CN116514774A - Crystal form of minoprazan fumarate and preparation method thereof - Google Patents
Crystal form of minoprazan fumarate and preparation method thereof Download PDFInfo
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- CN116514774A CN116514774A CN202310480903.3A CN202310480903A CN116514774A CN 116514774 A CN116514774 A CN 116514774A CN 202310480903 A CN202310480903 A CN 202310480903A CN 116514774 A CN116514774 A CN 116514774A
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 107
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 92
- 239000013078 crystal Substances 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 230000002829 reductive effect Effects 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims 2
- 208000012895 Gastric disease Diseases 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 238000001228 spectrum Methods 0.000 claims 1
- 229960000590 celecoxib Drugs 0.000 abstract description 6
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 abstract description 5
- 238000012360 testing method Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 11
- 238000005303 weighing Methods 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 5
- 230000004584 weight gain Effects 0.000 description 5
- 235000019786 weight gain Nutrition 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003892 spreading Methods 0.000 description 2
- 230000007480 spreading Effects 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of pharmacy, and particularly relates to a crystal form of minoprazan fumarate and a preparation method thereof. The X-ray powder diffraction pattern of the first crystal form of the minoprazanol fumarate has characteristic diffraction peaks at 3.8 degrees+/-0.2 degrees, 7.6 degrees+/-0.2 degrees, 11.4 degrees+/-0.2 degrees, 13.6 degrees+/-0.2 degrees, 19.4 degrees+/-0.2 degrees, 19.9 degrees+/-0.2 degrees, 22.6 degrees+/-0.2 degrees and 26.7 degrees+/-0.2 degrees of 2 theta angles; the X-ray powder diffraction pattern of the second crystalline form of the minoprazanol fumarate has characteristic diffraction peaks at the angles of 12.1 DEG + -0.2 DEG, 12.4 DEG + -0.2 DEG, 15.1 DEG + -0.2 DEG, 15.5 DEG + -0.2 DEG, 16.1 DEG + -0.2 DEG, 19.3 DEG + -0.2 DEG, 20.1 DEG + -0.2 DEG, 20.9 DEG + -0.2 DEG, 21.4 DEG + -0.2 DEG, 24.4 DEG + -0.2 DEG, 24.7 DEG + -0.2 DEG, 25.0 DEG + -0.2 DEG, 26.3 DEG + -0.2 DEG. According to the invention, two crystal forms of the celecoxib fumarate are prepared, and the two different crystal forms have the advantages of stable quality, good water solubility, no hygroscopicity, low cost and the like.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a crystalline form of minoprazan fumarate and a preparation method thereof.
Background
Minoprazizane fumarate is a novel proton pump inhibitor, namely a potassium ion competitive acid retarder, researched by Zhuhai Sailong pharmaceutical industry Co-Ltd, and has stronger acid inhibiting effect compared with the traditional proton pump inhibitor. According to the gastric acid inhibition experiment, after injection administration, the pH of the digestive tract of the dogs is gradually increased within 1-8h, and the gastric acid inhibition effect is obvious. According to the test of inhibiting gastric mucosal injury by the minoprazix, the death rate of animals in a model control group is only 10 percent by taking 40 percent of the death rate of animals in a dosing group as a reference, compared with the model control group, the death rate is reduced by 75 percent, the survival rate is 90 percent, and the minoprazix fumarate has obvious effect of inhibiting gastric mucosal injury. The structural formula of the minoprazan fumarate is shown as I:
the sialon pharmaceutical industry discloses firstly the chemical structure and preparation of minoprazizanol fumarate in CN112812099B and secondly the preparation of an intermediate and finished product of minoprazizanol fumarate in CN15448907 a.
The prior art does not specify the crystal structure and physicochemical properties of minoprazizane fumarate, and thus the requirements of minoprazizane fumarate for the conditions of drug production and the storage environment characteristics are not clear.
