Crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid for the treatment of disease
AssigneePTC Therapeutics, Inc.
InventorsNeil G. Almstead, Peter Seongwoo Hwang, Young-Choon Moon
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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.
Claims16
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) Å3;
- Z=8;
- calculated density (dcalc, g cm−3) is 1,517 g cm−3;
- and the space group is P21/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.
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.
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).
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.
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.
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.
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.
Dependencies are inferred from the claim text.