WO2017140074A1 - Cefmenoxime hydrochloride new crystalline form and formulation - Google Patents

Abstract

Disclosed are a cefmenoxime hydrochloride new crystalline compound and crystallization preparation method thereof; said cefmenoxime hydrochloride new crystalline compound is formed using particle processing for molecular assembly and morphological optimization of a crystalline product. The present compound has the features of high purity, good fluidity, and good stability. Also disclosed is a formulation -- cefmenoxime hydrochloride used for injection -- fabricated using the described cefmenoxime hydrochloride compound.

Description

[Name of invention established by ISA according to Rule 37.2] New crystal form and preparation of cefmenoxime hydrochloride Technical field

The invention belongs to the field of medical technology, and particularly relates to a novel crystalline form compound and preparation of cefmenoxime hydrochloride using molecular assembly and morphology optimization technology of particle process crystal products.

Background technique

Cefmenoxime hydrochloride, its chemical name is: (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-[[ 1-methyl-1H-tetrazol-5-yl)-sulfo]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-A Acid hydrochloride (2:1), molecular formula: C ₁₆ H ₁₇ N ₉ O ₅ S ₃ ·1/2HC1, molecular weight: 529.79, structural formula:

Cefmenoxime Hydrochloride is a third-generation cephalosporin developed by Takeda, Japan. It was first introduced in Japan in 1983 and is a broad-spectrum antibiotic that achieves bactericidal action by inhibiting the biosynthesis of bacterial cell walls.

Regarding the synthesis method of cefmenoxime hydrochloride, according to reports in the literature, 7-ACA is mainly used as a raw material, (1) condensation is carried out at the 3rd position, and condensation is carried out at the 7th position; (2) condensation at the 7th position and condensation at the 3 position. At present, cefmenoxime hydrochloride prepared by the above method on the market has poor purity, poor color grade and poor stability, thereby affecting the quality of the preparation.

The conventional crystal form of cefmenoxime hydrochloride has poor stability and is unstable to heat, acid environment and alkaline environment. It is characterized by easy discoloration, reduced content and degradation products. To solve this problem, it is necessary to develop a new crystallization production technology to optimize process parameters such as solvent, temperature, reaction time, additives, etc., so that crystallization can be carried out under suitable conditions to ensure product quality.

The invention mainly aims at the above problems of cefmenoxime hydrochloride, and on the basis of sufficient investigation of factors such as solvent, temperature, external force and additives in the crystal formation process, the molecular assembly and morphology optimization technology of the particle process crystal product obtains a high purity. , good color grade, good fluidity, good stability, cefmenoxime hydrochloride The new crystal form compound, the synthesis step is more focused on the control of the reagents and parameters in the synthesis process than the previous preparation process, the steps are simple, the raw materials used are all cheap, non-toxic or low-toxic products, and are suitable for industrial scale production. Formulations made using the compounds described in the present invention have better stability than previous formulations.

Summary of the invention

A first object of the present invention is to provide a novel crystalline form of cefmenoxime hydrochloride, which is prepared by molecular assembly and morphology optimization technology of a particle process crystal product, and has the characteristics of high purity, good color grade and good stability.

The new crystalline form of cefmenoxime hydrochloride according to the present invention is determined by X-ray powder diffraction, and the X-ray powder diffraction pattern represented by the 2θ diffraction angle is 6.25°±0.2°, 13.04°±0.2°, 14.31°±0.2°, 17.21°±0.2°, 18.18°±0.2°, 19.95°±0.2°, 22.77°±0.2°, 23.76°±0.2°, 25.88°±0.2°, 29.19°±0.2°, showing characteristic diffraction peaks, as shown in the attached drawing 1 is shown.

The preparation of the new crystalline form of cefmenoxime hydrochloride according to the present invention comprises the following steps:

(1) Dichloromethane, ethanol, (6R,7R)-7-amino-3-[[(1-methyl-1-H-tetrazol-5-yl)thio]methyl]-8 -Oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid hydrochloride (7-ATCA·HCl) and triethylamine mixed reaction, added 2 -(2-Amino-4-thiazolyl)-2-(methoxyimino)acetic acid thiobenzothiazolyl ester (AE active ester), water extraction, combined with aqueous phase, decolorization of activated carbon, collection of filtrate, pH adjustment with hydrochloric acid The value, filtration, washing, and vacuum drying gave crude cefmenoxime hydrochloride.

