CN117209473A - Method for preparing micro-powder type fumaric acid voronoi - Google Patents
Method for preparing micro-powder type fumaric acid voronoi Download PDFInfo
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- CN117209473A CN117209473A CN202311162478.XA CN202311162478A CN117209473A CN 117209473 A CN117209473 A CN 117209473A CN 202311162478 A CN202311162478 A CN 202311162478A CN 117209473 A CN117209473 A CN 117209473A
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- fumaric acid
- futureen
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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 37
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 239000000843 powder Substances 0.000 title claims description 16
- 239000001530 fumaric acid Substances 0.000 title abstract description 13
- 238000000034 method Methods 0.000 title abstract description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 239000008213 purified water Substances 0.000 claims abstract description 14
- 239000012043 crude product Substances 0.000 claims abstract description 13
- 239000012046 mixed solvent Substances 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims description 22
- 238000004090 dissolution Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000002245 particle Substances 0.000 abstract description 26
- 239000007788 liquid Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 5
- 238000002425 crystallisation Methods 0.000 abstract description 4
- 230000008025 crystallization Effects 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000009826 distribution Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010036781 Fumarate Hydratase Proteins 0.000 description 2
- 102100036160 Fumarate hydratase, mitochondrial Human genes 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 210000003298 dental enamel Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FVGONCXGBYHBDK-TYYBGVCCSA-N (e)-but-2-enedioic acid;n-methylmethanamine Chemical compound C[NH2+]C.OC(=O)\C=C\C([O-])=O FVGONCXGBYHBDK-TYYBGVCCSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009858 acid secretion Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 231100000092 inhalation hazard Toxicity 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of micropowder-type voronoi fumarate, belonging to the technical field of preparation of bulk drugs. The method comprises the steps of dissolving a futureen crude product of fumaric acid in a mixed solvent of acetone and dimethyl sulfoxide, then dripping the dissolved feed liquid into purified water, cooling for crystallization, and drying to obtain the small-granularity futureen Fu Nuola, wherein the obtained small-granularity futureen Fu Nuola has a raw particle size Dv (10) of less than or equal to 1 mu m, a Dv (50) of less than or equal to 2 mu m, a Dv (90) of less than or equal to 5 mu m, has good agglomeration-free fluidity, solves the technical problems of poor futureen solubility, low bioavailability and the like by reducing the particle size, and is beneficial to the development of preparations.
Description
Technical Field
The invention particularly relates to a preparation method of micropowder-type voronoi fumarate, belonging to the technical field of preparation of bulk drugs.
Background
Fu Nuola raw (chemical name: 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl)]-NMethyl methylamine fumarate), a new generation of reversible proton pump inhibitors developed by the company wuta in japan, by inhibiting K in the final step of acid secretion by parietal cells after the product has entered the human body + For H + -K + Binding of atpase (proton pump) to terminate gastric acid secretion and achieve an acid inhibiting effect. The product has strong and durable gastric acid secretion inhibiting effect, and is superior to other medicines such as omeprazole, lansoprazole, etc. The chemical structure of the product is as follows:
fumaric acid Fu Nuola is white crystalline powder, has poor water solubility and belongs to insoluble medicines. For the insoluble drugs, in order to prepare solid preparations with better dissolution, the common mode is to adopt raw materials with small granularity to accelerate the dissolution and absorption of the solid preparations.
At present, 2 modes of obtaining small-granularity bulk drugs are available, one is obtained by crushing equipment, the crushing mode has the defects of high electrostatic property, easy agglomeration, poor fluidity and the like of products, and a large amount of dust is formed in the air, so that the pollution to the environment and the inhalation hazard to operators are large. The other is obtained by controlling the crystallization mode. No preparation method of small-granularity vonolamine fumarate has been disclosed in the prior literature.
Disclosure of Invention
The invention solves the technical problems that: in order to accelerate the dissolution and absorption of the solid solvent, the invention provides the preparation method of the micro-powder type voronoi fumarate, which has high stability and is beneficial to industrial production.
The technical scheme is as follows: and (3) dissolving the crude product of the Fu Nuola raw fumaric acid in a mixed solvent of acetone and dimethyl sulfoxide, then dripping the dissolved feed liquid into purified water, cooling for crystallization, and drying to obtain the small-granularity voronoi fumarate. The method specifically comprises the following steps:
step 1: adding the futured vonolamine crude product into a mixed solvent of acetone and dimethyl sulfoxide, heating to 50-60 ℃ for dissolution;
step 2: dropwise adding the solution obtained in the step 1 into purified water at a certain stirring speed, cooling to 0-10 ℃ after adding, and stirring for 1-2h under heat preservation;
step 3: and (3) carrying out suction filtration or centrifugation on the precipitated solid, and drying to obtain the micro-powder type fumosorosin fumarate.
The grain diameter of the obtained product is Dv (10) less than or equal to 1 mu m, dv (50) less than or equal to 2 mu m and Dv (90) less than or equal to 5 mu m.
