CN116715660A - Amorphous matter of terglazan and preparation method thereof - Google Patents
Amorphous matter of terglazan and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000000126 substance Substances 0.000 claims abstract description 27
- 238000010521 absorption reaction Methods 0.000 claims abstract description 9
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 9
- 238000002411 thermogravimetry Methods 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000002329 infrared spectrum Methods 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000012266 salt solution Substances 0.000 claims description 4
- 239000012047 saturated solution Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- RHMQNXNXUZLEIY-UHFFFAOYSA-N methanol;2-propan-2-yloxypropane Chemical compound OC.CC(C)OC(C)C RHMQNXNXUZLEIY-UHFFFAOYSA-N 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 3
- 238000000354 decomposition reaction Methods 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 239000001301 oxygen Substances 0.000 abstract description 3
- 238000004458 analytical method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- 238000007792 addition Methods 0.000 description 2
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CLIQCDHNPDMGSL-HNNXBMFYSA-N 7-[[(4s)-5,7-difluoro-3,4-dihydro-2h-chromen-4-yl]oxy]-n,n,2-trimethyl-3h-benzimidazole-5-carboxamide Chemical compound C1COC2=CC(F)=CC(F)=C2[C@H]1OC1=C(N=C(C)N2)C2=CC(C(=O)N(C)C)=C1 CLIQCDHNPDMGSL-HNNXBMFYSA-N 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229950001401 tegoprazan Drugs 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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 discloses an amorphous substance of terglaprazan and a preparation method thereof. The amorphous substance has a broad peak between 5 degrees and 40 degrees of 2 theta of an X-ray powder diffraction XRPD spectrogram and no sharp diffraction peak. In thermogravimetric analysis (TGA), decomposition starts at 280±2 ℃, and the Differential Scanning Calorimeter (DSC) has a gentle absorption peak at 110 ℃ and an exothermic peak at 271 ℃. The amorphous substance of the terglaprazan has good solubility and high bioavailability, so that the medicine can better play a clinical treatment role. The amorphous substance is stable to light, temperature and oxygen, easy to store, excellent in stability under the light-shielding condition, reliable in preparation method and high in medicinal value.
Description
Technical Field
The invention relates to an amorphous substance of terglazan and a preparation method thereof, belonging to the technical field of biological medicine.
Background
The traditional treatment of acid related diseases is Proton Pump Inhibitors (PPI), which, although satisfactory, have some drawbacks. Tergorazan (Tegoprazan), which is currently considered to be the most advanced drug for treating gastroesophageal reflux disease, is a novel competitive potassium acid blocker (p-cab), and has been approved in korea for the treatment of gastroesophageal reflux disease, gastric ulcer and eradication of helicobacter pylori since month 7 in 2018, and has the following structural formula:
patent CN107207478B discloses crystalline form a of tegrazan and a process for its preparation, which has a melting point of 220-225 ℃, and the reported crystalline form a is low in solubility, although high in stability, and thus low in bioavailability per unit weight. As mentioned in the background of the patent, currently amorphous forms of tegretazan have high solubility with the advantage of increasing the efficacy of the drug and exhibiting quick-acting properties. However, the amorphous form has disadvantages of short shelf life and difficulty in adjusting the release rate of the drug and the blood concentration due to instability. While crystalline forms have higher stability and lower solubility than non-crystalline forms, sacrificing solubility and failing to meet both high stability and high solubility.
Therefore, at present, new tegretazan with good stability, good solubility, high bioavailability and obvious advantages are further needed to be mined.
Disclosure of Invention
The purpose of the invention is that: aiming at the technical problem that the existing amorphous form and crystal form of the terglaprazix cannot meet the requirements of high stability and high solubility at the same time, the invention provides the amorphous substance of the terglaprazix and the preparation method thereof, and the amorphous substance of the terglalazix has good solubility and high bioavailability, so that the medicine can better play a clinical treatment role; the amorphous substance is stable to light, temperature and oxygen, easy to store, excellent in stability under the light-shielding condition, reliable in preparation method and high in medicinal value.
In order to solve the technical problems, the technical scheme adopted by the invention is to provide an amorphous substance of the terglazan, which has a chemical structural formula shown as a formula I, wherein the amorphous substance has a wide peak between 5 and 40 degrees of 2 theta in an X-ray powder diffraction spectrogram, is an obvious amorphous characteristic peak, has no sharp absorption peak and is dispersive;
preferably, in the thermogravimetric analysis of the amorphous material, decomposition is initiated at 280±2 ℃;
and/or, in the differential scanning calorimetry analysis of the amorphous substance, there is an endothermic peak at 113 ℃ and an exothermic peak at 271 ℃, respectively.
