Field of the invention :

The present invention relates to novel Perindopril (L)-Lysine salt. The present invention also relates to amorphous Perindopril (L)-Lysine and processes for the preparation of amorphous Perindopril (L)-Lysine.

Background of the invention :

US 4,508,729 first disclosed perindopril and its pharmaceutically acceptable salts. Perindopril is active as Angiotensin Converting Enzyme (ACE) inhibitor and is commercially important anti-hypertensive agent. However, it has proved very difficult to find a pharmaceutically acceptable salt having not only good bioavailability but also adequate stability to be suitable for the preparation and storage of pharmaceutical compositions.

The non-salt form has been studied, as well as the maleate and the sodium salt. In the course of temperature and humidity stability studies it was found that the sodium salt was not suitable for handling because it is immediately converted inot an oil on contact with the atmosphere; as for the non-salt form and the maleate, they degrade rapidly under such conditions (approximately 25 to 30% of product degraded in 8 days at 50° c.).

Perindopril is chemically described as (2S,3aS,7aS)-1 -((S)-N-((S)-1 -carboxybutyl)-alanyl)hexahydro-2-indoline carboxylic acid, 1-ethyl ester and is structurally represented as formula I shown below:

Formula I

The arginine salt of perindopril is preferentially the salt of natural arginine (L-arginine), The basic characteristics of this salt include great stability to heat and to humidity compared to the tert-butylamine salt. Perindopril arginine is 50 % more stable than Perindopril tert-butylamine salt.

Perindopril arginine, it's hydrate and pharmaceutical composition and a method of treatment was first disclosed in US 6,696,481. However, this patent does not specify the conditions obtaining the arginine salt of perindopril and its hydrates. This patent does not teach about the polymorphic forms.

According to our laboratory development in different salts preferentially the salt if natural (L)-lysine We have screened some of the selected amino acids to find the appropriate back up for the arginine salt and found that Lysine is the best suitable back up in terms of stability, purity and yields.

We have carried out the crystallization of Perindopril-(L)-Lysine in different solvents or mixture of solvents by applying different parameters to obtain amorphous Perindopril (L)-Lysine.

According to Konno T., Chem. Pharm. Bull., 1990, 38:2003-2007, the amorphous form of an individual pharmaceutical active substance has different dissolution characteristics and a different bioavailability in comparison to crystalline forms. For some therapeutical indications, bioavailability is one of the key parameters in determining the forms of the pharmaceutical active substance entering the pharmaceutical form. It is generally known that pharmaceutical active substances in amorphous form are better soluble, or dissolve more quickly than crystalline ones.

Further, amorphous and crystalline forms of a drug may have different physical forms, particle size, hardness and glass transition temperatures.

Also, amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug such as easy to make the solid dosage form, compressibility during the manufacture process.

Accordingly, the ordinary skilled person will appreciate that, if a drug can be readily obtained in a stable pure amorphous form, the above problem may be solved. Thus, in the manufacture of commercially viable and pharmaceutically acceptable drug compositions, it is important to provide drug in amorphous and stable form. The innovation of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product such as stability.

Object of the invention

The main object of the present invention provides Perindopril (L)-Lysine salt.
Another object of the present invention provides amorphous form of Perindopril (L)-Lysine.

Yet another object of the present invention provides a process for the preparation of amorphous Perindopril (L)-Lysine.

Summary of the Invention :

The main aspect of the present invention relates to Perindopril (L)-Lysine salt.
Another object of the present invention relates to amorphous form of Perindopril (L)-Lysine.

Yet another aspect of the present invention relates to a process for the preparation of amorphous form of Perindopril (L)-Lysine.

In one aspect, the present invention relates to a process for the preparation of amorphous form of Perindopril (L)-Lysine comprising the steps of dissolving or suspending Perindopril free acid in a suitable solvent, adding L-Iysine and removing the solvent to get amorphous Perindopril (L)-Lysine.

In another aspect, the present invention relates to a process for the preparation of amorphous form of Perindopril (L)-Lysine comprising the steps of dissolving or suspending Perindopril (L)-Lysine in a suitable solvent, adding antisolvent, and isolating amorphous Perindopril (L)-Lysine.

In yet another aspect, the present invention relates to a process for the preparation of amorphous form of Perindopril (L)-Lysine comprising the steps of dissolving or suspending Perindopril (L)-Lysine in a suitable solvent, and isolating the solvent to get amorphous Perindopril (L)-Lysine.

In yet another aspect, the present invention relates to a process for the preparation of amorphous form of Perindopril (L)-Lysine comprising the steps of dissolving or suspending Perindopril (L)-Lysine in a suitable solvent, adding polyvinylpyrrolidone, and removing the solvent to get amorphous Perindopril (L)-Lysine.

Brief description of the drawings :

Fig -1 is a typical powder X-ray diffraction diagram of amorphous Perindopril (L)-
Lysine.

Fig-2 is a typical powder X-ray diffraction diagram of amorphous Perindopril (L)-Lysine
obtained as per the example 7.

