U.S. patent application number 11/763156 was filed with the patent office on 2007-10-11 for novel polymorph v of torasemide.
This patent application is currently assigned to PLIVA farmaceutska industrija, dionicko drustvo. Invention is credited to Aleksandar Danilovski, Miljenko Dumic, Darko Filic, Bozena Klepic, Marijan Tudja.
Application Number | 20070238759 11/763156 |
Document ID | / |
Family ID | 10947111 |
Filed Date | 2007-10-11 |
United States Patent
Application |
20070238759 |
Kind Code |
A1 |
Filic; Darko ; et
al. |
October 11, 2007 |
Novel Polymorph V of Torasemide
Abstract
The invention relates to a novel polymorph V of torasemide, to a
process for its preparation, to its use as a raw material for the
preparation of crystalline modifications I and III of torasemide,
to amorphous torasemide modifications and to pharmaceutically
acceptable salts of torasemide, to pharmaceutical forms containing
the said novel polymorph V of torasemide as the active ingredient
as well as to its use.
Inventors: |
Filic; Darko; (Zagreb,
HR) ; Dumic; Miljenko; (Zagreb, HR) ; Klepic;
Bozena; (Jastrebarsko, HR) ; Danilovski;
Aleksandar; (Rijeka, HR) ; Tudja; Marijan;
(Zagreb, HR) |
Correspondence
Address: |
CONNOLLY BOVE LODGE & HUTZ LLP
1875 EYE STREET, N.W.
SUITE 1100
WASHINGTON
DC
20036
US
|
Assignee: |
PLIVA farmaceutska industrija,
dionicko drustvo
Zagreb
HR
|
Family ID: |
10947111 |
Appl. No.: |
11/763156 |
Filed: |
June 14, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10276881 |
Jun 11, 2003 |
7241782 |
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PCT/HR00/00033 |
Sep 25, 2000 |
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11763156 |
Jun 14, 2007 |
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Current U.S.
Class: |
514/347 ;
546/293 |
Current CPC
Class: |
A61P 27/02 20180101;
C07D 213/74 20130101; A61P 11/06 20180101; A61P 9/10 20180101; A61P
11/04 20180101; A61P 25/08 20180101; A61P 11/02 20180101; A61P 7/02
20180101; A61P 27/06 20180101; A61P 9/00 20180101; A61P 5/00
20180101; A61P 7/10 20180101; A61P 35/00 20180101; A61P 9/12
20180101; A61P 9/04 20180101; A61P 13/12 20180101; A61P 11/00
20180101; A61P 17/02 20180101; A61P 3/00 20180101 |
Class at
Publication: |
514/347 ;
546/293 |
International
Class: |
C07D 213/74 20060101
C07D213/74; A61K 31/44 20060101 A61K031/44 |
Foreign Application Data
Date |
Code |
Application Number |
May 19, 2000 |
HR |
P20000328A |
Claims
1-8. (canceled)
9. A process for the preparation of the crystalline modifications
I, II and III torasemide or of an amorphous torasemide modification
which comprises using as a raw material a polymorph V of torasemide
characterized by the following data: DSC: exothermic maximum at
about 157.59.degree. C. (onset at about 150.74.degree. C.) with the
heating rate of 10.degree. C./min; X-ray powder pattern (2.THETA.)
: 5.610; 6.130; 7.480; 7.970; 9.310; 9.615; 10.835; 11.020; 12.340;
13.075; 13.460; 13.920; 14.200; 15.090; 16.080; 16.710; 17.445;
17.720; 18.460; 18.850; 19.825; 20.340; 20.990; 21.980; 22.075;
22.630; 22.935; 23.410; 23.845; 24.880; 25.560; 26.035; 27.285;
27.540; 28.170; 28.645; 29.350; 29.975; 30.575; 31.265; 32.300;
34.050; 35.650; 36.375; 37.100 and 38.145; IR-characteristic
absorption bands at 2671 to 3327 and at 1468 to 1705cm.sup.-1.
10. A process for the preparation of pharmaceutically acceptable
salts of torasemide which comprises using a polymorph V of
torasemide characterized by the following data: DSC: exothermic
maximum at about 157.59.degree. C. (onset at about 150.74.degree.
