JPS608295A - Crystalline sodium amoxicillin, manufacture and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION Industrial Application The present invention relates to β-cyctam antibiotics, and in particular to the salts of the penicillin antibiotic amoxicillin.

The amoxicillin salts of the present invention are active against Durham-positive and Gram-negative bacteria and are useful as therapeutic and prophylactic agents against bacterial infections in animals, including humans.

BACKGROUND OF THE INVENTION There are many known methods for producing the widely used antibiotic amoxicillin sodium, but all such methods produce amorphous materials.

Problems that BA is intended to solve In the present invention, a method for producing amoxicillin sodium in crystalline form has been devised. This material is anhydrous, virtually pure and non-deliquescent, and has 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 is solvent-free. This is less than 2.5% solvent, preferably 1%
Contains less than 0.5% solvent. Crystalline anhydrous amoxicillin natri rum is less than 25 times water,
The present invention also provides a method of making crystalline amoxicillin sodium comprising removing solvent molecules from a solvate of amoxicillin sodium, preferably containing less than 1% water and preferably less than 0.5% water. [Accessories of the Invention] Means and Effects for Solving the Problems The crystalline material of the present invention is characterized by a sharp infrared spectrum and a multiple-ray X-ray powder diffraction pattern.

When producing the products of the invention, preference is given to using a crystalline solvate of amoxicillin sodium as starting material. Solvates can be made by any suitable method. In general, the solvate is a solvent that can easily form a solvate with the IJ compound, a non-aqueous solution of amoxicillin and amoxicillin sodium, preferably a solvent that is unstable, i.e. that can be easily removed from the solvate. Manufactured by mixing. The solvent is then precipitated from solution, eg, by precipitation in a solvent that does not dissolve the solvate. Excess solvating solvent itself is sufficient to cause precipitation. Crystalline solvates are preferably isolated in crystalline form by precipitation under conditions that allow crystallization to occur.

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. be done. A suitable solvent system for this step is methanol or a mixture containing methanol and a solvating solvent. Sufficient solvent is then added under conditions to allow crystallization of the solvate to occur.

Alternatively, amoxicillin trihydrate can be dissolved with the aid of an organic base, such as triethylamine, and the resulting solution can be dissolved using a sodium compound, such as sodium methoxide, sodium hydroxide or preferably a sodium salt of an alkanoic acid, such as 2- Can be treated with sodium ethylhexanoate. These steps can be conveniently combined by using a mixture of a basic base and a sodium compound that causes dissolution of amoxicillin trihydrate. A suitable solvent system for this step is methanol or methanol and solvating fB! A': It is a mixture of. A solvating solvent sufficient to effect crystallization of the solvate is then added.

Suitable solvates that form solvates with amoxicillin sodium include C6-8 aromatic hydrocarbons such as benzene and toluene; n-propanol.

C3-1° alkanols such as isopropanol, n-butanol and t-butanol; diethyl ether,
C2-12 alkyl and cyclic ethers such as diisoglobyl ether, bis(2-methoxyethyl) ether, 2-dimethoxyethane, dioxane and tetrahydrofuran: chlorinated hydrocarbons such as methylene chloride;
Included are C1-6 alkyl esters of C4-6 alkanoic acids such as methyl formate, ethyl Ilaate, methyl acetate and ethyl acetate, and amides. Preferably, the solvent used in the preparation of amoxicillin sodium of the present invention is pharmaceutically suitable.

A preferred solvating solvent is tetrahydrofuran.

They are methyl acetate and ethyl acetate. These solvents form solvates from which the solvent molecules are readily removed. One known group of solvates of amoxicillin sodium includes the amide solvates. Such solvates are particularly stable. Amoquincillin sodium noamide solvates include amide solvates of amoxicillin sodium. Such solvates are described in British Patent Nos. 1 and 4.
No. 65,694. A particular solvate using N-methylpyrrolidinone amide is described in European Patent Publication No. 39.967.

Amide solvates can be prepared by any convenient method.

Preferably, a source of sodium ions is added to the mixture of amoxicillin or its salt and amide.

