FIELD OF THE INVENTION

The present invention relates to novel malonate salt of Rosiglitazone and a process for preparing the same.

The present invention further relates to novel polymorphs of Rosiglitazone hydrogensulfate Form I, II, V; Rosiglitazone sulfate Form III, IV and processes for preparation thereof.

BACKGROUND OF THE INVENTION

Rosiglitazone, (5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione) is an anti-diabetic compound from the thiazolidinedione class which acts primarily by increasing insulin sensitivity. Its structural formula (I) is given below:

Rosiglitazone and its pharmaceutically acceptable salts are first known in US 5,002,953 and its use as an antihyperglycaemic agent. US 5, 741, 803 discloses maleic acid salt of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy] phenyl]methyl]-2,4-thiazolidinedione, which is currently marketed in US under the trade name AVANDIA® in 2mg, 4mg and 8 mg tablets for treatment of Type II diabetes.

PCT patent application WO 2003/050113 Al discloses Rosiglitazone hydrogensulfate salt and a process for preparation thereof.

PCT patent application WO 2003/050114 Al discloses Rosiglitazone sulfate salt and a process for preparation thereof.

OBJECT OF THE INVENTION

The main object of the present invention is to provide novel salt Rosiglitazone malonate and process for preparing the same.

Another object of the present invention relates to novel polymorphic forms of Rosiglitazone hydrogensulfate, hereafter referred as Rosiglitazone hydrogensulfate Form I, Form II and Form V.

Yet another object of the present invention relates to process for the preparation of polymorphic forms of Rosiglitazone hydrogensulfate such as Form I, Form II and Form V.

Yet another object of the present invention relates to novel polymorphic forms of Rosiglitazone sulfates hereafter referred as Rosiglitazone sulfate Form III and Form IV.

Yet another object of the present invention relates to process for the preparation of polymorphic forms of Rosiglitazone sulfate such as Form III and Form IV.

SUMMARY OF THE INVENTION

This invention encompasses acid addition salt of Rosiglitazone namely Rosiglitazone malonate and process for preparation of the same.

The present invention also encompasses Rosiglitazone hydrogensulfate polymorphic forms Form I, II and V.

The present invention also encompasses Rosiglitazone sulfate polymorphic forms Form III and IV.

In accordance, one aspect of the present invention there is provided crystalline Rosiglitazone malonate characterized by powder X-ray diffraction pattern as shown in Figure 1.

Another aspect of the present invention there is provided crystalline Rosiglitazone hydrogensulfate Form I characterized by powder X-ray diffraction pattern as shown in Figure 2.

Yet another aspect of the present invention there is provided crystalline Rosiglitazone hydrogensulfate Form II characterized by powder X-ray diffraction pattern as shown in Figure 3.

Yet another of the present invention there is provided crystalline Rosiglitazone sulfate Form III characterized by powder X-ray diffraction pattern as shown in Figure 4.

Yet another aspect of present invention there is provided crystalline Rosiglitazone sulfate Form IV characterized by powder X-ray diffraction pattern as shown in Figure 5.

Further aspect of the present invention there is provided crystalline Rosiglitazone hydrogensulfate Form V characterized by powder X-ray diffraction pattern as shown in Figure 6,

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects of present invention together with additional features contributing thereto and advantages occurring there from will be apparent from the following description of preferred embodiments of the invention, which are shown in the accompanying drawings, wherein:

Fig 1 is the X-ray powder diffraction pattern of Rosiglitazone malonate.

Fig 2 is the X-ray powder diffraction pattern of Rosiglitazone hydrogensulfate Form I.

Fig 3 is the X-ray powder diffraction pattern of Rosiglitazone hydrogensulfate Form II.

Fig 4 is the X-ray powder diffraction pattern of Rosiglitazone sulfate Form III.

Fig 5 is the X-ray powder diffraction pattern of Rosiglitazone sulfate Form IV.

Fig 6 is the X-ray powder diffraction pattern of Rosiglitazone hydrogensulfate Form V.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel crystalline malonate salt of Rosiglitazone, which exist as anhydrous crystalline form and are encompassed with in the scope of the present invention. The present invention also relates to novel polymorphic forms of Rosiglitazone hydrogensulfate: Form I, II, Form V and Rosiglitazone sulfate: Form III and Form IV. The said forms differ from each other in their physical properties, spectral data and methods of preparation.

One aspect of the present invention is to provide Rosiglitazone malonate.

