WO2014028473A1 - New salts of vilazodone and solid state forms thereof - Google Patents

New salts of vilazodone and solid state forms thereof Download PDF

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Publication number
WO2014028473A1
WO2014028473A1 PCT/US2013/054707 US2013054707W WO2014028473A1 WO 2014028473 A1 WO2014028473 A1 WO 2014028473A1 US 2013054707 W US2013054707 W US 2013054707W WO 2014028473 A1 WO2014028473 A1 WO 2014028473A1
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Prior art keywords
vilazodone
salts
provides
xrd pattern
powder xrd
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PCT/US2013/054707
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French (fr)
Inventor
Helena Ceric
Masa Rajic Linaric
Marina Ratkaj
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Assia Chemical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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Publication of WO2014028473A1 publication Critical patent/WO2014028473A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to new salts of Vilazodone, solid state forms thereof, processes for preparing them, and pharmaceutical compositions comprising one or more of these salts and solid state forms.
  • Vilazodone (HC1 salt marketed as VIIBRYD) is an SSRI antidepressant (selective serotonin reuptake inhibitor and a 5HTi A receptor partial antagonist) developed for the treatment of major depressive disorder.
  • the compound was originally developed by Merck KGaA, Germany, and is now owned by Forest Laboratories Inc, USA.
  • Different salts of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability and shelf-life. These variations in the properties of different salts may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single compound may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - “DSC”), powder X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state NMR spectrum.
  • TGA thermogravimetric analysis -
  • DSC differential scanning calorimetry -
  • XRD powder X-ray diffraction
  • Discovering new salts and polymorphic forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New salts and polymorphic forms of a pharmaceutically useful compound can also provide opportunities to improve the performance characteristics of a pharmaceutical product. They can also enlarge the repertoire of materials available to a formulation scientist for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling
  • the present invention provides new salts of Vilazodone and their solid state forms. These salts and solid state forms can be used to prepare different salts of Vilazodone, particularly Vilazodone hydrochloride, solid state forms of those different salts and pharmaceutical compositions and formulations thereof.
  • These salts and solid state forms can be used to prepare Vilazodone HC1 or the free base and/or formulations thereof.
  • the invention further provides the salts and solid state forms of Vilazodone as described below for use in the manufacture of a medicament for the treatment of major depressive disorders; and provides a method of treating major depressive disorders, said method comprising administering a therapeutically effective dose of one or more of the salts or solid state forms described herein.
  • the invention also provides a process to prepare formulation of Vilazodone salts comprising combining the below mentioned salts or forms and at least one excipient.
  • Figure 1 provides a powder XRD pattern of crystalline Form PI of Vilazodone phosphate.
  • Figure 2 provides a DSC thermogram of crystalline Form P2 of Vilazodone phosphate.
  • Figure 3 provides a powder XRD pattern of crystalline Form P3 of Vilazodone phosphate.
  • Figure 4 provides a powder XRD pattern of crystalline Form SI of Vilazodone hemi-sulfate.
  • Figure 5 provides a powder XRD pattern of crystalline Form S2 of Vilazodone hemi-sulfate.
  • Figure 6 provides a powder XRD pattern of crystalline Form MS 1 of Vilazodone mesylate.
  • Figure 7 provides a powder XRD pattern of crystalline Form MS2 of Vilazodone mesylate.
  • Figure 8 provides a powder XRD pattern of crystalline Form LI of Vilazodone lactate.
  • Figure 9 provides a powder XRD pattern of crystalline Form ML1 of Vilazodone maleate.
  • Figure 10 provides a powder XRD pattern of crystalline Form ML2 of Vilazodone maleate.
  • Figure 11 provides a powder XRD pattern of crystalline Form Bl of Vilazodone benzoate.
  • Figure 12 provides a powder XRD pattern of crystalline Form B2 of Vilazodone benzoate.
  • Figure 13 provides a powder XRD pattern of crystalline Form HBl of Vilazodone HBr.
  • Figure 14 provides a DSC thermogram of crystalline Form PI of Vilazodone phosphate.
  • Figure 15 provides a FTIR spectrum of crystalline Form PI of Vilazodone phosphate.
  • Figure 16 provides a Raman spectrum of crystalline Form PI of Vilazodone phosphate.
  • Figure 17 provides a DSC thermogram of crystalline Form SI of Vilazodone hemi- sulfate.
  • Figure 18 provides a FTIR spectrum of crystalline Form S 1 of Vilazodone hemi- sulfate.
  • Figure 19 provides a Raman spectrum of crystalline Form SI of Vilazodone hemi- sulfate.
  • Figure 20 provides a DSC thermogram of crystalline Form MSI of Vilazodone mesylate.
  • Figure 21 provides a FTIR spectrum of crystalline Form MS 1 of Vilazodone mesylate.
  • Figure 22 provides a Raman spectrum of crystalline Form MSI of Vilazodone mesylate.
  • Figure 23 provides a DSC thermogram of crystalline Form LI of Vilazodone lactate.
  • Figure 24 provides a FTIR spectrum of crystalline Form LI of Vilazodone lactate.
  • Figure 25 provides a Raman spectrum of crystalline Form LI of Vilazodone lactate.
  • Figure 26 provides a DSC thermogram of crystalline Form ML1 of Vilazodone maleate.
  • Figure 27 provides a FTIR spectrum of crystalline Form ML1 of Vilazodone maleate.
  • Figure 28 provides a Raman spectrum of crystalline Form ML1 of Vilazodone maleate.
  • Figure 29 provides a DSC thermogram of crystalline Form Bl of Vilazodone benzoate.
  • Figure 30 provides a FTIR spectrum of crystalline Form Bl of Vilazodone benzoate.
  • Figure 31 provides a Raman spectrum of crystalline Form Bl of Vilazodone benzoate.
  • Figure 32 provides a DSC thermogram of crystalline Form HB1 of Vilazodone HBr.
  • Figure 33 provides a FTIR spectrum of crystalline Form HB1 of Vilazodone HBr.
  • Figure 34 provides a Raman spectrum of crystalline Form HB1 of Vilazodone HBr.
  • the present invention provides new salts and solid state forms of Vilazodone. These salts and solid state forms can be used to prepare Vilazodone base and/or different salts of Vilazodone and/or formulations thereof.
