WO2010091169A2 - Preparation of valsartan - Google Patents

Abstract

Processes for preparing valsartan and essentially amorphous valsartan are described.

Description

PREPARATION OF VALSARTAN

INTRODUCTION

In its various aspects, the present invention relates to the preparation of valsartan. In particular aspects, the present invention relates to a process for the preparation of valsartan, valsartan alkali or alkaline earth metal salts, and amorphous valsartan.

Valsartan has the chemical names: (S)-N-(I -carboxy-2-methyl prop-1 -yl)-N- pentanoyl-N-[2'-1 H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine; or /V-(i -oxopentyl)- Λ/-[[2'-(1 H-tetrazol-5-yl) [1 ,1 '-biphenyl]-4-yl]methyl]-L-valine; and is structurally represented by Formula I.

I

Valsartan is a non-peptide, orally active, specific angiotensin Il antagonist, acting on the AT1 receptor subtype.

U.S. Patent No. 5,399,578 and its equivalent European Patent No. 0443983 B1 disclose valsartan, its pharmaceutically acceptable salts, pharmaceutical compositions comprising valsartan, and their use in treating high blood pressure and cardiac insufficiency. They also disclose a process for the preparation of valsartan.

Alternative processes for the preparation of valsartan and its intermediates have been described in various patents and applications.

Although many processes have been described for the preparation of valsartan and its intermediates, there remains a need for processes that are simple, efficient, cost effective, industrially feasible, and robust for preparing valsartan and its intermediates in high yield and purity. SUMMARY

Aspects of the present invention provide processes for the preparation of valsartan and its salts with a reduced number of synthetic steps, eliminating the need to isolate certain intermediates. The processes of the present invention may be practiced on an industrial scale, and also may be carried out without sacrifice of overall yield.

In an aspect, the present invention provides processes for the preparation of valsartan, or an alkaline or alkaline earth metal salt thereof, embodiments comprising: (a) reacting N-[2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride with valeryl chloride to give N-[2'-cyanobiphenyl-4-yl)methyl]-N- valeryl-(L)-valine methyl ester, which is not isolated;

(b) reacting N-[2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester with a thalkyl tin halide and sodium azide to give trialkyl tin-protected valsartan methyl ester, which is not isolated;

(c) hydrolyzing trialkyl tin-protected valsartan methyl ester to give valsartan, which is optionally isolated;

(d) converting valsartan to an alkaline or alkaline earth metal salt thereof; and (e) optionally, converting a valsartan alkaline or alkaline earth metal salt to valsartan.

In an aspect, the present invention provides processes for recovering trialkyl tin halide from a reaction mass obtained after a hydrolysis reaction, and use of the recovered trialkyl tin halide in a fresh reaction. In an aspect, the present invention provides processes for the preparation of amorphous valsartan, comprising:

(a) providing a solution of valsartan in a solvent;

(b) removing the solvent from the solution, to provide valsartan as a solid; and (c) optionally, drying the solid valsartan.

In an aspect, the present invention provides processes for the preparation of amorphous valsartan, comprising: a) providing a solution of valsartan in a solvent; b) combining an anti-solvent with the solution of a); c) isolating amorphous valsartan; and d) drying the amorphous valsartan, using a fluidized bed dryer. The present invention also includes pharmaceutical compositions comprising valsartan prepared according to a process of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a powder X-ray powder diffraction (PXRD) pattern of amorphous valsartan prepared in accordance with a process of the present invention.

Fig. 2 is a differential scanning calohmetry (DSC) curve of amorphous valsartan prepared in accordance with a process of the present invention.

DETAILED DESCRIPTION All percentages and ratios used herein are by weight and all measurements made are at about 25°C and about normal pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range "between" two values. The terms "about," "generally," "substantially," and the like are to be construed as modifying another term or value such that it is not an absolute, as defined by the circumstances and context as understood by those having skill in the art. This includes, at very least, the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value. Whether so indicated or not, all values recited herein are approximate.

This document may refer to a material, such as in this instance, valsartan and its salts, crystalline forms, solvates, or optical isomers by reference to patterns, spectra, or other graphical data "substantially" as shown in a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra, and other graphical data can be shifted in their positions, relative intensities, and/or values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X ray diffraction arts, such shifts in peak positions or the relative intensities of one or more peaks can occur because of, without limitation, the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, and the like. However, those of ordinary skill in the art will be able to compare the figures herein with a pattern generated of an unknown form of, in this case, valsartan, and confirm its identity as one of the forms disclosed and claimed herein. The same holds true for other techniques that may be reported herein.

In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure that uniquely define that crystalline form, salt, solvate, and/or optical isomer, within any associated and recited margin of error, for purposes of identification.

The PXRD data reported herein are obtained using copper Ka radiation, and are obtained using a Bruker AXS D8 Advance powder X-ray diffractometer.

DSC studies reported herein are carried out using a TA Instruments Q1000 differential scanning calorimeter. The thermogram is recorded from 40 to 200⁰C under a nitrogen flow of 50 mL/minute at a heating rate of 10°C/minute.

An aspect of the present invention provides processes for the preparation of valsartan, or alkaline or alkaline earth metal salts thereof, comprising:

(a) reacting N-[2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride with valeryl chloride, to give N-[2'-cyanobiphenyl-4-yl)methyl]-N- valeryl-(L)-valine methyl ester, which is not isolated;

(b) reacting N-[2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester with a thalkyl tin halide and sodium azide, to give trialkyl tin-protected valsartan methyl ester, which is not isolated;

(c) hydrolyzing trialkyl tin-protected valsartan methyl ester, to give valsartan, which is optionally isolated;

(d) converting valsartan to an alkaline or alkaline earth metal salt thereof; and (e) optionally, converting the valsartan alkaline or alkaline earth metal salt to valsartan.

