Crystalline complexes
The present invention relates to crystalline complexes of sulforaphane and alpha-cyclodextrin; pharmaceutical compositions comprising the complexes; methods for their manufacture; and the use of said complexes as a medicament.
1 . A crystalline complex of sulforaphane and alpha-cyclodextrin having a water content of less than 8% w/w, wherein the crystalline form of the complex is stable between 0% and 60% relative humidity at 25° C.
2 . The crystalline complex according to claim 1 having a water content of less than 6% w/w.
3 . The crystalline complex according to claim 1 , wherein the molar ratio of sulforaphane to alpha-cyclodextrin in the complex is in the range 0.9:1 to 1.1:1.
4 . The crystalline complex according to claim 1 , wherein the molar ratio of sulforaphane to alpha-cyclodextrin in the complex is about 1:1.
5 . A crystalline complex of sulforaphane and alpha-cyclodextrin (Form 3), wherein the crystalline form of the complex is characterized by XRPD peaks at 5.3 and 10.7±0.2° 2θ, when measured in reflection mode.
6 . The crystalline complex according to claim 5 , further characterized by further XRPD peaks at 8.1 and 16.1±0.2° 2θ, when measured in reflection mode.
7 . The crystalline complex according to claim 5 that exhibits an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 4 when measured at room temperature using Cu Kα radiation.
8 . The crystalline complex according to claim 1 , wherein the complex comprises less than 5% w/w of particles greater than 2000 μm in diameter.
9 . A method for forming a crystalline complex of sulforaphane and alpha-cyclodextrin according to claim 1 , the method comprising the steps:
a) providing a complex of sulforaphane and alpha-cyclodextrin;
b) drying the complex from step a) with agitation of the complex at a pressure of less than 200 mbar, until the water content of the complex is less than 6% w/w.
10 . A solid pharmaceutical composition comprising an effective amount of the crystalline complex according to claim 1 , and optionally at least one pharmaceutically acceptable excipient.
11 . The solid pharmaceutical composition according to claim 10 , wherein greater than 50% of the crystalline complex of sulforaphane and alpha-cyclodextrin is characterized by XRPD peaks at 5.3 and 10.7±0.2° 2θ, when measured in reflection mode.
12 . The solid pharmaceutical composition according to claim 10 , wherein greater than 80% of the crystalline complex of sulforaphane and alpha-cyclodextrin is characterized by XRPD peaks at 5.3 and 10.7±0.2° 2θ, when measured in reflection mode.
13 . The solid pharmaceutical composition according to claim 10 , wherein the composition is formulated as a tablet or a capsule.
14 . A combination comprising a complex according to claim 1 and one or more additional therapeutic agents.
15 . The combination according to claim 14 , wherein the one or more additional therapeutic agents are selected from an aromatase inhibitor, tamoxifen, exemestane, fulvestrant, an oral SERD and a CDK4/6 inhibitor.