WO2003066657A1

WO2003066657A1 - A process for preparing ursodeoxycholic acid dusulphate and pharmaceutically acceptable salts thereof

Info

Publication number: WO2003066657A1
Application number: PCT/IB2003/000479
Authority: WO
Inventors: Alberto Giraudi
Original assignee: ABC INTERNATIONAL PHARMA Srl
Current assignee: ABC INTERNATIONAL PHARMA Srl
Priority date: 2002-02-06
Filing date: 2003-02-06
Publication date: 2003-08-14
Anticipated expiration: 2004-08-06
Also published as: BR0303067A; ITTO20020102A1; ITTO20020102A0; AU2003244517A1

Abstract

The process for the preparation of ursodeoxycholic acid disulphate or its pharmaceutically acceptable salts comprises the operation of reacting the ursodeoxycholic acid dissolved in a solvent, selected from the group consisting of dimethylformamide, pyridine, acetonitrile, dimethyl sulphoxide, octanoic acid, acetic anhydride and their mixtures, with a sulphation agent selected from the group consisting of sulphuric anhydride, sulphuric acid and complexes containing sulphuric anhydride in a molar ratio of sulphonic groups to ursodeoxycholic acid of from 2.5:1 to 4:1.

Description

A PROCESS FOR PREPARING URSODEOXYCHOLIC ACID DISULPHATE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

The present invention relates to a novel process for the preparation of ursodeoxycholic acid disulphate and its pharmaceutically acceptable salts, particularly the alkali metal salts.

Ursodeoxycholic acid disulphate and its trisodium salt are described in EP-A-0 117 570; they are compounds derived from ursodeoxycholic acid which, unlike ursodeoxycholic acid, are very water-soluble and are therefore particularly useful in the preparation of liquid pharmaceutical formulations.

The above-mentioned compounds have a therapeutic activity, similar to or in some cases better than that of ursodeoxycholic acid, especially in the treatment of qualitative or quantitative changes in the bile-forming function, including the forms with bile supersaturated with cholesterol, in combating the formation of cholesterol calculi or for creating conditions suitable for dissolving them.

According to EP-A-0 117 570, ursodeoxycholic acid disulphate (referred to hereinafter simply as "ursosulphate" ) can be prepared by reacting ursodeoxycholic acid in anhydrous pyridine with gaseous sulphuric anhydride; however, a preparation process that uses the pyridine-sulphuric anhydride complex as the sulphation agent is preferred.

According to this process, the ursodeoxycholic acid is dissolved in N,N-dimethylformamide and reacted with the pyridine-sulphuric anhydride complex in a molar ratio of 1.95-2.1 moles of the complex to 1 mole of ursodeoxycholic acid in a temperature range of from 0 to 100°C.

After the removal of the dimethylformamide by evaporation under vacuum, the resulting oily residue constituted by free ursosulphate acid is neutralized using an aqueous, alcoholic or hydroalcoholic sodium hydroxide solution and the corresponding trisodium salt is precipitated in crystalline form by the addition of acetone.

As a result of experiments carried out by the applicant, it has been found that the process according to the prior art involves the disadvantage of leading to the formation of substantial quantities of the mono-substituted sulphate of ursodeoxycholic acid, which is an undesired secondary reaction product with associated problems of purity of the end product.

Furthermore, in the industrial implementation of the method, the addition of sodium hydroxide in aqueous methanolic or ethanolic solution to the reaction product in oily form involves, presumably owing to the highly exothermic acid-base reaction between soda and sulphuric pyridine (which is not completely eliminated during the evaporation of the solvent) , an increase in temperature with a high risk of decomposition of the desired end product .

The object of the present invention is to provide an improved process suitable for obtaining ursodeoxycholic acid disulphate and its salts in a highly purified form and with high yields . In view of this object, the invention relates to a process for the preparation of ursodeoxycholic acid disulphate and its pharmaceutically acceptable salts, characterized in that it comprises the step of reacting ursodeoxycholic acid dissolved in a solvent, selected from the group consisting of dimethylformamide, pyridine, acetonitrile, dimethyl sulphoxide, octanoic acid, acetic anhydride and their mixtures, with a sulphation agent selected from sulphuric anhydride, sulphuric acid and complexes containing sulphuric anhydride in a molar ratio of sulphonic group to ursodeoxycholic acid of from 2.5 to 4.

The reaction is carried out at a temperature of from 0 to 100°C, preferably at an ambient temperature of approximately 20-30°C, preferably for a period of from 4 to 24 hours, under intense agitation.

