PROCESS FOR THE PREPARATION OF EPOPROSTENOL SODIUM OF ENHANCED STABILITY

Abstract

The invention provides a stable epoprostenol sodium and a process for the preparation this pharmaceutically active ingredient.

Claims

1. Stable epoprostenol sodium drug substance which can be stored in deep freezer (205 C.) for at least 3 years, characterized by that the lyophilized drug substance contains epoprostenol sodium salt and, related to the amount of the epoprostenol sodium salt, it contains in 3-7.5 mass % inorganic base or basic-hydrolyzing inorganic salt.

2. Drug substance as defined in claim 1, wherein the lyophilized drug substance contains epoprostenol sodium salt and, related to the amount of the epoprostenol sodium salt, it contains in 4 mass % inorganic base or basic-hydrolyzing inorganic salt.

3. Drug substance as defined in claim 1, wherein the lyophilized drug substance contains epoprostenol sodium salt and, related to the amount of the epoprostenol sodium salt, it contains in 5 mass % inorganic base or basic-hydrolyzing inorganic salt.

4. Drug substance as defined in claim 1, wherein the lyophilized drug substance contains epoprostenol sodium salt and, related to the amount of the epoprostenol sodium salt, it contains in 6 mass % inorganic base or basic-hydrolyzing inorganic salt.

5. Drug substance as defined in claim 1, wherein as inorganic base it contains sodium hydroxide.

6. Process for the preparation of stable epoprostenol sodium which can be stored in deep freezer (205 C.) for at least 3 years, characterized by that the aqueous solution of the epoprostenol sodium salt is lyophilized in the presence of such an amount of inorganic base or basic-hydrolyzing inorganic salt ensuring a pH>11 medium, that the lyophilisate contains 3-7.5 mass %, preferably 4-6 mass % of excess sodium hydroxide, related to the amount of the epoprostenol sodium salt.

7. Process as defined in claim 6, wherein as inorganic base or basic-hydrolyzing inorganic salt, a base or salt is applied which contains sodium cation.

8. Process as defined in claim 6, wherein as base containing sodium cation sodium hydroxide or sodium carbonate, preferably sodium hydroxide is applied.

9. Process as defined in claim 6, wherein as inorganic salt containing sodium cation trisodium phosphate is applied.

10. Process for the preparation of stable epoprostenol sodium comprising cyclisation with iodine and by hydrogen iodide elimination, wherein a.) as starting material unprotected PGF2 is applied, b.) as iodine source, sodium iodide-sodium iodate mixture is applied, c.) the cyclisation and the hydrogen iodide elimination are performed in the same solvent, d.) the aqueous solution of the epoprostenol sodium salt is lyophilized in the presence of inorganic base or basic-hydrolysing inorganic salt ensuring a pH>11 medium.

11. Process as defined in claim 9, wherein a reaction mixture of PGF2:sodium iodide:sodium-iodate=3:2:1 ratio is applied.

12. Process as defined in claim 9, wherein as solvent tetrahydrofuran is applied.

13. Drug substance as defined in claim 2, wherein the inorganic base contains sodium hydroxide.

14. Drug substance as defined in claim 3, wherein the inorganic base contains sodium hydroxide.

15. Drug substance as defined in claim 4, wherein the inorganic base contains sodium hydroxide.

Description

EXAMPLES

5-iodo-9-desoxy-6,9-epoxyprostaglandin F1 (5-I-PGI.SUB.1.)

[0105] ##STR00008##

[0106] 1M sodium hydrogen sulfate solution is prepared from 3 l of water, 87.7 ml of cone. sulfuric acid and 247 g of sodium sulfate. To the solution are added 1.2 l of water, then under stirring the solution of 95.1 g of sodium iodate in 1.2 l of water, the solution of 473.4 g of prostaglandin F.sub.2alpha in 1.5 l of tetrahydrofuran, and finally the solution of 148.1 g of sodium iodide in 0.44 l of water. At the end of the reaction saturated sodium chloride solution and tetrahydrofuran:hexane=1:1 mixture are poured onto the reaction mixture. The phases are separated, the aqueous phase is extracted with tetrahydrofuran:hexane=1:1 mixture. The united organic phase is washed with 5% sodium metabisulfite solution, then with diluted and saturated salt solutions, dried over sodium sulfate and concentrated to approx. 1 kg.

[0107] The 5-I-PGI.sub.1 intermediate is carried into the next reaction step without further purification.

(5Z,9,11,13E,15S)-6,9-Epoxy-11,15-dihydroxyprosta-5,13-dien-1-acid sodium salt (5-I-PGI.SUB.1.)

[0108] ##STR00009##

[0109] To the 5-I-PGI.sub.1 intermediate (concentrated to approx. 1 kg) obtained in the previous step, 12.4 l of water-free tetrahydrofuran and 721 g of sodium methylate are added and the mixture is agitated at room temperature. At the end of the reaction 2M sodium hydroxide solution is added to the reaction mixture and tetrahydrofuran is distilled off in vacuum. The mixture is agitated at room temperature until a great amount of crystals precipitate, then it is cooled to 0 C. to complete the crystal precipitation. The crystals are filtered off, washed with 2M, and then with 1M sodium hydroxide solutions. The crystals are then dissolved in such an amount of 2M sodium hydroxide solution that the product contains 4 mass % excess of sodium hydroxide. The solution is lyophilized.

[0110] Yield: 250 g (50%) as calculated for PGF.sub.2a, the product is a white powder.