JPS6372691A - Hydrated cephalosporin crystal for oral administration - Google Patents

Abstract

NEW MATERIAL:7beta-[(Z)-2-(2-aimono-4-thiazolyl)-4-carboxy-2-butenoylamino ]-3- cephem-4-carboxylic acid hydrate crystal exhibiting the X-ray diffraction pattern shown in the table. USE:A preventive and remedy for bacterial infection diseases. PREPARATION:An acidic aqueous solution of 7beta-[(Z)-2-(2-amino-4-thiazolyl)-4- carboxy-2-butenoylamino]-3-cephem-4-carboxylic acid is adjusted to isoelectric point or thereabout and the precipitated hydrated crystal is dried in an inert gas having a relative humidity of >=15% under nearly normal temperature and pressure condition.

Description

Detailed Description of the Invention [Objective/Technical Field] The present invention relates to 7β-[(Z)-2-(2-amino-4-thiazolyl)-4-carboxy-2-butenoylaminoco-3-cepheme An object of the present invention is to provide a stable hydrate crystal of -4-carboxylic acid (hereinafter referred to as 7432-3). 7432-3 is an oral cephalosporin that can be used, for example, to prevent or treat bacterial infections.

[Prior Art/Problem to be Solved] This compound described in JP-A No. 60-78987 was dried under reduced pressure on a pentoxide groove by a conventional method to form an anhydride, and therefore is relatively unstable and cannot be stored for a long time. I couldn't. In order to utilize this compound as a medicine, a stable substance was required.

[Summary of the invention] As a result of examining various methods for improving stability, the inventor produced the product under specific conditions. The hydrate crystal of 432-5 has a certain X! 1
They discovered that it shows a diffraction pattern, is chemically stable, and can be stored for a long period of time, and completed this invention.

[Crystal Properties] This 7432-octahydrate crystal is a slightly yellowish white to pale yellowish white microcrystalline powder.

The elemental analysis value is 7432-, which contains 2 molecules of water and up to about 1 molecule of water depending on crystallization conditions, drying conditions, etc.
This agrees with the theoretical value of the hydrate of No. 3.

Moisture content measured by Karl Fischer method is also 7-14%
(especially 8.7 to 12.5%), indicating that it contains 2 to 3 molecules of water of crystallization.

The thermal analysis curve measured at normal pressure shows that the first and second molecules of water are retained up to around 140°C, but the water up to the third molecule is desorbed at around 30 to 60°C.

Based on the above facts, it is explained that the third molecule of water has a weak binding force within the crystal structure and is easily desorbed by heating, reduced pressure, etc.

All hydrate crystals in the above water content range (range of 2 to 3 molecules of crystal water) show the following XwA diffraction pattern.

This X-ray diffraction image was measured under the following conditions.

X-ray dual wavelength λ - 1,5418 people, (α for copper) (N Mee filter) 40 kV - 20 mA Grid spacing d is in units of people,
Relative strength 1/1. is expressed as a percentage based on the strength of 20.95 people.

(Space below) In the hydrate crystal of this invention, the ratio of geometric isomers in the 7-position side chain is independent of the ratio of geometric isomers in the raw material, and the main component is cis, that is, 2 isomers, and is 96 to 100% (especially A geometric isomeric purity of 99.0-99.8%) is maintained.

When the hydrate crystals of this invention are measured by the potassium bromide tablet method, the infrared absorption spectrum shows 1700C, unlike the anhydride.
A strong absorption is observed at m-'.

[Manufacturing method] (1) Overview This 7432-3 hydrate crystal is produced by the following method.

The raw material 7432-3 is made into an acidic aqueous solution, and the pH is adjusted to around 1 point (especially at pH 1.5 to 70°C) at room temperature (especially 0 to 70°C).
5. (3)! I11 is adjusted to precipitate crystals. After stirring to ripen the crystals if necessary, the water-containing crystals are separated. By drying this in an inert gas with a relative humidity of 15% or more at around room temperature under normal pressure, the desired hydrate crystal can be produced.

