KR20100034465A - Manufacturing method for crystallized pravastatin sodium salt purifying impure non-crystallized pravastatin sodium salt - Google Patents

Abstract

PURPOSE: A manufacturing method of crystallized pravastatin sodium salt is provided to mass produce the crystallized pravastatin sodium salt using ethanol and acetone solvent. CONSTITUTION: A manufacturing method of crystallized pravastatin sodium salt comprises the following steps: dissolving impure non-crystallized pravastatin sodium salt in a mixture of purified water and low-class carbon alcohol with 1~4 carbon atoms; decolorizing the solution from the previous step using activated charcoal; filtering the decolorized solution with diatomite and crystallizing impurities by adding the filtered solution into acetone; putting the solution filtered with the crystallized impurities into the acetone again to crystallize the pure pravastatin sodium salt; and cooling the solution at 0~25 deg C to obtain the white crystallized pravastatin sodium salt.

Description

Manufacturing method for crystallized pravastatin sodium salt purifying impure non-crystallized pravastatin sodium salt

The present invention relates to pravastatin sodium salt useful as a pharmaceutical substance known in the chemical name as 1-naphthaleneheptanoic acid, mono sodium salt, and more particularly, to an impure amorphous pravastatin sodium salt. It relates to a method for preparing crystalline pravastatin sodium salt by purification.

Lovastatin, pravastatin, simvastatin, simvastatin, mevastatin, atrovastatin, fluvastatin, cervastatin, rosuvastatin and their Derivatives and analogs are known as HMG-CoA reductase inhibitors and are used as antihypercholestrolemic agents.

Many of these substances are found in Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus. It is obtained by fermentation process using various kinds of microorganisms belonging to it, and some substances such as simvastatin are obtained by treating fermentation products by chemical synthesis method, and some such as fluvastatin, atorvastatin, cervastatin, roschvastatin, etc. The material is obtained through chemical synthesis.

The conventionally known process for preparing pravastatin sodium salt is, for example, subjected to a lyophilization step, and after lyophilization, only the solvent is removed so that impurities remain together with the pravastatin sodium salt. In addition, the lyophilization method is very uneconomical in a large scale manufacturing process.

In the case of the preparation process by precipitation, which is one of the known processes, impurities are precipitated together with a target substance, namely pravastatin sodium salt, during precipitation due to the non-selectivity of the process.

Considering the processes for preparing a conventional solid pharmaceutical substance as described above, it can be said that crystallization, in which molecules of the target substance can be selectively incorporated into crystals, is the only selective process. In the crystallization process, it is very unlikely that impurities will be contained within the crystals, since only impurities with a smaller size than the target can be incorporated into the intramolecular space, and the combination of these other molecules of this substance with pravastatin crystals is thermodynamic. Because it is not a favorable process.

The advantage of the material of the crystalline structure over the material of the amorphous structure is that the physical parameters as well as the chemical variables are clearer and more stable. In particular, chemical and physical stability are intrinsically important for materials that are sensitive to various ambient environments, such as light, pH, barometric pressure, and temperature. Pravastatin sodium salts are particularly sensitive to these negative effects.

In the past, pravastatin sodium salt was known to exist only in amorphous form, and the 1996 Merck Index also describes pravastatin sodium salt as an amorphous material.

Although the preparation method of pravastatin sodium salt is known by many patent inventions, such as US Patent 44,537,859, US Patent 4,448,979, US Patent 4,410,629, US Patent 4,346,227, these patents provide only the preparation method of the amorphous pravastatin sodium salt. do. In known methods, a solid columnar sodium salt is obtained by separating a pravastatin sodium salt using a chromatographic column and freezing-drying the fraction containing pravastatin sodium salt.

In WO-A-98 / 45410, pravastatin sodium salt is purified by reverse-phase chromatography, and then obtained in crystalline form by precipitation in an ethanol / ethyl acetate mixture. It can be reported.

However, as a result of experiments conducted by the method provided by the present invention, it was found that only the pravastatin sodium salt in amorphous form was obtained by the combination of the above solvents.

In International Publication No. WO 2001/10813, methanol is used as a dissolving solvent in the examples. In the ICH Harmonized Tripartitude Guideline, methanol is classified as a very harmful solvent belonging to Class 2 with a concentration limit of 3,000 ppm. In addition, it can be seen that the purification and crystallization amount is 1 to 2 mg, which is not suitable for mass production, as shown in the Examples.

Therefore, the problem to be solved by the present invention is to solve the problems of the prior art, to provide a method for purifying the pravastatin sodium salt to improve in purity and stability compared to the prior art, in addition to the purification and not harmful of the present invention The present invention provides a method for preparing a crystalline form of pravastatin sodium salt using ethanol and acetone solvent to be suitable for mass production.