Disclosure of Invention
Aiming at the technical problems, the invention provides a crystal form of the minoprazizane fumarate, the prepared first crystal form of the minoprazizane fumarate has a structure shown as a formula I,
the X-ray powder diffraction pattern of the first crystal form of the minoprazan fumarate has characteristic diffraction peaks at the angles of 3.8 degrees+/-0.2 degrees, 7.6 degrees+/-0.2 degrees, 11.4 degrees+/-0.2 degrees, 13.6 degrees+/-0.2 degrees, 19.4 degrees+/-0.2 degrees, 19.9 degrees+/-0.2 degrees, 22.6 degrees+/-0.2 degrees and 26.7 degrees+/-0.2 degrees of 2 theta.
The invention provides another crystal form of the minoprazizane fumarate, the prepared second crystal form of the minoprazizane fumarate has a structure shown as a formula I,
the X-ray powder diffraction pattern of the second crystalline form of the minoprazanol fumarate has characteristic diffraction peaks at the angles of 12.1+/-0.2 degrees, 12.4+/-0.2 degrees, 15.1+/-0.2 degrees, 15.5+/-0.2 degrees, 16.1+/-0.2 degrees, 19.3+/-0.2 degrees, 20.1+/-0.2 degrees, 20.9+/-0.2 degrees, 21.4+/-0.2 degrees, 24.4+/-0.2 degrees, 24.7+/-0.2 degrees, 25.0+/-0.2 degrees and 26.3+/-0.2 degrees of 2 theta.
In another aspect, the present invention provides a method for preparing a crystalline form of celeprazizan fumarate, comprising:
adding the minoprazan fumarate shown in the formula I into water and an organic solvent, and then heating to dissolve to obtain a fumarate solution;
and (3) reducing the temperature of the fumarate solution to precipitate the minoprazan fumarate crystals.
According to the invention, two crystal forms of the celecoxib fumarate are prepared, and the two different crystal forms have the advantages of stable quality, good water solubility, no hygroscopicity, low cost and the like.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of minoprazan fumarate form I of example 1;
FIG. 2 is an X-ray powder diffraction pattern of minoprazan fumarate form II of example 2;
FIG. 3 is an X-ray powder diffraction pattern of minoprazan fumarate form II of example 3;
FIG. 4 is an X-ray powder diffraction pattern of minoprazan fumarate form II of example 4;
FIG. 5 is an X-ray powder diffraction pattern of minoprazan fumarate form II of example 5.
Detailed Description
Some embodiments produce a first crystalline form of minoprazizane fumarate having the structure shown in formula I,
the X-ray powder diffraction pattern of the first crystal form of the minoprazan fumarate has characteristic diffraction peaks at the angles of 3.8 degrees+/-0.2 degrees, 7.6 degrees+/-0.2 degrees, 11.4 degrees+/-0.2 degrees, 13.6 degrees+/-0.2 degrees, 19.4 degrees+/-0.2 degrees, 19.9 degrees+/-0.2 degrees, 22.6 degrees+/-0.2 degrees and 26.7 degrees+/-0.2 degrees of 2 theta.
Some embodiments produce a second crystalline form of minoprazizan fumarate having the structure shown in formula I,
the X-ray powder diffraction pattern of the second crystalline form of the minoprazanol fumarate has characteristic diffraction peaks at the angles of 12.1+/-0.2 degrees, 12.4+/-0.2 degrees, 15.1+/-0.2 degrees, 15.5+/-0.2 degrees, 16.1+/-0.2 degrees, 19.3+/-0.2 degrees, 20.1+/-0.2 degrees, 20.9+/-0.2 degrees, 21.4+/-0.2 degrees, 24.4+/-0.2 degrees, 24.7+/-0.2 degrees, 25.0+/-0.2 degrees and 26.3+/-0.2 degrees of 2 theta.
Some embodiments relate to a method of preparing a first crystalline form of minoprazanol fumarate, comprising the step of crystallizing the first crystalline form of minoprazanol fumarate from water and an organic solvent by lowering the crystallization temperature. Wherein the solvent is methylene dichloride, and the dosage of the solvent is expressed by volume and is 5-15 times of the volume of the weight of the minoprazan fumarate; the amount of water is 3 to 6 times the volume of the weight of the minoprazan fumarate.
