DD276031A5 - PROCESS FOR PREPARING A HARTGELANTINE CAPSULE COMPOSITION OF A CRYSTALLINE HYDRATE OF THE 7BETA - [(Z) -2- (2-AMINOTHIAZOL-4-YL -) - 4-CARBOXYBUT-2-ENOYLAMINO] -3-CEPHEM-4-CARBON ACID - Google Patents

Abstract

The invention relates to a process for the preparation of a hard gelatin capsule composition containing a hydrate of 7b- & (Z) -2- (2-aminothiazol-4-yl) -4-carboxybut-2-enoylamino! -3-cephem-4-carboxylic acid , The hydrates are drugs for controlling bacterial infections.

Description

Field of application of the invention

The application of the present invention is on the goblet of drugs for combating bacterial infections.

Characteristic of the known technical solutions

The precursor 7β- (Z) -2- (2-amidlazhlazol-4-yl) - '1-carboxybut-2-onylamino] -3-cophomo-4-carboxylic acid is disclosed in Japanese Pat. Appln. Kokai 60-78987 ,

A capsule sequestering solution protected by gelatin poetry is described in Japanese Utility Model Publication 45-20800, which discloses an ancestor in which a liquid is filled into a capsule and the capsule is sealed.

i j ί. ]

Object of the invention

The object of the invention is to provide a stable composition of a pharmaceutically effective amount of a drug in a hard gelatin capsule.

Explanation of the essence of the invention

The invention has for its object to provide a stable composition of a pharmazautisch effective amount of a drug in ether hard gelatin capsule, the disadvantages of the prior art by the higher stability of the drug to be wounded.

According to the present invention, there is provided a process for preparing a hard gelatin capsule composition of a stable crystalline di-or trihydrate of the 7β - [(Z) -2- (2-aminothiazol-4-yl) -4-carboxybut-2-enoylamino) -3-cephem-4 carboxylic acid (hereinafter referred to as 7432-S), which are valuable for the treatment or prevention of bacterial infections. The capsule is sealed with a gelatin strip along the transition between the cap and the body. The inventors made studies to find a composition in which the 7432 S hydrates are stable for a long time. They found that when the hydrate is filled into a hard gelatin capsule and the capsule is sealed with a gelatin strip at the cap-body interface, it is protected from color change and loss of activity. This method was known to be valuable only to liquid keps and not to solid capsules prepared according to the invention.

The preparation of the capsules according to the invention may be made by mixing a pharmaceutically effective amount of the hydrate with an additive such as a filler or lubricant, filling in a capsule, applying an aqueous solution of gelatin to the cap-body interface of the capsule and then drying to a capsule Gelatin stripes take place.

The hard gelatin capsule may be a common commercially available capsule without any particular size or color limitation. It may contain dye and / or pigment.

Although the addition of an additive such as a filler or lubricant is not a prerequisite for the protection of the hydrate from discoloration or loss of activity, it is used to introduce a pharmaceutically effective amount of the hydrate into a capsule for ease of handling. The filler may be more common for powders or granules, such as sugars, for example, glucose, fructose or lactose, starch, such as corn starch or potato starch, or cellulose, such as crystalline cellulose, methyl cellulose or methyl ethyl cellulose. The lubricant may be conventional for powders, granules or tablets, for example, purified talc, stearic acid or its salts such as the sodium, magnesium or calcium salt, borax, liquid paraffin, sodium benzoate, polyethylene glycol (average molecular weight 6000) carnauba wax or hydrogenated oil.

The aqueous gelatin solution can be prepared by dissolving 10 to 30%, in particular 15 to 25%, gelatin in water which optionally contains 1 to 40% of a lower alkanol, such as 20 to 30% methanol, ethanol, propanol or glycerol, ether, such as 0, 5 to 10% Polyoxyäthylensorbitanmonooleat "= polysorbates, ketone or ester can be prepared in customary, so that the solution can be applied at the transition between the cap and body of the capsule and dried at 0 to 80 ° C, for example, by air flow or heat. Usually, 5 to 50 mg of the gelatin solution, optionally with a pharmaceutically acceptable pigment, are applied to a size 2 to 4 gelatin capsule. The crystalline hydrate is a slightly yellowish-white to pale yellowish-white microcrystalline powder. The hydrate contains 2 moles of water of crystallization plus b's to 1 mole of additional water of crystallization, depending on the conditions, e.g. during crystallization and drying. The water content is in the range of 7 to 14%, in particular 8.7 to 12.5%, which corresponds to the dihydrate to trihydrate or a mixture of these.