  • a polymorph may be referred to herein as substantially free of any other solid forms.
  • the expression “substantially free” will be understood to mean that the solid state form contains 20% or less, 10% or less, 5% or less, 2% or less, or 1% or less of any other solid form of the subject compound as measured, for example, by powder X-ray diffraction (PXRD).
  • PXRD powder X-ray diffraction
  • polymorphs of Vilazodone salts described herein as substantially free of any other solid forms would be understood to contain greater than 80% (w/w), greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the subject form of Vilazodone salts.
  • the described polymorphs of Vilazodone salts may contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of one or more other solid forms of Vilazodone salts.
  • the crystalline forms of the invention are disclosed herein as being polymorphically stable under certain recited conditions, for example under conditions of 40°C/ 75% relative humidity.
  • polymorphically stable is meant that less than 1% of any other solid state form of Vilazodone is detected when the recited solid state form of Vilazodone is maintained under the stated conditions.
  • a solid state form may be referred to herein as being characterized by graphical data "as shown in" a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
  • the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which factors are well known to the skilled person.
  • a solid state form may be referred to herein as being characterized by data selected from two or more different data groupings, for example, by a powder XRD pattern having a group of specific peaks; or by a powder XRD pattern as shown in a figure depicting a diffractogram, or by "a combination thereof (or “combinations thereof,” or “any combination thereof), These expressions, e.g., "any combination thereof contemplate that the skilled person may characterize a crystal form using any combination of the recited characteristic analytical data.
  • the skilled person may characterize a crystal form using a group of four or five characteristic powder XRD peaks, and supplement that characterization with one or more additional features observed in the powder X-ray diffractogram, e.g., an additional peak, a characteristic peak shape, a peak intensity, or even the absence of a peak at some position in the powder XRD pattern.
  • the skilled person may in some instances characterize a crystal form using a group of four or five characteristic powder XRD peaks and supplement that characterization with one or more additional features observed using another analytical method, for example, using one or more characteristic peaks in a solid state NMR spectrum, or characteristics of the DSC thermogram of the crystal form that is being characterized.
  • Room temperature refers to a temperature between about 20 °C and about 30 °C. Usually, room temperature ranges from about 20°C to about 25 °C.
  • the term “Overnight” refers to a period of between about 15 and about 20 hours, typically between about 16 to about 20 hours.
  • anhydrous in relation to crystalline Vilazodone or Vilazodone hydrochloride relates to a crystalline Vilazodone or Vilazodone hydrochloride which contains not more than 1% (w/w), more preferably not more than 0.5% (w/w) of either water or organic solvents as measured by TGA.
  • solvate refers to a crystal form that incorporates a solvent in the crystal structure.
  • the solvent is water, the solvate is often referred to as a "hydrate.”
  • the solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.
  • the salts and the solid state forms of the present invention have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, morphology or crystal habit, specific surface and pycnometric density, bulk/tap density, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
  • the present invention provides Vilazodone phosphate. [0060] The present invention also provides a crystalline Vilazodone phosphate.
  • Form PI a crystalline form of Vilazodone phosphate, designated Form PI .
  • Form PI can be characterized by data selected from: a powder XRD pattern with peaks at 8.2, 10.9, 14.7, 16.3 and 20.1 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 1; a Raman spectrum as shown in Figure 16; and any combinations thereof.
  • Form PI can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 7.1, 10.2, 21.8, 23.2 and 24.6 ⁇ 0.2 degrees two-theta.
  • Form PI can be further characterized by a DSC thermogram as shown in Figure 14.
  • Form PI can be also characterized by a FTIR spectrum as shown in Figure 15.
  • Form P2 provides a crystalline form of Vilazodone phosphate, designated Form P2.
  • Form P2 can be characterized by data selected from: a powder XRD pattern with peaks at 7.5, 10.2, 15.3, 19.2 and 20.5 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 2; and any combinations thereof.
  • Form P2 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 11.9, 12.7, 16.9 and 18.4 ⁇ 0.2 degrees two-theta.
  • Form P2 can be further characterized by a DSC thermogram as shown in Figure 2.
  • the present invention provides a crystalline form of Vilazodone phosphate, designated Form P3.
  • Form P3 can be characterized by data selected from: a powder XRD pattern with peaks at 12.7, 13.2, 14.5, 16.0 and 17.1 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 3; and any combinations thereof.
  • Form P3 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 6.6, 19.0, 20.7 and 22.6 ⁇ 0.2 degrees two-theta.
  • the present invention also provides Vilazodone hemi-sulfate.
  • the present invention also provides a crystalline Vilazodone hemi-sulfate.
  • the present invention provides a crystalline form of Vilazodone hemi-sulfate, designated Form SI .
  • Form SI can be characterized by data selected from: a powder XRD pattern with peaks at 8.4, 10.7, 15.2, 23.8 and 26.8 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 4; a Raman spectrum as shown in Figure 19; and any combinations thereof.
  • Form SI can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 12.3, 14.8, 16.9 and 22.7 ⁇ 0.2 degrees two-theta.
  • Form SI can be further characterized by a DSC thermogram as shown in Figure 17.
  • Form PI can be also characterized by a FTIR spectrum as shown in Figure 18.
  • Form S2 provides a crystalline form of Vilazodone hemi-sulfate, designated Form S2.
  • Form S2 can be characterized by data selected from: a powder XRD pattern with peaks at 9.9, 10.2, 12.8, 14.2 and 22.4 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 5; and any combinations thereof.
  • Form S2 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 17.6, 21.6, 23.6 and 24.3 ⁇ 0.2 degrees two-theta.
  • the present invention also provides Vilazodone mesylate.
  • the present invention also provides a crystalline Vilazodone mesylate.
  • Form MSI a crystalline form of Vilazodone mesylate, designated Form MSI.
  • Form MSI can be characterized by data selected from: a powder XRD pattern with peaks at 8.6, 10.6, 15.5, 17.2 and 21.2 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 6; a Raman spectrum as shown in Figure 22; and any combinations thereof.
  • Form MSI can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 14.5, 20.2, 23.3 and 23.8 ⁇ 0.2 degrees two-theta.
  • Form MSI can be further characterized by a DSC thermogram as shown in Figure 20.
