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 (−20±5° C.) for at least 3 years, wherein the lyophilized drug substance consists of epoprostenol sodium salt and, related to the amount of the epoprostenol sodium salt, 3-7.5 mass % sodium hydroxide.

2. Drug substance as defined in claim 1, wherein the sodium hydroxide is in an amount of 4 mass %.

3. Drug substance as defined in claim 1, wherein the sodium hydroxide is in an amount of 5 mass %.

4. Drug substance as defined in claim 1, wherein the sodium hydroxide is in an amount of 6 mass %.

5. Process for the preparation of stable epoprostenol sodium drug substance of claim 1, which can be stored in deep freezer (−20±5° C.) for at least 3 years, comprising lyophilizing an aqueous solution of an epoprostenol sodium salt in the presence of such an amount of sodium hydroxide ensuring a pH>11 medium, that 3-7.5 mass % of excess sodium hydroxide, related to the amount of the epoprostenol sodium salt, is present in the lyophilisate.

6. Process for the preparation of stable epoprostenol sodium drug substance of claim 1, comprising cyclizing unprotected PGF2α with sodium iodide—sodium iodate mixture and eliminating hydrogen iodide, wherein the cyclizing and eliminating are performed in the same solvent, and lyophilizing an aqueous solution of the epoprostenol sodium salt in the presence of such an amount of sodium hydroxide ensuring a pH>11 medium that 3-7.5 mass % of excess sodium hydroxide, related to the amount of the epoprostenol sodium salt, is present in the lyophilisate.

7. Process as defined in claim 6, wherein a reaction mixture of PGF2α: sodium iodide: sodium-iodate=3:2:1 ratio is applied.

8. Process as defined in claim 6, wherein as solvent tetrahydrofuran is applied.

9. Process for the preparation of stable epoprostenol sodium drug substance of claim 5, wherein 4-6 mass % of excess sodium hydroxide is present in the lyophilisate.

Description

EXAMPLES

5ξ-iodo-9-desoxy-6ξ,9α-epoxyprostaglandin F1α (5-I-PGI.SUB.1.)

(1) ##STR00008##

(2) 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.

(3) The 5-I-PGI.sub.1 intermediate is carried into the next reaction step without further purification.

(4) (5Z,9α,11α,13E,15S)-6,9-Epoxy-11,15-dihydroxyprosta-5,13-dien-1-acid sodium salt (PGI.sub.2-Na)

(5) ##STR00009##

(6) 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 2 M 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.

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