Process for the preparation of polymorphs of 5-[4-[4-(5-cyano- lH-indol-3-vnbutyll-l-piperazinyll-2-benzofuran carboxamide hydrochloride

Related Applications:

This application claims the benefit of priority of our Indian patent application numbers 6150/CHE/2013 filed on 30 ^th Dec. 2013 and 732/CHE/2014 filed on 17 ^th Feb. 2014 which are incorporated herein by reference.

Field of the Invention:

The present invention provides a formic acid salt as well as its crystalline form of antidepressant drug i.e., 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide compound of formula- la, which is useful in the preparation of 5-[4-[4-(5- cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb and process for its preparation.

. Formula- la Formula- lb

Back ground of Invention:

US 5,532,241 (hereafter referred to as "241 ") first disclosed 5-[4-[4-(5-cyano-lH- indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide and its hydrochloride salt compound of formula- lb which is commonly known as Vilazodone hydrochloride, an antidepressant agent, which acts as a serotonin reuptake inhibitor.

"241" first disclosed the process for the preparation of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide and its hydrochloride salt compound of formula-lb by reacting 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l-yl)benzofur an-2- carboxylic acid with 2-chloro-l-methylpyridinium methanesulfonate in the presence of N- methyl pyrrolidine and ammonia gas to provide vilazodone as free base. Further, vilazodone free base is dissolved in propanolic hydrochloric acid solution to precipitate hydrochloride salt of compound of formula- lb.

US7834020 (hereafter referred to as "020") describes several crystalline forms of vilazodone hydrochloride, such as Form-I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XIII, XIV, XV and XVI and process for their preparation.

"020" discloses the process for the preparation of vilazodone hydrochloride form- XVI (hereafter referred to as "form-XVI") using freeze-drying and spray drying methods. The process for the preparation of vilazodone hydrochloride form-XVI by the said patent is critical, laborious, time consuming and not suitable for the commercial scale.

Hence in view of above, there is a need to find an efficient and industrially advantageous process which is commercial viable and which overcomes the problems associated with the prior art.

Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile or improved shelf-life.

The present invention involves the novel crystalline forms of as acid addition salts of vilazodone.

The present invention also provides novel acid addition salts of vilazodone in solid state form. The novel salts of vilazodone of the present invention can be used to prepare vilazodone free base in pure form, which in turn useful in the preparation of highly pure vilazodone hydrochloride.

Brief description of the invention:

The first aspect of the present invention is to provide formic acid salt of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide compound of formula- la and its crystalline form herein after designated as Form-M.

The second aspect of the present invention is to provide a process for the preparation of formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide compound of formula- la.

The third aspect of the present invention is to provide a process for the preparation of crystalline form-XVI of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide hydrochloride compound of formula- lb.

The fourth aspect of the present invention is to provide an alternate process for the preparation of form-XVI of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofurancarboxamide hydrochloride compound of formula- lb. The fifth aspect of the present invention is to provide a process for the preparation of pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide hydrochloride compound of formula- lb.

The sixth aspect of the present invention is to provide a micro crystalline cellulose (MCC) pre-mixed 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide hydrochloride compound of formula- lb with an excipient.

The seventh aspect of the present invention is to provide a process for the preparation of pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide hydrochloride compound of formula- lb with an excipient.

The eighth aspect of the present invention is to provide a process for the preparation of pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide hydrochloride compound of formula- lb with an excipient.

Brief description of figures:

Figure 1: Illustrates the PXRD pattern of crystalline Form-M of formic acid salt of 5-[4-[4-

(5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide.

Figure 2: Illustrates the DSC thermogram of crystalline Form-M of formic acid salt of 5-[4- [4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide.

Figure 3: Illustrates the IR spectrum of crystalline Form-M of formic acid salt of 5-[4-[4-(5- cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide.

Figure 4: Illustrates the PXRD pattern of form-XVI of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l -piperazinyl]-2-benzofuran carboxamide hydrochloride obtained according to example-3.

Figure 5: Illustrates the DSC thermogram of form-XVI of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride obtained according to example-3.

Figure 6: Illustrates the PXRD pattern of MCC pre-mixed form of 5-[4-[4-(5-cyano-lH- indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride obtained according to example-4.

