KR101158517B1 - Process for preparing crystalline polymorphic form A of high purity Pitavastatin calcium salt - Google Patents

Abstract

The present invention relates to a method for producing crystalline Form A of pitavastatin calcium salt used as a therapeutic agent for hyperlipidemia having pharmacological action of inhibiting HMG-CoA reductase with high purity.

Description

Process for preparing crystalline polymorphic form A of high purity Pitavastatin calcium salt}

The present invention relates to a method for preparing pitavastatin calcium salt crystalline Form A with high purity, which is used as a therapeutic agent for hyperlipidemia having pharmacological action of inhibiting HMG-CoA reductase.

Pitavastatin is well known as a therapeutic agent for hyperlipidemia with pharmacological action that inhibits statin-based HMG-CoA reductase such as atorvastatin, rosuvastatin, etc. It is also built. The pitavastatin calcium salt may be represented by the following Chemical Formula 1, and its chemical name is (3R, 5S, E) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl]- 3,5-dihydroxyhept-6-enoate hemicalcium salt.

[Formula 1]

Synthesis of pitavastatin was first described in European Patent Publication No. 1096894, after which several et al., Tetrahedron Lett ., Vol 34 , 8267-8270; Bull. Chem. Soc. Jpn. , Vol 68 , 2649-2656. The above documents specify the method of preparing pitavastatin in detail, but there is no mention of the method of preparing pitavastatin calcium salt.

EP-A-0304063 discloses the synthesis of pitavastatin and the ammonium, sodium, potassium and hemicalcium salts of pitavastatin, and specific examples disclose the preparation of pitavastatin sodium salt in detail. That is, in the above-mentioned European Patent Publication No. 0304063, as shown in Scheme 1, pitavastatin ethyl ester was dissolved in ethanol and reacted by adding 0.5N aqueous sodium hydroxide solution, and then ethanol was removed by distillation under reduced pressure and water was added. The aqueous solution is lyophilized to produce pitavastatin sodium. However, the above-mentioned European Patent Publication No. 30406403 discloses no pitavastatin calcium salt or a preparation method thereof.

[Reaction Scheme 1]

A detailed method for preparing pitavastatin calcium salt is disclosed for the first time in European Patent Publication No. 0520406. In European Patent Publication No. 0520406, diastereomers having pharmacologically active phytavastatin racemates using an optical splitting agent of R-(+)-1-phenylethylamine, as shown in Scheme 2 below. The amine salt was produced and separated, and the optically separated pitavastatin R-(+)-1-phenylethylamine salt was reacted with 1N aqueous sodium hydroxide solution to prepare pitavastatin sodium salt. Substituted with Pitavastatin calcium salt is prepared.

Scheme 2

On the other hand, all compounds having crystals have a compound-specific crystal form, the crystal form may be a single crystal form or two or more polymorphic forms (polymorphic form). Among crystalline polymorphic compounds, especially in the case of crystalline polymorphic compounds, the physical properties such as solubility and melting point change with the change of moisture content, so that the stability and physiological activity of the substance change even if the compound has the same chemical formula. do. Therefore, it is required that the polymorphic compound used for medical use exists in crystal form with higher stability and physiological activity.

Pitavastatin calcium salt is also a polymorphic compound, which is known to exist in two or more crystal forms to date. Crystal forms of phytavastatin calcium salts were first disclosed in WO2004-072040, and disclose examples of crystalline and amorphous preparations of A, B, C, D, E, and F.

International Patent Publication No. WO2004-072040 discloses a solution obtained by suspending pitavastatin t-butyl ester in a mixed solution of methyl t-butyl ether and methanol (10: 3) and adding 4M aqueous sodium hydroxide solution to 2.5 at 50 ° C. After reacting for a time, the reaction mixture was cooled to room temperature, and water was added, followed by further stirring for 1 hour. Then, the aqueous layer was separated through layer separation, and a calcium chloride aqueous solution was slowly added dropwise to the aqueous layer over an hour, and the resulting suspension was stirred at room temperature for 16 hours, filtered, and dried under reduced pressure at 40 ° C. to obtain pitavastatin calcium salt. Form A was prepared. In addition, crystalline Form A of pitavastatin calcium salt is reacted by reacting phytavastatin sodium salt with calcium chloride in an aqueous reaction solution, or by reacting pitavastatin free base or a corresponding lactone with calcium hydroxide in an aqueous reaction solution. Prepared. Powder X-ray diffraction patterns of pitavastatin calcium salt crystalline Form A disclosed in WO2004-072040 are shown in Table 1 below.

