CN108976168B - Pitavastatin semi-calcium salt crystal form and preparation method thereof - Google Patents
Pitavastatin semi-calcium salt crystal form and preparation method thereof Download PDFInfo
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- CN108976168B CN108976168B CN201710406204.9A CN201710406204A CN108976168B CN 108976168 B CN108976168 B CN 108976168B CN 201710406204 A CN201710406204 A CN 201710406204A CN 108976168 B CN108976168 B CN 108976168B
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention provides a pitavastatin hemicalcium salt crystal form, named as crystal form I, which at least comprises the following characteristic peaks in an X-ray powder diffraction pattern measured by Cu-Kalpha ray: diffraction angle 2 theta values of 4.56 +/-0.1 degrees, 5.10 +/-0.1 degrees, 6.74 +/-0.1 degrees, 6.94 +/-0.1 degrees, 9.12 +/-0.1 degrees, 10.32 +/-0.1 degrees, 11.32 +/-0.1 degrees, 13.72 +/-0.1 degrees and 21.24 +/-0.1 degrees; the water content of the crystal form is 2-5%. The invention also provides a preparation method of the pitavastatin semi-calcium salt crystal form, which is simple and convenient, high in yield, good in reproducibility, high in purity of the obtained crystal form, good in stability and suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a crystal form of a pharmaceutical compound, and especially relates to a novel crystal form of pitavastatin hemicalcium salt and a preparation method thereof.
Background
Pitavastatin hemicalcium salt is chemically [ (3R, 5S, 6E) -7- (2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl) -3, 5-dihydroxy-6-heptenoic acid ] hemicalcium salt, and the structural formula is shown as the following formula:
pitavastatin hemicalcium salt the first fully synthesized selective, competitive 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitor developed by japan chemical company and xing and co, registered in japan 11 months in 1999, and first approved in japan for marketing on 7-17 days in 2003, is the most potent lipid lowering drug so far.
Patent WO 2004/072040 provides for the presence of polymorphism of pitavastatin hemicalcium salt and discloses pitavastatin hemicalcium salt crystalline forms: A. b, C, D, E, F and amorphous. Patent CN 102321019 a reports that pitavastatin hemicalcium salt crystal form a has a water content of 5-15%, and in its X-ray powder diffraction spectrum measured using CuK α ray, there is a peak with a relative intensity of more than 25% at a diffraction angle (2 θ) of 30.16 °. Patent US9034901B2 discloses a pitavastatin hemicalcium salt crystal form, which is prepared by preparing pitavastatin hemicalcium salt with water content of 8-12% and drying under reduced pressure to make the water content of the pitavastatin hemicalcium salt less than 5%, so that the amorphous content of the pitavastatin hemicalcium salt crystal form is far greater than that of the crystalline form. CN 101195603A discloses a new crystal form of pitavastatin hemicalcium salt and a preparation method thereof, wherein the water content of the new crystal form is 0.5-3%. The pitavastatin hemicalcium salt disclosed in WO 2012/063254Al is in the crystalline form H1.
It is generally reported that pitavastatin hemicalcium salt is generally prepared by adding calcium chloride aqueous solution to pitavastatin carboxylic acid sodium salt aqueous solution to form pitavastatin hemicalcium salt precipitate, and separating and purifying to obtain the product. However, because the solubility of pitavastatin hemicalcium salt in water solution is extremely low, precipitation is generated immediately after reaction, so that the generated product has fine particles, is easy to agglomerate and carry impurities. For this reason, patent CN 102653523 a discloses an improvement of the purity of pitavastatin hemicalcium salt by recrystallization in tetrahydrofuran-water solvent system, however, the HPLC purity of the product obtained by this method is only about 98%.
In view of the pharmaceutical value of the pitavastatin hemicalcium salt, the method has important significance for obtaining different crystal forms of the pitavastatin hemicalcium salt with high purity, simple preparation and good reproducibility.
