Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems

Definitions

• aspects of the present invention relate to an amorphous form of varenicline tartrate, an amorphous solid dispersion of varenicline tartrate, and processes for the preparation thereof.
• Varenicline is the first approved nicotinic receptor partial agonist and is pharmacologically different from other smoking cessation aids such as nicotinic antagonists (e.g., bupropion) and nicotine replacement therapies (e.g., nicotine patches and nicotine gum).
• nicotinic antagonists e.g., bupropion
• nicotine replacement therapies e.g., nicotine patches and nicotine gum.
• the drug compound having the adopted name "varenicline” has chemical names 5,8 J 14-thazatetracyclo[10.3.1.0 2 'l 1 0 4 ' 9 ]-hexadeca-2(11 ),3,5,7,9-pentaene, or 7,8,9, 10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine, and is structurally represented by Formula I.
• Varenicline as a nicotinic receptor partial agonist, reduces both cravings and the pleasurable affects of cigarettes and other tobacco products, and through these mechanisms it assists some patients with quitting smoking. Being known to be useful in modulating cholinergic function, it is indicated for the treatment of smoking cessation. Varenicline is present in the form of a salt with L-tartaric acid, i.e., varenicline tartrate, in products marketed as CHANTIXTM in the U.S. and CHAMPIXTM in Europe and Canada.
• Q may be chosen from groups such as COCF 3 , COCCI 3 , COOCH 2 CCI 3 , COO(CrC 6 )alkyl and COOCH 2 C 6 H 5 .
• the invention encompasses an amorphous form of varenicline tartrate.
• the amorphous form of varenicline tartrate described herein may have residual water content in the range of from about 0.1 % to about 10%, by weight.
• processes for the preparation of an amorphous form of varenicline tartrate comprising removing solvent from a solution of varenicline tartrate.
• compositions that include a therapeutically effective amount of an amorphous form of varenicline tartrate, which is described herein, and at least one pharmaceutically acceptable excipient.
• the present application provides amorphous solid dispersions of varenicline tartrate together with a pharmaceutically acceptable carrier.
• the present application provides processes for preparing amorphous solid dispersions of varenicline tartrate together with a pharmaceutically acceptable carrier, comprising removing solvent from a solution of varenicline tartrate and a pharmaceutically acceptable carrier.
• compositions comprising amorphous solid dispersions of varenicline tartrate together with at least one pharmaceutically acceptable excipient, optionally with one or more other pharmaceutically acceptable excipients.
• Fig. 1 is an X-ray powder diffraction (XRPD) pattern of an illustrative sample of varenicline tartrate amorphous form.
• Fig. 2 is an XRPD pattern of a stabilized amorphous solid dispersion of varenicline tartrate with hydroxypropyl cellulose, prepared according to Example 11.
• Fig. 3 is an XRPD pattern of a stabilized amorphous solid dispersion of varenicline tartrate with hydroxypropyl methylcellulose, prepared according to Example 12.
• Fig. 4 is an XRPD pattern of a stabilized amorphous solid dispersion of varenicline tartrate with povidone, prepared according to Example 13.
• New solid forms of pharmaceutically useful compounds provide an opportunity to improve the characteristics of formulated products, such as stability, solubility and formulation processing.
• solid forms e.g., polymorps, amorphous, etc.
• active pharmaceutical ingredients like varenicline tartrate
• solid forms having different physical characteristics and distinct physicochemical properties which may be characterized by various analytical methods e.g., X-ray powder diffraction patterns, infrared absorption spectra, solid state NMR spectra, and thermal analysis methods suchas differential scanning calorimetry (DSC) thermograms, thermogravimetric analysis (TGA) curves, etc.
• DSC differential scanning calorimetry
• TGA thermogravimetric analysis
• the amorphous form of varenicline tartrate described herein may be characterized by its XRPD pattern.
• the amorphous form of varenicline tartrate described herein has a pattern without intense focused reflections and is featureless except for a halo.
• Fig. 1 provides an example of the XRPD pattern of the amorphous form of varenicline tartrate. All X-ray powder diffraction pattern data provided herein were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer. XRPD patterns were generated using copper Ka radiation at a wavelength 1 .541 A.
• the amorphous form of varenicline tartrate described herein may have a water content in the range of from about 0.1 % to about 10%, by weight.
