IMPROVED PROCESS FOR PREPARATION OF ROSIGLITAZONE FORM II

INTRODUCTION

This disclosure relates to processes for the preparation of rosiglitazone freebase and pharmaceutical compositions containing it,

Rosiglitazone is 5-[4-[2-(N-methyl-N-methyl-N-(2-pyridyl)amino)ethoxy]-benzyl]-2,4-thiazolidinedione of Formula I.

Formula I

Rosiglitazone maleate is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity and improves glycemic control while reducing circulating insulin levels.

U.S. Patent No. 5,002,953 discloses rosiglitazone, its physiologically acceptable salts, pharmaceutical compositions comprising rosiglitazone or its physiologically acceptable salts, and their use in treatment of Type II diabetes.

U.S. Patent No. 5,741,803 discloses rosiglitazone maleate and processes for the preparation of the same, pharmaceutical composition comprising rosiglitazone maleate salt, and methods of treating Type II diabetes.

International Application Publication No. WO 2008/017398 discloses polymorphic forms of rosiglitazone freebase, as well as processes for their preparation and pharmaceutical formulations thereof. It also discloses polymorphic forms of rosiglitazone freebase characterized by powder X-ray diffraction and particle size.

However, the known processes for the preparation of rosiglitazone freebase require multiple recrystallizations, using mixture of solvents. Hence, there remains a need for an improved process for preparation of rosiglitazone freebase.

SUMMARY

This disclosure includes process for the preparation of rosiglitazone freebase Form II, comprising at least one of the steps of:

(a) adjusting phi of a mixture comprising a salt of rosiglitazone and a solvent to about 7 to about 10; and

(b) recovering rosiglitazone freebase

(c) recrystallizing the rosiglitazone freebase obtained from step (b) from an alcohol to afford rosiglitazone freebase Form II

This disclosure includes rosiglitazone freebase Form II and process for the preparation of rosiglitazone freebase Form II, substantially free of process related impurities and/or solvents,

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a powder x-ray diffraction (PXRD) diagram of rosiglitazone freebase Form II prepared according to Example 6.

DETAILED DESCRIPTION OF THE INVENTION

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about normal pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those 1hat recite a range "between" two values. The terms "about," "generally," Substantially," and the like, are to be construed as modifying another term or value such that it is not an absolute, but does not read on the prior art, as defined by the circumstances and context as understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value. Whether so indicated or not, all values recited herein are approximate.

This document may refer to a material, such as in this instance, rosiglitazone and its salts, crystalline forms, solvates, or optical isomers by reference to patterns, spectra, or other graphical data "substantially" as shown in a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra, and other graphical data can be shifted in their positions, relative intensities, and/or values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X-ray diffraction arts, such shifts in peak positions or the relative intensities of one or more peaks can occur because of, without limitation: the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, and the like. However, those of ordinary skill in the art should be able to compare the figures herein with a pattern generated of an unknown form of, in this case, rosiglitazone, and confirm its identity as one of the forms disclosed and claimed herein. The same holds true for other techniques that may be reported herein.

Crystalline forms may be characterized by such analytical methods as powder x-ray diffraction ("PXRD"), differential scanning calorimetry ("DSC"), and thermogravimetric analysis ("TGA").

In addition, where a reference is made to the data of an analytical method, e.g., PXRD reflection peaks, it is permissible to, and this document includes and contemplates, the selection of any number of data points that uniquely define the subject crystalline form, salt, solvate, and/or optical isomer, within any associated and recited margin of error, for purposes of identification.

This disclosure includes process for the preparation of rosiglitazone freebase Form II, which process comprise at least one of the steps of:

(a) adjusting pH of a mixture comprising a rosiglitazone salt and a solvent to about 7 to about 10; and

(b) recovering rosiglitazone freebase.

(c) recrystallizing the rosiglitazone freebase obtained from step (b) from an alcohol.

Step (a) involves adjusting pH of a mixture comprising a salt of rosiglitazone and a solvent to about 7 to about 10.

