DESC:Field of the invention
The present invention relates to substantially pure, stable solid dispersion comprising amorphous Vilazodone Hydrochloride and a pharmaceutically acceptable water soluble polymer as well as process for preparation of the same.
Background and the prior art
Vilazodone, 1-[4-(5-cyanoindol-3-yl) butyl]-4-(2-carbonyl benzofuran-5-yl) piperazine represented by formula (1), and its pharmaceutically acceptable acid addition salts are useful as anxiolytics, antidepressants and antipsychotic neuroleptic and / or antihypertensive agents.

A pharmaceutical preparation of Vilazodone and their pharmaceutically acceptable salt is mentioned in US5532241 for treating disorders of the central nervous system.
Vilazodone Hydrochloride is indicated for the treatment of major depressive disorder (MDD).
Process for preparation of vilazodone free base or its hydrochloride are described in US patent Nos. 5532241, 5723614 , 7799916 or 7834020.
Preparation of compound of formula (1) was first disclosed in US5532241A (hereinafter referred to as US’241). The process for preparation of Vilazodone illustrated in example-4 of US’241 involves reacting 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazinyl-1-yl)benzofuran-2-carboxylic acid with 2-chloro-1-methylpyridinium methanesulfonate in the presence of N-methyl pyrrolidine followed by treatment with dried ammonia gas to afford compound of formula I after customary workup. The Vilazodone base thus obtained was further converted to its hydrochloride salt. The experimental procedure of the salification step is not elaborated in the specification.
However, a later PCT publication No.WO2002102794A2 (hereinafter referred to as WO'794) by the same applicant teaches that the Vilazodone base obtained according to the process described in example 4 of US’241 is converted to Vilazodone Hydrochloride by treating the solution of the vilazodone base (700 mg) in 2-propanol (30 ml) with 2-propanolic HCl-solution (Merck-Art.No. 1.00326). The vilazodone hydrochloride obtained by the said process is a mixture of amorphous Vilazodone Hydrochloride, crystallized Vilazodone Hydrochloride and the Vilazodone free base having melting point 269-272° C.
The WO'794 publication discloses several crystalline modifications (Crystalline Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XIII, XIV, XV and XVI) of Vilazodone Hydrochloride, which include six anhydrate forms, three hydrated forms and six solvated forms, wherein 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, Infra-Red spectroscopy and thermal analysis.
Further the WO'794 publication discloses amorphous, Form-XVI, which is not a pure amorphous form as evident from the diffractogram corresponding to form XVI shown in figure-26 and the PXRD data corresponding to form-XVI provided in table- III of the specification. Though the WO'794 application mentions that a pure amorphous form of Vilazodone Hydrochloride has been found, however the WO '794 publication neither discloses the characterization data (X-ray diffractogram) nor describes the process for the preparation of a pure amorphous form of Vilazodone Hydrochloride.
WO2012131706 (IN 167/MUM/2011) discloses amorphous Vilazodone Hydrochloride and process for its preparation.
WO 2013078361 discloses new solid state form of vilazodone freebase and also discloses several solid state crystalline forms of Vilazodone Hydrochloride. The disclosed Vilazodone Hydrochloride crystalline forms are named such as form alpha, form beta, form gamma, form delta, form epsilon, form eta, form theta, form iota, form kappa, form lambda, form Mu, form Nu, form zeta, form Xi, form omicron, form pi, form Rho, form sigma, forma tau, amorphous form of Vilazodone Hydrochloride and amorphous solid dispersion of Vilazodone Hydrochloride with HPMC and PVP. However the patent has not dealt with stability issues of amorphous or amorphous solid dispersion of Vilazodone Hydrochloride.
WO2013088373 (IN 3608/DEL/2011) discloses amorphous form of Vilazodone Hydrochloride and its preparation.
1632/CHE/2013 describes a process for preparation of Vilazodone Hydrochloride crystalline form D in non-aqueous medium by treating the solution of the vilazodone freebase in isopropanol with trimethylsilyl chloride.
WO2013153492A2 describes process for preparation of pure amorphous form of Vilazodone Hydrochloride.
WO2013156935A1 provides a process for preparing crystalline Vilazodone Hydrochloride.