The present invention to achieve the above technical problem

(A) dissolving an impure amorphous pravastatin sodium salt in a mixed solution of lower carbon alcohol having 1 to 4 carbon atoms and purified water;

(B) decolorizing by adding activated carbon to the solution;

(C) filtering the decolored solution using diatomaceous earth and then adding the filtrate to acetone to crystallize impurities;

(D) filtering the crystallized impurities to re-add the removed solution to acetone to crystallize the pure pravastatin sodium salt; And

(E) cooling the solution of step (d) to 0-25 ° C. to provide a crystalline pravastatin sodium salt comprising the step of obtaining a white crystalline pravastatin sodium salt.

According to the present invention as described above can be prepared in the crystalline form of pravastatin sodium salt improved in purity and stability compared to the prior art, the method according to the invention is also very suitable for mass production, commercial production of crystalline pravastatin sodium salt is possible There is innovation done.

The present invention provides a crystalline form of pravastatin sodium salt. The crystal of pravastatin sodium salt according to the present invention has a unique crystal form, and when analyzed by X-ray diffraction analysis, diffractograms as shown in FIG. 2 can be obtained. . 2 is a result of analyzing the crystal obtained in Example 2 described later by X-ray diffraction analysis.

The present invention provides a process for preparing a crystalline pravastatin sodium salt, comprising the steps of: (a) dissolving an amorphous pravastatin sodium salt in low carbon alcohol and purified water; (b) decolorizing the mixed solution with activated carbon; (c) filtration with diatomaceous earth; (d) washing the diatomaceous earth used for filtration with ethanol; (e) removing the crystallized inorganic material by adding acetone to the filtration mixed solution; (f) re-adding acetone to the filtration mixed solution; (g) provides a preparation process consisting of cooling and crystallizing.

In addition, the present invention provides a pharmaceutical preparation containing the above-mentioned crystalline pravastin sodium salt, wherein the crystalline pravastatin sodium salt according to the present invention is particularly suitable for the preparation of a pharmaceutical product for the treatment of hypercholesterolemia and hyperlipidemia. .

Hereinafter, the present invention will be described in detail.

In this study, the inventors were surprisingly able to prepare pravastatin sodium salts with improved crystallinity compared to conventional solid pravastatin sodium salts through the selection of suitable solvents and the adoption of the proper order of use of the solvents. For example, while the pravastatin sodium salt known by WO-A-98 / 45410 has an amorphous white color, in the present invention, a white crystalline pravastatin sodium salt crystal can be obtained, which is a crystal of pravastatin sodium salt. This indicates that the sex is significantly improved.

Other physical properties of pravastatin sodium salts according to the invention also suggest an improvement in crystallinity. First, the crystals obtained by the present invention are generally in the form of radial clusters. Such crystalline forms can be easily observed through a microscope, and the results of the 200-fold magnification are shown in FIG. 4. On the other hand, the amorphous pravastatin sodium salt obtained by the conventional preparation process is in the form of granules as shown in FIG.

Second, the melting point of the crystalline pravastatin sodium salt according to the present invention is preferably 170 ° C to 174 ° C, more preferably 172 ° C to 174 ° C. This melting point range obtained in the present invention is very narrow compared to the complicated chemical structure of pravastatin sodium salt, which proves the high crystallinity of pravastatin sodium salt.

Third, a more prominent feature of the crystalline pravastatin sodium salt according to the present invention is that sharp and sharp peaks appear in the diffraction chart obtained as a result of X-ray diffraction analysis (Cu-Kα, 2θ). In particular, the shape of the X-ray diffraction peaks of the pravastatin sodium salt crystals according to the present invention is represented by a clear outline with a small half-value width formed, demonstrating the high crystallinity of the pravastatin sodium salt. Here, the half-sensitive layer means a value of a 2θ-range at a height of half of the maximum height of each peak. The diffractogram obtained as a result of the X-ray diffraction analysis has a clear peak having a half-depletion layer of preferably 2 ° or less, more preferably of less than 1 °, and most preferably of a half-depression layer of 0.5 ° or less. (2θ) will appear.