Disclosure of Invention
The invention aims to overcome the defects and provide a novel pitavastatin hemicalcium salt crystal form which has good stability, high purity and good reproducibility and is suitable for industrial production and a preparation method thereof.
In the study of the pitavastatin hemicalcium salt crystallization process, the inventor surprisingly discovers a novel pitavastatin hemicalcium salt crystal form, and the preparation method is simple, high in purity and good in stability, and is suitable for further research and development. The new crystal form has good reproducibility, good stability and high purity. Compared with the prior art, the method has the advantages that the purity is greatly improved.
The invention provides a novel pitavastatin hemicalcium salt crystal form which is named as a crystal form I;
which comprises at least the following characteristic peaks in an X-ray powder diffraction pattern measured by using Cu-Kalpha rays: diffraction angle 2 theta values were 4.56 + -0.1 deg., 5.10 + -0.1 deg., 6.74 + -0.1 deg., 6.94 + -0.1 deg., 9.12 + -0.1 deg., 10.32 + -0.1 deg., 11.32 + -0.1 deg., 13.72 + -0.1 deg., and 21.24 + -0.1 deg..
Preferably, said novel crystalline form of pitavastatin hemicalcium salt comprises at least the following characteristic peaks in an X-ray powder diffraction pattern measured using Cu-ka radiation: the values of 2 theta angle and relative intensity are shown in table 1 below:
TABLE 1
The X-ray powder diffraction pattern (or characteristic peak) of the novel pitavastatin hemicalcium salt crystal form is obviously different from the existing known crystal form. For example, the novel crystal form of the invention has characteristic peaks at 4.56 °, 6.74 ° and 6.94 °, but the existing pitavastatin hemicalcium salt crystal form A does not have the 3 characteristic peaks. The characteristic peaks of 6.2 degrees and 7.7 degrees do not exist in the novel crystal form, but exist in the existing pitavastatin hemicalcium salt crystal form B. The novel pitavastatin hemicalcium salt crystal form of the invention does not have characteristic peaks of 9.6 degrees and 13.0 degrees, while the existing pitavastatin hemicalcium salt crystal form F has 2 characteristic peaks. The pitavastatin hemicalcium salt new crystal form of the invention does not have characteristic peaks of 4.3 degrees, 8.6 degrees and 13.1 degrees, while the pitavastatin hemicalcium salt crystal form disclosed in the patent CN 101195603A has the 3 characteristic peaks, and the water content of the crystal form is 0.5% -3%. The novel pitavastatin hemicalcium salt crystal form of the present invention does not have a characteristic peak of 19.6 degrees, but the crystal form disclosed in US9034901B2 has a characteristic peak of 19.6 degrees, and the characteristic peak is the second strong peak of the crystal form; in addition, the relative intensity of the characteristic peak of the crystal form disclosed in US9034901B2 is obviously different from that of the crystal form of the invention, and the peak emergence position difference of the main strong peak is obvious.
Thus, in a particular embodiment of the invention, said novel crystalline form of pitavastatin hemicalcium salt has no characteristic peaks in the X-ray powder diffraction pattern as determined using Cu-ka radiation at least at the following diffraction angles 2 θ of 4.3 ± 0.1 °, 6.2 ± 0.1 °, 7.7 ± 0.1 °, 8.6 ± 0.1 °, 9.6 ± 0.1 °, 13.0 ± 0.1 °, 13.1 ± 0.1 ° and 19.6 ± 0.1 °.
Particularly preferably, the novel pitavastatin hemicalcium salt crystal form has an X-ray powder diffraction pattern as shown in figure 1.
