CN104151182A - Preparation method of bromfenac sodium sesquihydrate - Google Patents
Preparation method of bromfenac sodium sesquihydrate Download PDFInfo
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- CN104151182A CN104151182A CN201410267097.2A CN201410267097A CN104151182A CN 104151182 A CN104151182 A CN 104151182A CN 201410267097 A CN201410267097 A CN 201410267097A CN 104151182 A CN104151182 A CN 104151182A
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Abstract
The invention aims at providing a preparation method of bromfenac sodium sesquihydrate. The preparation method comprises the following steps: (1) adding bromfenac sodium and an antioxidant into a mixed solvent of water and an organic alcohol, heating, dissolving and adding a pH adjustor to adjust the pH to 7.0-10.5; (2) adding an anti-solvent into a solution obtained in the step (1), cooling the solution to 30 DEG C to 35 DEG C, adding bromfenac sodium monohydrate, bromfenac sodium sesquihydrate or a mixture thereof as a seed crystal, and stirring; and (3) cooling, crystallizing, collecting crystals and drying to obtain the bromfenac sodium sesquihydrate. The preparation method avoids use of ether agents and is mild in reaction condition and good in environmental benefit. The prepared bromfenac sodium sesquihydrate is high in purity.
Description
Technical field
The invention belongs to pharmaceutical technology field, 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; prostanoid inflammatory mediator synthetic that can suppress cyclooxygenase mediation; 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).
U.S. FDA subordinate's chemical classes CDER (Center for Drug Evaluation and Research, CDER) data of issue shows, the medicinal crystal-form of Bromfenac sodium (Application Number21-664) is a times semihydrate, i.e. crystal formation I.
Embodiment 74Ji China Medicine University journal (2003 in patent documentation EP0221753; 34 (5): 405～406) all reported in the mixed solvent of toluene and ethanol; the sodium hydroxide solution of employing 50% is by 7-(4-benzoyl)-1; 3-dihydro-indol-2-one " single stage method " hydrolysis salifying, isopropyl ether crystallization are prepared Bromfenac sodium crude product; through water and glycol dimethyl ether mixed solvent recrystallization, prepare the method for Bromfenac sodium times semihydrate, its route is again:
The method has been used 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 re-crystallization step use glycol dimethyl ether increased Bromfenac sodium times semihydrate in the residual risk of organic solvent.
Patent EP2311794 has reported preparation method and the mutual conversion process thereof of three kinds of crystal formations of Bromfenac sodium, 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 be by Bromfenac sodium without hydrate mixed solvent crystallization or the recrystallization through water, dialkoxy alkane (as glycol dimethyl ether) and anti-solvent (as t-butyl methyl ether), hydration obtains Bromfenac sodium times semihydrate; Path two be by Bromfenac sodium without hydrate mixed solvent crystallization or the recrystallization through water, dialkoxy alkane (as glycol dimethyl ether) and anti-solvent (as t-butyl methyl ether), 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, have all increased the residual risk of organic solvent in Bromfenac sodium times semihydrate.In addition, also provide crystallization or recrystallization in the mixed solvent of water and at least one alcohol by Bromfenac sodium monohydrate or Bromfenac sodium times semihydrate in this patent, then vacuum-drying obtains Bromfenac sodium without the method for hydrate.
At present, using environmentally friendly solvent is water and Organic Alcohol, Bromfenac sodium is carried out to crystallization or recrystallization can only obtain Bromfenac sodium without hydrate, and cannot obtain Bromfenac sodium times semihydrate.And prepare Bromfenac sodium times semihydrate in prior art, all need to use the ether organic solvents such as glycol dimethyl ether, environmental benefit is poor, and organic solvent residual risk is larger, is unfavorable for industrialization production.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of Bromfenac sodium times semihydrate, the method has been avoided the use of ethers reagent, and reaction conditions is gentle, and environmental benefit is good, and the purity of the Bromfenac sodium of preparation times semihydrate 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, dissolves, and adds pH adjusting agent to regulate pH to 7.0～10.5;
(2) in the solution obtaining to step (1), add anti-solvent, be cooled to 30～35 ℃, add Bromfenac sodium monohydrate, Bromfenac sodium times semihydrate or its mixture as crystal seed, stir;
(3) cooling, crystallization, collects crystal, dry, obtains Bromfenac sodium times semihydrate.
