JPH0720971B2 - Crystalline amoxicillin sodium, process for producing the same, and pharmaceutical composition containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Object of the invention The present invention relates to a β-lactam antibiotic, and in particular to the salt of the penicillin antibiotic amoxicillin. The amoxicillin salts of the present invention are active against Gram-positive and Gram-negative bacteria and are useful as therapeutic and prophylactic agents for bacterial infections in animals, including humans.

There are many known methods for producing the widely used antibiotic amoxicillin sodium, but all such methods have been for producing amorphous substances.

Problems to be Solved by the Invention In the present invention, a method for producing amoxicillin sodium in crystalline form was devised. This material is anhydrous, substantially pure and non-hygroscopic, and has a high stability.

Accordingly, the present invention provides crystalline amoxicillin sodium.

The present invention also provides crystalline anhydrous amoxicillin sodium.

The crystalline amoxicillin sodium of the present invention contains no solvent. It contains less than 2.5% solvent, suitably less than 1% and preferably less than 0.5%. Crystalline anhydrous amoxicillin sodium contains less than 2.5% water, preferably less than 1% and optimally less than 0.5%.

The present invention also provides a method of making crystalline amoxicillin sodium comprising removing solvent molecules from the solvate of amoxicillin sodium.

[Structure of Invention]

Means and Actions for Solving Problems The crystalline substance of the present invention is characterized by a sharp infrared spectrum and a multi-ray X-ray powder diffraction diagram.

When preparing the products of the present invention, it is preferred to use a crystalline solvate of amoxicillin sodium as a starting material. Solvates can be prepared by any suitable method.
In general, solvates are prepared by mixing a sodium compound, a non-aqueous solution of amoxicillin, and a solvent capable of forming a solvate with sodium amoxicillin, preferably an unstable, i.e., solvent that can be easily removed from the solvate. To be done. The solvent is then removed from the solution, for example
The solvate is precipitated by precipitation with a solvent that does not dissolve. An excess of itself for the solvate can sufficiently cause precipitation. Crystalline solvates are preferably isolated in crystalline form by precipitation under conditions in which crystallization occurs.

In one preferred method, a solution of amoxicillin is prepared by suspending amoxicillin trihydrate in a suitable solvent or mixture of solvents and then adding a strongly basic sodium compound such as sodium methoxide. . The preferred solvent system for this step is methanol or a mixture containing methanol and a solvent for the solvate. A sufficient amount of solvent for the solvate is then added under conditions capable of causing crystallization of the solvate.

Alternatively, amoxicillin trihydrate can be dissolved with the aid of an organic base such as triethylamine and the resulting solution is a sodium compound such as sodium methoxide,
It can be treated with sodium hydroxide or preferably the sodium salt of an alkanoic acid, for example sodium 2-ethylhexanoate. These steps can be conveniently combined by the use of a mixture of organic base and sodium compound which results in the dissolution of amoxicillin trihydrate. A suitable solvent system for this step is methanol or a mixture of methanol and a solvent for the solvate. A sufficient amount of solvate solvent is then added to cause solvate crystallization.

Suitable solvents which form solvates with sodium amoxicillin include _C6-8 aromatic hydrocarbons such as benzene and toluene; _C3-10 alkanols such as n-propanol, isopropanol, n-butanol and t-butanol. Diethyl ether, di-isopropyl ether, bis (2
-Methoxyethyl) ether, 1,2-dimethoxyethane,
Chlorinated hydrocarbons such as methylene chloride;; C _2-12 alkyl, and cyclic ethers such as dioxane and tetrahydrofuran methyl formate, of C _1-6 alkanoic acid such as ethyl formate, methyl acetate and ethyl acetate C _1-6 Includes alkyl esters and amides. The solvent used in the production of amoxicillin sodium of the present invention is preferably pharmaceutically acceptable.

Solvents for the preferred solvates are tetrahydrofuran, methyl acetate and ethyl acetate. These solvents form solvates in which the solvent molecules are easily removed.

A known group of amoxicillin sodium solvates includes amide solvates. Such solvates are particularly stable. Amoxicillin sodium amide solvate consists of amoxicillin sodium solvate and amide. Such solvates are described in British Patent 1,465,694. Certain solvates with N-methyl-pyrrolidinone amide are described in EP-A 39,967.

The amide solvate can be prepared by any convenient method.
Preferably, the sodium ion source is added to the solution of amoxicillin or a mixture of its salts and amides.

