Field of the invention
The present invention relates to an improved process for obtaining trandolapril Polymorphic Form II useful in the treatment of hypertension. The structure of Trandolapril is as follows :

Background of the Invention
The Angiotensin-converting Enzyme (ACE) inhibitor, trandolapril is commonly prescribed drug for the control and management of mild to severe hypertension and may be used alone or in combination with diuretics or other anti-hypertensive agents.
(2Ss3aR,7aS)-l-[(2S)-2-[[(lS)-l-(Ethoxycarbonyl)-3-phenylpropyl]amino-l-oxopropyl]octahydro-lH-indole-2-carboxylic acid (Trandolapril) was described along with related compounds in US 4,933,361. The process for the synthesis of trandolapril was described in US 4,933,361 and WO 96/33984.
According to US Pat No 4,933,361, benzyl N-(lS-carboethoxy-3-phenyl propyl)-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylate was hydrogenated under normal pressure in ethanol in the presence of 10% palladium charcoal and the solvent evaporated to yield trandolapril as a colourless foam.
The existence of two solid state forms of trandolapril has been described in US 2004/0220252 Al which are designated as Form I and Form IL This publication also discloses a process for the preparation of Trandolapril Form I and II from

diisopropyl ether and ethyl acetate respectively. The process involves dissolving the trandolapril in an organic solvent like ethyl acetate and refluxing for about 15 to 45 minutes and subsequently cooling to about 15 °C to about 35 °C and maintaining the solution at about 15 °C to about 35 °C for about 15 minutes to about 3 hrs and optionally seeding with Form II. Though this process uses only one solvent to prepare the required polymorph, it suffers from many drawbacks such as formation of degradation impurities at reflux temperature of the organic solvent used, temperature management and control of impurities.
The methods available for the preparation of the Form II in the literature seem to be limited and only to one solvent system, which makes the process left without any alternative options. The prior art does not show any other solvent or solvent mixtures for the preparing Form II.
In accordance with the present invention, a method has been found whereby trandolapril polymorph Form II can be readily produced without heating to reflux temperature and using simple crystallization techniques with a variety of solvent or solvent mixtures. This has been accomplished by simple recrystallization from a single or a mixture of solvents.
OBJECTIVES OF INVENTION
The objective of the present invention is to develop a new improved process for the preparation of Trandolapril Polymorphic Form II from a solvent or a mixture of solvents thereof.
Another objective of the present invention is to develop a process for the preparation of Polymorphic Form II of Trandolapril by simple crystallizations from suitable organic solvents or a mixture of organic solvents and water.

SUMMARY OF INVENTION
The present invention relates to a new improved process for the preparation of Trandolapril Form II by crystallizing in solvents and solvent mixtures selected from Ethyl acetate/water, isopropanol, Ethyl acetate/isopropanol, Ethyl acetate/isopropanol/water, Isopropanol/water and Ethyl acetate/ethanol/water. The process of preparing the required form II involves heating the crude trandolapril in the above mentioned solvents or solvent mixtures till dissolution, cooling the solution to ambient temperatures and subsequent cooling to 0-5 °C so as to obtain Form II. The pure trandolapril Form II was isolated by conventional techniques like filtration and drying.
DETAILED DESCRIPTION OF INVENTION
The present invention relates a new process for the preparation of Trandolapril Form II by crystallizing in a suitable solvent or solvent mixture selected from Ethyl acetate/water, isopropanol, Ethyl acetate/isopropanol, Ethyl acetate/isopropanol/water, Isopropanol/water and Ethyl acetate/ethanol/water. The process consists of dissolving crude trandolapril by heating in a solvent or solvent mixture of solvents, cooling the solution to ambient temperature and subsequent cooling to 0-5°C and stirring at the same temperature for 1 hr. The crystallized product was filtered and dried to yield pure trandolapril Form II.
In this present invention it is further found that, although not critical, it is preferred to add seed crystals of Form II to the solution of the reaction mixture to initiate crystallization and to yield Form II.
One of the advantages of the process of this invention is that in the present solvents and solvent mixtures, the product dissolves at low temperatures and the reaction temperature is heated only up to 55 °C thus avoiding degradation impurities that are usually associated with trandolapril above this temperatures.

