CN114191440A - Celecoxib composition and preparation method thereof - Google Patents
Celecoxib composition and preparation method thereof Download PDFInfo
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Abstract
The application relates to the field of medicines, and particularly discloses a celecoxib composition and a preparation method thereof. The celecoxib composition is prepared from the following raw materials in parts by weight: 20-30 parts of celecoxib, 40-80 parts of zein, 1-25 parts of hydroxypropyl-beta-cyclodextrin, 0-10 parts of curcumin and 0-10 parts of liquorice. A method of preparing a celecoxib composition comprising: dissolving the celecoxib solution in an organic solvent to obtain a celecoxib solution; uniformly stirring and mixing the celecoxib solution and the zein, and dropwise adding the mixture into water; adding hydroxypropyl-beta-cyclodextrin, curcumin and liquorice, stirring uniformly, filtering and drying to obtain the celecoxib composition. According to the celecoxib composition, the zein, the hydroxypropyl-beta-cyclodextrin and the celecoxib form an embedding structure, and the dissolution rate of the celecoxib composition is effectively improved through the synergistic effect of the celecoxib, the zein and the hydroxypropyl-beta-cyclodextrin.
Description
Technical Field
The application relates to the field of medicines, in particular to a celecoxib composition and a preparation method thereof.
Background
Celecoxib (Celecoxib, CLX) with the trade name of Celecoxib (Celebrex) and the molecular formula of C17H14F3N3O2Molecular weight of 381.37, and chemical name of 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1-hydrogen-1-pyrazol-1-yl]The benzenesulfonamide is white crystal powder, belongs to nonsteroidal anti-inflammatory analgesic, and is mainly used for treating acute or chronic osteoarthritis, rheumatoid arthritis and the like.
Celecoxib is the first cyclooxygenase-2 (COX-2) inhibitor in the world, and plays a strong role in resisting inflammation and relieving pain by inhibiting the activity of cyclooxygenase to block the formation of prostaglandin. Clinical application proves that celecoxib has strong selectivity on cyclooxygenase-2 (COX-2), is a good anti-inflammatory agent, and has great advantages in safety, such as little side effect on gastrointestinal tract and no addiction.
However, the main problem exists at present that the dissolution rate of celecoxib is low; therefore, deep research on the microstructure, correlation of the properties, changes the powder properties, improves the aqueous solubility, dissolution rate and bioavailability, and fully exerts the drug effect, which is becoming the urgent priority of modern pharmaceutical enterprises.
Disclosure of Invention
In order to improve the dissolution rate of celecoxib and give full play to the drug effect, the application provides a celecoxib composition and a preparation method thereof.
In a first aspect, a celecoxib composition and a preparation method thereof are provided, and the following technical scheme is adopted:
the celecoxib composition is prepared from the following raw materials in parts by weight:
20-30 parts of celecoxib, 40-80 parts of zein, 1-25 parts of hydroxypropyl-beta-cyclodextrin, 0-10 parts of curcumin and 0-10 parts of liquorice.
By adopting the technical scheme, the celecoxib is compatible with the zein, the hydroxypropyl-beta-cyclodextrin, the curcumin and the liquorice; the zein is loaded on the celecoxib, so that the stability is good; the zein, the hydroxypropyl-beta-cyclodextrin and the celecoxib form an embedding structure, so that the dissolution rate is obviously improved; meanwhile, curcumin and liquorice with anti-inflammatory effect are added, so that the anti-inflammatory treatment effect of the celecoxib composition is improved.
