MXPA00011833A - Process for preparing crystalline salts of amoxycillin - Google Patents

Abstract

A novel process for preparing a crystalline alkali metal salt of amoxycillin is dislcosed.

Description

PROCEDURE FOR PREPARING AMOXICILLIN CRYSTALLINE SALTS This application claims the benefit of US Provisional Application No 60 / 027.554 filed on June 1, 1998. This invention relates to a process for preparing crystalline salts of amoxycillin beta lactam antibiotic acid 6 - [[amino ( 4-hydroxy-phenyl) -acetyl] -amino] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid. In particular, this invention relates to a process for the preparation of crystalline sodium amoxycillin. Crystalline sodium amoxicillin is a known substance and methods for its preparation are described in the art. For example, EP 0131147A describes a process in which amoxicillin trihydrate is converted to a crystalline solvate of sodium amoxicillin from which the solvation solvent is removed. In a test example of this description, amoxicillin trihydrate is suspended in methylacetate, then a solution of a mixture of triethylamine and sodium 2-ethylhexanoate is added to this suspension. EP 0596262A in the amoxycillin trihydrate is dissolved in a mixture of methyl acetate / isopropanol / triethylamine, then this solution is added to a solution of 2-ethylhexanoate in a mixture of methylacetate / methanol. It is believed that a crystalline solvate of sodium amoxycillin is crystallized from the reaction mixture, from which the solvation solvent is removed. WO 97/15579 in the amoxycillin trihydrate is added to a mixture of ethanol / triethylamine to form a solution which was then reacted with 2-ethylhexanoate in ethanolic solution, and a crystalline product is obtained. In US 4737585 amoxycillin trihydrate is suspended in a mixture of an aprotic solvent such as methylene chloride, and a lower alcohol, the amoxycillin solubilized using an amine of low molecular weight, and to this mixture the sodium salt of dietiloxalacético acid is added . The sodium amoxycillin is then precipitated by the addition of a larger amount of the aprotic solvent. In processes used to prepare crystalline sodium amoxycillin it is desirable to reduce the amounts of solvents used and to improve the yield and purity of the product. Consequently, there is a continuous problem of improvement of this procedure. An objective of the present invention is to provide an alternative and improved method for the preparation of crystalline sodium amoxycillin. Other objects and advantages of the present invention will be apparent from the following description. In accordance with this invention, there is provided a process for the preparation of a crystalline alkali metal salt of amoxicillin, in which: a suspension of an amine salt of amoxicillin is formed in a first organic solvent. The suspension is mixed with a second organic solvent and the amine salt originates in the solution in the mixture thus formed of the first and second organic solvents, t «aaaaaa a > * ^^ the amine salt is reacted with an alkali metal salt-forming compound, the alkali metal salt thus formed of amoxicillin is isolated from the solution as a crystalline product. In the process of the invention, it is considered that the formation of the suspension of the amine salt in the first solvent, and the rapid dissolution of the salt when the second organic solvent is mixed 1-5is, leads to the reduced decomposition of amoxicillin , and consequently the yield and purity of the crystalline product is increased. In the process of this invention, reagents are formed in the solution, which facilitate the sterilization of the filtration and the consequent use of the product as an injectable pharmaceutical product. However, the method of the invention can be used equally effectively without the sterile filtration step to prepare crystalline sodium amoxycillin that can be administered orally. Preferably, the crystalline alkali metal salt of amoxicillin prepared by the process of this invention is crystalline sodium amoxycillin. Preferably, the amine salt of amoxicillin is a salt of a tri- or di- (C1-51-5) alkyl amine, such as triethylamine, diethylamine or diisopropylamine, especially the triethylamines, salt of amoxicillin. A mixture of amine salts such as a mixture of amoxicillin salts with triethylamine and diisopropylamine can be used. Other amines salts Suitable include salt with dicyclohexylamine. A first preferred organic solvent is an ester of (C1-51-5) alkyl-alkanoate (C1-51-5), a preferred ester is an ester of (C1-51-5) alkyl acetate, particularly methylacetate. The first organic solvent may comprise a single solvent or a mixture of solvents, for example a mixture of said esters or said esters and other co-solvents. Preferably, the suspension is formed by first forming a suspension of amoxycillin, preferably in the form of amoxycillin trihydrate, in the first organic solvent then mixing the amine with this suspension so that the amine reacts with the amoxycillin to form the amine salt. This reaction is preferably carried out at low room temperature, for example 10 ° C, especially at 0-5 ° C. Suitably, amoxycillin trihydrate can be suspended in a volume of methylacetate in a weight ratio of amoxicillin trihydrate: methylacetate volume 1: 1-1: 2.5, for example, typically 1: 1.7-1: 2, and can be suspended. mix this suspension with triethylamine in a stoichiometric excess to amoxicillin, for example at a molar ratio of amoxicillin: triethylamine 1: 1 - 1: 2, for example, typically 1: 1.3-1: 1.5. A second suitable organic solvent with which the suspension of the amine salt can be mixed is a (C1-51-5) alcohol, such as methyl alcohol, which is preferred, or ethyl alcohol, propyl alcohol, for example isopropyl alcohol or butyl alcohol, for example iso-butyl alcohol. The second organic solvent may comprise a single solvent or aMMMMMB a mixture of solvents, for example a mixture of said alcohols or said alcohols with other solvents. The mixture of the second solvent and the suspension of the amine salt in the first solvent causes the salt to enter the solution, and the volume of the second solvent, for example the alcohol used, can be determined experimentally as the minimum volume of the second solvent necessary to achieve this. Typically, when the first solvent is the ester described above and the second solvent is the alcohol described above, the ester should be in a volume: alcohol ratio of ca. 1: 0.3 - 0.6 which will be very suitable, for example, approximately 1: 0.4 - 0.5 methylacetate: methyl alcohol. If said volume ratio of methyl alcohol is mixed with the aforementioned suspension of the triethylamine salt of amoxicillin, then the salt generally dissolves immediately upon stirring. In this step, the solution thus formed of the amoxicillin amine salt can be for example filtered and / or treated by other standard purification steps, for example treatment with dicalite or other materials that selectively absorb impurities. If the solution is filtered, the filter medium can subsequently be washed with more of the second solvent, for example alcohol, for example corresponding to an amount of 0.5-1.0 of the amount already in the mixture with the salt solution. . A suitable salt-forming compound is a pharmaceutically acceptable salt-forming compound of a suitable alkali metal, For example, the sodium salt of an organic compound, for example an alcoholate such as (C1-51-5) alcohol, for example the methoxide and / or ethoxide, or a salt of an organic acid, for example a (C 1-121-5) carboxylic acid, such as substituted alkylalkanoate, for example a 2-ethylhexanoate. In the case of the preparation of crystalline sodium amoxicillin with sodium 2-ethylhexanoate sodium is a preferred salt-forming compound. The reaction of the amine salt is carried out suitably by mixing the solution of the amine salt with a solution of the salt-forming compound. The suitable salt-forming compound is in the solution in a solvent mixture comprising the aforementioned first and second organic solvents, for example the (C1-51-5) alkyl-alkanoate (C1-51-5) ester which was mentioned above and alcohol (C1-51-5), for example a methylacetate: methanol mixture predominantly comprising the ester, for example 9-12: 1 v: v, for example, 10-11: 1 v: v methylacetate: methanol mixture. Suitably, the stoichiometric excess of the salt-forming compound relative to amoxycillin is used, for example, in a molar ratio of 1.5-2.5: 1 sodium 2-ethylhexanoate: amoxicillin. Suitably, a solution of 2-ethylhexanoate can be used. sodium-ethylhexanoate in the solvent mixture mentioned above, having a concentration of about 1.8-2.5 M. This solution can be filtered and / or subjected to other purification steps suitable before the reaction amoxicillin.

