PROCESS FOR PREPARATION OF VALSARTAN WITH LOW RESIDUAL SOLVENT CONTENT

INTRODUCTION

The present application relates to a process for the preparation of valsartan containing low residual solvent content.

Valsartan is described chemically as (S)-N- (1-carboxy-2-methyl prop-1-yl)-N-pentanoyl-N- [2'-1H-tetrazol-5-yl)biphenyl-4-yl methyljamine, and is structurally represented by Formula (I).

Valsartan is a non-peptide, orally active, specific angiotensin II antagonist, acting on the AT1 receptor subtype. U.S. Patent No. 5,399,578 and its equivalent European Patent No. 0443983 B1 disclose valsartan and its pharmaceutical^ acceptable salts, pharmaceutical compositions comprising valsartan and their use in treating high blood pressure and cardiac insufficiency. It also discloses a process for the preparation of valsartan.

Various processes for the preparation of valsartan have been described in subsequent patents and applications which are cost effective and less hazardous. There is a well identified problem in the prior art related to drying of valsartan to get valsartan free of residual solvents. The density of the valsartan crystals is 1.201 ± 0.02 g/cm3 and its X-ray powder diffraction pattern consists essentially of a very broad, diffuse X-ray reflection; it is therefore characterized as amorphous under X- ray. Valsartan has a melting point of 105-110 °C. The melting point combined with the measured melting enthalpy of 12 kJ/mol unequivocally confirms the existence of a considerable residual re-arrangement in the particles or structural domains for valsartan during melting. Hence due to these properties of the free acid of valsartan, it is difficult to dry valsartan to remove the residual solvents completely.

Various solutions have been provided in the prior art for resolving this problem. Patent Publication US 20080293791 describes various salt forms of valsartan which are prepared in an attempt to form an improved form through salt formation, the forms ideally being as crystalline as possible in order to improve their physical properties. US 7,199,144 describes a process for preparing valsartan containing less than about 5000 ppm residual solvent comprising triturating the valsartan containing less than 10% organic solvent in water or with humid air in a fluidized bed drier, or maintaining the valsartan at a temperature of from about 5 to about 60 °C under a pressure of less than about 30 mm/Hg. WO 2007/088558 A2 discloses a process for preparation of valsartan of high purity containing residual solvents less than the specified limit as given in the International Conference on Harmonization (ICH) guideline by washing the crystallized valsartan with an aliphatic hydrocarbon solvent. WO 2006/058701 A1, US 7,659 406 B2, and WO 2008/035364 A2 also disclose various other processes for the preparation of valsartan having low residual solvent content involving the use of modified drying techniques.

The content of residual solvent in the final product is always a cause of concern with respect to Food and Drug Authorities (FDA) requirement. Therefore, it is required to have the solvent content well below the levels specified in the ICH guideline as per regulatory authority. It is therefore, a need to develop further processes for preparation of valsartan with less amount of residual solvent content preferably well below the level as per the ICH guideline for FDA requirement without any quantitative yield loss.

Throughout the prior art, the inventors have concentrated on use of multiple stage techniques to get the desired results. Initially, the wet valsartan obtained after filtration is treated to bring down the residual solvent level of the wet material to about 15 to 30% w/w and then further dried to meet the ICH limits.

Therefore, present inventors have directed their research work towards developing a simpler process for preparation of valsartan containing residual solvent less than the specified limit as given in ICH guideline. The present inventors have identified a filtration technique which provides a material having lower residual solvent content than the material obtained from conventional driers, thus providing a material which is easier to dry. The process of the present application is simple, efficient, cost effective, industrially feasible, and robust for preparing valsartan which is substantially free of residual solvents.

SUMMARY

The present application relates to a process for the preparation of valsartan containing low residual solvent content.

In an embodiment, the present invention relates to a filtration technique to provide Valsartan containing residual solvent content of about 15 to about 30% w/w.

In an embodiment, the process of the present application comprises the steps of:

a) filtration of a reaction mixture containing isolated valsartan in a solvent or a
combination of solvents from a thin cake rotary pressure filter to provide valsartan
containing about 15 to about 30% w/w residual solvent content; and

b) drying the wet valsartan obtained in step a) to get valsartan free of residual
solvents.

The present application also relates to pharmaceutical compositions comprising valsartan or its pharmaceutically acceptable salts produced according to the processes of the present application together with at least one pharmaceutically acceptable excipients

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a powder X-ray powder diffraction (PXRD) pattern of valsartan prepared according to Example 1.