Further, the novel crystal form of pitavastatin hemicalcium salt can be characterized by thermal analysis. A typical DSC diagram of said new form of pitavastatin hemicalcium salt is shown in figure 3. It is characterized by comprising an endothermic peak (peak top value about 55 ℃) at 30-100 ℃ and a melting endothermic peak (peak top value about 200 ℃) at 180-210 ℃; errors in DSC measurements are also taken into account, as is common in the art, and measurement of the peak top values is usually allowed to have an error of ± 1 ℃. Based on TGA tests of batches of the novel pitavastatin hemicalcium salt crystal form, the novel pitavastatin hemicalcium salt crystal form is determined to have about 2-5% of thermal weight loss in the temperature rising process from room temperature to 150 ℃, which indicates that the water content of the pitavastatin hemicalcium salt crystal form is about 2-5%. A typical TGA diagram of the new crystalline form of pitavastatin hemicalcium salt is shown in fig. 2, which has a 4.4% thermal weight loss during the temperature increase from room temperature to 150 ℃.
Further, the novel pitavastatin hemicalcium salt crystal form has the structure including 798 +/-2 cm-1、919±2cm-1、1028±2cm-1、1137±2cm-1、1193±2cm-1、1376±2cm-1、1412±2cm-1、1449±2cm-1、1564±2cm-1、1611±2cm-1、1658±2cm-1、3011±2cm-1、3068±2cm-1(ii) a Raman spectrum of the peak of the wavenumber of (2).
Preferably, the novel crystal form of pitavastatin hemicalcium salt has a raman spectrum as shown in fig. 4.
Another object of the present invention is to provide a process for the preparation of said novel crystalline form I of pitavastatin hemicalcium salt, which comprises: pitavastatin sodium salt and water-soluble calcium salt react in water solution containing methyl tert-butyl ether as cosolvent, crystallization, solid separation and decompression drying are carried out, thus obtaining the pitavastatin sodium salt.
The water-soluble calcium salt can be water-soluble calcium salt conventionally used in the art, and is selected from calcium chloride, calcium acetate, calcium lactate, etc.
Preferably, the "aqueous solution containing methyl tert-butyl ether as a cosolvent" refers to an aqueous solution containing 1-10% by volume of methyl tert-butyl ether.
More preferably, the "aqueous solution containing methyl tert-butyl ether as a cosolvent" refers to an aqueous solution containing 1-5% by volume of methyl tert-butyl ether.
The dosage of the aqueous solution is generally 5 to 50 times, preferably 5 to 30 times of the weight of pitavastatin sodium salt.
Preferably, the pH value of the reaction system is adjusted to 8-9 in the reaction, so that the pitavastatin hemicalcium salt can be obtained with higher reaction yield. More preferably, acetic acid is used for the pH adjustment.
The crystallization temperature is not particularly limited, and is generally in the range of-5 ℃ to 50 ℃, preferably 0 ℃ to 40 ℃, more preferably 10 ℃ to 20 ℃.
The crystallization time is not particularly limited, but is generally about 30 minutes to 24 hours.
The crystallization may be performed by standing, or may be performed under stirring. The crystallization is preferably carried out under stirring.
In the present invention, the term "crystal form" is understood not only as "crystal type" or "crystal structure"; in the technical scheme, "crystal form" is more understood as "a substance having a specific crystal structure" or "a crystal of a specific crystal type". For example, in the technical scheme, "a crystalline form of pitavastatin hemicalcium salt" may be understood as "pitavastatin hemicalcium salt having a specific crystal structure" or "crystals of pitavastatin hemicalcium salt of a specific crystal type".
In the invention, the new crystal forms are all confirmed by the representation of the shown X-ray diffraction patterns. Those skilled in the art will appreciate that the experimental error therein will depend on the conditions of the instrument, the sample preparation and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will generally vary with the conditions of the instrument. In addition, experimental errors in peak angles are typically 5% or less, and these angle errors should also be taken into account, typically allowing for errors of ± 0.1 °. In addition, due to the influence of experimental factors such as sample height, an overall shift in peak angle is caused, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that any crystalline form having a pattern identical or similar to the characteristic peaks in the pattern of the present invention is within the scope of the present invention.
