Polymorphic forms of (r)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide

Abstract

Disclosed herein are polymorphic and amorphous forms of anhydrate, hydrate, and solvates of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide and methods of using such compositions for treating or suppressing oxidative stress disorders, including mitochondrial disorders, impaired energy processing disorders, neurodegenerative diseases and diseases of aging. Further disclosed are methods of making such polymorphic and amorphous forms.

What is claimed is: 
     
         1 . An polymorph of an anhydrate, a hydrate, or a solvate of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, wherein the polymorph is selected from the group consisting of Form I, Form V, Form III, Form II, Form IV, or Form VI;
 wherein a powder X-ray diffraction pattern for polymorph Form I comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 12.06, 17.03, and 17.26;   wherein a powder X-ray diffraction pattern for polymorph Form V comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 9.61, 11.49, and 15.45;   wherein a powder X-ray diffraction pattern for polymorph Form III comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 14.02, 15.23, and 21.10;   wherein a powder X-ray diffraction pattern for polymorph Form II comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 9.63, 11.33, and 19.33;   wherein a powder X-ray diffraction pattern for polymorph Form IV comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 4.31, 12.97, and 13.20; and   wherein a powder X-ray diffraction pattern for polymorph Form VI comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 6.27, 9.91, and 12.94.   
     
     
         2 - 34 . (canceled) 
     
     
         35 . A pharmaceutical composition comprising the polymorph of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         36 - 38 . (canceled) 
     
     
         39 . A method of treating or suppressing an oxidative stress disorder, modulating one or more energy biomarkers, normalizing one or more energy biomarkers, or enhancing one or more energy biomarkers, comprising administering to an individual in need thereof a therapeutically effective amount or effective amount of the polymorph of  claim 1 . 
     
     
         40 - 52 . (canceled) 
     
     
         53 . A process for the preparation of a polymorph of anhydrous (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, wherein the process comprises the steps: (a) contacting (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide with a liquid comprising IPA; and (b) removing the liquid. 
     
     
         54 . The process of  claim 53 , wherein the liquid is 100% IPA. 
     
     
         55 . The process of  claim 53 , wherein the liquid is 98% IPA/2% water (v/v). 
     
     
         56 . The process of  claim 53 , wherein step (a) comprises dissolving the (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide in the liquid. 
     
     
         57 . The process of  claim 53 , wherein step (a) comprises slurrying the (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide in the liquid. 
     
     
         58 . The process of  claim 53 , wherein the process further comprises step (a)(i): adding heptane to the liquid. 
     
     
         59 . The process of  claim 53 , wherein step (b) comprises filtering the (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide. 
     
     
         60 . The process of  claim 53 , wherein the (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide in step (a) is at least 95% pure, exclusive of solvents. 
     
     
         61 . A process for the preparation of a polymorph of anhydrous (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, wherein the process comprises the steps: (a) dissolving (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide in EtOAc, (b) rapidly cooling the mixture from (a), and (c) isolating the (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide. 
     
     
         62 . The process of  claim 61 , wherein the initial (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide in step (a) is Form I, 
 wherein a powder X-ray diffraction pattern for polymorph Form I comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 12.06, 15.33, 17.03, and 17.26.   
     
     
         63 . A process for the preparation of a polymorph of a solvate of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, wherein the process comprises the steps: (a) combining (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide and 0.5% MC/2%Tween 80 in water to create a slurry; (b) slurrying the mixture from (a), and (c) removing the 0.5% MC/2%Tween 80 in water. 
     
     
         64 . The process of  claim 63 , wherein the initial (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide in step (a) is Form I, 
 wherein a powder X-ray diffraction pattern for polymorph Form I comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 12.06, 15.33, 17.03, and 17.26.   
     
     
         65 . The process of  claim 63 , wherein step (b) is performed for at least about 24 hours. 
     
     
         66 . A process for the preparation of a polymorph of a solvate of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, wherein the process comprises the steps: (a) combining (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide and 0.5% MC in water to create a slurry; (b) slurrying the mixture from (a) for at least about 7 days, and (c) removing the 0.5% MC in water. 
     
     
         67 . The process of  claim 66 , wherein the initial (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide in step (a) is Form I, II, IV, V or VI,
 wherein a powder X-ray diffraction pattern for polymorph Form I comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 12.06, 15.33, 17.03, and 17.26;   wherein a powder X-ray diffraction pattern for polymorph Form II comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 9.63, 10.85, 11.33, and 19.33;   wherein a powder X-ray diffraction pattern for polymorph Form IV comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 4.31, 8.76, 12.97, and 13.20;   wherein a powder X-ray diffraction pattern for polymorph Form V comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 9.61, 11.49, 12.93, and 15.45; and   wherein a powder X-ray diffraction pattern for polymorph Form VI comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 6.27, 9.91, 12.94, and 15.71.   
     
     
         68 . The process of  claim 57 , wherein the polymorph is Form I, 
 wherein a powder X-ray diffraction pattern for polymorph Form I comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 12.06, 15.33, 17.03, and 17.26.   
     
     
         69 . The process of  claim 58 , wherein the polymorph is Form I,
 wherein a powder X-ray diffraction pattern for polymorph Form I comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ± 0.2: 12.06, 15.33, 17.03, and 17.26.   
     
     
         70 - 125 . (canceled)