Field of Invention

The present invention describes a novel process for the preparation of vilazodone hydrochloride and its crystalline polymorph useful in treating major depressive disorders (MDD).

Background of the Invention

Vilazodone hydrochloride is chemically l-[4-(5-cyanoindol-3-yl) butyl]-4-(2-carbamoylbenzofuran-5-yl) piperazine hydrochloride (Figure 1).

Figure 1. Vilazodone.Hydrochloride

It is a serotonergic antidepressant and has been approved by US FDA for treating major depressive disorders (MDD). The U.S. Pat. 5532241 describes the preparation of vilazodone free base and its hydrochloride salt. The U.S. Pat. 7381726 describes the preparation of several of its polymorphs of vilazodone hydrochloride. A total of fifteen polymorphs are described which are referred to as I, II, III, IV,V, VI,VII,VIII,IX,X,XI,XIII,XIV,XV, and XVI. Out of these polymorphs, three are hydrates (V, VI, and VIII), four are anhydrous forms (IV, III, VII, and IX), six are various solvates derivatives from solvents such as acetone( I), tetrahydrofuran (II, XV, and X), methanol (XI), and heptanes (XIV), one dihydrochloride salt (XIII) and Form XVI which is obtained through spray-drying.

The solubility of some of the polymorphs has been described (U.S Pat. No. 7834020, Example-16). The Form-4 has shown highest solubility of 0.33 ug/ml, followed by Form-VI (0.23 ug/ml), and other polymorphs have generally shown < 0.2 ug/ml solubility (TABLE-1):

TABLE-1. Solubility of vilazodone hydrochloride polymorphs. (U.S Pat. No. 7834020)

These polymorphs are prepared by dissolving or suspending the free base in a solvent and reacting with IN hydrochloric acid. For example, Form-I is prepared by treating solution of vilazodone free base in acetone with IN hydrochloric acid at 50°C, and Form-II by treating solution of vilazodone free base in tetrahydrofuran with IN hydrochloric acid. Some of the polymorphs have also been prepared by stirring one polymorph in a specific solvent. For example, Form-I has also been prepared by stirring a suspension of Form-HI in acetone for 14 days. The U.S Patent No. 7,834,020 B2, which is a divisional patent of "726" specifically claims Form-IV and a method for its preparation by drying Form-XI at a temperature between 55° and 65° C. The PCT application, WO 2012/131706 Al describes an amorphous form of and a process for its preparation which involves dissolving vilazodone hydrochloride in a solvent and removing the solvent by distillation or spray/ freeze drying.

Summary of the Invention

The prior art of preparing hydrochloride salt of vilazodone using aqueous hydrochloric acid has certain limitations. The carboxamide group present on the benzofuran moiety is sensitive to aqueous acid and undergoes hydrolysis. Similarly the nitrile group on the indole moiety is also susceptible to aqueous hydrochloric acid. Hence it is beneficial to avoid an aqueous medium and also use a mild source of hydrogen chloride.

We have now discovered that vilazodone hydrochloride can be prepared in a non-aqueous medium by treating the solution of the free base of vilazodone in isopropanol with trimethylsilyl chloride (TMSC1).

In another embodiment, it has been found that the vilazodone hydrochloride thus obtained has a novel crystalline form. The new crystalline polymorph has shown better water solubility compared to other known polymorphs and has been designated as Form-D.

Detailed Description of the Invention

The present invention provides a novel process for the preparation of vialzodone hydrochloride which comprises the steps of:

a) dissolving vilazodone free base in isopropanol,
b) treating the solution with trimethylsilyl chloride,
c) isolating vilazodone hydrochloride as a crystalline solid.

The free base, l-[4-(5-cyanoindol-3-yl) butyl]-4-(2-carbamoylbenzofuran-5-yl) piperazine, vilazodone was prepared as reported in U.S. Pat. 5532241.

The free base shows poor solubility in most of the common solvents. It is soluble in aprotic solvents such as tetrahydrofuran, N-methylpyrrolidone, dimethylformamide etc. But these solvents being aprotic cannot be used as they do not generate hydrogen chloride when contacted with TMSC1. Only protic solvents such as alcohols react with TMSC1 to generate hydrogen chloride. The free base shows poor solubility in methanol and ethanol, but significant solubility in isopropanol. Hence isopropanol is selected as the solvent. Vilazodone free base is dissolved in isopropanol. About 40 mL isopropanol is required for dissolving one gram of the free base. Some undissolved free base, if present, can be solubilised by refluxing the suspension for a few minutes. On cooling to room temperature (25±2° C) the solution remains clear and no re-precipitation is observed. To this clear solution trimethylsilyl chloride is slowly added drop wise while stirring. About 2 to 6 mol equivalents of TMSC1 are used for the reaction. After a few minutes vilazodone hydrochloride crystallizes out. The suspension is further stirred for four to six hours and the crystals are filtered. The filtered crystals are washed with isopropanol to remove any traces of trimethylsilyl chloride. This also removes unreacted free base. The crystals are dried at 100° C for 24 hours to eliminate any residual solvent. The process gives vilazodone hydrochloride in good yield (>85%).