WO 2013164794 (IN 1382/DEL/2012) describes three different crystalline forms of Vilazodone Hydrochloride namely form A, form B & form C and also provides processes for preparation thereof.
WO 2013168126 (IN 1885/CHE/2012) describes several crystalline forms of Vilazodone Hydrochloride and Vilazodone freebase. The crystalline forms of Vilazodone Hydrochloride which disclosed in this application named as form B, form C, form D, form E, form F, form G, form H. It also provides process for the preparation of said crystalline forms. The specification also covers amorphous Vilazodone Hydrochloride and solid dispersion of Vilazodone Hydrochloride with PVP and HPMC.
US20130324554A1 (now U.S. patent, 8835635) covers amorphous co-precipitate comprising Vilazodone Hydrochloride and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose and hypromellose phthalate.
WO2013185209A1 discloses crystalline benzyl alcohol solvates of Vilazodone Hydrochloride.
WO2014064715A2 discloses amorphous form of Vilazodone Hydrochloride and process for preparation thereof.
WO2014049612A2 discloses crystalline form-S of Vilazodone Hydrochloride
WO2014087428 discloses process for the preparation of Vilazodone Hydrochloride in amorphous form, discloses amorphous Vilazodone Hydrochloride substantially free of N-oxide impurity and also covers crystalline n-propanol, n -butanol, ethanol, ethyl acetate and DMSO solvate of Vilazodone Hydrochloride characterized by PXRD, DSC and TGA and process for preparation of the same.
US20140179713 discloses crystalline form-Z of Vilazodone Hydrochloride.
US20140303185 discloses novel crystalline polymorphic forms A and B of Vilazodone Hydrochloride.
CN102977083A discloses novel crystalline form-XVII.
Polymorphism occurs when a solid material exists in more than one crystal structure or lattice form.
The discovery of further solid forms of an active pharmaceutical ingredient (API) can offer an opportunity to improve the performance profile of a pharmaceutical composition comprising said API. As evident from above, the known solid forms of Vilazodone Hydrochloride still leave room for improvement of the physicochemical as well as the pharmaceutical characteristics of Vilazodone containing pharmaceutical compositions. Processability of the API during manufacture of the pharmaceutical composition and characteristics of the finished dosage form, such as storage stability under difficult environmental conditions, such as high relative humidity and/or high temperature, can still be improved or optimized.
Amorphous solids consist of disordered arrangement of molecules and do not possess a distinguishable crystal lattice. The amorphous form is generally more soluble than the crystalline form and thus contributes more in the bioavailability.
The presence of this high energy amorphous form of the API in a pharmaceutical composition usually improves the dissolution rate. However, these systems are not often physically stable. Such an amorphous state is thermodynamically unstable and under certain conditions of temperature and relative humidity during storage it could crystallize causing the loss of the desired properties associated with the amorphous state and reduced shelf-life.
Hence, there is a need in the art for highly pure and stable amorphous form of Vilazodone Hydrochloride essentially free of crystalline forms and a process for its preparation
Solid dispersion could be an attractive alternative to stabilize such amorphous drug substances while improving the drug dissolution rate and bioavailability.
So there exists a scope to develop substantially pure and stable amorphous Vilazodone Hydrochloride meeting these norms.
Objects of the invention
It is an object of the present invention to provide a substantially pure, stable solid dispersion of amorphous Vilazodone Hydrochloride.
It is yet another object of the present invention to provide solid dispersion comprising amorphous Vilazodone Hydrochloride and a pharmaceutically acceptable water soluble polymer.
Another object of the present invention is to provide solid dispersion of amorphous Vilazodone Hydrochloride and a pharmaceutically acceptable water soluble polymer which is storage stable.
It is another object of the present invention to provide a process for preparing solid dispersion comprising amorphous Vilazodone Hydrochloride and a pharmaceutically acceptable water soluble polymer.
Brief Description of the drawing
Figure 1 is an illustration of a PXRD pattern of solid dispersion of amorphous vilazodone hydrochloride and copovidone
Figure 2 is an illustration of a PXRD pattern of solid dispersion of amorphous vilazodone hydrochloride and Eudragit ®
Definitions
The term "solid dispersion" , unless otherwise mentioned, defines a system in a solid state wherein one component is dispersed more or less evenly throughout the other component or components, e.g. in the context of the present invention amorphous vilazodone hydrochloride within the water soluble polymer.
