FI68055B - FOERFARANDE FOER FRAMSTAELLNING AV ETT SNABBLOESLIGT PULVER AVRISTALLINT CEFALOTINNATRIUM - Google Patents

Description

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C (45) r: .tc; .Lli Cj ::: n: Uy 13 J7 19''3 Pa tvn t coc 'do iät (51) Kv.lk//lnt.Ci.' C 07 D 501/12 , 501/3 ** FINLAND — FINLAND (21) Patent application - PatentansSkning 77356 * 4 (22) Application date - Ansökningsdag 2 * 4. 1 1. 77 (23) Start date - Giltighetsdag 2ij 1 1 ~ j ~ j (41) Become public — Blivit offentlig 25.05 * 79

Patent, and the National Board of Registration Date of display and publication. - ftr

Patent and ocean registration 'Ansökan utlagd och utl.skriften publicerad * -7'Uj · οζ> (32) (33) (31) Privilege claimed - Begärd priority (71) Eli Lilly and Company, 307 East McCarty Street, Indianapolis,

Indiana, USA (72) Michael David Cise, Indianapolis, Indiana, Michael Larry Roy, Indianapolis, Indiana, USA (7 **) Oy Kolster Ab (5 * 0 Method for preparing a rapidly dissolving powder of crystalline cephalothin sodium - Förfarande for framstälIning av ett snabblösligt Pulver av kristallini cefalotinnatrium

The preparation of crystalline cefalothin sodium 3- (acetoxymethyl) -8-oxo-Ί-Γ2- (2-thienyl) acetamide [5-5-thia-1-azabicyclo [4.2.07] oct-2-ene-2-carboxylic acid sodium salt) is carried out according to the invention pakastuskuivatusprosessilla.

Cephalothin sodium is usually prepared as a dry powder which is dissolved in an aqueous diluent just before use. The dry powder should be mainly in crystalline form, as amorphous cephalothin sodium tends to decompose on storage and dissolves slowly.

The invention thus relates to a process for the preparation of mainly crystalline, readily soluble cephalothin sodium of the formula ___: τ ___ 2 o 68055

__ CH - C-NH S

Il II 'rf Ί VS ^ L Nv .-' λ ^ H CH2OCOCH3 COONa 1) by maintaining a cooled, solid solution of cephalothin 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 a solvent characterized in that a) cephalothin sodium is dissolved as a 20-40% by weight solution in a solvent containing 2-10% by volume of C 1 -C 4 alkanol or acetone and 98-90% by volume of water; b) cooling the solution to at least -20 ° C; c) heating the cooled solution from step b) to a temperature of -3 ° C to -10 ° C; at which temperature it is kept for at least 3 hours; d) cooling the solution from step c) to at least -20 ° C, after which treatment of the completely solidified solution in a manner known per se according to 1) to 3) gives cephalothin sodium crystals containing not more than 1.0% by weight of water and not more than 1, 0% by weight of C 1 -C 4 alkanol or acetone.

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 sublimation rate 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, cephalothin sodium is obtained as a slowly dissolving powder.

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

However, such crystalline cephalothin sodium causes other problems. For example, there is no known effective way to sterilize cephalothin sodium recovered from organic solvents, so the entire crystallization process must be performed in an aseptic environment. In the complex process required to crystallize cephalothin 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 as accurate as when filling a liquid.

U.S. Patent Application Serial No. 744,552, which is consistent with the present application, discloses a freeze-drying process for preparing crystalline cephalothin sodium from an ethanol-water solution suitable for parenteral drug use.

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

While the process described above provides stable, sterile, crystalline cephalothin sodium for parenteral drug delivery, the process requires more than 24 hours to complete one cycle. As a result, scheduling the use of refrigeration dryers and arranging staff shifts 4 68055 is difficult due to the irregularity of operations. In practice, a cycle time of 28-36 hours from the start of the freeze-drying step is required before it is completed.

In the method according to the invention, this disadvantage is avoided, since it provides crystalline cephalothin sodium which, when reconstituted, is suitable for parenteral drug administration by a freeze-drying method which requires less than 24 hours.

