U.S. patent application number 11/647505 was filed with the patent office on 2011-03-17 for solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline- -3-carboxamide.
Invention is credited to Patrick R. Connelly, Adriana Costache, Yushi Feng, Yuchuan Gong, Patricia Hurter, Mariusz Krawiec, William Rowe, Martin Trudeau, Christopher R. Young.
Application Number | 20110064811 11/647505 |
Document ID | / |
Family ID | 38228833 |
Filed Date | 2011-03-17 |
United States Patent
Application |
20110064811 |
Kind Code |
A1 |
Hurter; Patricia ; et
al. |
March 17, 2011 |
Solid forms of
N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide
Abstract
The present invention relates to solid state forms of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide (Compound 1), pharmaceutical compositions thereof
and methods therewith.
Inventors: |
Hurter; Patricia; (Harvard,
MA) ; Rowe; William; (Medford, MA) ; Young;
Christopher R.; (Waltham, MA) ; Costache;
Adriana; (Roslindale, MA) ; Connelly; Patrick R.;
(Harvard, MA) ; Krawiec; Mariusz; (Marlborough,
MA) ; Gong; Yuchuan; (Waukegan, IL) ; Feng;
Yushi; (Malden, MA) ; Trudeau; Martin;
(Cambridge, MA) |
Family ID: |
38228833 |
Appl. No.: |
11/647505 |
Filed: |
December 28, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60754381 |
Dec 28, 2005 |
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Current U.S.
Class: |
424/489 ;
514/312; 546/156 |
Current CPC
Class: |
A61P 7/00 20180101; Y10T
428/2982 20150115; C07B 2200/13 20130101; A61P 43/00 20180101; A61P
3/00 20180101; A61P 7/10 20180101; A61P 25/14 20180101; A61P 27/02
20180101; A61P 5/14 20180101; A61P 21/02 20180101; A61P 1/12
20180101; A61K 2300/00 20130101; A61P 27/04 20180101; A61K 31/47
20130101; A61P 7/06 20180101; A61P 35/00 20180101; A61P 7/12
20180101; A61P 25/08 20180101; A61P 1/00 20180101; A61P 7/04
20180101; A61P 25/00 20180101; A61P 21/00 20180101; A61P 5/16
20180101; A61P 13/02 20180101; A61P 25/16 20180101; C07D 215/56
20130101; A61P 13/12 20180101; A61P 17/00 20180101; A61P 37/06
20180101; A61P 3/10 20180101; A61P 19/08 20180101; A61P 3/06
20180101; A61P 11/00 20180101; A61P 5/00 20180101; A61P 1/18
20180101; A61P 25/28 20180101 |
Class at
Publication: |
424/489 ;
546/156; 514/312 |
International
Class: |
A61K 9/14 20060101
A61K009/14; C07D 215/56 20060101 C07D215/56; A61K 31/47 20060101
A61K031/47; A61P 3/10 20060101 A61P003/10; A61P 11/00 20060101
A61P011/00; A61P 7/10 20060101 A61P007/10; A61P 3/00 20060101
A61P003/00; A61P 35/00 20060101 A61P035/00; A61P 25/28 20060101
A61P025/28; A61P 25/16 20060101 A61P025/16; A61P 27/04 20060101
A61P027/04; A61P 7/00 20060101 A61P007/00 |
Claims
1. Solid amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
2. The solid amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide of claim 1, comprising less than about 15%
crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
3. A preparation of amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide substantially free of crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
4. The preparation of claim 3, further comprising a surfactant,
polymer, or inert pharmaceutically acceptable substance.
5. The preparation of claim 3 or 4, wherein the preparation
comprises a solid dispersion, a mixture or a liquid dispersion.
6. The preparation of one of claims 3-5, wherein the preparation
comprises solid particles.
7. The preparation of one of claims 3-6, comprising less than about
15% of crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
8. The preparation of one of claims 3-7, wherein the amporphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide has a particle size distribution of D10, less than 5
.mu.m.
9. The preparation of one of claims 3-8, wherein the amporphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide have a particle size distribution of D50, less than
17 .mu.m.
10. The preparation of one of claims 3-9, wherein the amporphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide have a particle size distribution of D90, less than
100 .mu.m.
11. A solid dispersion comprising amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
12. The solid dispersion of claim 11, wherein the solid dispersion
comprises less than about 40% of crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
13. The solid dispersion of claim 11 or 12, wherein the solid
dispersion is substantially free of crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
14. The solid dispersion of one of claims 11-13, further comprising
a surfactant, polymer, or inert pharmaceutically acceptable
substance.
15. The solid dispersion of one of claims 11-14, comprising a
polymer, and wherein the polymer is one or more than one
water-soluble polymer or partially water-soluble polymer.
16. The solid dispersion of one of claims 11-15, wherein the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide has improved physical or chemical stability relative
to amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-ox-
oquinoline-3-carboxamide without being in the presence of
polymer.
17. The solid dispersion of one of claims 11-16, wherein the solid
dispersion has a higher glass transition temperature than the glass
transition temperature of neat amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
18. The solid dispersion of one of claims 11-17, wherein the
polymer is hydroxypropylmethylcellulose (HPMC).
19. The solid dispersion of one of claims 11-17, wherein the
polymer is hydroxypropylmethylcellulose acetate succinate
(HPMCAS).
20. The solid dispersion of one of claims 11-17, wherein the
polymer is vinylpyrrolidone/vinyl acetate copolymer (PVP/VA).
21. The solid dispersion of one of claims 11-20, wherein the
polymer is present in an amount of from about 10% by weight to
about 80% by weight.
22. The solid dispersion of claims 21, wherein the polymer is
present in an amount of less than about 70% by weight.
23. The solid dispersion of claim 21, wherein the polymer is
present in an amount of about 50% by weight.
24. The solid dispersion of claim 21, wherein the polymer is
present in an amount of about 49.5% by weight.
25. The solid dispersion of one of claims 11-24, wherein the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is present in an amount of from about 10% by weight
to about 80% by weight.
26. The solid dispersion of claim 24, wherein the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is present in an amount of less than about 70% by
weight.
27. The solid dispersion of claim 24, wherein the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is present in an amount of about 50% by weight.
28. The solid dispersion of one of claims 11-27, comprising a
surfactant.
29. The solid dispersion of claim 28, wherein the surfactant is
sodium lauryl sulfate.
30. The solid dispersion of one of claims 11-29, wherein the
surfactant is present in an amount from about 0.1 to about 5%.
31. The solid dispersion of claim 30, wherein the surfactant is
present in 0.5%.
32. The solid dispersion of one of claims 11-31, wherein at least
about 80% by weight of the N
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is in an amorphous form.
33. The solid dispersion of one of claim 32, wherein substantially
all the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquino-
line-3-carboxamide is in an amorphous form.
34. The solid dispersion according to one of claims 11-33, wherein
the solid dispersion is obtained by spray drying.
35. A pharmaceutical composition comprising amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
36. The composition of claim 35, wherein the amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is substantially free of crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
37. A pharmaceutical composition comprising an amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide as a solid dispersion and one or more of a
surfactant, polymer, inert pharmaceutically acceptable substance,
or pharmaceutically acceptable carrier.
38. The pharmaceutical composition of claim 37, comprising a
polymer and wherein the polymer is one or more than one
water-soluble polymer or partially water-soluble polymer.
39. The pharmaceutical composition of claim 37 or 38, wherein the
solid dispersion has a higher glass transition temperature than the
glass transition temperature of neat amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
40. The pharmaceutical composition of one of claims 37-39, wherein
the polymer is HPMC or HPMCAS.
41. The pharmaceutical composition of one of claims 37-39, wherein
the polymer is PVP/VA.
42. A pharmaceutical composition comprising: an amorphous solid
dispersion of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide wherein said
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide comprises about 30-75% wt/wt of the pharmaceutical
composition, one or more polymer selected from the group of HPMC
and HPMCAS, wherein said polymer is comprises about 30-75% wt/wt of
the pharmaceutical composition, and a surfactant, wherein said
surfactant comprises about 0.25-1% wt/wt of the pharmaceutical
composition.
43. The pharmaceutical composition of claim 42, wherein the polymer
is HPMCAS.
44. The pharmaceutical composition of claim 42, wherein the polymer
is HPMC.
45. The pharmaceutical composition of one of claims 42-44, wherein
the surfactant is sodium laurel sulfate.
46. The pharmaceutical composition of one of claims 42-45, wherein:
said
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide comprises about 50% wt/wt of the pharmaceutical
composition, said polymer is HPMCAS and comprises about 49.5% wt/wt
of the pharmaceutical composition, and a said surfactant is sodium
laurel sulfate and comprises about 0.5% wt/wt of the pharmaceutical
composition.
47. A pharmaceutical composition comprising; an aqueous suspension
comprising amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide particles and a pharmaceutically acceptable
carrier.
48. The pharmaceutical composition of claim 47, wherein the
pharmaceutically acceptable carrier is a polymer in solution
selected from the group of HPMC and HPMCAS.
49. The pharmaceutical composition of claim 47, wherein the
pharmaceutically acceptable carrier is a polymer in solution is
PVP/VA.
50. The pharmaceutical composition of one of claims 47-49, wherein
the amorphous compound is in the form of a solid dispersion.
51. The pharmaceutical composition of one of claims 47-50, further
comprising a surfactant, either in the solution or as a component
of the solid dispersion.
52. The pharmaceutical composition of one of claims 47-51, wherein
the surfactant is SLS.
53. The pharmaceutical composition of one of claims 47-52, wherein
the polymer is either in the solution or as a component of the
solid dispersion particles or both.
54. The pharmaceutical composition of one of claims 47-53, wherein
the aqueous suspension comprises from about 0.1% to about 20% by
weight of the surfactant.
55. The pharmaceutical composition of claim 54, wherein the aqueous
suspension comprises from about 0.1% to about 2.0% by weight of
polymer.
56. The pharmaceutical composition of claim 55, wherein the aqueous
suspension comprises about 1% by weight of polymer.
57. A process for preparing an amorphous form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide comprising spray-drying
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide to provide an amorphous form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
58. The process of claim 57, comprising combining
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide and a suitable solvent to form a mixture and then
spray-drying the mixture to obtain the amorphous form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
59. The process of claim 58, wherein the mixture is a solution
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide and the suitable solvent.
60. The process of one of claims 58-59, wherein the suitable
solvent comprises acetone or MEK.
61. The process of one of claims 58-60, wherein the suitable
solvent comprises a mixture of solvents.
62. The process of one of claims 58-61, wherein the solvent
comprises a mixture of acetone and water or a mixture of MEK and
water.
63. The process of one of claims 58-62, wherein the water in the
solvent mixture is present at about 10% wt.
64. The process of one of claims 58-63, comprising a) forming a
mixture comprising
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, a polymer, and a solvent; and b) spray-drying the
mixture to form a solid dispersion comprising
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
65. The process of claim 64, wherein the mixture comprises a
solution of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, the polymer, and the solvent.
66. The process of claim 65, wherein the polymer is selected from
HPMC and HPMCAS.
67. The process of claim 65, wherein the polymer is PVP/VA.
68. The process of one of claims 64-67, wherein the polymer is
present in an amount of from about 30% to about 70% by weight in
the solid dispersion.
69. The process of one of claims 64-68, wherein the mixture further
comprises a surfactant.
70. The process according to one of claims 64-69, wherein the
surfactant is sodium lauryl sulfate (SLS).
71. The process according to one of claims 64-70, wherein the
solvent comprises acetone.
72. The process of one of claims 64-71, wherein the solvent
comprises a mixture of acetone and water.
73. The process of one of claims 64-72, wherein the solvent
comprises from about 0% to about 20% water and from about 70% to
about 100% acetone.
74. A solid dispersion prepared according to the process of one of
claims 64-73.
75. A method for treating a CFTR-mediated disease in a mammal
comprising administering amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
76. The method of claim 75, comprising administering an amorphous
solid dispersion of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
77. The method according to claim 75 or 76, wherein the method
comprises administering an additional therapeutic agent.
78. A pharmaceutical pack or kit comprising amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide and a pharmaceutically acceptable carrier.
79. A crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, characterized by one or more peaks at 5.0 and 15.6
degrees in an X-ray powder diffraction pattern obtained using Cu K
alpha radiation.
80. The crystal form of claim 79, wherein the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide further characterized by the following peak 7.8.
81. The crystal form of one of claims 79-80, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
8.5.
82. The crystal form of one of claims 79-81, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
9.2.
83. The crystal form of one of claims 79-82, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
9.9.
84. The crystal form of one of claims 79-83, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
11.9.
85. The crystal form of one of claims 79-84, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
12.6.
86. The crystal form of one of claims 79-85, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
13.9.
87. The crystal form of one of claims 79-86, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
14.9.
88. The crystal form of one of claims 79-87, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
16.5.
89. The crystal form of one of claims 79-88, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
18.1.
90. The crystal form of one of claims 79-89, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
18.5.
91. The crystal form of one of claims 79-90, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
20.7.
92. The crystal form of one of claims 79-91, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
22.0.
93. The crystal form of one of claims 79-92, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
23.5.
94. The crystal form of one of claims 79-93, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
25.3.
95. The crystal form of one of claims 79-94, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
28.0.
96. The crystal form of one of claims 79-95, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
29.4.
97. The crystal form of one of claims 79-96, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide further characterized by the following peak
30.9.
98. The crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide according to claims 79-97, wherein said crystal form
is characterized by an X-ray powder diffraction pattern obtained
using Cu K alpha radiation substantially similar to FIG. 4.
99. A pharmaceutical composition comprising the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide according to one of claims 79-98, and a
pharmaceutically acceptable adjuvant or carrier.
100. A process for preparing a crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide according to claims 79-98, wherein said process
comprises the step of heating N
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide to about 250.degree. C. and cooling to room
temperature.
101. A method for treating a CFTR mediated disease in a mammal
comprising administering
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide according to claims 79-98.
102. The method of claim 101, wherein the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is a component of a pharmaceutical composition.
103. The method according to claim 101 or 102, wherein the method
comprises administering an additional therapeutic agent.
104. A pharmaceutical pack or kit comprising
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide according to claims 79-98 and a pharmaceutically
acceptable carrier.
105. A crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, characterized by one or more peaks at 6.2, 7.6,
12.3, and 18.0 degrees in an X-ray powder diffraction pattern
obtained using Cu K alpha radiation.
106. The crystal form of claim 105, wherein the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
8.40.
107. The crystal form of claim 105 or 106, wherein the crystal form
of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak
11.0.
108. The crystal form of one of claims 105-107, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
14.8.
109. The crystal form of one of claims 105-108, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
16.1.
110. The crystal form of one of claims 105-109, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
17.1.
111. The crystal form of one of claims 105-110, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
18.6.
112. The crystal form of one of claims 105-111, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
19.4.
113. The crystal form of one of claims 105-112, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
21.1.
114. The crystal form of one of claims 105-113, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
22.6.
115. The crystal form of one of claims 105-114, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
23.4.
116. The crystal form of one of claims 105-115, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
23.9.
117. The crystal form of one of claims 105-116, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
24.9.
118. The crystal form of one of claims 105-117, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
25.5.
119. The crystal form of one of claims 105-118, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
26.7.
120. The crystal form of one of claims 105-119, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
27.5.
121. The crystal form of one of claims 105-120, wherein the crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak
29.6.
122. The crystal form of one of claims 105-121, wherein the crystal
form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro
4-oxoquinoline-3-carboxamide is further characterized by the
following peak 33.5.