  • Form PI can be also characterized by a FTIR spectrum as shown in Figure 21.
  • Form MS2 provides a crystalline form of Vilazodone mesylate, designated Form MS2.
  • Form MS2 can be characterized by data selected from: a powder XRD pattern with peaks at 7.1, 14.9, 19.7, 22.9 and 23.7 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 7; and any combinations thereof.
  • Form MS2 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 17.5, 20.4, 23.5 and 26.7 ⁇ 0.2 degrees two-theta.
  • the present invention also provides Vilazodone lactate.
  • the present invention also provides a crystalline Vilazodone lactate.
  • Form LI a crystalline form of Vilazodone lactate, designated Form LI .
  • Form LI can be characterized by data selected from: a powder XRD pattern with peaks at 8.6, 10.4, 15.5, 19.8 and 20.8 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 8; a Raman spectrum as shown in Figure 25; and any combinations thereof.
  • Form LI can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 12.1, 14.7, 15.1 and 19.3 ⁇ 0.2 degrees two-theta.
  • Form LI can be further characterized by a DSC thermogram as shown in Figure 23.
  • Form PI can be also characterized by a FTIR spectrum as shown in Figure 24.
  • the present invention also provides Vilazodone maleate.
  • the present invention also provides a crystalline Vilazodone maleate.
  • Form ML1 a crystalline form of Vilazodone maleate, designated Form ML1.
  • Form ML1 can be characterized by data selected from: a powder XRD pattern with peaks at 10.9, 14.7, 15.5, 19.7 and 21.0 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 9; a Raman spectrum as shown in Figure 28; and any combinations thereof.
  • Form ML1 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 8.5, 17.0, 22.4 and 23.4 ⁇ 0.2 degrees two-theta.
  • Form ML1 can be further characterized by a DSC thermogram as shown in Figure 26.
  • Form PI can be also characterized by a FTIR spectrum as shown in Figure 27.
  • Form ML2 provides a crystalline form of Vilazodone maleate, designated Form ML2.
  • Form ML2 can be characterized by data selected from: a powder XRD pattern with peaks at 14.8, 15.8, 18.2, 19.1 and 22.1 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 10; and any combinations thereof.
  • Form ML2 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 6.9, 11.5, 14.0 and 24.8 ⁇ 0.2 degrees two-theta.
  • the present invention also provides Vilazodone benzoate.
  • the present invention also provides a crystalline Vilazodone benzoate.
  • Form Bl a crystalline form of Vilazodone benzoate, designated Form Bl.
  • Form Bl can be characterized by data selected from: a powder XRD pattern with peaks at 5.8, 10.5, 11.9, 17.0 and 17.5 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 11 ; a Raman spectrum as shown in Figure 31 ; and any
  • Form B 1 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 14.3, 15.3, 18.4 and 20.4 ⁇ 0.2 degrees two-theta.
  • Form B 1 can be further characterized by a DSC thermogram as shown in Figure 29.
  • Form PI can be also characterized by a FTIR spectrum as shown in Figure 30.
  • Form B2 provides a crystalline form of Vilazodone benzoate, designated Form B2.
  • Form B2 can be characterized by data selected from: a powder XRD pattern with peaks at 11.2, 12.5, 15.8, 19.1 and 24.7 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 12; and any combinations thereof.
  • Form B2 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 7.4, 13.8, 17.2 and 18.6 ⁇ 0.2 degrees two-theta.
  • the present invention also provides Vilazodone HBr.
  • the present invention also provides a crystalline Vilazodone HBr.
  • Form HB 1 provides a crystalline form of Vilazodone HBr, designated Form HB 1.
  • Form HB 1 can be characterized by data selected from: a powder XRD pattern with peaks at 8.6, 10.5, 15.4, 21.1 and 22.5 ⁇ 0.2 degrees two-theta; a powder XRD pattern as shown in figure 13; a Raman spectrum as shown in Figure 34; and any combinations thereof.
  • Form HB 1 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 7.4, 14.8, 17.1, 20.0 and 23.8 ⁇ 0.2 degrees two-theta.
  • Form HB1 can be further characterized by a DSC thermogram as shown in Figure 32.
  • Form PI can be also characterized by a FTIR spectrum as shown in Figure 33.
  • the above described Vilazodone salts and the solid state forms can be used to prepare Vilazodone base, for example by reacting any of the above mentioned Vilazodone salts with a base.
  • the above described Vilazodone salts and solid state forms can be used also to prepare a different Vilazodone salt, for example by reacting any of the above mentioned Vilazodone salts with an acid, i.e. salt switching; or, alternatively, by reacting any of the above mentioned Vilazodone salt with a base, and further reacting the product of that reaction with another acid.
  • the newly obtained slats or free base can be used to prepare formulations.
  • the present invention encompasses a process for preparing other Vilazodone salts.
  • the process comprising preparing any one of the Vilazodone salts and solid state forms of Vilazodone by the processes of the present invention, and converting that salt to said other Vilazodone salt.
  • the conversion can be done, for example, by a process comprising basifying any one or a combination of the above described Vilazodone salts and/or solid state forms thereof, and reacting the obtained Vilazodone base with an appropriate acid, to obtain the corresponding salt.
  • the conversion can be done by salt switching, i.e., reacting a Vilazodone salt, with an acid having a pKa which is lower than the pKa of the acid of the first Vilazodone salt.
  • the present invention further encompasses 1) a pharmaceutical composition comprising any one or any mixture of the salts or solid state Forms, as described above, and at least one pharmaceutically acceptable excipient and 2) the use of any one or any mixture of the above-described salts or solid state Forms, in the manufacture of a pharmaceutical composition.
  • the pharmaceutical composition can be useful for the treatment of major depressive disorder.
  • the invention also provides a process to prepare formulation of Vilazodone salts comprising combining the above mentioned salts or forms and at least one excipient.
  • FTIR spectrum was recorded on a Nicolet 6700 spectrometer between 4000 cm “1 and 400 cm “ 1 with resolution 4 cm “1 , in KBr technique.
  • Raman spectrum was acquired on a Nicolet 6700 interferometer, equipped with an NXR FT- Raman modul.
  • Nd-YAG laser (1064 nm, 500 mW) was used to excite the sample.