(2) The raw material 7432-8 may be hydrated or anhydrous, and may also be a free compound, a salt at an amino group (such as an acid addition salt),
Pretreatment (purification, cis isomerization, isolation, etc.) using a water-soluble salt (alkali metal salt, hydrochloride, etc.) for the yX material, which may be a salt at the carboxy group (alkali metal salt, etc.)
One of the preferred embodiments is to perform the following acidic aqueous solution preparation treatment in combination with

(3) Acid The acidic aqueous solution treatment includes a method of dissolving the raw material in an aqueous solution of an acid, a method of adding an acid to a neutral aqueous solution of the raw material, and the like. Acids used here include inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.), carboxylic acids (acetic acid, malic acid, fumaric acid, citric acid, etc.), sulfonic acids (methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, etc.), Any water-soluble acid, such as acid salts (dimethylamine hydrochloride, raw material hydrochloride, etc.) that can convert the raw material into an acidic aqueous solution, can be used. The amount of acid is preferably 0 to 20 molar equivalents (especially 1 to 10 molar equivalents). When the raw material is a mineral salt or the like, the acidity of the raw material itself can be used as the acid used here.

(4) Co-solvent Alcohol (methanol,
ethanol, impropatol, tertiary butanol, methoxyethanol, etc.), amides (dimethylformamide, etc.), nitriles (acetonitrile, etc.), sulfoxides (dimethylsulfoxide, etc.), ethers (dioxane, tetrahydrofuran, dimethoxyethane, etc.),
May contain 0% to 70% of water-miscible organic solvents such as ketones (acetone, methyl ethyl ketone, etc.) - (5) Concentration The raw material concentration in the acidic aqueous solution is 2.0 to 15.0%. (especially 3.0 to 5.0%) is preferable.

(6) Neutralized acidic aqueous solution near room temperature (approximately 0 to 70℃, especially 10 to 4℃)
5°C) near the isoelectric point (pH approximately 1.5 to 5.0, especially 2
．． 0 to 3.5), the base used for neutralization may be solid or liquid as long as it can neutralize the acidity of the acidic aqueous solution to a predetermined pH. Representative bases include organic bases (such as triethylamine). ), inorganic bases (ammonia,
Sodium carbonate, potassium carbonate, sodium bicarbonate,
Water-soluble bases such as potassium hydrogen carbonate (potassium hydrogen carbonate, etc.) are easy to use, but are not limited to these.For example, water-insoluble bases such as hydroxide type anion exchange resins can also be used.

(7) Crystallization/Aging To crystallize and ripen crystals, heat a solution adjusted to around the isoelectric point at 0 to 70°C (especially 5 to 35°C) for 10 to 50 minutes.
Stir for an hour.

(8) Drying For drying, use an inert gas (air, nitrogen, carbon dioxide, etc.) with a relative humidity of 15% or more, depending on stirring, powder flow conditions, etc.
Mild conditions such as normal pressure drying (stationary drying, ventilation drying, ventilation drying, fluidized bed drying, etc.) at medium to room temperature (approximately 0 to 60° C.) are preferred.

The following measurements have been obtained on a laboratory scale.

In the case of sealed stationary drying, for example, in normal pressure air, the relative humidity is 15 to 50% (especially 20 to 30%) and the temperature is 25 to 60".
In C, the water content is around the same as dihydrate after 1 to 8 hours, and at relative humidity of 45% or more (especially 50 to 80%) and air temperature of 30°C or less (especially 10 to 25°C), the water content is 1 to 8. After a period of time, dehydration almost stops at a water content corresponding to trihydrate.

In the case of ventilation and ventilation drying, it depends on the humidity, powder flow conditions, etc., but for example, the temperature is 25-40°C, the relative humidity is 50-60°C.
% air to around the inflection point of the time versus outlet temperature or time versus outlet humidity curve (approximately 2 to 10 hours when the moisture content of the raw material is 30 to 60%); hydrate crystals ( water content of 8 to 8.8%).

