IE45995B1 - Improvements in or relating to freeze drying cephalothin sodium - Google Patents

Description

Essentially crystalline cephalothin sodium for parenteral administration is prepared by a freeze-drying I: process wherein a alcohol or acetone)-water solution ; of cephalothin sodium containing from 2 to 10 percent of a C^-Cj alcohol or acetone by volume is chilled from room temperature to -20°C., or below, preferably -40°C., over a 1-3 hour period and then warmed from -3°C. to -10°C. and held for 3 hours or more, then cooled to -20°C, or below, preferably -40°C., before subjecting said frozen solution to a high vacuum and a moderate amount of heat to sublime the frozen solvent therefrom. The resulting powder dissolves rapidly in acceptable pharmaceutical diluents. Alternatively, from 2 to 5 percent by weight of sodium bicarbonate, related to the amount of cephalothin sodium present, is added to the solution before freeze-drying.

Freeze-drying is an old and often used process for removing a solvent from a solute. It provides a method for removing a solvent without damaging heat labile solutes. Antibiotics and other pharmaceuticals, and foods, particularly instant coffee, have been prepared by this method for many years. Ordinarily, a solution from which it is desired to recover the solute is frozen solid and then subjected to a high vacuum, and the temperature of the environment is raised to provide the units of heat absorbed in the sublimation of the frozen solvent. The temperature of the environment is kept below that which would result in the meltdown of the frozen solution. In practice, the temperature of the environment is coordinated with the vacuum to produce the highest reasonable sublimation rate, avoiding a melting of the frozen mass. -24599 5 Water is the solvent generally utilized in a freeze-drying process. Other solvents or combinations thereof can be employed but are limited to those which become solid in the range of temperatures which can be employed practically in the process and which will sublime under vacuum.

In freeze-drying antibiotics and other pharmaceuticals it has been the practice to follow the classic process outlined above; to wit, prepare solution, freeze to solid, subject to high vacuum, add heat, sublime solvent. However, when such a conventional procedure is followed, the process involving cephalothin sodium requires a cycle time of more than 24 hours to achieve a stable crystalline product.

The cephalothin sodium involved in this invention can be recovered from organic solvents, such as those identified above, in an essentially crystalline state.

However, such crystalline cephalothin sodium poses other problems. For example, there is no effective way known to sterilize the crystals of cephalothin sodium recovered from organic solvents so the entire crystallization process must be carried out in an aseptic environment. In the large and extensive process required to sterilely crystallize cephalothin sodium there are many opportunities for the admittance of contaminating foreign materials. Further, no one has yet developed an apparatus for filling dry material into an ampoule which will measure the material going into each ampoule with as good a consistency and precision as can be routinely achieved with liquid filling equipment. -345995 Patent Specification No.45994 teaches and claims a novel and useful freezedrying process for preparing crystalline cefazolin sodium for parenteral administration from an ethanol-water solution.

Moreover, United States .-Patent Specification No. 4,029,655 describes a process which embodies a procedure that includes a very rapid cooling of aqueous solution to nucleate the cephalothin sodium, among other cephalosporins, during the interval that the freezing takes place. Such nucleation crystallizes the bulk of the cephalothin sodium from the solution immediately prior to the solidification of the water. Consequently, when the sublimation procedure is initiated the cephalothin sodium already exists as crystals and does not depend on the crystallization to take place as the solvent is removed. The solvent is sublimed away and the cephalothin sodium remains behind.

While the above process provides stable sterile crystalline cephalothin sodium for parenteral administration, the process requires more than 24 hours for the completion of one cycle. Consequently, the scheduling of the use of the freeze-drying equipment and the work schedules of the personnel is unsatisfactory because of the irregularity of the operation. Following the teachings of the prior art requires a 28 to 36 hour cycle from the starting of the freeze-drying operation until it is completed. This relatively long time is a source of added cost to the product and annoyance and irritation to the personnel. -44599 5 Accordingly, this invention provides a process for preparing essentially crystalline cephalothin sodium for reconstitution for parenteral administration by a freezedrying process requiring less than 24 hours comprising the steps of: (a) dissolving from 20 to 40 percent (w/w) of said cephalothin sodium in a solvent comprised of from 2 to 10 percent of a C^-C3 alcohol or acetone and from 98 to 90 percent water (v/v); (b) cooling the solution from (a) to -20°C. or below; (c) warming the preparation from (b) to a temperature of between -3°C. and -10°C.; (d) maintaining the temperature of the preparation from (c) at from -3°C. to -10°C. for a period of 3 hours or more; (e) cooling the preparation from (d) to -20°C. or below; (f) reducing the pressure of the environment in which the preparation from (e) is maintained to a maximum of 1 mm of mercury absolute; (g) raising the temperature of the environment in which the preparation from (f) is maintained to a maximum of 50°C., avoiding the melting of such preparation; and (h) subliming the solvent from the preparation from (g) until the resulting crystals of said cephalothin sodium have a moisture content of not more than 1.0 percent (w/w), aid a C,- C3 alcohol -5. 459θδ or acetone content of not more than 1.0 percent (w/w).

