WO2014050874A1

WO2014050874A1 - Novel crystalline form of rosuvastatin calcium and production method therefor

Info

Publication number: WO2014050874A1
Application number: PCT/JP2013/075880
Authority: WO
Inventors: 茂信西口; 直人稲越
Original assignee: 東和薬品株式会社
Priority date: 2012-09-27
Filing date: 2013-09-25
Publication date: 2014-04-03
Also published as: TW201418227A

Abstract

Provided is a novel crystal of rosuvastatin calcium that exhibits suitable properties as a medicine. The present invention provides a TW-1 crystal of rosuvastatin calcium having a powder X-ray diffraction pattern that exhibits a characteristic peak when 2θ(°) = 5.4 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2 and 22.7 ± 0.2.

Description

Novel crystalline form of rosuvastatin calcium and process for its production

The present invention relates to the formula 1 having HMG-CoA reductase inhibitory action.

Rosuvastatin calcium represented by the formula: bis ((3R, 5S, 4E) -7- {4- (4-fluorophenyl) -6-isopropyl-2- [methanesulfonyl (methyl) amino] pyrimidin-5-yl) -3,5-dihydroxyhept-6-enoic acid} relates to a novel crystalline form of calcium.

Rosuvastatin calcium is an HMG-CoA reductase inhibitor sold as CRESTOR (registered trademark) in various countries around the world. In Japan, tablets that are effective or effective for hypercholesterolemia and familial cholesterolemia are on the market.

Conventionally, several crystalline polymorphs are known in addition to amorphous substance forms of rosuvastatin calcium. Japanese Patent No. 2664897 (Patent Document 1), Japanese Translation of PCT International Publication No. 2008-546730 (Patent Document 2), and Japanese Patent No. 4099333 (Patent Document 3) disclose methods for producing amorphous rosuvastatin calcium. In addition, Patent No. 4996786 (Patent Document 4) discloses rosuvastatin calcium A-type crystals, and WO2010 / 081861 International Publication (Patent Document 5) discloses rosuvastatin calcium anhydrous crystals and trihydrate crystals. ing.

Japanese Patent No. 2664897 Special table 2008-546730 gazette Japanese Patent No. 4099333 Japanese Patent No. 4996786 WO2010 / 081861 International Publication

In general, crystals are superior to amorphous materials in terms of stability and are excellent for providing high-quality pharmaceuticals. In fact, since amorphous rosuvastatin calcium has the property of being easily decomposed at room temperature, a more stable crystal can be said to be an industrially preferable form. However, crystals generally have lower solubility than amorphous, and crystal forms with low solubility can be disadvantageous from the viewpoint of pharmacology such as bioavailability.

Pharmaceutical compounds may have high hygroscopicity depending on the type and substance form. When handling a highly hygroscopic pharmaceutical compound, it is difficult to prevent exposure to water in the air in order to maintain a uniform moisture value in a general production facility. Therefore, the high hygroscopicity of a pharmaceutical compound is a disadvantageous factor in the manufacture of pharmaceutical products. Depending on the type of the pharmaceutical compound, the hygroscopicity may be suppressed by performing crystallization as compared with the amorphous body. When the hygroscopicity of rosuvastatin calcium was measured, it was found that not only the amorphous body but also the crystal showed high hygroscopicity, which was a problem in production.

From other viewpoints concerning crystals, it is known that chemical purity or optical purity is generally improved by crystallization, but purity is hardly improved by amorphization. In fact, Japanese Patent No. 26488897 (Patent Document 1) and Japanese Translation of PCT International Publication No. 2008-546730 (Patent Document 2) disclose methods for producing amorphous rosuvastatin calcium, but these documents improve the chemical purity. Is not shown.

Japanese Patent No. 4099333 (Patent Document 3) discloses a method for producing amorphous rosuvastatin calcium in which rosuvastatin is purified and isolated with another salt and then subjected to salt exchange. However, in consideration of commercial production, the production method via another salt is inefficient in terms of workability and production cost, and the remaining salt is also a problem.

In view of such circumstances, it is desired to provide a new crystal form of rosuvastatin calcium salt with improved low solubility and high hygroscopicity.

As a result of intensive studies, the present inventors found a new crystal form of rosuvastatin calcium salt named TW-1 and completed the present invention.