123. The crystal form of one of claims 105-122, wherein the crystal
form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro
4-oxoquinoline-3-carboxamide is further characterized by the
following peak 36.8.
124. The crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide according to one of claims 105-123, characterized by
an X-ray powder diffraction pattern obtained using Cu K alpha
radiation substantially similar to FIG. 7.
125. A pharmaceutical composition comprising the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide according to one of claims 105-124, and a
pharmaceutically acceptable adjuvant or carrier.
126. A process for preparing the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide according to one of claims 105-124, wherein said
process comprises the steps of alternatively heating and cooling a
slurry of Compound 1 and acetonitrile.
127. The process according to claim 126, wherein said heating step
comprises heating said slurry at about 50 C. for about 12
hours.
128. The process according to claim 126 or 127, wherein said
cooling step comprises placing said slurry at room temperature for
about 12 hours, followed by cooling at about 0.degree. C.
overnight.
129. A crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, having a monoclinic crystal system, a P2.sub.1
space grouping, and the following unit cell dimensions: a=11.8011
(7) .ANG. =90.degree. b=5.9819 (3) .ANG. .beta.=105.110 (4).degree.
c=14.7974 (8) .ANG..gamma.=90.degree..
130. A method of treating a CFTR mediated disease in a patient
comprising the step of administering to said patient a crystal form
of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide or a pharmaceutical composition comprising a crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide according to one of claim 105-124 or 129.
131. The method according to claim 75, 101, or 130, wherein said
disease is selected from cystic fibrosis, hereditary emphysema,
hereditary hemochromatosis, coagulation-fibrinolysis deficiencies,
such as protein C deficiency, Type 1 hereditary angioedema, lipid
processing deficiencies, such as familial hypercholesterolemia,
Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage
diseases, such as I-cell disease/pseudo-Hurler,
mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II,
polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron
dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism,
melanoma, glycanosis CDG type 1, hereditary emphysema, congenital
hyperthyroidism, osteogenesis imperfecta, hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),
neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome,
Perlizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, progressive supranuclear plasy, Pick's disease, several
polyglutamine neurological disorders such as Huntington,
spinocerebullar ataxia type I, spinal and bulbar muscular atrophy,
dentatorubal pallidoluysian, and myotonic dystrophy, as well as
spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob
disease, Fabry disease, Straussler-Scheinker syndrome, COPD,
dry-eye disease, and Sjogren's disease.
132. The method according to claim 131, wherein said disease is
cystic fibrosis.
Description
CLAIM OF PRIORITY
[0001] This application claims priority under 35 USC .sctn.119(e)
to U.S. Patent Application. Ser. No. 60/754,381, filed on Dec. 28,
2005, the entire contents of which are hereby incorporated by
reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to solid state forms, for
example, crystalline and amorphous forms, of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, pharmaceutical compositions thereof, and methods
therewith.
BACKGROUND OF THE INVENTION
[0003] CFTR is a cAMP/ATP-mediated anion channel that is expressed
in a variety of cells types, including absorptive and secretory
epithelia cells, where it regulates anion flux across the membrane,
as well as the activity of other ion channels and proteins. In
epithelia cells, normal functioning of CFTR is critical for the
maintenance of electrolyte transport throughout the body, including
respiratory and digestive tissue. CFTR is composed of approximately
1480 amino acids that encode a protein made up of a tandem repeat
of transmembrane domains, each containing six transmembrane helices
and a nucleotide binding domain. The two transmembrane domains are
linked by a large, polar, regulatory (R)-domain with multiple
phosphorylation sites that regulate channel activity and cellular
trafficking.
[0004] The gene encoding CFTR has been identified and sequenced
(See Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P.
et al. (1990) Nature 347:358-362), (Riordan, J. R. et al. (1989)
Science 245:1066-1073). A defect in this gene causes mutations in
CFTR resulting in cystic fibrosis ("CF"), the most common fatal
genetic disease in humans. Cystic fibrosis affects approximately
one in every 2,500 infants in the United States. Within the general
United States population, up to 10 million people carry a single
copy of the defective gene without apparent ill effects. In
contrast, individuals with two copies of the CF associated gene
suffer from the debilitating and fatal effects of CF, including
chronic lung disease.
[0005] In patients with cystic fibrosis, mutations in CFTR
endogenously expressed in respiratory epithelia leads to reduced
apical anion secretion causing an imbalance in ion and fluid
transport. The resulting decrease in anion transport contributes to
enhanced mucus accumulation in the lung and the accompanying
microbial infections that ultimately cause death in CF patients. In
addition to respiratory disease, CF patients typically suffer from
gastrointestinal problems and pancreatic insufficiency that, if
left untreated, results in death. In addition, the majority of
males with cystic fibrosis are infertile and fertility is decreased
among females with cystic fibrosis. In contrast to the severe
effects of two copies of the CF associated gene, individuals with a
single copy of the CF associated gene exhibit increased resistance
to cholera and to dehydration resulting from diarrhea--perhaps
explaining the relatively high frequency of the CF gene within the
population.
[0006] Sequence analysis of the CFTR gene of CF chromosomes has
revealed a variety of disease causing mutations (Cutting, G. R. et
al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell
61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080;
Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451).
To date, >1000 disease causing mutations in the CF gene have
been identified (http://www.genet.sickkids.on.ca/cftr/). The most
prevalent mutation is a deletion of phenylalanine at position 508
of the CFTR amino acid sequence, and is commonly referred to as
.DELTA.F508-CFTR. This mutation occurs in approximately 70% of the
cases of cystic fibrosis and is associated with a severe
disease.
[0007] The deletion of residue 508 in .DELTA.F508-CFTR prevents the
nascent protein from folding correctly. This results in the
inability of the mutant protein to exit the ER, and traffic to the
plasma membrane. As a result, the number of channels present in the
membrane is far less than observed in cells expressing wild-type
CFTR. In addition to impaired trafficking, the mutation results in
defective channel gating. Together, the reduced number of channels
in the membrane and the defective gating lead to reduced anion
transport across epithelia leading to defective ion and fluid
transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies
have shown, however, that the reduced numbers of .DELTA.F508-CFTR
in the membrane are functional, albeit less than wild-type CFTR.
(Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al.,
supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50).
In addition to .DELTA.F508-CFTR, other disease causing mutations in
CFTR that result in defective trafficking, synthesis, and/or
channel gating could be up- or down-regulated to alter anion
secretion and modify disease progression and/or severity.
[0008] Although CFTR transports a variety of molecules in addition
to anions, it is clear that this role (the transport of anions)
represents one element in an important mechanism of transporting
ions and water across the epithelium. The other elements include
the epithelial Na.sup.+ channel, ENaC, Na.sup.+/2CL.sup.-/K.sup.+
co-transporter, Na.sup.+--K.sup.+-ATPase pump and the basolateral
membrane K.sup.+ channels, that are responsible for the uptake of
chloride into the cell.
[0009] These elements work together to achieve directional
transport across the epithelium via their selective expression and
localization within the cell. Chloride absorption takes place by
the coordinated activity of ENaC and CFTR present on the apical
membrane and the Na.sup.+--K.sup.+-ATPase pump and Cl-channels
expressed on the basolateral surface of the cell. Secondary active
transport of chloride from the luminal side leads to the
accumulation of intracellular chloride, which can then passively
leave the cell via Cl.sup.- channels, resulting in a vectorial
transport. Arrangement of Na.sup.+/2Cl.sup.-K.sup.+ co-transporter,
Na.sup.+--K.sup.+-ATPase pump and the basolateral membrane K.sup.+
channels on the basolateral surface and CFTR on the luminal side
coordinate the secretion of chloride via CFTR on the luminal side.
Because water is probably never actively transported itself, its
flow across epithelia depends on tiny transepithelial osmotic
gradients generated by the bulk flow of sodium and chloride.
[0010] In addition to cystic fibrosis, modulation of CFTR activity
may be beneficial for other diseases not directly caused by
mutations in CFTR, such as secretory diseases and other protein
folding diseases mediated by CFTR. These include, but are not
limited to, chronic obstructive pulmonary disease (COPD), dry eye
disease, and Sjogren's Syndrome. COPD is characterized by airflow
limitation that is progressive and not fully reversible. The
airflow limitation is due to mucus hypersecretion, emphysema, and
bronchiolitis. Activators of mutant or wild-type CFTR offer a
potential treatment of mucus hypersecretion and impaired
mucociliary clearance that is common in COPD. Specifically,
increasing anion secretion across CFTR may facilitate fluid
transport into the airway surface liquid to hydrate the mucus and
optimized periciliary fluid viscosity. This would lead to enhanced
mucociliary clearance and a reduction in the symptoms associated
with COPD. Dry eye disease is characterized by a decrease in tear
aqueous production and abnormal tear film lipid, protein and mucin
profiles. There are many causes of dry eye, some of which include
age, Lasik eye surgery, arthritis, medications, chemical/thermal
burns, allergies, and diseases, such as cystic fibrosis and
Sjogrens's syndrome. Increasing anion secretion via CFTR would
enhance fluid transport from the corneal endothelial cells and
secretory glands surrounding the eye to increase corneal hydration.
This would help to alleviate the symptoms associated with dry eye
disease. Sjogrens's syndrome is an autoimmune disease in which the
immune system attacks moisture-producing glands throughout the
body, including the eye, mouth, skin, respiratory tissue, liver,
vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as
well as lung disease. The disease is also associated with
rheumatoid arthritis, systemic lupus, systemic sclerosis, and
polymypositis/dermatomyositis. Defective protein trafficking is
believed to cause the disease, for which treatment options are
limited. Modulators of CFTR activity may hydrate the various organs
afflicted by the disease and help to elevate the associated
symptoms.
[0011] As discussed above, it is believed that the deletion of
residue 508 in .DELTA.F508-CFTR prevents the nascent protein from
folding correctly, resulting in the inability of this mutant
protein to exit the ER, and traffic to the plasma membrane. As a
result, insufficient amounts of the mature protein are present at
the plasma membrane and chloride transport within epithelial
tissues is significantly reduced. In fact, this cellular phenomenon
of defective ER processing of ABC transporters by the ER machinery,
has been shown to be the underlying basis not only for CF disease,
but for a wide range of other isolated and inherited diseases. The
two ways that the ER machinery can malfunction is either by loss of
coupling to ER export of the proteins leading to degradation, or by
the ER accumulation of these defective/misfolded proteins [Aridor
M, et al., Nature Med., 5(7), pp 745-751 (1999); Shastry, B. S., et
al., Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J.,
et al., Swiss Med Wkly, 132, pp 211-222 (2002); Morello, J P et
al., TIPS, 21, pp. 466-469 (2000); Bross P., et al., Human Mut.,
14, pp. 186-198 (1999)]. The diseases associated with the first
class of ER malfunction are cystic fibrosis (due to misfolded
.DELTA.F508-CFTR as discussed above), hereditary emphysema (due to
a1-antitrypsin; non Piz variants), hereditary hemochromatosis,
hoagulation-fibrinolysis deficiencies, such as protein C
deficiency, Type 1 hereditary angioedema, lipid processing
deficiencies, such as familial hypercholesterolemia, Type 1
chylomicronemia, abetalipoproteinemia, lysosomal storage diseases,
such as I-cell disease/pseudo-Hurler, Mucopolysaccharidoses (due to
lysosomal processing enzymes), Sandhof/Tay-Sachs (due to
.beta.-hexosaminidase), Crigler-Najjar type II (due to
UDP-glucuronyl-sialyc-transferase),
polyendocrinopathy/hyperinsulemia, Diabetes mellitus (due to
insulin receptor), Laron dwarfism (due to growth hormone receptor),
myleoperoxidase deficiency, primary hypoparathyroidism (due to
preproparathyroid hormone), melanoma (due to tyrosinase). The
diseases associated with the latter class of ER malfunction are
Glycanosis CDG type 1, hereditary emphysema (due to
.alpha.1-Antitrypsin (PiZ variant), congenital hyperthyroidism,
osteogenesis imperfecta (due to Type I, II, IV procollagen),
hereditary hypofibrinogenemia (due to fibrinogen), ACT deficiency
(due to .alpha.1-antichymotrypsin), Diabetes insipidus (DI),
neurophyseal DI (due to vasopvessin hormone/V2-receptor),
neprogenic DI (due to aquaporin II), Charcot-Marie Tooth syndrome
(due to peripheral myelin protein 22), Perlizaeus-Meabacher
disease, neurodegenerative diseases such as Alzheimer's disease
(due to .beta.APP and presenilins), Parkinson's disease,
amyotrophic lateral sclerosis, progressive supranuclear plasy,
Pick's disease, several polyglutamine neurological disorders such
as Huntington, spinocerebullar ataxia type I, spinal and bulbar
muscular atrophy, dentatorubal pallidoluysian, and myotonic
dystrophy, as well as spongiform encephalopathies, such as
hereditary Creutzfeldt-Jakob disease (due to prion protein
processing defect), Fabry disease (due to lysosomal
.alpha.-galactosidase A) and Straussler-Scheinker syndrome (due to
Prp processing defect).
[0012] In addition to up-regulation of CFTR activity, reducing
anion secretion by CFTR modulators may be beneficial for the
treatment of secretory diarrheas, in which epithelial water
transport is dramatically increased as a result of secretagogue
activated chloride transport. The mechanism involves elevation of
cAMP and stimulation of CFTR.
[0013] Although there are numerous causes of diarrhea, the major
consequences of diarrheal diseases, resulting from excessive
chloride transport are common to all, and include dehydration,
acidosis, impaired growth and death.
[0014] Acute and chronic diarrheas represent a major medical
problem in many areas of the world. Diarrhea is both a significant
factor in malnutrition and the leading cause of death (5,000,000
deaths/year) in children less than five years old.
[0015] Secretory diarrheas are also a dangerous condition in
patients of acquired immunodeficiency syndrome (AIDS) and chronic
inflammatory bowel disease (IBD). 16 million travelers to
developing countries from industrialized nations every year develop
diarrhea, with the severity and number of cases of diarrhea varying
depending on the country and area of travel.
[0016] Diarrhea in barn animals and pets such as cows, pigs and
horses, sheep, goats, cats and dogs, also known as scours, is a
major cause of death in these animals. Diarrhea can result from any
major transition, such as weaning or physical movement, as well as
in response to a variety of bacterial or viral infections and
generally occurs within the first few hours of the animal's
life.
[0017] The most common diarrheal causing bacteria is
enterotoxogenic E. coli (ETEC) having the K99 pilus antigen. Common
viral causes of diarrhea include rotavirus and coronavirus. Other
infectious agents include cryptosporidium, giardia lamblia, and
salmonella, among others.
[0018] Symptoms of rotaviral infection include excretion of watery
feces, dehydration and weakness. Coronavirus causes a more severe
illness in the newborn animals, and has a higher mortality rate
than rotaviral infection. Often, however, a young animal may be
infected with more than one virus or with a combination of viral
and bacterial microorganisms at one time. This dramatically
increases the severity of the disease.
[0019] Accordingly, there is a need for stable polymorphic forms of
modulators of CFTR activity, such as Compound 1, that can be used
to modulate the activity of CFTR in the cell membrane of a
mammal.
[0020] There is a need for methods of treating CFTR-mediated
diseases using such modulators of CFTR activity.
SUMMARY OF THE INVENTION
[0021] The present invention relates to solid forms of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide (hereinafter "Compound 1") which has the structure
below:
##STR00001##
[0022] The solid forms of Compound 1 and pharmaceutically
acceptable compositions thereof are useful for treating or
lessening the severity of a variety of CFTR mediated diseases.
