WO2006010653A1

WO2006010653A1 - New polymorphous form of rosiglitazone maleate

Info

Publication number: WO2006010653A1
Application number: PCT/EP2005/052006
Authority: WO
Inventors: Stefano Turchetta; Pietro Massardo; Valentina Aromatario
Original assignee: Chemi Spa
Priority date: 2004-07-28
Filing date: 2005-05-03
Publication date: 2006-02-02
Also published as: ITMI20041537A1

Abstract

A new polymorphous crystalline form of rosiglitazone maleate, called form V, and the methods for obtaining it are described and characterized. Rosiglitazone maleate may be obtained in the form of the single polymorph V by mixing an approximately equimolar mixture of rosiglitazone base and maleic acid into a mixture of alcohols and water, heating the mixture under reflux and subsequently cooling it to ambient temperature.

Description

Title

New polymorphous form of rosiglitazonc maleate

FIELD OF THE INVENTION

The present invention relates to the synthesis and characterization of a new polymorphous form of rosiglitazone maleate. STATE OF THE ART

Rosiglitazone is a molecule having a thiazolidinedione structure which forms part of the class of antidiabetic agents. Its structural formula is given below.

US 5,002,953 describes for the first time the compound and its use as an antihyperglycaemic agent. In that patent, all of its pharmaceutically acceptable salts are also claimed.

US 5,741,803, on the other hand, describes specifically the maleate of rosiglitazone, indicated below, affirming that, of the possible salts, the maleate has particularly advantageous characteristics of stability and solubility in water.

That patent reports on two examples of the preparation of the salt in question. In the first example, the compound is prepared by the dissolution at high temperature of the rosiglitazone base in admixture with maleic acid and the slow precipitation of the resultant salt. After treatment of the suspension at 0-5⁰C for several hours, a product is isolated which, after being dried under vacuum at 50⁰C, yields a product having a melting point (m.p.) of 120-121⁰C. The ¹H-NMR of the product is obtained, in which there is a broad band between 2 and 5 ppm which the Applicant attributes to the residual water (not otherwise specified) contained in the solvent. In the second example, the maleate of rosiglitazone is treated in ethanol with one equivalent of maleic acid at high temperature until the solid dissolves; the mixture is rendered colourless with charcoal and the product is precipitated by cooling to 0-5⁰C.

Filtering is then carried out and the product is dried, having an m.p. of 119-119.5°C when the treatments are complete.

US 6,515,132 relates to a method for the synthesis of rosiglitazone maleate in which the step of forming the maleate of rosiglitazone is carried out in acetone.

WO0064892, WO0064893, WO0064896 and WO0226737 describe polymorphous forms of rosiglitazone maleate, while WO9931093, WO9931094 and WO9931095 describe the preparation of hydrates of rosiglitazone maleate.

DESCRIPTION OF THE INVENTION

It is known that many organic compounds and their salts can exist in the form of several different crystalline structures which exhibit various physical properties and which may also exhibit diversity from the biological point of view.

In the course of crystallization experiments carried out on the maleate of rosiglitazone, it was surprisingly found that this salt, under specific conditions, crystallizes in a polymorphous crystalline form different from those known.

The production of pure crystalline forms is very useful both because, through them, it is possible to provide an exact characterization of the physico-chemical properties and because those characteristics may be more favourable from a pharmacological point of view.

The present patent application therefore relates to a new polymorphous form V of rosiglitazone maleate, and also to the methods necessary for the crystallization of the polymorphous form V.

DETAILED DESCRIPTION OF THE INVENTION

Tests for the synthesis of rosiglitazone maleate carried out starting from equimolar amounts of rosiglitazone base and maleic acid have surprisingly led to the identification and characterization of a polymorphous crystalline form of the above-mentioned salt.

In particular, it has been found that the maleate of rosiglitazone exists in a polymorphous crystalline modification which may be very distinct in DSC, IR, and X-ray diffraction.

Rosiglitazone maleate exists in a polymorphous form V, which, according to DSC, has an endothermic peak with a maximum at 102.8°C (Figure 2). The DSC was carried out on a Perkin Elmer DSC7 differential scanning calorimeter.

The new form has an X-ray powder diffraction spectrum (shown in Figure 2) characterized by the following principal absorptions (radiation Cu Ka, generator voltage 40 kV, divergence slit 1°, receiving slit 0.2 mm, scan mode step start angle 5.000 end angle 35.000, time per step 2.000 s):

FORM V (Table 1)

The X-ray diffraction experiments were carried out on a Philips PW3710 diffractometer. In IR, form V exhibits characteristic absorptions at the following wavelengths (Figure 3): 3426; 3138; 1749; 1698; 1645; 1620; 1510; 1332; 1263; 1235; 1165; 1143; 1058; 1037; 864; 841; 807; 763 cm^"1.

