CN105566352A - New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation - Google Patents

Abstract

The invention discloses a new crystal form cefmenoxine hydrochloride compound and a crystallization preparation method thereof. The new crystal form cefmenoxine hydrochloride compound is prepared by adopting the particle process crystal product molecular assembling and morphology optimizing technology. The compound has the advantages of being high in purity and good in fluidity and stability. The invention also discloses a preparation which is prepared from the cefmenoxine hydrochloride compound, namely cefmenoxine hydrochloride for injection.

Description

A new crystal form compound and preparation of cefmenoxime hydrochloride using particle process crystal product molecular assembly and morphology optimization technology

technical field

The invention belongs to the technical field of medicine, and in particular relates to a new crystal form compound of cefmenoxime hydrochloride and a preparation using particle process crystal product molecular assembly and shape optimization technology.

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)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-metha 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 the third-generation cephalosporin developed by Takeda Corporation of Japan. It was first listed in Japan in 1983. It is a broad-spectrum antibiotic that achieves bactericidal effect by inhibiting the biosynthesis of bacterial cell walls.

Regarding the synthetic method of cefmenoxime hydrochloride, according to literature reports, mainly use 7-ACA as raw material, (1) first 3-position condensation, then 7-position condensation; (2) first 7-position condensation, then 3-position condensation. Adopt the cefmenoxime hydrochloride prepared by said method on the market at present, its purity is relatively poor, color level is bad, poor stability, thereby has influenced its preparation quality.

The conventional crystal form of cefmenoxime hydrochloride has poor stability, and is unstable to heat, acidic environment, and alkaline environment. It is manifested in problems such as easy discoloration of appearance, decreased content, and occurrence of degradation products. To solve this problem, new crystallization production technology must be developed to optimize process parameters such as solvent, temperature, reaction time, additives, etc., so that crystallization can be carried out under suitable conditions, thereby ensuring the quality of the product.

The present invention mainly aims at the above problems of cefmenoxime hydrochloride, and on the basis of fully investigating factors such as solvent, temperature, external force and additives in the crystal formation process, a crystal product with high purity is obtained by molecular assembly and shape optimization technology of particle process crystal product. , good color grade, good fluidity, and good stability as a new crystal compound of cefmenoxime hydrochloride. Compared with the previous preparation process, this synthesis step pays more attention to the control of reagents and parameters in the synthesis process. The steps are simple and the raw materials used are uniform. It is a cheap, non-toxic or low-toxic product, suitable for industrial scale production. The preparation made by using the compound described in the present invention has better stability than previous preparations.

Contents of the invention

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

The new crystal form compound of cefmenoxime hydrochloride of the present invention is measured by X-ray powder diffraction, and the X-ray powder diffraction pattern represented by 2θ diffraction angle is at 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° show characteristic diffraction peaks, as shown in the attached picture 1.

The preparation of the new crystal form compound of cefmenoxime hydrochloride of 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) mixed with triethylamine, adding 2 -(2-Amino-4-thiazolyl)-2-(methoxyimino)acetic acid thiobenzothiazole ester (AE active ester), water extraction, combined aqueous phase, activated carbon decolorization, collected filtrate, adjusted pH with hydrochloric acid value, filtered, washed, and vacuum-dried to obtain the crude product of cefmenoxime hydrochloride.

(2) Dissolve the crude cefmenoxime hydrochloride in water, slowly add lye, stir for reaction, adjust pH, decolorize with activated carbon, filter, and collect the filtrate. Add the filtrate dropwise to the mixed solution of acetone, purified water and concentrated hydrochloric acid, after the reaction is completed, decolorize the activated carbon, filter, add _NaHCO3 solution and water for injection to the filtrate, stir and grow crystals, filter, wash, and dry to obtain refined cephalexin hydrochloride oxime.

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

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

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

Preferably, in the above preparation method, the lye in the step (2) is 8-12% aqueous sodium bicarbonate solution. More preferably, the lye is 10% aqueous sodium bicarbonate.

Preferably, in the above preparation method, the pH adjusted by the alkaline solution 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 2-4 hours. More preferably, the crystal growing time is 3-3.5 hours.

