U.S. patent application number 10/871667 was filed with the patent office on 2004-11-18 for crystal modification of torasemide.
This patent application is currently assigned to PLIVA HRVATSKA d.o.o.. Invention is credited to Danilovski, Aleksandar, Dumic, Miljenko, Filic, Darko, Fistric, Ines, Klepic, Bozena, Mikulcic, Jasna Horvat, Oresic, Marina.
Application Number | 20040229919 10/871667 |
Document ID | / |
Family ID | 10946825 |
Filed Date | 2004-11-18 |
United States Patent
Application |
20040229919 |
Kind Code |
A1 |
Filic, Darko ; et
al. |
November 18, 2004 |
Crystal modification of torasemide
Abstract
The present invention relates to the characterization of a new
crystal modification III of torasemide, to a process for the
preparation thereof by the use of controlled acidifying of alkaline
solutions of torasemide with inorganic or organic acids with or
without addition of a crystal seed, 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 this new crystal modification III
of torasemide.
Inventors: |
Filic, Darko; (Zagreb,
HR) ; Dumic, Miljenko; (Zagreb, HR) ;
Danilovski, Aleksandar; (Rijeka, HR) ; Klepic,
Bozena; (Jastrebarsko, HR) ; Fistric, Ines;
(Zagreb, HR) ; Oresic, Marina; (Sesvete, HR)
; Mikulcic, Jasna Horvat; (Zagreb, HR) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Assignee: |
PLIVA HRVATSKA d.o.o.
|
Family ID: |
10946825 |
Appl. No.: |
10/871667 |
Filed: |
June 21, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10871667 |
Jun 21, 2004 |
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10096277 |
Mar 13, 2002 |
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10096277 |
Mar 13, 2002 |
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09434439 |
Nov 5, 1999 |
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6399637 |
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09434439 |
Nov 5, 1999 |
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09187046 |
Nov 6, 1998 |
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Current U.S.
Class: |
514/347 ;
546/294 |
Current CPC
Class: |
A61K 31/44 20130101;
A61P 27/06 20180101; A61P 35/00 20180101; C07D 213/71 20130101;
C07D 213/74 20130101; C07D 213/53 20130101; A61P 9/10 20180101;
A61P 7/02 20180101; A61P 9/00 20180101; A61P 9/12 20180101; A61P
25/08 20180101; A61P 7/10 20180101; A61P 11/00 20180101; A61P 11/06
20180101 |
Class at
Publication: |
514/347 ;
546/294 |
International
Class: |
C07D 213/62; A61K
031/44 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 2, 1998 |
HR |
P980532A |
Claims
1. New crystal modification III of torasemide, characterized in
that the characteristic X-ray powder pattern of its sample is
represented by the following spacings between lattice planes:
7 New crystal modification III of torasemide d(.ANG.) 15.3898
12.5973 11.4565 9.7973 9.5493 8.6802 8.2371 7.6351 7.3356 6.9759
6.5351 6.3240 6.1985 5.9521 5.6237 5.5623 5.4040 5.1119 4.8738
4.7865 4.6986 4.5985 4.4602 4.3405 4.2552 4.1829 4.0768 3.9377
3.8659 3.8429 3.7801 3.7248 3.6239 3.5556 3.4825 3.4130 3.3055
3.2298 3.1786 3.1278 3.0699 3.0078 2.9549 2.9056 2.8541 2.7686
2.6988 2.6610 2.6293 2.5549 2.5236 2.4485 2.4161 2.3671 2.3133
2.2788 2.2312 2.1852 2.1468 2.0957 2.0617 2.0273 1.9896 1.9688
1.9274 1.8853 1.7931 1.7449 1.7169 1.6512 1.6122 1.5601 1.5320
1.5057 1.4521 1.3773
2. New crystal modification III of torasemide according to claim 1,
characterized in that in accordance with X-ray diffraction on its
sample monocrystal it is represented by the following basis
crystallographic data:
8 New crystal modification of Parameter torasemide crystal
composition monoclinic space group P 2.sub.1/c a (.ANG.) 11.430 b
(.ANG.) 19.090 c (.ANG.) 16.695 .beta. (.degree.) 93.903 V
(.ANG..sup.3) 3634.7 Z 4 .times. 2
3. New crystal modification III of torasemide according to claim 1,
characterized in that it is chemically pure.
4. New crystal modification III of torasemide according to claim 1,
characterized in that it does not contain water.
5. New crystal modification III of torasemide according to claim 1,
characterized in that it does not contain a solvent.
