CN115947722B - Alisartan sodium salt crystal form and pharmaceutical composition containing same - Google Patents

Alisartan sodium salt crystal form and pharmaceutical composition containing same Download PDF

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CN115947722B
CN115947722B CN202310017139.6A CN202310017139A CN115947722B CN 115947722 B CN115947722 B CN 115947722B CN 202310017139 A CN202310017139 A CN 202310017139A CN 115947722 B CN115947722 B CN 115947722B
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sodium salt
crystal form
novel crystal
aliskirsite
alisrtan
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CN115947722A (en
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颜杰
许文杰
李松
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Shenzhen Salubris Pharmaceuticals Co Ltd
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Shenzhen Salubris Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a series of novel crystal forms of alisrtan medoxomil sodium salt and a preparation method thereof.

Description

Alisartan sodium salt crystal form and pharmaceutical composition containing same
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an alisartan ester salt crystal form, a preparation method thereof and a pharmaceutical composition containing the crystal form.
Background
Arisartan ester (CAS: 947331-05-7), chemical name: 2-butyl-4-chloro-1- [2'- (1H-tetrazol-5-yl) -1,1' -biphenyl-methyl ] -imidazole-5-carboxylic acid, 1- [ (isopropoxy) -carbonyloxy ] -methyl ester, trade name: the preparation method of the compound is characterized in that the compound is the sulbactam, which is a novel angiotensin II receptor antagonist (AT 1), and the patent WO2007095789 discloses the structural formula of the compound for the first time and the application of the compound in preparing antihypertensive drugs. Compared with products (such as losartan) which are the angiotensin II receptor antagonists, the antihypertensive effect of the alisrtan cilexetil shows obvious advantages, and the nephrotoxicity is lower than that of similar products.
In order to find the most suitable form of the active ingredient for pharmaceutical use, a series of salts of the active ingredient are generally studied in the process of drug development, specifically, for the carboxylate compound to which the alisrtan medoxomil belongs, the salt formed at the tetrazole position generally has better solubility in polar solvents, and in addition, the salt of the active ingredient may have unpredictable advantages in physicochemical properties such as stability and hygroscopicity.
Patent CN101195615a discloses a series of alisrtan medoxomil salts including potassium, sodium, calcium, magnesium, zinc, lithium, ammonium salts, etc., which in examples 2-9 disclose the preparation methods of the potassium, sodium, calcium salts of alisrtan medoxomil, respectively; specifically, according to the description of the patent specification, the melting point of the potassium salt of the alisrtan medoxomil obtained according to the patent method is 189.5-189.7 ℃, the melting point of the sodium salt of the alisrtan medoxomil obtained according to the patent method is 93.0-96.8 ℃, and the melting point of the calcium salt of the alisrtan medoxomil obtained according to the patent method is 156.2-156.7 ℃, and in the subsequent solubility experiment and drug absorption experiment, the potassium salt, the sodium salt and the calcium salt of the alisrtan medoxomil are all characterized by better solubility, shorter peak time and higher bioavailability than the alisrtan medoxomil.
Patent CN101715448A discloses the use of an alisrtan medoxomil compound in the treatment of target organ damage caused by a number of hypertension, which discloses in example 1 a process for the preparation of an alisrtan potassium salt, according to which the melting point of the alisrtan potassium salt prepared is 189.5-189.7 ℃, and in examples 6 and 7 further capsules and tablets containing the alisrtan potassium salt are disclosed.
Patent CN102088972a discloses a pharmaceutical composition containing alisrtan medoxomil salt, examples 1-3 thereof disclose preparation methods of alisrtan medoxomil potassium salt, sodium salt, calcium salt, respectively (consistent with the preparation method disclosed in patent CN 101195615), and discloses a pharmaceutical composition containing alisrtan medoxomil potassium salt; specifically, the alisrtan medoxomil salt disclosed in the patent shows better solubility in methanol and water than alisrtan medoxomil, and the alisrtan medoxomil potassium salt shows higher stability under the conditions of illumination, high temperature and high humidity.
Although the prior art provides a plurality of alisrtan medoxomil salts, the crystal forms which are most suitable for medicinal use are not screened, so that the search for the crystal forms of the alisrtan medoxomil salts which have better stability and are more suitable for medicinal use is an unresolved problem of the prior art.
Disclosure of Invention
The invention aims to solve the incomplete task of the prior art and provide a series of crystal forms of the alisrtan medoxomil salt and a corresponding method for stably preparing the same, wherein the crystal forms of the alisrtan medoxomil salt are different from the crystal forms of the alisrtan medoxomil salt disclosed in the prior art, and compared with the crystal forms of the alisrtan medoxomil salt disclosed in the prior art, the crystal forms of the alisrtan medoxomil salt disclosed in the prior art have the advantages of at least one aspect of solubility, stability (thermal stability, illumination stability, hygroscopicity and the like), fluidity and the like, and the comprehensive evaluation is more suitable for pharmaceutical use. Specifically, the novel crystal forms of the alisrtan medoxomil salt are potassium salt novel crystal forms, sodium salt novel crystal forms and calcium salt novel crystal forms.
