Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-12
2004-10-05
Powers, Fiona T. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06800761
ABSTRACT:
The present invention relates to a novel crystal habit of 2-n-butyl-4-spirocyclopentane-1-[(2′-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one of formula:
This compound and its method of preparation were disclosed for the first time in European patent EP 454 511. The compound of formula (I) is an angiotensin II antagonist which is useful in the treatment of cardiovascular diseases such as hypertension, cardiac insufficiency, cardiac arrhythmia, in the treatment of diseases of the central nervous system, in the treatment of glaucoma and diabetic retinopathy and in the treatment of renal insufficiency and diabetic nephropathy.
The common name of the compound of formula (I) is irbesartan and the term irbesartan is used in this description and in the claims to refer to the compounds of formula (I).
European patent application EP 708 103 discloses the existence of 2 crystalline forms of irbesartan:
one, known as form A, is the one obtained by crystallization in a solvent containing less than about 10% by volume of water,
the other, known as form B, is obtained by crystallization in a water-miscible solvent containing more than about 10% water.
Each of these two forms is characterized by a specific X-ray diffraction profile.
Patent application EP 708 103 discloses that form B is a tautomeric form.
Patent application EP 708 103 indicates that irbesartan in the form A is in the form of stable, non-hygroscopic needles of high electrostatic nature. Hereinbelow in the present description, the term “acicular habit” denotes this crystalline form of the irbesartan form A.
It also been found that these crystals of acicular habit are difficult to filter and to dry and that they display poor flowability.
A novel crystal habit of the form A has now been found, characterized in that the ratio between the length and the width of the crystals is between 1:1 and 10:1, preferably between 1:1 and 5:1. This novel crystal habit of the form A of irbesartan will be defined by the term “brick habit” of irbesartan hereinbelow in the present description.
A subject of the present invention is also processes for obtaining irbesartan crystals of form A which have the novel crystal habit according to which the ratio between the length and the width of the crystals is between 1:1 and 10:1, preferably between 1:1 and 5:1.
The higher this ratio, the longer are the needles relative to their width, and thus an improvement in this ratio means a decrease of the said ratio. It is preferable for this ratio to decrease such that it is between 1:1 and 10:1, preferably between 1:1 and 5:1.
The improvement of this ratio means that the crystals have less of a tendency to break or to aggregate when they are wet, they can be filtered and dried faster, and they are easier to handle when they are dry.
The processes according to the invention have no effect on the polymorphism.
The irbesartan crystals in the brick habit have the physicochemical characteristics described below.
The powder X-ray diffraction profile (diffraction angle) was established with a Siemens D 550 TT diffractometer, and the significant lines are given in Table I below:
TABLE I
d
I/I
0
11.22
100.00
7.90
12.02
7.52
13.79
7.23
18.60
6.27
20.14
6.09
6.47
5.86
7.42
5.60
98.76
5.41
19.45
5.05
24.67
4.97
20.36
4.91
12.92
4.80
27.33
4.61
15.90
4.49
14.73
4.36
9.86
4.17
62.84
4.07
15.39
3.97
30.34
3.88
14.32
3.83
13.56
3.75
37.28
3.53
26.48
3.46
12.42
3.40
27.88
3.27
11.03
3.18
10.42
3.15
7.28
3.12
6.11
3.05
15.50
3.01
9.49
2.81
7.11
2.78
9.40
This diffraction profile is that of the form A of irbesartan disclosed in EP 708 103.
The chargeability of the powder is measured by tribogeneration: the powder is subjected to a strong vibration during which it becomes charged on itself, and is then transferred into a Faraday cage connected to a very sensitive electrometer. The chargeability measured varies between 0 and −10 nanocoulomb/g. By way of comparison, the crystals of irbesartan in acicular form A have a chargeability, measured by the same process, of between −30 and −40 nanocoulomb/g.
The packing density of the irbesartan crystals having the new crystal habit, measured using a Hosokawa machine (180 gravity drops), is about 0.5 kg m
3
, whereas that of the crystals of the acicular form A is about 0.35 kg/M
3
.
The flowability index is calculated by the Carr method (R. Carr: Chemical Engineering, Jan. 18, 1965, page 163-168) and takes into account the results of four experimental values: compressibility, angle of repose, spatula angle and cohesion. This index is about 30 for the crystals of brick habit, whereas it is about 10 for the crystals of acicular habit.
It is found that the resistivity, the minimum inflammation energy, the minimum inflammation temperature, the results of the friction test and gravity of the explosion, measured in a 20-liter sphere, are similar for the two crystal habits of the form A of irbesartan.
The fact that the irbesartan crystals of brick habit are of reduced chargeability, i.e. they have a reduced tendency to store electrostatic charges, means that these crystals can be handled more easily and more safely.
The 50% increase in the packing density and in the flowability index of the brick habit with respect to the acicular habit represents an improvement which is reflected both in the chemical processability of the product and in their use for their preparation of pharmaceutical forms.
According to the present invention, the irbesartan of brick habit can be prepared using a process characterized in that a crystalline suspension of irbesartan of acicular habit form A is subjected to at least one sonication episode and at least one temperature oscillation episode.
Thus, the sonication episode can be either followed or preceded by the temperature oscillation episode.
It is also possible to envisage the sonication episode being carried out simultaneously with the temperature oscillation episode. According to the invention, a sonication episode can also be carried out between 2 phases of temperature oscillation.
Furthermore, the sonication and/or temperature oscillation episodes can be repeated independently of each other.
Preferably, a sonication episode is preceded by a temperature oscillation episode and more particularly a sonication episode is carried out between 2 temperature oscillation episodes.
The term “crystalline suspension” used in the present description refers to an irbesartan suspension prepared according to methods that are known to those skilled in the art. For example, the crystalline suspension can be prepared by growing irbesartan crystals in an organic solvent, for example an alcohol such as isopropanol, to prepare a supersaturated irbesartan solution, and cooling to a temperature at which the supersaturation is between 0% and 50%. The supersaturated solution is then seeded with 1% to 10% of irbesartan seed crystals of brick habit, the seed crystals originating from a previous batch. However, the seeds may also be generated by repeatedly subjecting the crystalline suspension to temperature oscillation and sonication episodes until crystals of brick habit are obtained. The seeded solution is then cooled to room temperature to form the crystalline suspension. The said crystalline suspension is then used according to the invention.
According to the present invention, a sonication episode consists in subjecting the crystalline suspension to a sonication energy whose frequency is from about 16 kHz to 10 MHz. It appears that the sonication episode limits the growth according to the length of the needles by breaking them and modifies the nature of the crystal surfaces such that the zones capable of accumulating the electrostatic charges are reduced. Sonication methods may be used either batchwise or semi-continuously or continuously.
For the batchwise sonication, an ultrasound probe is inserted into the crystalline suspension placed in a crystallizer.
The sonication episode can also be carried out continuously or semi-continuously by pumping the crystalline irbesartan suspension through
Franc Bruno
Hoff Christian
Kiang San
Lindrud Mark D.
Monnier Olivier
Alexander Michael D.
Dupont Paul E.
Powers Fiona T.
Sanofi-Synthelabo
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