WO2006125402A1

WO2006125402A1 - A process for the crystallization of rosiglitazone and its derivatives from mixed solvents

Info

Publication number: WO2006125402A1
Application number: PCT/CZ2006/000034
Authority: WO
Inventors: Ales Halama; Jlndrich Richter
Original assignee: Zentiva, A.S.
Priority date: 2005-05-24
Filing date: 2006-05-19
Publication date: 2006-11-30
Also published as: CZ2005324A3; CZ298424B6

Abstract

Crystallization of rosiglitazone of formula (I), its penultimate of formula (II), or salts with acids of formula (III), wherein HX stands for a mineral or carboxylic acid, is carried out from mixed organic solvents, consisting of mixtures of carboxylic acids, particularly formic acid, acetic acid or propionic acid, with aliphatic alcohols, particularly methanol, ethanol, 1-propanol, 2- propanol, butanols or amyl alcohols.

Description

A process for the crystallization of rosiglitazone and its derivatives from mixed solvents

Technical Field

The invention concerns a process for the crystallizations of rosiglitazone, an antihyperglycaemic, i.e. of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]- thiazolidine-2,4-dione, including crystallizations of its salts with acids, and the crystallizations of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]-thiazolidine-2,4-dione, i.e. of the penultimate of rosiglitazone, using mixed solvents.

Background Art

Rosiglitazone, 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione of formula I, is a well-known oral antihyperglycaemic, which was first described in patent EP306228 (1989) of Beecham. The free rosiglitazone base is prepared by reduction of 5-[4-[2- (N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione of formula II (hereinafter referred to as the penultimate of rosiglitazone) according to the following chemical equation:

REDUCTION

¹¹ I The reduction can be carried out either under conditions of catalytic hydrogenation (WO 9923095, WO 03053367), or using complex lithium hydrides under the catalysis of pyridine (WO 9837073), and also using sodium borohydride under the catalysis of complex compounds of cobalt (our findings which have not been published yet). The last solution mentioned is sensitive to the content of residual cobalt in the target substance. Rosiglitazone is in practice used in the form of salts or hydrates of salts. The reason for this is a higher solubility of the salts in water in comparison with the free base, and also a higher chemical stability of the salts (WO9405659). Of practical importance are especially salts of rosiglitazone with maleic acid of formula III a (WO 9405659 Al₅ WO 0064892/ WO 0064893, WO 0064896, WO 0226737, WO 04062667, and WO 04085435, the hydrates WO 9931093, WO 9931094, and WO 9931095) and with hydrochloric acid of formula in b (WO 0063205, WO 0063206). In general, all pharmaceutically acceptable salts with acids whose pKa values are less than 4 can be used. Specific examples are mineral acids (e.g. a salt with phosphoric acid of formula m c - our findings which have not been published yet, and WO 05023803) and strong carboxylic acids (particularly dicarboxylic acids, e.g. a salt with oxalic acid of formula III d - our findings which have not been published yet).

In view of the fact that rosiglitazone is used as a drug with an antihyperglycaemic effect, extraordinary requirements are posed on chemical purity of the substance. Crystallizations of free base I, penultimate II, and salts of rosiglitazone III can be of crucial importance for the purity of the target substance. However, rosiglitazone and its derivatives are characterized by low solubility in many organic solvents conventionally used for crystallizations. This causes technical problems during the practical execution of the crystallizations, which are, under standard conditions, characterized by a high consumption of solvents. The low concentration of the substance that can successfully be solubilized makes high demands on the size of production equipment.

Owing to a very low solubility of penultimate II, no method of crystallization of this substance useful for chemical purification of the substance has been described yet. Usually, for further synthesis, this substance was used in its crude state, or in the form of salts with strong organic acids (EP0306228, WO0144240).

Crystallization of crude free rosiglitazone base I from methanol was described in patent WO9837073. However, the consumption of the solvent was high in this case, 20 ml per gram of the crystallized free base, which is equivalent to a concentration of 0.05 g of the substance per ml of the solvent used. Crystallization of the free rosiglitazone base from methanol was also described in EP0306228 and J.Med.Chem. 1994, 37, 3997; however, without giving consumption of the solvent and the yield. The most of data concerning crystallizations of salts of rosiglitazone can be found for rosiglitazone maleate III a. Preparation of crystalline rosiglitazone maleate was first described in patent application WO9405659. The crystallization was carried out in ethanol, wherein the concentrations of the crystallized substance were within the range of 0.14 to 0.15 g/ml. The yields were, depending on what method was used, within the range of 73 to 87 %.

Many other patents dealt with preparations of various crystalline polymorphous forms of rosiglitazone maleate. Alcohols, particularly methanol, ethanol, isopropyl alcohol, and the like, were among the solvents most often used (WO0064893, WO2004062667, EP1468997, WO0226737, WO0064896). In individual cases, other solvents were also used for the crystallization of rosiglitazone maleate, e.g., acetone (WO0064893, EP1468997), acetonitrile (WO2004062667), ethyl acetate (EP1468997), isopropyl acetate (EP1468997), and 1,4- dioxane (WO0226737).

The aforementioned solutions of crystallizations of rosiglitazone maleate were characterized by the use of only one organic solvent. A different situation can be found in patent application WO2004085435, which deals with the preparation of crystalline polymorphous forms of rosiglitazone maleate, wherein the use of a number of solvents, including mixed solvents, was described. Specifically, the following solvents were used: anisole, isopropyl acetate, ethyl acetate, tetrahydrofuran, methyl isobutyl ketone, a mixture of methanol and ethyl acetate (7:3), 1,2-dichloroethane, 1-butanol, methyl ethyl ketone, isopropanol, a mixture of methanol and toluene (1:2.5), a mixture of methanol and dimethyl carbonate (1:1), or methanol. However, achievable concentrations of the crystallized substance were for some of the solvents only about 0.005 g/ml.

