CA1079720A - Method of preparing a rapidly dissolving powder of crystalline cephalothin sodium for parenteral administration - Google Patents
Method of preparing a rapidly dissolving powder of crystalline cephalothin sodium for parenteral administrationInfo
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- CA1079720A CA1079720A CA291,717A CA291717A CA1079720A CA 1079720 A CA1079720 A CA 1079720A CA 291717 A CA291717 A CA 291717A CA 1079720 A CA1079720 A CA 1079720A
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- cephalothin sodium
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Abstract
Abstract of the Disclosure Essentially crystalline cephalothin sodium for parenteral administration is prepared by a freeze-drying process wherein a (C1-C3 alcohol or acetone)-water solution of cephalothin sodium containing from 2 to 10 percent of a C1-C3 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 to 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.
Description
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Essentially crystalline cephalothin s~dium for parenteral administration is prepared by a freeze-drying process wherein a (Cl-C3 alcohol or acetone)-water solution of cephalothin sodium containing from 2 to 10 percent of a Cl-C3 alcohol or acetone by volume is chilled from room temperature to -20C., or below, preferably -40C. over a 1-3 hour period and then warmed to from -3C. to -10C. and held for 3 hours or more, then cooled to -20C, or below, preferably -40C., 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 sodlum 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, partic-ularly instant coffee, have been prepared by this method formany years. Ordinarily, a solution from which it is desired to reco~er 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.
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Water i~ the solvent generally u~ilized 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 pharma-ceuticals it has been the practice to follow the classic process outlined above; to wit, prepare solution, freeze to ; 10 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 iden-tified 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 crystalliza-tion 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.
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- United States Patent No. 4,02g,655 describes a process which embodies a procedure that includes a very rapid cooling of an 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. rrhe 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 ~reeze-drying equipment and the work schedules of the personnel is unsatisfactory becau~e of the irregularity of the operation. Following the teachings of the prior art X;~ 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.
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Accordingly, this invention provides a process for preparing essentially crystalline cephalothin sodium for reconstitution for parenteral administration by a freeze-drying process requiring less than 24 hours compxising the steps of: .
(a) dissolving from 20 to 40 percent (w/w) of said cephalothin sodium in a solvenk com-prised of from 2 to 10 percent of a Cl-C3 alcohol or acetone and from 98 to 90 percent water (v/v);
(b) cooling the solution from (a) to -20C. or below;
. (c) warming the preparation ~rom (b) to a tem-: perature of between -3C. and -10C.;
(d) maintaining the temperature of the prep-aration from (c) at from -3C. to -10C. for a period of 3 hours or more;
(e) cooling the preparation from (d) to -20C.
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 50C., 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, and a Cl-C3 alcohol 721~
or acetone content of not more than 1.0 percent.
The useful process of the present invention comprises a procedure utilizing a ~reez,e-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 Cl-C3 alcohol or acetone and from 98 to 90 percent water. Such a solution is achieved by heating the solution to a temperature of up to 70C. to effect complete solu-bilization. The resulting solution can be sterilizecl by filtration if desired. The solution is then exposed to an environment in which the solution is cooled rapidly to a temperature of -20C. or below, preferably -40C. The cooling period may be completed in from 1 to 3 hours.
After the rapid cooling to -20C. or below, preferably -40C., *he frozen solution is warmed to between -3C. and -10C. and held at such temperature for 3 hours, or more, to assure complete crystallization.
Once the frozen solution has been held at -3C.
to -10C. for 3 hours or more, it is again cooled to -20C.
or below, pre~erably -40C.
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 Cl-C3 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 ~;
' 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 (Cl-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 solukion to -20C. or ~elow, preferably -40C. The presence of the Cl-C3 alcohol or acetone i~ the solvent system acta 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 (Cl-C3 alcohol or acetone)-water solvent than in water alone. Consequently, by warming the frozen solution to from 3C. to -10C. the nucleation and crystalli~ation can be completed in 3 hours or sli~htly more as compared to the 14 to 20 hours required whell no alcohol or acetone is used.
