WO2004089952A1 - Novel crystalline forms of abacavir sulfate - Google Patents

Novel crystalline forms of abacavir sulfate Download PDF

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Publication number
WO2004089952A1
WO2004089952A1 PCT/IN2003/000145 IN0300145W WO2004089952A1 WO 2004089952 A1 WO2004089952 A1 WO 2004089952A1 IN 0300145 W IN0300145 W IN 0300145W WO 2004089952 A1 WO2004089952 A1 WO 2004089952A1
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Prior art keywords
abacavir sulfate
abacavir
crystalline form
suitable solvent
sulfate
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PCT/IN2003/000145
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French (fr)
Inventor
Reddy Bandi Parthasaradhi
Reddy Kura Rathnakar
Reddy Rapolu Raji
Reddy Dasari Muralidhara
Reddy Kesireddy Subash Chander
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Hetero Drugs Limited
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Priority to AU2003242983A priority Critical patent/AU2003242983A1/en
Priority to PCT/IN2003/000145 priority patent/WO2004089952A1/en
Publication of WO2004089952A1 publication Critical patent/WO2004089952A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms

Definitions

  • the present invention relates to novel crystalline forms of abacavir sulfate, to processes for their preparation and to pharmaceutical compositions containing them.
  • Abacavir of formula (1) is Abacavir of formula (1) :
  • Abacavir sulfate is a nucleoside reverse transcriptase inhibitor and used in the treatment of human immunodeficiency virus infection.
  • Abacavir sulfate and related compounds and their therapeutic uses are disclosed in US 5,034,394.
  • the object of the present invention is to provide stable novel crystalline forms of abacavir sulfate, processes for preparing these forms and pharmaceutical compositions containing them.
  • a novel crystalline form of abacavir sulfate designated as form I, characterized by an x- ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 8.6, 13.3, 14.8, 15.3, 17.2, 17.7, 19.3, 20.8, 21.4, 22.0, 22.9, 23.9, 25.3, 25.8 and 26.6 degrees.
  • Figure 1 shows typical form I x-ray powder diffraction spectrum.
  • a process for preparation of form I abacavir sulfate.
  • abacavir free base is dissolved in a suitable solvent, sulfuric acid is added to the solution and form I abacavir sulfate is isolated by filtration or centrifugation.
  • the quantity of sulfuric acid per mole of abacavir free base is not critical, but 0.5 - 1.0 mole of sulfuric acid per mole of abacavir free base is preferred.
  • the suitable solvents are ethyl acetate, acetone, diethyl ketone, methyl isobutyl ketone, n-butyl acetate, isopropyl acetate and methyl propyl ketone; and a mixture thereof.
  • the preferably solvents are ethyl acetate and acetone.
  • a novel crystalline form of abacavir sulfate designated as form II, characterized by an x- ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 9.3, 12.1 , 17.2, 17.8, 18.4, 20.9, 21.4, 22.7, 24.4, 28.4 and 29.3 degrees.
  • Figure 2 shows typical form II x-ray powder diffraction spectrum.
  • a process for preparation of form II abacavir sulfate.
  • abacavir free base is dissolved in a suitable solvent, sulfuric acid is added and form II abacavir sulfate is isolated by filtration or centrifugation.