Compound 1 is known as both
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide and
N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
[0023] In one aspect, the invention features solid amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide. In some embodiments, the solid amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide comprises less than about 15% crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
[0024] In one aspect, the invention features a preparation of
amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide substantially free of crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
[0025] In some embodiments, the preparation further comprises a
surfactant, polymer, or inert pharmaceutically acceptable
substance.
[0026] In some embodiments, the preparation comprises a solid
dispersion, a mixture or a liquid dispersion.
[0027] In some embodiments, the preparation comprises solid
particles.
[0028] In some embodiments, the preparation comprises less than
about 15% of crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
[0029] In some embodiments, the amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide has a particle size distribution of DI 0, less than
5 .mu.m. In some embodiments, the amporphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide have a particle size distribution of D50, less than
17 .mu.m. In some embodiments, the amporphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide have a particle size distribution of D90, less than
100 .mu.m.
[0030] In one aspect, the invention features a solid dispersion
comprising amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-ox-
oquinoline-3-carboxamide.
[0031] In some embodiments, the solid dispersion comprises less
than about 40% of crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide. In some embodiments, the solid dispersion is
substantially free of crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
[0032] In some embodiments, the solid dispersion further comprises
a surfactant, polymer, or inert pharmaceutically acceptable
substance. For example, the solid dispersion comprises a polymer,
and the polymer is one or more than one water-soluble polymer or
partially water-soluble polymer.
[0033] In some embodiments, the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide has improved physical or chemical stability relative
to amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-ox-
oquinoline-3-carboxamide without being in the presence of
polymer.
[0034] In some embodiments, the solid dispersion has a higher glass
transition temperature than the glass transition temperature of
neat amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-ox-
oquinoline-3-carboxamide.
[0035] In some embodiments, the polymer is
hydroxypropylmethylcellulose (HPMC). In some embodiments, the
polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS).
In some embodiments, the polymer is vinylpyrrolidone/vinyl acetate
copolymer (PVP/VA). In some embodiments, the polymer is present in
an amount of from about 10% by weight to about 80% by weight, for
example, the polymer is present in an amount of less than about 70%
by weight, the polymer is present in an amount of about 50% by
weight, or the polymer is present in an amount of about 49.5% by
weight.
[0036] In some embodiments, the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is present in an amount of from about 10% by weight
to about 80% by weight, for example, the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is present in an amount of less than about 70% by
weight or the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquino-
line-3-carboxamide is present in an amount of about 50% by
weight.
[0037] In some embodiments, the solid dispersion comprises a
surfactant, for example, sodium lauryl sulfate. In some
embodiments, the surfactant is present in an amount from about 0.1
to about 5%, for example, the surfactant is present in 0.5%.
[0038] In some embodiments, at least about 80% by weight of the N
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is in an amorphous form. In some embodiments,
substantially all the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoq-
uinoline-3-carboxamide is in an amorphous form.
[0039] In some embodiments, the solid dispersion is obtained by
spray drying.
[0040] In one aspect, the invention features a pharmaceutical
composition comprising amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide. In some embodiments, the amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is substantially free of crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
[0041] In one aspect, the invention features, a pharmaceutical
composition comprising an amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide as a solid dispersion and one or more of a
surfactant, polymer, inert pharmaceutically acceptable substance,
or pharmaceutically acceptable carrier.
[0042] In some embodiments, the solid dispersion comprises a
polymer and wherein the polymer is one or more than one
water-soluble polymer or partially water-soluble polymer.
[0043] In some embodiments, the solid dispersion has a higher glass
transition temperature than the glass transition temperature of
neat amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-ox-
oquinoline-3-carboxamide.
[0044] In some embodiments, the polymer is HPMC. In some
embodiments, the polymer is HPMCAS. In some embodiments, the
polymer is PVP/VA.
[0045] In one aspect, the invention features a pharmaceutical
composition comprising: an amorphous solid dispersion of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide wherein said
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide comprises about 30-75% wt/wt of the pharmaceutical
composition, one or more polymer selected from the group of HPMC
and HPMCAS, wherein said polymer is comprises about 30-75% wt/wt of
the pharmaceutical composition, and a surfactant, wherein said
surfactant comprises about 0.25-1% wt/wt of the pharmaceutical
composition.
[0046] In some embodiments, the polymer is HPMCAS. In some
embodiments, the polymer is HPMC.
[0047] In some embodiments, the surfactant is sodium laurel
sulfate.
[0048] In some embodiments, said
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide comprises about 50% wt/wt of the pharmaceutical
composition, said polymer is HPMCAS and comprises about 49.5% wt/wt
of the pharmaceutical composition, and a said surfactant is sodium
laurel sulfate and comprises about 0.5% wt/wt of the pharmaceutical
composition.
[0049] In one aspect, the invention features a pharmaceutical
composition comprising;
[0050] an aqueous suspension comprising amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide particles and a pharmaceutically acceptable
carrier.
[0051] In some embodiments, the pharmaceutically acceptable carrier
is a polymer in solution selected from the group of HPMC and
HPMCAS. In some embodiments, the pharmaceutically acceptable
carrier is a polymer in solution is PVP/VA.
[0052] In some embodiments, the amorphous compound is in the form
of a solid dispersion.
[0053] In some embodiments, the pharmaceutical composition further
comprises a surfactant, either in the solution or as a component of
the solid dispersion, for example, SLS. In some embodiments, the
polymer is either in the solution or as a component of the solid
dispersion particles or both. In some embodiments, the aqueous
suspension comprises from about 0.1% to about 20% by weight of the
surfactant. In some embodiments, the aqueous suspension comprises
from about 0.1% to about 2.0% by weight of polymer, for example,
about 1% by weight of polymer.
[0054] In one aspect, the invention features a process for
preparing an amorphous form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide comprising spray-drying
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide to provide an amorphous form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
[0055] In some embodiments, the method comprises combining
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide and a suitable solvent to form a mixture and then
spray-drying the mixture to obtain the amorphous form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
[0056] In some embodiments, the mixture is a solution
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide and the suitable solvent. In some embodiments, the
suitable solvent comprises acetone or MEK. In some embodiments, the
suitable solvent comprises a mixture of solvents, for example, a
mixture of acetone and water or a mixture of MEK and water. In some
embodiments, the water in the solvent mixture is present at about
10% wt.
[0057] In some embodiments, the method comprises a) forming a
mixture comprising
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, a polymer, and a solvent; and b) spray-drying the
mixture to form a solid dispersion comprising
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide.
[0058] In some embodiments, the mixture comprises a solution of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, the polymer, and the solvent. In some embodiments,
the polymer is selected from HPMC and HPMCAS. In some embodiments,
the polymer is PVP/VA. In some embodiments, the polymer is present
in an amount of from about 30% to about 70% by weight in the solid
dispersion. In some embodiments, the mixture further comprises a
surfactant, for example, SLS.
[0059] In some embodiments, the solvent comprises acetone, for
example, a mixture of acetone and water. In some embodiments, the
solvent comprises from about 0% to about 20% water and from about
70% to about 100% acetone.
[0060] In one aspect, the invention features a solid dispersion
prepared according a process described herein.
[0061] In one aspect, the invention features a method for treating
a CFTR-mediated disease in a mammal comprising administering
amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide. In some embodiments, the method comprises
administering an amorphous solid dispersion of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide. In some embodiments, the method comprises
administering an additional therapeutic agent.
[0062] In one aspect, the invention features a pharmaceutical pack
or kit comprising amorphous
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide and a pharmaceutically acceptable carrier.
[0063] In one aspect, the invention features a crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, characterized by one or more peaks at from about
4.8 to about 5.2 degrees, for example, about 5.0 degrees, and from
about 15.4 to about 15.8 degrees, for example, about 15.6 degrees
in an X-ray powder diffraction pattern obtained using Cu K alpha
radiation. In some embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak at
from about 7.6 to about 8.0, e.g., 7.8. In some embodiments, the
crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide is further characterized by the following peak at
from about 8.3 to about 8.7, for example, about 8.5. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak at
from about 9.0 to about 9.4, for example, about 9.2. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak at
from about 9.7 to about 10.1, for example about 9.9. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak at
from about 11.7 to about 12.1, for example, about 11.9. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak at
from about 12.4 to about 12.8, for example, about 12.6. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak at
from about 13.7 to about 14.1, for example about 13.9. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak at
from about 14.7 to about 15.1, for example, about 14.9. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 16.3 to about 16.7, for example about 16.5. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 17.9 to about 18.3, for example, about 18.1. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 18.3 to about 18.7, for example, about 18.5. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 20.5 to about 20.9, for example, about 20.7. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 21.8 to about 22.2, for example, about 22.0. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 23.1 to about 23.7, for example, about 23.5. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 25.1 to about 25.5, for example, about 25.3. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 27.8 to about 28.2, for example, about 28.0. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 29.2 to about 29.6, for example, about 29.4. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 30.7 to about 31.1, for example, about 30.9. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is characterized by an X-ray powder diffraction
pattern obtained using Cu K alpha radiation substantially similar
to FIG. 4.
[0064] In one aspect, the invention features a pharmaceutical
composition comprising the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide having the characteristics of Form A, for example as
described above, and a pharmaceutically acceptable adjuvant or
carrier.
[0065] In one aspect, the invention features a process for
preparing a crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide of Form A, for example as characterized above,
wherein said process comprises the step of heating N
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide to about 250.degree. C. and cooling to room
temperature.
[0066] In one aspect, the invention features a method for treating
a CFTR mediated disease in a mammal comprising administering
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide of Form A, for example as characterized above. In
some embodiments, the
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is a component of a pharmaceutical composition. In
some embodiments, the method comprises administering an additional
therapeutic agent.
[0067] In one aspect, the invention features a pharmaceutical pack
or kit comprising crystalline
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide of Form A, for example as characterized above and a
pharmaceutically acceptable carrier.
[0068] In one aspect, the invention features a crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, characterized by one or more peaks at from about
6.2 to about 6.6, for example, about 6.4, from about 7.5 to about
7.9, for example, about 7.7, from about 12.5 to about 12.9, for
example, about 12.7, and from about 17.9 to about 18.3, for
example, about 18.1 degrees in an X-ray powder diffraction pattern
obtained using Cu K alpha radiation.
[0069] In some embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 8.2 to about 8.6, for example, about 8.4. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 10.8 to about 11.2, for example, about 11.0. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 14.6 to about 15.0, for example, about 14.8. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 15.9 to about 16.3, for example, about 16.1. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 16.9 to about 17.3, for example, about 17.1. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 18.4 to about 18.8, for example, about 18.6. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 19.2 to about 19.6, for example, about 19.4. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 20.9 to about 21.3, for example, about 21.1. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 22.4 to about 22.8, for example, about 22.6. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 23.2 to about 23.6, for example, about 23.4. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 23.7 to about 24.1, for example, about 23.9. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 24.7 to about 25.1, for example, about 24.9. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 25.3 to about 25.7, for example, about 25.5. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 26.5 to about 26.9, for example, about 26.7. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 27.3 to about 27.7, for example, about 27.5. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is further characterized by the following peak from
about 29.4 to about 29.8, for example, about 29.6. In some
embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro
4-oxoquinoline-3-carboxamide is further characterized by the
following peak from about 33.3 to about 33.7, for example, about
33.5. In some embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro
4-oxoquinoline-3-carboxamide is further characterized by the
following peak from about 36.6 to about 37.0, for example, about
36.8. In some embodiments, the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide is characterized by an X-ray powder diffraction
pattern obtained using Cu K alpha radiation substantially similar
to FIG. 7.
[0070] In one aspect, the invention features a crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide, having a monoclinic crystal system, a P21 space
grouping, and the following unit cell dimensions:
[0071] a=11.8011 (7) .ANG. .alpha.=90.degree.
[0072] b=5.9819 (3) .ANG..beta.=105.110 (4).degree.
[0073] c=14.7974 (8) .ANG..gamma.=90.degree..
[0074] In one aspect, the invention features a pharmaceutical
composition comprising the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide according to Form B; for example, as characterized
above, and a pharmaceutically acceptable adjuvant or carrier.
[0075] In one aspect, the invention features a process for
preparing the crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide according to Form B, for example, as characterized
above, wherein said process comprises the steps of alternatively
heating and cooling a slurry of Compound 1 and acetonitrile. In
some embodiments, the process comprises heating said slurry at
about 50 C. for about 12 hours. In some embodiments, said cooling
step comprises placing said slurry at room temperature for about 12
hours, followed by cooling at about 0.degree. C. overnight.
[0076] In one aspect, the invention features a method of treating a
CFTR mediated disease in a patient comprising the step of
administering to said patient a crystal form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide or a pharmaceutical composition comprising a crystal
form of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinol-
ine-3-carboxamide according to Form B, for example, as
characterized above.
[0077] In one aspect, the invention features a method of treating a
disease is selected from cystic fibrosis, hereditary emphysema,
hereditary hemochromatosis, coagulation-fibrinolysis deficiencies,
such as protein C deficiency, Type 1 hereditary angioedema, lipid
processing deficiencies, such as familial hypercholesterolemia,
Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage
diseases, such as I-cell disease/pseudo-Hurler,
mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II,
polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron
dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism,
melanoma, glycanosis CDG type 1, hereditary emphysema, congenital
hyperthyroidism, osteogenesis imperfecta, hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),
neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome,
Perlizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, progressive supranuclear plasy, Pick's disease, several
polyglutamine neurological disorders such as Huntington,
spinocerebullar ataxia type I, spinal and bulbar muscular atrophy,
dentatorubal pallidoluysian, and myotonic dystrophy, as well as
spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob
disease, Fabry disease, Straussler-Scheinker syndrome, COPD,
dry-eye disease, and Sjogren's disease by administering a solid
form of Compound 1 as described above, for example, Form A, Form B,
or amorphous Compound 1, for example, neat or as a component of a
solid dispersion. In some embodiments, the disease is cystic
fibrosis.
[0078] Processes described herein can be used to prepare the
compositions of this invention. The amounts and the features of the
components used in the processes would be as described herein.
[0079] As used herein, the term "amorphous" refers to a solid
material having no long range order in the position of its
molecules Amorphous solids are generally supercooled liquids in
which the molecules are arranged in a random manner so that there
is no well-defined arrangement, e.g., molecular packing, and no
long range order. Amorphous solids are generally isotropic, i.e.
exhibit similar properties in all directions and do not have
definite melting points. For example, an amorphous material is a
solid material having no sharp characteristic crystalline peak(s)
in its X-ray power diffraction (XRPD) pattern (i.e., is not
crystalline as determined by XRPD). Instead, one or several broad
peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are
characteristic of an amorphous solid. See, US 2004/0006237 for a
comparison of XRPDs of an amorphous material and crystalline
material.
[0080] As used herein, the phrase "substantially amorphous Compound
1" is used interchangeably with the phrase "amorphous Compound 1
substantially free of crystalline Compound 1." In some embodiments,
substantially amorphous Compound 1 has less than about 30%
crystalline Compound 1, for example, less than about 30% of
crystalline Compound 1, e.g., less than about 25% crystalline
Compound 1, less than about 20% crystalline Compound 1, less than
about 15% crystalline Compound 1, less than about 10% crystalline
Compound 1, less than about 5% crystalline Compound 1, less than
about 2% crystalline Compound 1. In some preferred embodiments,
Compound 1 has less than about 15% crystalline compound 1. Some
embodiments include a preparation of substantially amorphous
Compound 1, for example having the degree of crystalline Compound 1
as described above.
