DESC:The following specification particularly describes the application and the manner in which it is to be performed:

CRYSTALLINE FORM OF ASENAPINE

FIELD OF THE INVENTION
The present application relates to a crystalline form of Asenapine free base, processes for its preparation and pharmaceutical formulation thereof.

BACKGROUND
Asenapine is chemically described as trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole or (3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole, and is represented by structural Formula I.

Asenapine, described for the first time in US patent 4,145,434, is suitable for the treatment of central nervous system disorders, particularly schizophrenia, due to its ability to act as receptor antagonist of dopamine and serotonin. Asenapine is marketed as the maleic acid salt under the trade name SAPHRIS®.
There were many publications describing process for the preparation of Asenapine free base but none of prior art publications isolated asenapine free base as a crystalline form. Isolating a pharmaceutical compound in crystalline form may provide advantages with desirable processing properties, such as ease of handling, ease of processing, storage stability and ease of purification in free base form. Such properties may significantly influence the processing, shelf life, and commercial acceptance of a product.
There remains a need to provide a crystalline form of Asenapine free base and process for making the same.

SUMMARY OF THE INVENTION
In the first embodiment, the present application provides a crystalline form of Asenapine free base.
In the second embodiment, the present application provides a crystalline form of Asenapine free base characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 8.9°, 18.0° and 21.5° ± 0.2°2?.
In the third embodiment, the present application provides a process for the preparation of crystalline form of Asenapine free base, comprising:
a) taking a salt of Asenapine in a solvent to obtain a mixture,
b) treating the mixture obtained in step (a) with a base;
c) isolating crystalline form of Asenapine free base.
In the fourth embodiment, the present application provides a process for the preparation of crystalline form of Asenapine free base having peaks expressed in degrees 2? at about 8.9°, 18.0° and 21.5° ± 0.2°2?, comprising:
a) taking a salt of Asenapine in a solvent to obtain a mixture,
b) treating the mixture obtained in step (a) with a base;
c) isolating crystalline form of Asenapine free base having peaks expressed in degrees 2? at about 8.9°, 18.0° and 21.5° ± 0.2°2?.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of X-ray diffraction pattern of crystalline form of Asenapine free base.