The preferred first crystalline form of celecoxib fumarate is crystallized as follows: the solid of the minoprazan fumarate is weighed and added into a reaction bottle, and the solid of the minoprazan fumarate is prepared by the following weight percent: volume = 1:3 purified water was added, 1:7 dichloromethane was added; heating to 40-50 ℃, stirring and dissolving, cooling to 10-20 ℃, continuously stirring and crystallizing for 4 hours, filtering, and drying under reduced pressure to obtain the minoprazan fumarate.
Some embodiments provide a method for preparing a second crystalline form of minoprazanol fumarate crystals, comprising the step of crystallizing the second crystalline form of minoprazanol fumarate crystals by lowering the crystallization temperature after dissolving by heating with an organic solvent. Wherein the solvent is methanol, ethanol, isopropanol, or acetone, and the amount is 4-20 times of the weight of the minoprazizan fumarate.
The preferred second crystalline form of celecoxib fumarate is crystallized as follows:
the solid of the minoprazan fumarate is weighed and added into a reaction bottle, and the solid of the minoprazan fumarate is prepared by the following weight percent: volume = 1:4-20 adding organic solvent (methanol, ethanol, isopropanol, acetone); heating, stirring, dissolving, cooling to 0-10deg.C, stirring for crystallization for 4 hr, filtering, and drying under reduced pressure to obtain celecoxib fumarate.
The following examples further illustrate the invention but are not to be construed as limiting the invention. Modifications and substitutions to methods, procedures, or conditions of the present invention without departing from the spirit and nature of the invention are intended to be within the scope of the present invention.
Example 1 preparation of Inprazan fumarate form I
80g of minoprazanol fumarate, 240ml of purified water and 560ml of dichloromethane are added into a reaction bottle, the temperature is raised to 50 ℃, stirring is carried out for dissolution, then the temperature is slowly lowered to 10 ℃, stirring is carried out for crystallization for 4 hours, filtering is carried out, a filter cake is collected, decompression drying is carried out for 5 hours at 60 ℃, and the minoprazanol fumarate type I is obtained, wherein the X-ray powder diffraction pattern is shown in figure 1.
The X-ray powder diffraction pattern has characteristic diffraction peaks at angles of 3.2 degrees, 3.3 degrees, 3.7 degrees, 3.92 degrees, 4.46 degrees, 5.0 degrees, 6.5 degrees, 7.76 degrees, 11.6 degrees and 23.2 degrees of 2 theta.
Example 2 preparation of Inprazan fumarate form II
10g of minoprazan fumarate and 40ml of methanol are added into a reaction bottle, the mixture is heated, stirred and dissolved, then the mixture is slowly cooled to 10 ℃, stirred and crystallized for 4 hours, filtered, a filter cake is collected, and the mixture is dried for 5 hours at 60 ℃ under reduced pressure, so that the type II minoprazan fumarate is obtained. The X-ray powder diffraction pattern is shown in figure 2.
The X-ray powder diffraction pattern has characteristic diffraction peaks at angles of 12.10 degrees, 12.40 degrees, 15.0 degrees, 19.3 degrees, 20.1 degrees, 20.88 degrees, 21.4 degrees, 24.39 degrees, 24.68 degrees, 25.0 degrees and 26.2 degrees of 2 theta.
Example 3 preparation of Inprazan fumarate form II
Adding 10g of minoprazan fumarate and 60ml of ethanol into a reaction bottle, heating, stirring and dissolving, then slowly cooling to 10 ℃, stirring and crystallizing for 4 hours, filtering, collecting a filter cake, and drying at 60 ℃ under reduced pressure for 5 hours to obtain the type II minoprazan fumarate. The X-ray powder diffraction pattern is shown in figure 3, and has characteristic diffraction peaks at angles of 27.98 degrees, 27.13 degrees, 26.26 degrees, 24.412 degrees, 20.88 degrees, 19.37 degrees, 20.130 degrees, 12.46 degrees and 12.10 degrees of 2 theta.
