Compositions of hydroxypropyl-beta-cyclodextrin and methods of purifying the same

1. A composition comprising a mixture of isomerically-purified hydroxypropyl β-cyclodextrin molecules comprising:

β-cyclodextrin substituted with eight hydroxypropyl groups (“DS-8”);

β-cyclodextrin substituted with nine hydroxypropyl groups (“DS-9”);

β-cyclodextrin substituted with ten hydroxypropyl groups (“DS-10”);

β-cyclodextrin substituted with eleven hydroxypropyl groups (“DS-11”);

β-cyclodextrin substituted with twelve hydroxypropyl groups (“DS-12”);

β-cyclodextrin substituted with thirteen hydroxypropyl groups (“DS-13”); and

β-cyclodextrin substituted with fourteen hydroxypropyl groups (“DS-14”),

wherein the composition comprises less than 1% β-cyclodextrin substituted with seven hydroxypropyl groups (“DS-7”), and wherein the composition comprises no more than 1 ppm propylene oxide.

2. The composition of claim 1 , wherein the composition comprises less than 1% β-cyclodextrin substituted with six hydroxypropyl groups (“DS-6”), 1% β-cyclodextrin substituted with five hydroxypropyl groups (“DS-5”), β-cyclodextrin substituted with four hydroxypropyl groups (“DS-4”), β-cyclodextrin substituted with three hydroxypropyl groups (“DS-3”), β-cyclodextrin substituted with two hydroxypropyl groups (“DS-2”), and β-cyclodextrin substituted with one hydroxypropyl group (“DS-1”).

3. The composition of claim 1 , wherein the DS-10 has the highest concentration in the mixture of isomerically-purified hydroxypropyl β-cyclodextrin molecules as compared to DS-8, DS-9, DS-11, DS-12, DS-13, and DS-14.

4. The composition of claim 1 , wherein the mixture of isomerically-purified hydroxypropyl β-cyclodextrin molecules comprises about 6% to about 12% DS-8.

5. The composition of claim 1 , wherein the mixture of isomerically-purified hydroxypropyl β-cyclodextrin molecules comprises about 18% to about 24% DS-9.

6. The composition of claim 1 , wherein the mixture of isomerically-purified hydroxypropyl β-cyclodextrin molecules comprises about 24% to about 30% DS-10.

7. The composition of claim 1 , wherein the mixture of isomerically-purified hydroxypropyl β-cyclodextrin molecules comprises about 18% to about 24% DS-11.

8. The composition of claim 1 , wherein the mixture of isomerically-purified hydroxypropyl β-cyclodextrin molecules comprises about 10% to about 16% DS-12.

9. The composition of claim 1 , wherein the mixture of isomerically-purified hydroxypropyl β-cyclodextrin molecules comprises about 4% to about 10% DS-13.

10. The composition of claim 1 , wherein the mixture of isomerically-purified hydroxypropyl β-cyclodextrin molecules comprises about 0% to about 6% DS-14.

11. The composition of claim 1 , wherein the average degree of substitution of the mixture of isomerically-purified hydroxypropyl β-cyclodextrin is about 9 to about 10.

12. The composition of claim 1 , wherein about 15% to about 21% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position.

13. The composition of claim 1 , wherein about 79% to about 85% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position.

14. The composition of claim 1 , wherein the composition has an HPLC-CAD chromatogram of FIG. 28 .

15. The composition of claim 14 , wherein the composition has a mean retention time of about 15.4 minutes.

16. The composition of claim 1 , wherein the composition has a −ESI-MS spectrum with peaks at about 770 m/z, about 798 m/z, about 828 m/z, about 857 m/z, about 885 m/z.

17. The composition of claim 1 , wherein the composition has a +ESI-MS spectrum with peaks at about 803 m/z, about 831 m/z, about 861 m/z, about 889 m/z, and about 919 m/z.

18. The composition of claim 1 , wherein the composition has a ESI-MS spectra of FIG. 29 .

19. The composition of claim 1 , having a MALDI-TOF spectrum with peaks at about 1614 m/z, about 1673 m/z, about 1733 m/z, about 1792 m/z, about 1852 m/z, about 1912 m/z, and about 1971 m/z.

20. The composition of claim 1 , having a MALDI-TOF spectrum of FIG. 30 .

21. The composition of claim 20 , wherein the area of DS-8 is 8.53%.

22. The composition of claim 20 , wherein the area of DS-9 is 21.33%; and/or

wherein the area of DS-10 is 26.58%;

and/or wherein the area of DS-11 is 20.90%;

and/or wherein the area of DS-12 is 13.31%;

and/or wherein the area of DS-13 is 6.74%;

and/or wherein the area of DS-14 is 2.60%.

23. The composition of claim 1 having a 1 H-NMR spectrum of FIG. 26 .

24. The composition of claim 1 having a DEPT-edited HSQC spectrum of FIG. 27 .

25. The composition of claim 1 , wherein the osmolality of the composition is about 635-695 mOs/kg; and/or wherein the true density of the composition is about 1.096-1.098 g/cm 3 .

26. The composition of claim 1 , wherein the composition comprises no more than 10 ppb of propylene glycol as measured by HPLC.

27. The composition of claim 1 , wherein the composition comprises no more than 10 ppb propylene glycol as measured by gas chromatography.

28. The composition of claim 1 , wherein the composition comprises no more than 10 ppb propylene glycol as measured by PG/EG-ratio of propylene glycol to ethylene glycol.

29. The composition of claim 1 , wherein the total amount of other unspecified impurities is less than or equal to 0.05% as measured by HPLC.

30. The composition of claim 1 , wherein the composition comprises between 0 and 10 ppm chloride.

31. The composition of claim 1 , wherein the composition has a conductivity between 0 and 8 μS/cm.

32. A composition comprising a mixture of isomerically-purified hydroxypropyl

β-cyclodextrin molecules comprising:

β-cyclodextrin substituted with eight hydroxypropyl groups (“DS-8”);

β-cyclodextrin substituted with nine hydroxypropyl groups (“DS-9”);

β-cyclodextrin substituted with ten hydroxypropyl groups (“DS-10”);

β-cyclodextrin substituted with eleven hydroxypropyl groups (“DS-11”);

β-cyclodextrin substituted with twelve hydroxypropyl groups (“DS-12”);

β-cyclodextrin substituted with thirteen hydroxypropyl groups (“DS-13”); and

β-cyclodextrin substituted with fourteen hydroxypropyl groups (“DS-14”),

wherein the composition comprises less than 1% β-cyclodextrin substituted with seven hydroxypropyl groups (“DS-7”), and wherein about 15% to about 21% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are located at the 3-O-position.

33. A composition comprising a mixture of isomerically-purified hydroxypropyl β-cyclodextrin molecules comprising:

β-cyclodextrin substituted with eight hydroxypropyl groups (“DS-8”);

β-cyclodextrin substituted with nine hydroxypropyl groups (“DS-9”);

β-cyclodextrin substituted with ten hydroxypropyl groups (“DS-10”);

β-cyclodextrin substituted with eleven hydroxypropyl groups (“DS-11”);

β-cyclodextrin substituted with twelve hydroxypropyl groups (“DS-12”);

β-cyclodextrin substituted with thirteen hydroxypropyl groups (“DS-13”); and

β-cyclodextrin substituted with fourteen hydroxypropyl groups (“DS-14”),

wherein the composition comprises less than 1% β-cyclodextrin substituted with seven hydroxypropyl groups (“DS-7”), and wherein about 79% to about 85% of the hydroxypropyl substitutions in the hydroxypropyl β-cyclodextrin molecules are located at the 2-O-position.