[0081] As used herein "crystalline solids" refers to compounds or
compositions where the structural units are arranged in fixed
geometric patterns or lattices, so that crystalline solids have
rigid long range order. The structural units that constitute the
crystal structure can be atoms, molecules, or ions. Crystalline
solids show definite melting points.
[0082] As used herein, a "dispersion" refers to a disperse system
in which one substance, the dispersed phase, is distributed, in
discrete units, throughout a second substance (the continuous phase
or vehicle). The size of the dispersed phase can vary considerably
(e.g. colloidal particles of nanometer dimension, to multiple
microns in size). In general, the dispersed phases can be solids,
liquids, or gases. In the case of a solid dispersion, the dispersed
and continuous phases are both solids. In pharmaceutical
applications, a solid dispersion can include a crystalline drug
(dispersed phase) in an amorphous polymer (continuous phase), or
alternatively, an amorphous drug (dispersed phase) in an amorphous
polymer (continuous phase). In some embodiments an amorphous solid
dispersion includes the polymer constituting the dispersed phase,
and the drug constitute the continuous phase. In some embodiments,
the dispersion includes amorphous. Compound 1 or substantially
amorphous Compound 1.
[0083] The term "solid amorphous dispersion" generally refers to a
solid dispersion of two or more components, usually a drug and
polymer, but possibly containing other components such as
surfactants or other pharmaceutical excipients, where Compound 1 is
amorphous or substantially amorphous (e.g., substantially free of
crystalline Compound 1), and the physical stability and/or
dissolution and/or solubility of the amorphous drug is enhanced by
the other components.
[0084] A solid dispersion as provided herein is a particularly
favorable embodiment of this invention. Solid dispersions typically
include a compound dispersed in an appropriate carrier medium, such
as a solid state carrier. In one embodiment, a carrier according to
this invention comprises a polymer, preferably, a water-soluble
polymer or a partially water-soluble polymer. It would be
understood that one or more than one water-soluble polymer could be
used in a solid dispersion of this invention.
[0085] An exemplary solid dispersion is a co-precipitate or a
co-melt of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]1,4-dihydro-4-oxoquinoline--
3-carboxamide with at least one polymer. A "Co-precipitate" is a
product after dissolving a drug and a polymer in a solvent or
solvent mixture followed by the removal of the solvent or solvent
mixture. Sometimes the polymer can be suspended in the solvent or
solvent mixture. The solvent or solvent mixture includes organic
solvents and supercritical fluids. A "co-melt" is a product after
heating a drug and a polymer to melt, optionally in the presence of
a solvent or solvent mixture, followed by mixing, removal of at
least a portion of the solvent if applicable, and cooling to room
temperature at a selected rate. In some cases, the solid
dispersions are prepared by adding a solution of a drug and a solid
polymer followed by mixing and removal of the solvent. To remove
the solvent, vacuum drying, spray drying, tray drying,
lyophilization, and other drying procedures may be applied.
Applying any of these methods using appropriate processing
parameters, according to this invention, would provide
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]1,4-dihydro-4-oxoquinoline--
3-carboxamide in an amorphous state in the final solid dispersion
product.
BRIEF DESCRIPTION OF THE DRAWINGS
[0086] The file of this patent contains at least one drawing
executed in color. Copies of this patent with color drawings will
be provided by the Patent and Trademark Office upon request and
payment of the necessary fee.
[0087] FIG. 1 is an X-Ray powder diffraction pattern of Compound
1.
[0088] FIG. 2 is the .sup.1H NMR spectrum of Compound 1.
[0089] FIG. 3 is the DSC trace of Compound 1.
[0090] FIG. 4 is the X-Ray powder diffraction pattern of Form
A.
[0091] FIG. 5 is the DSC trace of Form A.
[0092] FIG. 6 is the TGA trace of Form A.
[0093] FIG. 7 is the X-Ray powder diffraction pattern of Form
B.
[0094] FIG. 8 is the DSC trace of Form B.
[0095] FIG. 9 is the TGA trace of Form B.
[0096] FIG. 10 is a conformational picture of Form B, based on
single crystal X-Ray analysis.
[0097] FIG. 11 is the X-Ray powder diffraction pattern of the
Amorphous Form.
[0098] FIG. 12 is the TGA trace of the Amorphous Form.
[0099] FIG. 13 is the DSC trace of the Amorphous Form.
DETAILED DESCRIPTION OF THE INVENTION
Solid Forms of Compound 1
[0100] Form A
[0101] Form A of Compound 1 is characterized by one or more peaks
at from about 4.8 to about 5.2, for example, about 5.0, e.g., 4.99,
and from about 15.4 to about 15.8, for example, about 15.6 e.g.,
15.58 degrees in an X-ray powder diffraction pattern obtained using
Cu K alpha radiation (2.theta.). Other peaks (2.theta.), which can
be characteristic of Form. A, include the following: from about 7.6
to about 8.0, for example, about 7.8, e.g., 7.75; from about 8.3 to
about 8.7, for example, about 8.5, e.g., 8.46; from about 9.0 to
about 9.4, for example, about 9.2, e.g., 9.21; from about 9.7 to
about 10.1, for example, about 9.9, e.g., 9.92; from about 11.7 to
about 12.1, for example, about 11.9, e.g., 11.93; from about 12.4
to about 12.8, for example, about 12.6, e.g., 12.64; from about
13.7 to about 14.1, for example, about 13.9, e.g., 13.88; from
about 14.7 to about 15.1, for example, about 14.9, e.g., 14.91;
from about 16.3 to about 16.7, for example, about 16.5, e.g.,
16.46; from about 17.9 to about 18.3, for example, about 18.1,
e.g., 18.09; from about 18.3 to about 18.7, for example, about
18.5, e.g., 18.52; from about 21.5 to about 21.9, for example,
about 21.7, e.g., 20.65; from about 21.8 to about 22.2, for
example, about 22.0, e.g., 21.95; from about 23.1 to about 23.7,
for example, about 23.5, e.g., 23.49; from about 25.1 to about
25.5, for example, about 25.3, e.g., 25.26; from about 27.8 to
about 28.2 for example, about 28.0, e.g., 28.02; from about 29.2 to
about 29.6, for example, about 29.4, e.g., 29.35; and about from
about 30.7 to about 31.1, for example, 30.9, e.g., 30.85. For
example, Form A can be characterized by an X-ray powder diffraction
pattern obtained using Cu K alpha radiation substantially similar
to FIG. 4.
[0102] Pharmaceutical compositions including Form A and a
pharmaceutically acceptable adjuvant or carrier, such as a polymer
or surfactant are also described. Form A can be formulated in a
pharmaceutical composition, in some instances; with another
therapeutic agent, for example another therapeutic agent for
treating cystic fibrosis or a symptom thereof.
[0103] Processes for preparing Form A are exemplified herein.
[0104] Methods of treating a CFTR mediated disease, such as cystic
fibrosis, in a patient include administering to said patient Form A
or a pharmaceutical composition comprising Form A.
[0105] Form B
[0106] The solid state crystal Form B of Compound 1 is
characterized by one or more peaks at from about 6.0 to about 6.4
for example, about 6.2, e.g., 6.17, from about 7.4 to about 7.8 for
example, about 7.6, e.g., 7.61, from about 12.1 to about 12.5 for
example, about 12.3, e.g., 12.33, and from about 17.8 to about 18.2
for example, about 18.0, e.g., 17.96 degrees in an X-ray powder
diffraction pattern obtained using Cu K alpha radiation (2.theta.).
Other peaks (2.theta.), which can be characteristic of Form B,
include the following: from about 8.2 to about 8.6 for example,
about 8.4, e.g., 8.40; from about 10.8 to about 11.2 for example,
about 11.0, e.g., 11.02; from about 14.6 to about 15.0 for example,
about 14.8, e.g., 14.83; from about 15.9 to about 16.3 for example,
about 16.1, e.g., 16.14; from about 16.9 to about 17.3 for example,
about 17.1, e.g., 17.11; from about 18.4 to about 18.8 for example,
about 18.6, e.g., 18.55; from about 19.2 to about 19.6 for example,
about 19.4, e.g., 19.43; from about 20.9 to about 21.3 for example,
about 21.1, e.g., 21.05; from about 22.4 to about 22.8 for example,
about 22.6, e.g., 22.56; from about 23.2 to about 216 for example,
about 23.4, e.g., 23.37; from about 23.7 to about 24.1 for example,
about 23.9, e.g., 23.94; from about 24.7 to about 25.1 for example,
about 24.9, e.g., 24.86; from about 25.3 to about 25.7 for example,
about 25.5, e.g., 25.50; from about 26.5 to about 26.9 for example,
about 26.7, e.g., 26.72; from about 27.3 to about 27.7 for example,
about 27.5, e.g., 27.51; from about 29.4 to about 29.8 for example,
about 29.6, e.g., 29.60; from about 33.3 to about 33.7 for example,
about 33.5, e.g., 33.48; and from about 36.6 to about 37.0 for
example, about 36.8, e.g., 36.78. Form B can be further
characterized, for example, by an X-ray powder diffraction pattern
obtained using Cu K alpha radiation substantially similar to FIG.
7.
[0107] Applicants have determined crystal structure dimensions of
Form B by analysis of single crystal data. Form Bis a monoclinic
crystal system having a P2.sub.1 space grouping, and the following
unit cell dimensions: a=11.8011 (7) .ANG., .alpha.=90.degree.;
b=5.9819 (3) .ANG., .beta.=105.110 (4).degree.1; c=14.7974 (8)
.ANG., .gamma.=90.degree.. Additional details about the structure
and packing of Form B are provided in the Examples.
[0108] Pharmaceutical compositions including Form B and a
pharmaceutically acceptable adjuvant or carrier, such as a polymer
or surfactant are also described. Form B can be formulated in a
pharmaceutical composition, in some instances, with another
therapeutic agent, for example another therapeutic agent for
treating cystic fibrosis or a symptom thereof.
[0109] Processes for preparing Form B are exemplified herein.
[0110] Methods of treating a CFTR mediated disease, such as cystic
fibrosis, in a patient include administering to said patient Form B
or a pharmaceutical composition comprising Form B.
[0111] Amorphous Compound 1
[0112] Compound 1 can be present as an amorphous solid, for example
amorphous Compound 1 as a substantially neat preparation, or
amorphous compound 1 as a component as a dispersion such as a solid
amorphous dispersion.
[0113] In some embodiments, an amorphous form of Compound 1 is
substantially free of crystalline Compound 1 (e.g., Form A, Form B
or any crystalline form of Compound 1), for example Compound 1 has
less than about 30% of crystalline Compound 1, e.g., less than
about 25% crystalline Compound 1, less than about 20% crystalline
Compound 1, less than about 15% crystalline Compound 1, less than
about 10% crystalline Compound 1, less than about 5% crystalline
Compound 1, less than about 2% crystalline. Compound 1, preferably
less than about 15% crystalline compound 1. Compound 1 can be
characterized by an X-ray powder diffraction pattern obtained using
Cu K alpha radiation substantially similar to FIG. 11. For example,
the substantially amorphous form of Compound 1 can be characterized
as having an XRPD having no sharp characteristic crystalline
peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not
crystalline as determined by XRPD). Instead, one or several broad
peaks (e.g., halos) appear in its XRPD pattern.
[0114] Polymers
[0115] Solid dispersions including amorphous Compound 1 and a
polymer (or solid state carrier) also are included herein. For
example, Compound 1 is present as an amorphous compound as a
component of a solid amorphous dispersion. The solid amorphous
dispersion, generally includes Compound 1 and a polymer. Exemplary
polymers include cellulosic polymers such as HPMC or HPMCAS and
pyrrolidone containing polymers such as PVP/VA. In some
embodiments, the solid amporphous dispersion includes one or more
additional exipients, such as a surfactant.
[0116] In one embodiment, a polymer is able to dissolve in aqueous
media. The solubility of the polymers may be pH-independent or
pH-dependent. The latter include one or more enteric polymers. The
term "enteric polymer" refers to a polymer that is preferentially
soluble in the less acidic environment of the intestine relative to
the more acid environment of the stomach, for example, a polymer
that is insoluble in acidic aqueous media but soluble when the pH
is above 5-6. An appropriate polymer should be chemically and
biologically inert. In order to improve the physical stability of
the solid dispersions, the glass transition temperature (T.sub.g)
of the polymer should be as high as possible. For example,
preferred polymers have a glass transition temperature at least
equal to or greater than the glass transition temperature of the
drug (e.g., Compound 1). Other preferred polymers have a glass
transition temperature that is within about 10 to about 15.degree.
C. of the drug (e.g., Compound 1). Examples of suitable glass
transition temperatures of the polymers include at least about
90.degree. C., at least about 95.degree. C., at least about
100.degree. C., at least about 105.degree. C., at least about
110.degree. C., at least about 115.degree. C., at least about
120.degree. C., at least about 125.degree. C., at least about
130.degree. C., at least about 135.degree. C., at least about
140.degree. C., at least about 145.degree. C., at least about
150.degree. C., at least about 155.degree. C., at least about
160.degree. C., at least about 165.degree. C., at least about
170.degree. C., or at least about 175.degree. C. (as measured under
dry conditions). Without wishing to be bound by theory, it is
believed that the underlying mechanism is that a polymer with a
higher T.sub.g generally has lower molecular mobility at room
temperature, which can be a crucial factor in stabilizing the
physical stability of the amorphous solid dispersion.
[0117] Additionally, the hygroscopicity of the polymers should be
as low, e.g., less than about 10%. For the purpose of comparison in
this application, the hygroscopicity of a polymer or composition is
characterized at about 60% relative humidity. In some preferred
embodiments, the polymer has less than about 10% water absorption,
for example less than about 9%, less than about 8%, less than about
7%, less than about 6%, less than about 5%, less than about 4%,
less than about 3%, or less than about 2% water absorption. The
hygroscopicity can also affect the physical stability of the solid
dispersions. Generally, moisture adsorbed in the polymers can
greatly reduce the T.sub.g of the polymers as well as the resulting
solid dispersions, which will further reduce the physical stability
of the solid dispersions as described above.
[0118] In one embodiment, the polymer is one or more water-soluble
polymer(s) or partially water-soluble polymer(s). Water-soluble or
partially water-soluble polymers include but are not limited to,
cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC),
hydroxypropylcellulose (HPC)) or ethylcellulose;
polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl
alcohols (PVA); acrylates, such as polymethacrylate (e.g.,
Eudragit.RTM. E); cyclodextrins (e.g., .beta.-cyclodextrin) and
copolymers and derivatives thereof, including for example PVP-VA
(polyvinylpyrollidone-vinyl acetate).
[0119] In some preferred embodiments, the polymer is
hydroxypropylmethylcellulose (HPMC), such as HPMC E50, HPMCE15, or
HPMC60SH50).
[0120] As discussed herein, the polymer can be a pH-dependent
enteric polymer. Such pH-dependent enteric polymers include, but
are not limited to, cellulose derivatives (e.g., cellulose acetate
phthalate (CAP)), hydroxypropyl methyl cellulose phthalates
(HPMCP), hydroxypropyl methyl cellulose acetate succinate.
