WO2010013141A2 - Substantially pure rosiglitazone hydrogen sulfate - Google Patents

Abstract

Provided herein are impurities of rosiglitazone hydrogen sulfate, 4-[2-(N-methyl-2-(N- pyridinyl)amino)ethoxy]bromobenzene (bromo impurity) and 5-[[4-[2-[methyl-(2-pyridinyl- N-oxide)amino]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (N-oxide impurity), and processes for preparing and isolating thereof. Provided further herein is a highly pure rosiglitazone hydrogen sulfate substantially free of bromo and N-oxide impurities, process for the preparation thereof, and pharmaceutical compositions comprising highly pure rosiglitazone hydrogen sulfate substantially free of bromo and N-oxide impurities.

Description

SUBSTANTIALLY PURE ROSIGLITAZONE HYDROGEN SULFATE

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority to Indian provisional application No. 1848/CHE/2008, filed on August 1, 2008, which is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

Disclosed herein are impurities of rosiglitazone hydrogen sulfate, and processes for the preparation and isolation thereof. Disclosed further herein is a highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of impurities, process for the preparation thereof, and pharmaceutical compositions comprising highly pure rosiglitazone hydrogen sulfate substantially free of impurities.

BACKGROUND

Rosiglitazone, 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4- thiazolidinedione, is a member of the thiazolidinedione class of antidiabetic agents 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 AVANDIA® 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 produces rosiglitazone.

European Patent No. 0658161 discloses 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, pharmaceutical compositions thereof, and characterizes them by powder X-ray diffraction (P-XRD), differential scanning calorimetry (DSC) and Infrared (IR) spectroscopy. PCT Publication No. WO 03/050113 discloses hydrogensulfate salt of rosiglitazone, processes for the preparation, and pharmaceutical compositions thereof.

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 the preparation, pharmaceutical compositions thereof, and characterizes them by powder X-ray diffraction (P-XRD).

U.S. Patent Application No. 2007/0293546 discloses a column chromatographic process for purifying rosiglitazone and its salts to substantially remove the dehydro impurity comprising: a) adsorbing rosiglitazone onto an adsorbent resin, by contacting a resin with a rosiglitazone solution; and b) eluting purified rosiglitazone from a resin with a solvent comprising 5% v/v to 70% v/v linear gradient of methanol in phosphate buffer.

Rosiglitazone obtained by the processes described in the above prior art does not have satisfactory purity for pharmaceutical use. Unacceptable amounts of impurities are generally formed along with rosiglitazone. In addition, the processes involve the additional step of column chromatographic purifications. Methods involving column chromatographic purifications are generally undesirable for large-scale operations as they require additional expensive setup adding to the cost of production, thereby making the processes commercially unfeasible.

It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in an active pharmaceutical ingredient (API) may arise from degradation of the API itself, or during the preparation of the API. Impurities in rosiglitazone or any active pharmaceutical ingredient (API) are undesirable and might be harmful. Regulatory authorities worldwide require that drug manufactures isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels, even if structural determination is not possible. The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the active pharmaceutical ingredient, the product is analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. Purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. The United States Food and Drug Administration guidelines recommend that the amounts of some impurities limited to less than 0.1 percent. Generally, impurities are identified spectroscopically and by other physical methods, and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the "retention time" ("Rt"). This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use "relative retention time" ("RRT") to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker. It is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.

There is a need for highly pure rosiglitazone or a pharmaceutically acceptable salt thereof substantially free of impurities, as well as processes for preparing thereof.

SUMMARY

In one aspect, provided herein is a bromophenyl compound, 4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]bromobenzene, having structural formula II:

In another aspect, provided herein is an impurity of rosiglitazone, bromo impurity, 4- [2-(N-methyl-N-(2-pyridyl)amino)ethoxy]bromobenzene, of formula II.

In another aspect, encompassed herein is a process for synthesizing and isolating the bromophenyl compound of formula II, also referred to as the "bromo impurity".

In another aspect, provided herein is a rosiglitazone N-oxide compound, 5-[[4-[2- [methyl-(2-pyridyl-N-oxide)amino]ethoxy]phenyl]methyl]-2,4-thiazolidinedione, having structural formula III:

In another aspect, provided herein is an impurity of rosiglitazone, N-oxide impurity, 5-[[4-[2-[methyl-(2-pyridyl-N-oxide)amino]ethoxy]phenyl]methyl]-2,4-thiazolidinedione, of formula III.

In another aspect, encompassed herein is a process for synthesizing and isolating the rosiglitazone N-oxide compound of formula III, also referred to as the "N-oxide impurity".

In another aspect, provided herein is a highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities. In another aspect, provided herein is a highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities.

In still further aspect, encompassed herein is a process for preparing the highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities.

In still further aspect, encompassed herein is a process for preparing the highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities. In another aspect, provided herein is a pharmaceutical composition comprising highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities, and one or more pharmaceutically acceptable excipients.

In still another aspect, provided herein is a pharmaceutical composition comprising highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.

In still further aspect, encompassed is a process for preparing a pharmaceutical formulation comprising combining highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities with one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION

According to one aspect, there is provided a bromophenyl compound, 4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]bromobenzene, having the following structural formula II:

According to another aspect, there is provided an impurity of rosiglitazone, rosiglitazone bromo impurity, 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]bromobenzene, of formula II. The rosiglitazone bromo impurity has been identified, isolated and synthesized. The bromo impurity was detected and resolved from rosiglitazone by HPLC with an RRT of 1.5.

