Solid forms of bendamustine hydrochloride
Novel solid forms of bendamustine hydrochloride are described, as well as methods of their preparation and use.
1. A method of treating chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, or breast cancer in a patient in need thereof comprising
administering to the patient a solution prepared from a lyophilized composition comprising a crystalline form of bendamustine hydrochloride that is bendamustine hydrochloride Form 3 that produces an X-ray powder diffraction pattern comprising the following reflections: 7.9, 15.5, and 26.1±0.2 degrees 2θ.
2. The method according to claim 1 , wherein the non-Hodgkin's lymphoma is indolent B-cell non-Hodgkin's lymphoma.
3. The method of according to claim 1 , for treating chronic lymphocytic leukemia.
4. The method according to claim 1 , wherein the bendamustine hydrochloride Form 3 produces an X-ray powder diffraction pattern further comprising one or more of the following reflections: 10.6, 19.7 and/or 23.3±0.2 degrees 2θ.
5. The method according to claim 1 , wherein the lyophilized composition is substantially free of other crystalline forms of bendamustine hydrochloride.
6. The method according to claim 1 , wherein the lyophilized composition further comprises amorphous bendamustine hydrochloride.
7. The method according to claim 1 , wherein the lyophilized composition further comprises at least one pharmaceutically acceptable excipient.
8. The method according to claim 7 , wherein the 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.
9. The method according to claim 8 , wherein the excipient is mannitol.
10. The method according to claim 1 , wherein the lyophilized composition further comprises an organic solvent.
11. The method according to claim 10 , wherein the solvent is methanol, ethanol, n-propanol, iso-propanol, n-butanol, tert-butanol, or mixtures thereof.
12. The method according to claim 11 , wherein the solvent is tert-butanol.
13. A method for preparing a crystalline form of bendamustine hydrochloride that is bendamustine hydrochloride Form 3 that produces an X-ray powder diffraction pattern comprising the following reflections: 7.9, 15.5, and 26.1±0.2 degrees 2θ comprising
combining bendamustine hydrochloride, mannitol, water, and an organic solvent to form a solution; and
lyophilizing the solution to form the bendamustine hydrochloride Form 3.
14. The method according to claim 13 , wherein the bendamustine hydrochloride Form 3 produces an X-ray powder diffraction pattern further comprising one or more of the following reflections: 10.6, 19.7 and/or 23.3±0.2 degrees 2θ.
15. The method according to claim 13 , wherein the solvent is methanol, ethanol, n-propanol, iso-propanol, n-butanol, tert-butanol, or mixtures thereof.
16. The method according to claim 13 , wherein the solvent is tert-butanol.
17. The method according to claim 13 , 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. The method according to claim 13 , wherein the ratio of bendamustine hydrochloride to mannitol is 15:25.5.
19. A lyophilized composition comprising bendamustine hydrochloride prepared according to the method of claim 13 .
20. A method of treating chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma or breast cancer in a patient in need thereof comprising administering to the patient an injectable preparation prepared from the lyophilized composition of claim 19 .
21. The method according to claim 20 , wherein the non-Hodgkin's lymphoma is indolent B-cell non-Hodgkin's lymphoma.
22. The method of according to claim 20 , for treating chronic lymphocytic leukemia.