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Preferably, the reaction between the salt-forming compound and the amoxycillin is carried out at low room temperature, for example, below 10 ° C, especially at 0-5 ° C. Preferably, the solution of the amine salt is added to the solution of the salt-forming compound, although in the reverse mode of addition, that is, the addition of the solution of the salt-forming compound to the solution of the amine salt, or You can use concurrent mixing. Preferably, the mixing of the two solutions is carried out as quickly as possible, with rapid stirring. Spontaneous crystallization of the reaction product may occur, but it is preferred that crystallization be induced by the addition of seeds, for example of crystalline sodium amoxycillin or of a certain equivalent material in terms of its crystallography, for example, an amoxicillin solvate of crystalline sodium, to the reaction mixture immediately after mixing the solutions. In order to further encourage the crystallization of the aforementioned first organic solvent, for example the ester of (C1-51-5) alkyl-C1-51-alkanoate, for example methylacetate, it can be mixed with the reaction mixture, preferably in excess of the average volume of the reaction, for example in an excess of 1.5-2.0 x of the average volume of the reaction. This mixture of the first organic solvent can be carried out relatively slowly, for example in a period of 30-40 minutes. After mixing this additional amount of the first solvent, the mixture can be stirred for a time, for example, for 1 hour, preferably below room temperature, i.e., below 10 ° C, especially at 0-5 ° C. . After this step, the crystalline product can be separated from the reaction medium using standard procedures, for example filtering, and washing with a suitable washing liquid, preferably the first organic solvent. The crystalline product obtained in this way is considered to be a crystalline solvate of sodium amoxicillin, for example the methylacetate solvate from which the solvating solvent can be removed by a drying process, for example the process described in EP 0131147A, the content of which is incorporated herein by reference. This drying process can be under vacuum, preferably at an elevated temperature such as 50-65 ° C, 60-65 ° C, to remove the solvents from the residual reaction medium, the washing liquids and the dissolving solvents, for yield the crystalline alkali metal salt of amoxicillin. The crystalline sodium amoxycillin prepared by the process of this invention can be used as a pharmaceutical antibiotic product, for example in injectable form. For this purpose, a content in sealed sterile vials can be provided. Alternatively, sodium amoxycillin prepared by the process of this invention can be used in formulations for oral administration, for example, in formulations of tablets, granules, syrups, etc. and oral administration does not necessarily require a -ijMa _ ^ Ui_ ^ u ^ _ßail * aiB _ ^^^^^ _ ^ Éi ^ ^ _ ^^^ ÍtfMaíÍ # _ ^ sterile formulation. Preferably, for use as an antibiotic product, the crystalline alkali metal salt of amoxicillin is administered in combination with a pharmaceutically acceptable beta-lactamase inhibitor such as a salt of clavulanic acid, particularly potassium clavulanate. The invention will now be illustrated by way of non-limiting example.