Step (a) involves reacting N-[2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride with valeryl chloride, to give N-[2'-cyanobiphenyl-4- yl)methyl]-N-valeryl-(L)-valine methyl ester, which is not isolated.

Suitable solvents that may be used for the reaction in step (a) include, but are not limited to: hydrocarbons, such as, for example, toluene, xylene, and the like; esters, such as, for example, ethyl acetate, n-propyl acetate, isopropyl acetate, and the like; aprotic polar solvents, such as, for example, N₁N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide, and the like; halogenated solvents, such as, for example, dichloromethane, chloroform, and the like; water; and any mixtures thereof in various proportions.

Suitable bases which may be used for the reaction in step (a) include, but are not limited to: inorganic bases, such as, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, and the like, such as, for example, in a molar ratio of from about 0.5 to about 5 moles per mole of N-[2'-cyanobiphenyl-4- yl)methyl]-(L)-valine methyl ester hydrochloride; and organic bases, such as, for example, unsubstituted and substituted primary, secondary, and tertiary amines, and substituted amines.

The mole ratios of valeryl chloride may range form about 1 to about 5 moles, per mole of N-[2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride.

Suitable temperatures for step (a) may range from about 0⁰C to about 100⁰C, or from about 20⁰C to about 50°C.

Significantly, the product formed in the reaction of step (a) may remain in the organic layer and be used in a succeeding step as is, without the need for isolation.

Step (b) involves reacting N-[2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)- valine methyl ester with trialkyl tin halide and sodium azide, to give trialkyl tin- protected valsartan methyl ester, which is not isolated. The trialkyl tin chloride in step (b) may comprise a tri Ci_is alkyl tin chloride, such as, for example, trimethyl tin chloride, tributyl tin chloride, and trioctyl tin chloride.

Suitable temperatures for step (b) may range from about 50⁰C to about 250⁰C, or from about 100-150°C, for times about 10 to 50 hours. Shorter or longer times can also result in reaction completion. Suitable organic solvents for step (b) include, but are not limited to: aromatic hydrocarbons, such as, for example, toluene, o-xylene, and the like; high boiling polar aprotic solvents, such as, for example, dioxane, DMF, DMSO, and the like; water; and any mixtures thereof.

Significantly, the product formed in the reaction of step (b) may remain in the organic layer and be used in a succeeding step as is, without the need for isolation.

Step (c) involves hydrolyzing trialkyl tin-protected valsartan methyl ester to give valsartan, which is optionally isolated.

Suitable bases that may be used for hydrolysis in step (c) include, but are not limited to: alkaline metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, and the like; carbonates of alkali metals, such as, for example, sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals, such as, for example, sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and any mixtures thereof. These bases may be used in solid or aqueous solution forms.

If used, an aqueous solution may comprise about 5% to 50%, or about 10% to 20% (w/v) of the base. Hydrolysis of the ester may be carried out in a biphasic media, such as a hydrocarbon solvent and water. The resulting valsartan may be isolated from the aqueous layer by separating the aqueous layer and acidifying it to precipitate valsartan, and subsequently extracting the precipitated valsartan into a suitable organic solvent. For example, the aqueous layer may be acidified to pH values about 0.5 to

5.5, or about 2, by techniques known in the art. Suitable acids for acidification of the aqueous layer include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, and the like.

Suitable organic solvents for extracting the precipitated valsartan from the acidified aqueous layer include, but are not limited to: hydrocarbon solvents like xylene, and toluene; halogenated solvents, including, for example, dichloromethane, chloroform, ethylene dichlohde, carbon tetrachloride, and the like; esters, such as, for example, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate; and any mixtures thereof. In embodiments, acidification is carried out in an aqueous medium and the product is isolated and filtered. The valsartan isolated after acidification from an aqueous medium can be in substantially anhydrous form, enbodiments having a moisture content less than about 1 %.

The valsartan extracted according to step (c) may remain in the organic solvent and be used in a succeeding step as such, without the need for isolation.

Step d) involves converting valsartan obtained in step (c) to its alkali or alkaline earth metal salt.

Conversion of valsartan to its alkali or alkali earth metal salt may be achieved by reacting valsartan with a suitable alkaline or alkaline earth metal salt in a suitable solvent.

Suitable alkaline or alkaline earth metal salts which may be used include, but are not limited to: alkali or alkaline earth metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, and the like; and carbonates and bicarbonates of alkali or alkaline earth metals, such as, for example, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, and the like.

Suitably, the reaction is carried out in a biphasic medium containing water and an organic solvent. Suitable organic solvents include, but are not limited to: alcohols, such as, for example, esters, such as, for example, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate, and the like; and hydrocarbons, such as, for example, toluene, xylene, and the like. The alkaline or alkaline earth metal salt of valsartan may be isolated at temperatures ranging from about -10⁰C to 50⁰C, or from about 0°C to 10⁰C.

In embodiments, the alkaline earth metal salt may be a barium salt of valsartan, obtained by reacting valsartan with barium hydroxide. Isolation of the alkaline or alkaline earth metal salt may be carried out by methods such as, for example, cooling, complete or partial removal of the solvent from the mixture, combining an anti-solvent with the reaction mixture, or a combination thereof. The salt obtained may be further purified by recrystalization techniques known in the art. Step (e) involves optionally converting the valsartan alkaline or alkaline earth metal salt obtained in step (d) to valsartan.