For example, amoxicillin trihydrate or amoxicillin triethylamine salt can be suspended or dissolved in the amide or a mixture of the amide and an inert solvent such as methylene dichloride. This solution or suspension is then treated with a solution of at least 1 equivalent of a basic sodium salt, such as sodium 2-ethylhexanoate, or sodium methoxide or sodium hydroxide, dissolved in an aliphatic alcohol such as methanol or isopropyl alcohol. To process. Room temperature can be used, but lower temperatures (0-5 ° C.) are preferred to minimize decomposition.

The amide forming the amide solvate has the formula (I) R-CO-NR ¹ R ² (I) where R, R ¹ and R ² are the same or different and are each hydrogen or carbon. Represents a hydrogen group, or R and R ¹ together represent a saturated or unsaturated hydrocarbon chain of 3 or 4 carbon atoms).

The term "hydrocarbon" includes groups having up to 18 carbon atoms, preferably up to 10 carbon atoms, more preferably up to 6 carbon atoms. The preferred hydrocarbon group is C
_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7
Cycloalkyl, C _3-7 cycloalkyl (C _1-6 ) alkyl, (aryl and aryl (C _1-6 ) alkyl are included.

Suitable alkyl groups are straight-chain and branched alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl and butyl. A particular alkyl group is methyl.

A preferred aryl group is phenyl.

Preferably, the amide is a tertiary amide, ie both R ¹ and R ² represent hydrocarbon groups.

Suitably R represents hydrogen or C _1-6 alkyl.

Preferably R represents hydrogen or methyl.

Suitably R ¹ and R ² are the same or different and each is C _1-6.
Represents alkyl.

Preferably R ¹ and R ² represent methyl.

Alternatively, R and R ¹ together form propylene (-(C
H _{2) 3} - represents a) -) or butylene (- (CH _{2) 4.}

Suitable amides for inclusion in the amidocillin sodium amide solvate include dimethylformamide, dimethylacetamide, N-methylpyrrolidin-2-one or N-methylpiperidin-2-one.

In the method for producing crystalline amoxicillin sodium of the present invention, solvent molecules are removed from the amoxicillin sodium solvate. This removal must be done under conditions that do not degrade penicillin. The method of removing solvent molecules depends on the nature of the solvate. In the case of a large number of solvates, the solvent molecules can be easily removed, and the solvent-free crystalline anhydrous sodium amoxicillin of the present invention can be produced, for example, by a conventional drying means under vacuum. Conveniently, the solvate is exposed to an adsorbent for solvent molecules under or without vacuum. The adsorbent may be a conventional desiccant such as phosphorus pentoxide, calcium chloride or silica.

Solvents that can be removed directly by such methods include hydrocarbons, alkanols, ethers, chlorinated hydrocarbons and esters.

Another method of removing solvent molecules that is particularly useful for stable solvates is to convert the solvate to another solvate, thereby converting the solvent molecule to an easily removable solvate, and Consists of removing by drying means. Transformation is conveniently accomplished by dissolving or suspending the solvate in a non-aqueous solvent such as an alkanol, or a mixture of two or more non-aqueous solvents,
This is then done by adding excess solvate solvent.

This method is particularly useful for removing amides from amide solvates. Thus, the amide solvate of amoxicillin sodium is dissolved in the C _1-6 alkanol and the solvent with the lower dielectric constant is added.

Addition of a solvent having a lower dielectric constant causes crystallization of the solvate of sodium amoxicillin, the solvent molecules are easily removed from the solvate, and the crystalline anhydrous sodium amoxicillin of the present invention can be prepared.

Suitable C _1-6 alkanols include methanol and ethanol, preferably methanol. The initial dissolution of the amide solvate therein is -40 ° C to + 25 ° C, eg -40 ° C.
℃ ~ +10 ℃, preferably -10 ℃ ~ +10 ℃, convenient 0
Perform at 5 ° C.

Amoxicillin sodium formed by the method of the present invention is crystalline and usually has a prismatic or rod-like form. It is also anhydrous, typically contains less than 1% water, exhibits very good stability and does not decompose over 4 hours at 80 ° C. The previously known spray-dried or freeze-dried amorphous amoxicillin sodium is one of the most hygroscopic penicillins, but unlike these, this crystalline form is non-hygroscopic.

The infrared spectrum [Nujol (trademark) Mull] of the crystalline amoxicillin sodium of the present invention is attached to FIG.
It was shown to.

The crystalline sodium amoxicillin of the present invention is also characterized by an X-ray powder diffractogram showing a maximum within ± 0.1 ° of the values listed in Example 21 below.

