Soluble salts of ibuprofen and naproxen with N-(2-hydroxyethyl) pyrrolidine and pharmaceutic compositions containing said salts

Abstract: The salts, in the crystalline form, of ibuprofen and naproxen with N-(2-hydroxyethyl) pyrrolidine are prepared by dissolving ibuprofen and naproxen respectively in a suitable organic solvent, by adding N-(2-hydroxyethyl) pyrrolidine, by letting the compounds react, by removing the solvent and by crystallizing the obtained salt from a solution in an apolar and aprotic solvent. Said salts have a high solubility in water and are used for preparing pharmaceutic compositions for oral and other administrations.

Description: Ibuprofen (2-(4-isobutylphenyl)-propionic acid) and naproxen (6-methoxy-α-methyl-2-naphthalen acetic acid) are anti-inflammatory drugs (NSAID) which have been known for a long time and are described, for instance, in British patent 971.700 and in U.S. patent 3.637.767 respectively. The drawback of the salts with inorganic cations of aforesaid drugs is a low solubility in water. On the other hand, salts of diclofenac with cyclic organic bases are known, which salts are suitable for preparing aqueous pharmaceutic compositions and are obtained by crystallization from hexane or ligroine, as described in U.S patent 4.948.805. These salts crystallize easily from hexane and ligroine as well as from other solvents such as acetone and ethanol. However, up to now it was not possible to obtain ibuprofen and naproxen salts with cyclic organic bases in the form of crystalline solids, as no suitable solvent for the crystallization had been found. In fact it was noted that the ibuprofen and naproxen salts with the same cyclic organic bases, contrary to the diclofenac salts, do not crystallize from aforesaid solvents, even after several weeks of cooling at -20° and that, by evaporation of the solvent, said salts are often in the form of oils. The problem of obtaining ibuprofen and naproxen salts with N-(2-hydroxyethyl)pyrrolidine, in the crystalline form, has been now solved by dissolving ibuprofen or naproxen in a suitable organic solvent, to which freshly distilled N-(2-hydroxyethyl) pyrrolidine is then added by letting said compounds react, by removing the solvent and by crystallizing the obtained salt from a solvent selected from diethyl ether or ethyl acetate. Ibuprofen and naproxen salts with N-(2-hydroxyethyl)pyrrolidine in the crystallized form are thus obtained, which have a high solubility in water and are suitable for preparing pharmaceutic compositions both in the liquid form (aqueous solutions) and in the solid form. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to crystalline salts of ibuprofen (2-(4-isobutylphenyl)-propionic acid) and of naproxen (6-methoxy-α-methyl-2-naphthalen acetic acid) with N-(2-hydroxyethyl) pyrrolidine, to a process for preparing said salts and to pharmaceutic compositions containing same such as, for instance, monodose granular compositions, soft gelatin capsules, topical creams and gels, collyria, vaginal lavages, plasters and the like. A particular advantage of said salts consists in that these salts, when they are prepared in the granular form and kept in monodose light-proof and water-proof envelopes, contrary to the form in tablets used at present for oral administration of ibuprofen and naproxen, allow to prepare extemporaneous aqueous solutions, characterized by a very low gastroinjury, while keeping completely the activity level. Moreover the salts of the invention present the advantage of having no disagreable taste and can therefore be used, without any problem, for oral administration. Therefore the salts, in the crystalline form, of ibuprofen and naproxen with N-(2-hydroxyethyl) pyrrolidine are object of the present invention and the pharmaceutic compositions containing active therapeutic doses of said salts are a further object of the invention. The process for the preparation of these salts consists in dissolving ibuprofen and naproxen respectively in a suitable organic solvent, in adding freshly distilled N-(2-hydroxyethyl)pyrrolidine, in letting said compounds react, in separating the raw product by cooling, followed by solvent filtration or distillation, and in crystallizing the product obtained from a solvent selected from diethyl ether or ethyl acetate. Organic solvents suitable for dissolving ibuprofen and naproxen a well as for letting the reaction take place are the following: ethanol, methanol, acetone, diethyl ether, dichloromethane, chloroform, carbon tetrachloride, diisopropyl ether. Hydroxyethyl pyrrolidine, used for the reaction, must be distilled freshly and is employed in an equimolecular amount or in an