Polymorphs of 1-(2-Methylpropyl)-1H-Imidazo[4,5-C][1,5]Naphthyridin-4-Amine Ethane-Sulfonate

Abstract

The invention provides various crystalline forms of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate, pharmaceutical compositions, methods of making, and methods of use.

1 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate in crystalline Form A. 
   
   
       2 . The polymorph of  claim 1  having an X-ray powder diffraction pattern having peaks at 6.41 degrees two-theta, 9.20 degrees two-theta, and 26.40 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       3 . The polymorph of  claim 2  having an X-ray powder diffraction pattern having peaks at 6.41 degrees two-theta, 9.20 degrees two-theta, 12.77 degrees two-theta, 22.10 degrees two-theta, and 26.40 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       4 . The polymorph of  claim 1  having a unit cell with the following crystal interplanar spacings: about 13.76 Angstroms, about 9.60 Angstroms, and about 3.37 Angstroms. 
   
   
       5 . The polymorph of  claim 1  having a solid state  13 C NMR spectrum having peaks at 144.8 ppm, 124.7 ppm, and 55.9 ppm, wherein each of these values is ±0.3 ppm. 
   
   
       6 . The polymorph of  claim 5  having a solid state  13 C NMR spectrum having peaks at 144.8 ppm, 132.0 ppm, 124.7 ppm, and 55.9 ppm, wherein each of these values is ±0.3 ppm. 
   
   
       7 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having an X-ray powder diffraction pattern having peaks at 6.41 degrees two-theta, 9.20 degrees two-theta, 12.77 degrees two-theta, 15.87 degrees two-theta, 18.55 degrees two-theta, 19.15 degrees two-theta, 19.46 degrees two-theta, 22.10 degrees two-theta, 24.14 degrees two-theta, 26.40 degrees two-theta, and 28.49 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       8 . The polymorph of  claim 7  having a solid state  13 C NMR spectrum having peaks at 144.8 ppm, 124.7 ppm, and 55.9 ppm, wherein each of these values is ±0.3 ppm. 
   
   
       9 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having an X-ray powder diffraction pattern having peaks at 6.41 degrees two-theta, 7.72 degrees two-theta, 9.20 degrees two-theta, 11.63 degrees two-theta, 12.77 degrees two-theta, 15.39 degrees two-theta, 15.87 degrees two-theta, 16.32 degrees two-theta, 17.48 degrees two-theta, 18.55 degrees two-theta, 19.15 degrees two-theta, 19.46 degrees two-theta, 20.96 degrees two-theta, 22.10 degrees two-theta, 22.55 degrees two-theta, 23.00 degrees two-theta, 24.14 degrees two-theta, 24.97 degrees two-theta, 26.40 degrees two-theta, 27.36 degrees two-theta, 28.09 degrees two-theta, 28.49 degrees two-theta, 29.34 degrees two-theta, 30.87 degrees two-theta, 32.20 degrees two-theta, 33.68 degrees two-theta, and 34.21 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       10 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having an X-ray powder diffraction pattern substantially as depicted in  FIG. 1 . 
   
   
       11 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having a solid state  13 C NMR spectrum having peaks at 148.3 ppm, 144.8 ppm, 134.1 ppm, 132.0 ppm, 127.5 ppm, 124.7 ppm, 55.9 ppm, 45.8 ppm, 30.4 ppm, 21.3 ppm, and 9.8 ppm, wherein each of these values is ±0.3 ppm. 
   
   
       12 . The polymorph of  claim 11  having an X-ray powder diffraction pattern having peaks at 6.41 degrees two-theta, 9.20 degrees two-theta, and 26.40 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       13 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having a solid state  13 C NMR spectrum substantially as depicted in  FIG. 2 . 
   
   
       14 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate characterized by at least one of the following;
 an X-ray powder diffraction pattern having peaks at 6.41 degrees two-theta, 9.20 degrees two-theta, 12.77 degrees two-theta, 15.87 degrees two-theta, 18.55 degrees two-theta, 19.15 degrees two-theta, 19.46 degrees two-theta, 22.10 degrees two-theta, 24.14 degrees two-theta, 26.40 degrees two-theta, and 28.49 degrees two-theta, wherein each of these values is ±0.15 degree two-theta; or   a solid state  13 C NMR spectrum having peaks at 148.3 ppm, 144.8 ppm, 134.1 ppm, 132.0 ppm, 127.5 ppm, 124.7 ppm, 55.9 ppm, 45.8 ppm, 30.4 ppm, 21.3 ppm, and 9.8 ppm, wherein each of these values is ±0.3 ppm; and further characterized by at least one of the following:   a weight loss of 4.4% to 5.4% over a temperature range of 45° C. to 85° C. as measured by thermogravimetric analysis; or   an IR spectrum substantially as depicted in  FIG. 3 .   
   