X-ray Diffraction Patterns of Form A Diffraction Angle (2θ) (°) d-grid spacing (Å) Relative strength 5.0 17.6 s 6.8 13.0 s 9.1 9.7 s 10.0 8.8 w 10.5 8.4 m 11.0 8.1 m 13.3 6.7 vw 13.7 6.5 s 14.0 6.3 w 14.7 6.0 w 15.9 5.57 vw 16.9 5.25 w 17.1 5.17 vw 18.4 4.82 m 19.1 4.64 w 20.8 4.27 vs 21.1 4.20 m 21.6 4.10 m 22.9 3.87 m 23.7 3.74 m 24.2 3.67 s 25.2 3.53 w 27.1 3.29 m 29.6 3.02 vw 30.2 2.95 w 34.0 2.63 w

In International Patent Publication No. WO2004-072040, other crystal forms B, C, D, E, and F, except for pitavastatin calcium salt crystalline form A, are first prepared with phytavastatin calcium salt crystalline form A, and then a single solvent or mixed Each crystal form was prepared by suspending or dissolving in a solvent followed by crystallization.

In addition, International Patent Publication No. WO2005-63711 discloses pitavastatin calcium salt crystalline form A and a preparation method thereof. International Patent Publication No. WO2005-63711 indicates that the optimum water content to maintain a stable state through the stability test of the drug according to the water content is 5 to 15%, the crystalline form of pitavastatin calcium salt having an optimum water content It was confirmed that it is Form A. In addition, X-ray powder diffraction analysis of pitavastatin calcium salt crystalline Form A confirmed that the characteristic peak exceeding 25% of the relative intensity at a diffraction angle of 30.16 °. In addition, the pitavastatin calcium salts showed different X-ray diffraction patterns when the water content was in the range of 5 to 15% and the water content was 3.76%, thereby changing the crystal phase according to the change of the water content. .

WO 2005-63711 discloses a process for preparing crystalline Form A by adding calcium compounds to pitavastatin alkali metal salts dissolved in C ₁ to C ₄ alcohols containing at least 60% water. Specifically, the method of preparing pitavastatin calcium salt crystalline form A is as in Scheme 3 below.

Scheme 3

According to Scheme 3, pitavastatin ethyl ester was added to ethanol to dissolve, cooled after adding water, and hydrolyzed for 3 hours by adding 2M aqueous sodium hydroxide solution to prepare pitavastatin sodium salt. The reaction mixture was concentrated under reduced pressure to remove a certain amount of ethanol and water, and then the temperature was set at 10 to 20 ° C., and then the calcium chloride aqueous solution was slowly added dropwise over 2 hours, after which the precipitated crystals were filtered and filtered with water. After washing, the product was dried with caution under reduced pressure and at a temperature of 40 ° C. until the water content reached 10%, thereby preparing pitavastatin calcium salt crystalline Form A. Powder X-ray diffraction patterns of pitavastatin calcium salt crystalline Form A disclosed in WO2005-63711 are shown in Table 2 below.

X-ray Diffraction Patterns of Form A Diffraction Angle (2θ) (°) d-grid spacing (Å) Relative strength
(> 25%) 4.96 17.7999 35.9 6.72 13.1423 55.1 9.08 9.7314 33.3 10.40 8.4991 34.8 10.88 8.1248 27.3 13.20 6.7020 27.8 13.60 6.5053 48.8 13.96 6.3387 60.0 18.32 4.8386 56.7 20.68 4.2915 100.0 21.52 4.1259 57.4 23.64 3.7604 41.3 24.12 3.6866 45.0 27.00 3.2996 28.5 30.16 2.9607 30.6

As described above, pitavastatin calcium salt has a variety of crystals as a polymorphic compound, it is confirmed that Form A is a crystal form with excellent stability and high biological activity. However, the phytavastatin calcium salt has a slow crystallization rate due to the nature of the compound, and thus, the crystallization process should be performed for a long time of 12 hours or more. In addition, phytavastatin calcium salt crystalline form A used for pharmaceutical use requires high purity and high stability, but since the crystal form is easily changed by the change of water content in the crystal, it is possible to improve the drying process to maintain the optimum water content. Required.