The term ‘’substantially pure’’, unless otherwise mentioned, defines a solid dispersion of Vilazodone Hydrochloride containing no unidentified single impurity in amounts greater than about 0.1% by HPLC.
Description of the invention
The present inventors have found ways and means to obtain a pure, stable amorphous Vilazodone Hydrochloride of formula (1a)

Amorphous Vilazodone Hydrochloride obtained by standard methods i.e. freeze drying; spray drying, lyophilization, milling etc. shows appearance of crystalline peaks upon storage.
Previous attempts failed to prepare amorphous Vilazodone hydrochloride and the obtained crystalline products suggested that pure amorphous Vilazodone hydrochloride is not stable in the amorphous state and readily crystallizes.
Such a transition negates the solubility advantage of the amorphous state. To overcome this challenge, present invention is directed to provide a solid dispersion comprising amorphous vilazodone hydrochloride that prevents or retards API recrystallization.
In an embodiment the present invention relates to a solid dispersion comprising amorphous vilazodone hydrochloride of formula 1a and a pharmaceutically acceptable water soluble polymer.
In another embodiment the present invention relates to a solid dispersion comprising amorphous vilazodone hydrochloride and a pharmaceutically acceptable water soluble polymer such as vinylpyrrolidone based copolymer and methacrylic acid based copolymer and the like.
In a preferred aspect, such a copolymer of vinylpyrrolidone and vinyl acetate is copovidone.
In another preferred aspect, copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivative is Eudragit ® (an acrylic polymer manufactured by Evonik Industries).
Yet another embodiment of the present invention relates to a solid dispersion comprising amorphous vilazodone hydrochloride and a pharmaceutically acceptable water soluble polymer such as copovidone that can be characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 1.
In yet another embodiment the present invention relates to a solid dispersion comprising amorphous vilazodone hydrochloride and a pharmaceutically acceptable water soluble polymer such as Eudragit ® that can be characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 2.
In another aspect the present invention provides the solid dispersion comprising amorphous vilazodone hydrochloride and a pharmaceutically acceptable water soluble polymer having water content from about 0.5% to about 15% wt/wt, preferably from 1.0% to 12%, more preferably from 2.0% to about 10%w/w.
In another preferred embodiment the solid dispersion of the present invention is characterized in that the weight ratio of Vilazodone Hydrochloride and the water-soluble polymer is in the range of 1 : 1 to 1:10 , preferably in the range of 1 : 0.5 to 1 :5 , more preferably in the range of 1 :0.25 to 1 :3 , and most preferably in the range of 1 :0.2 to 1 :1.
In a further preferred embodiment the water-soluble polymer of the present invention have solubility in water of at least 10 g/l, more preferably of at least 30g/l.
In a further embodiment the present application relates to process for preparing a solid dispersion comprising amorphous vilazodone hydrochloride and a pharmaceutically acceptable water soluble polymer, which comprises:
(a) providing a mixture of vilazodone hydrochloride and pharmaceutically acceptable water soluble polymer in suitable solvent;
(b) heating the mixture of step (a) to obtain a clear solution;
(c) optionally filtering the solution of step (b); and
(d) isolating solid dispersion of amorphous vilazodone hydrochloride comprising amorphous vilazodone hydrochloride and a pharmaceutically acceptable water soluble polymer .
In yet another embodiment of the present invention, the suitable solvent medium for the reaction is selected from the group consisting of water, C1-C4 alcohol, C3-C6 ketone, nitriles such as acetonitrile, ethers such as dioxane and tetrahydrofuran amides such as dimethylformamide and N-methylpyrrolidone and a mixture thereof.
The solid dispersion comprising amorphous Vilazodone Hydrochloride and a pharmaceutically acceptable water soluble polymer may be isolated by removing the solvent. Generally, techniques providing a rapid solvent removal can be utilized to provide the desired solid dispersion of amorphous vilazodone hydrochloride. Suitable techniques which may be used for the removal of solvent include, without limitation thereto, distillation using a rotational evaporator device such as a Buchi Rotavapor, spray drying; agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like .
The isolated solid may be optionally further dried to afford amorphous solid dispersion of vilazodone hydrochloride.
