WO2010038154A2 - Polymorphic forms of rosiglitazone hydrogensulfate and processes for their preparation - Google Patents

Abstract

Provided also herein are novel polymorphic forms of rosiglitazone hydrogensulfate, processes for the preparation, pharmaceutical compositions, and method of treating thereof.

Description

POLYMORPHIC FORMS OF ROSIGLIT AZONE HYDROGENSULFATE AND PROCESSES FOR THEIR PREPARATION

CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of priority to Indian provisional application No.

2442/CHE/2008, filed on October 3, 2008, which is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE The present disclosure relates to novel polymorphic forms of rosiglitazone hydrogensulfate, processes for the preparation, pharmaceutical compositions, and method of treating thereof.

BACKGROUND Rosiglitazone, chemically named 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl] methyl]-2,4-thiazolidinedione, is a member of the thiazolidinedione class of antidiabetic agents that improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARg). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARg nuclear receptors regulates the transcription of insulin responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARg-responsive genes also participate in the regulation of fatty acid metabolism. Rosiglitazone is represented by the following structural formula I:

and its first synthesis was disclosed in U.S. Patent No. 5,002,953. Rosiglitazone is sold by SB PHARMCO under the brand name AV ANDI A® for the treatment of non-insulin dependent diabetes mellitus (NIDDM), also known as type 2 diabetes mellitus. It is orally administered as tablets containing 2 mg, 4 mg or 8 mg of rosiglitazone as the maleate salt.

Processes for the preparation of rosiglitazone and related compounds, pharmaceutically acceptable salts thereof and their polymorphs are disclosed in U.S. Patent Nos. 5,002,953; 7,241,895 and 7,368,574; European Patent Nos. 0658161 and 1173436; European Patent application No. EPl 887006; U.S. Patent Application Nos. US2006/0264639 and US2007/0293546; and PCT Publication Nos. WO03/050113, WO03/050114, WO05/049532, WO07/148141, and WO08/010089. According to U.S. Patent No. 5,002,953 (hereinafter referred to as the '953 patent), rosiglitazone is prepared by the reaction of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzaldehyde with 2,4-thiazolidinedione to produce 5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzylidene]-2,4-thiazolidinedione, followed by catalytic hydrogenation using palladium on charcoal to produce rosiglitazone. European Patent No. 0658161 discloses the maleate salt of rosiglitazone including its isomers, tautomeric forms and pharmaceutically acceptable solvates thereof, processes for their preparation, and pharmaceutical compositions thereof.

U.S. Patent No. 7,241,895 discloses four crystalline forms (Forms I, II, III and IV) of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione maleate (rosiglitazone maleate), processes for the preparation, and pharmaceutical compositions thereof. The crystalline forms are characterized by powder X-ray diffraction (P-XRD), differential scanning calorimetry (DSC) and Infrared (IR) spectroscopy.

PCT Publication No. WO 03/050113 (herein after referred to as the ' 113 application) discloses the hydrogensulfate salt of rosiglitazone, processes for the preparation, pharmaceutical compositions thereof, and characterizes it by powder X-ray diffraction (P- XRD), differential scanning calorimetry (DSC), Raman spectroscopy, Infrared (IR) spectroscopy and solid-state NMR spectroscopy. According the ' 113 application, the process yields the rosiglitazone hydrogensulfate salt in a crystalline form and characterized by an X- ray powder diffraction pattern having peaks expressed as 2-theta at about 6.2, 9.0, 13.2, 13.6, 14.6, 14.9, 15.6, 16.6, 17.4, 18.1, 18.6, 18.9, 19.8, 20.6, 21.0, 22.0, 22.9, 23.5, 24.3, 24.7, 25.1, 25.3, 25.9, 26.2, 27.4, 28.4, 28.9, 30.1, 31.4, 31.9, 32.3 and 33.5 degrees; a DSC thermogram having a T_onSet at 183.4⁰C and a T_peak at 188.1⁰C; and an IR spectrum having absorption bands at about 2980, 2778, 1753, 1693, 1644, 1616, 1547, 1513, 1466, 1442, 1418, 1388, 1366, 1313, 1219, 1160, 1069, 1053, 1029, 1012, 988, 957, 906, 862, 801, 770, 737, 712 and 662 cm^"1. As per the process exemplified in the '113 application, the crystalline rosiglitazone hydrogensulfate (herein after referred to as the crystalline Form A) is prepared by heating the mixture containing 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (rosiglitazone free base) and acetone at reflux until to form a clear solution, adding concentrated sulfuric acid to the solution followed by stirring the reaction mixture for 15 minutes at reflux, and then cooling to 21⁰C. The separated solid is collected by filtration, washed with acetone and then dried under vacuum for 16 hours at 20⁰C to provide the crystalline Form A of rosiglitazone hydrogensulfate. European Patent Application No. EPl 887006 discloses three polymorphic forms

(Forms I, II and III) of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4- thiazolidinedione (rosiglitazone base), processes for their preparation, and pharmaceutical compositions thereof. The forms are characterized by powder X-ray diffraction (P-XRD).

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecule in the crystal lattice." Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or configurations of the molecules. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and infrared spectrometry (IR).

Solvent medium and mode of isolation play very important role in obtaining one polymorphic form over another. The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Hence, there is a need in the art for novel and stable polymorphic forms of rosiglitazone hydrogensulfate. SUMMARY

We have now surprisingly and unexpectedly discovered four novel polymorphic forms (Forms Al, A2, A3 and A4) of rosiglitazone hydrogensulfate salt, different from the crystalline form obtained according to the ' 113 application, which we denote as crystalline Form A, and having adequate stability and good dissolution properties.

In one aspect, provided herein is a novel and stable crystalline form of rosiglitazone hydrogensulfate, designated as rosiglitazone hydrogensulfate crystalline Form Al, characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 8.3, 11.7, 16.7, 17.1 and 26.8 ± 0.2 degrees.

In another aspect, encompassed herein is a process for preparing the substantially pure and stable crystalline Form Al of rosiglitazone hydrogensulfate.

In one aspect, provided herein is a novel and stable crystalline form of rosiglitazone hydrogensulfate, designated as rosiglitazone hydrogensulfate crystalline Form A2, characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 4.8, 14.2, 17.7, 19.6 and 21.6 ± 0.2 degrees.

In another aspect, encompassed herein is a process for preparing the substantially pure and stable crystalline Form A2 of rosiglitazone hydrogensulfate.

In one aspect, provided herein is a novel and stable crystalline form of rosiglitazone hydrogensulfate, designated as rosiglitazone hydrogensulfate crystalline Form A3, characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 5.3, 12.1, 16.0, 21.8 and 23.6 ± 0.2 degrees.

In another aspect, encompassed herein is a process for preparing the substantially pure and stable crystalline Form A3 of rosiglitazone hydrogensulfate. In one aspect, provided herein is a novel and stable crystalline form of rosiglitazone hydrogensulfate, designated as rosiglitazone hydrogensulfate crystalline Form A4, characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 4.8, 6.8, 14.2, 15.1, 16.1 and 26.6 ± 0.2 degrees.

In another aspect, encompassed herein is a process for preparing the substantially pure and stable crystalline Form A4 of rosiglitazone hydrogensulfate.

In another aspect, encompassed herein is a novel process for preparing substantially pure crystalline Form A of rosiglitazone hydrogensulfate.

In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of any one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate disclosed herein, and one or more pharmaceutically acceptable excipients.

In another aspect, provided herein is a pharmaceutical composition comprising any one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate prepared according to processes disclosed herein and one or more pharmaceutically acceptable excipients.

In yet another aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining any one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate prepared according to processes disclosed herein, with one or more pharmaceutically acceptable excipients.

In another aspect, provided herein is a method for treating a patient suffering from non-insulin dependent diabetes mellitus (NIDDM); comprising administering any one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate disclosed herein, or a pharmaceutical composition that comprises any one or a mixture of the amorphous or polymorphic forms of rosiglitazone hydrogensulfate disclosed herein along with pharmaceutically acceptable excipients.

In still further aspect, each one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate disclosed herein for use in the pharmaceutical compositions has a Dg₀ particle size of less than or equal to about 400 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 200 microns, still more specifically less than or equal to about 100 microns, and most specifically less than or equal to about 15 microns.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a characteristic powder X-ray diffraction (XRD) pattern of Rosiglitazone hydrogensulfate crystalline Form Al .