Fig.-3 is the Infra Red spectrum of amorphous Perindopril (L)-Lysine
Detailed description of the invention :

Powder X-rav Diffraction (PXRD)

The said amorphous form of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorph of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 6/ 0 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40 KV and 30 mA. The experiments were conducted over the 2 0 range of 2.0°-5.0°, 0.030° step size and 50 seconds step time.

Infrared spectroscopy

Fourier transform infrared (FT-IR) spectra were recorded with a Perkin-Elmer spectrum one spectrophotometer. The samples were prepared as 13mm thickness potassium bromide discs by triturating 1 to 2mg of sample with 300mg to 400mg of KBR by applying pressure of about 1000 lbs/sq inch. Then theses discs were scanned in the spectral range of 4000 to 650 cm"1 with a resolution of 4 cm'1.

The present invention relates to Perindopril (L)-Lysine salt. The present invention also relates to amorphous form of Perindopril (L)-Lysine and process for the preparation of amorphous form of Perindopril (L)-Lysine.

According to the present invention, Perindopril-(L)-Lysine is prepared by dissolving perindopril in a suitable solvent, adding (L)-Lysine, removing the solvent and isolating Perindopril-(L)-Lysine.

According to the present invention, amorphous Perindopril (L)-Lysine is characterized by XRD pattern as shown in Figure-1 and Figure -2.

According to the present invention, amorphous Perindopril (L)-Lysine is further characterized by IR with absorption bands (cm'1) at 549, 670, 709, 747, 862, 1024, 1097, 1148, 1188, 1249, 1323, 1397, 1517, 1611, 1731, 2119, 2933, and 3444 respectively as depicted in Figure 3.

In one embodiment, the present invention encompasses the process for the preparation of amorphous Perindopril (L)-Lysine comprising the steps of:

a) suspending or dissolving Perindopril free acid in a solvent,
b) adding L-Lysine,
c) removing the solvent, and
d) isolating amorphous Perindopril (L)-Lysine.

In another embodiment, the present invention encompasses a process for the preparation of amorphous Perindopril (L)-Lysine comprising the steps of:

a) dissolving Perindopril (L)-Lysine in a solvent,
b) adding antisolvent, and
c) isolating amorphous Perindopril (L)-Lysine.

In yet another embodiment, of the present invention encompasses a process for the preparation of amorphous Perindopril (L)-Lysine comprising the steps of:

a) dissolving Perindopril (L)-Lysine in a solvent,
b) removing the solvent, and
b) isolating amorphous Perindopril (L)-Lysine.

In yet another embodiment, the present invention encompasses a process for the preparation of amorphous Perindopril (L)-Lysine comprising the steps of:

a) suspending Perindopril (L)-Lysine in a solvent,
b) heating the solution to reflux,
c) cooling to room temperature, and
d) isolating perindopril-(L)-Lysine.

In yet another embodiment, the present invention encompasses a process for the preparation of amorphous Perindopril-(L)-Lysine comprising the steps of;

a) suspending Perindopril -(L)-Lysine in a solvent,
b) adding Polyvinylpyrrolidone,
c) removing the solvent, and
d) isolating amorphous PerindopriI-(L)-Lysine.

According to the present invention, the perindopril free acid or Perindopril-(L)-Lysine is dissolved in a solvent selected from water, acetonitrile, ketones such as acetone, methyl isobutyl ketone, and cyclohexanone; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, tertiary-butyl alcohol, cyclohexan-1-ol, ethylene glycol; chlorinated solvents such as dichloromethane, chloroform, 1,2-dichloroethene; hydrocarbon solvents
such as toluene, xylene, n-hexane, n-heptane, cyclohexane, esters such as ethyl acetate or their mixtures thereof.

According to the present invention, the anti-solvent is selected from n-heptane, isopropyl ether, hexane, and pentane, more preferably n-heptane.

According to the present invention the solvent is removed by using conventional techniques such as distillation, spray drying, freeze drying or lyophilisation and the like.

According to the present invention, the solid obtained in the antisolvent method is gummy in nature and can be dried under vacuum thus isolating the amorphous Perindopril-(L)-Lysine.

According to the present invention, Perindopril-(L)-Lysine is prepared by solid dispersion method wherein Perindopril-(L)-Lysine and polyvinylpyrrolidine are used in the 1:7 ratio. The said materials are dissolved in a suitable solvent such as methanol and the resulting solution is concentrated under reduced pressure to isolate amorphous Perindopril-(L)-Lysine.

EXAMPLES

Example 1: Preparation of amorphous Perindopril (L)-Lysine by spray drying.
Perindopril free acid (lOg) was suspended in water (100ml) at 25-30 °C. To this solution L-Lysine (4.45g) was added and stirred for 15 min to get the clear solution. The resulting solution was subjected to spray drying by using Buchi mini spray dryer (Model: B-290). The solid obtained was identified as amorphous Perindopril (L)-Lysine. Example 2: Preparation of amorphous Perindopril (L)-Lysine by lyophilization. Perindopril free acid (30g) was dissolved in water (150ml) at 25-30 °C. L-lysine (13.3g) was added to it and stirred for 15 min to get clear solution. The resulting solution was filtered through hiflow bed to remove the undissolved particulate. The resulting clear solution was freeze dried (Model: Virtis Genesis SQ Freeze Dryer). The solid obtained was identified as amorphous form of Perindopril (L)-Lysine.

