Quinine Sulfate Polymorphs, Processes of Preparing, Compositions and Uses Thereof

1 . A solid state form of quinine sulfate comprising:

Form B quinine sulfate;

Form C quinine sulfate;

Form D quinine sulfate;

Form E quinine sulfate;

Form F quinine sulfate;

Form G quinine sulfate;

Form H quinine sulfate;

Form I quinine sulfate;

Form J quinine sulfate;

Form K quinine sulfate;

or a noncrystalline form of quinine sulfate.

2 . Form B quinine sulfate of claim 1 , comprising:

XRPD peak positions at 8.3, 11.9, 12.2, 16.8, 17.3, 18.5, 20.6, 24.5, 25.7, and 26.1 ±0.2 degrees 2-theta;

peaks according to Table 1 ±0.2 degrees 2-theta; or

an X-ray powder diffraction pattern which is substantially similar to FIG. 1 .

3 . A process for preparing quinine sulfate Form B of claim 1 , comprising:

dissolving quinine sulfate in ethanol to form a solution and evaporating the ethanol until quinine Form B forms; or

dissolving quinine sulfate in ethanol at about 31 to about 78° C. to form a solution, and

cooling the solution.

4 . Form C quinine sulfate of claim 1 , comprising:

XRPD peak positions at 6.2, 9.2, 12.9, 14.0. 15.3, 16.6, 17.5, and 18.4 ±0.2 degrees 2-theta;

peaks according to Table 2 ±0.2 degrees 2-theta; or

an X-ray powder diffraction pattern which is substantially similar to FIG. 2 .

5 . A process for preparing quinine sulfate Form C of claim 1 , comprising:

dissolving quinine sulfate in ethanol to form a solution and adding an aliphatic hydrocarbon antisolvent until quinine Form C forms.

6 . Form D quinine sulfate of claim 1 , comprising:

XRPD peak positions at 8.6, 9.7, 14.1, 16.8, 18.1, 19.9, and 21.3 ±0.2 degrees 2-theta;

peaks according to Table 3 ±0.2 degrees 2-theta; or

exhibiting an X-ray powder diffraction pattern which is substantially similar to FIG. 3 ,

wherein quinine sulfate Form D is substantially free of quinine sulfate Form A.

7 . A process for preparing quinine sulfate Form D of claim 1 , comprising:

vacuum drying quinine sulfate Form A at about 55 to about 65° C. for about 11 days or more to form quinine sulfate Form D.

8 . Form E quinine sulfate of claim 1 , comprising:

XRPD peak positions at 8.3, 14.4, 16.2, 17.9, 18.8, 22.4 and 26.0 ±0.2 degrees 2-theta;

peaks according to Table 4 ±0.2 degrees 2-theta; or

exhibiting an X-ray powder diffraction pattern which is substantially similar to FIG. 4 .

9 . A process for preparing quinine sulfate Form E of claim 1 , comprising:

dissolving quinine sulfate in methanol to form a solution, and

adding an aqueous antisolvent until quinine sulfate Form E forms; or

dissolving quinine sulfate in 2,2,2-trifluoroethanol and water with heating to form a solution and allowing the solution to cool until quinine sulfate Form E forms.

10 . Form F quinine sulfate of claim 1 , comprising:

XRPD peak positions at 7.5, 8.3, 15.4, 17.5, and 20.6 ±0.2 degrees 2-theta;

peaks according to Table 5 ±0.2 degrees 2-theta; or

exhibiting an X-ray powder diffraction pattern which is substantially similar to FIG. 5 .

11 . A process for preparing quinine sulfate Form F of claim 1 , comprising:

slurrying quinine sulfate in ethanol for 5 days or greater, wherein the slurrying is carried out at a temperature of about 40 to about 60° C., and

optionally the ethanol is allowed to evaporate during the slurrying process.

12 . Form G quinine sulfate of claim 1 , comprising:

XRPD peak positions at 6.1, 7.7, 16.8, 17.9, and 18.8 ±0.2 degrees 2-theta;

peaks according to Table 6 ±0.2 degrees 2-theta; or

exhibiting an X-ray powder diffraction pattern which is substantially similar to FIG. 6 .