Figure 2 is a characteristic infra red (IR) spectrum of Rosiglitazone hydrogensulfate crystalline Form Al.

Figure 3 is a characteristic differential scanning calorimetric (DSC) thermogram of Rosiglitazone hydrogensulfate crystalline Form Al .

Figure 4 is a characteristic powder X-ray diffraction (XRD) pattern of Rosiglitazone hydrogensulfate crystalline Form A2.

Figure 5 is a characteristic infra red (IR) spectrum of Rosiglitazone hydrogensulfate crystalline Form A2. Figure 6 is a characteristic differential scanning calorimetric (DSC) thermogram of

Rosiglitazone hydrogensulfate crystalline Form A2.

Figure 7 is a characteristic powder X-ray diffraction (XRD) pattern of Rosiglitazone hydrogensulfate crystalline Form A3. Figure 8 is a characteristic infra red (IR) spectrum of Rosiglitazone hydrogensulfate crystalline Form A3.

Figure 9 is a characteristic differential scanning calorimetric (DSC) thermogram of

Rosiglitazone hydrogensulfate crystalline Form A3.

Figure 10 is a characteristic powder X-ray diffraction (XRD) pattern of Rosiglitazone hydrogensulfate crystalline Form A4.

Figure 11 is a characteristic infra red (IR) spectrum of Rosiglitazone hydrogensulfate crystalline Form A4.

Figure 12 is a characteristic differential scanning calorimetric (DSC) thermogram of

Rosiglitazone hydrogensulfate crystalline Form A4. Figure 13 is a characteristic powder X-ray diffraction (XRD) pattern of Rosiglitazone hydrogensulfate crystalline Form A obtained according to the Example 5 disclosed herein.

Figure 14 is a characteristic infra red (IR) spectrum of Rosiglitazone hydrogensulfate crystalline Form A obtained according to the Example 5 disclosed herein.

Figure 15 is a characteristic differential scanning calorimetric (DSC) thermogram of Rosiglitazone hydrogensulfate crystalline Form A obtained according to the Example 5 disclosed herein.

DETAILED DESCRIPTION

Polymorphic forms of rosiglitazone hydrogensulfate, except the crystalline Form A, have not been reported, isolated, or characterized in the literature. The present inventors have surprisingly and unexpectedly found that the rosiglitazone hydrogensulfate can exist in distinct polymorphic forms.

It has also been found that the polymorphic forms of rosiglitazone hydrogensulfate are useful intermediates in the preparation of rosiglitazone or a pharmaceutically acceptable salt thereof in high purity. The polymorphic forms of rosiglitazone hydrogensulfate have good flow properties are stable at room temperature, enhanced temperature, at relative high humidities, and in aqueous media. The novel polymorphic forms of rosiglitazone hydrogensulfate are suitable for formulating rosiglitazone. In the formulation of drug compositions, it is important for the active pharmaceutical ingredient to be in a form in which it can be conveniently handled and processed. Convenient handling is important not only from the perspective of obtaining a commercially viable manufacturing process, but also from the perspective of subsequent manufacture of pharmaceutical formulations (e.g., oral dosage forms such as tablets) comprising the active pharmaceutical ingredient.

Chemical stability, solid state stability, and "shelf life" of the active pharmaceutical ingredient are important properties for a pharmaceutically active compound. The active pharmaceutical ingredient, and compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics of the active pharmaceutical ingredient, e.g., its chemical composition, density, hygroscopicity and solubility. Thus, in the manufacture of commercially viable and pharmaceutically acceptable drug compositions, it is important, wherever possible, to provide the active pharmaceutical ingredient in a stable form. New solid state forms of a pharmaceutical agent can further the development of formulations for the treatment of illnesses. For instance, solid forms of a compound are known in the pharmaceutical arts to affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, fractability, and compressibility of the compound, as well as the safety and efficacy of drug products based on the compound. The discovery of novel polymorphic forms of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds value to the material that a formulation scientist can use the same for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. According to one aspect, provided herein are novel polymorphic forms of rosiglitazone hydrogensulfate, wherein the polymorphic form is a crystalline Form Al, a crystalline Form A2, a crystalline Form A3, or a crystalline Form A4.

In one embodiment, the polymorphic forms of rosiglitazone hydrogensulfate exist in an anhydrous and/or solvent-free form or as a hydrate and/or a solvate form. Such solvated or hydrated forms may be present as hemi-, mono-, sesqui-, di- or tri- solvates or hydrates. Solvates and hydrates may be formed as a result of the solvents used during the formation of the rosiglitazone hydrogensulfate becoming imbedded in the solid lattice structure. Because formation of the solvates and hydrates occurs during the preparation of rosiglitazone hydrogensulfate, formation of a particular solvated or hydrated form depends greatly on the conditions and method used to prepare the salt. Solvents should be pharmaceutically acceptable.

In one embodiment, the polymorphic forms of rosiglitazone hydrogensulfate have the following characteristics, wherein: a) the crystalline Form Al of rosiglitazone hydrogensulfate is characterized by one or more of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with Figure 1 ; ii) a powder X-ray diffraction pattern having peaks at about 8.3, 11.7, 16.7, 17.1 and

26.8 ± 0.2 degrees 2-theta; iii) a powder X-ray diffraction pattern having additional peaks at about 10.3, 18.6, 19.8,

20.5, 20.9, 23.0, 23.3, 23.7, 24.1, 24.9, 28.0 and 28.2 ± 0.2 degrees 2-theta; iv) an IR spectrum substantially in accordance with Figure 2; v) an IR spectrum having absorption bands at about 3421, 3131, 3042, 2953, 2873, 2739, 1743, 1701, 1541, 1320, 1301, 1266, 1219, 1160, 1100, 1066, 998 and 824 ± 2 cm^"1; and vi) a DSC thermogram substantially in accordance with Figure 3; b) the crystalline Form A2 of rosiglitazone hydrogensulfate is characterized by one or more of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with Figure 4; ii) a powder X-ray diffraction pattern having peaks at about 4.8, 14.2, 17.7, 19.6 and

21.6 ± 0.2 degrees 2-theta; iii) a powder X-ray diffraction pattern having additional peaks at about 4.4, 13.1, 13.7,

15.0, 15.8, 17.2, 20.5, 22.0, 22.9, 24.6 and 26.4 ± 0.2 degrees 2-theta; iv) an IR spectrum substantially in accordance with Figure 5; v) an IR spectrum having absorption bands at about 3435, 3291, 3109, 2985, 2784, 2481,

1827, 1707, 1331, 1302, 1245, 1178, 1159, 1111, 1077, 935, 916, 827 and 760 ± 2 cm^"1 ; and vi) a DSC thermogram substantially in accordance with Figure 6; c) the crystalline Form A3 of rosiglitazone hydrogensulfate is characterized by one or more of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with Figure 7; ii) a powder X-ray diffraction pattern having peaks at about 5.3, 12.1, 16.0, 21.8 and 23.6 ± 0.2 degrees 2-theta; iii) a powder X-ray diffraction pattern having additional peaks at about 10.6, 11.7, 12.6,

13.8, 14.9, 17.8, 18.0, 20.4, 21.2, 22.1, 23.2 and 26.4 ± 0.2 degrees 2-theta; iv) an IR spectrum substantially in accordance with Figure 8; v) an IR spectrum having absorption bands at about 3388, 3138, 2986, 2774, 2479, 1831 , 1748, 1705, 1475, 1460, 1413, 1302, 1179, 1158, 1035, 1005, 897, 830, 820 and 763

± 2 cm^"1; and vi) a DSC thermogram substantially in accordance with Figure 9; d) the crystalline Form A4 of rosiglitazone hydrogensulfate is characterized by one or more of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with Figure 10; ii) a powder X-ray diffraction pattern having peaks at about 4.8, 6.8, 14.2, 15.1, 16.1 and

26.6 ± 0.2 degrees 2-theta; iii) a powder X-ray diffraction pattern having additional peaks at about 7.5, 9.9, 13.4,

15.6, 19.6, 20.8, 21.7, 22.7, 24.1, 24.5, 25.2 and 30.4 ± 0.2 degrees 2-theta; iv) an IR spectrum substantially in accordance with Figure 11 ; v) an IR spectrum having absorption bands at about 3395, 3042, 2786, 2555, 2478, 1868,

1764, 1708, 1558, 1397, 1301, 1231, 1177, 1151, 1079, 828 and 762 ± 2 cm^"1; and vi) a DSC thermogram substantially in accordance with Figure 12.