The invention has the positive effects that:
compared with the prior art, the novel pitavastatin hemicalcium salt crystal form provided by the invention has good stability, greatly improved purity, better medicinal value, and better purity and crystal form stability in a long-term storage period of 12 months. The preparation method of the novel pitavastatin hemicalcium salt crystal form has the advantages of simple operation, good reproducibility, high yield, suitability for industrial production and great application value.
Drawings
FIG. 1 is an X-ray powder diffraction (PXRD) pattern of a novel crystalline form of pitavastatin hemicalcium salt
The ordinate represents the diffraction angle 2 θ (°)
The abscissa is relative strength (CPS)
FIG. 2 is a thermogravimetric analysis (TG) diagram of the novel crystalline form of pitavastatin hemicalcium salt of example 2
Ordinate is temperature (. degree. C.)
The abscissa is weight (%)
FIG. 3 is a differential scanning analysis (DSC) chart of a novel crystal form of pitavastatin hemicalcium salt
Ordinate is temperature (. degree. C.)
The abscissa is heat flow (W/g)
FIG. 4 is a Raman spectrum (Raman) chart of a novel crystal form of pitavastatin hemicalcium salt
The ordinate is the Raman shift (cm)-1）
The abscissa is relative intensity (counts)
Detailed Description
The instrument for detecting the polymorphic structure and the performance of the medicine comprises the following instruments:
powder X-ray diffraction (XRD) characterization: the instrument comprises the following steps: rigaku D/Max-2550 PC, CuK alpha radiation, 40kV multiplied by 250mA power, 2 theta 3-40 degrees of scanning range, 0.02 degree of step width (step width) and 5 degrees/min of scanning speed.
Thermogravimetric analysis (TG) characterization instrument: TA company SDT Q600, purge gas: nitrogen gas 120 ml/min, heating rate: 10 ℃/min, temperature range: room temperature to 380 ℃.
Differential Scanning Calorimetry (DSC) characterization: the instrument comprises the following steps: TA DSC Q100, purge gas: nitrogen 50 ml/min, heating rate: 10 ℃/min, temperature range: room temperature to 230 ℃.
Raman spectroscopy (Raman) characterization: the instrument comprises the following steps: LabRAMHR Evolution of Horiba corporation, laser wavelength of 633nm, laser power of 100 percent, excitation time of 30s, cumulative test times of 2 times and grating of 600 gr/mm.
Example 1
Preparation of novel pitavastatin hemicalcium salt crystal form (crystal form I)
Suspending 5g of pitavastatin tert-butyl ester in 25ml of water, stirring for 0.5h to obtain a suspension, dripping 5.25ml of 3mol/L NaOH aqueous solution, stirring for 4h at 50 ℃ to obtain a uniform and transparent solution, and filtering. Then 20ml of water and 2ml of methyl tert-butyl ether were added and stirred well. And (3) dropwise adding 10ml of purified aqueous solution of 1.2g of calcium acetate, continuously stirring for 4 hours after dropwise adding, carrying out suction filtration, washing with a proper amount of purified water, and drying at 50 ℃ under reduced pressure to obtain the novel pitavastatin hemicalcium salt crystal form. Which has the X-ray powder diffraction pattern shown in figure 1. Thermogravimetric analysis of the new crystalline form obtained further revealed that its water content was about 4.7%. Differential scanning calorimetry revealed a melting point of about 200 ℃ (see fig. 3). The raman spectrum of the new form is shown in figure 4. Confirming as a crystal form I; the yield was 90% and the HPLC purity was 99.92%.
