Novel process

• US 20040258756A1
• Filed: 04/21/2004
• Published: 12/23/2004
• Est. Priority Date: 10/25/2001
• Status: Abandoned Application

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: McLoughlin, Martin John
• Application Number:
  US10/493,325
• Publication Number:
  US 20040258756A1
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51

Abstract

The present invention relates to a novel process for preparing crystalline particles of substance which comprises mixing a solution of the substance in a liquid solvent with a liquid anti-solvent for said substance, which liquid anti-solvent is miscible with the liquid solvent, characterised in that the resultant crystalline particles generated are harvested by a process which comprises: (i) mixing a first liquid phase formed from the resultant suspension of crystalline substance in solvent/anti-solvent mixture with a third liquid which is immiscible with said solvent/anti-solvent mixture or a component thereof thereby forming a second liquid phase and which is a non-solvent for the substance such that the substance is segregated into the second liquid phase; (ii) separating the two phases; and (iii) separating the crystalline particles of substance from the second liquid phase.

Claims

1. A process for preparing crystalline particles of substance which comprises mixing a solution of the substance in a liquid solvent with a liquid anti-solvent for said substance, which liquid anti-solvent is miscible with the liquid solvent, characterised in that the resultant crystalline particles generated are harvested by a process which comprises:

(i) mixing a first liquid phase formed from the resultant suspension of crystalline substance in solvent/anti-solvent mixture with a third liquid which is immiscible with said solvent/anti-solvent mixture or a component thereof thereby forming a second liquid phase and which is a non-solvent for the substance such that the substance is segregated into the second liquid phase;

(ii) separating the two phases; and

(iii) separating the crystalline particles of substance from the second liquid phase.

2. A process according to claim 1 wherein the mixing of a solution of the substance in a liquid solvent with a liquid anti-solvent for said substance is carried out in a continuous flow cell in the presence of ultrasonic radiation.

3. A process according to claim 1 in which the third liquid is immiscible with at least the anti-solvent component of the solvent/anti-solvent mixture.

4. A process according to claim 1 in which the volume of the third liquid added to the solvent/anti-solvent mixture is less than 25% of the total volume.

5. A process according to claim 1 in which the third liquid is a lower alkane which is a liquid at ambient temperature and pressure.

6. A process according to claim 5 in which the lower alkane is n-hexane.

7. A process according to claim 1 in which in step (ii) the liquid phases are separated by decanting the less dense phase off the more dense phase.

8. A process according to claim 1 in which in step (iii) the crystalline particles of substance are separated from the second liquid phase by evaporation.

9. A process according to claim 1 in which in step (iii) the crystalline particles of substance are separated from the second liquid phase by extraction into a supercritical fluid.

10. A process according to claim 1 in which the substance is a pharmaceutical suitable for inhalation therapy.

11. A process according to claim 10 in which the substance is fluticasone, beclomethasone, salmeterol, salbutamol or an ester, salt or solvate thereof.

12. A process according to claim 11 wherein the substance is fluticasone propionate.

13. A process according to claim 11 wherein the substance is salmeterol xinafoate.

14. A process according to claim 1 wherein the substance is a mixture.

15. A process according to claim 14 wherein the substance is a mixture of fluticasone propionate and salmeterol xinafoate.

16. A process according to claim 12 wherein the solvent is acetone and the anti-solvent is water.

17. A process according to claim 13 wherein the solvent is methanol and the anti-solvent is water.

18. A population of particles obtainable by a process according to claim 1.

19. A pharmaceutical composition comprising a population of particles according to claim 18.

20. A process according to claim 15 wherein the solvent is acetone and the anti-solvent is water.