A first object of the present invention is to provide a novel crystal form of alisartan potassium salt, wherein the novel crystal form of alisartan potassium salt has peaks at 2θ of 5.4, 5.7, 12.5, 16.9, 19.6, 19.9, 21.2, 21.8, 23.9, 24.3, 24.5, 25.2, 28.7, 30.0 with an error range of ±0.2°; for the group of absorption peaks, the relative intensity is more than 20%, those skilled in the art can understand that, due to different detection conditions and detection instruments, the probability of repeated occurrence of the peak with large absorption intensity is extremely high, and the peak can be used as the characteristic peak of the new crystal form in repeated detection among different batches and in the same batch.
The XRD spectrogram of the novel crystal form of the aliskirsite sylvite further has peaks at 7.3, 9.7, 10.8, 16.5, 17.9, 20.1, 20.4, 22.7, 23.4, 25.9 and 29.4, the error range is +/-0.2 degrees, and the relative intensity of the absorption peaks is lower than that of the characteristic peaks in the previous group (10% -20%), so that the relative intensity of the absorption peaks is influenced by objective factors such as detection conditions and detection instruments, displacement deviation or certain fluctuation of the absorption intensity correspondingly occurs, and the reproducibility is lower than that of the characteristic peaks.
The XRD spectrogram of the novel crystal form of the aliskirsite sylvite further has peaks at 31.8, 33.2, 33.7 and 34.7, the error range is +/-0.2 degrees, and the relative intensity of the absorption peaks is the lowest (not more than 10 percent), so that the absorption peaks are greatly influenced by objective factors such as detection conditions, detection instruments and the like, displacement deviation or fluctuation of the absorption intensity occurs, even the spectrogram of some repeated detection does not appear, and therefore the reproducibility of the group of peaks is the lowest.
The Differential Scanning Calorimetry (DSC) spectrum of the novel crystal form of the potassium salt of the alisartan has an endothermic peak at 169.8+/-5 ℃.
The thermal analysis (TG) spectrogram of the novel crystal form of the alisartan potassium salt shows that the mass change of the novel crystal form of the alisartan potassium salt is 1.58% from 0-120 ℃, and the DSC spectrogram and the TG spectrogram of the novel crystal form of the alisartan potassium salt are combined, so that the novel crystal form of the alisartan potassium salt is melted and decomposed at 169.8+/-5 ℃, and the melting point of the disclosed alisartan potassium salt in the prior art is 189.5-189.7 ℃.
The second purpose of the invention is to provide a method for stably preparing the novel crystal form of the aliskirsite potassium salt, which can stably prepare the novel crystal form of the aliskirsite potassium salt with high purity and high uniformity and can meet various requirements of large-scale production, such as cost reduction, recycling and the like. Specifically, the novel crystal form of the potassium salt of the aliskirsite comprises the following steps:
1) Weighing an initial sample of alisrtan medoxomil and potassium hydroxide, and placing the initial sample of alisrtan medoxomil and potassium hydroxide in a reaction bottle;
2) Adding a dehydrated organic solvent;
3) Stirring and heating to 30-40 ℃ and keeping the temperature for stirring for 8-12 hours;
4) Supplementing the organic solvent in the step 2), and reducing the temperature to 0 ℃ at 0.5-1 ℃/min;
5) Stirring at the temperature for 3-6 hours, vacuum filtering to separate solid under the protection of nitrogen, and vacuum drying at 30-50 ℃ for 6-12 hours.
In the preparation step, the molar ratio of the alisrtan cilexetil to the potassium hydroxide is 1:0.9-1.2, the types, the use amount, the temperature and the time of the organic solvent in the preparation method are important influencing factors for preparing the crystal forms, specifically, the different types and the use amount of the solvent possibly influence the acquisition of the alisrtan cilexetil potassium salt crystal forms, and the organic solvent is one or a mixed solvent of more than two of isopropyl acetate, isobutyl acetate, n-heptane and methyl tertiary butyl ether in any proportion, or acetone: n-heptane=1:1 to 4 (v/v) mixed solvent; isopropyl acetate and acetone are preferred: n-heptane=1:2 (v/v), the amount of organic solvent used in step (2) is: the mass volume ratio of the alisrtan cilexetil to the organic solvent is 0.1-0.3 g/ml, the use amount of the solvent supplemented in the step (4) is consistent with that in the step (2), the ratio of the solvent supplemented in the step (4) to the use amount of the solvent in the step (2) is 1-2:1 (v/v), and all the organic solvents in the preparation method are subjected to anhydrous pretreatment;
a third object of the present invention is to provide a novel crystalline form of the sodium salt of alisrtan medoxomil. For the novel crystal form of the sodium salt of the alisartan, the X-ray powder diffraction (XRD) spectrum of the crystal form has peaks at the positions of 5.0, 5.5, 6.0, 7.4, 11.2, 18.0, 19.1, 20.5, 21.9 and 23.1 of 2 theta, and the error range is +/-0.2 degrees; the group of absorption peaks are peaks with the relative intensity of more than 20%, and those skilled in the art can understand that the probability of repeated occurrence of the peak with large absorption intensity is extremely high due to the difference of detection conditions and detection instruments, and the peak can be used as the characteristic peak of the new crystal form in repeated detection among different batches and in the same batch.