Example 2
Preparation of novel pitavastatin hemicalcium salt crystal form (crystal form I)
Suspending 5g of pitavastatin tert-butyl ester in 20ml of water, stirring for 0.5h to obtain a suspension, dripping 5.25ml of 3mol/L NaOH aqueous solution, stirring for 4h at 50 ℃ to obtain a uniform and transparent solution, and filtering. Then adding 2ml of methyl tert-butyl ether, stirring uniformly, and adjusting the pH value of the solution to 8-9 by using acetic acid. And (3) dropwise adding 10ml of purified aqueous solution of 1.2g of calcium acetate, continuously stirring for 4 hours after dropwise adding, carrying out suction filtration, washing with a proper amount of purified water, and drying at 50 ℃ under reduced pressure to obtain the novel pitavastatin hemicalcium salt crystal form. Which has the X-ray powder diffraction pattern shown in figure 1. Thermogravimetric analysis of the new crystalline form obtained further revealed that its water content was about 4.4% (see fig. 2). Confirming as a crystal form I; the yield was 93% and the HPLC purity was 99.91%.
Example 3
Preparation of novel pitavastatin hemicalcium salt crystal form (crystal form I)
Suspending 5g of pitavastatin tert-butyl ester in 25ml of water, stirring for 0.5h to obtain a suspension, dripping 5.25ml of 3mol/L NaOH aqueous solution, stirring for 4h at 50 ℃ to obtain a uniform and transparent solution, and filtering. 70ml of water and 2ml of methyl tert-butyl ether are then added and stirred homogeneously. And (3) dropwise adding 10ml of purified aqueous solution of 1.2g of calcium acetate, continuously stirring for 4 hours after dropwise adding, carrying out suction filtration, washing with a proper amount of purified water, and drying at 50 ℃ under reduced pressure to obtain the novel pitavastatin hemicalcium salt crystal form. Which has the X-ray powder diffraction pattern shown in figure 1. Thermogravimetric analysis of the new crystalline form obtained further revealed that its water content was about 2.3%. Confirming as a crystal form I; the yield was 88% and the HPLC purity was 99.94%.
Example 4
Preparation of novel pitavastatin hemicalcium salt crystal form (crystal form I)
Suspending 2kg of pitavastatin tert-butyl ester in 10L of water, stirring for 0.5h to obtain a suspension, adding 2.1L of a 3mol/L NaOH aqueous solution dropwise, stirring for 4h at 50 ℃ to obtain a uniform and transparent solution, and filtering. Then 10L of water and 80ml of methyl tert-butyl ether were added and stirred well. And (3) 480g of calcium acetate 4L purified aqueous solution is dropwise added, stirring is continuously carried out for 1h after the dropwise addition, the suction filtration is carried out, and the mixture is washed by a proper amount of purified water and dried under reduced pressure at 50 ℃ to obtain the pitavastatin hemicalcium salt new crystal form. Which has the X-ray powder diffraction pattern shown in figure 1. Thermogravimetric analysis of the new crystalline form obtained further revealed that its water content was about 2.3%. Confirming as a crystal form I; the yield was 90% and the HPLC purity was 99.93%.
Example 5
Preparation of novel pitavastatin hemicalcium salt crystal form (crystal form I)
Suspending 2kg of pitavastatin tert-butyl ester in 10L of water, stirring for 0.5h to obtain a suspension, adding 2.1L of a 3mol/L NaOH aqueous solution dropwise, stirring for 4h at 50 ℃ to obtain a uniform and transparent solution, and filtering. Then, 10L of water and 50ml of methyl tert-butyl ether are added, the mixture is stirred uniformly, and the pH value of the solution is adjusted to 8-9 by acetic acid. And (3) 480g of calcium acetate 4L purified aqueous solution is dropwise added, stirring is continuously carried out for 2h after the dropwise addition, the suction filtration is carried out, and the mixture is washed by a proper amount of purified water and dried under reduced pressure at 50 ℃ to obtain the pitavastatin hemicalcium salt new crystal form. Which has the X-ray powder diffraction pattern shown in figure 1. Thermogravimetric analysis of the new crystalline form obtained further revealed that its water content was about 2.1%. Confirming as a crystal form I; the yield was 93% and the HPLC purity was 99.91%.
The long term stability data for this sample is shown in table 2.
