CA2012727A1

CA2012727A1 - Process and an apparatus for the preparation of sterile injectable powders of antibiotics

Info

Publication number: CA2012727A1
Application number: CA002012727A
Authority: CA
Inventors: Flavio Dusci
Original assignee: Flavio Dusci; Parenta Srl
Current assignee: PARENTA Srl
Priority date: 1989-04-27
Filing date: 1990-03-21
Publication date: 1990-10-27
Also published as: JPH02295926A; ES2019560A6; IT1230095B; GB9008756D0; DE4011956A1; GB2231266A; IT8920292A0

Abstract

ABSTRACT
A process and the relevant apparatus for the preparation of sterile injectable powders of antibiotics, wherein a solution of the active principle is atomized and dryed in presence of a sa-lification agent, said sprayed solutions being treated in pre-sence of a cycle of an inert gas.
In comparison with the known methods for the production of pharmaceuticals, the process of the present invention has the advantage of including few stages of treatment of the products, the quality and the stability of the antibiotics being not alte-red by the process of the invention which, for this reason, is particularly suitable for the preparation of sterile injectale powders of antibiotics.

Description

Z012~Z7 TITLE OF THE lNVENTION:
A process and an apparatus for the prcparation of sterile in-jectable powders of antibiotics.
DESCRIPTION OF THE INVENTION:
The present invention relates to a process and the relevant apparatus for the preparation of sterile injectable powders of antibiotics.
It is known to prepare pharmaceuticals by means of lyophi-lizing and cristallization methods and apparatus. In the lyophi-lizing process, the active principle is frozen, whereas the pre-cipitation from ~ solution and the purification of the active principle is carried out in the cristallization methods.
The main drawback of the lyophilizing methods is that the stability of the pharmaceutic compounds is altered or degrada-ted, owing to the severe treatments of the active principle. As a matter of fact, the quality and the stability of the lyophili-2ed compounds may be altered due to the high temperatures, the pH rates, the high times of dissolution of the active principle, the freezing and the sublimation stages of the lyophilizing pro-cess. This drawback often occurs when, as in the present inven~
tion, organic compounds are prepared, the therapeutic use there-of being compromised also by small alterations or modifications of their structure.
In the crystallization methods for the production of anti-biotics, a purification stage of the crystals of the final pro-duots is always needed. The solvents used in the step of purifi~
cation represent an additional cost of the main process. These solvents need also to be separated and eliminated to obtain a pure final compound. The extraction of the latter from the solu-tion of the solvents and reuse and drainage of the same solvents sre further problems of the crystallization methods.
Both methods of lyophilization and cristallization have the disadvantage they require a great number of stages such as, for example, the filtration of the crystals of the antibiotic, and the grinding and drying steps of the products. The yield of the whole process is consequently reduced, the times of production sre increased and the pharmaoeuticals are exposed to the risk of bacterial and particle contaminations. These disadvantages of the ~nown methods and apparatus are not negligible, because the sterile pharmaceuticals for injection of the present invention cannot be used in aase of any contamination.
It is an object of the present invention to overcome the mentioned limits and drawbacks of the known methods and appara-tus of.preparation of sterile injectable powders of antibiotics.
It is a particular object of the invention to carry out a pro-cess for the continuous or batch preparation of injectable pow-ders of ~-lactamic antibiotics, in particular the sodium deriva-tives of ampicillin, piperacillin, cefoperuzone, cefazolin, ce-furo~ime and the solid derivatives thereof, by means of a spray-, ~"

IJ~I! I( ` ~) dry process, said process being suitable to not alter the stabi- -lity and the sterility conditions of the sprayed products.
As it is hnown, indeed, the active substances used for the preparation of antibiotics, should not undergo a process of al-teration of their structure and pharmaceutic activity. The con-ventional sprQy-dry apparatus do not properly process the anti-biotics of the invention. For this reQson, the inventor has now realized Q spray-dry method wherein, unlike the known process, sterile injectable powders of antibiotics are prepared, due to the fact that no critical or severe treatment of the products are involved, the antibiotic stability and quality being thus guaranteed, and wherein no problem of drainage or recover of solvents arise.
These and further objects are obtained by the process of the present invention for the preparation of sterile injectable pow-ders of antibiotics, characterized in that a solution of tha ac-tive principle is atomized and dryed in presence of a salifica-tion agent, said sprayed solutions being treated iD. presence of a cycle of an inert gas.
According to another characteristic of the process of the invention, said antibiotics are ~-lactamic antibiotics, in par-ticular the antibiotics selected from the group formed of the sodium salts of: -- ampicillin, having general formula:
(I) H CCti~l, (~ ~ CN~

- piperacillin, having general formula:

~hr~o ~NJ~O
C,H, .~
- aefazolin, having general formula:
tIII) N=~ ~ N~SJ~5~C~
=, CH,CONH HF ~s 20~2727 .