The valsartan alkaline or alkaline earth metal salt may be converted to valsartan by reaction with a suitable acid.

Suitable acids that may be used include, but are not limited to: inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like; and organic acids, such as, for example, acetic acid, formic acid, and the like.

Suitable temperatures for step (e) may range from about 0°C to about 50°C, or from about 20⁰C to about 30°C. The reaction of step (e) may be conducted in the presence of a solvent.

Suitable solvents that may be used for conducting the reaction of step (e) include, but are not limited to: halogenated solvents, such as, for example, dichloromethane, chloroform, ethylene dichlohde, carbon tetrachloride, and the like; esters, such as, for example, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate, and the like; ketones, such as for example acetone, ethyl methyl ketone, and methyl isobutyl ketone; water; and any mixtures thereof.

An aspect of the present invention provides the recovery of a trialkyltin halide from a reaction mass obtained after a hydrolysis reaction, for re-use in a fresh reaction.

Trialkyl tin halide reacts with sodium azide to form trialkyl tin azide, which reacts with a nitrile to form a tetrazole ring. After a hydrolysis reaction and work up, such as in step (c) above, trialkyl tin hydroxide is left in the reaction mass as a by-product. The trialkyl tin hydroxide by-product may be recovered as a trialkyl tin halide and re-used in a fresh reaction by reacting it with a suitable acid halide.

Suitable acid halides that may be used for this purpose include, but are not limited to, hydrochloric acid, hydrobromic acid, and the like.

Suitable temperatures for the recovery reaction may range from about 0⁰C to about 50⁰C, or from about 10⁰C to about 50°C.

For example, the trialkyl tin halide used may be tributyl tin chloride and the acid used for converting tributyl tin hydroxide to tributyl tin chloride may be hydrochloric acid.

The recovered tributyl tin chloride may be used for at least about 5 to 10 cycles with or without addition of fresh tributyl tin chloride. The quality of valsartan obtained by using recovered tributyl tin chloride desirably meets ICH specifications. An aspect of the present invention provides processes for the preparation of amorphous valsartan, comprising:

(a) providing a solution of valsartan in a solvent;

(b) removing the solvent from the solution to provide valsartan as a solid; and (c) optionally, drying the solid valsartan.

Step (a) involves providing a solution of valsartan in a solvent. The solution of valsartan may be obtained by dissolving valsartan in a suitable solvent, or such a solution may be obtained directly from a reaction mixture in which valsartan is formed. When the solution is prepared by dissolving valsartan in a suitable solvent, any form of valsartan, such as, for example, any crystalline or amorphous form, including any solvates and hydrates, may be utilized.

Suitable solvents that may be used for dissolving valsartan include, but are not limited to: esters, such as, for example, methyl acetate, ethyl acetate, methyl tertiary-butyl acetate; alcohols, such as, for example, methanol, ethanol, isopropyl alcohol, n-propanol, and the like; ketones, such as, for example, acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; halogenated hydrocarbons, such as, for example, dichloromethane, chloroform, and the like; any mixtures thereof; and combinations thereof with water in various proportions.

Suitable temperatures for step (a) may range from about 20⁰C to 120⁰C, depending on the solvent used, as long as the stability of valsartan is not affected The quantities of solvent used for preparing the solution depend on the nature of the solvent and the temperature adopted for obtaining the solution. The concentration of valsartan in the solution may generally range from about 0.01 g/mL to about 10 g/mL.

The solution obtained may be optionally treated with activated charcoal to enhance the color of the compound, followed by filtration through a medium, such as, for example, a flux-calcined diatomaceous earth (HYFLO) bed, to remove the carbon.

The carbon treatment may be performed either at higher temperatures or at room temperature, or any temperature that is acceptable, as long as the valsartan remains in solution.

Step (b) involves removing the solvent from the solution to provide valsartan as a solid.

Solvent can be removed using an agitated thin film drying (ATFD) technique, which uses high vacuum along with elevated temperatures, allowing operation at relatively lower temperatures. This allows for a short residence time for the product in the dryer. The required evaporation may be achieved in a single pass, avoiding product recirculation and possible degradation. The operating pressures are from atmospheric down to 1 mbar. The equipment may be operated at a wide range of temperatures, such as, for example, 25-35⁰C or higher. The process is frequently carried out below atmospheric pressure, such as, for example, about 35°C to about 100⁰C, under a reduced pressure, such as, for example, about 0-50 torr. The temperature and pressure conditions may vary depending on properties of the solvent that is being removed, and may be higher or lower than the ranges mentioned. The solution of valsartan may be added drop-wise or continuously to the drying chamber. The rate of flow may range from 1 to 10 L/hour. The rate of addition and other parameters are well known to a person skilled in the art of drying using ATFD, and will vary depending upon characteristics of the actual apparatus being used.

ATFD helps in evaporating solvents by using heat transfer across the walls and prevents the growth of crystals and particles that may trap the solvent at higher levels. The resulting valsartan is amorphous and has a solvent content lower than the product obtained from other techniques of evaporation, such as, for example, rotary or spray drying.

The yields obtained using this technique are generally superior to those obtained using other techniques. Step c) involves optionally drying the solid valsartan to afford valsartan in amorphous form.

The material obtained from ATFD may be further dried to reduce residual solvent content in the material to be within ICH limits. The solvent level depends on the type of solvent, but is generally not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm, or about 1000 ppm.