Any crystalline hydrate with a water content in the above range, i. in the range of dihydrate to trihydrate, shows virtually the same values in de? X-ray structure analysis, these are shown in Table I.

Table! The X-ray diffraction analysis was carried out under the following conditions: X-rays: wavelength

λ = 0.15418nm (copper Ka, nickel filter) 4OkV- 20mA. The lattice plane distance d is given in Α units. The relative

Intensity 1 / I ₀ giot the intensity in percent at 2,095nm.

d 1 / I ₀ d l / l. d I / l, d 1 / I ₀ 6.90 12 20.95 100 28.70 17 35.93 8th 7.35 8th 21.16 70 29,40 27 36.38 24 9.45 92 21.75 25 29,60 11 37,00 7 10.16 21 22.25 49 29,90 16 38,30 26 12.08 46 23.85 62 30,40 19 38.65 10 14.87 30 24,60 39 31.10 63 39,20 16 16.65 14 24,80 16 31,60 23 39,60 21 16.20 13 25.50 34 31.78 34 40.27 15 18.35 24 25.85 66 33.02 28 41.22 22 18,90 71 26,60 16 33.65 23 42.65 8th 19.14 77 27.02 69 33.86 17 44,20 9 19.40 60 27,30 35 35,20 16 20.68 88 28.35 64 35.6? 10

The crystalline hydrate contains 96 to 100%, in particular 99.0 to 99.8%, of the cis-geometric isomer, ie the (Z) -geomeric leromeren on the side chain double bond in the 7-position, regardless of the ratio in Ausgangssetoff. The crystalline hydrate shows a strong absorption band at 1700 cm ^-1 in an IR absorption spectrum in a potassium bromide pellet This band is not found in anhydrous crystals.

Process for the preparation of the crystalline hydrate

(1) general procedure

The crystalline hydrate can be prepared according to the following procedure. The starting material 7432-S is dissolved in an aqueous acid and, to obtain crystals, the pH of this solution is raised at 0 to 70 ° C., in particular to a value of 1.5 to 5.0. Optionally, the mixture is stirred to complete the crystallization. The wet crystals are separated and dried at about room temperature and atmospheric pressure in an inert gas having a relative humidity of at least 15%.

(2) starting material

The starting material may be moist or anhydrous. It may be a free compound or a salt of the amino group, for example, an acid addition salt, or the carboxyl group, for example, an alkali metal salt.

(3) acid

The aqueous acidic solution of 7432-S can be prepared by suspending the free acid or an ammonium salt or by dissolving a carboxylate salt as the starting material in water followed by the addition of an acid; the acid can be an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid a carboxylic acid such as acetic acid, malic acid, fumaric acid of citric acid, a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid or toluenesulfonic acid, an acidic salt such as dimethylamine hydrochloride or 7432-S-sulfate or a similar hydrophilic acid which acidify the aqueous solution of the starting material may be. Preferably, about 0 to 20, in particular 1 to 10, molar equivalents of the acid are used.

(4) co-solvent

The aqueous solution may be 0 to 70% of a water-miscible organic solvent, for example, an alcohol such as methanol, ethanol, isopropanol, tert-butanol or methoxyethanol, an amide such as dimethylformamide, a NiUlI ₁ such as acetonitrile, a sulfoxide such as dimethylsulfoxide , an ether such as dioxane, tetrahydrofuran or dimethoxyethane, or a ketone such as acetone or methyl ethyl ketone as a co-solvent.

(5) concentration

The concentration of the starting material in the aqueous acidic solution is preferably in the range of 2.0 to 15.0%, especially 3.0 to 5.0%.

(6) Neutralization

May set a solid or liquid base, with which one cie aqueous acidic solution to the predetermined pH may be from about 0 to 7O ⁰ C, preferably 10 to 5O ⁰ C, (for classifying an aqueous acidic solution to the isoelectric point pH Value of about 1.5 to 5.0, especially 2.0 to 3.5) are used. Alternatively, the acidic solution may be diluted with water to increase the pH so that the hydrate can be separated. Typical examples are organic bases such as triethylamine, and inorganic bases such as ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, in which water-soluble compounds are usually handled. A water-insoluble base, e.g. As an anion exchange resin, can also be used for this purpose.

