EP1562551A1 - Media milling using nonspherical grinding media - Google Patents

Media milling using nonspherical grinding media

Info

Publication number
EP1562551A1
EP1562551A1 EP03786831A EP03786831A EP1562551A1 EP 1562551 A1 EP1562551 A1 EP 1562551A1 EP 03786831 A EP03786831 A EP 03786831A EP 03786831 A EP03786831 A EP 03786831A EP 1562551 A1 EP1562551 A1 EP 1562551A1
Authority
EP
European Patent Office
Prior art keywords
media
grinding
pharmaceutical
grinding media
substance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03786831A
Other languages
German (de)
French (fr)
Inventor
Sean Mark Dalziel
William Norman Ford
Henricus Jacobus Cornelis Gommeren
Douglas Eric Spahr
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
EIDP Inc
Original Assignee
EI Du Pont de Nemours and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by EI Du Pont de Nemours and Co filed Critical EI Du Pont de Nemours and Co
Publication of EP1562551A1 publication Critical patent/EP1562551A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
    • B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
    • B02C17/00—Disintegrating by tumbling mills, i.e. mills having a container charged with the material to be disintegrated with or without special disintegrating members such as pebbles or balls
    • B02C17/18—Details
    • B02C17/20—Disintegrating members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • This invention relates to a media milling method in which nonspherical grinding media are used to produce small particles that are particularly useful in the pharmaceutical, nutraceutical, and diagnostic fields.
  • Methods for producing fine particles have many commercial applications, such as in the production of oral, transdermal, injected or inhaled pharmaceuticals and biopharmaceuticals, nutraceuticals, diagnostic test components and diagnostic agents.
  • rate of dissolution of a solid compound will increase with increasing surface area of the solid.
  • particle dissolution rates can be increased by increasing the surface area to weight ratios of the particles that make up the solid through particle size reduction techniques.
  • bioavailability is related to dissolution kinetics and membrane permeability
  • the bioavailability of poorly water soluble pharmaceutical or diagnostic compounds in many instances can also be increased via a reduction in the particle size.
  • media milling is a frequently used method for producing fine and ultra fine (nano) particles.
  • the media milling process typically involves charging grinding media to the milling chamber together with the material to be ground.
  • the material to be ground is added to the mill as a slurry comprised of a solid suspended in a liquid. Often, a surfactant is added to stabilize the slurry.
  • a stirring device of some form can then be used to agitate the grinding media, thereby causing the solid particles to be ground.
  • the grinding media can be set in motion by either applying planetary, tumbling or vibratory motion to the milling chamber, or subjecting magnetic grinding media that has been charged to the milling chamber to an alternating/fluctuating magnetic field.
  • Typical wet mills include colloid mills, pressure homogenizers, rotor stators, and media mills. See, for example, "Technical Aspects of Dispersion” by D. A. Wheeler, Chapter 7 "Dispersion of Powders in Liquids", edited by G.D Parfitt, 3 rd edition, Applied Science Publishers hereby incorporated by reference.
  • the type of grinding media charged to the media mill is generally selected from any variety of dense, tough, hard materials, such as, for example, sand, stainless steal, zirconium silicate, zirconium oxide, yttrium oxide, glass, alumina, titanium, and the like. In situations involving either metal (oxide) contamination, or shifts in pH, a polymeric grinding media is utilized.
  • the grinding media charged to the milling chamber has consisted of spherically shaped media milling beads.
  • Spherically shaped grinding media had been thought to be the most mechanically stable form of hard grinding media, as theoretically there are no edges to be attrited or chipped off.
  • spherically shaped hard, rigid grinding media has been utilized in the milling process when chipping and attrition of the hard grinding media is sought to be avoided or reduced.
  • Liversidge et al U.S. Patent No. 5,145,684, and EPO 498,492, describe dispersible particles consisting of a drug substance or an x-ray contrast agent having a surface modifier absorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400nm.
  • the particles are prepared by dispersing a drug substance or contrast agent in a liquid dispersion medium and wet grinding in the presence of rigid spherically shaped or particulate grinding media.