  • the spectrometer utilizes a CaF 2 beamsplitter and a liquid nitrogen cooled Ge detector. The spectrum was recorded at resolution of 4 cm "1 .
  • the reaction mixture was stirred at reflux temperature (80-82°C) for 24 hours and then cooled down to room temperature.
  • Acetonitrile (310 ml) and aqueous ammonia (25%; 400 ml) were added.
  • the resulting suspension was stirred for 72 hours and then it was cooled down to about 0°C-5°C and stirred for 2h.
  • the suspension was then filtered and the collected product was washed with water and dried at 60°C under vacuum to obtain 11.2 g (69.4%) of 5-(4-(4-(5-cyano-lH-indol-3-yl)bu1yl)piperazin-l-yl)benzofuran-2- carboxamide.
  • Vilazodone phosphate is prepared by reacting Vilazodone base with phosphoric acid.
  • Example 1 Preparation of Vilazodone phosphate Form PI
  • Vilazodone hemi-sulfate is prepared by reacting Vilazodone base with sulfuric acid.
  • Example 7 Preparation of Vilazodone mesylate Form MS2
  • Vilazodone mey slate Form MSI was heated in a DSC instrument (TA Instruments, Q1000) up to 220°C. 3 mg of sample mass was heated in an aluminum pan, with 10°C/min heating rate, under nitrogen flow of 40 ml/min. The sample was analyzed after cooling.
  • Lactic acid, 90% (200 iL; 2 AO mmol) was added to a stirred solution of Vilazodone base (1.0 g; 2.26 mmol) in DMF (5 mL) and EtOH (5 mL) at RT. Water (20 mL) was added dropwise to the reaction mixture and precipitation occurs. The formed suspension is stirred at RT for 3 h. The solid was filtered, washed with water and dried in a vacuum oven at 50 °C to yield 745 mg of the title compound.

Abstract

The present invention provides salts of Vilazodone and solid state forms thereof, processes for preparing these salts and solid state forms, and pharmaceutical compositions comprising one or more of these salts and/or solid state forms.

Description

NEW SALTS OF VILAZODONE AND SOLID STATE FORMS THEREOF
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No.
61/682,502, filed August 13, 2012, the content of which is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to new salts of Vilazodone, solid state forms thereof, processes for preparing them, and pharmaceutical compositions comprising one or more of these salts and solid state forms.
BACKGROUND OF THE INVENTION
[0003] Vilazodone, 5-(4-[4-(5-cyano-17J-indol-3-yl)butyl]piperazin-l-yl)benzofuran-2- carboxamide, has the following chemical structure:
Figure imgf000002_0001
[0004] Vilazodone (HC1 salt marketed as VIIBRYD) is an SSRI antidepressant (selective serotonin reuptake inhibitor and a 5HTiA receptor partial antagonist) developed for the treatment of major depressive disorder. The compound was originally developed by Merck KGaA, Germany, and is now owned by Forest Laboratories Inc, USA.
[0005] A synthesis of Vilazodone is described in US Patent No. US 5,532,241.
[0006] Certain crystalline forms of Vilazodone hydrochloride, and of Vilazodone dihydrochloride are described in the PCT Publication No. WO2002102794.
[0007] Different salts of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability and shelf-life. These variations in the properties of different salts may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
[0008] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), powder X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
[0009] Discovering new salts and polymorphic forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New salts and polymorphic forms of a pharmaceutically useful compound can also provide opportunities to improve the performance characteristics of a pharmaceutical product. They can also enlarge the repertoire of materials available to a formulation scientist for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling
characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and/or polymorphs of Vilazodone.
SUMMARY OF THE INVENTION
[0010] The present invention provides new salts of Vilazodone and their solid state forms. These salts and solid state forms can be used to prepare different salts of Vilazodone, particularly Vilazodone hydrochloride, solid state forms of those different salts and pharmaceutical compositions and formulations thereof.
[0011] These salts and solid state forms can be used to prepare Vilazodone HC1 or the free base and/or formulations thereof. [0012] The invention further provides the salts and solid state forms of Vilazodone as described below for use in the manufacture of a medicament for the treatment of major depressive disorders; and provides a method of treating major depressive disorders, said method comprising administering a therapeutically effective dose of one or more of the salts or solid state forms described herein.
[0013] The invention also provides a process to prepare formulation of Vilazodone salts comprising combining the below mentioned salts or forms and at least one excipient.
BRIEF DESCRIPTION OF THE FIGURES
[0014] Figure 1 provides a powder XRD pattern of crystalline Form PI of Vilazodone phosphate.
[0015] Figure 2 provides a DSC thermogram of crystalline Form P2 of Vilazodone phosphate.
[0016] Figure 3 provides a powder XRD pattern of crystalline Form P3 of Vilazodone phosphate.
[0017] Figure 4 provides a powder XRD pattern of crystalline Form SI of Vilazodone hemi-sulfate.
[0018] Figure 5 provides a powder XRD pattern of crystalline Form S2 of Vilazodone hemi-sulfate.
[0019] Figure 6 provides a powder XRD pattern of crystalline Form MS 1 of Vilazodone mesylate.
[0020] Figure 7 provides a powder XRD pattern of crystalline Form MS2 of Vilazodone mesylate.
[0021] Figure 8 provides a powder XRD pattern of crystalline Form LI of Vilazodone lactate.
[0022] Figure 9 provides a powder XRD pattern of crystalline Form ML1 of Vilazodone maleate.
[0023] Figure 10 provides a powder XRD pattern of crystalline Form ML2 of Vilazodone maleate. [0024] Figure 11 provides a powder XRD pattern of crystalline Form Bl of Vilazodone benzoate.
[0025] Figure 12 provides a powder XRD pattern of crystalline Form B2 of Vilazodone benzoate.
[0026] Figure 13 provides a powder XRD pattern of crystalline Form HBl of Vilazodone HBr.
[0027] Figure 14 provides a DSC thermogram of crystalline Form PI of Vilazodone phosphate.
[0028] Figure 15 provides a FTIR spectrum of crystalline Form PI of Vilazodone phosphate.
[0029] Figure 16 provides a Raman spectrum of crystalline Form PI of Vilazodone phosphate.
[0030] Figure 17 provides a DSC thermogram of crystalline Form SI of Vilazodone hemi- sulfate.
