KR20100125124A - New crystalline form of pitavastatine hemi calcium salt and the preparation thereof - Google Patents

Abstract

PURPOSE: A method for preparing pitavastatin hemicalcium crystal salt A is provided to ensure excellent storage stability. CONSTITUTION: A method for preparing pitavastatin hemicalcium salt crystal A comprises: a step of mixing ethanol and water in a ratio of 2:1(wt/wt)~6:1(wt/wt); a step of adding pitavastatin hemicalcium salt in the mixture solvent and heating at 65-80°C; and a step of stirring the mixture at room temperature and crystallizing at 15-30°C for 5-10 hours. A pharmaceutical composition for preventing and treating hyperlipidemia contains the pitavastatin hemicalcium salt crystal A as an active ingredient.

Description

New crystalline form of pitavastatine hemi calcium salt and the preparation of the pitavastatin hemicalcium salt

The present invention relates to a pitavastatin hemicalcium salt crystalline form and a preparation method thereof.

Pitavastatine has a structural formula as shown in [Formula 1] and is an inhibitor of the activity of HMG CoA reducing agent (3-hydroxy-3-methyl-glutaryl coenzyme A reductase). It is sold as.

[Formula 1]

Methods for preparing such pitavastatin hemicalcium salts and crystal forms thereof are described in EP00304063, EP0520406, WO0281451, WO0263028, WO04072040, WO05063728, WO03064392, WO07132482 and the like.

On the other hand, crystalline forms and preparation methods reported to date are difficult to obtain pitavastatin hemicalcium salts with high purity, and the crystals produced by the method also have low storage stability, and thus are limited to use as direct medicines. Therefore, higher purity crystallization methods and stable crystal forms are required.

Therefore, the researchers conducted a crystalline study of the phytavastatin hemicalcium salt in a uniform form that is more stable and does not have a difference between batches according to the preparation method. The present invention was completed, and the present invention has been found to be useful in pharmaceutical compositions due to its excellent chemical stability.

In the present invention, pitavastatin hemicalcium salt crystal form having a peak having a relative intensity of 50% or more at 2θ values of 5.2 °, 6.2 °, 7.7 °, 19.9 °, and 23.1 ° in X-ray powder diffraction measured using CuKa radiation. Provide A.

Pitavastatin hemicalcium salt crystalline Form A of the present invention has a 2θ value of 5.2 °, 6.2 °, 7.7 °, 10.0 °, 11.2 °, 12.7 °, 19.2 °, 19.9 in X-ray powder diffraction measured using CuKa radiation. It has a peak with a relative intensity of 25% or more at °, 20.7 °, 23.1 °, and 23.8 °, and more specifically, as shown in Table 1 below.

The present invention also adds pitavastatin hemicalcium salt to a mixed solvent of ethanol: water mixed from 2: 1 (wt / wt) to 6: 1 (wt / wt), heated to dissolve, and then stirred at room temperature to crystallize. To provide pitavastatin hemicalcium salt Form A.

In the production method of the present invention, the pitavastatin hemicalcium salt, which is a starting material, may be prepared by a known method of preparing the pitavastatin hemicalcium salt, or may be commercially available. For example, one manufactured by the method described in Korean Patent Application No. 2008-0111156 can be used.

In the preparation method of the present invention, the ethanol: water mixing ratio is preferably 2.5: 1 (wt / wt) to 3: 1 (wt / wt) in consideration of the yield of the final product, and is 2.8: 1 (wt / wt). Even more preferred.

In the preparation method of the present invention, the mixed solvent is preferably used 6 to 15 times (wt / wt), more preferably 10 to 11 times (wt / wt) based on the weight of the pitavastatin hemicalcium salt. .

In the production method of the present invention, the heating is preferably carried out at 65 to 80 ℃, even more preferably carried out at 70 to 75 ℃. The heating time is preferably a time taken for the starting material phytavastatin hemicalcium salt to be completely dissolved in the solvent. For example, the time for reaching the heating temperature is suitably 1 to 3 hours, and the heating temperature is reached. It is preferable to further dissolve about 2 to 20 minutes later.

In the preparation method of the present invention, crystallization may be performed at -10 to 40 ° C, preferably at 15 to 30 ° C, and more preferably at 20 to 25 ° C.

In the production method of the present invention, the crystallization method can be carried out in a stirring or standing state, preferably stirring. If necessary, seed crystals of Form A may be added.

In the production method of the present invention, the crystallization time is preferably stirred for 5 hours to 10 hours, more preferably 6 hours to 7 hours.

In the production method of the present invention, it is preferable that the filtered solid is washed with purified water and then dried under vacuum (0-4 torr), which is a conventional crystal drying method, after the crystallization is performed.

