CN104151182B - The preparation method of a kind of Bromfenac sodium times semihydrate - Google Patents
The preparation method of a kind of Bromfenac sodium times semihydrate Download PDFInfo
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Abstract
The object of the present invention is to provide the preparation method of a kind of Bromfenac sodium times semihydrate, this preparation method comprises the following steps: Bromfenac sodium, antioxidant are added in the mixed solvent of water and Organic Alcohol by (1), heating, dissolves, and adds pH adjusting agent and regulates pH to 7.0 ~ 10.5; (2) add anti-solvent in the solution obtained to step (1), be cooled to 30 ~ 35 DEG C, add Bromfenac sodium monohydrate, Bromfenac sodium times semihydrate or its mixture as crystal seed, stir; (3) cool, crystallization, collect crystal, dry, obtain Bromfenac sodium times semihydrate.This preparation method avoids the use of ethers reagent, and reaction conditions is gentle, and environmental benefit is good, and the purity of the Bromfenac sodium times semihydrate of preparation is high.
Description
Technical field
The invention belongs to pharmaceutical technology sectors, be specifically related to the preparation method of a kind of Bromfenac sodium times semihydrate.
Background technology
The chemical name of Bromfenac sodium is 2-ammonia-3-(4-benzoyl bromide) sodium phenylacetate; it is one of 2-amino-3-benzoylphenylacetic acids analog derivative; its structure and Ketoprofen, diclofenac are similar; the synthesis of the prostanoid inflammatory mediator that cyclooxygenase can be suppressed to mediate; it is the most effective cyclooxygenase-2 inhibitors; have powerful anti-inflammatory analgesic action, action intensity is 10 times of other NSAID (non-steroidal anti-inflammatory drug).
Chemical classes CDER (the CenterforDrugEvaluationandResearch of U.S. FDA subordinate, CDER) data issued shows, the medicinal crystal-form of Bromfenac sodium (ApplicationNumber21-664) is a times semihydrate, i.e. crystal formation I.
Embodiment 74 in patent documentation EP0221753 and China Medicine University's journal (2003; 34 (5): 405 ~ 406) all report in the mixed solvent of toluene and ethanol; adopt the sodium hydroxide solution of 50% by 7-(4-benzoyl)-1; 3-dihydro-indol-2-one " single stage method " hydrolysis salifying, isopropyl ether crystallization prepare Bromfenac sodium crude product; prepare the method for Bromfenac sodium times semihydrate again through water and glycol dimethyl ether mixed solvent recrystallization, its route is:
The method employs the organic solvents such as toluene, isopropyl ether and glycol dimethyl ether in preparation process, and environmental benefit is poor.Wherein, toluene and glycol dimethyl ether are Equations of The Second Kind organic solvent, should limit use, and use glycol dimethyl ether to add the residual risk of organic solvent in Bromfenac sodium times semihydrate in re-crystallization step.
Patent EP2311794 reports the preparation method of Bromfenac sodium three kinds of crystal formations and mutual conversion process thereof, and its route is shown in accompanying drawing 6.
Two kinds of paths of preparing Bromfenac sodium times semihydrate are provided in this patent, path one is that hydration obtains Bromfenac sodium times semihydrate by Bromfenac sodium anhydrate through the mixed solvent crystallization of water, dialkoxyalkane (as glycol dimethyl ether) and anti-solvent (as t-butyl methyl ether) or recrystallization; Path two is through the mixed solvent crystallization of water, dialkoxyalkane (as glycol dimethyl ether) and anti-solvent (as t-butyl methyl ether) or recrystallization by Bromfenac sodium anhydrate, then vacuum-drying obtains Bromfenac sodium monohydrate, then obtains Bromfenac sodium times semihydrate by the hydration of Bromfenac sodium monohydrate.Above-mentioned two kinds of paths all need to use glycol dimethyl ether and t-butyl methyl ether, and environmental benefit is poor, all adds the residual risk of organic solvent in Bromfenac sodium times semihydrate.In addition, additionally provide in this patent by Bromfenac sodium monohydrate or Bromfenac sodium times semihydrate crystallization or recrystallization in the mixed solvent of water and at least one alcohol, then vacuum-drying obtains the method for Bromfenac sodium anhydrate.
