CN115947722A - Alisartan cilexetil sodium salt crystal form and pharmaceutical composition containing sodium salt crystal form - Google Patents
Alisartan cilexetil sodium salt crystal form and pharmaceutical composition containing sodium salt crystal form Download PDFInfo
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- CN115947722A CN115947722A CN202310017139.6A CN202310017139A CN115947722A CN 115947722 A CN115947722 A CN 115947722A CN 202310017139 A CN202310017139 A CN 202310017139A CN 115947722 A CN115947722 A CN 115947722A
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- allisartan
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- sodium salt
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- 239000013078 crystal Substances 0.000 title claims abstract description 126
- -1 cilexetil sodium salt Chemical class 0.000 title claims abstract description 54
- 159000000000 sodium salts Chemical class 0.000 title claims description 29
- 229950006523 cilexetil Drugs 0.000 title claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 title description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- XMHJQQAKXRUCHI-UHFFFAOYSA-N propan-2-yloxycarbonyloxymethyl 2-butyl-5-chloro-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound CCCCC1=NC(Cl)=C(C(=O)OCOC(=O)OC(C)C)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 XMHJQQAKXRUCHI-UHFFFAOYSA-N 0.000 claims description 90
- 229960004773 losartan Drugs 0.000 claims description 30
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 24
- 238000001228 spectrum Methods 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 10
- 229940011051 isopropyl acetate Drugs 0.000 claims description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 238000005303 weighing Methods 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 8
- 238000003828 vacuum filtration Methods 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 230000008859 change Effects 0.000 claims description 6
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 4
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 4
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 4
- 230000001502 supplementing effect Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 49
- 238000010521 absorption reaction Methods 0.000 description 39
- 238000001514 detection method Methods 0.000 description 33
- 238000002441 X-ray diffraction Methods 0.000 description 32
- 159000000007 calcium salts Chemical class 0.000 description 32
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 13
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- VTDCYOLLYVAJSY-UHFFFAOYSA-N cyclohexyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OC1CCCCC1 VTDCYOLLYVAJSY-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000006073 displacement reaction Methods 0.000 description 8
- 238000002411 thermogravimetry Methods 0.000 description 7
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 4
- 239000000920 calcium hydroxide Substances 0.000 description 4
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IXHOXXFTTQTNQS-UHFFFAOYSA-N [Ca].[Na].[K] Chemical compound [Ca].[Na].[K] IXHOXXFTTQTNQS-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- JYGYEBCBALMPDC-UHFFFAOYSA-N heptane;propan-2-one Chemical compound CC(C)=O.CCCCCCC JYGYEBCBALMPDC-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- AAZYNPCMLRQUHI-UHFFFAOYSA-N propan-2-one;2-propan-2-yloxypropane Chemical compound CC(C)=O.CC(C)OC(C)C AAZYNPCMLRQUHI-UHFFFAOYSA-N 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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Classifications
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a series of new crystal forms of allisartan isoproxil sodium salt and a preparation method thereof.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to an allisartan isoproxil crystal form, a preparation method thereof and a pharmaceutical composition containing the crystal form.
Background
Allisartan isoproxil (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: xinritan is a novel angiotensin II receptor antagonist (AT 1), the structural formula of which is disclosed in the patent WO2007095789 for the first time, and the application of the Xinritan in preparing a hypertension drug is disclosed. Compared with the product (such as losartan) which is an angiotensin II receptor antagonist, the allisartan isoproxil has obvious advantage in blood pressure reduction effect, and the renal toxicity is lower than that of the like product.
In order to find the most suitable form of the active ingredient for medicinal use, a series of salts of the active ingredient are generally researched in the process of medicament development, specifically, the carboxylate compound of the allisartan isoproxil corresponding to the salt formed at the tetrazole position generally has better solubility in a polar solvent, and in addition, the salt of the active ingredient may have unpredictable advantages in physicochemical properties such as stability, hygroscopicity and the like.
Patent CN101195615A discloses a series of allisartan isoproxil salts, including potassium salt, sodium salt, calcium salt, magnesium salt, zinc salt, lithium salt, ammonium salt, etc., which respectively disclose the preparation methods of the potassium salt, sodium salt, calcium salt of allisartan isoproxil in examples 2-9; specifically, according to the description of the patent specification, the melting point of the allisartan isoproxil potassium salt obtained according to the patent method is 189.5-189.7 ℃, the melting point of the allisartan isoproxil sodium salt obtained according to the patent method is 93.0-96.8 ℃, the melting point of the allisartan isoproxil calcium salt obtained according to the patent method is 156.2-156.7 ℃, and in the subsequent solubility experiment and the drug absorption experiment, the allisartan isoproxil potassium salt, the sodium salt and the calcium salt all show better solubility, shorter peak reaching time and higher bioavailability than the allisartan isoproxil.
