WO2007026372A2 - Novel crystalline polymorph of trandolapril and a process for preparation thereof - Google Patents

Novel crystalline polymorph of trandolapril and a process for preparation thereof Download PDF

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Publication number
WO2007026372A2
WO2007026372A2 PCT/IN2005/000292 IN2005000292W WO2007026372A2 WO 2007026372 A2 WO2007026372 A2 WO 2007026372A2 IN 2005000292 W IN2005000292 W IN 2005000292W WO 2007026372 A2 WO2007026372 A2 WO 2007026372A2
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WIPO (PCT)
Prior art keywords
trandolapril
polymorph
crystalline polymorph
crystalline
preparation
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PCT/IN2005/000292
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French (fr)
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WO2007026372A3 (en
Inventor
Mukarram Siddiqui Mohammed Jaweed
Aravind Yekanathsa Merwade
Shahid Akhtar Ansari
Anis Mushtaqeali Saiyad
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Wockhardt Limited
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Priority to PCT/IN2005/000292 priority Critical patent/WO2007026372A2/en
Publication of WO2007026372A2 publication Critical patent/WO2007026372A2/en
Publication of WO2007026372A3 publication Critical patent/WO2007026372A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a novel crystalline polymorph W of Trandolapril, and to a process for preparation thereof.
  • the present invention also relates to pharmaceutical compositions containing polymorph W of Trandolapril and their use in the treatment of hypertension.
  • Trandolapril is an angiotensin converting enzyme inhibitor and was first disclosed in the US Patent No. 4,933,361. Chemically, Trandolapril is (2 ⁇ 3ai?,7a5)-l-[(25)-2-[[(l 1 S)-l- (ethoxycarbonyl)-3-phenylpropyl]amino]-l-oxopropyl]octahydro-lH-indole-2-carboxylic acid (Formula I).
  • Trandolapril can exist in two crystalline forms (Form I and II).
  • Published PCT Patent Application WO 05/051909Al also incorporated herein by reference further discloses two more crystalline forms of Trandolapril (Form A and B).
  • the ability of a substance to exist in more than one different crystal structures is known as polymorphism and the different crystal forms are known as polymorphs.
  • the polymorphs have same chemical composition but differ in geometrical arrangement in the crystalline state and may have different physical properties such as crystal shape, colour, hardness, stability and so on.
  • the applicants of the present invention have comprehensively investigated possibilities of preparing stable crystalline form of Trandolapril and have surprisingly found highly stable crystalline form of Trandolapril, designated as polymorph W.
  • the present invention relates to a novel crystalline polymorph W of Trandolapril.
  • compositions containing novel crystalline polymorph W of Trandolapril are provided.
  • Figure 1 is the X-ray powder diffractogram of polymorph W of Trandolapril
  • Figure 2 is the Infrared spectrum of polymorph W of Trandolapril
  • FIG. 3 is the DSC thermogram of polymorph W of Trandolapril Detailed description of the invention
  • the present invention provides a novel crystalline polymorph W of Trandolapril characterized by its X-ray diffractogram, infrared spectrum and differential scanning calorimetry thermogram.
  • the novel polymorph W of Trandolapril has characteristics X- ray diffraction peaks expressed as 2 ⁇ values at approximately 7.32, 8.00, 8.88, 12.28, 12.86, 14.00, 14.60, 15.66, 16.38, 16.98, 17.72, 17.80, 18.64, 19.76, 21.06, 21.48, 22.08, 22.90, 24.32, 25.12, 25.94, 26.72, 27.78 and 29.42.
  • X-ray diffraction spectrum of polymorph W of Trandolapril is depicted in Figure 1.
  • the significant reflections of Trandolapril form W are given in Table 1 (the intensities are expressed as percentage of the most intense peak)
  • the novel crystalline polymorph W of Trandolapril exhibits characteristics differential scanning calorimetry pattern substantially the same as the differential scanning calorimetry pattern shown in Figure 2.
  • the novel crystalline polymorph W of Trandolapril exhibits characteristics infrared spectrum pattern substantially the same as the infrared spectrum pattern shown in Figure 3.
  • the alcoholic solvent in the instant process is preferably selected from a group comprising of methanol, ethanol and isopropyl alcohol.
  • the second solvent is selected from a group comprising of ethyl acetate and isopropyl ether.
  • the said polymorph W of Trandolapril is prepared by dissolving Trandolapril in isopropyl alcohol at an elevated temperature of about 60 0 C, adding about 5 volumes of isopropyl ether, cooling to room temperature and stirring for another 6 hours at room temperature to give the desired polymorph W of Trandolapril.
  • the contents may also be seeded with polymorph W of Trandolapril, if desired.
  • the skilled artisan will appreciate a variety of other procedures that essentially result in the formation of polymorph W of Trandolapril .
  • compositions containing novel crystalline polymorph W of Trandolapril are provided.
  • the pharmaceutical compositions according to the present invention can be formulated into a wide range of dosage forms such as tablet, capsule etc. depending on the requirement.
  • Such compositions can be used in the treatment of various medical conditions, and preferably in the treatment of hypertension.
  • the present invention is described in more details with reference to the following examples that are only illustrative and should not be construed as a limitation on the scope of the invention.
  • Trandolapril 25gm is suspended in methanol (100ml) with charcoal (0.5gm) and the contents are heated to 48-50 0 C. The solution is agitated at this temperature for 30 minutes and filtered. Methanol is distilled off to get solid material, which is then taken into methanol (25ml) and ethyl acetate (187ml). The contents are then heated to 45-50 0 C to get a clear solution. This solution is then cooled to room temperature and maintained at room temperature for another 6 hours and filtered to get a crystalline product. The crystalline product obtained is dried under vacuum (20-40 mm/Hg at 45-50 0 C for 8-10 hours). Dry weight of the polymorph W of Trandolapril is 18.20 gm.
  • Dry weight of polymorph W of Trandolapril is 44.30gm.
  • Trandolapril (85 gm) is dissolved in isopropyl alcohol (425 ml) at 60 0 C and filtered. The clear filtrate is diluted with isopropyl ether and further maintained at 60 0 C to get a clear solution. The contents are cooled to room temperature and stirred further for 6 hours. The product is filtered and washed with mixture of isopropyl alcohol: isopropyl ether and suck dried. The product is dried under vacuum (10-30 mm/Hg) at 45-50 0 C for 6.0 hours. Dry weight of polymorph W of Trandolapril 72.8 gm. Advantageous features of the present invention
  • the present invention provides stable polymorph W of Trandolapril
  • Trandolapril of exceptionally high purity.
  • Trandolapril obtained according the present invention contains less than 0.1 % of DKP (diketopiprazine) impurity.