In the case of fluidized bed drying, it depends on conditions such as air blowing speed, but for example, air at a temperature of 10 to 35°C (particularly 20 to 30'C) and a relative humidity of 50 to 60% is dried using a time versus outlet temperature curve or a time versus outlet humidity curve. The first inflection point of the curve (moisture content of raw materials 30~
If the trihydrate crystal is dried with air until it reaches the second inflection point (the moisture content of the raw material is 30 to 60%),
Trihydrate crystals can be produced by drying with air for up to about 1.5 hours).

For mass production, ventilation drying, ventilation drying, fluidized bed drying, etc. are used.

In the case of fluidized bed drying, although it depends on the conditions such as the air speed per water-containing crystal weight, in some cases the temperature is 10 to 60°C (particularly 20 to 60°C).
30℃), relative humidity 20-80% (especially 50-60%)
If the air of The crystals were heated near the second inflection point (w, the water content of the material was 30 to 60%).
trihydrate crystals can be produced by drying with air for about 3 to 7 hours).

Normal drying conditions (e.g., 0.Ol mmHg
, moisture content up to 1.5-4.8% within 3 hours at 25-28°C on calcium chloride, and 2% with dry nitrogen gas aeration.
(dehydrated to a water content of 1.08% within 30 minutes at 5°C), dehydration is completed to less than 2 molecules of crystal water, and a stable product cannot be obtained.

[Stability] As a result of confirming the stability of the hydrate crystal of this invention in an accelerated test at 50°C, the one-month survival rate was 97.6%, compared with the measured value of 73.6% for the anhydride crystal. It was found to be extremely stable.

[Applications] The hydrate crystals of this invention can be used in oral preparations (especially capsules,
It can be used in the form of granules, tablets, etc. for the prevention and treatment of bacterial infections.

(The following is a blank space.) The present invention will be described in detail below with reference to Examples. The moisture content is a value measured by the Karl Fischer method.

Example 1 25 g of crude 7432-S crystals were dissolved in 75 ml of 6N hydrochloric acid and left at 15 to 20° C. for 1 hour to precipitate the hydrochloride, and then the crystals were collected by filtration. If this is washed with 75ml of acetonitrile to which one drop of concentrated hydrochloric acid is added and dried, 7432-5
- Obtain 18 g of hydrochloride hydrate.

Dissolve 1.0 g of this crystal in 30 ml of water, and add 1.0 g of this crystal to 1.0 g of this crystal.
After stirring for 2.5 hours at 25 to 45°C, precipitated crystals were collected by filtration and washed with water. The crystals are dried with ventilation at 10° C. for 5 hours to obtain 0.9 g of 7432-octahydrate crystals.

Moisture content: 10.2%, geometric isomer ratio (cis vs. trans) -98.8:0.8° Example 2 1.17 g of 7432-3 crude crystals was mixed with 3 m of secondary butanol.
Suspend in 3 ml of acetonitrile mixture, add 1 ml of 35% hydrochloric acid
Add a+1 (5 molar equivalents) and dissolve. This solution is mixed with 3 ml of tertiary butanol, 9 ml of acetonitrile, and 5 ml of water.
Dilute with the mixed solution, add triethylamine to adjust the pH to 2.3, and stir at 30-35°C for 3 hours. Separate the precipitated crystals and mix with tertiary butanol, acetonitrile, water (1
:2:1) Wash with 5ml of the mixture and 10ml of water,
After air drying at ℃ for 2 hours, 7432-3 hydrate crystals 1.
Obtain 0.6g. Moisture content: 8.75%, geometric isomer ratio (
cis vs. trans) -99,210,8゜Example 3 1.0 g of 7432-3 crude crystals was suspended in a mixture of 8 ml of water and 1 ml of acetonitrile, and 0.41 g of sodium hydrogen carbonate was added.
(2 molar equivalents) and dissolve. This solution was diluted with 6 ml of methanol, 0.1 g of activated carbon was added, and after stirring at room temperature for 10 minutes, the activated carbon was removed by filtration. The filtrate is 6N
-Hydrochloric acid 1.62ml (4.5 molar equivalent)/water 3.4ml
- Pour into 5 ml of acetonitrile mixture. pH of the mixture
to pH 2.3 with 30% potassium carbonate solution. C,
Stir at 40°C for 1 hour and at 20-25°C for 1.5 hours.

