SK284307B6 - Process for the preparation of easily separable crystalline benzatin salt of phenoxymethyl penicillin - Google Patents

Abstract

Method of producing a crystalline benzatin salt of phenoxymethyl penicillin by adding benzatin-diacetate water solution to acetone or water-acetone solution of the free acid of phenoxymethyl penicillin. Benzatin salt of phenoxymethyl penicillin prepared by this method is characterized by its high quality and is suitable for the formulation of pharmaceutical treatment compositions containing penicillin V.

Description

The present invention relates to a process for the preparation of a readily separable crystalline benzoate salt of phenoxymethylpenicillin from free penicillin V acid and benzatin diacetate from aqueous acetone solution, thereby providing a suitable, well separable form of the substance for formulation of pharmaceutical formulations suitable for human and veterinary use.

BACKGROUND OF THE INVENTION

Benzatin phenoxymethylpenicillin is a sparingly soluble salt of penicillin V (phenoxymethylpenicillin), particularly suitable for the formulation of antibiotic powders for the preparation of oral suspensions, simply called dry syrups, which are widely used in the treatment of infectious diseases, especially in pediatric medicine. The prior art processes for the production of benzatin phenoxymethylpenicillin usually start from the potassium salt of phenoxymethylpenicillin and benzatin diacetate as starting materials. Solutions of these substances, usually in an aqueous or aqueous ethanolic solution, are mixed with each other to crystallize the benzoate salt of phenoxymethylpenicillin. E.g. A 0-203 864 describes the preparation of this salt by preparing an aqueous solution of N, N-dibenzylethylenediamine diacetate at 45 to 50 ° C, and a solution of phenoxymethylpenicillin potassium at 35 to 40 ° C, and these solutions are simultaneously slowly added to a heated environment of a mixture of ethanol and water in a ratio of 6: 1 to 1: 1. The product thus prepared after separation, drying and sieving is suitable for the preparation of dry syrups where strictly product particles of less than 100 µm, preferably 10 to 60 µm, are required. the product is relatively poorly separable, and during drying it is glued into hard lumps which adhere to the walls of the drying device and must be ground and sieved. These negative technological and rheological properties of the product largely depend on the size of the crystals, and therefore it is sought to prepare as large as possible regularly formed crystals of the product, which, with very low solubility of benzatin phenoxymethylpenicillin in conventional solvents, fails quite well. Some patents solve this problem by using polar organic solvents such as dimethylformamide, dimethylsulfoxide, or dimethylacetamide in which benzatin phenoxymethylpenicillin is better soluble and gradual crystallization results in a better separable large crystal of the product (e.g. French Patent 1,519,516, British: Patent 757 904 and Czechoslovak auto certificate 150 028). The disadvantages of the processes according to said patents are the higher cost of said solvents, their difficult regeneration due to their high boiling point, and the problematic removal of residues of these solvents from the product due to their low volatility.

