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. A pharmaceutical formulation comprising:
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 98% by weight based on the total weight of the pharmaceutical material, and the pharmaceutical material comprises 0.0001% to less than or equal to 0.15% of a compound of formula (VI):
and
a pharmaceutically acceptable excipient.
2. The pharmaceutical formulation of claim 1 , 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.
3. The pharmaceutical formulation of claim 1 , 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 .
4. The pharmaceutical formulation of claim 1 , wherein the crystalline form of the compound of formula (V) has a melting point onset as determined by differential scanning calorimetry in a range from 90° C. to 94° C.
5. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical material comprises the compound of formula (V), or a pharmaceutically acceptable salt thereof, in an amount greater than 99% by weight based on the total weight of the pharmaceutical material.
6. The pharmaceutical formulation of claim 1 , 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.
7. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical material comprises the compound of formula (V), or a pharmaceutically acceptable salt thereof, in an amount greater than 99.5% by weight based on the total weight of the pharmaceutical material.
8. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical material comprises less than or equal to 0.2% by weight of unknown impurities.
9. The pharmaceutical formulation of claim 1 , wherein the pharmaceutically acceptable excipient comprises a cellulose.
10. A pharmaceutical formulation comprising:
a pharmaceutical material comprising a crystalline form of the compound of formula (V):
wherein the pharmaceutical material comprises the compound of formula (V) in an amount of from 98% to 102% by weight based on the total weight of the pharmaceutical material, as determined by a high performance liquid chromatography (HPLC) assay, and the pharmaceutical material comprises 0.0001% to less than or equal to 0.15% of a compound of formula (VI):
and
a pharmaceutically acceptable excipient.
11. The pharmaceutical formulation of claim 10 , wherein the HPLC assay uses a Waters XBridge BEH C18 column having the dimensions of 4.6 mm i.d.×150 mm, with a particle size of 2.5 μm, at a temperature of 40° C., with isocratic elution of a mobile phase comprising 0.05% phosphoric acid in 50:50 water/acetonitrile at a flow rate of 1.2 mL/minute, and detection at 215 nm, wherein the retention time of the compound of formula (V) is 4.6 minutes.
12. The pharmaceutical formulation of claim 10 , 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.
13. The pharmaceutical formulation of claim 10 , wherein the pharmaceutical material has a melting point onset as determined by differential scanning calorimetry in a range from 90° C. to 94° C.
14. The pharmaceutical formulation of claim 10 , wherein the pharmaceutical material comprises less than or equal to 0.2% by weight of unknown impurities.
15. The pharmaceutical formulation of claim 10 , wherein the pharmaceutically acceptable excipient comprises a cellulose.
16. A pharmaceutical formulation comprising:
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 85% by weight based on the total weight of the pharmaceutical material, and the pharmaceutical material comprises 0.0001% to less than or equal to 0.15% of a compound of formula (VI):
and
a pharmaceutically acceptable excipient.
17. The pharmaceutical formulation of claim 16 , 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.
18. The pharmaceutical formulation of claim 16 , wherein the pharmaceutical material has a melting point onset as determined by differential scanning calorimetry in a range from 90° C. to 94° C.
19. The pharmaceutical formulation of claim 16 , wherein the pharmaceutical material comprises the compound of formula (V), or a pharmaceutically acceptable salt thereof, in an amount greater than 95% by weight based on the total weight of the pharmaceutical material.
20. The pharmaceutical formulation of claim 16 , wherein the pharmaceutically acceptable excipient comprises a cellulose.