KR20110011409A - Polymorphic form of pioglitazone potassium salt, process for preparing the same, and pharmaceutical composition containing the same - Google Patents

Abstract

PURPOSE: A polymorphic form of pioglitazone potassium and a pharmaceutical composition containing the same are provided to ensure quick absorption into the body and to control blood glucose. CONSTITUTION: A method for preparing polymorphic form of pioglitazone potassium salt comprises: a step of dissolving pioglitazone free base and potassium salt compound in an alcohol of 1-6 carbon atoms and filtering and concentrating; and a step of adding crystallizing solvent selected from an acetone single solvent or mixture solvent of acetone and ethyl acetate to form pioglitazone potassium salt. The potassium salt compound is potassium hydroxide, potassium halide, potassium carbonate, potassium hydrogen carbonate, or potassium sulfate. A pharmaceutical composition for treating diabetes contains the polymorphic form of pioglotazone potassium or mixture thereof. The composition is manufactured in the form of oral administration formulation and injection formulation.

Description

Polymorphic form of pioglitazone potassium salt, process for preparing the same, and pharmaceutical composition containing the same

The present invention relates to a polymorphic form of pioglitazone potassium salt, a method for preparing the compound, and a pharmaceutical composition containing the compound.

Pioglitazone is a thiazolidinedione having the compound name of 5- {4- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -benzyl} -thiazolidine-2,4-dione As a derivative, it is known that it exhibits an excellent glycemic effect. In particular, pioglitazone is known as a compound that improves the insulin resistance of type 2 diabetic patients, thereby enabling effective blood sugar control, and also protects insulin-producing pancreatic cells, kidneys, and stomach.

Pioglitazone or a pharmaceutically acceptable salt compound thereof was first disclosed as a thiazolidinedione compound in European Patent Publication No. 0193256 and US Patent No. 4,687,777. In addition, European Patent No. 06276273, European Patent No. 0257781, International Publication WO93 / 013905, International Publication WO2002 / 088120, International Publication WO2002 / 064577, International Publication WO2003 / 053367, International Publication WO2004 / 000810, International Publication Patent WO2004 / 007490, International Publication WO2004 / 024059, International Publication WO2004 / 108721, International Publication WO2005 / 049610, International Publication WO2005 / 058827, International Publication WO2005 / 080387, and US Patent Publication 2005/0187258 A method for preparing pioglitazone hydrochloride as a pharmaceutically acceptable formulation is proposed.

According to the general facts known to date, pioglitazone or pioglitazone hydrochloride is a poorly soluble compound, which is limited to oral preparations, so that it is difficult to expect the drug from the patient in a short time, and also has poor stability against moisture and heat. Attention is required of the city. Therefore, since the pioglitazone-based drug commercialized so far contains pioglitazone hydrochloride as an active ingredient, it does not eventually overcome the disadvantages of poorly soluble active ingredient.

On the other hand, it is very important to ensure the stability of water and heat of the effective drug contained in the pharmaceutical composition. The stability of the effective drug can directly affect the treatment efficacy and side effects of the patient. Prior inventions, including European Patent Publication No. 0193256 and U.S. Patent No. 4,687,777, which disclose pharmaceutically acceptable salt compounds of pioglitazone, only vaguely disclose the alkali metal salts of pioglitazone (eg, sodium salts, potassium salts, etc.). However, no efforts have been made to improve poor solubility and stability as pioglitazone-based drugs. Therefore, there is an urgent need for the development of a new pioglitazone-based drug that exhibits the same or better efficacy as the poorly soluble pioglitazone hydrochloride used as an anti-diabetic agent, and has excellent water-soluble properties and excellent stability against moisture and heat, thus ensuring long-term storage stability. have.

As described in the present invention, no literature has been reported to produce a pioglitazone potassium salt in a polymorphic form to improve water solubility and to secure storage stability of the drug.

The problem to be solved by the present invention is to provide a novel pioglitazone-based polycrystalline compound having excellent water solubility and storage stability, a method for preparing the compound, and a pharmaceutical composition containing the compound as an active ingredient.

The present invention solves the problems of the present invention by providing a polymorphic form of pioglitazone potassium salt.

