DESC:Field of the Invention

The specification discloses an amorphous form of valsartan disodium hydrate and process of preparation thereof.
Background of the invention

Valsartan is a non-peptide, orally active and specific angiotensin II (Ang II) antagonist acting on the AT1 receptor subtype. It is marketed under the trade name Diovan® by Novartis and indicated for the treatment of hypertension irrespective of age, sex or race. It is also known to be effective in the treatment of congestive heart failure. Valsartan is chemically known as N-(1-oxopentyl)-N-[[2’-(1H-tetrazol-5-yl) [1,1’-biphenyl]-4-yl]methyl]-L-valine, compound of Formula I

Formula-I

U.S. Patent No. 5,399,578 describes valsartan or pharmaceutically acceptable salt thereof and its process of preparation.

Other process of preparation of Valsartan is also disclosed in various Patent/ application No. including U.S. Pat. Nos. 5,399,578; 5,965,592; 5,260,325; 6,271,375; WO20030207930, WO 2002006253; WO 2001082858; WO 1999067231 and WO 1997030036.

Summary of the Invention

One embodiment discloses an amorphous form of valsartan disodium hydrate having the compound of Formula II

Another embodiment discloses an amorphous form of valsartan disodium hydrate having moisture content of about 3.0 % w/w to 15% w/w.

One another embodiment discloses an amorphous form of valsartan disodium hydrate, characterized by having one or more of the following properties;
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1;
ii. a melting point at about 300°C ±5

One another embodiment discloses a process of preparation of amorphous form of valsartan disodium hydrate, the process comprising the steps of:
a) providing a solution of valsartan in a suitable solvent;
b) adding suitable sodium source to the solution obtained in step (a); and
c) isolating amorphous valsartan disodium hydrate from the solution.

Another embodiment discloses an amorphous form of valsartan disodium having purity more than 99 % when measured by HPLC.

Another embodiment discloses a process of preparation of amorphous form of valsartan disodium hydrate, the process comprising the steps of:
a) providing a solution of valsartan in a suitable solvent;
b) adding suitable sodium source to the solution obtained in step (a); and
c) isolating amorphous valsartan disodium hydrate by lyophilizing or spray drying the solution obtained in step (b)

Brief Description of the Drawings

Figure 1 shows X-ray powder diffraction pattern of amorphous form of valsartan freebase.

Figure 2 shows X-ray powder diffraction pattern of amorphous form of valsartan disodium hydrate prepared according to Example 1.

Figure 3 shows X-ray powder diffraction pattern of amorphous form of valsartan disodium hydrate prepared according to Example 2.

Figure 4 shows X-ray powder diffraction pattern of amorphous form of valsartan disodium hydrate after 48 hrs exposure in air prepared according to Example 3.

Figure 5 shows X-ray powder diffraction pattern of amorphous form of valsartan disodium hydrate after 10 days exposure in air prepared according to Example 4.

Description of the Invention
One embodiment discloses an amorphous form of valsartan disodium hydrate having the compound of Formula II

Another embodiment discloses an amorphous form of valsartan disodium hydrate having moisture content of about 3.0 % w/w to 15% w/w.

One another embodiment discloses an amorphous form of valsartan disodium hydrate, characterized by having one or more of the following properties;
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1;
ii. a melting point at about 300°C ±5.

The amorphous form of valsartan disodium hydrate obtained according to the present invention, when stored at temperature 25°C for a period of 3 months did not show contamination of other polymorphic forms.

Another embodiment discloses an amorphous form of valsartan disodium hydrate having purity more than 99 % when measured by HPLC.

Another embodiment discloses a process of preparation of amorphous form of valsartan disodium hydrate, the process comprising the steps of:
a) providing a solution of valsartan in a suitable solvent;
b) adding suitable sodium source to the solution obtained in step (a); and
c) isolating valsartan disodium hydrate from the solution.

The process involves dissolving valsartan in suitable solvent and stirring for a period of 5 minute to obtain a clear solution, followed by addition of suitable sodium source, wherein the suitable sodium source may be selected from sodium-2-ethylhexanoate, sodium hydroxide, sodium-2-ethyl-2-methylhexanoate, sodium 2-ethylbutanoate or sodium 2-methylpropanoate. These sodium sources can be added in a solution form in a suitable solvent. The reaction mixture is stirred at temperature of about 25°C to 35°C for a period of 1 hour to obtain a clear solution. The preparation of valsartan monosodium or disodium salt is dependent on the molar ratio of sodium source in the reaction, more preferably valsartan disodium is formed.

The various hydrates including 1, 1.5, 2.5, 3.5 or 5.0 may be obtained by means of controlled exposure of valsartan disodium to humidity, wherein controlled exposure means exposure of valsartan disodium to humidity for the period of 1 hour for monohydrate, 8-12 hours for sesquihydrate, 1 to 2 days for hemipentahydrate, 4 to 5 days for hemiheptahydrate and 10 to 14 days for pentahydrate.