(2) Dissolve the crude cefmenoxime hydrochloride in water, slowly add the alkali solution, stir the reaction, adjust the pH, decolorize the activated carbon, filter, and collect the filtrate. The filter droplets are added to a mixed solution of acetone, purified water and concentrated hydrochloric acid, the reaction is finished, the activated carbon is decolorized, filtered, and the NaHCO ₃ solution and water for injection are added to the filtrate, and the crystals are stirred, filtered, washed, and dried to obtain refined cefmen hydrochloride. Hey.

Preferably, in the above preparation method, the weight ratio of the 7-ATCA·HCl to the AE active ester is 1:1 to 1:3. More preferably, the weight ratio is 1:2.

Preferably, in the above preparation method, the hydrochloric acid concentration in the step (1) is 5-8 mol/L. More preferably, the hydrochloric acid concentration is 6 mol/L.

Preferably, in the above preparation method, the hydrochloric acid adjusted pH in the step (1) is 1-3. More preferably, the pH is 2.5.

Preferably, in the above preparation method, the alkali liquid described in the step (2) is an aqueous solution of 8 to 12% sodium hydrogencarbonate. More preferably, the lye is a 10% aqueous solution of sodium hydrogencarbonate.

Preferably, in the above preparation method, the lye adjusted pH in the step (2) is 6-8. More preferably, the pH is 7.0.

Preferably, in the above preparation method, the crystal growth time in the step (2) is 2 to 4 hours. More preferably, the crystal growth time is from 3 to 3.5 hours.

A second object of the present invention is to provide a cefmenoxime hydrochloride pharmaceutical composition comprising the novel crystalline form of cefmenoxime hydrochloride of the present invention, which is simple in operation and has better stability than the prior products. The side effects are small.

The cefmenoxime hydrochloride pharmaceutical composition of the present invention comprises, by weight fractions, the following components by weight: 40-80 parts of cefmenoxime hydrochloride (calcium cefprozil) and 20-60 parts of sodium hydrogencarbonate.

DRAWINGS

Fig. 1: X-ray powder diffraction pattern of a new crystalline form of cefmenoxime hydrochloride, and the 2θ values corresponding to the diffraction peak numbers in the figure are shown in Table 1.

detailed description

The invention is further illustrated by the following detailed description of the invention, but is not intended to limit the invention to the scope of the embodiments, and those skilled in the art It is still within the scope of protection of the present invention.

Example 1: Preparation of a new crystalline form of cefmenoxime hydrochloride

(1) 250 ml of dichloromethane, 25 ml of ethanol, and (6R,7R)-7-amino-3-[[(1-methyl-1-H-tetrazol-5-yl)sulfide were sequentially added to the reaction flask. Generation] methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid hydrochloride (7-ATCA·HCl) 25 g, 20 ml of triethylamine, reacted at room temperature for 30 min, then added 2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid thiobenzothiazyl ester (AE active ester) 50.0 g, suitable for control The temperature was reacted for 8 h, extracted with water for 2 times, 150 ml each time, the aqueous phase was combined, decolorized by activated carbon at room temperature, filtered, and the carbon layer was washed with ethanol, and the washings were combined, adjusted to pH with 6 mol/L hydrochloric acid to 1.5, maintained for 3 h, filtered. The filtrate was washed with water and dried under vacuum at 40 ° C to obtain crude cefmenoxime hydrochloride.

(2) Add 25.9g of crude cefmenoxime hydrochloride and 230ml of water to the reaction flask, stir for 30min, slowly add 10% sodium bicarbonate solution, adjust the pH value of the solution to 6.5-7.0, stir the reaction at room temperature for 30min, 0.5g The activated carbon was decolorized for 10 min, filtered, washed with ice water, and the filtrate was combined. The filtrate was added to a mixed solution of 50 ml of acetone, 100 ml of purified water and 25 ml of concentrated hydrochloric acid. The reaction was completed, 0.5 g of activated carbon was added for 10 min, filtered, and 10% of the filtrate was added. Sodium bicarbonate solution, stirred for 3.5h, filtered, washed with ethanol 2 times, 50 ml each time, and dried under vacuum at 40 ° C to obtain purified cefmenoxime hydrochloride.

