5-c]pyrrol-l-one (5 gm) in methanol (500 ml) treated with Pd-C (7.5 gm) under nitrogen at a pressure of 2.0 kg H₂. The reaction mass was stirred for 3 hours at RT. Filtered the reaction mass, washed with methanol and distilled under reduced pressure to yield title compound. Yield: 4 gm

Stage-b: Preparation of (3aRS,12bRS)-2-methyl-2,3,3a,12b-tetrahydro-lHdibenz

[2,3:6,7]oxepino[4,5-c] pyrrole oxalate:

10% lithium aluminium hydride solution (prepared by dissolving 1.57 gm lithium aluminium hydride in 40 ml of THF at 5-10°C) was added to aluminium chloride solution (prepared by dissolving aluminium chloride (3.11 gm) in portion wise to THF (40 ml) at below 5°C and stirred for 15 minutes) over a period of 30 minutes at -5 to +5°C and stirred for 15 minutes at the same temperature. Added a solution of trans- 2,3,3a, 12b-tetrahydro-2-methyl- 1 H-dibenz[2,3 :6,7]oxepino[4,5-c]pyrrol- 1 -one (4 gm) in THF (40 ml) to the above reaction mass for about 45 minutes at -5 to +5°C and stirred further 45 minutes at the same temperature. After completion of the reaction, the reaction was quenched with 2.4% of sodium hydroxide solution at 0-5°C. Toluene and water were added to the reaction mass at RT. Filtered the reaction mass and separated both the organic and aqueous layers; the aqueous layer was extracted with toluene. Combined both the organic layers, washed with water, dried and distilled to remove the solvent completely to obtain a residue of title compound. To the obtained residue (3 gm) in ethanol (20 ml), a solution of oxalic acid (0.96 gm) in ethanol (10 ml) was added for about 30 minutes at RT. Filtered, washed with ethanol and dried to yield oxalate salt of title compound.

Yield: 2 gm;

FT-IR (KBr) 770.16, 1457.33, 1486.96, 2346.86 cm^"1; 1H NMR (CDC1₃) 2.93-2.86 (s, 3H), 3.84-3.94 (d, 4H), 3.63-3.66 (q, 2H), 7.18-7.33 (m, 8H) δ; MS (LCMS) 251 ( *+l).

Example-16: Preparation of (SaRS^bRSJ-S-chloro^-methyl-Z^a^b- tetrahydro -lHdibenz[2,3:6,7]oxepino[4,5-c]pyrrole-N-oxide:

Methylene chloride (25 ml) was added to a mixture of asenapine maleate (la) (5 gm) and water (50 ml) and stirred for 15 minutes at P^H 9-9.5 (adjusted by 10% sodium hydroxide solution). Both the organic and aqueous layers were separated; the aqueous layer was extracted with methylene chloride. Both the organic layers were combined, dried and distilled under reduced pressure to obtain a residue (3.8 gms). To the obtained residue in methylene chloride (75 ml) was added 30% hydrogen peroxide (30 ml) at RT. After the reaction was completed, the reaction mass cooled to 5-10°C and the reaction was quenched with 10% sodium sulphite solution. Both the organic and aqueous layers were separated; the aqueous layer was extracted with methylene chloride. Combined all the organic layers, dried and distilled under reduced pressure to obtain a solid.

Yield: 2.6 grams;

FT-IR (KBr) 768, 1444.36, 1480.79, 2776.16 cm ¹; NMR (CDC1₃) 3.083 (s, 3H), 3.938 (s, 4H), 3.696-3.746 (q, 2H), 7.01-7.32 (m, 7H), 6.30 (s, 2Η)δ; MS(LCMS) 302 (M⁺+1). Example-17: Preparation of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7] oxepino[4,5-c] pyrrol- 1-one (formula-11). To a mixture of magnesium(19.5 grams) and iodine (0.8 grams) in 1000 ml of methanol added 5-chloro-2,3-dihydro-2-methyl-lH-dibenz [2,3:6,7] oxepino [4,5- c]pyrrol-l-one (40 grams) at 25-30°C and stirred the reaction mixture for 30 minutes at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 1 hour at reflux. After completion of the reaction, the reaction mixture was cooled to 25-30°C and water (400 ml) was added. Adjusted the pH of the reaction mixture to 6.5 by using 20% dil.HCl at 10-15°C. Ethyl acetate (600 ml) was added to the reaction mixture and stirred for 30 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with 10% NaCl solution. Distilled off the solvent completely under reduced pressure. 120 ml of isopropyl alcohol was added to the obtained residue and the reaction mixture was cooled to 0-5°C. Stirred the reaction mixture for 2 hrs at 0-5°C. Filtered the obtained solid, washed with isopropyl alcohol and dried to get the title compound.

