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US 2004/0024031 A1Published application
Solvates and polymorphs of ritonavir and methods of making and using the same
AssigneeTransform Pharmaceuticals, Inc.
InventorsSherry L. Morissette, Orn Almarsson, Stephen Soukasene
Life of this patent
Estimating the term…
Abstract
Novel solvates and crystal polymorphs of Ritonavir are disclosed, as well as methods of making them. Specific solvates of the compound include a formamide solvate and a partially desolvated solvate. Also disclosed are methods of making previously known forms of Ritonavir. Methods of using the novel forms of Ritonavir for the treatment of diseases, such as HIV-infection, are disclosed, as are pharmaceutical compositions and unit dosage forms comprising the novel forms of Ritonavir.
Claims7
A composition comprising:
- a) ritonavir(III);
- b) a form of Ritonavir which has a melting point of about 78° C. to about 82° C.;
- c) a form of Ritonavir which has a powder X-ray diffraction pattem substantially the same as that shown in FIG. 8A;
- d) a form of Ritonavir which has at least one unique powder X-ray diffraction peaks selected from the group of:
- approximately 3.1, 6.8, 7.7, 8.3, 9.2, 10.5, 12.1, and 13.1 degrees 2-Theta;
- e) a form of Ritonavir which has at least two unique powder X-ray diffraction peaks selected from the group of:
- approximately 3.1, 6.8, 7.7, 8.3, 9.2, 10.5, 12.1, and 13.1 degrees 2-Theta;
- f) a form of Ritonavir which has at least three unique powder X-ray diffraction peaks selected from the group of:
- approximately 3.1, 6.8, 7.7, 8.3, 9.2, 10.5, 12.1, and 13.1 degrees 2-Theta;
- g) a form of Ritonavir which has at least four unique powder X-ray diffraction peaks selected from the group of:
- approximately 3.1, 6.8, 7.7, 8.3, 9.2, 10.5, 12.1, and 13.1 degrees 2-Theta;
- h) a form of Ritonavir which has at least five unique powder X-ray diffraction peaks selected from the group of:
- approximately 3.1, 6.8, 7.7, 8.3, 9.2, 10.5, 12.1, and 13.1 degrees 2-Theta;
- i) a form of Ritonavir which has at least six unique powder X-ray diffraction peaks selected from the group of:
- approximately 3.1, 6.8, 7.7, 8.3, 9.2, 10.5, 12.1, and 13.1 degrees 2-Theta;
- j) ritonavir (IV);
- k) a form of Ritonavir which has a melting point of about 97° C. to about 101 ° C.;
- l) a form of Ritonavir which has a powder X-ray diffraction pattern substantially the same as that shown in FIG. 12A;
- m) a form of Ritonavir which has at least one unique powder X-ray diffraction peaks selected from the group consisting of:
- approximately 3.1, 6.1, 9.2, 12.1, and 13.8 degrees 2-Theta;
- n) a form of Ritonavir which has at least two unique powder X-ray diffraction peaks selected from the group consisting of:
- approximately 3.1, 6.1, 9.2, 12. 1, and 13.8 degrees 2-Theta;
- o) a form of Ritonavir which has at least three unique powder X-ray diffraction peaks selected from the group consisting of:
- approximately 3.1, 6.1, 9.2, 12.1, and 13.8 degrees 2-Theta;
- p) a form of Ritonavir which has at least four unique powder X-ray diffraction peaks selected from the group consisting of:
- approximately 3.1, 6.1, 9.2, 12. 1, and 13.8 degrees 2-Theta;
- q) a form of Ritonavir which has at least five unique powder X-ray diffraction peaks selected from the group consisting of:
- approximately 3.1, 6.1, 9.2, 12. 1, and 13.8 degrees 2-Theta;
- r) a form of Ritonavir which has at least six unique powder X-ray diffraction peaks selected from the group consisting of:
- approximately 3.1, 6.1, 9.2, 12.1, and 13.8 degrees 2-Theta;
- s) ritonavir(V);
- t) a form of Ritonavir which has a melting point of from about 114° C. to about 118° C.;
- u) a form of Ritonavir which has a powder X-ray diffraction pattern substantially the same as that shown in FIG. 16A;
- v) a form of Ritonavir which has unique powder X-ray diffraction peaks at approximately 3.4, 6.4, 9.9, 12.7, 13.6, 15.3, 15.8, and 17.5 degrees 2-Theta;
- w) formamide, an immiscible or partially miscible solvent, and Ritonavir;
- or
- x) acetate, acetonitrile, and Ritonavir.
