SE416733B - PROCEDURE FOR MAINTAINING IN PRINCIPLE CRYSTALINE CEPHALOTIN SODIUM - Google Patents

Description

Y713318'9 in I 2 coffee, has been produced according to this method for many years. A solution from which it is desired to recover the solute is frozen in this method to a solid mass, which is subjected to a high vacuum at the same time as the temperature is raised so that the frozen solvent sublimes. The ambient temperature is kept below the temperature that would melt the frozen mass. The temperature and the pressure are coordinated in practice in such a way that the highest possible sublimation rate is obtained without the frozen mass melting.

Water is the solvent commonly used in freeze-drying processes. Other solvents or combinations thereof may be used, but only those solvents which solidify within the practically useful temperature range and also sublimate under vacuum may be used.

In lyophilization of antibiotics and other drugs, it has been common to use the classic procedure described above. A solution is prepared which is frozen to a solid mass, after which this mass is heated under high vacuum so that the solvent sublimes. However, freeze-drying of cephalothin sodium according to this conventional method requires a total freeze-drying time of more than 24 hours to obtain a stable crystalline product.

Cephalotin sodium in a substantially crystalline state can be recovered from organic solvents, such as those indicated above.

However, such crystalline cephalotin sodium presents other problems. You feel e.g. not to any effective way to sterilize crystals of cephalothin sodium recovered from organic solvents, therefore the whole crystallization process must be carried out in an aseptic environment. In the complicated process required to sterilize crystalline cephalotin sodium, there are many opportunities for foreign materials to contaminate the product. Dry filling machines, ie. devices for inserting dry material into ampoules, moreover, does not allow an equally accurate measurement of the material as liquid filling devices.

A new freeze-drying process for the production of crystalline cefazolin sodium based on an ethanol-water solution of this salt is described in Swedish Laid-Open Swivel 7713316-3. U.S. Pat. No. 4,029,655 discloses a lyophilization process for the preparation of crystalline ophalosporins, including cephalothin sodium.

According to this method, a water solution of e.g. cephalotin sodium so that the cephalotin sodium forms crystal nuclei during freezing. In such nucleation, the majority of the cephalotin sodium crystallizes immediately before the water changes to a solid state. Accordingly, when sublimation begins, the cephalotin sodium is already in the form of crystals, and no crystallization occurs when the solvent is removed. The solvent is sublimed, and the cephalothin sodium remains. Although this known method provides a stable, sterile, crystalline cephalothin sodium for parenteral administration, more than 24 hours are required to complete a lyophilization cycle.

The working hours for the staff and the times for using the freeze-drying equipment will therefore be unsatisfactory. According to the known method, 28-36 hours are required from the beginning of the freeze-drying operation until the freeze-drying is completed. This relatively long time entails increased product costs and personnel problems.

Thus, the present invention relates to a process for the preparation of substantially crystalline ephalothin sodium for parenteral administration according to a freeze-drying process which requires less than 24 hours. This process is characterized by (a) dissolving 20-0% by weight of cephalothin sodium in a solvent consisting of 2-10% by volume of a C1-G3 alcohol or acetone and 98-90% by volume of water; cooling (b) the resulting solution to a temperature of -20 ° C or lower; heating (c) the resulting mixture to a temperature of between -3 ° C and -10 ° C; keeping the temperature of the mixture between -} ° C and -10 ° C for a period of 3 hours or more; cooling the resulting mixture to a temperature of -20 ° C or lower; lowering the pressure in the space in which the frozen mixture is kept down to a maximum of 1 mm Hg absolute pressure; raising (g) the temperature in the space in which the frozen mixture is kept to a temperature not exceeding 50 ° C, avoiding melting of the mixture; and (h) subliming the solvent from the frozen mixture until the resulting crystals of cephalothin sodium have a moisture content of at most 1.0% by weight and a content of Cl-03 alcohol or acetone of at most 1.0% by weight.