In the process of the invention, cephalothin sodium is dissolved as a 20-40% by weight solution in a solvent containing 2-10% C 1 -C 4 alkanol or acetone and 98-90% water. Such a solution is obtained by heating the solution to a temperature of 70 ° C, at which point complete dissolution. If desired, the resulting solution can be sterilized by filtration. The solution is then introduced into an environment where it is rapidly cooled to -20 ° C or below, preferably to -40 ° C. The cooling step can be completed in 1-3 hours.

After rapid cooling, the frozen solution is heated to a temperature between -3 ° C and -10 ° C and maintained at that temperature for at least three hours to ensure complete crystallization.

After maintaining the frozen solution at a temperature between -3 ° C and -10 ° C for at least three hours, it is again cooled to -20 ° C or below, preferably to -40 ° C.

After the critical steps described above, a conventional freeze-drying step is used to agitate the ice to obtain crystals of cephalothin sodium having a water content of not more than 1% and a C 1 -C 4 alkanol content or an acetone content of not more than 1%. Such crystals have a suitable shelf life of at least three years at room temperature and dissolve in no more than one minute in an acceptable pharmaceutical solvent at concentrations suitable for parenteral drug administration. Compared to the known method, the time required to perform the method is 15-50% shorter.

Essential to this invention is a supersaturated solution of cephalothin sodium prepared in a solvent system, which is rapidly cooled to -20 ° C or below, preferably to -40 ° C, t 1 68055, with a C 1 -C 4 alcohol or acetone acting as an antisolvent in the solvent system and reducing solubility of cephalothin sodium. It was found that cephalothin sodium is significantly less soluble (C 1 -C 4 alcohol or acetone) in aqueous solvent than in water alone. As a result, by heating the frozen solution at a temperature between -3 ° C and -10 ° C, crystallization can be completed in three hours or over a period of 15-20 hours without alcohol or acetone.

The (C 1 -C 4 alcohol or acetone) aqueous solvent used in the process of this invention may contain 2-10% C 1 -C 4 alcohol or acetone and 98-90% by volume water. The preferred solvent system consists of 3-5% by volume of C 1 -C 6 alcohol or acetone and 97-95% by volume of water. In practice, cephalothin sodium is dissolved in water and a portion of a C 1 -C 4 alcohol or acetone, preferably 95% ethanol, corresponding to 4% by volume of the cephalothin sodium solution, is added to this solution.

C 1 -C 6 alcohols that can be used include methanol, ethanol, n-propanol and isopropanol.

A concentration of 20 to 40% by weight of cephalothin sodium in a C 1 -C 4 alcohol or acetone aqueous solvent is sufficient to generate large crystals on freeze-drying. The preferred range is 25-35% by weight. A 30% by weight solution of cephalothin sodium is particularly preferred. In practice, a solution of cephalothin sodium is preferably prepared by dissolving 30 g of cephalothin sodium in water, diluting to 100 grams and adding 3.55 ml of 95% ethanol to give a solution containing about 29% by weight of cephalothin sodium.

The aqueous solution of cephalothin sodium (C 1 -C 4 alcohol or acetone) is sterilized in a known manner, preferably by sterile filtration and collecting the filtrate in a pre-sterilized container. More specifically, sterile filtration can be performed using a heat-thorilized plate and a frame filtration press equipped with an asbestos pad or using a cellulose acetate or nitrate filter membrane or a "candle filter" having a porosity of less than 0.22.

Rapid cooling of an aqueous solution of cephalothin sodium (C 1 -C 4 alcohol or acetone) is best accomplished by bringing the solution to about -40 ° C. The temperature of the solution can be determined by placing a thermocouple in the center of the solution to indicate the temperature at that point.

When a temperature of -20 ° C, or lower, preferably -40 ° C, is reached according to the method described above, the frozen solution is heated to a temperature between -3 ° C and -10 ° C to initiate crystallization of cephalothin sodium. The frozen solution is maintained at that temperature for at least three hours to complete crystallization.