For example, amoxicillin trihydrate or amoxicillin triethylamine salt can be suspended or dissolved in an amide or a mixture of an amide and an inert solvent such as methyl chloride. This solution or suspension is then treated with a solution of at least one equivalent of a basic sodium salt, such as sodium 2-edylhexanoate, or sodium methoxide or sodium hydroxide, in an aliphatic alcohol such as methanol or isopropyl alcohol. . Although ambient temperature can be used, very low temperatures (0-5°C) are preferred to minimize decomposition.

The amide forming the amide II4 solvate is also of the formula (I) -
co-NR' R2(I) (wherein R, R' and R2 are the same or different,
each represents a hydrogen or hydrocarbon group, or R and R
1 - taken together to indicate a 3 or 4 carbon saturated or unsaturated hydrocarbon chain), the term "hydrocarbon" refers to carbon atoms containing up to 18 carbon atoms, preferably up to 10 carbon atoms Includes groups having carbon atoms, conveniently up to 6 carbon atoms. Suitable hydrocarbon groups include C4-6 alkyl #c2-
6 alkenyl.

C2-6 fulkynyl # C5-7 cycloalkyl.

Included are C3-7 cycloalkyl(C1-6)alkyl, aryl and aryl(C1-6)alkyl.

Suitable alkyl groups include straight-chain and branched alkyl groups containing 1 to 6 carbon atoms, such as methyl.

Ethyl, propyl and butyl. A special alkyl group is methyl.

A preferred aryl group is phenyl.

Preferably, the amide is a tertiary amide, i.e. R1 and R2
Both of these represent hydrocarbon groups.

Suitably R represents hydrogen or C4-6 alkyl.

Preferably, R represents hydrogen or methyl.

Preferably, R1 and R2 are the same or different and each represents C5-6 alkyl.

Preferably 1°C1 and Iζ2 represent methyl.

Alternatively, R and 1t1 can be taken together with propylene (
-(Cf(2)3-) or butylene(-(CH2)4
−).

Amides suitable for inclusion in the amide solvate of amoxicillin sodium 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 amoxicillin sodium solvate. This removal must be carried out under conditions that do not degrade the penicillin. The method for removing the solvent molecules depends on the nature of the solvate. In the case of many soluble compounds, the solvent molecules can be easily removed. 69 The solvent-free crystalline anhydrous amoxicillin sodium of the present invention can be prepared, for example, by conventional drying means under vacuum. adsorbent, which may be a conventional desiccant such as phosphorous pentoxide, calcium chloride or silica.

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

Another method of removing solvent molecules, which is particularly useful for stable solvates, is to convert the solvate into another solvate from which the solvent molecules can be more easily removed, and then by conventional drying means. Including removing.

Conversion is conveniently carried out by dissolving or suspending the solvate in a non-aqueous solvent, such as an alkanol or a mixture of non-aqueous solvents, and then adding excess solvating solvent.

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

Addition of a solvent with a lower nh'% rate causes crystallization of amoxicillin sodium, from which solvent molecules can be easily stripped off to produce the crystalline anhydrous amoxicillin sodium of the present invention.

Suitable C1-6 alkanols include methanol and ethanol, preferably methanol.

First, dissolving the amide solvate therein is carried out at -40°C.
~ +25°C, e.g. -40°C ~ +10°C, preferably -
It is carried out at 10°C to +10°C, conveniently at 5°C.

The amoxicillin sodium formed by the method of the invention is crystalline and usually in the form of prisms or rods. It is also anhydrous, typically containing less than 1% moisture, and exhibits very good stability, not degrading even over 4 hours at 80°C. This crystalline form is non-deliquescent, unlike the already known spray-dried or freeze-dried amorphous amoxicillin sodium, both of which are among the most deliquescent penicillins.

The infrared spectrum of the crystalline amoxicillin sodium of the present invention (NujOl® Mul) is shown in the attached FIG. 1.

The crystalline amoxicillin sodium of the present invention also exhibits a maximum value of X within ±0.1° of the value listed in Example 21 below.
It is characterized by a line powder diffractogram.

Another advantage of the process for making amoxicillin sodium is that it includes a step in which the amoxicillin is entirely a solution, so that the solution can be sterile filtered. This operation is important in the case of products to be used for parenteral administration.