The process according to the invention is thus a freeze-drying process, in which 20-40% by weight of cephalotin sodium is first dissolved in a solvent system consisting of 2-10% by volume of a C1-03 alcohol or acetone and 98-90% by volume of water. The dissolution is accomplished by heating the solution to a temperature of up to 70 ° C to achieve complete solubilization. The resulting solution can, if desired, be sterilized by filtration. The solution is then kept in a space in which it is rapidly cooled to a temperature of -20 ° C or lower, preferably -40 ° C. The cooling can be carried out in a time of 1-3 hours. After the rapid cooling down to -20 ° C or lower, preferably -40 ° C, the frozen mixture is heated to a temperature between -3 ° C and -10 ° C, after which it is kept at this temperature for a period of 5 hours or more to ensure complete crystallization.

When the frozen mixture has been kept at a temperature between -300 and -10 ° C for a period of 5 hours or more, it is re-cooled to a temperature of -20 ° C or lower, preferably -40 ° C.

Following the critical steps described above in the process according to the invention, a conventional freeze-drying is carried out for sublimation of the ice so as to obtain cephalothin sodium crystals with a moisture content of at most 1% by weight and a content of C1-G3 alcohol or acetone of at most 1% by weight. Such crystals are storage-stable at room temperature for 3 years or more, and they dissolve in 1 minute or less in a pharmaceutically acceptable diluent in concentrations suitable for parenteral administration. The increase in the freeze-drying rate of the process according to the invention relative to the freeze-drying rate in conventional production of cephalotin sodium crystals by freeze-drying an aqueous solution of cephalothin sodium results in an approximately 1-50% reduction in the time required To carry out a freeze-drying cycle. Particularly characteristic of the invention is the use of a solvent system consisting of water plus C1-G3 alcohol or acetone, the production of a supersaturated solution of cephalothin sodium in this solvent system, and the rapid cooling of the solution down to a temperature. of -20 ° C or lower, preferably -40 ° C. The C1-C3 alcohol or acetone present in the solvent system acts as an anti-solvent and reduces the solubility of cephalothin sodium. It has been found that cephalothin sodium is considerably less soluble in a solvent consisting of water plus C1-G3 alcohol or acetone than in water alone. Consequently, by heating the frozen mixture to a temperature between -3 ° C and -10 ° C, nucleation and crystallization can be completed in a time of 3 hours or more, which is to be compared with the reading hours required when no 7713318 -9 alcohol or acetone was used.

The solvent used in the process according to the invention consisting of water and a C1-G5 alcohol or acetone may contain 2-10% by volume of C1-G3 alcohol or acetone and 98-90% by volume of water. The preferred solvent system consists of 3-5% by volume of a Cl-03 alcohol or acetone and 97-95% by volume of water. In practice, the cephalotin sodium is preferably dissolved in the water, after which a C1-G3 alcohol or acetone, preferably 95% ethanol, is added to the resulting aqueous solution in a volume corresponding to 4% of the volume of the cephalotin sodium solution. The C1-33 alcohols which can be used in the process of the invention are methanol, ethanol, n-propanol and isopropanol.

A cephalothin sodium concentration of 20-40% by weight in the solvent mixture consisting of water and C1-G3 alcohol or acetone is sufficient for large crystals to develop during freeze-drying. The preferred concentration of cephalothin sodium is 25-35% by weight. Particularly preferred is a solution containing 50% by weight of cephalotin sodium. In practice, a particularly preferred concentration of cephalotin sodium is achieved by dissolving 30 g of cephalotin sodium in water to a total amount of 100 g, after which 3.55 ml of 95% ethanol are added. A solution containing about 29% by weight of the dissolved substance is obtained.

Sterilization of the solution of cephalothin sodium in the mixture of water and C1-G5 alcohol or acetone can be effected by filtering the solution through a sterilizing filter means of known type and collecting the filtrate in a pre-sterilized container. The sterilizing filtration can e.g. carried out using a heat-sterilized frame filter press fitted with an asbestos pad, or using a membrane filter made of cellulose acetate or cellulose nitrate, or using a filter light having a porosity of less than 0.22 Pm.

