GB2231266A - The preparation of sterile powders of antibiotics - Google Patents
The preparation of sterile powders of antibiotics Download PDFInfo
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- GB2231266A GB2231266A GB9008756A GB9008756A GB2231266A GB 2231266 A GB2231266 A GB 2231266A GB 9008756 A GB9008756 A GB 9008756A GB 9008756 A GB9008756 A GB 9008756A GB 2231266 A GB2231266 A GB 2231266A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D1/00—Evaporating
- B01D1/16—Evaporating by spraying
- B01D1/18—Evaporating by spraying to obtain dry solids
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- Communicable Diseases (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
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1 1 ' A ' j & ' [ TITLE OF THE INVENTION:
A process and an apparatus for the preparation of sterile injectable 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 lyophilizing process, the active principle is frozen, whereas the precipitation from a 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 degradated, owing to the severe treatments of the active principle. As a matter of fact, the quality and the stability of the lyophilized 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 process. This drawback often occurs when, as in the present invention, organic compounds are prepared, the therapeutic use thereof being compromised also by small alterations or modifications of their structure.
In the crystallization methods for the production of antibiotics, a purification stage of the crystals of the final products is always needed. The solvents used in the step of purification 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 solution of the solvents and reuse and drainage of the same solvents are 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 are increased and the pharmaceuticals are exposed to the risk of bacterial and particle contaminations. These disadvantages of the known methods and apparatus are not negligible. because the sterile pharmaceuticals for injection of the present invention cannot be used in case of any contamination.
It is an object of the present invention to overcome the mentioned limits and drawbacks of the known methods and apparatus of.preparation of sterile injectable powders of antibiotics. It is a particular object of the invention to carry out a process for the continuous or batch preparation of injectable powders of 13-lactamic antibiotics, in particular the sodium derivatives of ampicillin, piperacillin, cefoperazone. cefazolin, cefuroxime and the solid derivatives thereof, by means of a spray- 1 ) dry process, said process being suitable to not alter the stability and the sterility conditions of the sprayed products.
As it is known, indeed. the active substances used for the preparation of antibiotics, should not undergo a process of alteration of their structure and pharmaceutic activity. The conventional spray-dry apparatus do not properly process the antibiotics of the invention. For this reason. the inventor has now realized a 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 powders of antibiotics, characterized in that a solution of the active principle is atomized and dryed in presence of a salification agent, said sprayed solutions being treated in presence of a cycle of an inert gas.
According to another characteristic of the process of the invention, said antibiotics are 13-lactamic antibiotics, in particular the antibiotics selected from the group formed of the sodium salts of:
- ampicillin, having general formula:
(I) --- CONW--- p5 4% H H - piperacillin, having general formula:
C60% CH, no---c CONW- 5 ALC0 9 N t", 0 1 C^ (11) A4 H cefazolin, having general formula:
(III) N-N c it, C-42s 5!CH3 r 'N-CH 1 N=N At fi 'S 1 I- P,],p,:1 cefuroxime, having general formula:
COONa.0 11 0 CH2- 0 - C - NH2 0 N - C - NH--H H (IV) C 11 0) N 1_% OCH3 cefoperazone, having general formula:
(V) OH COON Q 1H3 0, CHs N ,C,-C_\ 0 ' ri 'IN, N-CONH C N-N and the solid derivatives thereof.
The process of the present invention further characterizes in that it consists of a spraydry process comprising the continuous atomization and dissolution stages of the active principle.
According to another characteristic 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 2401C, the antibiotic powders being extracted from the spray-dry reactor at a temperature of 90 - 200C, preferably 95 - 1300C.
The process of the invention is also characterized in that said solution is treated in the spray-dry reactor for 10 seconds and preferably 2 seconds at the most. the concentration-of the active principle in said solution ranging from 1 to 50% by weight, preferably 8 to 25% by weight.
The process of the invention is also characterized in that a solution of said active principle is prepared 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, in presence of an agent of salification, preferably sodium hydroxide, sodium bicarbonate or the sodium salt of the alcohol used for the dissolution of the active principle, the ratio of-the equivalents of sodium ranging from 1 to 1,15.
The dissolution of the active principle takes place through I,- 4 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 nitrogen, the solution of the active principle further undergoing 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 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 said reactor.
This apparatus is also characterized in that a line of vacuum 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 provided.
In comparison with the known methods for the production of pharmaceuticals, the process of the present invention has the advantage to include few stages of treatment of the products., the quality and the stability of the antibiotics being. contrary to the conventional methods, not altered by the process of the invention. As afore said, this invention is thus particularly suitable for the preparation of sterile injectale powders of antibiotics.