SUMMARY OF THE INVENTION

The above drawbacks are largely eliminated by the fact that benzatin phenoxymethylpenicillin can be prepared in a crystalline, easily separable and easily drying state by a process characterized by slowly adding to the acetone or aqueous acetone solution of free phenoxymethylpenicillin at 0 to 45 ° C. aqueous benzatin diacetate solution. The acetic acid free acid solution may contain 0 to 40% by volume water and 5 to 35% by weight phenoxymethylpenicillin free acid. The aqueous acetone solution of phenoxy methylpenicillin free acid is prepared, for example, by dissolving the free acid in a previously prepared acetone-water mixture containing preferably 10% by volume water and 90% by volume acetone. During the addition of an aqueous solution of benzatine diacetate at a concentration of 5 to 15% by weight, preferably 10% by weight, to a stirred aqueous acetone solution of phenoxymethylpenicillin free acid, this reaction mixture may be slightly warmed, preferably to 30 to 35 ° C. separable crystals. To support and accelerate the crystallization process, 0.5 to 5% by weight of benzatin phenoxymethylpenicillin based on the weight of phenoxymethylpenicillin free acid can be added to the reaction mixture as crystallization seeds at the beginning of the addition of an aqueous benzatin diacetate solution. After separation of the product from the mother liquors, it is advisable to cover the product with a suitable pure solvent to remove any residual acetic acid formed as a byproduct of the reaction, or to blunt the acidity of the reaction mixture caused by acetic acid by adding a suitable buffer, e.g. concentrated alkaline potassium acetate solution. The product thus prepared does not stick during drying, does not form hard lumps and, if necessary, it is directly suitable for the preparation of medicaments after sieving, or the crystal size is reduced by suitable grinding if a microfine quality is required, i.e. a very fine crystal. These examples illustrate the solution but do not limit it in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Dissolve 120 g of phenoxymethylpenicillin free acid in 1000 ml of acetone, add 100 ml of water to this solution and heat the mixture to 32 ° C. In particular, dissolve 62.5 g of benzatin diacetate in 450 ml of water and slowly add this solution dropwise to the heated mixture with free phenoxymethylpenicillin acid at such a rate that the total addition time of the benzatin diacetate solution is 4 hours. After addition, the mixture is cooled to 5 to 8 ° C. The cooled mixture is separated on a glass frit and washed directly on the filter with 500 ml of a 1: 1 mixture of acetone and water and 300 ml of pure acetone. Dry the product in a vacuum oven to give 154 g of benzatin phenoxymethylpenicillin as a white crystalline powder, which is 92.6% yield, with a water content of 6.3%, an active substance content of 99.5% (calculated as anhydrous) and a content of of decomposition products 0,35%. The prepared substance meets all required parameters and quality of USP-XXIV.

Example 2

Dissolve 120 g of phenoxymethylpenicillin free acid in 1000 ml of acetone, add 100 ml of water to this solution and heat the mixture to 32 ° C. In particular, 62.5 g of benzatin diacetate are dissolved in 450 ml of water and this solution is slowly added dropwise to the heated mixture with free phenoxymethylpenicillin acid at such a rate that the total addition time of the benzathieniacetate solution is 4 hours. After adding about 5% by volume (25 ml of the total volume of the solution of benzatin diacetate), stop the addition and add 5 g of benzatin penicillin V prepared according to example 1 to the reaction mixture. solution of benzatin diacetate.

After addition of the entire amount of benzatin diacetate, the mixture is cooled to 5 to 8 ° C. The cooled mixture is separated on a glass frit and washed directly on the filter with 500 ml of a 1: 1 mixture of acetone and water and 300 ml of pure acetone. Dry the product in a vacuum oven to give 159 g of benzatin phenoxymethylcnicillin as a white crystalline powder, which is 92.7% yield, with a water content of 6.2%, an active substance content of 99.6% (calculated as anhydrous) and a content of of decomposition products 0,34%. The prepared substance meets all required parameters and quality of USP-XXIV.

Industrial usability

The benzatin phenoxymethylpenicillin substance prepared according to the invention has utility in the pharmaceutical industry for the production of oral dosage forms, in particular for the production of antibiotic powders for the preparation of oral suspensions.

Claims (6)

PATENT CLAIMS Process for the preparation of a readily separable, crystalline phenoxymethylpenicillin benzatin salt, characterized in that an aqueous solution of benzatin diacetate is added in portions to an acetone or aqueous acetone solution of free phenoxymethylpenicillin acid at a temperature of 0 to 45 ° C. A process for the preparation of the phenoxymethylpenicillin benzatin salt according to claim 1, characterized in that an aqueous acetic acid solution of phenoxymethylpenicillin free acid is obtained which is formed by dissolving the free phenoxymethylpenicillin acid in a mixture containing 90% by volume of acetone and 10% by volume of water. A process for the preparation of the phenoxymethylpenicillin benzatin salt according to claim 1, characterized in that the temperature of the reaction mixture is maintained at 30 to 35 ° C. A process for the production of the phenoxymethylpenicillin benzatin salt according to claim 1, characterized in that 0.5 to 5% by weight of benzatin phenoxymethylpenicillin based on the weight of phenoxymethylpenicillin free acid is added to the reaction mixture prior to the addition of the aqueous benzatin diacetate solution. 5. The process of claim 1 wherein a solution containing 12% w / w benzatin diacetate in water is added to the acetone solution of the free phenoxymethylpenicillin acid. 6. A process for the production of phenoxymethylpenicillin according to claim 2, wherein the dissolved phenoxymethylpenicillin free acid content is 10% by weight, based on the weight of the acetone-water mixture.