In a specific embodiment, the celecoxib is prepared by the following steps:
p1, adding absolute ethyl alcohol accounting for 83.5-88wt% of the total amount and all sodium methoxide into the reactor under the protection of nitrogen, and uniformly mixing; controlling the temperature to 20-25 ℃, adding the rest of absolute ethyl alcohol, and stirring until the absolute ethyl alcohol is completely dissolved; dripping ethyl trifluoroacetate at 20-25 deg.C, and keeping the temperature for 10-20 min; then, dropwise adding p-methylacetophenone, reacting at 25-30 ℃ for 6-9h after the dropwise adding is finished, stopping the reaction until the content of the p-methylacetophenone is less than 0.5%, cooling to 0-5 ℃, and storing at low temperature to obtain a reaction body A;
p2, adding 4-sulfonylamino phenylhydrazine hydrochloride, absolute ethyl alcohol and deionized water into the reactant A obtained in the S1 at the temperature of 20-25 ℃, and stirring uniformly; then adding concentrated hydrochloric acid, keeping stirring, reacting at 25-28 deg.C for 8-10h, when the content of A is less than 0.5%, dripping 18-22% sodium carbonate solution at 25-28 deg.C, and adjusting pH to 7.5-9.0; then adding deionized water, stirring for 2.5-3.5h, filtering, and vacuum drying to obtain a crude product;
and P3, and recrystallizing the crude product obtained from the P2 to obtain the required celecoxib.
By adopting the technical scheme, the celecoxib is quenched under the alkaline condition during preparation, so that the increase of isomer impurities is avoided, the content of by-products is reduced, and the purity and yield of the product are improved; meanwhile, the celecoxib is simple in preparation process, low in cost and suitable for industrial popularization and use.
In a specific possible embodiment, in the P1, the mass ratio of the ethyl trifluoroacetate to the P-methylacetophenone is (1.2-1.3): 1.
by adopting the technical scheme, the proportion of the ethyl trifluoroacetate to the p-methylacetophenone is optimized, and the celecoxib is favorably synthesized.
In a specific embodiment, in the P1, the mass ratio of the absolute ethyl alcohol to the ethyl trifluoroacetate is (3-4): 1; the mass ratio of the sodium methoxide to the ethyl trifluoroacetate is (0.4-0.5): 1.
by adopting the technical scheme, the proportion of the ethyl trifluoroacetate to the absolute ethyl alcohol and the sodium methoxide is optimized, and the positive effect on the smooth synthesis of the celecoxib is achieved.
In a specific embodiment, in P2, the mass ratio of the reactant a to 4-sulfonylaminophenylhydrazine hydrochloride is (4.1-4.3): 1.
by adopting the technical scheme, the proportion of the reactant A and the 4-sulfonylamino phenylhydrazine hydrochloride is optimized.
In a second aspect, a preparation method of the celecoxib composition is provided, and the following technical scheme is adopted:
a method of preparing a celecoxib composition comprising:
s1, adding 20-30 parts by weight of celecoxib into an ethanol solution with enough amount to completely dissolve the celecoxib to obtain a celecoxib solution;
s2, stirring and uniformly mixing the celecoxib solution obtained in the step S1 and 40-80 parts by weight of zein at the temperature of 1000-1200r/min and 50-75 ℃, and then dropwise adding the mixture into a sufficient amount of deionized water;
s3, stirring and uniformly mixing the mixed solution obtained in the step S2 and 1-25 parts by weight of hydroxypropyl-beta-cyclodextrin at the temperature of 50-75 ℃ at 1400r/min under 1200-1400r/min, continuously stirring and uniformly mixing, standing for 10-40min, and filtering to obtain a celecoxib-zein-hydroxypropyl-beta-cyclodextrin composition;
s4, mixing the composition obtained in the step S3 with 0-10 parts by weight of curcumin and 0-10 parts by weight of liquorice, stirring and uniformly mixing, cooling to room temperature, filtering and drying to obtain the required celecoxib composition.
By adopting the technical scheme, the celecoxib composition is successfully prepared.
In a specific possible embodiment, in the S2, the celecoxib solution obtained in the S1 is dropwise added into 40 to 80 parts by weight of zein at the conditions of 1000-1200r/min and 50 to 75 ℃, and the dropwise adding time is controlled to be 25 to 35 min.
In a specific embodiment, in S2, the amount of deionized water added is 1.5 to 2 times the sum of the weight of the celecoxib solution and the weight of the zein.
In a specific embodiment, in S2, the dropping time of the mixture of celecoxib solution and zein into deionized water is controlled to be 20-30 mm.
In summary, the present application has at least one of the following beneficial technical effects:
1. according to the celecoxib composition, the zein, the hydroxypropyl-beta-cyclodextrin and the celecoxib form an embedding structure, and the dissolution rate of the celecoxib composition is effectively improved through the synergistic effect of the celecoxib, the zein and the hydroxypropyl-beta-cyclodextrin.