The present invention provides a method for preparing high purity pitavastatin calcium salt crystalline form A by performing a recrystallization method using a low purity pitavastatin calcium salt (hereinafter referred to as crude pitavastatin calcium salt) using a solvent. It aims to provide.

In the present invention, crystals are prepared by mixing crude pitavastatin calcium salt in a polar aprotic organic solvent consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide or a mixture thereof and water. It is characterized by the manufacturing method of the phytavastatin calcium salt crystalline form A produced | generated.

The present invention achieves the effect of selectively and in high yield of only pitavastatin calcium salt crystalline Form A by a short crystallization process of 6 hours or less by selecting and using a specific polar aprotic organic solvent.

In the present invention, since the specific polar aprotic organic solvent selected for use in the crystallization process has excellent solubility in impurities contained in the crude pitavastatin calcium salt, the effect of efficiently removing impurities is obtained.

The present invention obtains the effect of maintaining the water content of the crystalline Form A in the range of 10 to 13% by weight by controlling the temperature and humidity in the drying process of the pitavastatin calcium salt crystalline Form A to the optimum range.

1 is a powder X-ray diffraction pattern for pitavastatin calcium salt prepared by the preparation method of Example 1 of the present invention.
Figure 2 is a result of analyzing the pitavastatin calcium salt crystalline Form A prepared by the preparation method of Example 1 of the present invention by HPLC.

The present invention relates to a method of crystallizing crude pitavastatin calcium salt to produce crystalline form A of high purity pitavastatin calcium salt.

In the present invention, a polar aprotic organic solvent composed of dimethylformamide, dimethylacetamide, dimethyl sulfoxide or a mixture thereof and water are used as the crystallization solvent.

More specifically, in a solution in which a crude pitavastatin calcium salt is dissolved in a polar aprotic organic solvent consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide or a mixture thereof, water is added dropwise and mixed to determine it. Pitavastatin calcium salt crystalline Form A can be manufactured by the recrystallization method which produces | generates.

Pitavastatin calcium salt prepared by the production method of the present invention is a powder X-ray diffraction pattern is shown in Table 3 below.

X-ray Diffraction Patterns of Form A Diffraction Angle (2θ) (°) d-grid spacing (Å) Relative strength 6.73 13.12 59.32 9.13 9.67 27.90 10.23 8.47 31.73 10.93 8.09 24.45 13.23 6.68 20.99 13.68 6.46 47.94 14.02 6.31 52.85 14.63 6.05 8.01 15.86 5.58 13.90 16.93 5.23 6.18 18.41 4.81 41.45 19.07 4.65 16.40 20.72 4.28 100.00 21.09 4.21 80.27 21.62 4.10 45.36 22.89 3.88 17.82 23.72 3.75 34.20 24.15 3.68 41.20 25.17 3.53 14.68 26.98 3.30 21.32 28.38 3.14 9.67 30.26 2.95 22.21 31.48 2.84 4.87 33.96 2.63 7.00 35.77 2.50 2.88 37.99 2.36 2.54

According to the results of Table 3, the pitavastatin calcium salt prepared by the method of the present invention has a relative intensity of less than 25%, preferably 21% to 25% at an X-ray diffraction angle (2θ) of 30.26 °. Has a% range.

In addition, recrystallization in which the crude pitavastatin calcium salt is dissolved in a polar aprotic organic solvent consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide or a mixture thereof is added dropwise and mixed with water to form a crystal. Pitavastatin calcium salt crystalline form A can be manufactured by the method.

That is, in the crystallization method according to the present invention, the crude pitavastatin calcium salt is dissolved in a polar aprotic organic solvent, specifically dimethylformamide, dimethylacetamide, dimethyl sulfoxide or a mixture thereof. As a polar aprotic organic solvent, dimethylformamide alone is used, or a mixed solvent containing dimethylacetamide or dimethylsulfoxide in the range of 1: 0.5 to 1.5 by volume in dimethylformamide.