Figure 7: Illustrates the PXRD pattern of MCC pre-mixed form of 5-[4-[4-(5-cyano-lH- indol-3-yl)butyl]-l -piperazinyl]-2-benzofuran carboxamide hydrochloride obtained according to example-5 or example -6.

Figure 8: Illustrates the PXRD pattern of MCC pre-mixed form of 5-[4-[4-(5-cyano-lH- indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride obtained according to example-7.

Figure 9: Illustrates the PXRD pattern of ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl) piperazin-l-yl)benzofuran-2-carboxylate hydrochloride

Detailed description of invention:

As used herein the term "suitable solvent" is selected from "alcoholic solvents" such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, ethylene glycol and the like; "ester solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, "ether solvents" such as tetrahydrofuran, diethylether, methyl tert-butylether, 1 ,4-dioxane and the like; "hydrocarbon solvents" such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; "polar aprotic solvents" such as dimethyl formamide, dimethylacetamide, dimethylsulfoxide and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "ketone solvents" such as acetone, methyl isobutyl ketone, methyl ethyl ketone; polar solvent such as water and the like. The suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry

HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl.

As used herein the term "suitable acid" is selected from formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid and the like.

The term "MCC" used throughout the document is defined as micro crystalline cellulose.

The first aspect of the present invention provides a formic acid salt of 5-[4-[4-(5- cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide and its crystalline form herein after designated as Form-M. The said crystalline form-M is characterized by: a) Its powder X-ray diffractogram having peaks at 7.2, 7.7, 8.5, 10.4, 11.9, 12.2, 14.4, 14.7, 15.5, 16.6, 17.2, 18.0, 19.1, 20.0, 20.5, 21.0, 21.4, 21.9, 23.2, 24.0, 24.6, 26.4, 27.0 and 29.3 and 29.9 degrees of two-theta as illustrated in figure- 1 ;

b) its DSC thermogram showing endotherm at 204.69°C as illustrated in figure-2;

c) its IR spectrum as illustrated in figure-3.

The second aspect of the present invention provides a process for the preparation of formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide compound of formula- la, comprising of the following steps:

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide in formic acid,

b) adding a suitable solvent to the reaction mixture,

c) stirring the reaction mixture,

d) filtering the precipitated solid and drying to provide formic acid salt of 5-[4-[4-(5- cyano- 1 H-indol-3 -yl)butyl] - 1 -piperazinyl]-2-benzofuran carboxamide.

Wherein,

in step-b) the suitable solvent is selected from ester solvents, ketone solvents, chloro solvents, alcohol solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, polar solvents like water and mixture thereof;.

The preferred embodiment of the present invention provides a process for the preparation of formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide, comprising of the following steps:

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide in formic acid,

b) adding isopropanol to the reaction mixture,

c) stirring the reaction mixture,

d) filtering the precipitated solid and drying to provide formic acid salt of 5-[4-[4-(5- cyano- 1 H-indol-3-yl)butyl] - 1 -piperazinyl]-2-benzofurancarboxamide compound of formula- la. The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-M of formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide, comprising of the following steps:

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide in formic acid,

b) adding isopropanol to the reaction mixture,

c) stirring the reaction mixture,

d) filtering the precipitated solid and drying to provide crystalline form-M of formic acid salt of 5 - [4- [4-(5 -cyano- 1 H-indol-3 -y l)butyl] - 1 -piperazinyl] -2-benzofuran carboxamide compound of formula- la.

The starting material i.e., 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide utilized in the present invention can be prepared by any of the known prior art process. The third aspect of the present invention provides a process for the preparation of crystalline form-XVI of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]- l-piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb, comprising of the following steps: a) Dissolving the formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl] -2-benzofuran carboxamide in a suitable acid,

b) adding a suitable hydrochloric acid source to the reaction mixture,

c) filtering the reaction mixture,

d) adding a suitable solvent to the filtrate obtained in step-c),

e) stirring the reaction mixture,

f) filtering the precipitated solid,

g) adding a suitable hydrochloric acid source to the solid obtained in step-f),

h) stirring the reaction mixture,

i) filtering the solid and drying to provide form-XVI of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl] -2-benzofuran carboxamide hydrochloride compound of formula- lb.