I "il<,.le ':~

- cefuroxime, having general formula:
COONa O ~ IV ) O~ CH2- o - C- NH2 ;~
~C - C - NH~

- cefoperazone, having general formula: -( V ) ,: ; .' ~ :~
OH ", ~ N~H25rN~N -~
H~C2--N N--CONH ~ CONH ~5J N--N

and the solid derivatives thereof -:~::
The prooess of the present invention further characterizes :
in that it aonsists of a spray-dry proaess comprising the conti-nuous atomization and dissolution stages of the active principle, According to another characteristio of the process ~of the invention, the solution of the active principle in the spray-dry reactor has a temperature ranging from 50 to 550C, preferably from 150 to 240C, the antibiotic powders being extraated from the spray-dry reactor at a temperature of 90 - 200C, preferablY
95 - 130C. .- ~-- The process of the invention is also characterized in that - said solution is treated in the spray-dry reactor for 10 seconds and prefersbly 2 seconds at the most, the concentration of the active principle in said solution ranging from 1 to 50X by we-ight, preferably 8 to 25% ~by weieht. `-~
: The process of the in*ention is also charaaterized in that a solution of said active principle is prepared into water, metha- .. -nol or aqueous mixtures formed of up to 80X by volume of etha-. j nol, 70% by volume of aaetone and 50% by volume of isopropyl al-aohol, in presence of an agent of salifioation, preferably so-dium hydroxide, sodium bicarbonate or the sodium salt of the al--~ cohol used for the dissolution of the active prinaiple, the ra- ~ :
tio of.the equivalents of sodium ran~ing from 1 to 1,15.
The dissolution of the aative prinaiple takes plaae throu~h '-`'' ', '',.

~ ~ .' ,. .'"',.,~
:-~ ..

IJ~l(".` ~l a continuous or batch process, said active principle being left in the solution respectively for 10 and 30 minutes at the most.
The inert gas used in the process of the invention is nitro-gen, the solution of the Hctive principle further und~rgoing an ultrasonic and a degasification treatment.
The apparatus of the invention is characterized in that a reactor is provided, wherein said atomized solution of the acti-ve principle is contacted with a flow of a hot and inert gas, a collector of the powders being mounted at the bottom of said re-actor, a separator of the powders being mounted at the inert gas discharge from said reactor.
This apparatus is also characterized in that a line of vacu-um for the reactor is coMprised, said apparatus being further provided of a recycling circuit of the inert gases at the outlet of said separator of the powders.
The apparatus of the invention also comprises a condenser for the separation of the solvents from the gaseous phase of said separator of the powders, a recycling line of the condensed phase and a heater of the recycled inert gas being further pro-vided.
In comparison with the known methods for the production of pharmaceuticals, the process of the present invention has the advantaee to include few stages of treatment of the products, the ~uality and the stability of the antibiotics being, contrary to the conventional methods, not altered by the process of the invention. As aore said, this invention is thus particularly suitable for the preparation of sterile injectale powders of an-tibiotics.
The yield of the process of the invention is also higher and the times of dissolution of the active principle are lower as compared to the traditional methods of crystallization. The sta-bility and purity of the sntibiotics obtained by the process of the invention are also enhsnced in comparison with the conven-tional lyophilization methods. ~ -The invention provides a process for the continuous prepara- ~
tion of sterile powders of antibiotics and the solution of the ~h active principle in the form of a non sterile salt. Said anti-biotics can also be obtained by salification of the correspon-ding acids from solid mixtures of the same acids and the agents of salification.
The active principle is dissolved into a solution of the sa-lification agent, such as solutions of sodium hydroxide, sodium bicarbonate, or the sodium salt of the alcohol used to dissolve the active principle, and other sodium agents of salification.
In order to obtain a stable solution, the batch process is conduc.ted in presence of small volumes of the solution, at low temperatures (generally ranging from -10 to 45C, preferably from 0 to 35C).
The duration of the dissolution step of the continuous and batch process, is lowered due to the use of a reactor equipped with an ultrasonic device, in addition to a stirrer and a system 1 ~ , ` ;" ~ ,"" , ;, , , ` ~ , " ~ , ";~ ~ " ~ "~