The structure of the compound of formula II was deduced with the aid of ¹H, ¹³C NMR & IR spectroscopy and FAB mass spectrometry. The parent ion at 307.18 is consistent with the assigned structure.

According to another aspect, there is provided an isolated rosiglitazone bromo impurity.

According to another aspect, there is provided a rosiglitazone N-oxide compound, 5- [[4-[2-[methyl-(2-pyridyl-N-oxide)amino]ethoxy]phenyl]methyl]-2,4-thiazolidinedione, having the following structural formula III:

According to another aspect, there is provided an impurity of rosiglitazone, rosiglitazone N-oxide impurity, 5-[[4-[2-[methyl-(2-pyridyl-N-oxide)amino]ethoxy]phenyl] methyl]-2,4-thiazolidinedione, of formula III.

The rosiglitazone N-oxide impurity was identified, isolated and synthesized. The N- oxide impurity was detected and resolved from rosiglitazone by HPLC with an RRT of 1.05.

The structure of the compound of formula III was deduced with the aid of ¹H, ¹³C NMR & IR spectroscopy and FAB mass spectrometry. The parent ion at 373.4 is consistent with assigned structure.

According to another aspect, there is provided an isolated rosiglitazone N-oxide impurity.

In one embodiment, the bromophenyl compound of formula II is prepared as per the process exemplified in the Example 8 as disclosed herein.

In another embodiment, the rosiglitazone N-oxide compound of formula III is prepared as per the process exemplified in the Example 9 as disclosed herein. In addition to those two impurities (bromo and N-oxide impurities), there are three other impurities, whose presence was observed in rosiglitazone. The details of these three impurities of rosiglitazone are as follows: i) Desmethylrosiglitazone impurity: 5-[[4-[2-(2-pyridinylamino)ethoxy]phenyl]methyl]-2,4- thiazolidinedione, which has the following structural formula IV:

and it is detected and resolved from rosiglitazone by HPLC with an RRT of 0.91 (the "demethyl impurity"); ii) Rosiglitazone dehydro impurity: 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzylidene]-2,4-thiazolidinedione, which has the following structural formula V:

and it is detected and resolved from rosiglitazone by HPLC with an RRT of 1.22 ("the dehydro impurity"); iii) Rosiglitazone imino impurity: 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl] methyl]]-2-imino-4-thiazolidinone, which has the following structural formula VI:

and it is detected and resolved from rosiglitazone by HPLC ("the imino impurity").

Thus there is a need for a method for determining the level of impurities in rosiglitazone samples and removing the impurities.

Extensive experimentation was carried out by the present inventors to reduce the level of the bromo, N-oxide, desmethyl, dehydro and imino impurities in rosiglitazone. As a result, it has been found that the bromo, N-oxide, desmethyl, dehydro and imino impurities formed in the preparation of the rosiglitazone can be reduced or completely removed by the purification process disclosed herein.

According to another aspect, there is provided a highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N- oxide impurities. In one embodiment, the highly pure rosiglitazone or a hydrogen sulfate salt thereof disclosed herein is substantially free from at least one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities.

According to another aspect, there is provided a highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or more, of the bromo, N- oxide, desmethyl, dehydro and imino impurities.

As used herein, "highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities" refers to rosiglitazone or a hydrogen sulfate salt thereof comprising one, or both, of the bromo and N- oxide impurities, each one, in an amount of less than about 0.2 area-% as measured by HPLC. Specifically, the rosiglitazone, as disclosed herein, contains less than about 0.15 area-%, more specifically less than about 0.05 area-%, still more specifically less than about 0.02 area-% of one, or both, of the bromo and N-oxide impurities, and most specifically is essentially free of one, or both, of the bromo and N-oxide impurities. In one embodiment, the highly pure rosiglitazone or a hydrogen sulfate salt thereof disclosed herein comprises one, or both, of the bromo and N-oxide impurities, each one, in an amount of about 0.01 area-% to about 0.15 area-%, specifically in an amount of about 0.01 area-% to about 0.05 area-%, as measured by HPLC.

As used herein, "highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities" refers to rosiglitazone or a hydrogen sulfate salt thereof comprising one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities, each one, in an amount of less than about 0.2 area-% as measured by HPLC. Specifically, the rosiglitazone, as disclosed herein, contains less than about 0.15 area-%, more specifically less than about 0.05 area-%, still more specifically less than about 0.02 area-% of one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities, and most specifically is essentially free of one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities.

In another embodiment, the highly pure rosiglitazone or a hydrogen sulfate salt thereof disclosed herein has a total purity of greater than about 99%, specifically greater than about 99.5%, 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 highly pure rosiglitazone or a hydrogen sulfate salt thereof is about 99% to about 99.9%, or about 99.5% to about 99.99%. In another embodiment, the highly pure rosiglitazone or a hydrogen sulfate salt thereof disclosed herein is essentially free of one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities.

In yet another embodiment, the highly pure rosiglitazone or a hydrogen sulfate salt thereof disclosed herein is essentially free of dehydro impurity.

The term "rosiglitazone or a hydrogen sulfate salt thereof essentially free of at least one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities" refers to rosiglitazone or a hydrogen sulfate salt thereof contains a non-detectable amount of one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities as measured by HPLC.

The term "rosiglitazone or a hydrogen sulfate salt thereof essentially free of dehydro impurity" refers to rosiglitazone or a hydrogen sulfate salt thereof contains a non-detectable amount of dehydro impurity.

