Crystalline forms of morphine sulfate

1. A form of morphine sulfate selected from the group consisting of Form α, Form β, Form γ, Form δ, Form ε, Form ζ, Form η and Form θ; wherein:

Form α has an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at about 15.71 and about 17.08;

Form β has an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at about 15.43 and about 17.78;

Form γ has an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at about 14.28 and about 13.21;

Form δ has an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at about 15.68 and about 17.03;

Form ε has an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at about 14.40 and about 23.58;

Form ζ has an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at about 14.28 and about 20.44;

Form η has an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at about 15.49 and about 14.36; and

Form θ has an X-ray powder diffraction pattern comprising peaks, in terms of 2-theta, at about 14.22 and about 14.05.

2. A form of morphine sulfate according to claim 1 , wherein:

Form α has an X-ray powder diffraction pattern further comprising peaks, in terms of 2-theta, at about 17.63, about 13.45 and about 15.48;

Form β has an X-ray powder diffraction pattern further comprising peaks, in terms of 2-theta, at about 13.68, about 16.89 and about 20.58;

Form γ has an X-ray powder diffraction pattern further comprising peaks, in terms of 2-theta, at about 16.95, about 17.47 and about 15.63;

Form δ has an X-ray powder diffraction pattern further comprising peaks, in terms of 2-theta, at about 17.54, about 20.64 and about 26.20;

Form ε has an X-ray powder diffraction pattern further comprising peaks, in terms of 2-theta, at about 10.80, about 19.20 and about 13.54;

Form ζ has an X-ray powder diffraction pattern further comprising peaks, in terms of 2-theta, at about 13.67, about 24.24 and about 26.39;

Form η has an X-ray powder diffraction pattern further comprising peaks, in terms of 2-theta, at about 16.42, about 18.33 and about 21.96; and

Form θ has an X-ray powder diffraction pattern further comprising a peak, in terms of 2-theta, at about 12.36, about 20.73 and about 16.26.

3. A form of morphine sulfate selected from the group consisting of Form α, Form β, Form γ, Form δ, Form ε, Form ζ, Form η and Form θ; wherein:

Form α has an X-ray powder diffraction pattern substantially as shown in FIG. 2 ;

Form β has an X-ray powder diffraction pattern substantially as shown in FIG. 3 ;

Form γ has an X-ray powder diffraction pattern substantially as shown in FIG. 4 ;

Form δ has an X-ray powder diffraction pattern substantially as shown in FIG. 5 ;

Form ε has an X-ray powder diffraction pattern substantially as shown in FIG. 6 ;

Form ζ has an X-ray powder diffraction pattern substantially as shown in FIG. 7 ;

Form η has an X-ray powder diffraction pattern substantially as shown in FIG. 8 ; and

Form θ has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .

4. A form of morphine sulfate selected from the group consisting of Form α, Form β, Form γ, Form δ, Form ε, Form ζ, Form η and Form θ according to claim 1 ; wherein:

Form α has an X-ray powder diffraction pattern comprising peaks at d-spacing, in terms of Angstroms, of about 5.635 and about 5.187;

Form β has an X-ray powder diffraction pattern comprising peaks at d-spacing, in terms of Angstroms, of about 5.738 and about 4.984;

Form γ has an X-ray powder diffraction pattern comprising peaks at d-spacing, in terms of Angstroms, of about 6.195 and about 6.695;

Form δ has an X-ray powder diffraction pattern comprising peaks at d-spacing, in terms of Angstroms, of about 5.646 and about 5.203;

Form ε has an X-ray powder diffraction pattern comprising peaks at d-spacing, in terms of Angstroms, of about 6.145 and about 3.770;

Form ζ has an X-ray powder diffraction pattern comprising peaks at d-spacing, in terms of Angstroms, of about 6.198 and about 4.342;

Form η has an X-ray powder diffraction pattern comprising peaks at d-spacing, in terms of Angstroms, of about 5.717 and about 6.162; and

Form θ has an X-ray powder diffraction pattern comprising peaks at d-spacing, in terms of Angstroms, of about 14.215 and about 14.050.