Crystalline hydrates of rosiglitazone maleate were prepared from organic solvents diluted with water, e.g., methanol, ethanol, acetonitrile, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, isopropanol, acetic acid (WO9931095, WO9931094, WO9931093). Similarly as in the case of the maleate, other crystalline salts of rosiglitazone were also prepared in polar solvents, or in their mixtures with water. Alcohols, or their mixtures with water, are the solvents that are generally used most often.

As far as rosiglitazone hydrochloride III b is concerned, a mixture of water and hydrochloric acid, a mixture of ethanol and aqueous hydrochloric acid, or a mixture of isopropanol and aqueous hydrochloric acid were used for the preparation of the salt (WO0063205). Crystalline hydrochloride was also obtained from a mixture of acetic acid and aqueous hydrochloric acid, or of acetonitrile and aqueous hydrochloric acid, after, in both cases, diethyl ether was added to the solution obtained (WO0063206). Crystalline rosiglitazone phosphate III c was obtained from methanol, or isopropyl alcohol, or acetonitrile (WO 05023803).

The solution that we describe presents new and effective methods of crystallizations of rosiglitazone I, and its derivatives of formulae II and III from mixed organic solvents.

Disclosure of Invention

The invention concerns a new process for crystallizations of rosiglitazone I, and of its derivatives of formulae II and III from mixed solvents.

The process for the crystallization of rosiglitazone I, its penultimate II, and salts with acids III involves use of mixed organic solvents, wherein suitable carboxylic acids are one component, and aliphatic alcohols are the second component of the mixed solvent. Suitable carboxylic acids include those selected form the group consisting of formic acid, acetic acid, and propionic acid. Suitable aliphatic alcohols include methanol, ethanol, 1-propanol, 2-propanol, butanols, and amyl alcohols.

This method makes it possible to obtain crystallized substances while saving the total volume of solvents that has been needed for prior methods of crystallizing from one-component solvents. Other advantages of the new process include high yields of crystallizations and high effectiveness of chemical purification. The benefits of the crystallizations include, apart from reduction of the required volume of the one-component solvent, the removal of chemical impurities from substances I, II, and III, and reduction of the content of residual cobalt in substances of formulae I and III, if a catalyst based on salts of cobalt is used in the process of their preparation. Crystallizations from mixed solvents have an extraordinary influence on the achievable chemical purity of the substance, allowing for obtaining rosiglitazone I and its salts with acids III in the quality required for pharmaceutical substances. Moreover, it is possible, by using different conditions for performing the crystallizations, to control the distribution of particle sizes of the substance being crystallized. The distribution of particle sizes influences certain technological processes of the production of the substance, e.g. filtration and drying. The defined size of the particles can further be beneficial when preparing dosage forms of rosiglitazone. The invented process for the crystallizations is economically advantageous, and can also be used for production on a large scale.

The carrying out of crystallizations according to the invention is advantageous especially when a mixture of acetic acid and ethanol is used as a solvent. In addition to the high yields achieved for the crystalline substance, low toxicity of both components of the mixture is also of importance, wherein both acetic acid and ethanol have high limits for the content of residual solvents in pharmaceutically useful substances (the limit is 5000 ppm in both cases).

The method of crystallizing according to the invention is characterized, on one hand, by dissolving the substance being crystallized in a suitable carboxylic acid at temperatures from 2O ⁰C to the boiling points of said acid. The actual crystallizations then proceed upon controlled addition of a suitable aliphatic alcohol to the solution of the substance in the carboxylic acid. Alternatively, the crystallization can be performed by dissolving the substance in a mixture of a carboxylic acid and an aliphatic alcohol when hot, the actual crystallization occurring after cooling down of the solution obtained.

The yields of crystallization of the penultimate of rosiglitazone of formula II are usually within the range of 85 to 90 %. The concentrations of the substance of formula II to be crystallized are 0.07 to 0.12 g per ml of a solvent. Crystalline substance II with HPLC purity about 96.5 % is the result of crystallization, whereas the starting crude substance showed HPLC purity about 90.0 %. It follows from the achieved results that crystallization of the crude penultimate of rosiglitazone contributes to a significant increase in quality (by more than 6 % on average) while the amount of the raw substance lost is acceptable.

The crude free rosiglitazone base I used for crystallizations was obtained by the representative method according to example 8. The reductions according to the method we used were carried out by first dissolving the starting substance II was dissolved in an aqueous solution of sodium hydroxide, followed by addition of a salt of bivalent cobalt in a mixture with dimethylglyoxime and dimethylformamide. To the reaction mixture being heated, an aqueous solution of sodium borohydride was added gradually. The crude product was finally isolated from the reaction mixture by a method including the following steps: a) performing addition of ethyl acetate to the reaction mixture; b) adjusting the pH of the reaction mixture by adding a diluted acid; and c) performing addition of a 10% aqueous solution of sodium hydrogen carbonate to the reaction mixture, and filtering the precipitated product.

The crude free base of rosiglitazone I prepared according to the aforementioned method showed HPLC purity within the range of 98.5 to 99.2 %, and contained approximately 10 μg of residual cobalt per gram of the substance. By carrying out crystallizations from mixtures of carboxylic acids and alcohols, a crystalline product was obtained in yields of 81 to 87 %, which showed HPLC purity of approximately 99.9 % and the content of residual cobalt below 2 μg per gram of the substance, i.e. more than five times less than for the crude substance. It follows from the achieved results that crystallization of the crude free rosiglitazone base of formula I removes very effectively both chemical impurities of organic origin and residual cobalt that comes from the catalyst used during the preparation of the crude free base.