Fig. 2 is a differential scanning calorimetric (DSC) curve of valsartan prepared
according to Example 1.

DETAILED DESCRIPTION

In an embodiment, the present invention relates to a filtration technique to provide Valsartan containing residual solvent content of about 15 to about 30% w/w.

In an embodiment, the process of the present application comprises the steps of:
a) filtration of a reaction mixture containing isolated valsartan in a solvent or a combination of solvents from a thin cake rotary pressure filter to provide valsartan containing about 15 to about 30% w/w residual solvent content; and

b) drying the wet valsartan obtained in step a) to get valsartan free of residual solvents.
Step a) involves filtration of a reaction mixture containing isolated valsartan in a solvent or a combination of solvents from a thin cake rotary pressure filter to provide valsartan containing about 15 to about 30% w/w residual solvent content.

The reaction mixture containing valsartan in isolated form may be obtained by dissolving valsartan in a suitable solvent or mixture of solvents, or such a mixture may be obtained from a reaction in which valsartan is formed.

Suitably, the reaction mixture can be in solvents selected from, but not limited to esters such as ethyl acetate, propyl acetate or the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1,4-dioxane or the like; alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, or the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone or the like; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, methylcyclohexane or the like; aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, dimethylacetamide or the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride or the like and mixtures thereof; or their mixtures with water.

In an embodiment, the thin cake rotary pressure filter used for the purposes of this application is manufactured by BHS-SONTHOFEN™. It is a continuous-operating filter, wherein the cake is filtered continuously under pressure. The cake thickness is from about 1 mm to about 165 mm, and the operating pressure ranges from about 2 to 6 Kg/cm2. Because of the less cake thickness, the residual solvent content in the wet cake is substantially reduced to levels lower than that obtained from conventional filters. The reduced cake thickness prevents the formation of uneven lumps in the wet cake. The material obtained after the filtration is even and is easy to handle during further drying operations. The wet cake obtained after the filtration operation has a residual solvent content of about 15% to about 30 % w/w which is very less when compared to the residual solvent content in a wet cake obtained after filtration from a conventional filter which ranges from about 50% to about 60% w/w. The continuous filtration process aids in avoidance of the use of multiple conventional filtration equipments for filtration of a single batch. Also, because of the various sizes of the filtration equipment available, it is easy to choose a convenient size as per the requirement in order to avoid the use of multiple conventional equipments for filtration of a single batch.

Another advantage of the continuous filtration is better recovery of the solvent due to absence of evaporation of solvent during spin drying in a conventional filter.

Valsartan containing about 15 to about 30% w/w of residual solvent can be easily further dried to obtain valsartan substantially free of residual solvents. The wet cake obtained above may be further dried optionally under reduced pressure suitably in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, spherical drier, or the like. The drying can be carried out at temperatures of about 35 °C to about 70 °C. The drying can be carried out for any desired time periods such as from about 1 to 20 hours, or longer.

The dried product can be optionally milled to get the required particle size. Milling or micronization can be performed intermediary to 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, thus making the drying operation more efficient when milling is carried out intermediary. Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.
Drying can be carried out until the residual solvent content of the material reduces to an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm.

Valsartan prepared according to the processes of the present application, may have a purity of more than about 95%, or more than about 98%, or more than about 99%, or more than about 99.5%, and contains less than about 1%, or less than about 0.5%, or less than about 0.1% by weight of individual process related impurities, as characterized by HPLC

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

The pharmaceutical compositions of the present application 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, and spheronization. The compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.

Pharmaceutically acceptable excipients that find use in the present application include and are not limited, to: diluents, such as, for example, starch,.pregelatinized starch, lactose, powdered cellulose, mierocrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders, such as, for example, acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, or the like; disintegrants, such as, for example, starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants, such as, for example, stearic acid, magnesium stearate, zinc stearate, or the like; glidants, such as, for example, colloidal silicon dioxide, or 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 cyclodextrins, resins; release rate controlling agents, such as, for example, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include and are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

In the compositions of present application valsartan or its pharmaceutically acceptable salts is a useful active ingredient in the range of 40 mg to 120 mg, or 40 mg to 320 mg.