The TW-1 type crystals found by the present invention have 2θ (°) = 5.4 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2. And a powder X-ray diffraction pattern with an intrinsic peak at 22.7 ± 0.2.

TW-1 type crystals are extremely stable and do not exhibit hygroscopicity, so they are also defined by the moisture value.

2 is a powder X-ray diffraction spectrum of rosuvastatin calcium TW-1 type crystal.

The rosuvastatin calcium TW-1 type crystal of the present invention comprises a liquid selected from an ester group, a ketone group, an ether group, an aliphatic hydrocarbon group, an aromatic hydrocarbon group, a halogenated hydrocarbon group, and a mixed liquid group thereof. Prepared from a mixture with water.

More specifically, a liquid and water selected from an ester group, a ketone group, an ether group, an aliphatic hydrocarbon group, an aromatic hydrocarbon group, a halogenated hydrocarbon group, and a mixed liquid group thereof are added to rosuvastatin calcium. Thereafter, the obtained solid is separated, dried, and then conditioned to obtain a TW-1 type crystal. During this time, any material form may be used before the TW-1 type crystal is formed. The raw material rosuvastatin calcium may be in any substance form, and the raw material may or may not be dissolved in the solution.

In the amount of the solution in the solid formation stage of the present invention, a liquid selected from an ester group, a ketone group, an ether group, an aliphatic hydrocarbon group, an aromatic hydrocarbon group, a halogenated hydrocarbon group, and a mixed liquid group thereof; The total volume with water is preferably 0.3 to 35 mL, more preferably 10 to 30 mL, per 1 g of rosuvastatin calcium.

In the volume ratio of the solution, the mixing ratio of liquid and water selected from the ester group, ketone group, ether group, aliphatic hydrocarbon group, aromatic hydrocarbon group, halogenated hydrocarbon group, and mixed liquid group thereof is 24. Is preferably 1: 1 to 1: 1, more preferably 4: 1 to 2.5: 1.

In the solid-forming solution of the present invention, aliphatic esters and aromatic esters, preferably aliphatic esters, more preferably ethyl acetate, isopropyl acetate, and propyl acetate are used as the ester group.

As the ketone group, aliphatic ketones, aromatic ketones, preferably aliphatic ketones, more preferably lower aliphatic ketones, more preferably acetone, methyl ethyl ketone, and methyl isobutyl ketone are used.

As the ether group, aliphatic ethers, aromatic ethers, preferably aliphatic ethers, more preferably acyclic aliphatic ethers, cyclic aliphatic ethers, more preferably dimethyl ether, tetrahydrofuran, and cyclopentylmethyl ether are used.

As the aliphatic hydrocarbon, hexane, heptane or cyclohexane is preferably used.

As the aromatic hydrocarbon group, benzene, toluene and xylene are preferably used.

As the halogen hydrocarbon group, aliphatic halogen and aromatic halogen, preferably dichloromethane, 1,2-dichloroethane and chlorobenzene are used.

In the stirring time of the solid formation stage of the present invention, a liquid selected from an ester group, a ketone group, an ether group, an aliphatic hydrocarbon group, an aromatic hydrocarbon group, a halogenated hydrocarbon group, and a mixture thereof. After adding water, stirring can be performed for 3 hours, preferably 5 hours or more. At this time, a good yield can be obtained by adding seed crystals.

In the stirring temperature, stirring can be performed in an arbitrary temperature range, preferably 10 ° C. to 50 ° C., more preferably 23 ° C. to 35 ° C.

The drying time of the solid drying stage of the present invention can be performed for any time, preferably 5 hours or more, more preferably 8 hours or more.

The drying pressure can be carried out under reduced pressure, preferably under reduced pressure of 200 mmHg or less. Moreover, it can also carry out by ventilating dry gas, such as nitrogen. The drying temperature can be 20 ° C. to 60 ° C., preferably 30 ° C. to 50 ° C.

The humidity control used in the present specification is to adjust the moisture value of the solid. Although there is no particular limitation, the form of humidity control includes exposure of the solid to an atmosphere in a specific humidity condition, contact of the solid with water and water vapor, etc., and the solid is dynamic or static. The atmosphere may be either dynamic or static. Although not particularly limited, the optimum humidity control form is preferably exposed to a humidity of 40%, more preferably 50% or more.

Any temperature can be used as the temperature at the time of humidity control according to the present invention, but it can be preferably 15 to 40 ° C.