Wherein,

in step-a) the suitable acid is selected from formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid and the like;

in step-b) & g) the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl;

in step-d) the suitable solvent is same as defined in step-b) of the second aspect of the present invention.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-XVI of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]- 2-benzofuran carboxamide hydrochloride compound of formula- lb, comprising of the following steps;

a) Dissolving the formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l - piperazinyl] -2-benzofuran carboxamide in formic acid,

b) adding aqueous hydrochloric acid to the reaction mixture,

c) filtering the reaction mixture,

d) adding water to the filtrate obtained in step-c),

e) stirring the reaction mixture,

f) filtering the precipitated solid, g) adding aqueous hydrochloric acid to the solid obtained in step-f),

h) stirring the reaction mixture,

i) filtering the solid and drying to provide form-XVI of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l -piperazinyl] -2-benzofuran carboxamide hydrochloride compound of formula- lb.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-XVI of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]- 2-benzofuran carboxamide hydrochloride compound of formula- lb, comprising of the following steps;

a) Dissolving the crystalline form-M of formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide in formic acid,

b) adding aqueous hydrochloric acid to the reaction mixture,

c) filtering the reaction mixture,

d) adding water to the filtrate obtained in step-c),

e) stirring the reaction mixture,

f) filtering the precipitated solid,

g) adding aqueous hydrochloric acid to the solid obtained in step-f),

h) stirring the reaction mixture,

i) filtering the solid and drying to provide form-XVI of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l -piperazinyl] -2-benzofuran carboxamide hydrochloride compound of formula- lb.

The fourth aspect of the present invention provides an alternate process for the preparation of form-XVI of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydrochloride compound of formula- lb, comprising of the following steps;

a) Dissolving the 5- [4- [4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl] -2-benzofuran carboxamide in a suitable acid,

b) adding a suitable hydrochloric acid source to the reaction mixture,

c) filtering the reaction mixture, d) adding a suitable solvent to the filtrate obtained in step-(c),

e) stirring the reaction mixture,

f) filtering the precipitated solid and drying to provide form-XVI of 5-[4-[4-(5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb.

Wherein,

in step-a) the suitable acid is selected from formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid and the like;

in step-b) the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry

HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl;

in step-d) the suitable solvent is selected from ester solvents, ketone solvents, chloro

solvents, alcohol solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, polar solvents like water and mixture thereof; preferably the suitable solvent is selected from polar solvents such as water.

The preferred embodiment of the present invention provides an alternate process for the preparation of form-XVI of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydrochloride compound of formula- lb, comprising of the following steps:

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l -piperazinyl]-2-benzofuran carboxamide in formic acid,

b) adding hydrochloric acid to the reaction mixture,

c) filtering the reaction mixture,

d) adding water to the filtrate obtained in step-(c),

e) stirring the reaction mixture,

f) filtering the precipitated solid and drying to provide form-XVI of 5-[4-[4-(5-cyano- 1 H-indol-3 -yl)butyl] - 1 -piperazinyl] -2-benzofuran carboxamide hydrochloride compound of formula- lb.

Further, 5 - [4- [4-(5 -cyano- 1 H-indol-3 -yl)butyl] - 1 -piperazinyl] -2-benzofuran carboxamide hydrochloride form-XVI obtained according to the above aspect of the present invention is characterized by its X-ray powder diffractogram having peaks at 7.8, 8.6, 10.5, 12.3, 14.8, 16.6, 19.4, 20.1, 21.1, 22.4, 23.6, 24.3, 24.5, 26.7, 27.2 and 31.6 ± 0.2 degrees of two-theta and P-XRD pattern as illustrated in figure-4. The fifth aspect of the present invention provide a process for the preparation of pre- mixed form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide hydrochloride compound of formula- lb, which comprising of the following steps:

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide in a suitable acid,

b) adding a suitable hydrochloric acid source to the reaction mixture,

c) filtering the reaction mixture,

d) adding a suitable cellulose derivative to the filtrate obtained in step-(c),

e) adding a suitable solvent to the reaction mixture,

f) stirring the reaction mixture,

g) filtering the precipitated solid and drying to provide MCC pre-mixed form of 5-[4-[4- (5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb.