The present invention relates to crystal polymorphism of pioglitazone potassium salt by the method of solvent crystallization using a good solvent of a pioglitazone free base and a potassium salt and acetone alone or a mixed solvent of acetone and ethyl acetate as a crystallization solvent. By providing a method for producing a solution of the present invention.

The present invention solves the problems of the present invention by providing a pharmaceutical composition for treating diabetes, wherein the polymorphic form of pioglitazone potassium salt is contained as an active ingredient.

The polymorphic form of the pioglitazone potassium salt provided by the present invention is a water-soluble compound, which enables the preparation of oral administration drugs with faster absorption into the body, and can also be formulated as an injection to control the blood sugar of the patient more quickly. It works.

In addition, since the crystal polymorph of the pioglitazone potassium salt provided by the present invention is sufficiently secured against moisture and heat, there is an effect to enable long-term storage without reducing the efficacy.

The present invention is characterized by the crystalline forms A1, A2 and A3 of the pioglitazone potassium salt.

Form A1 of pioglitazone potassium salt was determined as 5.8, 8.9, 11.8, 12.8, 15.0, 15.9, 17.8, 19.2, 20.2, 21.0, 21.6, 22.4, 23.4, 23.9, 26.1, 26.8, 27.7, 30.1, It has a crystal structure with 2θ diffraction angles of 32.3, 33.5, 34.6, 36.9, 38.2, and 39.4. [See Table 1 below, Figure 1]

In addition, crystalline form A2 of pioglitazone potassium salt was 8.7, 11.8, 12.8, 15.8, 17.5, 18.8, 19.7, 20.0, 20.7, 21.1, 22.1, 22.8, 23.7, 25.5, 26.1, 27.4, 28.3, It has a crystal structure with 2θ diffraction angles of 29.6, 30.0, 30.4, 31.2, 32.0, 33.4, 34.3, 34.9, 35.9, and 37.2. [Table 2 below, and the accompanying drawings, see FIG. 2]

In addition, crystalline form A3 of pioglitazone potassium salt was 5.8, 8.7, 11.6, 12.9, 13.4, 14.1, 15.0, 15.9, 17.5, 19.0, 20.1, 21.6, 22.0, 23.5, 24.0, 25.2, 25.8, It has a crystal structure with 2θ diffraction angles of 26.5, 27.3, 27.8, 29.4, 31.5, 32.4, 33.3, 34.6, 37.0, and 39.3. [See Table 3 below, Figure 3]

On the other hand, the present invention is characterized by a method for producing polymorphic crystals of pioglitazone potassium salt. Crystalline polymorph of pioglitazone potassium salt is prepared by the reaction of pioglitazone free base and potassium salt compound, but the present invention has a technical feature in applying a specific solvent system. That is, the crystal form of pioglitazone potassium salt is selected by using an alcohol solvent having 1 to 6 carbon atoms as a solvent for dissolving the pioglitazone free base and the potassium salt compound, and using acetone alone solvent or a mixed solvent of acetone and ethyl acetate as the crystallization solvent. A1, A2 and A3 were obtained with high purity.

Hereinafter, the method for preparing a polymorph according to the present invention will be described in more detail.

The pioglitazone free base and potassium salt compound are dissolved in an alcohol solvent, followed by filtration and concentration. At this time, the potassium salt compound may be any potassium-containing compound including potassium hydroxide, potassium halide, potassium carbonate, potassium hydrogencarbonate, potassium sulfate, potassium hydrogen sulfate, and the like, and preferably potassium hydroxide. The potassium salt compound may be used in an amount of 1 to 3 molar ratios, preferably 1 to 1.5 molar ratios, based on 1 mole of pioglitazone free base. In addition, the alcohol used as a good solvent for dissolving the pioglitazone free base and the potassium salt compound is a lower alcohol having 1 to 6 carbon atoms, specifically methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, hexanol, cyclohexanol It is possible to use, preferably methanol, ethanol, propanol, isopropanol, butanol is used, particularly preferably ethanol. The amount of alcohol is used in an amount sufficient to dissolve the pioglitazone free base and the potassium salt compound, and generally ranges from 2 to 10 weight times, preferably 3 to 5 weight times relative to the total weight of the pioglitazone free base and the potassium salt compound. Can be used as