X-ray powder diffraction (XRPD) was used to study and characterize the new crystalline form of cefmenoxime hydrochloride.

Equipment: EMPYREAN X-ray diffractometer (Panalytical, the Netherlands).

The X-ray powder diffraction pattern of the product of Example 1 showed characteristic diffraction peaks at 6.25, 13.04, 14.31, 17.21, 18.18, 19.95, 22.77, 23.76, 25.88, 29.19. See Figure 1 of the specification for details.

The specific data of the XRPD diffraction is shown in the following table:

Table 1 Cefmenoxime hydrochloride crystal form

Numbering	d value	2θ(°)	I/I 0 %
1	14.13	6.25	54.15
2	6.79	13.04	26.06
3	6.19	14.31	65.95
4	5.15	17.21	21.99
5	4.88	18.18	96.81
6	4.45	19.95	22.17
7	3.91	22.77	100.00
8	3.74	23.76	31.26
9	3.44	25.88	13.91
10	3.06	29.19	16.74

Example 2: Preparation of a new crystalline form of cefmenoxime hydrochloride

(1) 250 ml of dichloromethane, 25 ml of ethanol, and (6R,7R)-7-amino-3-[[(1-methyl-1-H-tetrazol-5-yl)sulfide were sequentially added to the reaction flask. Generation] methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid hydrochloride (7-ATCA·HCl) 25 g, 20 ml of triethylamine, reacted at room temperature for 30 min, then added 25.0 g of 2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid thiobenzothiazyl ester (AE active ester), suitable for control The reaction was carried out for 8 hours, and extracted with water for 2 times, 150 ml each time. The aqueous phase was combined, decolorized by activated carbon at room temperature, filtered, and the carbon layer was washed with ethanol, and the washings were combined. The pH was adjusted to 2.0 with 8 mol/L hydrochloric acid, and the crystal was maintained for 3 hours. The filtrate was washed with water and dried under vacuum at 40 ° C to obtain crude cefmenoxime hydrochloride.

(2) Add 25.1 g of crude cefmenoxime hydrochloride and 230 ml of water to the reaction flask, stir for 30 min, slowly add 10% sodium bicarbonate solution, adjust the pH value of the solution to 6.7-6.9, and stir the reaction at room temperature for 30 min. After decolorization by 0.5g activated carbon for 10min, filtration, washing with ice water, the filtrate was combined, and the filtrate was added into a mixed solution of acetone 50ml, purified water 100ml and concentrated hydrochloric acid 25ml. The reaction was finished, 0.5g of activated carbon was added for decolorization for 10min, filtered, and the filtrate was added. 10% sodium bicarbonate solution, stirred for 2.5 h, filtered, washed twice with ethanol, 50 ml each time, and dried under vacuum at 40 ° C to obtain purified cefmenoxime hydrochloride.

The X-ray powder diffraction pattern of the product of Example 2 showed characteristic diffraction peaks at 6.25, 13.04, 14.31, 17.21, 18.18, 19.95, 22.77, 23.76, 25.88, 29.19.

Example 3: Preparation of a new crystalline form of cefmenoxime hydrochloride

(1) 250 ml of dichloromethane, 25 ml of ethanol, and (6R,7R)-7-amino-3-[[(1-methyl-1-H-tetrazol-5-yl)sulfide were sequentially added to the reaction flask. Generation] methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid hydrochloride (7-ATCA·HCl) 25 g, 20 ml of triethylamine, reacted at room temperature for 30 min, then added 2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid thiobenzothiazyl ester (AE active ester) 75.0 g, suitable for control The temperature was reacted for 8 h, extracted with water for 2 times, 150 ml each time, and the aqueous phase was combined, decolorized by activated carbon at room temperature, filtered, and the carbon layer was washed with ethanol, and the washings were combined, adjusted to pH 2.0 with 5 mol/L hydrochloric acid, crystallized for 3 h, filtered. The filtrate was washed with water and dried under vacuum at 40 ° C to obtain crude cefmenoxime hydrochloride.

