Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-13
2004-03-09
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...
C548S304400, C548S310400
Reexamination Certificate
active
06703410
ABSTRACT:
TECHNICAL FIELD
The present invention relates to crystal forms of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide having hypoglycemic activity or a PDE5 inhibitory effect, and a method for manufacturing the same.
BACKGROUND ART
When a compound containing crystal polymorphs is used as a medicine, it is often necessary to produce a drug substance having a specific crystal form to guarantee the consistency of physicochemical and biological properties of the compound. Futhermore, in the process of manufacturing a drug substance, it is often important to separate out a particular form of crystal during the crystallization procedure, in order to maintain defined levels of the yield and purification efficiency.
3-(2,4-Dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide has been disclosed as a benzimidazole compound having hypoglycemic activity or PDE5 inhibitory effect in WO97/24334 (cf. Example 251). However, the existence of crystal polymorphs of this compound has not hitherto been recognized, nor has a substantially and crystallographically pure crystal of this compound having a particular form been obtained.
DISCLOSURE OF THE INVENTION
It is an object of this invention to provide a substantially and crystallographically pure crystal form of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide that is useful as a medicine, a method for manufacturing the same, and a medical composition comprising the same.
The present inventors studied various conditions for crystallizing 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide. As a result, they found three forms of crystals in this compound. Herein, these three crystal forms are referred to as crystal forms A, B and C. The inventors also discovered that crystal forms A and B have advantages over other crystal forms, respectively. That is, crystal form A is crystallographically more stable than crystal form B and C, though it forms smaller crystals. It is thus more easily obtainable as substantially and crystallographically pure crystals, which is favorable for maintaining the quality of a pharmaceutical preparation as a medicine. On the other hand, crystal form B, while not as crystallographically stable as crystal form A, forms larger crystals than crystal form A, so that it can be isolated with greater ease, by filtration, and efficiently purified, by crystallization.
Furthermore, the present inventors found that each crystal form can be obtained in a substantially pure crystallographic form and in an industrially stable manner, by using a crystallization method preferable for the respective form, thereby accomplishing the present invention.
Thus, this invention relates to
(1) a substantially and crystallographically pure crystal form of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide having the following X-ray powder diffraction values (2&thgr;), with an error range of ±0.2, in an X-ray powder diffraction assay using CuK&agr;-ray as a characteristic X-ray:
Angle 2&thgr;(°): about 4.7, about 9.5, about 10.5, about 15.6, and about 18.4; and
(2) a substantially and crystallographically pure crystal form of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide having the following X-ray powder diffraction values (2&thgr;), with an error range of ±0.2, in an X-ray powder diffraction assay using CuK&agr;-ray as a characteristic X-ray:
Angle 2&thgr;(°): about 4.4, about 8.9, and about 13.4.
The present invention also relates to a pharmaceutical composition comprising crystal form of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide described in (1) as an active ingredient. The present invention also relates to a pharmaceutical composition comprising crystal form of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentyl-sulfonyl)-3H-benzimidazole-5-carboxamide described in (2) as an active ingredient.
The present invention further relates to a process for producing crystal form (1) above, which comprises crystallization of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide from an organic solvent or a mixture of an organic solvent and water. The present invention also relates to a process for producing crystal form (2) above, which comprises crystallization of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide by adding acid to the solution of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide dissolved in an organic solvent or a mixture of an organic solvent and water in the presence of alkali.
As used herein, the term “substantially and crystallographically pure” means that other crystal forms are not analytically identifiable. In this context, analysis refers to at least one of powder X-ray diffraction, infrared spectrophotometry (IR) and thermogravimetry/differential thermal analysis (TG/DTA), which are described below.
Crystal form A of 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide (often referred to as Compound (I) hereafter) is characterized as having the following X-ray powder diffraction values (2&thgr;), with an error range of ±0.2, in an X-ray powder diffraction assay using CuK&agr;-ray as the characteristic X-ray:
Angle 2&thgr;(°): about 4.7, about 9.5, about 10.5, about 15.6, and about 18.4.
More specifically, for example, crystal form A shows the following diffraction values.
Angle
Relative intensity
2&thgr; (°)
I/Imax (%)
4.7
67
9.5
45
10.5
21
15.6
58
16.2
19
18.4
100
19.1
21
20.6
93
21.4
29
22.9
58
23.4
30
24.0
14
24.7
10
25.2
27
26.4
31
27.6
31
28.9
10
29.1
11
30.8
27
32.9
37
Crystal form B of Compound (I) is characterized as having the following X-ray powder diffraction values (2&thgr;), with an error range of ±0.2, in an X-ray powder diffraction assay using Cuk&agr;-ray as a characteristic X-ray:
Angle 2&thgr;(°): about 4.4, about 8.9, and about 13.4.
More specifically, for example, crystal form B shows the following diffraction values.
Angle
Relative intensity
2&thgr; (°)
I/Imax (%)
4.4
58
8.9
65
10.8
49
13.4
47
14.0
44
17.8
39
18.2
12
18.9
33
19.3
35
20.1
18
20.9
24
21.4
100
21.7
94
22.4
30
23.2
38
24.0
19
24.6
45
24.8
53
26.1
41
27.1
57
27.8
14
28.3
11
29.6
12
30.5
15
31.7
14
36.1
15
38.3
15
Furthermore, crystal form C of Compound (I) has the following X-ray powder diffraction values (2&thgr;), with an error range of ±0.2, in an X-ray powder diffraction assay using CuK&agr;-ray as a characteristic X-ray:
Angle
Relative intensity
2&thgr; (°)
I/Imax (%)
8.0
27
9.3
100
11.9
12
12.5
30
14.9
63
18.8
16
20.2
38
22.1
24
22.9
26
23.9
39
25.2
30
25.6
11
26.3
27
27.2
13
29.0
25
29.9
17
The X-ray powder diffraction values (2&thgr;) described above were determined using the following apparatus and conditions:
Apparatus: Rigaku RINT-1500 (Rigaku Denki Kogyo Inc.);
Characteristic X-ray: CuK&agr; rays (using a monochrometer);
Tube electric current/tube voltage: 40 kV/30 mA;
Detector: proportional counter;
Scanning speed: 2&thgr;=3°-40°; and
Slit system: divergence slit, 1°; scattering slit, 1°; receiving slit 0.3 mm.
Crystal forms A, B and C of Compound (I) can also be discriminated by IR spectra. The significantly different peaks in the absorption pattern for each crystal form in IR (KBr) spectra,determined by infrared spectrophotometric analysis (KBr disk method), are contrasted in the following table:
Crystal form A
Crystal form B
Crystal form C
(cm
−1
)
(cm
−1
)
(cm
−1
)
3553
1673
1692
1690
1513
1520
1518
1463
1497
1496
1449
1470
1465
1409
1454
1447
1384
1404
1408
1392
1345
1354
1348
1329
1337
1335
1318
1157
1163
1146
1145
1148
1113
1128
1114
892
892
882
870
880
865
842
868
849
850
836
833
The IR spectra shown above were obtained using the following apparatus and conditions described below.
Apparatus: PERKIN ELMER 1650 FT-IR (Perkin-Elmer, Japan);
Measuring method: KBr-disk method; and
Disk: 3 mm in diameter.
IR data for each crystal form, determine
Dohtsu Kunihiko
Imoto Takafumi
Murai Yoshiyuki
Nishikawa Masahiro
Yamasaki Noritsugu
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