FI67855B - FRAMEWORK FOR THE FRAME STATION AND THE CRYSTALLINE CRYSTALLINE LAETTLOESLIGT CEFAZOLIN SODIUM - Google Patents

Description

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* 'a 1 “n' c L ': v' ^ (51) Kv.lk.4 / lnt.CI.4 c 07 D 501/12, 501/36 FINLAND —- FINLAND (21) Patent application - Patentansökning 773563 ( 22) Date of application - Ansöknlngsdag 24.11.77 ^ ^ (23) Starting date - Giltighetsdag 24.11.77 (41) Has become public - Blivit offentlig 25.05.79 National Board of Patents and Registration Date of publication and hearing— patent-och registerstyrelser »'Ansökan utl» och utl.skriften publicerad 28.02.85 (32) (33) (31) Privilege requested - Begärd priority (71) Eli Lilly and Company, 307 East McCarty Street, Indianapolis,

Indiana 46206, USA (72) Michael Borns ^ ein, Carmel, Indiana, Michael David Cise, Indianapolis, Indiana, USA (US) (74) Oy Kolster Ab (54) Process for the preparation of mainly crystalline, readily soluble cefazoline sodium - Förfarande för framstä11 Ning c ett väsentligen kristallini lättlösligt cefazolinnatrium

Sodium salt of crystalline cefazoline sodium (7- (1- (1H) -tetrazolylacetamido) -3- [2- (5-methyl-1,3,4-thiadiazolyl) thiomethyl] -3-cephem-4-carboxylic acid, standard antibiotic ) is carried out according to the invention by a freeze-drying process.

Cefazoline sodium is usually prepared as a dry powder that is dissolved in an aqueous diluent just prior to use. The dry powder should be mainly in crystalline form, as amorphous cefazoline sodium tends to decompose during storage and dissolves slowly.

The invention thus relates to a process for the preparation of mainly crystalline, readily soluble cefazoline sodium having the formula 2,67785 Γ “| °

N. N —CH - CNH S

V /> —f "'

I I j N ------ N

^ N r ,, i j || 1) by maintaining a cooled, solid solution of cefazoline sodium at not more than 1 mmHg in absolute pressure, 2) by raising the temperature to not more than 50 ° C to avoid melting the preparation, and 3) by sublimation of the solvent, characterized in that a) cefazoline sodium is dissolved in a solvent containing 2-25% by volume of C 1 -C 4 alkanol and 75-98% by volume of water, b) the solution is slowly cooled over 3-12 hours to -10 ° C and c) the solution cooled to -10 ° C is further cooled until it is completely solidified, after which cefazolin sodium crystals containing not more than 6.0% by weight of water are obtained in a manner known per se according to 1) to 3). and up to 1.0% by weight of alkanol.

Freeze-drying is an old and often used method for removing solvent from a solute. Although this method is cumbersome, expensive and slow, it can separate the solvent without damaging thermolabiles. For many years, this method has been used to make antibiotics and other drugs, as well as foods, especially instant coffee. The solution from which it is desired to recover the solute is usually cooled to a solid and subjected to a strong vacuum and the temperature is raised to sublime the solvent. The ambient temperature is kept below the value that would thaw the frozen solution. The ambient temperature is coordinated with the vacuum to obtain the maximum reasonable rate of sublimation while avoiding melting of the frozen mass.

In the freeze-drying, water is usually used as the solvent. Other solvents or combinations thereof may be used, but only those which solidify in the temperature range which can be used in the process and which sublime in vacuo.

When drying antibiotics and other drugs by freezing, the classical process outlined above has previously been followed, i. in which a solution is prepared, cooled to a solid, subjected to a strong vacuum, heat is added, the solvent is sublimed. However, in this conventional procedure, cefazol line sodium is obtained as a slowly dissolving powder.

Cefazoline sodium can be recovered from organic solvents as satisfactorily crystalline.

However, such crystalline cefazoline sodium causes other problems. For example, there is no known effective way to sterilize cefazoline sodium extracted from organic solvents, so the entire crystallization process must be performed in an aseptic environment. In the complex process required to crystallize cefazoline sodium, contaminating contaminants have many opportunities to enter the product. Moreover, a device for filling an ampoule with dry matter has not yet been developed so that the amounts of substance are uniform and accurate as when filling a liquid.

U.S. Patent 4,029,655 discloses a cooling-drying process for preparing crystalline cefazoline sodium. The process involves the very rapid cooling of an aqueous solution to form crystalline nuclei of cefazoline sodium. In this case, most of the cefazoline sodium crystallizes from solution before the water freezes. Thus, when the sublimation process is started, cefazoline sodium is already crystalline and no crystallization occurs when the solvent is removed. The solvent is sublimed and cefazoline sodium remains.

Although stable, sterile, crystalline cefazoline sodium is obtained in this process for parenteral drug delivery, the resulting crystals do not rapidly dissolve in pharmaceutically acceptable diluents. Generally, vigorous shaking for two or more minutes is required to reconstitute cefazoline sodium. This is a relatively long time when preparing a solution for injection.