  • Verhoff, et al, U.S. Patent Application No 2002/0003179 A1 describes a process for preparing a dispersion of solid particles of a milled substrate comprising using together a plurality of large size media and small size media in the same milling chamber.
  • U.S. Patent No. 3,210,016 discloses an apparatus and method for a process similar to ball milling which utilizes milling agents having planar rather than rounded surfaces.
  • U.S. Patent No 6,634,572 B2 discloses a process for milling a solid substrate in the presence of two or more different milling media bodies.
  • PCT Application International NO PCT/US02/16159 is a co-owned, co-pending application disclosing an apparatus and method for high pressure media milling.
  • U.S. Patent No. 5,891 ,231 relates to a grinding method for making colorants for inks wherein the grinding medium may be spherical, cylindrical or cubical.
  • Co-owned, co-pending patent application WO 03/040245 discloses the use of cubic grinding media to produce colorant particles for the ink industry.
  • a method of preparing fine particles of a pharmaceutical, nutraceutical, or diagnostic agent that comprises grinding the pharmaceutical, nutraceutical, or diagnostic agent using nonspherical grinding media.
  • the grinding media can be made essentially of any tough resilient material.
  • the grinding media can comprise particles comprising a core that has the tough resilient material adhered thereon.
  • the type of material selected to comprise the media will be determined, in part, by the toughness and hardness required to effectively mill the particular particles to be ground.
  • FIGURES Figure 1 is a light micrograph at 80X magnification showing a 500 micron cubic nylon grinding particle purchased from Norstone Inc., Wyncote, PA, USA.
  • Figure 2 is a light micrograph at 80X magnification showing a 500 micron spherical polystyrene grinding particle purchased from Norstone Inc., Wyncote, PA, USA.
  • Figure 3 is an electron micrograph showing the starting ibuprofen used in Example 2.
  • Figure 4 is an electron micrograph showing the ibuprofen after grinding according to the method of Example 2.
  • nonspherical means any three- dimensional shape that is not substantially spherical.
  • spherical is given its traditional meaning, and is defined as any three-dimensionally shaped object wherein all points as measured in straight lines from the center of the object to the surface of the object are equidistant.
  • nonspherically shaped media can include media shapes that are substantially cubic, rectangular, hexagonal, rod-like, needle-like, or ellipsoidal.
  • nonspherical the grinding media is not necessarily comprised of "perfectly shaped” cubes, rectangles, hexagons, rods, needles, etc., as such terms are classically used in the field of geometry.
  • media comprised of combinations of the aforementioned nonspherical shapes are contemplated for use in the method according to the invention.
  • a media mill, or media milling, as those terms are used by Applicants, describes generally any device or method that achieves reduction in the size of solid particulate materials through a grinding process utilizing grinding media.
  • the media milling process practiced in the invention can be any wet or dry grinding process that uses an attritor, a tumbling ball mill, a vibratory ball mill, a planetary ball mill, a horizontal media mill, a vertical media mill, or an annular media mill.
  • the carrier fluid can either be a gas, such as air or nitrogen, or an inert or reactive gas.
  • a typical wet milling process is called slurry milling, wherein a liquid is used as the carrier fluid. Possible liquids include water, salt solutions, buffered solutions, solvents (ethanol, hexane, glycol etc.), solvent/water mixtures, solvent/solvent mixtures, and the like.
  • the carrier fluid can be either a pressurized gas, e.g., pressurized nitrogen, or a gas under supercritical pressure or temperature conditions, e.g., CO 2 pressurized past its critical point.
  • a pressurized gas e.g., pressurized nitrogen
  • a gas under supercritical pressure or temperature conditions e.g., CO 2 pressurized past its critical point.
  • the invention can be practiced in accordance with the high pressure media milling process described in commonly owned, copending patent application PCT/US02/16159 entitled High Pressure Media Milling, the disclosure of which is hereby incorporated by reference.
  • the nonspherical shaped media milling beads of the invention can be comprised of any material of greater hardness and rigidity than the material to be ground into particles.
  • the grinding material can be comprised of almost any hard, tough material including, for example, nylon and polymeric resins, metals, and a range of naturally occurring substances, such as sand, silica, or chitin obtained from crab shells.