According to another aspect, there is provided a process for the preparation of a crystalline Form Al of rosiglitazone hydrogensulfate, comprising: a) providing an aqueous suspension of rosiglitazone free base in water; b) combining the aqueous suspension with sulfuric acid to produce a solution containing rosiglitazone hydrogensulfate; and c) optionally, subjecting the solution to carbon treatment or silica gel treatment; d) isolating and/or recovering the crystalline Form Al of rosiglitazone hydrogensulfate from the solution obtained in step-(b) or step-(c).

The process can produce crystalline Form Al of rosiglitazone hydrogensulfate in substantially pure form.

The term "substantially pure crystalline form of rosiglitazone hydrogensulfate" refers to the crystalline form of rosiglitazone hydrogensulfate having a purity of greater than about

98 wt%, specifically greater than about 99 wt%, more specifically greater than about 99.5 wt%, and still more specifically greater than about 99.9 wt%. The purity is preferably measured by High Performance Liquid Chromatography (HPLC). For example, the purity of crystalline form of rosiglitazone hydrogensulfate obtained by the process disclosed herein can be about 98% to about 99.95%, or about 99% to about 99.99%, as measured by HPLC.

The rosiglitazone hydrogensulfate crystalline Form Al is stable, consistently reproducible and has good flow properties, and is particularly suitable for bulk preparation and handling, and hence, the rosiglitazone hydrogensulfate crystalline Form Al disclosed herein is suitable for formulating rosiglitazone hydrogensulfate.

The term "stable crystalline form" refers to stability of the crystalline form under the standard temperature and humidity conditions of testing of pharmaceutical products, wherein the stability is indicated by preservation of the original polymorphic form. Step-(a) of providing an aqueous suspension of rosiglitazone free base includes suspending rosiglitazone free base in water while stirring at a temperature of about O⁰C to about 100⁰C, or obtaining an existing suspension from a previous processing step. In one embodiment, the suspension is stirred at a temperature of about 2O⁰C to about 9O⁰C for at least 10 minutes and more specifically at a temperature of about 5O⁰C to about 80⁰C for about 30 minutes to about 10 hours.

Alternatively, the suspension in step-(a) is prepared by treating an acid addition salt of rosiglitazone with a base to produce rosiglitazone free base followed by suspending the rosiglitazone in water at a temperature of about 0⁰C to about 100°C, specifically at about 2O⁰C to about 9O⁰C, and more specifically at about 5O⁰C to about 8O⁰C. In one embodiment, the acid addition salt of rosiglitazone is derived from a therapeutically acceptable acid such as hydrochloric acid, acetic acid, propionic acid, sulfuric acid, nitric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, citraconic acid, glutaconic acid, tartaric acid, malic acid, and ascorbic acid.

The treatment of an acid addition salt with a base is carried out in a solvent and the selection of solvent is not critical. A wide variety of solvents such as chlorinated solvents, alcohols, ketones, hydrocarbon solvents, esters, ether solvents etc., can be used.

In one embodiment, the base is an organic or inorganic base. Specific organic bases are triethyl amine, trimethylamine and N,N-diisopropylethylamine.

In another embodiment, the base is an inorganic base. Exemplary inorganic bases include, but are not limited to, aqueous ammonia; hydroxides, alkoxides, carbonates and bicarbonates of alkali or alkaline earth metals. Specific inorganic bases are aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide, and more specifically sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

The sulfuric acid in step-(b) may be used in the form of concentrated sulfuric acid or in the form of an aqueous solution. In one embodiment, the sulfuric acid used in step-(b) is in a molar ratio of about 1.0 to

1.5 moles, specifically about 1.0 to 1.2 moles, per mole of rosiglitazone free base.

Combining of the aqueous suspension with sulfuric acid in step-(b) is done in a suitable order, for example, the aqueous suspension is added to the sulfuric acid, or alternatively, the sulfuric acid is added to the aqueous suspension. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out at a temperature of about 0°C to about 9O⁰C, and more specifically at about 2O⁰C to about 8O⁰C under stirring. After completion of the addition process, the resulting mass is stirred at a temperature of about O⁰C to about 100⁰C for at least 10 minutes, specifically at about 2O⁰C to about 9O⁰C for about 20 minutes to about 10 hours, and more specifically at a temperature of about 4O⁰C to about 8O⁰C for about 30 minutes to about 4 hours to produce a solution.

The carbon treatment or silica gel treatment in step-(c) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 80⁰C for at least 15 minutes, specifically at a temperature of about 4O⁰C to about 7O⁰C for at least 30 minutes; and filtering the resulting mixture through hyflo to obtain a filtrate containing rosiglitazone hydrogensulfate by removing charcoal or silica gel. Specifically, the finely powdered carbon is an active carbon. A specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.

The isolation of crystalline Form Al of rosiglitazone hydrogensulfate in step-(d) is carried out by forcible crystallization, spontaneous crystallization, substantial removal of the solvent from the solution, or a combination thereof.

Spontaneous crystallization refers to crystallization without the help of an external aid such as seeding, cooling etc., and forcible crystallization refers to crystallization with the help of an external aid. Forcible crystallization may be initiated by a method usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof.

The term "anti-solvent" refers to a solvent which when added to an existing solution of a substance reduces the solubility of the substance. Exemplary anti-solvents include, but are not limited to, a hydrocarbon, an ether, and mixtures thereof. Specifically, the anti-solvent is selected from the group consisting of n- pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, and mixtures thereof; and most specifically diethyl ether, diisopropyl ether, and mixtures thereof.

In one embodiment, the crystallization is carried out by cooling the solution while stirring at a temperature of below 3O⁰C for at least 10 minutes, specifically at about O⁰C to about 25⁰C for about 30 minutes to about 20 hours.

The term "substantially removing" the solvent refers to at least 80%, specifically greater than about 85%, more specifically greater than about 90%, still more specifically greater than about 99%, and most specifically essentially complete (100%), removal of the solvent from the solution.

Removal of solvent is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent, under inert atmosphere.

In one embodiment, the solvent is removed by evaporation. Evaporation can be achieved at sub-zero temperatures by lyophilisation or freeze-drying techniques. The solution may also be completely evaporated in, for example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer ("ATFD"), or evaporated by spray drying to obtain a dry amorphous powder.

The distillation process can be performed at atmospheric pressure or reduced pressure. Specifically, the solvent is removed at a pressure of about 760 mm Hg or less, more specifically at about 400 mm Hg or less, still more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.

Solvents can also be removed by spray-drying, in which a solution of rosiglitazone hydrogensulfate is sprayed into the spray drier at the flow rate of 10 to 300 ml/hr, specifically

40 to 200ml/hr. The air inlet temperature to the spray drier used is about 3O⁰C to about

15O⁰C, specifically about 65⁰C to about HO⁰C and the outlet air temperature used is about 3O⁰C to about 9O⁰C.

Another suitable method is vertical agitated thin-film drying (or evaporation). Agitated thin film evaporation technology involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled conditions. In vertical agitated thin-film drying (or evaporation) (ATFD-V), the starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket. The rotor rotation agitates the downside-flowing solution while the heating jacket heats it.

The recovering in step-(d) is carried out by methods such as filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof. In one embodiment, the crystalline Form Al of rosiglitazone hydrogensulfate is recovered by filtration employing a filtration media of, for example, a silica gel or celite.

The substantially pure crystalline Form Al of rosiglitazone hydrogensulfate obtained by above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35⁰C to about 8O⁰C. The drying can be carried out for any desired time period that achieves the desired result, such as about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.

The purity of the crystalline Form Al of rosiglitazone hydrogensulfate obtained by the process disclosed herein is greater than about 98%, specifically greater than about 99%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the crystalline Form Al of rosiglitazone hydrogensulfate can be about 99% to about 99.95%, or about 99.5% to about 99.99%.

According to another aspect, there is provided a process for the preparation of a crystalline Form A2 of rosiglitazone hydrogensulfate, comprising: a) providing a first solution of rosiglitazone free base in an alcohol solvent; b) combining the first solution with sulfuric acid to produce a second solution containing rosiglitazone hydrogensulfate; c) optionally, subjecting the second solution to carbon treatment or silica gel treatment; d) substantially removing the solvent from the second solution obtained in step-(b) or step- (c) to provide a residue containing rosiglitazone hydrogensulfate; e) combining the residue obtained in step-(d) with an ether solvent to produce a reaction mass; and f) recovering the crystalline Form A2 of rosiglitazone hydrogensulfate from the reaction mass obtained in step-(e).