TABLE 2 long-term stability test results for new crystal form of pitavastatin hemicalcium salt
(temperature 30 +/-2 ℃ and humidity 75 +/-5%)
| 0 month | 6 month | 12 month | |
| Traits | Off-white powder | Off-white powder | Off-white powder |
| Moisture content | 2.1% | 2.2% | 3.2% |
| Related amount of substances | 0.09% | 0.10% | 0.13% |
| PXRD atlas | In accordance with FIG. 1 | In accordance with FIG. 1 | In accordance with FIG. 1 |
Comparative example 1
Pitavastatin hemicalcium salt form a was prepared according to the method described in japanese chemical industry co, patent application CN 102321019 a.
5g of pitavastatin tert-butyl ester was dissolved in 92.2g of ethanol, and the mixture was stirred and dissolved, and 107.9g of water was added. Cooling to-3 deg.C to 3 deg.C, dripping 6.22ml NaOH solution with concentration of 2mol/l, and stirring at the same temperature for 4h to complete hydrolysis reaction. The solvent was distilled off under reduced pressure, and after removing 110g of ethanol/water, the internal temperature was adjusted to 10-20 ℃ and a separately prepared calcium acetate solution (2.2 g of calcium acetate dissolved in 7.2g of water) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at the same temperature for 12 hours, filtered, rinsed with water, and dried under reduced pressure at 40 ℃ until the water content became 9.4%.
The product is proved to be the crystal form A of pitavastatin hemicalcium salt by X-ray powder diffraction, and the HPLC purity is 98.80%.
And (4) conclusion: the purity of the pitavastatin hemicalcium salt obtained by the invention is obviously superior to that of the method, and the preparation time of the method is long.
Claims (6)
1. The pitavastatin hemicalcium salt crystal form is a crystal form I, and at least comprises the following characteristic peaks in an X-ray powder diffraction pattern measured by Cu-K alpha rays: diffraction angle 2 theta values were 4.56 + -0.1 deg., 5.10 + -0.1 deg., 6.74 + -0.1 deg., 6.94 + -0.1 deg., 9.12 + -0.1 deg., 10.32 + -0.1 deg., 11.32 + -0.1 deg., 13.72 + -0.1 deg., and 21.24 + -0.1 deg..
2. A process for the preparation of the crystalline form of pitavastatin hemicalcium salt as defined in claim 1 comprising: pitavastatin sodium salt and water-soluble calcium salt react in aqueous solution containing methyl tert-butyl ether as a cosolvent, crystallization is carried out, solid is separated, and decompression drying is carried out to obtain pitavastatin semi-calcium salt crystal form I; the aqueous solution containing methyl tert-butyl ether as a cosolvent is an aqueous solution containing 1-10% of methyl tert-butyl ether by volume concentration; the dosage of the aqueous solution is 5 to 50 times of the weight of pitavastatin sodium salt; and/or adjusting the pH value of the reaction system to 8-9; the crystallization temperature is in the range of-5 ℃ to 50 ℃; the crystallization time is 30 minutes to 24 hours; the crystallization method is standing for crystallization or stirring for crystallization.
3. The process for the preparation of the crystalline form of pitavastatin hemi-calcium salt of claim 2 wherein the water soluble calcium salt is selected from calcium chloride, calcium acetate or calcium lactate.
4. The preparation method of the pitavastatin hemicalcium salt crystal form of claim 2, characterized in that the aqueous solution containing methyl tert-butyl ether as a cosolvent is an aqueous solution containing 1-5% by volume of methyl tert-butyl ether; the dosage of the aqueous solution is 5 to 30 times of the weight of pitavastatin sodium salt; and/or adjusting the pH value of the reaction system by using acetic acid.
5. The process for preparing the novel crystalline form of pitavastatin hemi-calcium as claimed in claim 2, wherein the crystallization temperature is from 0 ℃ to 40 ℃.
6. The process for the preparation of the crystalline form of pitavastatin hemicalcium salt as claimed in claim 5, characterized in that the crystallization temperature is in the range of 10-20 ℃.
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