[0031] Figure 18 provides a FTIR spectrum of crystalline Form S 1 of Vilazodone hemi- sulfate.
[0032] Figure 19 provides a Raman spectrum of crystalline Form SI of Vilazodone hemi- sulfate.
[0033] Figure 20 provides a DSC thermogram of crystalline Form MSI of Vilazodone mesylate.
[0034] Figure 21 provides a FTIR spectrum of crystalline Form MS 1 of Vilazodone mesylate.
[0035] Figure 22 provides a Raman spectrum of crystalline Form MSI of Vilazodone mesylate.
[0036] Figure 23 provides a DSC thermogram of crystalline Form LI of Vilazodone lactate.
[0037] Figure 24 provides a FTIR spectrum of crystalline Form LI of Vilazodone lactate.
[0038] Figure 25 provides a Raman spectrum of crystalline Form LI of Vilazodone lactate. [0039] Figure 26 provides a DSC thermogram of crystalline Form ML1 of Vilazodone maleate.
[0040] Figure 27 provides a FTIR spectrum of crystalline Form ML1 of Vilazodone maleate.
[0041] Figure 28 provides a Raman spectrum of crystalline Form ML1 of Vilazodone maleate.
[0042] Figure 29 provides a DSC thermogram of crystalline Form Bl of Vilazodone benzoate.
[0043] Figure 30 provides a FTIR spectrum of crystalline Form Bl of Vilazodone benzoate.
[0044] Figure 31 provides a Raman spectrum of crystalline Form Bl of Vilazodone benzoate.
[0045] Figure 32 provides a DSC thermogram of crystalline Form HB1 of Vilazodone HBr.
[0046] Figure 33 provides a FTIR spectrum of crystalline Form HB1 of Vilazodone HBr.
[0047] Figure 34 provides a Raman spectrum of crystalline Form HB1 of Vilazodone HBr.
DETAILED DESCRIPTION OF THE INVENTION
[0048] The present invention provides new salts and solid state forms of Vilazodone. These salts and solid state forms can be used to prepare Vilazodone base and/or different salts of Vilazodone and/or formulations thereof.
[0049] A polymorph may be referred to herein as substantially free of any other solid forms. As used herein in this context, the expression "substantially free" will be understood to mean that the solid state form contains 20% or less, 10% or less, 5% or less, 2% or less, or 1% or less of any other solid form of the subject compound as measured, for example, by powder X-ray diffraction (PXRD). Thus, polymorphs of Vilazodone salts described herein as substantially free of any other solid forms would be understood to contain greater than 80% (w/w), greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the subject form of Vilazodone salts. Accordingly, in some embodiments of the invention, the described polymorphs of Vilazodone salts may contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of one or more other solid forms of Vilazodone salts.
[0050] According to some embodiments the crystalline forms of the invention are disclosed herein as being polymorphically stable under certain recited conditions, for example under conditions of 40°C/ 75% relative humidity. By polymorphically stable is meant that less than 1% of any other solid state form of Vilazodone is detected when the recited solid state form of Vilazodone is maintained under the stated conditions.
[0051] A solid state form may be referred to herein as being characterized by graphical data "as shown in" a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. The skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which factors are well known to the skilled person.
Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirming whether the two sets of graphical data characterize the same solid state form or two different solid state forms. The skilled person would understand that a solid state form referred to herein as being characterized by graphical data "as shown in" a Figure would include any solid state form of the same chemical characterized by graphical data substantially similar to the Figure except for such small variations, the potential occurrence of which is well known to the skilled person.
[0052] A solid state form may be referred to herein as being characterized by data selected from two or more different data groupings, for example, by a powder XRD pattern having a group of specific peaks; or by a powder XRD pattern as shown in a figure depicting a diffractogram, or by "a combination thereof (or "combinations thereof," or "any combination thereof), These expressions, e.g., "any combination thereof contemplate that the skilled person may characterize a crystal form using any combination of the recited characteristic analytical data. For example, the skilled person may characterize a crystal form using a group of four or five characteristic powder XRD peaks, and supplement that characterization with one or more additional features observed in the powder X-ray diffractogram, e.g., an additional peak, a characteristic peak shape, a peak intensity, or even the absence of a peak at some position in the powder XRD pattern. Alternatively, the skilled person may in some instances characterize a crystal form using a group of four or five characteristic powder XRD peaks and supplement that characterization with one or more additional features observed using another analytical method, for example, using one or more characteristic peaks in a solid state NMR spectrum, or characteristics of the DSC thermogram of the crystal form that is being characterized.
[0053] As used herein, unless stated otherwise, XRPD peaks reported herein are preferably measured using CuK radiation, λ = 1.54184 A.
[0054] As used herein, unless indicated otherwise, the term "Room temperature" or "RT" refers to a temperature between about 20 °C and about 30 °C. Usually, room temperature ranges from about 20°C to about 25 °C.
[0055] As used herein, unless indicated otherwise, the term "Overnight" refers to a period of between about 15 and about 20 hours, typically between about 16 to about 20 hours.
[0056] As used herein, and unless stated otherwise, the term "anhydrous" in relation to crystalline Vilazodone or Vilazodone hydrochloride relates to a crystalline Vilazodone or Vilazodone hydrochloride which contains not more than 1% (w/w), more preferably not more than 0.5% (w/w) of either water or organic solvents as measured by TGA.
[0057] As used herein, and unless stated otherwise the term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.
[0058] The salts and the solid state forms of the present invention have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, morphology or crystal habit, specific surface and pycnometric density, bulk/tap density, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
[0059] The present invention provides Vilazodone phosphate. [0060] The present invention also provides a crystalline Vilazodone phosphate.
[0061 ] The present invention provides a crystalline form of Vilazodone phosphate, designated Form PI . Form PI can be characterized by data selected from: a powder XRD pattern with peaks at 8.2, 10.9, 14.7, 16.3 and 20.1 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 1; a Raman spectrum as shown in Figure 16; and any combinations thereof.
[0062] Alternatively, Form PI can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 7.1, 10.2, 21.8, 23.2 and 24.6 ± 0.2 degrees two-theta.
[0063] Form PI can be further characterized by a DSC thermogram as shown in Figure 14. Form PI can be also characterized by a FTIR spectrum as shown in Figure 15.