Concentrations of the free rosiglitazone base of formula I amount to 0.09 to 0.17 g of the substance per ml of the solvent in crystallizations from the mixed solvents used. For comparison, a crystallization of the free rosiglitazone base was carried out from ethanol, i.e. without adding any carboxylic acid (example 19). When ethanol was used as the one- component solvent, the maximum concentration reached at the boil was approximately 0.04 g of the substance per ml of the solvent. The total consumption of the solvent was thus 2 to 4 times higher than the consumption when carrying out crystallizations from mixed solvents (examples 9 to 13). The comparative crystallization from ethanol gave a yield of 89 %, HPLC purity of the product was 99.6 %, and the content of residual cobalt was 9 μg/g. Therefore, when only ethanol was used, as opposed to crystallizations from mixed solvents, a slightly higher yield was reached, but chemical purity of the product was lower and the content of residual cobalt was higher.

By using crystallizations from mixed solvents whose components are suitable carboxylic acids and aliphatic alcohols it is possible to prepare, with yields of 80 to 95 %, crystalline forms of salts of rosiglitazone with mineral and dicarboxylic acids of formula III, particularly rosiglitazone maleate (formula III a), rosiglitazone hydrochloride (formula III b), rosiglitazone phosphate (formula III c), and rosiglitazone oxalate (formula III d). The salts of rosiglitazone prepared by crystallizations from mixed solvents show chemical purity of 99.8 % and higher, and content of individual impurities less than 0.1 %. Therefore, they generally fulfil the required limits acknowledged for pharmaceutical substances. Due to crystallizations of the salts of rosiglitazone from mixed solvents a further decrease in the content of residual cobalt in the crystalline products occurs, namely to a level below 1 μg per gram of the crystalline substance. The obtained crystalline rosiglitazone I and its salts with mineral and dicarboxylic acids can be used for the preparation of pharmaceutically useful compositions, particularly of drugs having an antihyperglycaemic effect.

The more gradual regimen of cooling and the slower pace of adding the alcohol, and, optionally, the smaller volume of the alcohol added to the solution of the substance being crystallized in the carboxylic acid beneficially influence the contents of larger particles. By the used methods of crystallizations, it is possible to control preparation of crystalline substances of formulae I, II, and III having the particle size whose median of maximum size is found within the range of 0.5 - 100 μm. The results are demonstrated in Figures 1 to 3; the methods of preparing the crystalline substances used for the measurement of the particle size are described in the respective examples.

The invention is further illustrated in the following examples, which, however, have no influence on the extent of the invention defined in the claims.

Brief Description of Drawings

Fig. 1 shows a microscopic image of particles of crystalline rosiglitazone benzylidene prepared by crystallization of the crude substance from the mixed solvent of acetic acid - ethanol under different experimental conditions.

Fig. 2 shows results of the measurement of the distribution of particle sizes, using the

MaxFeret method, of crystalline rosiglitazone phosphate prepared according to Examples 21 to 24.

Fig. 3 shows results of the measurement of the distribution of particle sizes, using the MaxFeret method, of crystalline rosiglitazone oxalate prepared according to Examples 27 to

30. Examples

EXAMPLE 1

50 g of crude substance II was mixed with 250 ml of acetic acid, the mixture was stirred and heated slowly to a temperature of about 70 ⁰C. At this temperature, the mixture was stirred for

10 minutes. The heating was stopped after that, and 250 ml of ethanol was added in one portion. Three minutes after adding the first portion, another 250 ml of ethanol was added, and the suspension was further stirred for one hour. The lukewarm suspension (temperature of about 30 °C) was filtered, the filter cake was washed with 3 x 50 ml of ethanol, and finally dried in a vacuum drier. 47.3 g of a yellow crystalline powder was obtained (HPLC purity:

96 %). The yield was 94.6 %.

EXAMPLE 2

160 g of crude substance II was mixed with 800 ml of acetic acid, the suspension obtained was stirred and heated slowly to a temperature of 70 - 80 °C. The mixture was stirred for 20 minutes at this temperature. The heating was stopped after that, and 300 ml of ethanol was added in one portion at the moment the stirred solution ceased to boil. The mixture was stirred, freely cooling down, for ca 1 hour, resulting in gradual precipitation of a crystalline product.

After 1 hour of stirring, 500 ml of ethanol was added in one portion, and the suspension was further stirred for 30 minutes. The lukewarm suspension (about 30 °C) was filtered, the filter cake was washed with 3 x 100 ml of ethanol, and finally dried in a vacuum drier. 136.2 g of a yellow crystalline powder was obtained (HPLC purity: 96.3 %). The yield was 85.1 %.

EXAMPLE 3 160 g of the crude product was mixed with 800 ml of acetic acid (the acid was poured to the solid substance), the suspension obtained was stirred and heated slowly to a temperature of 70 - 80 °C. The stirring continued for about 20 minutes at this temperature, during which the charged substance dissolved. The heating was stopped after that, and 300 ml of ethanol was added in one portion at the moment the stirred solution ceased to boil. The mixture was stirred, freely cooling down, for ca 1 hour, resulting in gradual precipitation of a crystalline product. After 1 hour of stirring, 500 ml of ethanol was added in one portion, and the stirring continued for about 30 minutes. The mixture was allowed to stand overnight, on the following day filtration was carried out, and the filter cake was washed with 3 x 100 ml of ethanol. The product obtained was dried in a vacuum drier. 143.3 g of a yellow crystalline powder was obtained (HPLC purity: 95.8 %). The yield was 89.6 %.

