WO2015037010A1

WO2015037010A1 - Preparation of vilazodone hydrochloride crystalline form iv

Info

Publication number: WO2015037010A1
Application number: PCT/IN2013/000555
Authority: WO
Inventors: Dodda Mohan Rao; Aadepu Jithender
Original assignee: Symed Labs Limited
Priority date: 2013-09-13
Filing date: 2013-09-13
Publication date: 2015-03-19

Abstract

Provided herein are improved, commercially viable and consistently reproducible processes for the preparation of highly pure crystalline Form IV of Vilazodone hydrochloride, which is free from other polymorphs and undesired solvated forms. Provided also herein is a highly pure and stable Vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms. The highly pure Vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D(90) particle size of less than or equal to about 100 microns.

Description

PREPARATION OF VILAZODONE HYDROCHLORIDE CRYSTALLINE FORM IV

FIELD OF THE INVENTION

The present invention relates to improved, commercially viable and industrially advantageous processes for the preparation of highly pure Vilazodone hydrochloride crystalline Form IV.

BACKGROUND OF THE INVENTION

U.S. Patent No. 5,532,241 (hereinafter referred to as the US'241 patent) discloses a variety of piperidine and piperazine derivatives and their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds are active on the central nervous system, especially in terms of 5-HT!A-agonist and 5-HT-reuptake inhibition. They are furthermore active as serotonin agonists and antagonists. These compounds and their physiologically acceptable acid addition salts can, therefore, be used as active ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics, and antihypertensives. Among them, Vilazodone hydrochloride, 5-[4-[4-(5-Cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2- carboxamide hydrochloride, is a serotonergic antidepressant that is used for the treatment of major depressive disorder (MDD). Vilazodone hydrochloride is represented by the following structural formula:

Vilazodone hydrochloride was approved by 'the FDA for use in the United States to treat major depressive disorder and it is sold under the trade name VIIBRYD™. It is orally administered as tablets containing 10 mg, 20 mg and 40 mg of vilazodone as the hydrochloride salt. Various processes for the preparation of Vilazodone and its hydrochloride salt are apparently described in U.S. Patent Nos. US 5,532,241, US 5,723,614, US 5,977,112, US 5,418,237 and US 7,799,916; Journal of Medicinal Chemistry, 2004, Vol. 47, No. 19, Pages 4684-4692; and Drugs of the Future 2001, 26(3), 247.

Vilazodone hydrochloride is known to exhibit polymorphism. Various polymorphic forms of Vilazodone hydrochloride are apparently disclosed in PCT Publication Nos. WO 2002/102794 and WO 2013/078361.

PCT Publication No. WO2002/102794 (hereinafter referred to as WO'794 publication) and its US equivalent Patent No. US 7,381,726 B2 disclose several crystal modifications (Crystalline forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XIII, XIV, XV and XVI) of Vilazodone hydrochloride, which include four anhydrate forms, three hydrated forms and six solvated forms, characterized in that Form I is an acetone solvate; Forms II, XV and X are tetrahydrofuran solvates; Form XI is a methanol solvate; and Form XIV is an n-heptane solvate. Form V is monohydrate, Form VI is a sesquihydrate and Form VIII is a hemihydrate. Forms III, IV, VII and IX are anhydrate crystalline forms of vilazodone hydrochloride. Form XIII is a crystalline modification of vilazodone dihydrochloride. These crystalline modifications are characterized by powder X-ray diffraction (P-XRD), Infra Red spectroscopy (IR), Raman spectroscopy and thermal analysis.

The WO'794 publication teaches that example 4 of the US'241 patent describes the preparation of Vilazodone hydrochloride by reacting l -[4-(5-cyanoindol-3-yl)butyl]-4-(2- carboxybenzofuran-5-yl)piperazine at first with 2-chloro-l-methylpyridinium methanesulfonate in N-methylpyrrolidine and then with dried ammonia. Customary working up gives the vilazodone free base, and subsequent precipitation of vilazodone hydrochloride by dissolving vilazodone base (700 mg) in 2-propanol (30 ml) under heating, followed by treating with 2-propanolic-HCl solution (Merck- Art. No. 1.00326) until precipitation of hydrochloride is complete. The precipitate was filtered off and washed with diethylether and then dried at room temperature to yield vilazodone hydrochloride having a melting point of 269-272°C. The WO'794 publication further teaches that the former Vilazodone hydrochloride having a melting point of 269-272°C was a mixture of amorphous vilazodone hydrochloride, crystalline vilazodone hydrochloride and the vilazodone free base.

The WO' 794 publication further teaches that there is no clear teaching elsewhere in the US'241 patent of any alternative route or modification to the process which would generate new crystal modifications of vilazodone hydrochloride or new solvates or hydrates of vilazodone hydrochloride in different crystalline modifications.

A similar process for the precipitation of vilazodone hydrochloride is also reported in Journal of Medicinal Chemistry, 2004, Vol. 47, No. 19, pages 4684-4692 (hereinafter referred to as the 'JMC article'). As per the process reported in the JMC article (see column- 1, lines 47-57 of Page No. 4690), the vilazodone hydrochloride is precipitated by dissolving vilazodone free base (0.7 g) in hot 2-propanol (30 ml) to form a solution, followed by slow addition of HCl-saturated 2-propanol at room temperature until complete precipitation occurred to yield vilazodone hydrochloride (Melting Point: 277-279°C).