(HPMCAS), carboxymethylcellulose (CMC) or a salt thereof (e.g., a
sodium salt such as (CMC-Na)); cellulose acetate trimellitate
(CAT), hydroxypropylcellulose acetate phthalate (HPCAP),
hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and
methylcellulose acetate phthalate (MCAP), or polymethacrylates
(e.g., Eudragit.RTM. S). In some preferred embodiments, the polymer
is hydroxypropyl methyl cellulose acetate succinate (HPMCAS).
[0121] In yet another embodiment, the polymer is a
polyvinylpyrrolidone co-polymer, for example, a
vinylpyrrolidone/vinyl acetate co-polymer (PVP/VA).
[0122] In embodiments where Compound 1 forms a solid dispersion
with a polymer, for example with an HPMC, HPMCAS or PVP/VA polymer,
the amount of polymer relative to the total weight of the solid
dispersion ranges from about 0.1% to 99% by weight. Unless
otherwise specified, percentages of drug, polymer and other
excipients as described within a dispersion are given in weight
percentages. The amount of polymer is typically at least about 20%,
and preferably at least about 30%, for example, at least about 35%,
at least about 40%, at least about 45%, or about 50% (e.g., 49.5%).
The amount is typically about 99% or less, and preferably about 80%
or less, for example about 75% or less, about 70% or less, about
65% or less, about 60% or less, or about 55% or less. In one
embodiment, the polymer is in an amount of up to about 50% of the
total weight of the dispersion (and even more specifically, between
about 40% and 50%, such as about 49%, about 49.5%, or about 50%).
HPMC and HPMCAS are available in a variety of grades from ShinEtsu,
for example, HPMCAS is available in a number of varieties,
including AS-LF, AS-MF, AS-HF, AS-LG, AS-MG, AS-HG. Each of these
grades vary with the percent substitution of acetate and
succinate.
[0123] In some preferred embodiments, Compound 1 and polymer are
present in roughly equal amounts, for example each of the polymer
and the drug make up about half of the percentage weight of the
dispersion. For example, the polymer is present in about 49.5% and
the drug is present in about 50%.
[0124] In some preferred embodiments, the dispersion further
includes other minor ingredients, such as a surfactant (e.g., SLS).
In some preferred embodiments, the surfactant is present in less
than about 10% of the dispersion, for example less than about 9%,
less than about 8%, less than about 7%, less than about 6%, less
than about 5%, less than about 4%, less than about 3%, less than
about 2%, about 1%, or about 0.5%.
[0125] In embodiments including a polymer, the polymer should be
present in an amount effective for stabilizing the solid
dispersion. Stabilizing includes inhibiting or preventing, the
crystallization of Compound 1. Such stabilizing would inhibit the
conversion Compound 1 from amorphous to crystalline form. For
example, the polymer would prevent at least a portion (e.g., about
5%, about 10%, about 15%, about 20%, about 25%, about 30%, about
35%, about 40%, about 45%, about 50%, about 55%, about 60%, about
65%, about 70%, about 75%, or greater) of Compound 1 from
converting from an amorphous to a crystalline form. Stabilization
can be measured, for example, by measuring the glass transition
temperature of the solid dispersion, measuring the rate of
relaxation of the amorphous material, or by measuring the
solubility or bioavailability of Compound 1.
[0126] Suitable polymers for use in combination with Compound 1,
for example to form a solid dispersion such as an amorphous solid
dispersion, should have one or more of the following
properties:
[0127] The glass transition temperature of the polymer should have
a temperature of no less than about 10-15.degree. C. lower than the
glass transition temperature of Compound 1. Preferably, the glass
transition temperature of the polymer is greater than the glass
transition temperature of Compound 1, and in general at least
50.degree. C. higher than the desired storage temperature of the
drug product. For example, at least about 100.degree. C., at least
about 105.degree. C., at least about 105.degree. C., at least about
110.degree. C., at least about 120.degree. C., at least about
130.degree. C., at least about 140.degree. C., at least about
150.degree. C., at least about 160.degree. C., at least about
160.degree. C., or greater.
[0128] The polymer should be relatively non-hygroscopic. For
example, the polymer should, when stored under standard conditions,
absorb less than about 10% water, for example, less than about 9%,
less than about 8%, less than about 7%, less than about 6%, or less
than about 5%, less than about 4%, or less than about 3% water.
Preferably the polymer will, when stored under standard conditions,
be substantially free of absorbed water.
[0129] The polymer should have similar or better solubility in
solvents suitable for spray drying processes relative to that of
Compound 1. In preferred embodiments, the polymer will dissolve in
one or more of the same solvents or solvent systems as Compound 1.
It is preferred that the polymer is soluble in at least one
non-hydroxy containing solvent such as methylene chloride, acetone,
or a combination thereof.
[0130] The polymer, when combined with Compound 1, for example in a
solid dispersion or in a liquid suspension, should increase the
solubility of Compound 1 in aqueous and physiologically relative
media either relative to the solubility of Compound 1 in the
absence of polymer or relative to the solubility of Compound 1 when
combined with a reference polymer. For example, the polymer could
increase the solubility of amorphous Compound 1 by reducing the
amount of amorphous Compound 1 that converts to crystalline
Compound 1, either from a solid amorphous dispersion or from a
liquid suspension.
[0131] The polymer should decrease the relaxation rate of the
amorphous substance.
[0132] The polymer should increase the physical and/or chemical
stability of Compound 1.
[0133] The polymer should improve the manufacturability of Compound
1.
[0134] The polymer should improve one or more of the handling,
administration or storage properties of Compound 1.
[0135] The polymer should not interact unfavorably with other
pharmaceutical components, for example excipients.
[0136] The suitability of a candidate polymer (or other component)
can be tested using the spray drying methods (or other methods)
described herein to form an amorphous composition. The candidate
composition can be compared in terms of stability, resistance to
the formation of crystals, or other properties, and compared to a
reference preparation, e.g., a preparation of neat amorphous
Compound 1 or crystalline Compound 1. E.g., a candidate composition
could be tested to determine whether it inhibits the time to onset
of solvent mediated crystallization, or the percent conversion at a
given time under controlled conditions, by at least 50%, 75%, 100%,
or 110% as well as the reference preparation, or a candidate
composition could be tested to determine if it has improved
bioavailability or solubility relative to crystalline Compound
1.
[0137] Surfactants
[0138] A solid dispersion or other composition may include a
surfactant. A surfactant or surfactant mixture would generally
decrease the interfacial tension between the solid dispersion and
an aqueous medium. An appropriate surfactant or surfactant mixture
may also enhance aqueous solubility and bioavailability of Compound
1 from a solid dispersion. The surfactants for use in connection
with the present invention include, but are not limited to,
sorbitan fatty acid esters (e.g., Spans.RTM.), polyoxyethylene
sorbitan fatty acid esters (e.g., Tweens.RTM.), sodium lauryl
sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS) dioctyl
sodium sulfosuccinate (Docusate), dioxycholic acid sodium salt
(DOSS), Sorbitan Monostearate, Sorbitan Tristearate,
hexadecyltrimethyl ammonium bromide (HTAB), Sodium
N-lauroylsarcosine, Sodium Oleate, Sodium Myristate, Sodium
Stearate, Sodium Palmitate, Gelucire 44/14, ethylenediamine
tetraacetic acid (EDTA), Vitamin E d-alpha tocopheryl polyethylene
glycol 1000 succinate (TAGS), Lecithin, MW 677-692, Glutanic acid
monosodium monohydrate, Labrasol, PEG 8 caprylic/capric glycerides,
Transcutol, diethylene glycol monoethyl ether, Solutol HS-15,
polyethylene glycol/hydroxystearate, Taurocholic Acid, Pluronic
F68, Pluronic F108, and Pluronic F127 (or any other
polyoxyethylene-polyoxypropylene co-polymers (Pluronics.RTM.) or
saturated polyglycolized glycerides (Gelucirs.RTM.)). Specific
example of such surfactants that may be used in connection with
this invention include, but are not limited to, Span 65, Span 25,
Tween 20, Capryol 90, Pluronic F108, sodium lauryl sulfate (SLS)
Vitamin E TPGS, pluronics and copolymers. SLS is generally
preferred.
[0139] The amount of the surfactant (e.g., SLS) relative to the
total weight of the solid dispersion may be between 0.1-15%.
Preferably, it is from about 0.5% to about 10%, more preferably
from about 05 to about 5%, e.g., about 1%, about 2%, about 3%,
about 4%, or about 5%.
[0140] In certain embodiments, the amount of the surfactant
relative to the total weight of the solid dispersion is at least
about 0.1, preferably about 0.5%. In these embodiments, the
surfactant would be present in an amount of no more than about 15%,
and preferably no more than about 12%, about 11%, about 10%, about
9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%,
about 2% or about 1%. An embodiment wherein the surfactant is in an
amount of about 0.5% by weight is preferred.
[0141] Candidate surfactants (or other components) can be tested
for suitability for use in the invention in a manner similar to
that described for testing polymers.
[0142] Methods of Making Solid Forms of Compound 1
[0143] The solid form of Compound 1 can vary depending on the
method used to prepare Compound 1. For example, Compound 1 can be
prepared using a method to provide crystalline Compound 1, such as
Form A or Form B, or Compound 1 can be prepared using a method to
provide amorphous Compound 1, for example as a neat preparation or
where Compound 1 is a component in a dispersion such as a solid
amorphous dispersion (e.g., a dispersion of Compound 1 and a
polymer such as a cellulosic polymer e.g., HPMC or HPMCAS or a
pyrrolidone polymer such as PVP/VA).
[0144] Form A
[0145] Form A of Compound 1 can be prepared, for example, by
heating Compound 1 to at or above its melting point, for example to
about 250.degree. C. and then cooling the compound, thereby
providing Compound 1 having a solid state of Form A. Form A can be
characterized by one or more characteristic peaks as determined
using XRPD. For example, Compound 1 as Form A can be identified by
the presence of one or peaks at 2.theta., including one or more of
the following peaks at or about: about 5.0 e.g. 4.99; about 7.8,
e.g., 7.75; about 8.5, e.g., 8.46; about 9.2, e.g., 9.21; about
9.9, e.g., 9.92; about 11.9, e.g., 11.93; about 12.6, e.g., 12.64;
about 13.9, e.g., 13.88; about 14.9, e.g., 14.91; about 15.6, e.g.,
15.58; about 16.5, e.g., 16.46; about 18.1, e.g., 18.09; about
18.5, e.g., 18.52; about 21.7, e.g., 20.65; about 22.0, e.g.,
21.95; about 23.5, e.g., 23.49; about 25.3, e.g., 25.26; about
28.0, e.g., 28.02; about 29.4, e.g., 29.35; and about 30.9, e.g.,
30.85.
[0146] Form B
[0147] Form B of Compound 1 can be prepared, for example, by
subjecting a slurry of compound 1 in a solvent to heating and
cooling cycles.
[0148] In some preferred embodiments, the solvent is a solvent
where Compound 1 has limited solubility at room temperature, for
example, acetone.
[0149] The slurry is subject to a plurality of heat/cool cycles,
where the slurry is generally warmed to a temperature above room
temperature but below the boiling point of the solvent, for example
about 40.degree. C. to about 60.degree. C., e.g., about 50.degree.
C. The slurry is generally subjected to at least 2 heat/cool
cycles, for example, 2, 3, 4, 5, or 6, preferably 5 cycles. Each
cycle was timed to last at least about 8 hours (e.g., 4 hours of
heating followed by 4 hours at room temperature, 6 hours of heating
followed by 6 hours at room temperature, 8 hours of heating
followed by 8 hours at room temperature, preferably 12 hours of
heating followed by 12 hours at room temperature).
[0150] In an alternative embodiment crude Compound 1 can be
refluxed in as a slurry in acetonitrile (e.g., 27 volumes of
acetonitrile) for 24 hours. The mixture is then cooled, e.g., to
about room temperature, e.g., about 20.degree. C. Form B is then
isolated, for example, by filtration as a white to off-white. The
resulting wet cake is rinsed with acetonitrile (e.g., 5 volumes)
and dried under vacuum at 50.degree. C. until a constant weight is
attained.
[0151] Form B can be characterized by one or more characteristic
peaks as determined using XRPD. For example, Compound 1 as Form B
can be identified by the presence of one or peaks at 2.theta.,
including one or more of the following peaks at or about: about
6.2, e.g., 6.17; about 7.6, e.g., 7.61; about 8.4, e.g., 8.40;
about 11.0, e.g., 11.02; about 12.3, e.g., 1233; about 14.8, e.g.,
14.83; about 16.1, e.g., 16.14; about 17.1, e.g., 17.11; about
18.0, e.g., 17.96; about 18.6, e.g., 18.55; about 19.4, e.g.,
19.43; about 21.1, e.g., 21.05; about 22.6, e.g., 22:56; about
23.4, e.g., 23.37; about 23.9, e.g., 23.94; about 24.9, e.g.,
24.86; about 25.5, e.g., 25.50; about 26.7, e.g., 26.72; about
27.5, e.g., 27.51; about 29.6, e.g., 29.60; about 33.5, e.g.,
33.48; and about 36.8, e.g., 36.78.
[0152] Amorphous Compound 1
[0153] Amporphous compound 1 can be made using a variety of
techniques, including, for example spray drying a solution of
Compound 1 to provide amorphous Compound 1, e.g., as a neat solid
or as a component of a solid dispersion, said method utilizing
spray-drying means to effect said conversion. For example,
Amorphous Compound 1 can be made by converting a form of Compound
1, e.g., a crystalline form of Compound 1, such as Form A or Form
B, into a substantially amorphous form of Compound 1 by dissolving
Compound into a solution and spray drying the solution of Compound
1, thereby converting a form of Compound 1, such as crystalline
Compound 1, into amorphous Compound 1. An exemplary process for
making amorphous Compound 1 by converting Form B into a
substantially amorphous form of Compound 1 is recited in the
examples.
[0154] Any method for obtaining amorphous forms of Compound 1,
including neat amorphous Compound 1 and solid amorphous dispersions
of Compound 1, can be used including, for example, those described
in US 2003/0186952 (see the documents cited therein at paragraph
1092) and US 2003/0185891). In general, methods that could be used
include those that involve rapid removal of solvent from a mixture
or cooling a molten sample. Such methods include, but are not
limited to, rotational evaporation, freeze-drying (i.e.,
lyophilization), vacuum drying, melt congealing, and melt
extrusion. However, a preferred embodiment includes amorphous.
Compound 1, such as a neat preparation or a solid dispersion
obtained by spray-drying. Accordingly, in some embodiments, the
amorphous product obtained by spray-drying is further dried, for
example, to remove residual solvent.
[0155] Preparations disclosed herein, e.g., a pharmaceutical
composition, can be obtained by spray-drying a mixture comprising
Compound 1, a suitable polymer, and an appropriate solvent. Spray
drying is a method that involves atomization of a liquid mixture
containing, e.g., a solid and a solvent, and removal of the
solvent. Atomization can be done, for example, through a nozzle or
on a rotating disk.
[0156] Spray drying is a process that converts a liquid feed to a
dried particulate form. Optionally, a secondary drying process such
as fluidized bed drying or vacuum drying, may be used to reduce
residual solvents to pharmaceutically acceptable levels. Typically,
spray-drying involves contacting a highly dispersed liquid
suspension or solution, and a sufficient volume of hot air to
produce evaporation and drying of the liquid droplets. The
preparation to be spray dried can be any solution, coarse
suspension, slurry, colloidal dispersion, or paste that may be
atomized using the selected spray-drying apparatus. In a standard
procedure, the preparation is sprayed into a current of warm
filtered air that evaporates the solvent and conveys the dried
product to a collector (e.g., a cyclone). The spent air is then
exhausted with the solvent, or alternatively the spent air is sent
to a condenser to capture and potentially recycle the solvent.