The useful process of the present invention comprises a procedure utilizing a freeze-drying operation wherein from 20 to 40 percent (w/w) of cephalothin sodium is dissolved in a solvent system comprised of from 2 to 10 percent C-^-C^ alcohol or acetone and from 98 to 90 percent water. Such a solution is achieved by heating the mixture to a temperature of up to 70eC. to effect complete solubilization. The resulting solution can be sterilized by filtration if desired. The solution is then exposed to an environment in which the solution is cooled rapidly to a temperature of -20°C. or below, preferably ~40°C. The cooling period may be completed in from 1 to 3 hours.

After the rapid cooling to -20°C. or below, preferably -40°C., the frozen solution is warmed to between -3°C. and -10°C. and held at such temperature for 3 hours, or more, to assure complete crystallization.

Once the frozen solution has been held at -3°C. to -l0eC. for 3 hours or more, it is again cooled to -20°C. or below, preferably -40°C.

Following the critical steps just described, a conventional freeze-drying operation is employed to sublime the ice, leaving cephalothin sodium crystals having a moisture content of not more than 1 percent and a C^-C^ alcohol or acetone content of not more than 1 percent. Such crystals have a suitable storage stability of three years or more at room temperature, and dissolve in one minute or less in an acceptable pharmaceutical diluent in concentrations -645995 appropriate for parenteral administration. The improvement in the freeze-drying rate of the cephalothin sodium prepared by the process described above over the conventionally prepared cephalothin sodium crystals freeze-dried from an aqueous solution results in from about a 15 to about a 50 percent reduction in the time required to complete the freeze-drying cycle.

The crux of the instant invention is found in the combination of the use of the (Cq-C3 alcohol or acetone)-water solvent system and the establishment of a super-saturated solution of cephalothin sodium contained in such a solvent system, and the rapid cooling of the solution to -20°C. or below, preferably -40°C. The presence of the C^-C^ alcohol or acetone in the solvent system acts as an anti-solvent and reduces the solubility of the cephalothin sodium. It was discovered that the cephalothin sodium is substantially less soluble in a (C^-C3 alcohol or acetone)-water solvent than in water alone. Consequently, by warming the frozen solution to from -3°C. to -10°C. the nucleation and crystallization can be completed in 3 hours or slightly more as compared to the 14 to 20 hours required when no alcohol or acetone is used.

The (C^-C3 alcohol or acetone)-water solvent employed in the useful method of this invention can contain from 2 to 10 percent of a C^-C3 alcohol or acetone and from 98 to 90 percent water (v/v). The preferred solvent system is comprised of from 3 to 5 percent by volume of a C^-C3 alcohol or acetone and 97 to 95 percent by volume of water.

In practice the cephalothin sodium is dissolved preferably -745095 in the water and a volume of a C^-Cg alcohol or acetone, preferably 95 percent ethanol, equal to 4 percent of the final volume of the solution of the cephalothin sodium, is added to such solution.

The C^-Cg alcohols which may be used include methanol, ethanol, n-propanol and isopropanol.

A concentration of cephalothin sodium of from 20 to 40 percent w/w in the C^-Cg alcohol- or acetone-water solvent is satisfactory for developing the large crystals on freeze-drying. The preferred range is from 25 to 35 percent w/w. Especially preferred is a 30 percent (w/w) solution of cephalothin sodium. In practice, one especially preferred concentration of cephalothin sodium is provided by dissolving 30 gm of cephalothin sodium in water aid sddirg sufficient water to produce 100 grams of solution and adding thereto 3.55 ml of 95 percent alcohol, making a solution containing about 29 percent (w/w) of the solute.