The second object of the present invention is to provide a kind of cefmenoxime hydrochloride pharmaceutical composition comprising the new crystal form compound of cefmenoxime hydrochloride of the present invention, the preparation process of the pharmaceutical composition is simple to operate, has better stability than previous products and Small side effects.

The cefmenoxime hydrochloride pharmaceutical composition of the present invention comprises the following components in parts by weight: 40-80 parts of cefmenoxime hydrochloride (calculated as cefmenoxime) and 20-60 parts of sodium bicarbonate.

Description of drawings

Figure 1: X-ray powder diffraction pattern of the new crystal form of cefmenoxime hydrochloride, see Table 1 for the 2θ values corresponding to the diffraction peak numbers in the figure.

detailed description

The present invention will be further described below through specific embodiments, but the present invention is not limited to the scope of the embodiments. Those skilled in the art should understand that the content of the present invention is equivalently replaced, or correspondingly improved , still fall within the protection scope of the present invention.

Embodiment 1: Preparation of Cefmenoxime Hydrochloride New Crystal Form Compound

(1) Add 250ml of dichloromethane, 25ml of ethanol, (6R,7R)-7-amino-3-[[(1-methyl-1-H-tetrazol-5-yl)sulfur into the reaction bottle Substitute]methyl]-8-oxo-5-thia·1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate hydrochloride (7-ATCA·HCl) 25g, 20ml of triethylamine, after reacting at room temperature for 30min, add 50.0g of 2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid thiobenzothiazolyl ester (AE active ester), and control the appropriate React at temperature for 8 hours, add water to extract twice, 150ml each time, combine the water phases, decolorize with activated carbon at room temperature, filter, wash the carbon layer with ethanol, combine the washings, adjust the pH value to 1.5 with 6mol/L hydrochloric acid, grow crystals for 3 hours, filter , washed the filtrate with water, and dried under vacuum at 40°C to obtain crude cefmenoxime hydrochloride.

(2) Add 25.9 g of cefmenoxime hydrochloride crude product and 230 ml of water into the reaction flask, stir for 30 min, slowly add 10% sodium bicarbonate solution, adjust the pH value of the solution to 6.5 to 7.0, stir at room temperature for 30 min, and pass through 0.5 g Decolorize activated carbon for 10 minutes, filter, wash with ice water, combine the filtrates, add the filtrate dropwise to a mixed solution of 50ml of acetone, 100ml of purified water and 25ml of concentrated hydrochloric acid, after the reaction is complete, add 0.5g of activated carbon to decolorize for 10min, filter, and add 10% of Sodium bicarbonate solution, stirred for 3.5 hours to grow crystals, filtered, washed with ethanol twice, 50ml each time, and vacuum-dried at 40°C to obtain refined cefmenoxime hydrochloride.

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

Instruments and equipment: EMPYREAN (sharp shadow) X-ray diffractometer (Panalytical Company of the Netherlands).

The X-ray powder diffraction pattern of the product of Example 1 shows characteristic diffraction peaks at 6.25°, 13.04°, 14.31°, 17.21°, 18.18°, 19.95°, 22.77°, 23.76°, 25.88°, and 29.19°. For details, refer to Figure 1 of the description.

The concrete data of described XRPD diffraction is shown in the table below:

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

Embodiment 2: Preparation of new crystal form compound of cefmenoxime hydrochloride

(1) Add 250ml of dichloromethane, 25ml of ethanol, (6R,7R)-7-amino-3-[[(1-methyl-1-H-tetrazol-5-yl)sulfur into the reaction bottle Substitute]methyl]-8-oxo-5-thia·1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate hydrochloride (7-ATCA·HCl) 25g, 20ml of triethylamine, after reacting at room temperature for 30min, add 25.0g of 2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid thiobenzothiazolyl ester (AE active ester), and control the appropriate React at temperature for 8 hours, add water to extract twice, 150ml each time, combine the water phases, decolorize with activated carbon at room temperature, filter, wash the carbon layer with ethanol, combine the washings, adjust the pH value to 2.0 with 8mol/L hydrochloric acid, grow crystals for 3 hours, filter , washed the filtrate with water, and dried under vacuum at 40°C to obtain crude cefmenoxime hydrochloride.