The temperature of the organic solvent used for the crystallization of the present invention may be heated to room temperature (18 ° C) or 50 ° C to completely dissolve the crude pitavastatin calcium salt. The solution is then added dropwise to water or water is added dropwise to the solution to form crystals.

The polar aprotic organic solvent used for the crystallization of the present invention is used in the range of 2 to 10 times (v / w), preferably 3 to 5 times (v / w) to the crude pitavastatin calcium salt. do. When the amount of the polar aprotic organic solvent is used less than the above range, the impurities contained in the crude pitavastatin calcium salt may not be removed efficiently, and the yield of Form A may be lowered. When used in excess, the amount of crystals produced can be significantly reduced.

The water used for the crystallization of the present invention is used in the range of 6 to 12 times (v / v), preferably 6 to 8 times (v / v) of the polar aprotic organic solvent. When the amount of water used is less than the above range, the amount of crystals produced may be low, and when used in excess of the above range, the purity of Form A may be lowered.

The solvent recrystallization process as described above can be obtained in about 2 to 6 hours, preferably 3 to 4 hours, including the crystal aging time to obtain pitavastatin calcium salt crystalline Form A in high purity and high yield.

Crystals produced through the recrystallization process is obtained by filtration through the reaction mixture, and then dried for 24 to 72 hours at a temperature of 15 ℃ to 20 ℃ and 35% to 55% humidity. At this time, if the drying temperature is less than 15 ℃ drying time is required for a long time, if it exceeds 20 ℃ because the deformation of the crystalline form and a large amount of flexible material is generated, keep the drying temperature in the above range. In addition, if the dry humidity is less than 35%, the moisture content during drying may not meet the criteria and may cause a change in crystal form. If the dry humidity exceeds 55%, a drying time is required more, and a flexible material may be generated as the drying time increases. Therefore, to keep the dry humidity in the above range.

According to the recrystallization method of the present invention as described above, the purity measured by HPLC is 99.5% or more to maintain a sufficient degree of purity to be applied to pharmaceuticals, the water content measured by Karl-Fischer method 10 to 13 weight% of pitavastatin calcium salt crystalline form A can be obtained.

In addition, the crystallization solvent proposed in the conventional method for preparing pitavastatin calcium salt crystals has low solubility in impurities such as epimers and lactone bodies generated during the synthesis of pitavastatin calcium salts. The purity of the crystals produced by recrystallization was relatively low. However, when the present invention uses a combination of a specific polar aprotic organic solvent and water, crystalline A was produced in high purity and high yield. In other words, the polar aprotic organic solvent selected by the present invention as a recrystallization solvent has excellent solubility in impurities generated during the synthesis of pitavastatin calcium salt and can be easily removed. The toner content can be lowered to less than 0.06%.

In addition, although the crystallization time of the phytavastatin calcium salt known from International Patent Publication No. WO2005-63711 is required for a long time of 12 hours or more, in the case of the present invention, the crystallization time is greatly reduced to 6 hours, thereby maximizing process efficiency.

Therefore, the recrystallization method characterized by the present invention can be expected to reduce the cost and improve the productivity, there is much advantage in the commercial production of high purity pitavastatin calcium salt crystalline form A.

The present invention as described above will be described in more detail based on the following examples and the like, but the present invention is not limited by these examples and the like.

[Manufacturing Example]

Preparation Examples 1 and 2 below merely exemplify typical synthesis examples of the crude pitavastatin calcium salt. The crude pitavastatin calcium salt used in the recrystallization of the present invention may be used as long as it is a crude pitavastatin calcium salt prepared by a conventional method in the art, in addition to the methods of Preparation Examples 1 and 2.

Preparation Example 1 Preparation of Crude Pitavastatin Calcium Salts

(E) -3 (R) -5 (S) -dihydroxy-7- [4 ′-(4 ″ -fluorophenyl) -2′-cyclopropylquinolin-3′-yl] hept-6-ene To 12 g of acid D (+)-phenylethylamine salt, 24.3 ml of 1N aqueous sodium hydroxide solution and 200 ml of purified water were added and dissolved. A calcium chloride aqueous solution prepared with 1.47 g of calcium chloride and 200 ml of purified water was slowly added dropwise to the reaction solution, followed by stirring for at least 12 hours to precipitate crystals. Precipitated crystals were filtered and dried to obtain 9.0 g of crude pitavastatin calcium salt (containing 97.4% purity and 0.37% epimer).

