HU204046B - Process for producing anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenyl)-2-oxindole-1-carboxamide and pharmaceutical compositions comprising same - Google Patents

Abstract

The present invention relates to a process for the preparation of anhydrous crystalline 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide sodium. In the process, the appropriate hydrated form is mixed with acetonitrile and the anhydrous crystalline form is separated. Furthermore, the present invention also relates to the preparation of analgesic and anti-inflammatory pharmaceutical compositions containing the novel salt. EN 204 046 B Scope of the description: 4 pages (including Figure 1)

Description

The present invention relates to a novel crystalline anhydrous sodium salt of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide, which can be converted into an excellent analgesic and anti-inflammatory pharmaceutical composition. 5

U.S. Patent 4,556,672 discloses 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide of formula (I) (and pharmaceutically acceptable salts thereof) as a compound useful as an analgesic. or as an anti-inflammatory ÍC agent. As described herein, the sodium salt of the compound of formula (I) is isolated as a hemihydrate or hydrate. The monohydrate was made water-free by further drying. In our experiments, it has been found that several hydrates are formed, usually in the form of mixtures of different morphologies (e.g., amorphous and needle-shaped crystals). These various hydrated forms are generally fluid and have electrostatic properties, which makes it difficult to disassemble. It has also been found that the anhydrous product obtained by simple drying under elevated temperature and / or reduced pressure is amorphous and hygroscopic. Therefore, a crystalline form of the sodium salt is needed to overcome these difficulties.

In our experiments, an anhydrous crystalline form of the 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide sodium salt was prepared which had valuable and unexpected properties. This salt is easy to handle and convert into dosage units such as capsules.

Non-hygroscopic, the dosage units remain stable even at 90% relative humidity. When compressed into tablets, it dissolves faster than the hydrated salt.

This preferred crystalline salt may generally be formulated and used as an analgesic in the manner described in the aforementioned U.S. Patent.

Surprisingly, it is readily prepared by stirring the hydrated form of the sodium salt in acetonitrile at room temperature. This conversion is not observed in any of the other solvents or temperatures, although it is less convenient under reflux in toluene.

The process is easily carried out by first isolating the sodium salt of the compound (Γ) as its 45 hydrate and then simply mixing with acetonitrile to obtain the anhydrous, non-hygroscopic, crystalline sodium salt. The temperature of this conversion in acetonitrile is not critical and is preferably carried out at room temperature, thus avoiding the cost of heating or cooling. The conversion is also less convenient in toluene by removing the water azeotropically with a Dean-Stark trap at the boiling point of toluene.

Although lower boiling point benzene is much less effective in this process because it generally provides an amorphous anhydrous product, it is believed to be critical to use a higher temperature for the formation of anhydrous crystal in a solvent other than acetonitrile. 60

HU 204 046 Β

Water content: calculated: 0%, found: 0.07%.

Loss on drying at 100 ° C in vacuo: calculated: 0%, found: 0.07%.

Unlike the orange hydrated form, the anhydrous sodium salt is yellow.

Samples of both the hydrated form and the product prepared in this example were pulverized to a fine particle size and compressed into tablets at a final pressure of 13.3 MPa in a 1.27 cm diameter die. Thereafter, the extrusion die was removed from the paraffin-coated die in each case to determine the dissolution rate on a single, smooth surface of known size. The tool containing the pressed drug was placed on the bottom of a dissolution test flask prescribed in the U.S. Pharmacopoeia, with a stirrer placed 25 cm above the surface of the drug being tested. At 25 ° C, both in water and in a 0.05 M borate buffer at pH 9.0, the intrinsic dissolution rate (which is critical to the efficacy of oral dosage units) is about three times as fast in the anhydrous form as in the hydrate form.

The anhydrous form has only a slight tendency to convert to a hydrate. Even in the case of a preferred formulation of the capsules, the granulation with water moistened does not result in hydration (as evidenced by the fact that the product does not turn yellow to orange).

Example 2

Preparation of anhydrous 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide sodium capsule for oral administration

The following ingredients were mixed, wet granulated with 875 ml water and finally dried to 5% water (as determined by the Kari Fischer method).

Sodium salt of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide 600.00 g (561.52 g A *) microcrystalline cellulose (Avicel PH101) 885.75 g hydrated maize starch 236.25 g povidone (PVC-30) __ 105.00 g (A *: activity equivalent to free acid)

The dried wet granulated powder is then mixed with the following materials:

sodium starch glycolate (Explotab) 210.00 g magnesium stearate 42.00 g sodium lauryl sulfate 21.00 g

100 mg soft gelatine capsules were filled with 375 mg of the final blend in a conventional capsule filling device. When administered orally to dogs, the bioavailability of these capsules is excellent; compared to the oral solution, the blood level is 89%.

Claims (2)

PATENT CLAIMS A process for the preparation of the anhydrous crystalline sodium salt of 5-chloro-3- (2-tenoyl) -2-oxmdol-1-carboxamide comprising mixing the corresponding hydrated form with acetonitrile and separating the anhydrous crystalline form A process for the preparation of a pharmaceutical composition, preferably for the oral treatment of pain or inflammatory conditions, wherein the anhydrous crystalline compound of claim 1 is formulated with at least one pharmaceutically acceptable carrier in a customary dosage form.