Yield: 20 grams; Melting Point: 148-151°C.

Example-18: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formuIa-10).

To a solution of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7]oxepino[4,5-c]pyrrol-l-one (15 grams) in toluene (225 ml) added DBU (3.8 grams) at 15-20°C. The reaction mixture temperature was raised to 25-30°C and stirred for 12 hrs. Water (150 ml) was added to the reaction mixture followed by the addition of acetic acid (5 ml). Stirred the reaction mixture for 10 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene (45 ml). Distilled off the solvent completely under reduced pressure. Isopropyl alcohol (45 ml) was added to the obtained residue and heated to reflux temperature. The reaction mixture was cooled to 50-55°C and unwanted precipitate was removed by filtration. Distilled off the solvent completely from filtrate under reduced pressure to get the title compound (trans - isomer). Yield: 7.3 grams: Melting Point: 140-143°C. Example-19: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formula-10). To a solution of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula- 1 1 (15 grams) in toluene (225 ml) added DBU (3.8 grams) at 15-20°C. The reaction mixture was raised to 25- 30°C and stirred for 10-12 hours. Distilled off the solvent completely under reduced pressure to get the residue which contains mixture of cis and trans-isomers. Methyl tertiary butyl ether (45 ml) was added to the obtained residue and heated to reflux temperature. The reaction mixture was cooled to 50-55°C and unwanted precipitate was removed by filtration. Distilled off the solvent completely from filtrate under reduced pressure to get the title compound (trans - isomer). Yield: 7.0 grams.

Example-20: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formula-10).

To a solution of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-11 (15 grams) in toluene (225 ml) added DBU (3.8 grams) at 15-20°C. The reaction mixture was raised to 25- 30°C and stirred for 10-12 hours. Distilled off the solvent completely under reduced pressure to get the residue which contains mixture of cis and trans-isomers. Petroleum ether (45 ml) was added to the obtained residue and heated to reflux temperature. The reaction mixture was cooled to 50-55°C and unwanted precipitate was removed by filtration. Distilled off the solvent completely from filtrate under reduced pressure to get the title compound (trans - isomer). Yield: 7.8 grams.

Example-21: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formula-10).

To a solution of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz

[2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-11 (15 grams) in toluene (225 ml) added DBU (3.8 grams) at 15-20°C. The reaction mixture was raised to 25- 30°C and stirred for 10-12 hours. Distilled off the solvent completely under reduced pressure to get the residue which contains mixture of cis and trans-isomers. Isopropyl alcohol (45 ml) was added to the obtained residue and heated to reflux temperature. The reaction mixture was cooled to 50-55°C and unwanted precipitate was removed by filtration. Distilled off the solvent completely from filtrate under reduced pressure to get the title compound (trans - isomer).

Yield: 7.1 grams. Example-22: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formula-10)

The solution of mixture of cis and trans isomers of 5-chloro-2,3,3a,12b- tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one (15 grams) in isopropyl alcohol (150 ml) was heated to reflux temperature. The reaction mixture was cooled to 50-55°C and unwanted precipitate was removed by filtration. Distilled off the solvent completely from filtrate under reduced pressure to get the title compound (trans - isomer). Yield: 7.4 grams.

Example-23: Preparation of trans-ll-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formuIa-14).