The (Cl-C3 alcohol or acetone)-water solvent employed in the useful methoa of this invention can contain from 2 to 10 percent of a Cl-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 Cl-C3 alcohol or acetone and 97 to 95 percent by volume of water.
In practice the cephalothin sodium is dissolved preferably -107~7~0 in the water and a volume of a Cl C3 alcohol or acetone, preferably 95 percent ethanol, equal to 4 percent of the volume of the solution of the cephalothin sodium, is added to such solution.
The Cl-C3 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 Cl-C3 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 cephalothln sodium is provided by dis-~olving 30 gm of cephalothin sodium in water ~. s'd. to 100 grams and adding thereto 3.55 ml of 95 percent grain . alcohol, making a solution containing about 29 percent (w/w) of the solute.
Sterilization of (Cl-C3 alcohol or acetone)-water solution of cephalothin sodium can be achieved by filtering 20 such solution through sterile filtering means known to those :
skilled in the art and collecking the i}trate in a pre-~` viously ~terilized 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 ~m.
.i The rapid cooling of the (Cl-C3 alcohol or acetone)-water solution of cephalothin sodium can be best accomplished .
by exposing such solution to an environment of about -40C. -~7~7;~
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 -20C., or lower, preferably -40C.
temperature has been reached following ~he method outlined above, the frozen solution is warmed to from -3C. to -10C.
to initiate the nucleation and crystallization of the cephalothin sodium. The frozen solution is held at a tem-perature in that range for a period of 3 hours or more to complete the crystallization.
After such period of holding at from -3C. to -10C., the frozen solution is again chilled to -20C. or below, preferably -40C., to complete solidification. No apparent benefit was found in holding the Erozen mass at -~0C.
or below, preferably -40C. after solidification was complete.
At this point essentially all of the cephalothin sodium is present in the frozen mass as free crystals. A conventional reeze-drying operation is then utilized to sublime the solvent from the frozen mass leaving a deposit of essen-tially crystalline cephalothin sodium.
The frozen cephalothin sodium preparation wherein the nucleation of the crystals is substantially comp].ete is subjected to an environment where the pressure can be reduced to a practical maximum of no more than l mm mercury absolute. It is preferable to reduce the pressure much more than to l 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, 1~>i'97ZV
the design, construction and operation of which are all wel~
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 environ-ment. The temperature of the environment is raised to a point where the maximum sublimation rate can be achieved without melting the frozen mass. As a ~eneral rule, the temperature 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 50C. can be reached with a highly efEicent vacuum system where the absolute pressure is maintained at about 0.05 mm absolute ~50 ~m). In any event, the tem-perature should b~ ra~sed slowly so as to avoid overload~ng the pressure-reducing system which can produce an undesirable melting of the frozen mass. Preferably, the temperature of the environment in the subliming operation should be main-tained between 10C. and ~0C. with the pressure held at or below 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 Cl-C3 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 ana~yses of cephalothin sodium indicated a crystallinity of between 107~7~0 92 and 100 percent. In any event, a sufficient~y 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 ceph~lothin sodium solution and the freeze-drying is done under aseptic conditions the cephalothin sodium crystals can be sterile filled into previously sterili~ed ampoules in appropriate quantities or 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 o~ the (C~-C3 alcohol or acetone)-water solution a~ter suitable sterile iltration into a previously ster-ilized 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 (Cl-C3 alcohol or acetone) water solution o~ cephalothin sodium are then processed in the same manner as described above~ The resulting reeze-dried cephalothin sodium ampoule is ready ~or sterile stoppering and capping.