Another advantage of the method of making amoxicillin sodium is that it comprises a step in which amoxicillin is wholly in solution, so that the solution can be sterile filtered. This manipulation is important for the product to be used for parenteral administration.

The crystalline form of amoxicillin sodium can be reduced or removed without destroying its anhydrous nature, for example by mechanical decomposition of the crystals or by dissolution in anhydrous solvents. Similarly, it is possible to retain the crystalline form of amoxicillin sodium while allowing some hydration in the anhydrous state.

The present invention also provides a pharmaceutical composition comprising crystalline amoxicillin sodium and a pharmaceutically acceptable carrier.

The compositions of the present invention include those in dosage forms suitable for oral, topical or parenteral use and are used to treat infections in mammals, including humans.

However, the main use of amoxicillin sodium is parenteral use.

For parenteral administration, liquid unit doses are prepared with the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved in water for injection, filter sterilized, filled into suitable vials or ampoules, and sealed. Advantageously, agents such as local anesthetics, preservatives and buffers can be dissolved in the vehicle. Alternatively, the dry powder may be enclosed in vials and supplemented with additional vials containing water for injection to reconstitute the liquid formulation before use. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
The compound can be sterilized by exposure to ethylene oxide and then suspended in sterile medium. Advantageously, a surfactant or wetting agent is included in order to promote a uniform distribution of the compound.

The composition may contain from 0.1% by weight or more, preferably from 10-60% by weight, of the active material, depending on the method of administration. When the composition makes up the dosage unit, the core unit preferably contains 50-500 mg of the active ingredient. The dosage used to treat adults is preferably 100 to 3 per day depending on the route and frequency of administration.
It will be in the range of 000 mg, for example 1500 mg per day. Such a dosage is 1.5 to 50 mg / kg per day. Suitably the dosage is 5-20 mg / kg per day.

Advantageously, the injectable solution prepared from crystalline amoxicillin sodium is mixed with at least one water pharmaceutically acceptable alcoholic compound such as ethanol, n-
Contains propanol, isopropanol, ethoxyethanol, diethylene glycol and propylene glycol.

A particularly preferred alcohol for inclusion in injectable compositions is benzyl alcohol, which is included at a concentration of up to 10% of the composition, preferably 1-5%, suitably about 3%.

It is also advantageous to include a basic excipient with crystalline amoxicillin sodium in a composition suitable for administration by injection. In particular, the invention also provides an injectable composition comprising crystalline amoxicillin sodium and trisodium phosphate. A suitable weight ratio of crystalline amoxicillin sodium to trisodium phosphate is 8: 1 to 50: 1, preferably 10: 1 to 3
0: 1, especially 14: 1 to 28: 1. The inclusion of a base such as trisodium phosphate is particularly desirable for the rapid and complete dissolution of the high concentration of amoxicillin sodium (typically 1 g of amoxicillin sodium in 2 ml water in 2 ml) required for intramuscular injection in aqueous solution .

One preferred formulation is a twin pack consisting of a vial containing crystalline amoxicillin sodium and a separate vial containing an aqueous solution of a buffer such as trisodium phosphate.

Crystalline amoxicillin sodium may be the only therapeutic agent in the composition of the present invention, or a combination with other antibiotics or with β-lactamase inhibitors may be used.

Advantageously, the composition also has the formula (II) Also included are compounds of the formula where A is hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, mono- or di-hydrocarbyl substituted amino or mono- or di-acylamino, or a pharmaceutically suitable salt or ester thereof.

Preferably A represents hydroxy or methoxy. Thus, compound (II) is preferably in the form of a salt, which represents clavulanic acid or clavulanic acid methyl ester.

A preferred composition comprises crystalline amoxicillin sodium with a salt of glabrinic acid, especially the sodium or potassium salt, preferably potassium clavulanate. A particular composition of the present invention comprises crystalline amoxicillin sodium, potassium clavulanate and trisodium phosphate.

Another advantageous composition comprises crystalline amoxicillin sodium of formula (III) (Wherein B represents hydrogen or chlorine) or a pharmaceutically suitable salt or ester thereof that can be hydrolyzed in vivo.

The present invention provides a method of treating bacterial infections in animals other than humans, especially livestock, which comprises administering a composition of the present invention.

Hereinafter, the present invention will be illustrated by examples.