Abstract

The present invention relates to a novel crystalline polymorph of Trandolapril, a process for it's preparation and pharmaceutical compositions containing this polymorph.

Description

Novel crystalline polymorph of Trandolapril and a process for preparation thereof
Field of the invention
The present invention relates to a novel crystalline polymorph W of Trandolapril, and to a process for preparation thereof. The present invention also relates to pharmaceutical compositions containing polymorph W of Trandolapril and their use in the treatment of hypertension.
Background of the invention
Trandolapril is an angiotensin converting enzyme inhibitor and was first disclosed in the US Patent No. 4,933,361. Chemically, Trandolapril is (2^3ai?,7a5)-l-[(25)-2-[[(l1S)-l- (ethoxycarbonyl)-3-phenylpropyl]amino]-l-oxopropyl]octahydro-lH-indole-2-carboxylic acid (Formula I)..
Formula I
Figure imgf000002_0001
Published US Patent Application No. US 2004/0220252A1 incorporated herein by reference discloses that Trandolapril can exist in two crystalline forms (Form I and II). Published PCT Patent Application WO 05/051909Al also incorporated herein by reference further discloses two more crystalline forms of Trandolapril (Form A and B). The ability of a substance to exist in more than one different crystal structures is known as polymorphism and the different crystal forms are known as polymorphs. The polymorphs have same chemical composition but differ in geometrical arrangement in the crystalline state and may have different physical properties such as crystal shape, colour, hardness, stability and so on. The applicants of the present invention have comprehensively investigated possibilities of preparing stable crystalline form of Trandolapril and have surprisingly found highly stable crystalline form of Trandolapril, designated as polymorph W.
Summary of the invention
The present invention relates to a novel crystalline polymorph W of Trandolapril.
In one embodiment of the invention, there is disclosed a novel crystalline polymorph W of Trandolapril having characteristics physical properties.
In another embodiment of the invention, there is provided a process for preparation of the novel crystalline polymorph W of Trandolapril.
In a further embodiment of the invention, there are provided pharmaceutical compositions containing novel crystalline polymorph W of Trandolapril.
Further aspects and embodiments of the invention may become apparent to those skilled in the art from a review of the following detailed description, taken in conjunction with the examples and the claims. It must be understood that that the present disclosure is intended as illustrative only, and is not intended to limit the invention to the specific embodiments described herein.
Brief description of the drawings
Figure 1 is the X-ray powder diffractogram of polymorph W of Trandolapril
Figure 2 is the Infrared spectrum of polymorph W of Trandolapril
Figure 3 is the DSC thermogram of polymorph W of Trandolapril Detailed description of the invention
Accordingly, the present invention provides a novel crystalline polymorph W of Trandolapril characterized by its X-ray diffractogram, infrared spectrum and differential scanning calorimetry thermogram.
In one aspect of the invention, the novel polymorph W of Trandolapril has characteristics X- ray diffraction peaks expressed as 2Θ values at approximately 7.32, 8.00, 8.88, 12.28, 12.86, 14.00, 14.60, 15.66, 16.38, 16.98, 17.72, 17.80, 18.64, 19.76, 21.06, 21.48, 22.08, 22.90, 24.32, 25.12, 25.94, 26.72, 27.78 and 29.42. X-ray diffraction spectrum of polymorph W of Trandolapril is depicted in Figure 1. The significant reflections of Trandolapril form W are given in Table 1 (the intensities are expressed as percentage of the most intense peak)
Table 1.
2Θ (degree) d-spacing % Intensity
7.32 12.06 30
8.00 11.04 14
8.88 9.95 10
12.28 7.20 22
12.86 6.87 14
14.00 6.32 14
14.60 6.06 20
15.66 5.65 20
16.38 5.40 16
16.98 5.21 100
17.72 5.00 12
17.80 4.97 14
18.64 4.75 42
19.76 4.48 24
21.06 4.21 22
21.48 4.13 34
22.08 4.02 22
22.90 3.88 18
24.32 3.65 20
25.12 3.54 14
25.94 3.43 12
26.72 3.33 14
27.78 3.20 14