6. Process for the preparation of a new crystal modification III of
torasemide according to claim 1, characterized in that an alkaline
torasemide solution is subjected to controlled acidifying with
inorganic or organic acids with or without addition of a seed
crystal at a temperature between 0.degree. C. to 35.degree. C.
within 15 minutes to 25 hours.
7. Process for the preparation of a new crystal modification III of
torasemide according to claim 6, characterized in that as the
alkaline torasemide solution an alkaline extract of the original
reaction mixture for the synthesis of torasemide is used.
8. Process for the preparation of a new crystal modification III of
torasemide according to claim 6, characterized in that as the
alkaline torasemide solution an alkaline solution of any crystal
modification I, II or III of torasemide or an alkaline solution of
any mutual mixture of crystal modifications I, II or III of
torasemide is used.
9. Process according to claim 6, characterized in that for the
preparation of the alkaline torasemide solutions water solutions of
lithium, sodium and potassium hydroxide and water solutions of
sodium and potassium carbonate are used.
10. Process according to claim 6, characterized in that for
acidifying inorganic acids such as hydrochloric, sulfuric,
phosphoric or nitric acid or organic acids such as formic, acetic,
propionic, oxalic, tartaric, methanesulfonic or p-toluensulfonic
acid are used.
11. Process according to claim 6, characterized in that as the
crystal seed crystal powder of one of the isocrystallinic
substances is used, most preferably crystal powder of a crystal
modification III of torasemide.
12. A new crystal modification III of torasemide according to claim
1, characterized in that it is used as a raw material for the
preparation of crystal modification I of torasemide.
13. A new crystal modification III of torasemide according to claim
1, characterized in that it is used as a raw material for the
preparation of pharmaceutically acceptable salts of torasemide.
14. A new crystal modification III of torasemide according to claim
1, characterized in that it is used as a form of torasemide as a
diuretic, 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, for
decreasing 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.
15. A pharmaceutical form, characterized in that it contains as the
active ingredient the new crystal modification III of torasemide
according to claim 1 combined for this purpose with
pharmaceutically acceptable one or more carriers, additives or
diluents.
16. A pharmaceutical form according to claim 15, characterized in
that it is in tablet form.
Description
TECHNICAL FIELD
[0001] The present invention relates to a new crystal modification
of N-(1-methylethyl
aminocarbonyl)-4-(3-methyl-phenylamino)-3-pyridinesulfon- amide (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
[0002] 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.
[0003] 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, Wyvern
Cottage, 1996).
[0004] 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.
[0005] 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-Brandsttter, 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.
[0006] 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.
[0007] 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.degree. C. crystallizes monoclinically in the space group
P 2.sub.1/c (prisms), while the modification II with melting point
162.degree. C. crystallizes monoclinically in the space group P 2/n
(foils). Additionally, for the modification I the melting point
169.22.degree. C. is stated in Iyakuhin Kenkyu 25 (1994),
734-750.
[0008] According to Example 71 of DE 25 16 025 torasemide in a
crystal form with melting point 163-164.degree. C. is obtained.
[0009] In U.S. Pat. No. 4,743,693 and U.S. Pat. No. reissue 34,580
or US 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.degree. C. within 3 hours to 14 days. In U.S. Pat. No. 4,743,693
and US reissue 34,580 it is stated that the stable modification I
of torasemide (monoclinic, space group P2.sub.1/c) has a melting
point of 162.degree. C. and the unstable modification II of
torasemide (monoclinic, space group P 2/n) has a melting point
169.degree. 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.
[0010] In the abstract of U.S. Pat. No. 4,822,807 the authors
ascribe the melting point 162.degree. C. to the stable polymorph I
of torasemide and the melting point 169.degree. 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.degree. C. and for
polymorph II the melting point 162.degree. C.
[0011] In the abstract of U.S. Pat. No. reissue 34,672 the authors
ascribe the melting point 162.degree. C. to the pure modification I
of torasemide and the melting point 169.degree. C. to the
modification II of torasemide, whereas in the claims the melting
point 159-161.5.degree. C. for the pure polymorph I and the melting
point from about 157.5 to about 160.degree. C. for the unstable
polymorph II are stated.
SUMMARY OF INVENTION
[0012] 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.degree. C. within 15 minutes to 25
hours, a new crystal modification III of torasemide can be
prepared.
[0013] 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.
[0014] 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.