(7) crystallization

For separation or maturing of the crystals, the suspension is stirred to be separated crystals preferably at 0 to 70'C, especially 5 to 35 ⁰ C, 10 minutes to 50 hours.

(8) drying

The drying takes place vorz; Example under mild conditions by stationary, flow, circulating air or fluidized bed drying processes in an inert gas such as air, nitrogen or carbon dioxide, at a relative humidity of at least 15% at about 0 to 60 ⁰ C under atmospheric pressure, depending from the stirring conditions or the flowability of the powder

 On a laboratory scale the following was found:

For example, when dried under atmospheric pressure in a closed container, the water content of the diorethrhydrate corresponding orete plateau in air of a relative humidity of at least 45%, in particular 60 to 80%, at less than 35 ⁰ C, in particular 10 to 26 ⁰ C. In 1 to 8 hours, the dihydrate corresponding second plateau in air of a relative humidity of 16 to 60%, in particular 20 to 30%, at 26 to 60 ⁰ C within 1 to 8 hours. In a flow or Umlufttrockriung orhölt one, depending on the stirring conditions or the flowability of the powder, for example, if the flow drying in air of a relative humidity of 60 to 60% at 26 to 40 ⁰ C to the inflection point of '(urve is performed In which the time is plotted against the temperature of the outflowing air or the time against the humidity (otwa 2 to 10 hours, when the starting material contains 30 to 60% water), a product containing as the main component of the dihydrate.

When the drying is carried out according to the fluidized bed method, one obtains depending on the flow conditioner

the air, for example when drying with air of a relative humidity of 50 to 60% at 10 to 35 ⁰ C, in particular 20 to 30 * C, to the first inflection point of the curve in which the time against the temperature of the outflowing air or Time is plotted against the moisture of the effluent air (about 1 hour when the starting material contains 30 to 60% water), a product corresponding to the trihydrate and to the second inflection point of the same curve (about 1.5 hours when the Starting material contains 30 to 60% water) a product containing the dihydrate as the main component.

For a large-scale production, the circulating air drying, Ourchflußtrocknung and drying after the Fluidized bed process can be used. In a typical case of the fluidized bed process, one obtains depending on the flow rate of the air per Gowicht the damp crystals or other conditions, bai drying in air of a relative humidity of 20 to

80%, in particular 50 to 60%, at 10 to 60 ⁰ C, in particular 20 to 30 ⁰ C, until the first inflection point of the curve, in which the time against the temperature of the outflowing air or the Zoit against the moisture of the outflowing air ( about 1 to 5 hours when the starting material contains 30 to 60% water) is applied to the crystalline trihydrate, and to the second

Turning point (about 3 to 7 hours, when the starting material contains 30 to 60% water) dt * crystalline dihydrate as Main component. The drying at a temperature higher than about 60 ⁰ C in the presence of a drying agent, under reduced pressure or

similarly strict conditions, reduces the water of crystallization to less than 2, so that an unstable product is formed.

For example, the drying at 25 to 28 ⁰ C via calcium chloride at a pressure of 1.33 Pa, the water content lowers

1.5 to 4.8% within 3 hours. Drying in dry nitrogen by the forced air method at 25 ⁰ C within 30 minutes reduced the water content to 1.08%.

Use of the crystalline hydrate A pharmaceutically effective amount of the crystalline hydrate may be in the form of an oral composition (especially Capsules, granules or tablets) for the prevention or treatment of bacterial infections. In a

In another embodiment, the crystalline hydrate may be stored for reuse after a certain period of time

become. .

The examples illustrate the invention. The water content was determined by the Karl Fischer method. embodiments

I. hydrates

example 1 A solution of 25g crude 7432-S in 75ml 6N hydrochloric acid is allowed to stand for 1 hour at 15 to 20 ° C to give the Hydrochloric!

separate. The crystals are filtered off, washed with 75 ml 1 drop of concentrated hydrochloric acid-containing acetonitrile and dried. 18g of crystalline 7432-S-hydrochloride monohydrate are obtained.

