Crystalline and other forms of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactic acid salts

Abstract

The present invention relates to non-hydrate crystalline forms of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid salts, solid pharmaceutical formulations containing the same and methods of use. The present invention also relates to crystalline hydrates of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid salts, pharmaceutical formulations containing the same and methods of use related thereto. The present invention further relates to crystalline solvates of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid salts.

1 . A solid formulation of a lactic acid salt of the compound of formula I: 
       
         
           
           
               
               
           
         
         for oral administration wherein said formulation comprises a non-hydrate crystalline form of said lactic acid salt of the compound of formula I. 
       
     
     
         2 . The formulation of  claim 1  wherein said non-hydrate crystalline form is Form A. 
     
     
         3 . The formulation of  claim 2  wherein said Form A is prepared by stirring the compound of formula I in a solution comprising water, organic solvent and lactic acid. 
     
     
         4 . The formulation of  claim 3  wherein said organic solvent is an alcohol. 
     
     
         5 . The formulation of  claim 4  wherein said alcohol is ethanol. 
     
     
         6 . The formulation of  claim 1  wherein said lactic acid salt of formula I is a mono-lactic acid salt. 
     
     
         7 . The formulation of  claim 1  in the form of a powder. 
     
     
         8 . A method of treating a patient with a solid formulation of a lactic acid salt of a compound of formula I: 
       
         
           
           
               
               
           
         
         comprising orally administering said formulation, wherein said formulation comprises a non-hydrate crystalline form or of said lactic acid salt of the compound of formula I. 
       
     
     
         9 . The method of  claim 8  wherein said non-hydrate crystalline form is Form A. 
     
     
         10 . The method of  claim 8  wherein said patient is a cancer patient. 
     
     
         11 . The method of  claim 10  wherein said patient is diagnosed with multiple myeloma (MM), acute myelogenous leukemia (AML), prostate cancer, breast cancer, colon cancer, or melanoma. 
     
     
         12 . The method of  claim 10  wherein said patient is a refractory patient. 
     
     
         13 . The method of  claim 8 , wherein said formulation comprises said non-hydrate crystalline form of said lactic acid salt of the compound of formula I in an amount sufficient to provide to said patient between about 0.25 and about 30 mg of formula I free base per kg body weight. 
     
     
         14 . The method of  claim 8  wherein said formulation is in solid form at the time of administration. 
     
     
         15 . The formulation of  claim 1  wherein said formulation is prepared in the form of a pill, tablet, capsule, or a caplet. 
     
     
         16 . A crystalline form (Form A) of a lactic acid salt of the compound of formula I: 
       
         
           
           
               
               
           
         
         wherein said crystalline form has an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2θ, at about 5.7° and about 25.9°. 
       
     
     
         17 . The crystalline form of  claim 16  further having a characteristic peak, in terms of 2θ, at about 15.9°. 
     
     
         18 . The crystalline form of  claim 17  further having a characteristic peak, in terms of 2θ, at about 12.4°. 
     
     
         19 . The crystalline form of  claim 18  further having a characteristic peak, in terms of 2θ, at about 17.0°. 
     
     
         20 . A crystalline form (Form A) of a lactic acid salt of the compound of formula I: 
       
         
           
           
               
               
           
         
         wherein said crystalline form, has an X-ray powder diffraction pattern comprising at least 3 characteristic peaks, in terms of 2θ, selected from at about 5.7, about 11.3, about 12.4, about 15.3, about 15.9, about 17.0, about 19.1, about 19.7, about 20.5, about 20.9, about 22.8, about 23.4, about 23.7, about 24.7, about 25.0, about 25.9, about 26.9, and about 31.2 degrees. 
       
     
     
         21 . The crystalline form of  claim 16  having an X-ray powder diffraction pattern substantially as shown in  FIG. 1 . 
     
     
         22 . The crystalline form of  claim 16  having a differential scanning calorimetry thermogram showing an endotherm at about 210° C. 
     
     
         23 . The crystalline form of  claim 16  having a differential scanning calorimetry thermogram substantially as shown in  FIG. 2 . 
     
     
         24 . A composition comprising the crystalline form of  claim 16 . 
     