Patent CN101715448A discloses the use of an allisartan cilexetil compound for treating target organ damage caused by various hypertensions, which discloses a method for preparing an allisartan cilexetil potassium salt in example 1, wherein the melting point of the allisartan cilexetil potassium salt prepared according to the method is 189.5-189.7 ℃, and further discloses capsules and tablets containing the allisartan cilexetil potassium salt in example 6 and example 7.
Patent CN102088972A discloses a pharmaceutical composition containing alisartan medoxomil, examples 1-3 thereof respectively disclose preparation methods of potassium, sodium and calcium salts of alisartan medoxomil (consistent with the preparation method disclosed in patent CN 101195615), and disclose a pharmaceutical composition containing alisartan medoxomil potassium salt; specifically, the allisartan isoproxil disclosed in the patent shows better solubility than that of allisartan isoproxil in methanol and water, and the allisartan isoproxil potassium salt shows higher stability under the conditions of illumination, high temperature and high humidity.
Although the prior art provides a plurality of allisartan isoproxil salts, the most suitable medicinal crystal forms of the allisartan isoproxil salts are not screened, so that the problem that the prior art does not solve is to find the crystal forms of the allisartan isoproxil salts which have better stability and are more suitable for medicinal use.
Disclosure of Invention
The invention aims to solve the incomplete task of the prior art and provides a series of allisartan isoproxil crystal forms and a corresponding method capable of stably preparing the allisartan isoproxil crystal forms, wherein the allisartan isoproxil crystal forms are different from the allisartan isoproxil crystal forms disclosed by the prior art, and compared with the allisartan isoproxil crystal forms disclosed by the prior art, the allisartan isoproxil crystal forms have the advantages of at least one aspect of solubility, stability (thermal stability, light stability, hygroscopicity and the like), fluidity and the like, and the comprehensive evaluation is more suitable for pharmaceutical use. Specifically, the new crystal forms of the allisartan isoproxil salt are a new crystal form of sylvite, a new crystal form of sodium salt and a new crystal form of calcium salt.
The first purpose of the invention is to provide a new crystal form of the allisartan cilexetil potassium salt, wherein the X-ray powder diffraction (XRD) spectrum of the new crystal form of the allisartan cilexetil potassium salt has peaks at 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 degrees of 2 theta, and the error range is +/-0.2 degrees; for the group of absorption peaks with relative intensity of more than 20%, those skilled in the art can understand that, due to different detection conditions and detection instruments, the probability of repeated appearance of peaks with large absorption intensity is very high, and the peaks occur in repeated detection between different batches and in the same batch and can be used as characteristic peaks of the new crystal form.
The XRD spectrogram of the new crystal form of the alisartan medoxomil potassium salt 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 reproducibility of the new crystal form of the alisartan medoxomil potassium salt is lower than that of the characteristic peaks because the relative intensity of the absorption peaks is lower (10-20 percent) than that of the characteristic peaks in the previous group and the relative intensity of the absorption peaks is influenced by certain factors such as detection conditions, detection instruments and the like and correspondingly has displacement deviation or certain fluctuation of the absorption intensity.
The XRD spectrogram of the new crystal form of the alisartan medoxomil potassium salt further has peaks at 31.8, 33.2, 33.7 and 34.7 with an error range of +/-0.2 degrees, and the relative intensity of the group of absorption peaks is the lowest (not more than 10 percent), so that the group of absorption peaks is greatly influenced by objective factors such as detection conditions, detection instruments and the like, displacement deviation or fluctuation of absorption intensity occurs, and even certain repeatedly detected spectrograms do not occur, so that the reproducibility of the group of peaks is the lowest.
The Differential Scanning Calorimetry (DSC) spectrogram of the new crystal form of the allisartan isoproxil potassium salt has an endothermic peak at 169.8 +/-5 ℃.
A thermal analysis (TG) spectrogram of the new allisartan isoproxil crystal form shows that the mass change of the new allisartan isoproxil crystal form is 1.58% from 0-120 ℃, and the new allisartan isoproxil crystal form is melt and decomposed at 169.8 +/-5 ℃ by combining the DSC spectrogram and the TG spectrogram of the new allisartan isoproxil crystal form, while the melting point of the allisartan isoproxil potassium salt disclosed by the prior art is 189.5-189.7 ℃.
