SI8311558A8 - Process for obtaining very pure amorphous form of cephuroxim axetyle - Google Patents

Description

PROCEDURE FOR OBTAINING A HIGHLY PURE AMORPHIC FORM OF CEFUROXIM AXETYLES

FIELD OF TECHNOLOGY

The invention relates to the field of antibiotic production, and particularly relates to a process for the preparation of a new amorphous form of cefuroxime 1-acetoxy-ethyl ester (cefuroxime axetil).

TECHNICAL_PROBLEM

The invention solves a production problem for the oral administration of a suitable highly pure amorphous form of cefuroxime.axetil.

Engineering_technology

The compound (6R, 7R) -3 ~ carbamoyloxymethyl-7 - [(Z) -2- (fur-2yl) -2-methoxyiminoacetamido / cef-3-em-4-carboxylic acid has the recognized name cefuroxime ”. This compound is a valuable antibiotic characterized by a high broad spectrum of activity against gram-positive and gram-negative microorganisms, with this property being enhanced by the very high stability of the compound against beta-lactamase produced by a large number of gram-positive and gram-negative microorganisms. It is well tolerated in the body of mammals and is widely used as an antibiotic in clinical practice. Cefuroxime and its salts are generally used as injectable antibiotics since they are poorly absorbed in the gastro-intestinal system and are therefore present in the blood and urine only at very low concentrations after oral administration. Therefore, there was a need to arrive at a form of cefuroxime that would be able to be absorbed from the gastro-intestinal tract after oral administration.

We have found that proper esterification of the carboxyl group of cefuroxime improves the efficacy of oral administration. The presence of such a suitable esterifying group results in significant absorption of the compounds from the gastro-intestinal tract, after which the esterified group is hydrolyzed by enzymes present in, for example, blood and body tissue, to give an antibiotic-active basic acid. To be effective by oral administration, the ester must be stable enough to reach the site of absorption without significant degradation, must be sufficiently absorbed when it reaches the appropriate site, and must be sufficiently sensitive to hydrolysis with systemic esterases to release the basic acid briefly time after ester absorption. British Patent Application No.1571683 describes and seeks protection for a number of esters of cefuroxime with properties that make them potentially significant antibiotics for oral administration.

It is important that the cephalosporin compounds for oral administration be in a form that provides high biological value with the absorption of antibiotics in the bloodstream being maximum and the amount of antibiotics remaining in the gastrointestinal tract minimal. An antibiotic that is not absorbed will be therapeutically ineffective and may also cause side effects by lagging in the gastro-intestinal tract. Other factors besides biological value are also significant, including in particular the need for cephalosporin compounds to be in a pure form which is stable during storage. In general, cephalosporin compounds in very pure crystalline form have been found to give the best ratio of properties, with such compounds having good storage stability as well as high biological activity when taken.

i

Of the esters described in British patent application No.1571683, we have found that cefuroxir axetil is particularly significant. The processes for the preparation of the above ester have been experimentally implemented in British patent application No.1571683 and give the material either in relatively impure amorphous form or in the form of pure crystalline material.

In relation to past experience in the field of cephalosporins, we first prepared cefuroxime axetil for commercial determination in pure, crystalline form. We were surprised to find, however, that pure, crystalline cefuroxime axetil does not have the best ratio of properties for commercial use and that, contrary to previous experience in the field of cephalosporin, cefuroxime axetil is better used in a very pure, amorphous form. Thus, we have found that very pure cefuroxime axetil when used in amorphous form has high biological activity when taken orally, better than in crystalline form, and in addition the amorphous form of cefuroxime axetil has adequate chemical stability during storage. This is in contrast to the known tendency for amorphous materials to have less chemical stability than crystalline materials and also the known tendency for highly pure amorphous materials to crystallize. Thus, in contrast to earlier cephalosporin compounds that have been commercialized, cefuroxime axetil is preferably made and used in a highly pure amorphous form rather than in crystalline form.

According to one aspect of the present invention, cefuroxime axetil is provided in a very pure, amorphous form.

The cefuroxime axetil according to the invention preferably contains less than 5% w / w (w / w), better below 3% w / w, impurities. It is to be understood that impurities here are understood to mean residual solvents which are retarded after the process for preparing cefuroxime axetil according to the invention. The residual solvent present will preferably only be present in an amount below 6% w / w and preferably below 2% w / w.

Typical impurities that may be present are the Δ -isomers of cefuroxime axetil and the corresponding E-isomers of cefuroxime axetil.

The cefuroxime axetyl ester of the invention is preferably substantially free of crystalline material.