     
         25 . The composition of  claim 24  wherein at least about 50% by weight of total lactic acid salt of the compound of formula I in said composition is present as said crystal form. 
     
     
         26 . The composition of  claim 24  wherein at least about 70% by weight of total lactic acid salt of the compound of formula I in said composition is present as said crystal form. 
     
     
         27 . The composition of  claim 24  wherein at least about 80% by weight of total lactic acid salt of the compound of formula I in said composition is present as said crystal form. 
     
     
         28 . The composition of  claim 24  wherein at least about 90% by weight of total lactic acid salt of the compound of formula I in said composition is present as said crystal form. 
     
     
         29 . The composition of  claim 24  wherein at least about 95% by weight of total lactic acid salt of the compound of formula I in said composition is present as said crystal form. 
     
     
         30 . The composition of  claim 24  wherein at least about 97% by weight of total lactic acid salt of the compound of formula I in said composition is present as said crystal form. 
     
     
         31 . The composition of  claim 24  wherein at least about 98% by weight of total lactic acid salt of the compound of formula I in said composition is present as said crystal form. 
     
     
         32 . The composition of  claim 24  wherein at least about 99% by weight of total lactic acid salt of the compound of formula I in said composition is present as said crystal form. 
     
     
         33 . The composition of  claim 24  further comprising a pharmaceutically acceptable carrier. 
     
     
         34 . A composition consisting essentially of the lactic acid salt of the compound of formula I: 
       
         
           
           
               
               
           
         
         wherein at least 95% by weight of said lactic acid salt of the compound of formula I is present in said composition as said crystal form of  claim 16 . 
       
     
     
         35 . A composition consisting essentially of said lactic acid salt of the compound of formula I wherein at least 97% by weight of said lactic acid salt of the compound of formula I is present in said composition as said crystal form of  claim 16 . 
     
     
         36 . A composition consisting essentially of said lactic acid salt of the compound of formula I wherein at least 98% by weight of said lactic acid salt of the compound of formula I is present in said composition as said crystal form of  claim 16 . 
     
     
         37 . A composition consisting essentially of said lactic acid salt of the compound of formula I wherein at least 99% by weight of said lactic acid salt of the compound of formula I is present in said composition as said crystal form of  claim 16 . 
     
     
         38 . A method of preparing the crystalline form of  claim 16  comprising stirring the compound of formula I in a solution comprising water, organic solvent and lactic acid. 
     
     
         39 . A crystalline hydrate of a lactic acid salt of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
     
     
         40 . The hydrate of  claim 39  wherein the molar ratio of the hydrate water to the lactic acid salt of the compound of Formula I is about 1 or about 6. 
     
     
         41 . The hydrate of  claim 39  which is a monohydrate or hexahydrate. 
     
     
         42 . The hydrate of  claim 41  which is a mono-lactic acid salt. 
     
     
         43 . The hydrate of  claim 39  (Form B) having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2θ, at about 17.6°, about 19.3° and about 26.0°. 
     
     
         44 . The hydrate of  claim 43 , wherein said X-ray powder diffraction pattern of said hydrate further comprises characteristic peaks, in terms of 2θ, at about 23.3°, about 23.5° and about 28.2°. 
     
     
         45 . The hydrate of  claim 44 , wherein said X-ray powder diffraction pattern of said hydrate further comprises characteristic peaks, in terms of 2θ, at about 11.9°, about 15.3°, about 16.1°, and about 18.5°. 
     
     
         46 . The hydrate of  claim 45 , wherein said X-ray powder diffraction pattern of said hydrate further comprises characteristic peaks, in terms of 2θ, at about 10.2° and about 12.9°. 
     
     
         47 . The hydrate of  claim 43 , wherein said crystalline form has an X-ray powder diffraction pattern comprising at least 3 characteristic peaks, in terms of 2θ, selected from: at about 10.2, about 11.3, about 11.6, about 11.9, about 12.9, about 15.3, about 15.6, about 16.1, about 17.6, about 18.5, about 19.3, about 22.3, about 23.3, about 23.5, about 23.9, about 26.0, about 28.2, about 29.3, about 29.8, about 30.7, about 32.2, about 32.6, about 33.1 and about 34.3°. 
     