And/or the IR spectrum of the amorphous material is 830.39cm -1 、1071.09cm -1 、1125.24cm -1 、1325.91cm -1 、1402.51cm -1 、1440.25cm -1 、1598.24cm -1 、2932.68cm -1 、3062.53cm -1 And 3124.64cm -1 With a characteristic absorption peak.
The invention also provides a preparation method of the amorphous substance of the terglazan, which is selected from any one of the following methods:
the method comprises the following steps: the amorphous matter of the terglazan is prepared by cooling or pulping the mixed solution of the terglazan raw material and the solvent;
the second method is as follows: dissolving a raw material of the terlazan in an organic solvent, and preparing an amorphous substance of the terlazan by volatilizing the solvent at room temperature;
and a third method: dissolving or suspending the raw material of the terlazan in an organic solvent, removing the solvent by reduced pressure distillation, and then drying in vacuum to obtain the amorphous matter of the terlazan;
the method four: dissolving a tegrazan raw material in a solvent to form a saturated solution, and separating out the amorphous substance of tegrazan in a mode of mixing the saturated solution with water;
and a fifth method: dispersing a terlazan raw material in water, adding acid into the obtained dispersion system, and dissolving to obtain a salt solution of the corresponding acid in the formula I; adding an alkali solution into the salt solution system to obtain a free alkali system of the formula I; collecting the solid separated out from the free alkali system of the formula I, and obtaining the amorphous substance of the terglazane.
The tegrazan raw material can be tegrazan which is commercially available or prepared by a method of existing literature or patent report, namely, any crystal form or mixed crystal form of the existing commercially available or reported tegrazan.
Preferably, the solvent in the first method is at least one of methanol, ethanol, acetonitrile, a methanol-water mixed solvent and a methanol-isopropyl ether mixed solvent.
Preferably, the organic solvent in the second method is at least one of methanol, ethanol, isopropanol, n-butanol, acetone and acetonitrile.
Preferably, the organic solvent in the third method is at least one of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1.4 dioxane, acetonitrile and acetone.
Preferably, the solvent in the fourth method is at least one of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1.4 dioxane, acetonitrile and acetone.
Preferably, the acid in the fifth method is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid and trifluoromethane sulfonic acid;
and/or the alkali solution in the fifth method is at least one of ammonia water, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution, sodium bicarbonate aqueous solution and potassium bicarbonate aqueous solution.
Compared with the prior art, the invention has the beneficial effects that:
the amorphous substance of the terglaprazan has good solubility and high bioavailability, so that the medicine can better play a clinical treatment role; meanwhile, the amorphous substance is stable to light, temperature and oxygen, easy to store, excellent in stability under the light-shielding condition, reliable in preparation method and great in medicinal value and application prospect.
Drawings
FIG. 1 is an X-ray powder diffraction analysis chart of commercially available crystalline form A of terglaprazix;
FIG. 2 is a Differential Scanning Calorimetric (DSC) curve of commercially available terglaprazix form A;
FIG. 3 is an X-ray powder diffraction analysis chart of the amorphous form of terglaprazan;
FIG. 4 is a thermogravimetric analysis (TGA) curve of the amorphous form of terglapran;
FIG. 5 is a Differential Scanning Calorimetric (DSC) curve of a terglazane amorphous;
FIG. 6 is an infrared spectrum (IR) diagram of the amorphous form of terglapran.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments accompanied with figures are described in detail below.
Materials, reagents and the like used in the following examples are commercially available ones unless otherwise specified.
Example 1 preparation of amorphous form of terglazane
50g of commercial tegrazan sample and 500mL of ethanol are added into a 1L single-mouth bottle, the mixture is heated and dissolved at the temperature of 85 ℃ and cooled to 0-10 ℃ and then is pulped for 4-5 hours, filtered and washed by a small amount of frozen ethanol. The filter cake is dried in vacuum at 40-50 ℃ to obtain 35.4g amorphous terglazan with yield: 70.8%.
Example 2 preparation of amorphous form of terglaprazan
50g of commercial terglazan sample and 500mL of methanol are added into a 1L single-port bottle, the mixture is heated and dissolved at 45 ℃ outside and then slowly cooled to room temperature, the mixture is placed in an open state for 5 to 10 days, solids are scraped after the solvent volatilizes, and the mixture is dried in vacuum at 40 to 50 ℃ to obtain 50g of amorphous terglazan, and the yield is: 100%.
