JPS646170B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a process for the preparation of amoxicillin sodium of various quality suitable for use in injectable preparations, and injectable preparations containing the above-mentioned compounds,
The present invention relates to a method for producing amoxicillin sodium of improved quality by a freeze-drying method. The above method is known, for example, from Dutch published patent application No. 7707494. This patent application describes amoxicillin sodium in a solvent system containing water and at least one secondary or tertiary alkanol having 4 or 5 carbon atoms, which is at least 5% by weight soluble in water at 25°C as a stabilizer. A method is disclosed which consists of lyophilizing the solution, preferably in the presence of 4 to 50% by weight of secondary or tertiary alkanol. The tertiary alkanol is preferably tert-butanol, although it has been shown that the solvent system can also contain small amounts of other pharmaceutically acceptable solvents, such as primary alcohols. A disadvantage of this preparation is the presence of physically foreign solvent residues, which, although toxicologically acceptable, can give rise to some undesirable side effects after administration of the final injection preparation. The content of this solvent residue can be up to 6% in the dry product. A method for producing crystalline cephalosporin suitable for parenteral administration is also known, which is produced by lyophilization. For example, US Pat. No. 4,029,655, and more specifically Belgian Patent No. 861,135,
The present invention relates to a process for producing stable cephalothin sodium powder for parenteral administration by lyophilization of a pre-prepared solution of cephalothin sodium in an aqueous solution containing alcohol or acetone. Furthermore, one may mention Dutch published patent application No. 7712823,
This is done by gradually cooling the initial solution for 2 to 25 minutes.
% alkano-containing aqueous solution by freeze-drying. However, the same drawbacks as mentioned above are present in the preparations thus obtained. On the other hand, there has been a great deal of activity in the numerous patent publications that have appeared in recent years regarding the search for suitable amoxicillin formulations which can be readily converted into conventional sufficiently stable injection solutions and which must also be sufficiently stable in dry form. The commonly developed concept of those skilled in the art is that for the production of injectable preparations of amoxicillin, the usual methods as applied to previously developed semi-synthetic penicillins such as ampicillin are It is recognized from the above patent documents that due to their physical properties they cannot be used without some additional treatment. Therefore, on the one hand, all kinds of proposals have been made to obtain compatible preparations of compositions containing the usual alkali metal salts of amoxicillin and its derivatives, and on the other hand, the person skilled in the art will be able to understand the amoxicillin salts with other cations. There appears to be a strong focus on research into highly variable and injectable preparations containing. For example, Dutch published patent application no.
No. 7509698 discloses a method for producing arginine salt of amoxicillin. There is a need to develop new non-toxic, parenterally administrable forms of amoxicillin that preserve the antibiotic properties of these amoxicillin salts. Furthermore, as pointed out above, amoxicillin itself and its salts known to date cannot be administered parenterally in a satisfactory manner. Also, Example 4 of JP-A-51-32723 discloses a method for preparing a suitable injectable solution containing amoxicillin and glycine sodium salt. For example, German Published Patent Application No. 2540523 describes D-α-carboxyamino-p-
A method for preparing a salt of hydroxybenzylpenicillin is described. However, as clearly mentioned above, the production of injectable amoxicillin preparations appears to be much more difficult than originally anticipated by those skilled in the art, which is attributable to the instability of amoxicillin-containing solutions caused by the decomposition of amoxicillin salts in aqueous solutions. It was done. According to this last-mentioned patent application, preferably a mixture of the sodium salt of amoxicillin and the disodium salt of D-α-carboxyamino-p-hydroxybenzylpenicillin must be used. Dutch Published Patent Application No. 7602180 describes a method for preparing an injectable preparation of amoxicillin, which has good stability and is well tolerated by the administration of an easily injectable solution. The preparation consists of a powder which is easily converted into an injectable preparation by the addition of an aqueous vehicle. This powder consists of fine particles of amoxicillin trihydrate coated with a dispersant, and the ratio of amoxicillin trihydrate to dispersant is 1000.