C.) with the heating rate of 10.degree. C./min; X-ray powder
pattern (2.THETA.): 5.610; 6.130; 7.480; 7.970; 9.310; 9.615;
10.835; 11.020; 12.340; 13.075; 13.460; 13.920; 14.200; 15.090;
16.080; 16.710; 17.445; 17.720; 18.460; 18.850; 19.825; 20.340;
20.990; 21.980; 22.075; 22.630; 22.935; 23.410; 23.845; 24.880;
25.560; 26.035; 27.285; 27.540; 28.170; 28.645; 29.350; 29.975;
30.575; 31.265; 32.300; 34.050; 35.650; 36.375; 37.100 and 38.145;
IR-characteristic absorption bands at 2671 to 3327 and at 1468 to
1705 cm.sup.-1.
11. (canceled)
12. Pharmaceutical form, characterized in that as an active
ingredient it contains an effective amount of a polymorph V of
torasemide characterized by the following data: DSC: exothermic
maximum at about 157.59.degree. C. (onset at about 150.74.degree.
C.) with the heating rate of 10.degree. C./min; X-ray powder
pattern (2.THETA.): 5.610; 6.130; 7.480; 7.970; 9.310; 9.615;
10.835; 11.020; 12.340; 13.075; 13.460; 13.920; 14.200; 15.090;
16.080; 16.710; 17.445; 17.720; 18.460; 18.850; 19.825; 20.340;
20.990; 21.980; 22.075; 22.630; 22.935; 23.410; 23.845; 24.880;
25.560; 26.035; 27.285; 27.540; 28.170; 28.645; 29.350; 29.975;
30.575; 31.265; 32.300; 34.050; 35.650; 36.375; 37.100 and 38.145;
IR-characteristic absorption bands at 2671 to 3327 and at 1468 to
1705 cm.sup.-1, without or in combination with one or more
pharmaceutically acceptable additives.
13. Pharmaceutical form according to claim 12, characterized in
that it is a tablet, a capsule or an injection.
14. A method of treatment selected from the group consisting of
treating a patient in need of a diuretic; a patient suffering from
heart or heart tissue damages caused by metabolic or ionic
abnormalities associated with ischemia; and patient suffering from
a treating a cenaitium selected from the group consisting of
thrombosis, angina pectoris, asthma, hypertension, nephroedema,
pulmonary edema, primary and secondary aldosteronism, Bartter's
syndrome, tumors, glaucoma, decreasing of intraocular pressure,
acute or chronic bronchitis, cerebral edema caused by trauma,
ischemia, concussion of the brain, metastases or epileptic attacks,
and nasal infections caused by allergens; by administering to said
patient an effecture amount of a polymorph V of torasemide
characterized by the following data: DSC: exothermic maximum at
about 157.59.degree. C. (onset at about 150.74.degree. C.) with the
heating rate of 10.degree. C./min; X-ray powder pattern (2.THETA.)
: 5.610; 6.130; 7.480; 7.970; 9.310; 9.615; 10.835; 11.020; 12.340;
13.075; 13.460; 13.920; 14.200; 15.090; 16.080; 16.710; 17.445;
17.720; 18.460; 18.850; 19.825; 20.340; 20.990; 21.980; 22.075;
22.630; 22.935; 23.410; 23.845; 24.880; 25.560; 26.035; 27.285;
27.540; 28.170; 28.645; 29.350; 29.975; 30.575; 31.265; 32.300;
34.050; 35.650; 36.375; 37.100, and 38.145; IR-characteristic
absorption bands at 2671 to 3327 and at 1468 to 1705 cm.sup.-1.
15. Pharmaceutical form according to claim 12 wherein said
pharmaceutically acceptable additives are selected from the group
consisting of sugar, starch, starch derivatives, cellulose,
cellulose derivatives, mould release agents, antiadhesive agents
and agents for regulating flowability.
16. Pharmaceutical form according to claim 12 wherein said
polymorph V of torasemide is chemically pure.
17. Pharmaceutical form according to claim 12 wherein said
polymorph V of torasemide contains no water.
18. Pharmaceutical form according to claim 12 wherein said
polymorph V of torasemide contains no solvent.
19. Pharmaceutical form according to claim 15 wherein said
polymorph V of torasemide is chemically pure.
20. Pharmaceutical form according to claim 15 wherein said
polymorph V of torasemide contains no water.
21 Pharmaceutical form according to claim 15 wherein said polymorph
V of torasemide contains no solvent.
22. The method according to claim 14 wherein said polymorph V of
torasemide contains no water.
23. The method according to claim 14 wherein said polymorph V of
torasemide contains no solvent.