  • the quantity of sulfuric acid per mole of abacavir free base is not critical, but 0.5 - 1.0 mole of sulfuric acid per mole of abacavir free base is preferred.
  • the suitable solvents are acetonithle, chloroform, methyl tert-butyl ether, toluene, tetrahydrofuran, dimethyl formamide, dioxane; and a mixture thereof.
  • the preferable solvents are acetonitrile and methyl tert-butyl ether.
  • a novel crystalline form of abacavir sulfate designated as form III, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 7.4, 8.5, 8.7, 9.4, 12.1 , 13.3, 14.9, 15.2, 17.2, 17.9, 19.4, 20.8, 21.4, 22.8, 23.8, 25.2 and 26.6 degrees.
  • Figure 3 shows typical form 111 x-ray powder diffraction spectrum.
  • a process for preparation of form III abacavir sulfate which comprises the steps of; a) dissolving abacavir free base in an alcohol; b) adding sulfuric acid to the solution formed in (a); c) maintaining for about 15 minutes to 10 hours; d) adding diisopropyl ether; and e) isolating form III abacavir sulfate.
  • the suitable alcohol is methanol, isopropyl alcohol or ethanol; or a mixture thereof.
  • the quantity of sulfuric acid per mole of abacavir free base is not critical, but 0.5 - 1.0 mole of sulfu ⁇ c acid per mole of abacavir free base is preferred.
  • the contents are preferably maintained for about 1 to 3 hours at 10°C to 30°C.
  • Abacavir free base used in the above processes can be obtained from the previously known methods.
  • a pharmaceutical composition comprising a crystalline form of abacavir sulfate and pharmaceutically acceptable carrier or diluent.
  • the crystalline form includes form I, form II or form III.
  • Figure 1 s a x-ray powder d liffract on spectrum of form I abacavir sulfate.
  • Figure 2 s a x-ray powder d liffracti on spectrum of form II abacavir sulfate.
  • Figure 3 s a x-ray powder d liffracti on spectrum of form III abacavir sulfate.
  • x-Ray powder diffraction spectrum was measured on a Siemens D5000 x- ray powder diffractometer having a copper-K ⁇ radiation.
  • Abacavir free base (3.0 gm, obtained by the process described in example 21 of US 5,034,394) is dissolved in ethyl acetate (15 ml) and cone, sulfuric acid (0.3 ml) is added to the solution. Then the contents are stirred for 3 hours at 20°C and filtered to give 3.0 gm of form I abacavir sulfate.
  • Example 2 Abacavir free base (3.0 gm) is dissolved in acetone (20 ml) and cone, sulfuric acid (0.3 ml) is added to the solution. Then the contents are stirred for 6 hours at 25°C and filtered to give 2.8 gm of form I abacavir sulfate.
  • Example 3 Abacavir free base (3.0 gm) is dissolved in acetonitrile (15 ml) and sulfuric acid (0.3 ml) is added to the solution. Then the contents are stirred for 2 hours at 25°C and the separated solid is filtered to give 3.0 gm of form II abacavir sulfate.
  • Example 4 Abacavir free base (3.0 gm) is dissolved in methyl tert-butyl ether (25 ml) and sulfuric acid (0.3 ml) is added to the solution. Then the contents are stirred for 1 hours at 25°C and the separated solid is filtered to give 3.0 gm of form II abacavir sulfate.
  • Example 5 Abacavir free base (3.0 gm) is dissolved in methanol (15 ml) and sulfuric acid (0.3 ml) is added to the solution. The contents then are cooled to 0°C and diisopropyl ether (15 ml) is added. The reaction mass is stirred for 2 hours at about 25°C and the separated solid is filtered to give 3.0 gm of form III abacavir sulfate.

