PREPARATION OF NOVEL CRYSTALLINE Ti(ETA^ FORM OF PERINDOPRIL ERBUMINE

Field Of invention

The present invention relates to a novel crystalline η (ETA) form of perindopril erbumine of Formula II.

The present invention further relates to process for the preparation of a novel crystalline form η of perindopril erbumine of Formula II, by use of perindopril erbumine monohydrate of Formula III.

Perindopril erbumine η form Formula (II)

Perindopril erbumine monohydrate Formula (III)

Background Of The Invention

The chemical species, (2S)-2-[(1S)~1-Carboethoxybutylamino]-1- oxopropyl- (2S, 3aS, 7aS) - octahydroindole-2-carboxylic acid of the formula (I) is generically known as Perindopril.

Perindopril erbumine & its pharmaceutically acceptable salts are active as angiotensin converting enzyme (ACE) inhibitors and thus are commercially valuable antihypertensive agents.

US Patent 4508729 discloses perindopril & its preparative processes which are carried out in alcoholic medium, in the presence of neutral dehydrating agent and an organic or inorganic cyanoborohydride where deprotection processes can be carried out with reference to hydrolysis and / or hydrogenolysis wherever necessary.

US Patent 4914214 describes process for the preparation of perindopril and its t-butylamine salt. The process comprises condensation of protected ester of (2S, 3aS, 7aS)-2-carboxyperhydroindole with the (S, S) diastereoisomer of N- [(S)-I -carbethoxybutyl]-(S)-alanine, followed by deprotection employing charcoal containing 5% palladium and water. Tertiary-butylamine is then added to yield t- butylamine salt of perindopril. Its pharmaceutically acceptable salts, especially t-butylamine / erbumine salt is represented by Formula (II).

Different crystalline forms of perindopril erbumine exhibiting characteristic XRD pattern are described in various prior art.

US Patent application 2003/0186896 (Pfeiffer et al) describes a method for preparation of α forms of perindopril t-butylamine/erbumine in which perindopril t-butylamine/erbumine is dissolved in Ethyl acetate as specified in Patent EP 0308341 followed by reflux and then gradual cooling to temperature of 6O ⁰ C in the course of 21/2 hrs followed by stirring at ambient temperature. Then the solidified mass is filtered off and dried. WO2005108365 discloses a process for the preparation of an alpha polymorph of perindopril erbumine is provided comprising (a) forming a solution comprising perindopril erbumine in one or more ketones; (b) heating the solution

to reflux; and (c) cooling the solution to a temperature sufficient to form the alpha polymorph of perindopril erbumine. The alpha polymorphs of perindopril erbumine obtained herein have a high purity level.

US Application 2004/0029813 (Pfeiffer et al) describes a method for the preparation of 'β' forms of perindopril t-butylamine/erbumine. Perindopril

Erbumine is prepared as specified in EP0308341 and then dissolved in dichloromethane. The mass is brought to reflux followed by cooling to 0°C and then followed by filtering off the solid. This patent further describes that 'β' forms of Perindopril Erbumine can also be prepared by dissolving perindopril erbumine in ethyl acetate and heating it to reflux followed by rapid cooling to O ⁰ C and then filtering off the solid.

US Application No. 2004/0248817 describes a method for the preparation of γ form of Perindopril t-butylamine comprising steps of,

(i) Dissolving t-butylamine salt of Perindopril in ethyl acetate, (ii) Heating to reflux followed by cooling between the temperatures of

0-5 ⁰ C.

(iii) Filtering off the solid obtained in step (ii). (iv) Suspending the solid in chloroform and stirring for 5 to 10 days at ambient temperature. (v) Filtering off the solid obtained in step (iv).

PCT application WO 2004/113293 describes a method for the preparation of δ & ε forms of perindopril erbumine. Crystallization of Perindopril erbumine is carried out using methyl tertiary butyl ether containing 1.5 to 2.0 percent (V/V) of water. Temperature employed for the crystallization is between 30-45 ⁰ C and preferably between 34-45 ⁰ C.

PCT application WO 2004/113293 further describes a method for preparation of δ form by crystallization of α or β forms of Perindopril Erbumine in tertiary butyl methyl ether containing 0.9 to 1.4% (V/V) of water at a temperature of 33 to 38 ⁰ C.

