Methods of preparing matrix pellet compositions
Provided herein are methods of treating tuberous sclerosis complex in a subject in need thereof by administering to the subject compositions comprising an mGlu5 negative allosteric modulator (NAM), having the structure of Formula I:
1 . A method of preparing a matrix pellet composition comprising a crystalline anhydrate form (Form A) of a monosulfate salt of a compound of Formula I:
the method comprising:
granulating the Form A monosulfate salt and one or more polymers with purified water to form a mixture;
extruding, spheronizing, drying, and sieving the mixture to afford a solid material; and
blending the solid material with another pharmaceutical excipient to afford a matrix pellet,
wherein the Form A monosulfate salt is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained with a Cu Ka radiation at 2θ (2 Theta): 9.8±0.2°, 13.4±0.2°, 14.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.6±0.2°, 22.6±0.2°, 22.9±0.2°, 25.7±0.2°, 27.1±0.2°, and 29.9±0.2°, and has a particle size (Dv50) of about 3.3 μm to about 10 μm.
2 . The method of claim 1 , wherein the one or more polymers are selected from the group consisting of a cellulose, methacrylic acid copolymer, and hypromellose.
3 . The method of claim 1 , wherein the other pharmaceutical excipient comprises talc.
4 . The method of claim 1 , wherein the matrix pellet composition is a modified release matrix pellet composition.
5 . The method of claim 1 , wherein the Form A monosulfate salt is characterized by the following XRPD peaks obtained with a Cu Ka radiation at 2θ (2 Theta): 9.8±0.2°, 13.4±0.2°, 14.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.6±0.2°, 22.6±0.2°, 22.9±0.2°, 25.7±0.2°, 27.1±0.2°, and 29.9±0.2°.
6 . The method of claim 1 , wherein the Form A monosulfate salt is present in the matrix pellet composition in an amount from about 0.05 mg to about 20 mg.
7 . The method of claim 1 , wherein the Form A monosulfate salt is present in the matrix pellet composition in an amount from about 0.5 mg to about 4.0 mg.
8 . The method of claim 1 , wherein the Form A monosulfate salt is present in the matrix pellet composition in an amount of about 0.65 mg.
9 . The method of claim 1 , wherein the Form A monosulfate salt is present in the matrix pellet composition in an amount of about 1.3 mg.
10 . The method of claim 1 , wherein the Form A monosulfate salt is present in the matrix pellet composition in an amount from about 0.01% to about 20% by weight, based on the total weight of the matrix pellet composition.
11 . The method of claim 1 , wherein the Form A monosulfate salt is present in the matrix pellet composition in an amount from about 0.1% to about 2% by weight, based on the total weight of the matrix pellet composition.
12 . The method of claim 1 , wherein the Form A monosulfate salt is present in the matrix pellet composition in an amount of about 0.13% by weight, based on the total weight of the matrix pellet composition.
13 . The method of claim 1 , wherein the Form A monosulfate salt is present in the matrix pellet composition in an amount of about 1.3% by weight, based on the total weight of the matrix pellet composition.