According to the WO '794 publication, the crystalline Form IV of Vilazodone hydrochloride is characterized by a powder X-ray diffraction spectrum having main peaks expressed as 2-theta angle positions at about 9.08, 12.85, 14.50, 16.89, 18.89, 20.43, 21.72, 24.61, 27.35 and 28.18 ± 0.1 degrees; and an IR spectrum having bands at about 3437, 3328, 3273, 3030, 3006, 2987, 2938, 2915, 2875, 2660, 2459, 2222, 1899, 1670, 1602, 1577, 1475, 1444, 1370, 1320, 1304, 1281, 1275, 1249, 1227, 1186, 1162, 1141, 1131, 1112, 1099, 1082, 1032, 971, 951, 942, 909, 881, 854, 822, 768, 733, 691, 660, 642, 628, 607, 581, 526, 502, 493, 471 and 461 cm^"1. The WO'794 publication states that the crystalline Form IV of Vilazodone hydrochloride has surprising advantages with regard to its solubility and for its pharmaceutical processing into solid dosage forms. The solubility of Form IV in water is 0.328 μg/ml. The publication further states that the polymorphic Form IV has superior properties over the other crystalline forms and is more suitable for inclusion in pharmaceutical formulations.

The WO'794 publication describes two processes for the preparation of crystalline Form IV of Vilazodone hydrochloride characterized in that the processes involve the use of other specific crystalline modifications namely Form V (monohydrate), Form XI (monomethanolate) and Form VI of Vilazodone hydrochloride as starting materials. According to the WO'794 publication, the crystalline Form V of Vilazodone hydrochloride is characterized by a powder X-ray diffraction spectrum having main peaks expressed as 2-theta angle positions at about 9.34, 10.83, 13.00, 13.47, 18.70, 19.44, 20.09, 20.98, 25.41 and 26.13 ± 0.1 degrees; and an IR spectrum having bands at about 3483, 3460, 3222, 3192, 3007, 2947, 2864, 2838, 2784, 2682, 2606, 2478, 2461, 2219, 1669, 1604, 1575, 1474, 1461, 1444, 1402, 1382, 1371, 1362, 1321, 1304, 1271, 1263, 1247, 1226, 1185, 1160, 1137, 1 113, 1101, 1091, 1082, 1058, 1048, 1030, 1008, 972, 954, 942, 917, 883, 857, 822, 815, 767, 739, 682, 661, 641, 624, 591, 583, 529 and 499 cm^"1. The crystalline Form XI of Vilazodone hydrochloride is characterized by a powder X-ray diffraction spectrum having main peaks expressed as 2-theta angle positions at about 8.54, 12.50, 13.17, 18.56, 19.28, 19.76, 20.94, 21.21, 25.40, 26.26 ± 0.1 degrees; and an IR spectrum having bands at about 3415, 3290, 3282, 3234, 3196, 3176, 3005, 2993, 2938, 2849, 2678, 2629, 2592, 2473, 2457, 2217, 1680, 1673, 1608, 1594, 1576, 1474, 1457, 1440, 1427, 1401, 1372, 1365, 1354, 1321, 1304, 1281, 1263, 1247, 1236, 1222, 1185, 1175, 1169, 1160, 1128, 1121, 1100, 1086, 1032, 1019, 978, 958, 942, 921, 893, 884, 856, 813, 775, 764, 739, 731, 699, 673, 658, 634, 608, 567, 544, 535, 502, 492, 476, 466 and 455 cm^'1.

According to one method described in the WO'794 publication, the crystalline Form IV of vilazodone hydrochloride is prepared by dispersing vilazodone free base in tetrahydrofuran, converting the vilazodone free base by addition of aqueous hydrochloric acid into the hydrochloride salt at temperatures between 20°C and 30°C, precipitating Form V of vilazodone hydrochloride at room temperature, recovering the precipitated vilazodone hydrochloride monohydrate Form V by filtration, and then drying of Form V in vacuo at temperatures of 85°C to 90°C to give Form IV.

According to another method described in the WO'794 publication, the crystalline

Form IV of vilazodone hydrochloride is prepared by suspending Form VI of vilazodone hydrochloride in methanol at temperatures between 55°C and the boiling point of methanol, cooling down the reaction mixture temperature to -30°C, recovering the precipitated vilazodone hydrochloride methanolate (Form XI) by filtration at room temperature, and drying in vacuo at room temperature to produce Form XI of vilazodone hydrochloride, which is then subjected to drying at temperatures between 55°C and 65°C to produce crystalline Form IV of vilazodone hydrochloride.

PCT Publication No. WO2013/078361 Al (hereinafter referred to as WO'361 publication) discloses several crystal modifications (twelve crystalline forms A, B, C, D, E, F, G, H, I, El, Al, K, L, M) and amorphous form of Vilazodone free base, which include six solvated forms, two anhydrate forms and two hydrated forms, wherein Form A is a methanol solvate; Form B is a methyl isobutyl ketone solvate; Form C is an ethylene glycol solvate; Form D is a 1 -propanol solvate; Form E is an ethanol solvate; Form F is a 1-butanol solvate. Forms H and I are anhydrous crystalline forms. Forms El and Al are monohydrate forms of vilazodone. The WO'361 publication also discloses nineteen crystalline forms (Form alpha, beta, gamma, delta, Epsilon, Eta, Theta, Iota, Kappa, Lambda, Mu, Nu, Zeta, Xi, Omicron, Pi, Rho, Sigma, Tau) and amorphous form of Vilazodone hydrochloride, wherein Forms Alpha and Lambda are monohydrate crystalline forms; Form Mu is an anhydrate form; Form Zeta is an ethyl acetate solvate, Form Xi is a pentanoate solvate; Form Omicron is an ethanol solvate; Form Pi is a dimethylformamide solvate; Form Rho is a methyl acetate solvate; and Form Tau is a propanol solvate.