The solution is then cooled to -20 ° C or below, preferably to -40 ° C, to complete solidification. No obvious benefit was observed in keeping the frozen mass at or below -20 ° C, more preferably at -40 ° C after crystallization was complete. At this point, essentially all of the cephalothin sodium is present in the frozen mass as free crystals. The conventional freeze-drying step is then utilized to sublimate the solvent from the frozen pulp, leaving mainly crystalline cefaiotin sodium.

The frozen cephalothin sodium preparation, in which crystallization is practically complete, is introduced into an environment where the pressure can be reduced to a practical maximum of not more than 1 mercury-mm. It is preferred to reduce the pressure to much more than 1 mm of mercury. The best results are obtained if the absolute pressure is between 0.05 and 0.2 mmHg. The latter range is usually easily accessible in both laboratory and commercial freeze-drying equipment. After the ambient pressure is reduced to the level used, heat is conducted to this environment. The ambient temperature is raised to the point where the maximum rate of agitation can be reached without thawing the frozen mass. As a general rule, temperature and pressure are inversely proportional; the more effective the pressure reduction, the higher the temperature that can be used in the annealing step. As a general guideline, a maximum ambient temperature of 50 ° C can be achieved with a very efficient vacuum system in which the absolute pressure is maintained at about 0.05 mm of mercury. In any case, the temperature should be raised slowly to avoid overloading the depressurization system, which can cause unwanted melting of the frozen mass. Preferably, the teaspoon of 7,68055 at ambient temperature during the annealing phase should be maintained between 10 ° C and 40 ° C, and a pressure of 0.2 mm of mercury, or below.

Frosting of the ice from the frozen mass is continued until the water content of the cephalothin sodium crystals is less than 1% and the C 1 -C 4 alcohol or acetone content is less than 1%. Such a specification ensures the physical stability of the resulting crystals. Cephalothin sodium does not crystallize like a hydrate.

Cephalothin sodium, prepared as described above, is predominantly crystalline. For example, physical analyzes of cephalothin sodium showed a crystallinity of 92-100%.

In any case, the degree of crystallinity is high enough to provide storage stability; i. the product does not turn yellow when stored and its microbiological potency is maintained at room temperature for up to three years. When sterile filtration of the cephalothin sodium solution is used in the process, and freeze-drying is performed under aseptic conditions, the cephalothin sodium crystals can be filled into sterile sterilized ampoules for use reconstituted for parenteral drug delivery.

The process according to the invention can advantageously also be carried out by adding a sterile filtered (C 1 -C 3 alcohol or acetone) aqueous solution, measured in such a volume, to the sterilized ampoules as to obtain the desired amount of cephalothin sodium in the ampoules after the freeze-drying step. Ampoules containing an aqueous solution of cephalothin sodium (C 1 -C 4 alcohol or acetone) are then treated in the same manner as described above. The resulting lyophilized cephalothin sodium ampoule is ready for sealing and encapsulation. This method achieves at least two advantages. First, a more accurate and uniform amount of cephalothin sodium can be filled into the ampoule in the form of a liquid than in the form of solid crystals. And second, it is much easier to achieve and maintain sterile operating conditions in liquid filling than in dry filling. In addition, air pollution is a lesser problem when handling liquids than when handling dry substances.

Alternatively, 2-5%, preferably 3% of the amount of cephalothin sodium may be added to the cephalothin solution prior to sterile filtration. Such an addition gives crystalline cephalothin sodium which, after reconstitution, has a neutral pH of approximately 8,68055, which reduces stinging when administered intramuscularly.

The present invention is further illustrated by the following examples.

Preparation of an aqueous solution of cephalothin sodium 500 g of cefaiotin sodium with a water content of 1% was dissolved in 1,166.6 grams of water (suitable for injection).

The resulting aqueous solution of cephalothin sodium was heated at 62 ° C to complete dissolution, and the solution was filtered through a 0.45 μm Millipore membrane into a suitable vessel.

