US2022023268A1PendingUtilityA1
Crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid for the treatment of disease
Est. expirySep 25, 2026(~0.2 yrs left)· nominal 20-yr term from priority
A61P 21/00A61P 27/02A61P 25/00A61P 5/14C07D 271/06A61P 5/16A61P 9/10A61P 7/00A61P 37/02A61P 9/00A61P 3/10A61P 25/16A61K 31/4245A61P 43/00A61P 27/16A61P 3/06A61P 29/00A61P 19/02A61P 19/08A61P 35/00A61P 33/00A61P 3/04A61P 13/12A61P 11/00A61P 35/02A61P 37/00A61P 7/04A61P 37/06A61P 25/28A61P 3/00
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Claims
Abstract
The present invention relates to crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, pharmaceutical compositions and dosage forms comprising the crystalline forms, methods of making the crystalline forms and methods for their use for the treatment, prevention or management of diseases ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form A crystals characterized by at least one of the following:
(a) unit cell parameters when measured at 150 K: a=24,220 Å; b=3, 74640 Å; c=27, 4678 Å; α=90°; β=92, 9938°; γ=90°; V=2489, 38(17) Å 3 ; Z=8; calculated density (d calc , g cm −3 ) is 1,517 g cm −3 ; and the space group is P2 1 /n (no. 14); (b) an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2), when measured using Cu Kα radiation, selected from the group consisting of:
4.96
6.39
10.10
11.54
12.62
12.81
13.92
14.16
14.55
14.88
15.07
15.58
16.27
16.61
18.74
18.94
19.28
19.94
20.27
20.74
20.97
21.22
21.93
22.58
22.80
23.00
23.79
24.14
24.46
25.44
25.64
26.07
26.34
26.74
27.06
27.79
28.42
29.09
30.48
(c) a thermogravimetric analysis thermogram which has a mass loss of less than 1% of the total mass of the sample upon heating from 33° C. to 205° C.;
(d) a differential scanning calorimetry thermogram which has an endothermic event with a peak temperature at 244° C.; and
(e) fractional atomic coordinates equal to the following coordinates:
Átom
x
y
z
U(Å 2 )
F(122)
0.43198(12)
0.7655(8)
−0.17546(10)
0.0487(10)
F(222)
−0.20343(15)
0.7129(10)
0.06378(14)
0.0781(14)
O(13)
0.42977(13)
0.4875(8)
−0.08927(11)
0.0324(10)
O(23)
−0.12941(13)
0.4507(9)
0.12653(12)
0.0402(10)
O(151)
0.25519(13)
0.4795(9)
0.10765(12)
0.0382(10)
O(152)
0.29215(13)
0.2155(9)
0.17515(12)
0.0403(10)
O(251)
0.16226(13)
0.4813(9)
0.15012(12)
0.0385(10)
O(252)
0.19645(13)
0.1939(9)
0.21659(12)
0.0393(10)
N(11)
0.35817(15)
0.5856(9)
−0.04386(14)
0.0279(10)
N(14)
0.44373(16)
0.3409(10)
−0.04263(14)
0.0327(12)
N(21)
−0.04134(16)
0.5165(9)
0.11065(14)
0.0305(12)
N(24)
−0.09772(17)
0.3201(11)
0.16787(15)
0.0388(14)
C(12)
0.37827(18)
0.6256(11)
−0.08637(17)
0.0266(14)
C(15)
0.40019(19)
0.4091(11)
−0.01823(17)
0.0261(14)
C(22)
−0.0926(2)
0.5601(12)
0.09502(18)
0.0319(15)
C(25)
−0.0471(2)
0.3690(11)
0.15580(17)
0.0302(15)
C(121)
0.35225(19)
0.7961(11)
−0.12930(17)
0.0291(14)
C(122)
0.3784(2)
0.8567(12)
−0.17244(18)
0.0345(15)
C(123)
0.3519(2)
1.0117(12)
−0.21257(19)
0.0407(17)
C(124)
0.2973(2)
1.1101(13)
−0.21014(19)
0.0416(17)
C(125)
0.2694(2)
1.0543(12)
−0.1677(2)
0.0409(17)
C(126)
0.2966(2)
0.8996(12)
−0.12784(18)
0.0349(15)
C(151)
0.39702(19)
0.3013(11)
0.03319(16)
0.0260(14)
C(152)
