NL7809986A - PROCESS FOR PREPARING SODIUM AMOXICILLIN SUITABLE FOR INJECTION PREPARATIONS, AND FOR THEIR COMPOSITION CONTAINING DOSE INJECTION PREPARATIONS AND THEIR PREPARATION. - Google Patents

Description

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Gist-Brocades N.V. in Delft, the Netherlands.

A method of preparing sodium amoxicillin suitable for injection preparations, as well as this compound containing metered injection preparations and their preparation.

The applicant named the inventor: Annita Bagerman-Deetman,

Hayo de Jonge, Jan Willem Groenendaal and Gerrit Jan Sijbrands.

. The invention relates to a method of preparing sodium amoxicillin of improved quality, suitable for use in injection preparations, as well as this compound containing dosed injection preparations and their preparation, and more particularly a method of preparing sodium amoxicillin of improved quality. by means of a freeze-drying method.

Such a method is known from, for example, Dutch Patent Application No. 7707494 laid open to public inspection. It describes a method in which a solution of sodium 10, amoxicillin is freeze-dried in a solvent system, containing water having at least one secondary or tertiary alkanol with 4 as a stabilizer. or 5 carbon atoms are added, which are at least 5 w / v% soluble in water at 25 ° C, while further preferably at least 4-50 w / v% secondary or tertiary alkanol is present.

The tertiary alkanol is preferably 2-t-butanol, but it has also been indicated that the solvent system may also contain minor amounts of other pharmaceutically acceptable solvents, such as primary alcohols.

A disadvantage of these preparations is the presence of foreign solvent residues, which, although toxicologically acceptable, can give rise to all kinds of undesirable side effects when the final injection preparation is administered; in the dry final product, their content can be up to about 1 6%.

It was also known to prepare sterile crystalline cephalosporins suitable for parenteral administration by freeze drying. For example, from US patent no. 4,029,655 and more particularly from Belgian patent no.

861,135, concerning the preparation of a stable sodium cephalotin powder for parenteral administration by freeze-drying a pre-prepared solution of sodium cephalotin in a 2-10% alcohol or acetone-containing aqueous solution. Furthermore, it can be! Netherlands Patent Application No. 7712823, laid open to public inspection, concerning the preparation of crystalline, easily soluble sodium cefazoline by means of freeze-drying of a 2-25% proportion. alkanol-containing aqueous solution, wherein the starting solution is cooled slowly 1 '. The same drawbacks as those mentioned above apply to the preparations thus obtained.

On the other hand, a large number of patents published in recent years clearly demonstrate a great activity in the search for amoxicillin preparations which are easy; to the usual, sufficiently stable injection solutions; are constituted and which are also sufficiently stable in dry form; should be. It is also clear from said patent literature that the generally developed opinion of experts is that in the preparation of injection preparations of amoxicillin it is certainly not the case, quite simply the usual methods used for previously developed semi-synthetic penicillins, such as, for example, ampicillin, can be used because of the markedly different chemical and physical properties of amoxicillin. On the one hand, therefore, all sorts of proposals are being made to arrive at an adapted preparation of preparations containing the usual alkali metal salts of amoxicillin and their derivatives, and on the other hand the expert appears to be more inclined to search for well-constitutable and highly injectable preparations in which salts of amoxicillin with alternative cations.

7809986

For example, Dutch Patent Application No. 7509701 laid open to public disclosure discloses a process for the preparation of the choline salt or the N-methyl-D glucamine (salt of amoxicillin by methods customary in itself), while in Dutch Patent Application No. .

7509698 the preparation of the arginine salt of amoxicillin is described. These salts of amoxicillin would lead to new non-toxic, parenterally administrable forms of amoxicillin while maintaining antibiotic properties, while also explicitly stated on page 1 that both amoxicillin itself! if its hitherto known salts cannot be satisfactorily administered parenterally. Also, Example 4 of Japanese Laid-Open Application J 51032,723 describes the preparation of a suitable injection solution containing amoxicillin and the sodium salt of glycine.

For example, DT-0S-254-523 describes a process for the preparation of salts of D-α-carboxyamino-p-hydroxy-benzyl penicillin, also for the purpose of preparing satisfactory injectable amoxicillin preparations. Again, on page 2, it is explicitly stated again that the preparation of injectable preparations of amoxicillin turned out to be much more difficult than initially expected, due to the instability of solutions containing amoxicillin caused by the decomposition of amoxicillin salts in aqueous solutions .

According to said patent, mixtures of the sodium salt of amoxicillin and the disodium salt of D-α-carboxyamino-p-hydroxybenzyl penicillin should preferably be used.