The process can produce crystalline Form A2 of rosiglitazone hydrogensulfate in substantially pure form.

The rosiglitazone hydrogensulfate crystalline Form A2 is stable, consistently reproducible and has good flow properties, and is particularly suitable for bulk preparation and handling, and hence, the rosiglitazone hydrogensulfate crystalline Form A2 disclosed herein is suitable for formulating rosiglitazone hydrogensulfate.

Exemplary alcohol solvents used in step-(a) include, but are not limited to, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, and mixtures thereof. A most specific alcohol solvent is methanol.

Step-(a) of providing a first solution of rosiglitazone free base includes dissolving rosiglitazone free base in the alcohol solvent, or obtaining an existing solution from a previous processing step.

In one embodiment, the rosiglitazone is dissolved in the alcohol solvent at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at about 2O⁰C to about 100⁰C, and more specifically at about 25⁰C to about 8O⁰C.

As used herein, "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.

Alternatively, the first solution in step-(a) is prepared by treating an acid addition salt of rosiglitazone with a base to produce rosiglitazone free base followed by extracting or dissolving the rosiglitazone in the alcohol solvent at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at about 2O⁰C to about 100⁰C, and more specifically at about 25⁰C to about 8O⁰C. In one embodiment, the acid addition salt of rosiglitazone and the base are selected from the group as described above. The sulfuric acid in step-(b) may be used in the form of concentrated sulfuric acid, or in the form of an aqueous solution, or in the form of a solution containing the sulfuric acid and an alcohol solvent selected from the group as described above.

Combining of the first solution with sulfuric acid in step-(b) is done in a suitable order as described above, for example, the first solution is added to the sulfuric acid, or alternatively, the sulfuric acid is added to the first solution. The addition is specifically carried out at a temperature of below about 50°C, more specifically at about 15⁰C to about 35⁰C, and most specifically at about 2O⁰C to about 3O⁰C under stirring. After completion of the addition process, the resulting mass is stirred at a temperature of about O⁰C to the reflux temperature of the solvent used for at least 10 minutes, specifically at about 15⁰C to about HO⁰C for about 20 minutes to about 10 hours, and more specifically at a temperature of about 2O⁰C to about 3O⁰C for about 30 minutes to about 4 hours to produce a second solution.

The carbon treatment or silica gel treatment in step-(c) is carried out by methods as described above. Removal of solvent in step-(d) is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent under inert atmosphere, or a combination thereof, to substantial elimination of total solvent present in the reaction mass.

The distillation process can be performed at atmospheric pressure or reduced pressure. Specifically, the distillation is carried out at a temperature of about 3O⁰C to about HO⁰C, more specifically at about 35⁰C to about 9O⁰C, and most specifically at about 4O⁰C to about 8O⁰C.

Specifically, the solvent is removed at a pressure of about 760 mm Hg or less, more specifically at about 400 mm Hg or less, still more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.

Exemplary ether solvents used in step-(e) include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether, and mixtures thereof. A specific ether solvent is diisopropyl ether.

Combining of the residue with the ether solvent in step-(e) is done in a suitable order as described above. After completion of the addition process, the resulting mass is cooled and stirred at a temperature of below about 35⁰C for at least 10 minutes, specifically at about

15⁰C to about 3O⁰C for about 20 minutes to about 10 hours, and more specifically at a temperature of about 2O⁰C to about 3O⁰C for about 30 minutes to about 4 hours.

The recovering in step-(f) is carried out by methods such as filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof. In one embodiment, the crystalline Form A2 of rosiglitazone hydrogensulfate is recovered by filtration employing a filtration media of, for example, a silica gel or celite.

The rosiglitazone hydrogensulfate crystalline Form A2 obtained in step-(f) is further dried by the methods as described above. According to another aspect, there is provided a process for the preparation of a crystalline Form A3 of rosiglitazone hydrogensulfate, comprising: a) providing a first solution of rosiglitazone free base in a ketone solvent; b) combining the first solution with sulfuric acid to produce a second solution containing rosiglitazone hydrogensulfate; c) recovering the rosiglitazone hydrogensulfate as a solid from the second solution; d) dissolving the solid obtained in step-(c) in a solvent medium containing an alcohol solvent and a ketone solvent to produce a third solution; and e) isolating and/or recovering the crystalline Form A3 of rosiglitazone hydrogensulfate from the third solution.

The process can produce crystalline Form A3 of rosiglitazone hydrogensulfate in substantially pure form.

The rosiglitazone hydrogensulfate crystalline Form A3 is stable, consistently reproducible and has good flow properties, and is particularly suitable for bulk preparation and handling, and hence, the rosiglitazone hydrogensulfate crystalline Form A3 disclosed herein is suitable for formulating rosiglitazone hydrogensulfate.

Exemplary ketone solvents used in step-(a) include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof. A most specific ketone solvent is acetone. Step-(a) of providing a first solution of rosiglitazone free base includes dissolving rosiglitazone free base in the ketone solvent, or obtaining an existing solution from a previous processing step.

In one embodiment, the rosiglitazone is dissolved in the ketone solvent at a temperature of about 30°C to the reflux temperature of the solvent used, specifically at about 4O⁰C to about 100⁰C, and more specifically at about 5O⁰C to about 7O⁰C.

Alternatively, the first solution in step-(a) is prepared by treating an acid addition salt of rosiglitazone with a base to produce rosiglitazone free base followed by extracting or dissolving the rosiglitazone in the ketone solvent at a temperature of about 30°C to the reflux temperature of the solvent used, specifically at about 4O⁰C to about 100⁰C, and more specifically at about 5O⁰C to about 7O⁰C. In one embodiment, the acid addition salt of rosiglitazone and the base are selected from the group as described above.

The first solution obtained in step-(a) is optionally subjected to carbon treatment or silica gel treatment as described above. The sulfuric acid in step-(b) may be used in the form of concentrated sulfuric acid, or in the form of an aqueous solution, or in the form of a solution containing the sulfuric acid and a ketone solvent selected from the group as described above.

Combining of the first solution with sulfuric acid in step-(b) is done in a suitable order as described above, for example, the first solution is added to the sulfuric acid, or alternatively, the sulfuric acid is added to the first solution. The addition is specifically carried out at a temperature of above about 30°C, more specifically at about 4O⁰C to about 7O⁰C, and most specifically at about 5O⁰C to about 6O⁰C under stirring to produce a second solution. The second solution obtained in step-(b) is optionally subjected to carbon treatment or silica gel treatment as described above.

After completion of the addition process, the resulting second solution is cooled and stirred at a temperature of below about 35°C for at least 10 minutes, specifically at about

15⁰C to about 30⁰C for about 20 minutes to about 10 hours, and more specifically at a temperature of about 2O⁰C to about 3O⁰C for about 30 minutes to about 4 hours to form a precipitate.

The recovering in step-(c) is carried out, and the solid obtained is further dried, by methods as described above.

The alcohol and ketone solvents used in step-(d) are, each independently, selected from the group as described above. A specific ketone solvent is acetone and a specific alcohol solvent is methanol.

In one embodiment, about 2 to 20 volumes, specifically, about 8 to 12 volumes of the ketone solvent with respect to the amount of alcohol solvent are used.

In another embodiment, the solid rosiglitazone hydrogensulfate in step-(d) is dissolved in the solvent medium at a temperature of about 30°C to the reflux temperature of the solvent medium used, specifically at about 4O⁰C to about 8O⁰C, and more specifically at about 50⁰C to about 70⁰C.

The isolation of crystalline Form A3 of rosiglitazone hydrogensulfate in step-(e) is carried out by a crystallization method usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof.

In one embodiment, the crystallization is carried out by cooling the solution while stirring at a temperature of below 3O⁰C for at least 10 minutes, specifically at about O⁰C to about 25⁰C for about 30 minutes to about 20 hours. The rosiglitazone hydrogensulfate crystalline Form A3 obtained in step-(e) is recovered and further dried by the methods as described above.

