Crystal modification of torasemide

Details Crystal modification of torasemide Crystal modification of torasemide

2002-03-13

2004-12-21

Desai, Rita (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S294000, C514S347000

Reexamination Certificate

active

06833379

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a new crystal 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”), particularly to a new crystal modification III of torasemide, to processes for its preparation, to its use as a raw material for the preparation of the crystal modification I of torasemide and of pharmaceutically acceptable salts of torasemide as well as to pharmaceutical forms containing the said new modification III of torasemide as the active ingredient.
BACKGROUND OF INVENTION
Torasemide is a compound with interesting pharmacological properties, which is described in DE patent 25 16 025 (Example 71). 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 affected by the ability of a 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, Wyvem Cottage, 1996).
The different polymorphs of a substance possess different energies of the crystal lattice and, thus, in solid state they show different physical properties 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 interdisciplinary 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.] since 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 stability, dissolution and thermodynamic properties of each of them. Only on the basis of these determinations the appropriate polymorph can be selected for the development of pharmaceutical formulations.
From the great number of such efforts only a few will be mentioned. Thus, Gordon et al. (U.S. Pat. No. 4,476,248) protected a new crystal form of ibuprofen and a process for the preparation thereof; Bunnell et al. (EP 733 635) protected a new crystal form, a process for preparation thereof and a pharmaceutical formulation of the medicament olanzapine containing this new crystal form; R. B. Gandhi et al. (EP 749 969) protected a new process for the preparation of polymorph form I of stavudine from a mixture of one or more forms I, II and III; A. Caron et al. (EP 708 103) protected a new crystal form of irbesartane, a process for the preparation thereof and pharmaceutical formulations containing this crystal form.
It is known [
Acta Cryst.
B34 (1978), 2659-2662 and
Acta Cryst.
B34 (1978), 1304-1310] that torasemide can exist in two crystal modifications differing with regard to the parameters of a single cell, which is confirmed by X-ray diffraction on their monocrystals. Both modifications are formed simultaneously by the slow evaporation of the solvent from a solution of torasemide in a mixture petroleum ether/ethanol. The modification I with melting point 169° C. crystallizes monoclinically in the space group P 2
1
/c (prisms), while the modification II with melting point 162° C. crystallizes monoclinically in the space group P 2
(foils). Additionally, for the modification I the melting point 169.22° C. is stated in
Iyakuhin Kenkyu
25 (1994), 734-750.
According to Example 71 of DE 25 16 025 torasemide in a crystal form with melting point 163-164° C. is obtained.
In U.S. Pat. No. 4,743,693 and U.S. Pat. No. reissue 34,580 or U.S. Pat. No. 4,822,807 and U.S. Pat. No. reissue 34,672 there is disclosed a process for the preparation of a stable modification I of torasemide from an unstable modification II of torasemide by adding a catalytic amount (1%) of a stable modification I of torasemide into a suspension of the unstable modification in water and stirring the mixture at a temperature from room temperature to 90° C. within 3 hours to 14 days. In U.S. Pat. No. 4,743,693 and U.S. Pat. No. reissue 34,580 it is stated that the stable modification I of torasemide (monoclinic, space group P2
1
/c) has a melting point of 162° C. and the unstable modification II of torasemide (monoclinic, space group P 2
) has a melting point 169° C., which is contrary to the statements in
Acta Cryst.
B34 (1978), 2659-2662,
Acta Cryst.
B34 (1978), 1304-1310 and
Iyakuhin Kenkyu
25 (1994), 734-750.
In the abstract of U.S. Pat. No. 4,822,807 the authors ascribe the melting point 162° C. to the stable polymorph I of torasemide and the melting point 169° C. to the unstable polymorph II of torasemide, whereas in the claims of the said patent different melting points for either polymorph are stated, namely for polymorph I the melting point 169° C. and for polymorph II the melting point 162° C.
In the abstract of U.S. Pat. No. reissue 34,672 the authors ascribe the melting point 162° C. to the pure modification I of torasemide and the melting point 169° C. to the modification II of torasemide, whereas in the claims the melting point 159-161.5° C. for the pure polymorph I and the melting point from about 157.5 to about 160° C. for the unstable polymorph II are stated.
SUMMARY OF INVENTION
It has now been surprisingly found that by a controlled acidifying of alkaline solutions of torasemide with inorganic or organic acids with or without addition of a seed crystal at a temperature between 0 and 35° C. within 15 minutes to 25 hours, a new crystal modification III of torasemide can be prepared.
By the alkaline solutions of torasemide according to the process of the present invention there are meant an alkaline extract of the original reaction mixture for the synthesis of torasemide, alkaline solutions of any crystal modification I, II or III of torasemide or alkaline solutions of any mutual mixtures of crystal modifications I, II or III of torasemide.
In the process of the present invention for the preparation of alkaline solutions of torasemide modifications, water solutions of lithium, sodium and potassium hydroxide as well as water solutions of sodium and potassium carbonate can be used.
The acidifying of the alka

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