To a mixture of magnesium(19.5 grams) and iodine(0.8 grams) in 1000 ml of methanol was added 40 grams of 1 l-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino [4,5-c] pyrrol- 1 -one at 25-30°C and stirred the reaction mixture for 30 minutes at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 1 hr at reflux. After completion of the reaction, the reaction mixture was cooled to 25-30°C and water (400 ml) was added. Adjusted the pH of the reaction mixture to 6.4 by using 20 % dil. HC1 at 10-15°C. Ethyl acetate (600 ml) was added to the reaction mixture and stirred for 30 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with 10% NaCl solution. Distilled off the solvent completely under reduced pressure. Isopropyl alcohol (120 ml) was added to the obtained residue. The reaction mixture was cooled to 0-5°C and stirred for 2 hrs. Filtered the obtained solid, washed with isopropyl alcohol and dried to get the title compound. Yield: 21 grams. Example-24: Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formula-10). To a solution of cis-l l-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula- 13 (15 grams) in toluene (225 ml) was added DBU (3.8 grams) at 15-20°C. The reaction mixture was raised to 25-30°C and stirred for 10-12 hours. Distilled off the solvent completely under reduced pressure to get the residue which contains mixture of cis and trans-isomers. Isopropyl alcohol (45 ml) was added to the obtained residue and heated to reflux temperature. The reaction mixture was cooled to 50-55°C and unwanted precipitate was removed by filtration. Distilled off the solvent completely from filtrate under reduced pressure to get the title compound (trans - isomer). Yield: 7.5 grams: Melting Point: 140-143°C.

Formulation Examples: Example-(i):

Table- 1: Composition of Tablets equivalent to 10 mg and 5mg of asenapine.

Manufacturing process:

Asenapine maleate was mixed with microcrystalline cellulose to get uniform mass. Then povidone taken in isopropyl alcohol was added to the mixture of Asenapine maleate and microcrystalline cellulose to provide granules, which were air dried and and passed through 30 mesh The mixture of F-Melt, croscarmellose sodium, Aspartame, Peppermint was prepared and passed through 40 mesh. The mixture was then added to the the air dried granules. Magnesium stearate was then passed though 60 mesh and mixed with the above ingredients throughly to get a uniform mass, which was compressed into tablets. Example-(ii):

Table-2: Composition of 10 mg asenapine sublingual tablets:

Manufacturing process:

Asenapine maleate was mixed with microcrystalline cellulose to get uniform mass. Then PVP K-90 taken in isopropyl alcohol and added to the mixture of Asenapine maleate and microcrystalline cellulose to provide granules, which were air dried and sieved. The mixture of F-Melt, crospovidone, aspartame, peppermint flavour was prepared and sieved. The mixture was then added to the the air dried granules. Magnesium stearate was then sieved and mixed with the above ingredients thoroughly to get a uniform mass, which was compressed into tablets. TabIe-3: Physico chemical properties of the sublingual tablet of example-(ii)

Example-(iii):

Table-4: Composition of Tablets equivalent to 10 mg and 5mg of asenapine.

Manufacturing process:

The above composition was prepared according to the Example-(i), except that crospovidone was used in place of croscaramellose sodium Example-(iv):

Table-5: Composition of Tablets equivalent to 10 mg and 5mg of asenapine.

Manufacturing process:

Asenapine maleate was mixed with microcrystalline cellulose to get uniform mass. Then povidone taken in isopropyl alcohol was added to the mixture of Asenapine maleate and microcrystalline cellulose to provide granules, which were air dried and and passed through 30 mesh The mixture of Pearlitol flash , croscarmellose sodium, Aspartame, Peppermint was prepared and passed through 40 mesh. The mixture was then added to the the air dried granules. Magnesium stearate was then passed though 60 mesh and mixed with the above ingredients throughly to get a uniform mass, which was compressed into tablets. Example-(v):

Table-6: Composition of Tablets equivalent to 10 mg and 5mg of asenapine.

Manufacturing process: The above composition was prepared according to the Example-3, except that crospovidone was used in place of croscaramellose sodium. Example-(vi):

Table-7: Composition of 5 mg asenapine sublingual tablets:

Manufacturing process:

Asenapine maleate was mixed with macrocrystalline cellulose to get uniform mass. Then PVP K-90 taken in isopropyl alcohol was added to the mixture of Asenapine maleate and microcrystalline cellulose to provide granules, which were air dried and sieved. The mixture of F-Melt, crospovidone, aspartame, peppermint flavour, brilliant blue was prepared and sieved. The mixture was then added to the air dried granules. Magnesium stearate was then sieved and mixed with the above ingredients thoroughly to get a uniform mass, which was compressed into tablets.

Test Example- 1: Stability test:

v

The sublingual tablets of example (ii) of the present invention were evaluated as per the ICH guide lines. The sublingual tablets were stored at 40°C and 75%RH for 1, 2, 3 & 6 months.

Table-8:

It can be seen from the above data given above, the sublingual tablets made in accordance with the present invention displayed excellent stability characteristics under accelerated stability conditions of 40°C/75%RH even after 6 months.