Preparation Example 2 Preparation of Crude Pitavastatin Calcium Salt

5.22 g of phytavastatin sodium was added to a mixture of 75 ml of water and 15 ml of ethanol, and dissolved in a nitrogen stream at room temperature. Then, 12 ml of 1M calcium acetate solution was added dropwise for 20 minutes, stirred for 3 hours, filtered, and dried. 4.5 g of salt (purity 98.3%, containing 0.34% epimer) were obtained.

[Example]

In the following Examples and Comparative Examples as an example of preparing the pitavastatin calcium salt crystalline form A by recrystallization and drying the crude pitavastatin calcium salt, the scope of the present invention is limited by the Examples specifically illustrated below It doesn't happen.

Example 1 Preparation of Pitavastatin Calcium Salt Crystalline Form A

To 1.0 g of crude pitavastatin calcium salt (purity 97.2%, containing 0.34% epimer), 5.0 ml of dimethylformamide was added, dissolved, and stirred for 30 minutes. This solution was slowly added dropwise over 30 minutes with stirring to 30 ml of purified water. After stirring for 4 hours while maintaining the temperature at 20 ℃, the resulting crystals were cooled to 0 ℃ to 5 ℃, filtered and washed three times with cold purified water, then dried at 20 ℃ and 40% humidity conditions pita Vastatin calcium salt crystalline Form A was prepared.

Powder X-ray diffraction analysis of the crystals of pitavastatin calcium salt prepared by the method of Example 1 is shown in FIG. According to the X-ray diffraction analysis results of FIG. 1, it was confirmed that the pattern was the same as the X-ray diffraction analysis pattern for Form A shown in WO2004-072040.

Examples 2-9 and Comparative Examples 1-15.

Pitavastatin calcium salt crystalline Form A was prepared by performing a recrystallization and drying process in the same manner as in Example 1 except for using different solvents for the recrystallization process.

The yield, purity, epimer content and water content of the pitavastatin calcium salt crystalline form A prepared in Examples 1 to 9 and Comparative Examples 1 to 15 were measured and shown in Table 4 below.

The water content of Form A was measured by Karl-Fischer method, and the purity of Form A and the content of epimer were determined by HPLC analysis.

[HPLC Analysis Conditions]

Detector: UV absorbance photometer (wavelength: 245nm)

Column: 5 μm octadecylsilylated silica gel column with inner diameter of 4.6 mm and length 25 cm

Temperature: Constant temperature around 40 ℃

Mobile phase: A; 0.01 mol / L acetic acid sodium acetate buffer (pH 3.8)

         B; Acetonitrile

Mobile phase condition:

Flow rate: It adjusts so that retention time of pitavastatin calcium salt may be 23 minutes in the range of 0.5-1.0 ml / min.