The elemental analysis (C, H, and N) confirmed the purity of the substance. The analysis (NMR in DMSO and GC) indicated the absence of any residual isopropanol in the sample.

TABLE 2: X-ray powder diffraction pattern expressed in terms of d-spacing, 26 values and relative intensities for crystalline vilazodone hydrochloride shows the following:

The peaks at 29 values at 13.58, 14.63, 17.43, 21.74, 22.48, 27.36, 29.42, and 31.41 are characteristic of this polymorph. The x-ray powder diffraction diagram of the crystalline vilazodone hydrochloride is given in FIG. 2.

The crystalline vilazodone hydrochloride shows characteristic infra-red absorption at: 3392, 3262, 3206, 2982, 2932, 2501, 2425, 2218, 1669, 1626, 1598, 1567, 1512, 1461, 1438, 1412, 1370, 1272, 1241, 1203, 1171, 1142, 1024, 946, 877, 804, 770, 744, 677, 631, 582, 494 cm'1. The IR spectrum of the crystalline vilazodone hydrochloride is given in FIG. 3.

The crystalline vilazodone hydrochloride is further characterised by differential scanning calorimetry (DSC). The DSC thermogram shows a minor broad endotherm between 237o to 255oC, and a main endotherm at 289°C due to melting of the sample. Almost all reported polymorphs of vilazodone hydrochloride have shown a similar trend and is attributed to a phase transition at 200° to 260°C to Form-VII. The thermoanalytically resulting Form VII melts between 280° to 290°C (U.S.Pat. 7381726 Bl). Several earlier samples also showed a small endotherm at 204°C, and was attributed to the presence of residual free base. Washing the sample with isopropanol resulted in the elimination of the endotherm at 204°C. Thus DSC is also a useful criterion in evaluating the purity of the form. The DSC thermogram of crystalline vilazodone hydrochloride is given in FIG. 4.

The new crystalline vilazodone hydrochloride also showed good solubility in water. By shake-flask method, the solubility of the crystalline vilazodone hydrochloride was measured and found to be 3.30 (± 0.10) ug/ mL. This is higher than the solubility reported for other crystalline forms (TABLE. 1). The new crystalline form has been designated as Form-D.

The embodiments of the present invention are illustrated in the following examples, which are not intended in any way to limit the scope of the invention.

Brief Description of the Drawing

FIG. 1: Chemical structure of vilazodone hydrochloride.

FIG. 2: X-ray powder diffraction pattern of crystalline vilazodone hydrochloride.

FIG. 3: Infra-Red spectrum of crystalline vilazodone hydrochloride.

FIG. 4: DSC thermogram of crystalline vilazodone hydrochloride.

Example
Vilazodone free base (5-(4-[4-(5-cyano-l//-indol-3-yl) butyl] piperazin-1-yl) benzofuran-2-carboxamide) prepared according to U.S. Pat. 5532241 (1.0 g, 2.2 mmol) was stirred in isopropanol (50 mL) at 25±2° C.

The solution was heated and refluxed for a few minutes to dissolve any traces of free base. On cooling to room temperature the solution remained clear. To this clear solution trimethylsilyl chloride (0.68 g, 6.3 mmol) was slowly added dropwise while stirring. Precipitation of vilazodone hydrochloride was observed after a few minutes. Stirring was continued for four to six hours and the suspension was filtered. The solid obtained was washed with isopropanol to remove any unreacted free base and trimethylsilyl chloride. The crystals were dried at 100° C for 24 hours to eliminate any residual solvent. The process gave vilazodone hydrochloride in good yield (0.95 g, 88%). The analysis (NMR in DMSO and GC) indicated the absence of any residual isopropanol in the sample. Elemental analysis for C26H28N5O2CI: calculated%: C, 65.33; H, 5.90; N, 14.65; Found %: C, 65.18; H, 5.72; and N, 14.51.

We claim:

1. A process for the preparation of crystalline vilazodone hydrochloride, comprising the steps of:

a) dissolving vilazodone free base in isopropanol,
b) treating the isopropanolic solution with trimethylsilyl chloride and
c) isolating vilazodone hydrochloride as crystalline form D

2. The process according to claim 1 step (a), wherein the ratio of vilazodone free base to isopropanol is between 1: 40 to 1:100 (w/v), preferably between 1: 40 and 1: 60 (w/v)

3. The process according to claim 1 step (b), wherein the isopropanolic solution of vilazodone is treated with trimethylsilyl chloride, either as neat or as a solution in isopropanol.

4. The process according to claim 1 step (b), wherein the ratio between vilazodone and
trimethylsilyl chloride is 1:1 to 1:6, preferably 1: 2 to 1: 3.

5. The crystalline form of vilazodone hydrochloride as in claim 1, having an X-ray diffraction pattern with characteristic peaks at (29): 13.58, 14.63, 17.43, 21.74, 22.48, 27.36, 29.42, and 31.41

6. The crystalline form of vilazodone hydrochloride as in claim 1, having substantially the same X-ray diffraction pattern as shown in Figure 2.