The present invention provides a process for the preparation of revefenacin and polymorphs thereof. The present invention also provides pharmaceutical compositions comprising the crystalline revefenacin or prepared using the crystalline revefenacin, processes and intermediates for preparing the crystalline revefenacin thereof. The present invention further provides amorphous form, co-crystal and crystalline solvates of revefenacin.

BACKGROUND OF THE INVENTION
Revefenacin having a chemical name; 1-(2-{4-[(4-carbamoylpiperidin-1-yl)methyl]-N-methylbenzamido}ethyl)piperidin-4-yl N-({1,1’-biphenyl}-2-yl) carbamate is represented with structure as follows:

Formula I.

Revefenacin is a novel biphenyl carbamate tertiary amine agent that belongs to the family of the long-acting muscarinic antagonists (LABA). Revefenacin is currently being marketed in United States with brand name YUPELRI® as solution; inhalation dosage form.

US 7,288,657 disclose revefenacin and process for the preparation thereof. US’657 further disclose the process for extraction of revefenacin in isopropyl acetate.

US 8,541,451 disclose crystalline Form III and IV of revefenacin and process of preparation thereof. Form III as disclosed in US’451 is prepared by using toluene and Form IV is prepared by using acetonitrile as solvent.

US 9,249,099 discloses crystalline Form I and II of revefenacin and process of preparation thereof. Form I as disclosed in US’099 is prepared by using acetonitrile and water mixture in the ratio of (1:1) and Form II is prepared by using acetonitrile and methyl tert-butyl ether solvent mixture (1:1). The major drawback of above said process is long duration required for crystallization. As per the disclosure of US’099, it requires more than one day for appearance of crystals which is not suitable reaction conditions to be followed with large scale production. Moreover, the crystals isolated are of low purity i.e. 97-98%. Hence, there is required novel process for preparing crystalline and amorphous forms of revefenacin that are stable, highly soluble and can easily be formulated.

OBJECTIVE OF THE INVENTION
One object of the present invention provides a novel process for the preparation of revefenacin or pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide pure and stable crystalline form of revefenacin or pharmaceutically acceptable salt thereof, wherein said crystalline form is stable for atleast six months at 40oC ± 2oC and at relative humidity of 75% ± 5% RH and can be formulated easily for administering to patients, and wherein said process is reproducible and suitable for large scale production.

Another object of the present invention is to provide a composition comprising pure crystalline forms of revefenacin and atleast one pharmaceutically acceptable carrier.

Another object of the present invention is to provide a composition comprising amorphous revefenacin and atleast one pharmaceutically acceptable carrier.

Another object of the present invention is to provide a process of preparing pharmaceutical composition by using crystalline or amorphous revefenacin.

Another object of the present invention is to provide stable amorphous form of revefenacin and a process for the preparation of stable amorphous form of revefenacin or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable for atleast six months at 40oC ± 2oC and at relative humidity of 75% ± 5% RH and can be formulated easily for administering to patients.

In another object, the present invention provides a co-crystal and crystalline solvate of revefenacin.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for the preparation of revefenacin or pharmaceutically acceptable salt thereof,
a) converting compound of Formula II to Formula III or IV, wherein X is a leaving group, R and R1 are suitable protecting group,
b) reacting the compound of Formula III or IV with compound of Formula V to give compound of Formula VI,
c) converting compound of formula VI to revefenacin of Formula I, and
d) optionally converting revefenacin of Formula I to pharmaceutically acceptable salt
.

In another aspect, the present invention provides a crystalline form of revefenacin or pharmaceutically acceptable salt thereof, wherein said process comprising the step of:
a) treating revefenacin or its pharmaceutically acceptable salt with a suitable solvent;
b) optionally adding another solvent; and
c) isolating crystalline form of revefenacin or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of pure crystalline Form I of revefenacin, wherein said process comprising the steps of:
a) converting compound of Formula VIII to revefenacin in a suitable first solvent;
b) optionally isolating revefenacin from the first solvent of step a) and adding second solvent;
c) optionally adding third solvent either to first solvent of step a) or second solvent of step b); and
d) isolating crystalline Form I of revefenacin.

In one another aspect, the present invention provides a process for the preparation of pure crystalline Form II of revefenacin, wherein said process comprising the steps of:
a) treating revefenacin with a suitable solvent to get a solution;
b) adding a second solvent to the solution of step a); and
c) isolating crystalline Form II of revefenacin.

In another aspect, the present invention provides a stable amorphous form of revefenacin or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of a pure amorphous form of revefenacin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding revefenacin or pharmaceutically acceptable salt thereof in one or more suitable solvent;
b) removing the solvent from step a); and
c) isolating the pure amorphous form of revefenacin or a salt thereof.

In another aspect, the present invention provides a pharmaceutical composition prepared by using amorphous or crystalline Form I or Form II of revefenacin.

In another aspect, the present invention provides a process of preparing pharmaceutical composition using amorphous or crystalline Form I or Form II of revefenacin.

In another aspect, the present invention provides a process of preparing pharmaceutical composition using pure amorphous or pure crystalline Form I or Form II of revefenacin.

In another aspect, the present invention provides a pharmaceutical composition comprising pure crystalline Form I or Form II or pure amorphous form of revefenacin along with atleast one pharmaceutically acceptable excipient, wherein said crystalline form or amorphous form is having purity of about 99.0% and above.

In another aspect, the present invention provides a co-crystal of revefenacin with suitable cocrystal-former.

In another aspect, the present invention provides a process for the preparation of co-crystal of revefenacin, comprising the steps of:
(a) grinding, heating or contacting in solution of revefenacin with a co-crystal former; and
(b) isolating co-crystals comprising the revefenacin and the co-crystal former.

Another aspect of the present invention provides a crystalline solvate of revefenacin.