However, the processes for preparation of crystalline Form IV of Vilazodone hydrochloride described in the aforementioned prior art suffer from several disadvantages such as lack of reproducibility; contamination of the desired crystalline Form IV with other solid state forms and solvated forms; require the use of other crystalline forms of vilazodone hydrochloride including Form V (monohydrate) and Form XI (monomethanolate); the use of excess amounts of solvents which generate a large quantity of chemical waste which is difficult to treat; use of hazardous, highly flammable and expensive solvents like tetrahydrofuran; involve the use of tedious and cumbersome procedures like extremely low temperatures (-30°C), prolonged time periods under strict conditions, and drying other crystalline forms under vacuum at higher temperatures for prolonged time periods (2 to 7 days time); thereby making the processes unfeasible at large-scale operations. Moreover, the yields and purities of the crystalline Form IV of Vilazodone hydrochloride obtained according to the prior art processes are low.

The main drawback of the processes for the preparation of crystalline Form IV of

Vilazodone hydrochloride as described in the WO' 794 publication is that the prior art processes are unfeasible at commercial scale operations since they are required to first produce either monohydrate Form V or monomethanol solvate Form XI of Vilazodone hydrochloride (monomethanolate) and then subjected to desolvation by drying the solvated forms at higher temperatures under vacuum for prolonged time periods (2 to 7 days time) to produce Form IV, thereby leading to the poor product yield. Further, the preparation of Form XI itself requires the use of another crystalline form 'Form VI'. The present inventors have observed that the desolvation of the solvated forms (Form V and Form XI) is a time consuming and cumbersome process since it takes at least 2 days time, specifically 3 to 7 days time, to get Form IV, and hence not advisable for scale up operations.

A need still remains for simple, cost effective, consistently reproducible and environmentally friendly processes for preparing crystalline Form IV of Vilazodone hydrochloride with high yield and high purity. SUMMARY OF THE INVENTION

Extensive research and experimentation was carried out by the present inventors to produce Vilazodone hydrochloride in crystalline Form IV with high yield and purity, which is free from other polymorphs and undesired solvated forms. As a result, the present inventors have surprisingly and unexpectedly found that crystalline Form IV of Vilazodone hydrochloride can be prepared in an improved, efficient and cost effective process, in high purity and with high yield, by providing a solution of Vilazodone free base in isopropanol at reflux, optionally subjecting the solution to carbon treatment, combining the solution with hydrochloric acid saturated in isopropanol, followed by filtration to produce highly pure crystalline Form IV of Vilazodone hydrochloride.

Provided herein are simple, commercially viable, consistently reproducible and environmentally friendly processes for the preparation of highly pure Vilazodone hydrochloride crystalline Form IV, which is free of other crystalline forms and solvating agents such as water and organic solvents.

In one aspect, the process described herein comprises providing a solution of Vilazodone free base in isopropanol at reflux, optionally subjecting the solution to carbon treatment, combining the solution with hydrochloric acid saturated in isopropanol, followed by filtration to produce highly pure crystalline Form IV of Vilazodone hydrochloride.

In another aspect, the process described herein comprises providing a suspension of Vilazodone hydrochloride in isopropanol at reflux, stirring the suspension at reflux for at least 10 minutes, followed by filtration to produce highly pure crystalline Form IV of Vilazodone hydrochloride.

In another aspect, provided herein is a highly pure and stable Vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms of Vilazodone hydrochloride.

In another aspect, provided herein is a pharmaceutical composition comprising highly pure Vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.

In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure Vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms made by the process disclosed herein with one or more pharmaceutically acceptable excipients.

In another aspect, the highly pure Vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms, made by the process disclosed herein for use in the pharmaceutical compositions, has a D₉₀ particle size of less than or equal to about 100 microns, specifically about 5 microns to about 60 microns, and most specifically about 10 microns to about 50 microns.

By "highly pure" is meant having purity greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.9% as measured by HPLC.

The processes for the isolation/crystallization of vilazodone hydrochloride Form IV described herein have the following advantages over the processes described in the prior art:

i) the overall processes involve shorter time periods (2 to 5 hours) and less expensive solvents like isopropanol thereby making the processes cost effective;

ii) the processes produce the product with high yield and purity; iv) the processes avoid the use of hazardous, highly flammable and expensive solvents like tetrahydrofuran;

v) the processes avoid the formation and/or isolation of hydrated or solvated forms;

vi) the processes do not require the tedious and cumbersome procedures like desolvation by drying the solvated forms at higher temperatures under vacuum for prolonged time periods (2 to 7 days time); and

iv) the processes involve easy work-up methods and simple isolation/crystallization processes, and there is a reduction in chemical waste. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of Crystalline Form IV of Vilazodone Hydrochloride.

Figure 2 is a characteristic infra-red (IR) spectrum of Crystalline Form IV of Vilazodone Hydrochloride.

Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of Crystalline Form IV of Vilazodone Hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, there is provided a process for the preparation of crystalline Form IV of Vilazodone hydrochloride, comprising:

a) providing a solution of Vilazodone free base in isopropanol at reflux temperature; b) optionally, subjecting the hot solution obtained in step-(a) to carbon treatment or silica gel treatment to obtain a filtrate;

c) combining the solution obtained in step-(a) or step-(b) with hydrochloric acid saturated in isopropanol to cause crystallization of vilazodone hydrochloride; and

d) recovering the pure vilazodone hydrochloride crystalline Form IV formed in step-(c).

Step-(a) of providing a solution of vilazodone free base includes dissolving or extracting any form of vilazodone free base (e.g., in the form of a liquid, a solid or a semisolid) in isopropanol, or obtaining an existing solution from a previous processing step.

In one embodiment, the vilazodone free base is dissolved or extracted in isopropanol at a temperature of about 50°C to the reflux temperature, specifically at a temperature of about 60°C to the reflux temperature, and more specifically at the reflux temperature. After complete dissolution of vilazodone, the resulting solution is stirred at reflux for at least 5 minutes, and specifically for about 10 minutes to about 30 minutes.

Alternatively, the solution in step-(a) is also prepared by suspending vilazodone free base in isopropanol at room temperature, followed by heating the suspension at a temperature of about 50°C to the reflux temperature to form a solution. After complete dissolution of vilazodone, the resulting solution is stirred at reflux for at least 5 minutes, and specifically for about 10 minutes to about 30 minutes.

Alternatively, the solution in step-(a) is prepared by reacting methyl 5-[4-[4-(5- cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate with ammonia in a suitable solvent to produce a reaction mass containing vilazodone free base, followed by usual work up such as washings, extractions, evaporations or a combination thereof, and then dissolving or extracting the resulting vilazodone free base in isopropanol at a temperature of about 50°C to the reflux temperature, specifically at a temperature of about 60°C to the reflux temperature, and more specifically at the reflux temperature, wherein the ammonia is used in the form of aqueous ammonia or ammonia gas or ammonia saturated in an organic solvent. Specifically, the solvent used for amidation reaction is selected from the group consisting of water, methanol, ethanol, isopropanol, and mixtures thereof.

The carbon treatment or silica gel treatment in step-(b) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon or silica gel at a temperature of about 60°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature for about 5 minutes to about 20 minutes; and filtering the resulting mixture through hyflo bed to obtain a filtrate containing vilazodone free base by removing charcoal or silica gel. Specifically, finely powdered carbon is a special carbon or an active carbon. A specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.

Combining of the solution of vilazodone free base with hydrochloric acid saturated in isopropanol (hereinafter referred to as isopropanolic-HCl) in step-(c) is done in a suitable order, for example, the solution is added to the isopropanolic-HCl, or alternatively, the isopropanolic-HCl is added to the solution. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out under stirring at above 35°C for at least 5 minutes, specifically at a temperature of about 40°C to the reflux temperature of the solvent for about 10, minutes to about 1 hour, and most specifically at a temperature of about 50°C to the reflux temperature of the solvent used for about 20 minutes to about 40 minutes. After completion of the addition process, the resulting mixture is stirred at a temperature of below 35°C for at least 10 minutes and specifically at a temperature of about 20°C to about 30°C for about 15 minutes to about 2 hours to cause crystallization.

The recovering in step-(d) is carried out by methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof. In one embodiment, vilazodone hydrochloride crystalline Form IV can be recovered by filtration employing a filtration media of, for example, a silica gel or celite.

According to another aspect, there is provided a process for the preparation of crystalline Form IV of vilazodone hydrochloride, comprising:

a) providing a suspension of vilazodone hydrochloride in a solvent selected from the group consisting of isopropanol, acetonitrile, ethyl acetate, butyl acetate, and mixtures thereof;

b) stirring the suspension obtained in step-(a) at reflux temperature; and

c) recovering the pure vilazodone hydrochloride crystalline Form IV formed in step-(b).

Specifically, the solvent used in step-(a) is isopropanol or acetonitrile, and a most specific solvent is isopropanol.

Step-(a) of providing a suspension of vilazodone hydrochloride includes suspending vilazodone hydrochloride in the solvent at a temperature of about 20°C to the reflux temperature of the solvent used, or obtaining an existing suspension from a previous processing step.

In one embodiment, the suspension obtained in step-(a) is heated at a temperature of about 50°C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used.

In another embodiment, the suspension in step-(b) is stirred at the reflux temperature of the solvent used for about 10 minutes to about 3 hours, specifically for about 15 minutes to about 2 hours; and most specifically for about 20 minutes to about 40 minutes. The recovering in step-(c) is carried out by methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof. In one embodiment, vilazodone hydrochloride crystalline Form IV can be recovered by filtration employing a filtration media of, for example, a silica gel or celite.

a) providing a solution of vilazodone free base in dimethylformamide;

b) combining the solution obtained in step-(a) with isopropanolic-HCl to cause crystallization of vilazodone hydrochloride; and

Step-(a) of providing a solution of vilazodone free base includes dissolving or extracting any form of vilazodone free base (e.g., in the form of a liquid, a solid or a semisolid) in dimethylformamide, or obtaining an existing solution from a previous processing step.

In one embodiment, the vilazodone free base is dissolved or extracted in dimethylformamide at a temperature of about 20°C to the reflux temperature of the solvent, and specifically at a temperature of about 25°C to about 35°C. After complete dissolution of vilazodone, the resulting solution is stirred at a temperature of about 25°C to about 35°C for at least 5 minutes, and specifically for about 10 minutes to about 1 hour.

