CN102086213B

CN102086213B - Crystallization preparation method of cloxacillin sodium

Info

Publication number: CN102086213B
Application number: CN2010106032421A
Authority: CN
Inventors: 王静康; 智敏杰; 王永莉; 尹秋响; 张美景; 侯宝红; 鲍颖; 龚俊波
Original assignee: Tianjin University
Current assignee: Tianjin University
Priority date: 2010-12-23
Filing date: 2010-12-23
Publication date: 2012-11-28
Anticipated expiration: 2030-12-23
Also published as: CN102086213A

Abstract

The invention discloses a crystallization preparation method of cloxacillin sodium. The method is as follows: stirring added 0.03g/mL-0.2g/mL sodium isooctoate-alcohol solution in 0.1-0.2g/mL cloxacillin acid solution at the temperature of 5-25 DEG C, reacting and crystallizing, wherein the pH value of the final point of the reaction process is 5.5-7.5; then adding an ester or ether solventing-out agent in the solution for solventing-out crystallization, wherein the volume of the ester or ether solventing-out agent is 7-11 times that of cloxacillin acid solution; and carrying out centrifugal separation, solvent washing and drying on crystal slurry after crystallization, so that the cloxacillin sodium product is obtained. The crystal habit of the product is of a flaky shape, the particle size is large, the residue of the solvent is obviously improved, the crystal slurry is easy to filter, wash and dry, and the production period is greatly shortened. The high-performance liquid chromatography (HPLC) content of the product is above 99.4%, and the pH value is 5.7-6.0, thereby achieving the requirement of China Pharmacopeia 2010. The molar yield in the crystallization process is more than 88%.

Description

A kind of crystallization preparation method of cloxacillin sodium

Technical field

The invention belongs to the crystallization technique field, particularly a kind of crystallization preparation method of cloxacillin sodium.

Background technology

Cloxacillin sodium (Cloxacillin Sodium) is Tegopen again, and chemical name is: 6-[3-(2-the chloro-phenyl-)-different azoles formamido-of 5-methyl-4-] penicillanic acid sodium, chemical formula C ₁₉H ₁₇ClN ₃O ₅S.H ₂O.Na, molar mass is 475.88, its structural formula is as follows.

Cloxacillin sodium is acidproof and the De of anti-enzyme isoxazole microbiotic; Has stronger anti-microbial activity; It is through suppressing the synthetic curative effect that reaches of duplicating of cell walls, and the oral absorption rate is high, with protein binding rate up to 98%; Clinically anti-other antibiotic infection of staphylococcus aureus is brought into play specific function, formed a bright spot in the anti-infection drug.It is mainly used in treatment by the diseases such as septicemia, pneumonia, endocarditis, osteomyelitis or skin soft-tissue infection due to product enzyme streptococcus aureus or other staphylococcuses.In addition, the exploitation and the application of Ekvacilline+cloxacillin sodium compound are learnt from other's strong points to offset one's weaknesses, and have opened up the market of cloxacillin sodium, make it become the anti-infective medication of widespread use clinically gradually.

The crystalline product of the cloxacillin sodium of domestic production at present, dissolvent residual is higher, and the pH value is on the low side, and clarity can not reach 2010 editions Chinese Pharmacopoeia to the requirement of cloxacillin sodium; Both at home and abroad for the research report of cloxacillin sodium crystallisation process (Li Zhonghua, cloxacillin sodium synthetic, University Of Shanxi's journal (natural science edition) 25 (3): 224～226; 2002) mention in, in the butylacetate solution of 200mL cloxacillin acid, add 5mL methyl alcohol, be warming up to 50 ℃; The 7.7g Sodium isooctanoate that adding prepares and the mixed solution of 25mL butylacetate; Leave standstill the nature precipitation and crystallization, 2h after-filtration, product content 93.06%.There is following defective in this technology: 1. temperature of reaction is too high, and the high more cloxacillin sodium degradation rate of temperature is fast more, poor product quality; 2. the control method of Sodium isooctanoate consumption is reasonable inadequately, and this is because there are differences between batches in the quality (content) of the synthetic cloxacillin acid that obtains; 3. leaving standstill nature, to separate out the crystalline mode unreasonable, gained crystal product granularity heterogeneity and coalescence easily under the no stirring action, poor product quality.In addition, the document does not have the brilliant report of practising (crystal formalness) yet.

And in the production process because product granularity is little, and crystalline form is poor, causes filtration time long, difficult drying, life cycle of the product is long, throughput is low, directly affects the economic benefit of enterprises power that takes part in international competition.