The rapid cooling of the solution of cephalothin sodium in the mixture of water and C1-G3 alcohol or acetone can best be done by keeping the solution in a room with a temperature of about -40 ° C. The temperature of the solution can be determined by placing a thermocouple in the middle of the solution to indicate the temperature at this point.

When the temperature of the solution has been lowered to -20 ° C or lower, preferably -40 ° C, the frozen mixture is heated to a temperature between -3 ° C and -10 ° C to initiate nucleation and crystallization of the cephalothin sodium. The frozen mixture is kept at a temperature within said temperature range for a period of 3 hours or more to complete the crystallization.

After such a residence time at a temperature between -3 ° C and -10 ° C, the frozen mixture is re-cooled to a temperature of -20 ° C or lower, preferably -40 ° C, in order for the mixture to solidify completely. It has not been possible to demonstrate any advantage in keeping the frozen mass at -20 ° C or lower, preferably -40 ° C, after the mixture has completely solidified. At this point, essentially all of the cephalotin sodium is present in the frozen mass as free crystals.

A conventional lyophilization operation was then used to sublimate the solvent from the frozen pulp to obtain a residue of mainly crystalline cephalothin sodium.

The frozen mixture, in which the formation of cephalotin sodium crystal nuclei is substantially complete, is then introduced into a space where the pressure can be lowered to a practical maximum of no more than 1 mm Hg absolute pressure. It is preferred to lower the pressure well below 1 mm Hg. The best results are obtained with an absolute pressure of between 0.05 and 0.2 mm Hg. The latter pressure range can usually be easily achieved with both laboratory and commercial type freeze dryers.

The design and operation of such freeze dryers are well known to those skilled in the art. After the pressure has been lowered to the desired level, heat is supplied to the space. The temperature of the room is raised to such a temperature that maximum sublimation speed can be achieved without the frozen mass melting. Usually the temperature and the pressure are inversely related to each other. The lower the pressure, the higher the temperature that can be used for the sublimation. As a general guideline, it can be stated that a temperature of a maximum of 50 ° C can be used, if a highly efficient evacuation system is used which gives an absolute pressure of about 0.05 mm Hg.

In any case, the temperature should be raised slowly so as to avoid overloading the evacuation system, which could result in an undesired melting of the frozen mass. Preferably, a temperature of between 10 and # 0 ° C is used in the sublimation step, the pressure being kept at or below 0.2 mm Hg absolute pressure. The sublimation of the ice from the frozen mass is continued until the crystals of ephalothin sodium have a moisture content of less than 1% and a content of C1-C3 alcohol or acetone of less than 1%. If the levels are below these values, the resulting crystals are physically stable. Cephalotin sodium does not crystallize as hydrate.

The cephalotin sodium prepared according to the invention is substantially crystalline. Physical analyzes of the cephalotin sodium show e.g. a crystallinity of between 92 and 100%. In any case, a sufficiently high crystallinity is obtained for the crystals to be storage-stable for up to 5 years at room temperature without the crystals turning yellow or losing microbiological activity. When the cephalotin sodium solution is sterile filtered in the process of the invention and the lyophilization is carried out under aseptic conditions, the cephalotin sodium crystals can be sterile introduced into ampoules which have been sterilized in advance, each ampoule introducing a suitable amount for later reconstitution for parenteral administration. .

According to an embodiment of the invention, the method described above comprises a further step. In this step, after appropriate sterilizing filtration, a measured volume of the solution of cephalothin sodium in the mixture of water and C1-C3 alcohol or acetone is introduced into a pre-sterilized ampoule, the measured volume containing the amount of cephalotin sodium desired in the ampoule after lyophilization. .

The ampoule containing the solution of cephalothin sodium in the mixture of water and C1-G3 alcohol or acetone is then treated as described above. The ampoule containing lyophilised cephalothin sodium can then be sterile sealed and lined.