A solution of 1.0 g of this monohydrate in 4 ml of 3N hydrochloric acid is added to one by adding 30 ml of water and a base

Adjusted pH of 1.5 and then stirred at 25 to 45 ⁰ C for 2.5 hours. The precipitated crystals are filtered off and washed with

Washed water. The crystals are dried with a circulating air dryer for 5 hours at 10 ° C. It will be 0.7 g of crystalline

7432-S hydrate with a water content of 10.2%. The ratio of the geometric isomers cis / trans is

Example 2

1.17 g of crude crystalline 7432-S are suspended in a mixture of 3 ml of tert-butanol and 3 ml of acetonitrile. This suspension is added with 1 ml (5 molar equivalents) of 35% hydrochloric acid to obtain a solution. The solution is diluted with a mixture of 3 ml of tert-butanol, 9 ml of acetonitrile and 5 ml of water, the pH is adjusted to 2.3 with triethylamine and the solution bsi 30 to 35 ⁰ C for 3 hours. The precipitated crystals are collected, washed with 5 ml of a mixture of acetonitrile, tert-butanol and water (2: 1: 1) and washed with 10 ml of water and then dried with a flow dryer at 25 to 3O ⁰ C for 2 hours. There are obtained 1.06 g of the crystalline hydrate with a water content of 8.76%. The ratio of geometric isomers cis / trans is 99.2: 0.8.

Example 3

To a suspension of 1.0 g of crude crystalline 7432-S in a mixture of 8 ml of water and 1 ml of acetonitrile is added 0.41 g (2 molar equivalents) of sodium bicarbonate to give a clear solution. This solution is diluted with 6 ml of methanol and spiked with 0.1 g of activated charcoal. The solution is stirred at room temperature for 10 minutes and then the activated carbon is filtered off. The filtrate is acidified with 1.62 ml (4.6 molar equivalents) of 6N hydrochloric acid and poured into a mixture of 3.4 ml of water and 6 ml of acetonitrile. The gomish is adjusted to a pH of 2.3 with 30% potassium carbonate, stirred for 1 hour at 40 ^° C. and for a further 1.5 hours at 20 to 25 ^° C. The precipitated crystals are collected, washed successively with 5 ml of a mixture of methanol, acetonitrile and water (1: 1: 2), 20 ml of water and 6 ml of methanol and then dried for 1.6 hours at 20 to 25 ⁰ C with oinom Durchflußtrocknor. There are obtained 0.876 g of crystalline hydrate having a water content of 9.35%. The ratio of the geomeric isomers cis / trans is 99.6: 0.4.

BeUpIeU

A solution of 1.848 g (3 mol equivalents) of sodium bicarbonate in 42 ml of water is mixed with 4.66 g of crude crystalline

7432-S offset. The solution is treated with 19 ml of acetonitrile, 2.34 g of active alumina and 0.466 g of AHvkohlo, stirred for 30 minutes at 16 to 20 ⁰ C and filtered to remove the activated carbon and the alumina. The filtrate is in a

Mixture of 37ml acetonitrile, 3.95g 62% lgor sulfuric acid and 28ml water. The mixture is at 20 to 25 ⁰ C with

aqueous 30% potassium carbonate to adjust to a pH of 3.0 and stirred for 30 minutes at the same temperature. The precipitated crystals are filtered off and dried for 2 to 3 hours at 20 to 25 ⁰ C with a circulating air dryer. There are obtained 4.384 g of crystalline hydrate with a water content of 12.2%. The ratio of geometric isomers cis / trans is 99.6: 0.4.

Under similar conditions, a solution of 1.0 g of 7432-S in 12 ml of aqueous sodium bicarbonate is treated with active alumina and activated carbon. The solution is diluted with 6 ml of a solvent (water, isopropanol or acetonitrile) and acidified with 8 molar equivalents of 85% phosphoric acid. Subsequently, the pH is adjusted to 3.0 with aqueous 30% potassium carbonate at 20 to 25 ⁰ C and the solution was stirred at the same temperature for 30 minutes. The precipitated crystals are filtered off and dried for 2 to 3 hours at 20 to 25 ⁰ C in a flow dryer. About 0.9 g of crystalline hydrate having a water content of 11.0% is obtained. The ratio of geometric isomers cis / trans is 99.2 to 99.7: 0.8 to 0.3.