2. The celecoxib is quenched under the alkaline condition during preparation, so that the increase of isomer impurities is avoided, the content of by-products is reduced, and the purity and yield of the product are improved; meanwhile, the celecoxib is simple in preparation process, low in cost and suitable for industrial popularization and use.
Detailed Description
The present application will be described in further detail with reference to examples.
Preparation example 1
The preparation example discloses a synthesis method of celecoxib, which specifically comprises the following steps:
p1, adding 340g of absolute ethyl alcohol and 64.5g of sodium methoxide into a clean and dry 1000mL four-mouth reaction bottle under the protection of nitrogen, and uniformly mixing; then controlling the temperature to 20 ℃, adding 45g of absolute ethyl alcohol, and mechanically stirring until the absolute ethyl alcohol is completely dissolved; then keeping the temperature at 20 ℃, dropwise adding 129.2g of trifluoroacetic acid ethyl ester (TFAE), and preserving the temperature for 20min after the dropwise adding; then 100g of p-methylacetophenone (4-MAP) is dripped to react for 9 hours at 25 ℃, and the reaction is stopped when the content of the p-methylacetophenone is less than 0.5 percent; cooling to 0 ℃ and preserving at low temperature to obtain a reactant A; the purity of the obtained reactant A is 98.65 percent by liquid chromatography detection (external standard method of a reference substance), and the reactant A can be stored for one week. In this step, nitrogen gas was introduced to prevent the volatilization loss of the low boiling point starting material TFAE.
P2, adding 5.47g of 4-sulfonylaminophenylhydrazine hydrochloride (4-SAPH) to 23.5g of the reaction product A obtained from P1 at 20 ℃, and stirring the mixture uniformly at a speed of 800 r/m; then 20g of absolute ethyl alcohol is added, and the mixture is stirred for 10min at the rotating speed of 800 r/m; then 4g of deionized water is added and stirred evenly at the rotating speed of 800 r/m; then 3.25g of concentrated hydrochloric acid with the concentration of 36wt% is added, the mixture is stirred at the rotating speed of 800r/m, and the mixture reacts for 10 hours at the temperature of 25 ℃; when the content of the reactant A is less than 0.5 percent, slowly dripping 12g of sodium carbonate solution with the concentration of 18 weight percent at 25 ℃, and adjusting the pH value to 8; then 30g of deionized water is added, and the mixture is stirred for 2.5 hours at the rotating speed of 800 r/m; then filtering, washing a filter cake with water, pumping to dryness, and drying a wet product in vacuum at 60 ℃ to control the moisture to be less than 2.0 percent to obtain 9.04g of a crude product; the purity was 98.05%.
P3, mixing 80g of crude product obtained by P2 with 178g of isopropanol at the temperature of 20 ℃, heating the mixture to 75 ℃ in an oil bath to completely dissolve solids, and if solids are precipitated, heating the mixture to keep the solids completely dissolved; then 2g of activated carbon is added, stirred and decolored for 0.5 h; carrying out hot filtration, washing with 30g of isopropanol, transferring the hot filtrate into a 1000mL four-mouth reaction bottle, adding 282g of hot water with the temperature of 80 ℃, and preserving the heat at 83 ℃ for 0.5 h; seed crystals are added at 78 ℃ to gradually separate out solids; cooling to 10 deg.C every half hour, and maintaining the temperature for 1.5 hr when the temperature is reduced to 25 deg.C; filtering to obtain a primary crystal product; transferring the crystal product into a 1000mL four-mouth reaction bottle, adding 183g of isopropanol and 275g of deionized water, heating to 80 ℃, and preserving heat until the solid is completely dissolved; adding seed crystal at 78 deg.C to gradually separate out solid, maintaining the temperature for 0.5 hr, cooling to 10 deg.C every half hour, and maintaining the temperature for 1.5 hr when the temperature is reduced to 25 deg.C; filtering, and cooling to 5 ℃; washing the filter cake with 50g of mixed solution of isopropanol and water (the mass ratio of isopropanol to water is 4: 6) to obtain celecoxib, wherein the yield is 87.65 percent, and the purity is 99.98 percent; the mother liquor collected during the crystallization of the crude product recovered 80% isopropanol, with a water content of 18.92% being detected.