Example 3 preparation of amorphous form of terglaprazan
50g of a commercial tegrazan sample and 500mL of methanol are added into a 1L single-port bottle, after stirring and clearing at 40 ℃, the solvent is concentrated under reduced pressure at the temperature, the solid is scraped off, and 50g of amorphous tegrazan is obtained after vacuum drying at 40-50 ℃, and the yield is: 100%.
Example 4 preparation of amorphous form of terglazane
To a 250mL single-necked flask, 50g of a commercially available tegrazan sample and 150mL of methanol were added, and the solution was heated at 65℃outside. Adding 1.5L of purified water into a 2L three-mouth bottle with a dropping funnel hollow plug, starting stirring, cooling to 0-10 ℃, transferring the methanol solution dissolved with the terglazan sample into the dropping funnel while the methanol solution is hot, and leaching with a small amount of methanol; slowly dripping into water, and keeping the internal temperature at 10 ℃. After the dripping is finished, stirring and crystallizing for 1-2 hours at the temperature, filtering and washing with a small amount of purified water. Vacuum drying the filter cake at 40-50 ℃ to obtain 45g of amorphous terglazan with the yield: 95%.
Example 5 preparation of amorphous form of terglaprazan
To a 500mL three-necked flask, 50g of a commercially available tegrazan sample and 150mL of purified water were added, stirring was started, concentrated hydrochloric acid (11.9 mL,0.14 mol) was added at room temperature, and stirring was performed at room temperature for 0.5-1h until the system was cleared. The system is cooled to 0-10 ℃, 100mL of 2M sodium hydroxide aqueous solution is slowly added dropwise, and the internal temperature is kept to be not more than 10 ℃. After the dripping is finished, stirring and crystallizing for 1-2 hours at the temperature, filtering and washing with a small amount of purified water. The filter cake was dried in vacuo at 40-50 ℃ to give 42.3g amorphous terglazan, yield: 84.6%.
EXAMPLE 6X-ray diffraction Spectrometry analysis of the amorphous form of terglapran
For the X-ray powder diffraction analysis of the amorphous substance of tegrazan prepared in examples 1 to 5, the spectra were measured and analyzed by using an X-ray powder diffractometer (scanning range: 5 to 40 ° (2. Theta.) step: 0.02 °; scanning rate: 12 °/min) from Bruker, and the results are shown in FIG. 3.
Specifically, the amorphous form of tegrazan prepared in examples 1 to 5 was confirmed to have a broad peak between 5 ° and 40 ° in the X-ray powder diffraction XRPD spectrum 2θ (fig. 3), to be a distinct amorphous characteristic peak, and to be a dispersion form, without a sharp absorption peak being present.
Example 7 IR spectroscopic analysis of amorphous matter of terglapran
IR spectroscopic analysis was performed on the amorphous form of tegrazan prepared in examples 1 to 5. Spectral measurements and analysis were performed using a fourier infrared spectrometer (Thermo corporation), the results of which are shown in fig. 6. As can be seen from FIG. 6, it was confirmed that the amorphous form of terlazan prepared in examples 1 to 5 of the present invention was 830.39cm in IR spectrum -1 、1071.09cm -1 、1125.24cm -1 、1325.91cm -1 、1402.51cm -1 、1440.25cm -1 、1598.24cm -1 、2932.68cm -1 、3062.53cm -1 And 3124.64cm -1 With a characteristic absorption peak.
Example 8 thermogravimetric analysis and differential scanning calorimetry analysis of the amorphous form of terglaprazan
Thermogravimetric analysis (TGA) of the amorphous form of tegrazan prepared in examples 1 to 5, the results of which are shown in fig. 4, and Differential Scanning Calorimetry (DSC) analysis using a DSC thermogram of TA Instruments company, the DSC thermogram being shown in fig. 5, it is clear from fig. 5 that the amorphous form has one endothermic peak and one exothermic peak, and has one gentle solvent/moisture absorption peak at 110 ℃; above 271 ℃ (starting from 263 ℃), sample dissolution or decomposition occurs.
