CROSS REFERENCE TO RELATED. APPLICATION

This application claims the benefit of’ priority to Indian provisional application No. 908/CHE/2009, filed on April 20, 2009, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

Disclosed herein is a process for the preparation of highly pure varenicline free base. Disclosed further herein are solid state forms of acid addition salts of varenicline, wherein the acid counter ion is provided by an acid selected from the group consisting of oxalic acid and fumaric acid.

BACKGROUND OF THE iNVENTION

Varenicline, 5,8,1 4-triazatetracyclo[1 0.3.1 .02l ‘,049jhexadeca-2(I I ),3 ,5,7,9- pentaene, is known to bind to neuronal nicotinic acetyleholine specific receptor sites and is useful in modulating cholinergic function. This compound is useful in the treatment of inflammatory bowel disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, vasoconstriction, anxiety, panic disorder, depression, cognitive dysfunction, drug/toxin-induced cognitive impairment (e.g., from alcohol, barbiturates, vitamin deficiencies, recreational drugs, lead, arsenic, mercury), particularly, nicotine dependency, addiction and withdrawal; including use in smoking cessation therapy.

Varenicline is represented by the following structural formula:
and its first synthesis was disclosed in U.S. Patent No 6,410,550 (hereinafter referred to as the ‘550 patent). Varenicline is sold by Pfizer under the brand name CHANTIXTM to help adults quit smoking by blocking c1492 nicotinic acetyleholine receptor subtypes. It is orally administered as tablets containing 0.85 mg or 1.71 mg of varenicline tartrate equivalent to 0.5 mg or I mg of varenicline.

The ‘550 patent describes various processes for the preparation of aryl fused azapolycyclic compounds, including varenicline, and their pharmaceutically acceptable salts, combinations with other therapeutic agents, and methods of using such combinations in the treatment of neurogical and psychological disorders, Varenicline has been exemplified as a free base and a hydrochloride salt in the ‘550 patent
While the ‘550 patent mentions that some of the disclosed compounds can form salts with pharmaceutically acceptable organic or inorganic acids, such as, for example, hydrochloric acid, p..toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, malic acid, di-p-toluoyl tartaric acid and mandelic acid, only the hydrochloride salt of varenicline had been prepared and/or isolated.

U.S. Patent No 6,890,927 (hereinafter referred to as the ‘927 patent) discloses tartrate salts, including L-tartrate, D-tartrate, D,L-tartrate and meso-tartrate, of varenicline and their polymorphs, processes for their preparation, and pharmaceutical compositions thereof. The ‘927 patent further discloses various polymorphs of the varenicline L-tartrate salt, including two anhydrous polymorphs (Forms A & 13) and a hydrate polymorph (Form C), and characterizes them by powder X-ray diffraction (PXRD), X-ray crystal structure, solid state ‘3C NMR spcetroscopy, and Differential Scanning Calorimetry (DSC).

Varenicline tartrate, 7,8,9,1 0-tetrahydro-6,1 0-methano-6H-pyrazino[2,3- h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1), has a molecular weight of 361.35 Daltons, and a molecular formula of C,31-113N3.C41-k06. Varenicline tartrate is represented by the following structural formula:

U.S. Patent No. 6,787,549 discloses citrate salt of varenicline and its polymorphic forms including hydrate (Form A), anhydrous or nearly anhydrous form (Form B), processes for their preparation, and pharmaceutical compositions thereof.

U.S. Patent No. 6,794,388 discloses succinate salt of varenicline and its polymorphic forms including hydrate and anhydrous forms, processes for their preparation, and pharmaceutical compositions thereof.

