Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-01-21
1999-02-16
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544295, C07D40314, C07D40302, A61K 31495, A61K 31505
Patent
active
058721258
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to new polymorphs of the dihydrochloride of ("Lesopitron" dihydrochloride), and to its hydrated forms, to processes for its preparation and to compositions which contain them.
BACKGROUND TO THE INVENTION
The invention relates to the pyrimidinic compound has the following structural formula: ##STR1## generically termed Lesopitron, which exhibits pharmacological activity over the central nervous system, particularly an anxiolytic, tranquilizing and antidepressant activity. It can also be used in the treatment of dyskinesias, Parkinsonism and drug induced psychoses, in the treatment of cognitive functions, inhibition of the withdrawal symptoms, and in treatment vomit and gastric secretion related problems.
The synthesis of the compound and an account of its therapeutical properties are described in patents EP 382637B1, EP 429360B1, EP 497658A1 and FR 9314102.
Lesopitron dihydrochloride is particularly important in that it allows for the Lesopitron to be conveniently formulated, for instance, in tablets for oral administration. Therefore, there is the need to produce Lesopitron dihydrochloride in pure and crystalline form, in order to comply with the pharmaceutical requirements and specifications. The patent EP 382637B1 describes a process for the preparation of Lesopitron dihydrochloride.
From the point of view of its application for pharmaceutical use, it was important to obtain, at least, a single crystalline form of Lesopitron dihydrochloride which could be manufactured, stored and formulated without losing the required specifications of a pure pharmaceutical product. During the preparation of samples of Lesopitron dihydrochloride, it was observed that said samples did not meet a unique criterion with respect to their infrared spectrum. A closer study resulted in the unexpected discovery that the corresponding differences were not associated to impurities, but to the existence of a phenomenon of polymorphism. The authors of the present invention have discovered that, depending on the crystallization conditions of the samples of Lesopitron dihydrochloride, different crystalline forms are obtained, observing that they differ not only in their infrared spectrum but in their X-ray diffraction patterns as well.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1a shows the infrared diffuse reflectance spectrum of polymorph I of Lesopitron dihydrochloride. In this figure (a) indicates percentage transmission and (b) the wavenumber (cm.sup.-1).
FIG. 1b shows the X-ray powder diffraction spectrum of polymorph I of Lesopitron dihydrochloride, obtained at .lambda.=1.5418 .ANG., using a radiation source of CuK.sub..alpha., 40 kV and 30 mA (Siemens D-500 equipment).
FIG. 2a shows the infrared diffuse reflectance spectrum of polymorph II of Lesopitron dihydrochloride. In this figure (a) indicates percentage transmission and (b) the wavenumber (cm.sup.-1).
FIG. 2b shows the X-ray powder diffraction spectrum of polymorph II of Lesopitron dihydrochloride, obtained at .lambda.=1.5418 .ANG., using a radiation source of CuK.sub..alpha., 40 kV and 30 mA (Siemens D-500 equipment).
FIG. 3a shows the infrared diffuse reflectance spectrum of the hydrated crystalline form of Lesopitron dihydrochloride, termed I-hydrate. In this figure (a) indicates percentage transmission and (b) the wavenumber (cm.sup.-1).
FIG. 3b shows the X-ray powder diffraction spectrum of the hydrated crystalline form of Lesopitron dihydrochloride, termed I-hydrate, obtained at .lambda.=1.5418 .ANG., using a radiation source of CuK.sub..alpha., 40 kV and 30 mA (Siemens D-500 equipment).
FIG. 4a shows the infrared diffuse reflectance spectrum of the hydrated crystalline form of Lesopitron dihydrochloride, termed II-hydrate. In this figure (a) indicates percentage transmission and (b) the wavenumber (cm.sup.-1).
FIG. 4b shows the X-ray powder diffraction spectrum of the hydrated crystalline form of Lesopitron dihydrochloride, termed II-hydrate, obtained at .lambda.=1.5418 .ANG., using a radiation source of CuK.su
REFERENCES:
patent: 5128343 (1992-07-01), Pinol et al.
patent: 5162323 (1992-11-01), Frigola-Constansa et al.
patent: 5182281 (1993-01-01), Frigola-Constansa et al.
patent: 5536836 (1996-07-01), Merce-Vidal et al.
Frigola-Constansa Jordi
Lupon-Roses Pilar
Puig-Torres Salvador
Tomas-Navarro Jaime
Grumbling Matthew V.
Laboratorios Del Dr. Esteve, S.A.
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