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 stability and purity of the antibiotics obtained by the process of the invention are also enhanced in comparison with the conventional lyophilization methods.
The invention provides a process for the continuous preparation of sterile powders of antibiotics and the solution of the active principle in the form of a non sterile salt. Said antibiotics can also be obtained by salification of the corresponding acids from solid mixtures of the same acids and the agents of salification.
The active principle is dissolved into a solution of the salification 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 conducted in presence of small volumes of the solution, at low temperatures (generally ranging from -10 to 45C, preferably from 0 to 35IC).
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 1 1 ,-i of degasification. In order to increase the stability of the final products, the presence of oxygen in the solution is eliminated for both continuous and batch methods. The pH of the solutions is selected amongst the specific pH rates for each product, 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 temperature suitable to avoid the precipitation of the active principle from the solution thereof. The active principle is first dissolved 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 20%, 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 degradates, the active principle is left into the solution for 2 to 10 minutes (continuous process) or 20 to 30 minutes (batch process) at the most.
The physical parameters of the spray-dry process of the invention do not degradate or char the products, the solvents are easily removed and the final products meet the international pharmacopoeia standards (BP, USP, FU, Ph.Eur.).
These results are obtained by the spray-dry process of the present invention, said process being normally conducted in the presence of a cycle of a flow of nitrogen, the temperature of the solution at the inlet of the reactor being of 50 - 500-C, preferably 150 - 240C and, at the outlet, of 90 - 200C, preferably 95 - 130C.
These temperatures of the solution at the inlet of the reactor, lower the degradation risk of the antibiotic. The temperature of the same solution at the outlet is suitable to completely dry the powders of the antibiotic.
The products are left in the spray-dry reactor for 0,5 - 3 seconds, preferably 1 or 2 seconds. The solution to be dryed is counter-current or equi-current (with respect to the flow direction of the inert gas) sprayed in the drier. by means of rotary nozzles or atomizers, the phisical parameters of the hereinafter described process being referred to a rotary atomizer. the flow directions of the solution and the inert gas being equal (equicurrent. flows). The surface area of the spray generated by the atomizer is of 800 to 1500 m/l. The solution for the preparation of the antibiotics. is filtered by means of sterilizing cartridges. The powdered product is first collected into a cooled cyclone separator, and then into a sterile cooled mixer, a homogeneous batch o the final product being thus obtained.
11.1, 11,13 The process and the apparatus of the invention are now described with reference to the following non limitative examples of preparation of sterile injectable powders of antibiotics, and to the accompanying drawing.
The apparatus of figure 1 essentially consists of a reactor 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 active principle is fed from the 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-current, from the line 2. A powder of the active principle is thus obtained into the reactor 1, said powder being collected at the bottom 8 of this reactor. The flow of the exhausted gases is extracted 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 solvent 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 reactor 1. The powders of the active principle are extracted from the collectors 8 and 9 and subsequently treated for packaging and so on.
Example 1: Preparation of sodium ampicillin.
This example refers to the preparation of injectable powders of sodium salts of ampicillin, of general formula:
(I) COCKOL H J 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 hydroxide. corresponding to 1.02 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 atomization, after having been filtered, at the moment when the batch n.l had been already atomized. The batches nA, 4 and 5 were processed in the cl 1.1 ' 1 '.1 L ' ' 1 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 50C.
These solutions were spray-dryed at an inlet temperature in the reactor of 190 to 1950C and an outlet temperature of 95 to 12CC. The spray-dry reactor was equipped with a 45000 rpm rotary atomizer, the flow rate of nitrogen being of 80 kg/h. Under these conditions, 10 batches of sterile sodium ampicillin were prepared, and the practical average yield of transformation of the hereinafter described product was of 99.8%:
Ratio 92.5% of acid Water (K.F.) 0.4% Degradation products 1.1% Dimers and polymers 0.7% Isopropyl alcohol 90 ppm Particulate matter >10 p 130/g >25 p 151g Specific rotation (FU IX)+2800 Aspect of solution < solution 1 FU IX The estimate period of stability was of 5 years.
The same example was repeated, and the same results were obtained, with a solution of sodium ampicillin of 5 to 50% by weight, preferably 9 to 20% by weight. The solvents were water solutions of methanol (0 - 100% vol.), ethanol (0 - 60% vol.), isopropanol (0 - 40% vol.) and acetone (0 - 40% vol.).
