前苏联专利SU1266471A3 Method of producing cephuroxymaxethyl in amorphous state

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专利摘要:
There is described a product which is a highly pure substantially amorphous form of cefuroxime axetil (cefuroxime 1-acetoxyethyl ester) which is stable, which has increased absorption via the gastro-intestinal tract and has a correspondingly high level of bioavailability on oral or rectal administration. Methods of preparing the product are also described which involve the recovery of the product from a solution thereof. A preferred method is the use of spray drying techniques, though roller drying, solvent precipitation or freeze-drying are also described. Also disclosed are pharmaceutical compositions containing the product and methods for its use in medicine.
公开号:SU1266471A3
申请号:SU833624504
申请日:1983-07-29
公开日:1986-10-23
发明作者:Альфред Крипс Гарольд；Чарльз Клейтон Джон；Годфри Эллиотт Леонард；Маккензи Вильсон Эдвард
申请人:Глэксо Груп Лимитед (Фирма)；
IPC主号:

专利说明:

2. The method according to claim 1, which is an organic solvent selected from the group comprising acetone, acetonitrile, tetrahydrofuran, dioxane, alcohol, ester and chlorohydrocarbon, or their homogeneous mixture, or its homogeneous mixture with water.
3. Method according to paragraphs. 1 and 2, of which they are obtained by the fact that they get the amorphous form of cefuroxime axetil
in the form of a mixture of R-and-S-isomers with a ratio of R-and S-isomers (0.9-1.1):
4. Method according to paragraphs. 1-3, characterized in that it is spray dried. .
5. A method according to claim 4, wherein the spray dryer is carried out in the presence of an inert gas, such as nitrogen,
6. Method according to paragraphs. 1-3, characterized in that they are dried on a roller.
7. Method according to paragraphs. 1-3, characterized in that they are freeze-dried.
8. Method according to paragraphs. 1-3, characterized in that they are dried by solvent precipitation.
one
This invention relates to the preparation of a new structural form of a cephalosporin antibiotic, namely the amorphous form of cefuroxime axetil - 1-acetoxyethyl ether (6R, 7K) -3-carbamoyloxymethyl-7 (g) -2- (furyl-2) -2-methoxyimoacetamido cef-3-em-4-carboxylic acid with activity against gram-positive and gram-negative microorganisms.
V
The purpose of the invention is to obtain a new amorphous form of cefuroxime axethyl, which has a higher efficiency and higher adsorption capacity.
Using syntheses 1 and 2, starting materials are obtained.
Synthesis 1. Cefuroxime sodium, Chlorosulfonyl isocyanate (226 ml) is added to a solution of triethylamine (10 ml) in methyl acetate (l). The resulting clear solution is cooled to -15 ° C and a suspension is added (10R , 7K) -3-hydroxymethyl-7- (2) -2- (fur-2-yl) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid (763 g) in methyl acetate (2.3 l), pre-cooled to -15 ° C. The residual solid is rinsed with methyl acetate (700 ml). The mixture was stirred at -5 ° C for 30 minutes, and after 10 minutes a clear solution was obtained.
Water (1.2 L) is quickly added to the reaction mixture at 8 ° C and the temperature quickly rises to 10 ° C, and then slowly to 17 ° C. The mixture is stirred for 60 minutes at 15 ° C.
to obtain a thick white suspension. Methyl acetate (3.6 L) is added, followed by the gradual addition of sodium hydroxide solution (288 g)
in water (5.2 l). This gives a clear two-phase mixture at 26 ° C, having
pH 2.35. one
The layers are separated and the upper organic layer is washed with a solution of sodium chloride (600 g) in water (2 L). The two aqueous layers are successively washed with methyl acetate (2 L). The organic layers are poured into a single mass,
mixed with charcoal brand Norit SX Plus (76 g) for 30 min and filtered through a layer of product Nayflo-Supersel, and the layer is washed with methyl acetate (1.5 l).
The filtrate and washings are combined and stirred at 20 ° C while delivering a solution of sodium 2-ethylhexanoate (338 g) in a mixture of methyl acetate (2 l) and water over 20 minutes.
(40 ml) with a white suspension having a pH of 5.5. The suspension is stirred for 10 minutes and filtered, the filter cake is washed with methyl acetate (5-1 L), sucked to dryness and dried at 30 g in vacuum for 24 hours to obtain cefuroxime sodium (851.9 g) J + 60, (with 0.5, 0.1 M, pH4, buffer); L aacc () 273 nm; () impurities 2.0% according to high pressure liquid chromatography (HPLC). Synthesis 2. Crystalline tsefuro sim-axetil. (K5) -1-Acetoxyethyl bromide (12.5 g is added to the stirred mixture of cefuroxime-sodium (20 g) in dimethylacetamide (110 ml) at 0 ° C. The mixture is stirred at +1 for 90 minutes and potassium carbonate ( 0.5 g). Stirring is continued for 2 hours at 1-3 ° C. Lri adding the reaction mixture to a vigorously stirred mixture of ethyl acetate (200 ml) and aqueous 3% bicarbonate sodium (200 ml) to destroy possible excess 1- acetoxyethyl