At present, use environmentally friendly solvent and water and Organic Alcohol, crystallization is carried out to Bromfenac sodium or recrystallization can only obtain Bromfenac sodium anhydrate, and Bromfenac sodium times semihydrate cannot be obtained.And prepare Bromfenac sodium times semihydrate in prior art and all need to use the ether organic solvent such as glycol dimethyl ether, environmental benefit is poor, and organic solvent residual risk comparatively greatly, is unfavorable for that industrialization is produced.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of Bromfenac sodium times semihydrate, this method avoid the use of ethers reagent, reaction conditions is gentle, and environmental benefit is good, and the purity of the Bromfenac sodium times semihydrate of preparation is high.
The object of the invention is to be achieved through the following technical solutions:
A preparation method for Bromfenac sodium times semihydrate, this preparation method comprises the following steps:
(1) Bromfenac sodium, antioxidant are added in the mixed solvent of water and Organic Alcohol, heating, dissolve, add pH adjusting agent and regulate pH to 7.0 ~ 10.5;
(2) add anti-solvent in the solution obtained to step (1), be cooled to 30 ~ 35 DEG C, add Bromfenac sodium monohydrate, Bromfenac sodium times semihydrate or its mixture as crystal seed, stir;
(3) cool, crystallization, collect crystal, dry, obtain Bromfenac sodium times semihydrate.
Preferably, in described step (1), described Bromfenac sodium be selected from Bromfenac sodium anhydrate, Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate one or more;
Preferably, in described step (1), described antioxidant is S-WAT and/or Sulfothiorine;
Preferably, in described step (1), count by weight percentage, the add-on of described antioxidant is 0.05% ~ 0.50% of Bromfenac sodium add-on;
Preferably, in described step (1), the volume ratio of described water and Organic Alcohol is 1:1;
Preferably, in described step (1), described Organic Alcohol be selected from methyl alcohol, ethanol and Virahol one or more;
Preferably, in described step (1), described pH adjusting agent is acetic acid, regulates pH to 9.0 ~ 10.0.
Preferably, in described step (2), the ratio of described Bromfenac sodium and anti-solvent is 1g:2 ~ 3mL;
Preferably, in described step (2), described anti-solvent is Organic Alcohol, more preferably, described anti-solvent be selected from methyl alcohol, ethanol and Virahol one or more;
Preferably, in described step (2), count by weight percentage, the add-on of described crystal seed is 1% ~ 5% of Bromfenac sodium add-on, is preferably 3%;
Preferably, in described step (2), in the mixture of described Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate, count by weight percentage, the weight ratio of Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate is 1:1.
Preferably, in described step (3), described cooling temperature is 0 ~ 15 DEG C;
Preferably, in described step (3), the described crystallization time is 1 ~ 2h;
Preferably, the step of the crystal that vacuum-drying is separated out also is comprised in described step (3); Preferably, described vacuum tightness is-0.095MPa ~-0.090MPa; Described drying temperature is 40 ~ 50 DEG C; Described time of drying is 12 ~ 18h.
The preparation method of the present inventor to Bromfenac sodium times semihydrate has carried out a large amount of exploration, find to use water and Organic Alcohol as mixed solvent, add oxidation inhibitor, and add Bromfenac sodium monohydrate, Bromfenac sodium times semihydrate or its mixture and induce crystallization as crystal seed, highly purified Bromfenac sodium times semihydrate can be prepared.Result of study shows, the present inventor uses Bromfenac sodium times semihydrate as crystal seed, obtains high purity Bromfenac sodium times semihydrate; The present inventor uses Bromfenac sodium anhydrate as crystal seed, obtains Bromfenac sodium anhydrate; The present inventor uses Bromfenac sodium monohydrate as crystal seed, obtains Bromfenac sodium times semihydrate; Contriver uses the mixture of Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate as crystal seed, obtains Bromfenac sodium times semihydrate.Bromfenac sodium monohydrate can realize the preparation of Bromfenac sodium times semihydrate as crystal seed, be make use of the character that Bromfenac sodium monohydrate is unstable and Bromfenac sodium times semihydrate is stable, under the processing condition such as solvent provided by the invention and temperature, achieve the conversion of Bromfenac sodium monohydrate crystal seed to Bromfenac sodium times semihydrate.
