CN1304412A - Process for preparing crystalline salts of amoxycillin - Google Patents

Abstract

A novel process for the preparation of crystalline alkali metal salts of amoxycillin is disclosed.

Description

Process for preparing crystalline amoxicillin salt

This application claims the benefit of US Provisional Application 60/087,554, filed June 1,1998.

The present invention relates to the preparation of β-lactam antibiotic amoxicillin, namely 6-{[amino(4-hydroxyphenyl)acetyl]-amino}-3,3-dimethyl-7-oxo-4-thia- Method for crystalline salt of 1-azabicyclo[3.2.0]heptane-2-carboxylate. In particular, the present invention relates to a process for the preparation of crystalline amoxicillin sodium salt.

Crystalline amoxicillin sodium salt is a known material and methods for its preparation are disclosed in the art. For example EP 0131147A discloses a process for converting amoxicillin trihydrate to a crystalline solvate of amoxicillin sodium salt and removing the solvating solvent therefrom. In one experimental example of this disclosure, amoxicillin trihydrate was suspended in methyl acetate, and then a solution of a mixture of triethylamine and sodium 2-ethylhexanoate was added to the suspension. In EP 0596262A amoxicillin trihydrate is dissolved in a methyl acetate/isopropanol/triethylamine mixture and this solution is then added to a solution of sodium 2-ethylhexanoate in a methyl acetate/methanol mixture middle. It is believed that a crystalline solvate of amoxicillin sodium salt crystallized from the reaction mixture from which the solvating solvent was removed. In WO 97/15579 amoxicillin trihydrate was added to an ethanol/triethylamine mixture to form a solution which was subsequently reacted with sodium 2-ethylhexanoate in ethanol solution to give a crystalline product. In US 4737585, amoxicillin trihydrate is suspended in a mixture of an aprotic solvent such as dichloromethane and a lower alcohol, a low molecular weight amine is used to dissolve amoxicillin, and diethyloxalacetate sodium salt is added to the mixture. Amoxicillin sodium salt is then precipitated by adding more aprotic solvent.

In a process for the preparation of crystalline amoxicillin sodium salt it is desirable to minimize the amount of solvent used and to increase the yield and purity of the product. Therefore, there are problems in the current method improvement. It is an object of the present invention to provide an alternative and improved process for the preparation of crystalline amoxicillin sodium salt. Other objects and advantages of the invention will be apparent from the following description.

According to the present invention there is provided a method for preparing crystalline amoxicillin alkali metal salt, wherein:

forming a suspension of amoxicillin amine salt in a first organic solvent;

mixing the suspension with a second organic solvent and bringing the amine salt into solution in the mixture of the first and second organic solvents thus formed;

reacting an amine salt with a salt-forming compound of an alkali metal;

The amoxicillin alkali metal salt thus formed is isolated from solution as a crystalline product.

It is considered in the process of the present invention that the amine salt forms a suspension in the first solvent and the rapid dissolution of the salt when the second organic solvent 1-5 is mixed in reduces the decomposition of amoxicillin, thus increasing the yield of the crystalline product rate and purity. In the method of the present invention, the reagent is formed into a solution, which facilitates sterile filtration and subsequent application of the product as an injectable pharmaceutical product. However, the method of the present invention can be equally effectively used for the preparation of orally crystalline amoxicillin sodium salt without sterile filtration.

Preferably, the crystalline amoxicillin alkali metal salt prepared by the process of the present invention is crystalline amoxicillin sodium salt.

Preferred amine salts of amoxicillin are the salts of tri- or di-(C1-51-5)alkylamines of amoxicillin, such as triethylamine, diethylamine or diisopropylamine, especially triethylamine. Mixtures of amine salts such as amoxicillin with salts of triethylamine and diisopropylamine can be used. Other suitable amine salts include salts with dicyclohexylamine.

Preferred first organic solvents are (C1-51-5) alkyl (C1-51-5) alkane carboxylates, preferred such esters are (C1-51-5) alkyl acetates, especially methyl acetate. The first organic solvent may comprise a solvent or a mixture of solvents, such as a mixture of the ester or a mixture of the ester and other co-solvents.