EXAMPLE 4 160 g of the crude product was mixed with 800 ml of acetic acid (the acid was poured to the solid substance), the suspension obtained was stirred and heated slowly to a temperature of 70

- 80 ⁰C. The stirring continued for about 20 minutes at this temperature, during which the charged substance dissolved. The heating was stopped after that, and 300 ml of ethanol was added gradually over five minutes after the stirred solution ceased to boil. The mixture was stirred, freely cooling down, for ca 1 hour, resulting in gradual precipitation of a crystalline product. After 1 hour of stirring (mixture temperature of 45 °C), another 300 ml of ethanol was added, and the stirring continued for about 2 hours until the mixture reached a temperature of about 20 °C. Filtration was carried out after that, and the filter cake was washed with 2 x 100 ml of ethanol. The crystalline product obtained was dried in a vacuum drier. 137.4 g of a yellow crystalline powder was obtained (HPLC purity: 96.9 %). The yield was 85.9 %.

EXAMPLE 5

140 g of the crude product was mixed with 700 ml of acetic acid (the acid was poured to the solid substance), the suspension obtained was stirred and heated slowly to a temperature of 70

- 80 °C, during which the charged substance dissolved. The solution was stirred at about 80 °C for about 5 minutes, then 300 ml of ethanol was added, continuing to keep the temperature of the mixture at ~ 80 ⁰C (mild boil), the mixture was then stirred at about 70 ⁰C for 20 minutes and at 65 - 55 °C for 20 minutes (the product precipitated gradually). When the temperature of the mixture reached 55 °C, another 300 ml of ethanol was added in one portion, and the temperature dropped to 45 °C within 5 minutes. The mixture was further stirred for 20 minutes, the temperature dropped to 40 °C. The temperature dropped to 37 °C after another 10 minutes of stirring. Another 275 ml of ethanol was added, after which the temperature dropped to 35 °C. The suspension was further stirred for about 20 minutes until the temperature dropped slightly below 30 ⁰C. After the target temperature was reached, filtration was carried out, and the filter cake was washed with 2 x 150 ml of ethanol. The crystalline product obtained was dried in a vacuum drier. 121.O g of a yellow crystalline powder was obtained (HPLC purity: 96.7 %). The yield was 86.4 %. EXAMPLE 6

16O g of the crude product was mixed with 350 ml of formic acid, the suspension obtained was stirred and heated slowly to a temperature of 50 - 60 ⁰C. The mixture was stirred at this temperature for 20 minutes. The heating was stopped after that, and 500 ml of ethanol was added over 5 minutes. The mixture was stirred, freely cooling down, for ca 1 hour, resulting in gradual precipitation of a crystalline product. After 1 hour of stirring, another 500 ml of ethanol was added, and the stirring continued for about 2 hours. Filtration was carried out after that, and the filter cake was washed with 2 x 100 ml of ethanol. The crystalline product obtained was dried in a vacuum drier. 126.7 g of a yellow crystalline powder was obtained (HPLC purity: 96.5 %). The yield was 79.2 %.

EXAMPLE 7

16O g of the crude product was mixed with 1000 ml of propionic acid, the suspension obtained was stirred and heated slowly to a temperature of about 80 ⁰C. The mixture was stirred at this temperature for 20 minutes. The heating was stopped after that, and 500 ml of ethanol was added over 5 minutes. The mixture was stirred, freely cooling down, for ca 1 hour, resulting in gradual precipitation of a crystalline product. After 1 hour of stirring, 200 ml of ethanol was added, and the stirring continued for about 2 hours. Filtration was carried out after that, and the filter cake was washed with 2 x 100 ml of ethanol. The crystalline product obtained was dried in a vacuum drier. 141.3 g of a yellow crystalline powder was obtained (HPLC purity:

95.7 %). The yield was 88.3 %.

EXAMPLE 8 (REPRESENTATIVE EXAMPLE FOR THE PREPARATION OF THE CRUDE FREE BASE)

[1] Preparation of the catalyst: 1.2 g of cobalt(II) chloride hexahydrate was dissolved in

120 ml of DMF, followed by addition of 8.O g of dimethylglyoxime; a clear blue-green solution was obtained after a while of stirring.

[2] Preparation of a solution of the reducing agent: 27.2 g of sodium borohydride was dissolved, under stirring, in 300 ml of a 0.1 M solution of sodium hydroxide at room temperature.

[3] The actual reduction: 16.8 g of sodium hydroxide was dissolved in 1200 ml of distilled water and the resulting solution was subsequently poured to 12O g of reduced rosiglitazone benzylidene. The mixture was stirred until a solution was formed, and thus obtained solution was stirred and heated to a temperature of 55±5 °C. After the temperature conditions were reached, the catalyst (1/5 of the volume according to [1], over about 1 minute) was added dropwise to the solution, followed by addition of the reducing agent (1/5 of the volume according to [2], over about 2 minutes), and the mixture was stirred at 55±5 ⁰C for about 50 minutes. The addition of the catalyst (1/5 of the volume according to [I]) and of the reducing agent (1/5 of the volume according to [2]), including the stirring and heating of the reaction mixture at 55±5 °C, were repeated in the same way four times more (including about 50-minute pauses between the individual additions). [4] Isolation of the crude product: To the reaction mixture (according to [3]), being intensely stirred, still 55±5 ⁰C warm, 300 ml of ethyl acetate was added, followed by gradual addition of 260 ml of hydrochloric acid (1:1) in such a way that the temperature of the reaction mixture is maintained at 55±5 °C without any external heating. Very slow addition of 600 ml of a 10% solution of sodium hydrogen carbonate followed. The precipitated lumpy suspension was, while it cooled slowly, stirred for about 20 minutes until it reached the target temperature of 30 - 40 ⁰C. Filtration was carried out after that, and the filter cake was washed with water (6 x 200 ml) and ethanol (3 x 200 ml). The product obtained was dried in a vacuum drier until a constant weight. Crude free rosiglitazone base I with a melting point of 153 - 155 ⁰C was obtained. The yield was 93 % (HPLC 99,0 %, the content of residual cobalt 11 μg/g).