Collect the precipitated crystals by filtration and add methanol, acetonitrile,
Wash with 5 ml of water (1:1:2) mixture, 2 On+1 water, and 5 ml of methanol in sequence, and dry with ventilation at 20 to 25°C for 1.5 hours to obtain 7432-3 pale yellow-white hydrate crystals.
get g. Moisture content: 9.35%.

Geometric isomer ratio (cis vs. trans) -99,610,4
゜Example 4 4.6 7432-8 crude crystals were added to a solution of 1.848 g (3 molar equivalents) of sodium hydrogen carbonate in 42 ml of water at 15-20°C.
Add 6g of acetonitrile to this solution.
ml, 2.34 g of activated alumina and 0.466 g of activated carbon were added, stirred at 15-20°C for 30 minutes, and then filtered to remove activated carbon and alumina. Dilute the filtrate with acetonitrile 37
Pour into a mixture of 1ml of 62% sulfur v3.95g and 28ml of water. A 30% potassium carbonate solution was added to the mixture at 20-25°C to adjust the pH to 3.0, and the mixture was stirred at the same temperature for 30 minutes. If the precipitated crystals are collected by filtration and air-dried at 20-25°C for 2-3 hours, 4.384 g of 7432-S hydrate crystals will be obtained.
get. Moisture content: 12.2%, geometric isomer ratio (cis vs. trans) -99,610°4° Under similar conditions, 7432-81. 6 ml of a solvent (water, isopropanol or acetonitrile) and 8 mol of 85% phosphoric acid were added to a solution of 12 ml of an aqueous solution of Og sodium hydrogen carbonate treated with activated alumina and activated carbon to make it acidic.
pH 3.0 by adding 30% potassium carbonate solution at ~25°C
and stir for 30 minutes at the same temperature. What if the precipitated crystals are collected by filtration and air-dried at 20-25°C for 2-3 hours? 43
Approximately 0.90 g of 2-5 hydrate crystals are obtained. Moisture content: 11.
0%, geometric isomer ratio (cis vs. trans) -99.2 ~
99, 710, 8-0.3° Under the same conditions, using #4 mol of methanesulfone instead of phosphoric acid, the same procedure as above was performed to obtain 0.879 g of 7432-3 hydrate crystals. Moisture content: 11.4% 0ga What isomer ratio (cis vs. trans) -99,610,4゜Example 5 2.0g of 7432-8 crude crystals was added to 18ml of dimethoxyethane.
1. Suspend in 2 ml of ethanol mixture and incubate with 6N-
Add 89 ml (1.3 molar equivalents) of salt No. 2 and stir at the same temperature for 2 hours. The precipitated hydrochloride crystals are collected by filtration, washed successively with 10 ml of dimethoxyethane/ethanol (9:1) mixture and 10 ml of acetonitrile, and vacuum dried at 25-30°C for 2 hours to obtain 1.878 g of hydrochloride.