In practice it i~ preferred to sterile fill a measured volume of sterile (Cl-C3 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 illed into an ampoule in the liquid form than in the solid crystals form. And, second, :
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it is much easier to achieve and maintai~ sterile operatingconditions 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, preferably 3 percent, of the cephalothin sodium can be added to the cephalothin solution before sterile filtration. Such an addition provides a crystalline cephalothin sodium which after reconstitution will have approximately a neutral p~, helping to reduce the stinging experienced on I.M. 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 62C. to complete solution and filtered through a 0.45 ~m "Millipore"* membrane into an appropriate vessel.
The resulting aqueous solution containing 30 percent cephalothin sodium (w/w) was used in S0 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).
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1C~7~720 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 con~entional freeze-drying unit and the temperature of the solution was lowered rapidly to -35C. 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 about -7C.
Then the vials were cooled to -35C. after ~eing held for a little more than 3 hours at -7C.
The pressure in the ~reeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10C. for khe sublimation of the ethanol-water solvent.
Eventually the temperature was raised to 25C. taking care not to melt the frozen mass in the vials. When the sub-limation 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 or ekhanol 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.
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~L~7~720 EXAMPLE II
Two milliliters of methanol ~ere added to 50 ml.
of the 30 percent ~w/w) cephalothin sodium solution from Procedure I. (E~uivalent 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 freeze-drying unit arld the temperature of the solution was lowered rapidly to -35C. over a period of less than 3 hours and then the temperature was warmed to -7C. as quickly as possible. The vials were held Eor 3 hours plus aEter the frozen mass had reached a temperature of -7C.
Then thé vials were cooled to -35C. after being held for a little more than 3 hours at -7C.
The pressure in the freeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10C. for the sublimation of the methanol-water solvent.
Eventually the temperature was raised to 25C. taking care not to melt the frozen mas~ in the vials. When the sub-limation process was completed, the vacuum was released and the resulting vials were tested for moisture content, methanol content and reconstitution t1me.
Typical moisture content on individual vials was ~.10 and 0.11 percent.
Two vials tested for methanol residue showed less than 0.5 percent.
~07~7~0 Five vials examined for reconstitution time required between 30 and 60 seconds to dissolve the cephalo-thin sodium in 4.0 ml o~ 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 o solution was calculated to provide 1 gram ampoules of cephalothin sodium.
; The filled vials were placed in a conventional freeze-drying unit and khe temperature of the solutlon was lowered rapidly to -35C. over a period o~ less than 3 hours and then the temperature was warmed to -7C. as quickly as possible. The vials were held for 3 hours plus after the frozen mass had reached a temperature of -7C.
Then the vials were cooled to -35C. after being held for a little more than 3 hours at -7C.
The pressure in the freeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10C. or the sublimation of the acetone-water solvent.
Eventually the temperature was raised to 25C. 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.
~9720 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 cephalo-thin sodium in 4.0 ml of water for injection, W.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).
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 freeze-drying unit and the temperature o the solution was lowered rapidly to -35C. over a period o~ less than 3 hours and then the temperature was warmed to -7C. as quickly as possible. The vilas were held for 3 hours plus after the frozen mass had reached a temperature of -7C.
Then the vials were cooled to -35C. after being held for a little more than 3 hours at -7C.
The pressure in the ~reeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10C. for the sublimation of the isopropanol-water solvent. Eventually the temperature was raised to 25C.
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.
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Typical moisture content on individual vials was 0.10 and a. 11 percent.
Two vials tested for isopropanol residue showed less than 0.5 percent.
Five vials examined for reconr,titution time required between 30 and 60 seconds to dissolve the cephalo-thin 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 cooled to 5~C. Three hundred and seventy-five grams of cephalothin sodium were added with stirring and the qolution was hoated ~o 66.5C. to complete the dissolution of the cephalothin sodium. The resulting solution wa8 filtered through a 45 ~m 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 wa~ 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 -35C. over a period of less than 3 hours ; and then the temperature was warmed to -7C. as quickly as possible. The vials were held for 3 hours plus after the frozen mass had reached a temperature of -7C.