EXAMPLE 9 (representative example for the crystallization of free rosiglitazone base) 110 g of crude free rosiglitazone base I was, at about 70 - 80 ⁰C, dissolved in 200 ml of acetic acid (over about 15 minutes), and ethanol was added to the solution obtained in the following regimen: ► 250 ml of ethanol added over 5 minutes, followed by filtration, the temperature of the filtrate being 65 ⁰C;

► as the filtrate cooled slowly, it was stirred for about 15 minutes, and the temperature dropped to 57 °C, yielding a turbid solution;

► stirring continued for about 20 minutes, the temperature dropped from 57 to about 50 °C, a thick suspension of the product formed;

► 250 ml of ethanol added over 1 minute, stirring for about 10 minutes, the temperature dropped to 45 ⁰C; ► 250 ml of ethanol added over 1 minute, stirring for about 10 minutes, the temperature dropped to 38 ⁰C;

► 250 ml of ethanol added over 1 minute, stirred for about 10 minutes, the temperature dropped to 30 °C. 1000 ml of ethanol was added altogether in four doses over about 70 minutes, and the temperature of the suspension reached 30 °C. Finally, filtration was carried out, and the filter cake was washed with 2 x 150 ml of ethanol, yielding a white lumpy product. After the product was dried in a vacuum drier until a constant weight, 90 - 95 g of a white crystalline product with a melting point of 155 - 156 °C was obtained (HPLC 99.90 %, the content of residual cobalt lμg/g).

EXAMPLE 10

110 g of crude free rosiglitazone base I was, at 70 to 80 °C, dissolved in 200 ml of acetic acid, and ethanol was added to the solution obtained, under stirring, in the following regimen: ► 250 ml of ethanol added over 5 minutes, stirring for 10 minutes at 75 - 70 °C; ►250 ml of ethanol added over 5 minutes, stirring for 20 minutes at 65 - 60 °C;

► 250 ml of ethanol added over 1 minute, stirring for 10 minutes at 55 - 50 °C; ►250 ml of ethanol added over 1 minute, stirring for 10 minutes at 45 - 40 ⁰C.

1000 ml of ethanol was added altogether in the doses over about 1 hour, and the temperature of the suspension reached 40 °C. Finally, filtration was carried out, and the filter cake was washed with 2 x 150 ml of ethanol. After the product was dried in a vacuum drier until a constant weight, 92.2 g of a white crystalline product was obtained. The yield of crystallization was 83.8 % (HPLC > 99.95 %, the content of residual cobalt 1.5 μg/g).

EXAMPLE 11

12O g of crude free base of rosiglitazone I was, at about 80 ⁰C, dissolved in 200 ml of acetic acid, and ethanol was added to the solution obtained, under stirring, in the following regimen:

► 250 ml of ethanol added over 5 minutes (75 - 78 ⁰C), stirred for 20 minutes at 75-65 ⁰C;

► stirring for another 15 minutes, during which time the temperature dropped from 65 to 55 ⁰C;

► stirring for another about 15 minutes until the temperature dropped to 50 ⁰C, after which time 250 ml of ethanol was added in one portion (leading to a temperature of 48 ⁰C); ► stirring for another 10 minutes, 250 ml of ethanol was, at a temperature of about 46 °C, added (leading to a temperature of 45 °C);

► stirring for another 10 minutes, 250 ml of ethanol was, at a temperature of about 44 °C, added, and the stirring continued for about 10 minutes until reaching a temperature of 40 °C. 1000 ml of ethanol was added altogether in four equal doses over about 75 minutes, and the temperature of the suspension reached 40 ⁰C. Finally, filtration was carried out, and the filter cake was washed with ethanol (2 x 150 ml). After the product was dried in a vacuum drier until reaching a constant weight, 102.3 g of a white crystalline product was obtained. The yield of crystallization was 85.25 % (HPLC 99.87 %, the content of residual cobalt 2.7 μg/g).

EXAMPLE 12

120 g of crude free rosiglitazone base I was, at about 75 °C, dissolved in 220 ml of acetic acid (over 15 minutes), and ethanol was added to the solution obtained (about 70 °C) in the following regimen: ^250 ml of ethanol added over 5 minutes, filtration carried out, the temperature of the filtrate was 50 ⁰C;

►the temperature of the filtered solution was raised to 55 ⁰C over 10 minutes and to 60 °C after another 10 minutes, and the solution was stirred at this temperature for 15 minutes (the solution growing turbid gradually); ► the mixture was, at 60 °C, stirred for another 45 minutes, after which time 250 ml of ethanol was added and the stirring continued at 55 - 50 ⁰C for 30 minutes;

► external heating was stopped, and as the mixture was stirred, freely cooling down, for 90 minutes until reaching a temperature of 35 °C.

500 ml of ethanol was added altogether in two doses over about 3 hours and 25 minutes, and the temperature of the suspension reached 35 °C. Finally, filtration was carried out, and the filter cake was washed with ethanol (2 x 150 ml). After the product was dried in a vacuum drier until a constant weight, 97.7 g of a white crystalline product was obtained. The yield of crystallization was 81.4 % (HPLC > 99,95 %, the content of residual cobalt 0.95 μg/g).

EXAMPLE 13

HO g of crude free rosiglitazone base I was, at about 70 - 80 ⁰C, dissolved in 200 ml of acetic acid (over 15 minutes), and ethanol was added to the solution obtained in the following regimen: ►250 ml of ethanol added over 5 minutes, filtration carried out, the temperature of the filtrate was 65 °C;

►the filtrate was stirred, gradually cooling down, for about 15 minutes, leading to a drop in the temperature to 57 °C and yielding a turbid solution; ► stirring for another about 20 minutes, the temperature dropped from 57 to about 50 ⁰C, a thick suspension of the product formed;

► 250 ml of ethanol added over 1 minute, stirring for about 10 minutes, the temperature dropped to 45 ⁰C;

►250 ml of ethanol added over 1 minute, stirring for about 10 minutes, the temperature dropped to 38 ⁰C;

► 250 ml of ethanol added over 1 minute, stirring for about 10 minutes, the temperature dropped to 30 °C.

