Crystalline particles of bis-choline tetrathiomolybdate
Novel crystalline particles, methods for manufacture of crystalline particles, and solid unit dosage forms, particularly tablets or capsules, of bis-choline tetrathiomolybdate are provided. In particular, provided herein are crystalline particles that allow for a more stable solid unit dosage form of bis-choline tetrathiomolybdate.
1. Crystalline particles of bis-choline tetrathiomolybdate (BC-TTM) having a 50 th percentile of particle size (D 50 ) of at least 30 μm.
2. The crystalline particles of claim 1 wherein the D 50 is at least 40 μm.
3. The crystalline particles of claim 2 wherein the D 50 is between 40 μm and 90 μm.
4. The crystalline particles of claim 1 having a 90 th percentile of particle size (D 90 ) of between 60 μm and 550 μm.
5. The crystalline particles of claim 4 wherein the D 90 is between 75 μm and 135 μm.
6. The crystalline particles of claim 5 wherein the D 90 is between 75 μm and 100 μm.
7. The crystalline particles of claim 1 having a specific surface area (SSA) less than 0.25 square meter per gram (m 2 /g).
8. The crystalline particles of claim 1 wherein less than 40% percent of particles are greater than 100 μm.
9. A composition comprising the crystalline particles of claim 1 having less than 1 percent by mass of the bis-choline salt of Mo 2 S 6 O 2 2− .
10. A composition comprising the crystalline particles of claim 1 having less than 0.2 percent by mass of the bis-choline salt of Mo 2 S 7 O 2− .
11. The composition of claim 9 wherein percent by mass of Mo 2 S 6 O 2 2− and/or the bis-choline salt of Mo 2 S 7 O 2− is measured after storage at 40° C. and 75 percent relative humidity for three to six days.
12. A composition comprising the crystalline particles of claim 1 having less than 0.5 percent by mass of total impurities.
13. The crystalline particles of claim 12 , wherein the total impurities comprise at least one of the bis-choline salts of TM1, TM2, TM3, Mo 2 S 6 O 2 2− , and Mo 2 S 7 O 2− .
14. The crystalline particles of claim 1 having a D 90 -to-D 50 ratio less than 3.0.
15. The crystalline particles of claim 1 , wherein the D 50 is less than 35 μm and/or D 90 is less than 75 μm.
16. A method for manufacture of the crystalline particles of bis-choline tetrathiomolybdate (BC-TTM) of claim 1 , comprising:
(a) providing a solution of BC-TTM in at least one solvent;
(b) heating the solution of BM-TTM to a first temperature of between 35° C. and 50° C.;
(c) gradually adding at least one of ethanol or isopropanol to the solution of BC-TTM over a time period of at least one hour, optionally at least two hours or two to four hours;
(d) cooling the solution of BC-TTM to a second temperature of between 10° C. and 25° C. to produce BC-TTM crystalline particles;
(e) filtering the BC-TTM crystalline particles;
(f) drying the BC-TMM crystalline particles at a third temperature of between 20° C. and 30° C. under reduced pressure.
17. The method of claim 16 , further comprising washing the BC-TTM crystalline particles with ethanol, optionally anhydrous ethanol, after filtering the BC-TTM crystalline particles and prior to drying the BC-TTM crystalline particles.
18. The method of claim 16 , wherein the solution of BC-TTM is produced by dissolving solid BC-TTM that has previously been crystallized one or more times.
19. The method of claim 16 , wherein the first temperature is between 40° C. and 45° C., the second temperature is 15° C., and/or the third temperature is 25° C.
20. A solid unit dosage form, comprising the crystalline particles of bis-choline tetrathiomolybdate of claim 1 .