[0015] The acidifying of the alkaline torasemide solutions
according to the invention can be performed in inorganic acids such
as hydrochloric, sulfuric, phosphoric and nitric acids and in
organic acids such as formic, acetic, propionic, oxalic, tartaric,
methanesulfonic and p-toluenesulfonic acids.
[0016] As the seed crystal in the processes of the present
invention crystal powder of one of the isostructure substances,
particularly crystal powder of the crystal modification III of
torasemide can be used.
[0017] It has additionally been found that by using the process of
the present invention no decomposition of torasemide occurs and the
impurities that may be present in the alkaline extract of the
original reaction mixture for the synthesis of torasemide or in
modifications I, II or III of torasemide pass, by the present
process, into bases, i.e. a chemically pure crystal modification
III of torasemide is obtained.
[0018] Moreover, it has been found that the new crystal
modification III of torasemide is stable under normal storage
conditions as well as at being subjected to increased humidity,
which means that it is neither transformed into the unstable
modification II of torasemide nor into the stable modification I of
torasemide.
[0019] The new crystal modification III of torasemide has a
characteristic X-ray powder pattern obtained by X-ray diffraction
on a powder sample of the new crystal modification III of
torasemide in the instrument PHILIPS PW3710 under Cu X-rays
[.lambda. (CuK.alpha..sub.1)=1.54046 .ANG. and
.lambda.(CuK.alpha..sub.2)=1.54439 .ANG.]. Thus obtained
characteristic spacings between lattice planes designated by
)>d(< and expressed in Angstrom units and their corresponding
characteristic relative intensities designated by
>>I/I.sub.0<< and expressed in % are represented in
Table 1.
1TABLE 1 Modification III d(.ANG.) I/I.sub.0 (%) 15.3898 2.8
12.5973 5.4 11.4565 5.8 9.7973 69.8 9.5493 76.6 8.6802 28.5 8.2371
100.0 7.6351 10.2 7.3356 13.0 6.9759 1.2 6.5351 10.0 6.3240 7.9
6.1985 4.5 5.9521 0.6 5.6237 24.4 5.5623 29.7 5.4040 19.6 5.1119
10.3 4.8738 22.7 4.7865 46.9 4.6986 45.7 4.5985 17.9 4.4602 24.7
4.3405 90.0 4.2552 20.7 4.1829 19.9 4.0768 19.9 3.9377 47.1 3.8659
29.3 3.8429 35.3 3.7801 42.8 3.7248 11.9 3.6239 31.7 3.5556 20.5
3.4825 7.8 3.4130 8.1 3.3055 15.5 3.2298 8.2 3.1786 10.7 3.1278 5.6
3.0699 7.1 3.0078 17.5 2.9549 5.1 2.9056 4.3 2.8541 1.8 2.7686 13.9
2.6988 5.7 2.6610 6.3 2.6293 7.3 2.5549 3.7 2.5236 2.0 2.4485 5.3
2.4161 6.7 2.3671 2.0 2.3133 3.6 2.2788 7.6 2.2312 3.4 2.1852 6.2
2.1468 3.0 2.0957 4.7 2.0617 4.1 2.0273 3.3 1.9896 3.1 1.9688 4.1
1.9274 2.6 1.8853 2.7 1.7931 2.1 1.7449 1.0 1.7169 1.8 1.6512 1.0
1.6122 0.8 1.5601 0.8 1.5320 0.3 1.5057 0.5 1.4521 0.3 1.3773
0.6
[0020] In addition, by recording the monocrystal of the new crystal
modification III of torasemide in four circle PHILIPS PW
1100/Stoe&Cie diffractometer under Mo X-rays
[.lambda.(MoK.alpha.)=0.71073 .ANG.] there were obtained the basic
crystallographic data for a single cell, which show in comparison
with the literature data for crystal modifications I and II of
torasemide [Acta Cryst. B34 (1978), 2659-2662 and Acta Cryst. B34
(1978), 1304-1310] that this is an absolutely new crystal
modification III of torasemide.
[0021] The basic crystallographic data (diffraction on monocrystal)
for modifications I, II and the new crystal modification III of
torasemide are represented in Table 2.
2 TABLE 2 Crystal modification of torasemide Parameter I II III
crystal composition monoclinic monoclinic monoclinic space group P
2.sub.1/c P 2/n P 2.sub.1/c a (.ANG.) 13.308 20.446 11.430 b
(.ANG.) 8.223 11.615 19.090 c (.ANG.) 31.970 16.877 16.695 .beta.