Then, the crystallization solvent is added to the concentrate to form a polycrystalline form of pioglitazone potassium salt. At this time, the crystal form of the pioglitazone potassium salt may vary depending on the crystallization solvent used. For example, the use of acetone monosol as the crystallization solvent mainly produces crystalline form A1 of pioglitazone potassium salt, and the use of a mixed solvent in which acetone and ethyl acetate are maintained at a volume ratio of 1: 0.4 to 1: 0.5 produces crystalline form A2. When a mixed solvent in which acetone and ethyl acetate are maintained at a volume ratio of 1: 0.8 to 1: 1.2 as a crystallization solvent is used, crystalline form A3 is mainly produced.

On the other hand, the present invention is characterized by a pharmaceutical composition comprising a polymorph of the pioglitazone potassium salt as an active ingredient.

Since pioglitazone hydrochloride, which is conventionally used as an anti-diabetic drug, is a poorly soluble drug, it cannot be formulated as an injection and has a disadvantage of being limited to a few oral preparations. However, since the polymorphic form of the pioglitazone potassium salt of the present invention has excellent solubility in water, it is possible to formulate it as an injection as well as various oral administration preparations. In addition, the polymorphic form of the pioglitazone potassium salt of the present invention is excellent in storage stability, the effective drug is not deteriorated even if stored for a long time is expected to extend the shelf life.

The pharmaceutical composition of the present invention is formulated by a conventional formulation method (Remington's Pharmaceutical Scinences, Mack Publishing company, Easton, PA, 19 ^th Edition, 1995), including polymorphic forms of pioglitazone potassium salt, and other conventional carriers, adjuvants or diluents. It can be prepared in a form suitable for oral or parenteral administration. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, and the like. In the case of parenteral administration, it may be prepared in the form of injections that can be administered intraperitoneally, subcutaneously, intramuscularly, and transdermally. Can be.

Formulations for oral administration may be in the form of tablets containing starch or lactose, or in the form of capsules alone or in excipients, or in the form of elixirs or suspensions containing chemicals that flavor or color, orally, orally. Or under the tongue. Liquid formulations may be suspending agents (eg, methyl cellulose, semisynthetic glycerides such as witepsol or mixtures of apricot kernel oil with PEG-6 esters or PEG-8 with caprylic / capric glycerol). Pharmaceutically acceptable additives such as glyceride mixtures such as mixtures of lides). It may also be parenterally injected, for example, intravenously, intracavernosally, intramuscularly, subcutaneously and intratracheally. Injections for parenteral administration are most preferably used in the form of sterile aqueous solutions, in which the solution has other substances (e.g. salts or monosaccharides such as mannitol, glucose) to have isotonicity with the blood. It may contain.

Effective daily dosage of the pharmaceutical composition of the present invention as a diabetes treatment agent is 0.01 to 1000 mg / day based on an adult, but the dosage may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. In addition, depending on the judgment of the doctor or pharmacist may be divided into once or several times a day at a predetermined time interval.

The present invention as described above will be described in more detail based on the following Examples, Experimental Examples and Formulation Examples, but the present invention is not limited to these Examples, Experimental Examples, and Formulation Examples.

The analysis conditions of liquid chromatography (HPLC) applied to confirm the purity and stability of the polymorphic form of the pioglitazone potassium salt in the following Examples and Experimental Examples are as follows.

Column: C18 (ODS) or equivalent column, 5 um, 15 cm x 4.6 mm

Detector: Ultraviolet absorbance photometer (wavelength: UV 269 nm)

Mobile phase: Acetonitrile / 0.1M ammonium acetate / glacial acetic acid (25/25/1 volume ratio)

Flow rate: 0.7 mL / min

Column temperature: 25 ℃

Injection volume: 20 uL

Internal standard solution: 1.3 mg / mL benzophenone / methanol solution (e.g. 1 g of benzophenone is dissolved in methanol to make 750 mL)

[Example]

Example 1 Preparation of Form A1 of Pioglitazone Potassium Salt

10 g of pioglitazone free base having a purity of 99.0% or more was mixed with 100 ml of methyl alcohol, and 1.84 g of 85% potassium hydroxide was added, followed by stirring at room temperature for 1 hour to dissolve. The reaction solution was filtered and concentrated, and 100 ml of acetone was added and refluxed for 30 minutes. The mixture was cooled to room temperature, aged for 2 hours, filtered, and washed with acetone. It was dried at 50 ° C. to obtain 9.5 g (yield 85.6%) of crystalline A1 of the white pioglitazone potassium salt.