Fig. 2 shows a diffractogram as a result of X-ray diffraction analysis of the crystal of the preferred pravastatin sodium salt prepared according to the present invention (as formulated by Example 2). X-ray diffraction analysis (Cu-Kα, 2θ) of the crystals of pravastatin sodium salt showed that the crystallinity, purity, and stability of the crystals were remarkably improved when the results showed essentially similar results to the diffraction shown in FIG. As such, such crystalline pravastatin sodium salt constitutes a preferred embodiment of the present invention. In such a crystal, the unit lattice of the crystal cannot be defined because of the coexistence of low peaks and high foreign peaks in an area larger than 20 ° 2θ as a result of X-ray diffraction analysis. As a result of analyzing the diffraction chart obtained by the experiment, the crystal of pravastatin sodium salt according to the present invention is novel. For comparison, the diffractogram of the commercially available pravastatin sodium salt is shown in FIG. 1.

The process for preparing the crystal of pravastatin sodium salt according to the present invention consists of the following steps as described above.

(a) dissolving a sodium cation and pravastatin in a lower carbon alcohol, wherein it is suitable to dissolve a solid and / or amorphous pravastatin sodium salt in a lower carbon alcohol having 1 to 4 carbon atoms, preferably Preferably, it is dissolved using a mixed solvent of lower carbon alcohol and purified water having 1 to 4 carbon atoms. More preferably, even among lower aliphatic alcohols, a mixed solution of ethanol and purified water is used as a solvent, and in this case, best results are obtained.

When the lower carbon alcohol having 1 to 4 carbon atoms described above, preferably the lower carbon alcohol having 1 to 4 carbon atoms based on the weight ratio of ethanol and purified water, is 1 to 3 purified water.

(b) Activated carbon used as the step of decolorizing the mixed solution with activated carbon is more efficient in neutrality.

(c) Filtration with diatomaceous earth, which may aid in filtration by adding a little acetone to the mixed solution during filtration.

(d) removing foreign substances remaining in the diatomaceous earth using ethanol.

(e) adding the filtered mixed solution to acetone, preferably adding the mixed solution obtained in step (a) with continuous stirring, and adding the acetone to acetone slowly or continuously It is desirable to assist in the production of inorganic matter.

(f) The mixed solution is filtered to remove foreign substances, and the filtrate is re-added to purified acetone to crystallize.

(g) Crystallization by cooling the mixed solution / acetone mixture, crystals of pravastatin sodium salt are obtained from the cooled mixed solution, wherein the crystals are white in color and have a radial clustered form.

Finally, the crystals of the pravastatin sodium salt which passed the above process are filtered, washed with acetone and dried.

When the initial concentration of the pravastatin sodium salt dissolved in the mixed solvent is preferably 0.05 g / ml to 0.5 g / ml, more preferably 0.10 g / ml to 0.3 g / ml, especially about 0.2 g / ml Crystallization is easily performed.

The weight of the activated carbon added in the step (b) is 0.01 to 1.00 times the weight of the impure amorphous pravastatin sodium salt dissolved, the weight of the diatomaceous earth used for filtration in the step (c) is dissolved impure amorphous pravastatin sodium It is preferred that it is 0.2 to 2.00 times the salt weight.

In addition, the volume of ethanol used for washing in the step (d) is preferably 0.1 to 2.0 times the weight of the impure amorphous pravastatin sodium salt dissolved.

And the volume of acetone used in step (e) is preferably 5.0 to 50.0 times the weight of the impure amorphous pravastatin sodium salt in step (a), more preferably 40 times the initial weight. Crystallization takes place easily.

In order to further strengthen the crystallization it is required to carry out the following additional processes in addition to the above process according to the present invention.

(f) re-adding the mixture of step (e) to acetone, which must be done after a certain period of time to ensure sufficient time for crystals to form in the initial crystallization step.

In step (g) of recrystallizing the pravastatin sodium salt while cooling, the crystallization of pravastatin sodium salt can be obtained by 15 to 20% through the additional crystallization step.

The volume of acetone for re-adding the mixed solution filtered in step (f) is preferably 75% to 125% of the volume of acetone added in step (e), and more preferably 90% to 110%. Do. And when the total crystallization time is preferably 2 hours to 12 hours, more preferably 4 to 8 hours, particularly about 6 hours, crystals are well formed.

In addition, in order to obtain a higher crystallization rate, it is preferable to cool the mixed solution of ethanol and purified water to 0 to 25 ° C or lower, preferably a temperature of 15 ° C or lower, more preferably a temperature of 10 ° C or lower, particularly about 0 A temperature of ˜5 ° C. is required.

When the pravastatin sodium salt of the crystalline form obtained in Example 2 to be described later left at 100 ° C. for 24 hours, the stability was confirmed to be very high by HPLC, and the content was also 99.3% or more. The HPLC analysis results are shown in Figs. 5a to 5d.