According to another aspect, there is provided a process for preparing highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities, comprising: a) providing a first suspension of crude rosiglitazone in water; b) combining the suspension with an aqueous solution of sulfuric acid to form a first solution; c) optionally, subjecting the first solution to carbon treatment; d) precipitating rosiglitazone hydrogen sulfate salt from the solution obtained in step-(b) or step-(c) to produce precipitated rosiglitazone hydrogen sulfate salt; e) suspending the precipitated rosiglitazone hydrogen sulfate salt obtained in step-(d) in water to form a second aqueous suspension; f) neutralizing the second aqueous suspension with a base to produce precipitated rosiglitazone base; g) dissolving the precipitated rosiglitazone base in an alcohol solvent to form a second solution; h) optionally, substantially removing the solvent from the second solution to obtain a residue and combining the residue with an alcohol solvent to form a third solution or suspension; i) isolating and/or recovering highly pure rosiglitazone base substantially free of the impurities from the second solution obtained in step-(g) or the third solution or suspension obtained in step-(h); and j) optionally, converting the highly pure rosiglitazone base obtained in step-(i) into its hydrogen sulfate salt.

Step-(a) of providing a suspension of crude rosiglitazone includes suspending crude rosiglitazone in water while stirring at a temperature of below about 100⁰C. In one embodiment, the suspension is stirred at a temperature of about 4O⁰C to about 9O⁰C for at least 10 minutes and more specifically at a temperature of about 6O⁰C to about 8O⁰C for about

30 minutes to about 10 hours.

In one embodiment, the suspension in step-(a) is prepared by reacting 5 -[[4- [2- (methyl-2-pyridinylamino)ethoxy]phenyl]methyl]]-2-imino-4-thiazolidinone with aqueous hydrochloric acid solution to produce rosiglitazone hydrochloride salt, which is then treated with a base, such as sodium bicarbonate, to produce a reaction mass containing crude rosiglitazone base, followed by usual work up such as washings, extractions, evaporations, or a combination thereof. In one embodiment, the work-up includes suspending the resulting rosiglitazone base in water while stirring at a temperature of below about 100⁰C. Combining of the suspension with aqueous solution of sulfuric acid in step-(b) is done in a suitable order, for example, the aqueous solution of sulfuric acid is added to the suspension, or alternatively, the suspension is added to the aqueous solution of sulfuric acid. 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 30°C to about 90°C for at least 10 minutes and more specifically at a temperature of about 40°C to about 80⁰C for about 30 minutes to about 4 hours. After completion of addition process, the resulting mass is stirred at a temperature of below about 100⁰C for at least 5 minutes and more specifically at about 6O⁰C to about 80⁰C for about 10 minutes to about 10 hours.

The carbon treatment in step-(c) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at a temperature of below about 7O⁰C for at least 15 minutes, specifically at a temperature of about 4O⁰C to about 70⁰C for at least 30 minutes; and filtering the resulting mixture through a filtration bed such as hyflo to obtain a filtrate containing rosiglitazone hydrogen sulfate by removing charcoal. Specifically, the finely powdered carbon is an active carbon. The precipitation of rosiglitazone hydrogen sulfate in step-(d) is carried out by cooling the solution at a temperature of below 4O⁰C for at least 10 minutes, specifically at about O⁰C to about 3O⁰C for about 30 minutes to about 10 hours, and more specifically at about 2O⁰C to about 3O⁰C for about 1 hour to about 4 hours. The base used for neutralization in step-(f) is an inorganic base. Specifically the inorganic base is sodium carbonate and more specifically an aqueous solution of sodium carbonate.

In one embodiment, the alcohol solvent used in the steps-(g) and (h) is methanol. In another embodiment, the rosiglitazone base in step-(g) is dissolved in the alcohol solvent at a temperature of about 4O⁰C to the reflux temperature of the alcohol solvent and specifically at about 5O⁰C to about 7O⁰C.

The term "substantially removing" the solvent in step-(h) refers to at least 30%, specifically greater than about 50%, 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 solvent solution.

Removal of solvent in step-(h) 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 solution.

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 110⁰C, more specifically at about 4O⁰C to about 9O⁰C, and most specifically at about 45⁰C 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.

The isolation of highly pure rosiglitazone base in step-(i) is carried out, for example, by forcible or spontaneous crystallization. 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 is initiated by methods such as cooling, seeding, partial removal of the solvent from the solution, by combining an anti-solvent with 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 35⁰C for at least 15 minutes, specifically at about O⁰C to about 3O⁰C for about 30 minutes to about 20 hours, and more specifically at about 2O⁰C to about 3O⁰C for about 2 hours to about 10 hours. The recovery of highly pure rosiglitazone base in step-(i) is accomplished by techniques such as filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof. In one embodiment, the rosiglitazone base is recovered by filtration employing a filtration media of, for example, a silica gel or celite. In one embodiment, the conversion of highly pure rosiglitazone base to rosiglitazone hydrogen sulfate salt in step-(j) is carried out by a process comprising: 1) providing a first solution or suspension of pure rosiglitazone base in a first solvent; 2) combining the first solution or suspension with a solution of sulfuric acid in a second solvent to form a second solution or suspension containing rosiglitazone hydrogen sulfate; 3) isolating and/or recovering highly pure rosiglitazone hydrogen sulfate from the second solution or suspension; 4) optionally, dissolving or suspending the pure rosiglitazone hydrogen sulfate obtained in step-(3) in a third solvent to produce a third solution or suspension; and 5) isolating and/or recovering highly pure rosiglitazone hydrogen sulfate from the third solution or suspension obtained in step-(4). The first solvent used in step-(l) is selected from the group consisting of water, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, acetone, and mixtures thereof. Specifically, the first solvent is selected from the group consisting of water, tetrahydrofuran, methanol, and mixtures thereof.