The crystalline form of amoxicillin sodium can be realized or removed without destroying its anhydrous nature, for example by mechanical decomposition of the crystals or by dissolving it in an anhydrous solvent. Similarly, it is possible to retain the crystalline form of amoxicillin sodium while allowing some degree of water availability in anhydrous conditions.

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

Compositions of the 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 primary use of amoxicillin sodium is parenteral use.

For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile vehicle, preferably water.

The compound can be either suspended or dissolved in the vehicle depending on the vehicle and concentration used. In preparing the solution,
The compound can be dissolved in water for injection, filter sterilized, filled into a suitable vial or ampoule, and sealed. Advantageously, local anesthetics.

Agents such as preservatives and buffers can be dissolved in the vehicle. In some cases, the dry powder may be enclosed in a vial, supplemented by an attached vial 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 a sterile medium. Advantageously, a surfactant or wetting agent is included to promote uniform distribution of the compound.

The compositions can contain more than 0.1% by weight of active substance, preferably from 10 to 60%, depending on the method of administration.

When the composition consists of dosage units, each unit preferably contains from 50 to 500 μ of active ingredient. The dosage used for the treatment of adults is preferably j>1 on-aoo per day depending on the route and frequency of administration.

9. For example, the daily allowance would be in the range of 91,500FW.

Such a dosage ranges from 91.5 to 50 μ/kli/day.
It is. Suitably the dosage is 5 to 20 doses per day.

Advantageously, the injection solution prepared from crystalline amoxicillin sodium contains at least one pharmaceutically suitable alcoholic compound that can be mixed with water, such as ethanol, n
- Contains probanol, ingropanol, ethoxyethanol, diethylene glycol and propylene glycol.

A particularly advantageous alcohol for inclusion in the injectable composition is benzyl alcohol, which is present in a concentration of up to 10% of the composition, preferably from 1 to 5%, preferably about 3 liters.

It may also be advantageous to include a basic excipient with crystalline amoxicillin sodium in compositions suitable for administration by injection. In particular, the present invention also provides an injectable composition that still includes crystalline amoxicillin sodium and trisodium phosphate. A suitable ratio of crystalline amoxicillin sodium to trisodium phosphate is from 82 to 50:1, preferably from 10:1 to 30:1, preferably from 14:1 to 28:1.

The inclusion of a base such as trisodium phosphate allows for the high concentration required for intramuscular injection (typically 2 tnl of 1 in water).
y amoxicillin sodium) is particularly desirable for rapidly and completely dissolving amoxicillin sodium in an aqueous solution.

One advantageous 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 'tE amoxicillin sodium may be the only therapeutic agent in the compositions of the invention, or combinations with other antibiotics or with β-lactamase inhibitors may be used.

Advantageously, the composition also has formula (n) (Wherein A is hydroxyl, substituted hydroxyl.

Thiol, substituted thiol, amino, mono- or di-
Also included are compounds represented by hydrocarbyl-substituted amines or heptano- or di-acylamino) or pharmaceutically suitable salts or esters thereof.

Preferably A represents hydroxy or methoxy. That is, the compound (IT) is preferably in the form of a salt, which represents clapulic acid or clapulic acid methyl ester.

A preferred composition comprises crystalline amoxicillin sodium with a salt of clapranic acid, particularly the sodium or potassium salt, preferably potassium claplanate. A particular composition of the invention includes crystalline amoxicillin sodium, potassium clapulanate and trisodium phosphate.

Another advantageous composition comprises crystalline amoxicillin sodium together with a compound of formula (Ill), in which B represents hydrogen or chlorine, a pharmaceutically suitable salt or in vivo hydrolyzable ester thereof. include.

The present invention provides a method of treating a bacterial infection in an animal, particularly a human or domestic animal, comprising administering a composition of the invention.

The present invention will now be illustrated by way of examples.

Reference Example 1 Dimethylacetamide solvate of amoxicillin sodium Dimethylacetamide (200ml) and triethylamine (26.1m/0.186mol) were cooled to 0°C, and amoxicillin trihydrate (74.2f
.