bromide. After 1 h, the organic layer (1.5% D-isomer according to HPLC) is separated, washed with normal (n) hydrochloric acid 100 ml of sodium bicarbonate (30 ml). All three aqueous phases are successively washed with ethyl acetate (100 ml). The combined organic extracts are mixed for 30 minutes with charcoal ( Norit brand SX Plus, 2 g) is filtered through a bed of diatomaceous earth, which is washed with ethyl acetate (225 ml) .. The combined filtrate and washings are evaporated in vacuo to 150 g and stirred at ambient temperature for 1 hour until stable crystallization is established. Diisopropyl ether (250 ml) is added over 45 minutes to complete the crystallization and stirring is continued for another 1 hour. The product is collected by filtration, washed with (2: 1) diisopropyl ether and ethyl acetate (150 ml) and dried for 2 days in vacuo at 50 ° C to obtain crystalline cefuroxime axetil (19.3). The solvent content (GLC) 0.2 wt.%; impurities (HPLC) 1.8%; the ratio between isomers. (HPLC) 1.09: 1; o6 f (l% in dioxane) + Ef (278 mm, MeOH) 389. Individual R- and S-isomers of 1-acetoxyethyl zefira cefuroxy 714 mA are designated as A and B (the names of isomers A and B are not established). The values given for E and are not adjusted for solvent content. Example 1. A 10% (May / vol.) Acetone solution of a mixture of R- and S-isomers of cefuroxime-axetil is passed through a Niro Mobile Minor Spray Dryer apparatus (Microspray dryer) manufactured by Niro-Copenhagen, Dani, using air in the quality of the drying gas and the rotating atomizer at a speed of about 35,000 rpm. The temperatures at the gas inlet and outlet are 124 and 70 ° C, respectively. 75% by weight of the spray-dried product is recovered. The microscopic appearance of the product is typical of spray-dried products (hollow spheres). An HPLC analysis revealed that 97% by weight of the product and 2.0% by weight of impurities were converted to dry matter, taking into account the measured solvent content of 0.15% by weight (GLC), and a water content of 0.8% by weight (device firm Karl Fischer). The ratio of isomers of 1.04: 1 (ghvd). IR spectrum (nujol): max 34803210 (NH, NH -complex), 1782 (fJ-lactam), 1760 (acetate), 1720 (4 ester group), 1720 and 1594 (carbamate), 1676 and 1534 cm (7-amido ); MD (dioxane) + 38 (MeOH) 398. X-ray analysis of powder in a 0.3 mm capillary with the eb-Scherer method in a chamber with a diameter of 114.6 mm during exposure for 3 hours by emitting CuK gives a simple halo (no crystals that confirms the amorphous nature of the product). Example 2. A mixture of the R and S isoers of cefuroxime axetil (20.25 g) is dissolved in acetone (200 ml) at ambient temperature. The solution is clarified by passing through the baked glass and pumped through the aspirating nozzle for the two fluids using nitrogen under a pressure of 1 kg / cm as a sizing medium into a glass drying spray and drying apparatus of the Mini-Spray BUT type using a mixture of air and nitrogen (1: 1) as a drying gas. The gas temperatures at the inlet and outlet are respectively 75 and 55 ° C. 14.1 g (70.5%) of amorphous material is obtained, containing 1.1% by weight of acetone. (GLC) .. Impurities (according to HPLC) 1.7 masl, including 0.2 wt.% Cel-2em-av Ineni. The ratio of isomers of 1.03: 1.
IR spectrum (nudzhol) is similar to the one shown on the drawing; cijj, (diocoan) + 35 ° i ЕJ (Meon) 386.
Example 3. A 15% acetone solution of cefuroxime axetil (1: 1 mixture of R- and C-isomers) is passed through a closed-cycle spray dryer using nitrogen as the recirculation gas and a rotating nebulizer on skimmetilirovanny
80 72 alcohol
Acetonitrile
75
Tetrahydrofuran 63 Methyl acetate
Chloroform (anhydrous)
64 70 72
Acetone / water / Ethyl acetate / water
Methyl acetate / water 64
Methanol / water67-70
Methanol / Acetone63
Ethanol / acetone83
Acetone / methyl acetate63
Acetone85-90
ti 24,000 rpm The inlet and outlet gas temperatures are respectively 105 and 70 ° C. The recirculated gas is cooled to remove the bulk of the evaporated acetone. The degree of recovery of the amorphous product is 90% with an acetone content of 1.0% by weight (GLC) and water of 0.7% by weight (Karl Fischer device), an impurity level of 1.3% by weight (HPLC).
The IR spectrum (nudzhol) (plates of CB g) is shown in the drawing .ot (dioxane) + 38 °; E, (Meon) 398.
Examples 4-17. Getting
amorphous cefuroxime axetil The data are presented in table. 1. The methods of these examples are similar to those of example 2. The IR spectra (nujol) of each of the products are similar to those shown in the drawing.
Table 1
70 63
65 55
54 75
1.02: 1 1.6 Pure B 0.9 +9