Preparation example 2
Compared with the preparation example 1, the preparation example discloses a method for synthesizing celecoxib, wherein the process parameters of P1 and P2 are different, and the P3 is the same.
P1 and P2 are specifically:
p1, adding 400g of absolute ethyl alcohol and 48g of sodium methoxide into a clean and dry 1000mL four-mouth reaction bottle under the protection of nitrogen, and uniformly mixing; then controlling the temperature to 25 ℃, adding 80g of absolute ethyl alcohol, and mechanically stirring until the absolute ethyl alcohol is completely dissolved; then keeping the temperature at 25 ℃, dropwise adding 120.3g of trifluoroacetic acid ethyl ester (TFAE), and preserving the temperature for 10min after the dropwise adding; then 100g of p-methylacetophenone (4-MAP) is dripped to react for 6 hours at the temperature of 30 ℃, and the reaction is stopped when the content of the p-methylacetophenone is less than 0.5 percent; cooling to 5 ℃ and preserving at low temperature to obtain a reactant A; the purity of the obtained reactant A is 98.28 percent through liquid chromatography detection (a reference external standard method), and the reactant A can be stored for one week.
P2, adding 6.10g of 4-sulfonylamino phenylhydrazine hydrochloride (4-SAPH) into 25g of the reaction body A obtained from P1 at the temperature of 25 ℃, and uniformly stirring at the rotating speed of 800 r/m; then 22g of absolute ethyl alcohol is added, and the mixture is stirred for 10min at the rotating speed of 800 r/m; then 5g of deionized water is added and stirred evenly at the rotating speed of 800 r/m; then 3.66g of concentrated hydrochloric acid with the concentration of 36wt% is added, the mixture is stirred at the rotating speed of 800r/m and reacts for 8 hours at the temperature of 28 ℃; when the content of the reactant A is less than 0.5 percent, slowly dropwise adding 12g of sodium carbonate solution with the concentration of 22wt percent at the temperature of 28 ℃, and adjusting the pH value to 9; then 30g of deionized water is added, and the mixture is stirred for 3.5 hours at the rotating speed of 800 r/m; then filtering, washing a filter cake with water, pumping to dryness, and drying a wet product in vacuum at 60 ℃ to control the moisture to be less than 2.0 percent to obtain 9.12g of a crude product; the purity was 98.05%.
After recrystallization from P3 (same as in preparation example 1), celecoxib was obtained in 88.78% yield and 99.98% purity.
Example 1
The embodiment discloses a celecoxib composition, which is prepared from the following raw materials: 20g of celecoxib, 80g of zein and 25g of hydroxypropyl-beta-cyclodextrin. Wherein: celecoxib was prepared from preparation 1.
The preparation method of the celecoxib composition specifically comprises the following steps:
s1, adding 20g of celecoxib into 100g of ethanol, and stirring to completely dissolve the celecoxib to obtain a celecoxib solution.
S2, dropwise adding the celecoxib solution obtained in the step S1 to 80g of zein at the temperature of 75 ℃ at 1000r/min, uniformly stirring, and controlling the dropwise adding time to be 35 min; then, the mixture of the celecoxib solution and the zein is gradually dripped into 300g of deionized water, and the dripping time is controlled to be 30 min.
S3, uniformly stirring the mixed solution obtained in the step S2 and 25g of hydroxypropyl-beta-cyclodextrin at the temperature of 75 ℃ at 1200r/min, standing for 10min, and filtering to obtain a celecoxib-zein-hydroxypropyl-beta-cyclodextrin composition; then cooled to room temperature and dried to obtain the desired celecoxib composition.
Example 2
The embodiment discloses a celecoxib composition, which is prepared from the following raw materials: 20g of celecoxib, 80g of zein, 25g of hydroxypropyl-beta-cyclodextrin and 10g of curcumin. Wherein: celecoxib was prepared from preparation 1.
The preparation method of the celecoxib composition specifically comprises the following steps:
s1, adding 20g of celecoxib into 100g of ethanol, and stirring to completely dissolve the celecoxib to obtain a celecoxib solution.
