Methods of Manufacturing Crystalline Forms of Rapamycin Analogs

• US 20120028908A1
• Filed: 10/01/2011
• Published: 02/02/2012
• Est. Priority Date: 07/25/2006
• Status: Abandoned Application

• Current Assignee: Abbott Laboratories
• Original Assignee: Abbott Laboratories
• Inventors: Bartelt, Larry, Leanna, Robert, Rasmussen, Michael, Dhaon, Madhup, Henry, Rodger, Borchardt, Thomas, Chen, Shuang, Zhang, Geoff, VISWANATH, Shekhar
• Application Number:
  US13/251,207
• Publication Number:
  US 20120028908A1
• Time in Patent Office: Days
• US Class Current: 514/19.2
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 498/18 Bridged systems

Abstract

A process for preparing a crystalline rapamycin analog includes: combining the rapamycin analog with an organic medium to form a mixture; incubating the mixture until the rapamycin analog crystallizes; and recovering the crystalline rapamycin analog. The organic medium can be a solvent, and the process can include causing the rapamycin analog to dissolve into the solvent, and incubating the solvent until the rapamycin analog crystallizes. The following can also be performed: forming a slurry of crystalline rapamycin analog; stirring the rapamycin analog mixture until the rapamycin analog crystallizes; saturating the rapamycin analog solution; forming a supersaturated rapamycin analog solution; combining an antisolvent with the rapamycin analog and the solvent to form a biphasic mixture, and incubating the biphasic mixture to cause a liquid-liquid phase split.

Claims

1. A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier; and

a therapeutically effective amount of a crystalline form of a compound, or a pharmaceutically acceptable salt thereof, having a structure of Formula 4;

2. The composition of claim 1, wherein the crystalline compound or salt thereof is a solvate or a desolvate thereof.

3. The composition of claim 2, wherein the solvate comprises a solvent selected from the group consisting of acetone, ethyl acetate, methanol, ethanol, n-propanol, isopropanol, isobutanol, tertbutanol, 2-butanol, acetronitrile, tetrahydrofuran, isobutyl acetate, n-butyl acetate, ethyl formate, n-propyl acetate, isopropyl acetate, methylethyl ketone, toluene, N,N dimethyl formamide, anisole, methyl isopropyl ketone, nitromethane, propionitrile, 2-butanone, 1,2-dimethoxyethane, and combinations thereof.

4. The composition of claim 2, wherein the crystalline form of the compound or salt thereof is a solvate having a form according to the X-ray diffraction pattern substantially as shown in one of the following:

FIG. 2A;

FIG. 2B;

FIG. 4A;

FIG. 4B;

FIG. 5A;

FIG. 5B;

FIG. 7A;

FIG. 7B;

FIG. 9A;

FIG. 9B;

FIG. 10A;

FIG. 10B;

FIG. 11A;

FIG. 11B;

FIG. 13A;

FIG. 14A;

FIG. 16;

FIG. 15A;

FIG. 12A;

FIG. 17A;

FIG. 18A;

FIG. 19A;

FIG. 20A;

or

FIG. 21A.

5. The composition of claim 2, wherein the crystalline form of the compound or salt thereof is a desolvate having a form according to the X-ray diffraction pattern substantially as shown in one of the following:

FIG. 3A;

FIG. 3B;

FIG. 6A;

FIG. 6B;

FIG. 4E;

FIG. 13B;

FIG. 14B;

FIG. 15B;

FIG. 8;

FIG. 12B;

FIG. 17B;

FIG. 18B;

FIG. 19B;

FIG. 20B;

or

FIG. 21B.

6. The composition of claim 5, wherein the crystalline form or salt thereof is an acetonitrile solvate or a desolvate thereof, an acetone solvate or a desolvate thereof, a toluene solvate, an ethyl formate solvate, a hydrate, an isopropyl solvate, an isobutyl solvate, an ethanol solvate, a N,N-dimethyl formamide solvate, or an anisole solvate.

7. The composition of claim 1, further comprising a second pharmacological agent.

8. The composition of claim 7, wherein the second pharmacological agent is selected from the group consisting of anti-proliferative agents, anti-platelet agents, anti-inflammatory agent, anti-thrombotic agents, and thrombolytic agents.

9. The composition of claim 8, wherein the anti-proliferative agent is an anti-mitotic agent.

10. The composition of claim 9, wherein the anti-mitotic agent is a vinca alkaloid or an alkylating agent.

11. The composition of claim 8, wherein the anti-proliferative agent is selected from the group consisting of vincristine, paclitaxel, etoposide, nocodazole, indirubin, anthracycline derivatives, tauromustine, bofumustine, and fotemustine, and anti-mitotic metabolites.

12. The composition of claim 8, wherein the anti-platelet agent is selected from the group consisting of eptifibatide, tirofiban, RGD-base peptides, disagregin, and cilostazol.

13. The composition of claim 8, wherein the anti-inflammatory agent is selected from the group consisting of prednisone, dexamethasone, hydrocortisone, estradiol, fluticasone, clobetasol, acetaminophen, ibuprofen, naproxen, and sulindac.

14. A method of treating intimal smooth muscle cell hyperplasia, restenosis, or vascular occlusion in mammals, comprising administering the pharmaceutical composition of claim 1 to a subject in need thereof.

15. A method of treating intimal smooth muscle cell hyperplasia, restenosis, or vascular occlusion in mammals, comprising administering the pharmaceutical composition of claim 8 to a subject in need thereof.

19. The process of claim 1, further comprising:

combining at least one antisolvent with the compound and the solvent to form a biphasic mixture; and

incubating the biphasic mixture to cause a liquid-liquid phase split with a majority of the compound being in the solvent and a minority of the compound being in the antisolvent.

20. The process of claim 4, further comprising separating the organic solvent from the antisolvent.

16. A process for preparing a crystalline form of a compound of Formula 4:

17. The process of claim 16, further comprising causing the compound to dissolve into the organic solvent.

18. The process of claim 16, further comprising recovering the crystalline compound from the organic solvent.