Referring to FIGS. 5A to 5D, 30.2 mg of the standard and the obtained crystalline form of pravastatin sodium salt were respectively taken and measured by HPLC twice to obtain 12,018,850 and 12,305,119 contents of the standard and the obtained crystalline pravastatin sodium salt, respectively. Since the content of 95.21% of the calculated value of water correction by Karl Fisher 1.85% it can be seen that the content of 99.32% (Figs. 5a and 5b is a crystal of pravastatin sodium salt according to the present invention, Figs. 5c and 5d is a standard product) .

Hereinafter, the present invention will be described with reference to specific examples, but the scope of the present invention is not limited thereto.

<Example 1>

13.2 g of impure amorphous pravastatin sodium salt was dissolved in 10.6 g of ethanol and 19.8 g of purified water, and 21.1 g of acetone was added while stirring the solution. 1.32 g of neutral activated carbon was added thereto, stirred for 15 minutes, and filtered using diatomaceous earth. The filtered activated carbon was washed with 10.6 g of ethanol.

The filtered clear solution was added to 190 g of acetone and stirred for 10 minutes while maintaining 20 ℃. The undissolved impurities were gradually added to 208 g of acetone and then crystallized by stirring for 3 hours while maintaining 20 ° C. The crystal solution was stirred for 3 hours while maintaining 0-5 ° C.

After vacuum filtration, the crystals were washed with 56 g of acetone and dried under reduced pressure at 50 ° C. for 8 to 12 hours to obtain 11.0 g of white crystals having a melting point of 163 ° C. to 166 ° C.

<Example 2>

20 g of impure amorphous pravastatin sodium salt was dissolved in 20 g of purified water and 10 g of ethanol, and 10 g of ethanol was further added to dissolve completely. The solution was filtered using diatomaceous earth and the filtrate was poured into 632 g of acetone and stirred for 10 minutes while maintaining 20 ° C. 20 g of ethanol was further added and crystallized by stirring for 3 hours while maintaining 20 ℃.

The crystal solution was stirred for 2 hours while maintaining 0 ~ 5 ℃. After vacuum filtration, the crystals were washed with 40 g of acetone and dried under reduced pressure at 50 ° C. for 8 to 12 hours to obtain 17.4 g of white crystals having a melting point of 163 ° C. to 166 ° C.

<Example 3>

15 g of impure amorphous pravastatin sodium salt was dissolved in 10 g of ethanol and 20 g of purified water, and 20 g of acetone was added while stirring the solution. 1.35 g of neutral activated carbon was added thereto, stirred for 15 minutes, and filtered using diatomaceous earth. The filtered activated carbon was washed with 10 g of ethanol. The filtrate solution was poured into 200 g of acetone and stirred for 10 minutes while maintaining 20 ° C. The undissolved impurities are slowly added to 200 g of acetone and then crystallized by stirring for 3 hours while maintaining at 20 ° C. The crystal solution was stirred for 3 hours while maintaining 0-5 ° C. After vacuum filtration, the crystals were washed with 60 g of acetone and dried under reduced pressure at 50 ° C. for 8 to 12 hours to obtain 12.6 g of white crystals having a melting point of 163 ° C. to 166 ° C.

<Example 4>

20 g of impure amorphous pravastatin sodium salt was dissolved in 15 g of ethanol and 30 g of purified water, and 30 g of acetone was added while stirring the solution. 2 g of neutral activated carbon was added thereto, stirred for 15 minutes, and filtered using diatomaceous earth. The filtered activated carbon was washed with 15 g of ethanol. The filtrate solution was poured into 300 g of acetone and stirred for 20 minutes while maintaining 20 ° C. The undissolved impurities were filtered and then slowly added to 300 g of acetone and crystallized by stirring for 3 hours while maintaining 20 ° C.

The crystal solution was stirred for 3 hours while maintaining 0-5 ° C. After vacuum filtration, the crystals were washed with 80 g of acetone and dried under reduced pressure at 50 ° C. for 8 to 12 hours to obtain 16.1 g of white crystals having a melting point of 163 ° C. to 166 ° C.

Example 5

20 g of impure amorphous pravastatin sodium salt was dissolved in 20 g of purified water and 10 g of ethanol, and 10 g of ethanol was further added to dissolve completely. The solution was filtered, poured into 600 g of acetone, and stirred for 10 minutes while maintaining 20 ° C. 20 g of ethanol was further added and crystallized by stirring for 3 hours while maintaining 20 ℃.

The crystal solution was stirred for 3 hours while maintaining 0-5 ° C. After vacuum filtration, the crystals were washed with 40 g of acetone and dried under reduced pressure at 50 ° C. for 8 to 12 hours to obtain 16 g of white crystals having a melting point of 163 ° C. to 166 ° C.