The XRD spectrum of the novel crystal form of the aliskirsite sodium salt further has peaks at 10.8, 13.3, 21.1, 24.1 and 25.4, and the error range is +/-0.2 degrees; since the relative intensity of the absorption peak is lower (10% -20%) than that of the former characteristic peak, the relative intensity is affected by objective factors such as detection conditions and detection instruments, and displacement deviation or fluctuation of the absorption intensity correspondingly occurs, so that the reproducibility is lower than that of the former characteristic peak.
The XRD spectrogram of the novel crystal form of the aliskirsite sodium salt further has peaks at 9.6, 12.6, 13.9, 14.7 and 16.2, the error range is +/-0.2 degrees, and the relative intensity of the absorption peaks is lower (not more than 10 percent) than that of the characteristic peaks of the former group, so that the relative intensity is influenced by objective factors such as detection conditions, detection instruments and the like, displacement deviation or certain fluctuation of the absorption intensity correspondingly occurs, and the reproducibility is lower than that of the characteristic peaks and cannot become characteristic peaks.
The Differential Scanning Calorimetry (DSC) spectrum of the novel crystal form of the sodium salt of the alisartan has an endothermic peak at 123.0+/-5 ℃.
The thermal analysis (TG) spectrogram of the novel crystal form of the sodium salt of the aliskirsite shows that the mass of the novel crystal form of the sodium salt of the aliskirsite changes by 3.02 percent from 0-90 ℃, the mass of the novel crystal form of the sodium salt of the aliskirsite changes by 4.08 percent from 90-120 ℃, and the DSC spectrogram and the TG spectrogram of the novel crystal form of the sodium salt of the aliskirsite are combined, so that the novel crystal form of the sodium salt of the aliskirsite starts to be melted and decomposed at 123.0+/-5 ℃, and the melting point of the sodium salt of the aliskirsite disclosed in the prior art is 93.0-96.8 ℃.
The fourth object of the present invention is to provide a method for stably preparing a novel crystal form of the sodium salt of alisrtan cilexetil, which can stably prepare the novel crystal form of the sodium salt of alisrtan cilexetil with high purity and high uniformity, and is suitable for large-scale industrial production.
The preparation method of the novel crystal form of the aliskirsite sodium salt comprises the following steps:
1) Weighing an initial sample of alisrtan medoxomil and sodium hydroxide, and placing the initial sample of alisrtan medoxomil and sodium hydroxide in a reaction bottle;
2) Adding an organic solvent;
3) Stirring and heating to 30-40 ℃ and keeping the temperature for stirring for 48-72 hours;
4) Supplementing the organic solvent in the step 2), and reducing the temperature to 0 ℃ at 0.5-1 ℃/min;
5) Stirring at the temperature for 10-12 hours, vacuum filtering to separate solid under the protection of nitrogen, and vacuum drying at 30-50 ℃ for 6-12 hours.
In the preparation step, the molar ratio of the alisrtan cilexetil to the sodium hydroxide is 1:0.95-1.05, the types, the use amount, the temperature and the time of the organic solvent in the preparation method are important influencing factors for preparing the crystal form, specifically, the types and the use amount of the solvents are different and possibly influence the acquisition of the novel crystal form A of the alisrtan cilexetil sodium salt, and the organic solvent is one or more than two of isopropyl acetate, isobutyl acetate, n-heptane and methyl tertiary butyl ether, or acetone: n-heptane=1:1 to 4 (v/v) mixed solvent; preferably methyl tert-butyl ether, the amount of organic solvent used in step (2) is: the mass volume ratio of the alisrtan cilexetil to the organic solvent is 0.05-0.15 g/ml, the amount of the solvent supplemented in the step (4) is consistent with that of the step (2), and the ratio of the solvent to the amount of the step (2) is 1-2:1 (v/v).
A fifth object of the present invention is to provide a novel crystalline form of the calcium salt of alisartan ester. For the novel crystal form of the calcium salt of the alisartan, the X-ray powder diffraction (XRD) spectrum of the crystal form has peaks at 6.7, 14.2, 14.5, 15.3, 17.3, 20.3, 20.6, 24.2, 25.1 and 29.4 of 2 theta, and the error range is +/-0.2 degrees; for the group of absorption peaks, the relative intensity is more than 20%, those skilled in the art can understand that, due to different detection conditions and detection instruments, the probability of repeated occurrence of the peak with large absorption intensity is extremely high, and the peak can be used as the characteristic peak of the new crystal form in repeated detection among different batches and in the same batch.
The XRD spectrogram of the novel crystal form of the calcium salt of the aliskirsite has peaks at 16.4, 18.6, 19.3, 19.8, 22.2, 23.6 and 27.3, the error range is +/-0.2 degrees, and the relative intensity of the absorption peaks is lower than that of the characteristic peaks in the former group (10% -20%), so that the relative intensity of the absorption peaks can be influenced by objective factors such as detection conditions and detection instruments, displacement deviation or fluctuation of the absorption intensity correspondingly occurs, and the reproducibility is lower than that of the characteristic peaks.