Reference Example 1 Amoxicillin sodium dimethylacetamide solvate Dimethylacetamide (200ml) and triethylamine (26.1ml, 0.186mole) were cooled to 0 ° C, and amoxicillin trihydrate (74.2g, 0.177mole) at 0-5 ° C. It took 5 minutes to add. The mixture was stirred at 0-5 ° C for 30 minutes, filtered and filtered with sodium ethylhexanoate (33% as 100%, 0.2 g
1mole) dissolved in 60ml of methanol at 0-5 ℃
At room temperature over 5 minutes. The solution was stirred for 4 hours and allowed to return to 20 ° C. for the first hour. The product was filtered, washed with isopropyl alcohol (1000 ml) and dried at 35 ° C.
The product weighed 75.2 g and was analyzed for an amoxicillin content of 75% (theoretical 77%, yield 88%).

Reference Example 2 Amoxicillin sodium dimethylacetamide solvate The procedure of Reference Example 1 was repeated except that isopropyl alcohol (150 ml) was used in place of methanol to dissolve sodium ethylhexanoate, and the amoxicillin content was 72.9% (yield 89 %) Of the product was obtained.

Reference Example 3 Amoxicillin sodium dimethylformamide solvate Dimethylformamide (200 ml) and triethylamine (30 ml, 0.214 mole) were cooled to 5 ° C, and amoxicillin trihydrate (43%, 0.1012 mole as 100%) was added. The solution was cooled to 0-5 ° C and stirred for 1/2 hour. Sodium 2-ethylhexanoate (24.7 g, 0.16 mole) dissolved in 150 ml isopropyl alcohol was added and the solution was stirred for 3 hours. The suspension was filtered and the filter cake was washed with 100 ml isopropyl alcohol and 100 ml methylene chloride. The product was dried at 35 ° C. Yield of solvate 53 g, H.
Analysis by PLC 94%, amoxicillin content (as free acid) 76.5% Reference Example 4 Amoxicillin sodium N-methyl-2-pyrrolidinone solvate N-methyl-2-pyrrolidinone (170 ml) and triethylamine (26.1 ml, 0.187 mole) Was cooled to 0-5 ° C. and amoxicillin trihydrate (74.2 g, 0.177 mole) was added over 10 minutes. The solution was stirred for 1 hour and filtered. Then sodium ethylhexanoate (33.3 g, 0.2 mole) in 50 ml N-methyl-2-pyrrolidinone was added. After stirring for 1 hour, 400 ml of methylene chloride was added over 30 minutes. The mixture was stirred at 20 ° C. for a further 3 hours, filtered and the product washed with 150 ml of isopropyl alcohol. After drying at 35 ° C., the product weighed 77 g (86% yield) and had an analytical value of 726 mcg amoxicillin / mg.

Example 1 Preparation of Crystalline Amoxicillin Sodium from Dimethylformamide Solvate 10 g of Amoxicillin sodium dimethylacetamide solvate prepared in Reference Example 1 via tetrahydrofuran solvate at 60 ° C for 1 minute at 0-5 ° C. Added to methanol. The solution was stirred at 0-5 ° C for 25 minutes and filtered. Tetrahydrofuran (150 ml) was added to the filtrate which was kept at 0-5 ° C over 5 minutes and the mixture was stirred at 0-5 ° C. It was stirred. The suspension is filtered and the product is washed with methylene chloride (75
ml) and vacuum dried at 45 ° C. for 16 hours if blown with nitrogen. Crystalline amoxicillin sodium (6.7 g, yield 83%) was analyzed as 930 mcg / mg (amoxicillin free acid). The product contained 0.5% water.

Example 2 Via Toluene Solvate Amoxicillin sodium-as described in Example 1.
A DMA solution was prepared and precipitated with toluene (200 ml, 1 hour) to obtain 5.5 g of a crystalline product (yield 66%).
HPLC analysis 920 mcg amoxicillin / mg. This substance is 0.5
% Water.

Example 3 Via Isopropanol Solvate Amoxicillin sodium-DMA solution is prepared as described in Example 1 above and precipitated with 400 ml isopropanol. This gave 5.0 g of crystalline product (yield 56%, HPLC analysis 837 mcg / mg).