The mixture may be a suspension of a salt of rosiglitazone in a suitable solvent or a solution of a salt of rosiglitazone.

A solution comprising a rosiglitazone salt and a solvent may be obtained by dissolving a rosiglitazone salt in a suitable solvent, or such a solution may be obtained directly from a reaction in which a rosiglitazone salt is formed.

When the solution is prepared by dissolving a rosiglitazone salt in a suitable solvent, the rosiglitazone salt may be in any form including any crystalline form. Solvates and hydrates may be utilized for preparing the solution.

The rosiglitazone salt may be any pharmaceutical acceptable salt without any limitations.
Suitable solvents that may be used in the solution with the rosiglitazone salt include and are not limited to: alcohols, such as, for example, methanol, ethanol, isopropanol, n-butanol, and the like; ketonic solvents, such as, for example, acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; nitrile solvents, such as, for example, acetonitrile, propionitrile, and the like; water; or mixtures thereof in various proportions without limitation. The amount of solvent used to dissolve the rosiglitazone salt may range from about 10 to about 40 times to the weight of rosiglitazone salt.

If It is intended to obtain a clear solution of a salt of rosiglitazone, the dissolution temperature may be any temperature as long as the stability of the rosiglitazone salt is not compromised and a substantially clear solution is obtained. For example, the dissolution temperature may range from about 20°C to reflux temperature of the solvent.

The.pH of the reaction mass may be adjusted to within range from about 7 to about 13, or about 7 to 10.

Suitable bases that may be used to adjust the pH of the solution include and are not limited to organic bases, such as, for example, methylamine, dimethylamine, triethylamine, ethyl-di-isopropylamine, butylamine, and the like; and inorganic bases, such as, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like.

For the separation of rosiglitazone freebase as a solid in the pH adjusted solution, the pH adjusted solution may be maintained at a temperature from about 10°C to about 35°C for a suitable time period. A suitable time period may range from about 30 minutes to about 10 hours, or longer hours.

Step (b) involves recovering rosiglitazone freebase Form.

The method by which the solid material is recovered from the reaction mixture, with or without cooling below the operating temperature, may be any of techniques such as filtration by gravity, or by suction, centrifugatton, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the crystals may be washed with a solvent.

The obtained rosiglitazone freebase may be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, and the like. The drying may be carried out at a temperature of from about 35°C to about 90°C with or without vacuum. The drying may be carried out for any desired time until the required product purity is achieved, time periods from about 1 to about 20 hours.

Step (c) involves recrystallization of rosiglitazone freebase

The rosiglitazone freebase obtained in step(b) is recrystallized from an alcoholic solvent. The preferred solvent is isopropyl alcohol.

The rosiglitazone freebase obtained from step (b) is taken in isopropyl alcohol and heated to reflux temperature to obtain a clear solution, which may be filtered if required to remove extraneous matter. The clear solution is taken in to a clean and dry crystallization flask, which is preheated to 70-85 °C and heated to reflux temperature, to avoid nucleation. The solution is cooled to about 65 to 70°C and maintained further for about 20-30 min. The solution is further cooled to about 45 to 50°C for separation of the compound. The solution is optionally seeded with rosiglitazone freebase Form II. The reaction mixture is again heated to about 55-65 °C and maintained at the same temperature for 3-5 hrs. The solid separated is cooled to about 25 to 35 °C and maintained for about 30 minutes to 5 hours or longer.

The rosiglitazone freebase is recovered from the final mixture, with or without cooling below the operating temperature, by any of the techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the crystals may be washed with a solvent or the same solvent from which the compound is recrystallized.

The obtained rosiglitazone freebase may be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, and the like. The drying may be carried out at a temperature of from about 35°C to about 90°C with or without vacuum. The drying may be carried out for any desired time until the required product purity is achieved, time periods from about 1 to about 20 hours.