Wherein the mass ratio of the mixed solvent acetone to the dimethyl sulfoxide is 1-5:1, preferably 2:1; the mass ratio of the mixed solvent to the purified water of the crude Fu Nuola raw fumaric acid is 1:4-8:2-8, preferably 1:6:4; the certain stirring speed is 50-150 rpm, and the rotating speed exceeding the range is unfavorable for controlling the particle size.
The invention has the beneficial effects that:
(1) The crude product is directly crystallized to obtain the micro powder type Fu Nuola of fumaric acid without mechanical micronization, the condition is mild and controllable, the yield can reach more than 90 percent, and the industrial production is convenient.
(2) The prepared micro powder fumaric acid Fu Nuola has the particle size of Dv (10) less than or equal to 1 mu m, dv (50) less than or equal to 2 mu m, dv (90) less than or equal to 5 mu m, has good agglomeration-free fluidity, solves the technical problems of poor solubility, low bioavailability and the like of the fumaric acid voronoi by reducing the particle size, and is beneficial to the development of preparations.
Description of the terminology: dv (10) represents the diameter of 10% by volume of particles in the cumulative particle size distribution curve; dv (50) represents the diameter of 50% by volume of particles in the cumulative particle size distribution curve; dv (90) represents the diameter of 90% by volume of the particles in the cumulative particle size distribution curve.
Drawings
FIG. 1 is a chart of the detection of the size of Vonopraz fumarate particle according to example 4 of the present invention;
FIG. 2 is a chart of the detection of the size of Vonopraz fumarate in example 6 of the present invention.
Examples
Examples
Adding 20g of fumosin crude product, 100g of acetone and 20g of dimethyl sulfoxide into a 250ml reaction bottle, heating to 50-60 ℃ to dissolve, dropwise adding the dissolved feed liquid into the 250ml reaction bottle containing 80g of purified water at the stirring speed of 100 revolutions per minute, stirring and cooling to 0-10 ℃, preserving heat and stirring for 1h, filtering, and drying. 18.4g of micro powder type fumaric acid Fu Nuola are obtained, the yield is 92%, and the HPLC is 99.85%. (particle diameter Dv (10) =0.752 μm, dv (50) =1.478 μm, dv (90) =3.127 μm).
Example 2:
50g of fumarase crude product, 100g of acetone and 100g of dimethyl sulfoxide are added into a 500ml reaction bottle, the mixture is heated to 50-60 ℃ to dissolve, the dissolved feed liquid is dripped into a 1000ml reaction bottle containing 400g of purified water at the stirring speed of 50 revolutions per minute, the mixture is stirred and cooled to 0-10 ℃, the temperature is kept for 1h, the mixture is filtered by suction and dried, 48.0g of micro powder type fumarase Fu Nuola is obtained, the yield is 96%, and the HPLC is 99.82%. (particle size Dv (10) =0.881 μm, dv (50) = 1.742 μm, dv (90) = 2.867 μm).
Example 3:
50g of fumosin crude product, 300g of acetone and 100g of dimethyl sulfoxide are added into a 500ml reaction bottle, the mixture is heated to 50-60 ℃ to dissolve, the dissolved feed liquid is dripped into a 1000ml reaction bottle containing 100g of purified water at the stirring speed of 150 revolutions per minute, the mixture is stirred and cooled to 0-10 ℃ after being added, the mixture is stirred for 2 hours, filtered and dried, and 45.0g of micro powder type fumosin Fu Nuola is obtained, the yield is 90%, and the HPLC is 99.95%. (particle size Dv (10) =0.885 μm, dv (50) = 1.858 μm, dv (90) = 3.587 μm).
Example 4:
adding 10kg of voronoi fumarate crude product, 40kg of acetone and 20kg of dimethyl sulfoxide into a 100L enamel reaction kettle, heating to 50-60 ℃ to dissolve, dropwise adding the dissolved feed liquid into a 200L enamel reaction kettle containing 40kg of purified water at a stirring speed of 100 revolutions per minute, stirring and cooling to 0-10 ℃, preserving heat and stirring for 2 hours, centrifuging, and drying. 9.3kg of micro powder type fumaric acid Fu Nuola raw was obtained, the yield was 93%, and the HPLC was 99.92%. (particle diameter Dv (10) =0.436 μm, dv (50) =1.159 μm, dv (90) =2.718 μm).
Example 5: stirring speed is higher than 150 rpm
Adding 1kg of fumosorosin crude product, 4kg of acetone and 2kg of dimethyl sulfoxide into a 10L glass reaction kettle, heating to 50-60 ℃ to dissolve, dropwise adding the dissolved feed liquid into a 20L glass reaction kettle containing 4kg of purified water at the stirring speed of 170 r/min, stirring and cooling to 0-10 ℃, preserving heat and stirring for 2h, filtering, and drying. 0.865kg of micro powder type fumaric acid Fu Nuola raw is obtained, the yield is 86.5%, and the HPLC is 97.52%. (particle size Dv (10) = 1.636 μm, dv (50) = 4.478 μm, dv (90) = 10.124 μm).