division Recrystallization solvent (ml) yield
(%) water
(%) Epimer
(%) moisture
(%) Example 1 DMF (5) Purified Water (30) 96 99.9 0.03 11.6 Example 2 DMAc (5) Purified Water (30) 87 99.8 0.04 11.2 Example 3 DMSO (5) Purified Water (30) 86 99.6 0.04 11.8 Example 4 DMF (3) + DMSO (2) Purified Water (30) 93 99.8 0.03 11.1 Example 5 DMF (2) + DMSO (3) Purified Water (30) 92 99.7 0.04 11.6 Example 6 DMF (3) + DMAc (2) Purified Water (30) 93 99.9 0.03 11.2 Example 7 DMF (2) + DMAc (3) Purified Water (30) 91 99.6 0.03 11.6 Example 8 DMAc (3) + DMSO (2) Purified Water (30) 84 99.5 0.04 11.5 Example 9 DMAc (2) + DMSO (3) Purified Water (30) 81 99.6 0.04 11.3 Comparative Example 1 MeOH (5) Purified Water (30) 89 99.4 0.21 12.8 Comparative Example 2 EtOH (5) Purified Water (30) 96 99.2 0.19 11.7 Comparative Example 3 IPA (5) Purified Water (30) 98 98.7 0.23 10.8 Comparative Example 4 MTBE (5) Purified Water (30) 97 98.8 0.24 11.7 Comparative Example 5 IPE (5) Purified Water (30) 97 98.4 0.31 10.6 Comparative Example 6 MTBE (4) + MeOH (1) Purified Water (30) 93 98.8 0.23 11.5 Comparative Example 7 MC (5) Purified Water (30) 98 99.1 0.18 10.2 Comparative Example 8 CHCl ₃ (5) Purified Water (30) 95 99.3 0.20 9.8 Comparative Example 9 DCE (5) Purified Water (30) 98 99.2 0.21 10.6 Comparative Example 10 THF (5) Purified Water (30) 97 99.4 0.19 7.3 Comparative Example 11 Acetone (5) Purified Water (30) 92 99.1 0.23 7.2 Comparative Example 12 MEK (5) Purified Water (30) 98 98.3 0.26 11.7 Comparative Example 13 MIBK (5) Purified Water (30) 98 98.2 0.29 10.3 Comparative Example 14 EtOAc (5) Purified Water (30) 97 98.4 0.27 10.6 Comparative Example 15 Purified water (5) Purified Water (30) 99 97.8 0.33 14.3 DMF: Dimethylformamide DMAc: Dimethylacetamide DMSO: Dimethylsulfoxide
MeOH: Methanol EtOH: Ethanol IPA: Isopropyl alcohol,
MTBE: methyl t-butyl ether IPE: isopropyl ether,
MC: methylene chloride DCE: dichloroethane, THF: tetrahydrofuran
MEK: methyl ethyl ketone MIBK: methyl isobutyl ketone EtOAc: ethyl acetate

According to the results of Table 4, the polar aprotic organic solvent and water consisting of dimethylformamide (DMF), dimethylacetamide (DMAC), dimethylsulfoxide (DMSO) or a mixture thereof, as characterized by the present invention. Examples 1 to 9, which are performing recrystallization using (purified water), have a purity of 99.5% or more in phytavastatin calcium salt crystalline form A, which is inferior to use in medicine, and has an epimer content of less than 0.04%. It was very low and it was also found that the water content in the crystals was in the range of 10 to 13% by weight.

In contrast, most of the organic solvents used through Comparative Examples 1 to 15, for example, methanol, ethanol, isopropyl alcohol, isopropyl ether, methyl t-butyl ether, methylene chloride, chloroform, dichloroethane and the like are mostly pitavastatin. The low solubility in calcium salts made it difficult to dissolve completely, and the mixed solution was further heated for complete dissolution. As a result, pitavastatin calcium salt crystalline Form A obtained by recrystallization showed little improvement in purity, and the level of epimer content in crystalline Form A was particularly high. Therefore, in order to use the crystalline form A obtained from the comparative example as a medicine, the problem of having to perform several purification processes further was raised.

Reference Example

This reference example is for confirming that phytavastatin calcium salt crystalline form A is easily changed according to drying conditions (particularly, drying temperature and drying humidity conditions).

To this end, the pitavastatin calcium salt crystals prepared by performing the recrystallization process was dried under the conditions of Table 5, and the content change confirmed through HPLC analysis for each dry matter is shown in Table 5 below.

Drying condition Metric Drying period Wet body 1 day 3 days 5 days 15th Condition 1 Temperature 20 ℃
Humidity 40% Moisture content (%) 32.0 12.38 11.88 11.66 11.82 Analog content (%) 0.012 0.013 0.017 0.021 0.022 Crystalline Purity (%) 99.94 99.92 99.89 99.84 99.81 Condition 2 Temperature 20 ℃
Humidity 50% Moisture content (%) 32.0 12.46 12.17 11.76 11.64 Analog content (%) 0.012 0.014 0.016 0.026 0.031 Crystalline Purity (%) 99.94 99.93 99.86 99.83 99.79 Condition 3 Temperature 40 ℃
Humidity 40% Moisture content (%) 32.0 6.21 5.57 4.43 3.84 Analog content (%) 0.012 0.034 0.066 0.089 0.201 Crystalline Purity (%) 99.94 99.74 99.52 99.23 97.25 Condition 4 Temperature 40 ℃
Humidity 50% Moisture content (%) 32.0 6.32 6.16 5.26 4.99 Analog content (%) 0.012 0.086 0.116 0.136 0.257 Crystalline Purity (%) 99.94 99.62 98.87 98.77 97.16

