Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-01-17
2004-03-16
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S121000
Reexamination Certificate
active
06706710
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel form of a serotonin h5-HT
1B
-receptor antagonist, namely a novel form of a salt of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide referred to as (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A. The invention also relates to processes for production of said Form A, which form has a potential use after suitable pharmaceutical formulation in medical treatment.
PRIOR ART
[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide, both the (R)- and (S)-enantiomer and the racemate and their methods of preparation are disclosed in WO 99/05134.
BACKGROUND OF THE INVENTION
Various central nervous system disorders such as depression, anxiety, etc. appear to involve the disturbance of the neurotransmitters noradrenaline (NA) and/or 5-hydroxytryptamine(5-HT), the latter also known as serotonin. The drugs most frequently used in the treatment of depression are believed to act by improving the neurotransmission of either or both of these physiological agonists. It appears that the enhancement of 5-HT neurotransmission primarily affects the depressed mood and anxiety, whereas the enhancement of noradrenaline neurotransmission affects the retardation symptoms occurring in depressed patients.
Serotonin, or 5-HT, activity is thought to be involved in many different types of psychiatric disorders. For instance it is thought that an increase in 5-HT activity is associated with anxiety, while a decrease in 5-HT release has been associated with depression. Serotonin has in addition been implicated in such diverse conditions as eating disorders, gastrointestinal disorders, cardiovascular regulation and sexual behaviour.
The compound N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide (both enantiomers as well as the racemate) has an extremely low solubility in water and a slow release rate which rate is pH dependent, i.e. the rate is different in the stomach and the intestines. From a pharmaceutical formulation point of view it is very difficult to dissolve the base rapidly enough and maintain the same dissolved in the gastric juice until a sufficient amount of substance has been absorbed.
DISCLOSURE OF THE INVENTION
The object of the invention is a novel form of a salt of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide, namely (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A, which is a specific crystal modification of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide.
Another object of the invention is a process which reproducibly gives (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A. In addition it has been shown that (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide can crystallize in other crystalline forms, for example Form B.
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A is a crystal modification form of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide, which has several advantageous properties:
it has a satisfactory solubility in water;
it has a satisfactory thermal stability;
it is non-hygroscopic;
it has a good stability against light exposure.
It is predicted that these advantageous properties will lead to satisfactory chemical stability and long shelf life both for the pure substance and for pharmaceutical dosage forms containing (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A. Consequently, there may be fewer demands on packages, in particular on the water permeability and light transmission. Packages can thus be made of materials that are less complicated and more environmentally friendly, for instance blister packs can be made of transparent material so that the tablets can be visible and the total package is smaller than in the case of aluminium blister packs.
Characteristics of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A
The novel form of a salt of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide of the invention, i.e. (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A, can be distinguished from other forms by methods such as Powder X-ray diffractometry (XRPD).
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the invention thus provides (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A, preferably substantially crystallographically pure (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide Form A. A crystallographically pure form is a crystal modification that, as far as can be judged from XRPD measurements, contains no peaks from other crystal modifications. The term “substantially crystallographically pure (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A” should thus be understood as (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A containing only small amounts of any other crystalline form of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide; preferably not more than 10% and most preferably not more than 3%, of any other crystalline form of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide. The term “form” is in this context equivalent to the term “crystal modification”.
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A can be characterized by the X-ray powder diffraction pattern:
Form A
d-value
Relative
d-value
Relative
d-value
Relative
(Å)
intensity
(Å)
intensity
(Å)
intensity
11.7
vs
4.24
vw
3.09
w
10.9
s
4.16
vw
3.03
w
8.0
w
4.10
s
2.97
w
7.4
m
3.99
w
2.90
m
7.1
w
3.96
m
2.87
w
6.3
w
3.92
vs
2.82
vw
6.2
s
3.89
m
2.79
vw
5.9
s
3.83
m
2.74
w
5.8
vw
3.80
s
2.71
w
5.6
m
3.71
m
2.66
w
5.5
vw
3.67
m
2.64
vw
5.4
m
3.65
m
2.61
vw
5.3
vs
3.61
vw
2.58
vw
5.1
vw
3.57
vw
2.53
vw
5.1
m
3.54
w
2.48
vw
4.95
vs
3.50
m
2.41
vw
4.82
s
3.45
s
2.39
vw
4.71
w
3.39
m
2.38
vw
4.60
s
3.31
s
2.36
vw
4.56
vs
3.21
m
2.34
vw
4.45
vs
3.17
m
2.28
vw
4.28
vw
3.11
m
2.27
vw
Preparation of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A
In a further aspect, the invention relates to a process for the preparation of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A. (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A may be prepared under controlled conditions from a mixture of one or more organic solvents. It is preferred to use a mixture of organic solvents, which is miscible with water. The optimal ratio or organic solvents in the mixture to obtain (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A is strongly dependent on the characteristics of the chosen organic solvents and the proce
Bergström Per-Olov
Hedberg Martin
Lindström Mona
Ståhle Erica
AstraZeneca AB
Ramsuer Robert W.
White & Case LLP
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