24. The method according to claim 14 polymorph V of torasemide is
chemically pure.
Description
[0001] The present invention relates to a novel crystalline form of
N-(1-methylethyl
aminocarbonyl)-4(3-methyl-phenylamino)-3-pyridinesulfonamide
(further referred to by its generic name "torasemide"), especially
to a novel polymorph V of torasemide, to a process for its
preparation, to its use as a raw material for the preparation of
crystalline modifications I and III of torasemide, to amorphous
torasemide modifications and to pharmaceutically acceptable salts
of torasemide, to pharmaceutical forms containing the said novel
polymorph V of torasemide as the active ingredient as well as to
its use.
[0002] Torasemide is a new potent diuretic in the class of the
so-called "loop diuretics", which is described in DE patent 25 16
025 Sample 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 antihypertensive
properties.
[0003] 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.
[0004] The ability of a substance to exist in more than one
crystalline form is defined as polymorphism and these different
crystalline 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 inter-molecular and intramolecular 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).
[0005] 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.
[0006] 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-Brandstatter, 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.
[0007] From the great number of such efforts only a few will be
mentioned as an example. Thus, Gordon et al. (U.S. Pat. No.
4,476,248) protected a novel crystalline form of ibuprofen and a
process for the preparation thereof. Bunnel et al. (EP 733,635)
protected a novel crystalline form, a process for the preparation
thereof and pharmaceutical formulations of the drug olanzapine
containing the said novel form. R. B. Gandhi et al. (EP 749,969)
protected a novel process for the preparation of a polymorphous
form I of stavudine from a mixture of one or more forms I, II and
III, whereas A. Caron et al. (EP 708,103) protected a novel
crystalline form of irbesartane, a process for the preparation
thereof as well as pharmaceutical formulations containing this
crystalline form. Chikaraishi et al. (WO 9626197) protected, in
addition to a polymorphous form, also an amorphous form of
piretanide as well as processes for the 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, whereas E.
Occeli et al. (WO 90/00553) protected crystal polymorphs I and II
and 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 polymorphs:
five crystal polymorphs and one amorphous one.
[0008] It is known that torasemide can exist in three crystalline
modifications differing with regard to the parameters of a unit
cell, which is confirmed by X-ray diffraction on their
monocrystals, and in one amorphous modification (HR patent
application P20000162A). Modification I with melting point
169.degree. C. [Acta Cryst. B34 (1978), 1304-1310] and modification
III with melting point 165.degree. C. (WO 00/20395) crystallize
monoclinically in the space group P 2.sub.1/n (prisms), while
modification II with melting point 162.degree. C. crystallizes
monoclinically in the space group P 2/n (foils) [Acta Cryst. B34
(1978), 2659-2662].
[0009] In addition to the above, U.S. Pat. No. 5,914,336 protected
the use of a new torasemide polymorph, however, only some of its
physical-chemical properties such as melting point, heat of
formation, solubility, first band in IR-spectum, but no X-ray
patterns of the powder and monocrystals were stated therein. Since
the data as stated are not relevant for the characterization of
polymorphism, the claimed subject-matter of U.S. Pat. No. 5,914,336
is not believed to be reliable.
[0010] In our further research in the field of torasemide we have
surprisingly found a novel crystalline torasemide modification,
i.e. a novel polymorph V of torasemide which has hitherto not been
known.
[0011] The novel polymorph V of torasemide is prepared according to
the inventive process in the form of a flowable crystalline powder
having the property of flowability, i.e. it is obtained in a
"free-flow" form which is statically not chargeable.
[0012] In a solution the novel polymorph V of torasemide is
identical to 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 a difference in
comparison to the known torasemide modifications.
[0013] DSC of the novel polymorph V of torasemide (FIG. 1) shows
one exothermic maximum at about 157.59.degree. C. (onset at about
150.74.degree. C.) (heating rate of 10.degree. C./min) resulting
from decomposition (also evident on the basis of IR spectroscopy
and thin-layer chromatography).
[0014] The X-ray powder pattern of the novel polymorph V of
torasemide differs from the X-ray powder patterns of the known
torasemide modifications (FIG. 2).
[0015] The IR spectrum of a sample of the novel polymorph V of
torasemide recorded in KBr (FIG. 3) differs from IR spectra of the
known torasemide modifications. The novel polymorph V of torasemide
shows characteristic absorption bands at 2671 to 3327 cm.sup.-1 and
at 1468 to 1705 cm.sup.-1.