• the amorphous varenicline tartrate produces a product with desired characteristics like stability and is suitable for preparing pharmaceutical compositions for pharmaceutical use.
• the present invention provides substantially pure amorphous varenicline tartrate, having less than about 20%, or less than about 10%, or less than about 5%, or less than about 1 %, by weight of a crystalline form of varenicline tartrate.
• the substantially pure amorphous varenicline tartrate can have less than about 20%, or less than about 10%, or less than about 5%, or less than about 1 %, by weight of all crystalline forms of varenicline tartrate.
• the present application provides processes for the preparation of an amorphous form of varenicline tartrate.
• the amorphous form of varenicline tartrate described herein may be prepared by removing the solvent from the solution of varenicline tartrate.
• a solution may be provided by forming a solution of varenicline tartrate, alone or together with a soluble pharmaceutically acceptable excipient, in a suitable solvent. If the solution of varenicline tartrate and an excipient is provided, the excipient may be chosen to enable stabilization of the amorphous solid formed upon solvent removal.
• Providing a solution of varenicline tartrate in a suitable solvent includes any of:
• varenicline free base in a suitable solvent with L-tartaric acid, either alone or in combination with a pharmaceutically acceptable carrier.
• suitable solvents include, but are not limited to, alcohol solvents such as methanol, ethanol, isopropyl alcohol and n-propanol; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and carbon tetrachloride; ketone solvents such as acetone, ethyl methyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate; ether solvents such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t- butyl ether,
• Amorphous varenicline tartrate together with a pharmaceutically acceptable carrier may be prepared by combining the pharmaceutically acceptable carrier with a solution of varenicline tartrate, or combining varenicline tartrate with a solution of pharmaceutically acceptable carrier, and removal of the solvent.
• a solution of pharmaceutically acceptable carrier may be dissolved in the same or a different solvent and added to a varenicline tartrate solution.
• varenicline tartrate When amorphous varenicline tartrate is prepared from varenicline free base by reaction with L-tartaric acid, the solvents that are utilized for the dissolution of varenicline free base and L-tartaric acid may be the same or different, and the solutions are then combined for further processing.
• Suitable pharmaceutically acceptable carriers which may be used in the processes of the present application include, but are not limited to, hydrophilic carriers like polymers of N-vinylpyrrolidone, commonly known as polyvinyl pyrrolidines (“PVP” or “povidone”), gums, cellulose derivatives, cyclodextrins, gelatins, hypromellose phthalate, sugars, polyhydhc alcohols, polyethylene glycol, polyethylene oxides, polyoxyalkylene derivatives, methacrylic acid copolymers, polyvinylalcohols, and propylene glycol derivatives.
• the carriers will stabilize amorphous varenicline tartrate.
• the solution of varenicline tartrate obtained above may be formed with heating to obtain a more concentrated solution.
• the temperature at which dissolution takes place varies from room temperature to the boiling point of the solvent.
• the temperature at which the dissolution occurs depends on the nature of the solvent and may be determined by person skilled in the art. Any undissolved particles may be removed suitably by filtration, such as passing the solution through paper, glass fiber, or other membrane material, centrifugation, decantation, and other techniques.
• the solvent may be removed using any of the suitable methods such as evaporation, atmospheric distillation, or distillation under vacuum.
• the techniques which may be used for the removal of solvent include use of rotational evaporating devices such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), lyophilization, freeze drying, and the like.
• Distillation of the solvent may be conducted under a vacuum, such as below about 100 mm Hg, or below about 600 mm Hg, at elevated temperatures such as about 20 0 C to about 70 0 C. Any temperature and vacuum conditions may be used as long as they do not adversely influence the nature of the product.
• the vacuum and the temperature used for the removal of the solvent depend on parameters such as the boiling point of the solvent, and may readily be determined by persons skilled in the art.
• Isolation of the product thus obtained includes collection of the material, with or without cooling below the operating temperature, by any techniques such as filtration by gravity or suction, centhfugation, and the like, and optional washing with the solvent.
• the amorphous varenicline tartrate obtained may also be collected from the equipment using techniques such as by scraping, or by shaking a container.
• the solid material obtained by any of the techniques described above may be optionally further dried. Drying may be suitably carried out by any methods such as using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out under reduced pressures and at various temperatures. The temperatures may range from about ambient temperature to about 100 0 C, for a time period that produces the desired residual solvent content.