WO2005068425 of LEK pharmaceuticals discloses a new crystalline form of perindopril and a process where stereospecific amino acid N-[(S)-carbethoxy- 1-butyl]-(S)-alanine, is protected by trimethylsilyl group and converted to reactive acid chloride using thionylchloride or its complex with 1-H-benzotriazole (1:1), which reacts with (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid with a protected carboxyl group.

WO2005068425 of LEK pharmaceuticals discloses the new crystalline form of Perindopril. Where purification of crude perindopril obtained is done by filtration through the column. Column are prepared with silica gel and is eluted with methylene dichloride / ethanol (94/6 v/v). Amorphous Perindopril so obtained is then dissolved in ethyl ether and crystallized first at room temperature followed by cooling to get new crystalline form having the melting range of 110-114°C.

WO2005037788 discloses a process for preparation of crystalline perindopril erbumine. The process comprises reacting a solution of perindopril of formula (I), in a solvent selected from N, N-dimethylformamide or dimethyl acetals of lower aliphatic aldehydes and ketones with tertiary butylamine and crystallization of the erbumine salt thus obtained by heating the reaction mixture to reflux, filtering hot, cooling gradually to 2O ⁰ C to 3O ⁰ C, and further cooling to 0° C to 15 ⁰ C for 30 minutes to 1 hour and finally filtering off and drying the crystals.

Perindopril Formula (I)

The processes disclosed in prior art for the preparation of Perindopril erbumine monohydrate of 99.8% purity are associated with unknown nonpolar impurities.

The present inventors have developed a process for the preparation of a novel crystalline form of Perindopril erbumine exhibiting characteristic 2θ values.

The processes disclosed in prior art for the preparation of Perindopril erbumine of various forms did not describe as such for the removal of the undesirable associated impurities completely. Therefore there is a long felt need for an improved process for the preparation of purified perindopril erbumine η form giving high yield and purity where Purity is 99.9%.

Object Of Invention

Therefore it is an object of the invention to provide a process for the preparation of novel crystalline form of perindopril erbumine denoted as η form. It is further object of the present invention to provide a novel process for preparation of a novel crystalline η form of Perindopril erbumine of high purity and free from unknown non polar impurities.

Another object of the present invention is to provide a novel crystalline form of perindopril erbumine denoted as η form exhibiting characteristic 2θ values4.07, 5.26, 9.46, 15.75, 21.04, 21.35, 23.15, 24.13, 26.38, 31.8, 27.18.

Yet another object of the present invention to provide a novel crystalline form of perindopril erbumine denoted as η form with high purity of 99.9% with very good solubility.

Summary Of Invention

Thus according to an aspect of the present invention, there is provided a novel crystalline η form of Perindopril erbumine represented by Formula (II).

Perindopril erbumine η form Formula (II)

Wherein the novel crystalline form of perindopril erbumine denoted as η form exhibiting characteristic 2θ values as follows: (2θ values) 4.07, 5.26, 9.46, 15.75, 21.04, 21.35, 23.15, 24.13, 26.38, 31.8, 27.18

According to another aspect of the present invention there is also provided a process for the preparation of the novel crystalline η (ETA) form of Perindopril erbumine represented by formula (II).

Thus according to an aspect of the present invention there is provided a novel process of preparing perindopril erbumine free of unknown nonpolar impurities resulting into high purity of 99.9% with very good solubility.

Detailed Description

The inventors of the present invention have provided a novel crystalline η form of perindopril erbumine of Formula (II) exhibiting characteristic 2θ values. The novel crystalline η form of perindopril erbumine of the present invention has a purity of 99.9%.

The powder X-ray diffraction spectrum of novel crystalline η form of perindopril erbumine (formula II) was measured under the following experimental conditions: where instrument was analytical "X"pertpro, MPD system/multipurpose diffractometer, Holand. Measurement Temperature was 25

⁰ C, Anode material used was Cu and Generator setting was 3OmA, 40 kV.The

Measurement range of (°2θ) was 4 to 49.98°, and Step size (°2θ) was 0.0170, the PSD mode was scanning and scan type was continuous.