In Dutch patent application no.

7602180 discloses a method of preparing an injectable preparation of amoxicillin which after preparation for injection has good stability and is well tolerated on administration. This formulation consists of a powder which can be easily constituted into an injectable formulation by adding an aqueous vehicle. The powder consists of fine particles of amoxicillin trihydrate coated with a dispersant, the ratio of amoxicillin trihydrate to dispersant being from 1000: 1 to 1: 1. The intended fine particles; should have an average diameter of 2 μ to 20 μ, 5 with at least 95% having a diameter between 0.5 μ and 50 μ, while 10 to 100% of the surface should be coated with dispersant. As a dispersant it is proposed a mixture of substances containing at least one water-soluble polymer material with an average molecular weight of 6000 to 400,000, such as polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, sodium carboxymethylcellulose, polyvinyl alcohol, dextran and sodium alginate and preferably polyvinylpyrrolidone. , and a wetting agent, such as lecithin, phospholipids, sorbitan fatty acid esters and more particularly lecithin.

For the same reasons, the search was for chemically modified amoxicillin derivatives, which decompose after administration in the body in such a way that (again) amoxicillin. arises. Reference can be made to US patent no. 4,035,381! and Dutch Patent Application Laid-open No. 7701480.

Surprisingly, it has now been found that improved, relatively long-lasting, stable sodium amoxicillin preparations can be prepared, which can be readily constituted into stable, highly injectable solutions, free of allergic chemicals, by dissolving 25 L of amoxicillin trihydrate in water. add an excess of sodium hydroxide as quickly as possible until the amoxicillin has completely dissolved, after which a portion of the excess caustic is immediately neutralized with hydrochloric acid, keeping the temperature between 0 and + 30 ° C and preferably at 20 -25 ° C, followed by sterile filtration of the resulting solution, filling in vials, freezing and freeze drying.

Preferably, the starting amounts of amoxicillin trihydrate, caustic soda and hydrochloric acid are chosen such that a final a concentration of 2.5-15 wt.% and preferably of 5 wt.% of sodium; Amoxicillin is reached. !

The clear solution of the amoxicillin salt is obtained by adding a sodium hydroxide solution to a molar excess of sodium hydroxide of at most 15 mol% with a 7809986-4 suspension of amoxicillin trihydrate in water with vigorous stirring. preferably greater than 9 mol%, after which the excess NaOH is partially neutralized as quickly as possible to at least about 3 mol%, and preferably about 5 mol% of sodium hydroxide is present in excess.

As a result of this partial neutralization, about 10 mol% sodium chloride is then also present in the solution.

It will be clear that the amoxicillin solution will need to be filtered, filled into vials, frozen and freeze-dried under aseptic conditions. Preferably use is made of vials and rubber stoppers, especially intended for the freeze-drying process. The vials are filled in such a way that they resp. 0.10-5 g and preferably 0.25, 0.5 and 1 g of the final sodium amoxicillin preparation. Freezing and freeze drying can be carried out in commonly used equipment such as, for example, a Sec.Froid SA CH-1024 lyolab D freeze drying plant or Leybold freeze dryer. It will be clear that freezing can also take place outside the actual freeze-drying equipment.

Before freezing, the obtained amoxicillin solution is preferably cooled to -20 ° to -60 ° C in 1 to 2.5 hours and preferably -20 ° to -30 ° C at atmospheric pressure. Then the pressure is reduced to 9.0 - 12.0 N / m and preferably 10 N / m and the temperature is then slowly raised to 0 ° C in 24-30 hours and preferably in about 25 hours where the vacuum slowly rises to about 8 N / m. After this, the temperature is raised by heating to room temperature in 4-5 hours while maintaining the vacuum rising to 8 N / m.

Surprisingly, it has now been found that, according to the above-described method, sodium amoxicillin preparations can be obtained which contain less than 3.5 decomposition products and which exhibit improved stability both in the form of dry preparation and in solution, while moreover no stabilizers or organic solvents. are present, which may give rise to the undesired side effects.

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According to the present method, preferably 0.5 g vials are prepared by filling, freezing and freeze-drying 10 ml of a 5 wt% sodium amoxicillin solution, or vials of 1 g prepared by 20 ml of a 5 wt% sodium amoxicillin; 5 fill the solution and freeze-dry.

Per 500 mg of sodium amoxicillin, 5-12 mg, and preferably 7-8 mg, of sodium chloride are present in the final preparation.