Although not limited to, one of the preferred techniques for evaporation is spray-drying.
The product obtained by the process of the present invention is substantially pure, stable solid dispersion of amorphous Vilazodone Hydrochloride having purity >99% by HPLC.
In another embodiment of the present invention solid dispersion of amorphous Vilazodone Hydrochloride is substantially pure having purity greater than about 99% or greater than about 99.5% , or greater than about 99.7% or greater than about 99.9% as determined using high performance liquid chromatography (HPLC). Solid dispersion of amorphous Vilazodone Hydrochloride produced by a method of present invention is substantially pure having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC. Solid dispersion of amorphous Vilazodone Hydrochloride produced by the methods of present invention can be substantially pure having purity in amounts greater than about 99.8% and containing no single impurity in amounts greater than about 0.1% by HPLC.
Another object of the present invention is to provide storage stable solid dispersion of amorphous Vilazodone Hydrochloride and a pharmaceutically acceptable water soluble polymer.
The storage stable solid dispersion of amorphous vilazodone hydrochloride is kept under vacuum sealing with or without nitrogen atmosphere and packed in a double and/or triple bag system. The samples of solid dispersion of amorphous vilazodone hydrochloride when stored at 2-5o C or at relative humidity of 60% at 25 o C or at relative humidity of 75% at 40 o C shows no sign of presence of crystalline peaks for three months.
The Vilazodone Hydrochloride used for the preparation of solid dispersion comprising amorphous vilazodone hydrochloride of the present invention is either obtained as per the process demonstrated in prior art or may be synthesized by methods as it is described in the PCT International Application No. PCT/IB2014/062132 which in its entirety is incorporated herein by reference
The solid dispersion of amorphous vilazodone hydrochloride of the present invention can be used in the preparation of pharmaceutical composition for depressive disorders. Such pharmaceutical composition can be prepared by methods known in the literature.
Present invention is further illustrated by the following non-limiting examples.
Example-1
Preparation of pure Vilazodone
To a clean round bottomed flask were added DM water (900ml) and sodium carbonate (26g, 1.1 mol) The reaction mass was stirred for 15-20 min. Then PBA (100gm, 0.408 mol) was added and the reaction mass was stirred for 5-10 min. To this was added 3-(4-chlorobutyl)-1H-indole-carbonitrile (CBCl) (95g, 0.408 mol), stirred for 5-10 min. and flushed with DM water (100ml).Thereafter isopropyl alcohol (200ml) was added and reaction mass was stirred for 5-10 min. The reaction mass was then heated to reflux (75-85deg) and maintained for about 12 hrs (till CBCI content NMT 2.0%).Then the reaction mass was cooled to room temperature and the deposited solid was filtered, washed with DM water (500ml) and suck dried. The wet solid thus obtained was slurried with acetone (700 ml) for 30-45min. The solid was collected by filtration and again washed with 200ml acetone. The wet solid obtained was dissolved in DMF (700ml) and filtered through celite to remove insoluble. The celite bed was washed with DMF (100ml).The DMF filtrate and washings were combined and preserved. Thereafter an aqueous solution of sodium carbonate (15gm) and sodium metabisulphite (15gm) prepared in DM water (600ML) was gradually added (in about 60 min, temp. 20-40 deg.) to the preserved DMF filtrate and washings taken in a RBF. The resulting mixture was stirred for 60-90 min at 20-35 deg and the precipitated solid was filtered. The wet solid was slurry washed with water (1500ml; 30-45 min.) followed by slurry wash with acetone (700ml; 30-45min.), filtered, suck dried and dried in vacuum oven to yield pure vilazodone.
Yield = 72 to 94%
HPLC purity = >99%
Example-2
Preparation of Vilazodone Hydrochloride
To a clean round bottomed flask was added pure Vilazodone (100 g) and isopropyl alcohol (6500ml).The reaction mass was refluxed for 45 min to obtain a solution. IPA-HCl (2500ml, 0.1 N) was added to the reaction mass at 60-70oC till precipitation of material. The reaction mass was gradually cooled to room temperature. The reaction mass was stirred for additional 60 min at room temperature. The solid obtained was filtered washed with 300ml isopropyl alcohol, suck dried and dried under vacuum.
