Stable crystalline form of bifeprunox mesylate (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate)
AssigneeSolvay Pharmaceuticals GmbH
InventorsIrene Eijgendaal, Gerrit Klein, Maria J. L. Terhorst-Van Amstel, Klaas Zwier, Nico Bruins, Hendrikus T. Rigter, Erik Gout
Life of this patent
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Abstract
The invention relates to a stable polymorphic form of the compound 7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate (INNM bifeprunox mesylate), a method for the preparation of said polymorphic form and its use in pharmaceutical products, especially in pharmaceutical products for the treatment of psychotic disorders and Parkinson's disease.
Claims25
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.
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.
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.
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.
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.
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 13C solid state NMR chemical shifts expressed relative to glycine (δc=176.03 for the C═O resonance) at approximately 40.4, 48.7, 56.5, 106.8 and 137.7 ppm.
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 13C solid state NMR chemical as shown in FIG. 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 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/cm3)
- 1.481
- and (b) atomic positions of all atoms relative to the origin of the unit cell as recited in Table 5.
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.
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.
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.
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.
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.
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.
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.
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.
Dependencies are inferred from the claim text.