The second solvent used in step-(2) is selected from the group consisting of water, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, and mixtures thereof. Specifically, the second solvent is selected from the group consisting of water, tetrahydrofuran, methanol, and mixtures thereof.

The third solvent used in step-(4) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, and mixtures thereof. Specifically, the third solvent is selected from the group consisting of methanol, acetone, and mixtures thereof.

The isolating and recovering highly pure rosiglitazone hydrogen sulfate in the steps- (3) and (5) are carried out by the methods described hereinabove.

In one embodiment, the isolation of highly pure rosiglitazone hydrogen sulfate is carried out by cooling the solution while stirring at a temperature of below 35⁰C for at least 15 minutes, specifically at about O⁰C to about 3O⁰C for about 30 minutes to about 20 hours, and more specifically at about 2O⁰C to about 3O⁰C for about 2 hours to about 10 hours.

In another embodiment, the isolation of highly pure rosiglitazone hydrogen sulfate is carried out by adding an anti-solvent to the solution. In one embodiment, the anti-solvent is an ether solvent and a specific anti-solvent is diisopropyl ether. The highly pure rosiglitazone or a hydrogen sulfate salt thereof obtained by the 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 70⁰C. The drying can be carried out for any desired time period that achieves the desired result, such as times 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.

Further encompassed herein is the use of the highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

A specific pharmaceutical composition of highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities is selected from a solid dosage form and an oral suspension. According to another aspect, there is provided pharmaceutical compositions comprising highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities prepared according to the 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 highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities prepared according to processes disclosed herein, with one or more pharmaceutically acceptable excipients. According to another aspect, there is provided pharmaceutical compositions comprising highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities prepared according to the processes disclosed herein and one or more pharmaceutically acceptable excipients.

Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities. 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 highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N-oxide impurities 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 hereinabove.

In one embodiment, capsule dosage forms contain highly pure rosiglitazone or a hydrogen sulfate salt thereof substantially free of at least one, or both, of the bromo and N- oxide impurities within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. Suitable enteric coating agents 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 like 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.

High Performance Liquid Chromatography (HPLC);

The purity was measured by High Performance Liquid Chromatography (HPLC) under the following conditions:

Column : Unison C18 (150 x 4.6mm) x 3μ; Make: Imtak corporation P/N: UK005

Detector : UV at 220nm

Flow rate : 0.80 mL / min

Injection volume : 20.0 μL Run time : 50 min Column temperature : 4O⁰C Elution : Gradient

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 4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]nitrobenzene A solution of 2-(N-methyl-N-(2-pyridyl)amino)ethanol (350 g) and 4-fluoro-nitrobenzene (357 g) in dimethylformamide (350 ml) was added to a mixture of dimethylformamide (1400 ml) and potassium hydroxide (193 g) at 5-1O⁰C, and the reaction mixture was maintained for 5-6 hours. The reaction mass was poured into ice water and the isolated product was filtered. The wet material was stirred with hexane (1400 ml) for 30 minutes and filtered. The product was finally dried under vacuum to give 595 g of 4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]nitrobenzene.

Example 2 Preparation of 4- [2-(N-methyl-N-(2-py ridy l)amino)ethoxy ] benzenamine A solution of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]nitrobenzene (590 g) in ethyl acetate (5.8 L) was hydrogenated at 8-10 kg/cm² pressure and 30-40⁰C in the presence of palladium on carbon catalyst (14.5 g). The reaction mass was then filtered and the filtrate was concentrated under vacuum at below 5O⁰C to give crude 4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzenamine followed by recrystallization from a mixture of ethyl acetate (290 ml) and hexane (1740 ml) to yield 434 g of pure 4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzenamine.

Example 3

Preparation of 5-[[4-[2-(Methyl-2-pyridinylamino)ethoxy]phenyl]methyl]]-2-imino-4- thiazolidinone A solution of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzenamine (420 g) in a mixture of acetone (3.78 L) and methanol (2.1 L) was cooled to 5-1O⁰C and followed by the addition of an aqueous hydrobromic acid (1164 g) and aqueous sodium nitrite (142 g in 252 ml of water). The reaction mixture was maintained at 0-5⁰C for one hour. The resulting mixture was slowly warmed to 30-35⁰C and then methyl acrylate (891 g) was added. The resulting mixture was followed by the slow addition of cuprous oxide (17 g), stirring the reaction mixture at 35-4O⁰C for 2-3 hours and adjusting pH of the reaction mixture to 4 to 5 with aqueous ammonia solution. The solvent was distilled out (approx.70%) from the reaction mass under vacuum, the reaction mass was diluted with water and then extracted with ethyl acetate (10 L). The organic layer was washed with 2% aqueous solution of ethylenediaminetetraacetic acid (EDTA, 4.8 L) and the solvent was concentrated completely under vacuum at below 5O⁰C. The resulting crude product was dissolved in methanol (2.1 L), followed by the addition of sodium acetate (281 g) and thiourea (157 g) and refluxing the resulting reaction mixture for 4-5 hours. The precipitated product was filtered and washed with methanol. The wet product was suspended in water (3.3 L) and then stirred for 1 hour at 25-3O⁰C. The separated solid was dried under vacuum at 50-60⁰C to yield 240 g of 5-[[4-[2- (Methyl-2-pyridinylamino)ethoxy]phenyl]methyl]]-2-imino-4-thiazolidinone.