29.42 3.03 12 In another aspect of the invention, the novel crystalline polymorph W of Trandolapril exhibits characteristics differential scanning calorimetry pattern substantially the same as the differential scanning calorimetry pattern shown in Figure 2.
In yet another aspect of the present invention, the novel crystalline polymorph W of Trandolapril exhibits characteristics infrared spectrum pattern substantially the same as the infrared spectrum pattern shown in Figure 3.
In a further aspect of the present invention, there is provided a process for the preparation of polymorph W of Trandolapril comprising:
(a) dissolving Trandolapril in an alcoholic solvent at an elevated temperature,
(b) adding a second solvent, and
(c) cooling the contents to room temperature under stirring to get the desired polymorph W of Trandolapril.
The alcoholic solvent in the instant process is preferably selected from a group comprising of methanol, ethanol and isopropyl alcohol. The second solvent is selected from a group comprising of ethyl acetate and isopropyl ether. In one of the preferred methods, the said polymorph W of Trandolapril is prepared by dissolving Trandolapril in isopropyl alcohol at an elevated temperature of about 600C, adding about 5 volumes of isopropyl ether, cooling to room temperature and stirring for another 6 hours at room temperature to give the desired polymorph W of Trandolapril. The contents may also be seeded with polymorph W of Trandolapril, if desired. The skilled artisan will appreciate a variety of other procedures that essentially result in the formation of polymorph W of Trandolapril .
In a still further aspect of the invention, there are provided pharmaceutical compositions containing novel crystalline polymorph W of Trandolapril. The pharmaceutical compositions according to the present invention can be formulated into a wide range of dosage forms such as tablet, capsule etc. depending on the requirement. Such compositions can be used in the treatment of various medical conditions, and preferably in the treatment of hypertension. The present invention is described in more details with reference to the following examples that are only illustrative and should not be construed as a limitation on the scope of the invention.
Examples
Example 1
Semipure Trandolapril (25gm) is suspended in methanol (100ml) with charcoal (0.5gm) and the contents are heated to 48-500C. The solution is agitated at this temperature for 30 minutes and filtered. Methanol is distilled off to get solid material, which is then taken into methanol (25ml) and ethyl acetate (187ml). The contents are then heated to 45-500C to get a clear solution. This solution is then cooled to room temperature and maintained at room temperature for another 6 hours and filtered to get a crystalline product. The crystalline product obtained is dried under vacuum (20-40 mm/Hg at 45-500C for 8-10 hours). Dry weight of the polymorph W of Trandolapril is 18.20 gm.
Example 2
Semipure Trandolapril (81 gm) is dissolved in isopropyl alcohol (325 ml) at 600C and filtered. To the hot clear filtrate (500C), ethyl acetate (325 ml) is added and the contents are cooled to room temperature and. stirred for another 10 hours. The crystalline solid material obtained is filtered and washed with chilled isopropyl alcohol: ethyl acetate mixture. The product is died under vacuum (20-40 mm/Hg) at 45-500C for 3.0 hours.
Dry weight of polymorph W of Trandolapril is 44.30gm.
Example-3
Semipure Trandolapril (85 gm) is dissolved in isopropyl alcohol (425 ml) at 600C and filtered. The clear filtrate is diluted with isopropyl ether and further maintained at 600C to get a clear solution. The contents are cooled to room temperature and stirred further for 6 hours. The product is filtered and washed with mixture of isopropyl alcohol: isopropyl ether and suck dried. The product is dried under vacuum (10-30 mm/Hg) at 45-500C for 6.0 hours. Dry weight of polymorph W of Trandolapril 72.8 gm. Advantageous features of the present invention
1. The present invention provides stable polymorph W of Trandolapril
2. The crystallization step involved in the preparation of polymorph W of Trandolapril according to the present invention provides Trandolapril of exceptionally high purity. Typically, Trandolapril obtained according the present invention contains less than 0.1 % of DKP (diketopiprazine) impurity.