Rosiglitazone freebase Form II is characterized by at least one of the PXRD peaks at approximately: 13.47, 14.19. 17.07, 17.55, 18.92, 21.28, 22.06, 22.82, 23.39, and 25.93 degrees 2 theta, ± 0.1 degree, as measured on Bruker AXS D8 Advance Powder X-ray Diffractometer with a Cu K alpha-1 radiation source, Rosiglitazone freebase Form II is also characterized by an PXRD pattern substantially as shown in Figure 1.

This disclosure includes the rosiglitazone free base form II provides a particle size distribution having mean particle size of lesser than 30 microns before micronisation, and having mean particle size lesser than 15 microns after micronisation.

The Dio,"wid D90 values are useful ways for indicating a particle size distribution. D90refers to at least 90 volume percent of the particles having a size smaller than the said value. Likewise D10 refers to 10 volume percent of the particles having a size smaller than the said value. D50 refers to at least 50 volume percent of the particles having a size smaller than the said value. Methods for determining Dio, D50 and D90 include laser diffraction using Malvern equipment.

Rosiglatazone free base form II according to the present invention has a D1D less than 10 jim or less than 8 urn; D5o less than 30 jam or less than 20 µm; and Dgo less than 60 µm or less than 40 µm before micronisation. In addition to that rosiglitazone free base form II prepared according to the present invention has and D10 less than 5 µm or less than 2 µm; D5o less than 20 µm or less than 10 µm; and Dgo less than 30 µm or less than 20 µm after micronisation There is no specific lower limit for any of the D values.

This disclosure includes rosiglitazone freebase Form II and processes for the preparation of rosiglitazone freebase Form II, substantially free of related impurities, such as, for example, process, structural, and isomeric impurities.

"Substantially free of related impurities" means that rosiglitazone freebase Form II may be at least about 98%, or at least about 99.5%, or at least about 99.9% pure, and, correspondingly, the level of impurities may be less than about 2%, or less than about 0.5%, or less than about 0.1%, by weight as determined by high performance liquid chromatography (HPLC).

This disclosure includes rosiglitazone freebase Form II substantially free of residual solvent.

"Substantially free of residual solvent" means that the amount of residual solvent is at least within the limits as specified by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines, For example, rosiglitazone freebase Form II may have an amount of residual methanol less than or equal to about 100 ppm (ICH limit: 3000 ppm); residual acetone less than or equal to about 100 ppm (ICH limit: 5000ppm); and residual isopropanol less than or equal to about 500 ppm (ICH limit: 5000 ppm).

This disclosure includes pharmaceutical compositions comprising rosiglitazone freebase Form II together with at least one pharmaceutical^ acceptable excipients.

The pharmaceutical compositions of the present invention may be formulated as: solid oral dosage forms, such as, for example, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms, such as, for example, syrups, suspensions, dispersions, and emulsions; and inject able preparations, such as, for example, solutions, dispersions, and freeze dried compositions. The formulations may be immediate release, delayed release, or modified release formulations. Immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations. Modified release compositions may comprise hydrophilic and/or hydrophobic release rate controlling substances to form matrix and/or reservoir systems. The compositions may be prepared by direct blending, dry granulation, wet granulation, extrusion, and spheronization. The compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.

Pharmaceutically acceptable excipients that find use in the present invention include and are not limited to: diluents, such as, for example, starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders, such as, for example, acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, and the like; disintegrants, such as, for example, starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants, such as, for example, stearic acid, magnesium stearate, zinc stearate, and the like; glidants, such as, for example, colloidal silicon dioxide, and the like; solubility or wetting enhancers, such as, for example, anionic or cationic or neutral surfactants; complex forming agents, such as, for example, various grades of cyclodextrins, resins; release rate controlling agents, such as, for example, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are of use include and are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
Certain specific aspects and embodiments of this disclosure will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES REFERENCE EXAMPLE 1: PREPARATION OF ROSIGLTAZONE MALEATE