1000 ml of ethanol was added altogether in four doses over about 70 minutes, and the temperature of the suspension reached 30 ⁰C. Finally, filtration was carried out, and the filter cake was washed with ethanol (2 x 150 ml). After the product was dried in a vacuum drier until a constant weight, 95.2 g of a white crystalline product was obtained. The yield of crystallization was 86.5 % (HPLC 99.90 %, the content of residual cobalt 4.1 μg/g).

EXAMPLE 14 25 g of crude free rosiglitazone base I was, at 70 - 80 ⁰C, dissolved in 50 ml of acetic acid, and ethanol (250 ml) was added to the solution obtained, the mixture was boiled for a while, and then stirred, under slow cooling, for 45 minutes. Ethanol (50 ml) was added to the suspension of the product before filtration. The precipitated crystals were sucked off, washed with ethanol (2 x 50 ml), and dried in a vacuum drier. 21.2 g of crystalline free rosiglitazone base I was obtained. The yield of crystallization was 85 %.

EXAMPLE 15

25 g of crude free rosiglitazone base I was, at 70 - 80 °C, dissolved in 50 ml of acetic acid, and methanol (200 ml) was added to the solution obtained. The mixture was stirred, under slow cooling, for about 120 minutes. Methanol (150 ml) was added to the suspension of the product before filtration. The precipitated crystals were sucked off, washed with methanol (2 x 50 ml), and dried in a vacuum drier. 18 g of crystalline free rosiglitazone base I was obtained. The yield of crystallization was 72 %. EXAMPLE 16

25 g of crude free rosiglitazone base I was, at 70 - 80 °C, dissolved in 50 ml of acetic acid, and isopropyl alcohol (300 ml) was added to the solution obtained. The mixture was stirred, under slow cooling, for about 60 minutes. Isopropyl alcohol (250 ml) was added to the suspension of the product before filtration. The precipitated crystals were sucked off, washed with isopropyl alcohol (2 x 50 ml), and dried in a vacuum drier. 22.3 g of crystalline free rosiglitazone base I was obtained. The yield of crystallization was 89 %.

EXAMPLE 17

25 g of crude free rosiglitazone base I was, at 70 - 80 °C, dissolved in 50 ml of acetic acid, and N-butyl alcohol (300 ml) was added to the solution obtained. The mixture was stirred, under slow cooling, for about 60 minutes. N-butyl alcohol (250 ml) was added to the suspension of the product before filtration. The precipitated crystals were sucked off, washed with n-butyl alcohol (2 x 50 ml), and dried in a vacuum drier. 21.8 g of crystalline free rosiglitazone base I was obtained. The yield of crystallization was 87 %.

EXAMPLE 18

25 g of crude free rosiglitazone base I was, at 70 - 80 ⁰C, dissolved in 50 ml of acetic acid, and isoamyl alcohol (200 ml) was added to the solution obtained. The mixture was stirred, under slow cooling, for about 60 minutes. Isoamyl alcohol (300 ml) was added to the suspension of the product before filtration. The precipitated crystals were sucked off, washed with isoamyl alcohol (2 x 50 ml), and dried in a vacuum drier. 22.6 g of crystalline free rosiglitazone base I was obtained. The yield of crystallization was 90 %.

EXAMPLE 19 (comparative example)

140 g of crude rosiglitazone base I was, at the boil, dissolved in 3.5 1 of ethanol. The solution obtained was stirred for 4 hours and then allowed to stand overnight. After the product was filtered, the filter cake washed with 200 ml of ethanol and dried in a vacuum drier, 125 g of a white crystalline powder with HPLC purity of 99.6 % was obtained. The content of residual cobalt was 9 μg/g. The yield of crystallization was 89 %. EXAMPLE 20

A mixture of 100 ml of acetic acid and 500 ml of ethanol was poured to 50 g of crude free rosiglitazone base I. The suspension obtained was stirred and heated to the boil until a solution was formed. The heating was stopped after that, and the mixture was stirred, under slow cooling, for 4 hours, leading to the formation of a thick suspension of the product. Filtration was carried out, and the filter cake was washed with ethanol (2 x 50 ml). 43.4 g of a finely crystalline product was obtained after drying in a vacuum drier. The yield of crystallization was 87 %.

EXAMPLE 21

80 ml of acetic acid was poured to 40 g of free rosiglitazone base I, and the suspension obtained was, while being heated gently (about 50 °C), stirred for 15 minutes, leading to the formation of a yellow-coloured solution. 200 ml of ethanol was poured into this solution, making it turbid and finally leading to precipitation of a part of the free base. The suspension was heated to the boil, and at the moment the boil was reached, another 200 ml of ethanol was poured in. A clear solution was obtained, which was subjected to immediate filtration, and the isolated filtrate was again brought to mild boil. A previously prepared solution of 8 ml of phosphoric acid (85%) in 50 ml of ethanol was poured into the solution (75 - 80 °C warm), and the mixture obtained was refluxed for 5 minutes. The heating was stopped after that, and the mixture was stirred, under slow cooling, for 2.5 hours, leading to the formation of a thick slurry of the product. The final temperature of the suspension was 28 ⁰C. The suspension was filtered, and the filter cake was washed with ethanol (2 x 50 ml). After the product was dried in a vacuum drier, 48.3 g of crystalline rosiglitazone phosphate (1:1) was obtained, HPLC 99.85 %, the content of residual cobalt 0.66 μg/g. The yield: 94.8 %.

