Field of the Invention

The present invention relates to novel co-crystals of (2S,3aS,7aS)-1-[(2S)-2-{[{2S)-1-ethoxy-1-oxopentan-2-yllamino}propanoyl]-octahydro-1H-indole-2-carboxylic acid, arginine [(Perindopril arginine) with mannitol. The present invention also relates to the process for the preparation of novel mannitol co-crystal of Perindoprll (L)-Arginine

Background of the Invention

Perindoprll,{2S)-2-[{IS)-l-carbethoxybutylamlno]-l-oxopropyl-{2S,3aS,7aS)-perhydroindo-le-2-carboxylic acid, is a potential angiotensin-converting enzyme (ACE) inhibitor.

Perindoprll (L)-Arginine represented by formula (1), its hydrate and pharmaceutical composition and a method of treatment is first disclosed in US 6,696,481. This patent also disclosed that the Arginine salt of Perindoprll is an alternate to tert-butylamine salt having superior properties in terms of stability towards heat and humidity

Formula (I)

WO 2007099216 claims a crystalline polymorphic form of perindoprll arginine, designated as beta and process for the preparation thereof, WO 2007099217 claims crystalline polymorphic form of the arginine salt of perindoprll designated as alpha and process for the preparation thereof The said polymorphs of perindoprll arginine are found to be unstable. Hence there is a need for an Improved form with good stability, having fewer impurities and easy to prepare atindustrial level.

We now discovered a novel mannitol co-crystal of Perindopril {L)-Arginine having
improved stability.

Object and Summary of the Invention

The main object of the present invention Is to provide a novel co-crystal of Perindopril (L)-Arginine with mannitol.

Another object of the present invention provides the process for the preparation of novel
mannitol co-crystal of Perindopril (L)-Arginine.

In yet another object, the present invention relates to novel mannitol co-crystal of
Perindopril (L)-Arginine, shown in figure 1,

According to the present invention, the process for the preparation of novel mannitol co-
crystal of Perindopril (L)-Arginine comprises the steps of hydrolysing benzyl perindopril to perindopril free acid followed by addition of L-arginine and mannitol. The resulting solution can be treated with an antisolvent thus isolating mannitol co-crystal of Perindopril (L)-Arginine
Drawings

Figure 1 represents powder X - ray diffraction diagram of mannitol co-crystal of Perindopril (L)- Arginine

Detailed description of the Invention

According to the present invention is to provide a novel mannitol co-crystal of Perindopril (L)-Arginine

In one embodiment, the present invention relates to novel mannitol co-crystal of Perindopril (L)-Arginine, shown in figure 1.

In another embodiment, the present invention provides the process for the preparation of hovel mannitol co-crystal of Perindopril (L)-Arginine, as summarized in scheme 1

In yet another embodiment, the present invention relates to the process for the preparation of novel mannitol co-crystal of Perindopril (L)-Arginine comprises the steps of:

a) dissolving benzyl perindopril In a organic solvent;
b) hydrolyzing benzyl perindopril to perindopril free acid;
c) treating the free acid of step b) with L-arginine and mannitol;
d) adding antisolvent; and
e) isolating mannitol co-crystal of Perindopril (L)-Arginine

According to the present invention, the process for the preparation of novel mannitol co-
crystal of Perindopril (L)-Arginine comprises the steps of hydrolysing benzyl perindopril to perindopril free acid followed by addition of L-arginine and mannitol. The resulting solution can be treated with an antisolvent thus isolating mannitol co-crystal of Perindopril (L)-Arginine

In yet another embodiment, the present invention relates to the process for the
[preparation of novel mannitol co-crystal of Perindopril (L)-Arginine comprises the steps of:

a) dissolving benzyl perindopril in a organic solvent;
b) hydrolyzing of benzyl perindopril to perindopril free acid;
c) treating the free acid of step b) with L-arginlne and mannitol;
d) cooling the reaction mixture; and
e) isolating mannitol co-crystal of Perindopril (L)-Arginine

According to the present invention, the process for the preparation of mannitol co-crystal of Perindopril (L)-Arginine comprises the steps of hydrolysing benzyl perindopril to obtain perindopril free acid followed by addition of L-arginine and mannitol, The resultant mixture can be cooled below the room temperature under maintenance thus isolating novel mannitol co-crystal of Perindopril (L)-Arginine.