The present invention also provides a pharmaceutical composition for preventing and treating hyperlipidemia, which contains the pitavastatin hemicalcium salt crystalline form A of the present invention as an active ingredient.

The compositions of the present invention can be parenterally administered in the form of, for example, injections (subcutaneous, intravenous, intramuscular or intraperitoneal), ointments, suppositories, aerosols, or the like, or as tablets, capsules, granules, pills, syrup drugs, It can be administered orally in the form of potions, emulsion drugs, suspension drugs.

The effective dosage of the composition of the present invention is usually about 0.003 to 100 mg, preferably about 0.01 to 10 mg per day for adults, but may vary depending on the age, weight, sensitivity or severity of symptoms of the patient.

The composition of the present invention comprises about 0.001 to 30% (wt / wt), preferably about 0.01 to 10%, of the pitavastatin hemicalcium salt crystalline Form A of the present invention based on the total weight of the composition.

The composition of the present invention comprises phytavastatin hemicalcium salt crystalline form A of the present invention as a pharmacologically active ingredient, and in addition to the pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusting agents, antioxidants, dissolution aids and the like It may include.

The composition of the present invention can be formulated according to a conventional pharmaceutical production method for administration. In other words, tablets, capsules or granules for oral administration include, for example, excipients such as sucrose, lactose, glucose, starch EH mannitol; Binders such as hydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose EH are polyvinylpyrrolidone; Disintegrants such as starch, carboxymethyl cellulose EH, calcium salts thereof, microcrystalline cellulose EH, polyethylene glycols; lubricants such as talc, magnesium or calcium stearate, EH silica; lubricant agents such as sodium larurate E or glycerol Can be formulated.

Injection drugs, potions, emulsion drugs, suspension drugs, syrup drugs and aerosol drugs are, for example, solvents for the active ingredient, such as water, ethanol, isopropanol, propylene glycol, 1,3-butylene glycol or polyethylene glycol; surfactants Such as sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ethers of hydrogenated castor oil, or lecithin; suspending agents such as carbomethylmethyl sodium salts, or cellulose derivatives such as methyl cellulose, Tragacanth, natural rubber such as gum arabic; preservatives such as p-hydroxybenzoate, benzalkonium chloride EH can be prepared using sorbate.

Ointments that are transdermal absorption formulations may, for example, use white petrolatum, liquid paraffin, higher alcohols, macrogol ointments, hydrophilic ointments or aqueous gel base materials.

Suppositories can be prepared using, for example, cacao butter, polyethylene glycol, lanolin, fatty acid triglycerides, coconut oil or polysorbate.

The novel crystalline Form A of the present invention has excellent storage stability and physical properties with little difference between batches according to the preparation method. In addition, the production method of the present invention is economical and industrially useful because it is produced in high purity and high yield of Form A.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Reagents used in the following examples were purchased from Aldrich, TCI, Acros, unless otherwise noted, ¹ H-NMR was measured using a Varian Inova 500 MHz FT-NMR (manufacturer Varian), The pitavastatin hemicalcium salt used as a starting material in the examples was prepared according to the method described in Korean Patent Application No. 10-2008-0111156.

The X-ray powder diffraction (XRD) measuring apparatus and method measured in this example are as follows.

The powder X-ray diffractometer used MXLabo (manufactured by MacScience), the source of the light source was Cu, the wavelength was 1.54056A, the protractor was used a vertical goniometer, and the measurement method was 100 mg. After that, it is measured under the following conditions.

Data range: 3.040 to 40.000 deg,

Number of data points: 925

Scan axis: 2θ / θ

Sample interval: 0.0400 deg,

-Scanning speed: 4.800 deg / min

< Example  1> Pitavastatin Hemicalcium salt  Form A Preparation

1148 g of ethanol (alcohol) was injected into a 2000 ml reaction part, and pitavastatin hemicalcium (144.0 g) prepared according to Korean Patent Application No. KR10-2008-0111156 was added thereto. After injecting 409 g of purified water into the solution, the mixture was stirred at 20 to 25 ° C. for 5 minutes, the temperature was raised to 70 to 75 ° C. over about 2 hours, and dissolved at that temperature for 5 minutes. The reaction was then cooled to 20-25 ° C. for 3 hours and further stirred at 20-25 ° C. for 3 hours. The resulting white solid was filtered under reduced pressure, washed with purified water (300 ml), and dried under vacuum (0-4 torr) at 40 ° C. or lower for about 12 hours to obtain pitavastatin hemi calcium crystalline Form A of white crystals (130 g). Obtained. The yield was 90%, the X-RD measurement value of the obtained crystal form was shown in Table 2 and FIG.