According to another aspect, there is provided a process for the preparation of a crystalline Form A4 of rosiglitazone hydrogensulfate, comprising: a) providing a first solution of rosiglitazone free base in a ketone solvent; b) combining the first solution with sulfuric acid to produce a second solution containing rosiglitazone hydrogensulfate; c) isolating and/or recovering the rosiglitazone hydrogensulfate as a solid from the second solution; and d) drying the solid obtained in step-(c) under vacuum at a temperature above about 50⁰C to produce crystalline Form A4 of rosiglitazone hydrogensulfate.

The process can produce crystalline Form A4 of rosiglitazone hydrogensulfate in substantially pure form.

The rosiglitazone hydrogensulfate crystalline Form A4 is stable, consistently reproducible and has good flow properties, and is particularly suitable for bulk preparation and handling, and hence, the rosiglitazone hydrogensulfate crystalline Form A4 disclosed herein is suitable for formulating rosiglitazone hydrogensulfate.

Exemplary ketone solvents used in step-(a) include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof. A most specific ketone solvent is acetone.

Step-(a) of providing a first solution of rosiglitazone free base includes dissolving rosiglitazone free base in the ketone solvent, or obtaining an existing solution from a previous processing step.

In one embodiment, the rosiglitazone is dissolved in the ketone solvent at a temperature of about 30°C to the reflux temperature of the solvent used, specifically at about 4O⁰C to about 100⁰C, and more specifically at about 50⁰C to about 7O⁰C.

Alternatively, the first solution in step-(a) is prepared by treating an acid addition salt of rosiglitazone with a base to produce rosiglitazone free base followed by extracting or dissolving the rosiglitazone in the ketone solvent at a temperature of about 30°C to the reflux temperature of the solvent used, specifically at about 4O⁰C to about 100⁰C, and more specifically at about 50⁰C to about 7O⁰C. In one embodiment, the acid addition salt of rosiglitazone and the base are selected from the group as described above.

The first solution obtained in step-(a) is optionally subjected to carbon treatment or silica gel treatment as described above. The sulfuric acid in step-(b) may be used in the form of concentrated sulfuric acid, or in the form of an aqueous solution, or in the form of a solution containing the sulfuric acid and a ketone solvent selected from the group as described above.

Combining of the first solution with sulfuric acid in step-(b) is done in a suitable order as described above, for example, the first solution is added to the sulfuric acid, or alternatively, the sulfuric acid is added to the first solution. The addition is specifically carried out at a temperature of above about 30°C, more specifically at about 4O⁰C to about 7O⁰C, and most specifically at about 5O⁰C to about 6O⁰C under stirring to produce a second solution. The second solution obtained in step-(b) is optionally subjected to carbon treatment or silica gel treatment as described above.

The isolation of solid rosiglitazone hydrogensulfate in step-(c) is carried out by a crystallization method such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof. In one embodiment, the crystallization is carried out by cooling the solution while stirring at a temperature of below 3O⁰C for at least 10 minutes, specifically at about O⁰C to about 25⁰C for about 30 minutes to about 20 hours.

The solid rosiglitazone hydrogensulfate obtained in step-(c) is recovered by the methods as described above. The drying in step-(d) is carried out by the methods as described above. In one embodiment, the drying is carried out at a temperature of about 5O⁰C to about 7O⁰C for at least 1 hour and specifically at a temperature of about 5O⁰C to about 6O⁰C for about 5 hours to about 25 hours.

According to another aspect, there is provided a process for the preparation of a crystalline Form A of rosiglitazone hydrogensulfate, comprising: a) providing a first solution of rosiglitazone free base in tetrahydrofuran; b) optionally, subjecting the first solution to carbon treatment or silica gel treatment; c) combining the first solution obtained in step-(a) or step-(b) with sulfuric acid to produce a second solution containing rosiglitazone hydrogensulfate; and d) optionally, subjecting the second solution to carbon treatment or silica gel treatment; e) precipitating the crystalline Form A of rosiglitazone hydrogensulfate by cooling the second solution obtained in step-(c) or step-(d) at a temperature below about 3O⁰C.

The process can produce crystalline Form A of rosiglitazone hydrogensulfate in substantially pure form. In one embodiment, the rosiglitazone hydrogensulfate crystalline Form A obtained by the process disclosed herein is characterized by one or more of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with Figure 13 ; ii) a powder X-ray diffraction pattern having peaks at about 6.27, 9.05, 13.20, 13.58, 14.53, 14.90, 15.53, 16.59, 17.43, 18.06, 18.65, 18.90, 19.74, 20.95, 22.14, 22.86, 23.56, 24.28,

24.73, 24.98, 25.30, 25.88, 26.17, 27.38, 28.39, 28.92, 30.05, 31.35, 31.83, 32.31 and 33.57 ± 0.2 degrees 2-theta; iii) an IR spectrum substantially in accordance with Figure 14; iv) an IR spectrum having absorption bands at about 2979, 2779, 1754, 1697, 1645, 1618, 1546, 1514, 1466, 1440, 1418, 1388, 1366, 1314, 1222, 1166, 1070, 1053, 1028, 1012,

987, 956, 905, 864, 800, 772, 736 and 663 ± 2 cm^"1; and v) a DSC thermogram having an endotherm peak at about 187.88°C substantially as depicted in Figure 15.

Step-(a) of providing a first solution of rosiglitazone free base includes dissolving rosiglitazone free base in tetrahydrofuran, or obtaining an existing solution from a previous processing step.

In one embodiment, the rosiglitazone is dissolved in the tetrahydrofuran at a temperature below about reflux temperature of tetrahydrofuran, specifically at about 25⁰C to about 60⁰C, and more specifically at about 3O⁰C to about 50⁰C. The carbon treatment or silica gel treatment in steps-(b) and (d) is carried out by the methods as described above.

The sulfuric acid in step-(b) may be used in the form of concentrated sulfuric acid or in the form of a solution containing the sulfuric acid and tetrahydrofuran.

Combining of the first solution with sulfuric acid in step-(c) is done in a suitable order as described above, for example, the first solution is added to the sulfuric acid, or alternatively, the sulfuric acid is added to the first solution. The addition is specifically carried out at a temperature of above about 25°C, more specifically at about 30⁰C to about

6O⁰C, and most specifically at about 4O⁰C to about 5O⁰C under stirring to produce a second solution. After completion of the addition process, the resulting second solution is stirred at a temperature of above about 35⁰C for at least 10 minutes, specifically at about 4O⁰C to about

5O⁰C for about 20 minutes to about 10 hours.

In one embodiment, the precipitation in step-(e) is carried out by cooling the solution while stirring at a temperature of about O⁰C to about 3O⁰C for at least 20 minutes and specifically at a temperature of about 15⁰C to about 25⁰C for about 30 minutes to about 10 hours.

The crystalline Form A of rosiglitazone hydrogensulfate obtained in step-(e) is recovered and further dried by the methods as described above. In one embodiment, the crystalline Form A of rosiglitazone hydrogensulfate obtained in step-(e) is further optionally subjected to usual work up such as a washing, an extraction, a layer separation, an evaporation, a filtration, or a combination thereof.

Further encompassed herein is the use of the polymorphic forms of rosiglitazone hydrogensulfate disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

A specific pharmaceutical composition of the polymorphic forms of rosiglitazone hydrogensulfate is selected from a solid dosage form and an oral suspension.

In one embodiment, each one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate (Form Al, Form A2, Form A3 and Form A4) disclosed herein has a D₉₀ particle size of less than or equal to about 400 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 200 microns, still more specifically less than or equal to about 100 microns, and most specifically less than or equal to about 15 microns.

In another embodiment, each one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate disclosed herein for use in the pharmaceutical compositions has a 90 volume-percent of the particles (D₉₀) of less than or equal to about 400 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 200 microns, still more specifically less than or equal to about 100 microns, and most specifically less than or equal to about 15 microns. In another embodiment, the particle sizes of the polymorphic forms of rosiglitazone hydrogensulfate can be achieved by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range. According to another aspect, there is provided a method for treating a patient suffering from non-insulin dependent diabetes mellitus (NIDDM); comprising administering any one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate disclosed herein, or a pharmaceutical composition that comprises any one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate disclosed herein along with pharmaceutically acceptable excipients.

According to another aspect, there is provided pharmaceutical compositions comprising a therapeutically effective amount of any one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate disclosed herein, and one or more pharmaceutically acceptable excipients.