In another embodiment, the solution obtained in step-(a) is optionally subjected to carbon treatment or silica gel treatment by the methods as described hereinabove.

Combining of the solution of vilazodone free base with hydrochloric acid saturated in isopropanol (hereinafter referred to as isopropanolic-HCl) in step-(b) is done in a suitable order, for example, the solution is added to the isopropanolic-HCl, or alternatively, the isopropanolic-HCl is added to the solution. The addition is, for example, canied out drop wise or in one portion or in more than one portion. The addition is specifically carried out under stirring at a temperature of about 15°C to the reflux temperature of the solvent for at least 5 minutes, specifically at a temperature of about 20°C to 50°C for about 10 minutes to about 1 hour, and most specifically at a temperature of about 25°C to 35°C for about 20 minutes to about 40 minutes. After completion of the addition process, the resulting mass is stirred at a temperature of below 35°C for at least 10 minutes and specifically at a temperature of about 20°C to about 30°C for about 15 minutes to about 2 hours to cause crystallization.

The recovering in step-(c) is carried out by methods as described hereinabove.

As used herein, the term "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.

As used herein, the terms "room temperature" or "RT" refer to a temperature of about 15°C to about 35°C. For example, "RT" can refer to a temperature of about 25°C to about 30°C.

The term "crystalline Form IV of vilazodone hydrochloride", otherwise called "polymorph IV of vilazodone hydrochloride" or "vilazodone hydrochloride Form IV", as used herein is intended to mean the crystalline form IV of vilazodone hydrochloride as described in the WO '794 publication.

In one embodiment, the crystalline Form IV of vilazodone hydrochloride obtained by the processes disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 9.03, 11.58, 12.80, 14.47, 16.82, 18.84, 20.40, 21.69, 24.57, 27.31 and 28.17 ± 0.2 degrees substantially in accordance with Figure 1 ; an infra red (FT-IR) spectrum having main bands at about 3438, 3329, 3274, 3029, 3007, 2987, 2938, 2915, 2876, 2847, 2660, 2460, 2223, 1900, 1669, 1604, 1578, 1475, 1445, 1371, 1321, 1304, 1282, 1276, 1250, 1228, 1186, 1 162, 1 142, 1132, 1113, 1099, 1083, 1032, 971, 952, 942, 909, 882, 854, 822, 768, 734, 691 and 661 ± 2 cm^"1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) , thermogram having a small endotherm at about 241 °C and a sharp endotherm peak at about 286°C substantially in accordance with Figure 3.

In one embodiment, disclosed herein is an efficient, convenient, industrially advantageous and consistently reproducible processes for the preparation of crystalline Form IV of vilazodone hydrochloride, and the crystalline Form IV obtained by these processes is essentially free from other solid state forms of vilazodone hydrochloride detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.

The term "crystalline Form IV essentially free of other solid state forms of vilazodone hydrochloride" means that no other solid state forms of vilazodone hydrochloride can be detected within the limits of a powder X-ray diffractometer. "Other solid state forms of vilazodone hydrochloride" means solid state forms other than Form IV, including crystalline forms, amorphous form, solvated forms, hydrated forms and mixtures thereof.

The highly pure vilazodone hydrochloride crystalline Form IV obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.

Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 35°C to about 80°C and most preferably at about 70°C to about 75°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably shorter periods of time such as about 1 to 8 hours and more preferably about 2 to 4 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.

The purity of the highly pure Vilazodone hydrochloride crystalline Form IV substantially free of other solid state forms obtained by the processes disclosed herein is greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the Vilazodone hydrochloride crystalline Form IV obtained by the processes disclosed herein can be about 99% to about 99.95, or about 99.5% to about 99.99%.

Unless otherwise specified, the Vilazodone free base or its hydrochloride salt as used herein as starting materials can be obtained by the processes described in the prior art, for example, as per the process described in the U.S. Patent No. 5,532,241 or the JMC Article, or alternatively obtained by the process exemplified in example 1 disclosed hereinafter.

The highly pure crystalline Form IV of vilazodone hydrochloride obtained by the processes disclosed herein is free from other solid state forms and solvated forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The crystalline Form IV of vilazodone hydrochloride obtained by the processes disclosed herein exhibits properties making it suitable for formulating Vilazodone hydrochloride.

Further encompassed herein is the use of the vilazodone hydrochloride crystalline

Form IV essentially free of other solid state forms, made by the process disclosed herein, for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

A specific pharmaceutical composition of the vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms is selected from a solid dosage form and an oral suspension.

In one embodiment, the vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms made by the processes disclosed herein, for use in the pharmaceutical compositions, has a D₉₀ particle size of less than or equal to about 100 microns, specifically about 5 microns to about 60 microns, and most specifically about 10 microns to about 50 microns.

In another embodiment, the vilazodone hydrochloride crystalline Form IV made by the processes disclosed herein is having a specific surface area of at least about 2.2 m²/g and specifically from about 2.28 m /g to about 2.34 m /g, which has good flow properties and better dissolution properties to obtain formulations with greater bioavailability.

