Lyophilization method and apparatus for producing particles

• US 20040154317A1
• Filed: 05/08/2003
• Published: 08/12/2004
• Est. Priority Date: 02/07/2003
• Status: Active Grant

• Current Assignee: Ferro Corporation
• Original Assignee: Ferro Corporation
• Inventors: Chattopadhyay, Pratibhash, Seitzinger, Jeffrey S., Shekunov, Boris Y.
• Granted Patent: US 6,931,888 B2
• Time in Patent Office: Days
• US Class Current: 62/64
• 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

11. An apparatus for producing particles comprising:

a solution source supplying a solution comprising a solvent and a solute, and a fluid source supplying a compressed fluid;

a mixer in fluid communication with the sources for mixing the solution and the compressed fluid together to form a mixture, and for maintaining the mixture at a first pressure sufficiently high so as to maintain the compressed fluid in a compressed state;

an expansion assembly in fluid communication with the mixer for spraying the mixture across a pressure drop to form mixture droplets, the mixture droplets comprising the solute and frozen solvent; and

a freeze-dry apparatus that is in communication with the expansion assembly for subliming the frozen solvent, and thereby removing the frozen solvent from the solute, whereby solute particles are produced that are generally free of the solvent.

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

mixing a solution and a compressed fluid together to form a mixture, the solution comprising a solute dissolved in a solvent;

flowing the mixture across a pressure drop into an expansion chamber, whereby the mixture forms droplets and at least a portion of the compressed fluid expands from a compressed state to a relatively uncompressed state, thereby reducing a temperature of the droplets to be below a freezing point of the solution; and

freeze-drying the frozen droplets of solution to sublime the frozen solvent and form generally solvent free solute particles.

2. The method as defined in claim 1 further comprising the step of selecting a fluid having a freezing point that is less than or about the same temperature as the freezing point of the solution, whereby another portion of the fluid is frozen with the frozen solvent to thereby form a mixture of solid particles with frozen fluid, and the step of freeze-drying the droplets comprises the step of subliming the frozen fluid and thereby to remove the frozen fluid from the solid solute particles.

3. The method as defined in claim 1 further comprising the step of controlling the temperature in the expansion chamber to be in a range that is below the freezing point of the solvent but above a freezing point temperature of the fluid, whereby during the step of expanding the mixture the solvent freezes but no portion of the fluid freezes.

4. The method as defined in claim 1 further comprising the step of adjusting the size or morphology of the solid solute particles by controlling the pressure drop differential.

5. The method as defined in claim 4 wherein the pressure in the expansion chamber is controlled to be less than atmospheric pressure.

6. The method as defined in claim 1 further comprising the steps of metering the solution into a mixer, and metering the fluid into the mixer, and thereby controlling a ratio of solution to fluid in the mixture prior to the step of expanding the mixture.

7. The method as defined in claim 1 further comprising the steps of pumping the solution from a first tank to a mixer, and pumping the fluid from a second tank to the mixer, and thereby continuously supplying solution and fluid to the mixer, the mixer continuously mixing the solution and the fluid to form the mixture, and the step of expanding the mixture is a continuous expansion of the mixture.

8. A plurality of particles produced by the method as defined in claim 1 wherein the solid solute particles have a size in a range of from about 0.01 to about 200 micrometers (μ

m), and the particles are generally free of residual amounts of the solvent and the fluid, and the 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 as defined in claim 8 wherein the solid solute particles have a porous or hollow structure and high surface to mass ratio.

10. A plurality of particles as defined in claim 8 wherein the particles form a homogeneous, easily-flowing powder that is readily dispersible by an air flow, the powder having a low bulk density of below about 0.5 g/cm³ forming open structures with large and interconnected network of channels, the powder further having an increased level of uniformity and consistency.

12. The apparatus as defined in 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 apparatus as defined in 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 apparatus as defined in claim 11 wherein the solute is selected from the group consisting of polymer, filler, disintegrant, binder, solubilizer, excipient, surfactant, and combinations thereof.

15. The apparatus as defined in 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 apparatus as defined in 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 apparatus as defined in claim 16 wherein the solute further comprises a polymer, filler, disintegrant, binder, solubilizer, stabilizer, buffer or combinations thereof.

18. The apparatus as defined in claim 16 wherein the solution further comprises a surfactant or a processing aid.

19. The apparatus as defined in claim 11 wherein the compressed fluid comprises carbon dioxide, nitrous oxide, propane, ethane, or other compressed fluid capable of exhibiting a sufficient Joule-Thomson effect and having a partial solubility in the solution.

20. The apparatus as defined in claim 11 wherein the compressed fluid is a supercritical fluid, compressed gas or liquefied gas.

21. The apparatus as defined in claim 11 wherein the droplets further comprise a solid fluid particle, and the freeze-dry apparatus is further operable to sublime the solid fluid particle, and thereby to remove the solid fluid particle from the solid solute particle.

22. The apparatus as defined in claim 11 further comprising a controller communicating with the sources, the mixer and the freeze-dry apparatus, the controller being operable to:

control flow rates of solution and compressed fluid from the sources to the mixer,

control the mixing rate of the mixer to mix the solution and fluid to form the mixture,

control the mixer to supply the mixture to the expansion assembly at a predetermined flow rate, and

control the freeze-dry apparatus to sublime the solid solvent particles at a predetermined rate of solvent extraction.

23. The apparatus as defined in claim 11 wherein the mixer is further operable to mix the solution and the fluid such that the solution is saturated with the fluid or is dispersed within the fluid.

24. The apparatus as defined in claim 11 wherein the frozen solvent constitutes the same phase as the solute particles.

25. The apparatus as defined in claim 11 wherein the fluid comprises a first and a second fluid component, the first and second components having freezing point at a different temperatures relative to each other, and the first component having a higher freezing point relative to the second component, the expansion assembly comprising a nozzle configured so that the solution and fluid are sprayed therethrough, the nozzle being further configured to have a contra-current, co-axial, single or multiple opening configuration, whereby the first component operates as a blowing or expanding agent and the second component operates as a freezing agent.

26. The apparatus as defined in claim 25 wherein the blowing or expanding agent and the freezing agent have different chemical structures from each other, and optionally have the same or a different temperature immediately subsequent to mixing with the solution.

21-1. The apparatus as defined in claim 11 further comprising a thermostat, and wherein the expansion assembly comprises an expansion vessel having an inner surface defining an expansion chamber, and the thermostat is operable to control a temperature in the expansion chamber to be below the solution freezing temperature.

27. An apparatus for producing particles comprising:

means for mixing a solution and a compressed fluid together to form a mixture, the solution comprising a solute dissolved in a solvent;

means for flowing the mixture across a pressure drop into an expansion chamber, whereby the mixture forms droplets and at least a portion of the compressed fluid expands from a compressed state to a relatively uncompressed state, thereby reducing a temperature of the droplets to be below a freezing point of the solution; and

means for freeze-drying the frozen droplets of solution to sublime the frozen solvent and form generally solvent free solute particles.