0.177 mole) was added over 5 minutes at 0-5°C. The mixture was stirred for 30 min at 0-5 °C, filtered and treated with sodium ethylhexanoate (33 f as 100%).
, 0.21 molle) dissolved in 60-methanol was added over 5 minutes at 0 to 5°C.

The solution was stirred for 4 hours and allowed to warm to 20°C during the first hour. The product was filtered and diluted with isopropyl alcohol (1000
ml) and dried at 35°C.

The product weighed 75.2 grams and was analyzed to contain 75% amoxicillin (theoretical 77 grams, yield 88 grams).

Reference Example 2 Dimethylacetamide G medium f++ of amoxicillin sodium! The method of Reference Example 1 was repeated except that 150ml of isopropyl alcohol (150ml) was used instead of methanol to dissolve the antisodium. 78.9 f of product was obtained.

Reference Example 3 Dimethylformamide solvate of amoxicillin sodium Dimethylformamide (200m) and triethylamide 7 (30me, 0.214 mo, T!e) were combined into 5
It was cooled to °C and amoxicillin trihydrate (<a?, 0.10 i 2 moue as 100%) was added. The solution was cooled to 0-5°C and stirred for 1/2 hour.

150m7! 2- dissolved in isopropyl alcohol of
Ethylhexane rj sodium receptor (24,7f, 0
．． 16 mole) was added and the solution was incubated for 3 hours. The suspension was filtered and the filter cake was washed with 100 ml of isopropyl alcohol and 100 ml of methylene chloride. The product was dried at 35°C. Yield of solvent filtrate 53f.

Analysis by H, P, L, C, 94%, amoxicillin content (as free acid) 76.5% Reference example 4 N-methyl-2-pyrrolidinone solvate of amoxicillin sodium N-methyl-2-pyrrolidinone (170 ml. ) and triethylamine (26,1me, 0.187 mo
ue) to 0-5°C, amoxicillin trihydrate (
74,21F, 0.177 rnole) was added over 10 minutes. The solution was stirred for 1 hour and filtered. Sodium ethylhexane (33.3f, 0.00%) was then added to 50ml of N-methyl-2-pyrrolidinone.
2mojie) was added. After stirring for 1 hour, 400mg
of methylene chloride was added over a period of 30 minutes. 2 of the mixture
Stir for an additional 3 hours at 0°C, filter, and obtain 150 mg of the product.
was washed with isopropyl alcohol.

After drying at 35°C, the product weighed 772 (86% yield) and analyzed 726 ml amoxicillin/my
Met.

Example 1 Preparation of crystalline amoxicillin sodium from dimethylformamide solvate Via tetrahydrofuran solvate The dimethylacetamide solvate of amoxicillin sodium prepared in Reference Example 1 of 101F was heated to 60 rn1. of methanol. solution to 0
Stir for 25 minutes at ~5°C and filter.

Tetrahydrofuran (150m/) took 5 minutes to
Add to the filtrate kept at 5°C and stir the mixture to 1+ at 0-5°C.
Stir for hours. The suspension was filtered and the product was washed with methylene chloride (75 mJ) and incubated at 45°C for 1 hour with nitrogen bubbling.
It was vacuum dried for 6 hours. Crystalline amoxicillin sodium (6,7f, yield 83%) was 930 mcf/y
y (amoxicillin free acid). The product had a moisture content of 0.5-.

Example 2 Amoxicillin sodium via toluene solvate as described in Example 1.
A crystalline product (66% yield) of l)s,sf was obtained by preparing a DMA solution and precipitating with toluene (200 g, 1 h). H, P, L, C analysis 920 m
ef amoxicillin/TrPg. This material contained 0.5% water.

Example 3 Via the inglopanol solvate A amoxicillin sodium-DMA solution was prepared as described in Example 1 above and crystals of 5.02 were obtained by precipitation (1 ÷ hours) with 400 - of inglopanol. Product (yield 56%, H, P.

L, C, analysis 837 mc-) was obtained.