Specific surface area of an active pharmaceutical ingredient may be affected by various factors. There is a general connection between 'Specific Surface Area' and 'Particle Size'; the smaller the Particle size, the higher the Specific surface area. The rate of dissolution of a poorly-soluble drug is a rate-limiting factor in its absorption by the body. A reduction in the particle size can increase the dissolution rate of such compounds through an increase in the surface area of the solid phase that is in contact with the liquid medium, thereby resulting in an enhanced bioavailability of the compositions containing such compounds. It is generally not possible to predict the exact particle size and distribution required for any particular drug substance to achieve a specific dissolution profile or a specific in vivo behavior, as different drugs show differing dissolution characteristics with a reduction in the particle size. Vilazodone hydrochloride is a white to cream colored solid and which is poorly soluble in water since its aqueous solubility is 0.328 μg/ml. The lack of solubility of vilazodone hydrochloride creates a problem since bioavailability of a water insoluble active ingredient is usually poor. Hence, there is a need in the art to prepare active pharmaceutical ingredients such as vilazodone hydrochloride particles with a desired surface area to obtain formulations with greater bioavailability.

In another embodiment, the particle sizes of the vilazodone hydrochloride crystalline Form IV obtained by the process disclosed herein can be further reduced by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known¹ in the art, to bring the solid state form to the desired particle size range.

According to another aspect, there is provided vilazodone hydrochloride crystalline Form IV having a D90 particle size of less than or equal to about 100 microns, specifically about 5 microns to about 60 microns, and most specifically about 10 microns to about 50 microns.

According to another aspect, there is provided vilazodone hydrochloride crystalline Form IV having specific surface area of at least about 2.2 m²/g, and specifically from about 2.28 m²/g to about 2.34 m²/g.

According to another aspect, there is provided a pharmaceutical composition comprising vilazodone hydrochloride crystalline Form IV having a D₉₀ particle size of less than or equal to about 100 microns and one or more pharmaceutically acceptable excipients.

In one embodiment, the pharmaceutical composition comprises vilazodone hydrochloride crystalline Form IV having a D₉₀ particle size of about 10 microns to about 50 microns.

According to another aspect, there is provided a pharmaceutical composition comprising vilazodone hydrochloride crystalline Form IV having specific surface area of at least about 2.2 m²/g and one or more pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical composition comprises vilazodone hydrochloride crystalline Form IV having specific surface area of about 2.28 m /g to about 2.34 m²/g.

The term "micronization" used herein means a process or method by which the size of a population of particles is reduced.

As used herein, the term "micron" or "μιη" both are equivalent and refer to "micrometer" which is 1 x 10^~6 meter.

As used herein, "crystalline particles" means any combination of single crystals, aggregates and agglomerates.

As used herein, "Particle Size Distribution (P.S.D)" means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 2000 equipment or its equivalent.

The important characteristics of the PSD is the D₉₀ or D(0.90), which is the size, in microns, below which 90% of the particles by volume are found, and the D₅o, which is the size, in microns, below which 50% of the particles by volume are found. Thus, a D₉₀ or D(0.90) of less than 100 microns means that 90 volume-percent of the particles in a composition have a diameter less than 100 microns.

According to another aspect, there is provided a method for treating a patient suffering from major depressive disorder (MDD) comprising administering a pharmaceutical composition that comprises a therapeutically effective amount of the vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms, made by the process disclosed herein, along with pharmaceutically acceptable excipients, wherein the vilazodone hydrochloride crystalline Form IV is having specific surface area of at least about 2.2 m /g, and specifically from about 2.28 m /g to about 2.34 m /g.

According to another aspect, there are provided pharmaceutical compositions comprising vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms prepared according to the processes disclosed herein and one or more pharmaceutically acceptable excipients.

According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms, prepared according to processes disclosed herein, with one or more pharmaceutically acceptable excipients.

Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms made by the process disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The vilazodone hydrochloride crystalline Form IV essentially free of other solid state forms made by the process disclosed herein may also be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.

The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.

Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low- substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:

X-Ray Powder Diffraction (P-XRD):

The X-ray powder diffraction spectrum was measured on a BRUKE AXS D8 FOCUS X- ray powder diffractometer equipped with a Cu-anode (copper-Κα radiation). Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 38 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.

Infra-Red Spectroscopy (FT-IR):

FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 5 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm^" to 650 cm^"1.

Differential Scanning Calorimetry (DSC):

Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200 V23.10 Build 79, Universal V4.4A TA Instruments) equilibrated at 40°C and Ramp at a scan rate of 10°C per minute to 210°C. Particle Size Method of Analysis (PSD):

Particle Size Distribution (PSD) is determined by laser diffraction in a Malvern Mastersizer 2000 (Ver. 5.22) equipment or its equivalent.

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES

Example 1

Preparation of 5-[4-[4-(5-Cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2- carboxamide (Vilazodone)

Methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-l-yl]benzofuran-2-carboxylate (41 g) was added to saturated methanolic ammonia solution (8200 ml) under stirring at 25-30°C, the resulting mixture was stirred for 3 to 4 hours at the same temperature to form a clear solution. The reaction mass was stirred for 24 hours at 25-30°C, followed by filtration of the separated solid and then dried to produce 28 g of vilazodone. The mother liquors were taken and the solvent was distilled off under vacuum until the solvent quantity reaches around 15% of the initial volume. The resulting mass was cooled to 25-30°C, followed by filtration and then drying to produce 11 g of Vilazodone free base (Purity by HPLC: 99.5%).