It is admittedly known, for example from German patent specification 2623835, to prepare sodium ampicillin by freeze-drying by adding an aqueous suspension of ampicillin at a temperature not higher than 4eC, an aqueous solution of an equimolecular amount or an amount up to to 10% of sodium hydroxide, sodium bicarbonate or sodium carbonate, such that locally too high an concentration of alkali I - does not occur, the sterile filtration is obtained immediately; and freezing and lyophilizing the filtrate. In view of the known differences in chemical and physical properties between ampicillin and amoxicillin, it was certainly not predictable that a method of preparation useful in the preparation of sodium ampicillin in any analogous form would be useful for the preparation of substantially pure sodium amoxicillin. Where so many attempts had already failed or at least led to only partial successes, predictability of the usefulness of a new method can no longer be said.

Neither the prevailing views already mentioned by those skilled in the art as stated in or implicitly apparent from the recently proposed solutions to the problem of arriving at suitable injection preparations of amoxicillin, nor the indications given in German PS 2623835 for at most an equimolecular the amount of sodium hydroxide to be used and to prevent over-alkalization, suggest to those skilled in the art to use larger than strictly necessary amounts of caustic soda. Moreover, this measure according to the invention was certainly not obvious, o.a. the stated in, for example

Canadian Journal of Pharmaceutical Sciences 1_2 (1977) no. 3, p. 83 78 0 9 9 8 8 _ 6 _ right column, showing that the pH of the maximum stability of amoxicillin is 5.77 and that the decomposition rate does not seem to increase to adjust the pH to below 5.5 or above 6.5, while the optimum conditions for stability of aqueous solutions of amoxicillin are in the range of pH 5.8 to 6.5 using a citrate buffer, while according to the currently proposed method a pH of 8-9 is temporarily reached.

The compositions obtained according to the invention can be constituted into the desired aqueous injection solutions by methods known per se. '

The invention is illustrated by the following examples.

Example 1

At 20-25 ° C, 64.5 mmol (27.06 g) of 1 amoxicillin trihydrate is suspended within 5 minutes using an Ila homogenizer type X-1020 in about 350 ml of sterile pyrogen-free water.

Within 5 minutes, 74.2 mmol (2.97 g in 50 ml sterile pyrogen-free water) NaOH is added dropwise with vigorous stirring.

The clear solution is neutralized immediately afterwards with 6.45 mmol (12.9 ml 20.50 N) HCl. The solution is transferred to a 500 ml volumetric flask and made up with sterile pyrogen-free water. The solution is filtered free of bacteria under aseptic conditions using, for example, a stainless steel Sartorius filter holder type 16245 fitted with a Sartorius mem-25 bran fliter with a pore size of 0.2 Mm, type 11307, coupled to a Sartorius air corapressor type AL-17. 10 ml portions of the filtered solution are each filled into 20 ml vials under aseptic conditions using a Brand dispenser type 7050-15. Temperature sensors 30 are provided in three bottles belonging to the Sec.Proid freeze-drying installation type lyolab D. The bottles are provided with rubber stoppers specially intended for freeze-drying.

The filled vials are transferred to one of the three drying plates of the drying chamber, after the plates have previously been brought to -20 ° -25 ° C by means of the freezing bath, whereby the drying chamber is purged with approximately 78 0 99 86-7. 600 l / h, through 0.2 µm filtered nitrogen. One temperature sensor is mounted in the drying plate, on which the bottles are placed. During the entire process afterwards, the temperature of the three vials and the drying plate 5 are recorded using the Sec.Proid recorder.

In Fig. 1, by way of example, a characteristic course of resp. the temperature of the product, the temperature of the drying plate and the absolute pressure with time displayed from the start of freezing. The development of the temperature of the product is indicated by means of curve (a), the course of the temperature of the drying plate by means of curve (b) and the course of the absolute pressure by means of curve (c). The point (1) in the curve (c) indicates the starting of the vacuum pump, ter; while the point (2) in the curve (b) indicates the activation of the DROCG-plate heating.

After ice has formed in the vials and the temperature has fallen to approximately -20eC after about 1 hour, the drying chamber is evacuated after the nitrogen supply has been shut off and the condenser has been switched on.

The cooling of the drying plates is switched off, as a result of which they slowly rise in temperature. The drying period lasts about 24 hours. The plate heating thermostat is turned on after the product temperature has risen above 10 ° C and equals the plate temperature and after no more ice can be seen in the vials. The temperature of the thermostat is set at 30 ° C and it is dried for about 5 hours. The thermostat, vacuum pump and condenser cooling are turned off and the vacuum of the drying chamber is released by supplying 0.2 µm filtered nitrogen. The vials are closed in the freeze-dryer. After removal from the freeze dryer, the vials are removed. 30 aluminum flanged capsules using a Fermpress hand crimper! type type H-207 sealed.

