Formulation of syk inhibitors
Disclosed are pharmaceutical compositions comprising a compound having the formula: or a pharmaceutically acceptable salt thereof, or a hydrate of thereof, and at least one pharmaceutically acceptable polymer. The pharmaceutically acceptable salt of the compound of Formula I, or a hydrate thereof, can be a mesylate salt, including, for example, a mono-mesylate or a bis-mesylate salt, or a hydrate thereof. Also disclosed are methods of use for the pharmaceutical composition.
1. A method of manufacturing a tablet, comprising:
a) forming spray-dried powder from a feed solution, wherein the feed solution comprises:
(i) a compound of Formula I:
or a cation thereof;
(ii) methanesulfonic acid, or an anion thereof;
(iii) at least one pharmaceutically acceptable carrier; and
(iv) water; and
b) dry granulating the spray-dried powder and at least one additional pharmaceutically acceptable carrier to form a granulation; and
c) compressing the granulation to form the tablet.
2. The method of claim 1 , wherein the methanesulfonic acid or an anion thereof, and the compound of Formula I or a cation thereof, are present in the feed solution in a molar ratio of the methanesulfonic acid or an anion thereof, to the compound of Formula I or a cation thereof, of between 2:1 and 3:1.
3. The method of claim 1 , wherein the tablet comprises a bis-mesylate salt of the compound of Formula I, or a hydrate thereof.
4. The method of claim 3 , wherein the bis-mesylate salt of the compound of Formula I, or a hydrate thereof is a monohydrate, bis-mesylate salt of the compound of Formula I.
5. The method of claim 1 , wherein the spray-dried powder is characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, at 6.3 and between 26.1 to 26.6.
6. The method of claim 1 , wherein the spray-dried powder has a mean particle size between 1 μm to 100 μm.
7. The method of claim 1 , wherein the granulation has a mean particle size between 200 μm to 400 μm.
8. The method of claim 1 , wherein the at least one pharmaceutically acceptable carrier is crospovidone.
9. The method of claim 1 , wherein the at least one pharmaceutically acceptable carrier is hydroxypropylmethylcellulose.
10. A method of manufacturing a tablet, comprising:
a) dry granulating:
(i) a bis-mesylate salt of a compound of Formula I:
or a hydrate thereof, and
(ii) at least one pharmaceutically acceptable carrier to form a granulation; and
b) compressing the granulation to form the tablet.
11. The method of claim 10 , wherein the bis-mesylate salt of the compound of Formula I or a hydrate thereof is a monohydrate, bis-mesylate salt of the compound of Formula I that is characterized by an X-ray diffraction pattern comprising 2θ-reflections, plus or minus 0.2 degrees 2θ, selected from the group consisting of A: 13.8, 16.9, 22.9, and 26.1; B: 7.7, 12.9, 17.7, and 18.1; and C: 7.7, 12.9, 13.8, 16.9, 17.7, 18.1, 22.9, and 26.1.
12. The method of claim 10 , wherein the granulation has a mean particle size between 200 μm to 400 μm.
13. The method of claim 10 , wherein the at least one pharmaceutically acceptable carrier comprises crospovidone.
14. The method of claim 10 , wherein the at least one pharmaceutically acceptable carrier comprises hydroxypropylmethylcellulose.