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Then the vials were cooled to -35C. after being held for a little more than 3 hours at -7C.
The pressure in the ~reeze-dryer was reduced to below 0.2 mm mercury a~solute and the temperature was raised to about 10C. for the sublimation of the ethanol-water solvent. Eventually the temperature was raised to 25C.
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 O.S percent.
Five vials examined for reconstitution time required between 30 and 60 seconds to dissolve the cephalo-thin sodium in 4.5 ml. of water for injection, U.S.P.
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Essentially crystalline cephalothin s~dium for parenteral administration is prepared by a freeze-drying process wherein a (Cl-C3 alcohol or acetone)-water solution of cephalothin sodium containing from 2 to 10 percent of a Cl-C3 alcohol or acetone by volume is chilled from room temperature to -20C., or below, preferably -40C. over a 1-3 hour period and then warmed to from -3C. to -10C. and held for 3 hours or more, then cooled to -20C, or below, preferably -40C., 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 sodlum 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, partic-ularly instant coffee, have been prepared by this method formany years. Ordinarily, a solution from which it is desired to reco~er 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.
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Water i~ the solvent generally u~ilized 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 pharma-ceuticals it has been the practice to follow the classic process outlined above; to wit, prepare solution, freeze to ; 10 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 iden-tified 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 crystalliza-tion 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.
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- ~ ( 1079~ZO
- United States Patent No. 4,02g,655 describes a process which embodies a procedure that includes a very rapid cooling of an 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. rrhe 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 ~reeze-drying equipment and the work schedules of the personnel is unsatisfactory becau~e of the irregularity of the operation. Following the teachings of the prior art X;~ 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.
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Accordingly, this invention provides a process for preparing essentially crystalline cephalothin sodium for reconstitution for parenteral administration by a freeze-drying process requiring less than 24 hours compxising the steps of: .
(a) dissolving from 20 to 40 percent (w/w) of said cephalothin sodium in a solvenk com-prised of from 2 to 10 percent of a Cl-C3 alcohol or acetone and from 98 to 90 percent water (v/v);
(b) cooling the solution from (a) to -20C. or below;
. (c) warming the preparation ~rom (b) to a tem-: perature of between -3C. and -10C.;
(d) maintaining the temperature of the prep-aration from (c) at from -3C. to -10C. for a period of 3 hours or more;
(e) cooling the preparation from (d) to -20C.
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 50C., 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, and a Cl-C3 alcohol 721~
or acetone content of not more than 1.0 percent.
The useful process of the present invention comprises a procedure utilizing a ~reez,e-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 Cl-C3 alcohol or acetone and from 98 to 90 percent water. Such a solution is achieved by heating the solution to a temperature of up to 70C. to effect complete solu-bilization. The resulting solution can be sterilizecl by filtration if desired. The solution is then exposed to an environment in which the solution is cooled rapidly to a temperature of -20C. or below, preferably -40C. The cooling period may be completed in from 1 to 3 hours.
After the rapid cooling to -20C. or below, preferably -40C., *he frozen solution is warmed to between -3C. and -10C. and held at such temperature for 3 hours, or more, to assure complete crystallization.
Once the frozen solution has been held at -3C.
to -10C. for 3 hours or more, it is again cooled to -20C.
or below, pre~erably -40C.
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 Cl-C3 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 ~;
' 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 (Cl-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 solukion to -20C. or ~elow, preferably -40C. The presence of the Cl-C3 alcohol or acetone i~ the solvent system acta 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 (Cl-C3 alcohol or acetone)-water solvent than in water alone. Consequently, by warming the frozen solution to from 3C. to -10C. the nucleation and crystalli~ation can be completed in 3 hours or sli~htly more as compared to the 14 to 20 hours required whell no alcohol or acetone is used.
The (Cl-C3 alcohol or acetone)-water solvent employed in the useful methoa of this invention can contain from 2 to 10 percent of a Cl-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 Cl-C3 alcohol or acetone and 97 to 95 percent by volume of water.