EXAMPLE 1 Scale to laboratory 1. 1 Dissolution of sodium 2-ethyl hexanoate. Sodium 2-ethylhexanoate (160 g) was dissolved in a mixture of methylacetate (310 ml) and methanol (30 ml). The mixture was stirred at room temperature until the solution was complete and the solution was filtered through a Whatman No. 1 filter paper to remove the turbulence. The solution was transferred to a crystallization vessel, followed by washing methylacetate (210 ml) and stirred at 0-5 ° C. This solution was consequently 2.15 M in sodium 2-ethylhexanoate. 1. 2 Dissolution of amoxicillin trihydrate. Amoxicillin trihydrate (250 g) in methylacetate (450 ml) was reduced to suspension. Triethylamine (120 ml) was added to the suspension creating a thick suspension. Methanol (200 ml) was added, causing the triethylamine salt of amoxicillin to dissolve instantaneously. The solution was stirred for 5 minutes before dicalite (10 g) was added and the mixture was allowed to stir for an additional 5 minutes. Subsequently, the solution was filtered through a Whatman No. 1 filter paper, followed by washing with methanol (120 ml) and transferred to the crystallization vessel containing sodium 2-ethylhexanoate of number 1.1 above. 1. 3 Reaction and crystallization. The mixture was stirred vigorously in the crystallization vessel at 0-5 ° C and a seed of crystalline sodium amoxycillin was added. As soon as the crystallization started, methylacetate (2300 ml) was added over a period of 30-40 minutes. The mixture was allowed to stir for 1 hour at 0-5 ° C. The product was filtered and washed with methylacetate (750 ml). 1. 4 Drying The crystalline product of 1.3 was dried under vacuum at 50-55 ° C for 36 hours, or alternatively at 65 ° C for the shorter period of 16 hours. It was found that the quality of the product was not accepted by the drying temperature. The product was confirmed to be crystalline sodium amoxycillin by chemical analysis, infrared spectroscopy and X-ray powder diffractometry. The product obtained had an amoxicillin content of 91.0% with a total impurity content of 2.13-2.16%. ^^^^^ t tm EXAMPLE 2 Extrapolation 2. 1 Sodium 2-ethylhexanoate solution Methylacetate (124 I) was added to sodium 2-ethylhexanoate (64 kg), and methanol (12 I) was added with stirring until the sodium 2-ethylhexanoate was dissolved. It was filtered and the solution was transferred to a crystallization vessel, washing it with methylacetate (84 I). 2. 2 Amoxicillin trihydrate solution Methylacetate (124 I) was added to amoxicillin trihydrate (87.1 kg) and the resulting suspension was cooled to 0-5 ° C. Triethylamine (4811) was added to the suspension and the suspension was stirred for 5 minutes. Methanol (80 I) was added causing the triethylamine salt of amoxicillin to dissolve and the solution was stirred for 5 minutes. Dicalite (2 kg) was added and the mixture was stirred for a further 5 minutes. The solution was filtered and the cake was washed with methanol (48 I). 2. 3 Reaction v crystallization The triethylamine salt solution of amoxicillin 2.2 was added to the sodium 2-ethylhexanoate solution 2.1 as fast as possible and the mixture was cooled to 0-5 ° C. Crystalline sodium amoxycillin seed (400 g) was added. Methylacetate (921 I) was added at a rate of 27 liters per minute. The mixture was stirred for 1 hour at 0-5 ° C. Subsequently, the suspension was transferred to a Nutrex ™ mixer and the original liquid was filtered. The product was washed with methylacetate (84 I). 2. 4 Drying The crystalline product of 2.3 was dried with nitrogen with air, and then dried under vacuum at 60-65 ° C. The product obtained had an amoxicillin content of 2.3 89.7 - 93.6%, with a total impurity content of 1.72-1.42% in the three batches. ~ ^ jjj ^