DETAILED DESCRIPTION
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1% of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C
In the present application, the isolation of products after completion of the reactions can be effected by removing the solvent. Suitable techniques which can be used for the removal of the solvent include evaporation techniques such as evaporation using a Büchi® Rotavapor®, spray drying, thin film drying, nauta drying, tray drying, freeze drying (lyophilization) or any other suitable technique.
Isolated product can be optionally further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, Büchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
In an aspect, the present invention provides a crystalline form of Asenapine free base. The crystalline form of Asenapine free base can be characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 8.9°, 18.0° and 21.5° ± 0.2°2?. It may be further characterized by XRD peaks located at about 10.9°, 11.2°, 13.1° and 22.6° ± 0.2°2?.
Figure 1 shows typical X-ray powder diffraction pattern of crystalline Asenapine free base.
In an aspect, the present invention provides a crystalline form of Asenapine free base, characterized by an X-ray powder diffraction pattern substantially as illustrated by Figure 1.
In another aspect, the present application provides a process for preparing crystalline form of Asenapine free base, comprising:
a) taking a salt of Asenapine in a solvent to obtain a mixture,
b) treating the mixture obtained in step (a) with a base;
c) isolating, crystalline form of Asenapine free base.
The salt of asenapine used in step a) includes but not limited to maleate, pamoate, hemipamoate, phosphate, di-acid or tri-acid salts, hydrochloride, Hydrobromide. Preferably selected Asenapine maleate is used.
The resulting mixture in step (a) may be a solution or a suspension.
The solvents that may be used for the present invention include, but are not limited to, alcohol, aliphatic hydrocarbon, alicyclic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ester, ether, nitrile, ketone, or mixtures thereof. Alcoholic solvents include, but are not limited to, methanol, ethanol, 1-propanol, 2-propanol or mixtures thereof. Hydrocarbon solvents include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, n-heptane and isoheptane or mixtures thereof. Aromatic hydrocarbon solvents include, but are not limited to, benzene, toluene, xylene and chlorobenzene or mixtures thereof. Ester solvents include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate or mixtures thereof. Halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, or mixtures thereof. Ketone solvents include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone or mixtures thereof. Nitrile solvents include, but are not limited to, acetonitrile, propionitrile, C2-6 nitriles, or mixtures thereof. Preferably heptane is used.
The suitable base includes but not limited to, inorganic bases selected from alkali metal hydroxide such as sodium hydroxide, lithium hydroxide or potassium hydroxide; carbonates of alkali metals such as sodium carbonate, lithium carbonate or potassium carbonate; or bicarbonates of alkali metals such as sodium bicarbonate or potassium bicarbonate or mixtures thereof. Organic bases selected from DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-Diazabicyclo[4.3.0]non-5-ene), DABCO (1,4-diaza-bicyclo[2.2.2]octane), ABCO (1-azabicyclo [2,2,2]octane), TBD (1,5,7-Triazabicyclo[4.4.0]dec-5-ene) or DMAP (4-dimethylaminopyridine), TEA (Triethylamine), DIPEA (N,N-diisopropylethylamine), DIEA (Diethylamine), N-methyl morpholine, lutidine, pyridine or collidine. Preferably sodium bicarbonate is used.
The neutralization can be carried out at atmospheric pressure or under a reduced pressure, at temperatures of less than about 55°C, or less than about 45°C, or less than about 35°C, or any other suitable temperatures. In one variant step (a) can be preferably carried out at room temperature.
The isolation in step (c) may be effected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, concentrating or any other suitable fast evaporation technique. The concentration of the solution can be up to 50% or up to 40% or up to 30% or up to 20% or up to 10 % of the total volume of reaction mass. Optionally, the resultant mixture obtained after concentration may be cooled to a temperature of less than about 300C or less than about 200C or less than about 100C or less than about 50C or less than about 00C or less than about -50C or less than about -100C or less than about -200C. Alternatively, crystalline Asenapine free base may be isolated from the concentrate by adding an anti-solvent. The anti-solvent that may be used for isolation can be selected from but not limited to water, alcoholic solvents include, but are not limited to, methanol, ethanol, 1-propanol, 2-propanol or mixtures thereof. Nitrile solvents include, but are not limited to, acetonitrile, propionitrile, or mixtures thereof, aromatic hydrocarbon solvents include, but are not limited to, benzene, toluene, xylene and chlorobenzene or mixtures thereof, ester solvents include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate or mixtures thereof, halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, or mixtures thereof, ketone solvents include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone or mixtures thereof.