In another aspect, the present invention provides crystalline solvate of revefenacin, wherein said crystalline solvate is prepared by a process comprising the steps of:
a) dissolving revefenacin in a solvent to get a solution;
b) optionally, cooling to a suitable temperature to get crystals; and
c) isolating the crystals to get crystalline solvate of revefenacin.

DETAILED DESCRIPTION

Drawings:
Fig. 1 represents XRPD of amorphous form of revefenacin.

Definitions:
The terms “amorphous form of revefenacin or a pharmaceutically acceptable salt thereof" and “amorphous revefenacin or a pharmaceutically acceptable salt thereof” indicate that the revefenacin or a salt thereof is present in substantially amorphous state and is substantially free from crystalline form. It may be present in the form of solid dispersion, adsorbate or pharmaceutical composition. "Pure amorphous” denotes that atleast 90%, preferably atleast 95%, more preferably atleast 99% of the revefenacin or a pharmaceutically acceptable salt thereof is amorphous. In other words, “substantially free from crystalline form” preferably means that the amorphous form does not contain more than about 5% w/w of any crystalline form.

The term "co-crystal" according to present invention is defined as solids that are crystalline materials composed of two or more molecules in the same crystal lattice.

The term “pure” as referred in the context of the present invention relates to substance that has purity preferably 99% and more by HPLC and total impurities and/or other polymorphic forms between about 1%w/w to a non-detectable limit, more preferably 99.5% and more of purity by HPLC and total impurities and/or other polymorphic form between about 0.5%w/w and non-detectable limit, and, most preferably, 99.9% and more of purity by HPLC and about 0.1%w/w to a non-detectable limit of total impurities and/or other polymorphic form.

The term “pharmaceutically acceptable salt” or “salt” is used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like.

The term “suitable solvent” as used in the context of the present invention is selected from, but not limited to, the group comprising of alcohols such as 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, methanol, ethanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketone solvents such as methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, acetone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbons such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.

In one embodiment, the present invention provides a process for the preparation of revefenacin or pharmaceutically acceptable salt thereof,
a) converting compound of Formula II to Formula III or IV, wherein X is a leaving group, R and R1 are suitable protecting group,
b) reacting the compound of Formula III or IV with compound of Formula V to give compound of Formula VI,
c) converting compound of Formula VI to revefenacin of Formula I, and
d) optionally converting revefenacin of Formula I to pharmaceutically acceptable salt.

In another embodiment, the protecting groups R and R1 may be same or different and may include, but not limited to, suitable carbon containing moiety. Preferably, the protecting group is selected from tetrahydropyranyl (THP), trityl (triphenylmethyl), methoxymethyl ether (MOM), ß-Methoxyethoxymethyl ether (MEM), Methylthiomethyl ether, benzyl, tert-butoxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz), and ethoxyethyl ethers (EE).

In another embodiment, leaving group used in Formula III may include, but not limited to, halogen, acyloxy, mesylate, tosylate and the like.

In another embodiment, the present invention provides process of preparing revefenacin, or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) converting compound of Formula VI to compound of Formula VIII in presence of suitable solvent;
b) reacting compound of Formula VIII with piperidine-4-carboxamide to get compound of Formula I; and
c) isolating revefenacin and optionally converting to is pharmaceutically acceptable salt
.

In another embodiment, the present invention provides a crystalline form of revefenacin or pharmaceutically acceptable salt thereof, wherein said crystalline form is prepared by a process comprising the step of:
a) treating revefenacin or its pharmaceutically acceptable salt with a suitable solvent;
b) optionally adding another solvent; and
c) isolating crystalline form of revefenacin or pharmaceutically acceptable salt thereof.

In one another embodiment, the crystalline form of revefenacin or pharmaceutically acceptable salt thereof, is having purity of about 99.0% and above.

In another embodiment, the present invention provides a process for the preparation of pure crystalline Form I of revefenacin, wherein said process comprising the steps of:
a) converting compound of Formula VIII to revefenacin in a suitable first solvent;
b) optionally isolating revefenacin from the first solvent of step a) and adding second solvent;
c) optionally adding third solvent either to first solvent of step a) or second solvent of step b); and
d) isolating crystalline Form I of revefenacin.

In another embodiment, the first solvent is either same or different from the second solvent and is selected from, but not limited to, ketones, halogenated solvent, alcohols, hydrocarbons, nitriles, ethers, esters, water and mixture thereof.

In another embodiment, the first and/or second solvent used for preparing crystalline Form I of revefenacin is a polar or non-polar solvent selected from, but not limited to, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, acetone, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, methanol, ethanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, glycerol, octanol, toluene, ethyl acetate, isopropyl acetate, methyl acetate, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, methyl tert butyl ether, dioxane, acetonitrile, propionitrile, butanenitrile, toluene, xylene, hexane, n-heptane, n-pentane, anisole, octane, ethyl benzene, cyclohexane, water and mixture thereof.

In another embodiment, the third solvent is preferably different from first and second solvent and is selected from, but not limited to, the group comprising of ketones, halogenated solvent, alcohols, hydrocarbons, nitriles, ethers, esters, water and mixture thereof.

In a preferred embodiment, the third solvent is selected from the group comprising of water, cyclohexane, heptane, octane, hexane, n-pentane, tetrahydrofuran, methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, n-propyl acetate, butyl acetate, acetone, methyl ethyl ketone, methyl tert butyl ether, diisopropyl ether, acetonitrile, propionitrile, butanenitrile, methanol, ethanol, isopropanol, butanol and mixture thereof.

In another embodiment, the present invention provides pure crystalline Form I of revefenacin, wherein said crystalline form is characterized by:
a) powder x-ray diffraction pattern having peaks at 4.8, 12.7, 16.7, 21.0 ±0.2o?; and
b) having a purity of about 99.0% and above.