   
       15 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate in crystalline Form B. 
   
   
       16 . The polymorph of  claim 15  having an X-ray powder diffraction pattern having peaks at 6.11 degrees two-theta, 15.15 degrees two-theta, and 25.55 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       17 . The polymorph of  claim 16  having an X-ray powder diffraction pattern having peaks at 6.11 degrees two-theta, 12.13 degrees two-theta, 15.15 degrees two-theta, 25.55 degrees two-theta, and 27.13 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       18 . The polymorph of  claim 15  having a unit cell with the following crystal interplanar spacings: about 14.45 Angstroms, about 5.84 Angstroms, and about 3.48 Angstroms. 
   
   
       19 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate having an X-ray powder diffraction pattern having peaks at 6.11 degrees two-theta, 6.46 degrees two-theta, 12.13 degrees two-theta, 12.80 degrees two-theta, 15.15 degrees two-theta, 15.95 degrees two-theta, 18.62 degrees two-theta, 19.12 degrees two-theta, 19.52 degrees two-theta, 20.60 degrees two-theta, 21.14 degrees two-theta, 24.21 degrees two-theta, 25.55 degrees two-theta, 27.13 degrees two-theta, and 28.52 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       20 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate having an X-ray powder diffraction pattern having peaks at 6.11 degrees two-theta, 6.46 degrees two-theta, 7.48 degrees two-theta, 8.76 degrees two-theta, 9.20 degrees two-theta, 10.64 degrees two-theta, 11.62 degrees two-theta, 12.13 degrees two-theta, 12.80 degrees two-theta, 14.77 degrees two-theta, 15.15 degrees two-theta, 15.95 degrees two-theta, 16.48 degrees two-theta, 17.47 degrees two-theta, 18.62 degrees two-theta, 19.12 degrees two-theta, 19.52 degrees two-theta, 19.88 degrees two-theta, 20.60 degrees two-theta, 21.14 degrees two-theta, 21.82 degrees two-theta, 22.24 degrees two-theta, 22.57 degrees two-theta, 22.81 degrees two-theta, 24.21 degrees two-theta, 25.55 degrees two-theta, 26.48 degrees two-theta, 27.13 degrees two-theta, 28.52 degrees two-theta, 29.94 degrees two-theta, 31.39 degrees two-theta, 32.19 degrees two-theta, 33.69 degrees two-theta, and 34.50 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       21 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate having an X-ray powder diffraction pattern substantially as depicted in  FIG. 4 . 
   
   
       22 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate characterized by:
 an X-ray powder diffraction pattern having peaks at 6.11 degrees two-theta, 6.46 degrees two-theta, 12.13 degrees two-theta, 12.80 degrees two-theta, 15.15 degrees two-theta, 15.95 degrees two-theta, 18.62 degrees two-theta, 19.12 degrees two-theta, 19.52 degrees two-theta, 20.60 degrees two-theta, 21.14 degrees two-theta, 24.21 degrees two-theta, 25.55 degrees two-theta, 27.13 degrees two-theta, and 28.52 degrees two-theta, wherein each of these values is ±0.15 degree two-theta; and   an IR spectrum substantially as depicted in  FIG. 19 .   
   
   
       23 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate in crystalline Form C. 
   
   
       24 . The polymorph of  claim 23  having an X-ray powder diffraction pattern having peaks at 6.98 degrees two-theta, 10.50 degrees two-theta, and 16.70 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       25 . The polymorph of  claim 24  having an X-ray powder diffraction pattern having peaks at 6.98 degrees two-theta, 10.50 degrees two-theta, 16.70 degrees two-theta, 18.11 degrees two-theta, and 26.02 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       26 . The polymorph of  claim 23  having a unit cell with the following crystal interplanar spacings: about 12.66 Angstroms, about 8.42 Angstroms, and about 5.30 Angstroms. 
   
   
       27 . The polymorph of  claim 23  having a solid state  13 C NMR spectrum having peaks at 127.5 ppm, 126.0 ppm, and 122.9 ppm, wherein each of these values is ±0.3 ppm. 
   
   
       28 . The polymorph of  claim 27  having a solid state  13 C NMR spectrum having peaks at 131.9 ppm, 127.5 ppm, 126.0 ppm, 122.9 ppm, and 56.2 ppm, wherein each of these values is ±0.3 ppm. 
   