amount slightly in excess with respect to ibuprofen and naproxen. The synthesis process concerning the raw product to be obtained, is characterized by the following conditions : concentration of the reaction product in the reaction mixture ranging from 10% to 70% by weight, reaction temperature ranging from 20° to 30°C over a period of time ranging from 0.1 to 2 hours, with or without stirring, cooling temperature for the separation of the raw product ranging from -10° to -40°C over a period of time ranging from 10 to 30 hours. The raw product, both in the crystalline and in the oily form, is purified by crystallization under the following conditions : diethyl ether or ethyl acetate, or mixtures of said solvents, concentration ranging from 10% to 70% by weight, temperature ranging from -10° to -40°C, period of time ranging from 10 to 30 hours. The final products are then obtained by the customary processes of filtration, drying and so on. Ibuprofen / N-(2-hydroxyethyl)pyrrolidine salt, has a melting point ranging from 52° to 55°C and molecular weight 321,4 ; Naproxen / N-(2-hydroxyethyl)pyrrolidine salt has a melting point ranging from 70° to 72°C and molecular weight 345.4. The aforesaid salts are hygroscopic, crystalline, white solids, having a fresh, neutral taste and no particular smell. Owing to their hygroscopicity, they tend to absorb the environment humidity, if they are not kept in air tight containers, giving rise to highly concentrated solutions with the characteristic smell of the base. The naproxen and ibuprofen / N-(2-hydroxyethyl)pyrrolidine salts, on the contrary, are characterized by a good stability, when they are sheltered from light and humidity. The stability proves to be satisfactory also in both solid and liquid pharmaceutic forms. The solubility characteristics of the ibuprofen (IH) and naproxen (NH) salts with N-(2 hydroxyethyl)pyrrolidine, compared with the respective sodium salts (INa) and (NNa), are set forth in the following table : Compound Solubility (% w/v) pH of the solution (1% w/w) IH > 50% 6.75 NH > 50% 6.70 INa < 5% 7.53 NNa < 15% 7.63 The pharmaceutic compositions according to the present invention, which are useful in the anti-inflammatory therapy, contain a therapeutically active amount of ibuprofen or naproxen salt with N-(2-hydroxyethyl)pyrrolidine and liquid or solid excipients, of the organic or inorganic type, for pharmaceutic use, suitable for preparing formulations for oral, parenteral or topic use. The following examples are reported with an illustrating, but not limiting purpose of the present invention. EXAMPLE 1 Preparation of naproxen salt with N-(2-hydroxyethyl)pyrrolidine 10 g (0.0434 moles) of naproxen were dissolved in ethanol (15 ml) and 5.1 g (0.0442 moles) of freshly distilled N-(2-hydroxyethyl)pyrrolidine were added to the thus obtained solution. The mixture was kept under stirring for 1 hour at room temperature and after addition of 150 ml of ethylether, was put into a freezer at -20°C for 24 hours. The obtained raw product, after having been separated by filtration and cold-dried under vacuum, presented a melting temperature equal to 55-60° C. This product, after having been dissolved again in the same amount by weight of anhydrous diethyl ether, was crystallized at a temperature of -20° C for 24 hours. 12 g of a crystalline salt (yield 80%) were obtained which have a melting temperature of 70-72° C. EXAMPLE 2 Preparation of ibuprofen salt with N-(2-hydroxyethyl) pyrrolidine 10 g of ibuprofen (0.0485 moles) were dissolved in 10 g of anhydrous diethyl ether ; 5.60 g (0.0486 moles) of freshly distilled N-(2-hydroxythyl)pyrrolidine were added to the solution. The solution was stirred at room temperature for 1 hour, afterwards it was put into a freezer at -20°C for 24 hours. The raw product was separated by filtration and cold-dried under vacuum: melting point 48°C. The product was dissolved at room temperature in the same amount by weight of anydrous diethyl ether. The solution was cooled at -20°C for 24 hours . 13 g of a crystalline salt (yield 83%) were obtained which have a melting point of 52-55°C. EXAMPLE 3 10 g of ibuprofen (0.0485 moles) were dissolved in 15 g of anhydrous ethyl acetate; 5.60 g (0.0486 moles) of freshly distilled N-(2-hydroxyethyl)pyrrolidine were added to the solution. The solution was stirred at room temperature for 1 hour till complete dissolution of the reactants, afterwards it was put into a freezer at -20°C, in the presence of a seed consisting of salt crystals previously obtained. After 4 hours the salt precipitation began; the solution was kept in the freezer for 24 hours. The raw product was separated by filtration and cold-dried under vacuum: melting point 48-50°C. The raw product was crystallized by dissolving it at room temperature in the same amount by weight of anhydrous ethyl acetate and by cooling the solution in the freezer at -20°C for 24 hours. 