The XRD spectrogram of the novel crystal form of the calcium salt of the aliskirsite has peaks at 11.0, 26.0, 26.7, 30.9, 32.3 and 37.5, the error range is +/-0.2 degrees, and the relative intensity of the absorption peaks is the lowest (not more than 10 percent), so that the absorption peaks can be greatly influenced by objective factors such as detection conditions, detection instruments and the like, displacement deviation or fluctuation of the absorption intensity occurs, even in some repeated detection spectrograms, the reproducibility of the group of peaks is the lowest.
The Differential Scanning Calorimetry (DSC) spectrum of the novel crystal form of the calcium salt of the aliskirsite has exothermic peaks/endothermic peaks at 113.7+/-5 ℃ and 143.6+/-5 ℃.
The thermal analysis (TG) spectrogram of the novel crystal form of the aliskirsite calcium salt shows that the mass change of the novel crystal form of the aliskirsite calcium salt is 3.85 percent from 0-90 ℃, the mass change of the novel crystal form of the aliskirsite calcium salt is 7.28 percent from 90-160 ℃, and the mass change of the novel crystal form of the aliskirsite calcium salt is 12.29 percent from 160-220 ℃ combined with the DSC spectrogram and the TG spectrogram of the novel crystal form of the aliskirsite calcium salt, so that the novel crystal form of the aliskirsite calcium salt is melted and decomposed at 143.6+/-5 ℃, and the melting point of the aliskirsite calcium salt disclosed in the prior art is 156.2-156.7 ℃.
The sixth object of the present invention is to provide a method for stably preparing a novel crystal form of aliskirsite calcium salt, which is suitable for mass production, and which can stably prepare the novel crystal form of aliskirsite calcium salt with high purity and high uniformity.
The preparation method of the novel crystal form of the calcium salt of the alisartan comprises the following steps:
1) Weighing an initial sample of alisartan and calcium hydroxide, and placing the initial sample of alisartan and the calcium hydroxide in a reaction bottle;
2) Adding a dehydrated organic solvent;
3) Stirring and heating to 30-40 ℃ and keeping the temperature for stirring for 96-120 hours;
4) Supplementing the organic solvent in the step 2), and reducing the temperature to 0 ℃ at 0.5-1 ℃/min;
5) Stirring at 30-50deg.C for 12-24 hr, vacuum filtering under nitrogen protection, separating solid, and vacuum drying at 30-50deg.C for 6-12 hr.
In the preparation step, the molar ratio of the alisrtan cilexetil to the calcium hydroxide is 1:0.49-0.51, the types, the use amount, the temperature and the time of the organic solvent in the preparation method are important influencing factors for preparing the crystal forms, specifically, the different types and the use amount of the solvent possibly influence the acquisition of the alisrtan cilexetil potassium salt crystal forms, and the organic solvent is one or a mixed solvent of more than two of isopropyl acetate, isobutyl acetate, n-heptane and methyl tertiary butyl ether in any proportion, or acetone: n-heptane=1:1 to 4 (v/v) mixed solvent; isopropyl acetate is preferred, and the amount of the organic solvent used in the step (2) is as follows: the mass volume ratio of the alisrtan cilexetil to the organic solvent is 0.1-0.2 g/ml, the amount of the solvent supplemented in the step (4) is consistent with that of the step (2), the ratio of the solvent to the amount of the solvent in the step (2) is 1-2:1 (v/v), and all the organic solvents in the preparation method are subjected to anhydrous pretreatment.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. compared with the prior art, the obtained novel crystal forms are superior to the corresponding crystal forms of the aliskirsite salt disclosed in the prior art in at least one aspect of solubility, stability (thermal stability, illumination stability, hygroscopicity and the like), fluidity and the like, and the comprehensive evaluation is also more suitable for pharmaceutical use;
2. the method can stably prepare the novel crystal forms of the potassium salt, the sodium salt and the calcium salt of the alisrtan cilexetil with high purity and good uniformity, and is suitable for industrial mass production.
Drawings
Figure 1 XRD spectrum of novel crystal form of potassium salt of alisrtan cilexetil obtained in example 2
FIG. 2 DSC-TG spectrum of novel crystal form of potassium salt of alisrtan medoxomil obtained in example 2
FIG. 3 XRD spectrum of novel crystal form of potassium salt of alisrtan medoxomil obtained in example 2
FIG. 4 XRD spectrum of novel crystal form of potassium salt of alisrtan cilexetil obtained in example 3
FIG. 5 XRD spectrum of novel crystal form of sodium salt of alisrtan cilexetil obtained in example 4
FIG. 6 DSC-TG spectrum of novel crystal form of sodium salt of alisrtan medoxomil obtained in example 4
FIG. 7 XRD spectrum of novel crystal form of calcium salt of alisrtan cilexetil obtained in example 5
FIG. 8 DSC-TG spectrum of novel crystal form of calcium salt of alisrtan cilexetil obtained in example 5
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the invention are not limited thereto.