Example 4 Via Isopropyl Ether and Toluene Solvate Amoxicillin sodium-as described in Example 1.
By making a DMA solution and precipitating it with 150 ml of toluene followed by 90 ml of isopropyl ether (20-25 ° C) 8.
0 g (96%) of crystalline amoxicillin sodium was obtained.
HPLC analysis 906 mcg amoxicillin / mg Example 5 Via n-propanol solvate 4.6 g by making amoxicillin sodium-DMA solution as described in Example 1 above and precipitating with 200 ml n-propanol (1 hour). Product (51% yield)
Got Analysis 823 mcg amoxicillin / mg Example 6 Via 1,2-dimethoxyethane solvate A solution of amoxicillin sodium-DMA is prepared as described in Example 1 above and precipitated with 100 ml of 1,2-dimethoxyethane (1 hour). This gave 7.5 g of crystalline product (yield 67%). HPLC analysis 666 mcg amoxicillin / mg.

Example 7 Via Methyl Acetate Solvate Amoxicillin sodium-DMA solution is prepared as described in Example 1 above and precipitated with 100 ml of methyl acetate. This yielded 5.5 g of crystalline amoxicillin sodium containing 836 mg amoxicillin / mg.

Example 8 Via Dioxane Solvate Amoxicillin sodium-DMA solution was prepared as described in Example 1 above and precipitated with 200 ml dioxane (1 hour) to give 6.6 g of crystallinity containing 863 mcg amoxicillin / mg. Amoxicillin sodium was obtained.

Example 9 Via bis (2-methoxyethyl) ether solvate An amoxicillin sodium-DMA solution is prepared as described in Example 1 above and precipitated with 200 ml bis (2-methoxyethyl) ether. This gave 7.4 g (79% yield) of crystalline amoxicillin sodium containing 800 mcg amoxicillin / mg (HPLC).

Example 10 Via t-Butanol Solvate 802 mcg amoxicillin / mg by preparing amoxicillin sodium-DMA solution as described in Example 1 above and precipitating with 150 ml t-butanol (15 minutes).
6.9 g (74% yield) of crystalline Amoxicillin sodium containing (HPLC) were obtained.

Example 11 Via Tetrahydrofuran Solvate As described in Example 1 above, except that 6 ml of water was added to make a solution of amoxicillin sodium-DMA and 0.5% water and 927 mcg amoxicillin / precipitated with 200 ml of tetrahydrofuran. 6.1 g (75% yield) of crystalline amoxicillin sodium containing mg (HPLC) was obtained.

Example 12 Via Benzene Solvate An amoxicillin sodium-DMA solution was prepared as described in Example 1 above and precipitated with 150 ml of benzene (15 minutes) to give 2.0 g of crystalline amoxicillin sodium. Analysis 918 mcg amoxicillin / mg.

Example 13 Via n-Butanol Solvate Sodium amoxicillin solution was prepared as described in Example 1 above and precipitated with 150 ml of n-butanol to yield 6.0 g of crystalline product (66.2% yield). Obtained.
Analysis 827 mcg amoxicillin / mg.

Example 14 Via di-isopropyl ether solvate 7.5 g of crystalline amoxicillin sodium (yield 84.3 was prepared by preparing an amoxicillin sodium-DMA solution as described above and precipitating with 150 ml di-isopropyl ether (10 minutes). %) Was obtained. Analysis 843 mcg amoxicillin
/ mg.

Example 15 Via tetrahydrofuran solvate 60 ml of methanol was cooled to 0-5 ° C. and amoxicillin-dimethylformamide solvate (10 g for this) was added over 30 seconds. Stir at 0-5 ° C for 25-30 minutes. To the filtrate (0 to 5 ° C), 150 ml of tetrahydrofuran was added over 5 minutes, and the mixture was stirred at 0 to 5 ° C. The suspension was filtered and the product washed with 100 ml tetrahydrofuran containing 2% water and then 50 ml methylene chloride. The product was vacuum dried at 45 ° C. with nitrogen bubbling. The product obtained by this method is crystalline amoxicillin, the weight is 7.2 g (yield 89.3%), 0.72%
Moisture content of HPLC analysis 931mcg amoxicillin / m
It was g.

Example 16 Via Tetrahydrofuran Solvate The amoxicillin sodium-DMA solution described in Example 1 was used and after stirring for an additional 10 minutes, tetrahydrofuran (15
Amoxicillin sodium was crystallized by adding 0 ml). Crystallization After proceeding, the product was isolated, washed with tetrahydrofuran and methylene chloride and dried in vacuum at 45 ° C. Thus, amoxicillin sodium (7.) as crystalline rods with an analytical value of 919 mcg amoxicillin / mg by HPLC.
6 g, 93%) was isolated. The water content was 0.67%.