The isolated crystalline form of Asenapine free base may be optionally washed with a solvent or a mixture of solvents.
The isolated crystalline form of Asenapine free base may contain some amount of occluded mother liquor or higher than desired level of impurities. If desired, the crystalline form may be washed with a solvent or a mixture of solvents to wash out the impurities.
Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
In another aspect, the present application provides a process for the preparation of crystalline form of Asenapine free base having peaks expressed in degrees 2? at about 8.9°, 18.0° and 21.5° ± 0.2°2?, comprising:
a) taking a salt of Asenapine in a solvent to obtain a mixture,
b) treating the mixture obtained in step (a) with a base;
c) isolating crystalline form of Asenapine free base having peaks expressed in degrees 2? at about 8.9°, 18.0° and 21.5° ± 0.2°2?.
Asenapine salt used as a starting material in the present application can be any physical form of Asenapine maleate, such as crystalline, amorphous or their mixtures.
Asenapine salt used as a starting material used in the present application is having a purity of at least about 95% or about 96% or about 97% or about 97.5% or about 97.8% or about 97.9% or 98%.
Crystalline form of Asenapine free base obtained in the present application is having a purity of at least about 98% or about 98.5% or about 99% or about 99.5% or about 99.8% or about 99.9% or 100%.
Powder X-ray diffraction (PXRD) data reported herein was obtained by a Bruker AXS D8 Advance Powder X-ray Diffractometer with Lynxeye detector and Copper anode (wavelength 1.5418Å). The diffraction profile was collected using following setting parameters of the diffractometer: the X-Ray tube was operated at a voltage of 40 kV and current of 40 mA; Ni filtered Cu Ka1 radiation (?=1.5418 ?); scan type - continuous mode; scan range (2?) 3° to 45°; step size 0.013° 2?; time per step 0.1 sec.
Thermal analysis was carried out using a Differential Scanning Calorimeter (DSC) (TA Instruments-Q 1000) equipped with refrigerated cooling accessory. The temperature and heat flow was calibrated using Indium. Analysis was performed by taking 3 to 7 mg of the sample encapsulated into aluminium sample pan with pierced lid. The thermogram was recorded from 30°C to 150°C under nitrogen atmosphere of 50 mL/min at a heating rate of 10°C/min.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.
EXAMPLES
Example 1: Preparation of crystalline form of Asenapine free base
In a round bottom flask charge 5.0% NaHCO3 (750 ml) solution and degassed with nitrogen for 20 minutes at 25-30°C. In another round bottom flask charge n-heptane (500 ml) and degassed with nitrogen for 20 minutes at 25-30°C. To this, Asenapine maleate (50 gm) was added and stirred for 5 minutes at 25-30°C. To this, add above sodium bicarbonate solution and stir for 1 hour at 25-30°C. Separate the layers and extract the aqueous layer with n-heptane (500 ml). Combine both organic layers and wash with 5.0% NaHCO3 (50 ml) and 10.0% NaCl (100 ml) solution. Dry the organic layer with sodium sulphate and concentrate the organic layer below 45°C under vacuum until the reaction mass volume reaches approximately up to 30% of the total reaction mass. Cool the reaction mass and stir for 1 hour at 5-10°C. The obtained solid was filtered and dried at 35°C under vacuum for 5h to obtain crystalline Asenapine free base (27 gm).
Example 2: Preparation of crystalline form of Asenapine free base
In a round bottom flask charge n-heptane (3000 ml) and stirred for 5 minutes at room temperature and asenapine maleate (200 gm), 5% NaHCO3 (3000 ml) was added and stirred for 4 hours. Now separate the layers and wash the organic layer with 5% NaHCO3 (1000 ml). Combine both aqueous layers and extract with n-heptane (2000 ml). Now combine both organic layers and wash with 10% NaCl (1000 ml) solution. Filter the organic layer through 0.4 micron filter and distilled under vacuum at 35oC for about 3 hours. The crude was chased with acetonitrile (1200 ml) and to the crude acetonitrile (1200 ml) was added and stirred for 10 minutes. Cooled to 20oC and Asenapine free base (5 gm) seed was added and further cooled to 5oC and water (3600 ml) was added and stirred for about 3 hours at the same temperature. Now filter the solid and washed with water (1200 ml) and dried under vacuum at 35oC to give crystalline Asenapine free base (142.2 gm).
,CLAIMS:We Claim:
1) A process for the preparation of crystalline form of Asenapine having peaks expressed in degrees 2? at about 8.9°, 18.0° and 21.5° ± 0.2°2?, comprising:
a) taking a salt of Asenapine in a solvent to obtain a mixture,
b) treating the mixture obtained in step (a) with a base;
c) isolating crystalline form of Asenapine having peaks expressed in degrees 2? at about 8.9°, 18.0° and 21.5° ± 0.2°2?.
2) The process according to claim 1, wherein salt of Asenapine is selected from a group comprising maleate, pamoate, hemipamoate, phosphate, di-acid or tri-acid salts, hydrochloride, Hydrobromide.
3) The process according to claim 1, wherein the base is selected from a group comprising inorganic and organic bases.
4) The process of claim 3, wherein the base is Sodium bicarbonate.