One embodiment of the present invention is to provide Rosiglitazone malonate, characterized by X-ray powder diffraction pattern as shown in Figure 1 with 20 values at 4.45, 7.74, 8.91, 10.08, 13.39, 15.31, 17.07, 17.47, 17.88, 20.53, 21.78, 22.46, 23.16, 23.91, 24.77, 25.21, 25.59, 26.40, 26.67, 27.29, 27.89, 28.49, 30.57, 31.35, 32.43, 33.11, 34.01, 34.63,36.84, 38.36 and 38.91 ±0.20.

One more embodiment of the present invention is to provide novel process for the preparation of crystalline Rosiglitazone malonate, comprising the steps of:

a) dissolving Rosiglitazone base and malonic acid in a suitable solvent at reflux temperature,

b) cooling the solution and

c) isolating Rosiglitazone malonate salt.

According to the present invention, Rosiglitazone base and malonic acid are dissolved in a suitable solvent selected from the group of lower aliphatic ketones, preferably acetone.

The dissolution can be carried out at about 50-70°C, preferably at 50-60°C. The clear solution is then cooled to 20-30°C, preferably 25-30°C. Filtered the solid obtained and dried to isolate Rosiglitazone malonate. The drying can be carried out at a temperature of about 40-60°C, preferably 50°C under vacuum for about 12 hrs.

Another aspect of the present invention is to provide crystalline Rosiglitazone hydrogensulfate Form I, characterized by X-ray powder diffraction pattern as shown in Figure 2 with 20 values at 13.16, 13.62, 14.93, 17.35, 17.67, 18.17, 18.39, 18.66, 19.01, 20.65, 21.06, 22.04, 22.99, 23.54, 24.28, 24.68, 25.12, 25.48, 25.86, 26.25, 27.40, 28.47, 29.10, 30.15, 31.91, 32.28 and 35.37 ±0.29.

Another embodiment of the present invention provides novel process for the preparation of crystalline Rosiglitazone hydrogensulfate Form I, comprising the steps of:

a) dissolving Rosiglitazone base in a solvent at reflux temperature,

b) cooling the solution,

c) adding sulfuric acid at 20-30°C and

d) isolating the Rosiglitazone hydrogensulfate Form I.

According to the present invention, Rosiglitazone base is dissolved in lower aliphatic ketones, preferably acetone. The dissolution can be carried out at about 40-60°C preferably at 50-60°C. The clear solution is then cooled to 20-30°C, preferably 25-30°C and sulfuric acid is added. The precipitated solid is filtered and dried to isolate Rosiglitazone hydrogensulfate Form I. The drying can be carried out at a temperature of about 40-60°C, preferably 50°C under vacuum for about 12 hrs.

Yet another aspect of the present invention provides crystalline Rosiglitazone hydrogensulfate Form II, characterized by X-ray powder diffraction pattern as shown in Figure 3 with 26 values at 4.95, 14.82, 16.05, 18.75, 19.92, 20.26, 21.03, 21.88, 22.28, 22.49, 22.70,23.27, 23.86,24.49,24.96, 25.75, 26.12, 29.43 and 29.87 ±0.20.

Another embodiment of the present invention provides novel process for the preparation of crystalline Rosiglitazone hydrogensulfate Form II, comprising the steps of:

a) dissolving Rosiglitazone base in a solvent at reflux temperature,

b) adding sulfuric acid to the solution of step (a) at 40-50°C and

c) isolating the Rosiglitazone hydrogensulfate Form II.

According to the present invention, Rosiglitazone base is dissolved in lower aliphatic ketones, preferably acetone. The dissolution can be carried out at about 30-60°C, preferably at 40-60°C. To this clear solution sulfuric acid is added at 40-50°C. The precipitated solid is filtered and dried to isolate Rosiglitazone hydrogensulfate Form II. The drying can be carried out at a temperature of about 40-60°C, preferably 50°C under vacuum for about 12 hrs.

Another aspect of the present invention is to provide crystalline Rosiglitazone sulfate Form III, characterized by X-ray powder diffraction pattern as shown in Figure 5 with 28 values at 11.69, 16.67, 17.06, 18.56, 19.83, 20.50, 20.84, 22.93, 23.28, 24.07, 25.78, 26.36, 26.80, 28.01, 28.20 and 31.40 ±0.29.

Another embodiment of the present invention provides novel process for the preparation of crystalline Rosiglitazone sulfate Form III, comprising the steps of:

a) suspending Rosiglitazone base in water,

b) adding sulfuric acid and

c) isolating the Rosiglitazone Form III.

According to the present invention, Rosiglitazone base is suspended in water at ambient temperature. To this slurry sulfuric acid is added. The precipitated solid is filtered and dried to isolate Rosiglitazone sulfate Form III. The drying can be carried out at a temperature of about 40-60°C, preferably 50°C under vacuum for about 12 hrs.