13 . A process for preparing quinine sulfate Form G of claim 1 , comprising:

slurrying quinine sulfate in tert-butanol for 3 days or greater, wherein the slurrying is carried out at a temperature of about 40 to about 60° C.

14 . Form H quinine sulfate of claim 1 , comprising:

XRPD peak positions at 7.9, 9.1, 13.9, 15.8, 16.5, 17.2, 17.8, and 18.1 ±0.2 degrees 2-theta;

peaks according to Table 7 ±0.2 degrees 2-theta; or

exhibiting an X-ray powder diffraction pattern which is substantially similar to FIG. 7 .

15 . A process for preparing quinine sulfate Form H of claim 1 , comprising:

dissolving quinine sulfate in hexafluoroisopropanol and allowing the solvent to evaporate until quinine sulfate Form H forms.

16 . Form I quinine sulfate of claim 1 , comprising:

XRPD peak positions at 8.3, 10.5, 14.8, 15.6, 17.2, 17.6, 18.9, 19.2, and 20.9 ±0.2 degrees 2-theta;

peaks according to Table 8 ±0.2 degrees 2-theta; or

exhibiting an X-ray powder diffraction pattern which is substantially similar to FIG. 8 .

17 . A process for preparing quinine sulfate Form I of claim 1 , comprising:

slurrying quinine sulfate in methanol for 5 days or greater, wherein the slurrying is carried out at a temperature of about 40 to about 60° C., and

optionally the methanol is allowed to evaporate during the slurrying process.

18 . Form J quinine sulfate of claim 1 , comprising:

XRPD peak positions at 4.2, 6.1, 15.8, 18.4, 20.4, 21.4, and 23.6 ±0.2 degrees 2-theta;

peaks according to Table 9 ±0.2 degrees 2-theta; or

exhibiting an X-ray powder diffraction pattern which is substantially similar to FIG. 9 .

19 . A process for preparing quinine sulfate Form J of claim 1 , comprising:

suspending quinine sulfate in a combination of 1,1,1-trifluoroethanol and tetrahydrofuran to form a mixture;

sonicating the mixture; and

allowing the 1,1,1-trifluoroethanol and tetrahydrofuran to evaporate under ambient conditions or under reduced pressure.

20 . Form K quinine sulfate of claim 1 , comprising:

XRPD peak positions at 4.3, 6.1, 6.4, 8.9, 17.7, 19.1, and 23.3 ±0.2 degrees 2-theta;

peaks according to Table 10 ±0.2 degrees 2-theta; or

exhibiting an X-ray powder diffraction pattern which is substantially similar to FIG. 10 .

21 . A process for preparing quinine sulfate Form K of claim 1 , comprising:

slurrying quinine sulfate in tetrahydrofuran for 8 days or greater, wherein the slurrying is carried out at a temperature of about 40 to about 60° C.

22 . Quinine sulfate Form A, B, C, D, E, F, G, H, I, J, or K of claim 1 substantially free of other quinine sulfate polymorphs.

23 . Quinine sulfate Form A, B, C, D, E, F, G, H, I, J, or K of claim 1 having a purity of greater than or equal to about 95, 96, 97, 98, 99 or 99.5%.

24 . Non-crystalline quinine sulfate of claim 1 exhibiting an X-ray powder diffraction pattern is substantially free of peaks of crystalline quinine sulfate forms.

25 . A composition comprising:

quinine sulfate Form A, B, C, D, E, F, G, H, I, J, K or a noncrystalline form; and

a pharmaceutically acceptable excipient.

26 . A method of treating a patient, comprising:

administering to a patient in need thereof quinine sulfate Form A, B, C, D, E, F, G, H, I, J, K; a noncrystalline form; or a combination thereof.

27 . A method of treating a patient, comprising:

administering to a patient in need thereof the composition of claim 25 .

28 . The method of claim 27 , wherein the composition is used to treat malaria caused by Plasmodium species, uncomplicated Plasmodium falciparum malaria, severe or complicated Plasmodium falciparum malaria, malaria caused by Plasmodium vivax , leg muscle cramps, or babesiosis; or for the prophylaxis of malaria or leg muscle cramps.