Example 9 hygroscopicity test of amorphous matter of terglazan
The moisture of a proper amount of amorphous matter samples of the terglazan is respectively weighed, then the amorphous matter samples are exposed to different humidity conditions for 0-30 days, the moisture is measured again, and the moisture absorption and weight gain of the product are inspected, so that the results are shown in the following table 1:
table 1 hygroscopicity test
As shown in table 1, the amorphous substance of tegrazan of the present invention has a certain hygroscopicity, and as the ambient humidity increases, the hygroscopicity becomes significantly strong, but this hygroscopicity degree is evaluated within an acceptable range from the viewpoint of drug development; moreover, the sealed package can reduce the hygroscopicity of the sample to be very low, and has little influence on the preparation and storage of the preparation.
Example 10 stability test of amorphous form of terglapran
Stability studies were performed on the amorphous form of tegrazan obtained in example 3 above, and the stability results under various conditions for 30 days are shown in table 2 below:
table 2 stability experiments for 30 days under different conditions
As shown in table 2, the appearance and crystal form of amorphous samples of tegrazan under different conditions were not significantly changed within 30 days; the isomer is obviously increased under the illumination condition, the purity is obviously reduced, and the isomer and the purity are almost unchanged under the rest conditions. This indicates that the physicochemical properties and crystalline forms of the amorphous terlazan sample remain unchanged even after long-term storage after being packaged in a dark place.
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to be limiting in any way and in nature, and it should be noted that several modifications and additions may be made to those skilled in the art without departing from the invention, which modifications and additions are also intended to be construed as within the scope of the invention.
Claims (8)
1. An amorphous substance of terglazan has a chemical structural formula shown in a formula I, and is characterized in that the amorphous substance has a wide peak between 5 and 40 degrees of 2 theta in an X-ray powder diffraction spectrogram, is an obvious amorphous characteristic peak, has no sharp absorption peak and is dispersive;
2. the amorphous form of tegretazan according to claim 1, wherein the amorphous form starts to decompose at 280±2 ℃ in a thermogravimetric analysis;
and/or, in the differential scanning calorimetry analysis of the amorphous substance, there is an endothermic peak at 113 ℃ and an exothermic peak at 271 ℃, respectively.
And/or the IR spectrum of the amorphous material is 830.39cm -1 、1071.09cm -1 、1125.24cm -1 、1325.91cm -1 、1402.51cm -1 、1440.25cm -1 、1598.24cm -1 、2932.68cm -1 、3062.53cm -1 And 3124.64cm -1 With a characteristic absorption peak.
3. A process for the preparation of amorphous form of tegretazan as claimed in claim 1 or 2, characterized in that said preparation process is selected from any one of the following processes:
the method comprises the following steps: the amorphous matter of the terglazan is prepared by cooling or pulping the mixed solution of the terglazan raw material and the solvent;
the second method is as follows: dissolving a raw material of the terlazan in an organic solvent, and preparing an amorphous substance of the terlazan by volatilizing the solvent at room temperature;
and a third method: dissolving or suspending the raw material of the terlazan in an organic solvent, removing the solvent by reduced pressure distillation, and then drying in vacuum to obtain the amorphous matter of the terlazan;
the method four: dissolving a tegrazan raw material in a solvent to form a saturated solution, and separating out the amorphous substance of tegrazan in a mode of mixing the saturated solution with water;
and a fifth method: dispersing a terlazan raw material in water, adding acid into the obtained dispersion system, and dissolving to obtain a salt solution of the corresponding acid in the formula I; adding an alkali solution into the salt solution system to obtain a free alkali system of the formula I; collecting the solid separated out from the free alkali system of the formula I, and obtaining the amorphous substance of the terglazane.
4. The process for producing amorphous form of tegretazan as claimed in claim 3, wherein the solvent in the first process is at least one of methanol, ethanol, acetonitrile, a methanol-water mixed solvent and a methanol-isopropyl ether mixed solvent.
5. The method for preparing amorphous form of tegretazan as claimed in claim 3, wherein the organic solvent in the second method is at least one of methanol, ethanol, isopropanol, n-butanol, acetone and acetonitrile.
6. The method for preparing amorphous form of tegretazan as claimed in claim 3, wherein the organic solvent in the third method is at least one of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1.4 dioxane, acetonitrile and acetone.
7. The method for preparing amorphous form of tegretazan as claimed in claim 3, wherein the solvent in the fourth method is at least one of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1.4 dioxane, acetonitrile and acetone.
8. A process for the preparation of amorphous form of tegretazan according to claim 3, wherein the acid of process five is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid and trifluoromethanesulfonic acid;
and/or the alkali solution in the fifth method is at least one of ammonia water, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution, sodium bicarbonate aqueous solution and potassium bicarbonate aqueous solution.
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