Cefuroxime axetil has an asymmetric carbon atom in position 1, 1-acetoxyethyl group and can therefore exist in the form of R and S isomers and mixtures thereof. The amorphous cefuroxime axil til ester of the invention is preferably in the form of a mixture of its RiS isomers, wherein these mixtures have substantially improved solubility when compared to the amorphous R isomer or the amorphous S isomer when alone. For example, the molar ratio of the R isomer to the S isomer may be in the range of 3: 2 to 2: 3, with ratios of 1.1: 1 to 0.9: 1, especially about 1: 1, being particularly preferred.

%

Cefuroxime axetil according to the invention preferably has at svojoj ⁱⁿ methanol, the correction for the koji was Contents of the solvent, from about 395 to 415. In addition to rigid, cefuroxime axetil according to the invention ^ IAA relationship R axle S i2omeru from 0.9: 1 to 1.1: 1, from narocito about 1: 1, preferably having / oi / value in dioxane from about + 35 ° to + 41 °, again when corrected for any solvent content. Figures 1 and 2 of the accompanying drawings are respectively infra-red and nmr spectra for the type of particularly pure, amorphous cefuroxy axetil of the invention.

After absorption, cefuroxime axetil is converted to the basic antibiotic acid, cefuroxime, which is known to exhibit high antibiotic activity over a wide range of gram-positive and gram-negative organisms. Cefuroxime axetil is therefore useful for the oral and rectal treatment of various diseases or infections of prc 'caused by pathogenic bacteria.

The cefuroxime axetil according to the invention is conveniently obtained by a process which constitutes a further aspect of the present invention and which comprises isolating the cefuroxime axetil from its solution under conditions that allow for a very pure, amorphous product.

Techniques that can be used to isolate the amorphous cefuroxime axetil from its solution include those in which the solvent is removed from the solution, preferably rapidly, and the product precipitates, and those in which the product precipitates from the solution. Methods that require the application of these procedures that have been found satisfactory include spray drying, roller drying, solvent precipitation and freeze drying.

The solvents for cefuroxime axetil will be selected depending on the technique used and the conditions. Suitable solvents for dissolving cefuroxime axetil to form solutions from which isolation will be possible include organic solvents, for example ketones, e.g. acetone; alcohols, e.g. methanol or ethanol, if desired in the form of methylated spirit (eg IMS); acetonitrile; tetrahydrofuran; dioxane; esters, e.g. methyl or ethyl acetate; chlorinated solvents e.g. dichloromethane or chloroform; and mixtures thereof, if desired with other solvents, e.g. with water, whereby this gives a homogeneous phase.

The concentration of cefuroxime axetil in the solvent is preferably as high as possible, in proportion to the amorphous product obtained, with concentrations above 1% w / w, preferably over 10% w / w. The maximum concentration of cefuroxime axetil in the solvent will depend on the * solvent used and will usually be below 30% w / w. For example, the concentration of cefuroxime axetil in acetone will conveniently be in the range of 10 to 20% w / w. Solvents may, if desired, be heated to aid solubility and solvent removal.

In the general case, we have found that cefuroxime axetil has sufficient heat stability to withstand spray drying and therefore spray drying is the preferred method for performing insulation. Spray drying systems can operate in a known manner to obtain an amorphous product substantially free of crystalline material and free of particulate impurities. The closed cycle of the spray drying system, in which the drying medium is recycled, is particularly safe and economical for use in the preparation of the product of the present invention.

When spray drying is used, suitable solvents for dissolving cefuroxime axetil before spray drying 'include organic solvents, for example ketones, e.g. acetone; alcohols, e.g. methanol or ethanol, if desired in the form of methylated spirit (eg IMS); acetonitrile; tetrahydrofuran; esters, e.g. methyl or ethyl acetate; chlorinated solvents e.g. dichloromethane or chloroform; and mixtures thereof, if desired with other solvents, e.g. water to give a homogeneous phase.

Drying gas can be air, but this is undesirable with sedimentary solvents, in which case inert gases such as nitrogen, argon and carbon dioxide are preferred. The gas inlet temperature of the oven will be selected according to the solvent used, but may for example be in the range of 5O-14O ° C, preferably C0-125 ° C. The temperature at which the gas is released will similarly depend on the solvent but may for example be in the range of 45-100 ° C, preferably 50-80 ° C.

The use of rapid evaporation techniques, in particular the application of spray drying, also leads to particularly easy cropping, under appropriate conditions, of products of a consistent range of particle sizes. The spray drying product has the form of microspheric cavities that can be easily combined in pharmaceutical preparations.

When roller drying is used, suitable solvents for dissolving cefuroxime axetil before drying include ketones, e.g. acetone; alcohols, eg methanol or ethanol, if desired in the form of methylated spirit (e.g. IMS); acetonitrile; tetrahydrofuran; dioxane; esters, e.g. methyl or ethyl acetate; chlorinated solvents, eg dichloromethane or chloroform; and mixtures thereof, if desired with other solvents, e.g. with water, whereby this gives a homogeneous phase.