[0016] FIG. 1 represents a characteristic thermogram of
differential scanning calorimetry (DSC) of the novel polymorph V of
torasemide.
[0017] FIG. 2 represents a characteristic X-ray powder pattern of
the novel polymorph V of torasemide.
[0018] FIG. 3 represents a characteristic IR spectrum of the novel
polymorph V of torasemide recorded in KBr.
[0019] The novel polymorph V of torasemide according to the present
invention can be obtained by a rapid acidification of alkaline
torasemide solutions with inorganic or organic acids.
[0020] A process for the preparation of the novel polymorph V of
torasemide comprises: [0021] (i) the preparation of a polymorph I
of torasemide according to a known process, [0022] (ii) the
dissolution of the polymorph I of torasemide in an aqueous solution
of a base, [0023] (iii) the filtration of the obtained solution,
[0024] (iv) a rapid acidification of the obtained solution with an
aqueous solution of an acid at temperatures between 0.degree. C.
and 35.degree. C., [0025] (v) the filtration of the obtained
suspension, [0026] (vi) washing the thus obtained crystals of the
novel polymorph V of torasemide with demineralized water and drying
them in a vacuum dryer during 3 hours at 50.degree. C., the
obtained crystals being characterized by the following data: [0027]
DSC: exothermic maximum at about 157.59.degree. C. (onset at about
150.74.degree. C.) (FIG. 1); [0028] X-ray powder pattern
(2.THETA.): 5.610; 6.130; 7.480; 7.970; 9.310; 9.615; 10.835;
11.020; 12.340; 13.075; 13.460; 13.920; 14.200; 15.090; 16.080;
16.710; 17.445; 17.720; 18.460; 18.850; 19.825; 20.340; 20.990;
21.980; 22.075; 22.630; 22.935; 23.410; 23.845; 24.880; 25.560;
26.035; 27.285; 27.540; 28.170; 28.645; 29.350; 29.975; 30.575;
31.265; 32.300; 34.050; 35.650; 36.375; 37.100, and 38.145 (FIG.
2); [0029] IR-characteristic absorption bands (cm.sup.-1): at 2671
to 3327 and at 1468 to 1705 (FIG. 3).
[0030] According to a further embodiment of the present invention,
a process for the preparation of the novel polymorph V of
torasemide also comprises: [0031] (i) the preparation of a
polymorph II of torasemide according to a known process, [0032]
(ii) the dissolution of the polymorph II of torasemide in an
aqueous solution of a base, [0033] (iii) the filtration of the
obtained solution, [0034] (iv) a rapid acidification of the
obtained solution with an aqueous solution of an acid at
temperatures between 0.degree. C. and 35.degree. C., [0035] (v) the
filtration of the obtained suspension, [0036] (vi) washing the thus
obtained crystals of the novel polymorph V of torasemide with
demineralized water and drying them in a vacuum dryer during 3
hours at 50.degree. C., the obtained crystals being characterized
by the data represented in the previous process.
[0037] According to a further embodiment of the present invention,
a process for the preparation of the novel polymorph V of
torasemide also comprises: [0038] (i) the preparation of a
polymorph III of torasemide according to a known process, [0039]
(ii) the dissolution of the polymorph III of torasemide in an
aqueous solution of a base, [0040] (iii) the filtration of the
obtained solution, [0041] (iv) a rapid acidification of the
obtained solution with an aqueous solution of an acid at
temperatures between 0.degree. C. and 35.degree. C., [0042] (v) the
filtration of the obtained suspension, [0043] (vi) washing the thus
obtained crystals of the novel polymorph V of torasemide with
demineralized water and drying them in a vacuum dryer during 3
hours at 50.degree. C., the obtained crystals being characterized
by the data represented in the previous process.
[0044] According to a further embodiment of the present invention,
a process for the preparation of the novel polymorph V of
torasemide also comprises: [0045] (i) the preparation of an
amorphous torasemide modification according to a known process,
[0046] (ii) the dissolution of the amorphous torasemide
modification in an aqueous solution of a base, [0047] (iii) the
filtration of the obtained solution, [0048] (iv) a rapid
acidification of the obtained solution with an aqueous solution of
an acid at temperatures between 0.degree. C. and 35.degree. C.,
[0049] (v) the filtration of the obtained suspension, [0050] (vi)
washing the thus obtained crystals of the novel polymorph V of
torasemide with demineralized water and drying them in a vacuum
dryer during 3 hours at 50.degree. C., the obtained crystals being
characterized by the data represented in the previous process.