   
       29 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having an X-ray powder diffraction pattern having peaks at 6.98 degrees two-theta, 10.50 degrees two-theta, 10.70 degrees two-theta, 16.70 degrees two-theta, 18.11 degrees two-theta, 18.88 degrees two-theta, 21.11 degrees two-theta, 26.02 degrees two-theta, and 28.51 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       30 . The polymorph of  claim 29  having a solid state  13 C NMR spectrum having peaks at 127.5 ppm, 126.0 ppm, and 122.9 ppm, wherein each of these values is ±0.3 ppm. 
   
   
       31 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having an X-ray powder diffraction pattern having peaks at 6.98 degrees two-theta, 8.96 degrees two-theta, 10.50 degrees two-theta, 10.70 degrees two-theta, 11.60 degrees two-theta, 14.46 degrees two-theta, 16.70 degrees two-theta, 17.27 degrees two-theta, 18.11 degrees two-theta, 18.47 degrees two-theta, 18.88 degrees two-theta, 20.57 degrees two-theta, 21.11 degrees two-theta, 21.39 degrees two-theta, 22.52 degrees two-theta, 23.04 degrees two-theta, 23.35 degrees two-theta, 23.84 degrees two-theta, 24.35 degrees two-theta, 26.02 degrees two-theta, 27.33 degrees two-theta, 27.92 degrees two-theta, 28.51 degrees two-theta, 29.42 degrees two-theta, 30.19 degrees two-theta, 31.47 degrees two-theta, 31.80 degrees two-theta, 32.45 degrees two-theta, 33.02 degrees two-theta, and 33.73 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       32 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having an X-ray powder diffraction pattern substantially as depicted in  FIG. 7 . 
   
   
       33 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having a solid state  13 C NMR spectrum having peaks at 148.0 ppm, 134.2 ppm, 131.9 ppm, 131.0 ppm, 127.5 ppm, 126.0 ppm, 122.9 ppm, 56.2 ppm, 45.5 ppm, 29.7 ppm, 21.8 ppm, and 10.5 ppm, wherein each of these values is ±0.3 ppm. 
   
   
       34 . The polymorph of  claim 33  having an X-ray powder diffraction pattern having peaks at 6.98 degrees two-theta, 10.50 degrees two-theta, and 16.70 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       35 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having a solid state  13 C NMR spectrum substantially as depicted in  FIG. 8 . 
   
   
       36 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate characterized by at least one of the following;
 an X-ray powder diffraction pattern having peaks at 6.98 degrees two-theta, 10.50 degrees two-theta, 10.70 degrees two-theta, 16.70 degrees two-theta, 18.11 degrees two-theta, 18.88 degrees two-theta, 21.11 degrees two-theta, 26.02 degrees two-theta, and 28.51 degrees two-theta, wherein each of these values is ±0.15 degree two-theta; or   a solid state  13 C NMR spectrum having peaks at 148.0 ppm, 134.2 ppm, 131.9 ppm, 131.0 ppm, 127.5 ppm, 126.0 ppm, 122.9 ppm, 56.2 ppm, 45.5 ppm, 29.7 ppm, 21.8 ppm, and 10.5 ppm, wherein each of these values is ±0.3 ppm; and further characterized by at least one of the following:   a weight loss of 4.3% to 5.3% over a temperature range of 70° C. to 100° C. as measured by thermogravimetric analysis; or   an IR spectrum substantially as depicted in  FIG. 16 .   
   
   
       37 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate in crystalline Form D. 
   
   
       38 . The polymorph of  claim 37  having an X-ray powder diffraction pattern having peaks at 7.35 degrees two-theta, 8.68 degrees two-theta, and 12.61 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       39 . The polymorph of  claim 33  having an X-ray powder diffraction pattern having peaks at 6.33 degrees two-theta, 7.35 degrees two-theta, 8.68 degrees two-theta, 12.61 degrees two-theta, and 17.35 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       40 . The polymorph of  claim 37  having a unit cell with the following crystal interplanar spacings: about 12.02 Angstroms, about 10.18 Angstroms, and about 7.02 Angstroms. 
   