The IR spectrum was run on an FT-IR Perkin Elmer 16 PC spectrometer. Rosiglitazone maleate can be obtained in the form of the single polymorph V by mixing an approximately equimolar mixture of rosiglitazone base and maleic acid into a series of mixtures of alcohols and water, by heating the suspension to the reflux temperature of the solvent and subsequently cooling the mixture to ambient temperature. A crystalline suspension of the product is thus obtained which, when it has been filtered, washed and dried under vacuum for 12 hours at 45-50⁰C, provides form V rosiglitazone maleate as a single crystalline form, as confirmed by the IR, XRD and DSC analyses. The alcohols are preferably Ci-C₆ alcohols and may be selected from methanol, ethanol, isopropanol, n-propanol, isobutanol, sec-butanol, tert-butanol; ethanol is the preferred alcohol. In particular, the mixture of water and alcohol has a water:alcohol ratio ranging from 1 : 2 to 4 : 1 volumes, preferably 2 : 1 volumes. According to the best embodiment of the invention, the alcohol is ethanol and has a wateπalcohol ratio of 2 : 1. The following experimental Examples provide further clarification of the invention and do not in any way constitute a limitation thereof. EXAMPLE l Synthesis of form V rosiglitazone maleate.

10 g (28.0 mmol) of rosiglitazone base, 3.25 g (28.0 mmol) of maleic acid and 120 ml of a 2 : 1 mixture of water and ethanol are introduced into a 250-ml flask provided with mechanical agitation, a cooler and a thermometer. The mixture is heated under reflux and maintained under those conditions for 30 minutes. The mixture is then slowly cooled to ambient temperature and the product is filtered on a Buchner funnel, washing twice with 10 ml of water. The filtered product is then dried for 12 hours at 45-50⁰C. 9.7 g of form V rosiglitazone maleate are obtained (yield 73%).

EXAMPLE 2

Synthesis of form V rosiglitazone maleate

20 g (56.0 mmol) of rosiglitazone base and 6.50 g (56.0 mmol) of maleic acid are introduced into a 500-ml flask. 160 ml of water and 80 ml of ethanol are added to those solids and the mixture obtained is heated under reflux for 60 minutes. The mixture is then slowly cooled to ambient temperature and 80 ml of water are added thereto. The resultant solid is filtered on a Buchner funnel, washing twice with 20 ml of water each time. A product is discharged which, after being dried under vacuum at 45-50°C for 12 hours, weighs 19.9 g (yield 75%) and is constituted by form V rosiglitazone maleate.

The water content of the dried product is 1.3%.

EXAMPLE 3

Synthesis of form V rosiglitazone maleate

15 g (42.0 mmol) of rosiglitazone base and 4.85 g (42.0 mmol) of maleic acid are introduced into a 500-ml flask. 60 ml of ethanol and 120 ml of water are added to those solids and the mixture obtained is heated under reflux for 60 minutes. The mixture is then cooled to 80°C and is seeded with a small amount of form V rosiglitazone maleate.

The mixture is then cooled slowly to ambient temperature and the resultant solid is filtered on a Buchner funnel, washing twice with 20 ml of a 2 : 1 water-ethanol mixture.

A product is discharged which, after being dried under vacuum at 45-50°C for 12 hours, weighs 19.9 g (yield 75%) and is constituted by form V rosiglitazone maleate.

Claims

1. Form V crystalline rosiglitazone maleate having an X-ray powder diffraction spectrum with the following principal absorptions:

2. Form V crystalline rosiglitazone maleate having an X-ray powder diffraction spectrum as shown in Figure 1.

3. Form V crystalline rosiglitazone maleate having a DSC graph as shown in Figure 2.

4. Form V crystalline rosiglitazone maleate having an ER. spectrum as shown in Figure 3.

5. Pharmaceutical compositions containing form V crystalline rosiglitazone maleate according to claims 1 to 4 together with pharmaceutically acceptable coadjuvants and/or excipients.

6. Use of form V crystalline rosiglitazone maleate according to claims 1 to 4 for the preparation of pharmaceutical compositions for the treatment of diabetes.

7. A process for the crystallization of form V rosiglitazone maleate, characterized in that it comprises the following steps: a. heating under reflux an approximately equimolar mixture of rosiglitazone base and maleic acid in solvent mixtures constituted by water and Ci -C^ alcohols; b. optionally seeding the mixture at high temperature with small amounts of the crystalline form V of rosiglitazone maleate; c. cooling the mixture to ambient temperature; d. filtering and washing the product; e. drying.

8. A process according to claim 7, characterized in that the alcohols are selected from methanol, ethanol, isopropanol, n-propanol, isobutanol, sec-butanol, tert-butanol.

9. A process according to claim 8, wherein the alcohol is ethanol.

10. A process according to claims 7-9, characterized in that the mixture of water and alcohol has a waterralcohol ratio ranging from 1 : 2 to 4 : 1 volumes.

11. A process according to claim 10, characterized in that the mixture of water and alcohol has a waterralcohol ratio of 2 : 1 volumes.

12. A process according to claims 7-9, characterized in that the alcohol of the mixture of water and alcohol is ethanol and has a water:alcohol ratio of 2 : 1.

13. A process according to claims 7-9, characterized in that the reaction mixture may be seeded with form V rosiglitazone maleate.

14. A process according to claims 7-9, characterized in that the reaction mixture can be seeded with form V rosiglitazone maleate at a temperature of approximately 80°C.

15. A process according to claims 7-9, characterized in that the mixture is maintained under reflux for a time of approximately from 20 to 40 minutes.

16. A process according to claims 7-9, characterized in that the reaction mixture can be cooled to ambient temperature within a time of from 1 to 10 hours.

17. A process according to claims 7-9, characterized in that the reaction mixture can be cooled to ambient temperature within a time of from 2 to 7 hours.

18. A process according to claims 7-9, characterized in that the reaction mixture can be cooled to ambient temperature within a time of approximately 5 hours.