The drying may be carried out at reduced pressures, such as, for example, below 200 torr or below 50 torr, at temperatures ranging from about 40⁰C to about 80⁰C. The drying may be carried out for any desired time periods, such as, for example, about 1 to 20 hours, or longer. An aspect of the present invention provides processes for preparing amorphous valsartan, comprising: a) providing a solution of valsartan in a solvent; b) combining the solution with an anti-solvent; c) isolating amorphous valsartan; and d) drying the amorphous valsartan, using a fluidized bed dryer.

Suitable solvents that may be used include, but are not limited to: alcohols, such as, for example, methanol, ethanol, isopropyl alcohol, and the like; ketones, such as, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like; esters such as, for example, ethyl acetate, isopropyl acetate, isobutyl acetate, propyl acetate and the like; halogenated hydrocarbons, such as, for example, dichloromethane, chloroform, and the like; and any mixtures thereof. Suitable anti-solvents that may be used include, but are not limited to: C₅_8 cyclic, linear and branched alkanes, such as, for example, n-pentane, n-hexane, n-heptane, cyclohexane, and the like; ethers such as for example, diisopropyl ether, diethyl ether, and the like; and water. The organic solvent for dissolution may be present in an amount of about

0.5 to about 5 volumes (ml_ per gram of valsartan), or from about 0.5 to about 2 volumes. Dissolution may be carried out at temperatures ranging from about 25°C to about 100⁰C, or from about 25°C to about 60⁰C, to facilitate complete dissolution of valsartan and produce higher solute concentrations. A larger initial volume of solvent may be used for dissolution, and then the initial volume reduced to a desired volume at higher temperatures and reduced pressures.

The solution may be combined with anti-solvent slowly over a period of time, such as about 30 minutes to about 4 hours. The anti-solvent may be present in an amount of about 5 to about 50 volumes (ml_ of antisolvent per gram of valsartan), to obtain a suspension. A solution can be added to an anti-solvent, or an anti-solvent can be added to a solution.

The ratio of the organic solvent to anti-solvent used can affect the efficiency of precipitation of the product. The ratios may range from about 1 :0.5 to about 1 :10 volumes of the solvent to the anti-solvent.

Optionally, the suspension is cooled to lower temperatures of about -10⁰C to about 25°C, to increase precipitation.

The methods by which the solid material is recovered from the final mixture, with or without cooling below the operating temperature, may be any suitable techniques, such as, for example, filtration by gravity or suction, decantation, centhfugation, and the like. If desired, the solid may be washed with a solvent to wash out the mother liquor.

Drying of the product may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer (FBD), spin flash dryer, flash dryer, and the like.

In embodiments, drying is carried out using a FBD, suitably in the presence of air or under a nitrogen atmosphere. Drying may be carried out using stepwise rises in temperature with appropriate holding times chosen at each temperature, for example 35°C to 4O⁰C for 1 to 4 hours, 45°C to 5O⁰C for 1 to 4 hours, 50⁰C to 65⁰C for 1 to 4 hours, 60⁰C to 65⁰C for 1 to 4 hours, and 70°C to 75⁰C for 1 to 4 hours. Other temperature profiles may also be used.

The dried product may optionally be milled to get a desired particle size distribution. Milling or micronization may be performed prior to drying, intermittently during drying or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high speeds.

Milling may be performed prior to the drying operation, because drying is more efficient when the particle size of the material is smaller and the surface area is higher.

Milling may be done suitably using jet milling equipment, such as, for example, an air jet miller, or using other conventional milling equipment, at pressures from about 2 to 10 Kg/cm².

In embodiments, the valsartan produced from the processes of the present invention is essentially amorphous valsartan characterized by a PXRD pattern substantially as shown in Fig. 1 , and/or by a DSC pattern substantially as shown in Fig. 2.

As described in U.S. Patent No. 7,105,557, in column 12, "essentially amorphous" valsartan relates to amorphous material containing substantial amounts of crystalline material. The percentage of crystalline material in an essentially amorphous valsartan may range from about 1 % to about 30%, or from about 1 % to about 5%.

Valsartan, or a salt thereof, when prepared according to processes of the present invention, may have chemical purities greater than about 95%, or greater than about 98%, or greater than about 99%, or greater than about 99.5%, or greater than about 99.7%, and may contain less than about 1 %, or less than about 0.5%, or less than about 0.1 % by weight of corresponding impurities, such as, for example, the D-isomer, the isoleucine impurity, and other process related impurities, as determined using high performance liquid chromatography (HPLC). Valsartan or a salt thereof, when prepared according to the processes of the present invention, contains less than about 100 ppm, or less than about 50 ppm, or less than about 10 ppm, of tin and azide derivatives.

Amorphous valsartan, when obtained by the processes of the present invention, may contain less than about 5000 ppm, or less than about 3000 ppm, or less than about 1000 ppm of ethyl acetate, and less than about 200 ppm, or less than about 100 ppm of other individual residual organic solvents.

Amorphous valsartan, when obtained by the processes of the present invention, may have the particle size distribution values: Di₀ less than about 10 μm, or less than about 5 μm; D₅₀ less than about 50 μm, or less than about 40 μm; and D₉₀ less than about 300 μm, or less than about 200 μm. These "D" values are maximum sizes for the specific fractions of particles, e.g., respectively 10, 50, or 90 percent of particles in a sample.

In a further aspect, the present invention includes pharmaceutical compositions comprising valsartan or its pharmaceutically acceptable salts produced according to the processes of the present invention, together with at least one pharmaceutically acceptable excipient.