According to another aspect, there is provided pharmaceutical compositions comprising any one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate prepared according to processes disclosed herein and one or more pharmaceutically acceptable excipients.

According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining any one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate prepared according to processes disclosed herein, with one or more pharmaceutically acceptable excipients. Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of any one or a mixture of the polymorphic forms of rosiglitazone hydrogensulfate disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The polymorphic forms of rosiglitazone hydrogensulfate may also be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.

The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described herein.

In one embodiment, capsule dosage forms contain the polymorphic forms of rosiglitazone hydrogensulfate within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. Suitable enteric coating include phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.

Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions described herein may contain diluents such as cellulose-derived materials such as powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.

Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low- substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS: X-Rav Powder Diffraction (P-XRD): The X-Ray powder diffraction was measured by an X-ray powder Diffractometer equipped with a Cu-anode (λ=l .54 Angstrom), X-ray source operated at 4OkV, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 1976, Corundum standard. The sample was analyzed using the following instrument parameters: measuring range= 3-45° 2Θ; step width = 0.01579°; and measuring time per step = 0.11 second.

Infra-Red Spectroscopy (FT-IR):

FT-IR spectroscopy was carried out with a Perkin Elmer Spectrum 100 series spectrometer. For the production of the KBr compacts approximately 2 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 to 650 cm^"1.

Differential Scanning Calorimetry (DSC): DSC (Differential Scanning Calorimetry) measurements were performed with a Differential Scanning Calorimeter (Diamond DSC, Perkin-Elmer) at a scan rate of 5°C per minute. The nitrogen gas purge was at 40 ml/min. The instrument was calibrated for temperature and heat flow using indium as standards. The samples were encapsulated in to closed aluminium pans without hole subsequently crimped to ensure a tight seal. Data acquisition and analysis were performed using pyris software.

The following examples are given for the purpose of illustrating the present disclosure and should not be considered as limitation on the scope or spirit of the disclosure.

EXAMPLES Example 1

Preparation of crystalline Form Al of Rosiglitazone hydrogensulfate

A mixture of rosiglitazone base (30 g, 0.083 mol) and water (180 ml) was heated at 75-8O⁰C to form a suspension, followed by the addition of a solution of sulfuric acid (9.05 g, 0.092 mol) in water (60 ml), and stirring the reaction mixture at 75-8O⁰C to form a clear solution. Charcoal (3 g) was added to the hot solution and then filtered. The filtrate was cooled to 25- 3O⁰C and stirred for 1 hour. The precipitated product was filtered and washed with water (150 ml). The wet product was dried under vacuum at 60-65⁰C to produce 24 g of crystalline Form Al of rosiglitazone hydogensulfate (Purity by HPLC: 99.82%).

Example 2

Preparation of crystalline Form A2 Rosiglitazone hydrogensulfate

Sulfuric acid (6.03 g, 0.061 mol) was added to a solution of rosiglitazone base (20 g, 0.056 mol) in methanol (300 ml) at 25-3O⁰C followed by stirring for 10-15 minutes. Charcoal (2 g) was added to the solution followed by filtering the solution. The filtrate was concentrated under vacuum at below 5O⁰C followed by the addition of diisopropyl ether (200 ml) to the residue and stirring for 1 hour. The precipitated product was filtered and washed with diisopropyl ether (40 ml). The wet product was dried under vacuum at 45-5O⁰C to produce 22 g of crystalline Form A2 of rosiglitazone hydogensulfate (Purity by HPLC: 99.83%). Example 3 Preparation of crystalline Form A3 of Rosiglitazone hydrogensulfate

A mixture of acetone (270 ml) and rosiglitazone base (15 g, 0.042 mol) was heated at 60- 65⁰C to form a clear solution, followed by the addition of charcoal (1.5 g) to the hot solution and filtering the solution. The filtrate was collected and sulfuric acid (4.73 g, 0.048 mol) was added at 55-6O⁰C. The reaction mass was cooled to 25-30⁰C and stirred for 1 hour. The precipitated product was filtered and suction dried. The dried product was dissolved in a mixture of methanol (22.5 ml) and acetone (230 ml) at 55-6O⁰C. The resulting solution was cooled to 25-30°C and stirred for 2 hours. The resulting solid was filtered and washed with acetone (22.5 ml) and then dried at 50-55°C for 10 to 12 hours to produce 7.5 g of crystalline Form A3 of rosiglitazone hydogensulfate (Purity by HPLC: 99.36%).

Example 4

Preparation of crystalline Form A4 of Rosiglitazone hydrogensulfate A mixture of acetone (100 ml) and rosiglitazone base (3 g, 0.0084 mol) was heated at 60- 65⁰C to form a clear solution, followed by the addition of charcoal (0.3 g) to the hot solution and filtration. The filtrate was collected and sulfuric acid (0.86 g, 0.0087 mol) was added at 55-60°C. The resulting mass was cooled to 25-30°C and stirred for 1 hour. The precipitated product was filtered and washed with acetone (15 ml) and then dried under vacuum at 55- 60°C for 15 to 20 hours to produce 3.2 g of crystalline Form A4 of Rosiglitazone hydogensulfate (Purity by HPLC: 99.69%).

Example 5

Preparation of crystalline Form A of Rosiglitazone hydrogensulfate Charcoal (0.5 g) was added to a solution of rosiglitazone base (5 g, 0.014 mol) in tetrahydrofuran (50 ml) at 25-30°C, and the resulting mass was filtered. Sulfuric acid (1.5 g, 0.015 mol) was added to the resulting filtrate and the reaction mass was heated at 40-45°C for 1 hour and subsequently cooled to 25-30°C. The precipitated product was filtered and washed with tetrahydrofuran (10 ml) and then dried under vacuum at 50-55°C to produce 4.5 g of crystalline Form A of Rosiglitazone hydogensulfate (Purity by HPLC: 99.82%; Content of sulfated ash: 0.04% w/w). Example 6

Preparation of crystalline form A of Rosiglitazone hydrogensulfate A solution of sulfuric acid (18.1 g, 0.185 mol) in tetrahydrofuran (120 ml) was added to a solution of rosiglitazone base (60 g, 0.168 mol) in tetrahydrofuran (360 ml) at 40-45°C. The resulting mass was stirred for 2 hours at 40-45⁰C and the precipitated product was cooled to 15-20°C and then filtered. The wet product was dissolved in methanol (1500 ml) at 60-65°C followed by treatment with charcoal (6.0 g). The charcoal was filtered out and the filtrate was concentrated completely under vacuum at below 45⁰C. The resulting residue was stirred with acetone (240 ml) for 2 hours at 25-30°C. The precipitated product was filtered, washed with acetone (120 ml) and then dried under vacuum at 55-60°C to produce 70 g of crystalline Form A of Rosiglitazone hydogensulfate (Purity by HPLC: 99.82%; Moisture content: 0.3% by weight; and Content of sulfated ash: 0.06% w/w).

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

The term "crystalline polymorph" refers to a crystal modification that can be characterized by analytical methods such as X-ray powder diffraction, IR-spectroscopy, differential scanning calorimetry (DSC) or by its melting point.

The term "stable crystalline form" refers to stability of the crystalline form under the standard temperature and humidity conditions of testing of pharmaceutical products, wherein the stability is indicated by preservation of the original polymorphic form.

The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use. The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.

The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.

The term "buffering agent" as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.

The term "sweetening agent" as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC(™) F68,

PLURONICC™) F 127), collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.

The term "diluent" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "glidant" as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti- caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "lubricant" as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "disintegrant" as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g., Avicel(™)), carsium (e.g., Amberlite(™)), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "wetting agent" as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEEN( )s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type) is another useful wetting agent, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "micronization" used herein means a process or method by which the size of a population of particles is reduced.

As used herein, the term "micron" or "μm" refers to "micrometer" which is 1 x 10^"6 meter.

As used herein, "crystalline particles" means any combination of single crystals, aggregates and agglomerates. As used herein, "Particle Size Distribution (P.S.D)" means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 2000 equipment or its equivalent.

As used herein, Dx means that X percent of the particles have a diameter less than a specified diameter D. Thus, a D₉₀ or d(0.9) of less than 300 microns means that 90 volume- percent of the particles in a composition have a diameter less than 300 microns.