Example 4 Preparation of 5- [ [4- [2-(Methyl-2-pyridinylamino)ethoxyl phenyll methyll -2,4- thiazolidinedione hydrogen sulfate (Rosiglitazone hydrogen sulfate)

Step-I: Preparation of crude 5-[[4-[2-(Methyl-2-pyridinylamino)ethoxy]phenyl] methyl] -2,4-thiazolidinedione (Rosiglitazone base)

A mixture of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]]-2-imino-4- thiazolidinone (220 g) and 2N hydrochloric acid (1870 ml) was heated at 89-93⁰C for 10-11 hours. The reaction mass was then cooled to 0-5⁰C and maintained for 2 hours. The precipitated product was filtered and the wet material was suspended in water (4 L) and then neutralized with aqueous sodium bicarbonate solution. The resulted free base was filtered and washed with water and suck dried for 1 hour. The wet material was then suspended in methanol (9.9 L) followed by heating to dissolve at reflux temperature. The solvent was distilled out completely under vacuum at below 45⁰C and the residue was suspended in fresh methanol (1.1 L). The suspended product was cooled to 5-1O⁰C and filtered and then dried under vacuum at 50-55⁰C to yield 198 g of crude Rosiglitazone base (HPLC purity 99.31%). Content of Impurities; Imino impurity: Below detection limit (BDL); Desmethyl impurity: 0.08%; Bromo impurity: Below detection limit; Dehydroimpurity: 0.47%; and N-oxide impurity: 0.02%.

Step-II: Purification of crude Rosiglitazone base

A suspension of crude rosiglitazone base (180 g, obtained in step-I) in water (1.4 L) was heated to 65-7O⁰C and followed by the addition of a solution of sulfuric acid (54 g) in water (180 ml) over a period of 10 minutes. The reaction mass was stirred for 10 minutes at 65- 7O⁰C to get a clear solution. Charcoal was added to the solution (18 g) and reaction mass was maintained for 20-30 minutes. The hot suspension was filtered and the filtrate was cooled to 25-3O⁰C. The precipitated salt was filtered and washed with water. The salt was then suspended in water (2.7 L) and neutralized with sodium carbonate solution. The precipitated base was filtered and washed with water and then suction dried. The wet base was suspended in methanol (7.2 L) and heated to 60-65⁰C to provide a clear solution, followed by the distillation of solvent. The resulting residue was stirred with methanol (720 ml) for 1 hour. The precipitated solid was filtered and dried under vacuum at 50-55⁰C to yield 145 g of pure Rosiglitazone base (HPLC purity 99.75%).

Content of Impurities: Imino impurity: Below detection limit; Desmethyl impurity: 0.05%; Bromo impurity: Below detection limit; Dehydroimpurity: 0.01%; and N-oxide impurity: 0.02%.

Step-III: Preparation of Rosiglitazone hydrogen sulfate

A solution of sulfuric acid (18.1 g) in tetrahydrofuran (120 ml) was added to a solution of pure rosiglitazone base (60 g, obtained in step-II) in tetrahydrofuran (360 ml) at 40-45⁰C and maintained for 2 hours. The reaction mass was cooled to 15-2O⁰C and then filtered the product. The wet material was dissolved in methanol (1500 ml) at 60-65⁰C and the solvent was distilled out completely under vacuum at below 45⁰C. This was followed by the addition of acetone (120 ml) and distilled out completely under vacuum at below 45⁰C to get a solid. Acetone (240 ml) was added to the resulting solid and the contents were cooled to 25-3O⁰C. The resulted product was filtered and washed with acetone (120 ml) and then dried under vacuum at 50-60⁰C to yield 70.5 g of pure rosiglitazone hydrogen sulfate (HPLC purity 99.93%).

Content of Impurities: Imino impurity: Below detection limit; Desmethyl impurity: 0.02%; Bromo impurity: Below detection limit; Dehydroimpurity: Below detection limit; and N- oxide impurity: 0.01 %.

Example 5

Preparation of 5- [ [4- [2-(Methy 1-2-py ridiny lamino)ethoxy ] phenyl] methyl] -2,4- thiazolidinedione hydrogen sulfate (Rosiglitazone hydrogen sulfate) To a suspension of pure rosiglitazone base (30 g, obtained in step-II of example 4) in water (180 ml), a solution of sulfuric acid (9.05 g) in water (60 ml) was added at 75-8O⁰C and stirred for 10-20 minutes. The reaction mixture was cooled to 25-30⁰C and stirred for 1 hour. The product was filtered and washed with water (60 ml). The wet material was dried under vacuum at 50-60⁰C to yield 24 g of pure rosiglitazone hydrogen sulfate (HPLC purity 99.82%). Content of Impurities: Imino impurity: Below detection limit (BDL); Desmethyl impurity: 0.12%; Bromo impurity: BDL; Dehydroimpurity: 0.01%; and N-oxide impurity: BDL. Example 6

Preparation of 5- [ [4- [2-(Methy 1-2-py ridiny lamino)ethoxy ] phenyl] methyl] -2,4- thiazolidinedione hydrogen sulfate (Rosiglitazone hydrogen sulfate)

A solution of sulfuric acid (6.04 g) in methanol (40 ml) was added to a solution of pure rosiglitazone base (20 g, obtained in step-II of example 4) in methanol (300 ml) at 25-3O⁰C and stirred for 15-20 minutes. The precipitated product was filtered and the wet material was dissolved in methanol (40 ml) at 60⁰C and followed by the addition of diisopropyl ether (200 ml). The reaction mixture was cooled to 25-30⁰C and stirred for 1 hour. The reaction mixture was further cooled to 0-5⁰C and stirred for 30 minutes. The product was filtered and then dried under vacuum at 50-60⁰C to yield 22 g of pure rosiglitazone hydrogen sulfate

(HPLC purity: 99.83%).