Under the same conditions, with 4 molar equivalents of methanesulfonic acid instead of the phosphoric acid, 0.879 g of the crystalline hydrate having a water content of 11.4% is obtained. The ratio of geometric isomers cis / trans is 99.6: 0.4.

example

To a suspension of 2.0 g of crude crystalline 7432-S in a mixture of 18 ml of dimethoxyethane and 2 ml of ethanol is added 0.89 ml (1.3 molar equivalents) of 6N hydrochloric acid at 2 to 5 ° C and the mixture is then allowed to stand for 2 hours . the same temperature for the precipitated crystals of the hydrochloride is filtered, washed with 10ml of a mixture of dimethoxyethane and ethanol (9: 1). washed and 10 ml of acetonitrile and dried for 2 hours at 25 to 3O ⁰ C are obtained 1,878g of the hydrochloride.

An assay of 1% of this hydrochloride in a mixture of 6 ml of methanol and 5 ml of water is dissolved by the addition of 0.61 g (3 molar equivalents) of sodium bicarbonate. Dtase solution is mixed with 0.1 g of activated charcoal, stirred for 10 minutes at 25 to 30 ⁰ C and the activated carbon filtered off. The filtrate is poured into a mixture of 1.01 ml (4 molar equivalents) of 35% hydrochloric acid, 3 ml of water and 6 ml of acetonitrile, the pH is adjusted to 3.0 with aqueous 30% potassium carbonate and the solution is stirred for 30 minutes at 25 to 30 ° C and 1 hour at 5 to 7 ⁰ C stirred. The precipitated crystals are filtered off, washed successively with 5 ml of ethanol and 10 ml of water and dried for 2 hours at 20 to 25 ⁰ C in a flow dryer. There are obtained 0.82 g of the crystalline hydrate with a water content of 10.6%. The ratio of geometric isomers cis / trans is 99.5: 0.5.

Examples A solution of 1.3 g (2.2 molar equivalents) of sodium bicarbonate in 18 ml of water is mixed with 3.0 g of crude crystalline 7432-S

added. The solution is treated with 1.5 g of active alumina and 0.3 g of activated carbon, stirred for 30 minutes at 20 to 25 ⁰ C and the activated carbon and the alumina filtered off. The filtrate is poured into a mixture of 17 ml (10 molar equivalents) of malic acid and 36 ml of acetonitrile. The mixture is adjusted hydrogenated at 20 to 25 ⁰ C with aqueous 30% potassium carbonate to a pH value of 3.0, and stirred at the same ^T emperature for 30 minutes. The precipitated crystals are filtered off and dried for 2 hours at 20 to 30 ⁰ C in a circulating air dryer. There are 2,665g of the crystalline hydrate with a

Water content of 11.7%. The ratio of geometric isomers cis / trans is 99.1: 0.9. Under the same conditions, using 10 molar equivalents of fumaric acid instead of the malic acid)

obtained crystalline hydrate with a water content of 10.1%.

Similarly, a solution of 1.0 g of 7432-S in aqueous sodium bicarbonate with active alumina and Activated carbon treated. The solution is treated with a solution of 4 molar equivalents of formic acid in aqueous acetonitrile

mixed. The mixture is treated as described above to give 0.925 g of crystalline hydrate having a water content of 12.7%. The ratio of the geometric isomers cis / trans is 99.8: 0.2. The specified amount

Formic acid can be increased to 75 mol equivalents to give the same crystalline hydrate. Example 7 Samples of each 1 g of 7432 S hydrate prepared according to the method of Example 3 are sealed Container, the relative humidity of which is selected by selecting a suitable desiccant to values of 0%, 12%,

20%, 44%, 67% and 75%, respectively, and the samples are stored at room temperature for β hours. Then the

Water content of each sample is determined by the Ksr Fisher method, with values of 1.05%, 5.83%, 8.54%, 11.21%, 12.19% and

12.21% can be obtained.

The values show that the major component at a relative humidity of 20% is the dihydrate (calculated Water content 8.07%) and at a relative humidity of more than 44% the trihydrate (calculated water content When the drying process is continued for 30 hours, the loss of water content is in the period of β to 30 hours

less than 0.2% at relative humidity of more than 20%.

Example 8

Probonion of 1 g of 7432-S prepared according to the method of Example 3 are each placed in tightly sealed containers, the relative humidity being 20%, 44%, 57% and 75%, respectively, by selecting a suitable desiccant, and 1 Month boi 40 ⁰ C held. Then, the water content jodor sample is determined according to Karl-Fischor-Mothodo to obtain values of 7.92%, 10.69%, 11.73% and 12.4%, respectively. The loss of water content in the period of 30 hours to 1 month provides less than 0.5%. Dlos shows no constant water content.

