Solid states of atorvastatin potassium

Abstract

Atorvastatin potassium crystalline Forms A, B, E, F, and G are provided. Also provided are methods of preparing atorvastatin potassium crystalline Forms A, B, E, F, and G. Atorvastatin potassium crystalline Forms A, B, E, F, and G may be used to prepare pharmaceutical compositions useful for the treatment of hypercholesterolemia or hyperlipidemia.

1 - 17 . (canceled) 
     
     
         18 . A process for preparing atorvastatin potassium Form A comprising mixing atorvastatin, tetrahydrofuran or an ethanol:water mixture, and potassium hydroxide to form a reaction mixture, and precipitating atorvastatin potassium Form A out of the reaction mixture by removing the solvent or by combining the reaction mixture with an antisolvent that is a liquid C 4 -C 6  ether or a C 5 -C 10  alkane. 
     
     
         19 . The process of  claim 18 , wherein the antisolvent is methyl tert butyl ether or heptane. 
     
     
         20 . The process of  claim 18 , wherein the atorvastatin is prepared from the pyrrole acetonide ester compound (PAE). 
     
     
         21 . The process of  claim 20 , wherein the solvent is an ethanol:water mixture. 
     
     
         22 . The process of  claim 21 , wherein the ethanol:water mixture is used at a volume ratio of about 1:0.1 to about 1:0.25 (v/v) ml ethanol to ml water. 
     
     
         23 . The process of  claim 22 , wherein the ethanol:water mixture is used at a volume ratio of about 1:0.19 (v/v). 
     
     
         24 . The process of  claim 20 , wherein the PAE and potassium hydroxide are added at a ratio of about 1:0.01 to about 1:0.3 (w/w) of grams PAE to grams potassium hydroxide. 
     
     
         25 . The process of  claim 24 , wherein the ratio is about 1:0.2 (w/w). 
     
     
         26 . The process of  claim 18 , wherein the atorvastatin is in its lactone form. 
     
     
         27 . The process of  claim 26 , wherein the solvent is tetrahydrofuran. 
     
     
         28 . The process of  claim 26 , wherein the atorvastatin lactone and potassium hydroxide are added at a ratio of about 1:0.1 to about 1:1.05 (w/w) of grams lactone atorvastatin to grams potassium hydroxide. 
     
     
         29 . The process of  claim 28 , wherein the ratio is about 1:0.16 (w/w). 
     
     
         30 . A crystalline form of atorvastatin potassium, denominated as Form B, characterized by data selected from the group consisting of:
 an X-ray powder diffraction pattern having peaks at 8.8, 19.0 and 20.5±0.3 degrees 2θ, and at least two peaks selected from the group consisting of 7.7, 9.8, 21.6, 23.9 and 26.9±0.3 degrees 2θ,   an XRPD pattern having peaks at 8.8, 19.0, 20.5, 23.9, and 26.9±0.3 degrees 2θ,   a solid-state  13 C NMR spectrum with signals at 129.2, 166.2 and 177.2±0.2 ppm,   a solid-state  13 C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another signal in the chemical shift range of 100 to 200 ppm of 11.6, 48.6 and 59.6±0.1 ppm wherein the lowest chemical shift in the chemical shift area of 100 to 200 ppm is at 117.6±1 ppm, and combinations thereof.   
     
     
         31 . The crystalline form of  claim 30 , characterized by an X-ray powder diffraction pattern having peaks at 8.8, 19.0 and 20.5±0.3 degrees 2θ, and at least two peaks selected from the group consisting of 7.7, 9.8, 21.6, 23.9 and 26.9±0.3 degrees 2θ. 
     
     
         32 . The crystalline form of  claim 30 , characterized by an XRPD pattern having peaks at 8.8, 19.0, 20.5, 23.9, and 26.9±0.3 degrees 2θ. 
     
     
         33 . The crystalline form of  claim 30 , characterized by a solid-state  13 C NMR spectrum with signals at 129.2, 166.2 and 177.2±0.2 ppm. 
     
     
         34 . The crystalline form of  claim 30 , characterized by a solid-state  13 C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another signal in the chemical shift range of 100 to 200 ppm of 11.6, 48.6 and 59.6±0.1 ppm wherein the lowest chemical shift in the chemical shift area of 100 to 200 ppm is at 117.6±1 ppm. 
     
     
         35 . The crystalline form of  claim 30 , characterized by XRPD patterns having peaks at: 7.7, 8.8, 9.8, 12.3, 15.9, 19.0, 20.5, 21.6, 23.9 and 26.9±0.3 degrees 2θ. 
     
     
         36 . The crystalline form of  claim 30 , characterized by an X-ray powder diffraction pattern as depicted in  FIG. 8  or a solid-state  13 C NMR spectrum as depicted in  FIG. 9  or  10 . 
     
     
         37 . The crystalline form of  claim 30 , characterized by having about 12% weight loss at the range of 30° C.-200° C. as determined by TGA. 
     
     
         38 . A process for preparing atorvastatin potassium Form B comprising mixing atorvastatin, ethanol and potassium hydroxide to form a reaction mixture, and precipitating atorvastatin potassium Form B out of the reaction mixture by combining the reaction mixture with an antisolvent that is a C 6 -C 10  aromatic hydrocarbon. 
     
     
         39 . The process of  claim 38 , wherein the antisolvent is toluene. 
     
     
         40 . The process of  claim 38 , wherein the atorvastatin is prepared from the PAE compound. 
     