Claims (16)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for the preparation of a crystalline alkali metal salt of amoxicillin is provided, in which; a suspension of an amoxicillin amine salt is formed in a first organic solvent; the suspension is mixed with a second organic solvent and the amine salt originates in solution in the mixture thus formed of the first and second organic solvents, the amine salt is reacted with an alkali metal salt-forming compound, the salt of the The alkali metal thus formed of amoxicillin is isolated from a solution as a crystalline product.

2. The process according to claim 1, further characterized in that the crystalline alkali metal salt of amoxicillin prepared by the process is crystalline sodium amoxycillin.

3. The process according to claim 1, further characterized in that the amoxicillin amine salt is a triethylamine, diethylamine or diisopropylamine salt of amoxicillin.

4. The process according to claim 1, further characterized in that the first organic solvent is an ester of (C1-51-5) alkyl-alkanoate (C1-51-5).

5. The process according to claim 4, further characterized in that the ester of (C1-51-5) alkyl-alkanoate (C1-51-) ^^ t ^ t miáSi lb * - * 5) is methylacetate.

6. The process according to claim 1, further characterized in that the suspension of the amine salt is formed by first forming a suspension of amoxicillin trihydrate in the first solvent, then mixing the amine with this suspension so that said amine reacts with Amoxicillin to form the amine salt.

7. The process according to claim 1, further characterized in that the second organic solvent is a (C1-51-5) alcohol.

8. The process according to claim 8, further characterized in that the alcohol (C1-51-5) is methyl alcohol.

9. The process according to claim 1, further characterized in that the salt-forming compound is a sodium salt of an organic compound.

10. The process according to claim 9, further characterized in that the salt-forming compound is a (C1-51-5) alcohol or a salt of a carboxylic acid (C1-121-5).

11. The process according to claim 8, further characterized in that the salt-forming compound is sodium 2-ethylhexanoate.

12. The process according to claim 1, further characterized in that the reaction of the amine salt is carried out by mixing the solution of the amine salt with a solution of the compound ^^ i t i i i i i i i i i iii iii salt trainer.

13. The process according to claim 10, further characterized in that the salt-forming compound is in a solution in a solvent mixture comprising the first and second organic solvents.

14. The process according to claim 13, further characterized in that the solvent mixture is a methylacetate: methanol mixture comprising predominantly methylacetate.

15. The process according to claim 12, further characterized in that the solution of the amine salt is added to the solution of the salt-forming compound.

16. A crystalline alkali metal salt of amoxicillin which is the product of a process according to any of the preceding claims.