1.0 g of this crystal was suspended in a mixture of 6 ml of methanol and 5 ml of water, and 0.61 g (3 molar equivalents) of sodium hydrogen carbonate was added.
Add 0.1g of activated carbon to this solution and dissolve.
After stirring for 10 minutes at 5-30°C, filter the activated carbon to remove the filtrate, which is 35% hydrochloric acid 1.01% l1l (4 molar equivalents)
・Pour into a mixture of 3 ml of water and 6 ml of acetonitrile, and add 30
25% potassium carbonate solution was added to adjust the pH to 3.0.
Stir at ~30°C for 30 minutes and at 5-7°C for 1 hour. The precipitated crystals are collected by filtration, washed sequentially with 5 ml of ethanol and 10 ml of water, and dried with ventilation at 20-25°C for 2 hours to obtain 7432.
-0.82 g'+ of S hydrate crystals are obtained. Moisture content: 10.6
%, geometric isomer ratio (cis vs. trans) -99, 510
, 5゜Example 6 1.3 g (2.2 molar equivalents) of sodium hydrogen carbonate was added to 1 mol of water.
To this solution, add 3.0 g of 7432-5 crude crystals and dissolve. 1.5 g of activated alumina and 0.3 g of activated carbon are added to this solution, stirred at 20-25°C for 30 minutes, filtered, and dissolved with activated carbon. After removing the alumina, pour the aliquot into a solution of 10 molar equivalents of malic acid in 17 ml of water and 36 ml of acetonitrile, adjust the pH to 3.0 by adding 30% potassium carbonate solution at 20-25°C, and stir for 30 minutes. The precipitated crystals are collected by filtration and air-dried at 25-30"C for 2 hours to obtain 2.665 g of 7432-octahydrate crystals. Water content: 11.7%, geometric isomer ratio (cis vs. trans). -9
9,110,9° Even if 10 moles of malic acid were replaced with 10 mole equivalents of fumaric acid, the same hydrate crystals (water content 10.1%) were obtained.

Similarly, 7432-31. Dissolve Og in sodium bicarbonate water, add 4 molar equivalents of formic acid dissolved in a mixture of water and acetonitrile to a solution purified with activated alumina and activated carbon, and proceed in the same manner as above to obtain 0.925 g of 7432-S hydrate crystals. get. Moisture content: 12.7%, geometric isomer ratio (cis vs. trans): 99, 810, 2°. Even if the amount of formic acid added was increased to 75 molar equivalents, the same hydrate crystals were obtained.

Example 7 Undried 7432-81g of 6 produced by the method of Example 3
Each sample was placed in a sealed container, and the relative humidity at room temperature was adjusted to 0%, 12%, 20%, 44%, depending on the selection of the water-containing desiccant.
It was fixed at 57% and 75% and left for 6 hours. If the moisture content of each sample is determined by the Karl Fischer method, it will be 1.05%, 5.83%, 8.54%, and 1%, respectively.
Showing values of 1.21%, 12.19% and 12.21%.

At 20% relative humidity, dihydrate (calculated water content = 8.07
%), and at 44% or more, trihydrate (calculated water content: 11.
64%) is the main component.

Even if this drying is continued for up to 30 hours, the relative humidity is 20
% or more, the water content decrease value for 6 to 30 hours is 0.
It remains below 2%.

Example 8 Undried 7432-51g of 6 produced by the method of Example 3
Each sample was placed in a sealed container, and the relative humidity was adjusted to 20%, 44%, 57%, and 7% by selecting a hydrous desiccant at 40°C.
Fix it at 5% and leave it for one month. If the moisture content of each sample is measured using the Karl Fischer method, each sample will be 7.92%.
, 10.69%, 11.73%, and 12.4%, and the difference from the value at room temperature for 30 hours is within 0.5%, and the moisture content is extremely stable.

Patent applicant: Shionogi & Co., Ltd. Representative Patent Attorney Ushio 1) G.

Claims (3)

[Claims] (1) 7β-[(Z)-2-(2
-amino-4-thiazolyl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxylic acid hydrate crystals. (2) 7β-[(Z)-2-(2-amino-4-thiazolyl)-4-carboxy-2-butenoylamino]-3
-Preparing an acidic aqueous solution of cefem-4-carboxylic acid near its isoelectric point and crystallizing it, and drying the resulting water-containing crystals in an inert gas with a relative humidity of 15% or more at room temperature and pressure. A method for producing hydrate crystals according to claim (1). (3) 7β-[(Z)-2-(2
-Amino-4-thiazolyl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxylic acid hydrous crystals are dried in an inert gas with a relative humidity of 15% or more at room temperature and pressure. Claims (1)
) method for producing hydrate crystals.