In practice, it is preferred to sterilize a metered volume of a sterile solution of cephalothin sodium in a mixture of water and C1-G3 alcohol or acetone in a pre-sterilized ampoule, as this provides at least two benefits. First, a more accurate amount of cephalotin sodium can be introduced into the ampoule in liquid form than in solid form (crystals). Second, it is much easier to achieve and maintain sterile conditions with liquid filling than with dry filling.

In addition, air pollution is a lesser problem when handling liquids than when handling dry materials.

According to an embodiment of the invention, sodium bicarbonate may be added to the cephalothin sodium solution before sterile filtration in an amount of 2-5% by weight, preferably 5% by weight, based on the amount of cephalotin sodium. By such an addition crystalline cephalotin sodium is obtained, which after reconstitution has approximately neutral pH value.

This reduces the stabbing pain that often occurs after intramuscular administration.

The invention is illustrated by the following examples.

Examples 1-4 start from an aqueous solution of cephalotin sodium prepared in the following manner. 500 g of cephalotin sodium with a moisture content of 1% were dissolved in 666 g of water for injection (USP). The resulting aqueous solution of ufalotin sodium was heated to 62 ° C to complete the solution and then filtered through a 0.45 μm Millipore membrane into a suitable vessel. The resulting aqueous solution containing 30% by weight of cephalotin sodium was used in Examples 1-4 below in volumes of 50 ml.

Example 1. To 50 ml of the above-described aqueous solution containing 50% by weight of cephalotin sodium was added 2 ml of 95% ethanol (corresponding to 4% by volume).

The resulting ethanol-water solution of cephalotin sodium was introduced into ampoules (vials), which had been pre-sterilized, in an amount of 3.56 ml per ampoule. The amount of solution was calculated so that each ampoule contained 1 g of cephalothin sodium.

The filled ampoules were placed in a conventional lyophilizer, and the temperature of the solution was rapidly lowered to -55 ° C in a time of less than 3 hours. Thereafter, the temperature was raised to -7 ° C as quickly as possible. After the frozen mass had reached a temperature of about -7 ° C, the ampoules were kept at this temperature for slightly more than 5 hours. Thereafter, the ampoules were cooled to -111 -55 ° C.

The pressure in the lyophilizer was then lowered to an absolute pressure of less than 0.2 mm Hg, and the temperature was raised to 10 ° C to sublimate the ethanol and water. Finally, the temperature was raised to 25 ° C, taking precautions so that the frozen mass did not melt. When the sublimation process was completed, the evacuation was stopped, and the crystals obtained in the ampoules were analyzed to determine the moisture content and ethanol content. In addition, the solubility properties of the crystals were examined. Typical moisture contents of crystals from different ampoules were 0.10 and 0.1% by weight. Crystals from two different ampoules had an ethanol content of less than 0.5% by weight. The cephalotin sodium crystals in five different ampoules were each dissolved in 4.0 ml of water suitable for injection. It was found that it took between 30 and 60 seconds to dissolve the crystals in the water. Example 2 To 50 ml of the 30% aqueous solution of cephalothin sodium was added 2 ml of methanol (corresponding to 4% by volume).

The resulting methanol-water solution of cephalothin sodium was introduced into ampoules (pre-sterilized) in an amount of 3.56 ml per ampoule. The amount of solution was calculated so that each ampoule contained 1 g of cephalothin sodium. The filled ampoules were placed in a conventional lyophilizer, and the temperature of the solution was rapidly lowered to -35 ° C in less than 3 hours. Thereafter, the temperature was raised to -7 ° C as quickly as possible. After the frozen mass had reached a temperature of -7 ° C, the ampoules were kept at this temperature for slightly more than 3 hours. Then the ampoules were cooled to -35 ° C.