S2, dropwise adding the celecoxib solution obtained in the step S1 to 80g of zein at the temperature of 75 ℃ at 1000r/min, uniformly stirring, and controlling the dropwise adding time to be 35 min; then, the mixture was gradually dropped into 300g of deionized water, and the dropping time was controlled at 30 min.
S3, mixing the mixed solution obtained in the step S2 and 25g of hydroxypropyl-beta-cyclodextrin uniformly under the conditions of 1200r/min and 75 ℃, standing for 10min, and filtering to obtain the celecoxib-zein-hydroxypropyl-beta-cyclodextrin composition.
S4, mixing the composition obtained in the step S3 with 10g of curcumin, uniformly stirring, cooling to room temperature, filtering and drying to obtain the required celecoxib composition.
Example 3
The embodiment discloses a celecoxib composition, which is prepared from the following raw materials: 30g of celecoxib, 40g of zein, 1g of hydroxypropyl-beta-cyclodextrin and 10g of liquorice. Wherein: celecoxib was prepared from preparation 1.
The preparation method of the celecoxib composition specifically comprises the following steps:
s1, adding 30g of celecoxib into 80g of ethanol, and stirring to completely dissolve the celecoxib to obtain a celecoxib solution.
S2, dropwise adding the celecoxib solution obtained in the step S1 into 40g of zein at 1200r/min and 50 ℃, uniformly stirring, and controlling the dropwise adding time to be 25 min; then, the mixture was gradually dropped into 300g of deionized water, and the dropping time was controlled at 20 min.
S3, mixing the mixed solution obtained in the step S2 and 1g of hydroxypropyl-beta-cyclodextrin uniformly under the conditions of 1400r/min and 50 ℃, standing for 40min, and filtering to obtain the celecoxib-zein-hydroxypropyl-beta-cyclodextrin composition.
S4, mixing the composition obtained in the step S3 with 10g of liquorice, uniformly stirring, cooling to room temperature, filtering and drying to obtain the required celecoxib composition.
Example 4
The embodiment discloses a celecoxib composition, which is prepared from the following raw materials: 25g of celecoxib, 60g of zein, 12g of hydroxypropyl-beta-cyclodextrin, 5g of curcumin and 5g of liquorice. Wherein: celecoxib was prepared from preparation 1.
The preparation method of the celecoxib composition specifically comprises the following steps:
s1, adding 25g of celecoxib into 75g of ethanol, and stirring to completely dissolve the celecoxib to obtain a celecoxib solution.
S2, dropwise adding the celecoxib solution obtained in the step S1 into 60g of zein at the temperature of 60 ℃ at 1100r/min, uniformly stirring, and controlling the dropwise adding time to be 30 min; then, the mixture was gradually dropped into 300g of deionized water, and the dropping time was controlled to be 25 min.
S3, mixing the mixed solution obtained in the step S2 and 12g of hydroxypropyl-beta-cyclodextrin uniformly under the conditions of 1300r/min and 60 ℃, standing for 30min, and filtering to obtain the celecoxib-zein-hydroxypropyl-beta-cyclodextrin composition.
S4, mixing the composition obtained in the step S3 with 5g of curcumin and 5g of liquorice, stirring and uniformly mixing, cooling to room temperature, filtering and drying to obtain the required celecoxib composition.
Example 5
This example is substantially the same as example 4, except that: the composition of the raw materials is different.
The method specifically comprises the following steps: 28g of celecoxib, 50g of zein, 18g of hydroxypropyl-beta-cyclodextrin, 5g of curcumin and 5g of liquorice.
Example 6
This example is substantially the same as example 4, except that: the composition of the raw materials is different.
The method specifically comprises the following steps: 23g of celecoxib, 70g of zein, 5g of hydroxypropyl-beta-cyclodextrin, 5g of curcumin and 5g of liquorice.
Example 7
This example is substantially the same as example 4, except that: celecoxib was prepared from preparation 2.
Comparative example 1
This comparative example differs from example 4 in that: zein and hydroxypropyl-beta-cyclodextrin were not added.
The method specifically comprises the following steps: 25g of celecoxib, 5g of curcumin and 5g of liquorice.
Comparative example 2
This comparative example differs from example 4 in that: zein was not added.