Form A1 of the pioglitazone potassium salt obtained in Example 1 was analyzed as follows.

Melting Point (TGA): 241.86 to 241.97 ° C (see Figure 2)

Karl-Fisher: 5.0% or less

Purity (HPLC): 99.5% or more

Infrared Absorption Spectroscopy (IR, KBr, cm ^-1 ): 2955, 2923, 2853, 2359, 1746, 1665, 1611, 1554, 1511, 1488, 1464, 1437, 1385, 1312, 1264, 1241, 1220, 1196, 1179, 1133, 1105, 1028, 965, 928, 901, 843, 817, 783, 745, 731, 692, 662 (see Figure 3)

It was confirmed that the crystalline form A1 of the pioglitazone potassium salt was a crystalline form having a characteristic diffraction angle from the X-ray powder diffraction (XRD) shown in Table 1 and FIG. 1. The case of I / I _o ≧ 20% of the characteristic diffraction angle peaks shown in the X-ray powder diffraction spectrum is shown in Table 4 below.

Form A1 of Pioglitazone Potassium Salt 2θ (± 0.2) d (± 0.2) I / I _o ≥20% 2θ (± 0.2) d (± 0.2) I / I _o ≥20% 8.9 9.8 55.8 23.9 3.7 37.7 15.0 5.8 100.0 26.8 3.3 45.5 15.9 5.5 25.2 27.7 3.2 21.6 21.0 4.2 40.9 30.1 2.9 31.6 22.4 3.9 45.9 32.3 2.7 29.1 23.4 3.7 27.7 2θ: diffraction angle, d: distance between crystal planes (Å), I / I _o : relative magnitude of peak

Example 2 Preparation of Form A2 of Pioglitazone Potassium Salt

10 g of pioglitazone free base having a purity of 99.0% or more was mixed with 100 ml of methyl alcohol, and 1.84 g of 85% potassium hydroxide was added, followed by stirring at room temperature for 1 hour to dissolve. The reaction solution was filtered and concentrated, and 100 ml of acetone and 50 ml of ethyl acetate were added and refluxed for 30 minutes. The mixture was cooled to room temperature, aged for 2 hours, filtered, and washed with acetone. It was dried at 50 ° C. to obtain 9.7 g (yield 87%) of crystalline A2 of the white pioglitazone potassium salt.

Crystalline A2 of the pioglitazone potassium salt obtained in Example 2 was analyzed as follows.

Melting Point (TGA): 245.40 to 246.80 ° C. (see FIG. 5)

Karl-Fisher: 5.0% or less

Purity (HPLC): 99.8% or more

Infrared Absorption Spectroscopy (IR, KBr, cm ^-1 ): 2922, 2853, 1665, 1611, 1554, 1534, 1511, 1454, 1437, 1385, 1311, 1265, 1241, 1220, 1179, 1133, 1105, 10455, 1027, 965, 927, 902, 843, 816 (see FIG. 6)

Form A2 of the pioglitazone potassium salt was confirmed to have a characteristic diffraction angle from the X-ray powder diffraction spectroscopy (XRD) shown in Table 2 and FIG. 2. The case of I / I _o ≧ 20% of the characteristic diffraction angle peaks shown in the X-ray powder diffraction spectrum is shown in Table 5 below.