Yield = 90 to 98 %
HPLC purity = > 99%
Example-3
To a clean round bottomed flask were added acetone (3600ml), DM water (1560ml) and Vilazodone Hydrochloride (60 g). To the mixture was added 60 g of Copovidone. The reaction mass was heated to 50-55 oC for 20-30 min. The solution was cooled to 25-30 oC, filtered through micron filter and washed with acetone. The solution ( ?5650ml) was charged to the feed tank of the spray dryer at 25-30 oC and spray-dried under the following conditions:
· Average feed rate: 40ml/min
· Inlet temp.: 140-150 oC
· Outlet temp.: 95-100 oC
· Vacuum : greater than 150mm of WC
When the feed was finished in the feed tank, heating was stopped, the outlet temperature was set to 30-35 oC and nitrogen circulation was continued to cool the spray dryer to 30-35 oC. The product was collected from the primary and secondary cyclone separator catch pots.
Dry wt.: 96 g
HPLC purity = > 99%

Example-4
To a clean round bottomed flask were added acetone (4800ml), DM water (2080ml) and Vilazodone Hydrochloride (60 g). To the mixture was added 20 g of EUDRAGIT®. The reaction mass was heated to 50-55 oC for 20-30 min. The solution was cooled to 25-30 oC, filtered through micron filter and washed with acetone. The solution ( ?6650ml) was charged to the feed tank of the spray dryer at 25-30 oC and spray-dried under the following conditions:
· Average feed rate: 40ml/min
· Inlet temp.: 140-150 oC
· Outlet temp.: 95-100 oC
· Vacuum : greater than 150mm of WC
When the feed was finished in the feed tank, heating was stopped, the outlet temperature was set to 30-35 oC and nitrogen circulation was continued to cool the spray dryer to 30-35 oC. The product was collected from the primary and secondary cyclone separator catch pots.
Dry wt.: 67g
HPLC purity = > 99%
,CLAIMS:1. A solid dispersion comprising amorphous Vilazodone hydrochloride of formula 1a

and a pharmaceutically acceptable water soluble polymer.
2. The solid dispersion according to claim 1 characterized by a PXRD pattern as illustrated in the pattern of Figure 1.
3. The solid dispersion according to claim 1, wherein the weight ratio of amorphous Vilazodone hydrochloride and the pharmaceutically acceptable water-soluble polymer is in the range of 1 : 0.2 to 1 :1
4. The solid dispersion according to any one of the preceding claims, wherein the pharmaceutically acceptable water soluble polymer has solubility in water of at least 10 g/l.
5. The solid dispersion of amorphous of vilazodone hydrochloride according to any one of the preceding claims having water content of from about 0.5% to about 10% wt/wt.
6. The solid dispersion according to any one of the preceding claims, which is storage stable.
7. The storage stable solid dispersion according to claim 6 wherein the solid dispersion has no change in PXRD after storage for three months under vacuum sealing at 25 o C/ 60% RH or at 2-5o C.
8. The solid dispersion according to any one of the preceding claims, wherein the pharmaceutically acceptable water soluble polymer is vinylpyrrolidone based copolymer and methacrylic acid based copolymer.
9. A solid dispersion comprising amorphous vilazodone hydrochloride and Copovidone.
10. A process for the preparation of a solid dispersion of amorphous Vilazodone hydrochloride with a water soluble polymer comprising the steps of:
(a) providing a mixture of vilazodone hydrochloride and pharmaceutically acceptable water soluble polymer in a suitable solvent;
(b) heating the mixture of step (a) to obtain a clear solution;
(c) optionally filtering the solution of step (b); and
(d) isolating the solid dispersion of amorphous vilazodone hydrochloride.
11. The process according to claim 10 wherein in the step (a) the suitable solvent is selected from the group consisting of water, C1 -C4 alcohol, C3-C6 ketone, nitrile such as acetonitrile and a mixture thereof.
12. The process according to claim 11 wherein in the step (a) the suitable solvent is a mixture of acetone and water.
13. The process according to claim 10 wherein in the step (b) heating the mixture of step (a) is performed at 55-60 o C.
14. Process according to claim 10 wherein the solid dispersion of amorphous vilazodone hydrochloride is isolated by spray drying.