     
         48 . The hydrate of  claim 43 , wherein said X-ray powder diffraction pattern of said hydrate is substantially as shown in  FIG. 6 . 
     
     
         49 . The hydrate of  claim 43 , having a differential scanning calorimetry thermogram comprising an endotherm at about 155° C. 
     
     
         50 . A composition comprising a hydrate according to  claim 39 ,  40 ,  41 ,  42  or  43 . 
     
     
         51 . The composition of  claim 50 , wherein at least about 50% by weight of hydrate present in said composition is present as Form B. 
     
     
         52 . The composition of  claim 50 , wherein at least about 70% by weight of hydrate present in said composition is present as Form B. 
     
     
         53 . The composition of  claim 50 , wherein at least about 80% by weight of hydrate present in said composition is present as Form B. 
     
     
         54 . The composition of  claim 50 , wherein at least about 90% by weight of hydrate present in said composition is present as Form B. 
     
     
         55 . The composition of  claim 50 , wherein at least about 95% by weight of hydrate present in said composition is present as Form B. 
     
     
         56 . The composition of  claim 50 , wherein at least about 99% by weight of hydrate present in said composition is present as Form B. 
     
     
         57 . The composition of  claim 50 , further comprising a pharmaceutically acceptable carrier. 
     
     
         58 . A method for preparing the hydrate of  claim 43 , comprising suspending Form. A in a solution comprising water and an organic solvent at a temperature of about 20° C. to about 60° C., wherein said water is present in said solution in an amount of about 5% to about 20% by volume. 
     
     
         59 . The method of  claim 58 , wherein said organic solvent comprises an alcohol, a ketone, an organic nitrile, or mixture thereof. 
     
     
         60 . The method of  claim 58 , wherein said organic solvent comprises one or more of ethanol, acetone, methyl ethyl ketone, and acetonitrile. 
     
     
         61 . A hydrate of a lactic acid salt of a compound of Formula I prepared by the method of  claim 58 . 
     
     
         62 . A solid formulation for oral administration comprising a hydrate according to  claim 39 ,  40 ,  41 ,  42 ,  43 , or  61 . 
     
     
         63 . The formulation of  claim 62 , wherein said formulation is in the form of a powder. 
     
     
         64 . The formulation of  claim 62  wherein said hydrate remains substantially intact under ambient conditions for a period greater than about 36 hours. 
     
     
         65 . The formulation of  claim 62  wherein said hydrate remains substantially intact under ambient conditions for a period greater than about 1 week. 
     
     
         66 . The formulation of  claim 62  wherein said hydrate remains substantially intact under ambient conditions for a period greater than about 1 month. 
     
     
         67 . The formulation of  claim 62  wherein said hydrate remains substantially intact under ambient conditions for a period greater than about 6 months. 
     
     
         68 . The formulation of  claim 62  wherein said hydrate remains substantially intact under ambient conditions for a period greater than about 1 year. 
     
     
         69 . A dosage form comprising a formulation according to  claim 62 . 
     
     
         70 . The dosage form of  claim 69 , wherein said dosage form is a powder, pill, tablet, capsule, caplet, pellets, or granules. 
     
     
         71 . A method of treating a patient, said method comprising administering to said patient a pharmaceutical formulation comprising a hydrate of  claim 39 ,  40 ,  41 ,  42 ,  43 , or  61 . 
     
     
         72 . The method of  claim 71 , wherein said patient is a cancer patient. 
     
     
         73 . The method of  claim 71 , wherein said patient has been diagnosed with multiple myeloma (MM), acute myelogenous leukemia (AML), prostate cancer, breast cancer, colon cancer, or melanoma. 
     
     
         74 . The method of  claim 71 , wherein said patient is a refractory patient. 
     
     
         75 . The method of  claim 71  wherein said patient is treated with a dose that is less than the maximum tolerated dose (MTD). 
     
     
         76 . The method of  claim 71  wherein said dose comprises 0.25 to 30 mg/kg of the lactic acid salt of the compound of formula I. 
     
     
         77 . The method of  claim 71 , wherein said formulation is in solid form at the time of administration. 
     
     
         78 . The hydrate of  claim 39  which is a monohydrate.