[0051] According to a further embodiment of the present invention,
a process for the preparation of the novel polymorph V of
torasemide also comprises: [0052] (i) the preparation of a novel
polymorph V of torasemide according to the process of the present
invention, [0053] (ii) the dissolution of the novel polymorph V of
torasemide in an aqueous solution of a base, [0054] (iii) the
filtration of the obtained solution, [0055] (iv) a rapid
acidification of the obtained solution with an aqueous solution of
an acid at temperatures between 0.degree. C. and 35.degree. C.,
[0056] (v) the filtration of the obtained suspension, [0057] (vi)
washing the thus obtained crystals of the novel polymorph V of
torasemide with demineralized water and drying them in a vacuum
dryer during 3 hours at 50.degree. C., the obtained crystals being
characterized by the data represented in the previous process.
[0058] According to a further embodiment of the present invention,
a process for the preparation of the novel polymorph V of
torasemide also comprises: [0059] (i) the preparation of polymorphs
I, II and III of torasemide according to known processes, the
preparation of an amorphous torasemide modification according to a
known process and the preparation of the novel polymorph V of
torasemide according to the process of the present invention,
[0060] (ii) the dissolution of any mixture of the polymorphs I, II
and III of torasemide, of the amorphous torasemide modification or
the novel polymorph V of torasemide in an aqueous solution of a
base, [0061] (iii) the filtration of the obtained solution, [0062]
(iv) a rapid acidification of the obtained solution with an aqueous
solution of an acid at temperatures between 0.degree. C. and
35.degree. C., [0063] (v) the filtration of the obtained
suspension, [0064] (vi) washing the thus obtained crystals of the
novel polymorph V of torasemide with demineralized water and drying
them in a vacuum dryer during 3 hours at 50.degree. C., the
obtained crystals being characterized by the data represented in
the previous process.
[0065] According to the present process, aqueous solutions of
lithium hydroxide, sodium hydroxide and potassium hydroxide as well
as aqueous solutions of sodium carbonate and potassium carbonate
may be used for the preparation of alkaline solutions of torasemide
modifications.
[0066] The acidification of alkaline torasemide solutions may,
according to the present process, be carried out with inorganic
acids such as hydrochloric, sulfuric, phosphoric and nitric acids,
and with organic acids such as formic, acetic, propionic, oxalic,
tartaric, methanesulfonic and p-toluenesulfonic acids.
[0067] It has also been established that at using the present
process no decomposition of torasemide takes place, i.e. a
chemically pure novel polymorph V of torasemide (TLC and HPLC) is
obtained.
[0068] It has been additionally established that under normal
storage conditions the novel polymorph V of torasemide is stable at
milling and pressing, i.e. it is not transformed into crystalline
modifications I, II and III of torasemide or into an amorphous
torasemide modification.
[0069] The novel polymorph V of torasemide prepared according to
the present process may be converted to crystalline modifications
I, II or III of torasemide or to an amorphous torasemide
modification according to conventional processes, i.e. it may serve
as a starting material for the preparation of well-known
crystalline modifications I, II or III of torasemide or an
amorphous torasemide modification.
[0070] The novel polymorph V of torasemide prepared according to
the present invention may be converted into pharmaceutically
acceptable salts of torasemide in a well-known manner.
[0071] The examination of the release (USP 24) of the novel
polymorph V of torasemide in water in comparison with the release
profile of known crystalline torasemide modifications in the same
medium revealed a slower release thereof. This makes the novel
polymorph V of torasemide suitable for the preparation of
pharmaceutical preparations having immediate or prolonged
action.
[0072] The novel polymorph V of torasemide prepared according to
the present process may be, as a suitable torasemide form, used as
a diuretic or 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.
[0073] The present invention also relates to pharmaceutical forms
such as tablets, capsules or injections containing an effective
amount of the novel polymorph V of torasemide as an active
ingredient, without or in combination with one or more
pharmaceutically acceptable additives such as sugar, starch, starch
derivatives, cellulose, cellulose derivatives, mould release
agents, and antiadhesive agents and, possibly, agents for
regulating flowability.
[0074] The present invention is illustrated by the following
non-limiting Examples.