The ratio will be 1 to 20 to 1. This fine particle averages 2μ to 20μ
and at least 95% should have a diameter of 0.5
Should have a diameter between ~50μ and 10% of the surface
to 100% must be coated with dispersant. As dispersant at least one polymeric substance soluble in water and having an average molecular weight of 6000 to 40000, such as polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymer, sodium carboxymethyl cellulose, polyvinyl alcohol, dextran, sodium alginate, preferably has proposed mixtures of compounds containing polyvinylpyrrolidone and wetting agents such as lecithin, phospholipids, sorbitan fatty acid esters, especially lecithin. For the same reason, the direction of chemically modified amoxicillin derivatives, which break down in the body and form amoxicillin again, was also investigated. In this regard, US Pat. No. 4,035,381 and Dutch Published Patent Application No.
You can cite issue 7701480. A 9 to 15 mole % excess of sodium hydroxide over the amount required to form amoxicillin sodium is added to the aqueous suspension of amoxicillin trihydrate until the amoxicillin is completely dissolved.
Add slowly but as quickly as possible with good mixing and then add a portion of the excess base to 0 to 30
At a temperature of °C (preferably at 20-25 °C),
Immediately neutralize with hydrochloric acid to obtain a final excess of 3-5 mol% sodium hydroxide relative to the amoxicillin, then sterile filter the resulting solution, freeze the solution, and finally lyophilize. It has been found that by doing so, it is possible to produce an improved amoxicillin sodium formulation that is free of allergic agents and has a relatively long stability that can be easily made into a stable, fully injectable solution. Preferably a large excess of sodium hydroxide is used, followed by partial neutralization by addition of hydrochloric acid solution. Preferably, the final concentration of amoxicillin sodium is 2.5-15% by weight, more preferably 5% by weight.
Select the initial amounts of amoxicillin trihydrate, sodium hydroxide, and hydrochloric acid such that: In the present invention, "gradually addition"
This means adding large amounts of sodium hydroxide in a manner that avoids highly localized concentrations from time to time. This is achieved by vigorous stirring. This also avoids decomposition of amoxicillin caused by incomplete stirring. On the other hand, the method of the invention should in principle be carried out "as soon as possible". That is, it is necessary to allow amoxicillin to remain in the high PH solution for as short a time as possible. This partial neutralization results in approximately
10 mol% sodium chloride is also present in the solution. It is understood that the amoxicillin solution must be filtered under sterile conditions, frozen and lyophilized in flasks or in bulk. If the solution is frozen and lyophilized in a flask, it is preferred to use a syringe flask and rubber stopper specifically designed for lyophilization. Final amoxicillin sodium preparation 0.10 flask dry
~5g, preferably 0.25g, 0.5g, and 1g
Fill the flask to contain. Equipment commonly used for this purpose, e.g.
Freezing and lyophilization can be performed using a Sec.Floyd SA CH-1024 Riolab D Laboratory Freeze Dryer or a Raybold Production Freeze Dryer. It can be seen that freezing can also be carried out outside the actual freeze-drying apparatus. For freezing, the obtained amoxicillin solution is cooled at normal pressure, preferably at -20°C to -70°C for 0.5 to 2.5 hours, more preferably at -20 to -30°C for 0.5 to 1.0 hours. The pressure is then reduced to 9.0-12.0N/ ^m2 , preferably 10N/ ^m2 , and the temperature is gradually increased to 0°C over 24-30 hours, preferably about 25 hours, while the vacuum is gradually reduced to about 8N/m2. Climb to ^m2 . After that, reduce the pressure to 8N/
The temperature is increased by heating to room temperature for 4 to 5 hours while maintaining the temperature at m ² . According to another further preferred embodiment of the method of the invention, the amoxicillin solution after sterilization is applied under aseptic conditions to a plate of sterile plastic foil, for example both supported by a sterile metal frame having upright rims up to about 4 cm in height. Alternatively, the solution can be frozen and lyophilized in bulk by placing it in a shallow stainless steel box. Adapt the plastic foil to obtain optimal contact between solution and drying plate. The final level of liquid is 0.5~
It can be 3 cm, preferably about 1 cm. The drying plate of the freeze dryer is approximately -25℃ to -50℃
Pre-cooling is preferred, preferably to about -40°C. The cooling capacity of the freeze-drying equipment is such that the solution with a level of 0.5 to 3 cm, preferably 1 to 2 cm, can be heated to -10 to -30°C within 60 to 30 minutes, preferably within 50 to 40 minutes.