Wherein,

in step-a) the suitable acid is same as defined in step-a) of the fourth aspect of the present invention;

in step-b) the suitable hydrochloric acid source is same as defined in step-b) of the fourth aspect of the present invention;

in step-d) the suitable cellulose derivatives is selected from cellulose acetate, cellulose

nitrate, cellulose xanthate, carboxy methyl cellulose, micro crystalline cellulose, methyl cellulose, ethyl cellulose and hydroxy ethyl cellulose,

in step-e) the suitable solvent is same as defined in step-d) of the fourth aspect of the present invention.

The preferred embodiment of the present invention provides a process for the preparation of MCC pre-mixed form of 5-[4-[4-(5-cyano-l H-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb, which comprising of the following steps:

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide in formic acid,

b) adding hydrochloric acid to the reaction mixture,

c) filtering the reaction mixture,

d) adding micro crystalline cellulose to the filtrate obtained in step-(c),

e) adding water to the reaction mixture,

f) stirring the reaction mixture,

g) filtering the precipitated solid and drying to provide MCC pre-mixed form of 5-[4-[4- (5-cyano-lH-indol-3-yl)butyl]-l -piperazinyl]-2-benzofurancarboxamide

hydrochloride compound of formula- lb.

The process according to the present invention involves vilazodone hydrochloride form-XVI comprising of pharmaceutical excipient.

Further, the present invention also provides a pharmaceutical composition comprising the stable form-XVI of vilazodone hydrochloride together with one or more pharmaceutically acceptable carriers, excipients or diluents.

The sixth aspect of the present invention provides MCC pre-mixed form of 5-[4-[4- (5 -cyano- 1 H-indol-3 -yl)buty 1] - 1 -piperazinyl] -2-benzofurancarboxamide hydrochloride compound of formula- lb.

The P-XRD of pre-mixed form of vilazodone hydrochloride obtained according to the present invention is shown in figure-7.

The seventh aspect of the present invention provides a process for the preparation of pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide hydrochloride compound of formula- lb with an excipient, which comprising of the following steps:

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide in a suitable acid, b) adding a suitable hydrochloric acid source to the reaction mixture,

c) filtering the reaction mixture,

d) adding a suitable cellulose derivative to the filtrate obtained in step-(c),

e) distilling off the acid completely from the reaction mixture,

f) adding a suitable solvent to the compound obtained in step-(e),

g) stirring the reaction mixture,

h) filtering the precipitated solid and drying to provide MCC pre-mixed form of 5-[4-[4- (5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb.

Wherein,

in step-a) the suitable acid is selected from formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid and the like;

in step-b) the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry

HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl;

in step-d) the suitable cellulose derivatives is selected from cellulose acetate, cellulose

nitrate, cellulose xanthate, carboxy methyl cellulose, micro crystalline cellulose, methyl cellulose, ethyl cellulose and hydroxy ethyl cellulose;

in step-f) the suitable solvent is selected from ester solvents, ketone solvents, chloro solvents, alcohol solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, polar solvents like water and mixture thereof; preferably the suitable solvent is selected from ester solvents such as ethyl acetate.

The preferred embodiment of the present invention provides a process for the preparation of MCC pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb, which comprising of the following steps:

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide in formic acid,

b) adding hydrochloric acid to the reaction mixture,

c) filtering the reaction mixture,

d) adding micro crystalline cellulose to the filtrate obtained in step-(c), e) distilling off the formic acid completely from the reaction mixture,

f) adding ethyl acetate to the compound obtained in step-(e),

g) stirring the reaction mixture,

h) filtering the precipitated solid and drying to provide MCC pre-mixed form of 5-[4-[4- (5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb.

The eighth aspect of the present invention provides a process for the preparation of pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- 1 b with an excipient, which comprising of the following steps;

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide hydrochloride in a suitable acid,

b) filtering the reaction mixture,

c) adding a suitable cellulose derivative to the filtrate obtained in step-(b),

d) distilling off the acid completely from the reaction mixture,

e) adding a suitable solvent to the compound obtained in step-(d),

f) stirring the reaction mixture,

g) filtering the precipitated solid and drying to provide MCC pre-mixed form of 5-[4-[4- (5-cyano-lH-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb.