II. Sealed capsules In Examples 9-14 below and Examples 1 to 6, the 7432 S hydrate is in crystalline form with a Water content of 10% (determined by dor Karl Fischer Methodo). Example 9

1 kg of the hydrate, 1.18 kg of crystalline cellulose and 0.02 kg of magnesium stearate (each 0.25 mm, 60 mesh powder) are mixed for 20 minutes using a 10 liter V-type mixer. Each 253 mg of the mixed powder is filled into a white Hartfjelatinekapsel no.2 containing 3.5% titanium dioxide. Subsequently, the gelatin sealing solution (17 to 26 mg at 60 ° C, aqueous solution of 21.13% gelatin and 2% Polysorvate 80) along the transition between the cap and the body of the capsule using a hard-capsealer S-100 (Japan Elanco Company) and dried for 5 minutes at room temperature in a stream of air. The product contains 100 mg of active ingredient 7432-S per capsule.

Example / 0

1 kg of the hydrate, 1.9 kg of lactose and 0.1 kg of hydrogenated Castorö! (each 0.25 mm, 60 mesh powder) are mixed for 20 minutes using a 10 liter V-type mixer. Each 172 mg of the mixed powder are filled into a white Hartge'atine capsule No.2, containing 6% titanium dioxide. Then, the gelatin-sealing solution is (20 to 25mg at 55 ^C C aqueous solution of 22% gelatin, 5% glycerol and 30% ethanol) along the junction between the cap and body of the capsule by using a capsule-Hard-Dichtungsmasc'.iine S-100 (Japn Elanco Company) and dried for 5 minutes at room temperature in a stream of air. The product contains 50mg active ingredient 7432-S per capsule.

Bel 'pl' M1

1 kg of hydrate, 0.5 kg of crystalline cellulose and 0.02 kg of powdered carnauba wax (powder of 0.25 mm, 60 mesh) are mixed for 20 minutes using a 10 liter V-type mixer. Each 171 mg of the mixed powder is filled in a Wfiißo hard gelatin capsule No. 4, which contains 2.1% of titanium dioxide. Subsequently, the gelatin sealing solution (10 to

20 mg at 60 ° C, aqueous solution of 22% gelatin and 2% Polysorvate 80) along the transition between cap and body capsule using a hard-capsule sealing machine S-100 (Japan Elanco Company) applied and 4 minutes at room temperature dried in a stream of air. The product contains 100mg active ingredient 7432-S per capsule.

dalipiel 12

According to the method of Example 9, using a transparent hard gelatin capsule No. 4, a capsule

zuboreitet.

Example 13

Following the procedure of Example 9 using a non-transparent blue hard gelatin capsule No.4, blue dye No. 1 (trace blue dye No. 1 according to JSFA, brilliant blue FCF), red dye Ni. 3 according to JSFA, erythrosine) and titanium dioxide, one capsule prepared. ₍

Example 14

Following the procedure of Example 9, using a non-transparent red hard gelatin capsule! No.4. The blue dye No. 1, red dye No. 3, yellow dye No. 5 (yellow Ti ^ No. 5 according to JSFA, sunset yellow FCF) and titanium dioxide contains a capsule prepared.

Vergloichsbelsplel 1

1 kg of the hydrate, 1.08 kg of crystalline cellulose, benzylhydroxyanisole as an antioxidant (10 mg of 0.25 mm powder, 60 mesh) and 0.02 kg of magnesium stearate are mixed in a 10 liter V-type mixer. In each case 253 μm of the mixed powder are filled into white hard gelatine capsule No. 2, which contains 3.5% of titanium dioxide. The product contains 100 mg of the active ingredient 7432-S per capsule.

Verglolchsbelsplel 2

1 kg of hydrate, 1.18 kg of crystalline cellulose and 0.02 kg of magnesium stearate (powder of 0.25 mm, 60 mesh) are mixed for 20 minutes in a 10 liter V-type mixer. In each case 253 mg of the mixed powder are placed in a white hard gelatine capsule No. 2 containing 3.5% of titanium dioxide. The product contains 100mg active ingredient 7432-S per capsule.

Verglelchsbelsplele 3 to 6 Capsules of Examples 11 to 14 before application of the gelatin sealing solution are used as capsules of Comparative Examples 3 to

used for the following investigations.