PCT Publication No. WO 2008/060487 (hereinafter referred to as the ‘487 application) discloses crystal forms of intermediates used in the process for the preparation of varenieline tartrate including the varenicline free base. According to the ‘487 application, the varenicline free base exists in four crystalline forms (Form A, Form C, Form D and Form E). The ‘487 application further describes a process for preparing substantially pure varenicline free base crystalline form C suitable for administration to a human subject comprising a) less than 2% by weight of N-formylvarenicline, and b) less than 2% by weight of N-carboxyvarenicline adduct, comprising the step of crystallizing varenicline from the crystallization solvent or solvent combination comprising an organic non-chlorinated solvent, wherein the crystallization solvent or solvent combinations used to isolate substantially pure varenicline free base form C is an organic non-chlorinated solvent selected from the group consisting of toluene, xylene, hexane, cyclohexane, heptane, octane, nonane and decane PCT Publication No. WO 2009/109651 (hereinafter referred to as the ‘651 application) discloses various crystalline salt forms of varenicline, including varenicline hemi-adipate (Form 1), fumarate (Form 1), glutarate (Form 1), glycolate (Form I), hydrochloride (Forms 1, and III), a-ketoglutarate (Form I), L-malate (Forms 1, II, 111, and IV), malcate (Form J), malonate (Form 1), DL-mandelate (Form 1), di-(methane sulfonate) (Form 1), oxalate (Form J), phosphate (Forms I, Il, and III), S-2-pyrrolidinon- 5-carboxylate (Form I), galactarate (Form 1), DL-lactate (Form 1), hemi-l,2-ethane disulfonate (Form 1), and hemi-L-lactate (Form I); and characterizes them by powder Xray diffraction (P-XRD) and JR spectroscopy; processes for their preparation; and pharmaceutical compositions thereof.

According to the ‘651 application, the varenicline oxalate Form I is characterized by an XRD pattern (2-theta) (± 0.2 degrees) having characteristics peaks at 10.7, 13.2,
13.4, 14.5, 15.4, 17.8, 19.4, 19.9, 21.4, 21.7, 22.4, 23.8, 26.5, 26.9, 30.4 and 32.6 degrees with further peaks at 16.9, 18.6, 25,2, 2g.6 and 34.9 degrees.

The references cited above do not describe solid forms of varenicline oxalate and varenicline fumarate salts.

In the formulation of drug compositions, it is important for the active pharmaceutical ingredient to be in a form in which it can be conveniently handled and processed. Convenient handling is important not only from the perspective of obtaining a commercially viable manufacturing process, but also from the perspective of subsequent manufacture of pharmaceutical formulations (e.g., oral dosage forms such as tablets) comprising the active pharmaceutical ingredient.

Chemical stability, solid state stability, and “shelf life” of the active pharmaceutical ingredient are important properties for a pharmaceutically active compound. The active pharmaceutical ingredient, and compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics of the active pharmaceutical ingredient, e.g., its chemical composition, density, hygroscopicity and solubility. Thus, in the manufacture of commercially viable and pharmaceutically acceptable drug compositions, it is important, wherever possible, to provide the active pharmaceutical ingredient in a stable form.

New solid state forms of a pharmaceutical agent can further the development of formulations for the treatment of illnesses. For instance, solid forms of a compound are known in the pharmaceutical arts to affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, fractability, and compressibility of the compound, as well as the safety and efficacy of drug products based on the compound.

The discovery of novel salts in solid state form of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds value to the material that a formulation scientist can use the same for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

There remains a need for novel solid state forms of varenicline salts and use thereof for preparing highly pure varenicline free base or a pharmaceutically acceptable salt thereof.

SUMMARY9F THE INVENTION

The present inventors have now surprisingly and unexpectedly found solid state forms of varenicline salts with high purity, adequate stability, good flowability and good dissolution properties.

According to one aspect, provided herein are novel solid state forms of a varenicline salt, wherein the salt is an oxalate or a fumarate.

In another aspect, varenicline salts in a crystalline form is provided. In yet another aspect, varenicline salts in an amorphous form is provided. In still another aspect, the solid state forms of varenicline salts exist in art anhydrous and/or solvent-free form or as a hydrate and/or a solvate.

It has also been found that the novel solid state forms of varenicline salts are useful intermediates in the preparation of varenicline free base or a pharmaceutically acceptable salt thereof, preferably varenicline tartrate, in high purity. The solid state forms of varenicline salts have good flow properties and are far more stable at room temperature, enhanced temperature and at relative high humidities and in aqueous media, and so, the novel solid state forms of varenicline salts are suitable for formulating varenicline.
in another aspect, encompassed herein is a process for preparing the novel solid state forms of varenieline salts comprising contacting varenicline free base with an acid counter ion in a suitable solvent under suitable conditions, and isolating the solid state form of varenicline acid addition salt, wherein the acid counter ion is provided by an acid selected from the group consisting of oxalic acid and fumaric acid.

In another aspect, provided herein is a method for treating a patient suffering from diseases caused by neurogical and psychological disorders, inflammatory bowel disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, vasoconstriction, anxiety, panic disorder, depression, cognitive dysfunction, drug/toxin-induced cognitive impairment, nicotine dependency and addiction; comprising administering the novel solid
state forms of varenicline salts, or a pharmaceutical composition that comprises novel solid state forms of varenicline salts, along with pharmaceutically acceptable excipients.
In another aspect, encompassed herein is a process for preparing the highly pure and stable crystalline form of varenicline free base by using the solid state forms of varenicline salts disclosed herein.