Example 1
Preparation method of alisrtan medoxomil
An alisartan ester starting material was prepared using the method disclosed in example 1 of patent CN101195615 a.
Example 2
Preparation method of novel crystal form of alisartan potassium salt
1) 5.1g of alisrtan medoxomil and 0.6g of potassium hydroxide are weighed and placed in a reaction bottle;
2) Adding 30ml of anhydrous isopropyl acetate, stirring and heating to 35 ℃;
3) Stirring for 10 hours at the maintained temperature;
4) Slowly adding 50mL of anhydrous isopropyl acetate, and then reducing the system temperature to 0 ℃ at 0.5-1 ℃/min;
5) Stirring at the temperature for 4 hours, vacuum filtering to separate solid under the protection of nitrogen, and vacuum drying at 30-50 ℃ for 8 hours to obtain 4.4g of white solid;
the XRD spectrum of the novel crystal form of the obtained alisartan potassium salt is shown in figure 1, the DSC-TG spectrum is shown in figure 2, and the repeated XRD detection spectrum is shown in figure 3.
Example 3
Preparation method of novel crystal form of alisartan potassium salt
1) 5.2g of alisrtan medoxomil and 0.51g of potassium hydroxide are weighed and placed in a reaction bottle;
2) Adding 30ml of a mixed solvent of acetone-n-heptane 1:2 (v/v) subjected to anhydrous treatment, stirring and heating to 35 ℃;
3) Stirring for 10 hours at the maintained temperature;
4) Slowly adding 50mL of anhydrous acetone-n-heptane, and reducing the system temperature to 0 ℃ at 0.5-1 ℃/min;
5) Stirring at the maintained temperature for 4 hours, vacuum filtering and separating solid under the protection of nitrogen, and vacuum drying at 30-50 ℃ for 8 hours to obtain 4.2g of white solid, wherein the white solid is detected as the crystal form of the alisartan ester potassium salt consistent with the embodiment 2;
the XRD spectrum of the novel crystal form of the aliskirsite sylvite is shown in figure 4 and is basically consistent with the product obtained in the example 2, and the DSC-TG spectrum is basically consistent with the product obtained in the example 2.
The XRD spectrograms obtained by repeated detection of samples in the same batch and between batches represented by the figures 1, 3 and 4 are combined, so that the XRD spectrograms of the novel crystal form of the potassium salt of the alisartan have peaks at positions of 5.4, 5.7, 12.5, 16.9, 19.6, 19.9, 21.2, 21.8, 23.9, 24.3, 24.5, 25.2, 28.7 and 30.0, the error range is +/-0.2 DEG, the group of absorption peaks have peaks with the relative intensity of more than 20 percent, the repeated occurrence probability of the group of peaks is high, and the peaks appear in repeated detection between different batches and in the same batch and can be used as characteristic peaks of the novel crystal form;
the XRD spectrum of the novel crystal form of the aliskirsite sylvite further has peaks at 7.3, 9.7, 10.8, 16.5, 17.9, 20.1, 20.4, 22.7, 23.4, 25.9 and 29.4, the error range is +/-0.2 DEG, the relative intensity of the absorption peaks is between 10 and 20 percent, and the reproducibility of the peaks is lower than that of the characteristic peaks;
the XRD spectrum of the novel crystal form of the aliskirsite sylvite further has peaks at 31.8, 33.2, 33.7 and 34.7, the error range is +/-0.2 degrees, the relative intensity of the absorption peaks does not exceed 10 percent, and the reproducibility of the peaks is the lowest.
Example 4
Preparation method of novel crystal form of alisartan sodium salt
1) 3g of alisrtan medoxomil and 0.21 sodium hydroxide are weighed and placed in a reaction bottle;
2) Adding 30ml of methyl tertiary butyl ether, stirring and heating to 35 ℃;
3) Stirring for 60 hours at the maintained temperature;
4) Slowly adding 60mL of methyl tertiary butyl ether, and reducing the system temperature to 0 ℃ at a speed of 0.5-1 ℃/min;
5) Stirring at the temperature for 10 hours, vacuum filtering to separate solid under the protection of nitrogen, and vacuum drying at 30-50 ℃ for 10 hours to obtain 2.3g of white solid;
the XRD spectrum of the novel crystal form of the obtained alisartan sodium salt is shown in figure 5, and the DSC-TG spectrum is shown in figure 6.