The time required for conditioning the humidity of the present invention may vary depending on other conditions, but is any time, preferably 3 hours or more, more preferably 5 hours or more.

The water content of the TW-1 type crystal obtained by the present invention is about 2.1 to 2.4%. The production of TW-1 type crystals by humidity control can be based on the presence or absence of a change in water content.

DSC of rosuvastatin calcium TW-1 has a characteristic peak.

The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.

The powder X-ray diffraction pattern was measured with X'Pert PRO PW3040 / 60 (X'CELERATOR detector) manufactured by PANalytical using CuKα radiation.

The moisture value of the rosuvastatin calcium TW-1 type crystal obtained by the production method of the present invention was measured with a Karl Fischer moisture meter (AQUACOUNTER AQV-2200, Hiranuma Sangyo Co., Ltd.) or a device equivalent thereto.

HPLC (High Performance Liquid Chromatography) is equipment: Waters 1525 separation module, detector: UV, software Empower2, column: (L-Column ODS, 3 μm, 4.6 × 150 mm), mobile phase: 0.1% acetic acid aqueous solution. / Acetonitrile, column temperature: room temperature, flow rate: 1.0 mL / min, wavelength: 242 nm, injection volume: 10 μL.

(Example 1)
Preparation of rosuvastatin calcium TW-1 type crystal 1
To 5 g of rosuvastatin calcium, 100 mL of ethyl acetate and 25 mL of water were added and stirred at 25 ° C. overnight. The resulting solid was collected by filtration, washed with 5 mL of ethyl acetate, and dried under reduced pressure at 40 ° C. This solid was allowed to stand at room temperature for 5.5 hours in the presence of a saturated sodium chloride aqueous solution in a desiccator to obtain 3.7 g of the title compound.

(Example 2)
Preparation of rosuvastatin calcium TW-1 type crystal 2
Rosuvastatin calcium (HPLC purity 98.6%) 30.0 g was added to 510 mL of ethyl acetate and dissolved by heating to 30 ° C., followed by foreign matter filtration. The remaining instrument attachment and filtration path were washed with 90 mL of ethyl acetate. The filtrates were combined and warmed to 30 ° C., 150 mL of water was added, and the mixture was stirred at 25-30 ° C. for 40 hours. The resulting crystals were collected by filtration and washed 3 times with 30 mL of water to obtain 45.0 g of wet crystals. 43.4 g of this wet crystal was combined with 121 mL of water and 484 mL of ethyl acetate and stirred at 30 ° C. for 7 hours. The crystals were collected by filtration, washed with 25 mL of water three times, and dried under reduced pressure at 50 ° C. This was left in a humidity chamber adjusted to 25 ° C. and a relative humidity of 75% for 67 hours while analyzing the moisture of the crystals on the way, to obtain 19.2 g of the title compound. The moisture was 2.1%.

(Example 3)
Preparation of rosuvastatin calcium TW-1 type crystal 3
Rosuvastatin calcium (HPLC purity 99.8%) 30.0 g was added to ethyl acetate 510 mL and dissolved by heating to 30 ° C., followed by foreign matter filtration. The remaining instrument attachment and filtration path were washed with 90 mL of ethyl acetate. The filtrates were combined and warmed to 30 ° C., 150 mL of water was added, and the mixture was stirred at 30 ° C. for 23 hours. The resulting crystals were collected by filtration, washed 3 times with 30 mL of water each time, and dried under reduced pressure at 50 ° C. to obtain 21.7 g of dry crystals. This was left in a humidity chamber adjusted to 25 ° C. and relative humidity 82% for 20 hours while analyzing the moisture of the crystals on the way, to obtain 21.8 g of the title compound. The HPLC purity was 99.9% and the water content was 2.2%.

Example 4
Preparation of rosuvastatin calcium TW-1 type crystal 4
12.0 kg of rosuvastatin calcium was added to 204 L of ethyl acetate and dissolved by heating to 30 ° C., followed by foreign matter filtration. The dissolution tank and filtration path were washed with 36 L of ethyl acetate. The filtrates were combined and heated to 30 ° C., 60 L of purified water was added, 0.24 kg of seed crystals were further added, and the mixture was stirred at 30 ° C. for 20 hours. The resulting crystals were collected by filtration, washed with 30 L of purified water, and dried by blowing nitrogen at 50 ° C. to obtain 21.7 kg of dry crystals. Nitrogen adjusted to 25 ° C. and a relative humidity of 60 to 65% was passed through the crystal layer for 24 hours while analyzing the water content to obtain 10.3 kg of the title compound. The water content was 2.4%.

