Amorphous torasemide modification

Details Amorphous torasemide modification Amorphous torasemide modification

2003-03-17

2004-07-27

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S291000

Reexamination Certificate

active

06767917

ABSTRACT:

The present invention relates to an amorphous modification of N-(1-methylethyl aminocarbonyl)-4-(3-methyl-phenylamino)-3-pyridinesulfonamide (in the further text of the application designated by its generic name “torasemide”), to a process for its preparation, to its use as a raw material for pharmaceutically acceptable salts of torasemide, to pharmaceutical forms containing the said amorphous torasemide modification as the active ingredient as well as to its use as diuretic.
Torasemide is a new potential diuretic in the class of the so-called “loop diuretics”, which is described in DE patent 25 16 025 (Example 71). Structurally, it entirely differs from diuretics of the same class such as furosemide, bumetanide and azosemide. In addition to diuretic properties it also possesses antihypertension properties.
As a diuretic of Henle's loop it is useful as an agent for preventing heart or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Bartter's syndrome, tumours, glaucoma, decreasing of intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
The ability of a substance to exist in more than one crystal form is defined as polymorphism and these different crystal forms are named “polymorph modifications” or “polymorphs”. In general, polymorphism is caused by the ability of the molecule of a substance to change its conformation or to form different intermolecular or intra-molecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs. Polymorphism is found in several organic compounds. Among medicaments polymorphism is found in about 70% of barbiturates, 60% of sulfonamides and 60% of steroids, and about 50% of medicaments of the said classes are not present on the market in their most stable forms (T. Laird, Chemical Development and Scale-up in the Fine Chemical Industry, Principles and Practices, Course Manual, Scientific Update, Wyvern Cottage, 1996).
The different polymorphs of a substance possess different energies of the crystal lattice and, thus, they show different physical properties of the solid state such as form, density, melting point, colour, stability, dissolution rate, milling facility, granulation, compacting etc., which in medicaments may affect the possibility of the preparation of pharmaceutical forms, their stability, dissolution and bioavailability and, consequently, their action.
Polymorphism of medicaments is the object of studies of interdisciplinar expert teams [J. Haleblian, W. McCrone,
J. Pharm. Sci
. 58 (1969) 911; L. Borka,
Pharm. Acta Helv
. 66 (1991) 16; M. Kuhnert-Brandstätter,
Pharmazie
51 (1996) 443; H. G. Brittain,
J. Pharm. Sci
. 86 (1997) 405; W. H. Streng, DDT 2 (1997) 415; K. Yoshii,
Chem. Pharm. Bull
. 45 (1997) 338, etc.]. A good knowledge of polymorphism represents a precondition for a critical observation of the whole process of medicament development. Thus, at deciding on the production of a pharmaceutical form in solid state and with regard to the dose size, stability, dissolution and anticipated action, it is necessary to determine the existence of all solid state forms (on the market some computer programmes can be found, e.g. >>Polymorph<< as a module of >>Cerius2<< programme, MSI Inc., USA) and to determine the physical-chemical properties of each of them. Only on the basis of these determinations the appropriate polymorph can be selected for the development of pharmaceutical formulations of desired properties.
From the great number of such efforts only a few will be mentioned as an example. Thus, Chikaraishi et al. (WO 9626197) protected, in addition to a polimorph form, also an amorphous form of piretanide as well as processes for preparation thereof. J.-B. Cha et al. (WO 9857967) protected an amorphous form, a process for the preparation thereof and pharmaceutical formulations of the medicament itraconazole containing this amorphous form; E. Occeli et al. (WO 9000553) protected crystal polimorphs I and II and the amorphs of the medicament rifapentine hydrochloride and hydrobromide. Further, for the new antidiabetic troglitazone G. Om Reddy et al. (U.S. Pat. No. 5,700,820) protected six polimorphs: five crystal polimorphs and one amorphous one. It is known that torasemide can exist in three crystal modifications differing with regard to the parameters of a single cell, which is confirmed by X-ray diffraction on their monocrystals. Modification I with melting point 169° C. [
Acta Cryst
. . . B34 (1978), 1304-1310] and modification III with melting point 165° C. [HR patent application P980532A (U.S. patent application Ser. No. 09/187046)] crystallize monoclinically in the space group P 2
1
/c (prisms), while modification II with melting point 162° C. crystallizes monoclinically in the space group P 2
(foils) [
Acta Cryst
. B34 (1978), 2659-2662].
In addition to the above, U.S. Pat. No. 5,914,336 protected the use of a new torasemide polimorph, however, only some of its physical-chemical properties such as melting point, heat of formation, solubility, first band in IR-spectrum, but no X-ray patterns of the powder and monocrystal were stated.
In our further research in the field of torasemide we have surprisingly found an amorphous torasemide modification which has hitherto not been known.
The amorphous torasemide modification has the form of an amorphous voluminous powder, which—in the same way as the powder obtained by the grinding thereof—does not show any diffraction maxima at recording the X-ray powder pattern, which demonstrates the amorphous nature thereof.
In the solution the amorphous modification is identical with other known torasemide modifications, which is evident from NMR and UV spectra. On the other hand, solid state analysis techniques such as differential scanning calorimetry (DSC), X-ray powder pattern (XRD) and IR spectroscopy reveal the difference in comparison to the known torasemide modifications.
DSC of the amorphous torasemide modification (
FIG. 1
) shows one exothermic maximum at about 147° C. (onset at about 144° C.) resulting from decomposition (also evident on the basis of IR spectroscopy and thin-layer chromatography).
The X-ray powder pattern of the amorphous torasemide modification differs from the X-ray powder patterns of the known torasemide modifications and does not show any diffraction maxima, which confirms the amorphous nature (FIG.
2
).
The IR spectrum of a sample of the amorphous modification recorded in KBr (
FIG. 3
) differs from IR spectra of the known torasemide modifications. The amorphous torasemide modification shows characteristic absorption bands at 2900 to 3366 cm
−1
and at 1400 to 1703 cm
−1
.


REFERENCES:
patent: 4743693 (1988-05-01), Topfmeier et al.
patent: 5700820 (1997-12-01), Vyas et al.
patent: 5914336 (1999-06-01), Dreckmann-Behrendt
patent: 6465496 (2002-10-01), Aronhime et al.
patent: 2516025 (1975-11-01), None
patent: WO 9000553 (1990-01-01), None
patent: WO 9626197 (1996-08-01), None
patent: WO 0020395 (2000-04-01), None
L. Dupont et al., “Structure Cristalline et Moleculaire d' un Diuretique I'Alkyl-1′(Phenylamino-4-pyridyl-3)sulfony1-3 Uree: la Torasemide (C15H20N4S03)” Acta Crystallogrphica, vol. B, No. 34, 1978, pp. 1304-1310.
L. Dupont et al., “Structure d' une Seconde Variete de la Torasumide”, Acta Crystallographica, vol. B. No. 34, 1978, pp. 2659-2662.
B. Masereel et al., “Synthesis and Pharmacology of pyrid-3-ylsulfonylcyanoguanidines as diuretics”, European Journal of Medicinal Chemistry, vol. 30, 1995, pp. 343-351.

Affiliated with

Also associated with

Rating

Amorphous torasemide modification does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Amorphous torasemide modification, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Amorphous torasemide modification will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3220417