0.34897(19)
0.3623(11)
0.05704(16)
0.0261(15)
C(153)
0.34631(18)
0.2594(11)
0.10554(16)
0.0253(14)
C(154)
0.39150(19)
0.0970(11)
0.13029(17)
0.0279(14)
C(155)
0.43977(19)
0.0412(11)
0.10614(17)
0.0291(15)
C(156)
0.44250(19)
0.1421(11)
0.05765(17)
0.0292(15)
C(157)
0.2955(2)
0.3188(12)
0.13209(18)
0.0312(15)
C(221)
−0.1109(2)
0.7083(12)
0.04727(19)
0.0388(17)
C(222)
−0.1643(3)
0.7823(15)
0.0331(2)
0.053(2)
C(223)
−0.1825(3)
0.9272(15)
−0.0122(3)
0.064(2)
C(224)
−0.1415(4)
0.9930(16)
−0.0433(3)
0.068(3)
C(225)
−0.0870(3)
0.9202(15)
−0.0316(2)
0.066(2)
C(226)
−0.0678(3)
0.7766(12)
0.01365(17)
0.0543(19)
C(251)
0.00110(19)
0.2695(11)
0.18877(17)
0.0300(15)
C(252)
0.05426(19)
0.3352(11)
0.17481(17)
0.0289(15)
C(253)
0.09949(19)
0.2449(11)
0.20524(17)
0.0277(15)
C(254)
0.0919(2)
0.0940(11)
0.25087(17)
0.0296(15)
C(255)
0.0389(2)
0.0335(11)
0.26491(17)
0.0300(15)
C(256)
−0.0064(2)
0.1185(12)
0.23430(17)
0.0322(15)
C(257)
0.1559(2)
0.3165(12)
0.18902(17)
0.0305(15)
H(123)
0.371
1.050
−0.241
0.048
H(124)
0.278
1.217
−0.238
0.050
H(125)
0.232
1.123
−0.166
0.049
H(126)
0.278
0.862
−0.099
0.042
H(151)
0.227
0.491
0.125
0.057
H(152)
0.318
0.473
0.041
0.031
H(154)
0.389
0.025
0.163
0.033
H(155)
0.471
−0.066
0.123
0.035
H(156)
0.475
0.103
0.041
0.035
H(223)
−0.220
0.975
−0.020
0.077
H(224)
−0.151
1.094
−0.074
0.082
H(225)
−0.061
0.969
−0.055
0.080
H(226)
−0.030
0.729
0.021
0.065
H(252)
0.226
0.213
0.202
0.059
H(254)
0.123
0.034
0.272
0.035
H(255)
0.033
−0.068
0.296
0.036
H(256)
−0.043
0.074
0.244
0.039
H(25A)
0.060
0.443
0.144
0.035
wherein the process comprises:
(1) crystallizing Form A from a solvent; or
(2) exposing a Form B crystal to a relative humidity of 79% at 60° C.; or
(3) milling a Form B crystal at ambient or sub-ambient temperature; or
(4) slurrying a Form B crystal in methyl isobutyl ketone, or a 1:1 mixture of dioxane and water; or
(5) subliming or heating a Form B crystal.
2 . The process of claim 1 , wherein crystallizing Form A from a solvent comprises:
(a) crystallizing Form A from methanol, t-butanol, 1-butanol, acetonitrile, isopropyl alcohol (IPA), isopropyl ether, dimethyl formamide, heptane, isopropyl acetate, toluene or water; (b) crystallizing Form A by slow evaporation from acetonitrile; t-butanol; isopropyl alcohol; or isopropyl ether; or (c) crystallizing Form A by fast evaporation from 1-butanol; dimethoxyether; t-butanol; a mixture of dimethyl formamide and water; isopropyl ether; or a mixture of t-butanol:water (in a 3:2 ratio), 1 molar equivalent methanol and 1 molar equivalent sodium chloride.
3 . The crystal form produced by the process of claim 1 , wherein said crystal form is physically stable: (1) when stored for six days at one or more of the following relative humidity conditions: 53% relative humidity at 40° C.; 75% relative humidity at 40° C.; 50% relative humidity at 60° C. or 79% relative humidity at 60° C., (2) when milled at ambient and at sub-ambient temperatures, or (3) when slurried at one or more of the following conditions: in 1-BuOH for four days at ambient temperature, in chloroform for two days at 50° C. or in dichloromethane for two days at 50° C.