Example 17 Preparation of crystalline sodium amoxicillin from dimethylformamide solvate Via tetrahydrofuran solvate 10 g of amoxicillin sodium dimethylformamide solvate prepared as in Reference Example 3 in methanol (60 ml) cooled to 0-5 ° C. Was added. 0 to solution
Stir for 30 minutes at 5 ° C. and filter. In this filtrate at 0-5 ℃
150 ml of tetrahydrofuran was added over 20 minutes.
The suspension was stirred at 0-5 ° C for 1 hour, filtered and the product
Wash with ml of methylene chloride. After vacuum drying, the crystalline product weighed 6.5 g (yield 79.4%) and the analytical value was HPLC.
The result was 916 mcg amoxicillin / mg.

Example 18 Production of crystalline amoxicillin sodium from N-methyl-2-pyrrolidinone solvate Via toluene solvate Methanol (60 ml) was cooled to 0-5 ° C, and amoxicillin sodium N-methyl produced in Reference Example 4 2-Pyrrolidinone solvate was added. The solution was stirred at 0-5 ° C for 25 minutes and filtered. Toluene (200ml) was added over 15 minutes keeping at 0-5 ° C and the product washed with 50ml methanol: toluene (1: 5) and 50ml methylene chloride. The crystalline amoxicillin sodium after vacuum drying at 45 ° C. while blowing nitrogen was 4.0 g in weight (48% yield), and the analytical value was 909 mcg amoxicillin / mg.

Example 19 Via Tetrahydrofuran Solvate Amoxicillin sodium-as described in Example 18
A solution of N-methyl-2-pyrrolidinone was prepared, provided that
913 m by precipitation with 0 ml of tetrahydrofuran and washing with tetrahydrofuran and methylene chloride
7.0 g amoxicillin sodium (yield 85%) containing cg amoxicillin / mg was obtained.

Example 20 Preparation of Crystalline Anhydrous Amoxicillin Sodium via Tetrahydrofuran Solvate Amoxicillin trihydrate (4.19g, 0.010mole) and sodium 2-ethylhexanoate (1.70g, 0.0102mole) in methanol (30ml) and Triethylamine (1.50 ml,
0.0108 mole) and the mixture was stirred at room temperature. After 15 minutes, a clear solution was obtained which was mixed with tetrahydrofuran (THF) (1
00 ml) and seeds were added. Crystallization started immediately. The mixture was cooled to about 5 ° C. for 0.75 hours, the product was collected, washed with THF / methanol (5: 1,25 ml) then methylene chloride (50 ml) and dried in vacuo with phosphorus pentoxide.

Yield 2.74 g (70%) The infrared spectrum (Suzyolnull) was unchanged from that of the material prepared according to Example 1.

Example 21 Preparation of crystalline anhydrous sodium amoxicillin via methyl acetate solvate Amoxicillin trihydrate (83.8 g) was added to methyl acetate (300 m
l) and dissolved in methanol (300 ml) sodium 2-ethylhexanoate (36.0 g) and triethylamine (35 m
The solution of l) was added in one portion at room temperature with vigorous stirring. A substantially clear solution was obtained after 3 minutes. This was filtered, seeds were added, and ethyl acetate (300 m
l) diluted. As crystallization progressed, more methyl acetate (600 ml total) was added as a trickle stream over 30 minutes. The mixture was stirred at room temperature for a further 15 minutes and then stored at about 5 ° C for 2 hours.

Combine the products and methyl acetate / methanol (4: 1,250ml)
It was slurried in and washed on the filter with methyl acetate / methanol (6: 1, 100 ml) then methyl acetate and finally methylene chloride. The product was dried for 30 minutes under low vacuum. (The nmr spectrum of the material thus dried showed the presence of about 1 mole of methyl acetate).

Yield 65.5 g solvated sodium amoxicillin was dried under high vacuum over phosphorus pentoxide until the expected weight loss was achieved.

 Yield 55.3g Weight yield 71.4% This material had the following analytical values.

Purity (imidazole) 96.4% (as sodium salt) Indium Absorbent substance 0.78% Water (KF) 0.17% Solvent Methylene chloride 0.01% Methanol 0.008% Methyl acetate 1.0% The product of Example 21 is a Phillips scanning diffractometer. And Cu Kα lines were used to study by X-ray powder diffraction with a time constant of 0.3 seconds set at 46 kv and 35 mA. The diffraction maximum was observed from 30 ° to 8 ° 2θ. The following lines were observed.