The pharmaceutical compositions of the present invention may be formulated as solid oral dosage forms, such as, for example, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms, such as, for example, syrups, suspensions, dispersions, and emulsions; and injectable preparations, such as, for example, solutions, dispersions, and freeze dried compositions. The formulations may be immediate release, delayed release, or modified release formulations. Immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations. Modified release compositions may comprise hydrophilic and/or hydrophobic release rate controlling substances to form matrix and/or reservoir systems. The compositions may be prepared by direct blending, dry granulation, wet granulation, extrusion, spheronization, and the like. The compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Pharmaceutically acceptable excipients that are useful in the present invention include, but are not limited to, diluents, such as, for example, starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, thcalcium phosphate, mannitol, sorbitol, sugar, and the like; binders, such as, for example, acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants, such as, for example, starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants, such as, for example, stearic acid, magnesium stearate, zinc stearate, and the like; glidants, such as, for example, colloidal silicon dioxide, and the like; solubility or wetting enhancers, such as, for example, anionic or cationic or neutral surfactants; complex forming agents, such as, for example, various grades of cyclodexthns; resins; release rate controlling agents, such as, for example, hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like. In the compositions of present invention, valsartan or its pharmaceutically acceptable salts is a useful active ingredient in the range of about 40 mg to 120 mg, or about 40 mg to 320 mg, per dosage unit.

Certain specific aspects and embodiments of this invention are described in further detail by the examples below, being provided only for purposes of illustration and not intended to limit the scope of the appended claims in any manner.

EXAMPLE 1 : PREPARATION OF VALSARTAN BARIUM SALT.

Water (450 L) was placed into a reactor and sodium carbonate (44 Kg) was added. The mixture was stirred for about 25 minutes. o-Xylene (450 L) was added, followed by addition of N-[2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride (150 Kg). The mixture was stirred at 25 to 35⁰C for about 60 minutes. The mixture was allowed to settle and the aqueous layer was separated. Another 44.4 Kg of sodium carbonate was added to the organic layer with stirring for about 20 minutes at 25 to 35⁰C. Valeryl chloride (90.0 Kg) was slowly added in three equal portions at the same temperature. After completion of addition of each portion, the mixture was maintained for about 3 hours. Reaction completion was determined using thin layer chromatography. After the completion of the reaction, water (150 L) was added and the mixture was stirred for about 30 minutes. The aqueous layer was separated and a solution of water (338 L) and HCI (38 L) was added to the organic layer with stirring for about 30 minutes. The organic layer was again separated and washed with water (300 L).

To the organic layer, o-xylene (450 L) was added followed by addition of tributyl tin chloride (340 Kg). The mass was stirred for about 30 minutes, followed by addition of sodium azide (67.8 Kg). The mass was stirred for about 30 minutes and then heated to about 145⁰C and maintained for 16 hours. Reaction completion was determined using thin layer chromatography and, after the reaction completed, the mass was allowed to cool to 30⁰C and was filtered. The filter cake was washed with o-xylene (120 L). The combined filtrate was added to a pre-cooled solution of sodium hydroxide (100.5 Kg) in water (780 L) and maintained for 18 hours at 10-15⁰C. Reaction completion was determined using TLC and, after the reaction completed, the mass temperature was raised to about 3O⁰C. The aqueous layer was separated and washed with o-xylene (450 L) in two equal portions. The combined organic layer was set aside for recovery of tributyl tin chloride.

The aqueous layer was placed into a reactor, dichloromethane (600 L) was added, and the pH of the mixture was adjusted to about 6.5 to about 7 using a solution of HCI (150 L) in water (150 L). The organic layer was separated and the aqueous layer was washed with dichloromethane (750 L) in two portions. Ethylenediaminetetraacetic acid disodium (12 Kg) was then added and stirred for about 30 minutes. Carbon and Hyflow (flux-calcined diatomaceous earth) was added, then the mixture was stirred for about 30 minutes and filtered. The filter cake was washed with water (75 L) cooled to 0-5⁰C. To the combined aqueous layer, ethyl acetate (450 L) was added and the pH was adjusted to about 3 with a solution of HCI (120 L) in water (120 L). The aqueous layer was separated and extracted with ethyl acetate (450 L). To the combined organic layer was added a solution of ethylenediaminetetraacetic acid disodium (3.0 Kg) in water (150 L), and the mixture was stirred at about 3O⁰C for about 45 minutes. Carbon and Hyflow were added, then the mixture was filtered and the solid washed with ethyl acetate (75 L). The pH of the filtrate was adjusted to 3 to 4 using a solution of HCI (4 L) in water (12 L). To the filtrate, a solution of sodium chloride (22.5 Kg) in water (150 L) was added. The organic layer was separated and water (900 L) was added to it, followed by addition of barium hydroxide (165 Kg). The mixture was stirred for about 2 hours and then filtered. The filter cake was washed with ethyl acetate (150 L) in two equal portions. The wet solid was dried in a cone vacuum drier at a pressure of about 620 mm Hg at about 75⁰C for 8 hours. The material was milled and again dried at about 75⁰C for about 10 hours, to yield 183 Kg of the title material with a purity by HPLC of about 99.6%.

EXAMPLE 2: PREPARATION OF VALSARTAN FROM VALSARTAN BARIUM SALT. Ethyl acetate (500 L) was placed into a reactor. Water (600 L) and valsartan barium salt (125 Kg) from Example 1 were added and the mixture was stirred for about 30 minutes. The pH of the mixture was adjusted to 2.5 to 3.5 using a solution of HCI (50 L) and water (50 L). The mass was stirred for 30 to 45 minutes. The aqueous layer was separated and extracted with ethyl acetate (125 L). The combined organic layer was filtered and the filter bed was washed with ethyl acetate (125 L). The combined filtrate was distilled at about 45⁰C and a vacuum of at least 625 mm Hg. Fresh ethyl acetate (625 L) was added to the distillation residue and the mixture cooled to about 25⁰C under stirring. Heptane (1880 L) was added slowly to the mass, and the mixture was maintained at the same temperature for about 2 hours. The mixture was centrifuged under vacuum, and the centrifuge cake was washed with heptane (15 L) to yield 132.4 Kg of wet valsartan. EXAMPLE 3: DRYING OF WET VALSARTAN.