(.degree.) 107.01 108.90 93.903 V (.ANG..sup.3) 3345.5 3791.9
3634.7 Z 4 .times. 2 4 .times. 2 4 .times. 2
[0022] The new crystal modification III of torasemide prepared
according to the process of the present invention can be
transformed by the use of common processes to the crystal
modification I of torasemide, i.e. it can be used as a starting
material for the preparation of known crystal modification I of
torasemide.
[0023] The new crystal modification III of torasemide prepared
according to the invention can be transformed to pharmaceutically
acceptable salts of torasemide by the use of common processes.
[0024] The dissolution profile (U.S. Pat. No. 23) of the new
crystal modification III of toresamide in water and in artificial
intestinal juice in comparison to dissolution profiles of known
crystal modifications I and II of toresamide, in the same fluids,
shows a significant difference.
[0025] IDR (Intrinsic Dissolution Rate) of the new crystal
modification III of torasemide in a model of artifical gastric
juice exceeds 1 mg cm.sup.-2min.sup.-1, which indicates a potential
good bioavailability.
[0026] The new crystal modification III of torasemide is prepared
according to the process of the present invention in the form of a
flowable crystal powder of a prismatic habitude, which exhibits
flowability, i.e. it comes in a "free flow" form, wherein no static
charge accumulation occurs.
[0027] The new crystal modification III of torasemide prepared
according to the process of the present invention can be used as a
suitable torasemide form as a diuretic as well 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, for decreasing 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 present invention also relates to pharmaceutical
forms such as tablets containing the new crystal modification III
of torasemide as the active ingredient combined 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 flowability
regulation. When using the new crystal modification III of
torasemide for the preparation of pharmaceutical forms, also
process steps taking place in water, e.g. granulation, can be
used.
[0028] The starting materials for the process of the present
invention i.e. the alkaline extract of the original reaction
mixture for torasemide synthesis can be prepared according to DE 25
16 025, whereas the modifications I and II of torasemide can be
prepared according to Acta Cryst. B34 (1978), 1304-1310.
SUMMARY OF DRAWINGS
[0029] FIG. 1 is a graph of dissolution tests of torasemide in
water.
[0030] FIG. 2 is a graph of dissolution tests of torasemide in
artificial intestinal juice.
BEST AND VARIOUS MODES FOR CARRYING OUT INVENTION
[0031] The present invention is illustrated but in no way limited
by the following Examples.
EXAMPLE 1
[0032] Technically pure new crystal modification III of
torasemide:
[0033] The original alkaline extract of the reaction mixture for
torasemide synthesis (1000 ml) prepared according to DE 25 16 025
was acidified with 10% aqueous acetic acid solution under the
addition of 1.4 g of a crystal modification III of torasemide. The
suspension was stirred at room temperature for 90 minutes. The
crystals were sucked off, washed with 1 litre of demineralized
water and dried in a vacuum dryer at 50.degree. C. for 3 hours.
There were obtained 125 g of a crystal modification III of
torasemide, m.p. 162-165.degree. C.
[0034] The X-ray powder pattern of the thus obtained sample
corresponded to the new crystal modification III of torasemide. The
content of torasemide according to the HPLC method was >99%.
EXAMPLE 2
[0035] The crystal modification III of torasemide (1000 g) prepared
according to the Example 1 was dissolved in a 10-fold amount of 5%
aqueous potassium hydroxide solution and at the temperature of
20.degree. C. the obtained solution was acidified with 5% aqueous
hydrochloric acid solution under the addition of 10 g of a crystal
modification III of torasemide. The suspension was stirred at
20.degree. C. for 120 minutes. The crystals were sucked off, washed
with 4 litres of demineralized water and dried in a vacuum dryer at
50.degree. C. for 3 hours. There were obtained 961 g of a
modification III of torasemide, m.p. 165.degree. C.
[0036] The X-ray powder pattern of the thus obtained sample
corresponded to the crystal modification III of torasemide. The
content of torasemide according to the HPLC method was >99.5%,
i.e. it corresponded to chemically pure torasermide.
EXAMPLE 3
[0037] The crystal modification I of torasemide (1.00 g) prepared
according to Acta Cryst. B34 (1978), 1304-1310 was dissolved in a
10-fold amount of 10% aqueous sodium carbonate solution and at the
temperature of 15.degree. C. the obtained solution was acidified
with 5% aqueous sulfuric acid solution under the addition of 0.10 g
of the modification III of torasemide. The suspension was stirred
at 15.degree. C. for 120 minutes. The crystals were sucked off,
washed with 4 ml of demineralized water and dried in a vacuum dryer
at 50.degree. C. for 3 hours. There were obtained 0.95 g of a
crystal modification III of torasemide, m.p. 165-166.degree. C.