It should preferably be chosen large enough to freeze at a temperature of -15°C to -20°C. The time between suspending the amoxicillin trihydrate and closing the lyophilizer after transporting the flask or pouring the solution onto a plate is preferably less than 30 minutes, while the solution is prepared, filtered and the flask is closed. Nimitashi and (or)
The time required to transfer the solution to a lyophilizer and freeze it is preferably no more than 90 minutes. It can be seen that freezing can also be carried out outside the actual freeze-drying equipment. According to a particular example of another embodiment of freeze-drying in bulk, as described above, the condenser is switched on and the drying chamber is moved as soon as ice formation occurs and the temperature of the product drops to about -10 °C. The pressure of approx.
Lower to 100N/ ^m2 . After 0.5 to 2 hours at the same pressure, stop cooling the plate,
Turn on the drying plate heater, and the temperature of the heated liquid gradually rises to room temperature within 60 minutes in a linear manner. The subsequent drying time is between 20 and 40 hours, preferably about 30 hours. During the entire freezing and freeze-drying process, record the temperature of the product, the heating liquid of the plate, the freezing plate itself, and the condenser and pressure of the drying chamber and condenser. Post-drying can be carried out, for example, at a drying plate temperature of 30 DEG C. for 5 to 8 hours. The vacuum in the drying chamber was released by supplying dry nitrogen that had passed through a 0.2 μm filter, and then the dried amoxicillin sodium was removed from the drying chamber and dried under aseptic conditions.
Store under nitrogen at ~10 °C. Finally, the obtained amoxicillin sodium was ground to a particle size that could pass through a 2 mm sieve under aseptic conditions, and then 250 mg, 500 mg, or 1000 mg amounts were placed into sterilized injection flasks under dry and sterile conditions.
The flask is then closed and sealed in the usual manner. Surprisingly, without the presence of stabilizers or organic solvents that could cause undesirable side reactions,
4.5-3.0% by weight, showing improved stability in solution as well as in dry formulation form according to the above method,
It has been found that it is possible to produce amoxicillin sodium formulations containing preferably about 3.5% by weight of degradation products. According to another embodiment of the method of the invention with a prefilled flask, 0.5 g of the final dry preparation is obtained by filling the flask with 10 ml of a 5% by weight amoxicillin sodium solution, freezing and lyophilizing.
It is preferable to prepare a flask containing a 5% by weight amoxicillin sodium solution.
A flask containing 1.0 g of the final formulation is made by placing 20 ml, freezing and lyophilizing. For every 500 mg of amoxicillin sodium preparation, 5 to 12 mg, preferably 7 to 8 mg of sodium chloride are present in the final formulation. For example from German Patent Application No. 2 623 835, an aqueous suspension of ampicillin in an equimolar amount or up to 10% of an aqueous solution of sodium hydroxide, sodium bicarbonate, or sodium carbonate is added to an aqueous suspension of ampicillin at a temperature below 4° C. It is known to produce ampicillin sodium by a freeze-drying method, by adding ampicillin sodium in such a way that concentration does not occur locally, immediately sterilizing the resulting solution, freezing and freeze-drying the solution. However, given the well-known differences in chemical and physical properties between ampicillin and amoxicillin, it is important to note that the manufacturing methods applicable to the production of ampicillin sodium can be used in similar fashion to produce practically pure amoxicillin sodium. This certainly could not have been predicted by a person skilled in the art. Since so many efforts have already failed or have yielded only partial results, the prediction of the suitability of new methods can never be debated. The concepts of those skilled in the art of penicillin chemistry, which at that time were shown as certain, were also stated or seemingly absolute in the solutions to the problems proposed in recent years to obtain suitable injectable preparations of amoxicillin, or at most equimolar amounts. The instructions in German Patent No. 2,623,835 stating that sodium hydroxide can be used and that the use of excess base must be avoided also explain to those skilled in the art the concept of using an excess of sodium hydroxide than is strictly necessary. cannot be guided. moreover,
For example, Canadian Journal of Pharmaceutical Sciences, Volume 12 (1977) 3
No. 83, page 83, right column, this procedure according to the invention cannot be considered obvious. According to the above content, the pH of maximum stability of amoxicillin is 5.77, and its decomposition rate does not seem to increase until the pH is below 5.5 or above 6.5, and the optimal condition for the stability of amoxicillin aqueous solution is quenching. When using an acid salt buffer, the pH is in the range of 5.8 to 6.5, whereas according to this method, the pH is temporarily in the range of 8 to 6.5.