4 . The crystal form produced by the process of claim 2 , wherein said crystal form is physically stable: (1) when stored for six days at one or more of the following relative humidity conditions: 53% relative humidity at 40° C.; 75% relative humidity at 40° C.; 50% relative humidity at 60° C. or 79% relative humidity at 60° C., (2) when milled at ambient and at sub-ambient temperatures, or (3) when slurried at one or more of the following conditions: in 1-BuOH for four days at ambient temperature, in chloroform for two days at 50° C. or in dichloromethane for two days at 50° C.
4 . A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form B crystals characterized by at least one of the following:
(a) an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2), when measured using Cu Kα radiation, selected from the group consisting of:
6.14
6.39
6.96
7.92
10.78
12.44
12.61
12.88
13.52
13.78
13.97
14.30
15.46
15.68
15.89
16.33
16.76
17.03
20.10
21.03
23.34
23.86
24.18
24.42
24.64
26.62
26.96
27.29
27.64
27.96
28.81
31.05
32.38
32.58
36.23
37.81
38.28
38.44
39.16
(b) a thermogravimetric analysis thermogram which has a mass loss of less than 5% of the total mass of the sample upon heating from 25° C. to 165° C.; and
(c) a differential scanning calorimetry thermogram which has an endothermic event with a peak temperature at 243° C.,
wherein the process comprises heating Form A in 1-propanol.
6 . The crystal form produced by the process of claim 5 , wherein said crystal form is physically stable: (1) upon storage for six days at one or more of the following relative humidity conditions: 53% relative humidity at 40° C., 75% relative humidity at 40° C. or 50% relative humidity at 60° C., (2) when under compression alone, (3) when under compression in the presence of a 1:1 mixture of t-BuOH and water, or (4) when slurried for 1 day at ambient temperature in THF:heptane (1:1).
7 . A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form B crystals characterized by an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2) (shifted 1), when measured using Cu Kα radiation, selected from the group consisting of:
6.42
7.00
7.89
10.85
12.61
12.92
13.47
13.97
15.81
16.45
17.12
20.05
21.05
23.92
24.28
27.00
27.39
27.84
28.04
28.94
31.10
32.58
36.11
37.71
38.15
38.61
wherein the process comprises slurrying Form A in 1-butyl acetate.
8 . A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form B crystals characterized by an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2) (shifted 2), when measured using Cu Kα radiation, selected from the group consisting of:
6.10
6.38
6.54
7.10
8.02
10.91
12.71
13.50
13.62
13.86
14.10
15.56
15.70
15.91
16.55
16.96
17.22
17.50
19.82
20.08
20.34
21.15
23.78
23.93
24.38
24.56
26.88
27.16
27.48
27.88
28.04
28.78
29.02
32.71
36.01
38.10
38.56
39.38
wherein the process comprises slurrying a mixture of the crystal form and Form A in a 1:1 mixture of tetrahydrofuran:heptanes with heating.
9 . A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form B crystals characterized by an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2) (shifted 3), when measured using Cu Kα radiation, selected from the group consisting of:
1.79
2.30
2.57
2.78
3.29
3.59
3.89
4.07
4.34
4.49
4.76
5.06
6.47
6.91
7.96
10.89
12.87
13.58
13.99
15.97
16.48
17.10
20.00
20.36
21.04
23.40
24.29
24.89
26.87
27.49
27.80
28.07
29.08
38.61
wherein the process comprises storing the crystal form in 75% relative humidity at 40° C.
10 . A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form B crystals characterized by an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2) (shifted 3), when measured using Cu Kα radiation, selected from the group consisting of:
6.22
6.51
7.13
8.17
10.91
12.87
13.80
14.12
14.28
15.78
16.23
16.54
17.15
20.33
21.22
21.36
23.94
24.30
27.30
27.58
28.00
28.74
28.96
32.70
36.74
38.18
38.38
38.52
39.31
wherein the process comprises crystallizing the crystal form by slow evaporation from dimethoxy ether.
11 . A pharmaceutical composition comprising a crystal form obtainable by the process of claim 1 , and optionally one or more carriers, excipients or diluents.
12 . The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is for oral, mucosal, parenteral, transdermal or topical administration.
13 . The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is a single unit oral dosage form.
14 . A pharmaceutical composition comprising a crystal form obtainable by the process of claim 2 , and optionally one or more carriers, excipients or diluents.
15 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is for oral, mucosal, parenteral, transdermal or topical administration.
16 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is a single unit oral dosage form.Join the waitlist — get patent alerts
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