Fig. 1 is a diffraction diagram of a conventional pravastatin sodium salt which is commercially available. The diffraction diagram has a spacing of 0.02 ° 2θ and is in a region of 5 ° to 35 ° 2θ under conditions of 1 second / step at the time of integration. It was obtained by scanning with an X-ray powder diffractometer.

FIG. 2 is a diffractogram of the pravastatin sodium salt crystals prepared according to Example 2 of the present invention, which has a spacing of 0.02 ° 2θ, and has a 5 ° to 35 ° 2θ area under an integrated condition of 1 second / step Obtained by scanning with an X-ray powder diffractometer.

FIG. 3 is an image of an amorphous form of pravastatin sodium salt showing the result of X-ray diffraction analysis of FIG. 1 through a microscope 200 times. FIG.

FIG. 4 is a 200 times magnified image of pravastatin sodium salt crystals prepared according to Example 2 of the present invention through a microscope. FIG.

5A to 5D are graphs of HPLC analysis results for the pravastatin sodium salt crystals prepared according to the standard and Example 2 of the present invention (FIGS. 5A and 5B are crystals of pravastatin sodium salt according to the present invention, and FIGS. 5C and 5D are standard products). ).

X-ray diffraction analysis performed in the process of obtaining the above drawings was carried out through an X-ray powder diffractometer (RIGAKU MINIFLEX) using a Cu-Kα (0.5kw, λ = 1.5418Å) light source, for microscopic observation A microscope equipped with a digital camera (C-5060) (OLYMPUS BX 41microscope) was used and observed at a magnification of 200 times.

Claims (11)

(A) dissolving an impure amorphous pravastatin sodium salt in a mixed solution of lower carbon alcohol having 1 to 4 carbon atoms and purified water; (B) decolorizing by adding activated carbon to the solution; (C) filtering the decolored solution using diatomaceous earth and then adding the filtrate to acetone to crystallize impurities; (D) filtering the crystallized impurities to re-add the removed solution to acetone to crystallize the pure pravastatin sodium salt; And (E) cooling the solution of step (d) to 0-25 ° C. to obtain a white crystalline pravastatin sodium salt. The lower carbon alcohol having 1 to 4 carbon atoms in the step (a) is ethanol, and the concentration at which the impure amorphous pravastatin sodium salt dissolved in the mixed solution is dissolved is 0.05 g / ml to 0.5. g / ml. A process for producing a crystalline form of pravastatin sodium salt. The method according to claim 1 or 2, wherein the weight of the activated carbon added in step (b) is 0.01 to 1.00 times the weight of the impure amorphous pravastatin sodium salt dissolved. The method for producing crystalline pravastatin sodium salt according to claim 1 or 2, wherein the weight of the diatomaceous earth used for filtration in step (c) is 0.2 to 2.00 times the weight of the impure amorphous pravastatin sodium salt dissolved. The method according to claim 1 or 2, further comprising the step of washing the diatomaceous earth used for filtration with ethanol, wherein the volume of ethanol used for the washing is 0.1 to 2.0 times the weight of the impure amorphous pravastatin sodium salt dissolved. A method for producing a crystalline form of pravastatin sodium salt, which is a pear. The method of claim 1 or 2, wherein the volume of acetone used for the crystallization of impurities in the step (c) is the production of crystalline pravastatin sodium salt, characterized in that 5.0 to 50.0 times the weight of the impure amorphous pravastatin sodium salt Way. 3. The crystalline form of claim 1 or 2, wherein the volume of acetone used for crystallization of pure pravastatin sodium salt in step (d) is 75 to 125% of the volume of acetone used in step (c). Method for the preparation of pravastatin sodium salt. The method for producing a crystalline form of pravastatin sodium salt according to claim 1 or 2, wherein the total crystallization time of step (d) is from 2 hours to 12 hours. The process for producing crystalline pravastatin sodium salt according to claim 1 or 2, wherein the cooling temperature in step (e) is 0 to 5 ° C. The method according to claim 1 or 2, further comprising the step of filtering the crystals obtained in the step (e) and washing the filtered crystals with acetone, wherein the volume of acetone used is dissolved impure amorphous pravastatin A method for producing a crystalline form of pravastatin sodium salt, characterized in that it is 2.0 to 20.0 times the weight of the sodium salt. The method for preparing pravastatin sodium salt according to claim 10, further comprising drying the washed crystals under reduced pressure at 35 to 70 ° C. for 8 to 24 hours.

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