The wet valsartan from Example 2 was de-lumped and loaded into a fluidized bed drier (FBD) bowl at an inlet air temperature of about 35⁰C and dried for about 3 hours. The dried material was unloaded and placed into a polyethylene bag. The dried material was milled through a 1 mm mesh screen, and again loaded into the FBD bowl. The inlet temperature of the FBD was raised to about 65⁰C and the material was dried for about 4 hours. The dried material was then milled in a jet mill at a mill pressure of about 2.5 Kg/cm² and a feed pressure of about 1.5 Kg/cm². The milled material was again dried in a FBD at about 65⁰C for 10 hours. The dried material was passed through a No. 20 mesh sieve to yield 72.89 Kg of the title compound, which was packed in a HDPE drum. Purity by HPLC: 99.91 %.

EXAMPLE 4: RECOVERY OF TRIBUTYL TIN CHLORIDE. The organic layer from Example 1 (after the hydrolysis reaction) was placed into a reactor and stirred for about 15 minutes. 50% of the organic layer was distilled at about 85⁰C and under a vacuum of about 600 mm Hg. The distillation residue was washed with a solution of HCI (1 L) in water (100 L) in two equal portions, followed by washing with water (100 L) in two equal portions. Water (490 L) was added to the washed residue, followed by addition of a solution of HCI (124 L) and water (124 L), and stirring for about 2 hours. The organic layer was separated, and the aqueous layer was extracted with o-xylene (100 L). The combined organic layer was washed with water (520 L) in two equal portions, to yield 650 liters of the title compound.

EXAMPLE 5: PREPARATION OF VALSARTAN USING RECOVERED TRIBUTYL

TIN CHLORIDE.

The o-xylene layer obtained after the hydrolysis reaction using a process similar to that described in Example 1 was placed into a round bottom flask. A solution of cone, hydrochloric acid (100 mL) in water (500 mL) was added, and the mixture was stirred for about 30 minutes. The organic layer containing recovered tributyl tin chloride was separated and sodium azide (10 g) was added. N-[(2- cyanobiphenyl-4-yl)-methyl]-N-valeryl-(L)-valine methyl ester (88 mL, equivalent to 25 g) was added and heated to reflux. The mass was maintained under reflux for about 15 hours, and reaction progress was monitored by thin layer chromatography until completion. The mass was then allowed to cool to 25-35°C and filtered. The filter cake was washed with o-xylene (50 mL), and the combined filtrate was placed into a round bottom flask. A solution of sodium hydroxide (15 g in 150 mL of water) was slowly added to the organic layer, and the mixture was maintained at the same temperature for about 24 hours. Reaction completion was determined using thin layer chromatography and, after completion of the reaction, the layers were separated. The aqueous layer was cooled to 0-5⁰C. The pH of the aqueous layer was adjusted to 2-3 with 20% aqueous HCI, and maintained at the same temperature for about 30 minutes. The formed solid was filtered under vacuum and dried under suction. The wet solid was dried at 50-60⁰C for about 6 hours, to yield 24.5 g of the title compound. Purity by HPLC: 97.1 %.

Chiral purity: 96.9%.

EXAMPLE 6: PREPARATION OF VALSARTAN BARIUM SALT.

Valsartan (10 g), ethanol (17.5 mL), and water (17.5 mL) were placed into a round bottom flask and stirred. Barium hydroxide (8.8 g) was added. The mixture was heated to 40-50°C and maintained for about 1 hour. The mass was then cooled to 25-35°C and filtered. The filter bed was washed with ethanol (10 mL) followed by water (10 mL). Another 20 mL of water was added to the filtrate, which was then cooled to 0-5⁰C. 60 mL of acetone was added and the mixture was maintained at 0-5°C for about 10 hours. The formed solid was filtered and washed with acetone (10 mL). The wet solid was dried at 50-60⁰C for about 8 hours, to yield 6.8 g of the title compound. Purity by HPLC: 99.7% Chiral purity: 99.9% EXAMPLE 7: PREPARATION OF VALSARTAN BARIUM SALT.

Valsartan (5 g) and acetone (30 mL) were placed into a round bottom flask and stirred. Water (30 mL) was added, followed by barium hydroxide (3.6 g). The mixture was maintained for about 1 hour, and then filtered. The filtrate was cooled to 0-5⁰C and was maintained at 0-5⁰C for about 3 hours, then the formed solid was filtered and washed with acetone (5 mL). The wet solid was dried at 50-60°C for about 8 hours, to yield 4.0 g of the title compound. Purity by HPLC: 99.6%. Chiral purity: 99.9%.

EXAMPLE 8: PREPARATION OF VALSARTAN BARIUM SALT.

Valsartan (5 g) and methyl isobutyl ketone (30 mL) were placed into a round bottom flask and stirred. Water (30 mL) was added, followed by barium hydroxide (3.6 g). The mixture was maintained for about 1 hour. The mass was then cooled to 0-5⁰C and maintained for about 2 hours. The formed solid was filtered and washed with methyl isobutyl ketone (5 mL). The wet solid was dried at 50-60°C for about 8 hours, to yield 4.5 g of the title compound. Purity by HPLC: 99.1 % Chiral purity: 99.5%.