Commercially available types of apparatus may be used to conduct
the spray-drying. For example, commercial spray dryers are
manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray
driers manufactured by Niro) (see, US 2004/0105820; US
2003/0144257).
[0157] Spray-drying typically employs solids loads of material from
about 3% to about 30% by weight, (i.e., drug plus and excipients),
for example about 4% to about 20% by weight, preferably at least
about 10%. In general, the upper limit of solids loads is governed
by the viscosity of (e.g., the ability to pump) the resulting
solution and the solubility of the components in the solution.
Generally, the viscosity of the solution can determine the size of
the particle in the resulting powder product.
[0158] Techniques and methods for spray-drying may be found in
Perry's Chemical Engineering Handbook, 6th Ed., R. H. Perry, D. W.
Green & J. O. Maloney, eds.), McGraw-Hill book co. (1984); and
Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog.
Monogr. Series 2 (1954). In general, the spray-drying is conducted
with an inlet temperature of from about 60.degree. C. to about
200.degree. C., for example, from about 95.degree. C. to about
185.degree. C., from about 110 C. to about 182.degree. C., from
about 96.degree. C. to about 108.degree. C., e.g., about
175.degree. C. The spray-drying is generally conducted with an
outlet temperature of from about 30.degree. C. to about 80.degree.
C., for example from about 31.degree. C. to about 72.degree. C.,
about 37.degree. C. to about 41.degree. C. e.g., about 60.degree.
C. The atomization flow rate is generally from about 4 kg/h to
about 12 kg/h, for example, from about 4.3 kg/h to about 10.5 kg/h,
e.g., about 6 kg/h or about 10.5 kg/h. The feed flow rate is
generally from about 3 kg/h to about 10 kg/h, for example, from
about 3.5 kg/h to about 9.0 kg/h, e.g., about 8 kg/h or about 7.1
kg/h. The atomization ratio is generally from about 0.3 to 1.7,
e.g., from about 0.5 to 1.5, e.g., about 0.8 or about 1.5.
[0159] Removal of the solvent may require a subsequent drying step,
such as tray drying, fluid bed drying (e.g., from about room
temperature to about 100.degree. C.), vacuum drying, microwave
drying, rotary drum drying or biconical vacuum drying (e.g., from
about room temperature to about 200.degree. C.).
[0160] In one embodiment, the solid dispersion is fluid-bed
dried.
[0161] In preferred processes, the solvent includes a volatile
solvent, for example a solvent having a boiling point of less than
about 100.degree. C. In some embodiments, the solvent includes a
mixture of solvents, for example a mixture of volatile solvents or
a mixture of volatile and non-volatile solvents. Where mixtures of
solvents are used, the mixture can include one or more non-volatile
solvents, for example, where the non-volatile solvent is present in
the mixture at less than about 15%, e.g., less than about 12%, less
than about 10%, less than about 8%, less than about 5%, less than
about 3%, or less than about 2%.
[0162] Preferred solvents are those solvents where Compound 1 has a
solubility of at least about 10 mg/ml (e.g., at least about 15
mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml,
50 mg/ml, or greater). More preferred solvents include those where
Compound 1 has a solubility of at least about 50 mg/ml.
[0163] Exemplary solvents that could be tested include acetone,
cyclohexane, dichloromethane, N,N-Dimethylacetamide (DMA),
N,N-Dimethylformamide (DMF), 1,3 Dimethyl-2-imidazolidinone (DMI),
dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether,
glacial acetic acid (HAc), methyl ethyl ketone (MEK),
N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether,
tetrahydrofuran (THF) and pentane. Exemplary co-solvents include
acetone/DMSO, acetone/DMF, acetone/water, MEK/water, THF/water,
dioxane/water. In a two solvent system, the solvents can be present
in of from about 0.1% to about 99.9%. In some preferred
embodiments, water is a co-solvent with acetone where water is
present from about 0.1% to about 15%, for example about 9% to about
11%, e.g., about 10%. In some preferred embodiments, water is a
co-solvent with MEK where water is present from about 0.1% to about
15%, for example about 9% to about 11%, e.g., about 10%. In some
embodiments the solvent solution include three solvents. For
example, acetone and water can be mixed with a third solvent such
as DMA, DMF, DMI, DMSO, or HAc. In instances where amorphous
Compound 1 is a component of a solid amorphous dispersion,
preferred solvents dissolve both Compound 1 and the polymer.
Suitable solvents include those described above, for example, MEK,
acetone, water, and mixtures thereof.
[0164] The particle size and the temperature drying range may be
modified to prepare an optimal solid dispersion. As would be
appreciated by skilled practitioners, a small particle size would
lead to improved solvent removal. Applicants have found however,
that smaller particles can lead to fluffy particles that, under
some circumstances do not provide optimal solid dispersions for
downstream processing such as tabletting. At higher temperatures,
crystallization or chemical degradation of Compound 1 may occur. At
lower temperatures, a sufficient amount of the solvent may not be
removed. The methods herein provide an optimal particle size and an
optimal drying temperature.
[0165] In general, particle size is such that D10 (.mu.m) is less
than about 5, e.g., less than about 4.5, less than about 4.0, or
less than about 3.5, D50 (.mu.m) is generally less than about 17,
e.g., less than about 16, less than about 15, less than about 14,
less than about 13, and D90 (.mu.m) is generally less than about
175, e.g., less than about 170, less than about 170, less than
about 150, less than about 125, less than about 100, less than
about 90, less than about 80, less than about 70, less than about
60, or less than about less than about 50. In general bulk density
of the spray dried particles is from about 0.08 g/cc to about 0.20
g/cc, e.g., from about 0.10 to about 0.15 g/cc, e.g., about 0.11
g/cc or about 0.14 g/cc. Tap density of the spray dried particles
generally ranges from about 0.08 g/cc to about 0.20 g/cc, e.g.,
from about 0.10 to about 0.15 g/cc, e.g., about 0.11 g/cc or about
0.14 g/cc, for 10 taps; 0.10 g/cc to about 0.25 g/cc; e.g., from
about 0.11 to about 0.21 g/cc, e.g., about 0.15 g/cc, about 0.19
g/cc, or about 0.21 g/cc for 500 taps; 0.15 g/cc to about 0.27
g/cc, e.g., from about 0.18 to about 0.24 g/cc, e.g., about 0.18
g/cc, about 0.19 g/cc, about 0.20 g/cc, or about 0.24 g/cc for 1250
taps; and 0.15 g/cc to about 0.27 g/cc, e.g., from about 0.18 to
about 0.24 g/cc, e.g., about 0.18 g/cc, about 0.21 g/cc, about 0.23
g/cc, or about 0.24 g/cc for 2500 taps.
[0166] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention. All tautomeric forms of the Compound 1 are included
herein. E.g., Compound 1 may exist as tautomers, both of which are
included herein:
##STR00002##
[0167] Additionally, unless otherwise stated, structures depicted
herein are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds of formula (I), wherein one or more hydrogen atoms are
replaced deuterium or tritium, or one or more carbon atoms are
replaced by a 13C- or 14C-enriched carbon are within the scope of
this invention. Such compounds are useful, for example, as
analytical tools, probes in biological assays, or compounds with
improved therapeutic profile.
[0168] Uses, Formulation and Administration
[0169] Pharmaceutically Acceptable Compositions
[0170] In another aspect of the present invention, pharmaceutically
acceptable compositions are provided, wherein these compositions
comprise any of the compounds as described herein, and optionally
comprise a pharmaceutically acceptable carrier, adjuvant or
vehicle. In certain embodiments, these compositions optionally
further comprise one or more additional therapeutic agents.
[0171] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate; as a pharmaceutically acceptable derivative or a
prodrug thereof. According to the present invention, a
pharmaceutically acceptable derivative or a prodrug includes, but
is not limited to, pharmaceutically acceptable salts, esters, salts
of such esters, or any other adduct or derivative which upon
administration to a patient in need thereof is capable of
providing, directly or indirectly, a compound as otherwise
described herein, or a metabolite or residue thereof.
[0172] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. A "pharmaceutically acceptable salt" means any
non-toxic salt or salt of an ester of a compound of this invention
that, upon administration to a recipient, is capable of providing,
either directly or indirectly, a compound of this invention or an
inhibitorily active metabolite or residue thereof.
[0173] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge, et al. describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66,
1-19, incorporated herein by reference. Pharmaceutically acceptable
salts of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersable products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts
include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0174] As described above, the pharmaceutically acceptable
compositions of the present invention additionally comprise a
pharmaceutically acceptable carrier, adjuvant, or vehicle, which,
as used herein, includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, or potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0175] Uses of Compounds and Pharmaceutically Acceptable
Compositions
[0176] In yet another aspect, the present invention provides a
method of treating a condition, disease, or disorder implicated by
CFTR. In certain embodiments, the present invention provides a
method of treating a condition, disease, or disorder implicated by
a deficiency of CFTR activity, the method comprising administering
a composition comprising a solid state form of Compound 1 described
herein (e.g., Form A, Form B, or amorphous Compound 1, e.g., neat
or as a component in a dispersion) to a subject, preferably a
mammal, in need thereof.
[0177] A "CFTR-mediated disease" as used herein is a disease
selected from cystic fibrosis, Hereditary emphysema, Hereditary
hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as
Protein C deficiency, Type 1 hereditary angioedema, Lipid
processing deficiencies, such as Familial hypercholesterolemia,
Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage
diseases, such as I-cell disease/Pseudo-Hurler,
Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II,
Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron
dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism,
Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital
hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),
Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome,
Perlizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease, Amyotrophic lateral
sclerosis, Progressive supranuclear plasy, Pick's disease, several
polyglutamine neurological disorders such as Huntington,
Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,
Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as
Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob
disease, Fabry disease, Straussler-Scheinker syndrome, COPD,
dry-eye disease, and Sjogren's disease.
[0178] In certain embodiments, the present invention provides a
method of treating cystic fibrosis, hereditary emphysema,
hereditary hemochromatosis, coagulation-fibrinolysis deficiencies,
such as protein C deficiency, Type 1 hereditary angioedema, lipid
processing deficiencies, such as familial hypercholesterolemia,
Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage
diseases, such as I-cell disease/pseudo-Hurler,
mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II,
polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron
dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism,
melanoma, glycanosis CDG type 1, congenital hyperthyroidism,
osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT
deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic
DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,
neurodegenerative diseases such as Alzheimer's disease, Parkinson's
disease, amyotrophic lateral sclerosis, progressive supranuclear
plasy, Pick's disease, several polyglutamine neurological disorders
such as Huntington, spinocerebullar ataxia type I, spinal and
bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic
dystrophy, as well as spongiform encephalopathies, such as
hereditary Creutzfeldt-Jakob disease (due to prion protein
processing defect), Fabry disease, Straussler-Scheinker syndrome,
COPD, dry-eye disease, or Sjogren's disease, comprising the step of
administering to: said mammal an effective amount of a composition
comprising a solid state form of Compound 1 described herein (e.g.,
Form A, or Form B, or amorphous Compound 1, e.g., neat or as a
component in a dispersion).
[0179] According to an alternative preferred embodiment, the
present invention provides a method of treating cystic fibrosis
comprising the step of administering to said mammal a composition
comprising a solid state form of Compound 1 described herein (e.g.,
Form A, or Form B, or amorphous Compound 1, e.g., neat or as a
component in a dispersion).
[0180] According to the invention an "effective amount" of a solid
state form of Compound 1 (e.g., Form A, or Form B, or amorphous
Compound 1, e.g., neat or as a component in a dispersion) or a
pharmaceutically acceptable composition thereof is that amount
effective for treating or lessening the severity of any of the
diseases recited above.
[0181] A solid state form of Compound 1 (e.g., Form A, or Form B,
or amorphous Compound 1, e.g., neat or as a component in a
dispersion) or a pharmaceutically acceptable composition thereof
may be administered using any amount and any route of
administration effective for treating or lessening the severity of
one or more of the diseases recited above.
[0182] In certain embodiments, a solid state form of Compound 1
described herein (e.g., Form A, or Form B, or amorphous Compound 1,
e.g., neat or as a component in a dispersion) or a pharmaceutically
acceptable composition thereof is useful for treating or lessening
the severity of cystic fibrosis in patients who exhibit residual
CFTR activity in the apical membrane of respiratory and
non-respiratory epithelia. The presence of residual CFTR activity
at the epithelial surface can be readily detected using methods
known in the art, e.g., standard electrophysiological, biochemical,
or histochemical techniques. Such methods identify CFTR activity
using in vivo or ex vivo electrophysiological techniques,
measurement of sweat or salivary CF concentrations, or ex vivo
biochemical or histochemical techniques to monitor cell surface
density. Using such methods, residual CFTR activity can be readily
detected in patients heterozygous or homozygous for a variety of
different mutations, including patients homozygous or heterozygous
for the most common mutation, .DELTA.F508.
[0183] In one embodiment, a solid state form of Compound 1
described herein (e.g., Form A, or Form B, or amorphous Compound 1,
e.g., neat or as a component in a dispersion) or a pharmaceutically
acceptable composition thereof is useful for treating or lessening
the severity of cystic fibrosis in patients within certain
genotypes exhibiting residual CFTR activity, e.g., class III
mutations (impaired regulation or gating), class IV mutations
(altered conductance), or class V mutations (reduced synthesis)
(Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V
cystic fibrosis Tansmembrane conductance Regulator Defects and
Opportunities of Therapy; Current Opinion in Pulmonary Medicine
6:521-529, 2000). Other patient genotypes that exhibit residual
CFTR activity include patients homozygous for one of these classes
or heterozygous with any other class of mutations, including class
I mutations, class II mutations, or a mutation that lacks
classification.
[0184] In one embodiment, a solid state form of Compound 1
described herein (e.g., Form A, or Form B, or amorphous Compound 1,
e.g., neat or as a component in a dispersion) or a pharmaceutically
acceptable composition thereof is useful for treating or lessening
the severity of cystic fibrosis in patients within certain clinical
phenotypes, e.g., a moderate to mild clinical phenotype that
typically correlates with the amount of residual CFTR activity in
the apical membrane of epithelia. Such phenotypes include patients
exhibiting pancreatic insufficiency or patients diagnosed with
idiopathic pancreatitis and congenital bilateral absence of the vas
deferens, or mild lung disease.
[0185] The exact amount required will vary from subject to subject,
depending on the species, age, and general condition of the
subject, the severity of the infection, the particular agent, its
mode of administration, and the like. The compounds of the
invention are preferably formulated in dosage unit form for ease of
administration and uniformity of dosage. The expression "dosage
unit form" as used herein refers to a physically discrete unit of
agent appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific effective dose level for any particular patient or
organism will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed, and like
factors well known in the medical arts. The term "patient", as used
herein, means an animal, preferably a mammal, and most preferably a
human.
[0186] The pharmaceutically acceptable compositions of this
invention can be administered to humans and other animals orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops),
bucally, as an oral or nasal spray, or the like, depending on the
severity of the infection being treated. In certain embodiments,
the compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg
and preferably from about 1 mg/kg to about 25 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0187] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0188] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0189] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0190] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0191] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0192] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar--agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0193] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets; dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polyethylene
glycols and the like.