The second purpose of the invention is to provide a method for stably preparing the new crystal form of the allisartan isoproxil potassium salt, which can stably prepare the new crystal form of the allisartan isoproxil potassium salt with high purity and high uniformity, and also consider various requirements of large-scale production, such as cost reduction, recycling and the like. Specifically, the new crystal form of the allisartan isoproxil potassium salt comprises the following steps:
1) Weighing initial samples of allisartan isoproxil and potassium hydroxide and placing the initial samples in a reaction bottle;
2) Adding a dehydrated organic solvent;
3) Then stirring and heating to 30-40 ℃, keeping the temperature and stirring for 8-12 hours;
4) Supplementing the organic solvent in the step 2), and reducing the temperature to 0 ℃ at the speed of 0.5-1 ℃/min;
5) Keeping the temperature and stirring for 3-6 hours, carrying out vacuum filtration to separate solid under the protection of nitrogen, and carrying out vacuum drying for 6-12 hours at 30-50 ℃.
In the above preparation steps, the molar ratio of alisartan medoxomil to potassium hydroxide is 1.9-1.2, the type, amount, temperature and time of the organic solvent in the preparation method are important factors for obtaining the crystal form, specifically, the type and amount of the solvent are different, which may affect the obtaining of the crystal form of alisartan medoxomil potassium salt, and the organic solvent is one or more than two mixed solvents obtained by mixing isopropyl acetate, isobutyl acetate, n-heptane and methyl tert-butyl ether in any proportion, or acetone: a mixed solvent of n-heptane =1 to 4 (v/v); preferred are isopropyl acetate, acetone: n-heptane =1 (v/v), and the amount of the organic solvent used in the step (2) is: the mass volume ratio of the allisartan isoproxil to the organic solvent is 0.1-0.3 g/ml, the dosage of the solvent supplemented in the step (4) is consistent with that in the step (2), the ratio of the dosage to that in the step (2) is 1-2 (v/v), and all the organic solvents in the preparation method are subjected to anhydrous pretreatment;
the third purpose of the invention is to provide a new crystal form of the alisartan sodium ester salt. For the new crystal form of the alisartan medoxomil sodium salt, the X-ray powder diffraction (XRD) spectrogram of the crystal form has 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 of 2 theta, and the error range is +/-0.2 degrees; the group of absorption peaks is peaks with relative intensity of more than 20%, and those skilled in the art can understand that due to different detection conditions and detection instruments, the probability of repeated appearance of peaks with large absorption intensity is extremely 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 new crystal form.
The XRD spectrogram of the new allisartan isoproxil sodium salt crystal form further has peaks at 10.8, 13.3, 21.1, 24.1 and 25.4, and the error range is +/-0.2 degrees; the relative intensity of the group of absorption peaks is lower (10-20%) than that of the previous group of characteristic peaks, and the group of absorption peaks is influenced by objective factors such as detection conditions and detection instruments to a certain extent and correspondingly has displacement deviation or certain fluctuation of absorption intensity, so that the reproducibility of the group of absorption peaks is lower than that of the previous group of characteristic peaks.
The XRD spectrogram of the new crystal form of the alisartan medoxomil 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 reproducibility of the new crystal form of the alisartan medoxomil sodium salt is lower than that of the characteristic peaks because the relative intensity of the absorption peaks is lower (not more than 10 percent) than that of the characteristic peaks in the previous group, which is influenced by certain factors such as detection conditions, detection instruments and the like and correspondingly has displacement deviation or certain fluctuation of the absorption intensity, so that the new crystal form of the alisartan medoxomil sodium salt cannot become the characteristic peaks.
The Differential Scanning Calorimetry (DSC) spectrogram of the new crystal form of the alisartan medoxomil sodium salt has an endothermic peak at 123.0 +/-5 ℃.
A thermal analysis (TG) spectrogram of the new allisartan cilexetil sodium salt crystal form shows that the mass of the new allisartan cilexetil sodium salt crystal form changes by 3.02% from 0-90 ℃, the mass of the new allisartan cilexetil sodium salt crystal form further changes by 4.08% from 90-120 ℃, and the new allisartan cilexetil sodium salt crystal form starts to melt and decompose at 123.0 +/-5 ℃ by combining the DSC spectrogram and the TG spectrogram of the new allisartan cilexetil sodium salt crystal form, but the melting point of the allisartan cilexetil sodium salt disclosed by the prior art is 93.0-96.8 ℃.
The fourth purpose of the invention is to provide a method for stably preparing the novel crystal form of the alisartan medoxomil sodium salt, which can stably prepare the novel crystal form of the alisartan medoxomil sodium salt with high purity and high uniformity and is suitable for large-scale industrial production.
