Lyophilization cakes of proteasome inhibitors

1. A lyophilized cake comprising:

(a) a compound of Formula I or a pharmaceutically acceptable salt or ester thereof:

wherein R 1 is an optionally substituted 5-, 6-, or 10-membered heteroaryl having at least one N or R 1 is an optionally substituted 6- or 10-membered aryl;

(b) a cyclodextrin; and

(c) a bulking agent comprising a monosaccharide.

2. The lyophilized cake of claim 1 , wherein the compound of Formula I is

3. The lyophilized cake of claim 1 , wherein the compound of Formula I is Compound 1

or a pharmaceutically acceptable salt or ester thereof.

4. The lyophilized cake of claim 3 , wherein the drug is Compound 1.

5. The lyophilized cake of claim 3 , further comprising a surfactant.

6. The lyophilized cake of claim 3 , wherein the cyclodextrin is methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin, 2-hydroxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, β-cyclodextrin sulfate, β-cyclodextrin sulfonate, β-cyclodextrin sulfobutyl ether, or a mixture thereof.

7. The lyophilized cake of claim 3 , wherein the lyophilized cake reconstitutes in about 90 seconds or less to provide a clear solution free of particulate matter.

8. The lyophilized cake of claim 3 , further comprising a pH modifier.

9. The lyophilized cake of claim 8 , wherein the pH modifier comprises an acid.

10. The lyophilized cake of claim 9 , wherein the pH of the lyophilized cake is adjusted to a pH of about 4 or lower.

11. The lyophilized cake of claim 3 , wherein the lyophilized cake exhibits a decrease in drug purity of no more than about 1% after storage for 6 months under accelerated conditions.

12. The lyophilized cake of claim 7 , wherein the lyophilized cake exhibits a decrease in drug purity of no more than about 1% after storage for 6 months under accelerated conditions.

13. The lyophilized cake of claim 7 , wherein the lyophilized cake exhibits a decrease in drug purity of no more than about 0.5% after storage for 6 month under accelerated conditions.

14. A method for manufacturing a lyophilized cake comprising the steps of:

(a) providing a first mixture comprising a cyclodextrin, a bulking agent comprising a monosaccharide, and water;

(b) mixing a surfactant and a portion of the first mixture to form a second mixture;

(c) combining a compound of Formula I, or a salt or ester thereof, and the second mixture to form a drug mixture;

wherein R 1 is an optionally substituted 5-, 6-, or 10-membered heteroaryl having at least one N or R 1 is an optionally substituted 6- or 10-membered aryl;

(d) mixing the remainder of the first mixture with the drug mixture to form a pre-lyophilization solution; and

(e) lyophilizing the pre-lyophilization solution.

15. A method for manufacturing a lyophilized cake comprising:

(a) providing a first mixture containing a cyclodextrin, a bulking agent comprising a monosaccharide, and water;

(b) providing a drug mixture containing a compound of Formula I, or a salt or ester thereof, and tert-butanol;

wherein R 1 is an optionally substituted 5-, 6-, or 10-membered heteroaryl having at least one N or R 1 is an optionally substituted 6- or 10-membered aryl;

(c) combining the first mixture and the drug mixture to provide a pre-lyophilization solution; and

(d) lyophilizing the pre-lyophilization solution.

16. The method of claim 14 , wherein the drug mixture contains Compound 10

17. The method of claim 15 , further comprising the step of adjusting the pH of the pre-lyophilization solution to a pH of about 4 or lower.