The suspension is preferably first formed by forming a suspension of amoxicillin, preferably in the form of amoxicillin trihydrate, in a first organic solvent, followed by mixing the amine and the suspension to react the amine with the amoxicillin to form the amine salt. The reaction is preferably carried out below ambient temperature, for example below 10°C, especially at 0-5°C. It is suitable for amoxicillin trihydrate to be suspended in a large amount of methyl acetate, the volume ratio of the weight of amoxicillin trihydrate to methyl acetate is about 1:1-1:2.5, for example generally 1:1.7-1 : 2, and the suspension may be mixed with triethylamine in excess of the stoichiometric amount of amoxicillin, e.g. the molar ratio of amoxicillin:triethylamine is 1:1-1:2, for example typically 1:1.3 -1:1.5.

A suitable second organic solvent with which the amine salt suspension may be mixed is a (C1-51-5)alcohol, such as methanol, which is preferred, or ethanol, propanol, such as isopropanol, or butanol, such as isobutanol. The second organic solvent may comprise a solvent or a mixture of solvents, such as the alcohol or a mixture of the alcohol and other co-solvents.

The second solvent is mixed with a suspension of the amine salt in the first solvent so that the salt goes into solution, and the volume of the second solvent used, such as alcohol, can be determined experimentally, the minimum amount of the second solvent necessary for this purpose volume. Generally when the first solvent is the above-mentioned ester and the second solvent is the above-mentioned alcohol, it has been found that a volume ratio of ester:alcohol of about 1:0.3-0.6 will be suitable, for example about 1:0.4-0.5 methyl acetate: Methanol. If methanol in this volume ratio is mixed with the suspension of the above-mentioned triethylamine salt of amoxicillin, the salt will generally dissolve immediately upon stirring.

The amoxicillin amine salt solution so formed at this stage may be treated, for example, by filtration and/or by other standard purification steps such as treatment with decalide or other materials which selectively absorb impurities. If the solution is filtered, the filter medium may then be washed with more of the second solvent, such as alcohol, for example 0.5-1.0 times the amount that has been mixed with the saline solution.

Suitable salt-forming compounds are pharmaceutically acceptable alkali metal salt-forming compounds, for example sodium salts of organic compounds, for example alkoxides such as (C1-51-5) alkoxides such as methoxide and/or ethoxide, or organic acids Such as salts of (C1-121-5) carboxylic acids such as alkyl substituted alkanoic acid salts such as 2-ethylhexanoate. In the case of preparing crystalline amoxicillin sodium salt, sodium 2-ethylhexanoate is the preferred salt-forming compound.

The reaction of the amine salt is suitably carried out by mixing a solution of the amine salt and a solution of the salt-forming compound. The salt-forming compound is suitably present in solution in a solvent mixture comprising the first and second organic solvents described above, such as the (C1-51-5)alkyl(C1-51-5)alkane carboxylates described above and (C1-51-5)alcohols, for example methyl acetate:methanol mixtures comprising mainly esters, for example 9-12:1 v:v, such as 10-11:1 v:v methyl acetate:methanol mixtures. It is appropriate to use a stoichiometric excess of the salt-forming compound relative to amoxicillin, for example sodium 2-ethylhexanoate:amoxicillin in a molar ratio of 1.5-2.5:1. A solution of sodium 2-ethylhexanoate at a concentration of about 1.8-2.5 M in the above solvent mixture may suitably be used. The solution may be filtered and/or subjected to other suitable purification steps prior to reaction with amoxicillin.

Preferably the reaction between the salt-forming compound and amoxicillin is carried out below ambient temperature, for example below 10°C, especially at 0-5°C. Preferably, the amine salt solution is added to the salt-forming compound solution, although the reverse mode of addition, ie, the salt-forming compound solution is added to the amine salt solution, or mixed simultaneously, may be used. Preferably the mixing of the two solutions is done as quickly as possible with rapid agitation.