EXAMPLE 22

100 ml of acetic acid was poured to 50 g of free rosiglitazone base I, and the suspension obtained was, while being heated gently (about 50 ⁰C), stirred for 20 minutes, leading to the formation of a yellow-coloured solution. This solution was heated to 70 ⁰C, and, under these conditions, 500 ml of ethanol was added in one portion. After the solution obtained was heated from 65 to 70 °C, a previously prepared solution of 10 ml of phosphoric acid in 50 ml of ethanol was added. The heating was stopped, and the mixture was stirred, under slow cooling, for 4 hours, leading to the formation of a thick suspension of the product. The final temperature of the suspension was 26 °C. The suspension was filtered, and the filter cake was washed with ethanol (2 x 50 ml). After the product was dried in a vacuum drier, 59.7 g of crystalline rosiglitazone phosphate (1:1) was obtained, HPLC 99.84 %, the content of residual cobalt 1.6 μg/g. The yield: 93.7 %.

EXAMPLE 23

190 ml of acetic acid was poured to 47 g of free rosiglitazone base I, and the suspension obtained was, while being heated gently (about 50 °C), stirred for 10 - 15 minutes, leading to the formation of a thick, light yellow solution. This solution was heated to 75 °C, and, under these conditions, 250 ml of ethanol was added in one portion. After the solution obtained was heated to the boil and cooled gently to 70 ⁰C, filtration was carried out, and a previously prepared solution of 9.4 ml of phosphoric acid in 50 ml of ethanol was added, under stirring, to the filtrate. The solution obtained was brought to the boil, the external heating was stopped, after which 200 ml of ethanol was added in one portion. A solution with a temperature of 70 - 75 °C was obtained. It was stirred, under slow cooling, for 4 hours; the final temperature of the suspension was 25 °C. The suspension was filtered, and the filter cake was washed with ethanol (2 x 50 ml). After the product was dried in a vacuum drier, 50.3 g of crystalline rosiglitazone phosphate (1:1) was obtained, HPLC 99.91 %, the content of residual cobalt 0.2 μg/g. The yield: 84 %.

EXAMPLE 24

190 ml of acetic acid was poured to 46 g of free rosiglitazone base I, and the suspension obtained was, while being heated gently (about 50 ⁰C), stirred for 10 - 15 minutes, leading to the formation of a thick, light yellow solution. This solution was heated to 75 °C, and, under these conditions, 250 ml of ethanol was added in one portion. After the solution obtained was heated to the boil and cooled gently to 75 °C, filtration was carried out. A previously prepared solution of 9.2 ml of phosphoric acid in 50 ml of ethanol was added, under stirring, to the filtrate, immediately followed by 200 ml of ethanol. The mixture was stirred, under slow cooling, for 3.5 hours. The temperature of the suspension was 52 °C after 1 hour of stirring, 33 °C after 2 hours, 28 ⁰C after 3 hours, and the final temperature of the suspension was 27 ⁰C. The suspension was filtered, and the filter cake was washed with ethanol (2 x 50 ml). After the product was dried in a vacuum drier, 54.0 g of crystalline rosiglitazone phosphate (1:1) was obtained, HPLC 99.83 %, the content of residual cobalt 1.8 μg/g. The yield: 92.1 %. EXAMPLE 25

In a stirred mixture of 120 ml of ethanol and 20 ml of acetic acid, 20 g of rosiglitazone hydrochloride was dissolved at the boil. The mixture was allowed to cool naturally to reach a temperature below 30 °C, during which time a crystalline product precipitated gradually. After filtration, washing the filter cake with 2 x 20 ml of ethanol, and drying the product in a vacuum drier, 16.5 g of crystalline rosiglitazone hydrochloride was obtained. The yield: 82.5 %.

EXAMPLE 26

In a stirred mixture of 110 ml of ethanol and 20 ml of acetic acid, 11.3 g of rosiglitazone oxalate was dissolved at the boil. The mixture was allowed to cool naturally to reach a temperature below 30 °C, during which time a crystalline product precipitated gradually. After filtration, washing the filter cake with 2 x 20 ml of ethanol, and drying the product in a vacuum drier, 10.5 g of crystalline rosiglitazone oxalate (1:1) with a melting point of 154 - 157 °C was obtained. The yield: 93 %.

EXAMPLE 27

80 ml of acetic acid was poured to 40 g of free rosiglitazone base I, and the suspension obtained was, while being heated gently (about 50 °C), stirred for 15 minutes, leading to the formation of a yellow-coloured solution. 400 ml of ethanol was poured into this solution, making it turbid and finally leading to the precipitation of a part of the free base. The suspension was heated to the boil (about 80 °C), and after the free base dissolved, the solution was allowed to cool mildly. A previously prepared solution of 15.4 g of oxalic acid dihydrate in 100 ml of ethanol was poured into the clear solution obtained (about 75 ⁰C), and the mixture obtained was refluxed for 5 minutes. The clear solution was filtered (at 70 - 75 ⁰C), and the isolated filtrate was stirred, under slow cooling, for 2.5 hours, leading to the formation of a thick suspension of the product. The final temperature of the suspension was 29 ⁰C. The suspension was filtered, and the filter cake was washed with ethanol (2 x 50 ml). After the product was dried in a vacuum drier, 44.O g of crystalline rosiglitazone oxalate (1:1) was obtained, HPLC 99.90 %, the content of residual cobalt 0.7 μg/g. The yield: 87.9 %. EXAMPLE 28

100 ml of acetic acid was poured to 50 g of free rosiglitazone base I, and the suspension obtained was, while being heated gently (about 50 ⁰C), stirred for 20 minutes, leading to the formation of a yellow solution. This solution was heated to 70 ⁰C, and, under these conditions, 500 ml of ethanol was added in one portion, immediately followed by a solution of 19.3 g of oxalic acid dihydrate in 100 ml of ethanol. The mixture was brought to the boil, and the clear solution obtained was filtered when hot (ca 70 ⁰C). The filtrate was stirred, under slow cooling, for 3.5 hours, leading to the formation of a thick suspension of the product. The final temperature of the suspension was 27 ⁰C. The suspension was filtered, and the filter cake was washed with ethanol (2 x 50 ml). After the product was dried in a vacuum drier, 55.6 g of crystalline rosiglitazone oxalate (1:1) was obtained, HPLC 99.82 %, the content of residual cobalt 1.7 μg/g. The yield: 88.8 %.