• Amorphous varenicline tartrate thus obtained may be milled to get a desired particle size distribution.
• a milling operation can reduce the size of particles and increase surface areas of particles, by colliding particles with each other at high velocities.
• the present application also provides stable amorphous solid dispersions of varenicline tartrate together with a pharmaceutically acceptable carrier, processes for preparation thereof, and pharmaceutical compositions prepared therefrom.
• amorphous solid dispersions of varenicline tartrate together with a pharmaceutically acceptable carrier described herein may be characterized by their XRPD patterns.
• a completely amorphous solid dispersion of varenicline tartrate together with a pharmaceutically acceptable carrier described herein has a pattern without intense focused reflections, and is generally featureless except for a halo. In particular, peaks characteristic of a solid form of varenicline tartrate are absent.
• An amorphous solid dispersion of varenicline tartrate described herein may have a water content in the range of from about 0.1 % to about 10%, by weight.
• a solid dispersion of amorphous varenicline tartrate together with a pharmaceutically acceptable carrier provides a product with desired characteristics like stability, and is suitable for preparing pharmaceutical compositions for pharmaceutical use.
• the present invention provides substantially pure amorphous solid dispersions of varenicline tartrate, having less than about 20%, or less than about 10%, or less than about 5%, or less than about 1 %, by weight of any crystalline form of varenicline tartrate.
• the substantially pure amorphous solid dispersions of varenicline tartrate can have less than about 20% , or less than about 10%, or less than about 5%, or less than about 1 %, by weight of all crystalline forms of varenicline tartrate.
• the present application provides processes for preparing amorphous solid dispersions of varenicline tartrate together with a pharmaceutically acceptable carrier, an embodiment comprising removing the solvent from a solution of varenicline tartrate and a pharmaceutically acceptable carrier.
• a solution may be provided by dissolving varenicline tartrate and a soluble pharmaceutically acceptable excipient, in a suitable solvent. The excipient may be chosen to stabilize the amorphous solid formed upon solvent removal.
• Providing a solution of varenicline tartrate and a pharmaceutically acceptable excipient in a suitable solvent includes any of:
• varenicline tartrate Any physical form of varenicline tartrate, such as crystalline, amorphous, and their mixtures, may be utilized for providing a solution of varenicline tartrate along with a pharmaceutically acceptable carrier.
• Pharmaceutically acceptable carriers that may be used for the preparation of stabilized amorphous solid dispersions of varenicline tartrate of the present application include, but are not limited to: pharmaceutical hydrophilic carriers such as polyvinylpyrrolidones (homopolymers of N-vinylpyrrolidone, called povidones), copolymers of N-vinylpyrrolidone, gums, cellulose derivatives (including hydroxypropyl methylcelluloses, hydroxypropyl celluloses, and others), polymers of carboxymethyl celluloses, cyclodextrins, gelatins, hypromellose phthalates, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, polyvinylalcohols, propylene glycol derivatives, and the like; and organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aral
• the solvents that may be utilized for providing a solution of varenicline tartrate along with a pharmaceutically acceptable carrier include, but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol and n- propanol; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and carbon tetrachloride; ketone solvents such as acetone, ethyl methyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate; ether solvents such as diethyl ether, dimethyl ether, diisopropylether, methyl t-butyl ether, tetrahydrofuran and 1 ,4-dioxane; hydrocarbon solvents such as tolu
• the solution may be obtained by dissolving varenicline tartrate and the pharmaceutically acceptable carrier in a solvent or in different solvents, optionally with heating. Generally the temperatures at which dissolution takes place vary from room temperature to the boiling point of the solvent. The temperature at which the dissolution occurs depends on the nature of the solvent and may be determined by person skilled in the art. Any undissolved particles may be removed suitably by filtration, such as passing a solution through paper, glass fiber, or other membrane material, centrifugation, decantation, and other techniques. The solution may optionally be treated with materials such as carbon to remove colour or to improve clarity of the solution.
• Removal of the solvent from the solution can be accomplished using any suitable technique.
• the solvent may be removed by techniques known in art which include but are not limited to: distillation, evaporation, oven drying, tray drying, rotational drying (such as with a Buchi Rotavapor), spray drying, freeze- drying, fluidized bed drying, flash drying, spin flash drying, agitated thin film drying, and the like.