The reaction product may crystallize spontaneously, but crystallization is preferably induced by adding seeds, such as crystalline amoxicillin sodium salt or some crystalline equivalent such as a solvate of crystalline amoxicillin sodium salt, to the reaction mixture immediately after the solutions have been mixed. In order to further promote crystallization, some of the above-mentioned first organic solvent such as (C1-51-5) alkyl (C1-51-5) alkane carboxylate such as methyl acetate can be added to mix with the reaction mixture, preferably using an excess of The volume of the medium is, for example, 1.5-2.0 times the volume of the reaction medium in excess. This mixing of the first organic solvent can be done relatively slowly, for example in about 30-40 minutes. After mixing this additional amount of the first solvent, the mixture may be stirred for a further period of time, eg about 1 hour, preferably at subambient temperature, eg below 10°C, especially at 0-5°C.

After this stage the crystalline product can be separated from the reaction medium by standard methods such as filtration and washing with a suitable wash, preferably a first organic solvent.

The crystalline product obtained in this way is considered to be a solvate of crystalline amoxicillin sodium salt, e.g. methyl acetate solvate, from which the solvating solvent can be removed by a drying process such as that disclosed in EP 0131147A, incorporated herein The contents are for reference. This drying process can be carried out in vacuum preferably at high temperature such as 50-65°C, such as 60-65°C to remove residual reaction medium solvent, washing liquid and solvating solvent to obtain crystalline amoxicillin alkali metal salt.

The crystalline amoxicillin sodium salt prepared by the method of the present invention can be used, for example, as an injectable pharmaceutical antibiotic product. For this purpose it is supplied in sealed sterile vials. Or the amoxicillin sodium salt prepared by the method of the present invention is used in oral preparations such as tablets, pills, syrups, etc., and does not require sterile preparations for oral use. As an antibiotic product it is preferred to use the crystalline amoxicillin alkali metal salt product in combination with a pharmaceutically acceptable β-lactamase inhibitor such as a salt of clablanate, especially potassium clablanate.

The invention will now be illustrated by way of non-limiting examples.

Example 1: Dissolution of Sodium 1.12-Ethylhexanoate on Laboratory Scale

Sodium 2-ethylhexanoate (160 g) was dissolved in a mixture of methyl acetate (310 ml) and methanol (30 ml). The mixture was stirred at room temperature until complete dissolution and the solution was filtered through Whatman No. 1 filter paper to remove turbidity. The solution was transferred to a crystallization vessel, then rinsed with methyl acetate (210ml) and stirred at 0-5°C. The solution is thus 2.15M sodium 2-ethylhexanoate. 1.2 Dissolution of amoxicillin trihydrate

Amoxicillin trihydrate (250 g) was slurried in methyl acetate (450 ml). Triethylamine (120ml) was added to the slurry resulting in a thick suspension. Methanol (200ml) was added and amoxicillin triethylamine salt dissolved immediately. The solution was stirred for 5 minutes before adding decalide (10 g) and the mixture was allowed to stir for a further 5 minutes. The solution was then filtered through Whatman No. 1 filter paper, rinsed with methanol (120 ml) and transferred to a crystallization vessel containing sodium 2-ethylhexanoate from 1.1 above. 1.3 Reaction and crystallization

The mixture in the crystallization vessel was stirred vigorously at 0-5°C and seeded with amoxicillin sodium salt (1 g). Methyl acetate (2300ml) was added within 30-40 minutes after crystallization started. The mixture was stirred at 0-5°C for 1 hour. The product was then filtered and rinsed with methyl acetate (750ml). 1.4 drying

The crystalline product from 1.3 was dried under vacuum at 50-55°C for 36 hours, or at 65°C for a shorter period of 16 hours. The quality of the product was found to be unaffected by the drying temperature. The product was proved to be crystalline amoxicillin sodium salt by chemical analysis, infrared spectrum and X-ray powder diffraction.

The amoxicillin content of the obtained product is 91.0%, and the total impurity content is 2.13-2.16%.