The suitable solvent may be one or more of halogenated solvent, ether solvent, alcoholic solvent ketone solvent, nitrile solvent, ester solvent, water or mixtures thereof. The halogenated solvent is selected from dichloromethane, dichloroethane or chloroform; ether is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran or diisopropyl ether; alcoholic solvent is selected from one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol or propylene glycol; ketone solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or methyl tert-butyl ketone; nitrile solvent is selected from acetonitrile or propionitrile; ester solvents is selected from ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate or ethyl butanoate.

Further, the process involves isolation of Valsartan Sodium, wherein the reaction mixture is concentrated under vacuum at temperature 45°C to 50°C, followed by addition of suitable mixture of solvent to precipitate solid. The obtained precipitate is filtered, washed and dried under vacuum at temperature of about 45°C to 50°C for a period of 6 hours to get Valsartan Sodium.

The suitable mixture of solvent may be one or more of, ketone solvent, ether solvent, hydrocarbon solvent, water or mixtures thereof. The ketone solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or methyl tert-butyl ketone (MTBE); the hydrocarbon solvent is selected from cyclohexane, methylcyclohexane, cycloheptane, n-pentane, isopentane, n-hexane, isohexane, n-heptane, isoheptane, n-octane or isooctane; ether is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran or isopropyl ether.

The solvent may be removed by one or more of distillation, evaporation, spray drying, freeze-drying, lyophilization, filtration, filtration under vacuum, decantation and centrifugation

The amorphous form of the valsartan disodium hydrate can be prepared by lyophilizing or spray drying the solution resulting from the addition of sodium sources to valsartan in a suitable solvent.

The resulting solution is filtered, followed by lyophilizing with freezing it to temperatures below -30°C, typically about -45°C, under pressures below 100 mbars, with a lyophilization temperature gradient ranging from about 0 to about 50°C.

Alternatively, as mentioned above, the solution can be subjected to spray drying using conventional techniques.

Another embodiment discloses a process of preparation of amorphous form of valsartan disodium hydrate, the process comprising the steps of:
a) providing a solution of valsartan in a suitable solvent;
b) adding suitable sodium source to the solution obtained in step (a); and
c) isolating valsartan disodium hydrate by lyophilizing or spray drying the solution obtained in step (b).

Another embodiment discloses a process of preparation of amorphous valsartan disodium hydrate, comprising the step of grinding or milling crystalline valsartan disodium. Preferably, the milling is conducted for a time period ranging between about 10 minutes and about 500 minutes.

In one another embodiment process of compound of Formula II is schematically presented in the following scheme 1:

Another embodiment discloses an amorphous form of valsartan disodium forms complex via non-covalent bonds with (2R, 4S)-5-biphenyl -4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the amorphous form of valsartan disodium forms complex with monosodium salt of (2R, 4S)-5-biphenyl -4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester.

In a preferred embodiment, the amorphous form of valsartan and the (2R, 4S)-5-biphenyl -4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester or a pharmaceutically acceptable salt thereof are present in a molar ratio of 1:1,1:2,1:3, 3:1, 2:1, more preferably 1:1 in the combination as well as in the complex.

Another embodiment discloses the amorphous form of valsartan disodium hydrate having 90% of the particles less than 400 microns. The particle size may be measured by any suitable method preferably the laser diffraction technique can be used for the measurement of particle size of the active ingredient alone or in the composition.

The particle size of the active ingredient is determined by measuring the characteristic equivalent sphere diameter, by laser diffraction using a Malvern apparatus. The parameter taken into consideration was VD (volume diameter) in microns of 90% of the particles.

Advantageously at least 90% of the particles have a volume diameter lower than 50 microns, preferably lower than 30 microns, more preferably lower than 10 microns.

The amorphous form of valsartan disodium hydrate may be micronized in a suitable milling device such as ball milling, jet milling or milling using a high pressure homogenizer or by other techniques such as spray drying to achieve the desired particle size.

The embodiments of the specification are further illustrated by way of following examples, which do not limit the scope of the claims. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the claims.

EXAMPLES

Example 1: Preparation of amorphous valsartan disodium hydrate
Charged Valsartan free base (100 gm; 0.230 moles) in isopropyl alcohol (1000 mL) and stirred for 5 minutes to obtain clear solution followed by addition of sodium hydroxide (20.2 gm; 0.506 moles) and purified water (20 mL). The reaction mixture was stirred for a period of 1 hour at temperature 25°C to 35°C to get a clear solution, which was further stirred for a period of 12 hours. The Reaction mixture was concentrated under vacuum at temperature of about 45°C to 50 °C. Cyclohexane (300 mL) was added to the obtained semisolid mass and again concentrated under vacuum at temperature 45°C to 50 °C to obtain precipitate. The obtained precipitate was filtered, washed with cyclohexane (200 mL) and dried in an oven under vacuum at temperature 45°C to 50°C for a period of 6 hours to get the titled compound.
Yield: 106 gm
Moisture content: 4.20% w/w
Sodium Content: 9.20%w/w
Residue of Ignition (ROI): 23.37%w/w
HPLC Purity: >99.0%w/w
M.P.: 300°C ±5.

