Methods of converting amorphous drug substance into crystalline form

• US 8,669,360 B2
• Filed: 09/23/2011
• Issued: 03/11/2014
• Est. Priority Date: 08/05/2011
• Status: Active Grant

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Original Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Inventors: Zeng, Maggie, Chen, Yen-Lane, Romanshek, Maura, Meyer, Erin
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US13/242,433
• Publication Number:
  US 20130035483A1
• Time in Patent Office: 900 Days
• Field of Search: 540/456
• US Class Current: 540/456
• CPC Class Codes: C07D 498/18 Bridged systems

Abstract

A method for converting an amorphous drug, such as everolimus, or other macrolide immunosuppressive drug, into a crystalline form. The method utilizes a slurry of the drug in organic liquid phase and ages the slurry to achieve the conversion.

Claims

1. A method of converting an amorphous form of a drug to a crystalline form of said drug comprising the steps of

providing an amount of said drug in a solid amorphous form, the drug is everolimus;

providing a volume of a solvent for the drug, the solvent is selected from the group consisting of tetrahydrofuran/heptane, tetrahydrofuran/ethyl acetate, isopropyl alcohol and p-xylene, the volume being insufficient to fully dissolve said amount of the drug,

forming a slurry with said volume of said solvent and said amount of said drug; and

aging the slurry for a time to allow substantial conversion of the solid amorphous drug into crystalline drug.

2. A method as in claim 1 wherein during at least a portion of the aging time the slurry is subjected to agitation.

3. A method as in claim 1 wherein the volume of said solvent is no more than 50%, the amount of solvent needed to fully dissolve said amount of the drug at the temperature of aging.

4. A method as in claim 3 wherein the volume of said solvent is no more than 30% of the amount of solvent needed to fully dissolve said amount of the drug at the temperature of aging.

5. A method as in claim 3 wherein the volume of said solvent is from about 2% to about 20% of the amount of solvent needed to fully dissolve said amount of the drug at the temperature of aging.

6. A method as in claim 1 wherein seed crystals of the crystalline drug form are be added to the slurry.

7. A method as in claim 1 wherein during said aging step the slurry is agitated in a manner that breaks formed crystals of the drug into a predetermined size distribution.

8. A method as in claim 1 wherein a mixture of two or more organic solvents are used as the solvent for the drug.

9. A method as in claim 1 wherein the slurry is aged at a temperature of from about 4°

C. to about 80°

C.