13 g of crystalline salt (yield 80%) were obtained, which have a melting point of 52-55°C. EXAMPLE 4 Granular compositions in monodose envelopes, to be dissolved in water before being taken mg per dose Ibuprofen / N-(2-hydroxyethyl)pyrrolilidine salt from 312 to 936 or Naproxen/N-(2-hydroxyethyl)pyrrolidine salt from 375 to 750 Edulcorating substances (Saccharin, Aspartame, Acesulfame) from 10 to 80 Optional binders (Sorbitol, PVP) from 5 to 20 Flavours (Fruit taste, Mint, Liquorice, and the like) from 100 to 200 Optional anti-adhering agents (precipitated colloidal silica) from 1 to 5 Acariogenic sugars (Sorbitol, Xylitol, Maltitol, and the like) in an amount sufficient to reach 2000 or 3000 The granular compositions were prepared by wet way, by a fluid bed or by dry way by compression and subsequent grinding. The aromatic fraction could be added by mixing.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, LI, LU, NL, SE Soluble salt, in the crystalline form, of a non-steroidal anti-inflammatory drug (NSAID) selected from the group consisting of ibuprofen and naproxen with N-(2-hydroxyethyl)pyrrolidine. A process for preparing a soluble salt, in the crystalline form, of a non-steroidal anti-inflammatory drug (NSAID) selected from the group consisting of ibuprofen and naproxen with N-(2-hydroxyethyl)pyrrolidine characterized in that: a. Naproxen or Ibuprofen are dissolved in a suitable organic solvent and freshly distilled N-(2-hydroxyethyl)pyrrolidine is added to the obtained solution; b. the mixture is let react at a temperature ranging from 20 to 30°C; c. the raw product is separated by cooling at a temperature ranging from -10 to -40°C over a period of time ranging from 10 to 30 hours, followed by solvent filtration and cold-drying under vacuum; d. the obtained raw product is dissolved again in a solvent selected from diethyl ether or ethyl acetate and crystallized at a temperature ranging from -10 to -40°C over a period of time ranging from 10 to 30 hours. A process according to claim 2, characterized in that said crystallization is carried out with an equal weight amount by weight of said solvent selected from diethylether or ethyl acetate with respect to the reaction product. Pharmaceutical compositions, useful in the anti-inflammatory therapy, characterized in that they contain therapeutically active amounts of a salt consisting of a non-steroidal anti-inflammatory drug (NSAID) selected from the group consisting of ibuprofen and naproxen with N-(2-hydroxyethyl)pyrrolidine together with pharmaceutical excipients, suitable for oral, parenteral and topical administration. Claims for the following Contracting States : ES, GR A process for preparing a soluble salt, in the crystalline form, of a non-steroidal anti-inflammatory drug (NSAID) selected from the group consisting of ibuprofen and naproxen with N-(2-hydroxyethyl)pyrrolidine characterized in that: a. Naproxen or Ibuprofen are dissolved in a suitable organic solvent and freshly distilled N-(2-hydroxyethyl)pyrrolidine is added to the obtained solution; b. the mixture is let react at a temperature ranging from 20 to 30°C; c. the raw product is separated by cooling at a temperature ranging from -10 to -40°C over a period of time ranging from 10 to 30 hours, followed by solvent filtration and cold-drying under vacuum; d. the obtained raw product is dissolved again in a solvent selected from diethyl ether or ethyl acetate and crystallized at a temperature ranging from -10 to -40°C over a period of time ranging from 10 to 30 hours. A process according to claim 1, characterized in that said crystallization is carried out with an equal weight amount by weight of said solvent selected from diethyl ether or ethyl acetate with respect to the reaction product. Process according to claim 1, for preparing pharmaceutical compositions, useful in the anti-inflammatory therapy, characterized in that they contain therapeutically active amounts of a salt consisting of a non-steroidal anti-inflammatory drug (NSAID) selected from the group consisting of ibuprofen and naproxen with N-(2-hydroxyethyl)pyrrolidine together with pharmaceutical excipients, suitable for oral, parenteral and topical administration.

Inventors: DONATI ELISABETTA, LUALDI PAOLO, RAPAPORT IRINA, DONATI, ELISABETTA, LUALDI, PAOLO, RAPAPORT, IRINA
Applicants: ALTERGON SA, ALTERGON S.A.
Application year: 1992
Main classification: C07C57
IPC codes: C07C57, C07D295, A61K31, C07C59