According to the present invention, the solvent for dissolution of benzyl perindopril Is selected from water, alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether nitriles such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide and dioxane or a mixture of thereof.

According to the present invention, the anti solvent is selected form ketones such as acetone, methyl Isobutyl ketone, methyl ethyl ketone and cyclohexanone.

According to the present invention, the hydrolysis of benzyl perindopril is carried out by hydrogenation in the presence of conventional catalysts such as palladium on carbon, platinum on carbon and the like.

EXAMPLES

Example 1:

PREPARATION OF MANNITOL CO-CRYSTAL OF PERINDOPRIL (L)-ARGININE COCRYSTAL Benzyl perindopril (10g) was added 40 ml of cyclohexane & 30 ml of water at 20-25°C. Stirred the eaction mixture at 20-25°C for about 15 minutes. Added 1 g of 10 % Palladium on carbon at 20-25 C under nitrogen atmosphere. Surged hydrogen gas at atmospheric pressure till reaction was completed. Filtered the catalyst under nitrogen atmosphere. Washed the bed with 10 mi of water. Transferred the filtrate to a separating funnel and separated the lower aqueous layer and 3reserved. Extracted the organic layer with 50 ml of water. Combined all aqueous layers and L-Arglnine { 2 g) & Mannitol { 10 g) was added to the combined aqueous layer and stirred for 1 lour. Acetone 4 litres was added to this clear solution and stirred overnight, filtered and dried at Ho-45°C under vacuum to get 13 g of mannitol co-crystal of PERINDOPRIL L- ARGININE.

Example 2:

PREPRATION OF MANNITOL CO-CRYSTAL OF PERINDOPRIL L- ARGINIIME COCRYSTAL Benzyl perindopril (l0g) was dissolved in 153 m! of ethyl acetate and the resulting mixture was lydrogenated using 10 psi of hydrogen pressure in presence of 1.6 gm of 5% Palladium on carbon at 10 -15C for 6 hours. After the completion of the reaction, the catalyst was removed by iltration. To the filtrate containing perindopril base was added 5.5 gm of L-ARGININE & mannitol at 10 -15°C. Cooled the reaction mixture to 0-5 °C and stirred for 1 hour. Filtered the solid and dried at 40-45°C under vacuum to get 9 gm of mannitol co-crystal of PERINDOPRIL L-ARGININE

We claim:

1) Mannitol co-crystal of Perindopril (L)-Arginine

2) A process for the preparation of mannitol co-crystal of Perindopril (L)-Arginine comprising the steps of:

a) dissolving benzyl perindopril in a solvent;

b) hydrolyzing benzyl perindopril to perindopril free acid;

c) treating the free acid of step b) with L-arginine and mannitol;

d) adding antisolvent; and

e) isolating mannitol co-crystal of Perindopril (L)-Arginine

3) The process of claim 1, wherein solvent is selected from water, alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol, hydrocarbons such as pentane, cyclohexane, n-hexane, n-heptane, and esters such as ethyl ester or their mixtures thereof.

4) The process of claim 1, wherein the hydrogenation reaction is carried out under a hydrogen pressure of less than 30 bars.

5) The process of claim 1, wherein the antisolvent is selected ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone.

6) A process for the preparation of mannitol co-crystal of Perindopril {L)-Arginine comprising the steps of:

a) dissolving benzyl perindopril in a solvent;

b) hydrolyzing of benzyl perindopril to perindopril free acid;

c) treating the free acid of step b) with L-arginine and mannitol;

d) cooling the reaction mixture; and

e) isolating mannitol co-crystal of Perindopril (L)-Arginine

7) The process of claim 6, wherein solvent is selected from water, hydrocarbons such as pentane, cyclohexane, n-hexane, n-heptane, and esters such as ethyl ester or their mixtures thereof.

8) The process of claim 6, wherein the hydrogenation reaction is carried out under a hydrogen pressure of less than 30 bars.

9) Mannitol co-crystal of Perindopril (L)-Arginine characterized by powder X - ray diffraction as shown in fig.1