Lyophilization method and apparatus for producing particles

• US 20050178020A1
• Filed: 03/11/2005
• Published: 08/18/2005
• Est. Priority Date: 02/07/2003
• Status: Active Grant

• Current Assignee: Ferro Corporation (Vibrantz Technologies, Inc.)
• Original Assignee: Ferro Corporation (Vibrantz Technologies, Inc.)
• Inventors: Chattopadhyay, Pratibhash, Seitzinger, Jeffrey S., Shekunov, Boris Y.
• Granted Patent: US 7,073,349 B2
• Time in Patent Office: Days
• US Class Current: 34/284
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: F25B 9/02 using Joule-Thompson effect; using vortex effect
• CPC Class Codes: F25D 3/102 Stationary cabinets
• CPC Class Codes: F26B 5/065 the product to be freeze-dried being sprayed, dispersed or pulverised

Abstract

A method and apparatus for producing particles, the apparatus includes a solution source that supplies a solution, and a fluid source that supplies a fluid. The solution includes a solvent and a solute. A mixer receives the solution and the fluid from the sources, and mixes the solution and the fluid together to form a mixture. The mixture is supplied from the mixer to an expansion assembly at first pressure. The expansion assembly sprays and expands the mixture substantially simultaneously to form frozen droplets, and preferably to form a low-density powder of frozen droplets. A freeze-dry apparatus sublimes the solvent from the particles. A high mass-transfer rate and a uniform open-structure of the powder bed enhances the freeze-drying process. Solid particles having a controlled size distribution are obtained. The particles preferably have a hollow or porous morphology suitable for differing drug delivery applications to include aerosol formulations.

Claims

1. A method of producing particles comprising the steps of:

providing a solution comprising a solute dissolved in a solvent;

mixing the solution with a compressed fluid to form a mixture;

flowing the mixture across a pressure drop into an expansion chamber, wherein the mixture nebulizes into droplets, at least a first portion of the compressed fluid expands and decompresses and thereby reduces the temperature of the droplets below the freezing point of the solution, and the droplets thereby freeze to form frozen solution droplets; and

freeze-drying the frozen solution droplets to sublime the solvent and produce substantially solvent-free solid solute particles.

2. The method according to claim 1 wherein the compressed fluid has a freezing point that is less than or equal to the freezing point of the solution when the mixture is flowed across the pressure drop into the expansion chamber, and wherein a second portion of the compressed fluid freezes is frozen in solution droplets, and wherein the freeze-drying step further comprises subliming the frozen compressed fluid from the frozen solution droplets.

3. The method according to claim 1 further comprising the step of controlling the temperature in the expansion chamber to a temperature that is below the freezing point of the solvent but above the freezing point the compressed fluid so that the solvent freezes but no portion of the compressed fluid freezes.

4. The method according to claim 1 further comprising the step of adjusting the pressure drop differential to control the size and/or morphology of the solid solute particles.

5. The method according to claim 4 wherein the pressure in the expansion chamber is adjusted to be less than atmospheric pressure.

6. The method according to claim 1 further comprising the steps of metering the solution into a mixer, and metering the compressed fluid into the mixer, and thereby controlling a ratio of solution to compressed fluid in the mixture prior to the step of flowing the mixture across the pressure drop.

7. The method according to claim 1 further comprising the steps of pumping the solution from a first tank to a mixer, and pumping the compressed fluid from a second tank to the mixer, and thereby continuously supplying solution and compressed fluid to the mixer, the mixer continuously mixing the solution and the compressed fluid to form the mixture, and the step of flowing the mixture across a pressure drop into an expansion chamber is a continuous process.