Content of Impurities: Imino impurity: Below detection limit (BDL); Desmethyl impurity: 0.04%; Bromo impurity: BDL; Dehydroimpurity: 0.02%; and N-oxide impurity: BDL.

Example 7

Preparation of 5-[[4-[2-(Methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4- thiazolidinedione hydrogen sulfate (Rosiglitazone hydrogen sulfate)

A solution sulfuric acid (4.36 g) in methanol (45 ml) was added to a solution of pure rosiglitazone base (15 g, obtained in step-II of example 4) in acetone (270 ml) at 55-6O⁰C and maintained for 30 minutes. The reaction mixture was cooled to 25-3O⁰C and stirred for 1 hour. The product was filtered and washed with acetone (30 ml). The wet material was dried under vacuum at 40-50⁰C to yield 9.1 g of pure rosiglitazone hydrogen sulfate (HPLC purity: 99.75%). Content of Impurities: Imino impurity: Below detection limit; Desmethyl impurity: Below detection limit; Bromo impurity: Below detection limit; Dehydroimpurity: 0.01%; N-oxide impurity: Below detection limit.

Example 8

Preparation of 4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]bromobenzene (Bromo Impurity or Bromophenyl compound) A solution of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzenamine (20 g) in a mixture of acetone (180 ml) and methanol (100 ml) was cooled to 5-1O⁰C and followed by slow addition of aqueous solution of hydrobromic acid (48%, 56.8 g) at 10-15⁰C. The reaction mass obtained after completion of the addition process was cooled to 0-5⁰C, followed by slow addition of a solution of sodium nitrite (6.84 g) in water (13 ml) at 0-5⁰C and maintaining the reaction mass for 45 minutes. After completion of the reaction, the reaction mass was concentrated under vacuum at below 4O⁰C and the residue was extracted with ethyl acetate (2 x 100 ml) and washed the organic solution with water (100 ml). The solvent was evaporated from the solution and the crude product was purified by column chromatography using silica gel (200 g) and a mixture of ethyl acetate (400 ml) and hexane (1600 ml) to give 4.0 g of 4- [2-(N-methyl-N-(2-pyridyl)amino)ethoxy]bromobenzene.

Example 9

Preparation of 5-[[4-[2-[Methyl-(2-pyridyl-N-oxide)amino] ethoxy]phenyl]methyI]-2,4- thiazolidinedione (Rosiglitazone N-oxide) m-Chloroperbenzoic acid (5.79 g, 0.033 moles) was added to a solution of 5-[[4-[2-(methyl- 2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (5.0 g, 0.014 moles) in dichloromethane (50 ml) at 5-1O⁰C and the reaction mixture was maintained at 5-1O⁰C for 1-2 hours. After completion of the reaction, the reaction mass was washed with 5% sodium bicarbonate solution (250 ml) followed by water (100 ml). The resulting mass was concentrated under vacuum at below 4O⁰C and the crude product was purified by column chromatography using silica gel and a mixture of methanol (180 ml) and dichloromethane (420 ml) to get 1.4 g of 5-[[4-[2-[Methyl-(2-pyridyl-N-oxide)amino]ethoxy]phenyl]methyl]- 2,4-thiazolidinedione. 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 "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 (PLURONICt™) F68,

PLURONIC(™) 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).

The term "crude rosiglitazone or a hydrogen sulfate salt thereof as used herein refers to rosiglitazone or a hydrogen sulfate salt thereof containing greater than about 0.2 area-%, more specifically greater than about 0.3 area-%, still more specifically greater than about 0.4 area-% and most specifically greater than about 1 area-% of at least one, or more, of the bromo, N-oxide, desmethyl, dehydro and imino impurities. As used herein, the term, "detectable" refers to a measurable quantity measured using an HPLC method having a detection limit of 0.01 area-%.

As used herein, in connection with amount of impurities in rosiglitazone or a hydrogen sulfate salt thereof, the term "not detectable" means not detected by the herein described HPLC method having a detection limit for impurities of 0.01 area-%.

As used herein, "limit of detection (LOD)" refers to the lowest concentration of analyte that can be clearly detected above the base line signal, is estimated is three times the signal to noise ratio.

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. All 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. Isolated 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]bromobenzene, of formula II:

2. Isolated rosiglitazone N-oxide compound, 5-[[4-[2-[methyl-(2-pyridyl-N-oxide)amino] ethoxy]phenyl]methyl]-2,4-thiazolidinedione, of formula III:

3. Rosiglitazone or a hydrogen sulfate salt thereof comprising one, or both, of a 4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]bromobenzene impurity of formula II and a 5-[[4-[2- [methyl-(2-pyridyl-N-oxide)arnino]ethoxy] phenyl]methyl]-2,4-thiazolidinedione impurity of formula III, wherein the impurity in an amount of less than about 0.2 area-% as measured by HPLC.