     
         41 . The process of  claim 40 , wherein the PAE compound and potassium hydroxide are added at a ratio of about 1:0.1 to about 1:0.85 (w/w) of grams of the PAE compound to grams potassium hydroxide. 
     
     
         42 . The process of  claim 41 , wherein the ratio is about 1:0.22 (w/w). 
     
     
         43 . The process of  claim 18  or  38 , wherein the process is conducted at a temperature of about 25° C. to about 50° C. 
     
     
         44 . The process of  claim 43 , wherein the temperature is about 40° C. 
     
     
         45 . The process of  claim 18  or  38 , wherein, following the addition of the antisolvent, the reaction mixture is preferably cooled to a temperature of about 2° C. to about 20° C. 
     
     
         46 . The process of  claim 45 , wherein, following the addition of the antisolvent, the reaction mixture is preferably cooled to a temperature of about 5° C. 
     
     
         47 . The process of  claim 18  or  38 , wherein the potassium hydroxide is in a solid form. 
     
     
         48 . A process for preparing atorvastatin potassium Form III comprising suspending atorvastatin potassium Form A in ethanol. 
     
     
         49 . The process of  claim 48 , wherein the atorvastatin Form A and ethanol are added at a ratio of about 1:10 to about 1:20 (w/v) of grams Form A to ml ethanol. 
     
     
         50 . The process of  claim 49 , wherein the ratio is about 1:15 (w/v). 
     
     
         51 . The process of  claim 48 , conducted at a temperature of about 30° C. to about 50° C. 
     
     
         52 . The process of  claim 51 , conducted at a temperature of about 40° C. 
     
     
         53 . A crystalline form of atorvastatin potassium, denominated as Form E, characterized by an X-ray powder diffraction pattern having peaks at 4.5, 6.5-8.3 (broad peak) and 9.2±0.3 degrees 2θ. 
     
     
         54 . The crystalline form of  claim 53 , characterized by an X-ray powder diffraction pattern as depicted in  FIG. 19 . 
     
     
         55 . A process for preparing atorvastatin potassium Form E, comprising grinding atorvastatin potassium Form A in the presence of water. 
     
     
         56 . The process of  claim 55 , wherein about 1 to about 5 drops of water per 200 mg of atorvastatin potassium Form A are used. 
     
     
         57 . The process of  claim 56 , wherein about 2 to about 3 drops of water are used. 
     
     
         58 . A crystalline form of atorvastatin potassium, denominated as Form F, characterized by an X-ray powder diffraction pattern having peaks at 4.5, 5.1, 7.6, 11.2 and 17.6±0.2 degrees 2θ. 
     
     
         59 . The crystalline form of  claim 58 , characterized by an X-ray powder diffraction pattern as depicted in  FIG. 20 . 
     
     
         60 . A process for preparing atorvastatin potassium Form F, comprising grinding atorvastatin potassium Form A in the presence of ethanol. 
     
     
         61 . The process of  claim 60 , wherein 96% ethanol is used. 
     
     
         62 . The process of either  claim 60  or  61 , wherein about 1 to about 5 drops of ethanol per 200 mg of atorvastatin potassium Form A are used. 
     
     
         63 . The process of  claim 62 , wherein about 2 to about 3 drops of ethanol are used. 
     
     
         64 . A crystalline form of atorvastatin potassium, denominated as Form G, characterized by an X-ray powder diffraction pattern having two broad peaks with maxima at 7.1-7.4 and at 18.4-20.4±0.2 degrees 2θ. 
     
     
         65 . The crystalline form of  claim 64 , characterized by an X-ray powder diffraction pattern as depicted in  FIG. 21 . 
     
     
         66 . A process for preparing atorvastatin potassium Form G comprising grinding amorphous atorvastatin potassium in the presence of water. 
     
     
         67 . A process for preparing atorvastatin potassium Form G comprising exposing amorphous atorvastatin potassium to about 70% to about 100% relative humidity. 
     
     
         68 . The process of  claim 67 , wherein the relative humidity is about 100%. 
     
     
         69 . A process for preparing amorphous atorvastatin potassium comprising grinding atorvastatin potassium Form I in the presence of water. 
     
     
         70 . The process of  claim 69 , wherein about 1 to about 5 drops of water per 50 mg of atorvastatin potassium Form I are used. 
     
     
         71 . The process of  claim 70 , wherein about 2 to about 3 drops of water are used. 
     
     
         72 . The process of any one of  claim 55 ,  60 ,  66 , or  69 , wherein grinding is performed for a period of about 0.5 minute to about 5 minutes. 
     
     
         73 . The process of  claim 72 , wherein grinding is performed for a period of about 1 minute. 
     
     
         74 . A process for preparing amorphous atorvastatin potassium comprising exposing atorvastatin potassium Form I to about 70% to about 100% relative humidity. 
     
     
         75 . The process of  claim 74 , wherein the relative humidity is about 100%. 
     
     
         76 . The process of any one of  claim 67  or  74 , wherein the exposure is for a period of about 5 to about 14 days. 
     
     
         77 . The process of  claim 76 , wherein the exposure is for about 7 days. 
     
     
         78 . The process of any one of  claim 67  or  74 , wherein the process is conducted at a temperature of about 15° C. to about 25° C. 
     
     
         79 . A pharmaceutical composition comprising at least one of atorvastatin potassium crystalline Forms B, E, F or G and at least one pharmaceutically acceptable excipient. 
     
     
         80 . A process for preparing a pharmaceutical composition comprising at least one of atorvastatin potassium crystalline Forms B, E, F or G comprising combining atorvastatin potassium crystalline Forms B, E, F or G with at least one pharmaceutically acceptable excipient.