5. A form of morphine sulfate according to claim 4 , wherein:

Form α has an X-ray powder diffraction pattern further comprising peaks at d-spacing, in terms of Angstroms, of about 5.026, about 6.576 and about 5.721;

Form β has an X-ray powder diffraction pattern further comprising peaks at d-spacing, in terms of Angstroms, of about 6.468, about 5.246 and about 4.313;

Form γ has an X-ray powder diffraction pattern further comprising peaks at d-spacing, in terms of Angstroms, of about 5.227, about 5.073 and about 5.666;

Form δ has an X-ray powder diffraction pattern further comprising peaks at d-spacing, in terms of Angstroms, of about 5.051, about 4.299 and about 3.398;

Form ε has an X-ray powder diffraction further comprising peaks at d-spacing, in terms of Angstroms, of about 8.189, about 4.620 and about 6.535;

Form ζ has an X-ray powder diffraction pattern further comprising peaks at d-spacing, in terms of Angstroms, of about 6.475, about 3.668 and about 3.374;

Form η has an X-ray powder diffraction pattern further comprising peaks at d-spacing, in terms of Angstroms, of about 5.394, about 4.835 and about 4.045; and

Form θ has an X-ray powder diffraction further comprising peaks at d-spacing, in terms of Angstroms, of about 12.359, about 20.733 and about 16.255.

6. A form of morphine sulfate according to claim 1 , wherein, as measured by differential scanning calorimetry:

Form α is characterized by an endotherm at about 173° C.;

Form β is characterized by an endotherm at about 177° C.;

Form γ is characterized by an endotherm at about 234° C.;

Form δ is characterized by an endotherm at about 58° C.;

Form ε is characterized by an endotherm at about 160° C.;

Form ζ is characterized by an endotherm at about 163° C.;

Form η is characterized by an endotherm at about 284° C.; and

Form θ is characterized by an endotherm at about 158° C.

7. A form of morphine sulfate according to claim 1 , wherein:

Form α is characterized by a differential scanning calorimetry pattern substantially as shown in FIG. 11 ;

Form β is characterized by a differential scanning calorimetry pattern substantially as shown in FIG. 12 ;

Form γ is characterized by a differential scanning calorimetry pattern substantially as shown in FIG. 13 ;

Form δ is characterized by a differential scanning calorimetry pattern substantially as shown in FIG. 14 ;

Form ε is characterized by a differential scanning calorimetry pattern substantially as shown in FIG. 15 ;

Form ζ is characterized by a differential scanning calorimetry pattern substantially as shown in FIG. 16 ;

Form η is characterized by a differential scanning calorimetry pattern substantially as shown in FIG. 17 ; and

Form θ is characterized by a differential scanning calorimetry pattern substantially as shown in FIG. 18 .

8. A composition comprising at least one Form of morphine sulfate according to claim 1 .

9. The composition according to claim 8 , wherein the composition is a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

10. A method of treating pain comprising administering a pharmaceutical formulation according to claim 9 to a subject in need thereof.

11. A method of making morphine sulfate Form α according to claim 1 , comprising exposing a starting material comprising morphine free base to acetone and an acid at a temperature in the range of about 20 to 26° C. for a time sufficient to yield morphine sulfate Form α.

12. A method of making morphine sulfate Form α according to claim 1 , comprising exposing a starting material comprising morphine free base to water and an acid at a temperature in the range of about 55 to 65° C. for a time sufficient to yield morphine sulfate Form α.

13. A method of making morphine sulfate Form β according to claim 1 , comprising exposing a starting material comprising morphine free base to isopropyl acetate and an acid at a temperature in the range of about 20 to 26° C. for a time sufficient to yield morphine sulfate Form β.

14. A method of making morphine sulfate Form γ according to claim 1 , comprising exposing a starting material comprising morphine free base to acetone and an acid at a temperature in the range of about 55 to 65° C. for a time sufficient to yield morphine sulfate Form γ.

15. A method of making morphine sulfate Form δ according to claim 1 , comprising exposing a starting material comprising morphine free base to ethanol and an acid at a temperature in the range of about 20 to 26° C. for a time sufficient to yield morphine sulfate Form δ.

16. A method of making morphine sulfate Form ε according to claim 1 , comprising exposing a starting material comprising morphine free base to methanol and an acid at a temperature in the range of about 20 to 26° C. for a time sufficient to yield morphine sulfate Form ε.

17. A method of making morphine sulfate Form ζ according to claim 1 , comprising exposing a starting material comprising morphine free base to water and an acid at a temperature in the range of about 20 to 26° C. for a time sufficient to yield morphine sulfate Form ζ.

18. A method of making morphine sulfate Form η according to claim 1 , comprising exposing a starting material comprising morphine free base to an ethanol/methanol mixture and an acid at a temperature in the range of about 20 to 26° C. for a time sufficient to yield morphine sulfate Form η.

19. A method of making morphine sulfate Form θ according to claim 1 , comprising exposing a starting material comprising morphine to water and an acid at a temperature in the range of about 65 to 75° C. for a time sufficient to yield morphine sulfate Form θ.