(m/c = 1.83 %, HPLC purity = 99.61%)
Example 3: Preparation of amorphous Perindopril (L)-Lysine by distillation
Perindopril free acid (3.6g) was dissolved in methanol (10ml) at 25-30 °C. L-Lysine
(1.6g) was dissolved in methanol (15ml) and added to the above solution. The resulting
solution was filtered through hiflow bed to remove the undissolved particulate. The
resulting solution was distilled out completely under vacuum at 50 °C. The solid obtained
was identified as amorphous form of Perindopril-(L)-Lysine salt.

Example 4: Preparation of Amorphous Perindopril (L)-Lysine by anti-solvent
Method Perindopril (L)-Lysine (2g) (as prepared in example-2) was dissolved in methanol (10ml) at 25-30 °C. The resulting solution was added to n-heptane under stirring at 25-30 °C.

The solid obtained was gummy in nature which was dried under vacuum at 50 °C for 18
h. The free solid obtained was identified as amorphous Perindopril (L)-Lysine.

Example 5: Preparation of amorphous Perindopril (L)-Lysine by distillation
Perindopril (L)-Lysine (Ig) (as prepared in example-2) was dissolved in ethyl acetate (5
ml) at 25-30 °C. The solution was filtered through hiflow bed to remove the undissolved
particulates. The resulting solution was distilled out completely under vacuum at 50°C till
it was free powder. The solid obtained was identified as amorphous Perindopril (L)-Lysine.

Example 6: Preparation of amorphous Perindopril (L)-Lysine by slurry method
Amorphous Perindopril (L)-Lysine (lg) was suspended in acetonitrile (10 ml) at 25-30 °C
and refluxed for 18 hours. The resulting mass was cooled to 25-30 °C, filtered and dried
under vacuum at 50°C for 18 h. The solid obtained was identified as amorphous
Perindopril (L)-Lysine.

Example 7: Preparation of a 1:7 wt: wt Perindopril (L)-Lysine and PVP solid
Dispersion Perindopril (L)-Lysine (1.5g) was suspended in methanol (50ml) and PVP (lOg) was added to it and stirred so that the solid dissolved at 25-30 °C . The resulting solution was concentrated at 50°C under reduced pressure to give the product as a white solid.

We claim

1. Perindopril (L)-Lysine salt,

2. Amorphous Perindopril (L)-Lysine.

3. Amorphous Perindopril (L)-Lysine according to claim 2, having a powder X-ray diffraction pattern as substantially depicted in figures 1 and 2 and IR as substantially depicted in figure 3.

4. A process for the preparation of amorphous Perindopril (L)-Lysine comprising the steps of:

a) suspending or dissolving Perindopril free acid in a solvent,
b) adding L-Lysine,
c) removing the solvent, and
d) isolating amorphous Perindopril (L)-Lysine.

5. A process for the preparation of amorphous Perindopril (L)-Lysine comprising the
steps of:
a) dissolving Perindopril (L)-Lysine in a solvent,
b) adding antisolvent, and
c) isolating amorphous Perindopril (L)-Lysine.

6. A process for the preparation of amorphous Perindopril (L)-Lysine comprising the
steps of:
a) dissolving Perindopril (L)-Lysine in a solvent,
b) removing the solvent, and
b) isolating amorphous Perindopril (L)-Lysine.

7. A process for the preparation of amorphous Perindopril (L)-Lysine comprising the
steps of:
a) suspending Perindopril (L)-Lysine in a solvent,
b) heating the solution to reflux,
c) cooling to room temperature, and
d) isolating perindopril-(L)-Lysine.

8. A process for the preparation of amorphous Perindopril-(L)-Lysine comprising the
steps of;
a) suspending Perindopril -(L)-Lysine in a solvent,
b) adding Polyvinylpyrrolidone,
c) removing the solvent, and
d) isolating amorphous Perindopril-(L)-Lysine,

9. The process according to claims 4 to 8, wherein the perindopril free acid or
Perindopril-(L)-Lysine is dissolved in a solvent selected from water, acetonitrile, ketones
such as acetone, methyl isobutyl ketone, and cyclohexanone; alcohols such as methanol,
ethanol, isopropanol, n-propanol, n-butanol, tertiary-butyl alcohol, cyclohexan-1-ol,
ethylene glycol; chlorinated solvents such as dichloromethane, chloroform, 1,2-
dichloroethene; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane,
cyclohexane, esters such as ethyl acetate or their mixtures thereof.

10. The process according to claim 5, wherein the anti-solvent is selected from n-heptane,
isopropyl ether, hexane, and pentane, more preferably n-heptane.