Example 4 preparation method of Inprazan fumarate form II
Adding 10g of minoprazan fumarate and 200ml of isopropanol into a reaction bottle, heating, stirring and dissolving, then slowly cooling to 10 ℃, stirring and crystallizing for 4 hours, filtering, collecting a filter cake, and drying at 60 ℃ under reduced pressure for 5 hours to obtain the type II minoprazan fumarate. The X-ray powder diffraction pattern is shown in figure 4.
The X-ray powder diffraction pattern has characteristic diffraction peaks at angles of 12.10 degrees, 12.40 degrees, 15.0 degrees, 15.58 degrees, 19.36 degrees, 20.119 degrees, 20.88 degrees, 21.41 degrees and 24.39 degrees of 2 theta.
Example 5 preparation of Inprazan fumarate form II
Adding 10g of minoprazan fumarate and 200ml of acetone into a reaction bottle, heating, stirring and dissolving, then slowly cooling to 10 ℃, stirring and crystallizing for 4 hours, filtering, collecting a filter cake, and drying at 60 ℃ under reduced pressure for 5 hours to obtain the type II minoprazan fumarate. The X-ray powder diffraction pattern is shown in figure 5.
The X-ray powder diffraction pattern has characteristic diffraction peaks at angles of 5.148 degrees, 12.07 degrees, 12.413 degrees, 15.066 degrees, 15.547 degrees, 16.10 degrees, 19.356 degrees, 20.093 degrees, 20.866 degrees, 21.416 degrees, 24.38 degrees, 24.66 degrees and 26.232 degrees of 2 theta.
The technical effects of the present invention are verified as follows.
Test example 1-2 stability of minoprazan fumarate of example 1-2 was tested. Wherein the purity and the maximum single impurity are detected by adopting a high-performance liquid phase; the method for testing the moisture absorption refers to the guiding principle of the moisture absorption of 9103 medicine in the edition 2020 of Chinese pharmacopoeia. The purity test method adopts an area normalization method.
Test example 1 stability of Inprazan fumarate form I
Stability test for minoprazan fumarate form i prepared in example 1, stability data obtained in test example 1 were as follows:
TABLE 1 stability data sheet for form I minoprazan fumarate prepared in EXAMPLE 1
| Sequence number | Conditions of placement | Traits (3) | Purity (%) | Maximum mono-hetero (%) | Moisture permeability |
| 1 | 25 ℃ for 10 days | Off-white solid | 100.00％ | Not detected | Without any means for |
| 2 | 40 ℃ for 10 days | Off-white solid | 100.00％ | Not detected | Without any means for |
| 3 | 60 ℃ for 10 days | Off-white solid | 100.00％ | Not detected | Without any means for |
Test example 2 stability of Inprazan fumarate form II
Stability data obtained by stability test of the form i minoprazizane fumarate prepared in example 2 are as follows:
TABLE 2 stability data sheet for Inprazan fumarate form II prepared in EXAMPLE 2
| Sequence number | Conditions of placement | Traits (3) | Purity (%) | Maximum mono-hetero (%) | Moisture permeability |
| 1 | 25 ℃ for 10 days | Off-white solid | 100.00％ | Not detected | Without any means for |
| 2 | 40 ℃ for 10 days | Off-white solid | 100.00％ | Not detected | Without any means for |
| 3 | 60 ℃ for 10 days | Off-white solid | 100.00％ | Not detected | Without any means for |
The humidity-guiding properties of minoprazan fumarate of examples 1 and 2 were tested by test examples 3 to 4. The method for the moisture absorption test refers to the guiding principle of the moisture absorption property of 9103 medicine in the 2020 edition of Chinese pharmacopoeia, and is as follows:
1. the dried glass weighing bottle with plug (with the outer diameter of 50mm and the height of 15 mm) is taken, and is placed in a proper constant temperature dryer (with ammonium chloride or ammonium sulfate saturated solution placed at the lower part) or a climatic chamber (with the set temperature of 25+/-1 ℃ and the relative humidity of 80% +/-2%) at the temperature of 25 ℃ for 1 ℃ one day before the test, and precisely weighing (m 1 )。
2. Spreading the sample in the weighing bottle, wherein the sample is about 1mm thick, and precisely weighing (m 2 )。
3. The weighing bottle is opened and placed under the constant temperature and humidity condition for 24 hours together with the bottle cap.