EXAMPLE 1
[0075] The crystalline modification I of torasemide (1.0 g)
prepared according to Acta Cryst. B34 (1978) 1304-1310, was
dissolved in a 5% aqueous sodium hydroxide solution (3 ml) and then
at the temperature of 20.degree. C. the solution was acidified for
15 seconds with a 5% aqueous hydrochloric acid solution. The
crystals were sucked off, washed with demineralized water and
acetone and dried in a vacuum dryer for 3 hours at 50.degree. C. A
chemically pure novel polymorph V of torasemide (0.9 g), m.p.
153-155.degree. C. was obtained.
[0076] The characteristic DSC curve of the sample as shown in FIG.
1 was recorded on the apparatus Perkin-Elmer DSC7 at a heating rate
of 10.degree. C./minute.
[0077] The characteristic X-ray powder pattern as shown in FIG. 2
was recorded on the instrument PHILIPS PW3710 under Cu X-rays
[.lamda.(CuK.alpha..sub.1)=1.54046 .ANG. and
.lamda.(CuK.alpha..sub.2)=1.54439 .ANG.].
[0078] The characteristic IR spectrum of the sample as shown in
FIG. 3 was recorded in KBr on the IR-spectrophotometer
Nicolet-Magna 760.
EXAMPLE 2
[0079] The crystalline modification II of torasemide (1.0 g)
prepared according to Acta Cryst. B34 (1978) 1304-1310, was
dissolved in a 5% aqueous potassium hydroxide solution (3 ml) and
then at the temperature of 20.degree. C. the solution was acidified
for 15 seconds with a 10% aqueous acetic acid solution. The
crystals were sucked off, washed with demineralized water and
acetone and dried in a vacuum dryer for 3 hours at 50.degree. C. A
chemically pure novel polymorph V of torasemide (0.9 g), m.p.
153-155.degree. C. was obtained.
[0080] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 3
[0081] The crystalline modification III of torasemide (10.0 g)
prepared according to WO 00/20395, was dissolved in a 10% aqueous
sodium carbonate solution (30 ml) and then at the temperature of
20.degree. C. the solution was acidified for 60 seconds with a 5%
aqueous sulfuric acid solution. The crystals were sucked off,
washed with demineralized water and acetone and dried in a vacuum
dryer for 3 hours at 50.degree. C. A chemically pure novel
polymorph V of torasemide (8.1 g), m.p. 153-155.degree. C. was
obtained.
[0082] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 4
[0083] The amorphous torasemide modification (10.0 g) prepared
according to HR patent application P20000162A, was dissolved in a
10% aqueous potassium carbonate solution (30 ml) and then at the
temperature of 20.degree. C. the solution was acidified for 90
seconds with a 10% aqueous tartaric acid solution. The crystals
were sucked off, washed with demineralized water and acetone and
dried in a vacuum dryer for 3 hours at 50.degree. C. A chemically
pure novel polymorph V of torasemide (8.0 g), m.p. 153-155.degree.
C. was obtained.
[0084] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 5
[0085] The novel polymorph V of torasemide (10.0 g) according to
Example 3 of the present invention was dissolved in a 5% aqueous
lithium hydroxide solution (30 ml) and then at the temperature of
20.degree. C. the solution was acidified for 120 seconds with a 5%
aqueous phosphoric acid solution. The crystals were sucked off,
washed with demineralized water and acetone and dried in a vacuum
dryer for 3 hours at 50.degree. C. A chemically pure novel
polymorph V of torasemide (7.9 g), m.p. 153-155.degree. C. was
obtained.
[0086] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 6
[0087] A mixture (1.0 g) of crystalline modifications I and II of
torasemide prepared according to Acta Cryst. B34 (1978) 1304-1310,
was dissolved in a 10% aqueous sodium carbonate solution (3 ml) and
then at the temperature of 20.degree. C. the solution was acidified
for 15 seconds with a 5% aqueous p-toluenesulfonic acid solution.
The crystals were sucked off, washed with demineralized water and
acetone and dried in a vacuum dryer for 3 hours at 50.degree. C. A
chemically pure novel polymorph V of torasemide (0.9 g), m.p.
153-155.degree. C. was obtained.
[0088] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 7
[0089] A mixture (1.0 g) of crystalline modifications I and III of
torasemide prepared according to Acta Cryst. B34 (1978) 1304-1310
and WO 00/20395, was dissolved in a 5% aqueous sodium hydroxide
solution (3 ml) and then at the temperature of 20.degree. C. the
solution was acidified for 15 seconds with a 5% aqueous nitric acid
solution. The crystals were sucked off, washed with demineralized
water and acetone and dried in a vacuum dryer for 3 hours at
50.degree. C. A chemically pure novel polymorph V of torasemide
(0.9 g), m.p. 153-155.degree. C. was obtained.