The preparation method of the novel crystal form of the allisartan isoproxil sodium salt comprises the following steps:
1) Weighing initial samples of allisartan isoproxil and sodium hydroxide and placing the initial samples in a reaction bottle;
2) Adding an organic solvent;
3) Then stirring and heating to 30-40 ℃, keeping the temperature and stirring for 48-72 hours;
4) Supplementing the organic solvent in the step 2), and reducing the temperature to 0 ℃ at the speed of 0.5-1 ℃/min;
5) Keeping the temperature and stirring for 10-12 hours, carrying out vacuum filtration to separate solid under the protection of nitrogen, and carrying out vacuum drying for 6-12 hours at 30-50 ℃.
In the above preparation steps, the molar ratio of alisartan medoxomil to sodium hydroxide is 1.95-1.05, the type, amount, temperature and time of an organic solvent in the preparation method are important factors for obtaining the crystal form, specifically, the type and amount of the solvent are different and may affect the obtaining of the new crystal form a of alisartan medoxomil sodium salt, and the organic solvent is one or a mixture of more than two of isopropyl acetate, isobutyl acetate, n-heptane and methyl tert-butyl ether, or acetone: a mixed solvent of n-heptane =1 to 4 (v/v); methyl tert-butyl ether is preferred, and the amount of the organic solvent in the step (2) is as follows: the mass volume ratio of the allisartan isoproxil to the organic solvent is 0.05-0.15 g/ml, the dosage of the solvent supplemented in the step (4) is consistent with that in the step (2), and the ratio of the dosage to that in the step (2) is 1-2 (v/v).
A fifth object of the present invention is to provide a novel crystalline form of the calcium salt of allisartan isoproxil. For the new crystal form of the calcium salt of the allisartan isoproxil, 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 degrees of 2 theta, and the error range is +/-0.2 degrees; for the group of absorption peaks with relative intensity of more than 20%, those skilled in the art can understand that, due to different detection conditions and detection instruments, the probability of repeated appearance of peaks with large absorption intensity is very high, and the peaks occur in repeated detection between different batches and in the same batch and can be used as characteristic peaks of the new crystal form.
The XRD spectrogram of the new allisartan isoproxil calcium salt crystal form further 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 reproducibility of the new allisartan isoproxil calcium salt crystal form is lower than that of the characteristic peaks because the relative intensity of the absorption peaks is lower (10-20 percent) compared with that of the characteristic peaks in the previous group, and the relative intensity of the absorption peaks is influenced by certain factors such as detection conditions, detection instruments and the like and correspondingly has displacement deviation or certain fluctuation of the absorption intensity, so that the reproducibility of the new allisartan isoproxil calcium salt crystal form is lower than that of the characteristic peaks.
The XRD spectrogram of the new allisartan isoproxil calcium salt crystal form further has peaks at 11.0, 26.0, 26.7, 30.9, 32.3 and 37.5 with an error range of +/-0.2 degrees, and the repeatability of the group of peaks is lowest because the relative intensity of the group of absorption peaks is lowest (not more than 10 percent), which is greatly influenced by objective factors such as detection conditions, detection instruments and the like, and displacement deviation or fluctuation of absorption intensity occurs, even some repeatedly detected spectrograms do not occur.
The Differential Scanning Calorimetry (DSC) spectrogram of the new crystal form of the alisartan medoxomil calcium salt has exothermic peaks/endothermic peaks at 113.7 +/-5 ℃ and 143.6 +/-5 ℃.
The Thermogravimetry (TG) spectrogram of the new allisartan isoproxil calcium salt crystal form shows that the mass change of the new allisartan isoproxil calcium salt crystal form from 0-90 ℃ is 3.85 percent, the mass change of the new allisartan isoproxil calcium salt crystal form from 90-160 ℃ is 7.28 percent, the mass change of the new allisartan isoproxil calcium salt crystal form from 160-220 ℃ is 12.29 percent, and the combination of the DSC spectrogram and the TG spectrogram of the new allisartan isoproxol calcium salt crystal form shows that the new allisartan isoproxol calcium salt crystal form is molten and decomposed at 143.6 +/-5 ℃, while the melting point of the allisartan isoproxol calcium salt disclosed by the prior art is 156.2-156.7 ℃.
The sixth purpose of the present invention is to provide a method for stably preparing a new crystal form of calcium salt of allisartan cilexetil, which is suitable for large-scale production, and which can stably prepare the new crystal form of calcium salt of allisartan cilexetil with high purity and high uniformity.
The preparation method of the new allisartan isoproxil calcium salt crystal form comprises the following steps:
1) Weighing initial samples of allisartan isoproxil and calcium hydroxide and placing the initial samples in a reaction bottle;
2) Adding a dehydrated organic solvent;
3) Then stirring and heating to 30-40 ℃, keeping the temperature and stirring for 96-120 hours;
4) Supplementing the organic solvent in the step 2), and reducing the temperature to 0 ℃ at the speed of 0.5-1 ℃/min;
5) Keeping the temperature and stirring for 12-24 hours, carrying out vacuum filtration to separate solids under the protection of nitrogen, and carrying out vacuum drying for 6-12 hours at 30-50 ℃.