In preparation method of the present invention, the crystal formation important that temperature when adding crystal seed obtains crystallization, add crystal seed when being cooled to the temperature lower than 30 DEG C, what crystallization obtained is Bromfenac sodium anhydrate; And higher than adding crystal seed when 35 DEG C, the mixed crystal of what crystallization obtained is Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate.
In preparation method of the present invention, add the stability that antioxidant can improve recrystallization process, acquired character is jonquilleous crystalline powder; And when not adding oxidation inhibitor, the crystalline powder of acquisition is orange-yellow, and the content of its related substance 7-(4-benzoyl)-1,3-dihydro-indol-2-one is more than 0.1%, is difficult to the medicinal requirements meeting Bromfenac sodium.
Compared with prior art, the present invention has following beneficial effect:
By reforming the existing crystallization technology of Bromfenac sodium, only use environmentally friendly solvent water and Organic Alcohol just to achieve the preparation of high purity Bromfenac sodium times semihydrate, avoid the use of ethers reagent, environmental benefit is good; By adding oxidation inhibitor, improve the stability of Bromfenac sodium times semihydrate at recrystallization process, the content of related substance is effectively controlled, and the product crystalline powder proterties of acquisition is good.
In addition, preparation method provided by the invention is simple, and reaction conditions is gentle, and reduce production cost, Bromfenac sodium times semihydrate purity >=99.5% obtained, content≤0.1% of single impurity, three waste discharge is few, and environmental benefit is good.
Accompanying drawing explanation
Fig. 1 is the HPLC figure of Bromfenac sodium times semihydrate related substance prepared by embodiment 1;
Fig. 2 is the infrared spectrogram of Bromfenac sodium times semihydrate prepared by embodiment 1;
Fig. 3 is the X-ray powder diffraction spectrogram of Bromfenac sodium times semihydrate prepared by embodiment 1;
Fig. 4 is the means of differential scanning calorimetry spectrogram of Bromfenac sodium times semihydrate prepared by embodiment 1;
Fig. 5 is the thermal weight loss spectrogram of Bromfenac sodium times semihydrate prepared by embodiment 1.
The preparation method of Bromfenac sodium three kinds of crystal formations that Fig. 6 is patent EP2311794 described in background technology and mutual conversion process route map thereof.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments are only for illustration of the present invention, its scope do not limited the present invention in any way.
Experimental technique in following embodiment, if no special instructions, is ordinary method.
embodiment 1
In 5L reaction flask, by 500g Bromfenac sodium anhydrate, 0.75g S-WAT joins in the mixed solvent of 500mL water and 500mL ethanol, after heating for dissolving, add acetic acid adjust pH to 9.0, then 1500mL ethanol is added, be cooled to 30 DEG C, add 15g Bromfenac sodium times semihydrate as crystal seed, after stirring, be cooled to 5 DEG C, leave standstill crystallization 1h, collected by centrifugation crystal, at 50 DEG C, vacuum-drying 15h under-0.095MPa ~-0.090MPa, obtain Bromfenac sodium times semihydrate 341.5g, mass yield is 68.3%, purity is 99.69%, the content of single maximum contaminant is 0.054%, moisture content is 6.97%.
The HPLC figure of Bromfenac sodium times semihydrate related substance prepared by the present embodiment as shown in Figure 1.
The infrared spectrogram of Bromfenac sodium times semihydrate prepared by the present embodiment as shown in Figure 2.
The X-ray powder diffraction spectrogram of Bromfenac sodium times semihydrate prepared by the present embodiment as shown in Figure 3.
The means of differential scanning calorimetry spectrogram of Bromfenac sodium times semihydrate prepared by the present embodiment as shown in Figure 4.