Claims

ClaimsWe claim:
1. A crystalline polymorph of Trandolapril, designated as polymorph W
2. The crystalline polymorph W of Trandolapril of claim 1 having characteristics X-ray diffraction peaks expressed as 2Θ values at approximately 7.32, 12.28, 14.60, 15.66, 16.98, 18.64, 19.76, 21.06, 21.48, 22.08 and 24.32.
3. The crystalline polymorph W of Trandolapril of claim 1 exhibiting characteristics an X-ray powder diffraction pattern as depicted in Figure 1
4. The crystalline polymorph W of Trandolapril of claim 1 exhibiting characteristics differential scanning calorimetry pattern as depicted in Figure 2.
5. The crystalline polymorph W of Trandolapril of claim 1 exhibiting characteristics infrared spectrum pattern as depicted in Figure 3.
6. A process for preparing polymorph W of Trandolapril comprising the steps of (a) dissolving Trandolapril in an alcoholic solvent at elevated temperature, (b) adding a second solvent, (c) cooling the contents to room temperature, and (d) isolating the product.
7. A process according to claim 6 wherein the alcoholic solvent is selected from a group comprising of methanol, ethanol and isopropyl alcohol
8. A process according to claim 6 wherein the second solvent is selected from a group comprising of ethyl acetate and isopropyl ether.
9. A process for preparing polymorph W of Trandolapril comprising the steps of (a) dissolving Trandolapril in isopropyl alcohol at about 6O0C, (b) adding isopropyl ether to the contents of step (a) and, (c) isolating the solid product.
10. A pharmaceutical composition comprising the polymorph W of Trandolapril in combination with a pharmaceutically acceptable carrier.
11. Use of crystalline polymorph W of Trandolapril according to any of claims 1-5 for the preparation of a medicament for the treatment of hypertension.
PCT/IN2005/000292 2005-09-01 2005-09-01 Novel crystalline polymorph of trandolapril and a process for preparation thereof WO2007026372A2 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4933361A (en) * 1981-12-29 1990-06-12 Hoechst Aktiengesellschaft Derivatives of bicyclic aminoacids agents containing these compounds and their use
WO2004076417A1 (en) * 2003-02-27 2004-09-10 Hetero Drugs Limited Novel crystalline forms of trandolapril

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4933361A (en) * 1981-12-29 1990-06-12 Hoechst Aktiengesellschaft Derivatives of bicyclic aminoacids agents containing these compounds and their use
WO2004076417A1 (en) * 2003-02-27 2004-09-10 Hetero Drugs Limited Novel crystalline forms of trandolapril

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