Preparation of 2-(N-methvl-N-(2-pyridinyl)amino) ethanol: 2-chloropyridine (15 kg) is charged into a reactor containing 2-methyl amino ethanol and stirred for about 15-20 minutes. The reaction mass is heated to 145-155°C and maintained for about 10-12 hours up to completion of the reaction. After the completion of the reaction, the reaction mass is quenched with sodium chloride solution (9 kg dissolved in 38 L of water) and stirred for about 15-30 minutes at 25-30° C. The reaction solution is extracted by toluene (4x19 L). The resultant organic layer is distilled off completely under vacuum below 906C to obtain 7 kg of the title compound as residue.

Preparation of 5-f4-f2-(N-methvl-N-(2-pyridinvhamino)ethoxv1benzvlidine]-2.4- Thiazolidinedione Dimethyl formamide (21 L) is charged into the a reactor containing 2-(N-methyl-N-(2-pyridinyl)amino) ethanol (7 kg) and caustic potash flakes (6.65 kg) and stirred for about 15-30 minutes. Tetrabutyl ammonium bromide (0.08 kg) and 4-fluoro benzaldehyde (6 kg) is added to the above reaction solution and maintained for 8 to 10 hours at room temperature up to completion of the reaction. After completion of the reaction, the reaction mass is quenched with water (350 L) and stirred for solid separation. The separated solid is filtered and washed with water (14 L) and spin dried for about 1 hour.

The resultant wet solid is charged into a fresh reactor containing toluene (58 L) and stirred for 15 minutes. 2,4-thiazolidinedione (3.85 kg), benzoic acid (0.43 kg) and piperidine (0.35 kg) is charged and heated to reflux and maintained for about 8 hours up to completion of the reaction. After completion of the reaction, the reaction mass is cooled to room temperature and filtered the separated solid and washed the solid with toluene (8 L) and suction dried for about 30 minutes.

The above obtained wet caked is charged into a reactor contained methanol (35 L) and stirred for about 30-45 minutes. The resultant solid is filtered and washed with methanol (8 L) and suction dried. The obtained wet solid is dried under vacuum at 60-70°C to give 8 kg of the title compound.

Preparation of rosialitazone: 5-[4-[2-(N-methyl-N-(2-pyrldinyl)amino)ethoxy]benzylidine]- 2,4- thiazolidinedione ( 8 kg) is charged into the reactor containing methanol and 4% sodium hydroxide solution (56 L) and stirred for about 20 min. A mixture of dimethyl formamide (11 kg), cobalt chloride (0.057 kg) and dimethyl glyoxime (1.03 kg) is prepared in a separate container and this mixture is charged to the above obtained reaction mass, and stirred for about 30 minutes.

A solution of sodium borohydride (1.9 kg) and 4% sodium hydroxide solution (3.2 L) is charged into the above reaction mixture and stirred for about 9 hours up to completion of the reaction. After completion of the reaction methylene chloride (80 L) is added to the reaction mass and pH of the reaction mass is adjusted to 6-7 using acetic acid (2 L) and stirred for about 45 min. The organic layer are separated from the aqueous layer and washed the aqueous layer with methylene chloride (4x80 L). The obtained organic layer is combined and washed with water (2x8 L).

The above obtained organic layer is treated with activated carbon (0.8 kg) and stirred for about 30 minutes at room temperature and passed through hyflow bed. The obtained clear solution is distilled off completely below 50° C under vacuum to give residue. To the obtained residue isopropanol (16 L) is added and stirred for about 45 min at 50-60°C and cooled to 0-5°C for 30-45 minutes.

The separated solid is filtered and washed with isopropanol (8 L) to suction dried for 30 minutes. The obtained solid is dried under vacuum at 60-70°C to give rosiglitazone freebase.