• Distillation of the solvent may be conducted under a vacuum, such as below about 100 mm Hg, or below about 600 mm Hg, at elevated temperatures such as about 20 0 C to about 100 0 C. Any temperature and vacuum conditions may be used as long as they do not influence the nature of the product.
• the vacuum and the temperature used for the removal of the solvent depend on parameters such as the boiling point of the solvent, and may readily be determined by persons skilled in the art.
• Isolation of the product thus obtained includes collection of the material, with or without cooling below the operating temperature, by any techniques such as filtration by gravity or suction, centrifugation, and the like, and optionally washing with the solvent.
• the amorphous solid dispersion obtained may also be collected from the equipment using techniques such as by scraping, or by shaking a container.
• the solid material obtained by any of the techniques described above may be optionally further dried. Drying may be suitably carried out by any known methods such as using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out under reduced pressures and at various temperatures. The temperatures may range from about ambient temperature to about 100°C for a time period that produces the desired residual solvent content.
• Solid dispersions of varenicline tartrate thus obtained may be milled to get a desired particle size distribution.
• a milling operation reduces the size of particles and increases surface areas of particles by colliding particles with each other at high velocities.
• XRPD X-ray powder diffraction
• the present application also provides stabilized amorphous solid dispersions of varenicline tartrate together with a pharmaceutically acceptable carrier, processes for preparation thereof, and pharmaceutical compositions comprising them.
• the solid dispersions of amorphous varenicline tartrate together with a pharmaceutically acceptable carrier provide a product with desired characteristics like stability, and are suitable for preparing pharmaceutical compositions for pharmaceutical use.
• the starting varenicline tartrate used to prepare an amorphous solid described herein may be prepared, for example, by reacting varenicline free base with L-tartaric acid.
• the amount L-tartahc acid used for the preparation of varenicline tartrate may vary from about 1 to about 5 molar equivalents, per equivalent of varenicline free base.
• the amount L-tartaric acid used for the preparation of varenicline tartrate may vary from about 1 to about 2.3 molar equivalents, per equivalent of varenicline free base.
• the amount L-tartaric acid used for the preparation of varenicline tartrate may vary from about 2.3 to about 5 molar equivalents, per equivalent of varenicline free base.
• a chemical pathway for the preparation of varenicline is as shown in
• the compound of Formula B may be prepared by treating the compound of Formula A with a hydroxylating reagent in a suitable organic solvent.
• hydroxylating agents include osmium tetraoxide, potassium permanganate, potassium dichromate, and iodine/silver acetate.
• other oxidants such as, but not limited to, N- methylmorpholine-N-oxide, pyridine-N-oxide, sodium peroxydisulfate, iodine, hydrogen peroxide, and potassium ferhcyanide may also be used.
• Organic solvents that may be utilized for this step include, but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol and n-propanol; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and carbon tetrachloride; ketone solvents such as acetone, ethyl methyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate; ether solvents such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran and 1 ,4- dioxane; hydrocarbon solvents such as toluene, xylene, n-heptane,
• the reaction is typically carried out at room temperature, however, if desired the reaction may be carried out at higher temperatures to enhance the progress of the reaction.
• the obtained product may be purified using methods such as column chromatography, preparative HPLC purification, and/or crystallization using a solvent or a mixture of solvents.
• the hydroxylation reaction for the preparation of the compound of formula B may be carried out under ultrasonic conditions which may reduce the reaction time significantly.
• the compound of Formula B may also be prepared by initially converting the compound of Formula A to an epoxide compound of Formula D, and subsequntly converting the compound of Formula D into the compound of Formula B.
• the compound of Formula D may be prepared by treating the compound of
• Formula A using methods capable of making epoxides from alkenes as known in the art. This reaction may be accomplished, for example, by using peroxyacids, hydrogen peroxide, sodium hypochloride, perchloric acid, etc.
• the compound of Formula D may then be converted to a diol of Formula B.
• the conversion of compound of Formula D to the compound of Formula B may be carried out in the presence of acids or bases.
• Acids that are useful for the conversion of compound of formula D into compound of formula B include, but are not limited to, hydrochloric acid, sulfuric acid, etc.
• Bases that are useful for such conversion include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.
• Other acids and bases known to a person skilled in the art are also contemplated, without limitation.
