METHODS OF MAKING BEMPEDOIC ACID AND COMPOSITIONS OF THE SAME
The invention provides methods of preparing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid and methods of making a pharmaceutical material comprising a purified amount of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid. Also provided are compositions and pharmaceutical materials including a purified amount of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid as well as methods of treating various diseases and conditions using the compositions and pharmaceutical materials.
1 - 38 . (canceled)
39 . A pharmaceutical material comprising a crystalline form of the compound of formula (V):
or a pharmaceutically acceptable salt thereof;
wherein the pharmaceutical material comprises the compound of formula (V), or a pharmaceutically acceptable salt thereof, in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material.
40 . The pharmaceutical material of claim 39 , wherein the crystalline form of the compound of formula (V) exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 10.3±0.2, 10.4±0.2, 17.9±0.2, 18.8±0.2, 19.5±0.2, and 20.7±0.2.
41 . The pharmaceutical material of claim 39 , wherein the crystalline form of the compound of formula (V) is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ:
Angle [2θ]
5.2
10.3
10.4
11.8
13.7
15.5
15.6
17.3
17.6
17.9
18.8
19.5
19.7
20.4
20.7
21.1
22.0
22.6
23.1
23.6
23.9
24.7
25.8
26.3
27.5
29.2
30.2
30.8
31.3
31.9
32.9
34.4
35.1
36.2
37.2
37.9
42 . The pharmaceutical material of claim 39 , wherein the crystalline form of the compound of formula (V) exists in a monoclinic crystal system and has a P2 1 /c space group.
43 . The pharmaceutical material of claim 42 , wherein the crystalline form of the compound of formula (V) is characterized by the following crystallographic unit cell parameters:
Unit cell
a = 17.9209(8) Å
α = 90°
dimensions
b = 9.8547(5) Å
β = 106.834(10)°
c = 12.2775(6)
γ = 90°
Volume
2075.35 Å 3
Z
4
Density
1.102 Mg/m 3
(calculated)
44 . The pharmaceutical material of claim 39 , wherein the crystalline form of the compound of formula (V) is characterized by an X-ray powder diffraction pattern substantially the same as shown in FIG. 4 .
45 . The pharmaceutical material of claim 39 , wherein the crystalline form of the compound of formula (V) has a melting point onset as determined by differential scanning calorimetry in the range of from about 90° C. to about 94° C.
46 . The pharmaceutical material of claim 45 , wherein the crystalline form of the compound of formula (V) has a melting point onset as determined by differential scanning calorimetry at about 92° C.
47 . The pharmaceutical material of claim 39 , wherein the crystalline form of the compound of formula (V) has a differential scanning calorimetry curve substantially the same as shown in FIG. 5 .
48 . The pharmaceutical material of claim 39 , wherein the pharmaceutical material comprises the compound of formula (V) in an amount greater than 99.5% by weight based on the total weight of the pharmaceutical material.
49 . The pharmaceutical material of claim 39 , wherein the pharmaceutical material comprises the compound of formula (V) in an amount greater than 99.7% by weight based on the total weight of the pharmaceutical material.
50 . The pharmaceutical material of claim 39 , wherein the pharmaceutical material comprises the compound of formula (V) in an amount greater than 99.9% by weight based on the total weight of the pharmaceutical material.
51 . The pharmaceutical material of claim 39 , wherein the pharmaceutical material comprises the compound of formula (V) in an amount of from about 98% to about 102% by weight based on the total weight of the pharmaceutical material, as determined by a high performance liquid chromatography (HPLC) assay.
52 . The pharmaceutical material of claim 51 , wherein the HPLC assay uses a Waters XBridge BEH C18 column (4.6 mm i.d.×150 mm, 2.5 μm) at a temperature of about 40° C., with isocratic elution of a mobile phase comprising about 0.05% phosphoric acid in water/acetonitrile (about 50:50) at a flow rate of about 1.2 mL/minute, and detection at 215 nm, wherein the retention time of the compound of formula (V) is about 4.6 minutes.
53 . The pharmaceutical material of claim 39 , further comprising a compound of formula (VI):
or a pharmaceutically acceptable salt thereof.
54 . The pharmaceutical material of claim 53 , wherein the pharmaceutical material comprises the compound of formula (IX), or a pharmaceutically acceptable salt thereof, in an amount no greater than about 0.15% by weight based on the total weight of the pharmaceutical material.
55 . The pharmaceutical material of claim 53 , further comprising a compound of formula (VII):
or a pharmaceutically acceptable salt thereof.
56 . The pharmaceutical material of claim 55 , wherein the pharmaceutical material comprises the compound of formula (VII), or a pharmaceutically acceptable salt thereof, in an amount no greater than about 0.15% by weight based on the total weight of the pharmaceutical material.
57 . The pharmaceutical material of claim 53 , further comprising less than or equal to 0.2% by weight of unknown impurities.
58 . A pharmaceutical formulation comprising:
the pharmaceutical material of claim 39 ; and
a pharmaceutically acceptable excipient.
59 - 61 . (canceled)