When performing the above spray drying or rolling techniques, it is particularly desirable that the boiling point of the solvent used is below the coagulation point of the product - according to the invention under the conditions used. In the general case, the boiling point of the solvent will preferably be below 80 ° C except when a reduced pressure is used whereby the solvents are allowed to have a higher boiling point.

When solvent precipitation is used, suitable solvents from which cefuroxime axetil may be deposited include ketones, e.g. acetone; alcohols, e.g. methanol or ethanol, if desired in the form of methylated spirits (e.g. IMS); acetonitrile; tetrahydrofuran; dioxane; esters, e.g. methyl or ethyl acetate; chlorinated solvents e.g. dichloromethane or chloroform; and mixtures thereof, if desired with other solvents, e.g. with water, thereby giving a homogeneous phase. Deposition can be performed by adding appropriate amounts of non-solvent to cefuroxime axetil.

d ^

Suitable non-solvents include water, alkanes and alkane mixtures, e.g. hexane or petroleum boiling points (e.g. 60-80 ° C), ethers, e.g. isopropyl ether, or aromatic hydrocarbons e.g. benzene or toluene. Solvent and non-solvent should be mixed ie. they should be at least partially mixed and preferably mixed completely. Typical solvent and non-solvent combinations are dichloromethane / isopropyl ether, ethyl acetate / petroleum and acetone / water. The solid should be removed from the solution as quickly as possible and dried as quickly as possible to avoid any formation of crystalline material. To aid faster isolation, a carrier gas may be drawn into the solution, e.g. the air.

The solvent precipitation technique can be advantageously applied to the reaction mixture obtained after the esterification reaction in which cefuroxime axetil is formed to obtain amorphous cefuroxime axetil directly. This can be achieved by adding a solvent e.g. esters such as ethyl acetate in the reaction mixture and then a suitable non-solvent, e.g. oil.

When freeze drying is used, suitable solvents for dissolving cefuroxime axetil before drying include dioxane and t-butanol. The temperature at which the insulation will take place will depend on the freezing point of the solvent used e.g. with dioxane the insulation will be carried out at a temperature of about 12 ° C.

In order to obtain high purity cefuroxime axetil ester by the above techniques, it is necessary to take the starting material of suitable purity - i. at least as pure as the final product should be. This starting material can be obtained by any suitable method, e.g. by crystallization.

The solution from which cefuroxime axetil is isolated preferably contains a mixture of both R- and S-isomers, whereby the product is obtained as a mixture of R- and S-isomers. In the general case, the ratio of R./S isomers of the product in solution is accurately reflected on the final product obtained, e.g. by spray drying, this ratio for the final product is accordingly controlled by friction if desired by adjusting the ratio of R / S isomers in solution.

The residual solvent may be present in the final product in varying amounts immediately after evaporation or precipitation. This can be removed if necessary by further treatment, e.g. by vacuum drying.

The cefuroxime axetyl ester of the invention may be formulated for oral (including oral) or rectal administration.

Oral administration preparations are the best, with increased ester absorption via the gastro-intestinal system. Such pharmaceutical preparations may be in the form, for example, of tablets or capsules prepared in a conventional manner with pharmaceutically acceptable excipients such as binders, e.g. pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose; fillers e.g. starch, lactose, microcrystalline cellulose or calcium phosphate; lubricants e.g. magnesium stearate, hydrogenated vegetable oils, talc, silica, polyethylene glycols; disintegrators e.g. potato starch or sodium starch glycolate; or happiness for wetting e.g. sodium lauryl sulfate. Auxiliary happiness for highlighting e.g. silica can also be used if desired. The tablets may be coated by methods well known in the art.

The preparation of preparations suitable for forming into tablets, capsules or granules may also be accomplished by spray drying or by drying on a roller suspension of pure amorphous cefuroxime axetil with suitable * excipients for said tablets, capsules or granules.

Liquid preparations for oral administration may be in the form of, for example, solutions, syrups or suspensions, or they may be dry products for any costing with water or with other suitable. prior to use for use as fluid, or for direct administration and then rinsing with water or other suitable fluid. Such liquid preparations can be prepared in a conventional manner with pharmaceutically acceptable additives such as suspensions for example. sorbitol syrup, methyl cellulose or hydrogenated edible fats and oils such as hydrogenated castor oil; the happiness of emulsifying or mumping e.g. lecithin, aluminum stearate or acacia; non-aqueous carriers e.g. almond oil, fractionated coconut oil, ester oils or ethyl alcohol; and protective fortunes e.g. methyl or butyl p-hydroxybenzoates or sorbic acid; and a convenient fortune to taste and sweeten.