Example 4 Amoxicillin sodium-DMA as described in Example 1 via isopropyl ether and toluene solvate
A solution was prepared and 150 tnI! , toluene then 90
Crystalline amoxicillin sodium of 9s, or (c+64) was obtained by precipitation with isopropyl ether of tnt (20-25°C). H4F, L, C, analysis 906 mar amoxicillin/rq Example 5 via n-propanol solvate Amoxicillin sodium-DM A fa solution was prepared as described in Example 1 above and 200 rn! , no n
- by precipitation with propatool (1 hour), 94
．． 6? A product (yield 51%) was obtained. Analysis 823
mcf amoxicillin y/my Example 6 Via 1,2-dimethoxyethane solvate An amoxicillin sodium-DMA solution is prepared as described in Example 1 above and precipitated with 100-1,2-dimethoxyethane (1 time) 7. A crystalline product of sy (yield: 67 cm) was obtained. H, P, L, C, analysis 66
6 ml F amoxicillin/mq.

Example 7 Amoxicillin sodium-DMA solution was prepared as described in Example 1 above via methyl acetate solvate and room/! 5,520 crystalline amoxicillin sodium containing 836 μ amoxicillin/η was obtained by precipitation with methyl acetate (1 ÷ h).

Example 8 Via Dioxane Solvate An amoxicillin sodium-DMA solution was prepared as described in Example 1 above and 200 tnl. 863mc? by precipitation with dioxane (1 hour). 6,62 crystalline amoxicillin sodium containing amoxicillin/rrf 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 tnl of bis(2-methoxyethyl) ether (1-r time), possibly 9800 mcf amoxicillin/t (H, P
, L, C,) containing 7,4y (yield 79th)
of crystalline amoxicillin sodium was obtained.

Example 10 Via the t-butanol solvate By preparing an amoxicillin sodium-DMA solution as described in Example 1 above and precipitating with 150 m/l of t-butanol (15 minutes).
Amoxicillin/#+5' (H, P, L, C,
) 6,97 (yield 74%) crystalline/moxicillin/sodium was obtained.

Example 11 Via Tetrahydrofuran Solvent Oxide A 0.5φ water and 927 mclF amoxicillin 7
/mW(H,P,L,C,) 6,1ji'(
Crystalline amoxicillin sodium with a yield of 75% was obtained.

Example 12 Via benzene hotsolvate A amoxicillin sodium-DMA solution was prepared as described in Example 1 above and crystalline amoxicillin sodium of sz02 was obtained by precipitation with 150-benzene (15 minutes). Ta. Analysis 91.8 mcf of amoxicillin/rrv.

Example 13 Via n-Butanol Solvate A solution of amoxicillin sodium was prepared as described in Example 1 above and precipitated with 150-h of n-butanol to give a crystalline product of 6.01 mm (yield 66. 2%
) was obtained. Analysis 827 me/amoxicillin l rn
y.

Example 14 Amoxicillin sodium-DMA solution was prepared as described above via di-isoglobil ether solvate and 150
m/! precipitated with globyl ether (10
7.5 min) of crystalline amoxicillin sodium (yield: 84.3%) was obtained. Analysis 843 mar
Amoxicillin/my.

Example 15 60ml via tetrahydrofuran solvate! ! The methanol was cooled to 0-5°C and amoxicillin-dimethylformamide solvate (10F as such) was added over a period of 30 seconds.

Stirred at 0-5°C for 25-30 minutes. Filtrate (0-5℃)
150rnI! of tetrahydrofuran was added over 5 minutes and stirred at 0-5°C. The suspension was filtered and the product was washed with IDOmA tetrahydrofuran containing 2% water and then with 50-methylene chloride. The product was dried under vacuum at 45° C. with a nitrogen purge. The product C obtained by this method is crystalline amoxicillin, weighing 7.2 F (yield 89.3 kg), containing 0.72 mm water, H, P, L,
C, analysis was 931 mcf amoxicillin/■.

Example 16 Described in Example via Tetrahydrofuran Solvate/ζAmoxicillin Sodium-DM
After stirring for an additional 10 minutes using solution A, cyamoxicillin sodium was crystallized by adding tetrahydrofuran (ls 0m6). After crystallization had proceeded for 1+ hours, the product was isolated, washed with tetrahydrofuran and methylene chloride, and dried under vacuum at 45°C. Thus, H
Amoxicillin sodium (7,6F, 93T) was isolated as a crystalline rod with an analytical value of JL919 mcf amoxicillin/R, according to , P, L, C,. The moisture content was 0.67 inches.