Wherein,

in step a) the suitable acid is same as defined in step-a) of the seventh aspect of the present invention;

in step-c) the suitable cellulose derivatives is same as defined in step-d) of the seventh aspect of the present invention;

in step-e) the suitable solvent is same as defined in step-f) of the seventh of the present

invention. The preferred embodiment of the present invention provides a process for the preparation of MCC pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]- l- piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb, which comprising of the following steps:

a) Dissolving the 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide hydrochloride in formic acid,

b) filtering the reaction mixture,

c) adding micro crystalline cellulose to the filtrate obtained in step-(b),

d) distilling off the formic acid completely from the reaction mixture,

e) adding ethyl acetate to the compound obtained in step-(d),

f) stirring the reaction mixture,

g) filtering the precipitated solid and drying to provide MCC pre-mixed form of 5-[4-[4- (5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide hydrochloride compound of formula- lb.

The formic acid salt as well as its crystalline form-M of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofurancarboxamide of the present invention is useful in the preparation of pure Vilazodone as well as form-XVI of Vilazodone hydrochloride.

The formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofurancarboxamide of the present invention can be converted in to its freebase by treating with a suitable base or by using any known methods.

The crystalline form-XVI 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2- benzofuran carboxamide hydrochloride compound of formula- lb obtained from the process of the present invention is stable at room temperature.

PXRD analysis of compound produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10° per minute. HPLC Method of Analysis of formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3-yI)butyl]- l-piperazinyI]-2-benzofuran carboxamide.

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Symmetry CI 8, 150 x 4.6mm, 3.5 μηα (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 242 nm; Column Temperature: 40°C; Injection volume: 5 μΐ,; Run time: 35 min; Diluent: Water : Isopropyl alcohol (1 : 1) v/v; Needle wash: Water : Isopropyl alcohol (1 : 1) v/v; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (70:30) v/v; Buffer: 2.72 grams of potassium dihydrogen phosphate and 3.0 grams of 1 -Octane sulphonic acid in 1000 ml of water. Adjust pH to 2.0 with diluted orthophosphoric acid and filtered through 0.22μπι Nylon membrane filter paper and sonicate to degas it.

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-be nzofuran carboxamide hydrochloride compound of formula-lb.

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Symmetry C 18, 150 x 4.6mm, 3.5 μιη (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 242 nm; Column Temperature: 40°C; Injection volume: 5 μΐ,; Run time: 35 min; Diluent: Water : Isopropyl alcohol (1 :1) v/v; Needle wash: Water : Isopropyl alcohol (1 :1) v/v; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (70:30) v/v; Buffer: 2.72 grams of potassium dihydrogen phosphate and 3.0 grams of 1 -Octane sulphonic acid in 1000 ml of water. Adjust pH to 2.0 with diluted orthophosphoric acid and filtered through 0.22μηι Nylon membrane filter paper and sonicate to degas it.

The compound produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

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 formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide [Formula-la]

Formic acid (300 ml) was added to 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide (100 gms) at 25-30°C and stirred for 15 minutes. Isopropanol (1500 ml) was added to the reaction mixture at 25-30°C and stirred for 2-3 hours at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 95.5 gms. Melting point: 199-204°C.

Purity by HPLC 99.65 %; Diamide Impurity: Not detected; Acid Impurity: 0.04 %; Ester

Impurity: Not detected; Unknown Impurity: 0.05 %.

The PXRD of the obtained compound is shown in figure- 1. Example-2: Preparation of Form-XVI of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide hydrochloride [Formula-lb]

Formic acid (250 ml) was added to formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l -piperazinyl]-2-benzofuran carboxamide (100 gms) obtained in example-1 at 25- 30°C and stirred for 15 minutes at the same temperature. Slowly aqueous hydrochloric acid (34.5 ml) was added to the reaction mixture at 25-30°C. Filtered the reaction mixture through hy-flow bed and washed with formic acid (50 ml). To the obtained filtrate, slowly water (1000 ml) was added at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with water. To the obtained wet solid, aqueous hydrochloric acid was added at 25-30°C and stirred the reaction mixture for 1 ½ hours at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 96.2 gms. Melting point 284-288°C.

Formic acid content: 1100 ppm.