The cefuroxime axetil of the invention can also be formulated for rectal administration such as suppositories or retention enemas, e.g. containing a conventional base for suppositories such as cocoa butter or other glycerides.

The compositions may contain between 0.1-99% of the active ingredient, preferably 30-90% for tablets and capsules and 3-50% for liquid medicines. Single dose preparations contain 50500 mg of active ingredient. The doses used to treat humans would be in the range of 100-300 mg per day, e.g. 1000 to 1500 mg per day for adults and 250 to 1000 mg per day for children, although the precise dose will depend, among other things, on the frequency of administration.

Thus, in a further aspect, the invention provides a pharmaceutical composition comprising cefuroxime axetil in a very pure, completely amorphous form, in admixture with one or more pharmaceutical carriers and / or excipients. Such preparations are preferably adjusted for absorption via the gastro-intestinal tract,

In e.g. for oral administration. In a preferred embodiment, such preparations will preferably include the form of cefuroxime ester of the invention which is completely free of crystalline material.

In another aspect of the invention, we provide a method of combating bacterial infections in the body of humans and animals comprising administering an orally or rectally effective amount of a very pure, completely amorphous form of cefuroxime axetil.

The following examples without limitation illustrate the invention.

In all examples, the cefuroxime axetyl starting materials used are in very pure crystalline form. Such starting materials can, for example, be obtained by the procedures described in British Patent Application No. 4/2004. 1571683, or alternatively obtained by crystallizing a very pure form of cefuroxime axetil from an organic solvent, for example an ester such as ethyl acetate in admixture with an ether such as isopropyl ether or an aromatic hydrocarbon such as toluene; or aqueous alcohol such as industrial methylated spirit. The crystallization can conveniently be carried out at from 10 to 30 ° C.

Highly pure sodium cefuroxime which can be used as a starting material for the above esterification process can be obtained, inter alia, by reaction of (6R, 7R) -3-hydroxymethyl-7 - [(Z) -2- (fur-2-yl) -2-methoxyimino acetamido / cef ~ 3-em4-carboxylic acid with chlorosulfonyl isocyanate in alkyl acetate as solvent at -25 ° C to + 10 ° C, followed by in situ hydrolysis at +10 to + 30 ° C and crystallization by the addition of sodium 2-ethylhexanoate in acetone or methyl acetate as a solvent.

The preparation of these materials is illustrated by the following preparations. All temperatures are in ° C.

Preparation 1

Chlorosulfonyl isocyanate (226 mil.) Was added to a solution of triethylamine (10 ml) in methyl acetate (3.8 l). The resulting clear solution was cooled to -15 ° and a (6R, 7R) -3-hydroxymethyl-7 - / (Z) -2- (fur-) suspension was previously cooled to -15 ° C over a period of 10 minutes. 2-yl) -2-methoxyiminoacetamido / cef-3-em-4-carboxylic acid (763 g) in methyl acetate (2.3 L). The residual solid was washed with methyl acetate (700 ml). The mixture was stirred at -5 ° for 30 minutes to give a clear solution after 10 minutes. Water (1.2 l) was rapidly added to the reaction mixture at 18 °, with the temperature rapidly rising to 10 ° and then slowly to 17 °. The mixture was stirred for 60 minutes at 15 ° to give a thick white suspension. Methyl acetate (3.6 l) was added followed by sodium hydroxide solution (288 g) in water (5.2 l). This gave a clear two-phase mixture at 26 ° with a pH of 2.35. The layers were separated and the upper, organic layer was washed with sodium chloride solution (600 g) in water (2 L). The two aqueous layers were washed sequentially with methyl acetate (2 L). The organic layers were mixed, mixed with Dorit SX Plus charcoal (76 g) for 30 minutes and processed through a layer of Hyflo Supercel, with the layer washed with methyl acetate (1.5 L). The filtrate and the rinsing liquids were combined and stirred at 20 ° while sodium solution was added over 20 minutes

Of 2-ethylhexanoate (338 g) in a mixture of methyl acetate (2 L) and water (40 ml) to give a white suspension with a pH of 5.5. The suspension was stirred for 10 minutes and then graded and the cake was washed with methyl acetate (5x11), dried, and dried at 30 ° in vacuo for 24 h to give cefuroxime sodium.

high pressure (HPLC) 2.0%.

Preparation 2

Crystalline cefuroxime acetyl (RS) -1-Acetoxyethyl bromide (12.5 g) was added to a stirred mixture of sodium cefuroxime (20 g) in dimethyl acetamide (110 ml) at 0 ° C. The mixture was stirred at + 1 ° for 90 minutes and potassium carbonate (0.5 g) was added. Stirring was continued for 2 h at

1-3 ° when the reaction mixture was added to a rapidly stirring mixture of ethyl acetate (200 ml) and aqueous 3% sodium bicarbonate (200 ml) to destroy any excess 1-acetoxyethyl bromide.