By "substantially pure" is meant having purity greater than about 98%, specifically greater than about 99%, and more specifically greater than about 99.9% measured by HPLC. The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The term wt% refers to percent by weight. AU methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

We claim:

1. Rosiglitazone hydrogensulfate: a) in a crystalline Form Al ; b) in a crystalline Form A2; c) in a crystalline Form A3; or d) in a crystalline Form A4; wherein: e) the crystalline Form Al of rosiglitazone hydrogensulfate is characterized by one or more of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with Figure 1 ; ii) a powder X-ray diffraction pattern having peaks at about 8.3, 11.7, 16.7, 17.1 and

26.8 ± 0.2 degrees 2-theta; iii) a powder X-ray diffraction pattern having additional peaks at about 10.3, 18.6,

19.8, 20.5, 20.9, 23.0, 23.3, 23.7, 24.1, 24.9, 28.0 and 28.2 ± 0.2 degrees 2-theta; iv) an IR spectrum substantially in accordance with Figure 2; v) an IR spectrum having absorption bands at about 3421, 3131, 3042, 2953, 2873, 2739, 1743, 1701, 1541, 1320, 1301, 1266, 1219, 1160, 1100, 1066, 998 and 824 ± 2 cm^"1; and vi) a DSC thermogram substantially in accordance with Figure 3; f) the crystalline Form A2 of rosiglitazone hydrogensulfate is characterized by one or more of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with Figure 4; ii) a powder X-ray diffraction pattern having peaks at about 4.8, 14.2, 17.7, 19.6 and

21.6 ± 0.2 degrees 2-theta; iii) a powder X-ray diffraction pattern having additional peaks at about 4.4, 13.1,

13.7, 15.0, 15.8, 17.2, 20.5, 22.0, 22.9, 24.6 and 26.4 ± 0.2 degrees 2-theta; iv) an IR spectrum substantially in accordance with Figure 5; v) an IR spectrum having absorption bands at about 3435, 3291, 3109, 2985, 2784, 2481, 1827, 1707, 1331, 1302, 1245, 1178, 1159, 1111, 1077, 935, 916, 827 and 760 ± 2 cm^"1; and vi) a DSC thermogram substantially in accordance with Figure 6; g) the crystalline Form A3 of rosiglitazone hydrogensulfate is characterized by one or more of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with Figure 7; ii) a powder X-ray diffraction pattern having peaks at about 5.3, 12.1, 16.0, 21.8 and

23.6 ± 0.2 degrees 2-theta; iii) a powder X-ray diffraction pattern having additional peaks at about 10.6, 11.7,

12.6, 13.8, 14.9, 17.8, 18.0, 20.4, 21.2, 22.1, 23.2 and 26.4 ± 0.2 degrees 2-theta; iv) an IR spectrum substantially in accordance with Figure 8; v) an IR spectrum having absorption bands at about 3388, 3138, 2986, 2774, 2479,

1831, 1748, 1705, 1475, 1460, 1413, 1302, 1179, 1158, 1035, 1005, 897, 830, 820 and 763 ± 2 cm^"1; and vi) a DSC thermogram substantially in accordance with Figure 9; h) the crystalline Form A4 of rosiglitazone hydrogensulfate is characterized by one or more of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with Figure 10; ii) a powder X-ray diffraction pattern having peaks at about 4.8, 6.8, 14.2, 15.1, 16.1 and 26.6 ± 0.2 degrees 2-theta; iii) a powder X-ray diffraction pattern having additional peaks at about 7.5, 9.9, 13.4,

15.6, 19.6, 20.8, 21.7, 22.7, 24.1, 24.5, 25.2 and 30.4 ± 0.2 degrees 2-theta; iv) an IR spectrum substantially in accordance with Figure 11 ; v) an IR spectrum having absorption bands at about 3395, 3042, 2786, 2555, 2478,

1868, 1764, 1708, 1558, 1397, 1301, 1231, 1177, 1151, 1079, 828 and 762 ± 2 cm^"1; and vi) a DSC thermogram substantially in accordance with Figure 12.

2. The rosiglitazone hydrogensulfate of claim 1, wherein the polymorphic form is anhydrous and/or solvent-free form, or a hydrate and/or a solvate form.

3. A process for the preparation of rosiglitazone hydrogensulfate crystalline Form Al of claim 1, comprising: a) providing an aqueous suspension of rosiglitazone free base in water; b) combining the aqueous suspension with sulfuric acid to produce a solution containing rosiglitazone hydrogensulfate; and c) optionally, subjecting the solution to carbon treatment or silica gel treatment; d) isolating and/or recovering the crystalline Form Al of rosiglitazone hydrogensulfate from the solution obtained in step-(b) or step-(c).

4. The process of claim 3, wherein the suspension in step-(a) is provided either i) by suspending rosiglitazone free base in water while stirring at a temperature of about 0⁰C to about 100⁰C; or ii) by treating an acid addition salt of rosiglitazone with a base to produce rosiglitazone free base followed by suspending the rosiglitazone in water at a temperature of about O⁰C to about 100°C.

5. The process of claim 4, wherein the suspension is stirred at a temperature of about 5O⁰C to about 8O⁰C for about 30 minutes to about 10 hours.

6. The process of claim 3, wherein the combining in step-(b) is accomplished by adding the aqueous suspension to the sulfuric acid or by adding the sulfuric acid to the aqueous suspension at a temperature of about 0°C to about 90⁰C.

7. The process of claim 6, wherein the reaction mass obtained after completion of the addition process is stirred at a temperature of about 4O⁰C to about 8O⁰C for about 30 minutes to about 4 hours to produce a solution.

8. The process of claim 3, wherein the isolation of crystalline Form Al of rosiglitazone hydrogensulfate in step-(d) is carried out by forcible crystallization, spontaneous crystallization, substantial removal of the solvent from the solution, or a combination thereof.

9. The process of claim 8, wherein the crystallization is initiated by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof; and wherein the removal of solvent is accomplished by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent under inert atmosphere, spray drying, vacuum drying, agitated thin-film (ATFD) drying, or a combination thereof.

10. The process of claim 9, wherein the crystallization is carried out by cooling the solution while stirring at a temperature of below 3O⁰C for at least 10 minutes.

11. The process of claim 10, wherein the crystallization is carried out by cooling the solution while stirring at a temperature of about O⁰C to about 25⁰C for about 30 minutes to about 20 hours.

12. The process of claim 3, wherein the recovering in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof; and wherein the substantially pure crystalline Form Al of rosiglitazone hydrogensulfate obtained is further dried under vacuum or at atmospheric pressure, at a temperature of about 35⁰C to about 8O⁰C.

13. A process for the preparation of rosiglitazone hydrogensulfate crystalline Form A2 of claim 1, comprising: a) providing a first solution of rosiglitazone free base in an alcohol solvent; b) combining the first solution with sulfuric acid to produce a second solution containing rosiglitazone hydrogensulfate; c) optionally, subjecting the second solution to carbon treatment or silica gel treatment; d) substantially removing the solvent from the second solution obtained in step-(b) or step-(c) to provide a residue containing rosiglitazone hydrogensulfate; e) combining the residue obtained in step-(d) with an ether solvent to produce a reaction mass; and f) recovering the crystalline Form A2 of rosiglitazone hydrogensulfate from the reaction mass obtained in step-(e).

14. The process of claim 13, wherein the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n- butanol, tert-butanol, and mixtures thereof; and wherein the ether solvent used in step-(e) is selected from the group consisting of diethyl ether, diisopropyl ether, methyl tert-butyl ether, and mixtures thereof.

15. The process of claim 14, wherein the alcohol solvent is methanol; and wherein the ether solvent is diisopropyl ether.

16. The process of claim 13, wherein the sulfuric acid in step-(b) is used in the form of concentrated sulfuric acid, or in the form of an aqueous solution, or in the form of a solution containing the sulfuric acid and an alcohol solvent.

17. The process of claim 13, wherein the combining in step-(b) is accomplished by adding the first solution to the sulfuric acid, or by adding the sulfuric acid to the first solution at a temperature of below about 50°C.

18. The process of claim 17, wherein the reaction mass obtained after completion of the addition process is stirred at a temperature of about 15⁰C to about HO⁰C for about 20 minutes to about 10 hours to produce a second solution.

19. The process of claim 13, wherein the removal of solvent in step-(d) is accomplished by substantially complete evaporation of the solvent, concentrating the solution, or distillation of solvent under inert atmosphere, or a combination thereof.