of degasification. In order to increase the stability of the fi-nal products, the presence of oxygen in the solution is elimina-ted for both continuous and batch methods. The pH of the solu-tions is selected amongst the specific pH rates for each pro-duct, the degradation and polymerization reactions being thus eliminated.
The solutions of the spray-dry process are water solutions of isopropyl, methyl and ethyl alcohols or water-acetone mixtu-res, pure methanol or similar solvents wherein the active prin-ciple is dissolved.
The batch process of the invention takes place at a tempera-ture suitable to avoid the precipitation of the active principle from the solution thereof. The active principle is first dissol- :
ved in water, and than the solvent is added or, alternativelY, the active principle is directly added to the mixture of the solvents.
The concentration of the active principle in the solution.
normally ranges from 5 to 50%, preferably 8 to 20X, by weight.
These concentrations of the active principle and the mentioned percentages of the solvents give a solution having the higher ~
stability. ,-In order to avoid the antibiotic degrsdAtes, the active principle is left into the solution for 2 to 10 minutes (conti-nuous process) or 20 to 30 minutes (batch process) at the most.
The physical parameters of the spray-dry process of the in- -vention do not degr~date or char the products, the solvents are easily removed and the final products meet the international pharmacopoeia stand~rds (BP, USP, FU, Ph.Eur.).
These results are obtsined by the spray-dry process of the present invention, said process being normally conducted in the presence of a oycle of a flow of nitrogen, the temperature of the solution at the inlet of the reactor being of 50 - 500C, preferably 150 - 240C and, at the outlet, of 90 - 200C, prefe- ~z rsbly 95 - 130C.
These temperatures of the solution at the inlet of the reac-tor, lower the degradation risk of the antibiotic. The tempera-ture of the same solution at the outlet is suitable to complete-ly dry the powders of the antibiotic. -~
The products are left in the spray-dry reactor for 0,5 - 3 seconds, preferably 1 or 2 seoonds. The solution to be dryed is counter-current or equi-current (with respect to the flow direc-tion of ,the inert gas) sprayed in the drier, by mean~ of rotary~
nozzles or atomizers, the phisioal parameters of the hereinafter described process being referred to a rotary atomizer, the flow direotions of the solution and the inert gas being equal (equi- :~
current. flows). The surface area of the spray generated by the atomizer is of 800 to 1500 m'/l. The solution for the prepara- ~ -tion of the antibiotics, is filtered by means of sterilizing cartridges. The powdered product is first collected into a co-oled cyclone separator, and then into a sterile cooled mi~er, a ~
homogeneous batch of the final product being thus obtained. , ~:

.: `:~'~';.

~ 20127Z7 I J ~
The process and the apparatus of the invention are now de-scribed with reference to the following non limitative examples of prepsration of sterile injectuble powders of antibiotics. snd to the accompanying drawing.
The apparatus of figure 1 essentially consists of a reaotor 1 connected, by means of lines 2 and 3, to the hot inert gas supply 4 and a cyclone 5 respectively. The solution of the acti-ve principle is fed from th~ stirrer 14 to the reactor 1 through the line 6 and a plurality of nozzles 7.
In order to enhance the atomization of the solution, the latter is mixed with an inert gas fed, by equi- or counter-cur-rent, from the line 2. A powder of the active principle is thus obtained into the reactor 1, said powder being collected nt the bottom 8 of this reactor. The flow of the exhausted gases is ex-tracted from the line 3 and is sent to the cyclone 5, wherein the remaining powders are collected into the bottom 9.
A flow of inert gases and solvent fumes free~of powders is discharged from the cyclone 5 and recycled via the line 10. A
condenser 11 separates the solvant condensates from the inert gas: the condensates are forwarded to the stirrer 14 for the preparation of the solution of the active principle, and the inert gas passes through a heater 14 and is then conveyed into the reactor 1. The line of recycle is connected to a vacuum line 13 which is suitable to create vacuum conditions into the reac-tor l. The powders of the active principle are extracted from the collectors 8 and 9 and subsequently treated for packaging and so on.
Exam~le 1: Preparation of sodium ampicillin.
This example refers to the preparation of injectable powders of sodium salts of ampicillin, of general formula:
(I) H C~
~ .;c"~