After 1 h, the organic layer (1.5% Δ isomer via HPLC) was separated, washed with N hydrochloric acid (100 ml) and aqueous 20% sodium chloride containing 2% sodium bicarbonate (30 ml). All three aqueous phases were sequentially washed with ethyl acetate (100 ml). The combined organic extracts were stirred for 30 minutes with charcoal (Korit SX Plus; 2 g), filtered through a kieselguhr layer and washed with ethyl acetate (2 x 25 ml). The combined filtrate and washings were evaporated in vacuo to give 150 g and stirred at ambient temperature for 1 h until complete crystallization. Di-isopropyl ether (250 ml) was added over 45 minutes to complete crystallization and stirring continued for another 1 h. The product was collected by filtration, washed with 2: 1 diisopropyl ether / ethyl acetate (150 ml) and dried in vacuo at 50 ° over the weekend to give crystalline cefuroxime acetyl (19.3 g).

Solvent content (GLC) 0.2% w / w. Impurities of HPLC 1.8%.

%

Isomer Ratio (HPLC) 1.09: 1 / όί / ^ (1% in dioxane) +37;

(278 nm, MeOH) 389.

t

The individual isomers R and S of cefuroxime 1-aoethoxyethyl ester are conveniently indicated by letters A and B, the letters being used to denote the isomers respectively as in British Patent No.1571683. The identities of isomers A and B have not been determined. The isomer ratio given in the following examples is expressed as 1%

A; B. Temperatures are given in ° C. The values given for ^Ε 1απ and / c // _{D have} not been corrected for the solvent content.

Example 1 * ·

A 10% w / v acetone solution of a mixture of R and S isomers of cefuroxime axetil was poured into Niro Mobile Minor Spray Drier, Niro Copenhagen, Denmark, which uses air as a drying gas and a rotary atomizer rotating at 35,000 revolutions per minute (rpm). . Gas inlet and outlet temperatures were 124 ° and 70 ° respectively. 75% w / w spray-dried product was isolated. The microscopic appearance was typical of a spray-dried product (hollow). The HPLC sample is 97% w / w impurity by HPLC 2.0% w / w, both values determined on dry basis from a measured solvent content of 0.15% w / w (GLC), and a water content of 0.8% w / w (Karl Fischer) . The isomer ratio was 1.04: 1 (HPLC). Infrared (Nujol), 3480-3210 (ΝΗ, ΝΗ complex),

ΙΏ3.Χ £

1782 (beta-lactam), 1760 (acetate), 1720 (4-ester group),

1720 and 1594 (carbamate), and 1676 and 1534 cm < ¹ >(7-amido); / 2 / _D (dioxane) +38; E, (MeOH) 398. X-ray nuts analysis of solder in 0.3mm capillary diameter by Debye Scherrer method in 114.6 mm diameter camera by exposing ^CuK a ^ f for 3 h, _{and the} radiation gave a bright halo (absence of crystals, which confirms amorphous product structure).

Example 2

A mixture of the R and S isomers of cefuroxime axetil (20.25 g) was dissolved in acetone (200 ml) at ambient temperature. The solution was clarified cross sintered glass and pumped through an atomizer two-fluid nozzle into a glass chamber for drying the Mini Spray HO drying apparatus using approximately 50:50 of air and nitrogen as the drying gas. Gas inlet and outlet temperatures were 75 ° and 55 ° respectively. 14.1 g (70.5%) of an amorphous material containing 1.1% w / w acetone (GLC) was isolated. Impurities (by HPLC) 1.7% w / w including 0.2% w / w cef-2 compounds. Isomer ratio of 1.03: 1.

• e

J. (Nujol) similar to that shown in Figure I. / c ^ / _n ΓΠ3.Χ _ _ U (dioxane) + 35 °; E, (MeOH) 386. Solder

Example 3

A 15% acetone solution of cefuroxime axetil (about 1: 1 of the mixture of RiS isomers) was passed through a closed cycle spray dryer using nitrogen as a recycling gas and a rotating atomizer wheel rotating at 24,000 rpm. Gas inlet and outlet temperatures were respectively 105 ° and 70 °. The recycle gas is cooled to remove most of the evaporating acetone. The isolation of the amorphous product was 90% with acetone content of 1.0% w / w (GLC), water 0.7% w / w (Karl Fischer), HPLC impurity 1.3% w / w. The infrared (Nujol) (KBr plates) and nmr spectra (DMSO-άθ) are shown in Figures 1 and 2 respectively.