[0090] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 8
[0091] A mixture (1.0 g) of crystalline modifications II and III of
torasemide prepared according to Acta Cryst. B34 (1978) 1304-1310
and WO 00/20395, was dissolved in a 5% aqueous potassium hydroxide
solution (3 ml) and then at the temperature of 20.degree. C. the
solution was acidified for 15 seconds with a 10% aqueous propionic
acid solution. The crystals were sucked off, washed with
demineralized water and acetone and dried in a vacuum dryer for 3
hours at 50.degree. C. A chemically pure novel polymorph V of
torasemide (0.9 g), m.p. 153-155.degree. C. was obtained.
[0092] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 9
[0093] A mixture (1.0 g) of crystalline modifications I, II and III
of torasemide prepared according to Acta Cryst. B34 (1978)
1304-1310 and WO 00/20395, was dissolved in a 5% aqueous lithium
hydroxide solution (3 ml) and then at the temperature of 20.degree.
C. the solution was acidified for 15 seconds with a 10% aqueous
oxalic acid solution. The crystals were sucked off, washed with
demineralized water and acetone and dried in a vacuum dryer for 3
hours at 50.degree. C. A chemically pure novel polymorph V of
torasemide (0.9 g), m.p. 153-155.degree. C. was obtained.
[0094] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 10
[0095] A mixture (1.0 g) of a crystalline modification I of
torasemide and an amorphous torasemide modification prepared
according to Acta Cryst. B34 (1978) 1304-1310 and HR patent
application P20000162A, was dissolved in a 10% aqueous sodium
carbonate solution (3 ml) and then at the temperature of 20.degree.
C. the solution was acidified for 15 seconds with a 5% aqueous
methanesulfonic acid solution. The crystals were sucked off, washed
with demineralized water and acetone and dried in a vacuum dryer
for 3 hours at 50.degree. C. A chemically pure novel polymorph V of
torasemide (0.9 g), m.p. 153-155.degree. C. was obtained.
[0096] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 11
[0097] A mixture (1.0 g) of a crystalline modification I of
torasemide and of the novel polymorph V of torasemide prepared
according to Acta Cryst. B34 (1978) 1304-1310 and according to
Example 1 of the present invention, was dissolved in a 10% aqueous
potassium carbonate solution (3 ml) and then at the temperature of
20.degree. C. the solution was acidified for 15 seconds with a 5%
aqueous hydrochloric acid solution. The crystals were sucked off,
washed with demineralized water and acetone and dried in a vacuum
dryer for 3 hours at 50.degree. C. A chemically pure novel
polymorph V of torasemide (0.9 g), m.p. 153-155.degree. C. was
obtained.
[0098] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 12
[0099] A mixture (10.0 g) of crystalline modifications I, II and
III of torasemide, of an amorphous torasemide modification and of
the novel polymorph V of torasemide prepared according to Acta
Cryst. B34 (1978) 1304-13 10, WO 00/20395, HR patent application
P20000162A and Example 1 of the present invention, was dissolved in
a 5% aqueous sodium hydroxide solution (30 ml) and then at the
temperature of 20.degree. C. the solution was acidified for 60
seconds with a 10% aqueous acetic acid solution. The crystals were
sucked off, washed with demineralized water and acetone and dried
in a vacuum dryer for 3 hours at 50.degree. C. A chemically pure
novel polymorph V of torasemide (8.0 g), m.p. 153-155.degree. C.
was obtained.
[0100] The IR spectrum of the sample thus obtained corresponded to
the IR spectrum of the novel polymorph V of torasemide obtained
according to Example 1.
EXAMPLE 13
[0101] The novel polymorph V of torasemide obtained according to
Example 1 of the present invention was subjected to testing the
release of the active substance in water at the temperature of
37.degree. C. (USP 24) and the results are given in Table 1.
TABLE-US-00001 TABLE 1 Release of the novel polymorph V of
torasemide in water (USP 24) (37.degree. C., 50 rpm, 1000 ml) Time
Released torasemide (min) (%) 0 0 15 11.3 30 20.5 45 26.0 60 30.0
90 36.0 120 40.7
* * * * *