[0064] The present invention provides a crystalline form of Vilazodone phosphate, designated Form P2. Form P2 can be characterized by data selected from: a powder XRD pattern with peaks at 7.5, 10.2, 15.3, 19.2 and 20.5 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 2; and any combinations thereof.
[0065] Alternatively, Form P2 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 11.9, 12.7, 16.9 and 18.4 ± 0.2 degrees two-theta.
[0066] Form P2 can be further characterized by a DSC thermogram as shown in Figure 2.
[0067] The present invention provides a crystalline form of Vilazodone phosphate, designated Form P3. Form P3 can be characterized by data selected from: a powder XRD pattern with peaks at 12.7, 13.2, 14.5, 16.0 and 17.1 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 3; and any combinations thereof.
[0068] Alternatively, Form P3 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 6.6, 19.0, 20.7 and 22.6 ± 0.2 degrees two-theta.
[0069] The present invention also provides Vilazodone hemi-sulfate.
[0070] The present invention also provides a crystalline Vilazodone hemi-sulfate. [0071] The present invention provides a crystalline form of Vilazodone hemi-sulfate, designated Form SI . Form SI can be characterized by data selected from: a powder XRD pattern with peaks at 8.4, 10.7, 15.2, 23.8 and 26.8 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 4; a Raman spectrum as shown in Figure 19; and any combinations thereof.
[0072] Alternatively, Form SI can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 12.3, 14.8, 16.9 and 22.7 ± 0.2 degrees two-theta.
[0073] Form SI can be further characterized by a DSC thermogram as shown in Figure 17. Form PI can be also characterized by a FTIR spectrum as shown in Figure 18.
[0074] The present invention provides a crystalline form of Vilazodone hemi-sulfate, designated Form S2. Form S2 can be characterized by data selected from: a powder XRD pattern with peaks at 9.9, 10.2, 12.8, 14.2 and 22.4 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 5; and any combinations thereof.
[0075] Alternatively, Form S2 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 17.6, 21.6, 23.6 and 24.3 ± 0.2 degrees two-theta.
[0076] The present invention also provides Vilazodone mesylate.
[0077] The present invention also provides a crystalline Vilazodone mesylate.
[0078] The present invention provides a crystalline form of Vilazodone mesylate, designated Form MSI. Form MSI can be characterized by data selected from: a powder XRD pattern with peaks at 8.6, 10.6, 15.5, 17.2 and 21.2 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 6; a Raman spectrum as shown in Figure 22; and any combinations thereof.
[0079] Alternatively, Form MSI can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 14.5, 20.2, 23.3 and 23.8 ± 0.2 degrees two-theta. [0080] Form MSI can be further characterized by a DSC thermogram as shown in Figure 20. Form PI can be also characterized by a FTIR spectrum as shown in Figure 21.
[0081] The present invention provides a crystalline form of Vilazodone mesylate, designated Form MS2. Form MS2 can be characterized by data selected from: a powder XRD pattern with peaks at 7.1, 14.9, 19.7, 22.9 and 23.7 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 7; and any combinations thereof.
[0082] Alternatively, Form MS2 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 17.5, 20.4, 23.5 and 26.7 ± 0.2 degrees two-theta.
[0083] The present invention also provides Vilazodone lactate.
[0084] The present invention also provides a crystalline Vilazodone lactate.
[0085] The present invention provides a crystalline form of Vilazodone lactate, designated Form LI . Form LI can be characterized by data selected from: a powder XRD pattern with peaks at 8.6, 10.4, 15.5, 19.8 and 20.8 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 8; a Raman spectrum as shown in Figure 25; and any combinations thereof.
[0086] Alternatively, Form LI can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 12.1, 14.7, 15.1 and 19.3 ± 0.2 degrees two-theta.
[0087] Form LI can be further characterized by a DSC thermogram as shown in Figure 23. Form PI can be also characterized by a FTIR spectrum as shown in Figure 24.
[0088] The present invention also provides Vilazodone maleate.
[0089] The present invention also provides a crystalline Vilazodone maleate.
[0090] The present invention provides a crystalline form of Vilazodone maleate, designated Form ML1. Form ML1 can be characterized by data selected from: a powder XRD pattern with peaks at 10.9, 14.7, 15.5, 19.7 and 21.0 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 9; a Raman spectrum as shown in Figure 28; and any combinations thereof. [0091] Alternatively, Form ML1 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 8.5, 17.0, 22.4 and 23.4 ± 0.2 degrees two-theta.
[0092] Form ML1 can be further characterized by a DSC thermogram as shown in Figure 26. Form PI can be also characterized by a FTIR spectrum as shown in Figure 27.
[0093] The present invention provides a crystalline form of Vilazodone maleate, designated Form ML2. Form ML2 can be characterized by data selected from: a powder XRD pattern with peaks at 14.8, 15.8, 18.2, 19.1 and 22.1 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 10; and any combinations thereof.
[0094] Alternatively, Form ML2 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 6.9, 11.5, 14.0 and 24.8 ± 0.2 degrees two-theta.
[0095] The present invention also provides Vilazodone benzoate.
[0096] The present invention also provides a crystalline Vilazodone benzoate.
[0097] The present invention provides a crystalline form of Vilazodone benzoate, designated Form Bl. Form Bl can be characterized by data selected from: a powder XRD pattern with peaks at 5.8, 10.5, 11.9, 17.0 and 17.5 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 11 ; a Raman spectrum as shown in Figure 31 ; and any
combinations thereof.
[0098] Alternatively, Form B 1 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 14.3, 15.3, 18.4 and 20.4 ± 0.2 degrees two-theta.
[0099] Form B 1 can be further characterized by a DSC thermogram as shown in Figure 29. Form PI can be also characterized by a FTIR spectrum as shown in Figure 30.
[00100] The present invention provides a crystalline form of Vilazodone benzoate, designated Form B2. Form B2 can be characterized by data selected from: a powder XRD pattern with peaks at 11.2, 12.5, 15.8, 19.1 and 24.7 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 12; and any combinations thereof. [00101] Alternatively, Form B2 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 7.4, 13.8, 17.2 and 18.6 ± 0.2 degrees two-theta.