Reaches a pH of 9. The preparations obtained according to the invention can be converted into the desired aqueous injection solutions by known methods. The invention is illustrated in the following examples. Example 1 Amoxicillin trihydrate 64.5 mmol (27.06
g) by an Ila homogenizer of type X-1020.
Suspended in approximately 350 ml of sterile pyrogen-free water at 20-25°C within 5 minutes. Sodium hydroxide 74.2 mmol (2.97 in 50 ml sterile pyrogen-free water)
g) was added dropwise within 5 minutes while stirring vigorously. Immediately add 6.45 mmol of hydrochloric acid (0.50N,
12.9ml). The solution was transferred to a 500 ml volumetric flask and sterile, pyrogen-free water was added to accurately adjust the volume. For example type AL
- Type connected to 17 Sartorius air compressors
The solution was filtered free of bacteria under aseptic conditions through a stainless steel Sartorius filtration device, model 16245, equipped with a Sartorius filtration device having a 11307 pore size of 0.2 μm. A 10 ml aliquot of the supersolution was dispensed into a 20 ml injection flask under aseptic conditions using a blunt dispenser model 7050-15. A thermosensor attached to a model Riolab D Sec. Floyd freeze-drying apparatus was attached to three flasks. The flask was equipped with a rubber stop specifically designated for lyophilization.
After adjusting the drying plate to -20 to -25°C in a freezing bath, the filled flask was transferred to one of the three drying plates in the drying chamber, and the drying chamber was heated with nitrogen gas passed through a 0.2 μm filter. It flashed at 600/hour. A thermosensor was connected to the drying plate on which the flask was placed. After that, during the entire process, the temperature of the three flasks and drying plate was controlled.
Sec. Recorded with a Floyd recorder. In Figure 1, the temperature of the product changes according to curve a.
The course of the temperature of the drying plate is shown by curve b, and the course of the absolute pressure by curve c. Point 1 of curve c indicates when the vacuum pump is switched on, and point 2 of curve b indicates the start of heating of the drying plate. After ice formation occurred in the flask and the temperature dropped to -20°C within 1 hour, the nitrogen supply was stopped, the drying chamber was evacuated, and the condenser was switched on. When cooling of the dry plate was stopped, the temperature of the dry plate gradually increased. Drying time was approximately 24 hours. After the product temperature rose above 10°C and equalized the plate temperature, and after the ice in the flask was no longer visible, the thermostat was switched on to heat the plate. The temperature of the thermostat was adjusted to 30°C, and drying was carried out for about 5 hours. Turn off the thermostat, vacuum pump, and condenser cooling switch to reduce the temperature to 0.2 μm.
The vacuum in the drying chamber was released by supplying nitrogen passed through a strainer. The flask was closed in a lyophilizer.