DEFINITIONS

The following definitions are used in connection with the present invention unless the context indicates otherwise. A Rotary Pressure Filter works on the principle of cake filtration. The feed suspension enters each cell, under constant pressure, to form a filter cake. Internal divisions called separating elements of the housing allow the cake to be processed in completely separate zones. Each zone can operate under different pressures depending upon the compressibility of the cake at each stage of filtration, washing and drying.

An "aliphatic hydrocarbon solvent" refers to a liquid, non-aromatic hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of an aliphatic hydrocarbon solvent include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methyfpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, Cs-Csaliphatic hydrocarbons, petroleum ether, and mixtures thereof.

Certain specific aspects and embodiments of this application are described in further detail by the examples below, which examples are not intended to limit the scope of the appended claims in any manner.

EXAMPLES

EXAMPLE 1: PREPARATION OF VALSARTAN.

Ethyl acetate (320 liters) was taken into a reactor and water (400 liters) was added to it. Valsartan barium salt (80 Kg) was added to it and stirred for about 10 minutes. The pH of the reaction mass was adjusted to 2.5 to 3.5 using an aqueous solution of HCI. The reaction mass was stirred for about 20 minutes, and the organic layer was separated. The aqueous layer was extracted into ethyl acetate, and the combined organic layer was distilled off under vacuum. To the residue obtained, ethyl acetate (400 liters) was added and stirred for about 30 minutes, followed by addition of n-heptane (1212 liters), and stirred for about 2 hours. The reaction mass was then fed into the thin cake rotary pressure filter manufactured by BHS-SONTHOFEN™ at a feed pressure of 3-4 Kg/cm2 using a slurry pump, the material was press filtered and transferred to the semi drying zone where it was subjected to a nitrogen atmosphere of 2-2.5 Kg/cm . The semi dried wet cake was collected and the rotary pressure filter cloth was washed with ethyl acetate (320 liters). The obtained material showed a residual solvent content of about 15 to 25% w/w. The wet material was then dried in a Nauta dryer under a vacuum of about not less than 600 mmHg at a temperature of 60 to 70 °C. The dried material was milled in a Multi-Mill through a 1.0 mm mesh. The milled material was again dried in a Nauta dryer under a vacuum of about 600 mmHg at a temperature of 60 to 70 °C. The dried material was again milled with a mill pressure of 3.0 Kg/cm2 and again dry the material in a Nauta dryer at about 60-70 °C to give 35.5 Kg of the title compound.

Residual solvent content: Methanol: 86 ppm, ethyl acetate: 2801 ppm, n-heptane
4385 ppm, methyl cyclohexane: 44 ppm. All other solvents are not detected.
Purity by HPLG: 99.7% by HPLG;

EXAMPLE 2: PREPARATION OF VALSARTAN

Valsartan barium salt (200 Kg) and ethylacetate (800 ml) were taken into a reactor and pH of the reaction mass was adjusted to 2.5 to 3.5 using a solution of HCI (80 liters) in water (80 liters). The reaction mass was stirred for about 30 minutes and then the organic layer was separated. The aqueous layer was extracted into ethyl acetate (200 liters). The combined organic layer was distilled off and again ethyl acetate (1000 liters) was added to it. The reaction mass was cooloed to about 25 °C and maintained under stirring for about 30 minutes. N-heptane (3010 liters) was added to the reaction mass at the same temperature and maintained for about 2 hours. The isolated solid was filtered in a rotary pressure filter, and the filtered cake was washed with heptane (500 liters). The wet material was delumped in a conical delumper and delumped under vacuum for about 3 hours. The delumped material was dried in an FBD at about 65 °C for 8 hours. The dried material was milled though a 0.5 mm mesh in a jet mill to yield 116.3 Kg of the title compound. Residual solvent content: Methanol: 165 ppm, ethyl acetate: 2683 ppm, n-heptane 3704 ppm, methyl cyclohexane: 32 ppm. All other solvents are not detected. Purity by HPLC: 99.7% by HPLC.

We Claim:

1. A process for preparing valsartan comprising:

a) filtration of a reaction mixture containing isolated valsartan in a solvent or a combination of solvents from a thin cake rotary pressure filter to provide valsartan containing about 15 to about 30% w/w residual solvent content;

b) drying the wet valsartan obtained in step a) to get valsartan free of residual solvents.

2. A process of claim 1, wherein the reaction mixture in step a) comprises of valsartan in a combination of ethyl acetate and n-heptane.

3. A process of claim 1, wherein the drying is carried out in a nauta dryer.