Sterilization of (Cj_Cg alcohol or acetone)-water solution of cephalothin sodium can be achieved by filtering such solution through sterile filtering means known to those skilled in the art and collecting the filtrate in a previously sterilized container. Illustratively, sterile filtering can be effected using a heat sterilized plate and frame filter press equipped with an asbestos pad, or a filtering membrane of cellulose acetate or nitrate, or a candle having a porosity below 0.22 pm.

The rapid cooling of the (C^-Cg alcohol or acetone)water solution of cephalothin sodium can be best accomplished by exposing such solution to an environment of about -40°C. -845995 The temperature of the solution can be determined by locating a thermocouple approximately in the center of the solution to indicate the temperature at that point.

When the -20°C., or lower, preferably -40°C. temperature has been reached following the method outlined above, the frozen solution is warmed to from -3°C. to -10°C. to initiate the nucleation and crystallization of the cephalothin sodium. The frozen solution is held at a temperature in that range for a period of 3 hours or more to complete the crystallization.

After such period of holding at from -3°C. to -10°C., the frozen solution is again chilled to -20°C. or below, preferably -40°C., to complete solidification. No apparent benefit was found in holding the frozen mass at -20°C. or below, preferably -40°C.f after solidification was complete. At this point essentially all of the cephalothin sodium is present in the frozen mass as free crystals. A conventional freeze-drying operation is then utilized to sublime the solvent from the frozen mass leaving a deposit of essentially crystalline cephalothin sodium.

The frozen cephalothin sodium preparation wherein the nucleation of the crystals is substantially complete is subjected to an environment where the pressure can be reduced to a practical maximum of no more than 1 mm mercury absolute. It is preferable to reduce the pressure much more than to 1 mm mercury absolute. The best results are obtained with an absolute pressure of between 0.05 mm and 0.2 mm.

This latter pressure range is ordinarily readily attainable in both laboratory and commercial freeze-drying apparatus, -94 5995 the design and operation of which are all well known to those skilled in the art. After the pressure of the environment described above has been reduced to an operating level, heat is introduced into such an environ5 ment. The temperature of the environment is raised to a point where the maximum sublimation rate can be achieved without melting the frozen mass, -typically between 0°C and 50°C. As a general rule, the tsiroerature and the pressure are inversely related; the more effective the pressure reduction, the higher the temperature which can be employed in the subliming operation. As a common guide it can be said that a maximum environment temperature of 50°C. can be reached with a highly efficient vacuum system where the absolute pressure is maintained at about 0.05 mm absolute (50 pm). In any event, the tem15 perature should be raised slowly so as to avoid overloading the pressure-reducing system which can produce an undesirable melting of the frozen mass.and the pressure maintained at no more than 0.20 mm HJ. Preferably, the temperature of the envixoiment in the subliming operation should be maintained between 10°C. and 4O°C. with the nressure held at or belcw 0.2 mm absolute.

Subliming of the ice from the frozen mass is continued until the moisture content of the cephalothin sodium crystals is below 1 percent and the C^-C^ alcohol or acetone content is below 1 percent. Such a specification assures physical stability of the resulting crystals.

Cephalothin sodium does not crystallize as a hydrate.

The cephalothin sodium prepared as detailed above is essentially crystalline. For example, physical analyses of cephalothin sodium indicated a crystallinity of between -1045995 and 100 percent. In any event, a sufficiently high amount of crystallinity was obtained to impart storage stability; i.e., an absence of a yellowing of the substance and loss of microbiological potency for up to 3 years at room temperature. When the process is operated to include the sterile filtering of the cephalothin sodium solution and the freeze-drying is done under aseptic conditions the cephalothin sodium crystals can be sterile filled into previously sterilized ampoules in appropriate quantities for reconstitution for parenteral administration.

In another aspect of this invention the procedure outlined and discussed in detail hereinbefore is augmented by an additional step which comprises filling a measured volume of the alcohol or acetone)-water solution after suitable sterile filtration into a previously sterilized ampoule, such measured volume containing the quantity of cephalothin sodium which is desired in such ampoule after the freeze-drying operation. The ampoules containing the (C1-C3 alcohol or acetone)-water solution of cephalothin sodium are then processed in the same manner as described above. The resulting freeze-dried cephalothin sodium ampoule is ready for sterile stoppering and capping.

In practice it is preferred to sterile fill a measured volume of sterile (C^-C^ alcohol or acetone)-water cephalothin sodium solution into a previously sterilized ampoule as at least two beneficial results are obtained. First, a more precise and consistent quantity of the cephalothin sodium can be filled into an ampoule in the liquid form than in the solid crystals form. And, second. -1145995 it is much easier to achieve and maintain sterile operating conditions in liquid filling operations than in dry filling operations. Moreover, air pollution is less of a problem when handling liquids than dry materials.