Consequently, the pharmacoepial impurities are also reduced thereby making the process more simpler in terms of regulatory view point. In a way this process demonstrates that no extra effort is needed to make the product pharmacoepially compliant.
Additionally, another advantage of the present invention carries over the prior art is that the crystallization is simply achieved by bringing down the temperature to ambient temperature immediately. No intermediate cooling at different temperatures is needed in this process.
The X-ray diffraction pattern of trandolapril Form II obtained by the process of the invention matches with the known data available in literature.
The invention is further described by the following examples and is not intended to limit the scope of the invention.
EXPERIMENTAL
Preparation of Trandolapril Form-II
Example 1
10 g of crude trandolapril was dissolved in a mixture of ethyl acetate (107.58 ml) and DM water (2.42 ml) at 50-55 °C. The resulting solution was cooled to 37- 45°C and stirred for that 37-45°C. The mixture was cooled to 0-5 °C and stirred for 1 h at 0-5 °C. The crystallized product was filtered and dried to yield pure Trandolapril [(2S,3aR,7aS)-l-[(S)-2-[[(S)-l-(ethoxycarbonyl)-3- phenylpropyl]amino]propanoyl]octahydro-lH-indole-2-carboxylic acid] (8.5 g) in Form-II.

Example 2
10 g of crude trandolapril was dissolved isopropanol (60 ml) at 50-55 °C. The resulting solution was cooled to 40-45 °C and stirred for lh at 40-45 °C. The mixture was cooled to 0-5 °C and stirred for 1 h at 0-5 °C. The crystallized product was filtered and dried to yield pure Trandolapril [(2S,3aR,7aS)-l-[(S)-2-[[(S)-l-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]octahydro-lH-indole-2-carboxylic acid] (9.26 g) in Form-II.
Example 3
To the mixture of ethyl acetate (102 ml) and isopropanol (5 ml), DM water (2.7 ml) was added and stirred for 5 min. To the resulting mixture, crude trandolapril (10 g) was added and dissolved below 55 °C. The resulting solution was cooled to 35-40 °C and stirred for lh at 35-40°C. The mixture was cooled to 0-5°C and stirred for 1 h at 0-5 °C. The crystallized product was filtered and dried to yield pure Trandolapril [(2S,3aR,7aS)-l-[(S)-2-[[(S)-l-(ethoxycarbonyl)-3- phenylpropyl]amino]propanoyl]octahydro-lH-indole-2-carboxylic acid] (8.8 g) in Form-II.
Example 4
10 g of crude trandolapril was dissolved in a mixture of isopropanol (58.5ml) and DM water (1.5 ml) at below 60 °C. The resulting solution was cooled to 40-45 °C and stirred for that 40-45 °C. The mixture was cooled to 0-5 °C and stirred for 1 h at 0-5 °C. The crystallized product was filtered and dried to yield pure Trandolapril [(2S53aR,7aS)-l-[(S)-2-[[(S)-l-(ethoxycarbonyl)-3- phenylpropyl]amino]propanoyl]octahydro-lH-indole-2-carboxylic acid] (9.06 g) in Form-II.

Example 5
To the mixture of ethyl acetate (101.9 ml) and ethanol (4,87 ml), and DM water (2.68 ml) was added stirred for 5 min. To the resulting mixture, crude trandolapril (10 g) was added and dissolved at below 55 °C. The resulting solution was cooled to 35-40 °C and stirred for 1 h at 35-40 °C. The crystallized product was cooled to 0-5 °C and stirred for 1 h at 0-5 °C. The crystals were filtered and dried to yield pure trandolapril [(2S,3aR,7aS)-l-[(S)-2-[[(S)-l-(ethoxycarbonyl)-3-
phenylpropyl]amino]propanoyl]octahydro-lH-indole-2-carboxylic acid] (8.6 g) in Form -II.