Yet another aspect of the present invention provides crystalline Rosiglitazone sulfate Form IV, characterized by X-ray powder diffraction pattern as shown in Figure 6 with 26 values at 6.01, 11.37, 11.95, 13.27, 13.95, 15.46, 18.33, 19,68, 21.21, 22.05, 24.02, 25.26, 26.03, 26.50 and 27.49 ±0.20.

Another embodiment of the present invention provides novel process for the preparation of crystalline Rosiglitazone sulfate Form IV, comprising the steps of:

a) dissolving the Rosiglitazone sulfate Form III in a solvent at reflux temperature,

b) cooling the reaction mass and

c) isolating the Rosiglitazone sulfate Form IV.

According to the present invention, Rosiglitazone sulfate Form III is dissolved in a suitable solvent selected from the group of lower aliphatic alcohols, preferably methanol at 20-30°C, preferably 25-30°C. The dissolution can be carried out at a temperature of about 60-80°C, preferably 70-80°C. The clear solution is then cooled to 20-30°C, preferably 25-30°C. The precipitated solid is filtered and dried to isolate Rosiglitazone sulfate Form IV. The drying can be carried out at a temperature of about 40-60°C, preferably 50°C under vacuum for about 12 hrs.

Yet another aspect of the present invention is to provide crystalline Rosiglitazone hydrogensulfate Form V, characterized by X-ray powder diffraction pattern as shown in Figure 4 with 20 values at 9.04, 12.13, 14.40, 15.05, 15.68, 16.32, 17.71, 18.16, 18.60, 19.24, 19.80, 20.84, 21.57, 22.96, 23.84, 24.08, 24.38, 24.67, 25.00, 25.39, 25.91, 27.04, 27.68,28.64,29.12, 30.00, 30.70, 31.33, 32.09, 33.04, 34.61, 35,90 and 38.37±0.28.

Another embodiment of the present invention provides novel process for the preparation of crystalline Rosiglitazone hydrogensulfate Form V, comprising the steps of:

a) dissolving Rosiglitazone hydrogensulfate Form I in a suitable solvent at 60-80°C,

b) cooling the solution to 20-30°C,

c) adding the solution of step (b) to an antisolvent seeded with Rosiglitazone hydrogensulfate Form V and

d) isolating the Rosiglitazone hydrogensulfate Form V.

According to the present invention, Rosiglitazone hydrogensulfate Form I is dissolved in a suitable solvent selected from the group of polar aprotic solvents such as dimethylformamide, dimethylsulfoxide and preferably dimethylformamide. The dissolution can be carried out at about 60-80°C, preferably at 70-80°C. The clear solution is then cooled to 20-30°CJ preferably 25-30°C. Seed of Rosiglitazone hydrogensulfate is dissolved in a suitable solvent selected from the group of lower aliphatic ethers, preferably diethylether. The precipitated solid is filtered and dried to isolate Rosiglitazone hydrogensulfate Form V. The drying can be carried out at a temperature of about 40-60°C, preferably 50°C under vacuum for about 12 hrs.

Powder X-ray Diffraction (PXRD)

The PXRD measurements were carried out using PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 6/6 configuration and X'Celerator detector. The Cu- anode X-ray tube is operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2,0°-50.0C 0.030° step size and 50 seconds step time.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.

EXAMPLES

Example 1; Preparation of Rosiglitazone malonate.

10 g of Rosiglitazone base and Malonic acid (9g) were suspended in acetone (100 ml) at 50-60°C to form a clear solution and stirred for 15-30 min. Filtered the hot solution through hyflow to remove any undissolved particulate. The resulting clear filtrate was then cooled to 25-30°C and stirred for 1hr. The solid obtained was filtered, washed with acetone (20 ml) and dried under vacuum at 50°C for 5hr. The product obtained was identified as crystalline Rosiglitazone Malonate.

XRD of the sample show it to be crystalline Rosiglitazone Malonate.

Example 2: Preparation of Rosiglitazone hydrogensulfate Form I.
10g of Rosiglitazone base was dissolved in acetone (100 ml) at reflux condition. The clear solution was then cooled to 25-30°C. To this clear solution sulfuric acid (8.2g) was added slowly at 25-30°C. The solution was stirred for 2hrs at 25-30°C. The solid obtained was filtered, washed with acetone (20 ml) and dried under vacuum at 50°C for 12hrs. The product obtained was identified as crystalline Rosiglitazone hydrogensulfate Form I. XRD of the dry sample shows it to be Rosiglitazone hydrogensulfate Form I.