FIG. 1 shows a powder X-ray diffraction pattern of rosuvastatin calcium TW-1 type crystal. As shown in FIG. 1, 2θ (°) = 5.4 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, and 22.7 ± 0. A powder X-ray diffraction spectrum showing an intrinsic peak in 2 was obtained.

The effects of the TW-1 type crystal of the present invention are shown below. Trihydrate and anhydride crystals were prepared based on Patent Document 5, and A-type crystals were prepared based on Patent Document 4.

(Test Example 1) Purity Test HPLC purity before and after conversion from amorphous rosuvastatin calcium to TW-1 type crystals and A type crystals was measured.

When amorphous rosuvastatin calcium was converted to TW-1 type crystals, it showed a significant purification effect, and in particular, an excellent purification effect on 5-oxorosuvastatin, which is a main related substance. It was confirmed that the related substances can be greatly reduced from 1.53% to 0.18% by one crystallization operation. On the other hand, in the case of A-type crystals, the purification effect of 5-oxorosuvastatin was limited, and 0.29% remained even when a higher-purity amorphous material was used as a raw material.

The structural formula of 5-oxorosuvastatin analog is shown below.

Test Example 2 Stability Test Rosuvastatin calcium TW-1 type crystals were sealed in an aluminum pillow, stored in a chamber controlled at 70 ° C. for 9 days, and then analyzed by HPLC. The test results of the rosuvastatin calcium amorphous material used as a raw material in the same manner are shown in Table 2 as comparison targets.

The rosuvastatin calcium TW-1 type crystal of the present invention did not show any deterioration at 70 ° C. for 9 days, and was found to be an extremely stable crystal form.

(Test Example 3) Solubility test The concentration of the supernatant obtained by adding 10 ml of water to 0.1 g of each substance form and stirring at 37 ° C for 30 minutes was measured by HPLC to calculate the solubility. Chromatographic purity was determined by HPLC method. The results are shown in Table 3.

The rosuvastatin calcium TW-1 type crystal of the present invention is stable compared to the amorphous body, and surprisingly, contrary to the general tendency that the crystal is less soluble than the amorphous body, In contrast, it was more soluble than amorphous. That is, the solubility of the TW-1 type crystal in water was 8.03 mg / mL which is higher than 7.50 mg / mL of the amorphous substance. Furthermore, the solubility of the trihydrate crystal and the A type crystal was 1.89 mg / mL and 3.13 mg / mL, and the TW-1 type crystal showed solubility of 4 times and 2.5 times or more thereof, respectively. .

(Test Example 4) Hygroscopicity test Each substance form was allowed to stand for 2 days at 75% humidity, and the moisture values before and after were measured. The results are shown in Table 4.

The rosuvastatin calcium TW-1 type crystal of the present invention did not show any hygroscopicity that is a manufacturing defect found in the amorphous, A-type and anhydrous crystals of rosuvastatin calcium disclosed heretofore. Even when the TW-1 type crystal was left to stand at 75% humidity for 2 days, the water content was 2.2%, and no increase in the water content was observed. On the other hand, the anhydrous crystal showing the same solubility as the TW-1 type crystal showed a significant improvement in moisture value, and it became clear that it had hygroscopicity.

From the above, only the TW-1 type crystal has both excellent solubility and hygroscopic properties, and the superiority of the TW-1 type crystal has been clarified.

Claims

2θ (°) = 5.4 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 13.2 ± 0.2, and 22.7 ± 0.2 exhibit unique peaks A TW-1 type crystal of rosuvastatin calcium having a powder X-ray diffraction pattern.
2. The crystal according to claim 1, wherein the moisture content is 2.0 to 2.5%.
Rosuvastatin calcium was added to a mixture of water selected from an ester group, a ketone group, an ether group, an aliphatic hydrocarbon group, an aromatic hydrocarbon group, a halogenated hydrocarbon group, and a mixture thereof, and water. 2. The method for producing a crystal according to claim 1, wherein the solid is separated and dried, and then the humidity is adjusted.
The manufacturing method according to claim 3, wherein the humidity is adjusted under a humidity of 40% or more.