• the solvents and the conditions contemplated for the conversion of compound of formula A into the compound of formula B may also be useful for the conversion of the compound of formula A into D, and from D into B.
• the compound of Formula B may be further converted to a compound of Formula E through the compound of Formula C, such as using the process given in U.S. Patent No. 6,410,550.
• the compound of Formula B may be reacted with sodium periodate in a mixture of a chlorinated hydrocarbon, such as dichloroethane (DCE), and water, or with lead tetraacetate in a chlorinated hydrocarbon solvent, at a temperature from about 0 0 C to about room temperature, to generate a dialdehyde or glycal compound of Formula C.
• a chlorinated hydrocarbon such as dichloroethane (DCE)
• lead tetraacetate in a chlorinated hydrocarbon solvent
• benzylamine such as ammonia, hydroxylamine, alkoxyamines, methylamine, allylamine, and substituted benzylamines (e.g., diphenylmethylamine and 2- and 4-alkoxy substituted benzylamines) may also be used. They may be used as free bases, or as their salts, preferably their acetate salts, and can be subsequently removed by methods described in the literature.
• the compound of Formula E, wherein R is hydrogen may be reacted with a protecting group such as trifluoroacetic anhydride to form the compound of Formula E, where R is -COCF 3 .
• This reaction is typically conducted in an inert organic solvent such as methylene chloride at a temperature from about 0 0 C to about room temperature.
• the reaction may be optionally conducted in the presence of a base.
• the base used for the reaction may be an organic or inorganic base.
• the compound of Formula E may be subjected to nitration to obtain a dinitro compound of Formula F.
• the compound of Formula E may be added to a mixture of trifluoromethanesulfonic acid (CF 3 SO 2 OH) and nitric acid, in a chlorinated hydrocarbon solvent, such as chloroform, dichoroethane, or methylene chloride.
• CF 3 SO 2 OH trifluoromethanesulfonic acid
• nitric acid nitric acid
• chlorinated hydrocarbon solvent such as chloroform, dichoroethane, or methylene chloride.
• This reaction is generally conducted at a temperature ranging from about -78°C to about O 0 C for about 2 hours, and then allowed to warm to room temperature for the remaining time.
• the amount of nitric acid used for this step may vary from about 1 to about 6 molar equivalents, per equivalent of the compound of Formula E. In a particular variant, the amount of nitric acid used for this step may vary from about 2 to about 3 molar equivalents, per equivalent of the compound of Formula E. In another variant, the amount of nitric acid used for this step may vary from about 3 to about 6 molar equivalents, per equivalent of the compound of Formula E.
• the amount of trifluoromethanesulfonic acid (CF 3 SO 2 OH) used for this step may vary from about 1 to about 6 molar equivalents , per equivalent of the compound of Formula E.
• the amount trifluoromethanesulfonic acid used for this step may be about 4 or more molar equivalents, per equivalent of the compound of Formula E. In another variant, the amount trifluoromethanesulfonic acid used for this step may vary from about 1 to about 4 molar equivalents, per equivalent of the compound of Formula E.
• the reaction may also be carried out using sulfuric acid instead of trifluoromethanesulfonic acid.
• Reduction of the compound of Formula F using methods well known to those of skill in the art, yields the compound of Formula G. This reduction may be accomplished, for example, using hydrogen and a palladium catalyst such as palladium hydroxide in methanol at about room temperature.
• this reduction of the compound of Formula F may be accomplished using Raney nickel, which is inexpensive and easy to handle in commercial production quantities.
• the process includes contacting the compound of Formula E with Raney nickel in a suitable solvent with hydrogen.
• suitable solvents that may be used for this reduction include, but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol and n-propanol; halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform and carbon tetrachloride; ketone solvents such as acetone, ethyl methyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate; ether solvents such as diethyl ether, dimethyl ether, diisopropyl ether, methyl
• the reaction may be carried out in an autoclave vessel.
• the compound of Formula F, Raney nickel and an organic solvent may be mixed together and stirred under hydrogen pressure until the reaction is complete.
• the reaction time typically varies from about 5 hours to 20 hours.
• the reaction may be conducted at higher temperatures to enhance progress of the reaction as may be determined by person skilled in the art.
• the product may be isolated by conventional techniques known in the art.
• the obtained product of Formula G may be subjected to cyclization to obtain the compound of Formula H.