(2) Add 23.7g of crude cefmenoxime hydrochloride and 230ml of water to the reaction flask, stir for 30min, slowly add 10% sodium bicarbonate solution, adjust the pH value of the solution to 6.0-6.5, stir the reaction at room temperature for 30min, 0.5g The activated carbon was decolorized for 10 min, filtered, washed with ice water, and the filtrate was combined. The filtrate was added to a mixed solution of 50 ml of acetone, 100 ml of purified water and 25 ml of concentrated hydrochloric acid. The reaction was completed, 0.5 g of activated carbon was added for 10 min, filtered, and 10% of the filtrate was added. The sodium bicarbonate solution was stirred and crystallized for 3.0 h, filtered, washed twice with ethanol, 50 ml each time, and dried under vacuum at 40 ° C to obtain purified cefmenoxime hydrochloride.

The X-ray powder diffraction pattern of the product of Example 3 showed characteristic diffraction peaks at 6.25, 13.04, 14.31, 17.21, 18.18, 19.95, 22.77, 23.76, 25.88, 29.19.

Example 4: Preparation of cefmenoxime hydrochloride pharmaceutical composition

The cefmenoxime hydrochloride compound was prepared according to the procedure of Example 1, and the raw material was used to prepare cefmenoxime hydrochloride for injection, and the specification was 0.25 g.

prescription:

Preparation Process:

(1) Ingredients: Under the 10,000-class clean condition, the sterile powder of cefmenoxime hydrochloride and the anhydrous powder of anhydrous sodium carbonate are weighed into the mixer and mixed for 60 minutes;

(2) Packing: Under the 100-level clean condition, the evenly mixed sterile powder is placed in the filling machine to adjust the loading, dispensing, and tamping;

(3) rolling cover;

Comparative Example 1: Preparation of cefmenoxime hydrochloride compound

The cefmenoxime hydrochloride compound was prepared according to the method described in CN 102675344 A.

making process:

To the reaction flask were added 260 ml of dichloromethane, 50 ml of ethanol and 35 ml of isopropyl alcohol, and the temperature was lowered to -8 ° C, and 7-ACT 40 g of hydrochloride and 40 g of AE active ester were sequentially added thereto, and 20 ml of triethylamine was added dropwise thereto, and the mixture was added dropwise thereto for 20 minutes. The condensation reaction was carried out for 4 hours at a temperature of -4 ° C. The endpoint was detected by high performance liquid chromatography. After completion of the reaction, 20 ml of brine-free solution was added, and the layers were separated. The organic phase was extracted once more with 90 ml of anhydrous brine. The aqueous phase was combined and the aqueous phase was stripped with dichloromethane. The aqueous phase was adjusted to pH 6-7 with acid, 0.5 g of activated carbon was added for 20 min, filtered, and the filter cake was washed with 70 ml of water. 20 ml of acetone and 90 ml of 35% concentrated hydrochloric acid were added to the other reaction flask, and the filtrate was added dropwise to the mixture, and the temperature was controlled at 35 ° C to precipitate a white solid. The crystals were crystallized at 25 ° C for 2 h, suction filtered, washed with 100 ml of water, washed with 120 ml of acetone, and dried by suction filtration to give 50 g.

Comparative example 2:

The cefmenoxime hydrochloride compound was prepared in the same manner as in Comparative Example 1. The raw material was used to prepare cefmenoxime hydrochloride for injection, and the specification was 0.25 g.

prescription:

Preparation Process:

(1) Ingredients: Under the 10,000-class clean condition, the sterile powder of cefmenoxime hydrochloride and the anhydrous powder of anhydrous sodium carbonate are weighed into the mixer and mixed for 60 minutes;

(2) Packing: Under the 100-level clean condition, the evenly mixed sterile powder is placed in the filling machine to adjust the loading, dispensing, and tamping;

(3) rolling cover;

Test Example 1:

The inventors conducted a purity test on the cefmenoxime hydrochloride compound prepared in Example 1 of the present invention and Comparative Example 1.

Table 2 purity test results

Results: The purity of the new crystalline form of cefmenoxime hydrochloride prepared by the invention was significantly higher than that of the cefmenoxime compound prepared by the prior art.