[00102] The present invention also provides Vilazodone HBr.
[00103] The present invention also provides a crystalline Vilazodone HBr.
[00104] The present invention provides a crystalline form of Vilazodone HBr, designated Form HB 1. Form HB 1 can be characterized by data selected from: a powder XRD pattern with peaks at 8.6, 10.5, 15.4, 21.1 and 22.5 ± 0.2 degrees two-theta; a powder XRD pattern as shown in figure 13; a Raman spectrum as shown in Figure 34; and any combinations thereof.
[00105] Alternatively, Form HB 1 can be characterized by a powder XRD pattern having the above mentioned peaks and also having any one or more peaks selected from 7.4, 14.8, 17.1, 20.0 and 23.8 ± 0.2 degrees two-theta.
[00106] Form HB1 can be further characterized by a DSC thermogram as shown in Figure 32. Form PI can be also characterized by a FTIR spectrum as shown in Figure 33.
[00107] The above described Vilazodone salts and the solid state forms can be used to prepare Vilazodone base, for example by reacting any of the above mentioned Vilazodone salts with a base. The above described Vilazodone salts and solid state forms can be used also to prepare a different Vilazodone salt, for example by reacting any of the above mentioned Vilazodone salts with an acid, i.e. salt switching; or, alternatively, by reacting any of the above mentioned Vilazodone salt with a base, and further reacting the product of that reaction with another acid.
[00108] The newly obtained slats or free base can be used to prepare formulations.
[00109] The present invention encompasses a process for preparing other Vilazodone salts. The process comprising preparing any one of the Vilazodone salts and solid state forms of Vilazodone by the processes of the present invention, and converting that salt to said other Vilazodone salt. The conversion can be done, for example, by a process comprising basifying any one or a combination of the above described Vilazodone salts and/or solid state forms thereof, and reacting the obtained Vilazodone base with an appropriate acid, to obtain the corresponding salt. Alternatively, the conversion can be done by salt switching, i.e., reacting a Vilazodone salt, with an acid having a pKa which is lower than the pKa of the acid of the first Vilazodone salt.
[00110] The present invention further encompasses 1) a pharmaceutical composition comprising any one or any mixture of the salts or solid state Forms, as described above, and at least one pharmaceutically acceptable excipient and 2) the use of any one or any mixture of the above-described salts or solid state Forms, in the manufacture of a pharmaceutical composition. The pharmaceutical composition can be useful for the treatment of major depressive disorder. The invention also provides a process to prepare formulation of Vilazodone salts comprising combining the above mentioned salts or forms and at least one excipient.
[00111] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
XRPD method
Samples after being powdered in a mortar and pestle are applied directly on a silicon plate holder. The X-ray powder diffraction pattern was measured with Philips X ert PRO X-ray powder diffractometer, equipped with Cu irradiation source =1.54184 A (Angstrom), X'Celerator (2.022° 2Θ) detector. Scanning parameters: angle range: 3-40 deg., step size 0.0167, time per step 37 s, continuous scan. The described peak positions were determined using silicon powder as an internal standard in an admixture with the sample measured. The position of the silicon (Si) peak was corrected to silicone theoretical peak: 28.45 degrees two theta, and the positions of the measured peaks were corrected respectively.
DSC method
DSC analysis was performed on Q1000 MDSC instrument (TA instruments) with heating rate of 10 °C/min, under nitrogen flow of 50 ml/min. hermetic aluminum, closed pan (with hole) was used, sample mass was about 1-5 mg. FTIR method
FTIR spectrum was recorded on a Nicolet 6700 spectrometer between 4000 cm"1 and 400 cm" 1 with resolution 4 cm"1, in KBr technique.
FT Raman method
Raman spectrum was acquired on a Nicolet 6700 interferometer, equipped with an NXR FT- Raman modul. Nd-YAG laser (1064 nm, 500 mW) was used to excite the sample. The spectrometer utilizes a CaF2 beamsplitter and a liquid nitrogen cooled Ge detector. The spectrum was recorded at resolution of 4 cm"1.
EXAMPLES
(A) A procedure for preparation of Vilazodone base:
[00112] Ethyl 5-(piperazine-l-yl)benzofuran-2-carboxylate (10.0 g; 36.5 mmol) was suspended in acetonitrile (84 ml) and water (1 ml). Potassium carbonate (2.52 g; 18.2 mmol), 3-(4-chlorobutyl)-lH-indole-5-carbonitrile (8.5 g; 36.5 mmol), potassium iodide (24.21g; 145.8 mmol) and tetrabutylammonium bromide (1.18 g; 3.65 mmol) were added sequentially at ambient temperature. The reaction mixture was stirred at reflux temperature (80-82°C) for 24 hours and then cooled down to room temperature. Acetonitrile (310 ml) and aqueous ammonia (25%; 400 ml) were added. The resulting suspension was stirred for 72 hours and then it was cooled down to about 0°C-5°C and stirred for 2h. The suspension was then filtered and the collected product was washed with water and dried at 60°C under vacuum to obtain 11.2 g (69.4%) of 5-(4-(4-(5-cyano-lH-indol-3-yl)bu1yl)piperazin-l-yl)benzofuran-2- carboxamide.
Vilazodone phosphate is prepared by reacting Vilazodone base with phosphoric acid. Example 1. Preparation of Vilazodone phosphate Form PI
Vilazodone base (500 mg; 1.13 mmol) was suspended in EtOH (20 mL). Phosphoric acid, 85% (70 ; 1.22 mmol) and water (5 mL) were added and the reaction mixture stirred at room temperature for 3 h. The solid is filtered, washed with water and dried in a vacuum oven at 50 °C to yield 560 mg of the title compound. Example 2. Preparation of Vilazodone phosphate Form P2
Vilazodone phosphate Form PI was heated in a DSC instrument (TA Instruments, Q1000) up to 150°C. 3 mg of sample mass was heated in an aluminum pan, with 10°C/min heating rate, under nitrogen flow of 40 ml/min. The sample was analyzed after cooling.
Example 3. Preparation of Vilazodone phosphate Form P3
Vilazodone phosphate Form PI was heated in a DSC instrument (TA Instruments, Q1000) up to 230°C. 3 mg of sample mass was heated in an aluminum pan, with 10°C/min heating rate, under nitrogen flow of 40 ml/min. The sample was analyzed after cooling.