After removal from the lyophilizer, the flask was sealed with an aluminum folding capsule using a Felumpress hand crimper model H-207. The samples thus obtained were then analyzed for amoxicillin sodium content, decomposition product content, water content, sodium chloride content, solution transparency, solution PH, infrared spectrum, and PMR spectrum. The results of the analysis of the Tsukutsuta batches were as follows. Amoxicillin sodium content 93.3% (microbial method) Amoxicillin sodium content 94.4% (mercury() titration) Decomposition product content 3.6% (mercury() titration) Solubility; 10 g/vol% solution in water is at least 1
Remains transparent for hours. Freshly prepared aqueous solution 10 g/vol% PH 8.7 Water content (Karl Fitscher method) 2.2% The structure of amoxicillin sodium is shown in the infrared and
Confirmed by PMR spectrum. Example 2 Several samples of the amoxicillin sodium composition were prepared following the same manufacturing method as in Example 1, except that a number of parameters were changed compared to the corresponding parameters of Example 1. The results obtained according to Examples 1 and 2 are summarized in Table 1 and Figures 1, 2, and 3 below.

[Table] The characteristic amoxicillin structure of all samples was confirmed by infrared and PMR spectra. amoxicillin trihydrate suspended in water at room temperature;
Then, a 15 mol% excess of sodium hydroxide was added, neutralized with hydrochloric acid solution to a 5 mol% excess of sodium hydroxide, and the resulting solution was filtered through a 0.2 μ filter.
10ml of amoxicillin sodium 5% by weight solution
A lyophilized raw material preparation as used in Figure 3 was prepared by placing it in an F20 flask, followed by freezing and lyophilization. The flask containing the lyophilized preparation was stored at 5°C for 10 weeks. Example 3 2.58 mol (1082 g) of amoxicillin trihydrate
Suspended in pyrogen-free water by Vibro Mitscher within 10 minutes at 20-25°C. 2.97 moles (119 g) of sodium hydroxide in 2 parts of pyrogen-free water were added at a rate of about 380 ml/min with vigorous stirring. The clear solution was immediately neutralized with 0.26M hydrochloric acid (0.50N, 516ml). The solution was adjusted to 20.0 (20.28 Kg) with pyrogen-free water and mixed. 9 EKS of 20 x 20 cm under sterile conditions.
Passed through a Seitz strainer with plates. The liquid was collected in 4 flasks under sterile conditions. The solution was transferred under aseptic conditions onto a sterile plastic foil fixed on a drying board and a thermosensor fixed thereon, and the drying chamber was closed. The foil was pre-fixed on the drying plate and had a 4 cm high upright rim supported by a sterile metal frame, while the foil was fixed in place to ensure optimum contact between the solution and the drying plate. Fixed. Preferably, the drying plate of the freeze dryer is pre-cooled to -40°C. The cooling capacity of the freeze dryer should be chosen to be large enough to freeze the solution having a size of about 1 cm to -10°C within 60 minutes. The time between suspending amoxicillin trihydrate and closing the freeze-drying apparatus after pouring the solution onto the plate did not exceed 30 minutes. As soon as ice formation occurred and the product temperature dropped to approximately -10°C, the condenser was switched on and the pressure in the drying chamber was reduced to 1 Torr. After maintaining the pressure in the drying chamber at 1 Torr for 1 hour, cooling of the plate was stopped. Heating of the drying plate was started, and the temperature of the heating device gradually and linearly increased to 25°C over 60 minutes. During the approximately 35 hour drying time, the temperatures of the product, the plate heater, the drying plate itself, the condenser, and the pressure in the drying chamber and condenser were recorded. It was determined when the product was practically dry by briefly breaking the connection between the drying chamber and the condenser and measuring the pressure difference between the drying chamber and the condenser. Post-drying was started with a diffusion pump and took 6 hours. At the same time, the heating of the drying plate was adjusted to 30°C. The vacuum in the drying chamber was released by supplying dry nitrogen passed through a sterile 0.2 μm filter. Dried amoxicillin sodium was removed from the drying room and stored under nitrogen at 5°C under aseptic conditions. Three additional amoxicillin sodium samples were lyophilized according to the method described above. Four 1 Kg samples were ground in a grinder such as a Pepin mill under aseptic conditions until they could pass through a 2 mm sieve. Samples were collected and 250 mg, 500 mg, or 1000 mg amounts placed into injection flasks that were sterilized under dry, sterile conditions, such as by a Hofritzherr-Karg filling device. Under the same conditions, the flask was fitted with a sterile rubber stopper and sealed with an aluminum folding capsule. The analysis results of the collected samples were as follows. Amoxicillin sodium content 931 μg/mg (microbial method) Amoxicillin sodium content 94.1 g (mercury() titration) Degradation product content 3.7% (mercury() titration) Solubility: w/v % solution in water remained clear for at least 1 hour. Freshly prepared aqueous solution 10w/v% PH 8.8 Water content (Karl-Fitscher method) 2.9% Comparative Example 1 2.58 mol (1083 g) of amoxicillin trihydrate containing less than 1% by weight of decomposition products was incubated at 20-25°C for 10 minutes. The mixture was suspended in about 14 mL of pyrogen-free water by vigorous stirring in a Vibro Mitscher. Then sodium hydroxide in pyrogen-free water 2
A solution containing 2.7 mol (108.73 g) was added at a rate of 350-400 ml/min such that the excess base was 5.3 mol % at the end. The clear solution was stirred and adjusted to a total weight of 20.3 Kg with pyrogen-free water, and the pH was measured. This solution was poured into a 20 x 20 cm 9-tube tube under sterile conditions.