   
       41 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having an X-ray powder diffraction pattern having peaks at 6.33 degrees two-theta, 7.04 degrees two-theta, 7.35 degrees two-theta, 8.68 degrees two-theta, 12.61 degrees two-theta, 14.74 degrees two-theta, 15.82 degrees two-theta, 17.35 degrees two-theta, 19.80 degrees two-theta, 21.68 degrees two-theta, and 24.12 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       42 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having an X-ray powder diffraction pattern having peaks at 6.33 degrees two-theta, 7.04 degrees two-theta, 7.35 degrees two-theta, 8.68 degrees two-theta, 10.61 degrees two-theta, 11.68 degrees two-theta, 12.61 degrees two-theta, 14.74 degrees two-theta, 15.82 degrees two-theta, 17.35 degrees two-theta, 18.08 degrees two-theta, 18.93 degrees two-theta, 19.80 degrees two-theta, 21.20 degrees two-theta, 21.68 degrees two-theta, 22.02 degrees two-theta, 22.81 degrees two-theta, 23.06 degrees two-theta, 24.12 degrees two-theta, 25.25 degrees two-theta, 26.23 degrees two-theta, 27.31 degrees two-theta, 27.64 degrees two-theta, 28.21 degrees two-theta, 29.51 degrees two-theta, 30.03 degrees two-theta, 31.02 degrees two-theta, 31.47 degrees two-theta, 32.30 degrees two-theta, and 34.39 degrees two-theta, wherein each of these values is ±0.15 degree two-theta. 
   
   
       43 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate having an X-ray powder diffraction pattern substantially as depicted in  FIG. 23 . 
   
   
       44 . A polymorph of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate monohydrate characterized by:
 an X-ray powder diffraction pattern having peaks at 6.33 degrees two-theta, 7.04 degrees two-theta, 7.35 degrees two-theta, 8.68 degrees two-theta, 12.61 degrees two-theta, 14.74 degrees two-theta, 15.82 degrees two-theta, 17.35 degrees two-theta, 19.80 degrees two-theta, 21.68 degrees two-theta, and 24.12 degrees two-theta, wherein each of these values is ±0.15 degree two-theta;   and further characterized by at least one of the following:   a weight loss of 4.2% to 5.2% over a temperature range of 55° C. to 95° C. as measured by thermogravimetric analysis; or   an IR spectrum substantially as depicted in  FIG. 20 .   
   
   
       45 . A mixture of two or more polymorphs of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate as described in  claims 1  through  44 . 
   
   
       46 . A pharmaceutical composition prepared by a method comprising combining a pharmaceutically acceptable carrier and a polymorph of any one of  claims 1  through  44  or a mixture of  claim 45  in an amount effective to provide a therapeutically effective amount of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate. 
   
   
       47 . A pharmaceutical composition comprising a therapeutically effective amount of a polymorph of any one of  claims 1  through  44  or a mixture of  claim 45 . 
   
   
       48 . A method of treating a neoplastic disease in an animal comprising administering a pharmaceutical composition of  claim 46  or  claim 47 . 
   
   
       49 . A method of treating a viral disease in an animal comprising administering a pharmaceutical composition of  claim 46  or  claim 47 . 
   
   
       50 . A method of inducing cytokine biosynthesis in an animal comprising administering a pharmaceutical composition of  claim 46  or  claim 47 . 
   
   
       51 . A method for preparing a crystalline form of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate, the method comprising:
 combining the free base of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine with ethanesulfonic acid and a carrier to form a mixture, wherein the carrier comprises an organic liquid and optionally water;   heating the free base, ethanesulfonic acid, and/or carrier prior to combining them, and/or heating the mixture thereof; and   forming a precipitate in the mixture.   
   
   
       52 . The method of  claim 51  wherein forming a precipitate comprises cooling the mixture to form a precipitate. 
   
   
       53 . The method of  claim 52  wherein cooling occurs at a rate less than 2.0° C. per minute. 
   
   
       54 . The method of  claim 53  wherein the carrier comprises at least 2 moles of water per mole of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free base present. 
   
   
       55 . The method of  claim 52  or  53  wherein the crystalline form of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate is Form C. 
   
   
       56 . The method of  claim 52  wherein cooling occurs at a rate greater than or equal to 2.0° C. per minute. 
   
   
       57 . The method of  claim 56  wherein the carrier comprises 1 vol-% to 15 vol-% water in an organic liquid. 
   
   
       58 . The method of  claim 56  or  claim 57  wherein the crystalline form of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate is Form A. 
   
   
       59 . The method of  claim 51  wherein the carrier comprises at least 2 moles of water per mole of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free base present. 
   
   
       60 . The method of  claim 59  wherein the crystalline form of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate is either Form A or Form C. 
   
   
       61 . The method of any one of  claims 51 ,  54 ,  57 , and  59  wherein the organic liquid is a C 1-4  alcohol. 
   
   
       62 . The method of  claim 51  wherein the carrier comprises less than 1 vol-% water. 
   