Perindopril Erbumine monohydrate is prepared as per the process disclosed in the prior art. The process is reproduced as follows:

1) Preparation of (2S, 3aS, 7aS)-octahydroindole-2-benzyloxy carbonyl tosylate:

(2S, 3aS, 7aS)-octahydroindole-2-benzyloxycarbonyl tosylate an important intermediate required for the purpose is made by reacting octahydro indole-2-carboxylic acid, para toluene sulphonic acid and benzyl alcohol using toluene as solvent followed by heating the contents at 85-125 ⁰ C preferably at 100-118 ⁰ C. Reflux is continued till water is completely removed. Reaction mass is cooled to -5 to 15°C preferably at 0-5 ⁰ C followed by addition of hexane and cooling is continued for 3-5 hours preferably 2-3 hours. Product is collected by filtration and is vacuum dried at 35-65 ⁰ C preferably at 40-45 ⁰ C. Crude so obtained is purified using isopropanol resulting into purity of (NLT 98%) with yield of 85-95% with respect to octahydro indole-2-carboxylic acid.

(2S,3aS,7aS)-octahydroindole-2-carboxylic acid (2S ₎ 3aS,7aS)-octaliydroindole-2-benzoyloxycarbonyl tosylate

2) Preparation of Intermediate 1-[N (1 -(S)-carboethoxy) butyl] alanine: lnsitu preparation of 1-[N (i-(S)-carboethoxy) butyl]-alanine required for the purpose is prepared by reaction between ethyl-L-norvalinate and sodium pyruvate in acidic conditions. Ethyl-L-norvalinate for the purpose is prepared by adding thionyl chloride into mixture of L-norvaline and ethyl

alcohol preferably pre-saturated with hydrogen chloride and heating the contents at 55-85°C preferably at 65-7O ⁰ C for 2-7 hours preferably 3-6 hours. Solvent is removed under the reduced pressure followed by stripping of toluene and also with cyclohexane to remove the excess of thionyl chloride followed by addition of water .Aqueous layer is separated and reacted with sodium pyruvate in acidic condition. Contents so obtained are subjected for hydrogenation using 5%Pd/C at 25-50 ⁰ C preferably at 35-4O ⁰ C for 3-7 hours preferably 5-6 hours preferably after reaction mixture is charcoalised to avoid the poisoning of catalyst due to the inorganic impurities coming from thionyl chloride. After completion of hydrogenation, catalyst is filtered off and sent for the recovery. Water is removed from the contents under the reduced pressure. Crude so obtained is finally purified by using acetonitrile resulting into 98% purity. Product so obtained remains associated with water in the range 7-9% thus providing monohydrate of the product.

L-norvaline

1-[N-(S)-ethoxycarbonyl)butyl]alanine

3) Preparation of (2a, 3aS, 7aS)-1 -[N-[I (S)-carboethoxybutyl]-aIanyl]-2-

[benzyloxy) carbonyl-octahydro indole]:

(2a, 3aS,- 7aS)-1 -[N-[I (S)-carboethoxybutyl]-alanyl]-2-[benzyloxy) carbonyl-octahydro indole is obtained by the procedure which comprises of condensation of N-[(S)-1-carboethoxybutyl]-(S)-alanine (98%) and (2S, 3aS, 7aS)~octahydroindole-2-benzyloxycarbonyl tosylate (98%) using 1- hydroxybenzotriazole, dicyclhexylcarbodiimide, triethylamine and ethyl acetate as solvent. After the completion of reaction organic layer is washed with water followed by its concentration under reduced pressure to get crude benzyl ester i.e.(2S,3aS,7aS)-1-[N-[1 (s)-carboethoxybutyl]- alanyl-2[(benzyloxy)carbonyl octahydro indole] which is further purified by making its hydrochloride using acetone as solvent to get final purity of 98% HPLC

(2S,3aS,7aS)-octahydroindole-2-benzoyloxycarbonyl tosylate

1-[N-(S)-ethoxycarbonyl)butyl]aianine

(2S,3aS,7aS)-1[N[1-(S)-carboethoxybutyl]-alanyl]-2-[(benz oyloxy)carbonyl octahydro indole]

Preparation of perindopril erbumine:

Perindopril erbumine i.e. (2S,3aS,7aS)-1 -[N-[I (s)-carboethoxybutyl]-alariyl]- octahydro indole]-2-carboxylic acid tertiary butylamine salt of (98%) purity is obtained by process comprising of debenzylation of (2S,3aS,7aS)-1-[N-[1(s)- carboethoxybutyl]-alanyl-2[(benzyloxy)carbonyl octahydro indole] using Pd/C as catalyst and ethanol as solvent at 5-30 ⁰ C preferably 10-20 ⁰ C for 1-4 hours preferably 1.5-2.5 hours. Reaction mass is then taken for the recovery of solvent under reduced pressure keeping temperature is the range of 15-35°C preferably 20-30 ⁰ C more preferably at 25-28°C is resulting into Perindopril base which is then converted lnsitu into Perindopril erbumine of 98% purity by

adding tert.butyl amine in to it using ethylacetate as solvent. Salt thus obtained is further purified from ethyl acetate to get purity of 99%.