Test Example-2: Dissolution Profile Test:

A comparative dissolution test was carried out with Example-(ii) of the present invention and Saphris. Figures 1-4 show the result of the comparative dissolution test. Based on the results of figures 1-4 and tables 9-12, Table- 13 shows the two pharmaceutical preparations were equivalent in all dissolution mediums. Therefore, a pharmaceutical drug containing asenapine maleate in the present invention is expected to have superior activity of treatment from the uniform dissolution pattern.

Comparative dissolution profile of Example-(ii) of the present invention and Saphris: Dissolution medium: 900 ml of 0.1N HC1

Dissolution apparatus: USP type-II, 50RPM

Table-9:

Comparative dissolution profile of Example-(ii) of the present invention and Saphris: Dissolution medium: 900 ml of pH 4.5 buffer

Dissolution apparatus: USP type-II, 50RPM

Table-10

Comparative dissolution profile of Example-(ii) of the present invention and Saphris: Dissolution medium: 900 ml of pH 6.5 buffer

Dissolution apparatus: USP type-II, 50RPM

Table-11

Comparative dissolution profile of Example-(ii) of the present invention and Saphris: Dissolution medium: 900 ml-of pH 7.4 buffer

Dissolution apparatus: USP type-II, 50RPM

Table-12

Table-13 Analysis of bioequivalance according to the analogous properties:

Claims

We Claims:

1. A process for the preparation of asenapine, compound of formula- 1 ,

Formula- 1

which comprising of reducing trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-10

Formula- 10

with a suitable reducing agent in a suitable solvent to provide compound of formula- 1, characterized in that the reducing agent is selected from BF₃- etherate/sodium borohydride, lithium aluminium hydride (LAH), vitride, sodium borohydride/aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN.

A process for the preparation of asenapine compound of formula- 1 comprising of reducing trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c] pyrrol- 1 -one compound of formula-10 with BF₃-etherate/sodium borohydride in tetrahydrofuran.

A process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl- lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-10, which comprising of reducing 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino [4,5-c]pyrrol-l-one compound of formula-9

Formula-9

with a suitable reducing agent in presence of an activator in a suitable solvent to provide compound of formula- 10, characterized in that the reduction is carried out in the presence of proton donor like formic acid or acetic acid.

4. An improved process for the preparation of asenapine maleate compound of formula- la, which comprising of the following steps:

a) Esterification of 2-chlorophenyl acetic acid compound of formula-2

Formula-2

with alcohol in presence of an acid to provide alkyl 2-chlorophenylacetate compound of general formula-3,

Formula-3

where 'R' refers to C1-C4 alkyl

b) condensation of the compound of formula-3 with 4-chloro phenol compound of formula-4

Formula-4

in the presence of a base, Cu catalyst and a ligand in suitable solvent provides 2- (2-(4-chlorophenoxy)phenyl)acetic acid ester which is insitu hydrolyzed in the presence of a base in a suitable solvent to provide 2-(2-(4-chlorophenoxy) phenyl)acetic acid, followed by reaction with a suitable amine in a suitable solvent to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid amine salt compound of general formula-5,

. Amine

Formula-5

c) converting the compound of general formula-5 into free base by treating with a suitable acid in a suitable solvent and in-situ treating it with 2- (methylamino)acetic acid e formula-6

Formula-6

in presence of a suitable reagent in a suitable solvent produces alkyl 2-(2-(2-(4- chlorophenoxy)phenyl)-N-methylacetamido)acetate compound of general formula-7,

Formula-7

d) reacting the compound of general formula-7 in presence of a suitable reagent in a suitable solvent produces 3-(2-(4-chlorophenoxy)phenyl)-l -methyl pyrrolidine-2,4-dione compound of formula-8,

Formula-8

e) cyclization of the compound of formula-8 with a suitable dehydrating agent in a suitable solvent, followed by purification from a suitable solvent to provide pure 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l- one compound of formul -9,

Formula-9

f) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent, followed by recrystallization with suitable solvent to provide the desired compound trans-5-chloro-2,3 ,3 a, 12b-tetrahydro-2-methyl- 1 H-dibenz [2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula- 10,

Formula- 10

g) reducing the compound of formula- 10 with a suitable reducing agent in a suitable solvent to provide asenapine compound of formula- 1,

h) reacting the asenapine compound of formula- 1 with maleic acid in a suitable solvent, followed by recrystallization with a suitable solvent to provide asenapine maleate compound of formula- la.