According to the results of Table 5, as the drying time elapsed, the water content in the crystal was significantly reduced, and the change in analog content was different according to the drying temperature and humidity conditions. For example, under the condition that the drying temperature is 20 ° C and the humidity is maintained at 40% or 50%, the change in the amount of the generated analogues is insignificant for each drying period, and the purity of the crystalline form is still maintained even after a long time of 15 days. Could confirm. In contrast, when the drying temperature was maintained at 40 ° C. (conditions 3 and 4), the water content was lowered to less than 7% in one day, and the production of analogs (epimers or lactone bodies) increased significantly. After 15 days, the crystalline purity was less than 97.5%, so it could not be used as a medicine.

As described above, the pitavastatin calcium salt crystal prepared by the method of the present invention can be prepared in Form A having a stable water content, it was confirmed that the purity and yield is very high. In addition, the recrystallization time is also greatly reduced to less than 6 hours is expected to increase the overall process efficiency.

Therefore, the present invention can be expected to improve the productivity and cost reduction effect, it is useful as a commercial production method of phytavastatin calcium salt crystalline form A of high purity.

Claims (11)

Crystalline was formed by dropwise addition of water to a solution of crude pitavastatin calcium salt dissolved in a polar aprotic organic solvent consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide or a mixture thereof.
The reaction mixture in which the crystals were formed was aged for 2 to 6 hours while the crystals were aged, cooled to 0 ° C to 5 ° C, and then filtered to obtain crystals.
Obtained crystals of pitavastatin calcium salt crystalline Form A having an X-ray powder diffraction pattern of Table 6, characterized in that the drying is 24 to 72 hours at a temperature of 15 ℃ to 20 ℃ and a humidity of 35% to 55% Manufacturing method. X-ray Diffraction Patterns of Form A Diffraction Angle (2θ) (°) d-grid spacing (Å) Relative strength 6.73 13.12 59.32 9.13 9.67 27.90 10.23 8.47 31.73 10.93 8.09 24.45 13.23 6.68 20.99 13.68 6.46 47.94 14.02 6.31 52.85 14.63 6.05 8.01 15.86 5.58 13.90 16.93 5.23 6.18 18.41 4.81 41.45 19.07 4.65 16.40 20.72 4.28 100.00 21.09 4.21 80.27 21.62 4.10 45.36 22.89 3.88 17.82 23.72 3.75 34.20 24.15 3.68 41.20 25.17 3.53 14.68 26.98 3.30 21.32 28.38 3.14 9.67 30.26 2.95 22.21 31.48 2.84 4.87 33.96 2.63 7.00 35.77 2.50 2.88 37.99 2.36 2.54
The method according to claim 1,
A method for producing pitavastatin calcium salt crystalline Form A, wherein the polar aprotic organic solvent is dimethylformamide.
The method according to claim 1,
The polar aprotic organic solvent is a mixed solvent of dimethylformamide and dimethylacetamide or dimethylsulfoxide.
The method according to any one of claims 1 to 3,
The polar aprotic organic solvent is a method for producing pitavastatin calcium salt crystalline Form A, characterized in that used in the range of 2 to 10 times (v / w) relative to crude pitavastatin calcium salt.
The method of claim 4,
The polar aprotic organic solvent is used in the preparation of pitavastatin calcium salt crystalline Form A, characterized in that used in 3 to 5 times (v / w) relative to the crude pitavastatin calcium salt (crude pitavastatin calcium salt).
The method according to claim 1,
The water is a method for producing pitavastatin calcium salt crystalline Form A, characterized in that used in 6 to 12 times (v / v) range with respect to the polar aprotic organic solvent.
The method of claim 6,
The water is a method for producing pitavastatin calcium salt crystalline Form A, characterized in that used in 6 to 8 times (v / v) range with respect to the polar aprotic organic solvent.
delete The method according to claim 1,
Method for producing pitavastatin calcium salt crystalline form A, characterized in that the crystals are aged while stirring the reaction mixture is produced for 3 to 4 hours.
delete The method according to claim 1,
The dried crystals have a purity of 99.5% or more and a water content of 10 to 13% by weight of the method of producing pitavastatin calcium salt crystalline Form A.

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