According to another preferred aspect of the process, at the end of the sulphation reaction, the reaction mixture is diluted with water in order to hydrate the sulphation agent ; the amount of water added is preferably equal to the amount necessary to bring the exothermic hydration reaction to completion. Alkali metal hydroxide in aqueous solution is then added to obtain a pH of preferably from 7 to 8, taking care that the temperature of the reaction mixture does not exceed 50°C, preferably 30°C.

The solution is then concentrated, preferably under vacuum, keeping the temperature below 50°C, and the reaction product (constituted by the triple alkali metal salt of ursodeoxycholic acid disulphate) is precipitated by the addition of a solvent, which is preferably selected from acetone, alcohols or other alkanes, diethyl ether, tetrahydrofuran or dimethyl- formamide, and recovered.

Preferably, the crude reaction product is further purified by crystallization in a water/methanol solution and precipitation in acetone.

The process permits the manufacture of the alkali metal salt of ursodeoxycholic acid disulphate in a highly purified form with yields higher than 80% based on the ursodeoxycholic acid.

Further characteristics of the process according to the invention will emerge from the following embodiment .

Example

In a 6000 I reactor, 150 kg (0.382 kmoles) of ursodeoxycholic acid are dissolved in 1130 i of dimethylformamide. 180 kg (1.13 kmoles) of the sulphuric anhydride-pyridine complex are added to the resulting solution and the whole is maintained under agitation for 4 hours at ambient temperature and then agitation is maintained for a further 20 hours. At the end of the reaction, the pH of the solution is approximately 3. 1900 t of water are then added and, under agitation, 740 I of caustic soda at 10% weight/volume are added to give a pH of from 7.5 to 8, taking care that the reaction temperature does not exceed 30°C.

The solution is then concentrated to half its volume under vacuum, keeping the temperature below 50°C (internal temperature) . While still maintaining the temperature at from 40 to 50°C, 2250 I of acetone are added and, when the addition of acetone is complete, the mixture is maintained at 50°C for 20 minutes and then cooled to 20°C.

The crude trisodium salt of the ursodeoxycholic acid disulphate precipitates from the reaction medium and is recovered by centrifuging and dried at 40°C for 12 hours to give 330 kg of crude product.

In order to proceed with further purification, the 330 kg of the trisodium salt so obtained are placed in a 4000 I , reactor where 1700 I of methanol and 900 i of water are added thereto. The whole is maintained under agitation for 30 minutes at ambient temperature.

15 kg of charcoal are then added and the whole is maintained under agitation for a further 30 minutes. The suspension is filtered by means of a filter press and the filter cakes are washed with a mixture of acetone (625 I ) and water (150 t ) and the resulting clarified solution is transferred to a 6000 I reactor. The solution is maintained under agitation and the reactor is placed under vacuum in order to concentrate the solution to 400 I (residual volume) , keeping the internal temperature at from 30 to 35°C. At ambient temperature, 1200 t of acetone are added dropwise and the whole is maintained under agitation for 8 hours .

The suspension is centrifuged and the solid is washed with 200 t of acetone. The product is dried under vacuum at 70°C for 15 hours to give 200 kg of trisodium salt of ursodeoxycholic acid disulphate. Molar yield: 84.5% (based on the ursodeoxycholic acid) .

Claims

1. A process for the preparation of ursodeoxycholic acid disulphate or its pharmaceutically acceptable salts, characterized in that it comprises the step of reacting ursodeoxycholic acid dissolved in a solvent, selected from the group consisting of dimethylformamide, pyridine, acetonitrile, dimethyl sulphoxide, octanoic acid, acetic anhydride and their mixtures, with a sulphation agent selected from the group consisting of sulphuric anhydride, sulphuric acid and complexes containing sulphuric anhydride in a molar ratio of sulphonic groups to ursodeoxycholic acid of from 2.5:1 to 4:1.

2. A process according to claim 1, for the preparation of alkali metal salts of ursodeoxycholic acid disulphate, characterized in that, after the reaction between the ursodeoxycholic acid and the sulphation agent, it comprises the operations of : diluting the reaction product with water; adding an alkali metal hydroxide in an amount sufficient to obtain a pH of from 7 to 8, keeping the temperature below 50°C; concentrating the solution; and causing the precipitation of the alkali metal salt of the ursodeoxycholic acid disulphate by the addition of a solvent selected from the group consisting of acetone, Cι-C₄ alcohols, diethyl ether, tetrahydrofuran and dimethylformamide.

3. A process according to claim 2, characterized in that the precipitated alkali metal salt of ursodeoxycholic acid disulphate is recovered and further purified by crystallization in a water/methanol mixture and precipitation in acetone.

4. A process according to claim 1, 2 or 3, characterized in that the sulphation reaction is carried out at a temperature of from 20 to 30°C.

5. A process according to any one of claims 1 to 4 , wherein the sulphation agent is the pyridine-sulphuric anhydride complex.