5. An improved process for the preparation of asenapine maleate compound of formula- la, which comprising of the following steps:

a) Esterification of 2-chlorophenyl acetic acid compound of formula-2

Formula-2

with methanol in presence of sulfuric acid to provide methyl 2- chlorophenylacetate c

Formula-3a

b) condensation of compound of formula-3a with 4-chloro phenol compound of formula-4 in the presence of Cs₂C0₃, CuCl and dimethyl glycine in dioxane provides 2-(2-(4-chlorophenoxy)phenyl)acetic acid ester which is insitu hydrolyzed in the presence of KOH in methanol to provide 2-(2-(4- chlorophenoxy)phenyl)acetic acid, which on in-situ reaction with tributyl amine in pet.ether to provide 2-(2-(4-chlorophenoxy)phenyl)acetic acid tributyl amine salt compound of formula-5a,

Formula-5a

c) treating the compound of formula-5a with hydrochloric acid in ethyl acetate and water to provide its free acid, which on in-situ reaction with methyl 2- (methylamino)acetate compound of formula-6a in presence of DCC in combination with DMAP in methylene chloride provides methyl 2-(2-(2-(4- chlorophenoxy)phenyl)-N-methylacetamido) acetate compound of formula-7a, d) reacting the compound of formula-7a with potassium tertiary butoxide in toluene provides 3-(2-(4-chlorophenoxy)phenyl)- 1 -methylpyrrolidine-2,4-dione, compound of formula-8,

e) cyclization of the compound of formula-8 with polyphosphoric acid or P₂0₅ and phosphoric acid in xylene, followed by purification of the obtained compound in methanol to provide pure 5-chloro-2,3-dihydro-2-methyl-lH-dibenz [2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-9,

1 -one compound of formula- 10,

g) reducing the compound of formula- 10 with BF₃-etherate and sodium boro hydride in THF to provide asenapine compound of formula- 1,

An improved process for the preparation of asenapine maleate compound of formula- la, which comprising of the following steps:

a) Condensation of 2-chlorophenyl acetic acid compound of formula-2 with 4- chloro phenol compound of formula-4 in the presence of K₂C0₃, CuCl in toluene provides 2-(2-(4-chlorophenoxy)phenyl)acetic acid compound of formula- 15,

Formula- 15

b) treating the compound of formula- 15 with methyl 2-(methylamino)acetate compound of formula-6a in presence of DCC in combination with DMAP in methylene chloride provides methyl 2-(2-(2-(4-chlorophenoxy)phenyl)-N- methylacetamido) acetate compound of formula-7a,

e) reducing the compound of formula-9 with Mg in presence of I₂ in methanol and formic acid in toluene and methanol mixture, followed by recrystallization of the obtained compound from methanol provides the desired compound trans-5- chloro-2,3,3a, 12b-tetrahydro-2-methyl- 1 H-dibenz[2,3 :6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10,

f) reducing the compound of formula- 10 with lithium aluminium hydride (LAH) in tetrahydrofuran to provide asenapine compound of formula- 1,

Stable crystalline form H of asenapine maleate under micronization.

The stable crystalline form of claim-7, wherein the particle size distribution has a D 0 of 100 urn or less.

An improved process for the preparation of stable asenapine maleate form-H, which comprising of:

a) Stirring asenapine maleate in ethanol for 15 minutes at 60-65°C,

b) subjecting the reaction mixture to carbon treatment,

c) stirring for 10 minutes at 60-65°C,

d) cooled to - 15°C to - 10°C over a period of 2 hours,

e) filtered, washed with ethanol and dried to get the stable crystalline form H of asenapine maleate.

10. Novel amine salts of 2-(2-(4-chlorophenoxy)phenyl)acetic acid represented by the following structural formula:

1 1. Amine salt of 2-(2-(4-chlorophenoxy)phenyl)acetic acid according to claim-8 is selected from methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, isobutyl amine, sec-butyl amine, tertiarybutyl amine, dimethyl amine, diethyl amine, di(n-propyl)amine, di(isopropyl)amine, di(n-butyl)amine, di(isobutyl)amine, di(sec-butyl)amine, di(tertiarybutyl)amine, trimethyl amine, triethyl amine, tri(n-propyl)amine, tri(isopropyl)amine, tri(n-butyl)amine, tri(isobutyl)amine, tri(sec-butyl)amine and tri(tertiarybutyl)amine.