• the cyclization may be accomplished by following the processes described in the literature, using reagents such as 2,3- dihydroxy-1 ,4-dioxane, glyoxal or glyoxal sodium bisulfite hydrate.
• the compound of Formula H obtained according to the process described herein may have a nitrogen-protecting group, which may be removed by suitable reagents depending upon the nature of the protecting group to obtain varenicline.
• Deprotection may be accomplished using methods well known to those of skilled in the art, for example, reacting the protected compound with a lower alkanol and an aqueous alkali metal, alkaline earth metal, or ammonium hydroxide or carbonate, such as aqueous sodium carbonate, at a temperature from about 50 0 C to about 100 0 C, such as at about 70°C, for about two to about six hours.
• the varenicline free base thus obtained may be converted in to varenicline tartrate by a process such as: i) providing a solution of varenicline free base in an organic solvent; ii) treating the solution with between about 1 and about 5 equivalents of L-tartaric acid, per equivalent of varenicline, to cause precipitation of a solid; and iii) collecting the precipitating solid, which is varenicline tartrate.
• Providing a solution of varenicline tartrate in a suitable solvent includes either of:
• the amount L-tartaric acid used for the preparation of varenicline tartrate may vary from about 1 to 2.3 molar equivalents, per equivalent of varenicline free base. In another variant, the amount L-tartaric acid used for the preparation varenicline tartrate may vary from about 2.3 to about 5 molar equivalents, per equivalent of varenicline free base.
• the solvents that may be used in this process include: Ci-C ⁇ alkyl alcohols such as methanol and ethanol; Ci -C ⁇ alkyl ketones such as acetone, methyl ethyl ketone; CrC 6 alkyl ethers such as diethyl ether, methyl ethyl ether, and diisopropyl ether; nitriles such as acetonitrile; Ci -C 6 alkyl esters such as ethyl acetate and isopropyl acetate; etc.
• the intermediates of varenicline tartrate obtained may be converted into acid-addition salts by reacting with a pharmaceutically acceptable acid.
• a pharmaceutically acceptable acid examples include: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.
• the conversion of a intermediate into its salt increases the stability of the compound and hence these salts may be stored for an extended time depending on their stability after their manufacture.
• the intermediates of varenicline tartrate that are obtained may have sufficient purity which may be used in the subsequent step without further purification.
• the intermediates may be purified by any of the general techniques such as recrystallization, crystallization, slurry washing, distillation, column chromatography, etc., to produce substantially pure intermediates having greater than about 90%, or greater than about 95%, or greater than about 98%, by weight purity, such as can be determined using high performance liquid chromatography (HPLC).
• HPLC high performance liquid chromatography
• Amorphous varenicline tartrate, or solid dispersions of amorphous varenicline tartrate or crystalline varenicline tartrate, of the present application may contain less than about 0.5% by weight of total impurities, as determined by HPLC. In another embodiment, the total impurities are less than about 0.2%, or less than about 0.1 %, or less than about 0.05%, by weight.
• compositions that include a therapeutically effective amount of an amorphous form of varenicline tartrate or a solid dispersion of amorphous varenicline tartrate, and at least one pharmaceutically acceptable excipient.
• Amorphous varenicline tartrate, or a solid dispersion of amorphous varenicline tartrate or crystalline varenicline tartrate, described herein may be formulated into solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, pills and capsules, liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions, and injectable preparations such as but not limited to solutions, dispersions, and freeze-dried compositions.
• Formulations may be in the form of immediate release, delayed release or modified release.
• immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combinations of matrix and reservoir systems.
• the compositions may be prepared using techniques such as direct blending, dry granulation or wet granulation, or by extrusion and spheronization.
• Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.
• Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
• the active product according to the invention is mixed with one or more pharmaceutically acceptable excipients.
• the drug substance may be formulated as liquid compositions for oral administration including for example solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin etc.
• compositions for parenteral administration may be suspensions, emulsions, aqueous or non-aqueous sterile solutions.
• a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g., ethyl oleate, may be employed.
• These compositions may contain adjuvants, especially wetting, emulsifying and dispersing agents.
• Sterilization may be carried out in several ways, e.g., using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which may be dissolved at the time of use in sterile water or any other sterile injectable medium.