In practice the cephalothin sodium is dissolved preferably -107~7~0 in the water and a volume of a Cl C3 alcohol or acetone, preferably 95 percent ethanol, equal to 4 percent of the volume of the solution of the cephalothin sodium, is added to such solution.
The Cl-C3 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 Cl-C3 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 cephalothln sodium is provided by dis-~olving 30 gm of cephalothin sodium in water ~. s'd. to 100 grams and adding thereto 3.55 ml of 95 percent grain . alcohol, making a solution containing about 29 percent (w/w) of the solute.
Sterilization of (Cl-C3 alcohol or acetone)-water solution of cephalothin sodium can be achieved by filtering 20 such solution through sterile filtering means known to those :
skilled in the art and collecking the i}trate in a pre-~` viously ~terilized 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 ~m.
.i The rapid cooling of the (Cl-C3 alcohol or acetone)-water solution of cephalothin sodium can be best accomplished .
by exposing such solution to an environment of about -40C. -~7~7;~
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 -20C., or lower, preferably -40C.
temperature has been reached following ~he method outlined above, the frozen solution is warmed to from -3C. to -10C.
to initiate the nucleation and crystallization of the cephalothin sodium. The frozen solution is held at a tem-perature in that range for a period of 3 hours or more to complete the crystallization.
After such period of holding at from -3C. to -10C., the frozen solution is again chilled to -20C. or below, preferably -40C., to complete solidification. No apparent benefit was found in holding the Erozen mass at -~0C.
or below, preferably -40C. after solidification was complete.
At this point essentially all of the cephalothin sodium is present in the frozen mass as free crystals. A conventional reeze-drying operation is then utilized to sublime the solvent from the frozen mass leaving a deposit of essen-tially crystalline cephalothin sodium.
The frozen cephalothin sodium preparation wherein the nucleation of the crystals is substantially comp].ete is subjected to an environment where the pressure can be reduced to a practical maximum of no more than l mm mercury absolute. It is preferable to reduce the pressure much more than to l 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, 1~>i'97ZV
the design, construction and operation of which are all wel~
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 environ-ment. The temperature of the environment is raised to a point where the maximum sublimation rate can be achieved without melting the frozen mass. As a ~eneral rule, the temperature 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 50C. can be reached with a highly efEicent vacuum system where the absolute pressure is maintained at about 0.05 mm absolute ~50 ~m). In any event, the tem-perature should b~ ra~sed slowly so as to avoid overload~ng the pressure-reducing system which can produce an undesirable melting of the frozen mass. Preferably, the temperature of the environment in the subliming operation should be main-tained between 10C. and ~0C. with the pressure held at or below 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 Cl-C3 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 ana~yses of cephalothin sodium indicated a crystallinity of between 107~7~0 92 and 100 percent. In any event, a sufficient~y 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 ceph~lothin sodium solution and the freeze-drying is done under aseptic conditions the cephalothin sodium crystals can be sterile filled into previously sterili~ed ampoules in appropriate quantities or 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 o~ the (C~-C3 alcohol or acetone)-water solution a~ter suitable sterile iltration into a previously ster-ilized 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 (Cl-C3 alcohol or acetone) water solution o~ cephalothin sodium are then processed in the same manner as described above~ The resulting reeze-dried cephalothin sodium ampoule is ready ~or sterile stoppering and capping.
In practice it i~ preferred to sterile fill a measured volume of sterile (Cl-C3 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 illed into an ampoule in the liquid form than in the solid crystals form. And, second, :
~0797Z~
it is much easier to achieve and maintai~ sterile operatingconditions 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, preferably 3 percent, of the cephalothin sodium can be added to the cephalothin solution before sterile filtration. Such an addition provides a crystalline cephalothin sodium which after reconstitution will have approximately a neutral p~, helping to reduce the stinging experienced on I.M. 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 62C. to complete solution and filtered through a 0.45 ~m "Millipore"* membrane into an appropriate vessel.
