RU2190410C1 - Method of injection form of erythromycin phosphate preparing - Google Patents

Abstract

FIELD: pharmaceutical industry, antibiotics. SUBSTANCE: invention relates to a technology of preparing erythromycin phosphate that is a water-soluble form of erythromycin. Method involves the suspension of erythromycin base in water, suspension acidification at temperature from 4 C to 7 C with ortho-phosphoric acid solution in mass part 5% up to pH value of obtained solution from 6.4 to 6.6. Then method involves sterile filtration and lyophilic drying by freezing an erythromycin phosphate solution at temperature from 30 C to 35 C and drying under deep vacuum by step-by-step increase of temperature of a heat carrier from 20 C to +60 C. The drying is performed at the heating rate preferably 14 C/h, not above. The novel method provides the quality enhancement of erythromycin phosphate by an index "the content of anhydroerythromycine" 1.5%. EFFECT: improved method of preparing, enhanced quality. 2 cl, 1 ex

Description

 The invention relates to the production of antibiotics, and in particular to a technology for producing a water-soluble salt of erythromycin - erythromycin phosphate.

 Erythromycin phosphate is the phosphate salt of the erythromycin base produced by Actinomyces erythreus, and is intended as an intravenous drug.

In addition to erythromycin phosphate, the following water-soluble salts of erythromycin are known:
erythromycin lactobionate (US Patent No. 2761859, NCI 536-7.2, publ. 04.09.1956);
erythromycin ascorbate (aut. St. USSR 249562, A 61 K 31/335, C 07 H 17/08, publ. 07.25.1977).

Said erythromycin salts, in contrast to erythromycin phosphate, have the following disadvantages:
erythromycin lactobionate - has increased toxicity;
erythromycin ascorbate - is not resistant during storage, especially with regard to the indicator "appearance".

 In 1998, in connection with the revision of FS 42-2931-92 to erythromycin phosphate in order to tighten quality control, a new indicator “contaminants of related substances” was introduced into the draft FS, the requirements of which limit the content of anhydroerythromycin in erythromycin phosphate to 5%.

 The aim of the present invention is to improve the quality of erythromycin phosphate in terms of "anhydroerythromycin content".

 This goal is achieved by the fact that upon receipt of a solution of erythromycin phosphate, the acidification of an aqueous suspension of erythromycin base is carried out with a solution of phosphoric acid with a mass fraction of 5% and the pH of the solution is adjusted to a value of 6.4-6.6.

 In the proposed method, the optimal parameters were worked out at the stages of freezing erythromycin phosphate solutions and drying solutions, providing an increase in the quality of erythromycin phosphate in terms of anhydroerythromycin content and solution color.

 Signs of the proposed method.

 1. Obtaining an aqueous solution of erythromycin phosphate is carried out using a solution of phosphoric acid with a mass fraction of 5% and the pH value is maintained at 6.4-6.6.

2. Freezing an aqueous solution of erythromycin phosphate is carried out at a temperature of from -30 to -35 ^o C and drying under high vacuum, providing for a stepwise increase in the temperature of the coolant from -20 to +60 ^o C.

3. Drying is carried out with a heating rate of the substance 0 ^o -14 ^o C / h

The proposed technology allows to obtain the drug in accordance with the requirements of the draft Pharmacopoeia article on the indicator "anhydroerythromycin content" due to the optimally selected parameters for the production of erythromycin phosphate at the stages of:
1) obtaining an aqueous solution of erythromycin phosphate (phosphoric acid concentration and pH);
2) freeze drying (temperature during freezing solutions and drying).

 The following is an example implementation of the method.

0.8 kg of erythromycin base with an activity of 875 units / mg, erythromycin content of 0.7 billion units and 0.88 liter of phosphoric acid solution with a mass fraction of 5% to pH are loaded into 20 l of water for injection with a temperature of 4-7 ^o C 6.5, the contents are stirred for 30 minutes until a clear solution is formed.

Get 23.3 l of a solution of erythromycin phosphate with an activity of 30,000 units / ml, the content of erythromycin 0.7 billion units, then the resulting solution is subjected to sterile filtration through a filter system. The temperature during filtration is maintained at 4-7 ^o C. The resulting sterile solution of erythromycin phosphate is fed to a dosing unit for bottling. The output at the stages of obtaining a solution of erythromycin phosphate, sterile filtration and bottling is 93% of the loaded erythromycin base.

Freeze drying involves removing moisture from the preparation in a frozen state, the solution is frozen in bottles at a temperature of -30 ^o С, then they are dried under high vacuum with a stepwise increase in the temperature of the coolant from -20 to +60 ^o С with a heating rate of not more than 14 ^o С in h. The end of drying is determined by the coincidence of the temperature of the substance at three points on different surfaces, but the temperature should not exceed 60 ^o C. The output at the stage is 92.4%. The output of erythromycin phosphate in vials from the powder of erythromycin base is 85.9%. The content of anhydroerythromycin in erythromycin phosphate is 1.5%.

Claims (2)

1. A method of producing erythromycin phosphate, including the suspension of erythromycin base in water, acidification of the suspension at 4-7 ^o With a solution of phosphoric acid with a mass fraction of 5% to a pH of the resulting solution 6.4-6.6, sterile filtration and freeze drying by freezing a solution of erythromycin phosphate at a temperature of from -30 to -35 ^o C and drying under high vacuum with a stepwise increase in the temperature of the coolant from -20 to +60 ^o C. 2. The method according to claim 1, wherein the drying is carried out with a heating rate of not more than 14 ^o C / h