• compositions that find use in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, thcalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxides, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxides, and the like; solubility or wetting enhancers such as
• EXAMPLE 1 1 A: Preparation of 1 ,2,3,4-tetra hvdro-1 ,4-methanonaphthalene-2,3-diol. 1 ,4-Dihydro-1 ,4-methanonaphthalene (100 g), acetone (1006 ml_), water
• the reaction mass was stirred for 10 minutes and filtered through a Hyflow (flux- calcined diatomaceous earth) bed.
• the aqueous and organic layers were separated and the aqueous layer was extracted with t-butyl methyl ether (100 ml_).
• the organic layers were combined and distilled under vacuum at 40 0 C to obtain a residue.
• Petroleum ether (10 ml_) was added to the residue at 28°C, stirred for 25 minutes and filtered to obtain the product (yield, 0.5 g).
• EXAMPLE 2 2A Preparation of 10-benzyl-10-aza-tricvclor6.3.1.0 2 ' 7 1dodeca-2(7), 3,5-triene hydrochloride.
• the obtained residue was dissolved in dichloromethane (75 ml_) and combined with silica gel (10 g), then solvent was evaporated under vacuum followed by drying the solid at 40-45 0 C for 15 minutes.
• the product was purified by column chromatography through silica gel by eluting with a mixture of ethyl acetate and petroleum ether (4:96 by volume). The pure drug fractions were combined, the solvent was distilled under vacuum, and the drug compound in the obtained residue was dissolved in ethyl acetate.
• Thfluoroacetic anhydride (20.3 mL) was added slowly to the reaction mass at 3 0 C. The reaction mass was stirred at 3-5 0 C for 3 hours. 0.5 N HCI solution (100 mL) was added to the reaction mass slowly and the layers were separated. The aqueous layer was extracted with dichloromethane (3*50 mL). The organic layers were combined and washed with HCI (0.5 N, 50 mL), water (2*75 mL) and aqueous sodium bicarbonate (75 mL). The solvent was distilled completely under vacuum below 40 0 C to obtain the product (yield, 21 g).
• EXAMPLE 5 5A Preparation of 1 -(4,5-dinitro-10-aza-tricvclor6.3.1.0 2 ' 7 1dodeca-2(7),3,5-trien-4- yl)-2,2,2-trifluoroethanone.
• Thfluoromethanesulphonic acid 49.6 mL
• dichloromethane (221 mL) were placed into a flask at 28°C and cooled to 5 0 C.
• Fuming nitric acid (12.4 mL) was added at the same temperature and maintained for 30 minutes at 4-5°C.
• a solution of 1 -(10-Azatricyclo[6.3.1.0 2 7 ]dodeca-2(7),3,5-trien-10-yl)-2,2,2- trifluoroethanone 31 g
• dichloromethane 217 mL
• the reaction mixture was stirred at 4-7 0 C for 2 hours.
• the temperature of the reaction mass was raised to 25 0 C and stirred for about 1 hour at 25-28 0 C.
• Water (700 mL) was added to the reaction mixture and the layers were separated.
• the aqueous layer was extracted with dichloromethane (280 mL).
• the organic layers were combined and washed with water (2*700 mL).
• the solvent was distilled from the organic layer under vacuum below 45°C.
• Acetone (140 mL) and n-hexane (280 mL) were added to the residue at 28°C and stirred for about 25 minutes at 0-5 0 C.
• EXAMPLE 6 6A Preparation of 1 -(4.5-Diamino-1 Q-aza-thcvclor6.3.1.0 2 ' 7 1dodeca-2(7),3,5-trien- 4-yl)-2,2,2-trifluoroethanone.
• Varenicline free base (10 g) and methanol (75 mL) were placed into a flask at 27°C and stirred for 5 minutes for complete dissolution.
• a solution of L-tartahc acid (8.0 g) in methanol (75 ml_) was added into the above reaction mass slowly over 30 minutes at 27°C.
• the reaction mixture was stirred at 28 0 C for 1 hour, 45 minutes.
• the precipitated solid was collected by filtration and washed with methanol (10 ml_) and then dried at 45°C for 3 hours (yield, 13 g).
• Varenicline free base (70 g) and methanol (400 ml_) were placed into a flask at 28°C and stirred for 10 minutes for complete dissolution, and carbon (14 g) was added. The mixture was stirred for about 30 minutes and filtered, and the bed was washed with methanol (70 ml_). To the filtrate, a solution of L-tartahc acid (55 g) in methanol (350 ml_) was added slowly over 45 minutes at 28-33°C. The mixture was stirred at 28 0 C for about 1 hour, 15 minutes. The precipitated solid was isolated by filtration and washed with methanol (210 ml_) and then dried at 60-63 0 C for about 7 hours (yield, 105 g).