EXAMPLE 9: PREPARATION OF VALSARTAN BARIUM SALT.

Valsartan (5 g) and isopropyl alcohol (30 mL) were placed into a round bottom flask and stirred. Water (30 mL) was added, followed by barium hydroxide (3.6 g). The mixture was maintained for about 1 hour, and then filtered. The filtrate was cooled to 0-5°C and maintained for about 2 hours. The solvent was evaporated from the mass to 50 % of the initial volume. Acetone (30 mL) was added. The mass was then cooled to 0-5⁰C and stirred for about 2 hours. The formed solid was filtered and washed with isopropyl alcohol (5 mL). The wet solid was dried at 50-60°C for about 8 hours, to yield 4.0 g of the title compound. Purity by HPLC: 99.5%.

Chiral purity: 99.8%. EXAMPLE 10: PREPARATION OF VALSARTAN BARIUM SALT.

Valsartan (5 g) and ethyl acetate (30 mL) were placed into a round bottom flask and stirred. Water (30 mL) was added, followed by barium hydroxide (3.6 g). The mixture was maintained for about 1 hour. The mass was cooled to 0-5⁰C and maintained for about 5 hours. The formed solid was filtered and washed with ethyl acetate (5 mL). The wet solid was dried at 50-60⁰C for about 8 hours, to yield 5.0 g of the title compound.

Purity by HPLC: 99.4%. Chiral purity: 99.7%.

EXAMPLE 11 : PREPARATION OF ESSENTIALLY AMORPHOUS VALSARTAN.

Valsartan barium salt (5 g) and water (50 mL) were placed into a round bottom flask. 30 mL of ethyl acetate was added into the mixture, followed by addition of 20% aqueous HCI (10 mL). The mixture was maintained for about 1 hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was distilled under vacuum at 55-60°C. The obtained solid was dried at 55-60⁰C for about 5 hours, to yield 3.2 g of the title compound.

Purity by HPLC: 99.6%. Chiral purity: 99.8%.

PXRD: Essentially amorphous valsartan.

EXAMPLE 12: PREPARATION OF ESSENTIALLY AMORPHOUS VALSARTAN.

A solution of 100 g of valsartan in 3000 ml of ethyl acetate was subjected to agitated thin film drying at a feed rate of 4.5 L per hour, temperature of 50-55°C, and a pressure of 5-10 torr, to obtain 20 g of essentially amorphous valsartan characterized by a PXRD pattern similar to that shown in Fig. 1. Purity by HPLC: 99.7%. Chiral Purity: 99.6%. Residual solvent content: ethyl acetate 4902 ppm; acetone 265 ppm; methanol 147 ppm; ethanol 124 ppm; o-xylene 81 ppm; all other solvents below limits of detection. DSC: endotherms at 65°C (1.7 J/g) and 89°C (16.9 J/g). Particle size distribution: D₉₀ 141.1 μm; D₅₀ 66.9 μm; Di₀ 6.4 μm.

EXAMPLE 13: PREPARATION OF ESSENTIALLY AMORPHOUS VALSARTAN. A solution of 80 g of valsartan in a combination of 320 ml of acetone and

480 ml of ethyl acetate was subjected to agitated thin film drying at a feed rate of 3-4 L per hour, temperature about 55°C, and a pressure of 10-20 torr, to obtain 8 g of essentially amorphous valsartan.

Purity by HPLC: 99.9%. Chiral Purity: 99.7%.

PXRD: Essentially amorphous valsartan.

EXAMPLE 14: PREPARATION OF ESSENTIALLY AMORPHOUS VALSARTAN.

A solution of 100 g of Valsartan in 1500 ml of acetone was subjected to agitated thin film drying at a feed rate of 3.0 L per hour, temperature about 40⁰C, and a pressure of 10-20 torr, to obtain 34 g of essentially amorphous valsartan.

Purity by HPLC: 99.7%.

Chiral Purity: 98.8%.

PXRD: Essentially amorphous valsartan.

EXAMPLE 15: PREPARATION OF ESSENTIALLY AMORPHOUS VALSARTAN.

Valsartan (10 g) and acetone (10 mL) were placed into a round bottom flask and stirred for about 10 minutes. N-pentane (150 mL) was added slowly at about 25°C and the mass was stirred for about 3 hours. The formed solid was filtered and washed with n-pentane. The wet material was dried at about 55°C for about 8 hours to get 8.9 g of the title compound. Purity by HPLC: 99.8%. Chiral Purity: 99.6%. PXRD: Essentially amorphous valsartan. EXAMPLE 16: PREPARATION OF ESSENTIALLY AMORPHOUS VALSARTAN.

Valsartan (5 g) and ethyl acetate (25 mL) were placed into a round bottom flask and stirred for dissolution. The solution was cooled to 0-5⁰C. Diisopropyl ether (150 mL) was added and maintained at the same temperature for about 2 hours. The formed solid was filtered and dried at about 6O⁰C for 4 hours to yield 3.6 g of the title compound.

Purity by HPLC: 99.8%.

DSC: endotherm at 91⁰C.

PXRD: Essentially amorphous valsartan. Residual solvent content: ethyl acetate 1 12 ppm; diisopropyl ether 381 ppm; all other solvents below ICH limits.

EXAMPLE 17: PREPARATION OF ESSENTIALLY AMORPHOUS VALSARTAN.