Abstract

The present invention relates to novel crystalline forms of abacavir sulfate, to processes for their preparation and to pharmaceutical compositions containing them.

Description

NOVEL CRYSTALLINE FORMS OF ABACAVIR SULFATE
FIELD OF THE INVENTION
The present invention relates to novel crystalline forms of abacavir sulfate, to processes for their preparation and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Abacavir of formula (1) :
Figure imgf000002_0001
or (1 S,4R)-4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1 - methanol and its salts are nucleoside reverse transcriptase inhibitors. Abacavir sulfate is a nucleoside reverse transcriptase inhibitor and used in the treatment of human immunodeficiency virus infection. Abacavir sulfate and related compounds and their therapeutic uses are disclosed in US 5,034,394.
Crystalline forms of abacavir sulfate have not been reported in the literature. Moreover, the processes described in the literature do not produce abacavir sulfate in a stable, well-defined and reproducible crystalline form. It has now been discovered that abacavir sulfate can be prepared in three stable, well-defined and consistently reproducible crystalline forms.
The object of the present invention is to provide stable novel crystalline forms of abacavir sulfate, processes for preparing these forms and pharmaceutical compositions containing them. DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided a novel crystalline form of abacavir sulfate, designated as form I, characterized by an x- ray powder diffraction spectrum having peaks expressed as 2Θ at about 8.6, 13.3, 14.8, 15.3, 17.2, 17.7, 19.3, 20.8, 21.4, 22.0, 22.9, 23.9, 25.3, 25.8 and 26.6 degrees. Figure 1 shows typical form I x-ray powder diffraction spectrum.
In accordance with the present invention, a process is provided for preparation of form I abacavir sulfate. In this process, abacavir free base is dissolved in a suitable solvent, sulfuric acid is added to the solution and form I abacavir sulfate is isolated by filtration or centrifugation. The quantity of sulfuric acid per mole of abacavir free base is not critical, but 0.5 - 1.0 mole of sulfuric acid per mole of abacavir free base is preferred. The suitable solvents are ethyl acetate, acetone, diethyl ketone, methyl isobutyl ketone, n-butyl acetate, isopropyl acetate and methyl propyl ketone; and a mixture thereof. The preferably solvents are ethyl acetate and acetone.
In accordance with the present invention, there is provided a novel crystalline form of abacavir sulfate, designated as form II, characterized by an x- ray powder diffraction spectrum having peaks expressed as 2Θ at about 9.3, 12.1 , 17.2, 17.8, 18.4, 20.9, 21.4, 22.7, 24.4, 28.4 and 29.3 degrees. Figure 2 shows typical form II x-ray powder diffraction spectrum.
In accordance with the present invention, a process is provided for preparation of form II abacavir sulfate. In this process, abacavir free base is dissolved in a suitable solvent, sulfuric acid is added and form II abacavir sulfate is isolated by filtration or centrifugation. The quantity of sulfuric acid per mole of abacavir free base is not critical, but 0.5 - 1.0 mole of sulfuric acid per mole of abacavir free base is preferred. The suitable solvents are acetonithle, chloroform, methyl tert-butyl ether, toluene, tetrahydrofuran, dimethyl formamide, dioxane; and a mixture thereof. The preferable solvents are acetonitrile and methyl tert-butyl ether.
In accordance with the present invention, there is provided a novel crystalline form of abacavir sulfate, designated as form III, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 7.4, 8.5, 8.7, 9.4, 12.1 , 13.3, 14.9, 15.2, 17.2, 17.9, 19.4, 20.8, 21.4, 22.8, 23.8, 25.2 and 26.6 degrees. Figure 3 shows typical form 111 x-ray powder diffraction spectrum.
In accordance with the present invention, a process is provided for preparation of form III abacavir sulfate which comprises the steps of; a) dissolving abacavir free base in an alcohol; b) adding sulfuric acid to the solution formed in (a); c) maintaining for about 15 minutes to 10 hours; d) adding diisopropyl ether; and e) isolating form III abacavir sulfate.
The suitable alcohol is methanol, isopropyl alcohol or ethanol; or a mixture thereof. The quantity of sulfuric acid per mole of abacavir free base is not critical, but 0.5 - 1.0 mole of sulfuπc acid per mole of abacavir free base is preferred. After the addition of sulfuric acid, the contents are preferably maintained for about 1 to 3 hours at 10°C to 30°C. Preferably at least 20 ml of diisopropyl ether is used per 100 ml of alcohol.
Abacavir free base used in the above processes can be obtained from the previously known methods.
In accordance with the present invention, there is provided a pharmaceutical composition comprising a crystalline form of abacavir sulfate and pharmaceutically acceptable carrier or diluent. The crystalline form includes form I, form II or form III.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 s a x-ray powder d liffract on spectrum of form I abacavir sulfate.
Figure 2 s a x-ray powder d liffracti on spectrum of form II abacavir sulfate. Figure 3 s a x-ray powder d liffracti on spectrum of form III abacavir sulfate. x-Ray powder diffraction spectrum was measured on a Siemens D5000 x- ray powder diffractometer having a copper-Kα radiation.
The following examples further illustrate the present invention.
Example 1
Abacavir free base (3.0 gm, obtained by the process described in example 21 of US 5,034,394) is dissolved in ethyl acetate (15 ml) and cone, sulfuric acid (0.3 ml) is added to the solution. Then the contents are stirred for 3 hours at 20°C and filtered to give 3.0 gm of form I abacavir sulfate. Example 2 Abacavir free base (3.0 gm) is dissolved in acetone (20 ml) and cone, sulfuric acid (0.3 ml) is added to the solution. Then the contents are stirred for 6 hours at 25°C and filtered to give 2.8 gm of form I abacavir sulfate.
Example 3 Abacavir free base (3.0 gm) is dissolved in acetonitrile (15 ml) and sulfuric acid (0.3 ml) is added to the solution. Then the contents are stirred for 2 hours at 25°C and the separated solid is filtered to give 3.0 gm of form II abacavir sulfate.
Example 4 Abacavir free base (3.0 gm) is dissolved in methyl tert-butyl ether (25 ml) and sulfuric acid (0.3 ml) is added to the solution. Then the contents are stirred for 1 hours at 25°C and the separated solid is filtered to give 3.0 gm of form II abacavir sulfate.
Example 5 Abacavir free base (3.0 gm) is dissolved in methanol (15 ml) and sulfuric acid (0.3 ml) is added to the solution. The contents then are cooled to 0°C and diisopropyl ether (15 ml) is added. The reaction mass is stirred for 2 hours at about 25°C and the separated solid is filtered to give 3.0 gm of form III abacavir sulfate.