Example 6: stirring speed is lower than 50 rpm
Adding 1kg of fumosorosin crude product, 4kg of acetone and 2kg of dimethyl sulfoxide into a 10L glass reaction kettle, heating to 50-60 ℃ to dissolve, dropwise adding the dissolved feed liquid into a 20L glass reaction kettle containing 4kg of purified water at a stirring speed of 40 revolutions per minute, stirring and cooling to 0-10 ℃, preserving heat and stirring for 2 hours, filtering, and drying. 0.89kg of micro powder type fumaric acid Fu Nuola raw was obtained, the yield was 89%, and the HPLC was 98.91%. (particle size Dv (10) = 2.436 μm, dv (50) = 15.159 μm, dv (90) = 28.718 μm).
Comparative example 1 according to patent CN105566295a
The futures voronoi crude product (1 g) is suspended in a mixed solvent of ethanol/water (3:1, 10 mL), heated and dissolved at an internal temperature of 60-65 ℃, slowly cooled to room temperature, stirred for 1h, cooled to an internal temperature of 0-10 ℃, stirred and crystallized for 1h, filtered, and dried at 50 ℃ in vacuum for 8h to obtain 0.741g of white crystalline powder with a yield of 74.1%.
Comparative example 2 example 1 according to patent CN106478601a
160g of the crude product is added into 1.6L of ethyl acetate, 0.64L of methanol and 0.1L of purified water, the mixture is heated to 65 ℃ to dissolve solids, filtered, cooled to 0-5 ℃ for crystallization for 6 hours, suction filtration and reduced pressure drying at 50 ℃ to obtain 121.9g of white crystals, the yield is 76.2%, the impurity is 0.027%, and the total impurity is 0.043%.
Analysis of results: 1) Yield: the yield of the invention reaches 90-96%, which is far higher than that of comparative examples 1 and 2;
2) Particle size: the particle size distribution obtained by the malvern particle sizer is shown in table 1, it being evident that the particle size data for comparative examples 1 and 2 are much higher than for the present invention;
3) Dissolution rate: tablet dissolution data are shown in Table 1 for the samples prepared in example 6 and other particle size products of the comparative example. As can be seen from the data in table 1: the dissolution of the small tablet with the particle size is quickened, the particle size is positively correlated with the in-vivo release, and the small particle size is beneficial to the development of the preparation.
Note that: release degree measurement according to the second method of the second appendix of the 2015 edition of Chinese pharmacopoeia, a voronoi cell fumarate is put into 900ml of a hydrochloric acid solution of 0.1mol/L at 37+ -0.5 ℃ and operated according to the method by using a first dissolution degree measurement method device at a rotation speed of 100 rpm.
Claims (6)
1. The preparation method of the micro-powder type fumosorosin is characterized by comprising the following steps of:
step 1: adding the futured vonolamine crude product into a mixed solvent of acetone and dimethyl sulfoxide, heating to 50-60 ℃ for dissolution;
step 2: dropwise adding the solution obtained in the step 1 into purified water at a certain stirring speed, cooling to 0-10 ℃ after adding, and stirring for 1-2h under heat preservation;
step 3: and (3) carrying out suction filtration or centrifugation on the precipitated solid, and drying to obtain the micro-powder type fumosorosin fumarate.
2. The method of manufacturing according to claim 1, characterized in that: the mass ratio of the mixed solvent acetone to the dimethyl sulfoxide in the step 1 is 1-5:1.
3. The preparation method according to claim 2, characterized in that: and (2) the mass ratio of the mixed solvent acetone to the dimethyl sulfoxide in the step (1) is 2:1.
4. The preparation method according to claim 1, wherein the mass ratio of the mixed solvent to the purified water is 1:4-8:2-8.
5. The preparation method according to claim 4, wherein the mass ratio of the mixed solvent to the purified water is 1:6:4.
6. The method of manufacturing according to claim 1, characterized in that: the stirring speed in the step 2 is 50-150 rpm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311162478.XA CN117209473A (en) | 2023-09-11 | 2023-09-11 | Method for preparing micro-powder type fumaric acid voronoi |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311162478.XA CN117209473A (en) | 2023-09-11 | 2023-09-11 | Method for preparing micro-powder type fumaric acid voronoi |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117209473A true CN117209473A (en) | 2023-12-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311162478.XA Pending CN117209473A (en) | 2023-09-11 | 2023-09-11 | Method for preparing micro-powder type fumaric acid voronoi |
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| Country | Link |
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| CN (1) | CN117209473A (en) |
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2023
- 2023-09-11 CN CN202311162478.XA patent/CN117209473A/en active Pending
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Inventor after: Xiao Yang Inventor after: Liu Lixia Inventor after: Liu Yi Inventor after: Li Huiling Inventor after: Hao Xianxiao Inventor before: Hao Xianxiao Inventor before: Li Ying |