[0038] The X-ray powder pattern of the thus obtained sample
corresponded to the crystal modification III of torasemide. The
content of torasemide according to the HPLC method was >99.5%,
i.e. it corresponded to chemically pure torasemide.
EXAMPLE 4
[0039] The crystal modification II of torasemide (1.00 g) prepared
according to Acta Cryst. B34 (1978), 1304-1310 was dissolved in a
10-fold amount of 10% aqueous pottasium carbonate solution and then
at the temperature of 15.degree. C. the obtained solution was
acidified with 5% aqueous ritric acid solution under the addition
of 0.10 g of a modification III of torasemide. The suspension was
stirred at 15.degree. C. for 120 minutes. The crystals were sucked
off, washed with 4 ml of demineralized water and dried in a vacuum
dryer at 50.degree. C. for 3 hours. There were obtained 0.96 g of a
crystal modification III of torasemide, m.p. 164-166.degree. C.
[0040] The X-ray powder pattern of the thus obtained sample
corresponded to the crystal modification III of torasemide. The
content of torasemide according to the HPLC method was >99.5%,
i.e.it corresponded to chemically pure torasemide.
EXAMPLE 5
[0041] A mixture of crystal modifications I and II of torasemide
(1.00 g) prepared according to Acta Cryst. B34 (1978), 1304-1310
was dissolved in a 10-fold amount of 10% aqueous lithium hydroxide
solution and then at room temperature the obtained solution was
acidified with 5% aqueous phosphoric acid solution under the
addition of 0.10 g of a modification III of torasemide. The
suspension was stirred at 15.degree. C. for 240 minutes. The
crystals were sucked off, washed with 4 ml of demineralized water
and dried in a vacuum dryer at 50.degree. C. for 3 hours. There
were obtained 0.97 g of a crystal modification III of torasemide,
m.p. 165-166.degree. C.
[0042] The X-ray powder pattern of the thus obtained sample
corresponded to the crystal modification III of torasemide. The
content of torasemide according to the HPLC method was >99.5%,
i.e. it corresponded to chemically pure torasemide.
EXAMPLE 6
[0043] A mixture of crystal modifications I and III of torasemide
(1.00 g) prepared according to Acta Cryst. B34 (1978), 1304-1310
and Example 1 was dissolved in a 10-fold amount of 5% aqueous
potassium hydroxide solution and then at the temperature of
30.degree. C. the obtained solution was acidified with 10% aqueous
tartaric acid solution under the addition of 0.10 g of a
modification III of torasemide. The suspension was stirred at
30.degree. C. for 180 minutes. The crystals were sucked off, washed
with 4 ml of demineralized water and dried in a vacuum dryer at
50.degree. C. for 3 hours. There were obtained 0.93 g of a crystal
modification III of torasemide, m.p. 164-166.degree. C.
[0044] The X-ray powder pattern of the thus obtained sample
corresponded to the crystal modification III of torasemide. The
content of torasemide according to the HPLC method was >99.5%,
i.e. it corresponded to chemically pure torasemide.
EXAMPLE 7
[0045] A mixture of crystal modifications II and III of torasemide
(1.00 g) prepared according to Acta Cryst. B34 (1978), 1304-1310
and Example 1 was dissolved in a 10-fold amount of 5% aqueous
sodium hydroxide solution and then at the temperature of 35.degree.
C. the obtained solution was acidified with 5% aqueous propionic
acid solution under the addition of 0.10 g of a modification III of
torasemide. The suspension was stirred at 35.degree. C. for 90
minutes. The crystals were sucked off, washed with 4 ml of
demineralized water and dried in a vacuum dryer at 50.degree. C.
for 3 hours. There were obtained 0.87 g of a crystal modification
III of torasemide, m.p. 165.degree. C.
[0046] The X-ray powder pattern of the thus obtained sample
corresponded to the crystal modification III of torasemide. The
content of torasemide according to the HPLC method was >99.5%,
i.e. it corresponded to chemically pure torasemide.
