Stable crystalline form of bifeprunox mesylate (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate)

1. A pharmaceutical composition comprising an effective amount of a crystalline polymorph of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate and at least one pharmaceutically acceptable excipient,

wherein the crystalline polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 θ at approximately 7.0, 9.3, 10.0, 12.5, 15.4, 16.7, 17.2, 17.4, 17.7, 18.7, 21.3, 22.2, 25.2, 27.2, 28.3, 28.8 and 30.1.

2. A pharmaceutical composition comprising an effective amount of a crystalline polymorph of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate and at least one pharmaceutically acceptable excipient,

wherein the crystalline polymorph has a melting point of about 277° C.

3. A pharmaceutical composition comprising an effective amount of a crystalline polymorph of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate and at least one pharmaceutically acceptable excipient,

wherein the crystalline polymorph exhibits a DSC trace as shown in FIG. 2 .

4. A pharmaceutical composition comprising an effective amount of a crystalline polymorph of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate and at least one pharmaceutically acceptable excipient,

wherein the crystalline polymorph exhibits an attenuated total reflectance infrared spectrum having characteristic absorption bands expressed in reciprocal centimeters at approximately 1764, 1217, 795, 746 and 694.

5. The pharmaceutical composition according to claim 4 , wherein the crystalline polymorph exhibits an attenuated total reflectance infrared spectrum having characteristic absorption bands expressed in reciprocal centimeters at approximately 1764, 1636, 1284, 1217, 809, 795, 746, 694, 663 and 509.

6. A pharmaceutical composition comprising an effective amount of a crystalline polymorph of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate and at least one pharmaceutically acceptable excipient

wherein the crystalline polymorph exhibits an IR spectrum as shown in FIG. 3 .

7. A pharmaceutical composition comprising an effective amount of a crystalline polymorph of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate and at least one pharmaceutically acceptable excipient,

wherein the crystalline polymorph exhibits 13 C solid state NMR chemical shifts expressed relative to glycine (δ c =176.03 for the C═O resonance) at approximately 40.4, 48.7, 56.5, 106.8 and 137.7 ppm.

8. The pharmaceutical composition according to claim 7 , wherein the crystalline polymorph exhibits 13 C solid state NMR chemical shifts expressed relative to glycine (δ c =176.03 for the C═O resonance) at approximately 40.4, 48.7, 50.3, 56.5, 106.8, 110.7, 124.9, 126.9, 127.8, 129.2, 130.8, 134.2, 137.7, 141.6, and 153.8 ppm.

9. A pharmaceutical composition comprising an effective amount of a crystalline polymorph of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate and at least one pharmaceutically acceptable excipient,

wherein the crystalline polymorph exhibits a complete 13 C solid state NMR chemical as shown in FIG. 4 .

10. A pharmaceutical composition comprising an effective amount of a crystalline polymorph of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate and at least one pharmaceutically acceptable excipient,

wherein the crystalline polymorph exhibits a single crystal X-ray crystallographic analysis at 150K with (a) crystal parameters that are approximately equal to the following:

Cell dimensions

a = 9.283 Å

b = 10.737 Å

c = 12.690 Å

α = 98.553°

β = 93.749°

γ = 116.097°

 Crystal system

 triclinic

 Space group

P-1

 Molecules/unit cell

2

 Density (g/cm 3 )

 1.481

and (b) atomic positions of all atoms relative to the origin of the unit cell as recited in Table 5.

11. A pharmaceutical composition comprising an effective amount of a crystalline polymorph of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate and at least one pharmaceutically acceptable excipient,

wherein the crystalline polymorph exhibits a single X-ray diffraction substantially as shown in FIG. 5 .

12. A pharmaceutical composition comprising an effective amount of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate wherein the effective amount of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate is a mixture of the crystalline polymorphic forms α and γ, and at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising an effective amount of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate in which at least about 50 weight % of the 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate is in the crystalline polymorphic form α, and at least one pharmaceutically acceptable excipient.

14. The composition according to claim 13 , wherein at least about 60 weight % of the 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate is in the crystalline polymorphic form α.

15. The composition according to claim 14 , wherein at least about 80 weight % of the 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate is in the crystalline polymorphic form α.

16. The composition according to claim 15 , wherein at least about 90 weight % of the 7-[1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate is in the crystalline polymorphic form α.

17. The composition according to claim 16 , wherein at least about 95 weight % of the 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate is in the crystalline polymorphic form α.

18. A pharmaceutical composition comprising an effective amount of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate and at least one auxiliary material chosen from lactose monohydrate, microcrystalline cellulose, sodium starch glycolate type A and sodium stearyl fumarate.

19. The pharmaceutical composition according to claim 18 , wherein:

said effective amount of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate comprises an effective amount of crystalline polymorphic form α;

said lactose monohydrate is present in an amount ranging from about 70% to about 90% w/w;

said microcrystalline cellulose is present in an amount ranging from about 10% to about 15% w/w;

said sodium starch glycolate type A is present in an amount ranging from about 0.3% to about 0.7% w/w;

said sodium stearyl fumarate is present in an amount ranging from about 0.6% to about 1.3% w/w;

and optionally comprising colloidal anhydrous silica present in an amount ranging from 0 to about 0.5% w/w.

20. The pharmaceutical composition according to claim 18 , wherein said effective amount of 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate comprises an effective amount of a mixture of the crystalline polymorphic forms α and γ.

21. The pharmaceutical composition according to claim 20 , wherein:

said effective amount of 7-[4-([1,1′-biphenyl]-3-ylmethyl )-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate comprises an effective amount of the crystalline polymorphic forms α and γ;

said lactose monohydrate is present in an amount ranging from about 70% to about 90% w/w;

said microcrystalline cellulose is present in an amount ranging from about 10% to about 15% w/w;

said sodium starch glycolate type A is present in an amount ranging from about 0.3% to about 0.7% w/w;

said sodium stearyl fumarate is present in an amount ranging from about 0.6% to about 1.3% w/w;

and optionally comprising colloidal anhydrous silica present in an amount ranging from 0 to about 0.5% w/w.

22. A method for treating a CNS disorder in a human patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising the crystalline polymorphic form αof 7 [4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate in an amount effective for treatment of the disorder, wherein said CNS disorder is schizophrenia.

23. A method for treating a CNS disorder in a human patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising the crystalline polymorphic form αof 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate in an amount effective for treatment of the disorder, wherein said CNS disorder is chosen from a psychotic disorder and Parkinson's disease.

24. A method for treating a CNS disorder in a human patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a mixture of the polymorphic forms α and γ of 7-[4-([1,1′-biphenyl]3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate in an amount effective for treatment of the disorder, wherein said CNS disorder is schizophrenia.

25. A method for treating a CNS disorder in a human patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a mixture of the polymorphic forms αand γ of 7-[4-([1,1′-biphenyl]3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate in an amount effective for treatment of the disorder, wherein said CNS disorder is chosen from a psychotic disorder and Parkinson's disease.