In another aspect, provided herein is a pharmaceutical composition comprising solid state forms of varenicline salts disclosed herein and one or more pharmaceutically acceptable excipients.

In still another aspect, provided herein is a pharmaceutical composition comprising solid state forms of varenicline salts made by the process disclosed herein, and one or more pharmaceutically acceptable excipients

In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining solid state forms of varenicline salts with one or more pharmaceutically acceptable exeipients.

In another aspect, the solid state forms of varenicline salts disclosed herein for use
in the pharmaceutical compositions has a 90 volume-percent of the particles (D90) having a size of less than or equal to about 500 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 200 microns, still more
specifically less than or equal to about 100 microns, and most specifically less than or
equal to about 15 microns.

BREEF DESCRIPTION OF THE DRAWING

Figure 1 is a characteristic powder X-ray diffraction (XRD) pattern of crystalline
Varenicline oxalate.

Figure 2 is a characteristic powder X-ray diffraction (XRD) pattern of crystalline
Varenicline fumarate.

Figure 3 is a characteristic powder X-ray diffraction (XRD) pattern of crystalline
Varenicline hydrochloride.

Figure 4 is a characteristic powder X-ray diffraction (XRD) pattern of crystalline
Varenicline free base.

The X-Ray powder diffraction was measured by an X-ray powder diffractometer equipped with a Cu-anode (=l .54 Angstrom), X-ray source operated at 40kv, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 1976, Corundum standard. The sample was analyzed using the following instrument parameters: measuring range= 3-45° 29; step widtlr0.01579°; and measuring time per stcp=0. 11 second.

DETAILED DESCRIPT. .ION OF THE INVENTION

According to one aspect of the present invention, there is provided solid state forms of 7,8,9,1 O-tetrahydro-6, 1 0-methano-6H-pyrazino[2,3hJ[3]benzazcpine salts (varenicline salts), wherein the salt is an oxalate or a fumarate.

In another aspect, varenicline salts in a crystalline form are provided. In yet another aspect, varenicline salts in an amorphous form are provided.

In one embodiment, the solid state forms of vareniclinc salts exist in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate form, Such solvated or hydrated forms may be present as hemi-, mono, sesqui-, di- or tn- solvates or hydrates. Solvates and hydrates may be formed as a result of solvents used during the formation of the varenicline salts becoming imbedded in the solid lattice structure Because formation of the solvates and hydrates occurs during the preparation of varenicline salts, formation of a particular solvated or hydrated form depends greatly on the conditions and method used to prepare the salt. Solvents should be pharmaceutically acceptable.

In one embodiment, the solid state form of varenicline oxalate salt, designated as crystalline Form Ii, is characterized by at least one, or more, of the following properties:

i) a powder X-ray diffraction pattern substantiaily in accordance with Figure 1;

ii) a powder X-ray diffraction pattern having peaks at about 10.06, 15.49, 16.75, 20.32, 26.13 and 26.54 ± 0.2 degrees 2-theta substantially as depicted in Figure 1; and

iii) a powder X-ray diffraction pattern having additional peaks at about 5.68, 6.96, 8.56, 11.94, 17.57, 22.19, 22.72, 25.48, 28.52 and 28.91 ± 0.2 degrees 2-theta substantially as depicted in Figure 1.

In another embodiment, the solid state form of varenicline fumarate salt is characterized by at least one, or more, of the following properties:

1) a powder X-ray diffraction pattern substantially in accordance with Figure 2;

ii) a powder X-ray diffraction pattern having peaks at about 10.70, II 95, 16.27, 25.84 and 29.21 + 0.2 degrees 2-theta substantially as depicted in Figure 2; and

iii) a powder X-ray diffraction pattern having additional peaks at about 7.21, 13.26, 1184, 14.47, 16.65, 18.06, 21.53, 22.72, 23.80 and 28.56 + 0.2 degrees 2-theta substantially as depicted in Figure 2.

The solid state forms of varenicline oxalate and varenicline fumarate salts are stable, consistently reproducible, and are particularly suitable for bulk preparation and handling. Moreover, the solid state forms of varenicline oxalate and varenicline fumarate salts are useful intermediates in the preparation of varenicline free base or a pharmaceutically acceptable salt thereot preferably varenicline tartrate, in high purity.