In another embodiment, the present invention provides a pure crystalline Form I of revefenacin characterized by a powder x-ray diffraction pattern having peaks at 4.8, 12.7, 16.7, 21.0 ±0.2o?, wherein said crystalline form is stable for atleast six months at 40oC ± 2oC and at relative humidity of 75% ± 5% RH. The pure crystalline Form I of revefenacin of the present invention remains stable and does not convert to any other solid form when stored at a temperature of up to about 40oC and at a relative humidity of about 25% to about 75% for about six months or more.

In one another embodiment, the present invention provides a process for the preparation of pure crystalline Form II of revefenacin, wherein said process comprising the steps of:
a) treating revefenacin with a suitable solvent to get a solution;
b) adding a second solvent to the solution of step a); and
c) isolating pure crystalline Form II of revefenacin.

In another embodiment, the present invention provides pure crystalline Form II of revefenacin, wherein said crystalline form is characterized by:
a) powder x-ray diffraction pattern having peaks at 4.7, 19.5, 24.0 ±0.2o?; and
b) having a purity of about 99.0% and above.

In another embodiment, the present invention provides a pure crystalline Form II of revefenacin characterized by a powder x-ray diffraction pattern having peaks at 4.7, 19.5, 24.0 ± 0.2o?, wherein said crystalline form is stable for atleast six months at 40oC ± 2oC and at relative humidity of 75% ± 5% RH. The pure crystalline Form II of revefenacin of the present invention remains stable and does not convert to any other solid form when stored at a temperature of up to about 40oC and at a relative humidity of about 25% to about 75% for about six months or more.

In another preferred embodiment, the crystalline Forms I and II are isolated with high crystallinity of about 98% and above.

In another embodiment, the present invention provides a process of preparing pharmaceutical composition using amorphous or crystalline Form I or Form II of revefenacin.

In another embodiment, the present invention provides a process of preparing pharmaceutical composition using pure amorphous or pure crystalline Form I or Form II of revefenacin.

In one more embodiment, the present invention provides a method for preparing a pharmaceutical composition of revefenacin comprising the steps of: dissolving revefenacin in an aqueous pharmaceutical carrier to form an aqueous solution; wherein said revefenacin is selected from pure amorphous revefenacin or pure crystalline Form I or Form II of revefenacin.

In one more embodiment, the present invention provides a method for preparing a pharmaceutical composition of revefenacin comprising the steps of:
a) dissolving revefenacin in an aqueous pharmaceutical carrier to form an aqueous solution and
b) adjusting the pH to 5.0;
wherein said revefenacin is selected from pure amorphous revefenacin or pure crystalline Form I or Form II of revefenacin.

In one embodiment, the present invention provides pure amorphous form of revefenacin or pharmaceutical acceptable salt thereof.

In another embodiment, the pure amorphous form of revefenacin of the present invention remains stable and does not convert to any other solid form when stored at a temperature of up to about 40oC and at a relative humidity of about 25% to about 75% for about three months or more.

In another embodiment, the present invention provides pure amorphous form of revefenacin or pharmaceutically acceptable salt thereof, wherein said revefenacin or pharmaceutically acceptable salt thereof is having a chemical purity of atleast 99% or atleast 99.5% or atleast 99.9%.

In another embodiment, the present invention provides a pharmaceutical composition prepared by using amorphous or crystalline Form I or Form II of revefenacin along with atleast one pharmaceutically acceptable excipient, wherein said amorphous or crystalline Form I or Form II is prepared as per the process of the present invention.

In another embodiment, the present invention provides a pharmaceutical composition comprising pure crystalline Form I or Form II of revefenacin along with atleast one pharmaceutically acceptable excipient, wherein said crystalline form possess purity of about 99.0% and above.

In a preferred embodiment, the pharmaceutically acceptable excipients are selected from the group comprising tonicity agent, buffering agent, pH adjusting agent, vehicle or combination thereof. It may optionally comprises surfactants, chelating agent, anti-oxidants or combination thereof.

Suitable buffering agent includes one or more of buffers selected from, but not limited to, citrate, phosphate, acetate, borate, tris, tromethamine, amino acids including but not limited to, glycine, aspartate and histidine or combination thereof. The most preferred buffers are selected from sodium citrate, citric acid or combination thereof.

Suitable tonicity agent includes, but are not limited to, sodium chloride, potassium chloride, glycerine, dextrose, mannitol or combination thereof.

Suitable vehicles are selected from, but not limited to, the group comprising of water for injection, ethanol, glycerine, propylene glycol, polyethylene glycol, corn oil, peanut oil, cotton seed oil or combination thereof.

Suitable pH adjusting agent includes, but are not limited to, hydrochloric acid, sodium hydroxide, succinic acid or combination thereof.

Suitable antioxidants include, water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate sodium sulfite and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and/or combinations thereof.

Suitable chelating include, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and/or combinations thereof.

Suitable surfactants include, such as sorbitan trioleate, oleic acid, lecithin, and glycerin and/or combinations thereof.

In another embodiment, the present invention provides a process for the preparation of a pure amorphous form of revefenacin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding revefenacin or pharmaceutically acceptable salt thereof in one or more suitable solvent;
b) removing the solvent; and
c) isolating the pure amorphous form of revefenacin or a salt thereof.

In another embodiment, solution of revefenacin or a salt thereof may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product.

In another embodiment, crystalline and amorphous form is isolated by extracting from a suitable solvent or by removal of solvent selected from the methods such as solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilization and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of 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, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

In another embodiment, the present invention provides a process for the preparation of amorphous revefenacin or pharmaceutically acceptable salts thereof, comprising the steps of:
a) milling/grinding revefenacin or its pharmaceutically acceptable salts under suitable milling conditions optionally in presence of excipient; and
b) isolating the amorphous form of revefenacin or pharmaceutically acceptable salt thereof.