Form A2 of Pioglitazone Potassium Salt 2θ (± 0.2) d (± 0.2) I / I _o ≥20% 2θ (± 0.2) d (± 0.2) I / I _o ≥20% 8.7 10.0 38.4 20.7 4.02 33.3 12.8 6.9 39.9 22.8 3.8 84.0 18.8 4.7 33.6 26.1 3.4 43.1 19.7 4.04 36.7 27.4 3.2 20.2 20.0 4.4 100.0 28.3 30.1 37.3 2θ: diffraction angle, d: distance between crystal planes (Å), I / I _o : relative magnitude of peak

Example 3. Preparation of Form A3 of Pioglitazone Potassium Salt

10 g of pioglitazone free base having a purity of 99.0% or more was mixed with 100 ml of ethyl alcohol, and 1.84 g of 85% potassium hydroxide was added, followed by stirring at room temperature for 1 hour to dissolve. The reaction solution was filtered and concentrated, and 50 ml of acetone and 50 ml of ethyl acetate were added and refluxed for 30 minutes. The mixture was cooled to room temperature, aged for 2 hours, filtered, and washed with acetone. It was dried at 50 ° C. to obtain 9.8 g (yield 88.3%) of crystalline A3 of the white pioglitazone potassium salt.

Form A3 of the pioglitazone potassium salt obtained in Example 3 was analyzed as follows.

Melting Point (TGA): 242.44 to 242.79 ° C (see Figure 8)

Karl-Fisher: 5.0% or less

Purity (HPLC): 99.6% or more

Infrared Absorption Spectroscopy (IR, KBr, cm ^-1 ): 2956, 2923, 2853, 2358, 23338, 1665, 1611, 1582, 1554, 1511, 1488, 1464, 1437, 1384, 1312, 1264, 1241, 1220, 1196, 1179, 1133, 1105, 1055, 1027, 965, 927, 901, 843, 817, 783, 745, 731, 692, 663 (see Figure 9)

It was confirmed that Form A3 of the pioglitazone potassium salt was a crystalline form having a characteristic diffraction angle from the X-ray powder diffraction (XRD) shown in Table 3 and FIG. 3. Excerpts of I / I _o ≧ 20% of the characteristic diffraction angle peaks shown in the X-ray powder diffraction spectrum are shown in Table 6 below.

Form A3 of Pioglitazone Potassium Salt 2θ (± 0.2) d (± 0.2) I / I _o ≥20% 2θ (± 0.2) d (± 0.2) I / I _o ≥20% 8.7 10.0 63.4 23.5 3.7 72.0 15.0 5.9 31.2 24.0 3.7 25.4 15.9 5.5 100.0 25.8 3.4 31.2 20.1 4.4 29.5 26.5 3.3 21.2 21.1 4.1 39.2 27.3 3.2 35.2 22.0 4.0 52.8 29.4 3.0 29.9 2θ: diffraction angle, d: distance between crystal planes (Å), I / I _o : relative size of peak

[Experimental Example]

Experimental Example 1. Comparison of water solubility characteristics

Table 7 shows the results of comparing the polycrystalline form of the pioglitazone potassium salt prepared in Examples 1 to 3 and the existing pioglitazone hydrochloride (amorphous) or pioglitazone potassium salt (amorphous) in water dissolution characteristics.

Pioglitazone Solubility (g / 100g, water) 20 ℃ 30 ℃ 40 ℃ Pioglitazone Hydrochloride (Amorphous) 0.01 0.01 0.01 Pioglitazone Potassium Salt (Amorphous) 50 60 70 Pioglitazone Potassium Salt Crystalline Form A1 50 60 70 Pioglitazone Potassium Salt Crystalline Form A2 50 60 70 Pioglitazone Potassium Salt Crystalline Form A3 50 60 70

According to Table 7, pioglitazone hydrochloride (amorphous) was extremely poor in solubility at 20 ° C as 0.01 as a poorly soluble drug, and the solubility was almost unchanged even when the temperature was raised to 40 ° C.

In contrast, the crystal polymorph and pioglitazone potassium salt amorphous form of pioglitazone potassium salt had a solubility of 50 or more at 20 ° C and a solubility at 40 ° C of 70 or more.

Therefore, the polymorphic form of pioglitazone potassium salt characterized by the present invention has superior water solubility characteristics compared to the currently commercialized pioglitazone hydrochloride (amorphous), so that the absorption rate in the body is greatly improved when compared to conventional drugs when administered as an oral dosage form. This can help control blood sugar quickly in diabetics. In addition, since the pioglitazone potassium salt crystal polymorph of the present invention has excellent water solubility characteristics and can be administered as an injection, it can also control blood glucose quickly in diabetic patients.

