Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1989-07-18
1991-07-30
Ceperley, Mary E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548468, A61K 3140, C07D40906
Patent
active
050360990
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to a novel crystalline anhydrous sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide having advantageous properties for pharmaceutical formulation as an analgesic or antiinflammatory agent.
Kadin, U.S. Pat. No. 4,556,672 has disclosed said 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide, of the formula ##STR1## (or a pharmaceutically acceptable salt) as an especially preferred compound for use as an analgesic or antiinflammatory agent. In that disclosure the sodium salt of the compound of the formula (I) was alternatively isolated as a hemihydrate or hydrate. The monohydrate was rendered anhydrous by further drying. We have now determined that several hydrates are formed, generally as mixtures having various morphologies (e.g., amorphous and needle shaped crystals). These various hydrated forms generally have flow and electrostatic properties which make formulation difficult. We have also determined that the anhydrous product obtained by simple drying at elevated temperature and/or reduced pressure is amorphous and hygroscopic. It was therefore highly desirable to find a crystalline form of the sodium salt which might overcome these difficulties.
SUMMARY OF THE INVENTION
We have now found an anhydrous, crystalline form of the sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide which possesses valuable and unobvious properties. Thus, this salt is readily handled and formulated into dosage forms such as capsules. It is not hygroscopic, remaining stable in dosage forms even at 90% relative humidity. When compacted into tablets, it dissolves more rapidly than the hydrated salt.
This advantageous crystalline salt is generally formulated and used as an analgesic according to earlier disclosure of Kadin, cited above, hereby incorporated by reference.
Surprisingly, it is simply prepared by stirring a hydrated form of the sodium salt in acetonitrile at ambient temperature. This transformation has been observed in no other solvent at that temperature, although it does occur less conveniently in refluxing toluene.
DETAILED DESCRIPTION OF THE INVENTION
Once discovered, the present invention is readily carried out. In this process the sodium salt of the compound of the formula (I) is preferably first isolated in the form of its hydrate, which is then simply stirred in acetonitrile to obtain the present advantageous, anhydrous, non-hygroscopic, crystalline sodium salt. The temperature of this transformation in acetonitrile is not critical, but it is conveniently carried out at ambient temperature, avoiding the energy costs of either heating or cooling. The transformation is alternatively, but much less conveniently carried out in toluene with azeotropic removal of water by means of a Dean-Stark trap at the reflux temperature of toluene. Since lower boiling benzene is much less efficient in this process, generally producing anhydrous product which is amorphous, it is believed that use of higher temperatures are critical to the anhydrous crystal formation when the solvent is other than acetonitrile.
The present crystalline salt is characterized by its particular physical properties as noted below. It is generally formulated and used as earlier disclosed by Kadin, cited above. A particular, stable and clinically useful capsule formulation comprising the present salt is exemplified below.
The following examples are given by way of illustration and are not to be construed as limitation of this invention, many variations of which are possible within the scope and spirit thereof.
PREPARATION 1
Hydrated Sodium Salt of 5-Chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide
Title hydrates are prepared according to Example 10 of Kadin, U.S. Pat. No. 4,556,672. Alternatively, 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide (Example 8 of said Kadin; 51.2 g., 0.16 mol) was suspended in 400 ml. CH.sub.3 CN at 40.degree. C. Concurrently, NaHCO.sub.3 (14.1 g., 0.168 mol) was dissolved in 200 ml. of H.sub.2 O and warmed to 40.degree. C. The warm aqu
REFERENCES:
patent: 3767653 (1973-10-01), Krapcho
patent: 4556672 (1985-12-01), Kadin
Allen Douglas J. M.
O'Neill Brian T.
Blackwood Robert K.
Ceperley Mary E.
Lumb J. Trevor
Pfizer Inc.
Richardson Peter C.
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