(2) Add 25.1 g of cefmenoxime hydrochloride crude product and 230 ml of water into the reaction flask, stir for 30 min, slowly add 10% sodium bicarbonate solution, adjust the pH value of the solution to 6.7 to 6.9, stir at room temperature for 30 min, and dissolve 0.5 g Decolorize activated carbon for 10 minutes, filter, wash with ice water, combine the filtrates, add the filtrate dropwise to a mixed solution of 50ml of acetone, 100ml of purified water and 25ml of concentrated hydrochloric acid, after the reaction is complete, add 0.5g of activated carbon to decolorize for 10min, filter, and add 10% of Sodium bicarbonate solution, stirred for 2.5 hours to grow crystals, filtered, washed with ethanol twice, 50ml each time, and vacuum-dried at 40°C to obtain refined cefmenoxime hydrochloride.

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

Embodiment 3: Preparation of new crystal form compound of cefmenoxime hydrochloride

(1) Add 250ml of dichloromethane, 25ml of ethanol, (6R,7R)-7-amino-3-[[(1-methyl-1-H-tetrazol-5-yl)sulfur into the reaction bottle Substitute]methyl]-8-oxo-5-thia·1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate hydrochloride (7-ATCA·HCl) 25g, 20ml of triethylamine, after reacting at room temperature for 30min, add 75.0g of 2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid thiobenzothiazolyl ester (AE active ester) to control the appropriate React at temperature for 8 hours, add water to extract twice, 150ml each time, combine the water phases, decolorize with activated carbon at room temperature, filter, wash the carbon layer with ethanol, combine the washings, adjust the pH value to 2.0 with 5mol/L hydrochloric acid, grow crystals for 3 hours, filter , washed the filtrate with water, and dried under vacuum at 40°C to obtain crude cefmenoxime hydrochloride.

(2) Add 23.7 g of cefmenoxime hydrochloride crude product and 230 ml of water into the reaction flask, stir for 30 min, slowly add 10% sodium bicarbonate solution, adjust the pH value of the solution to 6.0 to 6.5, stir at room temperature for 30 min, and pass through 0.5 g Decolorize activated carbon for 10 minutes, filter, wash with ice water, combine the filtrates, add the filtrate dropwise to a mixed solution of 50ml of acetone, 100ml of purified water and 25ml of concentrated hydrochloric acid, after the reaction is complete, add 0.5g of activated carbon to decolorize for 10min, filter, and add 10% of Sodium bicarbonate solution, stirred for 3.0 hours to grow crystals, filtered, washed with ethanol twice, 50ml each time, and vacuum-dried at 40°C to obtain refined cefmenoxime hydrochloride.

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

Embodiment 4: the preparation of cefmenoxime hydrochloride pharmaceutical composition

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

prescription:

Preparation Process:

(1) Ingredients: under ten thousand grade clean conditions, weigh cefmenoxime hydrochloride aseptic powder and anhydrous sodium carbonate aseptic powder and put them into a mixer, and mix for 60 minutes;

(2) Dispensing: Under Class 100 clean conditions, place the uniformly mixed aseptic powder in the dispensing machine, adjust the filling volume, dispensing, and plugging;

(3) capping;

Comparative Example 1: Preparation of Cefmenoxime Hydrochloride Compound

The cefmenoxime hydrochloride compound was prepared according to the method described in CN102675344A.

making process:

Add 260ml of dichloromethane, 50ml of ethanol and 35ml of isopropanol to the reaction bottle, cool down to -8°C, add 40g of 7-ACT hydrochloride and 40g of AE active ester in sequence, and add 20ml of triethylamine dropwise, and the dripping is completed in 20 minutes. At the end of the drop, keep warm at -4°C for 5 hours for condensation reaction. The endpoint was detected by high performance liquid chromatography. After the reaction was completed, 20 ml of anhydrous salt was added, and the layers were separated. The organic phase was extracted once more with 90 ml of anhydrous salt, the aqueous phases were combined, and the aqueous phase was back-extracted with dichloromethane. The pH value of the aqueous phase was adjusted to 6-7 with acid, and 0.5 g of activated carbon was added for decolorization for 20 min, filtered, and the filter cake was washed with 70 ml of water. Add 20 ml of acetone and 90 ml of 35% concentrated hydrochloric acid to another reaction flask, add the filtrate dropwise to the mixture, control the temperature at 35° C., and precipitate a white solid. Cultivate the crystal at 25°C for 2 hours, filter with suction, wash with 100ml of water and then wash with 120ml of acetone, and dry with suction to obtain 50g of the product.