In a preferred embodiment, any solid forms, either crystalline or amorphous form of revefenacin or its pharmaceutically acceptable salts can be used to mill it with one or more pharmaceutically acceptable carriers.

In another embodiment, the present invention provides a process for the preparation of a pure amorphous form of revefenacin or salt thereof, comprising the steps of:
a) providing a solution of revefenacin or pharmaceutically acceptable salt thereof in a suitable solvent;
b) lyophilizing the solution obtained in step a); and
c) isolating the stable amorphous form of revefenacin or salt thereof.

In another embodiment, the amorphous form of revefenacin or salt thereof, obtained after lyophilization, is isolated by a process such as drying at room temperature, drying under vacuum, or by any known conventional method. Moreover, Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.

In another embodiment, the present application provides pharmaceutical composition comprising pure amorphous form of revefenacin or pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient.

In one more embodiment, the present invention provides a pure amorphous form of revefenacin or pharmaceutically acceptable salt thereof, wherein said amorphous form is substantially free from crystalline form.

In one another embodiment, the present invention provides a process for preparing pure solid forms of revefenacin or salt thereof, wherein said process comprising of:
a) dissolving revefenacin in a suitable solvent and treating with suitable acid or base to form revefenacin salt;
b) neutralizing or desalting the revefenacin salt to give revefenacin free base;
c) optionally converting the revefenacin to its pharmaceutically acceptable salt;
d) providing a solution of revefenacin of step b) or its salt of step c) in a suitable solvent (s); and
e) removing the solvent from the solution obtained in step e) to get pure solid form of revefenacin or pharmaceutically acceptable salt thereof, wherein said solid form is selected from amorphous, or crystalline form of revefenacin.

In an embodiment, a solution of revefenacin or pharmaceutically acceptable salt thereof in a suitable solvent can be prepared at any suitable temperature, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In an embodiment, a solution of revefenacin or salt thereof in a suitable solvent may be filtered to make it clear, free of unwanted particles. In an embodiment, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove coloured components, etc., before filtration.

In another embodiment, the present invention provides a process for the preparation of acid addition salt of revefenacin, comprising the steps of:
a) reacting revefenacin and suitable acid in a solvent; and
b) isolating the acid addition salt revefenacin.

In another embodiment, the present invention provides a co-crystal of revefenacin with suitable co- crystal former.

In another embodiment, the present invention provides a process for the preparation co-crystal of revefenacin, comprising the steps of:
(a) grinding, heating or contacting revefenacin with a co-crystal former; and
(b) isolating co-crystals comprising the revefenacin and the co-crystal former.

The ratio of revefenacin to co-crystal former may be stoichiometric or non-stoichiometric according to the present invention. For example, 1:1, 1:1.5 and 1:2 ratios of revefenacin: co-crystal former are acceptable.

The co-crystals of the present invention are formed where the revefenacin and co-crystal former are bonded together through hydrogen bonds. Other non-covalent interactions, including pi-stacking and van der Waals interactions, may also be present.

In another embodiment, the present invention provides a crystalline solvate of revefenacin.

In another embodiment, the present invention provides a crystalline solvate of revefenacin, wherein said crystalline solvate is prepared by process comprising the steps of:
a) dissolving revefenacin in a suitable solvent to get a solution;
b) optionally, cooling to a suitable temperature to get crystals; and
c) isolating the crystals to get crystalline solvate of revefenacin.

In another embodiment, the solvent used for preparing crystalline solvate of revefenacin is selected from, but not limited to, the group comprising of esters, alcohols, ketones, hydrocarbons, ethers, nitrile, sulfoxides, acetamides, pyrrolidines, halogenated solvents and the like.

In another embodiment, revefenacin, its pharmaceutically acceptable salt, or solid form thereof, obtained by the process of the present invention is characterized by particle size distribution having D90 less than about 300µm, preferably less than about 200µm and most preferably about 100µm.

In another embodiment, the present invention provides a pharmaceutical composition prepared by using co-crystal/crystalline solvate of revefenacin.

In another embodiment, the present invention provides method for preparing a pharmaceutical composition of revefenacin, comprising the steps of:
a) converting compound of Formula VI to compound of formula VIII in a suitable solvent;
b) treating compound of Formula VIII with piperidine-4-carboxamide,
;
c) isolating revefenacin of Formula I and optionally converting to pharmaceutically acceptable salt;
d) treating revefenacin or its pharmaceutically acceptable salt with a suitable solvent;
e) optionally adding another solvent; and
f) isolating crystalline form of revefenacin or pharmaceutically acceptable salt thereof, and combining with atleast one pharmaceutically acceptable excipient.

In an embodiment, the pharmaceutical composition of the present invention is suitable for inhalation administration. Suitable pharmaceutical composition for inhalation administration will typically be in the form of an aerosol or a powder. Such composition is generally administered using well-known delivery devices such as a nebulizer inhaler, a metered-dose inhaler (MDI), a dry powder inhaler (DPI) or a similar delivery device.

In a preferred embodiment, the crystalline form or amorphous form of revefenacin of present invention is stable on storage as shown in Table-1 which represents the data related to crystallinity and impurity profile and purity as measured by HPLC.

