Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-30
2004-05-18
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S305400
Reexamination Certificate
active
06737432
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a crystalline form of the sodium salt of telmisartan, processes for preparing it and the use thereof for preparing a pharmaceutical composition.
BACKGROUND OF THE INVENTION
Telmisartan is the nonproprietary name (NN, USAN and BAN) for 4′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid. It has the following chemical structure
and is known from European Patent EP 502 314 B1 and U.S. Pat. No. 5,591,762.
Telmisartan, and the physiologically acceptable salts thereof, have valuable pharmacological properties. Telmisartan is an angiotensin antagonist, particularly an angiotensin-II-antagonist which by virtue of its pharmacological properties may be used for example to treat hypertension and cardiac insufficiency, to treat ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), to prevent the progression of cardiac insufficiency after myocardial infarct, to treat diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases. Other possible therapeutic applications can be found in EP 502314 B1 and U.S. Pat. No. 5,591,762.
A pharmaceutical formulation comprising telmisartan as the active ingredient, Micardis® (telmisartan) Tablets, is commercially available. Starting from the free acid of telmisartan, the preparation in the form in which telmisartan is marketed is produced by a complex spray drying process. Because of the limited solubility of the free acid, less complex methods of preparing an alternative preparation are difficult to achieve.
Thus, one objective of the present invention is to find a less complex and easier means for preparing a crystalline form of telmisartan that would be suitable for use in the preparation of pharmaceutical formulations.
It has to be borne in mind that generally the production of a composition containing a pharmaceutically active substance is based on various parameters which are linked to the nature of the active ingredient itself. Without being tied thereto, examples of these parameters are the stability of effect of the starting material under different environmental conditions, the stability during the manufacture of the pharmaceutical formulation and the stability in the final compositions of the pharmaceutical preparation. The pharmaceutically active substance used to prepare the abovementioned pharmaceutical compositions should be as pure as possible and its stability on long-term storage must be guaranteed under various environmental conditions. This is absolutely essential, in order to prevent pharmaceutical compositions being used which contain, in addition to the active substance proper, breakdown products thereof. In such a case the content of active substance present in a preparation produced therefrom may be less than the specified amount.
Another aspect which is important in the production of solid preparations is that the active substance should have the most stable possible crystalline morphology for pharmaceutical quality. If this is not the case, the morphology of the active substance may change in certain circumstances under the conditions of manufacture of the preparation. Such a change may in turn affect the reproducibility of the manufacturing process and thus lead to final formulations which do not meet the high quality requirements imposed on formulations of pharmaceutical compositions. To this extent it should be generally borne in mind that any change to the solid state of a pharmaceutical composition which can improve its physical and chemical stability gives a significant advantage of less stable forms of the same drug.
Thus, a further object of the invention is to provide a new, stable, crystalline form of telmisartan which complies with the abovementioned stringent requirements imposed on pharmaceutically active substances.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has been found that telmisartan can be obtained in crystalline form, as the sodium salt of the below formula 1.
In accordance with conventions respecting the use of nonproprietary names, the telmisartan salt of formula 1 may be referred to as telmisartan sodium. Therefore, as used herein, the term “telmisartan sodium” is defined to mean the telmisartan salt of formula 1.
By a suitable choice of manufacturing conditions, the polymorphic form of the crystalline sodium salt which meets the requirements mentioned above can be obtained selectively.
This crystalline form of the sodium salt of telmisartan is characterised by having a melting point of T=245±5° C. (determined by DSC=Differential Scanning Calorimetry; heating rate: 10 K/min).
The present invention therefore relates to a crystalline form of telmisartan sodium that is characterised by having a melting point of T=245±5° C. (determined by DSC). The above value was obtained using a DSC821 made by Messrs Mettler-Toledo.
BRIEF DESCRIPTION OF THE DRAWING
The crystalline form of telmisartan sodium according to the invention was examined more closely by x-ray powder diffraction. The X-ray powder diagram obtained is shown in FIG.
1
.
The following Table 1 summarizes the data obtained in this x-ray powder diffraction analysis:
TABLE 1
2 &THgr; [°]
d [Å]
rel. intensity [%]
2 &THgr; [°]
d [Å]
rel. intensity [%]
3.54
24.96
7
13.17
6.72
7
4.21
20.95
100
13.68
6.47
7
4.45
19.83
20
14.36
6.16
10
4.98
17.72
54
14.98
5.91
13
5.69
15.52
8
15.51
5.71
14
6.32
13.97
34
15.70
5.64
12
6.48
13.63
35
16.21
5.46
8
7.12
12.41
12
17.09
5.18
10
7.49
11.80
11
17.48
5.07
9
8.08
10.93
4
18.10
4.90
9
8.49
10.41
6
19.18
4.62
11
8.96
9.86
7
19.43
4.56
13
9.50
9.31
5
19.95
4.45
11
10.19
8.68
5
20.89
4.25
11
10.80
8.18
8
21.29
4.17
10
11.16
7.92
18
22.19
4.00
9
11.88
7.44
7
23.07
3.85
10
12.51
7.07
7
23.76
3.74
9
12.79
6.92
11
24.43
3.64
8
In the above Table the value “2&THgr;[°]” denotes the angle of diffraction in degrees and the value “d [Å]” denotes the lattice plane spacings determined in Å.
According to the findings given in Table 1, the crystalline form of telmisartan sodium that constitutes the invention is characterised in that, when subjected to analysis by x-ray powder diffraction, it exhibits a characteristic set of d-spacings that includes values at d 20.95 Å, 17.72 Å, 13.97 Å and 13.63 Å.
The X-ray powder diagrams were recorded within the scope of the present invention using a Bruker D8 Advanced with an SSD (=site-sensitive detector) (CuK
&agr;
—radiation, &lgr;=1.5418 Å, 30 kV, 40 mA).
The present invention also comprises the solvates and hydrates of the above-described crystalline form of telmisartan sodium, especially the hydrates, most especially the hemihydrate thereof.
In another aspect, the present invention comprises a method of producing the crystalline form of telmisartan sodium according to the invention. The starting material used to prepare the crystalline telmisartan sodium according to the invention may be the free acid of telmisartan, which may be obtained by methods known in the art (e.g. according to EP 502314 A1 and U.S. Pat. No. 5,591,762).
To prepare the crystalline telmisartan sodium according to the invention the free acid of telmisartan is taken up in a suitable solvent, preferably in an organic aprotic solvent, most preferably in an organic, aprotic and non-polar solvent. The solvents used according to the invention are most preferably toluene, chloroform, dichloromethane, tetrahydrofuran, diethylether, diisopropylether, methyl-tert, butylether, acetone, methylisobutylketone, benzene or acetonitrile, of which toluene, benzene and methylisobutylketone are particularly preferred. Of outstanding importance according to the invention is toluene as solvent.
Preferably, between 0.5 and 5 ml, more preferably between 1 and 3 ml, most preferably between 1.5 and 2.5 ml of the abovementioned solvent are used per gram of telmisartan (free acid).
A suitable sodium salt i
Donsbach Kai
Hof Irmgard
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Pocchiari Susan K.
Raymond Robert P.
Stockton Laura L.
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