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The C 1 -C 4 alkanol used in the process of the invention may be methanol, ethanol, propanol or isopropanol. Of course, mixtures of alkanols as well as denatured ethanol can also be used, as long as the denaturant is pharmaceutically acceptable or volatile. A particularly suitable alkanol is ethanol denatured with methanol. Preferred alkanols are ethanol and denatured ethanols.

In the process according to the invention, cefazoline sodium is dissolved in a solvent containing 2 to 25% by volume of alkanol and 75 to 98% by volume of water. The solution is then placed in an environment where it is slowly cooled from room temperature to -10 ° C. The cooling time should be 3-12 hours, during which time 50% or more of the dissolved cefazoline sodium crystallizes from solution before freezing begins.

After slow cooling to 3-12 hours, the cooled solution is further cooled until the mixture is completely solidified. After the critical steps described, conventional freeze-drying is used to sublime the ice to give cefazoline sodium crystals with a water content of up to 6% and an alkanol content of up to 1%.

These crystals are stable at room temperature for at least 3 years and dissolve in a minute or less in a pharmaceutically acceptable diluent at a concentration suitable for parenteral administration. By improving the dissolution properties of the cefazoline sodium prepared by the described method, its dissolution rate is about 50% higher than that of the cefazoline sodium crystals prepared in the usual manner.

The invention is based on the use of an alkanol-water solvent and the slow cooling of the cefazoline sodium solution to -10 ° C. Thanks to the alkanol in the solvent, the solution can be cooled to -10 ° C without the formation of ice. It has been found that cefazoline sodium is less soluble in an alkanol-water solvent than in water alone. At -10 ° C, 50% or more of the cefazoline sodium thus crystallizes out of solution before ice begins to form. In addition, by slowly lowering the temperature of the solution from room temperature to -10 ° C, the crystals formed are large with a small surface area compared to the crystals, 5 67855 obtained from conventional freeze-drying of cefazoline sodium.

As soon as ice begins to form, the temperature of the solution is preferably lowered rapidly to promote the formation of dendritic ice, which promotes the formation of crystalline nuclei of cefazoline sodium remaining in solution. In the preferred method, the temperature is rapidly reduced to -30 ° to -40 ° C and held for 1-2 hours to ensure complete freezing.

The alkanol-water solvent used in the invention may contain 2-25% by volume of alkanol and 75-98% by volume of water. The preferred solvent contains 10% by volume of alkanol and 90% by volume of water. A suitable concentration of cefazoline sodium in the solvent is 20-40% w / v, preferably 23-28% w / v.

The crystalline product is preferably sterilized by sterile filtration of the aqueous alkanol solution in a known manner and collecting the filtrate in a sterilized container before the start of the freeze-drying according to the invention. Sterile filtration can be performed, for example, with a filtration press using heat-sterilized asbestos, or using a membrane filter with a porosity of less than 0.22 μm. This makes the whole solution sterilized and the crystalline product is certainly sterile.

Slow cooling of cefazoline sodium is best accomplished by first maintaining it at a temperature of about 15 ° C and slowly lowering that temperature to about 4 ° C every thirty minutes until the temperature of the solution remains at -10 ° C. The temperature of a solution can be determined by placing a thermocouple approximately in the center of the solution, where it indicates the temperature.

Once the temperature of -10 ° C has been reached, the solution can be cooled rapidly until the mixture has completely solidified. The cooling rate is not critical. It is obviously not advisable to lower the temperature below -40 ° C. If the temperature of the frozen solution is lowered to about -30 ° C or lower, a period of 1-2 hours is sufficient to completely cure the mass. In this case, cefazoline sodium is mainly in the form of completely free crystals in the frozen mass.

When cefazoline sodium is substantially completely crystallized, conventional freeze-drying is used to sublimate the solvent from the frozen mass, leaving mainly crystalline cefazoline sodium. The frozen cefazoline sodium preparation is maintained in an environment where the absolute pressure can be reduced to less than 1 germHg, preferably to a pressure of 0.05 to 0.2 mmHg.

When the pressure is reduced to the operating level, the temperature is raised to the point where the highest sublimation rate is obtained without thawing the frozen mass. As a general rule, temperature and pressure are inversely related, the more effective the pressure reduction, the higher the temperature that can be used in sublimation. As a general guideline, a maximum temperature of 50 ° C can be achieved with a very efficient vacuum system in which the absolute pressure is kept at about 0.05 mmHg. In any case, the temperature must be raised slowly to avoid overloading the depressurization system, which could lead to harmful thawing of the frozen mass. The ambient temperature during the sublimation should preferably be kept in the range of 10 to 40 ° C and the absolute pressure at 0.2 mmHg or lower.

Sublimation of the ice from the frozen mass is continued until the water content of the cefazoline sodium crystals is less than 6% by weight and the alkanol content is less than 1% by weight. This ensures the physical stability of the resulting crystals. Cefazoline sodium crystallizes as pentahydrate. Keeping the crystals at 25-30 ° C after the ice has been completely sublimated converts the pentahydrate to a hemihydrate which may contain up to about 6% by weight of water.