Table 1:

Amorphous Form I Form II
25°C±2°C, 60%±5%
(RH) Initial 3rd month 6th month Initial 3rd month 6th month Initial 3rd month 6th month
Crystallinity
(%) ND ND ND 99.85 99.85 99.8 99.8 99.8 99.8
Any individual impurity (%) ND ND 0.02 ND ND 0.03 ND ND 0.01
Purity by HPLC (%) 99.95 99.95 99.93 99.97 99.96 99.96 99.95 99.95 99.95
40°C±2°C, 75%±5% (RH) Crystallinity
(%) ND ND ND 99.85 99.8 99.8 99.8 99.8 99.8
Any individual impurity (%) ND ND 0.03 ND ND 0.03 ND ND 0.01
Purity by HPLC (%) 99.95 99.95 99.9 99.97 99.96 99.96 99.95 99.95 99.95
2-8oC Crystallinity
(%) ND ND ND 99.85 99.8 99.8 99.8 99.8 99.8
Any individual impurity (%) ND ND ND ND ND ND ND ND ND
Purity by HPLC (%) 99.95 99.95 99.95 99.97 99.96 99.96 99.95 99.95 99.95

Certain specific aspects and embodiments of the present application will be explained in detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES
Example 1: Preparation of tert-butyl (2-chloroethyl)(methyl)carbamate of Formula III (R represents –Boc)
A solution of triphenylphosphine (6 mmol) in THF (7 mL) was added slowly via syringe to a solution of N-chlorosuccinimide (6.3 mmol, 0.84 g) in THF (36 mL). Additional THF (6 mL) was used to rinse the syringe, and this was added to the reaction flask. The pale pink, turbid mixture was stirred at room temperature for several minutes and then to this was quickly added, via syringe, a solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.73 g,5.7 mmol) in THF (7 mL). Additional THF (6 mL) was used to rinse the syringe, and this rinse was added to the reaction mixture, which then was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to get the title compound (1.6 gm).
Alternate process:
A solution of triphenylphosphine (6 mmol) in THF (7 mL) was added slowly via syringe to a solution of thionyl chloride (6.3 mmol) in THF (36 mL). Additional THF (6 mL) was used to rinse the syringe, and this was added to the reaction flask. The pale pink, turbid mixture was stirred at room temperature for several minutes and then to this was quickly added, via syringe, a solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.73 g,5.7 mmol) in THF (7 mL). Additional THF (6 mL) was used to rinse the syringe, and this rinse was added to the reaction mixture, which then was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to get the title compound.

Example 2: Preparation of tert-butyl N-(2-(4-(([1,1'-biphenyl]-2 ylcarbamoyl)oxy) piperidin-1-yl)ethyl)-N-methylglycinate (Formula VI wherein R represents –Boc)
Added Biphenyl-2-yl-carbamic acid piperidin-4-yl ester (100 mmol) to methyl tetrahydrofuran (140 mL) and added a solution of tert-butyl (2-chloroethyl)(methyl)carbamate (108 mmol) in methyl tetrahydrofuran (140 mL). The resulting mixture was heated to 30°C for a few minutes, then cooled to room temperature over 1 hour. The mixture was then cooled to 5°C and the temperature was maintained for 1 hour. Sodium hydroxide (160 mmol) was added portion-wise. After complete addition, the mixture was allowed to warm to room temperature until the reaction was complete. A saturated solution of NaHCO3 (2500 mL) in water was added, stirred for 30 minutes, and separated the layers. This was repeated, after which the organic layer was dried over Na2SO4. The material was filtered, concentrated and dried under high vacuum to afford the title compound (40 g).

Example 3: Preparation of tert-butyl methyl(2-oxoethyl)carbamate of Formula IV (R1 is Boc)
To an ice-cooled solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.71 mmol)) in dry dichloromethane (8.5 mL) under argon was added portion wise Dess-Martin periodinane or TEMPO (1.8 mmol). Once finished the addition, the reaction mixture was stirred at room temperature for 3 h. The mixture was poured into saturated solutions of NaHCO3 (45 mL) and Na2S2O3 (45 mL) and dichloromethane (95 mL). It was well-stirred at room temperature for 30 minutes. The organic phase was separated and washed with sat. aq. NaHCO3 (1×30 mL). It was dried over magnesium sulphate and concentrated to afford the title compound (360mg, 97%).

Example 4: Preparation of tert-butyl N-(2-(4-(([1,1'-biphenyl]-2 ylcarbamoyl)oxy) piperidin-1-yl)ethyl)-N-methylglycinate (Formula VI wherein R represents –Boc)
Added Biphenyl-2-yl-carbamic acid piperidin-4-yl ester (100 mmol) to methyl tetrahydrofuran (140 mL) and added a solution of tert-butyl methyl(2-oxoethyl)carbamate. (108 mmol) in methyl tetrahydrofuran (140 mL). The resulting mixture was heated to 30°C for a few minutes, then cooled to room temperature over 1 hour. The mixture was then cooled to 5°C and the temperature was maintained for 1 hour. NaHB(OAc)3 (165 mmol) was added portion-wise while maintaining the internal temperature at 8±1° C. After addition, the mixture was allowed to warm to room temperature until the reaction was complete. A saturated solution of NaHCO3 (2500 mL) in water was added, stirred for 30 minutes, and separated the layers. This was repeated, after which the organic layer was dried over Na2SO4. The material was filtered, concentrated and dried under high vacuum to afford the title compound (40 g).