The resulting aqueous solution containing 30 percent cephalothin sodium (w/w) was used in S0 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).
*Trademark - X-4905 -12- !
; :
1C~7~720 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 con~entional freeze-drying unit and the temperature of the solution was lowered rapidly to -35C. 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 about -7C.
Then the vials were cooled to -35C. after ~eing held for a little more than 3 hours at -7C.
The pressure in the ~reeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10C. for khe sublimation of the ethanol-water solvent.
Eventually the temperature was raised to 25C. taking care not to melt the frozen mass in the vials. When the sub-limation 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 or ekhanol 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.
, . .
. .
;.. ' .
~ ' ' `. ' ' ; : , :
~L~7~720 EXAMPLE II
Two milliliters of methanol ~ere added to 50 ml.
of the 30 percent ~w/w) cephalothin sodium solution from Procedure I. (E~uivalent 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 freeze-drying unit arld the temperature of the solution was lowered rapidly to -35C. over a period of less than 3 hours and then the temperature was warmed to -7C. as quickly as possible. The vials were held Eor 3 hours plus aEter the frozen mass had reached a temperature of -7C.
Then thé vials were cooled to -35C. after being held for a little more than 3 hours at -7C.
The pressure in the freeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10C. for the sublimation of the methanol-water solvent.
Eventually the temperature was raised to 25C. taking care not to melt the frozen mas~ in the vials. When the sub-limation process was completed, the vacuum was released and the resulting vials were tested for moisture content, methanol content and reconstitution t1me.
Typical moisture content on individual vials was ~.10 and 0.11 percent.
Two vials tested for methanol residue showed less than 0.5 percent.
~07~7~0 Five vials examined for reconstitution time required between 30 and 60 seconds to dissolve the cephalo-thin sodium in 4.0 ml o~ 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 o solution was calculated to provide 1 gram ampoules of cephalothin sodium.
; The filled vials were placed in a conventional freeze-drying unit and khe temperature of the solutlon was lowered rapidly to -35C. over a period o~ less than 3 hours and then the temperature was warmed to -7C. as quickly as possible. The vials were held for 3 hours plus after the frozen mass had reached a temperature of -7C.
Then the vials were cooled to -35C. after being held for a little more than 3 hours at -7C.
The pressure in the freeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10C. or the sublimation of the acetone-water solvent.
Eventually the temperature was raised to 25C. 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.
~9720 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 cephalo-thin sodium in 4.0 ml of water for injection, W.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).
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 freeze-drying unit and the temperature o the solution was lowered rapidly to -35C. over a period o~ less than 3 hours and then the temperature was warmed to -7C. as quickly as possible. The vilas were held for 3 hours plus after the frozen mass had reached a temperature of -7C.
Then the vials were cooled to -35C. after being held for a little more than 3 hours at -7C.
The pressure in the ~reeze-dryer was reduced to below 0.2 mm mercury absolute and the temperature was raised to 10C. for the sublimation of the isopropanol-water solvent. Eventually the temperature was raised to 25C.
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.
:
.. :
- -~L075~72~
Typical moisture content on individual vials was 0.10 and a. 11 percent.
Two vials tested for isopropanol residue showed less than 0.5 percent.
Five vials examined for reconr,titution time required between 30 and 60 seconds to dissolve the cephalo-thin 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 cooled to 5~C. Three hundred and seventy-five grams of cephalothin sodium were added with stirring and the qolution was hoated ~o 66.5C. to complete the dissolution of the cephalothin sodium. The resulting solution wa8 filtered through a 45 ~m 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 wa~ 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 -35C. over a period of less than 3 hours ; and then the temperature was warmed to -7C. as quickly as possible. The vials were held for 3 hours plus after the frozen mass had reached a temperature of -7C.
lV797ZO
Then the vials were cooled to -35C. after being held for a little more than 3 hours at -7C.