Cefazoline sodium prepared as described is predominantly crystalline. For example, physical analysis of cefazoline sodium hemihydrate showed a degree of crystallinity of greater than 90%. In any case, a sufficiently high crystallinity was obtained to achieve storage stability. Cefazoline sodium crystals can be filled into sterile pre-sterilized ampoules in appropriate amounts to provide a parenteral reconstituted solution for injection.

In a preferred embodiment of the invention, an additional step is added to the procedure described above, in which a pre-sterilized ampoule is filled with an amount of sterile aqueous alkanol-solution containing the desired amount of cefazoline sodium in the ampoule after freeze-drying. Ampoules containing cefazoline-7 67855 sodium solution are then treated as described above. The resulting freeze-dried ampoule of cefazoline sodium is ready to be sealed.

Freeze-drying in an ampoule provides at least two advantages. First, a more accurate and consistent amount of cefazoline sodium can be measured in the ampoule as a liquid than as a solid (crystals). And second, it is much easier to achieve and maintain sterile conditions in liquid filling than in dry filling. In addition, air pollution is a lesser problem when handling liquids than when handling dry substances.

The following examples further illustrate the invention.

Example 1 348 grams of cefazoline sodium having a moisture content of about 3.5% was dissolved in water (for injection purposes), and the volume of the resulting solution was adjusted to 1200 ml by adding water,

To a 1200 ml aqueous solution of cefazoline sodium was added 120 ml of absolute ethanol with vigorous stirring.

The ethanolic aqueous solution of cefazoline sodium was filtered through a 0.45 μm Millipore membrane into a suitable vessel.

The ethanolic aqueous solution of cefazoline sodium was filled into sterilized vials at 4.35 ml per vial. The amount of solution was calculated to give 1 gram of cefazoline sodium ampoules in an excess of about 7%.

The filled vials were placed in a conventional freeze-dryer and the temperature of the solution was slowly lowered to -10 ° C over 3-4 hours, and then the temperature was lowered below -30 ° C as quickly as possible. Once the frozen mass reached a temperature below -30 ° C, the vials were kept at this temperature for 1-2 hours.

The pressure in the freeze dryer was reduced to less than 0.2 mmHg absolute pressure and the temperature was raised to 10 ° C for sublimation of the ethanol-water solvent. Finally, the temperature was raised to 25 ° C while being careful not to thaw the frozen mass in the vial. When the sublimation was completed, the vacuum was removed and the water and ethanol content of the product as well as the recrystallization time were examined.

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Typical water contents in the various vials were 2.16, 2.11, 2.05 and 2.24% by weight. When examining the ethanol content for two vials, the values were 0.42 and 0.45% by weight.

The redissolution time of the cefazoline sodium in the five vials in 2.5 ml of water was 3-60 sec.

Example 2 1 g of cefazoline sodium was dissolved in 3 ml of water, and 1 ml of 95% methanol was added to the solution. The solution was placed in an ampoule and lyophilized in the same manner as in Example 1. When the process was completed, the dried product was examined under a microscope to find that it consisted mostly of crystalline cefazoline sodium.

Example 3 1 g of cefazoline sodium was dissolved in 3 ml of water, and 1 ml of 95% ethanol was added to the solution. Freeze-drying was performed as in Example 1, and the dried product was examined under a microscope. The product was about 100% crystalline cefazoline sodium.

Example 4

A solution of 1 g of cefazoline sodium and 3 ml of water was made at room temperature. To the solution was added 1 ml of isopropanol, and the solution was lyophilized according to Example 1. On microscopic examination, the dried product was found to consist of about 100% crystalline cefazoline sodium.

Example 5 1 g of cefazoline sodium was dissolved in 3 ml of water and 1 ml of n-propanol was added. The aqueous-alcoholic solution was freeze-dried according to Example 1, and the product was examined under a microscope. It was found to consist of crystalline cefazoline sodium and contained essentially no amorphous compound.

Claims (1)

A process for the preparation of mainly crystalline, readily soluble cefazoline sodium of the formula s 67855 Claim N-N! I?, N N —CH - CNH S 2 \ _____ S \! | NN d_N AI il 0 "\ ^ XCH S_i J! COONa ö ^ n3 1. by maintaining a cooled, solid solution of cefazoline sodium at not more than 1 mmHg in absolute pressure, 2. by raising the temperature to not more than 50 ° C to avoid melting the preparation, and 3. by subliming the solvent, known that a) cefazoline sodium is dissolved in a solvent containing 2-25% by volume of C 1 -C 4 alkanol and 75-98% by volume of water, b) the solution is slowly cooled to -10 ° C over 3-12 hours, and c) The solution cooled to -10 ° C is further cooled until it is completely solidified, after which cefazoline sodium crystals containing not more than 6.0% by weight of water and not more than 1.0% by weight are obtained in a manner known per se according to 1) to 3). -% alkanol.