387 Example 18. A solution of purified crystalline cefuroxime 1-acetoxyethyl ester (isomer A) (77 g) in acetone (1.8 l) at 45 ° C is spray dried according to the method of example 2 through a spray nozzle for two fluids spraying nitrogen 0.5 kg / cm. The gas temperature at the inlet is 85–90 ° C, and at the outset it is about 75 ° C. The product (39 g) has an acetone content of 0.15 wt.% And impurities (according to HPLC) 2.8 wt.%. The infrared spectrum (nudzhol) confirms the amorphous nature of the product. X-ray powder analysis gives several low-luminous lines, which indicate the presence of a few numbered crystals. “Jn (EE; (MeOH) 386. San) +64; Example 19. A mixture of R- and S-from measures of cefuroxime axetil (10 g) is dissolved in hot acetone (70 ml and evaporated in vacuo to a foam-like product. It is destroyed and dried overnight in vacuum at 40 ° C to obtain 9.8 g of cefuroxime axetil According to the IR spectrum (nujol) (similar to that shown in the drawing) and microscopic examination of the amorphous product, the acetone content (gax) is 2.9%, the impurity content (according to HPLC) is 3.4 wt. %, and the ratio of isomers of 1.14: 1. Using the above method, pure amorphous cefuroxime-axetil was also obtained using as solvents for IME, methanol and ethyl acetate. Example 20. A mixture of R- and S-measures of cefuroxime axetil (5 g) taken 1: 1, dissolved in boiling ethyl acetate (200 ml) and concentrated at atmospheric pressure to 70 ml The solution is kept hot by the Scientific Research Institute and added dropwise over 27 minutes to intensively mixed petroleum ether (so kip. 6080 ° Ci 560 ml), the temperature of which is maintained below 3 ° C. After the addition, the suspension is stirred for another 10 minutes filtered, carried out forcing washing with petroleum ether (so kip. 60-80 C) and dried overnight in vacuum at 50 ° C to obtain 4.5 g of amorphous cefuroxime axetil Solvent content (GLC) 0.25 wt. (% in dioxane) (MeOH) 388. Microscopic examination confirms the amorphous nature of the product. Example 21 A mixture of the R and S isomers of cefuroxime axetil (6 g) taken 1: 1 was dissolved in boiling dichloromethane (240 ml), allowed to cool and filtered. The filtrate is rectified to a volume of 55 ml at atmospheric pressure and added dropwise over 42 minutes to the vigorously stirred diisopropyl ether (195 ml) cooled below 3 ° C. After the addition, the suspension is stirred for another 5 minutes, filtered, washed with diisopropyl ether ( 100 ml) and dried overnight in vacuo at 50 ° C to obtain 5.5 g of amorphous cefuroxime axetil. Microscopic examination reveals the presence of less than 1% crystalline material, fut (1% in dioxane) + 36 ° -, 387 (MeOH). Content of Solvent (GLC) 1 /. Example 22. Cold water is fed at a rate of 750 ml / min to a 5-liter plastic cup, provided with a horizontal gap immediately below its top edge. The water is additionally stirred using a paddle stirrer (600 rpm) while simultaneously bubbling a stream of nitrogen at a flow rate of 12 l / min. A solution of a mixture of the R- and S-isomers of cefuroxime axetil (200 g), dissolved in warm (45 ° C) mixture of acetone (600 ml) and water (66 ml) and added using a peristaltic pump at a constant flow rate for 13 minutes into the funnel formed water. The precipitated amorphous cefuroxime axetil is transferred through a horizontal slit in the form of a foam and collected. The amorphous cefuroxime axetil product is immediately collected and dried to constant weight under vacuum at 55 ° C to obtain 170 g of product. The solvent content (GLC) is less than 0.01 wt.%, Impurities (according to HVD) 1.8%; the ratio of isomers 1, J4: 1-, (1% in dioxane) + j; (MeOH) 395. X-ray data "1 O / l, lg1 OLS of crystal crystallographic evidence of significant amorphism of the product in the presence of a small amount of crystalline material. Example 23. A mixture of R- and S-isomers of cefuroximexetil (100 g), taken 1: 1, is dissolved with stirring in acetone (1 l) and heated to 40 C. The rollers of the drying apparatus are heated to 75 ° C. , steam is passed through the casing (pressure 2 bar) and a vacuum of 737 mm Hg is created in the apparatus. Under conditions of the rotation speed of rollers of 175 rpm, the prepared solution of cefuroxime axetil is sucked in at a rate of about 200 ml / min. The product is removed by squeegee from the rollers and collected with a recovery rate of 94% by weight. For mesas (according to HPLC) 1.1. Mac.% J solvent content (GLC) 1,6 mas. X-ray crystallography and IR spectra (nujol) indicate that the material is amorphous. The infrared spectrum in noujol is similar to that shown in the drawing. Example 24. A solution of a mixture of R- and S-isomers of cefuroxime axetil (10 g), taken 1: 1, in dioxane (100 ml) is freeze-dried to obtain a product (10.7 g) which contains 5.5 wt; % dioxane after sieving on a 40 mesh screen (hole diameter 0.21 mm) and drying in an oven under vacuum at 50 ° C for 20 hours. The IR spectrum (nujol) is similar to that shown in the drawing. The data of IR spectroscopy and microscopic examination confirm the amorphous nature of the product, "c (1% in dioxane) + 37 °; (MeOH) 388. Example 25. A suspension of cefuroxime sodium (20 g) in