The pressure in the ~reeze-dryer was reduced to below 0.2 mm mercury a~solute and the temperature was raised to about 10C. for the sublimation of the ethanol-water solvent. Eventually the temperature was raised to 25C.
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 O.S percent.
Five vials examined for reconstitution time required between 30 and 60 seconds to dissolve the cephalo-thin sodium in 4.5 ml. of water for injection, U.S.P.
; .
',, ; ' '~-' ; ' ' "
Claims (15)
1. A process for preparing essentially crys-talline 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 com-prised of from 2 to 10 percent of a C1-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 tem-perature of between -3°C. and -10°C.;
(d) maintaining the temperature of the prep-aration 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, and a C1-C3 alcohol or acetone content of not more than 1.0 percent.
(a) dissolving from 20 to 40 percent (w/w) of said cephalothin sodium in a solvent com-prised of from 2 to 10 percent of a C1-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 tem-perature of between -3°C. and -10°C.;
(d) maintaining the temperature of the prep-aration 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, and a C1-C3 alcohol or acetone content of not more than 1.0 percent.
2. The process according to claim 1 wherein the C1-C3 alcohol or acetone content of the (C1-C3 alcohol or acetone)-water solution of cephalothin sodium is 4 percent (v/v).
3. The process according to claim 2 wherein the temperature in step (b) is -40°C.
4. The process according to claim 3 wherein the concentration of cephalothin sodium is between 25 and 35 percent (w/w).
5. The process according to claim 4 wherein the concentration of cephalothin sodium is 30 percent (w/w).
6. The process according to claim 5 wherein the pressure is reduced to between 0.05 and 0.20 mm of mercury absolute (50 to 200 µm 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 0.20 mm. of mercury avoiding the melting of said cephalothin sodium preparation.
maintaining an absolute pressure of no more than 0.20 mm. of mercury avoiding the melting of said cephalothin sodium preparation.
7. The process according to claim 1 wherein the concentration of cephalothin sodium is between 25 and 35 percent (w/w).
8. The process according to claim 7 wherein the concentration of cephalothin sodium is 30 percent (w/w).
9. The process according to claim 8 wherein the C1-C3 alcohol or acetone content of the (C1-C3 alcohol or acetone)-water solution of cephalothin sodium is 4 percent (v/v).
10. A process according to any of claims 1-3 wherein the solution is contained in an ampoule.
11. A process according to any of claims 4-6 wherein the solution is contained in an ampoule.
12. A process according to any of claims 7-9 wherein the solution is contained in an ampoule.
13. A process according to any of claims 1-3 wherein the solution of cephalothin sodium additionally comprises from 2 to 5 percent, relative to the amount of cephalothin sodium present, of sodium bicarbonate.
14. A process according to any of claims 4-6 wherein the solution of cephalothin sodium additionally comprises from 2 to 5 percent, relative to the amount of cephalothin sodium present, of sodium bicarbonate.
15. A process according to any of claims 7-9 wherein the solution of cephalothin sodium additionally comprises from 2 to 5 percent, relative to the amount of cephalothin sodium present, of sodium bicarbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA291,717A CA1079720A (en) | 1977-11-24 | 1977-11-24 | Method of preparing a rapidly dissolving powder of crystalline cephalothin sodium for parenteral administration |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA291,717A CA1079720A (en) | 1977-11-24 | 1977-11-24 | Method of preparing a rapidly dissolving powder of crystalline cephalothin sodium for parenteral administration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1079720A true CA1079720A (en) | 1980-06-17 |
Family
ID=4110130
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA291,717A Expired CA1079720A (en) | 1977-11-24 | 1977-11-24 | Method of preparing a rapidly dissolving powder of crystalline cephalothin sodium for parenteral administration |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1079720A (en) |
-
1977
- 1977-11-24 CA CA291,717A patent/CA1079720A/en not_active Expired
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