The batches thus obtained were then analyzed for sodium amoxicillin content, decomposition products content, water content, sodium chloride content, clarity of the solution. pH of the solution, infrared spectrum and PMS spectrum, 78 0 9 9 8 6 - 8 -

The analysis results of the prepared batch were as follows: content (microbiological) sodium amoxicillin 93.3 / ¾ content (mercurimetric) sodium amoxicillin 94.3% content decomposition products (mercurimetric) 3.6% 5 solubility: 10 g / v% solution in water remains clear for at least 1 hour pH 10% w / v% in water 8.7 water content (Karl Fischer) 2.2%

The structure of sodium amoxicillin was confirmed by IR and PMR spectra.

Example 2 Following substantially the same preparation method of Example 1, a number of batches of sodium amoxicillin preparation are prepared, a number of parameters being varied from the corresponding ones in Example 1.

The results obtained according to Examples 1 and 2 are summarized in Table 1 below, and Figures 2, 3 and 4.

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Figure 2 shows the relationship between the stability of 5 and 10 wt% sodium amoxicillin solutions before lyophilization and time, with curve (d) referring to the 10 wt% solution and curve (e) referring to the 5 wt .% solution. Plotted along 5 axes resp. the d «m« v «mercurimetric titration measured percentage of decomposition products and time ·

Figure 3 shows the relationship between the stability in water of the freeze-dried sodium amoxicillin preparation and the time, where curve (f) is a 20 wt% solution, 10 curve (g) is a 10 wt% solution and curve (h) a 5 wt% solution.

The lyophilized starting preparation was prepared by suspending amoxicillin trihydrate in water at room temperature, adding 15 mol% excess NaOH, neutralizing with HCl solution 15 to a 5% molar excess NaOH, filtering the 5 wt% sodium amoxicillin solution using e.g. a 0.2 μ filter and fill in F 20 vials of 10 ml followed by lyophilization.

The vials with the lyophilized preparation were stored at 5 ° C for 10 weeks.

20 Plotted along the axes resp. the d * m »v · mercurimetric titration measured percentage of decomposition products and time · 78 0 9 9 8 6 \ -11-

Claims (11)

1. Sodium amoxicillin preparations, which are easily contained. f; be stable into stable, injectable solutions which are free of allergy-causing chemicals and which contain, in addition to sodium amoxicillin, sodium hydroxide and sodium chloride; 2, Sodium amoxicillin preparations according to claim 1, characterized in that per 500 mg of sodium amoxicillin, 5-12 mg of sodium chloride are present Sodium amoxicillin preparations according to claims 1 to 10 and 2, characterized in that per 500 mg of amoxicillin sodium, 7-8 mg of sodium chloride are present 4, Formed sodium amoxicillin preparations consisting of an ampoule, filled with a preparation according to claims 1-3. Dosed formulations according to claim 4, characterized in that a vial contains about 0.25 g, 0.5 g or 1 g of formulation; contains. 6. A method of preparing sodium amoxicillin preparations readily constitutable as injection liquids by freeze-drying, characterized in that an excess of sodium hydroxide is added as soon as possible to a suspension of 20 amoxicillin trihydrate in water until the amoxicillin is completely in; solution, after which a part of the excess caustic is immediately neutralized with hydrochloric acid, whereby the temperature! between 0 and 30 ° C, followed by sterile filtration of! 25 the solution obtained, filling into vials, freezing and freeze drying, 7. Process according to claim 6, characterized in that a sodium hydroxide solution is added to a suspension of 30 amoxicillin trihydrate in water until a molar excess of sodium hydroxide is reached, at most 15 mol%, after which the excess sodium hydroxide is neutralized as quickly as possible until at least about 3 mol% excess is present. 8. Process according to claims 6 and 7, characterized in that sodium hydroxide is added to an initial molar; excess of sodium hydroxide greater than 9 mol%. 7809986 O-- - 12 _ ^ Λ Λ ** » 9. Process according to claims 6-8f, characterized in that the excess sodium hydroxide is neutralized to about 5 mol%. ' 10. Process according to claims 6-9, characterized in that 5 starting amounts of amoxicillin trihydrate, caustic soda and brine. be chosen so that a final concentration of ^ 5% by weight of sodium amoxicillin is reached. 11. Process for preparing sodium amoxicillin-containing injection solutions according to methods known per se, characterized in that a sodium amoxicillin preparation according to claim 1 is dissolved into an aqueous solution. i i 78 0 99 «fi • υ - 13 -