20. The process of claim 13, wherein the reaction mass obtained in step-(e) is cooled and stirred at a temperature of about 15⁰C to about 3O⁰C for about 20 minutes to about 10 hours.

21. The process of claim 13, wherein the recovering in step-(f) is carried out by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof; and wherein the substantially pure crystalline Form A2 of rosiglitazone hydrogensulfate obtained is further dried under vacuum or at atmospheric pressure, at a temperature of about 35°C to about 8O⁰C.

22. A process for the preparation of rosiglitazone hydrogensulfate crystalline Form A3 of claim 1, comprising: a) providing a first solution of rosiglitazone free base in a ketone solvent; b) combining the first solution with sulfuric acid to produce a second solution containing rosiglitazone hydrogensulfate; c) recovering the rosiglitazone hydrogensulfate as a solid from the second solution; d) dissolving the solid obtained in step-(c) in a solvent medium containing an alcohol solvent and a ketone solvent to produce a third solution; and e) isolating and/or recovering the crystalline Form A3 of rosiglitazone hydrogensulfate from the third solution.

23. The process of claim 22, wherein the ketone solvent used in steps-(a) and (d) is, each independently, selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof; and wherein the alcohol solvent used in step-(d) is selected from the group consisting of methanol, ethanol, n- propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, and mixtures thereof.

24. The process of claim 23, wherein the ketone solvent is acetone; and wherein the alcohol solvent is methanol.

25. The process of claim 22, wherein the sulfuric acid in step-(b) is used in the form of concentrated sulfuric acid, or in the form of an aqueous solution, or in the form of a solution containing the sulfuric acid and a ketone solvent.

26. The process of claim 22, wherein the combining in step-(b) is accomplished by adding the first solution to the sulfuric acid or by adding the sulfuric acid to the first solution at a temperature of above about 30⁰C.

27. The process of claim 26, wherein the reaction mass obtained after completion of the addition process is cooled and stirred at a temperature of about 15⁰C to about 3O⁰C for about 20 minutes to about 10 hours to form a precipitate.

28. The process of claim 22, wherein the isolation of crystalline Form A3 of rosiglitazone hydrogensulfate in step-(e) is carried out by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof; and wherein the cooling is carried out while stirring at a temperature of below 30⁰C for at least 10 minutes.

29. The process of claim 22, wherein the recovering in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof; and wherein the substantially pure crystalline Form A3 of rosiglitazone hydrogensulfate obtained is further dried under vacuum or at atmospheric pressure, at a temperature of about 35⁰C to about 8O⁰C.

30. A process for the preparation of rosiglitazone hydrogensulfate crystalline Form A4 of claim 1, comprising: a) providing a first solution of rosiglitazone free base in a ketone solvent; b) combining the first solution with sulfuric acid to produce a second solution containing rosiglitazone hydrogensulfate; c) isolating and/or recovering the rosiglitazone hydrogensulfate as a solid from the second solution; and d) drying the solid obtained in step-(c) under vacuum at a temperature above about 5O⁰C to produce crystalline Form A4 of rosiglitazone hydrogensulfate.

31. The process of claim 30, wherein the ketone solvent used in step-(a) is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.

32. The process of claim 31, wherein the ketone solvent is acetone.

33. The process of claim 30, wherein the sulfuric acid in step-(b) is used in the form of concentrated sulfuric acid, or in the form of an aqueous solution, or in the form of a solution containing the sulfuric acid and the ketone solvent.

34. The process of claim 30, wherein the combining in step-(b) is accomplished by adding the first solution to the sulfuric acid or by adding the sulfuric acid to the first solution at a temperature of above about 30⁰C.

35. The process of claim 34, wherein the addition is carried out at a temperature of about 4O⁰C to about 7O⁰C.

36. The process of claim 30, wherein the second solution obtained in step-(b) is optionally subjected to carbon treatment or silica gel treatment.

37. The process of claim 30, wherein the isolation of solid rosiglitazone hydrogensulfate in step-(c) is carried out by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof; and wherein the solid obtained is recovered by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.

38. The process of claim 37, wherein the isolation is carried out by cooling the solution while stirring at a temperature of O⁰C to about 3O⁰C.

39. The process of claim 30, wherein the drying in step-(e) is carried out at a temperature of about 50⁰C to about 7O⁰C.

40. A process for the preparation of rosiglitazone hydrogensulfate crystalline Form A, comprising: a) providing a first solution of rosiglitazone free base in tetrahydrofuran; b) optionally, subjecting the first solution to carbon treatment or silica gel treatment; c) combining the first solution obtained in step-(a) or step-(b) with sulfuric acid to produce a second solution containing rosiglitazone hydrogensulfate; and d) optionally, subjecting the second solution to carbon treatment or silica gel treatment; e) precipitating the crystalline Form A of rosiglitazone hydrogensulfate by cooling the second solution obtained in step-(c) or step-(d) at a temperature below about 3O⁰C.

41. The process of claim 40, wherein the rosiglitazone hydrogensulfate crystalline Form A obtained is characterized by one or more of the following properties: i) a powder X-ray diffraction pattern substantially in accordance with Figure 13; ii) a powder X-ray diffraction pattern having peaks at about 6.27, 9.05, 13.20, 13.58, 14.53, 14.90, 15.53, 16.59, 17.43, 18.06, 18.65, 18.90, 19.74, 20.95, 22.14, 22.86, 23.56, 24.28, 24.73, 24.98, 25.30, 25.88, 26.17, 27.38, 28.39, 28.92, 30.05, 31.35, 31.83, 32.31 and 33.57 ± 0.2 degrees 2-theta; iii) an IR spectrum substantially in accordance with Figure 14; iv) an IR spectrum having absorption bands at about 2979, 2779, 1754, 1697, 1645, 1618, 1546, 1514, 1466, 1440, 1418, 1388, 1366, 1314, 1222, 1166, 1070, 1053, 1028, 1012, 987, 956, 905, 864, 800, 772, 736 and 663 ± 2 cm^"1; and v) a DSC thermogram having an endotherm peak at about 187.88⁰C substantially as depicted in Figure 15.

42. The process of claim 40, wherein the sulfuric acid in step-(b) is used in the form of concentrated sulfuric acid or in the form of a solution containing the sulfuric acid and tetrahydrofuran.

43. The process of claim 40, wherein the combining in step-(c) is accomplished by adding the first solution to the sulfuric acid or by adding the sulfuric acid to the first solution at a temperature of above about 25⁰C to produce a second solution; and wherein the second solution obtained after completion of the addition process is stirred at a temperature of about 40°C to about 5O⁰C for about 20 minutes to about 10 hours.

44. The process of claim 40, wherein the precipitation in step-(e) is carried out by cooling the solution while stirring at a temperature of about O⁰C to about 30⁰C for about 30 minutes to about 10 hours; and wherein the crystalline Form A of rosiglitazone hydrogensulfate obtained is recovered by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.

45. A pharmaceutical composition comprising a therapeutically effective amount of any one or a mixture of the rosiglitazone hydrogensulfate crystalline forms (Form Al, Form A2, Form A3 and Form A4) of claim 1, and one or more pharmaceutically acceptable excipients.

46. A process for preparing the pharmaceutical composition of claim 45, comprising combining any one or a mixture of the rosiglitazone hydrogensulfate crystalline forms of claim 1 with one or more pharmaceutically acceptable excipients.

47. The pharmaceutical composition of claim 45, wherein the pharmaceutical composition is a solid dosage form, an oral suspension, a liquid, a powder, an elixir, an aerosol, a syrup or an injectable solution.

48. The pharmaceutical composition of claim 45, wherein the crystalline form of rosiglitazone hydrogensulfate has a D₉₀ particle size of less than or equal to about 400 microns.

49. The pharmaceutical composition of claim 48, wherein the crystalline form of rosiglitazone hydrogensulfate has a D₉₀ particle size of less than or equal to about 300 microns; less than or equal to about 200 microns; less than or equal to about 100 microns; or less than or equal to about 15 microns.

50. A method for treating a patient suffering from non-insulin dependent diabetes mellitus (NIDDM); comprising administering any one or a mixture of the rosiglitazone hydrogensulfate crystalline forms (Form Al, Form A2, Form A3 and Form A4) of claim

1, or a pharmaceutical composition that comprises any one or a mixture of the rosiglitazone hydrogensulfate crystalline forms along with pharmaceutically acceptable excipients.