Summary of the invention

The crystallization preparation method that the purpose of this invention is to provide a kind of cloxacillin sodium improves the crystalline product quality.Concrete crystallization preparation method is following:

With concentration is the cloxacillin acid solution of 0.1-0.2g/mL; Under 5-25 ℃ of temperature; Stirring adding concentration is the Sodium isooctanoate solution of 0.03g/mL-0.2g/mL, and the solvent of Sodium isooctanoate solution is selected from alcohols, carries out reactive crystallization; Generate cloxacillin sodium, the pH value of reaction process terminal point is at 5.5-7.5; In solution, adding volume then is the 7-11 ester class or the agent of ethers dissolved doubly of cloxacillin acid solution, carries out dilution crystallization; After the crystallization magma is carried out spinning, solvent wash, drying, obtain the cloxacillin sodium product.

The solvent of described cloxacillin acid solution is the mixed solvent of one or more and water in ETHYLE ACETATE, butylacetate, the acetone.The content of water is in the 1%-6% scope in the solution.

The alcoholic solvent of described Sodium isooctanoate solution is selected from methyl alcohol or ethanol.

The ester class dissolved agent of said dilution crystallization is selected from ETHYLE ACETATE or butylacetate; The agent of ethers dissolved is selected from anhydrous diethyl ether or THF.The adding speed of dissolved agent is for per hour adding the 20%-45% of dissolved agent volume.

Described cleaning solvent is selected from ETHYLE ACETATE, butylacetate or acetone.

Under the drying conditions 20-60 ℃ temperature dry 1-5 hour, vacuum tightness 0～0.09MPa.

The present invention's employing is dissolved in Sodium isooctanoate and is mixed with certain density solution in the alcoholic solvent; The reaction dilution crystallization that control effectively with cloxacillin acid then, different fully with the crystallization method that document is reported, and cloxacillin sodium product of the present invention is brilliant, and to practise (crystalline formalness) be sheet; Granularity is big; Dissolvent residual obviously improves, magma easy filtration, washing and drying, and the production cycle shortens greatly.Product HPLC content reaches more than 99.4%, product pH value between 5.7-6.0, other quality index, especially clarity, the Chinese Pharmacopoeia that all reaches 2010 editions is to the requirement of cloxacillin sodium.The one way molar yield of crystallisation process is greater than 88%.

Description of drawings

The stereoscan photograph of Fig. 1: embodiment 1;

The stereoscan photograph of Fig. 2: embodiment 2;

The stereoscan photograph of Fig. 3: embodiment 3;

The stereoscan photograph of Fig. 4: embodiment 4.

Embodiment

Embodiment 1

Getting concentration is the butylacetate-aqueous solution 200mL of the cloxacillin acid of 0.1g/mL, solution water content 1%, and agitation and dropping concentration is the methanol solution of the Sodium isooctanoate of 0.03g/mL under 10 ℃ of temperature, the endpoint pH of control reaction process is 6.5.Drip butylacetate 1800mL then in the solution of the cloxacillin sodium behind 10 ℃ of temperature downhill reactions, rate of addition is 360mL/h, carries out dilution crystallization.Crystallization is carried out spinning after finishing, washing with acetone, and at 20 ℃, vacuum tightness is 0.03MPa dry 5 hours down with the crystal that obtains.The content 99.4% of final crystal product, pH value 5.7, quality meet 2010 editions Chinese Pharmacopoeia standards, crystallisation process once through yield 91.1% (molar yield).The brilliant habit of crystal (formalness) is a sheet.Its electromicroscopic photograph is as shown in Figure 1.

Embodiment 2

Getting concentration is the ETHYLE ACETATE-aqueous solution 120mL of the cloxacillin acid of 0.15g/mL, solution water content 3%, and agitation and dropping concentration is the methanol solution of the Sodium isooctanoate of 0.1g/mL under 5 ℃ of temperature, the endpoint pH of control reaction process is 5.5.Drip ETHYLE ACETATE 1200mL then in the solution of the cloxacillin sodium behind 5 ℃ of temperature downhill reactions, rate of addition is 360mL/h, carries out dilution crystallization.Crystallization is carried out spinning after finishing, the ETHYLE ACETATE washing, and at 30 ℃, drying is 4 hours under the normal pressure with the crystal that obtains.The content 99.5% of final crystal product, pH value 6.0, quality meet 2010 editions Chinese Pharmacopoeia standards, crystallisation process once through yield 88.5% (molar yield).The brilliant habit of crystal (formalness) is a sheet.Its electromicroscopic photograph is as shown in Figure 2.