Embodiment 2; Experimental amount enlarges the dissolving of 2.1 2-sodium ethylhexanoate

Methyl acetate (124 L) was added to sodium 2-ethylhexanoate (64 kg), and methanol (12 L) was added with stirring until the sodium 2-ethylhexanoate was dissolved. The solution was filtered and transferred to a crystallization vessel, rinsing with methyl acetate (84 L). 2.2 Dissolution of amoxicillin trihydrate

Methyl acetate (124 L) was added to amoxicillin trihydrate (87.1 kg) and the resulting suspension was cooled to 0-5°C. Triethylamine (48.1 L) was added to the slurry and the slurry was stirred for 5 minutes. Methanol (80 L) was added to dissolve the amoxicillin triethylamine salt and the solution was stirred for 5 minutes. Decalide (2 kg) was added and the mixture was stirred for a further 5 minutes. The solution was then filtered and the filter cake was rinsed with methanol (48 L). 2.3 Reaction and crystallization

As soon as possible add the amoxicillin triethylamine salt solution from 2.2 to the sodium 2-ethylhexanoate solution from 2.1 and cool the mixture to 0-5°C. Amoxicillin sodium salt seeds (400 g) were added. Methyl acetate (921 L) was added at a rate of 27 liters per minute. The mixture was stirred at 0-5°C for 1 hour. The slurry was then transferred to a Nutrex ^™ mixer and the mother liquor was filtered. The product was rinsed with methyl acetate (84 L). 2.4 drying

The crystalline product from 2.3 was blown dry with nitrogen and then dried under vacuum at 60-65°C.

The amoxicillin content of the obtained product is 89.7-93.6%, and the total impurity content is 1.72-1.42%.

Claims (16)

1. method for preparing crystallization amoxycilline Trihydrate bp an alkali metal salt, wherein:

In first kind of organic solvent, form the suspension of amoxycilline Trihydrate bp amine salt;

This suspension mixed with second kind of organic solvent and amine salt is entered in the mixture solution of first kind and second kind organic solvent of formation like this;

Make the reaction of amine salt and alkali-metal salt-forming compound;

The amoxycilline Trihydrate bp an alkali metal salt that so forms is separated from solution as crystallized product.

2. according to the process of claim 1 wherein that the crystallization amoxycilline Trihydrate bp an alkali metal salt by described method preparation is a crystallization amoxycilline Trihydrate bp sodium salt.

3. according to the process of claim 1 wherein that the amoxycilline Trihydrate bp amine salt is triethylamine, diethylamine or the diisopropyl amine salt of amoxycilline Trihydrate bp.

4. according to the process of claim 1 wherein that first kind of organic solvent is (C1-51-5) alkyl (C1-51-5) alkane carboxylicesters.

5. according to the method for claim 4, wherein (C1-51-5) alkyl (C1-51-5) alkane carboxylicesters is a methyl acetate.

6. according to the process of claim 1 wherein that amine salt suspension is by at first forming Utimox suspension and subsequently amine being mixed with this suspension so that amine and amoxycilline Trihydrate bp reaction formation amine salt form in first kind of solvent.

7. according to the process of claim 1 wherein that second kind of organic solvent is (C1-51-5) alcohol.

8. according to the method for claim 7, wherein (C1-51-5) alcohol is methyl alcohol.

9. according to the process of claim 1 wherein that salt-forming compound is the sodium salt of organic compound.

10. according to the method for claim 9, wherein salt-forming compound is (C1-51-5) sodium alkoxide or (C1-121-5) carboxylate salt.

11. method according to Claim 8, wherein salt-forming compound is a 2 ethyl hexanoic acid sodium.

12. according to the process of claim 1 wherein that the reaction of amine salt undertaken by mixed amine salts solution and salt-forming compound solution.

13. according to the method for claim 10, wherein salt-forming compound is present in the solution of the solvent mixture that comprises first kind and second kind organic solvent.

14. according to the method for claim 13, wherein solvent mixture is for mainly comprising the methyl acetate of methyl acetate: carbinol mixture.

15., wherein amine salt solution is joined in the salt-forming compound solution according to the method for claim 12.

16. crystallization amoxycilline Trihydrate bp an alkali metal salt is for requiring the product of any method according to aforesaid right.