Solid forms of bendamustine hydrochloride
Novel solid forms of bendamustine hydrochloride are described, as well as methods of their preparation and use.
1. A solid form of bendamustine hydrochloride, designated as bendamustine hydrochloride Form 1, that produces an X-ray powder diffraction pattern comprising the following reflections: 8.3, 16.8, and 18.5±0.2 degrees 2θ.
2. The solid form of bendamustine hydrochloride according to claim 1 that produces an X-ray powder diffraction pattern further comprising the following reflections: 14.0, 22.0, 22.9, 25.1, and 28.3±0.2 degrees 2θ.
3. The solid form of bendamustine hydrochloride according to claim 1 that produces an X-ray powder diffraction pattern further comprising a reflection at 14.0±0.2 degrees 2θ.
4. A composition comprising the solid form of bendamustine hydrochloride according to claim 1 .
5. A composition comprising the solid form of bendamustine hydrochloride according to claim 1 , wherein the composition is substantially free of other solid forms of bendamustine hydrochloride.
6. The composition according to claim 4 wherein the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.
7. The composition of claim 6 wherein the pharmaceutically acceptable excipient is sodium phosphate, potassium phosphate, citric acid, tartaric acid, gelatin, glycine, mannitol, lactose, sucrose, maltose, glycerin, dextrose, dextran, trehalose, hetastarch, or a mixture thereof.
8. The composition of claim 7 wherein the excipient is mannitol.
9. The composition according to claim 5 wherein the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.
10. The composition of claim 9 wherein the pharmaceutically acceptable excipient is sodium phosphate, potassium phosphate, citric acid, tartaric acid, gelatin, glycine, mannitol, lactose, sucrose, maltose, glycerin, dextrose, dextran, trehalose, hetastarch, or a mixture thereof.
11. The composition of claim 10 wherein the excipient is mannitol.
12. A method of treating chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma or breast cancer in a patient comprising administering to the patient a lyophilized composition comprising the solid form of bendamustine hydrochloride according to claim 1 .
13. The method according to claim 12 wherein the non-Hodgkin's lymphoma is indolent B-cell non-Hodgkin's lymphoma.
14. A method for preparing a lyophilized composition comprising bendamustine hydrochloride comprising:
combining the bendamustine hydrochloride Form 1, according to claim 1 , mannitol, water, and an organic solvent to form a solution; and
lyophilizing the solution to form the lyophilized composition comprising bendamustine hydrochloride.
15. The method of claim 14 , wherein the solvent is methanol, n-propanol, isopropanol, n-butanol, tert-butanol, or a mixture thereof.
16. The method of claim 14 , wherein the solvent is tert-butanol.
17. The method of claim 14 , wherein the lyophilization step comprises the following lyophilization cycle:
Process parameters
Target Setpoint
Loading temperature
5° C.
Freezing temperature
Hold at −50° C. for 4 hours
Primary drying vacuum
150 microns
Primary drying temperature
Hold at −15° C. for 27 hours
Intermediate drying temperature
Hold at −12° C. for 7 hours
Secondary drying vacuum
50 microns
Secondary drying temperature
Hold at 40° C. for 15 hours.
18. A lyophilized composition comprising bendamustine hydrochloride prepared according to the method of any one of claims 14 to 17 .
19. A method of treating chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma or breast cancer in a patient comprising administering to the patient an injectable preparation prepared from the lyophilized composition of claim 18 .