12. An improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2- methyl-lH-dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-10, comprising of;

Formula-10

Formula- 11 and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable inert solvent and heating the reaction mixture at a suitable temperature for a suitable period of time,

b) distilling off the solvent to provide a residue,

d) lowering the temperature of the solution to precipitate a solid,

e) filtering off the solid obtained and collecting the filtrate,

13. A process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl- lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-10, comprising of;

a) Suspending a mixture of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula- 11 and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable inert solvent, and heating the reaction mixture at a suitable temperature for a suitable period of time, b) distilling off the solvent to provide a residue,

d) filtering the suspension and collecting the filtrate,

e) distilling off the solvent from the filtrate obtained in step-d), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula-10.

14. A process according to claim- 12 and 13, wherein the suitable inert solvent used in step-a) is selected from "hydrocarbon solvents" like toluene, hexane, heptane preferably toluene and cyclohexane; and "chloro solvents" like dichloromethane, dichloroethane, carbon tetrachloride and chloroform or their mixture thereof.

15. A process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7]oxepino[4,5-c] pyrrol-l-one compound of formula-10, comprises of;

a) Suspending a mixture of cis and trans isomers of 5-chloro-2,3,3a,12b- tetrahydro-2 -methyl- 1 H-dibenz[2,3 ,6,7]oxepino[4,5-c]pyrrol- 1 -one in isopropyl alcohol,

b) heating the suspension to higher temperature,

c) filtering the suspension and collecting the filtrate,

d) distilling off the solvent from the filtrate obtained in step-c), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula-10.

16. A process for the preparation of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-11, comprising of;

a) Reacting the 5-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c] pyrrol-l-one compound of formula-9

Formula-9

with magnesium in presence of catalytic amount of iodine in methanol, b) heating the reaction mixture to reflux temperature and stirring the reaction mixture

c) cooling the reaction mixture and quenching the reaction mixture with water, d) adding ethyl acetate to the reaction mixture and stirred,

e) concentrating the organic layer obtained in step-c) and adding an appropriate amount of isopropyl alcohol and concentrate to obtain cis-5-chloro-2,3,3a,12b- tetrahydro-2-methyl- 1 H-dibenz[2,3 ,6,7]oxepino[4,5-c]pyrrol- 1 -one compound of formula-1 1 as a solid, f) filtering the mixture to isolate the solid and optionally recrystallizing it using isopropyl alcohol to provide pure cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl- lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-11.

17. An improved process for the preparation of trans- l l-chloro-2,3,3a,12b-tetrahydro- 2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-14, comprising of,

a) Suspending a mixture of cis-l l-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-13 and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable inert solvent, and heating the reaction mixture at a suitable temperature for a suitable period of time,

B) distilling off the solvent to provide a residue,

e) filtering off the solid obtained and collecting the filtrate,

f) distilling off the solvent from the filtrate obtained in step-e), to provide trans- 1 l-chloro-2,3,3a,12b-tetrahydro-2 -methyl- lH-dibenz[2,3,6,7]oxepino[4,5- c]pyrrol-l-one compound of formula-14.

18. A process for the preparation of trans-1 l-chloro-2,3,3a,12b-tetrahydro-2-methyl- lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-14, comprising of,

a) Suspending a mixture of cis-l l-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-13 and 1,8- Diaza bicycle [5.4.0]undec-7-ene (DBU), in a suitable inert solvent, and heating the reaction mixture at a suitable temperature for a suitable period of time, b) distilling off the solvent to provide a residue,

d) filtering the suspension and collecting the filtrate, e) distilling off the solvent from the filtrate obtained in step-d), to provide trans- l l-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5- c]pyrrol-l-one compound of formula- 14. 19. A process according to claim- 17 and 18, wherein the suitable inert solvent used in step-a) is selected from "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; and "chloro solvents" like dichloromethane, dichloroethane, carbon tetrachloride and chloroform or their mixture thereof. 20. A process according to claim 12-18, the suitable temperature is 0°C to reflux temperature of the solvent used in the reaction and the suitable time period is up to the conversion of '.eis' isomer into 'trans' isomer.