' Alternatively, a quantity of sodium bicarbonate, equal to from 2 to 5 percent, relative to the amount of cephalothin solium, preferably 3 percent (w/w), of the cephalothin sodium can be added to the ceohalothin solution before optional sterile filtration. Such an addition urovides a crystalline cephalothin sodium which after reconstitution will have approximately a neutral pH, helping to reduce the stinging experienced on intramuscular administration.

The instant invention is further illustrated by the following examples.

PROCEDURE I Five hundred grams of cephalothin sodium having a moisture content of 1 percent were dissolved in 1166.6 grams of water for injection, U.S.P.

The resulting water solution of cephalothin sodium was warmed to 62°C. to complete solution and filtered through a 0.45 pm Millipore (Registered Trade Mark) membrane into an appropriate vessel.

The resulting aqueous solution containing 30 percent cephalothin sodium (w/w) was used in 50 ml. aliquots in the following examples.

EXAMPLE I Fifty milliliters of the 30 percent (w/w) cephalothin sodium solution was combined with 2 ml. of 95% grain alcohol (equivalent to 4% v/v). -1245995 The ethanol-water solution of cephalothin sodium was filled into previously sterilized vials in an amount of 3.56 ml. per vial. The quantity of solution was calculated to provide 1 gram ampoules of cephalothin sodium.

The filled vials were placed in a conventional freeze-drying unit and the temperature of the solution was lowered rapidly to -35°C. over a period of less than 3 hours and then the temperature was warmed to -7°C. as quickly as possible. The vials were held for 3 hours plus after the go frozen mass had reached a temperature of about -7°C.

Then the vials were cooled to -35°C. after being held for a little more than 3 hours at -7°C.

The pressure in the freeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10°C. for the sublimation of the ethanol-water solvent. Eventually the temperature was raised to 25°C. taking care not to melt the frozen mass in the vials. When the sublimation process was completed, the vacuum was released and the resulting vials were tested for moisture content, ethanol content and reconstitution time.

Typical moisture content on individual vials was 0.10 and 0.11 percent.

Two vials tested for ethanol residue showed less than 0.5 percent.

Five vials examined for reconstitution time required between 30 and 60 seconds to dissolve the cephalothin sodium in 4.0 ml. of water for injection, U.S.P. -13I 4599S is EXAMPLE II Two milliliters of methanol were added to 50 ml. of the 30 percent (w/w) cephalothin sodium solution from Procedure I. (Equivalent to 4% v/v).

; The methanol-water solution of cephalothin sodium \ was filled into previously sterilized vials in an amount of 3.56 ml. per vial. - The quantity of solution was calculated to provide 1 gram ampoules of cephalothin sodium.

The filled vials were placed in a conventional 0 freeze-drying unit and the temperature of the solution was lowered rapidly to -35°C. over a period of less than 3 hours and then the temperature was warmed to -7°C. as quickly as possible. The vials were held for 3 hours plus after the frozen mass had reached a temperature of -7°C.

Then the vials were cooled to -35°C. after being held for a little more than 3 hours at -7°C.

The pressure in the freeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10°C. for the sublimation of the methanol-water solvent. ,q Eventually the temperature was raised to 25°c. taking care not to melt the frozen mass in the vials. When the sublimation process was completed, the vacuum was released and the resulting vials were tested for moisture content, methanol content and reconstitution time. ,5 Typical moisture content on individual vials was 0.10 and 0.11 percent.

Two vials tested for methanol residue showed less than 0.5 percent. -144599 5 Five vials examined for reconstitution time required between 30 and 60 seconds to dissolve the cephalothin sodium in 4.0 ml of water for injection, U.S.P, EXAMPLE III Acetone in a volume of 2.0 ml. was added to 50 ml. of the 30 percent (w/w) cephalothin sodium solution from Procedure I. (Equivalent to 4% v/v).

The acetone-water solution of cephalothin sodium was filled into previously sterilized vials in an amount of 3.56 ml. per vial. The quantity of solution was calculated to provide 1 gram ampoules of cephalothin sodium.

The filled vials were placed in a conventional freeze-drying unit and the temperature of the solution was lowered rapidly to -35eC. over a period of less than 3 hours and then the temperature was warmed to -7°C. as quickly as possible. The vials were held for 3 hours plus after the frozen mass had reached a temperature of -7°C.