300 g of ampicillin trihydrate are suspended in a mixture of water for injectable compoundings and isopropanol (910 ml and 400 ml respectively), collected into a reactor equipped with an ultrasonic dissolution device, a stirrer and a degasification system. This solution was added with 380 ml of 2 N sodium hydro-xide, c.orresponding to 1.02 gram equivalent of sodium. The solu-tion was prepared under 5 subsequent batches.
In order to minimize the time of permanence of the product in the solution, tha batch n.2 was ready for atomization, after having been filtered, at the moment when the batch n.1 had been already atomized. The batches n.3, 4 and 5 were processed in the 2(~1~7Z7 ¦ 1 ! 11 ~
same way, the time of permanence in the solution of the product being of 10 minutes at the most and the ttetmperature was ranging from -5 to 5C.
These solutions were spray-dryed ut an inlet temperature in the reactor of 190 to 195C and an outlet temperature of 95 to 120C. The spray-dry reactor was equipped with a 45000 rpm rota-ry atomizer, the flow rate of nitrogen being of 80 kg/h. Under these conditions, 10 batches of sterile sodium ampicillin were prepared, tand the practical aver~e yield of transformtatiorl of the hereinafter described product was of 99.8%:
Ratio 92.5% of acid Water (K.F.) 0.4%
Degradation products1.1%
Dimers and polymers0.7%
Isopropyl alcohol 90 ppm Particulate matter >10 ~ 130/g >25 ~, 16/g Specific rotation (FU IX)+280 hspect of solution < solution I FU IX
The estimate period of stability was of 5 years.
The same example was repeated, and the same results were ob-tained, with a solution of sodium ampicillin of 5 to 50% by wei-ght, preferably 9 to 20X by weight. The solvents were water so- -lutions of methanol (0 - 100% vol.), ethanol (0 - 60X vol.), ~ `
isopropanol (0 - 40% vol.) and acetone (0 - 40X vol.). -~
The sodium salt of ampicillin to be atomized, can be prepa-red by suspending the pure ampicillin (at a rste preferably hi-~her than 97X on the dry material) into a water-alcohol or water -aoetone mixture as above detailed, the agent of salification being gradually added in such a way as the pH of the solution lies within the limits of stability of the ampicillin. ;
As it was previously described, the dissolution can ben con-ducted through 8 continuous or a batch process, at a temperature -of 5 to 20C. Normally 1.02 to 1.15, preferably 1.05 equivalents of sodium are added. The temperature of atomization of the solu-tion of the active principle normally ranges from 150 to 550C, preferably 150 to 240C. The temperature at the outlet was 90 to 200C, preferably 95 to 130C.
E~ample 2: Preparation of sodium piperacillin. .
This example refers to the preparation of injectable powders of sodium salts of piperacillin, of general formula~
., (II) i ;CONH...F~5 ~N~ ,0 ~N~O
C,H, ,"' ' ' ~'' ' '"'" ~