< Example  2> Pitavastatin Hemicalcium salt  Form A Preparation

600 g of ethanol (alcohol) was injected into a 1000 ml reaction part, and pitavastatin hemicalcium (70.0 g) was added thereto. After injecting 150 g of purified water into the solution, the mixture was stirred at 20 to 25 ° C for 5 minutes, the temperature was raised to 70 to 75 ° C over about 2 hours, and dissolved at that temperature for 5 minutes. The temperature of the reaction was cooled to 20-25 ° C. for 3 hours and then further stirred at 20-25 ° C. for 3 hours. The resulting white solid was filtered under reduced pressure, washed with purified water (300 ml), and dried in vacuo for about 12 hours at a vacuum (0-4 torr) of 40 ° C. or lower to obtain pitavastatin hemi calcium crystalline Form A (50 g) as white crystals. Was obtained (yield 71%), and the X-RD value was the same as that described in Example 1.

< Example  3> Pitavastatin Hemicalcium salt  Form A Preparation

638 g of ethanol (alcohol) was injected into a 1000 ml reaction unit, and pitavastatin hemicalcium (70.0 g) was added thereto. After injecting 112 g of purified water, the mixture was stirred at 20 to 25 ° C. for 5 minutes, and the temperature was raised to 70 to 75 ° C. over about 2 hours to dissolve for 5 minutes. The temperature of the reaction was cooled to 20-25 ° C. for 3 hours and then stirred at 20-25 ° C. for 3 hours. The resulting white solid was filtered under reduced pressure, washed with purified water (300 ml) and dried for about 12 hours in a vacuum (0-4 torr) at 40 ° C. or lower to obtain pitavastatin hemi calcium (35 g) as white crystals. (Yield 58.3%) and the X-RD value were the same as those described in Example 1.

<Experiment> storage stability effect of pitavastatin hemicalcium salt crystal form A of the present invention make

The pitavastatin hemicalcium salt crystalline form A of the present invention and the pitavastatin hemicalcium salt crystalline forms A to F described in WO 2004/072040 were treated at 40 ± 2 ° C., RH 75 ± 5% at 1 month, 2 months, 4 months, After 6 months, impurities were measured using high performance liquid chromatography.

As a result, it was confirmed that the pitavastatin hemicalcium salt crystalline form A of the present invention had an excellent storage stability effect compared to the known pitavastatin hemicalcium salt crystalline form.

1 is a powder X-ray diffraction pattern of crystalline Form A of the pitavastatin hemicalcium salt prepared in the Example.

Claims (10)

Pitavastatin hemicalcium salt crystalline Form A having a peak with a relative intensity of 50% or more at 2θ values of 5.2 °, 6.2 °, 7.7 °, 19.9 °, and 23.1 ° in X-ray powder rotation measured using CuKa radiation. The X-ray powder rotation measured using CuKa radiation has a 2θ value of 5.2 °, 6.2 °, 7.7 °, 10.0 °, 11.2 °, 12.7 °, 19.2 °, 19.9 °, 20.7 °, 23.1. Pitavastatin hemicalcium salt crystalline Form A having a peak with a relative intensity of 25% or more at 23.8 °. Pitavastatin hemicalcium salt was added to a mixed solvent of ethanol: water 2: 1 (wt / wt) to 6: 1 (wt / wt), dissolved by heating, and then crystallized by stirring at room temperature. Method for preparing hemicalcium salt crystalline Form A. The method of claim 3, wherein the ethanol: water mixing ratio is 2.5: 1 (wt / wt) to 3: 1 (wt / wt). The method for preparing pitavastatin hemicalcium salt crystalline Form A according to claim 4, wherein the ethanol: water mixing ratio is 2.8: 1 (wt / wt). The method for preparing pitavastatin hemicalcium salt crystalline Form A according to claim 3, wherein the mixed solvent is used 6 to 15 times (wt / wt) based on the weight of the pitavastatin hemicalcium salt. The method for preparing pitavastatin hemicalcium salt crystalline Form A according to claim 6, wherein the use weight of the mixed solvent is 10 to 11 times (wt / wt) based on the weight of the pitavastatin hemicalcium salt. The process for preparing pitavastatin hemicalcium salt crystalline Form A according to claim 3, wherein the heating is performed at 65 to 80 ° C. The method for preparing pitavastatin hemicalcium salt crystalline Form A according to claim 3, wherein the crystallization is performed by stirring for 5 hours to 10 hours within a range of 15 to 30 ° C. A pharmaceutical composition for preventing and treating hyperlipidemia, comprising phytavastatin hemicalcium salt crystalline form A of claim 1 as an active ingredient.

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