The resulting aqueous solution containing 30% by weight of cephalothin sodium was used in 50 ml of the following examples.

Example 1 To 50 ml of 30% by weight cephalothin sodium was added 2 ml of 95% ethanol (corresponding to 4% by volume).

The ethanolic aqueous solution of cefaiotin sodium was filled into sterilized vials in amounts of 3.56 ml per vial. The amount of solution corresponded to 1 g of cephalothin sodium.

The filled vials were placed in a standard freeze-drying unit, and the temperature of the solution was rapidly lowered to -35 ° C over a maximum of three hours, and then the temperature was raised to -7 ° C as quickly as possible. The drug bottles were stored at this temperature for more than three hours after the frozen mass reached -7 ° C.

The vials were then cooled to -35 ° C after being held at -7 ° C for a little over three hours.

The pressure in the refrigeration dryer was reduced to less than 0.2 mm of mercury and the temperature was raised to 10 ° C to anneal the ethanol-water solution. Subsequently, the temperature was raised to 25 ° C, taking care not to melt the frozen mass in the vials. Once the annealing process was complete ,. the vacuum was released and the water and ethanol content and dissolution time of the obtained product were determined.

Typical water contents in individual vials were 0.10 and 0.11%.

The ethanol content was determined from the contents of two vials. It was less than 0.5%.

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The redissolution time of the contents of the five vials was determined. It took 30-60 sec to dissolve cephalothin sodium in 4.0 ml of water (for injection purposes).

Example II

2 ml of methanol was added to 50 ml of a 30% by weight solution of cephalothin sodium (corresponding to 4% by volume).

The methanol-aqueous solution of cephalothin sodium was filled into previously sterilized vials in amounts of 3.56 ml per vial. The amount of solution corresponded to 1 g per ampoule.

The filled vials were placed in a conventional refrigeration dryer, and the temperature of the solution was rapidly lowered to -35 ° C in up to three hours, and the temperature was raised to -7 ° C as quickly as possible. The vials were stored at this temperature for more than three hours after the frozen mass reached -7 ° C.

The vials were then cooled to -35 ° C after being held at -7 ° C for a little over three hours.

The pressure in the refrigeration dryer was reduced to less than 0.2 mm of mercury and the temperature was raised to 10 ° C to anneal the ethanol-water solution. Subsequently, the temperature was raised to 25 ° C, taking care not to melt the cooled mass in the vials. After the annealing process was completed, the voids were discharged, and the water and methanol content and redissolution time of the contents of the vials were determined.

Typical water% in individual vials was 0.10 and 0.11%.

Two vials tested for residual methanol showed a residue of less than 0.5%.

The five vials examined for redissolution time required 30-60 seconds to dissolve cephalothin sodium in 4.0 ml of water (for injection purposes).

Example III

Acetone was added to 2.0 ml of 50 ml of a 30% by weight cephalothin sodium solution (corresponding to 4% by volume).

10 68055

The acetone-aqueous solution of cephalothin sodium was filled into sterilized vials in amounts of 3.56 ml per vial. The amount of solution corresponded to 1 gram of cephalothin sodium ampoules.

The filled vials were placed in a standard freeze-drying unit, and the temperature of the solution was rapidly lowered to -35 ° C in up to three hours, and the temperature was raised to -7 ° C as quickly as possible. The vials were stored at this temperature for more than three hours after the frozen mass reached -7 ° C.

The vials were then cooled to -35 ° C after being held at -7 ° C for a little over three hours.

The pressure in the refrigeration dryer was reduced to less than 0.2 mm of mercury and the temperature was raised to 10 ° C to agitate the acetone-water solution. Subsequently, the temperature was raised to 25 ° C, taking care not to melt the frozen mass in the vials. After the annealing process was completed, the vacuum was released and the water and acetone content and redissolution time of the contents of the vials were determined.

Typical water% in individual vials was 0.10 and 0.11%.

Two vials tested for acetone residue showed a residue of less than 0.5%.