Preferably, in described step (1), described Bromfenac sodium is selected from Bromfenac sodium without one or more in hydrate, Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate;
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 is selected from one or more in methyl alcohol, ethanol and Virahol;
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, and more preferably, described anti-solvent is selected from one or more in methyl alcohol, ethanol and Virahol;
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 ℃;
Preferably, in described step (3), the described crystallization time is 1～2h;
Preferably, the step that also comprises the crystal that vacuum-drying is separated out in described step (3); Preferably, described vacuum tightness is-0.095MPa～-0.090MPa; Described drying temperature is 40～50 ℃; Be 12～18h described time of drying.
The inventor has carried out a large amount of explorations to the preparation method of Bromfenac sodium times semihydrate, discovery makes water and Organic Alcohol as mixed solvent, add oxidation inhibitor, and add Bromfenac sodium monohydrate, Bromfenac sodium times semihydrate or its mixture to induce crystallization as crystal seed, can prepare highly purified Bromfenac sodium times semihydrate.Result of study shows, the inventor uses Bromfenac sodium times semihydrate as crystal seed, obtains high purity Bromfenac sodium times semihydrate; The inventor use Bromfenac sodium without hydrate as crystal seed, obtain Bromfenac sodium without hydrate; The 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 be realized the preparation of Bromfenac sodium times semihydrate as crystal seed, to have utilized that Bromfenac sodium monohydrate is unstable and character that Bromfenac sodium times semihydrate is stable has realized the conversion of Bromfenac sodium monohydrate crystal seed to Bromfenac sodium times semihydrate under the processing condition such as solvent provided by the invention and temperature.
In preparation method of the present invention, the crystal formation important that the temperature while adding crystal seed obtains crystallization, what while being cooled to lower than the temperature of 30 ℃, add that crystal seed, crystallization obtain is that Bromfenac sodium is without hydrate; And what add that crystal seed, crystallization obtain during higher than 35 ℃ is the mixed crystal of Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate.
In preparation method of the present invention, add antioxidant can improve the stability of recrystallization process, acquired character is jonquilleous crystalline powder; And while not adding oxidation inhibitor, the crystalline powder of acquisition is orange-yellow, and its related substance 7-(4-benzoyl)-1, the content of 3-dihydro-indol-2-one surpasses 0.1%, is difficult to meet the medicinal requirements of Bromfenac sodium.
Compared with prior art, the present invention has following beneficial effect:
By the existing crystallization technology of Bromfenac sodium is reformed, only use environmentally friendly solvent water and Organic Alcohol just to realize the preparation of high purity Bromfenac sodium times semihydrate, avoided the use of ethers reagent, environmental benefit is good; By adding oxidation inhibitor, improved 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, has reduced production cost, the Bromfenac sodium obtaining times semihydrate purity >=99.5%, and 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 the Bromfenac sodium times semihydrate related substance of embodiment 1 preparation;
Fig. 2 is the infrared spectrogram of the Bromfenac sodium times semihydrate of embodiment 1 preparation;
Fig. 3 is the X-ray powder diffraction spectrogram of the Bromfenac sodium times semihydrate of embodiment 1 preparation;
Fig. 4 is the means of differential scanning calorimetry spectrogram of the Bromfenac sodium times semihydrate of embodiment 1 preparation;
Fig. 5 is the thermal weight loss spectrogram of the Bromfenac sodium times semihydrate of embodiment 1 preparation.
Fig. 6 is preparation method and the mutual conversion process route map thereof of the three kinds of crystal formations of Bromfenac sodium of patent EP2311794 described in background technology.
Embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment are only for the present invention is described, the scope that it does not limit 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 without hydrate, 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 add 1500mL ethanol, be cooled to 30 ℃, add 15g Bromfenac sodium times semihydrate as crystal seed, after stirring, be cooled to 5 ℃, standing crystallization 1h, centrifugal collection crystal, at 50 ℃, 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 prepared by the present embodiment times semihydrate related substance as shown in Figure 1.
The infrared spectrogram of Bromfenac sodium prepared by the present embodiment times semihydrate as shown in Figure 2.
The X-ray powder diffraction spectrogram of Bromfenac sodium prepared by the present embodiment times semihydrate as shown in Figure 3.
The means of differential scanning calorimetry spectrogram of Bromfenac sodium prepared by the present embodiment times semihydrate as shown in Figure 4.