The method specifically comprises the following steps: 25g of celecoxib, 12g of hydroxypropyl-beta-cyclodextrin, 5g of curcumin and 5g of liquorice.
Comparative example 3
This comparative example differs from example 4 in that: no hydroxypropyl-beta-cyclodextrin was added.
The method specifically comprises the following steps: 25g of celecoxib, 60g of zein, 5g of curcumin and 5g of liquorice.
Performance detection
The celecoxib compositions obtained in examples 1-7 and comparative examples 1-3 were subjected to performance tests.
Dissolution testing: the detection is carried out by adopting a Heisen DT12 dissolution instrument, and the ambient temperature is 37 ℃.
TABLE 1 dissolution of celecoxib compositions obtained in examples 1-7 and comparative examples 1-3
| Item | 10min dissolution (%) | 20min dissolution (%) | 30min dissolution (%) | 40min dissolution (%) | 50min dissolution (%) |
| Example 1 | 61.49 | 85.56 | 93.28 | 95.30 | 96.88 |
| Example 2 | 59.18 | 83.67 | 89.77 | 93.18 | 94.79 |
| Example 3 | 55.37 | 78.26 | 87.93 | 91.72 | 92.50 |
| Example 4 | 65.33 | 88.82 | 97.05 | 98.55 | 99.32 |
| Example 5 | 62.45 | 86.59 | 94.99 | 96.68 | 97.81 |
| Example 6 | 63.23 | 86.25 | 94.31 | 96.51 | 97.53 |
| Example 7 | 64.86 | 88.35 | 96.87 | 98.02 | 99.06 |
| Comparative example 1 | 40.33 | 67.83 | 77.37 | 82.65 | 85.62 |
| Comparative example 2 | 47.54 | 75.32 | 84.80 | 89.19 | 91.94 |
| Comparative example 3 | 49.77 | 78.02 | 86.57 | 86.85 | 89.85 |
Referring to table 1, the celecoxib compositions obtained in the examples of the present application have good dissolution rates as shown in the test results of examples 1 to 7 and comparative examples 1 to 3; after 10min of dissolution test, the dissolution rate of the celecoxib composition obtained in most examples is higher than 60%; after 40min of dissolution test, the dissolution rate of the celecoxib composition obtained in all the examples is higher than 90%. Meanwhile, the comparison of the detection results shows that: when the zein and the hydroxypropyl-beta-cyclodextrin are not added, the dissolution rate of the obtained celecoxib composition is low because an embedded structure cannot be formed. When the zein or the hydroxypropyl-beta-cyclodextrin is not added, the dissolution rate of the obtained celecoxib composition is not ideal due to poor embedded structure formation.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (9)
1. Celecoxib compositions characterized by: the health-care food is prepared from the following raw materials in parts by weight:
20-30 parts of celecoxib, 40-80 parts of zein, 1-25 parts of hydroxypropyl-beta-cyclodextrin, 0-10 parts of curcumin and 0-10 parts of liquorice.
2. The celecoxib composition according to claim 1, wherein: the celecoxib is prepared by the following steps:
p1, adding absolute ethyl alcohol accounting for 83.5-88wt% of the total amount and all sodium methoxide into the reactor under the protection of nitrogen, and uniformly mixing; controlling the temperature to 20-25 ℃, adding the rest of absolute ethyl alcohol, and stirring until the absolute ethyl alcohol is completely dissolved; dripping ethyl trifluoroacetate at 20-25 deg.C, and keeping the temperature for 10-20 min; then, dropwise adding p-methylacetophenone, reacting at 25-30 ℃ for 6-9h after the dropwise adding is finished, stopping the reaction when the content of the p-methylacetophenone is less than 0.5%, cooling to 0-5 ℃, and storing at low temperature to obtain a reaction body A;
p2, adding 4-sulfonylamino phenylhydrazine hydrochloride, absolute ethyl alcohol and deionized water into the reactant A obtained from P1 at the temperature of 20-25 ℃, and stirring uniformly; then adding hydrochloric acid, keeping stirring, and reacting for 8-10h at 25-28 ℃; when the content of the reactant A is less than 0.5%, dripping 18-22wt% of sodium carbonate solution at 25-28 ℃, and adjusting the pH to 8.0-9.0; then adding deionized water, stirring for 2.5-3.5h, filtering, and vacuum drying to obtain a crude product;
and P3, and recrystallizing the crude product obtained from the P2 to obtain the required celecoxib.
