BG62228B2 - Anhydrous crystalline sodium salt of 5-cholr-3-(2-tenoyl)-2-oxindole-1-carboxamide - Google Patents

Abstract

The anhydrous crystalline sodium salt of5-chlor-3(2-tenoyl)-2-oxindole-1-carboxamide has excellentproperties for the formulation of compositions of analgetic orantiphlogistic effect.3 claims

Description

The invention relates to a new crystalline anhydrous sodium salt of 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide with excellent formulations with analgesic or anti-inflammatory action.

Cadine, US 4 556 672 discloses said 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide of formula

NH1 or a pharmaceutically acceptable salt thereof as one particularly preferred compound for use as an analgesic or anti-inflammatory agent. In this patent, the sodium salt of the compound of formula I is alternatively isolated as a hemihydrate or a hydrate. The monohydrate is dehydrated by subsequent drying. It has been found that several hydrates are produced, usually in the form of mixtures of different morphologies, for example amorphous crystals or needle-shaped crystals. These various hydrate forms have electrostatic properties and flowability that make them difficult to process. The anhydrous product obtained by simple drying or elevated temperature and / or reduced pressure has also been found to be amorphous and hygroscopic. It is therefore necessary to create a crystalline form of the sodium salt that does not have these disadvantages.

An anhydrous crystalline form of the 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide sodium salt has been obtained which has valuable and unexpected properties. This salt is readily processed and formulated into various dosage forms, such as capsules. It is not hygroscopic, remains stable when dosed even at 90% relative humidity. When in tablet form, it dissolves faster than the hydrated salt.

This excellent crystalline salt is usually formulated and used as an analgesic as described by Kadin, as indicated in the prior art.

It is obtained quite unexpectedly by simply stirring the hydrated form of the sodium salt in acetonitrile at ambient temperature. This transformation is not observed in another solvent at this temperature, although it does, but not so readily in toluene, at the reflux temperature of the toluene.

The method of the invention is easy to carry out. By the method, the sodium salt of the compound of formula I is preferably initially isolated in the form of the finished hydrate, which is then only stirred in acetonitrile to give the anhydrous sodium salt. The temperature at which the conversion takes place is not critical, but the reaction is easily carried out at ambient temperature, avoiding energy costs for both heating and cooling. The conversion is carried out alternatively, but not so readily, in toluene by azeotropically removing water by a Dean-Stark trap at the reflux temperature of the toluene. The use of this low boiling point solvent generally results in an anhydrous product which is amorphous. The use of higher temperatures is assumed to be critical with respect to the formation of the anhydrous crystalline product when the solvent is other than acetonitrile.

The crystalline salt of the invention is characterized by its particular physical properties. It is usually formulated and used as described in the prior art by Cadine. A clinically stable and capsule capsule containing said salt is described below.

The examples merely illustrate the invention without limiting it, and many variants are possible within the scope of the invention.

Getting 1.

5-Chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide hydrate sodium salt.

The title hydrates are prepared according to Example 10 of US 4 556 672, Cadine. Alternatively, 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide (Example 8 of said patent, 51.2 g, 0.16 mol) was suspended in 400 ml of CH ₃ CN at 40 ° C. NaHCO ₃ (14.1 g, 0.168 mol) was dissolved in 200 ml of water and warmed to

40 ° C. The warm aqueous solution was added to the warm acetonitrile suspension for more than 20 min, with a slight foam formation during this time. The resulting solution was stirred at 40 ° C, treated with 5 g of decolourising carbon, stirred at 25 ° C for 30 min and filtered by washing with 50 ml of 1: 1 CH ₃ CN: H 2 O. The filtrate and washings were combined and concentrated in vacuo over a steam bath, the acetonitrile replaced with 200 ml of water to a final volume of about 500 ml, the mixture cooled to 25 ° C and the first extraction was performed by filtration. The solids were washed with 50 ml of water. The combined mother liquors and washings were evaporated to give 400 ml volume of the mixture, yielding a second crop. After air-drying, the first yield was 35.76 g (6.4% water) and the second yield 16.77 g (6.2% water). The yield is 90% corrected for water content. The water content of the monohydrate is 5.0%. The differential calorimetric analysis of these two yields shows the presence of four endothermic compounds (at about 110, 150, 237 and 255).