Experimental Example 2. Comparison of stability against moisture and heat

Table 8 shows the results of comparing the polymorphism of the pioglitazone potassium salt prepared in Examples 1 to 3 with the long-term storage stability of the existing pioglitazone hydrochloride (amorphous) or pioglitazone potassium salt (amorphous).

Table 8 shows the results of measuring the degree of degradation by HPLC after storing each pioglitazone salt under severe conditions (60 ± 2 ° C., 75 ± 5% relative humidity) for 28 days.

Pioglitazone Purity of pioglitazone salt (%), moisture content (%) Early 7 days later 14 days later 28 days later moisture water moisture water moisture water moisture water Pioglitazone Hydrochloride (Amorphous) 0.17 99.82 0.17 99.64 0.15 99.60 0.20 99.58 Pioglitazone Potassium (Amorphous) 4.83 99.75 4.85 99.40 4.85 99.00 4.86 98.50 Form A1 of Pioglitazone Potassium Salt 4.85 99.82 4.87 99.83 4.87 99.82 4.87 99.82 Form A2 of Pioglitazone Potassium Salt 4.83 99.70 4.85 99.70 4.85 99.70 4.85 99.70 Form A3 of Pioglitazone Potassium Salt 4.80 99.63 4.83 99.62 4.83 99.63 4.84 99.62

According to Table 8, the crystal polymorphs of pioglitazone hydrochloride (amorphous), pioglitazone potassium salt (amorphous), and pioglitazone potassium salt were found to have almost no difference in water content increase rate from about 0.02% to 0.03% after 28 days compared to the initial water content. It became. However, in the case of purity reduction after 28 days, the pioglitazone hydrochloride (amorphous) decreased by about 0.24%, the pioglitazone potassium salt (amorphous) decreased by about 1.25%, and the polymorphism of the pioglitazone potassium salt decreased by about 0.01%. Could confirm.

Therefore, the polymorphic form of the pioglitazone potassium salt characterized by the present invention is superior to the pioglitazone hydrochloride (amorphous) or pioglitazone potassium salt (amorphous), has excellent stability against moisture and heat and excellent long-term storage stability, pharmaceutical composition for treating diabetes It can be expected to be effective as it is contained as an active ingredient for a long time.

[Example]

On the other hand, the polymorphic form of the pioglitazone potassium salt according to the present invention can be formulated in various forms according to the purpose. The following illustrates some formulation methods containing crystalline forms A1, A2, and A3 of pioglitazone potassium salt as active ingredients, but the present invention is not limited thereto.

Formulation Example 1: Tablet (direct pressure)

After sifting 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

Formulation Example 2 Tablet (Wet Granulation)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation Example 3 Powder and Capsule

5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

Formulation Example 4 Injection

Injectables were prepared by containing 100 mg of the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

As described above, the crystalline forms A1, A2, and A3 of the pioglitazone potassium salt, which is characterized by the present invention, have excellent dissolution properties in water, overcoming the disadvantages of conventional poorly soluble pioglitazone drugs, and drugs that can lower blood sugar quickly. Development is now possible. In addition, the crystal form A1, A2, A3 of the pioglitazone potassium salt characterized by the present invention is excellent in stability against moisture and heat, so there is almost no change in drug efficacy during long-term storage.

Therefore, crystalline forms A1, A2, and A3 of pioglitazone potassium salt are expected to be used as a new drug that can replace the existing pioglitazone-based diabetes treatment.

1 is an X-ray diffractogram of crystalline Form A1 of pioglitazone potassium salt.

2 is a TGA analysis of crystalline Form A1 of pioglitazone potassium salt.

3 is an infrared absorption spectroscopy for crystalline Form A1 of pioglitazone potassium salt.

4 is an X-ray diffractogram of crystalline Form A2 of pioglitazone potassium salt.

5 is a TGA analysis of crystalline Form A2 of pioglitazone potassium salt.

6 is an infrared absorption spectrophotometer for crystalline Form A2 of pioglitazone potassium salt.

7 is an X-ray diffractogram of crystalline Form A3 of pioglitazone potassium salt.