In the above preparation steps, the molar ratio of alisartan medoxomil to calcium hydroxide is 1.49-0.51, the type, amount, temperature and time of the organic solvent in the preparation method are important factors for obtaining the crystal form, specifically, the type and amount of the solvent are different and may affect the obtaining of the crystal form of the alisartan medoxomil potassium salt, and the organic solvent is one or a mixture of more than two of isopropyl acetate, isobutyl acetate, n-heptane and methyl tert-butyl ether, or acetone: a mixed solvent of n-heptane =1 to 4 (v/v); isopropyl acetate is preferred, and the amount of the organic solvent in the step (2) is as follows: the mass volume ratio of the allisartan isoproxil to the organic solvent is 0.1-0.2 g/ml, the dosage of the solvent supplemented in the step (4) is consistent with that in the step (2), the ratio of the dosage to that in the step (2) is 1-2 (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 new crystal form is superior to the corresponding crystal form of the allisartan isoproxil in at least one aspect of solubility, stability (thermal stability, light stability, hygroscopicity and the like), fluidity and the like, and the comprehensive evaluation is more suitable for pharmaceutical use;
2. the method for preparing the new crystal forms of the potassium salt, the sodium salt and the calcium salt of the allisartan isoproxil is provided, the new crystal forms of the potassium salt, the sodium salt and the calcium salt of the allisartan isoproxil with high purity and good uniformity can be stably prepared, and the method is suitable for industrial large-scale production.
Drawings
FIG. 1 XRD spectrum of new crystal form of potassium allisartan isoproxil obtained in example 2
FIG. 2 DSC-TG spectrum of new crystal form of allisartan isoproxil potassium salt obtained in example 2
FIG. 3 shows XRD (X-ray diffraction) spectrum of new crystal form of allisartan isoproxil potassium salt obtained in detection example 2
FIG. 4 XRD spectrum of new crystal form of potassium allisartan isoproxil obtained in example 3
FIG. 5 XRD spectrum of new crystal form of sodium alisartan medoxomil in example 4
FIG. 6 DSC-TG spectrogram of new form of sodium allisartan cilexetil obtained in example 4
FIG. 7 XRD spectrum of new crystal form of calcium salt of allisartan isoproxil obtained in example 5
FIG. 8 DSC-TG spectrum of new crystal form of calcium salt of allisartan isoproxil obtained in example 5
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the invention are not limited thereto.
Example 1
Preparation method of allisartan isoproxil
The allisartan cilexetil starting material was prepared by the method disclosed in patent CN101195615A, example 1.
Example 2
Preparation method of novel allisartan isoproxil potassium salt crystal form
1) Weighing 5.1g of allisartan isoproxil and 0.6g of potassium hydroxide, and placing the allisartan isoproxil and the potassium hydroxide into a reaction bottle;
2) Adding 30ml of anhydrous isopropyl acetate, stirring and heating to 35 ℃;
3) Keeping the temperature and stirring for 10 hours;
4) Slowly adding 50mL of anhydrous isopropyl acetate, and reducing the temperature of the system to 0 ℃ at a speed of 0.5-1 ℃/min;
5) Keeping the temperature and stirring for 4 hours, carrying out vacuum filtration to separate solids under the protection of nitrogen, and carrying out vacuum drying for 8 hours at the temperature of 30-50 ℃ to obtain 4.4g of white solids;
an XRD spectrogram of the new crystal form of the allisartan isoproxil potassium salt is shown in figure 1, a DSC-TG spectrogram is shown in figure 2, and a spectrogram obtained by repeated XRD detection is shown in figure 3.
Example 3
Preparation method of allisartan isoproxil potassium salt new crystal form
1) Weighing 5.2g of allisartan isoproxil and 0.51g of potassium hydroxide, and placing the allisartan isoproxil and the potassium hydroxide into a reaction bottle;
2) Adding 30ml of anhydrous treated acetone-n-heptane 1 mixed solvent, and then stirring and heating to 35 ℃;
3) Keeping the temperature and stirring for 10 hours;
4) Slowly adding 50mL of acetone-n-heptane subjected to anhydrous treatment, and reducing the temperature of the system to 0 ℃ at the speed of 0.5-1 ℃/min;
5) Keeping the temperature and stirring for 4 hours, carrying out vacuum filtration to separate the solid under the protection of nitrogen, and carrying out vacuum drying for 8 hours at the temperature of 30-50 ℃ to obtain 4.2g of white solid, wherein the white solid is detected as the allisartan isoproxil potassium salt crystal form consistent with the example 2;
the XRD spectrum of the new crystal form of the allisartan isoproxil potassium salt is shown in figure 4 and is basically consistent with the product obtained in example 2, and the DSC-TG spectrum is also basically consistent with the product obtained in example 2.