(2S,3aS,7aS)-1 [N[1 -(S)-carboethoxybutyi]-alanyl]- (2S,3aS,7aS)-1 [N[1 -(S)-carboethoxybutyl]-amino]-1 -oxopropyl] 2-[(benzoyloxy)carbonyl octahydro indole] octahydro -1 H-indole-2-carboxylic acid tertiary bytul amine

The inventive process for preparation and purification of Perindopril erbumine monohydrate is described in Reaction scheme as follows:

Preparation of Perindopril erbumine monohydrate:

Perindopril erbumine monohydrate of high purity and exhibiting novel crystalline form of Perindopril erbumine is prepared by dissolving Perindopril erbumine obtained by process described above having~99% purity in water. Aqueous layer containing product is then taken for recovery of water till water content reaches to 10-20% in the reaction mass which is further reduced using polar solvent like acetone as co-solvent keeping the temperature at 25- 55°C preferably at 35-45°C, till the water content reaches to 5-7% preferably of 5.0%. Solid thus obtained is slurried in acetone, cooled at 2-20 ⁰ C preferably at 5 to 15°C and then filtered off. Solid is then dried at a temperature 25-75°C preferably at 45 to 50 ⁰ C more preferably 30-35 ⁰ C under vacuum till constant weight is achieved. Moisture content (NMT 4%), HPLC purity (~99.8%)Differential scanning calorimetry (167-170 ⁰ C).

(2S,3aS 7aSHIN[1-(S)-carbo ^β thoxybuy]-amlnoH-oxopropyl] octahydro -1 H-indole-2-carboxylic acid tertiary bytul amine

The inventive process for preparation and purification of perindopril erbumine η form is described in Reaction scheme as follows: Preparation of perindopril erbumine η form:

Perindopril erbumine η form of high purity and exhibiting novel crystalline form is prepared by dissolving Perindopril erbumine monohydrate obtained from above process in methylene dichloride in the range of (1 :8-12w/v) preferably (1 :9-11w/v) is then added with hexane (1 :18-25w/v) preferably (1 :19-21w/v) with recovering mixture of solvents in such a way so that ratio of Hexane: MDC remains (90-10) preferably 80:20 (v/v). HPLC method for Perindopril erbumine, Perindopril erbumine monohydrate remains same as described (2S, 3aS, 7aS)-1 -[N-[I (s)-carboethoxybutyl]-alanyl-2[(benzyloxy) carbonyl octahydro indole]

(2S,3aS,7aS)-1[N[1-(S)-carboethoxybutyl]-amino]-1-oxoprop yl] (2S,3aS,7aS)-1[N[1-(S)-carboethoxybutyl]-amino]-1-oxopropyl] octahydro -1 H-indole-2-carboxylic acid tertiary butyl amine monohydrate octahydro -1 H-indole-2-carboxylic acid tertiary butyl amine

The novel crystalline η form of perindopril erbumine thus obtained exhibits characteristic 2θ values as follows: 4.07, 5.26, 9.46, 15.75, 21.04, 21.35, 23.15, 24.13, 26.38, 31.8, 27.18

The most preferred volatile solvent according to present invention is hexane & methyelene di chloride.

A novel crystalline form of Perindopril erbumine η form as obtained by the purification of the present invention is highly pure with HPLC purity of ~99.9%.

The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to the non-limiting exemplary illustrations.

Examples: Example 1:

Preparation of (2S, 3aS, 7aS) octahydroindole-2-benzyloxycarbonyl tosylate:

Place toluene(4.4 L) & octahydro-indole-2-carboxylic acid (0.5kg, 2.95mol), p-toluene sulfonic acid (0.7kg, 3.68 mol) and benzyl alcohol (0.535kg,4.95mol) into a 20 L four neck flask well equipped with azeotropic unit and thermopocket under stirring and heat all the content to react at the temperature about 100- 118°C.Refluxion is continued till the water is removed completely & cooled at room temperature. Hexane is then added to the above contents and then cooled to temperature at 0-5 ⁰ C for 2hrs. Filter off the product and dry it at 40-45 ⁰ C under vacuum. Yield (1.3) Kg. Crude so obtained is further purified from isopropyl alcohol to get purified product (1.2kg, 2.78-mol), M. P.140-145 ⁰ C, and (purity of 98%).