The five vials examined for redissolution time required 30-60 seconds to dissolve cephalothin sodium in 4.0 ml of water (for injection purposes).

Example IV

2.5 ml of isopropanol was added to 50 ml of a 30% by weight solution of cephalothin sodium (corresponding to 5% by volume).

An aqueous solution of cephalothin sodium in isopropanol was filled into sterilized vials in 3.6 ml volumes per vial. The amount of solution corresponded to 1 g of cephalothin sodium.

The filled vials were placed in a standard freeze-drying unit, and the temperature of the solution was rapidly lowered to -35 ° C in up to three hours, and the temperature was raised to -7 ° C as quickly as possible. The vials were stored at this temperature for more than three hours after the frozen mass reached -7 ° C.

ti 68055

The vials were then cooled to -35 ° C after being held at -7 ° C for a little over three hours.

The pressure in the refrigeration dryer was reduced to less than 0.2 mm of mercury and the temperature was raised to 10 ° C to agitate the isopropanol-water solution. Subsequently, the temperature was raised to 25 ° C, taking care not to melt the frozen mass in the vials. When the agglomeration process was completed, the vacuum was released, and the water and isopropanol content and redissolution time of the contents of the vials were determined.

Typical water% in individual vials was 0.10 and 0.11%.

Two vials tested for isopropanol residue showed a residue of less than 0.5%.

The five vials examined for redissolution time required 30-60 seconds to dissolve cephalothin sodium in 4.0 ml of water (for injection purposes).

Example V

10.657 g of sodium carbonate was dissolved in 954 g of water (for injection) and the solution was cooled to 5 ° C.

357 g of cephalothin sodium was added with stirring and the solution was heated to 66.5 ° C to complete the dissolution of cephalothin sodium. The resulting solution was filtered through a 45 μm membrane.

1100 ml of the filtrate was collected and 44 ml of 95% ethanol was added. The concentration of cephalothin sodium was 28% by weight and ethanol 4% by volume.

The ethanolic aqueous solution of cephalothin sodium was filled into sterilized vials in an amount of 3.75 ml per vial. The amount of solution corresponded to 1 g of cephalothin sodium.

The filled vials were placed in a standard freeze-drying unit, and the temperature of the solution was rapidly lowered to -35 ° C over a maximum of three hours, and the temperature was raised to -7 ° C as quickly as possible. The vials were stored at this temperature for more than three hours after the frozen mass reached -7 ° C.

The vials were then cooled to -35 ° C after being held at -7 ° C for a little over three hours.

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The pressure in the refrigeration dryer was reduced to less than 0.2 mercury and the temperature was raised to 10 ° C to agitate the ethanol-water solution. Subsequently, the temperature was raised to 25 ° C, taking care not to melt the frozen mass in the vials. When the agglomeration process was completed, the vacuum was released and the water and ethanol content and redissolution time of the contents of the vials were determined.

Typical water% in individual vials was 0.10 and 0.11%.

Two vials tested for ethanol residue showed a residue of less than 0.5%.

The five vials examined for redissolution time required 30-60 seconds to dissolve cephalothin sodium in 4.0 no water (for injection purposes).

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Claims (1)

13 68055 Claim A process for the preparation of a substantially crystalline, readily soluble cephalothin sodium of the formula O-n-CH-j-C-NH-v li J f | VCH2OCOCH3 COONa 1. by keeping a cooled, solid solution of cephalothin 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, characterized in that a) cephalothin sodium is dissolved As a 20-40% by weight solution in a solvent containing 2-10% by volume of C 1 -C 4 alkanol or acetone and 98-90% by volume of water; b) cooling the solution to at least -20 ° C; c) heating the cooled solution from step b) to a temperature between -3 ° C and -10 ° C; at which temperature it is kept for at least 3 hours; d) cooling the solution from step c) to at least -20 ° C, after which treatment of the completely solidified solution in a manner known per se according to 1) to 3) gives cephalothin sodium crystals containing not more than 1.0% by weight of water and not more than 1, 0% by weight of C 1 -C 4 alkanol or acetone.