Particle size distribution: Di ₀ : 16.69 μηι; D ₅₀ : 78.92 μηι; D ₉₀ : 144.99 μπν, Example-3: Preparation of Form-XVI of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l- piperazinyl]-2-benzofuran carboxamide hydrochloride [Formula-lb]

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide (10 gms) was added to formic acid (25 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Hydrochloric acid (2.3 ml) was slowly added to the reaction mixture at 25- 30°C. Filtered the reaction mixture and washed with formic acid (5.0 ml) at 25-30°C. Water (100 ml) was slowly added to the obtained filtrate at 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and washed with water. To the obtained wet solid, water (100 ml) was added at 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 8.1 gms. The PXRD of the obtained compound is shown in figure-4.

Water content: 7.2 % w/w.

Formic acid content: 4417 ppm.

Purity by HPLC: 99.97 %.

Particle size distribution: D _]0 : 6.74 μηι; D ₅₀ : 31.20 μπι; D _% : 60.99 μπι;

Example-4: Preparation of MCC pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride [Formula-lb]

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide (10 gms) was added to formic acid (25 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Hydrochloric acid (2.3 ml) was slowly added to the reaction mixture at 25- 30°C. Filter the reaction mixture and washed with formic acid (5.0 ml) at 25-30°C. Micro crystalline cellulose (10 gms), followed by water (100 ml) was slowly added to the obtained filtrate at 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and washed with water. To the obtained wet solid, water (100 ml) was added at 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 8.0 gms.

The PXRD of the obtained compound is shown in figure-6.

Water content: 7.6 % w/w.

Formic acid content: 3465 ppm.

Purity by HPLC: 99.95 %. Example-5: Preparation of MCC pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride [Formula-lb]

5-[4-[4-(5-cyano- 1 H-indol-3-yl)butyl]- 1 -piperazinyl]-2-benzofuran carboxamide ( 10 gms) was added to formic acid (30 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Hydrochloric acid (2.5 ml) was slowly added to the reaction mixture at 25- 30°C. Filtered the reaction mixture and washed with formic acid (10 ml) at 25-30°C Micro crystalline cellulose (20.0 gms) was added to the filtrate at 25-30°C. Distilled off the formic acid completely from the reaction mixture under reduced pressure below 85°C. Ethyl acetate (300 ml) was added to the obtained compound at 15-20°C and stirred for 30 minutes at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 28.9.0 gms.

The PXRD of the obtained compound is shown in figure-7.

Example-6: Preparation of MCC pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride [Formula-lb]

5-[4-[4-(5-cyano-lH-indol-3-yl)butyl]-l-piperazinyl]-2-benzo furan carboxamide hydrochloride (10 gms) was added to formic acid (30 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture and washed with formic acid (10 ml) at 25-30°C. Micro crystalline cellulose (20.0 gms) was added to the filtrate at 25- 30°C. Distilled off the formic acid completely from the reaction mixture under reduced pressure below 85°C. Ethyl acetate (300 ml) was added to the obtained compound at 15-20°C and stirred for 30 minutes at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 29.2. gms.

The PXRD of the obtained compound is shown in figure-7.

Example-7: Preparation of MCC pre-mixed form of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide hydrochloride [Formula-lb]

5 - [4- [4-(5 -cyano- 1 H-indol-3 -y l)butyl] - 1 -piperazinyl] -2-benzofuran carboxamide hydrochloride (10 gms) was added to formic acid (30 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Filter the reaction mixture and washed with formic acid (10 ml) at 25-30°C. Micro crystalline cellulose (20.0 gms) was added to the reaction mixture at 25-30°C. Distilled off the formic acid completely from the reaction mixture under reduced pressure below 85°C. Water (300 ml) was added to the obtained compound at 15-20°C and stirred for 30 minutes at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 29.2. gms.

The PXRD of the obtained compound is shown in figure-8.