The sodium salt of ampicillin to be atomized, can be prepared by suspending the pure ampicillin (at a rate preferably higher than 97% on the dry material) into a water-alcohol or water -acetone 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 conducted through a continuous or a batch process, at a temperature of 5 to 200C. Normally 1.02 to 1.15, preferably 1.05 equivalents of sodium are added. The temperature of atomization of the solution of the active principle normally ranges from 150 to 550C, preferably 150 to 240'C. The temperature at the outlet was 90 to 2000C. preferably 95 to 13CC.
Example 2: Preparation of sodium piperacillin.
This example refers to the preparation of injectable powders of sodium salts of piperacillin, of general formula:
X C6ma 0 N' CH, C% O-C CONI.
NXCO 1 N 0 C^ (II) c 1 1 ' 1 ':1 ( t 5 350 g of anhydrous acid piperacillin are suspended in a mixture of water for injectable compoundings and isopropanol (1350 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 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 atomization, after having been filtered, at the moment when the batch n.l 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 10 minutes at the most and the temperature was ranging from -5 to 10C.
These solutions were spray-dryed at an inlet temperature in the reactor of 195 to 20CC and an outlet temperature of 110 to 115C. The spray-dry reactor was equipped with a 45000 rpm rotary atomizer, the flow rate of nitrogen being of 80 kglh. Under these conditions, 8 batches of sterile sodium piperacillin were prepared, and the practical average yield of transformation of the hereinafter described product was of 99.9%:
Ratio 93.2% of acid Water (K.F.) 0.4% Degradation products 0.1% Dimers and polymers 0.7% Isopropyl alcohol 130 ppm Particulate matter >10 p 150/g >25 p 13/g Specific rotation (FU IX)+187 Aspect of solution < solution I FU IX Time of dissolution - (50% water solution PPI) < 30 seconds The estimate period of stability was of 3 years.
The same example was repeated, and the same results were obtained, 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 - 40% vol.).
- The solution of the sodium salt of piperacillin to be atomized, can be prepared by suspending the acid piperacillin, or a different form of pure piperacillin, (at.a rate preferably higher than 98% on the dry material) into a water-alcohol or water acetone 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 piperacillin.
As.it was previously described, the dissolution can be conducted 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 solution of the active principle normally ranges from 150 to 55O.C, preferably 155 to 200C. The temperature at the outlet was 95 to n 1 ' 1 ' p 1 J 2200C, preferably 95 to 1150C.
Example 3: Preparation of sodium cefazolin.
This example refers to the preparation of injectable powders of sodium salts of cefazolin, of general formula:
(III) COC6k- N-N N CH'sAll 5 kcH, 2CO. -s N=N m H 390 g of anhydrous acid cefazolin are homogeneously mixed with 75 g of sodium bicarbonate, corresponding to 1.04 equivalents of sodium, to obtain a mixture which is quickly soluble in a mixture of water for injectable compoundings and methanol (1210 mI and 405 mI 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 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.l 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 reactor of 195 to 200C and an outlet temperature of 110 to 115C. The spray-dry reactor was equipped with a 44000 rpm rotary atomizer, the flow rate of nitrogen being of 80 kg/h. Under these conditions, 13 batches of sterile sodium cefazolin were prepared, and the practical average yield of transformation of the hereinafter described product was of 99.7%:
Ratio 93.1% of acid Water (K.F.) 1.3% Degradation products 0.1% Dimers and polymers 0.3% Methyl alcohol 30 ppm Particulate matter >10 M 133/g >25 p 9/g Specific rotation (FU IX) - 230 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 obtained, with a solution of sodium cefazolin of 5 to 50% by weight, preferably 8 to 24% by weight. The solvents were water solutions of methanol (0 - 50% vol.), ethanol (0 - 50% vol.), isopropanol (0 - 50% vol.) and acetone (0 - 55% vol.).
The solution of the sodium salt of cefazolin to be atomized.
C -1 P.1f-At' 1.0 can be prepared by suspending the pure acid cefazolin (at a rate preferably higher than 97% on the dry material) into a water-alcohol 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 conducted through a continuous or a batch process. Normally 1.02 to 1.09, preferably 1.03 equivalents of sodium are added. The temperature of atomization of the solution of the active principle was normally ranging from 150 to 55CC, preferably 160 to 200C. The temperature at the outlet was 95 to 200C, preferably 95 to 1150C.
Example 4: Preparation of sodium cefuroxime.