[0194] The active compounds can also be in microencapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredients) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0195] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, eardrops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
are prepared by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0196] It will also be appreciated that the solid state form of
Compound 1 described herein (e.g., Form A, or Form B, or amorphous
Compound 1, e.g., neat or as a component in a dispersion) or a
pharmaceutically acceptable composition thereof can be employed in
combination therapies, that is, Form A or Form B or a
pharmaceutically acceptable composition thereof can be administered
concurrently with, prior to, or subsequent to, one or more other
desired therapeutics or medical procedures. The particular
combination of therapies (therapeutics or procedures) to employ in
a combination regimen will take into account compatibility of the
desired therapeutics and/or procedures and the desired therapeutic
effect to be achieved. It will also be appreciated that the
therapies employed may achieve a desired effect for the same
disorder (for example, an inventive compound may be administered
concurrently with another agent used to treat the same disorder),
or they may achieve different effects (e.g., control of any adverse
effects). As used herein, additional therapeutic agents that are
normally administered to treat or prevent a particular disease, or
condition, are known as "appropriate for the disease, or condition,
being treated".
[0197] In one embodiment, the additional agent is selected from a
mucolytic agent, bronchodialator, an anti-biotic, an anti-infective
agent, an anti-inflammatory agent, a CFTR modulator other than a
compound of the present invention, or a nutritional agent.
[0198] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0199] A solid state form of Compound 1 described herein (e.g.,
Form A, or Form B, or amorphous Compound 1, e.g., neat or as a
component in a dispersion) or a pharmaceutically acceptable
composition thereof may also be incorporated into compositions for
coating an implantable medical device, such as prostheses,
artificial valves, vascular grafts, stents and catheters.
Accordingly, the present invention, in another aspect, includes a
composition for coating an implantable device comprising a solid
state form of Compound 1 described herein (e.g., Form A, or Form B,
or amorphous Compound 1, e.g., neat or as a component in a
dispersion) or a pharmaceutically acceptable composition thereof,
and in classes and subclasses herein, and a carrier suitable for
coating said implantable device. In still another aspect, the
present invention includes an implantable device coated with a
composition comprising a solid state form of Compound 1 described
herein (e.g., Form A, or Form B, or amorphous Compound 1, e.g.,
neat or as a component in a dispersion) or a pharmaceutically
acceptable composition thereof, and a carrier suitable for coating
said implantable device. Suitable coatings and the general
preparation of coated implantable devices are described in U.S.
Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are
typically biocompatible polymeric materials such as a hydrogel
polymer, polymethyldisiloxane, polycaprolactone, polyethylene
glycol, polylactic acid, ethylene vinyl acetate, and mixtures
thereof. The coatings may optionally be further covered by a
suitable topcoat of fluorosilicone, polysaccarides, polyethylene
glycol, phospholipids or combinations thereof to impart controlled
release characteristics in the composition.
[0200] In order that the invention described herein may be more
fully understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
EXAMPLES
Methods & Materials
[0201] Differential Scanning Calorimetry (DSC)
[0202] The Differential scanning calorimetry (DSC) data of Form A,
Form B, and amorphous Compound 1 were collected using a DSC Q100
V9.6 Build 290 (TA Instruments, New Castle, Del.). Temperature was
calibrated with indium and heat capacity was calibrated with
sapphire. Samples of 3-6 mg were weighed into aluminum pans that
were crimped using lids with 1 pin hole. The samples were scanned
from 25.degree. C. to 350.degree. C. at a heating rate of
10.degree. C./min and with a nitrogen gas purge of 50 ml/min. Data
were collected by Thermal Advantage Q Series.TM. version 2.2.0.248
software and analyzed by Universal Analysis software version 4.1D
(TA Instruments; New Castle, Del.). The reported numbers represent
single analyses.
[0203] Thermogravimetric Analysis (TGA)
[0204] Thermal gravimetric analysis (TGA) was performed with a TGA
Q500 V6.3 Build 189 (TA Instruments, New Castle, Del.) was used for
TGA measurement. Temperature was equilibrated by Curie point with
nickel. Samples of 10-20 mg were scanned from 25.degree. C. to
350.degree. C. at a heating rate of 10.degree. C./min. A nitrogen
gas balance purge of 10 ml/min and a sample purge of 90 ml/min were
used. Data were collected by Thermal Advantage Q Series.TM.
software version 2.2.0.248 and analyzed by Universal Analysis
software version 4.1 D (TA Instruments, New Castle, Del.). The
reported numbers represent single analyses.
[0205] XRPD (X-Ray Powder Diffraction)
[0206] The X-Ray diffraction (XRD) data of Form A, Form B, and
amorphous Compound 1 were collected on a Bruker D8 DISCOVER with
GADDS powder diffractometer with HI-STAR 2-dimensional detector and
a flat graphite monochromator. Cu sealed tube with K.quadrature.
radiation was used at 40 kV, 35 mA. The samples were placed on
zero-background silicon wafers at 25.degree. C. For each sample,
two data frames were collected at 120 seconds each at 2 different
2.quadrature. angles: 8.degree. and 26.degree.. The frames data
were integrated with GADDS software and merged with
DIFFRACT.sup.plusEVA software.
Synthesis of
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide (Compound 1)
##STR00003##
[0207] 2-Phenylaminomethylene-malonic acid diethyl ester
[0208] A mixture of aniline (25.6 g, 0.275 mol) and diethyl
2-(ethoxymethylene) malonate (62.4 g, 0.288 mol) was heated at
140-150.degree. C. for 2 h. The mixture was cooled to room
temperature and dried under reduced pressure to afford
2-phenylaminomethylene-malonic acid diethyl ester as a solid, which
was used in the next step without further purification. .sup.1H NMR
(DMSO-d.sub.6) .delta.11.00 (d, 1H), 8.54 (d, J=13.6 Hz, 1H),
7.36-7.39 (m, 2H), 7.13-7.17 (m, 3H), 4.17-4.33 (m, 4H), 1.18-1.40
(m, 6H).
4-Hydroxyquinoline-3-carboxylic acid ethyl ester
[0209] A 1 L three-necked flask fitted with a mechanical stirrer
was charged with 2-phenylaminomethylene-malonic acid diethyl ester
(26.3 g, 0.100 mol), polyphosphoric acid (270 g) and phosphoryl
chloride (750 g). The mixture was heated to 70.degree. C. and
stirred for 4 h. The mixture was cooled to room temperature and
filtered. The residue was treated with aqueous Na.sub.2CO.sub.3
solution, filtered, washed with water and dried.
4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as a
pale brown solid (15.2 g, 70%). The crude product was used in next
step without further purification.
4-Oxo-1,4'-dihydroquinoline-3-carboxylic acid
[0210] 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69
mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and
stirred for 2 h. at reflux. After cooling, the mixture was
filtered, and the filtrate was acidified to pH 4 with 2N HCl. The
resulting precipitate was collected via filtration, washed with
water and dried under vacuum to give
4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid
(10.5 g, 92%). .sup.1H NMR (DMSO-d.sub.6) .delta. 15.34 (s, 1H),
13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H),
7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H).
##STR00004##
Carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester
[0211] Methyl chloroformate (58 mL, 750 mmol) was added dropwise to
a solution of 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol),
Et.sub.3N (139 mL, 1000 mmol) and DMAP (3.05 g, 25 mmol) in
dichloromethane (400 mL) cooled in an ice-water bath to 0.degree.
C. The mixture was allowed to warm to room temperature while
stirring overnight, then filtered through silica gel (approx. 1 L)
using 10% ethyl acetate-hexanes (.about.4 L) as the eluent. The
combined filtrates were concentrated to yield carbonic acid
2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g,
quant.). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.35 (d, J=2.4
Hz, 1H), 7.29 (dd, J=8.5, 2.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.85
(s, 3H), 1.30 (s, 9H), 1.29 (s, 9H).
Carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester
and Carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl
ester
[0212] To a stirring mixture of carbonic acid
2,4-di-tert-butyl-phenyl ester methyl ester (4.76 g, 180 mmol) in
cone. sulfuric acid (2 mL), cooled in an ice-water bath, was added
a cooled mixture of sulfuric acid (2 mL) and nitric acid (2 mL).
The addition was done slowly so that the reaction temperature did
not exceed 50.degree. C. The reaction was allowed to stir for 2 h
while warming to room temperature. The reaction mixture was then
added to ice-water and extracted into diethyl ether. The ether
layer was dried (MgSO.sub.4), concentrated and purified by column
chromatography (0-10% ethyl acetate-hexanes) to yield a mixture of
carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester
and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl
ester as a pale yellow solid (4.28 g), which was used directly in
the next step.
2,4-Di-tert-butyl-5-nitro-phenol and
2,4-Di-tert-butyl-6-nitro-phenol
[0213] The mixture of carbonic acid
2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic
acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester (4.2 g,
14.0 mmol) was dissolved in MeOH (65 mL) before KOH (2.0 g, 36
mmol) was added. The mixture was stirred at room temperature for 2
h. The reaction mixture was then made acidic (pH 2-3) by adding
cone. HCl and partitioned between water and diethyl ether. The
ether layer was dried (MgSO.sub.4), concentrated and purified by
column chromatography (0-5% ethyl acetate-hexanes) to provide
2,4-di-tert-butyl-5-nitro-phenol (1.31 g, 29% over 2 steps) and
2,4-di-tert-butyl-6-nitro-phenol. 2,4-Di-tert-butyl-5-nitro-phenol:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.14 (s, 1H, OH), 7.34
(s, 1H), 6.83 (s, 1H), 1.36 (s, 9H), 1.30 (s, 9H).
2,4-Di-tert-butyl-6-nitro-phenol: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 11.48 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.66 (d, J=2.4 Hz,
1H), 1.47 (s, 9H), 1.34 (s, 9H).
5-Amino-2,4-di-tert-butyl-phenol
[0214] To a reluxing solution of 2,4-di-tert-butyl-5-nitro-phenol
(1.86 g, 7.40 mmol) and ammonium formate (1.86 g) in ethanol (75
mL) was added Pd-5% wt. on activated carbon (900 mg). The reaction
mixture was stirred at reflux for 2 h, cooled to room temperature
and filtered through Celite. The Celite was washed with methanol
and the combined filtrates were concentrated to yield
5-amino-2,4-di-tert-butyl-phenol as a grey solid (1.66 g, quant.).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.64 (s, 1H, OH), 6.84
(s, 10H), 6.08 (s, 1H), 4.39 (s, 211, NH.sub.2), 1.27 (m, 18H);
HPLC ret. time 2.72 min, 10-99% CH.sub.3CN, 5 min run; ESI-MS 222.4
m/z. [M+H].sup.+.
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline--
3-carboxamide
##STR00005##
[0216] To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic
acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL)
was added Et.sub.3N (63.0 mL, 451 mmol) at ambient temperature. The
mixture became homogeneous and was allowed to stir for 10 min
before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was
added in small portions. The mixture was allowed to stir overnight
at ambient temperature. The mixture became heterogeneous over the
course of the reaction. After all of the acid was consumed (LC-MS
analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo.
EtOH was added to the orange solid material to produce a slurry.
The mixture was stirred on a rotovap (bath temperature 65.degree.
C.) for 15 min without placing the system under vacuum. The mixture
was filtered and the captured solid was washed with hexanes to
provide a white solid that was the EtOH crystalate. Et.sub.2O was
added to the material obtained above until a slurry was formed. The
mixture was stirred on a rotovapor (bath temperature 25.degree. C.)
for 15 min without placing the system under vacuum. The mixture was
filtered and the solid captured. This procedure was performed a
total of five times. The solid obtained after the fifth
precipitation was placed under vacuum overnight to provide 8
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-
-3-carboxamide as a white powdery solid (38 g, 52%).
[0217] HPLC ret. time 3.45 min, 10-99% CH.sub.3CN, 5 min run;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.12.88 (s, 1H), 11.83 (s,
1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J=8.2, 1.0 Hz, 1H),
7.83-7.79 (m, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17
(s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS 393.3 m/z
[M+H].sup.+.
[0218] Set forth below is the characterizing data for Compound
1:
TABLE-US-00001 TABLE 2 md C-RT No. C-MS + 1 in 93.2 .71
[0219] The XRPD spectrum of Compound 1 is shown in FIG. 1.
[0220] .sup.1H NMR data for Compound 1 in shown in FIG. 2.
[0221] The DSC trace of Compound 1 is shown in FIG. 3.
[0222] Preparation of Form A
[0223] Form A was obtained by heating Compound 1 as a solid to
250.degree. C. and cooling to room temperature. The DSC thermogram
on Compound 1 (See FIG. 6) shows that the compound undergoes a melt
with an onset temperature of 195.degree. C., followed by a
re-crystallisation with onset at 220.degree. C.
[0224] The XRPD spectrum of Form A is shown in FIG. 4.
[0225] The DSC data for Form A is shown in FIG. 5.
[0226] The TGA trace for Form A is shown in FIG. 6.
[0227] Preparation of Form B
[0228] Crude Compound 1 was a slurry in refluxing acetonitrile (27
volumes) for 24 hours. After 24 hours, the mixture was allowed to
cool to 20.degree. C. Form B was isolated by filtration as a white
to off-white. The wet cake was rinsed with acetonitrile (5 volumes)
and dried under vacuum at 50.degree. C. until a constant weight is
attained, thereby providing Form B.
[0229] The XRPD spectrum of Form B is shown in FIG. 7.
[0230] The DSC trace of Form B is shown in FIG. 8.
[0231] The TGA trace for Form B is shown in FIG. 9.
[0232] Single crystal data was obtained for Form B, providing
detail additional detail about the crystal structure, including
lattice size and packing.
[0233] Crystal Preparation:
[0234] 1 g of Compound 1 was added to 10 ml of isopropanol acetate.
The suspension was heated and remained at 60.degree. C. for 3
hours. The suspension was cooled to room temperature and remained
stirred overnight. The suspended solid was filtered and washed with
isopropanol acetate. The collected solid was dried under vacuum at
room temperature. 300 mg of the dried solid was dissolved in 5 ml
of 10% aqueous ethyl acetate solution. The solution was heated to
70.degree. C. for 10 minutes before it was cooled to room
temperature. Over time, crystals grew in the vial.
[0235] Experimental:
[0236] A single crystal of Form B was mounted on a MicroMount loop
and centered on a Bruker Apex II diffractometer that was equipped
with a sealed copper X-ray tube and Apex II CCD detector.
Initially, 3 sets of 40 frames were collected to determine a
preliminary unit cell. Subsequently a full data set consisting of
15 scans and 6084 frames was acquired. Data collection was
performed at 100 K. Data were integrated and scaled using Apex II
software from Bruker AXS. Integration and scaling resulted in 7528
reflections, 3071 of which were unique [R(int))=0.0466]. Structure
was solved by direct methods in space group P2.sub.1 using SHELXTL
software. Refinement was performed with full-matrix least-square
method on F.sup.2 using SHELXTL software as well. Altogether 375
parameters were used in refinement resulting in reflection to
parameter ratio of 8.19. The final refinement afforded a chiral
structure with a Flack parameter of 0.0 (3). The final refinement
index was wR2=0.1242 and R1=0.0663 (wR2=0.1137 and R1=0.0482 for
reflections with 1>2 sigma (I)).
[0237] A conformational picture of Form B is provided in FIG. 10,
which is in color.
TABLE-US-00002 TABLE 1 Crystal data and structure refinement for
Compound 1. Identification code Compound 1 Empirical formula C24
H28 N2 O3 Formula weight 392.48 Temperature 100(2) K Wavelength
1.54178 .ANG. Crystal system monoclinic Space group P2.sub.1 Unit
cell dimensions a = 11.8011(7) .ANG. .alpha. = 90.degree.. b =
5.9819(3) .ANG. .beta. = 105.110(4).degree.. c = 14.7974(8) .ANG.