The thermal weight loss spectrogram of Bromfenac sodium prepared by the present embodiment times semihydrate as shown in Figure 5.
embodiment 2
In 1L reaction flask, by 100g Bromfenac sodium without hydrate, 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 add 250mL methyl alcohol, be cooled to 35 ℃, add 3.0g Bromfenac sodium monohydrate as crystal seed, after stirring, be cooled to 15 ℃, stirring and crystallizing 2h, centrifugal collection crystal, at 47 ℃, 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 add 300mL Virahol, be cooled to 32 ℃, add 1.0g Bromfenac sodium monohydrate and 1.0g Bromfenac sodium times semihydrate as crystal seed, after stirring, be cooled to 0 ℃, stirring and crystallizing 1h, centrifugal collection crystal, at 47 ℃, 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 add 200mL ethanol, be cooled to 35 ℃, add 2.0g Bromfenac sodium times semihydrate as crystal seed, after stirring, be cooled to 15 ℃, standing crystallization 1.5h, centrifugal collection crystal, at 50 ℃, 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 is joined in the mixed solvent of 500mL water and 500mL ethanol without hydrate, 0.75g S-WAT, after heating for dissolving, add acetic acid adjust pH to 9.0, then add 1500mL ethanol, be cooled to 30 ℃, vacuum-drying 15h under 50 ℃ ,-0.095MPa～-0.090MPa, obtain Bromfenac sodium without hydrate, moisture content is 0.14%.
Can find out, this comparative example carries out repetitive operation according to method described in embodiment 1, but do not add any crystal seed, the crystal detected result obtaining be Bromfenac sodium without hydrate, moisture content is 0.14%.
comparative example 2
In 5L reaction flask, 500g Bromfenac sodium is joined in the mixed solvent of 500mL water and 500mL ethanol without hydrate, 0.75g S-WAT, after heating for dissolving, add acetic acid adjust pH to 9.0, then add 1500mL ethanol, be cooled to 25 ℃, add 15g Bromfenac sodium times semihydrate as crystal seed, after stirring, be cooled to 5 ℃, standing crystallization 1h, centrifugal collection crystal, vacuum-drying 15h under 50 ℃ ,-0.095MPa～-0.090MPa, obtains Bromfenac sodium without hydrate, and 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 ℃, change into and be cooled to 25 ℃, the crystal detected result obtaining be Bromfenac sodium without hydrate, moisture content is 0.22%.
comparative example 3
In 5L reaction flask, 500g Bromfenac sodium is joined in the mixed solvent of 500mL water and 500mL ethanol without hydrate, 0.75g S-WAT, after heating for dissolving, add acetic acid adjust pH to 9.0, then add 1500mL ethanol, be cooled to 38 ℃, add 15g Bromfenac sodium times semihydrate as crystal seed, after stirring, be cooled to 5 ℃, standing crystallization 1h, centrifugal collection crystal, vacuum-drying 15h under 50 ℃ ,-0.095MPa～-0.090MPa, obtains Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate, and 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 ℃, changes into and is cooled to 38 ℃, obtains the mixed crystal of Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate, and 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 according to the present invention various changes or distortion, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (4)
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, dissolves, and adds pH adjusting agent to regulate pH to 7.0～10.5;
(2) in the solution obtaining to step (1), add anti-solvent, be cooled to 30～35 ℃, add Bromfenac sodium monohydrate, Bromfenac sodium times semihydrate or its mixture as crystal seed, stir;
(3) cooling, crystallization, collects crystal, dry, obtains Bromfenac sodium times semihydrate.
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 is selected from Bromfenac sodium without one or more in hydrate, Bromfenac sodium monohydrate and Bromfenac sodium times semihydrate;
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 is selected from one or more in methyl alcohol, ethanol and Virahol;
Preferably, in described step (1), described pH adjusting agent is acetic acid, regulates pH to 9.0～10.0.
3. 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;
Preferably, in described step (2), described anti-solvent is Organic Alcohol, and more preferably, described anti-solvent is selected from one or more in methyl alcohol, ethanol and Virahol;
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.
4. according to the preparation method of times semihydrate of the Bromfenac sodium described in any one in claims 1 to 3, it is characterized in that, in described step (3), described cooling temperature is 0～15 ℃;
Preferably, in described step (3), the described crystallization time is 1～2h;
Preferably, described step (3) also comprises the step of the crystal that vacuum-drying is separated out; Preferably, described vacuum tightness is-0.095MPa～-0.090MPa; Described drying temperature is 40～50 ℃; Be 12～18h described time of drying.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115093340A (en) * | 2022-06-27 | 2022-09-23 | 辰欣药业股份有限公司 | Preparation method of bromfenac sodium sesquihydrate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115093340A (en) * | 2022-06-27 | 2022-09-23 | 辰欣药业股份有限公司 | Preparation method of bromfenac sodium sesquihydrate |
| CN115093340B (en) * | 2022-06-27 | 2024-05-03 | 辰欣药业股份有限公司 | Preparation method of bromfenac sodium sesquihydrate |
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