The pressure in the freeze dryer was then lowered to an absolute pressure of less than 0.2 mxn fl g, and the temperature was raised to 10 ° C to sublimate the methanol and water. Finally, the temperature was raised to 25 ° C, taking precautions so that the frozen mass did not melt. When the sublimation process was completed, the evacuation was stopped, and the crystals obtained in the ampoules were analyzed to determine the moisture content and methanol content. In addition, the solubility properties of the crystals were examined. Typical moisture contents of crystals from different ampoules were 0.10 and 0.11% by weight.

Crystals from two different ampoules had a methanol content of less than 0.5% by weight.

The cephalotin sodium crystals in five different ampoules were each dissolved in 4.0 ml of water suitable for injection. It was found that it took between 30 and 60 seconds to dissolve the crystals in the water.

Example 2. To 50 ml of the 30% aqueous solution of cephalothin sodium was added 2.0 ml of acetone (corresponding to 4% by volume).

The resulting acetone-water solution of cephalothin sodium was introduced into ampoules (pre-sterilized) in an amount of 3.56 ml per ampoule. The amount of solution was calculated so that each vial contained 1 g of cephalothin sodium.

The filled ampoules were placed in a conventional lyophilizer, and the temperature of the solution was rapidly lowered to -3500 in a time of less than 3 hours. The temperature was then raised to -7 ° C as quickly as possible. After the frozen mass had reached a temperature of -7 ° C, the ampoules were kept at this temperature for slightly more than 3 hours. The ampoules were then cooled to -55 ° C.

The pressure in the lyophilizer was then lowered to an absolute pressure of less than 0.2 mm Hg, and the temperature was raised to 10 ° C to sublimate the acetone and water. Finally, the temperature was raised to 25 ° C, taking precautions so that the frozen mass did not melt. When the sublimation process was completed, the evacuation was stopped, and the crystals obtained in the ampoules were analyzed to determine the moisture content and the acetone content. In addition, the solubility properties of the crystals were examined.

Typical moisture contents of crystals from different ampoules were 0.10 and 0.11% by weight. Crystals from two different ampoules had an acetone content of less than 0.5% by weight.

The cefalctin sodium crystals in five different ampoules were each dissolved in 4.0 ml of water suitable for injection. It was found that it took between 30 and 60 seconds to dissolve the crystals in the water.

Example 4. To 50 ml of the 30% aqueous solution of cephalothin sodium was added 2.5 ml of isopropanol (corresponding to 5% by volume).

The resulting isopropanol-aqueous solution of cephalothin sodium was introduced into ampoules (pre-sterilized) in an amount of 5.6 ml per ampoule. The amount of solution was calculated so that each vial contained 1 g of cephalothin sodium. The filled ampoules were placed in a conventional lyophilizer, and the temperature of the solution was rapidly lowered to -35 ° C in a time of less than 3 hours. The temperature was then raised as quickly as possible to -7 ° C. After the frozen mass had reached a temperature of -7 ° C, the ampoules were kept at this temperature for slightly more than 3 hours. The vials were then recooled to -35 ° C.

The pressure in the lyophilizer was then lowered to an absolute pressure of less than 0.2 mm Hg, and the temperature was raised to 10 ° C to sublimate the isopropanol and water. Finally, the temperature was raised to 25 ° C, taking precautions so that the frozen mass did not melt. When the sublimation process was completed, the evacuation was stopped, and the crystals obtained in the ampoules were analyzed to determine the moisture content and isopropanol content. In addition, the solubility properties of the crystals were examined. Typical moisture contents of crystals from different ampoules were 0.10 and 0.11% by weight. Crystals from two different ampoules had an isopropanol content of less than 0.5% by weight.

The cefalctin sodium crystals in five different ampoules were each dissolved in 4.0 ml of water suitable for injection. It was found that it took between 30 and 60 seconds to dissolve the crystals in the water.

Example 5. 10.657 g of sodium bicarbonate was dissolved in 954 g of water suitable for injection, and the resulting solution was cooled to 5 ° C. To the solution was added with stirring 575 g of cephalotin sodium, after which the solution was heated to 66,500 to complete the dissolution of the cephalotin sodium. The resulting solution was filtered through a 45 .mu.m membrane.