3. The celecoxib composition according to claim 2, wherein: in the P1, the mass ratio of the ethyl trifluoroacetate to the P-methylacetophenone is (1.2-1.3): 1.
4. the celecoxib composition according to claim 2, wherein: in the P1, the mass ratio of the absolute ethyl alcohol to the ethyl trifluoroacetate is (3-4): 1; the mass ratio of the sodium methoxide to the ethyl trifluoroacetate is (0.4-0.5): 1.
5. the celecoxib composition according to claim 2, wherein: in the P2, the mass ratio of the reactant A to the 4-sulfonylamino phenylhydrazine hydrochloride is (4.1-4.3): 1.
6. a process for the preparation of a celecoxib composition according to any of claims 1-5 wherein: the method comprises the following steps:
s1, adding 20-30 parts by weight of celecoxib into sufficient ethanol to completely dissolve the celecoxib to obtain a celecoxib solution;
s2, stirring and uniformly mixing the celecoxib solution obtained in the step S1 and 40-80 parts by weight of zein at the conditions of 1000-1200r/min and 50-75 ℃, and then dropwise adding the mixture into enough deionized water;
s3, stirring and uniformly mixing the mixed solution obtained in the step S2 and 1-25 parts by weight of hydroxypropyl-beta-cyclodextrin at the temperature of 50-75 ℃ at the temperature of 1400r/min and 1200-75 ℃, standing for 10-40min, and filtering to obtain a celecoxib-zein-hydroxypropyl-beta-cyclodextrin composition;
s4, mixing the composition obtained in the step S3 with 0-10 parts by weight of curcumin and 0-10 parts by weight of liquorice, stirring uniformly, cooling to room temperature, filtering and drying to obtain the celecoxib composition.
7. A process for the preparation of a celecoxib composition according to claim 6 wherein: in the S2, the celecoxib solution obtained in the S1 is dropwise added into 40-80 parts by weight of zein under the conditions of 1000-1200r/min and 50-75 ℃, and the dropwise adding time is controlled to be 25-35 min.
8. A process for the preparation of a celecoxib composition according to claim 6 wherein: in the S2, the addition amount of the deionized water is 1.5-2 times of the sum of the weight of the celecoxib solution and the weight of the zein.
9. A process for the preparation of a celecoxib composition according to claim 8 wherein: in the S2, the time for dripping the mixture of the celecoxib solution and the zein into the deionized water is controlled to be 20-30 mim.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405782A (en) * | 2013-08-29 | 2013-11-27 | 江苏正大清江制药有限公司 | Inclusion compound containing celecoxib and preparation method thereof |
| CN109589883A (en) * | 2019-01-15 | 2019-04-09 | 广州城市职业学院 | A kind of preparation method of plants essential oil powder microcapsules |
| CN109607828A (en) * | 2019-02-20 | 2019-04-12 | 何美英 | A kind of high-performance bio water purification agent and its preparation method and application |
| CN111000112A (en) * | 2020-01-02 | 2020-04-14 | 中国农业科学院农产品加工研究所 | Natamycin composition and application thereof |
| CN111303033A (en) * | 2020-03-20 | 2020-06-19 | 千辉药业（安徽）有限责任公司 | Preparation method of celecoxib |
-
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405782A (en) * | 2013-08-29 | 2013-11-27 | 江苏正大清江制药有限公司 | Inclusion compound containing celecoxib and preparation method thereof |
| CN109589883A (en) * | 2019-01-15 | 2019-04-09 | 广州城市职业学院 | A kind of preparation method of plants essential oil powder microcapsules |
| CN109607828A (en) * | 2019-02-20 | 2019-04-12 | 何美英 | A kind of high-performance bio water purification agent and its preparation method and application |
| CN111000112A (en) * | 2020-01-02 | 2020-04-14 | 中国农业科学院农产品加工研究所 | Natamycin composition and application thereof |
| CN111303033A (en) * | 2020-03-20 | 2020-06-19 | 千辉药业（安徽）有限责任公司 | Preparation method of celecoxib |
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