/ <Λ (dioxane) + 38 °? E * ^% (MeOH) 398.

D lem

Further examples 4 to 17 illustrating the preparation of amorphous cefuroxime axetil are given in the following table. The procedure of these examples is similar to Example 2. The Nujol infrared spectrum for each of the products shown is similar to the spectrum in Figure 1.

Nr. Solvent Therapist. entrance ° C Temp. Exit ° C . 4. Acetone / water 62 55 5. Industrial methylated spirit 80 70 6. Acetonitrile 72 63 7. Tetrahydrofuran 75 65 8. Methyl acetate 63 55 9. Chloroform (aqueous) 64 58 10. Acetone / water 70 50 11. Ethyl acetate / water 72 64 12. Methyl acetate / water 64 57 13. Methanol / water 67-70 55-59 14. Methanol / acetone 63 54 15. Ethanol / acetone 83 65 16. Acetone / methyl acetate 63 54 17. Acetone 85-90 75

Nr. Relationship isomers in the product Impurities (% m / m) / = (/ _D (dioxane) P ^1% solder (MeOH) 4. 1.05: 1 1.8 + 35 ° 390 5. 1.05: 1 1.9 + S6 ° . 386 6. 1.00: 1 1.6 + 35 ° 389 7. 1.04: 1 2.0 + 34 ° 384 8. 0.94: 1 1.3 + 35 ° 387 9. 1.02: 1 1.5 10. 1.05: 1 1.2 11. 1.02: 1 1.4 12. 0.98: 1 1.2 13. 1.04: 1 1.9 14. 1.03: 1 1.4 15. 1.02: 1 1.6 16. 1.02: 1 1.6 17. pure B 0.9 + 9 ° 387

Example 18

A solution of the purified crystalline cefuroxime l-acetoxyethyl ester (isomer A) (77 g) in acetone (1.8 liters) at 45 ° was spray-dried as in Example 2 through the nozzles of a two-fluid atomizer 2 with a nitrogen atomization pressure of 0.5 kg / cm. The gas inlet temperature was 85-90 ° and the outlet temperature was about 75 °. Product (39

g) had an acetone content of 0.15% w / w impurity determined by HPLC 2.8 2.8 w / w. Infrared (Nujol) confirmed the amorphous nature of the product. X-ray powder analysis showed several weak lines, which may indicate the presence of several crystals./et/ (dioxane) + 64 ° E * ^% (MeOH) 386.

D lem

Example 19

The mixture of RiS isomers of cefuroxime axetil (10 g) was dissolved in hot acetone (70 ml) and evaporated in vacuo to a foam. This was broken and dried overnight at 40 ° C to give 9.8 g of cefuroxime axetil confirmed by IR (Nujol) (which was similar to the spectrum in Figure 1) and microscopically examined as amorphous. The acetone content (GLC) was 2.9%. The impurities by HPLC were 3.4% w / w and the isomer ratio was 1.14: 1.

Following the above procedure, pure amorphous cefuroxime axetil was also obtained using IMS, methanol and ethyl acetate as solvent.

Example 20

A mixture of about 1: 1 isomer of the RiS cefuroxime axetil (5 g) was dissolved in key ethyl acetate (200 ml) and concentrated at atmospheric pressure to 70 ml. The solution was maintained hot and added dropwise over 27 minutes to petroleum ether (m.p. 60-80 °; 560 ml), which was quickly stirred and maintained at 3 °. (bp 60-80 ° C) and dried overnight in vacuo at 50 ° affording 4.5 g of amorphous cefuroxime axetil. Solvent Content (GLC)

0.25% w / w; / << / _β (1% in dioxane) + 39 °; (MeOH) 388. Microscopic examination confirmed the amorphous nature of the product.

Example 21

A mixture of 1: 1 isomers of R and S cefuroxime axetil (6 g) was dissolved in boiling dichloromethane (240 ml), allowed to cool and treated. The filtrate was distilled to a volume of 55 ml at atmospheric pressure and added dropwise over 42 minutes, di-isopropyl ether (195 ml), stirred rapidly and cooled to below 3 ° C. After the addition, the suspensions were stirred for a further 15 minutes, treated, washed with di-isopropyl ether (100 ml) and dried overnight in vacuo at 50 ° yielding 5.5 g of amorphous cefuroxime axetil. Microscopic studies showed that it had less than 1% crystalline material. / cZ / _D (1¾ dioxane) + 36 °, Ε ^ ζ ^ 387 (MeOH). Solvent content (GLC), 1%.