Vilazodone hemi-sulfate is prepared by reacting Vilazodone base with sulfuric acid.
Example 4. Preparation of Vilazodone hemi-sulfate Form SI
Sulphuric acid, 96% (64 μΐ,; 1.20 mmol) was added to a stirred solution of Vilazodone base (500 mg; 1.13 mmol) in DMF (20 mL) and water (5 mL) at RT. Water (15 mL) was added dropwise to the reaction mixture and precipitation occurs. The formed suspension was stirred at RT for 3 h. The solid was filtered, washed with water and dried in a vacuum oven at 50 °C to yield 490 mg of the title compound.
Example 5. Preparation of Vilazodone hemi-sulphate Form S2
Vilazodone hemi-sulphate Form SI was placed in an open Petri dish (100 mg sample size) and was dried in a vaccum oven at 150°C for 15 min. Sample was analyzed after cooling.
Vilazodone mesylate is prepared by reacting Vilazodone base with methansulphonic acid. Example 6. Preparation of VLZ mesylate Form MSI
Vilazodone base (500 mg; 1.13 mmol) was suspended in EtOH (5 mL) and water (5 mL). Methanesulphonic acid (100 μί; 1.22 mmol) was added to the suspension, resulting in dissolution. The reaction mixture was stirred at RT for 3 h. The solid is filtered, washed with water and dried in a vacuum oven at 50 °C to yield 400 mg of the title compound.
Example 7. Preparation of Vilazodone mesylate Form MS2 Vilazodone mey slate Form MSI was heated in a DSC instrument (TA Instruments, Q1000) up to 220°C. 3 mg of sample mass was heated in an aluminum pan, with 10°C/min heating rate, under nitrogen flow of 40 ml/min. The sample was analyzed after cooling.
Vilazodone lactate is prepared by reacting Vilazodone base with lactic acid. Example 8. Preparation of Vilazodone lactate Form LI
Lactic acid, 90% (200 iL; 2 AO mmol) was added to a stirred solution of Vilazodone base (1.0 g; 2.26 mmol) in DMF (5 mL) and EtOH (5 mL) at RT. Water (20 mL) was added dropwise to the reaction mixture and precipitation occurs. The formed suspension is stirred at RT for 3 h. The solid was filtered, washed with water and dried in a vacuum oven at 50 °C to yield 745 mg of the title compound.
Vilazodone maleate is prepared by reacting Vilazodone base with maleic acid. Example 9. Preparation of VLZ maleate Form ML1
Vilazodone base (500 mg; 1.13 mmol) was suspended in DMF (10 mL), MeOH (10 mL) and water (10 mL) at RT. Maleic acid (140 mg; 1.21 mmol) was dissolved in MeOH (5 mL) and added to the suspension of Vilazodone base. Water (30 mL) was added dropwise to the reaction mixture and the formed suspension was stirred at RT for 3 h. The solid was filtered, washed with water and dried in a vacuum oven at 50 °C to yield 500 mg of the title compound.
Example 10. Preparation of VLZ maleate Form ML2
Vilazodone maleate Form ML1 was placed in an open Petri dish (100 mg sample size) and was dried in a vaccum oven at 160°C for 15 min. Sample was analyzed after cooling.
Vilazodone benzoate is prepared by reacting Vilazodone base with benzoic acid. Example 11. Preparation of VLZ benzoate Form Bl
Vilazodone base (500 mg; 1.13 mmol) was dissolved in DMF (2 mL) at RT. Benzoic acid (150 mg; 1.23 mmol) was dissolved in DMF (2 mL) and the solution added to the Vilazodone base solution. Water (4 mL) was added dropwise to the reaction mixture and the formed suspension was stirred at RT for 3 h. The solid was filtered, washed with water and dried in a vacuum oven at 50 °C to yield 550 mg of the title compound. Example 12. Preparation of VLZ benzoate Form B2
Vilazodone benzoate Form Bl was placed in an open Petri dish (100 mg sample size) and was dried in a vaccum oven at 170°C for 15 min. Sample was analyzed after cooling.
Vilazodone HBr is prepared by reacting Vilazodone base with HBr. Example 13. Preparation of Vilazodone HBr Form HB1
Vilazodone base (500 mg; 1.13 mmol) was suspended in DMF (7 mL) and water (4 mL) at RT. Hydrobromic acid, 47% (140 μΐ,; 1.2 mmol) was added to the suspension and dissolution occurs. Water (20 mL) was added dropwise to the reaction mixture and the formed suspension was stirred at RT for 1 h. The solid was filtered, washed with water and dried in a vacuum oven at 50 °C to yield 520 mg of the title compound.

Claims

Claims:
1. Salts of Vilazodone with acid selected from: phosphoric acid, sulfuric acid,
methanesulphonic acid, lactic acid, maleic acid, benzoic acid, and hydrobromic acid.
2. Crystalline forms of the salts of claim 1.
3. The use of the salts of claim 1 or the crystalline forms of claim 2, for the
preparation of a different salt of Vilazodone, preferably, Vilazodone
hydrochloride.
4. A process for preparing a Vilazodone hydrochloride, comprising reacting any one of the salts of claim lor any one of the crystalline forms of claim 2 with hydrochloric acid.
5. A process for preparing a Vilazodone hydrochloride, comprising reacting any one of the salts of claim 1 or any one of the crystalline form of claim 2 with a base, and further reacting the product of that reaction with hydrochloric acid.
6. A pharmaceutical composition comprising one or more salts according to claim 1 or one or more crystalline forms of claim 2, and at least one pharmaceutically acceptable excipient.
7. The use of one or more of the salts according to claim 1 or the crystalline forms of claim 2 for the manufacture of a medicament.
8. A process for preparing a pharmaceutical composition comprising combining any one or more of the salts of claim 1 or the crystalline forms of claim 2, and at least one pharmaceutically acceptable excipient.
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US9382233B2 (en) 2012-06-13 2016-07-05 Apotex Inc. Forms of vilazodone and processes for the preparation thereof
WO2023173182A1 (en) * 2022-03-16 2023-09-21 Eurofarma Laboratórios S.A. Vilazodone docusate salt, production process, pharmaceutical composition and use

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