dimethylacetamide (100 ml) is cooled to 14 ° C. and (RS) 1-acetoxyethyl bromide (10 ml) is added. The mixture is stirred at 45 minutes before adding anhydrous potassium carbonate (0.5 g). After stirring for an additional 45 minutes, ethyl diadetate (200 ml) and 3% sodium bicarbonate solution (200 ml) are added. The mixture is stirred at ambient temperature for 1 hour and the two phases are allowed to separate. The aqueous layer was washed with ethyl acetate (100 ml). Then the two organic layers were successively washed with 1 M hydrochloric acid (100 ml) and 20% sodium chloride solution (30 ml). The combined organic layers are mixed with charcoal (2 g) for 30 minutes before filtering. The filtrate is concentrated in vacuo to 176 ml. Water (, 9 ml) is added to the concentrate and everything is poured into stirred gasoline (so kip. 60-80 ° C) (1; 76 l) for 15 minutes. The precipitated product is filtered and washed with a mixture of gasoline (105 ml) and ethyl acetate (12 ml), and then more. once gasoline (118 ml). After drying under vacuum at 40 ° C., cefuroxime axetil (17.9 g) is obtained. Solvents (GLC): ethyl acetate 1.6%, gasoline 1.5%} impurities (HPLC) 4,.% Isomer ratio 1.06: 1 (MeOH) 364. The IR spectrum (nujol) is typical of an amorphous material. Example 26. Acetone (2000 ml), water (324 ml) and IMA (36 ml) were added to the flask with stirring, followed by the addition of 600 g of a mixture of R- and S-isomers of cefuroxime axetil, taken 1: 1. The contents of the flask are heated to 42 ° C and stirred until the solid is dissolved. Immediately before use, the solution is cooled to 20 ° C. B. A precipitation vessel is added water (2000 ml) and stirred at 800 rpm. Nitrogen is fed into the solution in the center of the funnel created by the stirrer at a rate of 10 l / min. Water (850 ml / min) and a solution of cefuroxime axetil (115 ml / min) are added simultaneously to the zone of the turbulent flow in the precipitator. The overflow from the precipitator is directed to a sieve with a hole size of 125 µm, where the precipitated product in the form of an aerated suspension is retained, and the transparent solutions passing through it are directed to the ejection. The precipitated product collected on the sieve is transferred to a filter, on which filter paper is provided for further dehydration. The dehydrated product is dried in vacuum at 45 ° C until the moisture content is below 1%. 410 g of cefuroxime axetil are obtained. The IR spectrum (nudzhol) confirms the essentially amorphous nature of the product. Preparing a few pharmaceuticals. Tablets Composition per tablet Cefuroxime 300, 00 (equivalent to 250 mg (cefuroxime) P starch. 1500 (Kolorkon company) (pregelatinized. Starch) 161.5 Sodium starch glycol 20.0 Sodium lauryl sulfate 10.0 Polyethylene glycol 6000 (micronized)). 5 Silicon Dioxide 1, O Total Weight 500.0 Preparation Method: Polyethylene glycol, sodium lauryl sulfate, sodium starch alkylate and silicon dioxide are passed through a 60 mesh black sieve (0.25 mm hole size) and mixed with a small amount of the active ingredient. Then all this is mixed with starch and osta Pill sheets are crushed, passed through a 20-mesh sieve (0.8 mm hole times), and the resulting granules are compressed using normal concave punches to form tablets of 500 mg. then a film of cellulose derivatives can be added, with the addition of plasticizers, coloring agents and preservatives, if necessary, using methods of application from aqueous or organic solvents. As an alternative to the preliminary stage of preparing the harvesting sheet, the mixture can be compacted with rolls or the mixture can be immediately pressed into tablets. Capsules Ingredients mg per capsule Cefuroxime 300, 00 (equivalent to 250 mg cefuroxime)
Microcrystalline cel24, 75 lulose
Composition
(per dose S ml)
Amount, mg 71 Hydrated vegetable oil 4.0 Sodium lauryl sulfate 9.0 Silica 1.25 Preparation procedure. The active ingredient is sealed with a roller, and then passed through a sieve, a follower. but, 20, 30, and 60 mesh (hole size 0.8, 0.5, and 0.25 mm). 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. After this, the mixture is filled into hard gelatin capsules with a weight of 339 mg. Powder for oral suspension (in sachet) Composition (per Amount, mg Cefuroxime Axetil Sodium Lauryl Sulfate Hydroxypropyl-methyl Cellulose Orange spray extract 150 Cachevial Up to 2220 Preparation Method. Sodium Lauryl Sulfate, Hydroxypropyl Methyl Cellulose and Gust-Free Sulfur Gel, Hydroxypropyl Methyl Cellulose and Gust, Chlorosulphate, Sodium Lauryl Sulfate, Hydroxypropyl Methyl Glucose; with a castor-bean achar, adding the latter in two tadias. The exact weight can be then filled into a suitable container, for example, a sachet from a suitable laminated foil, and germs Etizirovana accident. Before use, the powder is diluted by adding approximately 15 ml of water shortly before taking. Suspension in oil

