Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-20
2000-08-01
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548577, A61K 3140, C07D20704, C07D20712, C07D20716
Patent
active
06096779&
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a novel amorphous piretanide, a novel class of piretanide polymorphs, a process for their preparation and their use.
Piretanide [chemical name: 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid] is known to be a pharmaceutical agent as a diuretic drug. The amorphous piretanide and the piretanide polymorph of this invention have a high solubility in an aqueous solution at various pH values and consequently can show a higher bioavailability.
A substance having the same chemical composition, but a different crystalline structure and a crystalline form, has been referred to as "polymorph". In general, it is known that many organic compounds have their polymorphs, depending upon differences in the sort of recrystallization solvents, pH values, temperatures and pressures in recrystallization.
Piretanide is usually recrystallized from a mixed solvent of methanol and water (hereinafter referred to as piretanide form A: See, Japanese Patent Kokai No.: 83547/1977). However, it has a water solubility as low as 7.9 mg/100 ml (at 20.degree. C.) and, particularly, it is further slightly soluble in an acidic environment. For instance, piretanide form A has a solubility (at 37.degree. C.) of 7.5 mg/100 ml and 4.2 mg/100 ml in a buffer at a pH value of 1 and 3, respectively.
For improving the slight solubility of piretanide form A in an acidic environment, there has been suggested a piretanide polymorph obtained by crystallizing piretanide from a lower aliphatic alcohol or a cyclic ether to form a crystalline solvate and then heating the resultant solvate (hereinafter referred to as piretanide form B: See, Japanese Patent Kokai No.: 230044/1993 and Chem. Pharm. Bull., (1994), Vol. 42, pp. 1123-1128). Piretanide form B has a solubility (at 37.degree. C.) of 12.4 mg/ml and 6.4 mg/100 ml in a buffer at a pH value of 1 and 3, respectively, and its solubility in an acidic environment increased by a factor of 1.5-1.7 than that of piretanide form A. In view of a pH value of about 1 in gastric juice, piretanide form B has a crystalline form more suitable for oral administration.
Piretanide has been applied n to only as a pharmaceutical preparation for oral administration but also an injection and, in the latter case, its higher solubility at a pH value around neutrality is desirable. As piretanide forms A and B have a solubility of 193.8 mg/100 ml and 195.4 mg/100 ml at a pH value of 6.8 (at 37.degree. C.), respectively, they have a higher solubility than that in an acidic environment. Nevertheless, there has been desired a crystalline piretanide having a far higher solubility at a pH value around neutrality.
It is therefore a primary object of this invention to provide a crystalline piretanide having an excellent solubility at a pH value around neutrality.
According to this invention, there is provided diffraction analysis; and cm.sup.-1 in an infra-red absorption spectrum; and 22.8, 25.6 and 30.6.degree. in X-ray powder diffraction analysis, and cm.sup.-1 in an infra-red absorption spectrum.
According to this invention, there is also provided a process for preparing piretanide in an aqueous solution of a base, adjusting a pH value of the solution by an acid to a pH range from not less than 3.87 to not more than 4.37 and recovering the precipitate thus separated; piretanide in an aqueous solution of a base, adjusting a pH value of the solution to a pH range of less than 3.50 by an acid and recovering the precipitate thus separated.
Moreover, there is also provided a method for the treatment and prevention of edema having administering an effective amount of the above-mentioned amorphous piretanide or piretanide polymorph and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a differential thermal curve of the present amorphous piretanide.
FIG. 2 shows a differential thermal curve of the present piretanide polymorph.
FIG. 3 shows a differential thermal curve of piretanide form A.
FIG. 4 shows an X-ray powder diffraction pattern of the present amorphous piretanide
REFERENCES:
Y. Matsuda et al., "Amorphism and Physiochemical Stability of Spray-dried Frusemide", J. Pharm. Pharmacol., 44:627-633 (1992).
Y. Chikaraishi et al., "Preparation of Piretanide Polymorphs and Their Physicochemical Properties and Dissolution Behaviors", Chem. Pharm. Bull., 42(5):1123-1128 (1994).
CAS Online structure search; frusemide structures; pp. 5 and 6.
Chikaraishi Yuji
Matsuda Yoshihisa
Otsuka Makoto
Hoechst Pharmaceuticals & Chemicals K.K.
McKane Joseph
Oswecki Jane C.
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