350 g of ~nhydrous acid piperacillin are sus~ended in a mix-ture of water for injectable compoundings and isopropanol (1350 ml ~nd 400 ml respectively), collected into A reactor equipped with an ultrasonic dissolution device, a stirrer and a degasifi-CAtiOn system. This solution was added with 60 g of sodium bi-carbonate, corresponding to 1.06 gram equivalent of sodium. The solution was prepared under 5 subsequent batches.
In order to minimize the time of permanence of the product in the solution, the batch n.2 was ready for ato~ization, after having been filtered, at the moment when the batch n.1 had been alresdy atomized. The batches n.3, 4 and 5 were processed in the same way, the time of permanence in the solution of the product being of 10 minutes at the most and the temperature was ranging from -5 to 10~C.
These solutions were spray-dryed at an inlet temperature in the reactor of 195 to 200C and an outlet temperature of 110 to 115C. The spray-dry reactor was equipped with a 45000 rpm rota-ry atomizer, the flow rate of nitrogen being of 80 ~g/h. Under these conditions, 8 batches of sterile sodium piperacillin were prepared, and the prsctical average yield of transformation of the hereinafter described product was of 99.9X:
Ratio 93.2X of acid Water (K.F.) 0.4%
Degradation products 0.lY.
Dimers and polymers0.7X
Isopropyl alcohol130 ppm Particulate matter >10 ~ 150/g ~25 ~ 13/g Specifio rotation (FU IX)~187 Aspect of solutlon < solution I FU IX
Time of dissolution (50X water solution PPI) < 30 seconds The estimate period of stability was of 3 years.
The same example was repeated, and the same results were ob-tained, with a solution of sodium piperacillin of 5 to 50% by weight, preferably 10 to 25% by weight. The solvents were water solutions of methanol (0 - 100% vol.), ethanol (0 - 60% vol.), isopropanol (0 - 40% vol.) and acetone (0 - 40X vol.).
The solution of the sodium salt of piperacillin to be atomi-zed, can be prepared by suspending the acid piperacillin, or a different form of pure piperacillin, (at a rate prefer~bly hi-gher than 98% on the dry material) into a water-alcohol or water -acetone mixture as above detsiled, the agent of salifioation being gradually added in such a way as the pH of the solution lies within the limits of stability of the piperacillin.
As.it was previously described, the dissolution can be con-ducted through a continuous or a batch process, at a temperature of 5 to 20C. Normally 1.00 to 1.10, preferably 1.02 equivalents of sodium are added. The temperature of atomization of the solu-tion of the active principle normally ranges from 150 to 550C, preferably 155 to 200C. The temperature at the outlet was 95 to I J < 1~ ! ' J
220C, preferably 95 to 115C.
Example 3: Preparation of sodium cefazolin.
This example refers to the preparation of injecteble powders of sodium salts of cefazolin, of general formula:
(III) N=~, ~ N~CH~SJ~5~CH, ,N--CH,CONH-- F~s 390 g of anhydrous acid cefazolin are homogeneously mixed with 75 g of sodium bicarbonate, corresponding to 1.04 equiva- -lents of sodium, to obtain a mixture which is quickly soluble in a mixture of water for injectable compoundings and methanol (1210 ml and 405 ml respectively), collected into a reactor equipped with an ultrasonic dissolution device, a stirrer and a degasification system, said solution being kept at 35C. This solution was prepared und0r 5 subsequeDt batches. ~ -In order to minimize the time of permanence of the product -;~
in the solution, the batch n.2 was ready for atomization, after having been filtered, at the moment when the batch n.1 had been ~ ~`
already atomized. The batches n.3, 4 and 5 were processed in the same way, the time of permanence in the solution of the product -being of 7 minutes at the most.
These solutions were spray-dryed at an inlet temperature in the reaotor of 195 to 200C and an outlet temperature of 110 to -~
116C. The spray-dry reaotor was equipped with a 44000 rpm rota- !` ~ ~" ~
ry atomizer, the flow rate of nitrogen bein~ of 80 ~g/h. Under : ` -these oonditions, 13 batohes of sterile sodium cefazolin were prepared, and the practical average yield of transformation of ~ -the hereinafter described product was of 99.7X~
Ratio 93.lX of acid Water (K.F.~ 1.3X ~
Degradation products 0.1% ~-Dimers and polymers 0.3X
Methyl alcohol 30 ppm ~- .
Particulate matter >10 ~ 133/g I , >2~ ~ 9/g Specific rotation (FU IX) - 23 :~
Aspect of solution < solution I FU IX
The estimate period of stability was of 4 years.
The same example was repeated, and the same results were ob-tained, with a solution of sodium cefazolin of 5 to 50% by wei-ght, preferably 8 to 24X by weight. The solvents were water so-lutions of methanol (0 - 50% vol.), ethanol ~0 - 50% vol.), iso-propanol (0 - 50X vol.) and acetone (0 - 55X vol.). -~
- The solution of the sodium salt of cefazolin to be atomized, . , :

20~2727 can be prepsred by suspending the pure acid cefazolin (at a rate preferably higher than 97% on the dry material) into a water-al-cohol or water-acetone mixture, as above detailed, at a tempera-ture of 15 to 40C, the agent of salification being gradually added in such a way as the pH of the solution lies within the limits of stability of the cefazolin.
As it was previously described, the dissolution can ben con-ducted through a continuous or a batch process. Normally 1.02 to 1.09, preferably 1.03 equivalents of sodium are added. The tem-perature of atomization of the solution of the active principle was normally ranging from 150 to 550C, preferably 160 to 200C.
The temperature at the outlet was 95 to 200C, preferably 95 to 115C.
Example 4: ~reparation of sodiu~ cefuro~ime.
This example refers to the preparation of injectable powders of sodium salts of cefuroxime of general formula:
(IV) COONa ~ N~CH2 - O - C- NH2 C - C - N H---~ 5J