Claims (7)

1113 ml of filtrate were collected and then 44 ml of 95% ethanol. The resulting solution had a cephalothin sodium content of 28% by weight and an ethanol content of 4% by volume. The ethanol-water solution of cephalothin sodium was introduced into ampoules (pre-sterilized) in an amount of 3.75 ml per ampoule. The amount of solution was calculated so that each vial contained 1 g of cephalothin sodium. The filled ampoules were placed in a conventional lyophilizer, and the temperature of the solution was rapidly lowered to -55 ° C in a time of less than 5 hours. Thereafter, the temperature was raised as quickly as possible to -7 ° C. After the frozen mass had reached a temperature of -7 ° C, the ampoules were kept at this temperature for a little more than 3 hours. Then lcyiaes ampniier-nn again to -35 ° c. The pressure in the lyophilizer was then lowered to an absolute pressure of less than 0.2 mm Hg, and the temperature was raised to 10 ° C to sublimate the ethanol and water. Finally, the temperature was raised to 25 ° C, taking precautions so that the frozen mass did not melt. When the sublimation process was completed, the evacuation was stopped, and the crystals obtained in the ampoules were analyzed to determine the moisture content and ethanol content. In addition, the solubility properties of the crystals were examined. Typical moisture contents of crystals from different ampoules were 0.10 and 0.11% by weight. Crystals from two different ampoules had an ethanol content of less than 0.5% by weight. The cephalotin sodium crystals in five different ampoules were each dissolved in 4.5 ml of water suitable for injection purposes. It was found that it took between 30 and 60 seconds to dissolve the crystals in the water. P a t e n t k r a_y Process for the production of essentially crystalline cephalothin sodium, i.e. 7- (2-Thienylacetamideacephalosporanic acid sodium salt, for parenteral administration according to a freeze-drying process requiring less than 24 hours, characterized in that 20-40% by weight of cenlotin sodium is dissolved in a solvent consisting of 2- 10% by volume of a C1-C5 alcohol or acetone and 98-90% by volume of water; (b) cooling the resulting solution to a temperature of -20 ° C or lower; (c) heating the resulting mixture to a temperature of between -3 ° C and -10 ° C; (d) keeping the temperature of the mixture between -5 ° C and 10 ° C for a period of 3 hours or more; the resulting mixture to a temperature of -20 ° C or lower; (f) lowering the pressure in the space in which the resulting frozen mixture is needle down to an ebeelut pressure of not more than 1 mm Hg; the temperature in the space in which the frozen mixture is carried, up to a pile of 5 ° C, whereby melting of the mixture gene is avoided; and (h) subliming the solvent from the crushed mixture until the resulting crystals of cephalotin sodium have a moisture content of not more than 1.0% by weight and a content of C1-C3 alcohol or acetone of not more than 1.0% by weight. 2. A process according to claim 1, wherein the content of C1-C3 alcohol or acetone in the solution of cephalothin sodium in the mixture of water and C1-C3 alcohol or acetone is 4% by volume. 3. A process according to claim 1 or 2, characterized in that in step (b) the temperature is lowered to -40 ° C. Process according to one of Claims 1 to 3, characterized in that the content of cephalothin sodium in the solution is between 25 and 35% by weight. 7 5. A process according to claim 4, characterized in that the content of cephalothin sodium 1 solution is 50% by weight. Process according to one of Claims 1 to 5, characterized in that step 1 (1) lowers the pressure to an absolute pressure of between 0.05 and 0.20 mm Hg, and that in step (g) slowly raises the temperature to between 0 and 50 ° C, during which the absolute pressure is kept at a maximum of 0.20 mm Hg to avoid melting of the frozen mass. the Process according to one of Claims 1 to 6, characterized in that sodium bicarbonate is added to the solution of cephalothin sodium in an amount of 2-5% by weight, based on the amount of cephalotin sodium present. PROMISED PUBLICATIONS: US 4,029,655