Valsartan (5 g) and ethyl acetate (25 mL) were placed into a round bottom flask and stirred for dissolution. N-hexane (150 mL) was added and the solution was cooled to 0-5⁰C and maintained for about 2 hours. The formed solid was filtered and dried at about 6O⁰C for 4 hours to yield 4.5 g of the title compound.

Purity by HPLC: 99.8%.

DSC: endotherm at 101⁰C. PXRD: Essentially amorphous valsartan.

Residual solvent content: ethyl acetate 263 ppm; n-hexane 265 ppm; all other solvents below ICH limits.

EXAMPLE 18: PREPARATION OF ESSENTIALLY AMORPHOUS VALSARTAN. A barium salt of valsartan (5 g) and acetone (25 mL) were placed into a round bottom flask and stirred for about 20 minutes at 10-15⁰C. Sulfuric acid (0.9 g) was added slowly, and stirred for about 45 minutes at the same temperature.

The mass was filtered and the filter bed washed with acetone (25 mL). The filtrate was distilled to obtain a residue. The residue was dissolved in acetone (10 mL). N-pentane (100 mL) was added and the mixture stirred for about 45 minutes at about 25⁰C. The formed solid was filtered and washed with n-pentane (25 mL) to yield 2.5 g of the title compound. Purity by HPLC: 99.7%.

Chiral Purity: 99.9%.

PXRD: Essentially amorphous valsartan.

Claims

CLAIMS:

1. A process for preparing valsartan, or an alkaline or alkaline earth metal salt thereof, comprising: a) reacting N-[2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester or its hydrochloride with valeryl chloride, to give N-[2'-cyanobiphenyl-4-yl)methyl]-N- valeryl-(L)-valine methyl ester, which is not isolated; b) reacting N-[2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester with a trialky ltin halide and sodium azide, to give trilakyl tin-protected valsartan methyl ester, which is not isolated; c) hydrolyzing trilakyl tin-protected valsartan methyl ester to give valsartan, which is optionally isolated; d) converting valsartan to an alkaline or alkaline earth metal salt thereof; and e) optionally, converting valsartan alkaline or alkaline earth metal salt to valsartan.

2. The process of claim 1 , wherein a) and/or b) are conducted in a hydrocarbon solvent.

3. The process of claim 2, wherein a hydrocarbon solvent comprises o- xylene.

4. The process of claim 1 , wherein c) is carried out in the presence of an alkali or alkaline earth metal hydroxide.

5. The process of claim 4, wherein an alkali or alkaline earth metal hydroxide comprises sodium hydroxide.

6. The process of claim 1 , wherein c) is conducted in a biphasic medium.

7. The process of claim 1 , wherein c) is conducted in a biphasic medium comprising a hydrocarbon solvent and water.

8. The process of claim 7, wherein a hydrocarbon solvent comprises o- xylene.

9. The process of claim 1 , wherein d) is carried out in the presence of an alkaline or alkaline earth metal salt.

10. The process of claim 1 , wherein d) is carried out in the presence of lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, or calcium hydroxide.

11. The process of claim 1 , wherein d) is carried out in the presence of sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, or calcium bicarbonate.

12. The process of claim 1 , wherein converting in d) is carried out in the presence of a mixture comprising an organic solvent and water.

13. The process of claim 1 , wherein converting in d) is carried out in the presence of an organic solvent comprising ethyl acetate, isopropyl acetate, or isobutyl acetate.

14. The process of claim 1 , wherein the product of d) is a barium salt of valsartan.

15. A process for preparing essentially amorphous valsartan, comprising: a) providing a solution of valsartan in a solvent; b) removing the solvent from the solution using agitated thin film drying; and c) optionally, drying solid valsartan.

16. The process of claim 15, wherein a solution of valsartan comprises an esters, alcohol, ketone, or halogenated hydrocarbon solvent.

17. The process of claim 15, wherein c) is carried out using a tray dryer, vacuum oven dryer, air oven, or fluidized bed dryer.

18. A process for preparing essentially amorphous valsartan, comprising: a) providing a solution of valsartan in a solvent; b) combining the solution with an anti-solvent; c) isolating essentially amorphous valsartan; and d) drying the essentially amorphous valsartan, using a fluidized bed dryer.

19. The process of claim 18, wherein a solution of valsartan comprises an ester, alcohol, ketone, or halogenated hydrocarbon solvent.

20. The process of claim 18, wherein a solution of valsartan comprises an ethyl acetate, isobutyl acetate, propyl acetate, or isopropyl acetate solvent.

21. The process of claim 18, wherein the ester wherein a solution of valsartan comprises an ethyl acetate solvent.

22. The process of claim 18, wherein an anti-solvent comprises an ether or a C₅-S cyclic, linear, or branched alkane.

23. The process of claim 18, wherein an anti-solvent comprises n- pentane, n-hexane, n-heptane, cyclohexane, or isopentane.

24. The process of claim 18, wherein d) comprises exposing the essentially amorphous valsartan to a temperature profile of about 35 to 4O⁰C for about 1 to 4 hours, 45 to 5O⁰C for about 1 to 4 hours, and 70 to 75⁰C for about 1 to 10 hours.

25. The process of claim 18, wherein in d) the essentially amorphous valsartan is intermittently milled or micronized.

26. A process for recovering a trialkyl tin halide from an organic solution, comprising reacting with a halohydric acid.

27. The process of claim 26, wherein a halohydric acid comprises hydrochloric acid or hydrobromic acid.

28. The process of claim 26, wherein a halohydric acid comprises hydrochloric acid.

29. The process of claim 26, wherein a trialkyl tin halide comprises tributyl tin chloride.