140 g of anhydrous acid cefuroxime are homogeneously mixed with 29 g of sodium bicarbonate, corresponding to 1.05 equiva-lents of sodium, to obtain a mixture which is quichly soluble in 1400 ml mixture of water for injectable compoundings, collec-ted into a reaator equipped with an ultrasonic dissolution devi-ce, a stirrer and a degasification system, said solution being hept at 10 to 20C. This solution was added with 150 ml of ethanol. This solution was prepared under 5 subsequent batches.
In order to minimize the time of permanence of the product in the solution, the batch n.2 was ready for atomization, after ~laving been filtered, at the moment when the batch n.1 had been slready atomized. The batches n.3, 4 and 5 were processed in the same way, the time of permanence in the solution of the product being of 7 minutes at the most.
These solutions were spray-dryed at an inlet temperature in the reaotor of 195 to 200C and an outlet temperature of 1l10 to 115C. The spray-dry réactor was equipped with a 44000 rpm rota-ry atomizer, the flow rate of nitrogen being of 80 ~g/h. Under these conditions, 15 batches of sterile sodium cefuroxime were prepared, and the practical average yield of transformation of the hereinafter described product was of 99.9-/.:
Ratio 92.5% of acid Water (K.F.) 1.6X
Degrsdation products < O.lX
Dimers and polymers O.lX

20~27Z7 Methyl alcohol 110 ppm Particulste mutter >10 ~ 190/g >25 ~ 21/g Specific rotation (FU IX) + 65 Aspect of solution < solution I FU IX
The estimate period of stability was of 4 years.
The same example was repeated, and the same results were ob-tained, with a solution of sodium cefuroxime of 1 to 12% by wei-ght, preferably 8 to 10% by weight. The solvents were water so- ,, lutions of methanol (0 - 60% vol.), ethanol (0 - 80% vol.), iso- ~ -propanol (0 - 50% vol.) and acetone (0 - 70% vol.).
The solution of the sodium salt of cefuroxime to be atomized can be prepared by suspending the pure acid cefuroxime (at a ra-te preferably higher than 97% on the dry material) into a water-alcohol or water-acetone mixture, as above detailed, at a tempe- - -rature of 15 to 40C, the agent of salification being gradually added in such a way as the pH of the solution lies within the ~:
limits of stability of the cefuroxime. .
As it was previously described, the dissolution can be con- ~
ducted through a continuous or a batch process. Normally 1.02 to 5 1.10, preferably 1.04 equivalents of sodium are added. The tem- ~;~
perature of atomization of the solution of the active principle :
was normally ranging from 150 to 550C, preferably 180 to 220C.
The temperature at the outlet was 95 to 200C, preferably 105 to 115C.
E~ample 5: Preparation of sodium cefoperazone. :~
This example refers to the preparation of injectable powders : ~ -of sodium salts of cefoperazone of general formula: ~ ~
(V) '~:'::", ' H C N/X~ ~H~ ~ r " ~ ~:
. . . -440 g of anhydrous acid cefoperazone are homogeneously mixed with 59 g of sodium bicarbonate, corresponding to 1.03 equiva-lents of sodium, to obtain a mixture which is quic~ly soluble in water for injectable compoundings, added with isopropanol (1540 ml andl150 ml respectively), collected into a reactor equipped with an ultrasonic dissolution device, a stirrer and a degasifi-cation system, said solution being kept at 10 to 20C. This so-was prepared under 5 subsequent batches.
In order to minimize the time of permanence of the product in the solution, the batch n.2 was ready for atomization, after having been filtered, at the moment when the batch n.1 had been already atomized. The batches n.3, 4 and 5 were processed in the same way, the time of permanence in the solution of the product being of 7 minutes at the most.

