Nucleotide analog compositions
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1. A composition comprising crystalline adefovir dipivoxil.
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Abstract
The invention provides crystalline forms of adefovir dipivoxil and methods to prepare the crystals. The compositions and methods of the present invention have desirable properties for large scale synthesis of crystalline adefovir dipivoxil or for its formulation into therapeutic dosages. Invention compositions include an anhydrous crystal form of adefovir dipivoxil.
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47 Claims
- 1. A composition comprising crystalline adefovir dipivoxil.
- 21. A method comprising contacting a crystallization solvent and adefovir dipivoxil.
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24. A method comprising crystallizing adefovir dipivoxil from a solution comprising about 6-45% adefovir dipivoxil and about 55-94% crystallization solvent wherein the crystallization solvent is selected from the group consisting of (1) a mixture between about 1:
- 10 v/v to about 1;
3 v/v of acetone;
di-n-butyl ether, (2) a mixture between about 1;
10 v/v to about 1;
3 v/v of ethyl acetate;
di-n-propyl ether, (3) a mixture between about 1;
10 v/v to about 10;
1 v/v of t-butanol;
di-n-butyl ether, (4) a mixture between about 1;
10 v/v to about 1;
3 v/v of methylene chloride;
di-n-butyl ether, (5) a mixture between about 1;
10 v/v to about 10;
1 v/v of diethyl ether;
di-n-propyl ether, (6) a mixture between about 1;
10 v/v to about 1;
3 v/v of tetrahydrofuran;
di-n-butyl ether, (7) a mixture between about 1;
10 v/v to about 1;
3 v/v of ethyl acetate;
di-n-butyl ether, (8) a mixture between about 1;
10 v/v to about 1;
3 v/v of tetrahydropyran;
di-n-butyl ether, (9) a mixture between about 1;
10 v/v to about 1;
3 v/v of ethyl acetate;
diethyl ether, (10) t-butyl-methyl ether, (11) diethyl ether, (12) di-n-butyl ether, (13) t-butanol, (14) toluene, (15) isopropyl acetate, (16) ethyl acetate, and (17) a mixture consisting essentially of (A) a first crystallization solvent consisting of a first dialkyl ether of the formula R1—
O—
R2 wherein R1 is an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, R2 is an alkyl group having 2, 3, 4, 5 or 6 carbon atoms wherein R1 and R2 are the same or different, or both R1 and R2 are linked together to form a 5-, 6-, 7-, or 8-membered ring, provided that the dialkyl ether is not methyl-ethyl ether, and (B) a second crystallization solvent selected from the group consisting of (a) a second dialkyl ether of the formula R1—
O—
R2, wherein the second dialkyl ether is different from the first dialkyl ether, (b) toluene, (c) tetrahydrofuran, (d) t-butanol, (e) ethyl acetate, (f) methylene chloride, (g) propyl acetate and (h) isopropanol.
- 10 v/v to about 1;
- 25. A method for preparing Form 2 adefovir dipivoxil comprising forming adefovir dipivoxil crystals in the presence of water.
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27. A method comprising contacting adefovir dipivoxil with methanol.
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28. A method for preparing Form 4 adefovir dipivoxil comprising forming crystals comprising adefovir dipivoxil in the presence of fumaric acid.
- 29. A method for preparing adefovir dipivoxil comprising contacting 9-[2-(phosphonomethoxy)ethyl]adenine with chloromethyl pivalate in 1-methyl-2-pyrrolidinone and a trialkylamine and recovering adefovir dipivoxil.
- 33. A method comprising contacting 9-[2-(phosphonomethoxy)ethyl]adenine containing less than about 2% salt with chloromethyl pivalate.
- 35. A product produced by the process of compressing a mixture comprising Form 1 adefovir dipivoxil and a pharmaceutically acceptable excipient.
- 37. A product produced by the process of preparing wet granules from a mixture comprising a liquid, Form 1 adefovir dipivoxil and a pharmaceutically acceptable excipient.
- 40. A composition comprising a tablet containing adefovir dipivoxil, 20 mg pregelatinized starch, 24 mg croscarmellose sodium, lactose monohydrate, 24 mg talc and 4 mg magnesium stearate, wherein the adefovir dipivoxil comprises at least about 70% form 1 adefovir dipivoxil.
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47. A method for preparing 9-[2-(diethylphosphonomethoxy)ethyl]-adenine comprising contacting sodium alkoxide and 9-(2-hydroxyethyl)adenine.
Specification