Passed through a Seitzer with an EKS plate. The liquid was collected under aseptic conditions and transferred to 12 pre-chilled and sterilized stainless steel shallow boxes, each shallow box containing 1666 ml of solution, the level of liquid in the shallow boxes was approximately 1 cm, and the shallow boxes were placed in a freeze dryer. (two shallow boxes on one drying board). The thermosensor was fixed and the drying chamber was closed.
Preferably, the drying plate of the freeze dryer is precooled to -40 to -45°C for 3 hours. The cooling capacity of the freeze dryer is
It should be chosen large enough to freeze a solution with a level of about 1 cm to -10°C within 60 minutes. The time between suspending amoxicillin trihydrate and closing the lyophilizer after opening the solution did not exceed 30 minutes. As soon as the formation of ice under freezing occurs at the temperature indicated by the temperature sensor of -40 to -45 °C at normal pressure, the condenser is switched on and the pressure in the drying chamber is reduced to 0.3 Torr, while the plate Continued cooling. The plate was allowed to cool for a further 1 hour, after which the temperature of the heating liquid was increased to +45° C. over a period of 2 hours. The drying process continued until the product was practically dry. A post-drying process with a diffusion pump was started and took approximately 6 hours. The vacuum in the drying chamber was released by supplying dry nitrogen passed through a sterile 0.2 μm filter. Dried amoxicillin sodium was removed from the drying chamber and stored under nitrogen at 5° C. under aseptic conditions in double-walled plastic bags, and samples from each plate were taken as the desired sterile analytical control. During the approximately 30 hour drying time, the temperatures of the product, the plate heater, the drying plate itself, the condenser, and the pressures in the drying chamber and condenser were recorded. By briefly cutting the connection between the drying chamber and the condenser and measuring the pressure difference between the drying chamber and the condenser, it was determined when the product was practically dry. A batch of 1 kg was made according to the above method. This batch was cut to 2mm using a Pepink mill under sterile conditions.