Example 5: Preparation of 1-(2-(methylamino)ethyl)piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate (compound of Formula VI with R = H)
Tert-butyl N-(2-(4-(([1,1'-biphenyl]-2-ylcarbamoyl)oxy)piperidin-1-yl)ethyl)-N-methylglycinate (105 mmol,1 eq.), methanol (260 mL), and methyl tetrahydrofuran (45 mL) were combined under nitrogen. Added dioxane.HCl to the reaction mixture. Stirred the reaction at room temperature and after completion of reaction, quenched the reaction with sodium bicarbonate and extracted the compound in dichloromethane. Combined organic layer was concentrated under reduced pressure.
Methyl tert-butyl ether (MTBE) (95 mL) was added, and the solution again concentrated under reduced pressure (95mL removed). MTBE (190 mL) was added and the solution was seeded with a few milligrams of biphenyl-2-yl-carbamic acid 1-(2-methylaminoethyl) piperidin-4-yl ester, and the mixture was maintained for 3 hours. The solids were collected and the vessel and filter cake were washed with MTBE (2×20 mL). The material was dried to yield 12.2 g of the title compound (99.6% pure). This process was repeated to yield the title compound (12.2 g, 98.7% pure). The filtrate and washes were combined and concentrated under reduced pressure. MTBE (140 mL) was added and the solution was seeded with a few milligrams of biphenyl-2-yl-carbamic acid 1-(2-methylaminoethyl) piperidin-4-yl ester, and the mixture was maintained for 18 hours. The solids were collected and the vessel and filter cake were washed with MTBE (2×20 mL). The material was dried to yield the title compound (5 g, 97% pure).

Example 6: Preparation of 1-(2-(4-formyl-N-methylbenzamido)ethyl)piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate (Formula VIII)
To a three-necked 1-L flask was added 4-carboxybenzaldehyde (4.50 g, 31.8 mmol), EDC (6.64 g, 34.7 mmol), HOBT (1.85 g, 30 mmol), and DCM (180 mL). When the mixture was homogenous, a solution of the product of example 5 (9 g, 31 mmol) in DCM (90 mL) was added slowly. The reaction mixture was stirred at room temperature for 14 hours and then washed with water (1×90mL), 1N HCl (5×70 mL), 1N NaOH (1×90 mL) brine (1×40 mL), dried over sodium sulfate, filtered and concentrated to afford 12 g of the title compound (91% yield; 95% purity based on HPLC)

Example 7: Preparation of Biphenyl-2-ylcarbamic Acid 1-(2-{[4-(4-Carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl Ester (Revefenacin)
To a three-necked 2-L flask was added isonipecotamide (5 g, 35.0 mmol), acetic acid (2.50 mL), sodium sulfate (6.12 g) and IPA (350mL). The reaction mixture was cooled to 0-9° C. with an ice bath and a solution of the product of example 4 (10 g, 22 mmol) in IPA (280 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0-10° C. Sodium triacetoxyborohydride (15 g, 68 mmol) was added portion wise and this mixture was stirred at room temperature for 14 h. The reaction mixture was then concentrated under reduced pressure to a volume of about 45 mL and this mixture was acidified with 1N HCl (180 mL) to pH 3.5. The resulting mixture was stirred at room temperature for 1 hour and then extracted with DCM (3×220 mL). The aqueous phase was then cooled to 0-8° C. with an ice bath and 45% aqueous NaOH solution was added to adjust the pH of the mixture to 9.5. This mixture was then extracted with isopropyl acetate (3×280 mL) and the combined organic layers were washed with water (95 mL), brine (2×45 mL), dried over sodium sulfate, filtered and concentrated to afford 10.8 g of the title compound (80% yield).

Example 8: Preparation of crystalline Form I of revefenacin:
To a three-necked 2-L flask was added isonipecotamide (5 g, 35.0 mmol), acetic acid (2.50 mL), sodium sulfate (6.12 g) and IPA (350mL). The reaction mixture was cooled to 0-9° C. with an ice bath and a solution of the product of example 4 (10 g, 22 mmol) in IPA (280 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0-10° C. Sodium triacetoxyborohydride (15 g, 68 mmol) was added portion wise and this mixture was stirred at room temperature for 14 h. The reaction mixture was then concentrated under reduced pressure to a volume of about 45 mL and this mixture was acidified with 1N HCl (180 mL) to pH 3.5. The resulting mixture was stirred at room temperature for 1 hour and then extracted with DCM (3×220 mL). The aqueous phase was then cooled to 0-8° C. with an ice bath and 45% aqueous NaOH solution was added to adjust the pH of the mixture to 9.5. This mixture was then extracted with isopropyl acetate (3×280 mL) and added n-heptane to the combined organic layer at ambient temperature. Cooled the solution to initiate crystallization for 3h. filtered the crystals and dried under reduced pressure to get crystalline form I of revefenacin (purity 99.97% by HPLC)

Example 9: Preparation of crystalline Form I of revefenacin:
To the revefenacin obtained from example 7 was added acetone: water (1:1) solution at 30oC. Alternatively, reaction can be conducted at a temperature ranging from 20-30oC, followed by cooling at 5-10oC and reaction is maintained at this temperature for 3h. Filtered the crystals to get desired crystalline form I of revefenacin with purity 99.9%

Example 10: Preparation of crystalline Form II of revefenacin:
To the revefenacin obtained from example 7 was added ethanol and heated the solution at 40-50oC for 2h. Cooled the solution and added MTBE followed by filtration at room temperature. Dried the crystals to get desired crystalline form II of revefenacin with purity of 99.8% as measured by HPLC.

Example 11: Preparation of amorphous form of Revefenacin
To a stirred solution of revefenacin (0.7g) in acetone (25 mL) at 25°C, then heated to 50oC to get cleared solution, then filter then the filtrate was evaporated in rotavapour under reduced pressure at 50°C. Then the obtain product was re-dissolved in acetone (20 mL) at 25°C and the solvent was evaporated in rotavapour under reduced pressure at 60°C for 20 minutes to obtain title compound with purity 99.89% by HPLC.

Example 12: Preparation of amorphous form of Revefenacin
Revefenacin (1.1g) was dissolved in dimethylsulfoxide (50 mL) at 25°C and stirred at 60oC to get the reaction mixture for 4-6h. Lyophilized the solution so obtained to obtain title compound.

Example 13: Preparation of amorphous form of revefenacin
Revefenacin (7 gm), was dissolved in methyl isobutyl ketone (55ml), stirred for 1 hr at RT, then the solvent was evaporated under reduced pressure to obtain the title compound.