Investigations with capsules

The following experiments demonstrate the stability of the compositions described below. HPLC conditions are observed; As a column Polygosil 6O ₁₀ Cu 4mm x 250mm (M. Nagel &Co.); aqueous mobile phase 0.05M ammonium acetate / methanol (96/4); Flowing coagulum 1,5ml / minuto, as internor standard nicotinamide, UV determination at 264nm.

Trial 1

Jewell "10 capsules are placed in a 600 ml glass vial, sealed and placed in a chamber at 45 ± TC

kept. The content of 7432-S is determined monthly by HPLC for 4 months.

Table II shows the donlobloon Gohalt dos drug in%, prefers with dom content of freshly prepared capsules. A capsule without the seal, regardless of whether an antioxidant is present as a stabilizer, is obviously less stable,

compared to the previous invention.

tables

capsule Example 9 Example 10 Comparative Example 1 Comparative Example 2 month 1 Salary (%) 3 4 99.4 98.0 96.7 94.5 2 94.2 93.4 86.3 87.3 91.8 91.2 81.4 80.4 Invention comparison 96.5 95.8 93.0 89.4

Trial 2

Each 10 capsules are stored on white thick paper in a chamber at 25 ± 1 ° C and irradiated with a Fiuoreszenziampe of 10,000 lux. The content of the 7432-S is determined monthly by HPLC for 2 months and the color change in NBS color hues is determined using a color difference meter (Color-Studio of Nihon Densyoku Kojjyo). The values of the parts II! show the residual content and color change in NBS units compared to those made by frisc'i capsules.

Table III

Comparison Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Examples

capsule Example 11 Examples Example 13 Example 14 month Salary (%) / NBS unit 2 1 100.2 / 1.47 100.0 / 2.85 99.8 / 3.00 100.1 / 2.61 invention 99.7 / 0.68 100.1 / 1.35 100.1 / 0.07 99.7 / 0.04

98.3 / 1.62 98.0 / 6.9 " 97.0 / 4.06 96.1 / 7.33 98.0 / 3.23 98.3 / 8.12 99.6 / 0.87 99.8 / 4.65

An NMS unit is a unit of color difference according to U.S. Pat. National Bureau of Standards. The following list shows the criteria for appearance.

LIST

NBS unit difference NBS unit difference

0-0.5 0.5-1.5 1.5-3.0

insignificant

geling

significant

3.0-6.0

6.0-12.0

> 12.0

clear

large

sehrproß

It is apparent from the experiments that the compositions made according to the invention keep the 7432-S stable, even under accelerated conditions such as heat or irradiation, and protect it from color change. Contrast colors for the capsule and sealing solution can be chosen freely and make it easier to find a damaged Dlchtunjstripe.

Claims (8)

A process for the preparation of a hard gelatin capsule composition of a crystalline hydrate of the 7β - [(Z) -2- (2-aminothiazol-4-yl) -4-carboxybut-2-enoylamino] -3-cephem-4-carboxylic acid with the following X-ray structure analysis values: characterized in that applying an aqueous solution of gelatin containing a lower alkanol, ether, ketone or ester, along the transition between the cap and body of the capsule and dried at 0 to 80 ⁰ C. 2. The method according to claim 1, characterized in that the composition contains a filler such as glucose, fructose, lactose, corn starch, potato starch, crystalline cellulose, methyl cellulose or methyl ethyl cellulose. 3. The method according to claim 1, characterized in that the composition contains a lubricant such as purified talc, stearic acid, sodium stearate, magnesium stearate, calcium stearate, borax, liquid paraffin, sodium benzoate, polyethylene glycol, carnauba wax or hydrogenated oil. 4. The method according to claim 1, characterized in that the aqueous solution of gelatin contains 10 to 30% gelatin. 5. The method according to claim 1, characterized in that the aqueous solution of gelatin 10 to 40% methanol, ethanol, propanol or glycerol or 0.5 to 10% Pol / oxyäthylensorbitanmonooleat. 6. The method according to claim 1, characterized in that the aqueous solution of gelatin contains pharmaceutically acceptable dyes or pigments. 7. The method according to claim 1, characterized in that the amount of gelatin solution per capsule is between 5 and 50mg. 8. The method according to claim 1, characterized in that the drying process takes place at 0 to 8O ⁰ C in an air stream or by heat.