The solid state forms of varenicline oxalate and varenicline fumarate salts have good flow properties and are far more stable at room temperature, enhanced temperature, at relative high humidities, and in aqueous media’ The novel solid state forms of varenicline oxalate and varenicline fumarate salts are suitable for formulating varenicline.

According to another aspect, there is provided a process for the preparation of solid state form of a varenicline salt, wherein the salt is an oxalate or a fumarate, comprising:

a) proving a first solution of varenicline free base in a solvent;

b) combining the first solution with an acid to produce a second solution or suspension containing varenicline acid addition salt, wherein the acid is selected from the group consisting of oxalic acid and fumaric acid; and

c) isolating and)or recovering solid state form of varenicline salt from the second solution or suspension.

The solid state form of varenicline salt obtained by the process disclosed herein is optionally converted into varenicline free base or a pharmaceutically acceptable salt thereof.

The process can produce solid state forms of varenicline salts (oxalate and fumarate salts) in substantially pure form.

The term “substantially pure solid state form of varenicline salt” refers to the solid state form of varenicline salt having a purity of greater than about 99 wt%, specifically
greater than about 99.5 wt%, more specifically greater than about 99.8 wt%, and still more specifically greater than about 99.9 wt%. The purity is preferably measured by High Performance Liquid Chromatography (l-IPLC). For example, the purity of solid state form of varenicline salt obtained by the process disclosed herein can be about 99% to about 99.95%, or about 99.5% to about 99.99%, as measured by HPLC.

In one embodiment, the process disclosed herein provides stable crystalline forms of varenicline oxalate Form II and varenicline fumarate salts. The term “stable crystalline form” refers to stability of the crystalline form under the standard temperature and humidity conditions of testing of pharmaceutical products, wherein the stability is indicated by preservation of the original polymorphic form.

Exemplary solvents used in step-(a) include, but are not limited to, water, alcohols, ketones, chlorinated hydrocarbons, esters, and mixtures thereof. The term solvent also includes mixtures of solvents.

In one embodiment, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, methylene chloride, ethylene dichloride, and mixtures thereof; more specifically the solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, and mixtures thereof; and most specifically the solvent is methanol.

In a particular aspect, provided herein is a process for the preparation of varenicline oxalate crystalline Form II, comprising:

a) providing a first solution of varenicline free base in methanol;

b) combining the first solution with oxalic acid to produce a second solution or suspension containing varenicline oxalate;

c) isolating and/or recovering crystalline Form U of varenicline oxalate from the second solution or suspension.

Step-(a) of providing a first solution of varenicline free base includes dissolving varenicline free base in the solvent, or obtaining an existing solution from a previous processing step.

In one embodiment, the varenicline free base is dissolved in the solvent at a temperature of below boiling temperature of the solvent used, specifically at about 20°C to about 110°C, and more specifically at about 25°C to about 80°C.

In another embodiment, the first solution in step-(a) is prepared by reacting 1- (5,8,1 4-triazatetracyclo[ 10.3.1 .02l ‘.04’9jhexadeca-2( 11 ),3,5,7,9-pentaene)-2,2,2-trifluoro- ethanonc with a base in a reaction inert solvent under suitable conditions to produce a reaction mass containing crude varenicline free base, followed by usual work up such as washings, extractions, evaporations, etc. In one embodiment, the work-up includes dissolving or extracting the resulting varenicline free base residue in the solvent at a temperature of below boiling temperature of the solvent used, specifically at about 20°C to about 110°C, and more specifically at about 25°C to about 80°C.

In one embodiment, the base is an organic or inorganic base. Specific organic bases are triethyl amine, dimethyl amine and tert-butyl amine.

In another embodiment, the base is an inorganic base. In yet another embodiment, the inorganic base is used in the form of an aqueous solution. Exemplary inorganic bases include, but are not limited to, aqueous ammonia; hydroxides, carbonates and bicarbonates of alkali or alkaline earth metals. Specific inorganic bases are aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, socflum bicarbonate and potassium bicarbonate; and more specifically sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

Exemplary reaction inert solvents suitable for facilitating the reaction between 1- (5,8,1 4-triazatetracyclo[ 10.3.1.02.1 ‘.04’9]hexadeca-2(1 1),3,5,7,9-pentaene)-2,2,2-trifluoro- ethanone and the base include, but are not limited to, water, alcohols, ketones, cyclic ethers, aliphatic ethers, hydrocarbons, chlorinated hydrocarbons, nitriles, esters, polar aprotic solvents, and the like, and mixtures thereof. In one embodiment, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, hexanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, methylene chloride, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofliran, dioxane, diethyl ether,
diisopropyl ether, monoglyme, diglyme, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof. Most specific reaction inert solvents are water, methanol, ethanol, isopropanol, and mixtures thereof

The first solution obtained in step-(a) is optionally stirred at a temperature of about 30°C to the reflux temperature of the solvent used for at least 20 minutes, and specifically at a temperature of about 40°C to the reflux temperature of the solvent used for about 30 minutes to about 10 hours.