Example 3: Preparation of Rosiglitazone hydrogensulfate Form II.

10 g of Rosiglitazone base was dissolved in acetone (200 ml) at reflux condition. To this clear solution sulfuric acid (2.7g) was added slowly at 40-50°C. The solution was then cooled to 25-30°C and stirred for 2hrs. The solid obtained was filtered, washed with acetone (20 ml) and dried under vacuum at 50°C for 12hr. The product obtained was identified as crystalline Rosiglitazone hydrogen sulfate Form II. XRD of the dry sample shows it to be Form II.

Example 4: Preparation of Rosiglitazone sulfate Form III.

10g of Rosiglitazone base was suspended in water (100 ml) at 25-30°C. To this
suspension sulfuric acid (8.2g) was added slowly and the slurry was stirred for 2hr at 25-
30°C. The solid obtained is filtered, dried under vacuum at 50°C for 12hrs. The product
obtained was identified as crystalline Rosiglitazone sulfate Form III.

XRD of the dry sample shows it to be Form III.

Example 5; Preparation of Rosiglitazone sulfate Form IV.

10g of Rosiglitazone sulfate Form III was suspended in methanol (100ml) at 25-30°C. The suspension was heated to 70-80°C to get the clear solution and stirred for 15-30 min. Filtered the hot solution through hyflow to remove any undissolved particulate. The resulting clear filtrate then cooled to 25-30°C and stirred for 2-3hr. The solid obtained
was filtered, washed with methanol (20 ml) and dried under vacuum at 50°C for 12hr. The product obtained was identified as crystalline Rosiglitazone sulfate Form IV. XRD of the dry sample shows it to be Form IV.

Example 6: Preparation of Rosiglitazone hydrogensulfate Form V.

10g of Rosiglitazone hydrogensulfate Form I was suspended in DMF (2ml) at 25-30°C, heated to 70-80°C to get the clear solution and stirred for 15-30 min. Filtered the hot solution through hyflo to remove any undissolved particulate and cooled the filtrate to 25-30°C. In another flask diethyl ether (60ml) with the seeds of 0.2g of Rosiglitazone hydrogensulfate was charged at 25-30°C. The above clear DMF solution was added slowly to it at 25-30°C. After complete addition, the slurry was stirred for 1-2 hrs at 25-30°C. The solid obtained was filtered and dried under vacuum at 50°C for 12hr. The product obtained was identified as crystalline Rosiglitazone hydrogensulfate Form V, XRD of the sample shows it to be Form V.

We Claim:

1. Crystalline Rosiglitazone hydrogensulfate Form II having X-ray powder diffraction peaks at about 14.82,19.92 and 23.27 ±0.26 values.

2. A process for preparing crystalline Rosiglitazone hydrogensulfate Form II, which comprises:

a) dissolving Rosiglitazone base in a solvent at reflux temperature,

b) adding sulfuric acid to the solution of step (a) at 40-5 0°C and

c) isolating the Rosiglitazone hydrogensulfate Form II.

3. The process according to claim 2, wherein the solvent is selected from the group of lower aliphatic ketones such as acetone.

4. Crystalline Rosiglitazone hydrogensulfate Form V having X-ray powder diffraction peaks at about 15.05, 15.68, 19.24, 19.80, 21.57, 22.96, 24.38, 24.67, 25.39, 27.68 and 38.37±O.20.

5. A process for preparing crystalline Rosiglitazone hydrogensulfate Form V, which comprises:

a) dissolving Rosiglitazone hydrogensulfate Form I in a suitable solvent at 60-80°C,

b) cooling the solution to 20-3 0°C,

c) adding the solution of step (b) to an antisolvent seeded with Rosiglitazone hydrogensulfate Form V and

d) isolating the Rosiglitazone hydrogensulfate Form V.

6. The process according to claim 5, wherein the suitable solvent is selected from the
group of polar aprotic solvents such as dimethylformamide, dimethylsulfoxide.

7. The process according to claim 5, wherein anti-solvent is selected from the group of lower aliphatic ethers such as diethyl ether.

8. Crystalline Rosiglitazone sulfate Form III having X-ray powder diffraction peaks at about 16.67, 23.28, 24.07 and 26.80 ±0.29 values.

9. A process for preparing crystalline Rosiglitazone sulfate Form III, which comprises:

a) suspending Rosiglitazone base in water,

b) adding sulfuric acid and

c) isolating the Rosiglitazone Form III.

10. A process for preparing Rosiglitazone malonate, which comprises:

a) dissolving Rosiglitazone base and malonic acid in acetone at reflux temperature,

b) cooling the solution and

c) isolating Rosiglitazone malonate salt.