By combining XRD spectra obtained by repeated detection of samples in the same batch and between batches represented by the graph shown in FIG. 5, the XRD spectra of the novel crystal forms of the sodium salt of the alisartan are shown to have peaks at positions of 5.0, 5.5, 6.0, 7.4, 11.2, 18.0, 19.1, 20.5, 21.9 and 23.1, and the error range is +/-0.2 degrees; the relative intensity of the group of absorption peaks is more than 20%, the repeated occurrence probability is extremely high, the absorption peaks appear in repeated detection among different batches and in the same batch, and the absorption peaks are characteristic peaks of the new crystal form;
the XRD spectrogram of the novel crystal form of the aliskirsite sodium salt further has peaks at 10.8, 13.3, 21.1, 24.1 and 25.4, the error range is +/-0.2 degrees, the relative intensity of the absorption peaks is 10-20%, and the reproducibility of the absorption peaks is lower than that of the characteristic peaks;
the XRD spectrum of the novel crystal form of the aliskirsite sodium salt further comprises peaks at 9.6, 12.6, 13.9, 14.7 and 16.2, the error range is +/-0.2 degrees, the relative intensity of the absorption peaks does not exceed 10%, and the reproducibility of the peaks is the lowest.
Example 5
Preparation method of novel crystal form of alisartan ester calcium salt
1) Weighing 5g of alisartan and 0.34 calcium hydroxide, and placing the mixture into a reaction bottle;
2) Adding 30ml of anhydrous isopropyl acetate, stirring and heating to 35 ℃;
3) Maintaining the temperature and stirring for 100 hours;
4) Slowly adding 50mL of anhydrous isopropyl acetate, and then reducing the system temperature to 0 ℃ at 0.5-1 ℃/min;
5) Stirring at the temperature for 15 hours, vacuum filtering to separate solid under the protection of nitrogen, and vacuum drying at 30-50 ℃ for 10 hours to obtain 3.8g of white solid;
the XRD spectrum of the novel crystal form of the calcium salt of the alisartan is shown in figure 7, and the DSC-TG spectrum is shown in figure 8.
By combining XRD spectra obtained by repeated detection of samples in the same batch and between batches represented by FIG. 7, the XRD spectra of the novel crystal forms of the calcium salt of the alisartan are shown to have peaks at positions of 6.7, 14.2, 14.5, 15.3, 17.3, 20.3, 20.6, 24.2, 25.1 and 29.4 of 2 theta, and the error range is +/-0.2 degrees; the group of absorption peaks are peaks with the relative intensity of more than 20%, the repeated occurrence probability is extremely high, the absorption peaks occur in repeated detection among different batches and in the same batch, and the absorption peaks can be used as characteristic peaks of the new crystal forms;
the XRD spectrogram of the novel crystal form of the calcium salt of the aliskirsite has peaks at 16.4, 18.6, 19.3, 19.8, 22.2, 23.6 and 27.3, the error range is +/-0.2 degrees, the relative intensity of the absorption peaks is 10-20 percent, and the relative intensity is influenced by objective factors such as detection conditions, detection instruments and the like, and displacement deviation or certain fluctuation of the absorption intensity correspondingly occurs, so that the reproducibility is lower than that of the characteristic peaks;
the XRD spectrogram of the novel crystal form of the calcium salt of the aliskirsite has peaks at 11.0, 26.0, 26.7, 30.9, 32.3 and 37.5, the error range is +/-0.2 degrees, the relative intensity of the absorption peaks of the group is not more than 10 percent, the relative intensity is greatly influenced by objective factors such as detection conditions, detection instruments and the like, displacement deviation or fluctuation of the absorption intensity occurs, even the spectrogram of some repeated detection does not appear, and therefore the reproducibility of the group of peaks is the lowest.
Comparative example 1
Using the same preparation conditions and feed ratio as in example 2, the solvent was changed to isopropyl ether: ethanol=3:1 (v/v) as in example 2 of CN101195615A only, and the melting point of the obtained potassium salt of alisartan ester was 189.5℃in agreement with that reported in patent CN 101195615A.
Comparative example 2
Using the same preparation conditions and feed ratio as in example 4, the solvent was changed to only isopropyl ether: ethanol solvent system (3:1, v/v) similar to that in example 5 of CN101195615A, and the melting point of the obtained alisartan ester sodium salt was 94.7℃in accordance with that reported in patent CN 101195615A.
Comparative example 3
Using the same preparation conditions and feed ratio as in example 5, the solvent was changed to only isopropyl ether: acetone solvent system (3:1, v/v) similar to that in example 7 of CN101195615A, and the melting point of the resulting calcium salt of alisartan ester was 156.5℃in accordance with that reported in patent CN 101195615A.
Stability comparative test
(one) high temperature experiment
The corresponding solid samples 8-12mg of examples 2-5 and comparative examples 1-3 were weighed into 1.5ml HPLC vials, respectively, and the sample vials were subjected to 25 ℃/60% RH and 40 ℃/60% RH conditions, usingAfter the sealing film is sealed, about 20 small pinholes are pricked, the sealing film is placed for storage, samples are sampled for HPLC test after one week, samples under the condition of 80 ℃ are sealed by a bottle cap, the sealing film is placed for storage, samples are sampled for HPLC test after one day, and the results are shown in Table 1.
TABLE 1 results of high temperature experiments
From the above results, it can be seen that: the novel crystal form of the potassium salt of the alisrtan cilexetil, the novel crystal form of the sodium salt and the novel crystal form of the calcium salt are stable under the high-temperature condition.