   
       63 . The method of  claim 59  wherein the organic liquid is ethyl acetate. 
   
   
       64 . The method of  claim 63  wherein the crystalline form of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate is Form C. 
   
   
       65 . The method of  claim 51  wherein combining comprises adding ethanesulfonic acid to the free base in the carrier. 
   
   
       66 . The method of  claim 51  further comprising:
 optionally adding an additional organic liquid to the mixture comprising the precipitate;   separating at least a portion of the precipitate from at least a portion of the mixture;   washing the precipitate; and   at least partially drying the precipitate.   
   
   
       67 . The method of  claim 66  wherein the additional organic liquid is an ether. 
   
   
       68 . The method of  claim 67  wherein the additional organic liquid is tert-butyl methyl ether. 
   
   
       69 . The method of  claim 68  wherein 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate is prepared in crystalline Form B or crystalline Form C. 
   
   
       70 . The method of  claim 66  wherein at least partially drying the precipitate occurs at a temperature range of 25° C. to 60° C. 
   
   
       71 . The method of  claim 70  wherein at least partially drying the precipitate occurs under at least a partial vacuum. 
   
   
       72 . A method of obtaining crystalline Form C of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate from crystalline Form B, the method comprising:
 combining Form B with a carrier comprising an organic liquid and optionally water to form a mixture; and   agitating the mixture for a time sufficient to provide at least a portion of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate in crystalline Form C.   
   
   
       73 . The method of  claim 72  wherein the carrier comprises water, isopropyl alcohol, or tert-butyl methyl ether. 
   
   
       74 . The method of  claim 73  wherein the carrier contains 2% to 5% water, 5% to 10% isopropyl alcohol, and 85% to 93% tert-butyl methyl ether. 
   
   
       75 . The method of  claim 72  wherein the mixture is agitated for at least 8 hours. 
   
   
       76 . The method of  claim 72  further comprising separating at least a portion of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate from at least a portion of the mixture. 
   
   
       77 . The method of  claim 76  further comprising washing and at least partially drying 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate. 
   
   
       78 . A method of obtaining crystalline Form A of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate from crystalline Form B, the method comprising exposing Form B to an atmosphere comprising water vapor. 
   
   
       79 . The method of  claim 78  wherein the atmosphere comprising water vapor has at least 30% relative humidity. 
   
   
       80 . A method of forming crystalline Form B of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate from crystalline Form A, the method comprising removing at least a portion of the water from crystalline Form A. 
   
   
       81 . The method of  claim 80  wherein removing water from crystalline Form A comprises exposing crystalline Form A to a desiccant. 
   
   
       82 . The method of  claim 80  wherein removing water from Form A comprises exposing Form A to at least a partial vacuum. 
   
   
       83 . The method of  claim 81  or  claim 82  further comprising heating crystalline Form A for a period of time and temperature sufficient to convert at least a portion of crystalline Form A to crystalline Form B. 
   
   
       84 . The method of  claim 83  wherein heating crystalline Form A is carried out at a temperature greater than or equal to 40° C. 
   
   
       85 . A method for preparing 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine, the method comprising:
 providing 1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in a carrier comprising a lower alcohol;   combining the 1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an ammonia- or ammonium-containing reagent to form a first mixture;   combining an arylsulfonyl halide with the first mixture to form a second mixture;   allowing the components of the second mixture to react for a period of time sufficient to form 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine; and   combining the second mixture with an aqueous base.   
   
   
       86 . The method of  claim 85  wherein the ammonia- or ammonium-containing reagent comprises ammonium hydroxide in water. 
   
   
       87 . The method of  claim 85  wherein the arylsulfonyl halide is benzenesulfonyl chloride or p-toluenesulfonyl chloride. 
   
   
       88 . The method of  claim 85  wherein the ammonia- or ammonium-containing reagent is added prior to the arylsulfonyl halide. 
   
   
       89 . The method of  claim 85  wherein the aqueous base comprises aqueous sodium hydroxide. 
   
   
       90 . The method of  claim 85  further comprising separating at least a portion of resultant 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine from at least a portion of the second mixture. 
   
   
       91 . The method of  claim 90  further comprising washing and at least partially drying the resultant 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. 
   
   
       92 . A process for making a pharmaceutical composition containing 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate comprising the step of adding crystalline 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate in polymorph Form A, B, C, D, or E as part of a composition manufacturing process. 
   
   
       93 . The process of  claim 92 , wherein Form C of the polymorph is used. 
   
   
       94 . The process of  claim 92  or  93 , wherein the polymorph Form A, B, C, D, or E is tested and controlled for.