This example refers to the preparation of injectable powders of sodium salts of cefuroxime of general formula:
COONa.0 11 0 o, N CH2- 0 - C-NH2 11 C- C-NH- 9:1SY 11 0 % OCH3 H H (IV) 1-40 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 quickly soluble in a 1400 ml mixture of water for injectable compoundings, collected into a reactor equipped with an ultrasonic dissolution device, a stirrer and a degasification system, said solution being kept 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 having been filtered, at the moment when the batch n.l had been already atomized. The batches n.3, 4 and 5 were processed in the sameway, 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 reactor of 195 to 2000C and an outlet temperature of 110 to 115C. The spray-dry reactor was equipped with a 44000 rpm rotary atomizer, the flow rate of nitrogen being of 80 kg/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.) 1.6% Degradation products < 0.1% Dimers and polymers 0.1% 1 1 1 llethyl alcohol 110 ppm Particulate matter >10 190/g >25 21/g Specific rotation (FU IX) + 650 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 obtained, with a solution of sodium cefuroxime of 1 to 12% by weight, preferably 8 to 10% by weight. The solvents were water solutions of methanol (0 - 60% vol.), ethanol (0 - 80% vol.), isopropanol (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 rate preferably higher than 97% on the dry material) into a wateralcohol or water-acetone mixture, as above detailed, at a temperature of 15 to WC, 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 conducted through a continuous or a batch process. Normally 1.02 to 1.10, preferably 1.04 equivalents of sodium are added. The temperature of atomization of the solution of the active principle was normally ranging from 150 to 55CC, preferably 180 to 220C. The temperature at the outlet was 95 to 200C, preferably 105 to 1150C.
Example 5: Preparation of sodium cefoperazone.
This example refers to the preparation of injectable powders of sodium salts of cefoperazone of general formula:
OM COONa CH.1 o', CH,5 N ri ',N H5C2-M N-CONH-,-C-.c, S N-N 01 (V) 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 quickly soluble in water for injectable compoundings, adde ' d with isopropanol (1540 ml and 150 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.l 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.
1),1!( 1 These solutions were spray-dryed at an inlet temperature in the reactor of 185 to 190C and an outlet temperature of 110 to 115C. The spraydry reactor was equipped with a 44000 rpm rotary atomizer. the flow rate of nit ' rogen being of 80 kglh. 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.M Ratio 92.1% of acid Water (K.F.) 1.0% Degradation products 0.6% Dimers and polymers 0.7% Isopropyl alcohol 230 ppm Particulate matter >10 ji 152/g >25 m 17/g Aspect of solution < solution I FU IX The estimate period of stability was of 2 years.
The same example was repeated, and the same results were obtained, 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 the sodium salt of cefoperazone to be atomized can be prepared by suspending the acid or pure hydrated cefoperazone (at a rate preferably higher than 97% on the dry material) into a water-alcohol or water-acetone mixture, as above detailed. at a temperature 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 cefoperazone.
As it was previously described, the dissolution can ben conducted through a continuous or a batch process. Normally 1.02 to 1.10, preferably 1.05 equivalents of sodium are added. The temperature 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 1150C.
Z X
Claims (12)
1. A process for the preparation of sterile injectable powders of antibiotics, characterized in that a solution of the active principle is atomized and dryed in presence of a salification 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 0-1actamic 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:
- piperacillin, having general formula:
K am N 0 N X0 1 C^ (I) (II) - cefazolin, having general formula:
C"qb N-Rd N CH a 1.111 cefuroxime, having general formula:
COONa 0 R'\' 11 0 N CH2- 0 - C - NHZ 11 C - C - NH--- 9 1 HH 0 %k OCH3 cefoperazone, having general formula:
CH3 0, o, ' %S N N ri&N 145ca-N W-CONH-C-COM4. N-N 1 5 0 A #
4 m and the solid derivatives thereof.
(III) (IV) (V) 4. A process as claimed in claim 1, wherein it consists of a spraydry process comprising the continuous atomization and dissolution stages of the active principle.
5. A process as claimed in claims 1 to 4, wherein the solution of the active principle in the spray-dry reactor has a temperature ranging from 50 to 5500C, preferably from 150 to 240'C, the antibiotic powders being extracted from the spray-dry reactor at a temperature of 90 - 2000C, preferably 95 - 130C.
6. A process as claimed in claims 1 to 3, wherein said solution 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 solution of the active principle is carried out in presence of an agent of salification, preferably sodium hydroxide, sodium bicarbonate or the sodium salt of the alcohol used for the dissolution 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 dissolution 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 45C, preferably 0 to 35C.
11. A process as claimed in claims 1 to 10, wherein said inert gas is nitrogen, the solution of the active principle further 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 said 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.