4. The lid of the weighing flask was closed, and the weight (m 3 )。
5. Characterization of hygroscopicity and definition of the weight gain of hygroscopicity
Deliquescence: absorbing a sufficient amount of moisture to form a liquid.
The moisture absorption performance is very good: the weight gain caused by moisture is not less than 15%.
Moisture permeability: the weight gain by moisture absorption is less than 15 percent but not less than 2 percent.
Slightly hygroscopic: the weight gain by moisture absorption is less than 2 percent but not less than 0.2 percent.
No or little hygroscopicity: the weight gain caused by moisture is less than 0.2 percent.
Instrument: constant temperature and humidity incubator (manufacturer: shaogou Tai medical instruments Co., ltd., room temperature-80 ℃ C., temperature control accuracy and reactances are less than or equal to + -0.5 ℃ C.).
Test example 3 moisture wicking test of Inprazan I fumarate of example 1
The sample tested was crystalline celecoxib fumarate form i described in example 1.
According to the temperature and humidity of the guiding principle, 3 parts in parallel, a dry glass weighing bottle with a plug is taken, and placed in a constant temperature and humidity incubator one day before the experiment, and the weight (m 1 ). Taking a certain amount of medicinal powder, spreading to a thickness of about 1mm, precisely weighing (m 2 ). The weighing bottle is opened and placed under the constant temperature and humidity condition for 24 hours together with the bottle cap. After 24 hours, the lid of the weighing flask was closed, and the weight (m 3 ). The hygroscopicity data of the samples are shown in Table 3.
TABLE 3 hygroscopicity data for form I minoprazan fumarate crystals at 25 ℃ + -1 ℃ and 80% + -2% relative humidity
| Number of tests | m 1 (g) | m 2 (g) | m 3 (g) | Percentage gain (%) |
| First time | 21.6441 | 22.1521 | 22.1530 | 0.18 |
| Second time | 20.4877 | 20.9962 | 20.9966 | 0.08 |
| Third time | 17.6341 | 18.1408 | 18.1413 | 0.10 |
| Average value of | —— | —— | —— | 0.12 |
Test example 4 hygroscopicity of minoprazan fumarate form II of example 2
The sample tested was crystalline form ii minoprazan fumarate as described in example 2. The test method was the same as in test example 3. The hygroscopicity data of the samples are shown in table 4.
TABLE 4 hygroscopicity data for form I minoprazan fumarate crystals at 25 ℃ + -1 ℃ and 80% + -2% relative humidity
| Number of tests | m 1 (g) | m 2 (g) | m 3 (g) | Percentage gain (%) |
| First time | 21.6955 | 22.2112 | 22.2118 | 0.12 |
| Second time | 21.9234 | 22.4255 | 22.4262 | 0.14 |
| Third time | 31.7626 | 32.2632 | 32.2641 | 0.18 |
| Average value of | —— | —— | —— | 0.14 |
From the test results of test examples 3 to 4, the samples of example 1 and example 2 of the present invention have no hygroscopicity, and are more favorable for storage of crude drugs and production of subsequent solid preparations.
Comparative example 1
The test samples were the crystalline form ii minoprazizane fumarate prepared in examples 3, 4, 5 as a control. The test method was the same as in test example 3. The hygroscopicity data of the samples are shown in table 5.
Table 5 data on hygroscopicity of the crystalline form I minoprazan fumarate at a temperature of 25 ℃ + -1℃and a relative humidity of 80% + -2%
| Test sample | m 1 (g) | m 2 (g) | m 3 (g) | Percentage gain (%) |
| Example 3 | 22.1155 | 22.7620 | 22.9982 | 0.27 |
| Example 4 | 22.1557 | 22.8202 | 23.0082 | 0.22 |
| Example 5 | 20.2539 | 21.9932 | 22.6461 | 0.27 |
The samples prepared in example 2 were better in hygroscopicity than examples 3, 4, 5, possibly because of the different weights: the moisture-wicking effect is different by the addition of organic solvent in volume=1:4 to 20, preferably with a composition of 10g of minoprazan fumarate and 40ml of methanol in example 2.