Example-8: Preparation of Form-IV of 5-[4-[4-(5-cyano-lH-indol-3-yl)butyI]-l- piperazinyl] -2-benzofuran carboxamide hydrochloride

Formic acid (250 ml) was added to formic acid salt of 5-[4-[4-(5-cyano-lH-indol-3- yl)butyl]-l-piperazinyl]-2-benzofuran carboxamide (100 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Aqueous hydrochloric acid (34.5 ml) was slowly added to the reaction mixture at 25-30°C. Filtered the reaction mixture through hyflow bed and washed with formic acid (50 ml). To the obtained filtrate^ Water (1000 ml) was slowly added to the filtrate at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with water. To the obtained wet solid, aqueous hydrochloric acid was added at 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Filtered the solid and washed with water. Ethanol (1000 ml) was added to the obtained wet compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with ethanol and dried to get the title compound.

Yield: 95 gms; Melting point: 280-284°C.

Example-9: Preparation of ethyl 5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yl)benzofuran-2-carboxylate hydrochloric acid.

A mixture of ethyl 5-(piperazin-l -yl)benzofuran-2-carboxylate hydrochloride (23 kgs), acetonitrile (160 lit), potassium carbonate (10.1 kgs), triethylamine (7.4 kgs), 3-(4- chlorobutyl)- lH-indole-5-carbonitrile (17.3 kgs), potassium iodide (1.2 kgs) and tetrabutyl ammonium bromide (1.2 kgs were stirred for 30 hours at 75-80°C. Distilled off solvent completely from the reaction mixture under reduced pressure. Water and then ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with acetone. Acetone (1 15 lit) was added to the obtained compound at 25-30°C and stirred for 15 minutes at the same temperature. Adjusted the pH of the reaction mixture to 2.5 by using aqueous hydrochloric acid solution at 25-30°C and stirred for 3 hours at the same temperature. Filter the precipitated solid, wash with acetone. To the obtained solid, water (9.5 lit was added at 25- 30°C. Heated the reaction mixture to 60-65°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes at the same temperature. Filter the solid, wash with water. Ethylacetate (104 lit) and formic acid(l 1.5 lit) was added to the obtained solid at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes at the same temperature. Filter the solid, wash with ethyl acetate and then dried to get the title compound. Yield: 20 kgs.

The PXRD of the obtained compound is shown in figure-9.

Example-10: Preparation of ethyl 5-(4-(4-(5-cyano-lH-indol-3-yI)butyl)piperaziii-l- yI)benzofuran-2-carboxy!ate hydrochloric acid

A mixture of ethyl 5-(piperazin-l-yl)benzofuran-2-carboxylate hydrochloride (23 kgs), acetonitrile (160 lit), potassium carbonate (10.1 kgs), triethylamine (7.4 kgs), 3-(4- chlorobutyl)- lH-indole-5-carbonitrile (17.3 kgs), potassium iodide (1.2 kgs) and tetrabutyl ammonium bromide (1.2 kgs were stirred for 30 hours at 75-80°C. Distilled off solvent completely from the reaction mixture under reduced pressure. Water and then ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with acetone. Acetone (1 15 lit) was added to the obtained compound at 25-30°C and stirred for 15 minutes at the same temperature. Adjusted the pH of the reaction mixture to 2.5 by using aqueous hydrochloric acid solution at 25-30°C and stirred for 3 hours at the same temperature. Filter the precipitated solid, wash with acetone. To the obtained solid, water (9.5 lit was added at 25- 30°C. Heated the reaction mixture to 60-65 °C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes at the same temperature. Filter the solid, wash with water. Ethyl acetate (104 lit) was added to the obtained solid at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes at the same temperature. Filter the solid, wash with ethyl acetate and then dried to get the title compound. Yield: 21 kgs

The PXRD of the obtained compound is shown in figure-9. Example-11: Preparation of 5-[4-[4-(5-cyano-IH-indol-3-yl)butyI]-l-piperazinyl]-2- benzofuran carboxamide

Mixture of dimethylformamide (450 ml) and ethyl 5-(4-(4-(5-cyano-lH-indol-3- yl)butyl)piperazin-l-yl)benzofuran-2-carboxylate hydrochloride (30.0 g) was cooled to 0-5°C and stirred for 20 minutes. Formamide (48.7 g) and followed by sodium methoxide in methanol ( 1.6 g) was added to reaction mixture at 0-5 °C and stirred the reaction mixture for 1 hour at same temperature. After completion of the reaction, water (900 ml) was added to the reaction mixture and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound as crystalline solid. Yield: 25.7 gm; Melting point: 203- 209°C.