Under the same conditions, the contrast ratio high-temperature test is carried out, and the novel crystal forms of the potassium salt, the novel crystal form of the sodium salt and the novel crystal form of the calcium salt of the alisartan have better stability compared with the potassium salt, the sodium salt and the calcium salt of the alisartan.
(II) high humidity experiment: the novel crystal forms of the potassium salt of the alisrtan cilexetil in example 2 and example 3, the novel crystal form of the sodium salt of the alisrtan cilexetil in example 4, the novel crystal form of the calcium salt of the alisrtan cilexetil in example 5 and the samples of comparative examples 1 to 3 are weighed 5 parts each, 1g each, and exposed to each other, placed in a culture dish, placed in a constant temperature and humidity box with an RH of 92.5% (temperature 25+ -1 ℃), and sampled and measured after 0 day, 1 day, 7 day and 14 days, and the results are shown in Table 2.
TABLE 2 results of high humidity experiments (RH 92.5%, 25+ -2 ℃ C.)
Detection index Day 0 For 1 day For 7 days 14 days
New crystalline form relative content (%) 100.00 99.05 98.69 98.62
Example 3 relative content (%) 99.99 99.21 99.02 98.54
New crystalline form relative content (%) 100.00 99.97 99.43 98.94
New crystalline form of the calcium salt of alisartan ester of example 5 relative content (%) 99.95 99.26 98.94 98.65
Relative content (%) 99.99 98.73 96.26 95.13
Comparative document 2 relative content (%) 99.98 97.15 96.42 94.89
Comparative document 3 relative content of calcium salt of alisartan ester (%) 100.00 96.78 96.71 95.80
From the above results, it can be seen that: the novel crystal forms of the potassium salt, the novel crystal forms of the sodium salt and the novel crystal forms of the calcium salt of the alisartan are basically consistent with 0 day after being placed for 7 days under the conditions of 25+/-2 ℃ and 92.5% RH, which proves that the product is very stable under the condition of high humidity.
Under the same conditions, the contrast ratio is tested, and the novel crystal forms of the potassium salt, the novel crystal form of the sodium salt and the novel crystal form of the calcium salt of the alisrtan cilexetil have obviously better stability compared with the potassium salt, the sodium salt and the calcium salt of the alisrtan cilexetil of a comparison document.
Fluidity comparative test
Taking appropriate amounts of corresponding solid samples of examples 2, 4 and 5 and comparative examples 1-3 respectively, and measuring powder repose angles by a fixed funnel method respectively; powder bulk density was measured by the cylinder knocking method and the results are shown in table 3:
TABLE 3 flowability test results
From the above results, it can be seen that: the novel crystal forms of the potassium salt of the alisrtan medoxomil, the novel crystal forms of the sodium salt and the novel crystal forms of the calcium salt have better fluidity compared with the potassium salt, the sodium salt and the calcium salt of the alisrtan medoxomil, the embodiment is that the repose angle of the novel crystal form of the potassium sodium calcium salt of the alisrtan medoxomil is smaller than that of the alisrtan medoxomil potassium sodium calcium salt of a comparison document, and the bulk density is larger than that of the alisrtan medoxomil potassium sodium calcium salt of the comparison document.
In conclusion, compared with the potassium salt, sodium salt and calcium salt obtained by the comparison document, the novel crystal forms of the potassium salt, sodium salt and calcium salt have the technical advantages of stability, fluidity and the like, and provide a better choice for preparing the potassium salt, sodium salt and calcium salt preparation of the alisrtan medoxomil.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (14)

1. A novel crystal form of an aliskirsite sodium salt, which is characterized in that the XRD spectrum of the novel crystal form of the aliskirsite sodium salt has peaks at 5.0, 5.5, 6.0, 7.4, 11.2, 18.0, 19.1, 20.5, 21.9 and 23.1 with an error range of + -0.2 degrees.
2. The novel crystalline form of the sodium salt of aliskirosartan according to claim 1, characterized in that the XRD pattern of the novel crystalline form of the sodium salt of aliskirosartan further has peaks at 10.8, 13.3, 21.1, 24.1, 25.4 with an error range of ± 0.2 °.
3. The novel crystal form of the sodium salt of aliskirsite according to any of claims 1 or 2, characterized in that the XRD pattern of the novel crystal form of the sodium salt of aliskirsite further has peaks at 9.6, 12.6, 13.9, 14.7, 16.2 with an error range of ± 0.2 °.
4. The novel crystal form of the sodium salt of aliskirsite according to any of claims 1-2, characterized in that the DSC profile of the novel crystal form of the sodium salt of aliskirsite has an endothermic peak at 123.0 ± 5 ℃.
5. A new crystalline form of the sodium salt of aliskirosartan according to claim 3, characterized in that the DSC profile of the new crystalline form of the sodium salt of aliskirosartan has an endothermic peak at 123.0 ± 5 ℃.
6. The novel crystal form of the sodium salt of alisrtan medoxomil according to any one of claims 1-2 and 5, characterized in that the TG profile of the novel crystal form of the sodium salt of alisrtan medoxomil shows a 3.02% change in mass of the novel crystal form of the sodium salt of alisrtan medoxomil from 0 to 90 ℃ and a further 4.08% change in mass of the novel crystal form of the sodium salt of alisrtan medoxomil from 90 to 120 ℃.