Test Example 2:

The inventors conducted an accelerated stability test on the injection of cefmenoxime hydrochloride for injection prepared in Example 4 and Comparative Example 2 of the present invention. The conditions of investigation were temperature 40 ° C ± 2 ° C, relative humidity 75% ± 5%. After 6 months of storage, samples were taken at the end of 0, 1, 2, 3, and 6 months, respectively. The indicators were traits, clarity, solution color, pH, content and related substances. See Table 3.

RESULTS: The examples and the comparative products were placed under the above test conditions for 6 months, and the pH value, content and related substances did not change significantly, and the quality was stable. In comparison, the color of the examples was better than that of the comparative examples, and the content was higher than that of the comparative examples.

The novel crystalline form of cefmenoxime hydrochloride and the preparation thereof of the invention have been tested by various indexes and accelerated tests, and the stability is good and the quality is reliable.

Claims (10)

1. A new crystalline form of cefmenoxime hydrochloride, characterized in that the X-ray powder diffraction pattern represented by the 2θ diffraction angle is 6.25°±0.2°, 13.04°±0.2°, 14.31°±0.2°, 17.21°±0.2° Characteristic diffraction peaks are shown at 18.18 ° ± 0.2 °, 19.95 ° ± 0.2 °, 22.77 ° ± 0.2 °, 23.76 ° ± 0.2 °, 25.88 ° ± 0.2 °, 29.19 ° ± 0.2 °.
2. A new crystalline form of cefmenoxime hydrochloride according to claim 1, wherein the specific steps of the preparation method are:

   (1) Dichloromethane, ethanol, (6R,7R)-7-amino-3-[[(1-methyl-1-H-tetrazol-5-yl)thio]methyl]-8 -Oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid hydrochloride (7-ATCA·HCl) and triethylamine mixed reaction, added 2 -(2-Amino-4-thiazolyl)-2-(methoxyimino)acetic acid thiobenzothiazolyl ester (AE active ester), water extraction, combined with aqueous phase, decolorization of activated carbon, collection of filtrate, pH adjustment with hydrochloric acid Value, filtration, washing, vacuum drying to obtain crude cefmenoxime hydrochloride;

   (2) Dissolve the crude cefmenoxime hydrochloride in water, slowly add the alkali solution, stir the reaction, adjust the pH, decolorize the activated carbon, filter, and collect the filtrate; add the filtrate to the mixed solution of acetone, purified water and concentrated hydrochloric acid, and the reaction ends. The activated carbon is decolorized, filtered, and the NaHCO ₃ solution and water for injection are added to the filtrate, and the crystals are stirred, filtered, washed, and dried to obtain purified cefmenoxime hydrochloride.
3. A method for preparing a novel crystalline form of cefmenoxime hydrochloride according to claim 2, wherein the weight ratio of 7-ATCA·HCl to AE active ester is 1:1 to 1:3.
4. A method for preparing a novel crystalline form of cefmenoxime hydrochloride according to claim 2, wherein the concentration of hydrochloric acid in the step (1) is 5 to 8 mol/L.
5. A method of preparing a novel crystalline form of cefmenoxime hydrochloride according to claim 2, wherein the hydrochloric acid adjusted in the step (1) has a pH of from 1 to 3.
6. A method for preparing a novel crystalline form of cefmenoxime hydrochloride according to claim 2, wherein the alkali solution in the step (2) is an aqueous solution of 8 to 12% sodium hydrogencarbonate.
7. A method for preparing a novel crystalline form of cefmenoxime hydrochloride according to claim 2, wherein the pH adjusted in the step (2) is from 6 to 8.
8. A method for preparing a novel crystalline form of cefmenoxime hydrochloride according to claim 2, wherein the crystal growth time in the step (2) is 2 to 4 hours.
9. A pharmaceutical composition of cefmenoxime hydrochloride, which comprises the novel crystalline form of cefmenoxime hydrochloride according to claim 1 or the hydrochloric acid obtained by the preparation method according to any one of claims 2 to 8. A new crystalline form of cefmenoxime.
10. The pharmaceutical composition according to claim 9, which comprises the following components by weight: 40 to 80 parts of cefmenoxime hydrochloride (from cefmenoxime) and 20 to 60 parts by weight of sodium hydrogencarbonate. .

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