By integrating XRD spectrograms obtained by repeated detection of samples in the same batch and in the same batch represented by figures 1, 3 and 4, the XRD spectrogram of the new crystal form of the alisartan medoxomil potassium salt has 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 of 2 theta, the error range is +/-0.2 degrees, the absorption peaks are peaks with the relative intensity of more than 20 percent, the probability of repeated appearance of the group of peaks is high, and the absorption peaks appear in repeated detection in different batches and in the same batch and can be used as characteristic peaks of the new crystal form;
the XRD spectrogram of the new crystal form of the allisartan isoproxil potassium salt 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, the relative intensity of the absorption peaks in the group is 10-20 percent, and the reproducibility of the peaks in the group is lower than that of the characteristic peaks;
the XRD spectrogram of the new crystal form of the allisartan isoproxil potassium salt 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 in the group is not more than 10 percent, and the reproducibility of the peaks in the group is lowest.
Example 4
Preparation method of novel crystal form of allisartan isoproxil sodium salt
1) Weighing 3g of allisartan isoproxil and 0.21 g of sodium hydroxide, and placing the allisartan isoproxil and the sodium hydroxide into a reaction bottle;
2) Adding 30ml of methyl tert-butyl ether, stirring and heating to 35 ℃;
3) Keeping the temperature and stirring for 60 hours;
4) Slowly adding 60mL of methyl tert-butyl ether, and reducing the temperature of the system to 0 ℃ at the speed of 0.5-1 ℃/min;
5) Keeping the temperature and stirring for 10 hours, carrying out vacuum filtration to separate solids under the protection of nitrogen, and carrying out vacuum drying for 10 hours at the temperature of 30-50 ℃ to obtain 2.3g of white solids;
the XRD spectrogram and DSC-TG spectrogram of the new crystal form of the alisartan medoxomil sodium salt are shown in figures 5 and 6 respectively.
By integrating XRD spectrograms obtained by repeated detection of samples in the same batch and among batches represented by figure 5, the XRD spectrograms of the new crystal form of the alisartan medoxomil sodium salt 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 of 2 theta, and the error range is +/-0.2 degrees; the relative intensity of the absorption peaks is more than 20%, the probability of repeated occurrence is extremely high, and the absorption peaks occur in repeated detection among different batches and in the same batch and are characteristic peaks of the new crystal form;
the XRD spectrogram of the new crystal form of the alisartan medoxomil 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 percent, and the reproducibility of the peaks is lower than that of the characteristic peaks;
the XRD spectrogram of the new crystal form of the alisartan medoxomil sodium salt further has 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 in the group is not more than 10 percent, and the reproducibility of the peaks in the group is the lowest.
Example 5
Preparation method of novel allisartan isoproxil calcium salt crystal form
1) Weighing 5g of allisartan isoproxil and 0.34 g of calcium hydroxide, and placing the allisartan isoproxil and the calcium hydroxide into a reaction bottle;
2) Adding 30ml of anhydrous isopropyl acetate, stirring and heating to 35 ℃;
3) Keeping the temperature and stirring for 100 hours;
4) Slowly adding 50mL of anhydrous isopropyl acetate, and reducing the temperature of the system to 0 ℃ at a speed of 0.5-1 ℃/min;
5) Keeping the temperature and stirring for 15 hours, carrying out vacuum filtration to separate solids under the protection of nitrogen, and carrying out vacuum drying for 10 hours at the temperature of 30-50 ℃ to obtain 3.8g of white solids;
the XRD spectrum of the new crystal form of the allisartan isoproxil calcium salt is shown in figure 7, and the DSC-TG spectrum is shown in figure 8.