  • the nonspherical shaped grinding media of the present invention is comprised of a tough resilient material having a low rate of attrition, and therefore a low incidence of contamination of the ground material with attrited media pieces.
  • the nonspherical shaped grinding media can either consist entirely of a single material that is tough and resilient, or in the alternative, be comprised of more than one material, i.e., comprise a core portion having a coating of tough resilient material adhered thereon.
  • the nonspherical shaped grinding media can be comprised of mixtures of any materials that are suitable for grinding.
  • polymeric resins suitable for use herein as grinding media are chemically and physically inert, preferably substantially free of metals, solvents and monomers, and of sufficient hardness and friability to avoid being chipped and crushed during grinding.
  • Suitable polymeric resins include, but are not limited to, crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polycarbonates, polyacetals, such as DelrinTM, vinyl chloride polymers and copolymers, polyurethanes, polyamides, poly(tetrafluoroethylenes), e.g., TeflonTM, and other fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers and esters such as cellulose acetate, polyhydroxymethacrylate, polyhydroxyethyl acrylate, silicone containing polymers such as polysiloxanes and the like.
  • Biodegradable polymeric resins are also suitable for use herein.
  • Exemplary biodegradable polymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino carbonates), poly(N-acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes).
  • Additional grinding media materials include digestible ingredients having "GRAS" (generally recognized as safe) status.
  • GRAS digestible ingredients having "GRAS" (generally recognized as safe) status.
  • starch based materials or other carbohydrates for instance, starch based materials or other carbohydrates, protein based materials, and salt based materials, e.g., cubic sodium chloride crystals.
  • the core material(s) preferably can be selected from materials known to be useful as grinding media when fabricated as spheres or particles.
  • Suitable core materials include, but are not limited to, zirconium oxides (such as 95% zirconium oxide stabilized with magnesia or yttrium), zirconium silicate, glass, stainless steel, titania, alumina, ferrite, and the like.
  • the core material(s) can also be magnetic.
  • Particle sizes produced according to the method of the invention can vary widely, depending upon the desired application. However, with regard to many pharmaceutical, nutraceutical and diagnostic applications, the desired size will range from 100 ⁇ m down to the nanometer range. Often, a useful size range in the pharmaceutical field, especially, will be approximately 500 nm or less.
  • nonspherically shaped grinding media may enable small particles of pharmaceuticals, nutraceuticals, and diagnostic agents to be produced on a large-scale.
  • the nonspherically shaped grinding media may reduce mill processing times, particularly when there is a need to produce ultra fine particles.
  • Applicants have noted, as demonstrated in Example 1 , that when grinding conditions and grinding materials are the same, grinding can progress faster with nonspherical shaped grinding media than with spherical shaped grinding media.
  • any size of grinding media suitable to achieve the desired particle size can be utilized.
  • the preferred size range of the grinding media will be in the 15 mm to 20 micron range for continuous media milling with media retention in the mill.
  • smaller nonspherical grinding media can be often utilized.
  • a variety of manufacturing processes can be employed to produce the nonspherical grinding media used according to the method of the present invention.
  • the media material can be cryogenically ground and then subjected to screening or air classification techniques to obtain the size class/fraction desired.
  • nonspherical grinding media can be formed by being 1 ) extruded through different die designs, 2) subjected to various cutting techniques, or 3) cast via available casting processes. In many instances, nonspherical grinding media having the desired size and material characteristics can be purchased commercially.
  • the present invention can be practiced to produce a wide variety of particle sizes, particularly in the pharmaceutical, nutraceutical, and diagnostic fields.
  • the pharmaceuticals, nutraceuticals, and diagnostic agents In the case of dry milling, the pharmaceuticals, nutraceuticals, and diagnostic agents must be capable of being formed into solid particles.
  • the pharmaceuticals, nutraceuticals, and diagnostic agents are preferably dispersible and poorly soluble in at least one fluid medium.
  • “poorly soluble” is meant that the pharmaceutical, nutraceutical, or diagnostic agent has a solubility in the liquid dispersion medium, e.g., water, of less than about 10mg/ml, and in most instances less than about 1mg/ml, at room temperature.