29.8 18.9 29.2 17.8 28.4 17.1 28.0 16.5 26.5 15.8 25.9 15.5 25.7 15.0 25.2 14.0 24.0 13.5 23.0 12.5 22.3 11.3 21.4 10.5 20.9 9.4 20.1 8.5 Example 22 Production of crystalline anhydrous amoxicillin from methyl acetate solvate 8 g amoxicillin trihydrate (86%) was suspended in a methanol / methyl acetate (50ml / 50ml) mixture precooled to -10 ° C. The product was added to sodium methoxide solution (10
It was dissolved by adding 1.1 g of sodium methoxide) dissolved in ml of methanol while maintaining the temperature at -8 ° C to -10 ° C. Precipitation was achieved by the rapid addition of 150 ml of methyl acetate (5 minutes). At this time, the temperature was raised to 0 to 5 ° C. Further, add 150 ml of methyl acetate to 1
It was added in 5 minutes and the suspension was stirred for 2 hours, keeping the temperature at 0-5 ° C. The product was isolated by filtration, 2 × 40
It was washed with ml of methylene chloride and dried in a vacuum oven at 60 ° C. while blowing nitrogen into it to obtain crystalline anhydrous amoxicillin sodium.

The average active yield of 6 runs was 81.5% and the product purity was 89.1% to 92.3% (as acid itself).

Comparative Example The following comparative test was carried out to determine the storage stability of the crystalline amoxicillin sodium of the present invention and the amorphous amoxicillin sodium spray-dried (powder-dried) product described in JP-A-53-29915. It is a comparison. The results are summarized below.

1. Improved shelf life of crystalline amoxicillin sodium: Titer sample % crystalline form 100 (product of Example 21) maintained after storage at a temperature of 80 ° C. for 24 hours Amorphous 83 (spray dried product) ) 2. Improved hygroscopicity of crystalline amoxicillin sodium: water content after 14 days storage at 20 ° C in relative humidity (RH) range As is clear from the above results, the crystalline amoxicillin sodium of the present invention exhibits remarkably excellent stability against storage heat and storage humidity as compared with amorphous amoxicillin sodium which is a spray-dried product.

[Brief description of drawings]

FIG. 1 is an infrared spectrum (Suzyolmul) of the crystalline sodium amoxicillin of the present invention.

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Claims (11)