20~27Z7 These solutions were spray-dryed ut un inlet temperature in the reactor of 185 to 190UC and an outlet temperature of 110 to 115~C. The spray-dry reactor was equipped with a 44000 rpm rota-ry atomizer, the flow rate of nitrogen being of 80 hg/h. Under these conditions, 17 batches of sterile sodium cefoperazone were prepared, and the practical average yield of transformation of the hereinafter described product was of 99.6%: -Ratio 92.lX of acid Water (K.F.) 1.0%
Degradation products0.6%
Dimers and polymers 0.7%
Isopropyl alcohol230 ppm Particulate mattcr >10 ~ 152/g >25 ~ 17/g `
Aspect of solutioa < solution l ~U IX
The estimate period of stability was of 2 years.
The ssme example was repeated, and the same results were ob-tained, with a solution of sodium cefoperazone of 5 to 50% by weight, preferably 8 to 25% by weight. The solvents were water solutions of methanol ~0 - 60% vol.), ethanol (0 - 80% vol.), isopropanol (0 - 25% vol.) and acetone (0 - 50% vol.).
The solution of Lhe sodium salt of cefoperszone to be stomi-zed csn be prepared by suspending the acid or pure hydrated ce-foperazone (st a rate preferably higher than 97% on the dry ma-terisl) into a water-alcohol or water-acetone mixture, ss abo~e detsiled, st a temperature of 15 to 40C, the agent of salifics-tion being gradually added in such a way as the pH of the solu-tion lies within the limits of stsbility of the cefoperazone. -As it was previously desoribed, the dissolution can ben con-duoted through a continuous or a-bstch prooess. Normally 1.02 to 1.10, prefer~bly 1.05 equivalents of sodium are udded. The tem-persture of stomizstion of the solution of the aotive prinoiple ~--wss normslly rsnging from 150 to 550C, preferably 180 to 220C.
The tempersture st the outlet was 95 to 200C, preferubly 105 to 115C.

,.`' - ;,~:-~

Claims

1. A process for the preparation of sterile injectable pow-ders of antibiotics, characterized in that a solution of the ac-tive principle is atomized and dryed in presence of a salifica-tion agent, said sprayed solutions being treated in presence of a cycle of an inert gas.

2. A process as claimed in claim 1, wherein said antibiotics are .beta.-lactamic antibiotics.

3. A process as claimed in claim 2, wherein said antibiotics are selected from the group formed of the sodium salts of:
- ampicillin, having general formula:
(I) - piperacillin, having general formula:
(II) - cefazolin, having general formula:
(III) - cefuroxime, having general formula:
(IV) - cefoperazone, having general formula:
(V) and the solid derivatives thereof.

4. A process as claimed in claim 1, wherein it consists of a spray-dry process comprising the continuous atomization and dis-solution stages of the active principle.

5. A process as claimed in claims 1 to 4, wherein the solu-tion of the active principle in the spray-dry reactor has a tem-perature ranging from 50 to 550°C, preferably from 150 to 240°C, the antibiotic powders being extracted from the spray-dry reac-tor at a temperature of 90 - 200°C, preferably 95 - 130°C.

6. A process as claimed in claims 1 to 3, wherein said solu-tion is treated in the spray-dry reactor for 10 seconds and pre-ferably 2 seconds at the most.

7. A process as claimed in claims 1 to 6, wherein the con-centration of the active principle in said solution is ranging from 1 to 50% by weight, preferably 8 to 25% by weight.

8. A process as claimed in claims 1 to 7, wherein a solution of said active principle is made into water, methanol or aqueous mixtures formed of up to 80% by volume of ethanol, 70% by volume of acetone and 50% by volume of isopropyl alcohol.

9. A process as claimed in claims 1 to 8, wherein said solu-tion of the active principle is carried out in presence of an agent of salification, preferably sodium hydroxide, sodium bi-carbonate or the sodium salt of the alcohol used for the disso-lution of the active principle. the ratio of the equivalents of sodium ranging from 1 to 1,15.

10. A process as claimed in claim 1, wherein said dissolu-tion of the active principle takes place through a continuous or batch process, said active principle being left in the solution respectively for 10 and 30 minutes at the most, in both cases the temperature of the solution being of -10 to 45°C, preferably 0 to 35°C.

11. A process as claimed in claims 1 to 10, wherein said inert gas is nitrogen, the solution of the active principle fur-ther undergoing an ultrasonic and a degasification treatment.

12. An apparatus for carrying out the process of claims 1 to 11, characterized in that a reactor is provided wherein said atomized solution of the active principle is contacted with a flow of a hot and inert gas, a collector of the powders being mounted at the bottom of said reactor, a separator of the powders being mounted at the inert gas discharge from sa-id reactor, a line of vacuum for the reactor being comprised, said apparatus being further provided with a recycle circuit of the inert gas at the outlet of said separator of the powders, a condenser for the separation of the solvents from the gaseous phase of said separator of the powders, a recycle line of the condensed phase and a heater of the recycled inert gas.