The thermal weight loss spectrogram of Bromfenac sodium times semihydrate prepared by the present embodiment as shown in Figure 5.
embodiment 2
In 1L reaction flask, by 100g Bromfenac sodium anhydrate, 0.20g Sulfothiorine joins in the mixed solvent of 100mL water and 100mL methyl alcohol, after heating for dissolving, add acetic acid adjust pH to 10.0, then 250mL methyl alcohol is added, be cooled to 35 DEG C, add 3.0g Bromfenac sodium monohydrate as crystal seed, after stirring, be cooled to 15 DEG C, stirring and crystallizing 2h, collected by centrifugation crystal, at 47 DEG C, vacuum-drying 14h under-0.095MPa ~-0.090MPa, obtain Bromfenac sodium times semihydrate 67.2g, mass yield is 67.2%, purity is 99.67%, the content of single maximum contaminant is 0.073%, moisture content is 7.04%.
embodiment 3
In 1L reaction flask, by 100g Bromfenac sodium monohydrate, 0.10g Sulfothiorine joins in the mixed solvent of 100mL water and 100mL Virahol, after heating for dissolving, add acetic acid adjust pH to 8.0, then 300mL Virahol is added, be cooled to 32 DEG C, add 1.0g Bromfenac sodium monohydrate and 1.0g Bromfenac sodium times semihydrate as crystal seed, after stirring, be cooled to 0 DEG C, stirring and crystallizing 1h, collected by centrifugation crystal, at 47 DEG C, vacuum-drying 16h under-0.095MPa ~-0.090MPa, obtain Bromfenac sodium times semihydrate 65.8g, mass yield is 65.8%, purity is 99.75%, the content of single maximum contaminant is 0.048%, moisture content is 6.49%.
embodiment 4
In 1L reaction flask, by 100g Bromfenac sodium monohydrate, 0.05g Sulfothiorine, 0.1g S-WAT joins in the mixed solvent of 100mL water and 100mL ethanol, after heating for dissolving, add acetic acid adjust pH to 7.0, then 200mL ethanol is added, be cooled to 35 DEG C, add 2.0g Bromfenac sodium times semihydrate as crystal seed, after stirring, be cooled to 15 DEG C, leave standstill crystallization 1.5h, collected by centrifugation crystal, at 50 DEG C, vacuum-drying 14h under-0.095MPa ~-0.090MPa, obtain Bromfenac sodium times semihydrate 67.6g, mass yield is 67.6%, purity is 99.54%, the content of single maximum contaminant is 0.051%, moisture content is 6.92%.
comparative example 1
In 5L reaction flask, 500g Bromfenac sodium anhydrate, 0.75g S-WAT are joined in the mixed solvent of 500mL water and 500mL ethanol, after heating for dissolving, add acetic acid adjust pH to 9.0, then add 1500mL ethanol, be cooled to 30 DEG C, at 50 DEG C, vacuum-drying 15h under-0.095MPa ~-0.090MPa, obtain Bromfenac sodium anhydrate, moisture content is 0.14%.
Can find out, this comparative example carries out repetitive operation according to method described in embodiment 1, but does not add any crystal seed, then the crystal detected result obtained is Bromfenac sodium anhydrate, and moisture content is 0.14%.
comparative example 2
In 5L reaction flask, 500g Bromfenac sodium anhydrate, 0.75g S-WAT are joined in the mixed solvent of 500mL water and 500mL ethanol, after heating for dissolving, add acetic acid adjust pH to 9.0, then 1500mL ethanol is added, be cooled to 25 DEG C, add 15g Bromfenac sodium times semihydrate as crystal seed, after stirring, be cooled to 5 DEG C, leave standstill crystallization 1h, collected by centrifugation crystal, at 50 DEG C, vacuum-drying 15h under-0.095MPa ~-0.090MPa, obtain Bromfenac sodium anhydrate, moisture content is 0.22%.
Can find out, this comparative example carries out repetitive operation according to method described in embodiment 1, but will be cooled to 30 DEG C changes into and be cooled to 25 DEG C, then the crystal detected result obtained is Bromfenac sodium anhydrate, and moisture content is 0.22%.
comparative example 3
In 5L reaction flask, 500g Bromfenac sodium anhydrate, 0.75g S-WAT are joined in the mixed solvent of 500mL water and 500mL ethanol, after heating for dissolving, add acetic acid adjust pH to 9.0, then 1500mL ethanol is added, be cooled to 38 DEG C, add 15g Bromfenac sodium times semihydrate as crystal seed, after stirring, be cooled to 5 DEG C, leave standstill crystallization 1h, collected by centrifugation crystal, at 50 DEG C, vacuum-drying 15h under-0.095MPa ~-0.090MPa, obtain Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate, moisture content is 5.88%.