21. A process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-10, which comprising of,

c) adding a suitable solvent to the residue obtained in step-b) and heating the suspension to high temperature to get a clear solution,

e) filtering off the solid obtained and collecting the filtrate,

f) distilling off the solvent from the filtrate obtained in step-e), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula-10.

22. A process according to claim 21, the solvent used in step-c) is methyl tertiarybutyl ether, hexane, heptane, diethyl ether, diisopropyl ether cyclohexane and petroleum ether.

23. A novel and orally disintegrating sublingual pharmaceutical composition comprising of, asenapine or its salts in combination with one or more of, h) Diluent(s),

i) binding agent(s),

j) solvents or binding fluids,

k) disintegrating agent(s),

1) lubricant(s),

m) sweetener(s),

n) flavoring agent(s) and optionally coloring agent(s).

24. A pharmaceutical composition according to claim-23, wherein the salt is selected from oxalate, maleate and succinate, preferably maleate salt.

25. An orally disintegrating sublingual pharmaceutical composition according to claim- 23, wherein the diluents are selected from microcrystalline cellulose, pearlitol flash and F-Melt or their mixture thereof.

26. An orally disintegrating sublingual pharmaceutical composition according to claim- 23, wherein the disintegrating agent is selected from either cross-linked sodium carboxymethyl cellulose(Ac-di-sol) and crospovidone; the binding agent is selected from povidone; flavoring agent is selected from peppermint flavor, strawberry flavor, magnasweet, grape flavor and black cherry flavor; sweetener is selected from aspartine, acesulfam potassium, sucralose, saccharine and sugars; and the lubricant is magnesium stearate.

27. A pharmaceutical composition according to claim-23, characterized in that the weight % of asenapine maleate is about 1% to 30%, preferably 2% to 25% by weight of the total composition.

28. A process for preparation of an oral disintegrating sublingual pharmaceutical composition by wet granulation method comprising;

h) Mixing asenapine maleate and diluent,

i) dissolving the binder in a suitable binder fluid or solvent,

j) adding the above formed binder solution to the mixture obtained in step-a), k) drying the above obtained granules,

1) adding the mixture of second diluent, disintegrant, sweetening agent and flavouring agent to the granules obtained in step-d,

m) adding the lubricant to the above mixture,

n) compressing the above blend into tablets.

29. An orally disintegrating sublingual pharmaceutical composition, which comprising of;

a) Therapeutical amount of asenapine maleate,

b) microcrystalline cellulose,

c) F-melt,

d) crospovidone,

e) povidone,

f) magnesium stearate,

g) aspartame and

h) peppermint flavour.

30. An orally disintegrating sublingual pharmaceutical composition, which comprising of;

i) Therapeutical amount of asenapine maleate,

j) microcrystalline cellulose,

k) F-melt,

1) crospovidone,

m) povidone,

n) magnesium stearate,

o) aspartame,

p) brilliant blue and q) peppermint flavour. 31. An orally disintegrating sublingual pharmaceutical composition, which comprising of;

a) Therapeutical amount of asenapine maleate,

b) microcrystalline cellulose,

c) F-melt,

d) croscarmellose sodium,

e) povidone,

f) magnesium stearate,

g) aspartame and

h) peppermint flavour.

32. A pharmaceutical composition according to claim-23, characterized in that the said composition is in the form of uncoated or coated sublingual tablet.

33. An uncoated or coated sublingual tablet according to claim-32, characterized in that the hardness of the said tablet is not less than 2 kg, preferably 2 to 4 kg.

34. An uncoated or coated sublingual tablet according to claim-32, characterized in that the dispersion time of the said tablet is in the range of 35-60 seconds.

35. An uncoated or coated sublingual tablet according to claim-32, characterized in that the diameter of the said tablet is in the range of 5 mm to 7 mm preferably of 6 mm.

36. An uncoated or coated sublingual tablet according to claim-32, characterized in that the dissolution time of the said tablet is in the range of 5 minutes to 10 minutes with 80% to 100% dissolution respectively.

37. 2-(2-(4-chlorophenoxy)phenyl)acetic acid tributyl amine salt compound of formula-5a:

Formula-5a

38. Use of novel amine salts of 2-(2-(4-chlorophenoxy)phenyl)acetic acid compound of general formula-5 in the preparation of asenapine maleate compound of formula- la.

Dated this day H ^S of September 2011.

(Manne Satyanarayana Reddy) MSN Laboratories Limited.

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