It was ground until it could pass through a sieve. Amounts of 250 mg, 500 mg, or 1000 mg were placed into injection flasks that were sterilized under dry, sterile conditions using a Hofritzherr and Karg filling apparatus. Under the same conditions, the flask was fitted with a sterile rubber stopper and sealed with an aluminum folding capsule. The analysis results of the batches created above were as follows. Degradation product content (Mercury() titration) 4.1% Solubility: 10 w/v % solution in water remained clear for at least 1 hour, freshly prepared solution was as clear as water. Color of freshly prepared solution 10w/v% Y6 PH of freshly prepared aqueous solution 10w/v% 8.79 Color of freshly prepared solution 20gw/v% Y5 PH of freshly prepared aqueous solution 20w/v% 8.85 Water content (Karl-Fitscher method ) 3.9% Y value was measured according to the European Pharmacy Act. Comparative Example 2 A 1 kg batch of amoxicillin sodium was prepared in exactly the same manner as in Comparative Example 1, and the analysis results were as follows. Degradation product content (Mercury() titration) 3.5% Solubility: 10 w/v % solution in water remained clear for at least 1 hour, freshly prepared solution was as clear as water. Color of freshly prepared aqueous solution 10w/v% Y6 PH of freshly prepared aqueous solution 10w/v% 8.69 Color of freshly prepared aqueous solution 20w/v% <Y5 PH of freshly prepared aqueous solution 20w/v% 8.80 Water content (Karl Fischer 4.1% Example 4 A 1 kg batch of lyophilized amoxicillin sodium was prepared in substantially the same manner as in Comparative Example 1, except that a solution containing 118.7 g of sodium hydroxide in 2 ml of pyrogen-free water was added to After addition at a rate of 400 ml/min, with vigorous stirring, 500 ml of 0.50N hydrochloric acid solution was added in about 1 minute to immediately neutralize a portion of the sodium hydroxide, bringing the final excess of sodium hydroxide to 5.3 mol%, and then clearing. This is essentially different from Comparative Example 1 in that the total weight of the solution was adjusted to 20.3 kg with pyrogen-free water and the pH was measured. The analysis results of the obtained batches were as follows. Decomposition product content (Mercury() titration) 4.3% Solubility: w/v% solution in water remained clear for at least 1 hour, freshly prepared solution was as clear as water. Color of freshly prepared aqueous solution 10w/v% <Y5 PH of freshly prepared aqueous solution 10w/v% 8.75 Color of freshly prepared aqueous solution 20w/v% <Y5 PH of freshly prepared aqueous solution 20w/v% 8.78 Water content (curl Fischer method) 3.85% Example 5 A 1 kg batch of amoxicillin sodium was prepared in exactly the same manner as in Example 4, and the analysis results were as follows. Degradation product content (Mercury() titration) 3.5% Solubility: 10 w/v % solution in water remained clear for at least 1 hour, freshly prepared solution was as clear as water. Color of freshly prepared aqueous solution 10w/v% <Y6 PH of freshly prepared aqueous solution 10w/v% 8.80 Color of freshly prepared aqueous solution 20w/v% Y6 PH of freshly prepared aqueous solution 20w/v% 8.88 Water content (Karl Fischer law) 3.3%

[Brief explanation of drawings]

FIG. 1 shows the evolution of the temperature of each product, the temperature of the drying plate, and the absolute pressure over time in Example 1 from the start of freezing as a characteristic example of this method. Figure 2 shows the stability versus time of 5% and 10% by weight solutions of amoxicillin sodium before freezing and lyophilization, where curve d is a 10% by weight solution of amoxicillin sodium and curve e is a 5% by weight solution of amoxicillin sodium. % solution. Figure 3 shows the relationship between the stability and time of freeze-dried amoxicillin sodium dissolved in water, where curve f is a 20% by weight solution and curve g is a 20% by weight solution.
10% by weight solution, curve h is for a 5% by weight solution.

Claims (1)

Claims: 1. Adding excess sodium hydroxide to dissolve amoxicillin trihydrate to produce a solution having a final excess of 3 to 5 mole percent sodium hydroxide relative to the amoxicillin; A process for the production of a dry amoxicillin sodium preparation that can be easily converted into an injectable solution, which comprises lyophilizing the solution, in which sodium hydroxide is present in an excess of 9 to 15 mol % over the amount required to form amoxicillin sodium; in the aqueous suspension of amoxicillin trihydrate until the amoxicillin is completely dissolved;
added slowly but as quickly as possible with good mixing and then immediately neutralizing a portion of the excess sodium hydroxide with hydrochloric acid at a temperature between 0 and 30°C to the final excess. An improved method for producing amoxicillin sodium preparations. 2. Claim 1 characterized in that the amounts of amoxicillin trihydrate, sodium hydroxide and hydrochloric acid are selected such that the concentration of amoxicillin sodium in the solution to be frozen does not exceed 5% by weight. The method described in. 3. The method according to claim 1 or 2, wherein the steps from preparation of the solution to freezing are completed within 90 minutes.