权利要求:
Claims (8)
[1]
1. METHOD FOR PRODUCING AN AMORPHIC FORM OF CEFUROXYM-ACHETYL containing not more than May 5, 2 impurities in the form of the R or S isomer or a mixture of R and S isomers, characterized in that the corresponding isomer of cefuroxime axetil in crystalline form is dissolved in organic solvent or in a homogeneous mixture of organic solvents, or in a homogeneous mixture of an organic solvent with water and the resulting solution with a concentration of cefuroxime-axetil of 1-30mA.Z is dried or the solvent is removed from it by extrusion with the removal of the desired product.
Apina Falls
SU <„, 1266471 AZ
12664 !
[2]
2. The method according to π. 1, with the fact that they use an organic solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dioxane, alcohol, ester and chlorocarbon, or a homogeneous mixture thereof, or its homogeneous mixture with water.
[3]
3. The method according to PP. 1 and 2, about t l and -
In particular, the amorphous form of cefuroxime axetil is obtained in the form of a mixture of R- and · S-isomers with a ratio of R-and S-isomers (0.9-1.1): 1.
[4]
4. The method according to PP. 1-3, characterized in that carry out spray drying.
[5]
5. The method according to p. 4, characterized in that the spray drying is carried out in the presence of an inert gas such as nitrogen.
[6]
6. The method according to PP. 1-3, characterized in that carry out drying on a roller.
[7]
7. The method according to PP. 1-3, characterized in that carry out freeze-drying.
[8]
8. The method according to PP. 1-3, characterized in that carry out drying by precipitation of the solvent.!

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引用文献:

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YU44680B|1982-07-30|1990-12-31|Glaxo Lab Ltd|Process for obtaining very pure amorphous form of cephuroxim axetile|YU44680B|1982-07-30|1990-12-31|Glaxo Lab Ltd|Process for obtaining very pure amorphous form of cephuroxim axetile|

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GB8320520D0|1983-07-29|1983-09-01|Glaxo Group Ltd|Chemical process|

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GB8222019|1982-07-30|

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