8 is a TGA analysis of crystalline Form A3 of pioglitazone potassium salt.

9 is an infrared absorption spectroscopy for crystalline Form A3 of pioglitazone potassium salt.

10 is a solubility curve of the polymorphic form of pioglitazone potassium salt.

Claims (15)

Crystalline polymorph of pioglitazone potassium salt, characterized by being Form A1, Form A2, or Form A3. The method according to claim 1, The crystalline form A1 is a crystal polymorph of pioglitazone potassium salt, characterized in that the 2θ diffraction angle is 8.9, 15.0, 15.9, 21.0, 22.4, 23.4, 23.9, 26.8, 27.7, 30.1, 32.3 kV, X-ray powder diffraction analysis. The method according to claim 2, The crystalline form A1 is a crystal polymorph of pioglitazone potassium salt, characterized in that in the X-ray powder diffraction analysis, the 2θ (± 0.2) diffraction angle having 100% of I / I _o is 15.0 ㅀ, or the TGA melting point is 241.86 to 241.97 ° C. The method according to claim 1, The crystalline form A2 is a crystal polymorph of pioglitazone potassium salt, characterized in that the 2θ diffraction angle of the X-ray powder diffraction analysis is 8.7, 12.8, 18.8, 19.7, 20.0, 20.7, 22.8, 26.1, 27.4, 28.3 ㅀ. The method according to claim 4, The crystal form A2 is I / I _o 100% of 2θ (± 0.2) diffraction angle is 20.0 °, pioglitazone or potassium salt crystal polymorphism, characterized in that a melting point of TGA 245.4~246.8 ℃ in X- ray powder diffraction analysis. The method according to claim 1, Crystalline Form A3 is a crystal of pioglitazone potassium salt characterized in that the 2θ diffraction angle is 8.7, 15.0, 15.9, 20.1, 21.1, 22.0, 23.5, 24.0, 25.2, 25.8, 26.5, 27.3, 29.4 ° X-ray powder diffraction analysis Polymorphism. The method according to claim 6, The crystalline form A3 is a crystal polymorph of pioglitazone potassium salt, characterized in that the 2θ (± 0.2) diffraction angle of 100% I / I ₀ in X-ray powder diffraction analysis, 15.9 °, or TGA melting point of 242.44 ~ 242.79 ℃. Filtration and concentration after dissolving the pioglitazone free base and the potassium salt compound in alcohol having 1 to 6 carbon atoms, and The crystallization solvent selected from acetone single solvent or a mixed solvent of acetone and ethyl acetate is added to the concentrated concentrate to produce a polymorph of the pyoglitazone potassium salt. Method for producing a crystal polymorph of pioglitazone potassium salt comprising a. The method according to claim 8, A method of producing a polymorphic crystal form of pioglitazone potassium salt comprising the step of adding the acetone single solvent as a crystallization solvent to form crystalline form A1 of pioglitazone potassium salt. The method according to claim 8, Method for producing a crystal polymorph of pioglitazone potassium salt, characterized in that the acetone and ethyl acetate comprising a mixed solvent having a volume ratio of 1: 0.4 to 1: 0.5 as a crystallization solvent to form the crystalline form A2 of the pioglitazone potassium salt. The method according to claim 8, Method for producing a crystal polymorph of pioglitazone potassium salt, characterized in that the acetone and ethyl acetate containing a mixed solvent maintaining a volume ratio of 1: 0.8 to 1: 1.2 as a crystallization solvent to form the crystalline form A3 of the pioglitazone potassium salt. The method according to claim 8, Wherein said potassium salt compound is selected from potassium hydroxide, potassium halide, potassium carbonate, potassium hydrogen carbonate, potassium sulfate, or potassium hydrogen sulfate. The method according to claim 8, And said alcohol is selected from methanol, ethanol, propanol, isopropanol or butanol. A pharmaceutical composition for treating diabetes, characterized in that the polymorphic form of the pioglitazone potassium salt of any one of claims 1 to 7 or a mixture thereof is contained. The method according to claim 14, Pharmaceutical composition for the treatment of diabetes, characterized in that the formulation oral administration or injection.

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