EXAMPLE 29 190 ml of acetic acid was poured to 47 g of free rosiglitazone base I, and the suspension obtained was, while being heated gently (about 50 ⁰C), stirred for 10 - 15 minutes, leading to the formation of a thick, yellow solution. This solution was heated to 75 ⁰C, and, under these conditions, 250 ml of ethanol was added in one portion. After the solution obtained was heated to the boil and cooled mildly to 70 ⁰C, filtration was carried out, and a previously prepared solution of 18.12 g of oxalic acid dihydrate in 100 ml of ethanol was added, under stirring, to the filtrate. The solution obtained was brought to the boil, the external heating was stopped, and 200 ml of ethanol was added in one portion. A solution with a temperature of about 70 ⁰C was obtained. It was stirred, under slow cooling, for 4 hours; the final temperature of the suspension was 26 ⁰C. The suspension was filtered, and the filter cake was washed with ethanol (2 x 50 ml). After the product was dried in a vacuum drier, 42.5 g of crystalline rosiglitazone oxalate (1:1) was obtained, HPLC 99.89 %, the content of residual cobalt 0.76 μg/g. The yield: 72.2 %.

EXAMPLE 30 190 ml of acetic acid was poured to 46 g of free rosiglitazone base I, and the suspension obtained was, while being heated gently (about 50 ⁰C), stirred for 10 - 15 minutes, leading to the formation of a thick, light yellow solution. This solution was heated to 75 ⁰C, and, under these conditions, 250 ml of ethanol was added in one portion. After the solution obtained was heated to the boil and cooled mildly to 75 ⁰C, filtration was carried out. A previously prepared solution of 17.7 g of oxalic acid dihydrate in 100 ml of ethanol was added, under stirring, to the filtrate, immediately followed by 200 ml of ethanol. It was stirred, under slow cooling, for 3 hours. The temperature of the suspension was 46 °C after 1 hour of stirring, 33 °C after 2 hours, and 27 ⁰C after 3 hours, which was also the final temperature of the suspension. The suspension was filtered, and the filter cake was washed with ethanol (2 x 50 ml). After the product was dried in a vacuum drier, 50.0 g of crystalline rosiglitazone oxalate (1:1) was obtained, HPLC 99.80 %, the content of residual cobalt 1.7 μg/g. The yield: 86.8 %.

EXAMPLE 31

A mixture of 30 ml of acetic acid and 350 ml of ethanol was poured to a mixture of 50 g of crude free rosiglitazone base I and 16.5 g of maleic acid. The suspension obtained was stirred and heated to the boil until a solution was formed. Then the heating was stopped, and the mixture was stirred, under slow cooling, for 4 hours, followed by stirring overnight at 10 °C. The mixture was filtered, and the filter cake was washed with ethanol (2 x 25 ml). After drying in a vacuum drier, 50.2 g of a finely crystalline product with a melting point of 121 - 125 ⁰C was obtained. The yield of crystallization was 76 %.

Claims

1. A process for the crystallization of rosiglitazone of formula I, its penultimate of formula II, or its salts with acids of formula IH

wherein HX stands for a mineral or carboxylic acid, characterized in that it is carried out from a mixed organic solvent, consisting of a mixture of at least one carboxylic acid with at least one aliphatic alcohol.

2. The process according to claim 1, characterized in that the carboxylic acid is selected from the group comprising formic acid, acetic acid, propionic acid, and mixtures thereof.

3. The process according to claims 1 or 2, characterized in that the aliphatic alcohol is selected from the group comprising methanol, ethanol, 1-propanol, 2- propanol, butanols, amyl alcohols, and mixtures thereof.

4. The process according to any of claims 1 to 3, characterized in that the crystallized substance of formula I, II, or III is dissolved in the carboxylic acid at temperatures from 20 °C to the boiling points of the acid, after which the aliphatic alcohol is added to the solution of the substance in the carboxylic acid.

5. The process according to any of claims 1 to 3, characterized in that the crystallized substance of formula I, II, or III is dissolved in a mixture of the carboxylic acid and the aliphatic alcohol when hot, followed by cooling down the solution to effect the crystallization.

6. Crystalline 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione of formula I

obtained by the process according to any of claims 1 to 5.

7. Crystalline 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]- thiazolidine-2,4-dione of formula II

π obtained by the process according to any of claims 1 to 5.

8. Crystalline salts of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]- thiazolidine-2,4-dione of formula IE

in wherein HX stands for an acid with the pKa value less than 4, obtained by the process according to any of claims 1 to 5.

9. The crystalline salt of rosiglitazone, which is rosiglitazone maleate of formula III a, rosiglitazone hydrochloride of formula III b, rosiglitazone phosphate of formula III c, or rosiglitazone oxalate of formula III d

m obtained by the process according to any of claims 1 to 5.

10. The process according to any of claims 1 to 5 for removing chemical impurities from substances of formulae I, II, and III.

11. The process according to any of claims 1 to 5 for reducing the content of residual cobalt from substances of formulae I and III prepared by chemical synthesis using a cobalt salt as the reducing catalyst.

12. The process according to any of claims 1 to 5 for controlled preparation of crystalline substances of formulae I, II, and III having the particle size whose median of maximum size is within the range of 0.5 - 100 μm.

13. Use of crystalline rosiglitazone I and its salts with acids of general formula DI, prepared by the process according to any of claims 1 to 5, for preparation of pharmaceutically useful compounds, particularly of drugs with antihyperglycaemic effect.