Novel solid forms of bendamustine hydrochloride

Abstract

Novel solid forms of bendamustine hydrochloride are described, as well as methods of their preparation and use.

1 . A solid form of bendamustine hydrochloride that comprises at least one of bendamustine hydrochloride Form 1, bendamustine hydrochloride Form 3, bendamustine hydrochloride Form 4, amorphous bendamustine hydrochloride, or a mixture thereof. 
     
     
         2 . The solid form of bendamustine hydrochloride according to  claim 1 , comprising bendamustine hydrochloride Form 1. 
     
     
         3 . The solid form of bendamustine hydrochloride according to  claim 1 , comprising bendamustine hydrochloride Form 3. 
     
     
         4 . The solid form of bendamustine hydrochloride according to  claim 1 , comprising bendamustine hydrochloride Form 4. 
     
     
         5 . The solid form of bendamustine hydrochloride according to  claim 1 , comprising amorphous bendamustine hydrochloride. 
     
     
         6 . The solid form of bendamustine hydrochloride according to  claim 1  further comprising bendamustine hydrochloride Form 2. 
     
     
         7 . The solid form of bendamustine hydrochloride according to  claim 1  that produces an X-ray powder diffraction pattern comprising one or more of the following reflections: 25.1, 24.9, 22.9, 22.0, and/or 14.1±0.2 degrees 2θ. 
     
     
         8 . The solid form of bendamustine hydrochloride according to  claim 7  that produces an X-ray powder diffraction pattern further comprising one or more of the following reflections: 16.8, 17.5, 18.5, 24.9, and/or 28.3±0.2 degrees 2θ. 
     
     
         9 . The solid form of bendamustine hydrochloride according to  claim 1  that produces an X-ray powder diffraction pattern comprising one or more of the following reflections: 26.1, 27.9, and/or 28.1±0.2 degrees 2θ. 
     
     
         10 . The solid form of bendamustine hydrochloride according to  claim 9  that produces an X-ray powder diffraction pattern further comprising one or more of the following reflections: 10.6, 15.6, and/or 19.8±0.2 degrees 2θ. 
     
     
         11 . The solid form of bendamustine hydrochloride according to  claim 1  that produces an X-ray powder diffraction pattern comprising one or more of the following reflections: 10.8, 15.5, 20.5, and/or 23.6±0.2 degrees 2θ. 
     
     
         12 . The solid form of bendamustine hydrochloride according to  claim 11  that produces an X-ray powder diffraction pattern further comprising one or more of the following reflections: 10.3, 19.6, 20.7, 21.2, 25.8 and/or 27.6±0.2 degrees 2θ. 
     
     
         13 . A composition comprising the solid form of bendamustine hydrochloride according to  claim 1 . 
     
     
         14 . 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. 
     
     
         15 . The composition according to  claim 13  wherein the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient. 
     
     
         16 . The composition of  claim 15  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. 
     
     
         17 . The composition of  claim 16  wherein the excipient is mannitol. 
     
     
         18 . The composition according to  claim 14  wherein the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient. 
     
     
         19 . The composition of  claim 18  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. 
     
     
         20 . The composition of  claim 19  wherein the excipient is mannitol. 
     
     
         21 . A lyophilized composition comprising the solid form of bendamustine hydrochloride according to  claim 1 . 
     
     
         22 . The lyophilized composition according to  claim 21 , wherein the composition is substantially free of other solid forms of bendamustine hydrochloride. 
     
     
         23 . The lyophilized composition according to  claim 21 , comprising a mixture of amorphous bendamustine hydrochloride and bendamustine hydrochloride Form 4. 
     
     
         24 . The lyophilized composition according to  claim 21  that produces an X-ray powder diffraction pattern comprising one or more of the following reflections: 7.98, 10.58, 15.43, 19.64, and/or 19.89±0.2 degrees 2θ. 
     
     
         25 . 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 . 
     
     
         26 . The method according to  claim 25  wherein the non-Hodgkin's lymphoma is indolent B-cell non-Hodgkin's lymphoma. 
     
     
         27 . A method for preparing a lyophilized composition that comprises at least one crystalline form of bendamustine hydrochloride, said method comprising the steps of:
 combining bendamustine hydrochloride with at least one solvent to form a solution; and   lyophilizing the solution.   
     
     
         28 . The method according to  claim 27 , wherein the solution further comprises at least one lyophilization excipient. 
     
     
         29 . The method according to  claim 28 , wherein the lyophilization 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. 
     
     
         30 . The method according to  claim 28 , wherein the lyophilization excipient is mannitol. 
     
     
         31 . The method according to  claim 27 , wherein the solvent is water, an organic solvent, or a mixture thereof. 
     
     
         32 . The method according to  claim 31 , wherein the organic solvent is methanol, ethanol, n-propanol, iso-propanol, n-butanol, tert-butanol, or a mixture thereof. 
     
     
         33 . The method according to  claim 32 , wherein the organic solvent is tert-butanol. 
     
     
         34 . The method according to  claim 27 , wherein the solvent is a mixture of water and an organic solvent. 
     
     
         35 . The method according to  claim 34 , wherein the ratio of the water to the organic solvent is about 7:3 (v/v). 
     
     
         36 . The method according to  claim 27 , wherein said crystalline form of bendamustine hydrochloride is bendamustine hydrochloride Form 1, bendamustine hydrochloride Form 2, bendamustine hydrochloride Form 3, bendamustine hydrochloride Form 4, or a mixture thereof. 
     
     
         37 . The method according to  claim 36 , wherein said lyophilized composition further comprises amorphous bendamustine hydrochloride. 
     
     
         38 . The method according to  claim 36 , wherein said lyophilized composition comprises a mixture of bendamustine hydrochloride Form 4 and amorphous bendamustine hydrochloride. 
     
     
         39 . The method according to  claim 38 , wherein said lyophilized composition further comprises mannitol. 
     
     
         40 . A lyophilized composition prepared according to the method of  claim 27 .