Example 14: Preparation of crystalline Form I of revefenacin
Revefenacin (9 gm) was added to 125 mL of methylene dichloride and heated at 50oC to get a clear solution followed by distillation atmospherically at 40-45°C. 100 mL of isopropanol was added to the residue and stirred for 15 minutes. The reaction mixture was distilled partially and then filtered. The wet-cake was dissolved in 125 mL methylene dichloride. The solution was distilled to remove methylene dichloride and the residue was triturated with 75 ml of methyl tert-butyl ether at 0° C. The precipitated product was filtered and washed with methyl tert-butyl ether. The product was dried under vacuum to get crystalline form I of revefenacin with purity 99.95%.

Example 15: Preparation of tartrate salt of revefenacin
Revefenacin (78 g) and absolute methanol (125 ml) were added to a clean reactor maintained under a nitrogen atmosphere. The mixture was stirred and heated to 50-55°C. After the solution was held at 50-55°C for 1 hour, a solution of tartaric acid (32 mg) in water (105 ml) was added over 10 minutes. The solution was heated to 60-65°C. The solution was maintained at reflux (60-65°C) for 4 hours during which a thick suspension formed. The slurry was cooled to 30-35°C over 1.5 hours and then filtered at 30-35°C. The cake was washed with methanol (500ml) and then dried in vacuo at 40-45°C for 20-30 hours. The tartrate salt of revefenacin 40% weight yield filtered, washed with MeOH (2 x 5 mL) and dried under vacuum, to obtain revefenacin tartrate (50 mg) (Purity: 99.8% by HPLC).

Example 16: Preparation of citrate salt of revefenacin
Revefenacin (14 g) and absolute methanol (100 ml) were added to a clean reactor maintained under a nitrogen atmosphere. The mixture was stirred and heated to 50-55°C. After the solution was held at 50-55°C for 1 hour, a solution of citric acid (8 mg) in water (50 ml) was added over 10 minutes. The solution was heated to 60-65°C. The solution was maintained at reflux (60-65°C) for 4 hours during which a thick suspension formed. The slurry was cooled to 20-25°Cover 1.5 hours and then filtered at 30-35°C. The cake was washed with methanol (60ml) and then dried in vacuo at 40-45°C for 20-30 hours. The tartrate salt of revefenacin 40% weight yield filtered, washed with MeOH (2 x 5 mL) and dried under vacuum, to obtain revefenacin citrate (50 mg) (Purity: 99.8% by HPLC).

Example 17: Preparation of Co-crystals of revefenacin and succinic acid
51.1 mg of revefenacin base, 0.75 mL of THF, and a magnetic stir bar were charged into a screw cap vial, heated to reflux to dissolve, and then the vial was closed with the screw cap and placed on top of a hot plate maintained at a temperature between 60 and 75oC. A solution of 77.7 mg of succinic acid in 1.58 mL of THF was prepared. 0.20 mL of the succinic acid solution was added to the revefenacin solution and the solution remained clear. 0.75 mL of iso-propylacetate was added and refluxed for 1 hr and cooled to 10oC. The cooled sample was suction filtered. It was rinsed with 0.2-0.3 mL of THF. The filter cake was broken-up and allowed to air-dry for 1 hour.

Example 18: Preparation of Co-crystals of revefenacin and fumaric acid
500 mg of revefenacin was placed in a 50 mL screw top bottle along with 33.33 mL of tetrahydrofuran (THF). 3.0887 mL of fumaric acid stock solution was then added to the beaker (resulting in a 1.05:1 ratio of salt former to free base). The cap was screwed on to seal the bottle and the bottle was placed in a 70o C in oven and heated for approximately 1 hour. Thereafter, the bottle was removed from the oven, the cap from the bottle was removed, and the sample was allowed to evaporate under flowing air under ambient conditions. When all but about 5 mL of the solvent had evaporated, the remaining solvent was removed by decantation and the solid was isolated by filtering over a Whatman filter using suction. This solid was returned back into the 50 mL bottle with the remaining solid and the bottle was placed into the vacuum oven at approximately 25 mm Hg and the solid was allowed to dry for 4 days.

Example 19: Preparation of Co-crystals of revefenacin and tartaric acid
100.4 mg of revefenacin free base, 0.90 mL of THF, and a magnetic stir bar were charged into a screw cap vial, heated to reflux to dissolve, and then the vial was closed with the screw cap and placed in an oil bath maintained at 70oC. A solution of 138.5 mg of L(+) tartaric acid in 1.15 mL of THF was prepared. 0.21 mL of the L(+)tartaric acid solution was added to the revefenacin solution and the solution remained clear. 0.90 mL of iso-propylacetate was added and the solution was seeded with <1 mg of the salt from a preparation of DL-tartaric acid co-crystal. The sample was allowed to crystallize over about 5 minutes in the 70oC. oil bath before it was removed and allowed to cool to room temperature. The cooled sample was suction filtered. It was rinsed with 0.2-0.3 mL of THF. The filter cake was broken-up and allowed to air-dry for 4 hours prior to analysis.

Example 20: Preparation of revefenacin isobutyl acetate solvate
Charged 0.2 mL DM water in a 10 mL vial. Revefenacin (500 mg) was dissolved in isobutyl acetate (2.5 mL) at 20-25 °C and stirred for 10-15 minute at 20-25 °C. revefenacin solution was added slowly to vial containing water with stirring. Cooled the final solution to -16 °C to -20 °C for 48 hour. The mass obtained was filtered under vacuum at -16 °C to -20 °C. Air dried the material to get 475.0 mg of desired compound.