34 more elements
A method selected from:
- a) a method of preparing Ritonavir(III), which comprises dissolving Ritonavir in a solvent system comprised of formamide and an immiscible or partially miscible solvent to provide a mixture, and.reducing the solubility of Ritonavir in the mixture under conditions sufficient to provide Ritonavir(III);
- b) a method of preparing Ritonavir(IV), which comprises partially desolvating Ritonavir(III) to an extent sufficient to form Ritonavir(IV);
- c) a method of preparing Ritonavir(V), which comprises dissolving Ritonavir in a solvent system comprised of an acetate and acetonitrile to provide a mixture, and reducing the solubility of Ritonavir in the mixture under conditions sufficient to provide Ritonavir(V);
- d) a method of preparing Ritonavir Form I, which comprises desolvating Ritonavir(IV) for an amount of time sufficient for the formation of Ritonavir Form I;
- e) the method of claim (d), which comprises incubating Ritonavir(IV) in an aqueous environment for an amount of time sufficient for the formation of Ritonavir Form I;
- or
- f) a method of preparing Ritonavir Form II, which comprises incubating Ritonavir(IV) in an aqueous environment for an amount of time sufficient for the formation of Ritonavir Form I and further incubating the Ritonavir Form I for an amount of time sufficient for the formation of Ritonavir Form II.
4 more elements
A method selected from:
- a) a method of inhibiting HIV-1 protease, which comprises contacting HIV-1 protease with Ritonavir(III), Ritonavir(IV), or Ritonavir(V);
- b) a method of inhibiting HIV-2 protease, which comprises contacting HIV-2 protease with Ritonavir(III), Ritonavir(IV), or Ritonavir(V);
- c) a method of treating, ameliorating, or managing HIV-infection, which comprises administering to a patient in need of such treatment a therapeutically effective amount of Ritonavir(III), Ritonavir(IV), or Ritonavir(V);
- d) the method of claim (a), (b), or (c), wherein the form of Ritonavir is Ritonavir(IV) or Ritonavir(V);
- e) the method of claim (d) wherein the form of Ritonavir is Ritonavir(V);
- f) the method of claim (a), (b), or (c), which further comprises administering a therapeutically effective amount of a second pharmacologically active compound to the patient;
- g) the method of claim (f) wherein the second pharmacologically active compound is a protease inhibitor, a nucleoside reverse transcriptase inhibitor, or a non-nucleoside reverse transcriptase inhibitor, or a pharmaceutically acceptable prodrug, salt, hydrate, solvate, or polymorph thereof;
- h) the method of claim (g) wherein the protease inhibitor is lopinavir, saquinavir, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, or tipranavir;
- i) the method of claim (g) wherein the nucleoside reverse transcriptase inhibitor is zidovudine, zalcitabine, lamivudine, didanosine, abacavir, tidoxil, stavudine, adefovir, adefovir dipivoxil, or fozivudine;
- j) the method of claim (g) wherein the non-nucleoside reverse transcriptase inhibitor is delavirdine, efavirenz, immunocal, loviride, nevirapine, or oltipraz;
- k) a method for improving the pharmacokinetics of a pharmacologically active compound, which comprises administering to a human in need of the pharmacologically active compound a combination of a therapeutically effective amount of Ritonavir(III), (IV), or (V), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the pharmacologically active compound, or a pharmaceutically acceptable prodrug, salt, hydrate, solvate, or polymorph thereof, wherein the pharmacologically active compound is metabolized by a cytochrome P450 monooxygenase;
- l) the method of claim (k) wherein the pharmacologically active compound is an antiretrovial compound;
- m) the method of claim (l) wherein the antiretroviral compound is a protease inhibitor, a nucleoside reverse transcriptase inhibitor, or a non-nucleoside reverse transcriptase inhibitor, or a pharmaceutically acceptable prodrug, salt, hydrate, solvate, or polymorph thereof;
- n) the method of claim (m) wherein the protease inhibitor is lopinavir, saquinavir, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, or tipranavir;
- o) the method of claim (m) wherein the nucleoside reverse transcriptase inhibitor is zidovudine, zalcitabine, lamivudine, didanosine, abacavir, tidoxil, stavudine, adefovir, adefovir, dipivoxil, or fozivudine;
- p) the method of claim (m) wherein the non-nucleoside reverse transcriptase inhibitor is delavirdine, efavirenz, immunocal, loviride, nevirapine, or oltipraz;
- q) a method of preparing a pharmaceutical composition comprising Ritonavir, which comprises contacting Ritonavir(III), Ritonavir(IV), or Ritonavir(V) with an aqueous solution;
- or
- r) a method of preparing a pharmaceutical composition comprising Ritonavir, which comprises contacting Ritonavir (III), Ritonavir (IV), or Ritonavir (V) with an alcohol-based solution.
16 more elements
A pharmaceutical composition comprising Ritonavir(V).
A kit comprising a single unit dosage form of Ritonavir(V) and a single unit dosage form of an antiviral compound.
Dependencies are inferred from the claim text.