The first solution obtained in step-(a) is optionally subjected to carbon treatment or silica gel treatment. The carbon treatment or silica gel treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 70°C for at least 15 minutes, specifically at a temperature of about 40°C to about 70°C for at least 30 minutes; and filtering the resulting mixture through hello to obtain a filtrate containing varenicline free base by removing charcoal or silica gel. Preferably, finely powdered carbon is an active carbon. A specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.
In another embodiment, the acid used in step-(b) in the molar ratio of about 1 .0 to 2.0 moles, specifically about 1.0 to 1,2 moles, per mole of varenicline free base.

Combining of the first solution with acid in step-(b) is done in a suitable order, for example, the first solution is added to the acid, or alternatively, the acid is added to the first solution. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out at a temperature of below about 100°C, more specifically at about 20°C to about 80°C, and most specifically at about 25°C to about 50°C under stirring. After completion of addition process, the resulting mass is stirred at a temperature of about 25°C to about I 0O’C for at least 10 minutes and specifically at a temperature of about 25°C to about 50°C for about 30 minutes to about 8 hours to produce a second solution or suspension.

The isolation of pure solid state form of varenicJine salt in step-(c) is carried out by forcible or spontaneous crystallization.

Spontaneous crystallization refers to crystallization without the help of an external aid such as seeding, cooling etc., and forcible crystallization refers to crystallization with the help of an external aid.

Forcible crystallization may be initiated by a method usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof, in one embodiment, the crystallization is carried out by cooling the solution at a temperature of below 25°C for at least 15 minutes, specifically at about 0°C to about 25°C for about 30 minutes to about 20 hours.
The recovering in step-(c) is carried out by methods such as filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof. in one embodiment, solid state form of varenicline salt is recovered by filtration employing a filtration media of, for example, a silica gel or celite.

The substantially pure solid static form of varenicline salt obtained by above process may be further dried in, for example, a Vacuum Tray Dryer, Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICR”) guidelines.

In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 70°C. The drying can be carried out for any desired time period that achieves the desired result, such as about I to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications.

Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.

In one embodiment, the organid solvent used in step-(b) s selected from the group consisting of methylene chloride, ethylene dichioride, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formatc, and mixtures thereof; more specifically the solvent is selected from the group consisting of methylene chloride, ethyl acetate, and mixtures thereof; and a most specific solvent is methylene chloride.

The term “substantially removing” the solvent refers to at least 30%, specifically grater than about 50%, more specifically grater than about 90%, still more specifically grater than about 99%, and most specifically essentially complete (100%), removal of the solvent from the solvent solution.
Removal of solvent in step-(c) is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent under inert atmosphere, or a combination thereof. Alternatively, the solvent may also be removed by evaporation. The solution may also be completely evaporated in, for example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer (“ATFD”), or evaporated by spray drying

The distillation process can be performed at atmospheric pressure or reduced pressure. Specifically, the distillation is carried out at a temperature of about 30°C to about 1 10°C, more specifically at about 40°C to about 90°C, and most specifically at about 45°C to about 80°C.

Specifically, the solvent is removed at a pressure of about 760 mm Hg or less, more specifically at about 400 mm Hg or less, still more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.

The pure varenicline free base obtained by above process is recovered and optionally further dried as described above.

The purity of the varenicline free base obtained by the process disclosed herein is of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the varenicline free base can be about 99% to about 99.95%, or about 99.5% to about 99.99%.

In another embodiment, the solid state form of varenicline free base obtained by the described herein is characterized by at least one, or more, of the following properties:
I) a powder X-ray diffraction pattern substantially in accordance with Figure 4;
ii) a powder X-ray diffraction pattern having peaks at about 11.22, 19.27, 19.77, 20.38, 20.65 and 26.80 + 0.2 degrees 2-theta substantially as depicted in Figure 4; and
iii) a powder X-ray diffraction pattern having additional peaks at about 1213, 14.16, 15.89, 17.18, 21.64, 21.89, 25.33, 27.34 and 28.16 + 0.2 degrees 2-theta substantially as depicted in Figure 4.