Claims

We claim:
1. A crystalline form I abacavir sulfate, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 8.6, 13.3, 14.8, 15.3, 17.2, 17.7, 19.3, 20.8, 21.4, 22.0, 22.9, 23.9, 25.3, 25.8 and 26.6 degrees.
2. A crystalline form I abacavir sulfate as defined in claim 1 , further characterized by an x-ray powder diffraction spectrum as in figure 1.
3. A process for preparation of form I abacavir sulfate as defined in claim 1 , which comprises the steps of: a) dissolving abacavir free base in a suitable solvent; b) adding sulfuric acid; and c) isolating form I abacavir sulfate; wherein the suitable solvent is selected from the group consisting of ethyl acetate, acetone, diethyl ketone, methyl isobutyl ketone, n-butyl acetate, isopropyl acetate and methyl propyl ketone.
4. A process according to claim 3, wherein the suitable solvent is ethyl acetate.
5. A process according to claim 3, wherein the suitable solvent is acetone.
6. A crystalline form II abacavir sulfate, characterized by an x-ray powder diffraction spectrum having peaks expressed as 26 at about 9.3, 12.1 , 17.2,
17.8, 18.4, 20.9, 21.4, 22.7, 24.4, 28.4 and 29.3 degrees.
7. A crystalline form II abacavir sulfate as defined in claim 6, further characterized by an x-ray powder diffraction spectrum as in figure 2.
8. A process for preparation of form II abacavir sulfate as defined in claim 6, which comprises the steps of: a) dissolving abacavir free base in a suitable solvent; b) adding sulfuric acid; and c) isolating form II abacavir sulfate; wherein the suitable solvent is selected from the group consisting of acetonitrile, chloroform, methyl tert-butyl ether, toluene, tetrahydrofuran, dimethyl formamide and dioxane.
9. A process according to claim 8, wherein the suitable solvent is acetonitrile.
10. A process according to claim 8, wherein the suitable solvent is methyl tert- butyl ether.
11. A crystalline form III abacavir sulfate, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 7.4, 8.5, 8.7, 9.4, 12.1, 13.3, 14.9, 15.2, 17.2, 17.9, 19.4, 20.8, 21.4, 22.8, 23.8, 25.2 and 26.6 degrees.
12. A crystalline form III abacavir sulfate as defined in claim 11 , further characterized by an x-ray powder diffraction spectrum as in figure 3.
13. A process for preparation of form III abacavir sulfate as defined in claim 11 , which comprises the steps of: a) dissolving abacavir free base in an alcohol; b) adding sulfuric acid to the solution formed in (a); c) maintaining for about 15 minutes to 10 hours at about 0°C to 40°C; d) adding diisopropyl ether; and e) isolating form III abacavir sulfate; wherein the suitable alcohol is selected from the group consisting of methanol, isopropyl alcohol and ethanol.
14. A process according to claim 13, wherein the contents in step ( c) is stirred for 1 to 3 hours at 10°C to 30°C.
15. A process according to claim 13, wherein the suitable alcohol is methanol.
16. A process according to claim 13, wherein the suitable alcohol is isopropyl alcohol.
17. A pharmaceutical composition comprising a crystalline form of abacavir sulfate and a pharmaceutically acceptable carrier or diluent.
18. A pharmaceutical composition as defined in claim 17, wherein the crystalline form is form I abacavir sulfate of claim 1.
19. A pharmaceutical composition as defined in claim 17, wherein the crystalline form is form II abacavir sulfate of claim 6.
20. A pharmaceutical composition as defined in claim 17, wherein the crystalline form is form III abacavir sulfate of claim 11.
PCT/IN2003/000145 2003-04-07 2003-04-07 Novel crystalline forms of abacavir sulfate WO2004089952A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1905772A1 (en) * 2006-09-28 2008-04-02 Esteve Quimica, S.A. Process for the preparation of abacavir
WO2008037760A1 (en) * 2006-09-28 2008-04-03 Esteve Quimica, S.A. Process for the preparation of abacavir

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003055377A (en) * 2001-08-16 2003-02-26 Mitsui Chemicals Inc Method for producing 2-amino-6-cyclopropylamino-9h- purine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003055377A (en) * 2001-08-16 2003-02-26 Mitsui Chemicals Inc Method for producing 2-amino-6-cyclopropylamino-9h- purine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] 28 August 2003 (2003-08-28), XP002904731, accession no. STN Database accession no. 2003:150139 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1905772A1 (en) * 2006-09-28 2008-04-02 Esteve Quimica, S.A. Process for the preparation of abacavir
WO2008037760A1 (en) * 2006-09-28 2008-04-03 Esteve Quimica, S.A. Process for the preparation of abacavir
JP2010504944A (en) * 2006-09-28 2010-02-18 エステヴェ キミカ， エス．エー． Abacavir manufacturing method
US8183370B2 (en) 2006-09-28 2012-05-22 Esteve Quimica, Sa Process for the preparation of abacavir

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