.gamma. = 90.degree.. Volume 1008.48(10) .ANG..sup.3 Z 2 Density
(calculated) 1.293 Mg/m.sup.3 Absorption coefficient 0.681
mm.sup.-1 F(000) 420 Crystal size 0.20 .times. 0.08 .times. 0.08
mm.sup.3 Theta range for data collection 3.09 to 68.67.degree..
Index ranges -14 <= h <= 14, -7 <= k <= 7, -14 <= l
<= 17 Reflections collected 7528 Independent reflections 3071
[R(int) = 0.0466] Completeness to theta = 68.67.degree. 94.6% Max.
and min. transmission 0.9475 and 0.8758 Refinement method
Full-matrix least-squares on F.sup.2 Data/restraints/parameters
3071/1/375 Goodness-of-fit on F.sup.2 1:001 Final R indices [I >
2sigma(I)] R1 = 0.0482, wR2 = 0.1137 R indices (all data) R1 =
0.0663, wR2 = 0.1242 Absolute structure parameter 0.0(3) Extinction
coefficient 0.0008(6) Largest diff. peak and hole 0.200 and -0.218
e .ANG..sup.-3
TABLE-US-00003 TABLE 2 Atomic coordinates (.times. 10.sup.4) and
equivalent isotropic displacement parameters (.ANG..sup.2 .times.
10.sup.3) for Compound 1. U(eq) is defined as one third of the
trace of the orthogonalized U.sup.ij tensor. x y z U(eq) N(1)
11624(2) 530(5) 8667(2) 33(1) C(3) 10407(3) 2650(6) 8133(2) 31(1)
C(4) 10335(3) 2115(6) 7158(2) 30(1) C(5) 11006(3) 150(6) 7013(2)
31(1) C(2) 11034(3) 1269(6) 8830(2) 32(1) C(8) 12233(3) -3643(7)
6701(3) 38(1) C(7) 11610(3) -2371(7) 5947(3) 37(1) C(6) 11015(3)
-530(6) 6093(2) 35(1) C(9) 12255(3) -3039(7) 7618(2) 36(1) C(11)
9786(3) 4549(6) 8431(2) 32(1) C(15) 6468(3) 9414(6) 7354(2) 30(1)
C(19) 7049(3) 7025(6) 6127(2) 31(1) C(18) 8461(3) 8580(6) 8706(2)
32(1) C(13) 8275(3) 7448(6) 7859(2) 29(1) C(16) 6578(3) 10442(6)
8223(2) 31(1) C(17) 7639(3) 10044(6) 8889(2) 30(1) C(14) 7271(3)
7965(6) 7130(2) 30(1) C(23) 5586(3) 11841(6) 8438(2) 34(1) C(21)
8075(3) 7722(7) 5705(2) 35(1) C(22) 5943(3) 8034(7) 5474(2) 35(1)
C(20) 6879(3) 4481(7) 6096(3) 37(1) C(24) 4478(3) 11888(7) 7605(3)
39(1) C(25) 5981(3) 14254(7) 8672(3) 39(1) C(26) 5207(3) 10760(7)
9264(3) 37(1) N(12) 9082(2) 5775(5) 7752(2) 31(1) O(11) 9923(2)
4910(4) 9289(2) 37(1) O(4) 9748(2) 3206(4) 6485(2) 35(1) O(17)
7888(2) 11078(5) 9758(2) 37(1) C(10) 11644(3) -1165(6) 7761(2)
32(1)
TABLE-US-00004 TABLE 3 Bond lengths [.ANG.] and angles [.degree.]
for Compound 1. Length Angle Angle Bond (.degree.A) Bond (deg) Bond
(deg) N(1)--C(2) 1.337(5) C(2)--N(1)--C(10) 122.0(3)
C(15)--C(16)--C(23) 122.4(3) N(1)--C(10) 1.400(5) C(2)--C(3)--C(4)
119.4(3) C(18)--C(17)--O(17) 118.2(3) C(3)--C(2) 1.377(5)
C(2)--C(3)--C(11) 116.6(3) C(18)--C(17)--C(16) 120.9(3) C(3)--C(4)
1.458(4) C(4)--C(3)--C(11) 123.9(3) O(17)--C(17)--C(16) 120.8(3)
C(3)--C(11) 1.481(5) O(4)--C(4)--C(3) 123.8(3) C(15)--C(14)--C(13)
116.3(3) C(4)--O(4) 1.240(4) O(4)--C(4)--C(5) 120.9(3)
C(15)--C(14)--C(19) 120.1(3) C(4)--C(5) 1.465(5) C(3)--C(4)--C(5)
115.3(3) C(13)--C(14)--C(19) 123.5(3) C(5)--C(10) 1.406(5)
C(10)--C(5)--C(6) 117.2(3) C(25)--C(23)--C(16) 110.9(3) C(5)--C(6)
1.423(5) C(10)--C(5)--C(4) 122.2(3) C(25)--C(23)--C(24) 107.9(3)
C(8)--C(7) 1.391(5) C(6)--C(5)--C(4) 120.6(3) C(16)--C(23)--C(24)
112.1(3) C(8)--C(9) 1.398(5) N(1)--C(2)--C(3) 123.4(3)
C(25)--C(23)--C(26) 110.5(3) C(7)--C(6) 1.353(5) C(7)--C(8)--C(9)
120.6(4) C(16)--C(23)--C(26) 109.2(3) C(9)--C(10) 1.379(5)
C(6)--C(7)--C(8) 120.3(4) C(24)--C(23)--C(26) 106.1(3) C(11)--O(11)
1.255(4) C(7)--C(6)--C(5) 121.2(3) C(11)--N(12)--C(13) 127.2(3)
C(11)--N(12) 1.343(4) C(10)--C(9)--C(8) 118.7(3) C(9)--C(10)--N(1)
120.5(3) C(15)--C(14) 1.387(5) O(11)--C(11)--N(12) 123.7(3)
C(9)--C(10)--C(5) 121.9(3) C(15)--C(16) 1.399(5) O(11)--C(11)--C(3)
119.4(3) N(1)--C(10)--C(5) 117.6(3) C(19)--C(22) 1.531(4)
N(12)--C(11)--C(3) 117.0(3) C(19)--C(20) 1.534(5)
C(14)--C(15)--C(16) 126.1(3) C(19)--C(14) 1.544(4)
C(22)--C(19)--C(20) 106.8(3) C(19)--C(21) 1.558(5)
C(22)--C(19)--C(14) 111.5(3) C(18)--C(17) 1.385(5)
C(20)--C(19)--C(14) 112.2(3) C(18)--C(13) 1.390(5)
C(22)--C(19)--C(21) 105.4(3) C(13)--C(14) 1.413(4)
C(20)--C(19)--C(21) 111.3(3) C(13)--N(12) 1.418(4)
C(14)--C(19)--C(21) 109.4(3) C(16)--C(17) 1.397(4)
C(17)--C(18)--C(13) 122.0(3) C(16)--C(23) 1.539(5)
C(18)--C(13)--C(14) 119.0(3) C(17)--O(17) 1.387(4)
C(18)--C(13)--N(12) 119.4(3) C(23)--C(25) 1.528(5)
C(14)--C(13)--N(12) 121.5(3) C(23)--C(24) 1.546(5)
C(17)--C(16)--C(15) 115.1(3) C(23)--C(26) 1.548(5)
C(17)--C(16)--C(23) 122.4(3)
Symmetry Transformations Used to Generate Equivalent Atoms:
TABLE-US-00005 [0238] TABLE 4 Anisotropic displacement parameters
(.ANG..sup.2 .times. 10.sup.3)for Compound 1. The anisotropic
displacement factor exponent takes the form: -2.pi..sup.2[h.sup.2a
* .sup.2U.sup.11 + . . . + 2 h k a * b * U.sup.12] U.sup.11
U.sup.22 U.sup.33 U.sup.23 U.sup.13 U.sup.12 N(1) 42(1) 41(2) 14(2)
5(1) 4(1) 3(1) C(3) 34(2) 40(2) 16(2) -1(1) 4(1) -4(1) C(4) 34(2)
38(2) 17(2) 0(1) 4(1) -1(1) C(5) 34(2) 42(2) 17(2) -2(1) 6(1) -6(1)
C(2) 37(2) 42(2) 16(2) 1(1) 5(1) 1(2) C(8) 44(2) 41(2) 30(2) -4(2)
10(1) 5(2) C(7) 46(2) 44(2) 22(2) -4(1) 9(1) -5(2) C(6) 41(2) 40(2)
23(2) 1(2) 9(1) -1(2) C(9) 41(2) 40(2) 24(2) 5(1) 4(1) 3(2) C(11)
35(2) 41(2) 18(2) 1(1) 4(1) -4(2) C(15) 37(2) 37(2) 15(2) 4(1) 3(1)
1(1) C(19) 38(2) 38(2) 14(2) 2(1) 5(1) 4(1) C(18) 36(2) 42(2) 14(2)
4(1) 0(1) 0(1) C(13) 39(2) 34(2) 16(2) 2(1) 9(1) -3(1) C(16) 46(2)
29(2) 19(2) 1(1) 10(1) -3(1) C(17) 43(2) 33(2) 14(2) -2(1) 7(1)
-6(1) C(14) 38(2) 38(2) 11(2) 1(1) 3(1) -3(2) C(23) 46(2) 40(2)
20(2) 2(1) 13(1) 3(2) C(21) 51(2) 45(2) 8(2) 2(1) 7(1) 0(2) C(22)
44(2) 41(2) 16(2) -7(1) 1(1) 2(2) C(20) 40(2) 46(2) 20(2) -1(2)
3(1) 1(2) C(24) 44(2) 49(2) 24(2) -2(2) 10(1) 5(2) C(25) 52(2)
43(2) 24(2) 3(1) 12(2) 9(2) C(26) 48(2) 40(2) 24(2) 1(1) 14(1) 0(2)
N(12) 40(1) 41(2) 12(2) 0(1) 5(1) 0(1) O(11) 48(1) 47(1) 13(1) 1(1)
4(1) 5(1) O(4) 46(1) 46(2) 12(1) 3(1) 4(1) 7(1) O(17) 44(1) 45(2)
18(1) -6(1) 4(1) 4(1) C(10) 37(2) 37(2) 21(2) 0(1) 8(1) -2(2)
TABLE-US-00006 TABLE 5 Hydrogen coordinates (.times. 10.sup.4) and
isotropic displacement parameters (.ANG..sup.2 .times. 10.sup.3)
for Compound 1. x y z U(eq) H(7) 11560(30) -2840(70) 5320(30)
35(10) H(9) 12670(30) -3980(70) 8120(30) 38(10) H(8) 12680(30)
-4860(70) 6660(30) 36(10) H(6) 10550(30) 350(80) 5580(30) 51(13)
H(15) 5770(30) 9730(70) 6900(30) 30(9) H(18) 9150(20) 8310(50)
9160(20) 12(7) H(17) 8620(30) 10600(60) 10030(30) 25(9) H(20A)
7470(30) 3650(70) 6460(30) 32(10) H(20B) 6130(30) 4320(80) 6280(30)
43(11) H(21A) 8840(30) 6840(70) 5980(30) 40(11) H(21B) 8160(30)
9370(80) 5790(30) 42(11) H(22B) 5990(30) 9620(70) 5480(30) 31(9)
H(22A) 5790(30) 7200(80) 4820(30) 48(12) H(24A) 3800(40) 12810(90)
7750(30) 57(13) H(24B) 4210(30) 10410(70) 7420(30) 34(10) H(25A)
5370(30) 15130(60) 8770(20) 24(9) H(25B) 6240(30) 15040(70)
8150(30) 41(11) H(25C) 6690(30) 14100(80) 9230(30) 44(11) H(26A)
4600(30) 11790(60) 9320(20) 17(8) H(26B) 5000(30) 9350(70) 9090(30)
28(9) H(1) 12000(30) -1450(70) 9140(30) 40(11) H(2) 11050(40)
1550(80) 9460(40) 56(13) H(26C) 5950(30) 10770(80) 9820(30) 51(12)
H(24C) 4720(40) 12850(100) 7170(40) 69(15) H(22C) 5150(40) 7470(70)
5610(30) 42(11) H(21C) 7820(40) 7310(90) 5040(40) 62(14) H(20C)
6780(30) 3790(70) 5480(30) 48(12) H(12) 9030(40) 5290(90) 7280(40)
62(16)
[0239] Preparation of Amorphous Form from Form B
[0240] A Buchi Spray drier was used in this method under the
following conditions:
[0241] Inlet temperature set point: 130.degree. C.
[0242] Outlet Temperature (start of run) 55.degree. C.
[0243] Outlet temperature (end of run): 58.degree. C.
[0244] Nitrogen pressure: 120 psi
[0245] Aspirator: 100%
[0246] Pump: 40%
[0247] Filter pressure 11 mbar
[0248] Condenser Temperature: 10.degree. C.
[0249] Run Time 15 min
[0250] Yield 86.5%
[0251] Dried in 25.degree. C. vacuum over for 24 hours.
[0252] 4 g of Form B was dissolved in 86.4 g of acetone and 9.6 g
water under the above conditions. The run time was 15 min. The
product was dried under vacuum at 25.degree. C. for over 24 hrs to
produce the Amorphous Form.
[0253] The XRPD spectrum of the Amorphous Form is shown in FIG.
11.
[0254] The TGA trace for Amorphous Form is shown in FIG. 12.
[0255] The DSC trace for Amorphous Form is shown in FIG. 13.
[0256] PK and Solubility of Different Solid State Forms of Compound
1
[0257] Bioavailability of crystalline Form B, 85% amorphous
Compound 1 and HPMCAS solid dispersion of Compound 1 were evaluated
in rat, the results of which are provided in Table 4 below. These
forms of the compound were dosed in an oral suspension with a
vehicle containing 0.5% methyl cellulose/0.5% SLS/99% water.
Bioavailability of various solid forms was evaluated as compared to
a multicomponent IV solution of Compound 1. Bioavailability of
crystalline polymorph B was 3-6%, compared to 61-95% for amorphous
material and 109-111% for solid dispersion. In FaSSIF, crystalline
polymorph B has a measured solubility of 1.0 .mu.g/ml, while the
85% amorphous material has a solubility of 67.4 .mu.g/ml. The
crystalline material showed 67-74% bioavailability when dosed as a
PEG solution, indicating that absorption was solubility
limited.
TABLE-US-00007 TABLE 4 Dose Drug (mg/ AUC Form Vehicle kg) (ug *
hr/mL) Tmax (h) % F 85% 0.5% 50 135.5 27.6 6.0 0.0 95.0 20.0 Amor-
MC/0.5% phous SLS 85% 0.5% 200 371.9 46.1 6.0 0.0 61.0 7.0 Amor-
MC/0.5% phous SLS Crystalline 0.5% 50 8.0 1.2 4.0 0.0 5.5 0.8
MC/0.5% SLS Crystalline 0.5% 200 16.9 3.0 4.7 1.2 3.1 0.3 MC/0.5%
SLS Crystalline PEG 50 135.1 43.0 5.5 1.0 74.0 23.0 Crystalline PEG
200 431.5 101.1 14.5 11.0 67.0 16.0 Solid 0.5% 25 90.1 8.1 6.0 0.0
111.0 10.0 Dispersion MC/0.5% SLS Solid 0.5% 100 260.8 28.4 6.0 0.0
109.0 12.0 Dispersion MC/0.5% SLS
* * * * *
References