4. Rosiglitazone of claim 3, having a total purity of about 99% to about 99.99% as measured by HPLC.

5. Rosiglitazone of claim 3, comprising one, or both, of the 4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]bromobenzene impurity of formula II and the 5-[[4-[2-[methyl-(2- pyridyl-N-oxide)amino]ethoxy] phenyl]methyl]-2,4-thiazolidinedione impurity of formula III each in an amount of about 0.01 area-% to about 0.15 area-%.

6. Rosiglitazone of claim 3, having a non-detectable amount of one, or both, of the 4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]bromobenzene impurity of formula II and 5-[[4-[2- [methyl-(2-pyridyl-N-oxide)amino]ethoxy] phenyl]methyl]-2,4-thiazolidinedione impurity of formula III as measured by HPLC.

7. Rosiglitazone of claim 3, further comprising at least one, or more, of the desmethyl, dehydro and imino impurities, each one, in an amount of less than about 0.2 area-% as measured by HPLC; wherein the desmethyl impurity is 5-[[4-[2-(2-pyridinylamino) ethoxy]phenyl]methyl]-2,4-thiazolidinedione, the dehydro impurity is 5-[4-[2-(N-methyl- N-(2-pyridyl)amino)ethoxy] benzylidene]-2,4-thiazolidinedione, and the imino impurity is 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]]-2-imino-4-thiazolidinone.

8. Rosiglitazone of claim 7, comprising at least one, or more, of the desmethyl, dehydro and imino impurities, each one, in an amount of about 0.01 area-% to about 0.15 area-%.

9. Rosiglitazone of claim 7, having a non-detectable amount of at least one, or more, of the desmethyl, dehydro and imino impurities as measured by HPLC.

10. Rosiglitazone of claim 3, having a non-detectable amount of dehydro impurity as measured by HPLC.

11. A process for preparing highly pure rosiglitazone or a hydrogen sulfate salt thereof of claim 3, comprising: a) providing a first suspension of crude rosiglitazone in water; b) combining the suspension with an aqueous solution of sulfuric acid to form a first solution; c) optionally, subjecting the first solution to carbon treatment; d) precipitating rosiglitazone hydrogen sulfate salt from the solution obtained in step-(b) or step-(c) to provide precipitated rosiglitazone hydrogen sulfate salt; e) suspending the precipitated rosiglitazone hydrogen sulfate salt obtained in step-(d) in water to form a second aqueous suspension; f) neutralizing the second aqueous suspension with a base to produce precipitated rosiglitazone base; g) dissolving the precipitated rosiglitazone base in an alcohol solvent to form a second solution; h) optionally, substantially removing the solvent from the second solution to obtain a residue and combining the residue with an alcohol solvent to form a third solution or suspension; i) isolating and/or recovering highly pure rosiglitazone base substantially free of the impurities from the second solution obtained in step-(g) or the third solution or suspension obtained in step-(h); and j) optionally, converting the highly pure rosiglitazone base obtained in step-(i) into its hydrogen sulfate salt.

12. The process of claim 11, wherein the suspension in step-(a) is provided by suspending crude rosiglitazone in water while stirring at a temperature of below about 100⁰C.

13. The process of claim 12, wherein the suspension is stirred at a temperature of about 4O⁰C to about 9O⁰C for about 10 minutes to about 10 hours.

14. The process of claim 11, wherein the suspension in step-(a) is prepared by a process comprising: a) reacting 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]]-2-imino-4- thiazolidinone with aqueous hydrochloric acid solution to produce rosiglitazone hydrochloride salt; b) treating the rosiglitazone hydrochloride salt with a base to produce a reaction mass containing crude rosiglitazone base; c) subjecting the reaction mass obtained in step-(b) to washings, extractions, evaporations, or a combination thereof to isolate crude rosiglitazone base; and d) suspending the crude rosiglitazone base in water while stirring at a temperature of below about 100⁰C.

15. The process of claim 11, wherein the combining in step-(b) is accomplished by adding the aqueous solution of sulfuric acid to the suspension or by adding the suspension to the aqueous solution of sulfuric acid.

16. The process of claim 15, wherein the addition is carried out at a temperature of about

30°C to about 9O⁰C for at least 10 minutes.

17. The process of claim 15, wherein the reaction mass obtained after completion of the addition process is stirred at a temperature of about 6O⁰C to about 8O⁰C for about 10 minutes to about 10 hours.

18. The process of claim 11, wherein the precipitation of rosiglitazone hydrogen sulfate in step-(d) is carried out by cooling the solution at a temperature of about O⁰C to about 3O⁰C for about 10 minutes to about 10 hours.

19. The process of claim 11, wherein the base used for neutralization in step-(f) is an inorganic base.

20. The process of claim 19, wherein the inorganic base is sodium carbonate.

21. The process of claim 11, wherein the alcohol solvent used in steps-(g) and (h) is methanol.

22. The process of claim 11, wherein the rosiglitazone base in step-(g) is dissolved in the alcohol solvent at a temperature of about 4O⁰C to the reflux temperature of the alcohol solvent.

23. The process of claim 11, wherein the isolation of highly pure rosiglitazone base in step-(i) is carried out by forcible or spontaneous crystallization; and wherein the forcible crystallization is initiated by cooling, seeding, partial removal of the solvent from the solution, by combining an anti-solvent with the solution, or a combination thereof.