Preparation of rosialitazone maleate salt:

Acetone (55 L) is charged into the reactor containing rosiglitazone freebase (5.5 kg) and heated to reflux, A solution of maleic acid (1.82 kg dissolved in acetone 11 L) is charged into the reaction solution. Activated carbon (0.55 kg) is charged into the reaction solution and refluxed for 30 min and passed through HIFLO bed and washed the bed with acetone (35 L). The obtained clear solution is cooled and rosiglitazone maleate Form III (0.25 kg) is seeded. The obtained reaction mass is cooled to 0-5°C and stirred for solid separation.

The separated solid is filtered and washed with acetone (5.5 L) to afford title compound.

EXAMPLE 1: PREPARATION OF ROSIGLITAZONE FREEBASE

Rosiglitazone maleate (4 g) and water (60 mL) are charged into a clean, dry, round-bottom flask and stirred at 25-35°C for about 20 minutes. The reaction mixture pH is adjusted to 9.0 by using 10% sodium hydroxide solution (10 mL), and stirred for about 30 minutes 25-35°C. The reaction mixture is heated to about 40- 45°C and maintained for about 30 to 60 minutes The separated solid is filtered and washed with water 40 mL. The obtained solid is suction dried under vacuum for about 30 minutes. The resultant solid is dried under vacuum at 60°C to about 70°C to afford 2. 67 g of rosiglitazone freebase. Purity by HPLC 99.79%.

EXAMPLE 2: PREPARATION OF ROSIGLITAZONE FREEBASE

Rosiglitazone maleate (90 g) and water (2250 mL) are charged into a clean, dry, round-bottom flask and stirred at 25-355C for about 20 minutes. The reaction mixture pH adjusted to 12.5 by using 10% sodium hydroxide solution (270 mL), and stirred for about 30 minutes to get a clear solution. The solution is pH adjusted to 7.51 by using 10% aqueous hydrochloric acid (210.3 mL) and stirred for solid separation at 25-35°C. The reaction mixture is heated to about 45- 50°C and maintained for about 3 hours. The separated solid is filtered and washed with hot water (1350 mL). The obtained solid is suction dried under vacuum for about 30 minutes. The resultant solid is dried under vacuum at 45 to 50°C to afford 55 g of rosiglitazone freebase. Purity by HPLC 99,88%.

EXAMPLE 3: PREPARATION OF ROSIGLITAZONE FREEBASE II USING DMF AND WATER

Rosiglitazone maleate (10 g), DMF (dimethyl formamide) (20 mL), and water (250 mL) are charged into an clean, dry, round-bottom flask and stirred for about 20 minutes at 25-35°C. pH of the reaction solution is adjusted to 12.8 by using 10% sodium hydroxide solution (29 mL), and stirred for about 10 minutes. To the reaction mixture water (2500 mL) is added and maintained for about 20 minutes. The solution is pH adjusted to 7.8 by using 10% aqueous hydrochloric acid (20 mL) and stirred for solid separation for 2 to 3 hours. The separated solid is filtered and washed with water (150 mL). The obtained solid is suction dried under vacuum for about 30 minutes. The resultant solid is dried under vacuum at 60°C to about 70°C to afford 6.8 g of rosiglitazone freebase. Purity by HPLC 9978%.

EXAMPLE 4: PREPARATION OF ROSIGLITAZONE FREEBASE USING DMF AND WATER (1:1)

Rosiglitazone maleate (5 g), DMF (50 mL), and water (50 mL) are charged into a clean, dry, round-bottom flask and stirred for about 20 minutes at 25-35°C. The reaction solution pH adjusted to 9.0 by using 10% sodium hydroxide solution (15.3 mL), and stirred for about 10 minutes and water (100 mL) is added, stirred for about 60 minutes. The separated solid is filtered and washed with water (25 mL). The obtained solid is suction dried under vacuum for about 30 minutes. The resultant solid is dried under vacuum at 60°C to about 70°C to afford 3.4 g of rosiglitazone freebase Form II. Purity by HPLC 99.90%.