Further encompassed herein is the use of the solid state forms of varenicline oxalate and varenicline fumarate salts for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

A specific pharmaceutical composition of the solid state forms of varenicline oxalate and varenieline fumarate salts is selected from a solid dosage form and an oral suspension.
in one embodiment, the solid state forms of varenicline oxalate and varenicline fumarate salts have a D90 particle size of less than or equal to about 500 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 100 microns, still more specifically less than or equal to about 60 microns, and most specifically less than or equal to about 15 microns.

In another embodiment, the particle sizes of the solid state forms of varenicline oxalate and varenicline fumarate salts are produced by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.

According to another aspect, there is provided pharmaceutical compositions comprising solid state form of varenicline oxalate salt and one or more pharmaceutically acceptable excipients,

According to another aspect, there is provided pharmaceutical compositions comprising the solid state form of varenicline oxalate prepared according to process disclosed herein and one or more pharmaceutically acceptable recipients.

According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining the solid state form of varenicline oxalate prepared according to process disclosed herein, with one or more pharmaceutically acceptable excipients.

According to another aspect, there is provided pharmaceutical compositions comprising solid state form of varenicline fumarate salt and one or more pharmaceutically acceptable excipients.

According to another aspect, there is provided pharmaceutical compositions comprising the solid state form of varenicline fumarate prepared according to process disclosed herein and one or more pharmaceutically acceptable exeipients.

According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining the solid state form of varenicline fumarate prepared according to process disclosed herein, with one or more pharmaceutically acceptable excipients.

According to another aspect, there is provided a method for treating a patient suffering from diseases caused by neurogical and psychological disorders, inflammatory bowel disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, vasoconstriction, anxiety, panic disorder, depression, cognitive dysfunction, drug/toxin- induced cognitive impairment, nicotine dependency and addiction; comprising administering any one of the novel solid state forms of varenicline oxalate and varenicline fumarate salts, or a pharmaceutical composition that comprises any one of the novel solid state forms of varenicline oxalate and varenicline fumarate salts, along with pharmaceutically acceptable excipients.

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

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

In one embodiment, capsule dosage forms contain any one of the solid state forms of varenicline oxalate and varenicline fumarate salts within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. Suitable enteric coating include phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl met hacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.

Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions described herein may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
The following examples are given for the purpose of illustrating the present disclosure and should not be considered as limitation on the scope or spirit of the disclosure.

EXAM PLES

Example I

Step-I: Process for the preparation of pure Varenieline oxalate crystalline Form II 1 -(5,8, 14-Triazatetracycloji 0.3.1 .O2I ‘ 04’9]hexadeca-2(l I ),3,5,7,9-pentaene)-2,2,2-
trifluoro-ethanone (10 g, 1-IPLC purity: 98.8%) was slurried in methanol (10 ml), followed by the addition of sodium hydroxide solution (2.6 g ) in water ( 50 ml). The mixture was warmed and stirred for 2 hours at 25-30°C and then concentrated under vacuum at below 50°C. The resuLting residue was washed with water (SO ml) and extracted three times with dichloromethane (3 x 100 ml). The total organic layer was dried over sodium sulfate and concentrated to give light yellow oil. This oil was dissolved in methanol (70 ml) at 25-30°C followed by the addition of oxalic acid (3.1 g) at 25-30°C. The resulting suspension was stirred for, 1 hour at 25-30°C. The resulting solid was filtered and washed with methanol (10 ml) and then dried to yield 6.5 & of varenicline oxalate in crystalline Form II.

Step-II: Process for the preparation of pure varenicline free base
Varenicline oxalate salt (5 g, obtained in step-I) was dissolved in water (25 ml) at 25- 30°C and the resulting clear solution was neutralized with saturated sodium bicarbonate solution at 25-30°C. The resulting mass was stirred for 1 hour at 25-30°C and then extracted three times with dichloromethane (3 x 50 ml) at 25-30°C. The organic layers were combined and the total organic layer was dried over sodium sulfate. The resulting
dichioromethane layer was evaporated to yield 3 g of varenicline free base (HPLC purity
= 99.9%).