24. The process of claim 23, wherein the crystallization is carried out by cooling the solution while stirring at a temperature of about O⁰C to about 3O⁰C for about 30 minutes to about 20 hours.

25. The process of claim 11, wherein the recovering in step-(i) 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.

26. The process of claim 11, wherein the conversion of highly pure rosiglitazone base to rosiglitazone hydrogen sulfate salt in step-(j) is carried out by a process comprising:

1) providing a first solution or suspension of pure rosiglitazone base in a first solvent; 2) combining the first solution or suspension with a solution of sulfuric acid in a second solvent to form a second solution or suspension containing rosiglitazone hydrogen sulfate; 3) isolating and/or recovering highly pure rosiglitazone hydrogen sulfate from the second solution or suspension; 4) optionally, dissolving or suspending the pure rosiglitazone hydrogen sulfate obtained in step-(3) in a third solvent to produce a third solution or suspension; and 5) isolating and/or recovering highly pure rosiglitazone hydrogen sulfate from the third solution or suspension obtained in step-(4).

27. The process of claim 26, wherein the first solvent used in step-(l) is selected from the group consisting of water, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, acetone, and mixtures thereof; wherein the second solvent used in step-(2) is selected from the group consisting of water, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, and mixtures thereof; and third solvent used in step-(4) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, and mixtures thereof.

28. The process of claim 27, wherein the first solvent is selected from the group consisting of water, tetrahydrofuran, methanol, and mixtures thereof; wherein the second solvent is selected from the group consisting of water, tetrahydrofuran, methanol, and mixtures thereof; and wherein the third solvent is selected from the group consisting of methanol, acetone, and mixtures thereof.

29. The process of claim 26, wherein the isolation of highly pure rosiglitazone hydrogen sulfate in steps-(3) and (5) is carried out by cooling the solution while stirring at a temperature of about O⁰C to about 3O⁰C for about 30 minutes to about 20 hours.

30. The process of claim 26, wherein the isolation of highly pure rosiglitazone hydrogen sulfate in steps-(3) and (5) is carried out by adding an anti-solvent to the solution; and wherein the anti-solvent is an ether solvent.

31. The process of claim 30, wherein the ether solvent is diisopropyl ether.

32. The process of claim 11, wherein the pure rosiglitazone or a hydrogen sulfate salt thereof obtained is further dried under vacuum or at atmospheric pressure, at a temperature of about 35⁰C to about 7O⁰C.

33. A pharmaceutical composition comprising highly pure rosiglitazone or a hydrogen sulfate salt thereof comprising one, or both, of a 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] bromobenzene impurity of formula II and a 5-[[4-[2-[methyl-(2-pyridyl-N-oxide)amino] ethoxy]phenyl]methyl]-2,4-thiazolidinedione impurity of formula III, in an amount of less than about 0.2 area-% (measured by HPLC), and one or more pharmaceutically acceptable excipients.

34. The pharmaceutical composition of claim 33, wherein the rosiglitazone or a hydrogen sulfate salt thereof contains one, or both, of the 4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy] bromobenzene impurity of formula II and 5-[[4-[2-[methyl-(2-pyridyl-N-oxide) amino]ethoxy]ρhenyl]methyl]-2,4-thiazolidinedione impurity of formula III, each one, in an amount of about 0.01 area-% to about 0.15 area-%.

35. The pharmaceutical composition of claim 33, wherein the rosiglitazone or a hydrogen sulfate salt thereof contains a non-detectable amount of one, or both, of the 4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]bromobenzene impurity of formula II and 5-[[4-[2- [methyl-(2-pyridyl-N-oxide)amino]ethoxy]phenyl]methyl]-2,4-thiazolidinedione impurity of formula III as measured by HPLC.

36. The pharmaceutical composition of claim 33, wherein the rosiglitazone or a hydrogen sulfate salt thereof contains at least one, or more, of the desmethyl, dehydro and imino impurities, each one, in an amount of less than about 0.2 area-% as measured by HPLC, wherein the desmethyl impurity is 5-[[4-[2-(2-pyridinylamino) ethoxy]phenyl]methyl]- 2,4-thiazolidinedione, the dehydro impurity is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzylidene]-2,4-thiazolidinedione, and the imino impurity is 5-[[4-[2-(methyl-2- pyridinylamino)ethoxy]phenyl]methyl]]-2-imino-4-thiazolidinone.

37. The pharmaceutical composition of claim 36, wherein the rosiglitazone or a hydrogen sulfate salt thereof contains one, or more, of the desmethyl, dehydro and imino impurities, each one, in an amount of about 0.01 area-% to about 0.15 area-%.

38. The pharmaceutical composition of claim 36, wherein the rosiglitazone or a hydrogen sulfate salt thereof having a non-detectable amount of one, or more, of the desmethyl, dehydro and imino impurities as measured by HPLC, wherein the desmethyl impurity is 5-[[4-[2-(2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, the dehydro impurity is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]-2,4- thiazolidinedione, and the imino impurity is 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy] phenyl]methyl]]-2-imino-4-thiazolidinone.

39. The pharmaceutical composition of claim 33, wherein the rosiglitazone or a hydrogen sulfate salt thereof having a non-detectable amount of dehydro impurity as measured by HPLC, wherein the dehydro impurity is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzylidene]-2,4-thiazolidinedione.

40. The pharmaceutical composition of claim 33, wherein the pharmaceutical composition is a solid dosage form, an oral suspension, a liquid, a powder, an elixir, an aerosol, syrups or an injectable solution.