Example 1. Anhydrous crystalline sodium salt of 5-chloro-3- (2-thenoyl) -2-oxindole-1carboxamide.

The 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide hydrate sodium salt (52.5 g, obtained by the method of Preparation 1) was stirred at ambient temperature in 52.5 ml of CH ₃ CN. The title product was removed by filtration, washed with 50 ml CH ₃ CN and dried at 55 ° C in vacuo. 46.7 g (95%) of the title product are obtained, which has a crystalline form under a polarization microscope, and differential calorimetric analysis in the 50300 ° C range shows a single strongly expressed endothermic compound at 255 ° ± 2 ° C. Chemical analysis:

Calculated for C ₁₄ H _g ClN ₂ 0 ₃ Sna: C, 49.06; H, 2.35; N, 8.18; S, 9.35; Cl, 10.34; sulfate ash, 20.72; H ₂ O, O; Vacuum drying loss at 100 ° C, 0.

Found: C, 48.85; H, 2.39; N, 8.22; S, 9.54; Cl, 10.43; sulfate ash, 20.58; H ₂ O, 0.07; Vacuum drying loss at 100 ° C, 0.07.

Unlike the hydrated form, which is orange in color, the colorless sodium salt is yellow. Samples of the hydrated form (Preparation 1) and the anhydrous form were reduced to a fine powder particle size and compressed into tablets through a 1/2 inch diameter mouthpiece at a final pressure of 2000 pounds. In both cases, the die is removed and the end of the mouthpiece is covered with parafilm, allowing the dissolution rate to be tested at a predetermined location from the surface of the tablet. The mouthpiece containing the compressed drug is placed at the bottom of the USP flask in which the dissolution is performed, equipped with a stirring blade located 2.5 cm above the surface of the test drug.

At 25 ° C, both in water and in 0.05 M borate buffer solution at pH 9.0, the inherent dissolution rate (which may be an important factor for the efficacy of oral dosage forms) is approximately three times higher for the anhydrous form compared to the hydrated form. The anhydrous form shows a slight tendency to improve the hydrated form. Even in the granulation with water used below, preferably in the formulation of capsules, the hydrated form is not formed, as evidenced by the lack of change in color from yellow to orange.

Example 2 Oral dosage form capsule containing the anhydrous sodium salt of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide.

The following ingredients are mixed, granulated with 875 ml of water and dried to contain up to 5% water by the Karl Fischer method:

5-Chloro-3 (2-tenoyl) sodium salt - 600,00 g

2-oxindole-1-carboxamide (561.52 g A *)

Microcrystalline Cellulose 885.75 g (Avicel PH 101)

Hydrated corn starch 236.25 g

Povidone (PVC 30) 105.00 g (A * denotes the active equivalent in the form of free acid).

The dried and granular powdered ingredients are then mixed with the following compounds in g:

Sodium glycolate (starch) 210,00 (Explotab)

Magnesium stearate 42.00

Sodium lauryl sulfate 21.00 5

Soft gelatin capsules containing 100 mg of the first mixture are prepared using a standard capsule filling machine and 375 mg of the final mixture. These capsules 10 show excellent bioavailability when used for oral treatment of dogs, demonstrated in a blood test, which shows 89% bioavailability compared to treatment when using a solution as a dosage form 15, also taken orally.

Claims (3)

Claims Anhydrous crystalline sodium salt of 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide. A pharmaceutical composition for oral administration to humans comprising an analgesic or anti-inflammatory effective amount of a salt according to claim 1 and a pharmaceutically acceptable carrier or diluent. A method for the oral treatment of pain or inflammation in humans, comprising administering an analgesic or anti-inflammatory effective amount of a salt according to claim 1.