Example 2

Step-I: Process for the preparation of pure crystalline Varenicline fumarate 1 -(5,8,1 4-Triazatetracyclo[ 10.3.1.02.1 1 04’9jhexadeca-2( 11 ),3,5,7,9-pentaene)-2,2,2-
trifluoro-ethanone (10 g, HPLC purity: 98.8%) was slurried in methanol (10 ml), followed by the addition of sodium hydroxide solution (2.6 g ) in water ( 50 ml). The mixture was warmed and stirred for 2 hours at 25-30°C and then concentrated under vacuum at below 50°C. The resulting residue was washed with water (50 ml) and extracted three times with dichloromethane (3 x 100 ml). The total organic layer was dried over sodium sulfate and concentrated to give light yellow oil, This oil was dissolved in methanol (70 ml) at 25-30°C followed by the addition of fumaric acid (3.93g) at 25-30°C. The resulting suspension was stirred for 1 hour at 25-30°C. The resulting solid was filtered and washed with methanol (10 ml) and then dried to yield 7 g of crystalline varenicline fumarate.

Step-II: Process for the preparation of pure varenicline free base
Varenicline fumarate salt (5 g, obtained in step-I) was dissolved in water (25 ml) at 25- 30°C and the resulting clear solution was neutralized with saturated sodium bicarbonate solution at 25-30°C. The resulting mass was stirred for 1 hour at 25-30°C and then extracted three times with dichloromethane (3 x 50 ml) at 25-30°C. The organic layers were combined and the total organic layer was dried over sodium sulfate. The resulting dichloromethane layer was evaporated to yield 2.5 g of varenicline free base (HPLC purity = 99.R5%).

Example 3

Step-I: Process for the preparation of pure Varenicline hydrochloride
1 -(5,8, 14-Triazatetracyclo[l 0.3.1.02.11 .04’lhexadeca-2(l vacuum at below 50°C. The resulting residue was washed with water (50 ml) and extracted three times with dichloromethane (3 x 100 ml). The total organic layer was dried over sodium sulfate and concentrated to give light yellow oil. This oil was dissolved in methanol (35 ml) and ethyl acetate (35 ml) at 25-30°C followed by the adjusting pH of the solution to I with a solution of 10% hydrochloric acid in ethyl acetate at 25-30°C. The resulting suspension was stirred for 1 hour at 25-30°C. The resulting solid was filtered and washed with ethyl acetate (10 ml) and then dried to yield 5 g of varenicline hydrochloride salt.

Step-II: Process for the preparation of pure is adrenaline free base
Varenicline hydrochloride salt (5 g) was dissolved in water (25 ml) at 2530°C and the resulting clear solution was neutralized with saturated sodium bicarbonate solution at 25- 30°C. The resulting mass was stirred for 1 hour at 25-30°C and then extracted three times with dichloromethane (3 x 50 ml) at 25-30°C. The organic layers were combined and the total organic layer was dried over sodium sulfate. The resulting dichloromethane layer was evaporated to yield 4 g of varenicline free base (HPLC purity 99+82%).

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “solid form of varenicline salts disclosed herein” includes crystalline forms, amorphous form, hydrated, and solvated forms of varenicline oxalate and vareniclinc fumarate salts.

The term “crystalline polymorph” refers to a crystal modification that can be characterized by analytical methods such as X-ray powder diffraction, IR-spectroscopy, differential scanning calorimetric (DSC) or by its melting point.

The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination,
1,3 ,5 ,7,9-pentaene)-2,2,2-tritluoro-ethanone (10 g, 1-PLC purity: 98.8%) was slurried in methanol (10 ml), followed by the addition of sodium hydroxide solution (2.6 g) in water (50 ml). The mixture was warmed and stirred for 2 hours at 2 5-30°C and then concentrated under complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

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

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

The term “buffering agent” as used herein is intended to mean a compound used to resist a change in p1-I upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.

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

The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC(TM) P68, PLURONIC(TM) F 127), collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester,
polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.

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

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

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

The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride,
calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEEN(TM)s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propyleellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type) is another useful wetting agent, combinations thereof and other such materials known to those of ordinary skill in the art.

The term “micron ization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “pm” both are same refers to “micrometer” which is lxl6 meter.

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

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

As used herein, Dx means that X percent of the particles have a diameter less than a specified diameter D. Thus, a D% or d(0.9) of less than 300 microns means that 90 volume-percent of the particles in a composition have a diameter less than 300 microns.

We claim:
1. A process for preparing highly pure varenicline free base, comprising:

a) contacting solid state form of a varenicline salt with a base in water to provide a reaction mass containing varenicline free base, wherein the salt is an oxalate, a fumarate or a hydrochloride salt;
b) extracting the varenicline free base with an organic solvent selected from the group consisting of chlorinated hydrocarbons, esters, and mixtures thereof; and
c) substantially removing the solvent from the organic layer obtained in step-(b) to afford substantially pure solid form of varenicline free base.