By integrating XRD spectrograms obtained by repeated detection of samples in the same batch and among batches represented by figure 7, the XRD spectrograms of the new crystal form of the calcium salt of the allisartan isoproxil have peaks at positions with 2 theta of 6.7, 14.2, 14.5, 15.3, 17.3, 20.3, 20.6, 24.2, 25.1 and 29.4, and the error range is +/-0.2 degrees; the absorption peaks are peaks with relative intensity of more than 20%, the probability of repeated occurrence 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 form;
the XRD spectrogram of the new allisartan isoproxil calcium salt crystal form further 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 can be influenced by certain factors such as detection conditions, detection instruments and the like and correspondingly has displacement deviation or certain fluctuation of the absorption intensity, so the reproducibility of the novel allisartan isoproxil calcium salt crystal form is lower than that of the characteristic peak;
the XRD spectrogram of the new allisartan isoproxil calcium salt crystal form further has peaks at 11.0, 26.0, 26.7, 30.9, 32.3 and 37.5 with an error range of +/-0.2 degrees, and the relative intensity of the absorption peaks does not exceed 10 percent, and the peaks can be greatly influenced by objective factors such as detection conditions, detection instruments and the like, and have displacement deviation or fluctuation of absorption intensity, even some repeatedly detected spectrograms do not appear, so the reproducibility of the peaks is lowest.
Comparative example 1
Using the same preparation conditions and dosage ratios as in example 2, the solvent was simply exchanged for isopropyl ether as in CN101195615A, example 2, ethanol =3 (v/v), and the melting point of the resulting potassium salt of allisartan isoproxil was 189.5 ℃, in agreement with that reported in patent CN 101195615A.
Comparative example 2
Using the same preparation conditions and charge ratios as in example 4, the solvent was simply exchanged for an isopropyl ether-ethanol solvent system (3, 1,v/v) similar to that of 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 dosage ratios as in example 5, the solvent was simply exchanged for an isopropyl ether acetone solvent system (3, 1,v/v) similar to that of example 7 of CN101195615A, and the melting point of the obtained alisartan medoxomil calcium salt was 156.5 ℃, consistent with that reported in patent CN 101195615A.
Comparative stability test
High temperature test
Weighing 8-12mg of the corresponding solid samples of examples 2-5 and comparative examples 1-3, respectively, in a 1.5ml HPLC vial, using the sample vials in the conditions of 25 ℃/60% RH and 40 ℃/60%
After the sealing film is sealed, about 20 small pinholes are pricked and placed for storage, samples are taken after one week for HPLC test, the samples under the condition of 80 ℃ are sealed by a bottle cap and placed for storage, and the samples are taken after one day for HPLC test, and the results are shown in table 1.
TABLE 1 high temperature test results
From the above results, it can be seen that: the new crystal forms of allisartan isoproxil potassium salt, sodium salt and calcium salt are relatively stable under the high-temperature condition.
Compared with the allisartan isoproxil potassium salt, the allisartan isoproxil sodium salt and the calcium salt, a high-temperature comparison test is carried out under the same condition, and the allisartan isoproxil potassium salt, the allisartan isoproxil sodium salt and the calcium salt have better stability compared with the allisartan isoproxil potassium salt, the allisartan isoproxil sodium salt and the calcium salt.
(II) high-humidity experiment: the new crystal forms of the potassium allisartan isoproxil of example 2 and example 3, the new crystal form of the sodium allisartan isoproxil of example 4, the new crystal form of the calcium allisartan isoproxil of example 5 and the samples of comparative examples 1-3 were weighed separately in 5 portions, each of 1g, and each was placed in a petri dish in a constant temperature and humidity chamber with RH92.5% (temperature 25 ± 1 ℃), and the samples were taken after 0 day, 1 day, 7 days and 14 days for measurement, and the results are shown in table 2.
TABLE 2 high humidity test results (RH 92.5%, 25. + -. 2 ℃ C.)
| Detecting the | Day | 0 | 1 day | 7 days | 14 days |
| Relative content of allisartan isoproxil potassium salt in new crystal form (%) | 100.00 | 99.05 | 98.69 | 98.62 | |
| Relative content of new crystal form of allisartan isoproxil potassium salt (%) | 99.99 | 99.21 | 99.02 | 98.54 | |
| Relative content of allisartan isoproxil sodium salt new crystal form (%) | 100.00 | 99.97 | 99.43 | 98.94 | |
| Relative content of the new form of the calcium salt of alisartan medoxomil (%) | 99.95 | 99.26 | 98.94 | 98.65 | |
| Relative content (%) | 99.99 | 98.73 | 96.26 | 95.13 | |
| |
99.98 | 97.15 | 96.42 | 94.89 | |
| |
100.00 | 96.78 | 96.71 | 95.80 |
From the above results, it can be seen that: the content of the allisartan isoproxil potassium salt new crystal form, the sodium salt new crystal form and the calcium salt new crystal form is basically consistent with that of 0 day after the allisartan isoproxil potassium salt new crystal form, the sodium salt new crystal form and the calcium salt new crystal form are placed for 7 days under the conditions of 25 +/-2 ℃ and RH92.5 percent, which indicates that the product is very stable under the high-humidity condition.