Comparative example 2:

Take comparative example 1 to prepare cefmenoxime hydrochloride compound, and use this raw material to prepare cefmenoxime hydrochloride for injection, specification 0.25g.

prescription:

Preparation Process:

(1) Ingredients: under ten thousand grade clean conditions, weigh cefmenoxime hydrochloride aseptic powder and anhydrous sodium carbonate aseptic powder and put them into a mixer, and mix for 60 minutes;

(2) Dispensing: Under Class 100 clean conditions, place the uniformly mixed aseptic powder in the dispensing machine, adjust the filling volume, dispensing, and plugging;

(3) capping;

Test example 1:

The inventors tested the purity of the cefmenoxime hydrochloride compound prepared in Example 1 and Comparative Example 1 of the present invention.

Table 2 Purity test results

Results: The purity of the new crystal form of cefmenoxime hydrochloride prepared by the present invention is obviously higher than that of the cefmenoxime compound prepared by the prior art.

Test example 2:

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

Results: The products of the example and the comparison example 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 embodiment is better than that of the comparative example, and the content is higher than that of the comparative example.

The new crystal form compound of cefmenoxime hydrochloride and the preparation thereof of the present invention show good stability and reliable quality through various index inspections and accelerated test investigations.

Claims (10)

1. a Cefmenoxime Hemihydrochloride crystal compound, it is characterized in that, the X-ray powder diffraction pattern represented with 2 θ diffraction angle at 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 ° place's indicating characteristic diffraction peak.

2. a kind of Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 1, it is characterized in that, preparation method's concrete steps are:

(1) by methylene dichloride, ethanol, (6R, 7R)-7-amino-3-[[(1-methyl isophthalic acid-H-tetrazole-5-base) sulfo-] methyl]-8-oxo-5-thia-1-azabicyclo [4, 2, 0] oct-2-ene-2-carboxylic acid hydrochloride (7-ATCAHCl) and triethylamine hybrid reaction, add 2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid sulfo-benzothiazole ester (MEAM), water extracts, merge aqueous phase, activated carbon decolorizing, collect filtrate, use salt acid for adjusting pH value, filter, washing, vacuum-drying, obtain Cefmenoxime Hemihydrochloride crude product,

(2) by soluble in water for Cefmenoxime Hemihydrochloride crude product, slowly add alkali lye, stirring reaction, regulate pH, activated carbon decolorizing, filter, collect filtrate; Entered by filtrate added drop-wise in the mixing solutions of acetone, purified water and concentrated hydrochloric acid, reaction terminates, activated carbon decolorizing, filters, adds NaHCO in filtrate ₃solution and water for injection, stir growing the grain, filters, and washing is dry, obtains the Cefmenoxime Hemihydrochloride refined.

3. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the weight ratio of described 7-ATCAHCl and MEAM is 1:1 ~ 1:3.

4. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the concentration of hydrochloric acid described in step (1) is 5 ~ 8mol/L.

5. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the pH that the hydrochloric acid described in step (1) regulates is 1 ~ 3.

6. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the alkali lye described in step (2) is the sodium bicarbonate aqueous solution of 8 ~ 12%.

7. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the pH that the alkali lye described in step (2) regulates is 6 ~ 8.

8. a kind of method preparing Cefmenoxime Hemihydrochloride crystal compound as claimed in claim 2, is characterized in that the rearing crystal time described in step (2) is 2 ~ 4h.

9. a Cefmenoxime Hemihydrochloride pharmaceutical composition, is characterized in that its Cefmenoxime Hemihydrochloride crystal compound containing Cefmenoxime Hemihydrochloride crystal compound according to claim 1 or the preparation method described in claim 2 ~ 8 any one and obtain.

10. pharmaceutical composition as claimed in claim 9, is characterized in that counting the component comprising following weight part by weight: Cefmenoxime Hemihydrochloride (in cefmenoxime) 40 ~ 80 parts and sodium bicarbonate 20 ~ 60 parts.