Example 2: lnsitu preparation of N-[(S)-1-carboethoxybutyl]-(S)-alanine with high purity:

To the mixture of Alcohol (20It) and L-Norvaline (1.5 kg, 12.8mol) presaturated with hydrogen chloride, thionyl chloride (1.1 L, 15.15mol) is charged slowly keeping the temperature in the range of 15-20°C. Contents are then heated to reflux at 65-7O ⁰ C for 3-6 hrs. Ethyl alcohol is completely evaporated, reaction mass is then added with fresh toluene (2X1.5It) and removed under reduced pressure to remove the excess of thionyl chloride. The obtained residue is then taken into cyclohexane (3.5 L). Cyclohexane is then partially distilled off, and to this (6 L) of water is charged under stirring. Collect the aqueous layer to which 25% solution of sodium pyruvate (0.775g, 7.0 mol) is then added under stirring. Reaction mass before hydrogenation is charcoalised using 0.25kg

activated charcoal to remove impurities coming from thionyl chloride which are responsible for poisoning of the catalyst.

Content obtained after filtration are then taken for hydrogenation using 5%

Pd/C (0.25kg) at 38-4O ⁰ C and 5-6 Kg/Cm ² till no more hydrogen is consumed (4- 5 hrs). Reaction mass is filtered off and filtrate is concentrated under reduced pressure. Treat the solid with ethanol, remove insoluble content if any. Ethanol is then removed under reduced pressure and finally it crystallized from acetonitrile

(3.75 L) resulting into (1.3kg) of 98% purity which is used as such. Product so obtained remains associated with water in the range 7-9% thus providing monohydrate of the product.

Example 3:

Preparation of Benzyl ester of (2S, 3aS, 7aS)-1-{2-[1-(ethoxycarbonyl)-(S)- butylamino]-(S)-propionyl} Octahydroindole-2-carboxylic acid:

Charge (2S, 3aS, 7aS) octahydroindole-2-benzyloxycarbonyl tosylate (2kg, 4.63mol) of (purity 98%) into a reactor containing ethyl acetate (28 L) under stirring and triethylamine (0.6kg, 5.94mol) is then added slowly to the contents at temperature of -5to10°C. To the resulting mass is then added with N-[(S)-1- carboethoxybutyl]-(S)alanine (1.05kg, 4.8mol) of 98% purity and hydroxyl benzotriazole (0.92 kg, 6.76mol) at temperature around -5 to 10 ⁰ C and then solution of N.N-dicyclohexylcarbodiimide (1.12 kg,5.43mol)diluted in (14 L) ethyl acetate is added slowly into the above contents in about one - two hours.

Reaction mass then slowly brought to temperature of 25-3O ⁰ C for about half an hour till the reaction gets over. Chill the reaction mass to a temperature 0-5 ⁰ C and remove the salt by filteration. Filtrate so obtained is washed with water. Organic phase then concentrated under reduced pressure to get crude of (2kg)

(88% HPLC).

Purification of benzyl ester of (2S, 3aS, 7aS)-1-{2[1-(ethoxycarbonyl)-(S)- butylamino]-(S)-propionyl} octahydroindole-2-carboxylic acid by making its hydrochloride:

Crude 2.0kg (88%) so obtained need purification for which it is dissolved in (11 L) of acetone and insolubles are removed by the filteration. Hydrochloric acid

is added to adjust the pH from 0.1 to 1.0 and acetone is distilled off. Hydrochloride so obtained is then dissolved into (9.6L) water to get clear solution. Washing of an organic solvent like toluene is given to remove the organic impurities. pH of aqueous layer is adjusted to 9 and then extracted with methylene dichloride till product is completely extracted. Methylene dichloride is removed under reduced pressure at ambient temperature to get thick oil (1.85kg) having the purity (HPLC 98%).

Example 4:

Preparation of perindopri erbumine: Benzyl ester of (2S,3aS,7aS)-1-{2[1-(ethoxycarbonyl)-(S)-butylamino]-(S)- propionyl}octahydroindole-2-carboxylic acid (1.6kg) of 98% purity obtained by the process as described under above example was taken into ethyl alcohol(6.4L) and subjected for hydrogenation using 5%Pd/C(160g)at a pressure of 3-5kg/cm ² for 1-2 hrs at a temperature range of 10-15°C as high temperature reduces the purity of the Perindopril erbumine formed. After the completion of reaction catalyst was removed by filteration and filtrate was concentrated to get a thick oil at a temperature of 30-35 ⁰ C. Thick oil so obtained was then dissolved in ethyl acetate(14L) to which was then added tert. butyl amine (256g) to get perindopril erbumine (1.3kg) with not less than 98% HPLC purity which was further purified using ethyl acetate to get the purity of 99%.