Can find out, this comparative example carries out repetitive operation according to method described in embodiment 1, but will be cooled to 30 DEG C changes into and be cooled to 38 DEG C, and obtain the mixed crystal of Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate, moisture content is 5.88%.
In a word, above specific description of embodiments of the present invention does not limit the present invention, and those skilled in the art can make various change or distortion according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (13)
1. a preparation method for Bromfenac sodium times semihydrate, is characterized in that, this preparation method comprises the following steps:
(1) Bromfenac sodium, antioxidant are added in the mixed solvent of water and Organic Alcohol, heating, dissolve, add pH adjusting agent and regulate pH to 7.0 ~ 10.5;
(2) add anti-solvent in the solution obtained to step (1), be cooled to 30 ~ 35 DEG C, add Bromfenac sodium monohydrate, Bromfenac sodium times semihydrate or its mixture as crystal seed, stir;
(3) cool, crystallization, collect crystal, dry, obtain Bromfenac sodium times semihydrate;
Wherein, in described step (1), described antioxidant is S-WAT and/or Sulfothiorine; In described step (1), described Organic Alcohol be selected from methyl alcohol, ethanol and Virahol one or more; Described anti-solvent be selected from methyl alcohol, ethanol and Virahol one or more.
2. the preparation method of Bromfenac sodium according to claim 1 times semihydrate, it is characterized in that, in described step (1), described Bromfenac sodium be selected from Bromfenac sodium anhydrate, Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate one or more.
3. the preparation method of Bromfenac sodium according to claim 1 and 2 times semihydrate, is characterized in that, in described step (1), counts by weight percentage, and the add-on of described antioxidant is 0.05% ~ 0.50% of Bromfenac sodium add-on.
4. the preparation method of Bromfenac sodium according to claim 1 and 2 times semihydrate, is characterized in that, in described step (1), the volume ratio of described water and Organic Alcohol is 1:1.
5. the preparation method of the Bromfenac sodium times semihydrate described in claim 1 or 2, is characterized in that, in described step (1), described pH adjusting agent is acetic acid, regulates pH to 9.0 ~ 10.0.
6. the preparation method of Bromfenac sodium according to claim 1 and 2 times semihydrate, is characterized in that, in described step (2), the ratio of described Bromfenac sodium and anti-solvent is 1g:2 ~ 3mL.
7. the preparation method of Bromfenac sodium according to claim 1 and 2 times semihydrate, is characterized in that, in described step (2), counts by weight percentage, and the add-on of described crystal seed is 1% ~ 5% of Bromfenac sodium add-on.
8. the preparation method of Bromfenac sodium according to claim 1 and 2 times semihydrate, is characterized in that, in described step (2), counts by weight percentage, and the add-on of described crystal seed is 3% of Bromfenac sodium add-on.
9. the preparation method of Bromfenac sodium according to claim 1 and 2 times semihydrate, it is characterized in that, in described step (2), in the mixture of described Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate, count by weight percentage, the weight ratio of Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate is 1:1.
10. the preparation method of Bromfenac sodium according to claim 1 and 2 times semihydrate, is characterized in that, in described step (3), described cooling temperature is 0 ~ 15 DEG C.
The preparation method of 11. Bromfenac sodium according to claim 1 and 2 times semihydrates, is characterized in that, in described step (3), the described crystallization time is 1 ~ 2h.
The preparation method of 12. Bromfenac sodium according to claim 1 and 2 times semihydrates, is characterized in that, described step (3) also comprises the step of the crystal that vacuum-drying is separated out.
The preparation method of 13. Bromfenac sodium according to claim 12 times semihydrates, is characterized in that, described in described step (3), vacuum drying vacuum tightness is-0.095MPa ~-0.090MPa; Described drying temperature is 40 ~ 50 DEG C; Described time of drying is 12 ~ 18h.
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| US4683242A (en) * | 1985-10-28 | 1987-07-28 | A. H. Robins Company, Incorporated | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
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| WO2011046733A1 (en) * | 2009-10-15 | 2011-04-21 | Johnson Matthey Public Limited Company | Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs |
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