• EXAMPLE 10 10A Preparation of amorphous varenicline tartrate.
• Varenicline tartrate (1 g) and water (5 ml_) were placed into a flask and stirred at 25°C for 10 minutes. Water (5 ml_) was added and stirred for 15 minutes for complete dissolution. The solution was then subjected to freeze-drying at - 10 0 C for 5 hours, followed by further drying at 60 0 C for about 4 hours (yield, 1 g).
• Varenicline tartrate (0.514 g) and water (10 ml_) were charged into a beaker and stirred for 10 minutes at 28°C for dissolution.
• the solution was spray dried in a Mini Buchi spray dryer under the conditions: feed rate, 3 mL/minute; aspirator 70%; inlet temperature 122°C; outlet temperature 71 0 C; and nitrogen pressure 6.5 Kg/cm 2 ; to produce 0.062 g of amorphous varenicline tartrate.
• Varenicline tartrate (1 g), methanol (50 ml_) and water (8 ml_) were charged into a beaker and stirred for 10 minutes at 28°C for dissolution.
• the solution was filtered and the filtrate was spray dried in a Mini Buchi spray dryer under the conditions: feed rate, 3 mL/minute; aspirator 70%; inlet temperature 122°C; outlet temperature 73°C; and nitrogen pressure 6.5Kg/cm 2 ; to produce 0.302 g of amorphous varenicline tartrate.
• EXAMPLE 1 1 Preparation of amorphous solid dispersion of varenicline tartrate with hydroxypropyl cellulose (HPC).
• Varenicline tartrate (3.0 g) and hydroxypropyl cellulose (3.0 g) were charged into a flask at 28°C and then 16% aqueous methanol (193.2 ml_ of methanol and 36.8 ml_ of water) was charged.
• the mixture was heated to 60 0 C to produce a solution, the solution was filtered, and the filtrate was spray dried using a Mini Buchi spray dryer under the conditions: feed rate 10% (3 mL/minute); aspirator 70%; inlet temperature 80 0 C; outlet temperature 55°C; and nitrogen pressure 5.0-kg/cm 2 ; to produce 2.8 g of an amorphous solid dispersion of varenicline tartrate with HPC.
• the product obtained was found to be stable for at least 20 days at room temperature, and for at least 35 days at 0-5 0 C, when stored in a double polyethylene container.
• EXAMPLE 12 Preparation of amorphous solid dispersion of varenicline tartrate with hvdroxypropyl methylcellulose (HPMC). Varenicline tartrate (4.0 g) and HPMC (4.0 g) were charged into a flask at
• aqueous methanol containing 168 mL of methanol and 32 mL of water
• the mixture was heated to 60°C to produce a solution.
• the solution was filtered and the filtrate was spray dried using a Mini Buchi spray dryer under the conditions: feed rate 20% (6 mL/minute); aspirator 70%; inlet temperature 80 0 C; outlet temperature 46°C; and nitrogen pressure 5.0 Kg/cm 2 ; to produce 5.24 g of an amorphous solid dispersion of varenicline tartrate with HPMC.
• the product obtained was found to be stable for at least 10 days at 0-5°C, when stored in a double polyethylene container.
• EXAMPLE 13 Preparation of amorphous solid dispersion of varenicline tartrate with povidone (PVP).
• Varenicline tartrate (4.0 g) and povidone K-30 (4.0 g) were charged into a flask at 28°C and then 16% aqueous methanol (containing 168 mL of methanol and 32 ml_ of water) was charged. The mixture was heated to 60 0 C to produce a solution. The solution was filtered and the filtrate was spray dried using a Mini Buchi spray dryer under the conditions: feed rate 20% (6 mL/minute); aspirator 70%; inlet temperature 80 0 C; outlet temperature 46°C; and nitrogen pressure 5.0 Kg/cm 2 ; to produce 4.8 g of an amorphous solid dispersion of varenicline tartrate with PVP.
• the product obtained was found to be stable for at least 50 days at room temperature, and at least 111 days at 0-5 0 C, when packaged under a nitrogen atmosphere.

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