7. The novel crystal form of the sodium salt of aliskirsite according to claim 3, characterized in that the TG profile of the novel crystal form of the sodium salt of aliskirsite shows a 3.02% change in mass of the novel crystal form of the sodium salt of aliskirsite from 0 to 90 ℃, and a further 4.08% change in mass of the novel crystal form of the sodium salt of aliskirsite from 90 to 120 ℃.
8. The novel crystal form of the sodium salt of aliskirsite according to claim 4, wherein the TG profile of the novel crystal form of the sodium salt of aliskirsite shows a 3.02% change in mass of the novel crystal form of the sodium salt of aliskirsite from 0 to 90 ℃, and a further 4.08% change in mass of the novel crystal form of the sodium salt of aliskirsite from 90 to 120 ℃.
9. The novel crystal form of the sodium salt of aliskirilowii in any one of claims 1-2, 5, 7-8, characterized in that the XRD spectrum of the novel crystal form of the sodium salt of aliskirilowii is shown in figure 5 and the DSC and/or TG spectrum is shown in figure 6.
10. A novel crystal form of the sodium salt of alisartan according to claim 3, characterized in that the XRD spectrum of the novel crystal form of the sodium salt of alisartan is shown in figure 5 and the DSC and/or TG spectrum is shown in figure 6.
11. The novel crystal form of the sodium salt of alisartan according to claim 4, characterized in that the XRD spectrum of the novel crystal form of the sodium salt of alisartan is shown in figure 5 and the DSC and/or TG spectrum is shown in figure 6.
12. The novel crystal form of the sodium salt of alisartan according to claim 6, characterized in that the XRD spectrum of the novel crystal form of the sodium salt of alisartan is shown in figure 5 and the DSC and/or TG spectrum is shown in figure 6.
13. A process for preparing a novel crystalline form of the sodium salt of aliskirsite according to any one of claims 1 to 12, comprising the steps of:
1) Weighing an initial sample of alisrtan medoxomil and sodium hydroxide, and placing the initial sample of alisrtan medoxomil and sodium hydroxide in a reaction bottle;
2) Adding an organic solvent;
3) Stirring and heating to 30-40 ℃ and keeping the temperature for stirring for 48-72 hours;
4) Supplementing the organic solvent in the step 2), and reducing the temperature to 0 ℃ at 0.5-1 ℃/min;
5) Stirring at the temperature for 10-12 hours, vacuum filtering to separate solid under the protection of nitrogen, and vacuum drying at 30-50 ℃ for 6-12 hours;
in the preparation step, the molar ratio of the alisrtan medoxomil to the sodium hydroxide is 1:0.95-1.05, and the organic solvent is one or a mixed solvent of more than two of isopropyl acetate, isobutyl acetate, n-heptane and methyl tertiary butyl ether in any proportion, or acetone: n-heptane=1:1 to 4 (v/v) mixed solvent; the dosage of the organic solvent in the step (2) is as follows: the mass volume ratio of the alisrtan cilexetil to the organic solvent is 0.05-0.15 g/ml, the types of the solvents supplemented in the step (4) are consistent with those of the step (2), and the proportion of the solvents to the dosage of the step (2) is 1-2:1 (v/v).
14. The preparation method of the novel crystal form of the sodium salt of the alisartan according to claim 13, wherein the organic solvent is methyl tertiary butyl ether.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101195615A (en) * 2006-12-06 2008-06-11 上海艾力斯医药科技有限公司 Salt of imidazole-carboxylic acid derivant, production method and pharmaceutical composition thereof
CN101407511A (en) * 2007-10-11 2009-04-15 上海艾力斯医药科技有限公司 Crystal type glyoxaline-5-carboxyl acid derivative
CN104610232A (en) * 2013-11-01 2015-05-13 深圳信立泰药业股份有限公司 Allisartan isoproxil amorphous substance and preparation method thereof, and pharmaceutical composition comprising allisartan isoproxil amorphous substance
CN106188012A (en) * 2014-06-20 2016-12-07 深圳信立泰药业股份有限公司 A kind of A Lishatan ester crystallization and preparation method thereof and the pharmaceutical composition containing this crystallization

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101195615A (en) * 2006-12-06 2008-06-11 上海艾力斯医药科技有限公司 Salt of imidazole-carboxylic acid derivant, production method and pharmaceutical composition thereof
CN101407511A (en) * 2007-10-11 2009-04-15 上海艾力斯医药科技有限公司 Crystal type glyoxaline-5-carboxyl acid derivative
CN104610232A (en) * 2013-11-01 2015-05-13 深圳信立泰药业股份有限公司 Allisartan isoproxil amorphous substance and preparation method thereof, and pharmaceutical composition comprising allisartan isoproxil amorphous substance
CN106188012A (en) * 2014-06-20 2016-12-07 深圳信立泰药业股份有限公司 A kind of A Lishatan ester crystallization and preparation method thereof and the pharmaceutical composition containing this crystallization

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