EXAMPLES: PREPARATION OF ROSIGLITAZONE FREEBASE USING ACETONE AND WATER (1:1)

Rosiglitazone maleate (100 g), acetone (1000 mL), and water (1000 mL) are charged into a clean, dry, round-bottom flask and stirred for about 20 minutes at 25 to 35°C, pH adjusted to 7.9 by using 10% sodium hydroxide solution (189 mL), and stirred for about 10 minutes and charged water (1000 mL) and pH of the reaction mixture is adjusted to 7.8 with sodium hydroxide solution. The separated solid is filtered and washed with water (1500 mL). The wet compound so obtained is taken into a round-bottom flask and water (2500 mL) is added to make a slurry, and maintained the slurry at 25 to 30 °C for about 1 to 2 hours. The obtained solid is filtered and washed with water (1500 mL) suction dried under vacuum for about 30 minutes. The resultant solid is dried under vacuum at 60°C to about 70°C to afford 68 g of rosiglitazone freebase. Purity by HPLC 99.88%.

EXAMPLE 6: PREPARATION OF ROSIGLITAZONE FREEBASE FORM II USING ISOPROPANOL

Rosiglitazone freebase (55 g) and isopropanol (1925 mL) are charged into a clean, dry, round-bottom flask and stirred for about 20 minutes. The reaction solution is heated to about 80°C (reflux), maintained for about 30 minutes, and then filtered. The filtrate is charged into a pre-heated round-bottomed flask at about 75-80°C.The obtained clear solution is cooled to 65-68°C and Form II rosiglitazone freebase crystals are seeded and cooled to 25-30°C for solid separation. The separated solid is filtered and washed with IPA (165 mL) and suction dried for about 30 minutes and dried under vacuum at about 60 to 70°C to afford rosiglitazone freebase Form II (50 g). Purity by HPLC 99,88%.

EXAMPLE 7: STABILITY PROFILE OF ROSIGLTAZONE FREEBASE FORM II
Rosiglitazone freebase Form II is packed in a clear polyethylene bag and sealed along with a silica pouch within a black polyethylene bag filled with nitrogen, which is kept in a triple laminated bag along with silica pouch and stored in a sealed DFPE drum. Initially, the rosiglitazone freebase Form II comprises 0.15% water and 0,16% impurities.
The stability of rosiglitazone freebase Form It during storage at 25°C and 60% relative humidity is listed in Table 1.

Table 1

The stability of rosiglitazone freebase Form II during storage at 40°C and 75% relative humidity is listed in Table 2.

Table 2

Stability of rosiglitazone freebase Form II during storage at 2-8°C is listed in Table 3.

Table 3

We claim;

1. A process for the preparation of rosiglitazone form II comprises the steps
of;

a) adjusting pH of a mixture comprising a rosiglitazone salt and a solvent to about 7 to about 10; and

(b) recovering rosiglitazone free base.

(c) recrystallizing the rosiglitazone freebase obtained from step (b) from an alcohol.

2. The process of claim 1, wherein base used to adjust the pH of the rosiglitazone salts is aqueous base.

3. The process of claim 2, wherein the aqueous base used to adjust the pH of the rosiglitazone salts is 10% sodium hydroxide solution.

4. The process of claim 1, wherein the used to adjusting the pH of the rosiglitazone salts is water and organic solvents or the mixtures thereof.

5. The process of claim 2, where the organic solvents used to adjust the pH of the rosiglitazone salts is DMF and acetone.

6. The process of claim 3, wherein the ratio of water and DMF used to adjust the pH of the rosiglitazone salts is (1:1).

7. The process of claim 3, wherein the temperature used to adjust the pH of the rosiglitazone salts is about 10°C to about 35°C.

8. The process of claim 1, wherein alcoholic solvent used in recrystallizing rosiglitazone free base is isopropyl alcohol.

9. The process of claim 8, wherein temperature used to dissolve rosiglitazone free base is about 75-85°C.

10. The process of claim 8, wherein temperature used to separate the rosiglitazone free base form II is about 25°C.