Example 2: Preparation of amorphous valsartan disodium hydrate
Charged Valsartan (100 gm; 0.230 moles) in isopropyl alcohol (1000 mL) and stirred for 5 minutes to obtain clear solution followed by addition of sodium hydroxide (20.2 gm; 0.506 moles) and purified water (20 mL). The reaction mixture was stirred for a period of 1 hour at temperature 25°C to 35°C to get a clear solution. The Reaction mixture was concentrated under vacuum at temperature of about 45°C to 50 °C to obtain a semisolid mass. Isopropyl alcohol (500 mL) was added to the obtained semisolid mass and again concentrated under vacuum at temperature of about 45°C to 50 °C to get solid mass. Acetone (400 mL), water (10 mL), followed by addition of methyl tert-butyl ether (1000mL) was added to the solid mass and stirred for 24 hrs at temperature 25°C to 35°C to obtain precipitate. The obtained precipitate was filtered, washed with methyl tert-butyl ether (200 mL) and dried in an oven under vacuum at temperature 45°C to 50°C for a period of 20 hours to get the titled compound.
Yield: 102gm
Moisture Content: 4.56% w/w
Sodium Content: 8.16%w/w
Residue of Ignition (ROI): 23.38%w/w
HPLC Purity: >99.0%w/w
M.P.: 300°C ±5.

Example 3: Preparation of amorphous valsartan disodium hydrate
Charged Valsartan (10.0 gm) in isopropyl alcohol (100 ml) followed by addition of sodium hydroxide (2.20 gm) and water (2.0 ml). The reaction mixture was stirred for 20 hours at temperature 25°C to 35°C and then concentrated under vacuum at temperature 40°C. Charged cyclohexane to the residue (50ml x 2) and degassed for 30 minutes and then add Cyclohexane (70 ml) followed by stirring for 2 hours. The precipitate is filtered, washed with cyclohexane (10 ml) and dried under vacuum at temperature 40°C to obtain titled product.
Yield: 10.47 gm
Moisture Content: 4.20% w/w
Residue of Ignition (ROI): 28.37%w/w
Sodium content=9.20%
M.P.: 300°C ±5.

Example 4: Preparation of amorphous valsartan disodium hydrate
The compound obtained from above Example 3 was exposed at temperature 25°C to 35° C for 48 hours to get the titled compound.
Yield Dry wt.: 10.40gm
Moisture Content: 9.96%w/w

Example 5: Preparation of amorphous valsartan disodium hydrate
Charged Valsartan (10.0 gm) in isopropyl alcohol (100 ml) followed by addition of sodium hydroxide (2.20 gm) and water (2.0 ml). The reaction mixture was stirred for 20 hours at temperature 25°C to 35°C and then concentrated under vacuum at temperature 40°C. Charged cyclohexane to the residue (50ml x 2) and degassed for 30 minutes and then add Cyclohexane (70 ml) followed by stirring for 2 hours. The precipitate is filtered, washed with cyclohexane (10 ml) and dried under vacuum at temperature 40°C to obtain titled product.
Yield: 10.47 gm
Moisture Content: 4.20%w/w
Residue of Ignition (ROI): 28.37%w/w
Sodium content: 9.20%
M.P.: 300°C ±5.

Example 6: Preparation of amorphous valsartan disodium
The compound obtained from above Example 5 was exposed at temperature 25°C to 35°C for 10 days to get the titled compound.
Yield Dry wt.:10.40gm
Moisture Content: 15.14%w/w
Na content: 8.22%
M.P.: 300°C ±5.
,CLAIMS:1. An Amorphous form of valsartan disodium hydrate.

2. The amorphous form of claim 1, having moisture content of 3.0 % w/w to 15% w/w.

3. The amorphous form of claim 1, characterized by having one or more of the following properties;
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1;
ii. a melting point of about 300°C ±5.

4. The amorphous form of claim 1, having purity more than 99 % when measured by HPLC.

5. A process of preparation of amorphous form of valsartan disodium hydrate, the process comprising the step of
a) providing a solution of valsartan in a suitable solvent;
b) adding suitable sodium source to the solution obtained in step (a); and
c) isolating amorphous valsartan disodium hydrate from the solution.

6. The process of claim 5, wherein suitable solvent selected from one or more of halogenated solvent, ether solvent, alcoholic solvent, ketone solvent, nitrile solvent, ester solvent, water or mixtures thereof.

7. The process of claim 5, wherein the suitable sodium source selected from one or more of sodium-2-ethylhexanoate, sodium hydroxide, sodium-2-ethyl-2-methyl hexanoate, sodium-2-ethylbutanoate or sodium 2-methylpropanoate.