EXAMPLE 8
[0047] A mixture of crystal modifications I, II and III of
torasemide (1.00 g) prepared according to Acta Cryst. B34 (1978),
1304-1310 and Example 1 was dissolved in a 10-fold amount of 10%
aqueous sodium carbonate solution and then at the temperature of
25.degree. C. the obtained solution was acidified with 5% aqueous
p-toluenesulfonic acid solution under the addition of 0.10 g of a
modification. III of torasemide. The suspension was stirred at
25.degree. C. for 60 minutes. The crystals were sucked off, washed
with 4 ml of demineralized water and dried in a vacuum dryer at
50.degree. C. for 3 hours. There were obtained 0.93 g of a crystal
modification III of torasemide, m.p. 164-166.degree. C.
[0048] The X-ray powder pattern of the thus obtained sample
corresponded to the crystal modification III of torasemide. The
content of torasemide according to the HPLC method was >99.5%,
i.e. it corresponded to chemically pure torasemide.
EXAMPLE 9
[0049] A crystal modification I of torasemide (1.00 g) prepared
according to Acta Cryst. B34 (1978), 1304-1310 was dissolved in a
10-fold amount of 10% aqueous potassium carbonate solution and then
at the temperature of 15.degree. C. the obtained solution was
stepwise acidified with 10% aqueous acetic acid solution under the
simultaneous stepwise lowering of the temperature of the mixture to
0.degree. C. At this temperature the suspension was stirred for 25
hours. The crystals were sucked off, washed with 4 ml of
demineralized water and dried in a vacuum dryer at 50.degree. C.
for 3 hours. There were obtained 0.94 g of a crystal modification
III of torasemide, m.p. 164-166.degree. C.
[0050] The X-ray powder pattern of the thus obtained sample
corresponded to the crystal modification III of torasemide. The
content of torasemide according to the HPLC method was >99.5%,
i.e. it corresponded to chemically pure torasemide.
EXAMPLE 10
[0051] Production of 2.5 mg tablets:
[0052] Torasemide of the crystal modification III was mixed with
lactose and corn starch in a common manner, granulated with water,
dried and sieved (granulate 1). Colloidal silicon dioxide and
magnesium stearate were mixed, sieved and admixed into granulate 1.
This mixture was then tabletized in a common manner. For the
production of 100 000 tablets the following is required:
3 torasemide-crystal modification III 0.25 kg lactose (Lactose
Extra Fine Crystal HMS .RTM.) 6.05 kg corn starch (Starch .RTM.)
1.60 kg colloidal silicon dioxide (Aerosil 200 .RTM.) 60.00 g
magnesium stearate 40.00 g redistilled water 1.20 kg
EXAMPLE 11
[0053] Production of 100 mg tablets:
[0054] Torasemide of crystal modification III was mixed with
lactose and corn starch and a part of magnesium stearate in a
common manner. The mixture was compressed and sieved to obtain the
desired grain size and distribution of grain size (granulate 1).
Colloidal silicon dioxide and magnesium stearate were mixed, sieved
and admixed into granulate 1. This mixture was then tabletized in a
common manner. For the production of 100 000 tablets the following
is required:
4 torasemide-crystal modification III 10.0 kg lactose (Lactose
Extra Fine Crystal HMS .RTM. 2.0 kg corn starch (Starch .RTM.) 7.7
kg colloidal silicon dioxide (Aerosil 200 .RTM.) 0.2 kg magnesium
stearate 0.1 kg
EXAMPLE 12
[0055] The microcrystallinic modifications I, II and III of
torasemide prepared according to Acta Crst. B34 (1978), 1304-1310
and Example 1 were subjected to dissolution testing in water, and
in artificial intestinal juice, at 37.degree. C. (U.S. Pat. No.
23), and results are reported in tables 3 and 4.
5TABLE 3 Dissolution test of torasemide in water (USP 23)
(37.degree. C., 50 rpm., 1000 ml) % Dissolved torasemide Minutes
Mod. I Mod. II Mod. III 0 0 0 0 10 6.7 15.1 15.6 20 13.0 27.8 28.1
30 18.5 39.2 37.7 40 23.5 48.8 43.6 50 28.5 56.3 48.5 60 32.8 65.1
51.1
[0056]
6TABLE 4 Dissolution test of torasemide in artificial intestinal
juice (USP 23) (37.degree. C., 50 rpm, pH 7.5, 1000 ml) % Dissolved
torasemide Minutes Mod. I Mod. II Mod. III 0 0 0 0 10 29.4 73.3
41.0 20 40.5 92.6 59.8 30 48.4 95.5 70.2 40 54.2 96.8 77.6 50 59.2
96.3 82.5 60 65.0 98.2 88.7
[0057] The results reported in Table 3 were plotted in the FIG. 1.
The results reported in Table 4 were plotted in FIG. 2.
* * * * *