Example 17 Preparation of crystalline amoxicillin sodium from dimethylformamide solvate Reference example 3 in methanol (60 mg) cooled to 0-5°C via tetrahydrofuran solvate
The dimethylformamide solvate of amoxicillin sodium prepared as in 102 was added. The solution was stirred for 30 minutes at 0-5°C and filtered. 150-Tetrahydrofuran was added to the filtrate at 0-5°C over a period of 20 minutes. The suspension was stirred for 1 hour at 0-5°C, filtered and the product was washed with 90-methylene chloride. After vacuum drying, the crystalline product weighs 6. s y (yield 79.
4 h) Yes, the analysis value is 11. P, L, C, YoF)
916 m+J amoxicillin/ri.

Example 18 Preparation of crystalline amoxicillin sodium from N-methyl-2-pyrrolidinone solvate Via toluene solvate Methanol (60 mg) was cooled to 0-5°C, Reference Example 4
Amoxicillin sodium N-methyl-2 manufactured by
- Pyrrolidinone solvate was added.

Solution 11/i was stirred at 0-5° C. for 25 minutes and filtered.

Toluene (200me) was added over 15 minutes while maintaining at 0-5°C and the product was washed with 50-methanol:toluene (1:s) and 5o-methylene chloride. Crystalline amoxicillin sodium after vacuum drying at 45°C while blowing nitrogen has a weight of 4.02 (yield: 48 cm), and an analytical value of 909 mc? Amoxicillin/Tq
Met.

Example 19 Via Tetrahydrofuran Solvate A solution of amoxicillin sodium-N-methyl-2-pyrrolidinone is prepared as described in Example 18, except that it is precipitated with 150 d of tetrahydrofuran and washed with tetrahydrofuran and methylene chloride. Yo'
j) 7, Of amoxicillin sodium containing 913 mclF amoxicillin/■ (yield 85 ti)
I got it.

Example 20 Preparation of crystalline anhydrous amoxicillin sodium via tetrahydrofuran solvate Amoxicillin trihydrate (4,1'lf, 0.01
0 mol e) in methanol (2 in 30 mJ)
-Sodium ethylhexanoate (1,70y, o,
A mixture of O 102 mo ji e ) and triethylamine (1.50 mg, 0.0108 mole) was stirred at room temperature. After 15 minutes a clear solution was obtained which was treated with tetrahydrofuran (THF) (10 ml) and seeded. Crystallization started immediately.

The mixture was cooled to about 5° C. for 0.75 hours, the product was collected,
It was washed with THF/methanol (5:1, 25 m) and then with methylene chloride (s On/) and dried under vacuum using phosphorous pentoxide.

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

Example 21 Preparation of crystalline anhydrous amoxicillin sodium via methyl acetate solvate Amoxicillin trihydrate (83,8f) was dissolved in methyl acetate (300 trt) and methanol (300 trt) was dissolved in methanol (300 trt).
Sodium 2-ethylhexanoate (36, Oy)
and triethylamine (35 mg) was added in one portion with vigorous stirring at room temperature.

A virtually clear solution was obtained after 3 minutes. This was filtered, crystal seeds were added, and ethyl acetate (300 ml) was added under strong stirring.
) was diluted with As crystallization progressed, more methyl acetate (60 omg total) was added in a trickle over 30 minutes. The mixture was stirred for an additional 15 minutes at room temperature and then stored at approximately 5°C for 2 hours.

The products were combined and diluted with methyl acetate/methanol (4:1.25
The mixture was slurried on the filter with methyl acetate/methanol (6:1, 100 m), then methyl acetate and finally methylene chloride. The product was dried under low vacuum for 30 minutes.

(The n, m, r spectrum of the material thus dried indicated the presence of about 1 mole of methyl acetate).

Yield 65.5f Solvated amoxicillin sodium was dried under high vacuum with phosphorous pentoxide until the expected weight loss was achieved.