Example 5:

Preparation of perindopril erbumine monohydrate:

Perindopril erbumine (150 g) of 99% purity as obtained in the above example is dissolved in DM water (0.450L) which was then extracted with (0.023 L) of toluene. Aqueous layer was collected and water was removed from the contents under the reduced pressure till water content reaches to 10-20% in the reaction mass which is further reduced using acetone as co-solvent keeping the temperature in the range of 20-45 ⁰ C preferably at 25-30 ⁰ C, till the moisture content is reached to the required (5-7%) Finally product so obtained was slurried in acetone (0.75L) and contents were cooled to 5-15°C and filtered off.

Product was dried under vacuum at 25-35 ⁰ C till required water content was reached. Dry weight of perindopril erbumine monohydrate(135g) with HPLC purity 99.8%,Moisture content NMT 4%, Differential scanning calorimetry (167-

170°C),characteristic 2θ values as 8.87, 9.43, 9.60, 15.36, 15.96, 16.02, 19.97, 21.00, 21.13, 21.5, 22.14, 24.13, 26.48.

Example 6:

Preparation of crystalline form of perindopril erbumine (η) form:

Example (A)

Perindopril erbumine monohydrate obtained by process as described under example 5 (0.1 kg) of 99.8 % HPLC purity is taken in dichloromethane (1 L) at 25-35°C Hexane (2L) is added in portions to the contents, and the mixture of solvents is removed from the contents keeping the temperature in the range of 20-45 ⁰ C. The product is finally slurried in hexane (0.5 L) and chilled to 0-10°C preferably at 5°C for 30 min. Product is filtered and dried under vacuum till constant weight (8Og) of HPLC purity 99.93% (1 g goes in 10 ml DM water in 5-7 seconds) very good solubility is obtained. Differential scanning calorimetry showed the endotherm at 144 ⁰ C. Characteristic 2θ values as: 4.07, 5.26, 9.46, 15.75, 21.04, 21.35, 23.15, 24.13, 26.38, 31.8, 27.18. Example (B) Perindopril erbumine monohydrate obtained by process as described under example 5 (1 kg) of 99.8 % HPLC purity is taken in dichloromethane (10 L) at 25-35°C. Hexane (20L) is added in portions to the contents, and the mixture of solvents is removed from the contents keeping the temperature in the range of 20-45°C. The product is finally slurried in hexane (4 L) and chilled to 0-10°C preferably at 5°C for 30 min. Product is filtered and dried under vacuum till constant weight (075kg) of HPLC purity 99.93% with (1 g goes in 10 ml DM water in 5-6 seconds)very good solubility is obtained. Differential scanning calorimetry showed the endotherm at 144°C. Characteristic 2θ values as: 4.07, 5.26, 9.46, 15.75, 21.04, 21.35, 23.15, 24.13, 26.38, 31.8, 27.18.

Perindopril erbumine monohydrate obtained by the process described under example 5 with purity (99.8%) is used to prepare novel crystalline form of perindopril erbumine of the present invention by the following process:

(i) Perindopril erbumine monohydrate is dissolved in dichloromethane in the ratio of 1 : 8 to 12(w/v) preferably (1 :9 to 11) (w/v) with respect to perindopril erbumine.

(ii) Hexane is added in the ratio of 1 :18-25(w/v) preferably, 1 :19 to21 (w/v) with respect to Perindopril erbumine monohydrate to precipitate perindopril erbumine.

(iii) Reaction mass is subjected for the recovery of mixture of solvents so that ratio remains in the range 80:20(hexane: MDC)

(iv) Temperature of the precipitated mass is maintained between O ⁰ C to 15 ⁰ C for 1 hour & then filtered.

(v) The solid is dried at 30-35 ⁰ C under reduced pressure.

A novel crystalline form of perindopril erbumine provided by the present invention denoted as η form exhibits characteristic 2θ values: 4.07, 5.26, 9.46, 15.75, 21.04, 21.35, 23.15, 24.13, 26.38, 31.8, 27.18.