Example 2

Preparation of Crystalline Form IV of Vilazodone Hydrochloride

Vilazodone free base (20 g) was added to isopropanol (1100 ml) at 25-30°C and the contents were heated to reflux to obtain a clear solution. Carbon powder (4 g) was added to the resulting solution at reflux and then stirred for 5 minutes at the same temperature, followed by filtration through hyflo bed. The resulting filtrate was cooled to 40-45°C, followed by drop- wise addition of a mixture of isopropanolic-HCl (15 ml) and isopropanol (440 ml) for 30 minutes at the same temperature. The resulting mass was refluxed for 1 hour, followed by cooling the reaction mass at 25-30°C and then stirring for 30 minutes at the same temperature. The separated solid was filtered, washed with isopropanol (40 ml) and then dried the material at 70-75°C for 2 to 4 hours to produce 20 g of pure Vilazodone hydrochloride crystalline Form IV [Purity by HPLC: 99.95%; Yield: 92%; Particle Size Data: D(0.90) = 14.04 microns, and Specific Surface Area = 2.28 m²/g].

Example 3

Preparation of Crystalline Form IV of Vilazodone Hydrochloride

Vilazodone free base (25 g) was added to isopropanol (1.7 Lt) at 75-80°C and the contents were heated to reflux to obtain a solution. Carbon powder (5 g) was added to the resulting solution at reflux and then stirred for 5 minutes at the same temperature, followed by filtration through hyflo bed and then washing the bed with isopropanol (220 ml). Isopropanolic-HCl (18.5 ml) was added to the hot filtrate. The resulting mass was refluxed for 1 hour and then cooled the reaction mass to 25-30°C, followed by stirring the mass for 20 minutes at the same temperature. The separated solid was filtered, washed with isopropanol (50 ml) and then dried the material at 70-75°C for 2 to 4 hours to produce 25 g of pure Vilazodone hydrochloride crystalline Form IV [Purity by HPLC: 99.95%; Yield: 92%; Particle Size Data: D(0.90) = 13.62 microns, and Specific Surface Area = 2.34 m²/g). Example 4

Preparation of Crystalline Form IV of Vilazodone Hydrochloride Isopropanol (1.5 Li) was taken into a reaction flask and then heated to reflux, followed by the addition of Vilazodone hydrochloride (12.5 g, obtained by the processes described in the Journal of Medicinal Chemistry, 2004, Vol. 47, No. 19, pages 4684-4692) at reflux. The resulting suspension was stirred for 20 minutes at reflux, followed by filtration of the solid. The resulting wet solid was washed with isopropanol (100 ml) and then dried the material at 70-75°C for 2 to 4 hours to produce 12 g of pure Vilazodone hydrochloride crystalline Form IV (Purity by HPLC: 99.9%).

Example 5

Preparation of Crystalline Form IV of Vilazodone Hydrochloride

Acetonitrile (50 ml) was added to Vilazodone hydrochloride (5 g, obtained by the processes described in the Journal of Medicinal Chemistry, 2004, Vol. 47, No. 19, pages 4684-4692) at 25-30°C and then contents were heated to reflux. The resulting mass was stirred for 30 minutes at reflux and then filtered. The resulting wet solid was washed with isopropanol (40 ml) and then dried the material at 70-75°C for 3 to 4 hours to produce 4.5 g of pure Vilazodone hydrochloride crystalline Form IV (Purity by HPLC: 99.9%).

Example 6

Preparation of Crystalline Form IV of Vilazodone Hydrochloride

Vilazodone free base (10 g) was dissolved in dimethylformamide (100 ml) at 25-30°C to obtain a clear solution. Isopropanolic-HCl (10 ml) was added to the solution at 25-30°C and then stirred for 10 minutes at the same temperature. The solid was separated, followed by the addition of dimethylformamide (100 ml) and then stirred for 20 minutes at 25-30°C. The separated solid was filtered, washed with isopropanol (20 ml) and then dried the material at 70-75°C for 2 to 4 hours to produce 9 g of pure Vilazodone hydrochloride crystalline Form IV (Purity by HPLC: 99.85%)

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein. The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.

The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.

The term "buffering agent" as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.

The term "sweetening agent" as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene^ ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.

The term "diluents" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "glidant" as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti^ caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "lubricant" as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "disintegrant" as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "wetting agent" as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, poly oxy ethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).

All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

We claim:

1. A process for the preparation of crystalline Form IV of Vilazodone hydrochloride, comprising:

c) combining the solution obtained in step-(a) or step-(b) with hydrochloric acid saturated in isopropanol to cause crystallization of vilazodone hydrochloride; and d) recovering the highly pure vilazodone hydrochloride crystalline Form IV formed in step-(c).

2. The process of claim 1, wherein the solution in step-(a) is prepared by dissolving or extracting vilazodone free base in isopropanol at a temperature of about 50°C to the reflux temperature, followed by stirring the solution at reflux.

3. The process of claim 1, wherein the solution in step-(a) is prepared by suspending vilazodone free base in isopropanol at room temperature, followed by heating the suspension at a temperature of about 50°C to the reflux temperature to form a solution and then stirring the solution at reflux.

4. The process of claim 1, wherein the solution in step-(a) is prepared by reacting methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin- 1 -yl]benzofuran-2-carboxylate with ammonia in a suitable solvent to produce a reaction mass containing vilazodone free base, followed by washings, extractions, evaporations or a combination thereof, and then dissolving or extracting the resulting vilazodone free base in isopropanol at reflux, wherein the ammonia is used in the form of aqueous ammonia or ammonia gas or ammonia saturated in an organic solvent.

5. The process of claim 4, wherein the solvent used for amidation reaction is selected from the group consisting of water, methanol, ethanol, isopropanol, and mixtures thereof.