Then the vials were cooled to -35°C. after being held for a little more than 3 hours at -7°C.

The pressure in the freeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10°C. for the sublimation of the acetone-water solvent. Eventually the temperature was raised to 25°C. taking care not to melt the frozen mass in the vials. When the sublimation process was completed, the vacuum was released and the resulting vials were tested for moisture content, acetone content and reconstitution time.

Typical moisture content on individual vials was 0.10 and 0.11 percent. -154599 5 Two vials tested for acetone residue showed less than 0.5 percent.

Five vials examined for reconstitution time required between 30 and 60 seconds to dissolve the cephalo5 thin sodium in 4.0 ml of water for injection, U.S.P.

EXAMPLE IV Two and one-half milliliters of isopropanol were added to 50 ml. of the 30 percent (w/w) cephalothin sodium solution from Procedure I. (Equivalent to 5% v/v). 1q The isopropanol-water solution of cephalothin sodium was filled into previously sterilized vials in an amount of 3.6 ml. per vial. The quantity of solution was calculated to provide 1 gram ampoules of cephalothin sodium.

The filled vials were placed in a conventional P5 freeze-drying unit and the temperature of the solution was lowered rapidly to -35°C. over a period of less than 3 hours and then the temperature was wanned to -7°C. as quickly as possible. The vials were held for 3 hours plus after the frozen mass had reached a temperature of -7°C. 2o Then the vials were cooled to -35°C. after being held for a little more than 3 hours at -7°C.

The pressure in the freeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10°C. for the-sublimation of the isopropanol-water solvent. Eventually the temperature was raised to 25°C. taking care not to melt the frozen mass in the vials. When the sublimation process was completed, the vacuum was released and the resulting vials were tested for moisture content, isopropanol content and reconstitution time. -1645995 Typical moisture content on individual vials was 0.10 and 0.11 percent.

Two vials tested for isopropanol residue showed less than 0.5 percent.

Five vials examined for reconstitution time required between 30 and 60 seconds to dissolve the cephalothin sodium in 4.0 ml of water for injection, U.S.P.

EXAMPLE V A total of 10.657 grams of sodium bicarbonate were dissolved in 954 grams of water for injection U.S.P. and 'x cooled to 5°C. Three hundred and seventy-five grams of cephalothin sodium were added with stirring and the solution was heated to 66.5°C. to complete the dissolution of the cephalothin sodium. The resulting solution was filtered through a 45 pm membrane.

Eleven hundred milliliters of the filtrate were collected and 44 ml. of 95% grain alcohol added thereto.

The concentration of cephalothin sodium was 28 percent (w/w) and the ethanol 4 percent (v/v).

The ethanol-water solution of cephalothin sodium was filled into previously sterilized vials in an amount of 3.75 ml. per vial. The quantity of solution was calculated to provide 1 gram ampoules of cephalothin sodium.

The filled vials were placed in a conventional freeze-drying unit and the temperature of the solution was lowered rapidly to -35°C. over a period of less than 3 hours and then the temperature was warmed to -7°C. as quickly as possible. The vials were held for 3 hours plus after the frozen mass had reached a temperature of -7°C. -17459 9 5 Then the vials were cooled to -35°C. after being held for a little more than 3 hours at -7’C.

The pressure in the freeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to about 10°C. for the sublimation of the ethanol-water solvent. Eventually the temperature was raised to 25°C. taking care not to melt the frozen mass in the vials. When the sublimation process was completed, the vacuum was released and the resulting vials were tested for moisture content, ethanol content and reconstitution time.

Typical moisture content on individual vials was 0.10 and 0.11 percent.

Two vials tested for ethanol residue showed less than 0.5 percent.

Five vials examined for reconstitution time required between 30 and 60 seconds to dissolve the cephalothin sodium in 4.5 ml. of water for injection, U.S.P.