Example 21: Preparation of Revefenacin Inhalation Solution, 175 mcg/3mL
The following ingredients are mixed to form a composition comprising 175 mcg/3mL of revefenacin crystalline form:
Ingredients Quantity
mg/3mL %w/v
(per mL)
Revefenacin pure crystalline form of present invention 0.175 0.00583
Sodium Chloride 23.55 0.785
Sodium Citrate dihydrate 12.00 0.40
Citric acid monohydrate 4.05 0.135
Hydrochloric Acid q.s to adjust pH 5.0 q.s to adjust pH 5.0
Sodium Hydroxide q.s to adjust pH 5.0 q.s to adjust pH 5.0
Water for Injection Q.s to 3 mL Q.s

Example 22: Preparation of Revefenacin Inhalation Solution, 175 mcg/3mL
The following ingredients are mixed to form a composition comprising 175 mcg/3mL of revefenacin crystalline form:

Ingredients Quantity
mg/3mL %w/v
(per mL)
Revefenacin pure crystalline form of present invention 0.175 0.00583
Sodium Chloride 24.00 0.80
Sodium Citrate dihydrate 12.00 0.40
Citric acid monohydrate 4.05 0.135
Water for Injection Q.s to 3 mL Q.s

Example 23: Preparation of Revefenacin Inhalation Solution, 175 mcg/3mL
The following ingredients are mixed to form a composition comprising 175 mcg/3mL of revefenacin crystalline form:
Ingredients Quantity
mg/3mL %w/v
(per mL)
Revefenacin pure crystalline form of present invention 0.175 0.00583
Sodium Chloride 23.25 0.775
Sodium Citrate dihydrate 12.00 0.40
Citric acid monohydrate 4.05 0.135
Hydrochloric Acid q.s to adjust pH 5.0 q.s to adjust pH 5.0
Sodium Hydroxide q.s to adjust pH 5.0 q.s to adjust pH 5.0
Water for Injection Q.s to 3 mL Q.s

Process:
WFI transferred to manufacturing Stainless steel vessel. Added Sodium Chloride to WFI (while maintaining temp. at 20°C to 25°C). To this was added Citric Acid Monohydrate (while maintaining pH). Then Sodium Citrate dihydrate was added to the solution so obtained (while maintaining pH). Adjusted the pH (pH-5.00) of above solution using Hydrochloric Acid/Sodium Hydroxide. Added Revefenacin crystalline form of the present invention to the above pH adjusted (pH 5.00) solution (while maintaining pH). Adjusted the pH (pH-5.00) by using Hydrochloric Acid/Sodium Hydroxide and made the volume up to 100% with pre-purged WFI. Filter the bulk solution through sterilized filter under nitrogen pressure followed by filling and sealing.

WE CLAIM:
1. A process for the preparation of revefenacin or pharmaceutically acceptable salt thereof,
a) converting compound of Formula II to Formula III or IV, wherein X is a leaving group, R and R1 are suitable protecting group,
b) reacting the compound of Formula III or IV with compound of Formula V to give compound of Formula VI,
c) converting compound of formula VI to revefenacin of formula I, and
d) optionally converting revefenacin of Formula I to pharmaceutically acceptable salt
.

2. Pure crystalline form of revefenacin or pharmaceutically acceptable salt thereof, wherein said crystalline form is prepared by a process comprising the step of:
a) treating revefenacin or its pharmaceutically acceptable salt with a suitable solvent;
b) optionally adding another solvent; and
c) isolating crystalline form of revefenacin or pharmaceutically acceptable salt thereof.

3. The crystalline form as claimed in claim 2, is having a purity of about 99.0% and above, and is stable for atleast six months at 40oC ± 2oC and at relative humidity of 75% ± 5% RH.

4. A process for the preparation of pure crystalline Form I of revefenacin, wherein said process comprising the steps of:
a) converting compound of Formula VIII to revefenacin in a suitable first solvent;
;
b) optionally isolating revefenacin from the first solvent of step a) and adding second solvent;
c) optionally adding third solvent either to first solvent of step a) or second solvent of step b); and
d) isolating crystalline Form I of revefenacin.

5. A process for the preparation of pure crystalline Form II of revefenacin, wherein said process comprising the steps of:
a) treating revefenacin with a suitable solvent to get a solution;
b) adding a second solvent to the solution of step a); and
c) isolating crystalline Form II of revefenacin.

6. The process as claimed in claims 4 and 5, wherein said crystalline Form I is characterized by one of the following:
a) a powder x-ray diffraction pattern having peaks at 4.8, 12.7, 16.7, 21.0 ±0.2o?;
b) having purity of about 99.0% and above; and
wherein said crystalline Form II is characterized by one of the following:
a) a powder x-ray diffraction pattern having peaks at 4.7, 19.5, 24.0 ±0.2o?; and
b) having purity of about 99.0% and above.

7. A process for the preparation of a pure amorphous form of revefenacin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding revefenacin or pharmaceutically acceptable salt thereof in one or more suitable solvent;
b) removing the solvent; and
c) isolating the pure amorphous form of revefenacin or pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising revefenacin and a pharmaceutically acceptable excipient wherein said revefenacin is selected from crystalline Form I, or Form II or amorphous revefenacin.

9. A pharmaceutical composition of revefenacin, wherein revefenacin is prepared by the process comprising the steps of:
a) converting compound of Formula VI to compound of formula VIII in a suitable solvent;
b) treating compound of Formula VIII with piperidine-4-carboxamide,
;
c) isolating revefenacin of Formula I and optionally converting to pharmaceutically acceptable salt;
d) treating revefenacin or its pharmaceutically acceptable salt with a suitable solvent;
e) optionally adding another solvent; and
f) isolating crystalline form of revefenacin or pharmaceutically acceptable salt thereof, and combining with atleast one pharmaceutically acceptable excipient.

10. A process of preparing pharmaceutical composition using amorphous or crystalline Form I or Form II of revefenacin.