Example 22

Cold water was poured at a rate of 750 ml min into a 5 l plastic container fitted with a horizontal opening just below its upper edge. The water was stirred further with a blender-stirrer (600 rpm) while a stream of nitrogen was blown in at a rate of 12 1 min. 66 ml) was then added to a water vortex using a peristatic pump at constant speed for 13 minutes. The precipitated amorphous cefuroxime axetil was carried through a horizontal opening as foam and collected there. The amorphous cefuroxime axetil was immediately collected and dried to constant weight under vacuum at 55 ° to give 170 g of product. Solvent content (GLC) · ^ 0.01 m / m. Impurities by HPLC were 1.8%. The ratio of 1% isomer was 1.14: 1. / ol / T (1% dioxane) + 40; E (MeOH)> D lem

395. X-ray crystallography confirmed that the product was quite amorphous with low crystalline material content.

Example 23

About 1: 1 a mixture of isomers R and S of cefuroxime axetil (100 g) was dissolved by stirring in acetone (11) and heating at 40 °. The rollers of the drying apparatus were heated to 75 °, steam (pressure of two bars) was applied over the surface and a vacuum of 737 reigned in the apparatus. Using a roll rate of 1.75 rpm, the prepared solution of cefuroxime axetil was aspirated at a rate of about 200 ml / min. The product is an estrogen from rollers and 94% w / w was collected. The impurities determined by HPLC were 1.1% w / w.

The solvent content (GLC) was 1.6% w / w. Xzracima crystallography and the infrared (Nujol) spectrum showed that the material was amorphous. Nujol infrared was ₍ similar to the spectrum shown in Figure I).

Example 24

A solution of about 1: 1 mixture of the R and S isomers of cefuroxime axetil (10 g) in dioxane (100 ml) was freeze-dried to give a product (10.7 g) containing dioxane 5.5% w / w after passing through a 40 mesh sieve and drying in a vacuum oven at 50 ° for 20 h. The infrared (Nujol) spectrum was similar to the spectrum shown in Figure I. The infrared (Nujol) spectrum and microscopic tests confirmed the amorphous nature of the product. / <// _D (1% in diosane) + 37 °; E ^ (MeOH) 388.

^J 'lem

Example 25

A mixture of sodium cefuroxime (20 g) in dimethylacetamide (100 ml) was cooled to 14 ° and (RS) 1-acetoxyethyl bromide (10 ml) was added. The mixture was stirred at 14 ° for 45 minutes before anhydrous potassium carbonate (0.5 g) was added. After stirring for another 45 minutes, ethyl acetate (200 ml) and 3% sodium bicarbonate solution (200 ml) were added. The mixture was stirred at ambient temperature for 1 h and allowed to separate two phases. The aqueous layer was washed with ethyl acetate (100 ml) and the two organic layers were washed sequentially with M hydrochloric acid (100 ml) and 20% sodium chloride solution (30 ml). The combined organic layers were stirred with charcoal (2 g) for 30 minutes before filtration. The filtrate was concentrated in vacuo to 176 ml. Water (1.9 ml) was added to the concentrate, which was poured into mixed petroleum (60-80 °) (1.76 l) for 15 minutes.

The precipitated product was treated and washed with a mixture of petroleum (60-80 °) (105 ml) and ethyl acetate (12 ml) followed by petroleum (118 ml).

Drying at 40 ° in vacuo gave cefuroxime axetil 17.9 g: Solvents (GLC), ethyl acetate 1.6%, petroleum 1.5%, impurities by HPLC 4.1% w / w, isomer ratio 1.06: 1; (meOH) 364. The infrared spectrum in Nujol is typical of amorphous material.

Example 26 i

Acetone (2000 ml), water (324 inl) and * IMS (36 ml) were added with stirring into a balloon and then a 1: 1 mixture of the R and S isomers of cefuroxime axetil (600 g) was added. The balloon contents were heated to 42 ° C and stirred until the solid dissolved. The solution was cooled to 20 ° immediately before use.

Water (2000 ml) was added to the sedimentation vessel and stirred at 800 rpm. Nitrogen was introduced into the solution in the central part of the vortex produced by the stirrer at 10 1 min \

Water (850 ml / min) and cefuroxime axillary solution (115 ml / min) were added simultaneously to the turbulent zone of the settling apparatus. The upper stream from the precipitator is directed to a 125-mesh sieve where the product precipitates, in the form of sludge with an air content that is retained and the clear flowing fluid is discarded.

The precipitated product is collected on a sieve and transferred to a filter equipped with filter paper for further water abstraction. The stripped product was vacuum dried at 45 ° until the moisture content was reduced to below 1% in a yield of 410 g of cefuroxime axetil.

The infrared (Nujol) spectrum confirmed the amorphous nature of the product.