Claims (16)

1. A process for preparing essentially crystalline cephalothin sodium for reconstitution for parenteral administration by a freeze-drying process requiring less than 24 hours comprising the steps of: (a) dissolving from 20 to 40 percent (w/w) of said cephalothin sodium in a solvent comprised of from 2 to 10 percent of a C^-C^ alcohol or acetone and from 98 to 90 percent water (v/v); (b) cooling the solution from (a) to -20°C. or below; (c) warming the preparation from (b) to a temperature of between -3°C. and -10°C.; (d) maintaining the temperature of the preparation from (c) at from -3°C. to -10°C. for a period of 3 hours or more; (e) cooling the preparation from (d) to -20°C. or below; (f) reducing the pressure of the environment in which the preparation from (e) is maintained to a maximum of 1 mm of mercury absolute; (g) raising the temperature of the environment in which the preparation from (f) is maintained to a maximum of 50°C., avoiding the melting of such preparation; and (h) subliming the solvent from the preparation from (g) until the resulting crystals of said cephalothin sodium have a moisture content of -19,459 9 5 not more than 1.0 percent (w/w) , and a C^-C 3 alcohol or acetone content of not more than 1.0 percent.

2. The process according to claim 1 wherein the C-^-C 3 alcohol or acetone content of the alcohol or acetone)-water solution of cephalothin sodium is 4 percent (v/v) .

3. The process according to either of claims 1-2 wherein the temperature in step (b) is -40°C.

4. The process according to any of claims 1-3 wherein the concentration of cephalothin sodium is between 25 and 35 percent (w/w).

5. The process according to any of claims 1-4 wherein the concentration of cephalothin sodium is 30 percent (w/w).

6. The process according to any of claims 1-5 wherein the pressure is reduced to between 0.05 and 0.20 mm of mercury absolute (50 to 200 pm absolute) and the temperature of the environment is raised slowly to between 0°C. and 50°C. maintaining an absolute pressure of no more than and 0.20 mm. of mercury/avoiding the melting of said cephalothin sodium preparation.

7. A process of claim 1 for preparing an ampoule of sterile, essentially crystalline cephalothin sodium for reconstitution for parenteral administration by a freezedrying process requiring less than 24 hours comprising the steps of: (a) dissolving from 20 to 40 percent (w/w) of said cephalothin sodium in a solvent comprised of from 2 to 10 percent of a C^-C^ alcohol or acetone and from 98 to 90 percent 5 water (v/v); (b) filtering the solution from (a) through a sterilizing filter into a previously sterilized container; (c) filling a volume of the sterile solution from lo (b) into a previously sterilized ampoule such that the quantity of solute therein is the amount of said cephalothin sodium desired in said ampoule; (d) cooling the filled ampoule from (c) rapidly 15 over a period of from 1 to 3 hours to -20°C., or below; (e) warming the ampoule from (d) to a temperature from -3°C. to -10°C.; (f) maintaining the temperature of the ampoule 2o from (e) at -3°C. to -10°C. for a period of 3 hours or more; (g) cooling the ampoule from (f) to -20°C., or below; (h) reducing the pressure of the environment in 25 which the ampoule from (g) is maintained to a maximum of 1 mm of mercury absolute; (i) raising the temperature of the environment in which the ampoule from (h) is maintained to a maximum of 50°C., avoiding the melting of the 30 contents of such ampoule; and -21459S5 (j) subliming the solvent from the preparation from (i) until the resulting crystals of said cephalothin sodium have a moisture content of not more than 1.0 percent (w/w) and a C^'-Cg alcohol or acetone content of not more than 1.0 percent (w/w).

8. The process according to claim 7 wherein the C^-Cg alcohol or acetone content of the solution of cephalothin sodium is 4 percent (v/v).

9. The process according to either of claims 7-8 wherein the temperature in step (d) is -40°C.

10. The process according to any of claims 7-9 wherein the concentration of cephalothin sodium is between 25 and 35 percent (w/w).

11. The process according to any of claims 7-10 wherein the concentration of cephalothin sodium is 30 percent (w/w).

12. The process according to any of claims 7-11 wherein the pressure is reduced to between 0.05 and 0.20 mm of mercury absolute (50 to 200 pm absolute) and the temperature is raised slowly to between 0 e C. and 50°C. maintaining an absolute pressure of no more than 0.20 mm of mercury and avoiding the melting of said cephalothin sodium preparation.

13. A process of any of claims 1-12 wherein the solution of cephalothin sodium additionally comprises from 2 to 5 percent (w/w), relative to the amount of cephalothin sodium present, of sodium bicarbonate. -2245995

14. Crystalline cephalothin sodium when prepared by a process as claimed in any of claims 1-13.

15. A process as claimed in claim 1 substantially as hereinbefore described with particular reference to any 5 one of the examples.

16. Crystalline cephalothin sodium when prepared by a process as claimed in claim 1 substantially as hereinbefore described with particular reference to any one of the examples.