2. The process of claim 1, wherein the base used in step-(a) is an organic or inorganic base selected from the group consisting of triethyl amine, dimethyl amine and tert-butyl amine, aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and potassium bicarbonate; wherein the reaction in step-(a) is carried out at a temperature of -25°C to about 100°C; wherein the organic solvent used in step-(b) is selected from the group consisting of methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, and mixtures thereof; and wherein the removal of solvent in step-(c) is accomplished by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent under inert atmosphere, spray drying, vacuum drying, agitated thin-film (ATFD) drying, or a combination thereof.

3. The process of claim 2, wherein the base is sodium bicarbonate or sodium carbonate; wherein the reaction is carried out at a temperature of about 25°C to about 50°C; and wherein the organic solvent is methylene chloride.

4. The process of claim 1, wherein the solid state form of varenicline free base obtained is characterized by at least one, or more, of the following properties:

i) a powder X-ray diffraction pattern substantially in accordance with Figure 4;
ii) a powder X-ray diffraction pattern having peaks at about 11.22, 19.27, 19.77,
20.38, 20.65 and 26.80 ± 0.2 degrees 2-theta substantially as depicted in Figure 4;
and

iii) a powder X-ray diffraction pattern having additional peaks at about 12.13, 14.16, 15.89, 17.18, 21.64, 21.89, 25.33, 27.34 and 28.16 ± 0.2 degrees 2-theta substantially as depicted in Figure 4.

5. The process of claim 1, wherein the solid state form of varenicline oxalate used in
step-(a) is varenicline oxalate crystalline Form II characterized by one, or more, of
the following properties:
i) a powder X-ray diffraction pattern substantially in accordance with Figure 1;
ii) a powder X-ray diffraction pattern having peaks at about 10.06, 15.49, 16.75,
20.32, 26.13 and 26.54 ± 0.2 degrees 2-theta substantially as depicted in Figure 1;
and iii) a powder X-ray diffraction pattern having additional peaks at about 5.68, 6.96,
8.56, 11.94, 17.57, 22.19, 22.72, 25.48, 28.52 and 28.91 ± 0.2 degrees 2-theta
substantially as depicted in Figure 1.

6. A process for the preparation of solid state form of a varenicline salt, wherein the salt
is an oxalate or a fumarate, comprising:

a) providing a first solution of varenicline free base in a solvent selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, methylene chloride, ethylene dichloride, and mixtures thereof;

b) combining the first solution with an acid to produce a second solution or suspension containing varenicline acid addition salt, wherein the acid is selected from the group consisting of oxalic acid and fumaric acid; and

c) isolating and/or recovering solid state form of varenicline salt from the second solution or suspension.

7. A process for the preparation of varenicline oxalate crystalline Form II, comprising:
a) providing a first solution of varenicline free base in methanol;
b) combining the first solution with oxalic acid to produce a second solution or suspension containing varenicline oxalate;

c) isolating and/or recovering crystalline Form II of varenicline oxalate from the second solution or suspension.

8. The process of claim 7, wherein the varenicline oxalate crystalline Form II obtained is
characterized by one, or more, of the following properties:

i) a powder X-ray diffraction pattern substantially in accordance with Figure 1;
ii) a powder X-ray diffraction pattern having peaks at about 10.06, 15.49, 16.75,
20.32,26.13 and 26.54 ± 0.2 degrees 2-theta substantially as depicted in Figure 1;
and iii) a powder X-ray diffraction pattern having additional peaks at about 5.68, 6.96,
8.56, 11.94, 17.57, 22.19, 22.72, 25.48, 28.52 and 28.91 ± 0.2 degrees 2-theta
substantially as depicted in Figure 1.

9. A pharmaceutical composition comprising crystalline Form II of varenicline oxalate obtained by the process of claim 7, and one or more pharmaceutically acceptable excipients.

10. A method of treating a patient suffering from diseases caused by neurogical and psychological disorders, inflammatory bowel disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, vasoconstriction, anxiety, panic disorder, depression, cognitive dysfunction, drug/toxin-induced cognitive impairment, nicotine dependency and addiction; comprising administering varenicline oxalate crystalline Form II obtained by the process of claim 7, or a pharmaceutical composition that comprises varenicline oxalate crystalline Form II, along with pharmaceutically acceptable excipients.