Yield: 55.3f Weight Yield: 71.4% This material had the following analytical values:

Purity (imidazole) 96.4% (as sodium salt) Indine absorbing material 0.78% Water (K-F,) 0.17% Solvent Methylene chloride 0.01 Timetano/L 10.008% Vinegar 119 Methyl 1. The product of Oq6 6 Run 21 was obtained from Phillips
) by X-ray powder diffraction using a scanning diffractometer and CukO radiation set at 46 kV and 35 mA with a time constant of 0.3 seconds ii! d solid. The diffraction maximum was observed from 30° to 8° 2θ. The following lines were observed.

29.8 18.9 29.2 17.8 28.417.1 28.0 16.5 2G, 5 15.8 25.9 15.5 25.7 15.0 25.2 14.0 24.0 13.5 23 , 0 1 2 , 5 22.3 11.3 21.4 10.5 20.9 9.4 20.1 8.5 Example 22 Preparation of crystalline anhydrous amoxicillin from methyl acetate solvate 82 Amoxicillin trihydrate (86%) was dissolved in methanol/acetic acid methane pre-cooled to -10°C.
Sodium methoxide (No. 11) was dissolved by addition while maintaining the temperature between -8°C and -10°C. The sedimentation is 150m7! This was achieved by rapidly (5 minutes) addition of 200 ml of methyl acetate. At this time, the temperature was raised to 0-5°C. A further 150 ml of methyl acetate was added over 15 minutes and the suspension was stirred for 2 hours while maintaining the temperature at low 5°C. The product was isolated by filtration, washed with 2×40 methylene chloride, and dried in a vacuum oven at 6 mC with nitrogen bubbling to yield crystalline anhydrous amoxicillin sodium.

The average activity yield for the six syntheses was 81.5%, and the product purity was between 89.1% and 92.3% (as the acid itself).

[Brief explanation of the drawing]

The 111th culprit is the infrared spectrum of the crystalline amoxicillin sodium of the present invention.

Claims (1)

[Claims] (t>microcrystalline amoxicillin sodium. (2) A method for producing crystalline amoxicillin sodium comprising removing solvent molecules from a solvate of amoxicillin sodium. (3) Solvent molecules are removed by drying means. (4) A method for producing crystalline anhydrous amoxicillin sodium comprising removing the amide from an amide solvate of amoxicillin sodium. (5) The amide has the formula (i) R-CO-NR'R2(I) (wherein, it, a' and R2 are the same or different and each represent hydrogen or a hydrocarbon group, or R and R1 taken together 3 or 4 carbon saturated or unsaturated hydrocarbon chain)
The method described in section. (6) Amide is dimethylformamide, dimethylacetamide, N-methylpyrrolidin-2-one - is N
-Methylpiperidin-2-one.The method according to claim (5). (7) The amide is produced by dissolving the amide solvate of amoxicillin sodium in C1-6 flukanol and adding a solvent with a lower dielectric constant to cause crystallization of the solvate of amoxicillin sodium in crystalline form. ,
4. The method of claim 4, wherein the amoxicillin sodium amide solvate is removed by removing solvent molecules therefrom. (8) A pharmaceutical composition useful for treating bacterial infections in humans and animals, comprising an antimicrobially effective amount of crystalline amoxicillin sodium together with a pharmaceutically suitable carrier. (9) Claim No. 81, further comprising trisodium phosphate. (11) Use of crystalline amoxicillin sodium as an antibiotic in the treatment of the human or animal body. (121β-2) A pharmaceutical composition useful for the treatment of bacterial infections in humans and animals, comprising a catamase-inhibiting amount of a β-2 catamase inhibitor and an antimicrobially effective amount of crystalline amoxicillin sodium, together with a pharmaceutically suitable carrier. (13) β - The composition according to claim (12), wherein the lactamase inhibitor is a pharmaceutically suitable salt of cudipranic acid. (J4) The composition according to claim 12, wherein the lactamase inhibitor is a pharmaceutically suitable salt of cudipranic acid. A method of treating bacterial infections in humans and animals comprising administering an inhibitor and an antimicrobially effective amount of crystalline amoxicillin sodium in a pharmaceutically suitable carrier.