Compared with the potassium salt, the sodium salt and the calcium salt of the allisartan isoproxil, which are shown in the specification, have obviously better stability compared with the potassium salt, the sodium salt and the calcium salt of the allisartan isoproxil under the same conditions in a comparison high-humidity test.
Comparative test for flowability
Appropriate amounts of the corresponding solid samples of examples 2, 4 and 5 and comparative examples 1 to 3 were taken, and the powder repose angle was measured by a fixed hopper method; the bulk density of the powder was measured by the cylinder tapping method, and the results are shown in table 3:
TABLE 3 flowability test results
From the above results, it can be seen that: the allisartan isoproxil potassium salt new crystal form, the allisartan isoproxil sodium new crystal form and the allisartan isoproxil calcium salt new crystal form have better flowability compared with the allisartan isoproxil potassium salt, the sodium salt and the calcium salt, and the fact that the angle of repose of the allisartan isoproxil potassium sodium calcium salt new crystal form sample is smaller than that of the allisartan isoproxil potassium sodium calcium salt of a comparison document, and the bulk density is larger than that of the allisartan isoproxil 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 new crystal forms of the potassium salt, sodium salt and calcium salt obtained by the invention have the technical advantages of stability, fluidity and the like, and provide a better choice for preparing the preparation of the potassium salt, sodium salt and calcium salt of the allisartan isoproxil.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (8)
1. The novel crystal form of the alisartan sodium ester salt is characterized in that an XRD spectrogram of the novel crystal form of the alisartan sodium ester salt has peaks at positions with 2 theta 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.
2. The new crystalline form of the alisartan sodium ester salt according to claim 1, characterised in that the XRD spectrum of the new crystalline form of the alisartan sodium ester salt further has peaks at 10.8, 13.3, 21.1, 24.1, 25.4 with a tolerance range of ± 0.2 °.
3. The new crystalline form of allisartan cilexetil sodium salt according to any one of claims 1 or 2 characterized in that the XRD spectrum of said new crystalline form of allisartan cilexetil sodium salt further has peaks at 9.6, 12.6, 13.9, 14.7, 16.2 with a margin of error ± 0.2 °.
4. The new crystalline form of allisartan cilexetil sodium salt according to any one of claims 1 to 3 characterized in that its DSC spectrum has an endothermic peak at 123.0 ± 5 ℃.
5. The new crystalline form of allisartan cilexetil sodium salt according to any one of claims 1 to 4 characterized in that the TG spectrum of the new crystalline form of allisartan cilexetil sodium salt shows a 3.02% change in mass of the new crystalline form of allisartan cilexetil sodium salt from 0-90 ℃ and a further 4.08% change in mass of the new crystalline form of allisartan cilexetil sodium salt from 90-120 ℃.
6. The new crystalline form of the allisartan cilexetil sodium salt according to any one of claims 1 to 5, characterized in that the XRD spectrum and the DSC and/or TG spectrum are shown in fig. 5 and 6, respectively.
7. A process for preparing a new crystalline form of the sodium salt of allisartan isoproxil according to any one of claims 1-6 comprising the steps of:
1) Weighing initial samples of allisartan isoproxil and sodium hydroxide and placing the initial samples in a reaction bottle;
2) Adding an organic solvent;
3) Then stirring and heating to 30-40 ℃, keeping the temperature and stirring for 48-72 hours;
4) Supplementing the organic solvent in the step 2), and reducing the temperature to 0 ℃ at the speed of 0.5-1 ℃/min;
5) Keeping the temperature, stirring for 10-12 hours, carrying out vacuum filtration to separate solids under the protection of nitrogen, and carrying out vacuum drying for 6-12 hours at 30-50 ℃;
in the above preparation steps, the molar ratio of alisartan medoxomil to sodium hydroxide is 1.95 to 1.05, and the organic solvent is one or more of isopropyl acetate, isobutyl acetate, n-heptane and methyl tert-butyl ether, or a mixed solvent obtained by mixing them at any ratio, or acetone: a mixed solvent of n-heptane =1 to 4 (v/v); the dosage of the organic solvent in the step (2) is as follows: the mass volume ratio of the allisartan isoproxil to the organic solvent is 0.05-0.15 g/ml, the dosage of the solvent supplemented in the step (4) is consistent with that in the step (2), and the ratio of the dosage to the dosage in the step (2) is 1-2 (v/v).
8. The method for preparing the new crystal form of the alisartan ester sodium salt according to claim 7, wherein the organic solvent is methyl tert-butyl ether.
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| 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 |
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| 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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| CN109694369B (en) | 2023-02-14 |
| CN115974848A (en) | 2023-04-18 |
| CN115947722B (en) | 2024-04-02 |
| CN109694369A (en) | 2019-04-30 |
| CN115974848B (en) | 2024-04-02 |
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