Pharmaceutical Examples

1. Tablet Composition

Cefuroxime axetil according to the invention

Starch 1500 (Colorcon, Inc.) (Pregelatinized starch)

Sodium Starch Glyconate Sodium Lauryl Sulfate

Polyethylene glycol 6000 (micronized)

Silica

Total weight

The way to get it

Polyethylene glycol, sodium lauryl sulfate, sodium starch glycolate and silica are passed through a 60 mesh sieve and mixed with a small amount of the active ingredient. This is then mixed with the starch and the rest of the ingredients and the tablets are prepared by direct compression. The lumps were broken through a 20 mesh sieve and the resulting granules were compressed using normal concave openings in 500 mg tablets.

The tablets can then be coated with a cellulose derivative film, plasticizers, staining fortunes and, if necessary, protecting the fortunes using aqueous or organic solvent methods.

As an alternative to the prior mixing step, the mixture may be compacted by rolling or may be compressed directly into tablets.

mg / tablet

300.00 (equivalent to 250 mg cefuroxime)

161.5

20.0

10.0

7.5

1.0

500.0 mg / capsule

300.00 (equivalent to 250 mg cefuroxime) 24.75.

4.0

9.0

1.25

2. Capsules

Composition

Cefuroxime axetil according to the invention

Microcrystalline cellulose Hydrogenated vegetable oil Sodium Lauryl Sulfate Silica

The way to get it

The active ingredient is thickened by rolling with a roller and then passed through a sieve of 20 meshes, then of 30 meshes and then of 60 meats. The remaining ingredients are passed through a 60 mesh sieve along with a small amount of the active ingredient and then mixed with the rest of the active ingredient.

The mixture was then filled into 0 hard gelatin capsules so that the weight was 339 mg.

3. Powder for oral suspension (in bags)

Composition (per bag)

Cefuroxime axetil according to the invention 300 mg Sodium lauryl sulfate 25 mg Hydroxypropyl methyl cellulose 90 mg Dried orange-scented agent 150 mg castor sugar to 2220 mg

The way to get it

Sodium lauryl sulfate, hydroxypropyl methyl cellulose and flavoring agent were triturated with the active ingredient. This mixture was further mixed with castor sugar, the latter being added in two stages. The correct weight can then be filled into suitable containers, e.g. the bags of suitably laminated foil are closed by warming them. Before use, the powder is constituted by adding about 15 ml of water immediately before administration.

4. Oil suspension

Composition (for 5 ml dose)

Cefuroxime axetil according to the invention Lecithin

Butylhydroxybenzoate

Aluminum monostearate

Aluminum distearate

Hydrogenated Castor Oil Liquid Flavor for Sugar Glaze Sugar Sodium Chloride Fractionated Coconut Oil

300 mg 35 mg mg 25 mg 25 mg

17.5 mg 25 mg

1,500 mg

2.5 mg to 5 ml

The way to get it

A portion of the coconut oil is heated, then lecithin, butylhydroxybenzoate, aluminum stearate, hydrogenated castor oil, glaze sugar and sodium chloride are added to this oil with stirring.

The mixture was cooled and cefuroxime axetil or happiness was added to improve the taste. The rest of the required coconut oil is then added and the preparation is stirred and purified.

Claims (12)

A process for the preparation of a highly pure, amorphous form of cefuroxime axetil, wherein a solution of cefuroxime axetil is prepared in an organic solvent or in a homogeneous mixture of organic solvents or in a homogeneous mixture of one or more organic solvents and water and a highly pure, amorphous form, cefuroxime axetil isolates from this solution rapidly by removing the solvent - or precipitating with the aid of the solvent. ^? '............... -..... The method of claim 1, wherein the product contains less than 5% w / w impurities. 3. The process according to claim 2, wherein the product is substantially free of crystalline material. The process according to any of claims 1-3, wherein the solution comprises an organic solvent selected from ketones, alcohols, acetonitrile, tetrahydrofuran, dioxane, esters, · chlorinated solvents, homogeneous mixtures of at least two of the aforementioned solvents and homogeneous mixtures of at least one of the solvents and water mentioned above. 5. A process according to any one of claims 1-4, wherein the concentration of the ester in the solution prior to isolation is at least 1% w / w. The method according to any of claims 1-4, wherein the concentration of the ester in the solution prior to isolation is at least 10% w / w. The method of any one of claims 1-6, wherein the product is a mixture of R and S isomers wherein the ratio of R to S isomers is from 0.9: 1 to 1.1: 1. 8. The method according to claim 1, wherein the isolation is spray dried. 9. The method of claim 8, wherein spray drying is carried out in the presence of an inert drying gas. The method of claim 8 or 9, wherein the product has a consistent particle size range and is in the form of microsphere cavities. A method according to any one of claims 1-7, characterized in that the insulation is carried out by drying with rollers. A method according to any one of claims 1-7, characterized in that the isolation is performed by freeze-drying.