8. A plurality of particles produced by the method according to claim 1 wherein the solid solute particles have a size in a range of from about 0.01 μ

m to about 200 μ

m, wherein the solid solute particles are substantially free of residual amounts of the solvent and the compressed fluid, wherein the solid solute particles comprise the solute, and wherein the solute is selected from the group consisting of biologically active materials, medicinal agents, nutritional materials, proteins, peptides, alkaloids, alkyloids, sugar, animal and/or plant extracts, antigens, nucleic acids, antibiotics, vitamins, lipids, polymers, polymer precursors, pigments, toxins, insecticides, viral materials, anti-bodies, diagnostic aids, agricultural chemicals, dyes, explosives, paints, cosmetics, enzymes, and catalysts.

9. A plurality of particles according to claim 8 wherein the solid solute particles have a porous or hollow structure and high surface to mass ratio.

10. A plurality of particles according to claim 8 wherein the particles form a homogeneous, easily-flowing powder that is readily dispersible by an air flow, the powder has a bulk density below about 0.5 g/cm³ and comprises open structures with an interconnected network of channels.

11. A method for producing particles comprising:

providing a solution comprising a solvent and a solute;

providing a supercritical fluid;

mixing the solution and the supercritical fluid together to form a mixture at a first pressure and temperature that sufficient to maintain the supercritical fluid in a supercritical state;

providing an expansion chamber maintained at a temperature below the freezing point of the solution;

flowing the mixture across a pressure drop into the expansion chamber to form frozen droplets that comprise the solute and frozen solvent; and

freeze-drying the frozen droplets to sublime the frozen solvent from the frozen droplets and thereby produce solid solute particles that are substantially free of solvent.

12. The method according to claim 11 wherein the expansion assembly receives the mixture from the mixer at the first pressure, and sprays the mixture at a second, lower pressure such that a portion of the fluid expands in response to a change from the first pressure to the second lower pressure, the expansion of the fluid portion reducing a temperature of the mixture so as to be below a freezing point of the solution.

13. The method according to claim 11 wherein the solvent is selected from the group consisting of water, alcohol, toluene, ethyl acetate, methyl chloride, methylene chloride, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), or other organic or inorganic solvents.

14. The method according to claim 11 wherein the solute is selected from the group consisting of a polymer, filler, disintegrant, binder, solubilizer, excipient, surfactant, and combinations thereof.

15. The method according to claim 14 wherein the solute is a polymer selected from the group consisting of polysaccharide, polyester, polyether, polyanhydride, polyglycolide (PLGA), polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol (PEG), or polypeptide.

16. The method according to claim 11 wherein the solute is selected from the group consisting of a biologically active material, drug, pharmaceutical, pharmaceutical excipient, therapeutic agent, medicinal agent, sugar, pigment, toxin, insecticide, viral material, diagnostic aid, agricultural chemical, nutritional material, protein, alkyloid, alkaloid, peptide, animal extract, plant extract, dye, explosive, paint, cosmetic, antigen, enzyme, catalyst, nucleic acid, zeolite, polymer precursor, and combinations thereof.

17. The method according to claim 16 wherein the solute further comprises a polymer, filler, disintegrant, binder, solubilizer, stabilizer, buffer or combinations thereof.

18. The method according to claim 16 wherein the solution further comprises a surfactant or a processing aid.

19. The method according to claim 11 wherein the supercritical fluid comprises carbon dioxide, nitrous oxide, propane and/or ethane.

20. A method for producing particles comprising:

providing a solution comprising a solvent and a solute;

providing a first compressed fluid and a second compressed fluid, the first compressed fluid having a higher freezing point than the second compressed fluid;

mixing the solution, the first compressed fluid and the second compressed fluid together to form a mixture;

providing an expansion chamber that is maintained at a temperature below the freezing point of the solution;

flowing the mixture across a pressure drop through a nozzle having a contra-current, co-axial, single or multiple opening configuration into the expansion chamber to form a spray of frozen droplets that comprise the solute and frozen solvent, wherein the first fluid component operates as a blowing or expanding agent and the second fluid component operates as a freezing agent; and

freeze-drying the frozen droplets to sublime the frozen solvent from the frozen droplets and thereby produce solid solute particles that are substantially free of solvent.