Embodiment 3

Getting concentration is the butylacetate-acetone-water solution 150mL of the cloxacillin acid of 0.18g/mL, solution water content 6%, and agitation and dropping concentration is the ethanolic soln of the Sodium isooctanoate of 0.2g/mL under 15 ℃ of temperature, the endpoint pH of control reaction process is 7.0.Drip THF 1650mL then in the solution of the cloxacillin sodium behind 15 ℃ of temperature downhill reactions, rate of addition is 660mL/h, carries out dilution crystallization.Crystallization is carried out spinning after finishing, the butylacetate washing, and at 40 ℃, vacuum tightness is 0.09MPa dry 3 hours down with the crystal that obtains.The content 99.6% of final crystal product, pH value 5.8, quality meet 2010 editions Chinese Pharmacopoeia standards, crystallisation process once through yield 91.2% (molar yield).The brilliant habit of crystal (formalness) is a sheet.Its electromicroscopic photograph is as shown in Figure 3.

Embodiment 4

Getting concentration is the ETHYLE ACETATE-acetone-water solution 160mL of the cloxacillin acid of 0.2g/mL, solution water content 4%, and agitation and dropping concentration is the ethanolic soln of the Sodium isooctanoate of 0.15g/mL under 25 ℃ of temperature, the endpoint pH of control reaction process is 7.5.Drip anhydrous diethyl ether 1120mL then in the solution of the cloxacillin sodium behind 25 ℃ of temperature downhill reactions, rate of addition is 504mL/h, carries out dilution crystallization.Crystallization is carried out spinning after finishing, washing with acetone, and at 60 ℃, vacuum tightness is 0.05MPa dry 1 hour down with the crystal that obtains.The content 99.4% of final crystal product, pH value 5.9, quality meet 2010 editions Chinese Pharmacopoeia standards, crystallisation process once through yield 90.7% (molar yield).The brilliant habit of crystal (formalness) is a sheet.Its electromicroscopic photograph is as shown in Figure 4.

Open and the cloxacillin sodium crystallization preparation method that proposes of the present invention, those skilled in the art can be through using for reference this paper content, and links such as appropriate change raw material, processing parameter realize.Method of the present invention and product are described through preferred embodiment; Person skilled obviously can be in not breaking away from content of the present invention, spirit and scope to method as herein described with product is changed or suitably change and combination, realize the present invention's technology.Special needs to be pointed out is, the replacement that all are similar and change apparent to those skilled in the artly, they are regarded as and are included in spirit of the present invention, scope and the content.

Claims

1. the crystallization preparation method of a cloxacillin sodium, concrete steps are following:

With concentration is the cloxacillin acid solution of 0.1-0.2g/mL; Under 5-25 ° of C temperature; Stirring adding concentration is the Sodium isooctanoate solution of 0.03g/mL-0.2g/mL, and the solvent of Sodium isooctanoate solution is selected from alcohols, carries out reactive crystallization; Generate cloxacillin sodium, the pH value of reaction process terminal point is at 5.5-7.5; In solution, adding volume then is the 7-11 ester class or the agent of ethers dissolved doubly of cloxacillin acid solution, carries out dilution crystallization; After the crystallization magma is carried out spinning, solvent wash, drying, obtain the cloxacillin sodium crystal product;

The alcoholic solvent of described Sodium isooctanoate solution is selected from methyl alcohol or ethanol; The ester class dissolved agent of said dilution crystallization is selected from ETHYLE ACETATE or butylacetate; The agent of ethers dissolved is selected from anhydrous diethyl ether or THF.

2. the crystallization preparation method of cloxacillin sodium as claimed in claim 1, the content that it is characterized in that water in the described cloxacillin acid solution is in the 1%-6% scope.

3. preparation method as claimed in claim 1, the adding speed that it is characterized in that the dissolved agent is for per hour adding the 20%-45% of dissolved agent volume.

4. preparation method as claimed in claim 1 is characterized in that the solvent that is used to wash is selected from ETHYLE ACETATE, butylacetate or acetone.

5. preparation method as claimed in claim 1 is characterized in that drying conditions is under 20-60 ℃ of temperature dry 1-5 hour, vacuum tightness 0～0.09MPa.

6. preparation method as claimed in claim 1, the profile of the cloxacillin sodium crystal product that it is characterized in that obtaining is a sheet.