6. The process of claim 1, wherein the combining in step-(c) is accomplished by adding the solution of vilazodone free base to the isopropanolic-HCl or by adding the isopropanolic-HCl to the solution, wherein the addition is carried out at above 30°C; and wherein the recovering in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof.

7. The process of claim 6, wherein the addition is carried out at a temperature of about 40°C to the reflux temperature for about 10 minutes to about 1 hour; and wherein the mixture obtained after completion of the addition process is stirred at a temperature of below 35°C for at least 10 minutes to cause crystallization.

8. The process of claim 7, wherein the addition is carried out at a temperature of about 50°C to the reflux temperature of the solvent used for about 20 minutes to about 40 minutes; and wherein the mixture obtained after completion of the addition process is stirred at a temperature of about 20°C to about 30°C for about 15 minutes to about 2 hours to cause crystallization.

9. A process for the preparation of crystalline Form IV of vilazodone hydrochloride, comprising:

b) stirring the suspension obtained in step-(a) at reflux temperature; and

c) recovering the highly pure vilazodone hydrochloride crystalline Form IV formed in step-(b).

10. The process of claim 9, wherein the solvent used in step-(a) is isopropanol or acetonitrile; wherein the suspension in step-(a) is provided by suspending vilazodone hydrochloride in the solvent at a temperature of about 20°C to the reflux temperature of the solvent used; wherein the suspension in step-(b) is stirred at the reflux temperature for about 10 minutes to about 3 hours; and wherein the recovering in step-(c) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

11. The process of claim 10, wherein the solvent used in step-(a) is isopropanol; and wherein the suspension in step-(b) is stirred at the reflux temperature for about 20 minutes to about 40 minutes.

12. A process for the preparation of crystalline Form IV of Vilazodone hydrochloride, comprising: a) providing a solution of vilazodone free base in dimethylformamide;

c) recovering the highly pure vilazodone hydrochloride crystalline Form IV formed in 5 step-(b).

13. The process of claim 12, wherein the solution in step-(a) is prepared by dissolving or extracting vilazodone free base in dimethylformamide; wherein the solution obtained in step-(a) is optionally subjected to carbon treatment or silica gel treatment; wherein the combining in step-(b) is accomplished by adding the solution of vilazodone free0 base to the isopropanolic-HCl or by adding the isopropanolic-HCl to the solution; and wherein the recovering in step-(c) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

14. The process of claim 13, wherein the vilazodone free base is dissolved or extracted in dimethylformamide at a temperature of about 20°C to the reflux temperature; wherein5 the addition in step-(b) is carried out under stirring at a temperature of about 15°C to the reflux temperature; and wherein the mass obtained after completion of the addition process is stirred at a temperature of below 35°C.

15. The process of claim 12, wherein the solution obtained in step-(a) is stirred at a temperature of about 25°C to about 35°C; and wherein the solution obtained in step-(a)0 is optionally subjected to carbon treatment or silica gel treatment.

' 16. The process of any one of claims T to 15, wherein the crystalline Form IV of vilazodone hydrochloride obtained is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 9.03, 11.58, 12.80, 14.47,

16.82, 18.84, 20.40, 21.69, 24.57, 27.31 and 28.17 ± 0.2 degrees substantially in5 accordance with Figure 1 ; an infra red (FT-IR) spectrum having main bands at about 3438, 3329, 3274, 3029, 3007, 2987, 2938, 2915, 2876, 2847, 2660, 2460, 2223, 1900, 1669, 1604, 1578, 1475, 1445, 1371, 1321, 1304, 1282, 1276, 1250, 1228, 1186, 1162, 1142, 1132, 1113, 1099, 1083, 1032, 971, 952, 942, 909, 882, 854, 822, 768, 734, 691 and 661 ± 2 cm^"1 substantially in accordance with Figure 2; and a Differential Scanning0 Calorimetric (DSC) thermogram having a small endotherm at about 241°C and a sharp endotherm peak at about 286°C substantially in accordance with Figure 3.

17. The process of claim 16, wherein the crystalline Form IV of vilazodone hydrochloride obtained is essentially free from other solid state forms of vilazodone hydrochloride including crystalline forms, amorphous form, solvated forms, hydrated forms and mixtures thereof; and wherein the vilazodone hydrochloride crystalline Form IV obtained has a purity greater than about 99.9% as measured by HPLC.

18. Vilazodone hydrochloride crystalline Form IV having a D₉₀ particle size of less than or equal to about 100 microns.

19. The compound of claim 18, wherein the vilazodone hydrochloride crystalline Form IV has a D₉o particle size of about 10 microns to about 50 microns.

20. Vilazodone hydrochloride crystalline Form IV having specific surface area of at least about 2.2 m /g.

21. The compound of claim 20, wherein the vilazodone hydrochloride crystalline Form IV has specific surface area of about 2.28 m²/g to about 2.34 m²/g.

22. A pharmaceutical composition comprising vilazodone hydrochloride crystalline Form IV having a D₉₀ particle size of less than or equal to about 100 microns and one or more pharmaceutically acceptable excipients.

23. The pharmaceutical composition of claim 22, wherein the vilazodone hydrochloride crystalline Form IV has a D₉₀ particle size of about 10 microns to about 50 microns.

24. A pharmaceutical composition comprising vilazodone hydrochloride crystalline Form IV having specific surface area of at least about 2.2 m²/g.

25. The pharmaceutical composition of claim 24, wherein the vilazodone hydrochloride crystalline Form IV has specific surface area of about 2.28 m 2 /g to about 2.34 m 2 /g.