While the invention has been described in detail in the foregoing general description, embodiments and experiments, it will be apparent to those skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (10)
1. A first crystal form of minoprazan fumarate with a structure shown as a formula I,
the method is characterized in that the X-ray powder diffraction pattern of the first crystal form of the minoprazan fumarate has characteristic diffraction peaks at angles of 3.8 degrees+/-0.2 degrees, 7.6 degrees+/-0.2 degrees, 11.4 degrees+/-0.2 degrees, 13.6 degrees+/-0.2 degrees, 19.4 degrees+/-0.2 degrees, 19.9 degrees+/-0.2 degrees, 22.6 degrees+/-0.2 degrees and 26.7 degrees+/-0.2 degrees of 2 theta.
2. A second crystal form of minoprazan fumarate with a structure shown in formula I,
the X-ray powder diffraction spectrum of the second crystalline form of the minoprazan fumarate has characteristic diffraction peaks at the angles of 12.1 degrees+/-0.2 degrees, 12.4 degrees+/-0.2 degrees, 15.1 degrees+/-0.2 degrees, 15.5 degrees+/-0.2 degrees, 16.1 degrees+/-0.2 degrees, 19.3 degrees+/-0.2 degrees, 20.1 degrees+/-0.2 degrees, 20.9 degrees+/-0.2 degrees, 21.4 degrees+/-0.2 degrees, 24.4 degrees+/-0.2 degrees, 24.7 degrees+/-0.2 degrees, 25.0 degrees+/-0.2 degrees and 26.3 degrees+/-0.2 degrees of 2 theta.
3. A process for preparing the minoprazan fumarate according to claim 1 or claim 2, comprising:
adding the minoprazan fumarate shown in the formula I into water and an organic solvent, and then heating to dissolve to obtain a fumarate solution;
and (3) reducing the temperature of the fumarate solution to precipitate the minoprazan fumarate crystals.
4. A method as recited in claim 3, further comprising: continuously stirring and crystallizing for 4 hours, filtering, and drying under reduced pressure.
5. A method according to claim 3, wherein the organic solvent comprises any one of an alcohol organic solvent, a ketone organic solvent, and a halogenated hydrocarbon organic solvent.
6. A method according to claim 3, wherein the amount of water is 3 to 6 times the volume by weight of the minoprazan fumarate; the amount of the halogenated hydrocarbon organic solvent is 5 to 15 times the volume amount of the weight of the minoprazan fumarate; the amount of the alcohol-type organic solvent or ketone-type organic solvent is 4 to 20 times the volume amount of the weight of the minoprazizan fumarate.
7. A method according to claim 3, wherein the fumarate solution is obtained by heating to a temperature of 40 to 50 ℃; the temperature of the fumarate solution was reduced to 10-20 ℃.
8. The method as recited in claim 5, comprising:
adding the minoprazizane fumarate shown in the formula I into purified water and a dichloromethane solvent, wherein the dosage of the purified water is 3-6 times of the volume of the minoprazizane fumarate, the dosage of the dichloromethane solvent is 5-15 times of the volume of the minoprazizane fumarate, heating to 50 ℃, and stirring and dissolving to obtain a fumarate solution;
slowly reducing the temperature of the fumarate solution to 10 ℃, stirring for crystallization for 4 hours, filtering, collecting a filter cake, and drying at 60 ℃ under reduced pressure for 5 hours to obtain the first crystal of the minoprazizanol fumarate according to claim 1.
9. The method as recited in claim 5, comprising:
adding the minoprazizane fumarate shown in the formula I into any one of organic solvents including methanol, ethanol, isopropanol and acetone in the volume amount of 4-20 times of the weight of the minoprazizane fumarate, and heating, stirring and dissolving to obtain a fumarate solution;
and (3) reducing the temperature of the fumarate solution to 0-10 ℃, continuing stirring and crystallizing for 4 hours, filtering, and drying under reduced pressure to obtain the second crystal of the minoprazan fumarate according to claim 2.
10. Use of crystalline minoprazan fumarate according to claim 1 or claim 2 in the manufacture of a medicament for the treatment of gastric disorders.
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