Pubbshed 1990 at The Patent Ofnce, State House,66171 High Holborn, LondonWC1R 4TP. Further copies maybe ObtainedfrOM The Patent 01noe. Wee Branch, St Mary Cray, Orpington, Kent BR5 3RD. Printed by Multiplex techniques ltd, St Maxy Cray, Kent. Con. 1187
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT8920292A IT1230095B (en) | 1989-04-27 | 1989-04-27 | PROCEDURE FOR THE PREPARATION OF STERILE FORMS OF INJECTABLE POWDERS OF ANTIBIOTICS. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9008756D0 GB9008756D0 (en) | 1990-06-13 |
| GB2231266A true GB2231266A (en) | 1990-11-14 |
Family
ID=11165487
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9008756A Withdrawn GB2231266A (en) | 1989-04-27 | 1990-04-19 | The preparation of sterile powders of antibiotics |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPH02295926A (en) |
| CA (1) | CA2012727A1 (en) |
| DE (1) | DE4011956A1 (en) |
| ES (1) | ES2019560A6 (en) |
| GB (1) | GB2231266A (en) |
| IT (1) | IT1230095B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007065862A1 (en) * | 2005-12-05 | 2007-06-14 | Sandoz Ag | Process for the perparation of lyophilized piperacilline sodium with improved stability after reconstitution |
| US8828443B2 (en) | 2002-02-01 | 2014-09-09 | Bend Research, Inc. | Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus |
| US10383941B2 (en) | 2003-08-04 | 2019-08-20 | Bend Research, Inc. | Spray drying processes for forming solid amorphous dispersions of drugs and polymers |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2404880B (en) | 2003-07-25 | 2005-10-12 | Ultrasound Brewery | Ultrasonic solution separator |
| WO2009081751A1 (en) * | 2007-12-21 | 2009-07-02 | Nipro Corporation | Novel method for producing antibiotic preparation |
| CN102372728B (en) * | 2011-11-28 | 2013-12-11 | 齐鲁安替制药有限公司 | Synthesizing method for cephalosporin compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1403584A (en) * | 1972-05-19 | 1975-08-28 | Beecham Group Ltd | Control medicaments |
| GB1479655A (en) * | 1974-03-08 | 1977-07-13 | Beecham Group Ltd | Antibiotic preparations |
| GB1532993A (en) * | 1975-03-07 | 1978-11-22 | Beecham Group Ltd | Injectable antibiotic compositions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| YU44680B (en) * | 1982-07-30 | 1990-12-31 | Glaxo Lab Ltd | Process for obtaining very pure amorphous form of cephuroxim axetile |
-
1989
- 1989-04-27 IT IT8920292A patent/IT1230095B/en active
-
1990
- 1990-03-21 CA CA002012727A patent/CA2012727A1/en not_active Abandoned
- 1990-04-12 DE DE4011956A patent/DE4011956A1/en not_active Ceased
- 1990-04-19 GB GB9008756A patent/GB2231266A/en not_active Withdrawn
- 1990-04-24 ES ES9001152A patent/ES2019560A6/en not_active Expired - Fee Related
- 1990-04-26 JP JP2108954A patent/JPH02295926A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1403584A (en) * | 1972-05-19 | 1975-08-28 | Beecham Group Ltd | Control medicaments |
| GB1479655A (en) * | 1974-03-08 | 1977-07-13 | Beecham Group Ltd | Antibiotic preparations |
| GB1532993A (en) * | 1975-03-07 | 1978-11-22 | Beecham Group Ltd | Injectable antibiotic compositions |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8828443B2 (en) | 2002-02-01 | 2014-09-09 | Bend Research, Inc. | Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus |
| US9339467B2 (en) | 2002-02-01 | 2016-05-17 | Bend Research, Inc. | Method for making homogeneous spray-dried solid amorphous drug dispersions utilizing modified spray-drying apparatus |
| US10383941B2 (en) | 2003-08-04 | 2019-08-20 | Bend Research, Inc. | Spray drying processes for forming solid amorphous dispersions of drugs and polymers |
| WO2007065862A1 (en) * | 2005-12-05 | 2007-06-14 | Sandoz Ag | Process for the perparation of lyophilized piperacilline sodium with improved stability after reconstitution |
| CN101299995B (en) * | 2005-12-05 | 2013-04-24 | 桑多斯股份公司 | Process for the preparation of lyophilized piperacilline sodium with improved stability after reconstitution |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1230095B (en) | 1991-10-05 |
| GB9008756D0 (en) | 1990-06-13 |
| ES2019560A6 (en) | 1991-06-16 |
| CA2012727A1 (en) | 1990-10-27 |
| JPH02295926A (en) | 1990-12-06 |
| IT8920292A0 (en) | 1989-04-27 |
| DE4011956A1 (en) | 1990-10-31 |
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