[Claims] 1. Crystalline amoxicillin sodium characterized by a sharp infrared spectrum and a diffraction maximum with a multi-line X-ray diffraction diagram in which the following lines are observed between 30 ° and 8 ° 2θ. 29.8 18.9 29.2 17.8 28.4 17.1 28.0 16.5 26.5 15.8 25.9 15.5 25.7 15.0 25.2 14.0 24.0 13.5 23.0 12.5 22.3 11.3 21.4 10.5 20.9 9.4 20.1 8.5 2. (i) C _6-8 aromatic hydrocarbons, such as benzene and toluene, capable of forming solvates with sodium amoxicillin; n-propanol, isopropanol, n-
C _3-10 alkanols such as butanol and t-butanol; diethyl ether, di-isopropyl ether,
C such as bis (2-methoxyethyl) ether, 1,2-dimethoxyethane, dioxane and tetrahydrofuran
_2-12 alkyl and cyclic ethers; chlorinated hydrocarbons such as methylene chloride; consisting of C _1-6 alkyl esters and amides of C _1-6 alkanoic acids such as methyl formate, ethyl formate, methyl acetate and ethyl acetate Combining amoxicillin and sodium compounds of the solution in a mixture containing a solvating solvent selected from the group and methanol, (ii) then precipitating the solvate from the solution, (iii) then solvating the amoxicillin sodium Diffraction maximum, which is characterized by removing solvent molecules from the product, is 30 °
A method for producing crystalline amoxicillin sodium characterized by a multi-line X-ray diffractogram in which the following lines are observed between 8 ° and 8 ° 2θ. 29.8 18.9 29.2 17.8 28.4 17.1 28.0 16.5 26.5 15.8 25.9 15.5 25.7 15.0 25.2 14.0 24.0 13.5 23.0 12.5 22.3 11.3 21.4 10.5 20.9 9.4 20.1 8.5 3. (i) A first solvate capable of forming with amoxicillin sodium, such as benzene and toluene.
C _6-8 aromatic hydrocarbons; C _3-10 alkanols such as n-propanol, isopropanol, n-butanol and t-butanol; diethyl ether, di-isopropyl ether, bis (2-methoxyethyl) ether, 1, C _2-12 alkyl and cyclic ethers such as 2-dimethoxyethane, dioxane and tetrahydrofuran; chlorinated hydrocarbons such as methylene chloride; C _1-6 alkanoic acids such as methyl formate, ethyl formate, methyl acetate and ethyl acetate A solution of amoxicillin and sodium compounds in a mixture containing a first solvating solvent selected from the group consisting of C _1-6 alkyl esters and amides and methanol; precipitating a first solvate, (iii) then dissolved the said first solvates C _1-6 alkanol or a mixture thereof Or suspended, and in the solution may form amoxicillin sodium and second solvates, benzene and C _6-8 aromatic hydrocarbons such as toluene; n-propanol, isopropanol, n-
C _3-10 alkanols such as butanol and t-butanol; diethyl ether, di-isopropyl ether,
C such as bis (2-methoxyethyl) ether, 1,2-dimethoxyethane, dioxane and tetrahydrofuran
_2-12 alkyl and cyclic ethers; chlorinated hydrocarbons such as methylene chloride; consisting of C _1-6 alkyl esters and amides of C _1-6 alkanoic acids such as methyl formate, ethyl formate, methyl acetate and ethyl acetate The second solvate is precipitated by adding an excess of a second solvate solvent selected from the group, whereby the first solvate is first added with the second solvate solvent. Converting the second solvent to the second solvate of amoxicillin sodium, which is more easily removable, and (iv) subsequently removing the second solvent molecule from the second solvate of amoxicillin sodium. A method for producing crystalline amoxicillin sodium characterized by a multi-line X-ray diffraction diagram in which the following lines are observed with a characteristic diffraction maximum between 30 ° and 8 ° 2θ. 29.8 18.9 29.2 17.8 28.4 17.1 28.0 16.5 26.5 15.8 25.9 15.5 25.7 15.0 25.2 14.0 24.0 13.5 23.0 12.5 22.3 11.3 21.4 10.5 20.9 9.4 20.1 8.5 4. The solvent molecule is removed by exposing the solvate to a vacuum state or to an adsorbent that adsorbs a solvent molecule in a vacuum state or a non-vacuum state, thereby removing the solvent molecule. The method described. 5. The method according to claim 2 or 3, wherein the amide is removed from the amoxicillin sodium amide solvate. 6. The amide has the formula (I): R—CO—NR ¹ R ² (I) where R, R ¹ and R ² are the same or different and each represents a hydrogen or hydrocarbon group. Or R and R ¹ together represent a saturated or unsaturated hydrocarbon chain of 3 or 4-carbon atoms). 7. The amide is dimethylformamide, dimethylacetamide, N-methylpyrrolidin-2-one or N-.
Claim 6 which is methylpiperidin-2-one
Method described in section. 8. A solvate of amoxicillin sodium in crystalline form is produced by dissolving the amide solvate in a C _1-6 alkanol and adding a solvent with a lower dielectric constant, and then the solvent. The method of claim 5, wherein the amide is removed from the amide solvate of amoxicillin sodium by removing the molecule. 9. An antibacterial effective amount containing less than 2.5% solvent and less than 2.5% water, non-hygroscopic and highly stable, with a diffraction maximum from 30 °. 8 °
Use in the treatment of bacterial infections in mammals, including humans, consisting of crystalline amoxicillin sodium characterized by a multi-line X-ray diffraction diagram in which the following lines are observed between 2θ and a pharmaceutically acceptable carrier A pharmaceutical composition comprising: 29.8 18.9 29.2 17.8 28.4 17.1 28.0 16.5 26.5 15.8 25.9 15.5 25.7 15.0 25.2 14.0 24.0 13.5 23.0 12.5 22.3 11.3 21.4 10.5 20.9 9.4 20.1 8.5 10. The composition according to claim 9, further containing trisodium phosphate. 11. An antibacterial effective amount containing less than 2.5% solvent and less than 2.5% water, non-hygroscopic and highly stable, the diffraction maximum is from 30 °. 8
Administering crystalline amoxicillin sodium characterized by a multi-line X-ray diffraction diagram in which the following lines are observed between ° 2θ and a pharmaceutically acceptable carrier to mammals other than humans in need thereof A method of treating bacterial infections in mammals, excluding humans, consisting of: 29.8 18.9 29.2 17.8 28.4 17.1 28.0 16.5 26.5 15.8 25.9 15.5 25.7 15.0 25.2 14.0 24.0 13.5 23.0 12.5 22.3 11.3 21.4 10.5 20.9 9.4 20.1 8.5