  • fluid as used by Applicants in the context of wet milling means that the continuous phase may be a liquid, a gas, a pressurized gas, a liquefied gas, a supercritical fluid, a subcritical fluid, or any combination thereof.
  • Suitable water soluble and water insoluble pharmaceuticals for use " in the " invention include, but are not limited to, anabolic steroids, analeptics, analgesics, anesthetics, antacids, anti-arrthymics, anti- asthmatics, antibiotics, anti-cariogenics, anticoagulants, anticolonergics, anticonvulsants, antidepressants, antidiabetics, antidiarrheals, anti- emetics, anti-epileptics, antifungals, antihelmintics, antihemorrhoidals, antihistamines, antihormones, antihypertensives, anti-hypotensives, anti- inflammatories, antimuscarinics, antimycotics, antineoplastics, anti-obesity drugs, antiplaque agents, antiprotozoals, antipsychotics, antiseptics, anti- spasmotics, anti-thrombics, antitussives, antivirals, anxio
  • Suitable biopharmaceutical substances include, but are not limited to, any therapeutic compound being derived from a biological source or chemically synthesized to be equivalent to a product from a biological source, for example, a protein, a peptide, a vaccine, a nucleic acid, an immunoglobulin, a polysaccharide, cell product, a plant extract, a phytochemical, an animal extract, a recombinant protein, an enzyme or combinations thereof.
  • Suitable pharmaceutical and biopharmaceutical substances are intended to include those delivered via a pulmonary delivery mechanism, a parenteral delivery mechanism, a transdermal delivery mechanism, an oral delivery mechanism, an ocular delivery mechanism, a suppository or vaginal delivery mechanism, an aural delivery mechanism, a nasal delivery mechanism and an implanted delivery mechanism.
  • Suitable diagnostic agents include, but are not limited to, ethyl-3,5- bisacetoamido-2,4,6-triiodobenzoate (WIN 8883), ethyl(3,5- bis(acetylamino)-2,4,6-triiodobenzoyloxy)acetate(WIN 12901 ), ethyl-2- (bis(acetylamino)-2,4,6- triiodobenzoyloxy)butyrate (WIN 16318), 6- ethoxy-6-oxohexyl-3,5-bis(acetylamino)-2,4,6- triiodobenzoate (WIN 67722).
  • Other suitable imaging agents are described in EPO 498, 482, the disclosure of which is hereby incorporated by reference. Diagnostic agents also include any other particulate material that is useful in vivo or in vitro in the detection or quantification of health or disease.
  • Suitable nutraceuticals may include, but are not limited to, dietary supplements, such as vitamins and minerals, herbal remedies, such as Asian ginseng, bilberry, black cohash, cascara, cat's claw, cayenne, cranberry, devil's claw, dong quai, echinacea, evening primrose oil, feverfew, garlic, ginger, ginkgo biloba, ginseng, golden seal, gotu kola, grape seed, green tea, hawthorn, kava, licorice, milk thistle, saw palmetto, Siberian ginseng, St. John's wort, valerian root, probiotics, and functional foods, such as Yakult, calcium-enriched milk, and high fiber bread.
  • herbal remedies such as Asian ginseng, bilberry, black cohash, cascara, cat's claw, cayenne, cranberry, devil's claw, dong quai, echinacea, evening primrose oil, feverfe
  • any matter that is normally ingested by humans or animals for sustenance, growth and maintenance of optimal health is considered a food or food substance that can be used as a source of nutraceuticals.
  • a skilled practitioner will be capable of identifying other fields and applications in which many other types of articles can be milled according to the method of the invention.
  • the substance to be ground by means of the invention will often be milled at a temperature that does not cause the substance to significantly degrade or lose efficacy. Processing temperatures of less than about 30° to 40° C. are ordinarily preferred if the ground substance is a pharmaceutical. Toward this end, the processing equipment can be cooled using conventional cooling equipment. Super cooling conditions can also be employed if the fluid selected is a gas at ambient temperature. Media milling methods can be carried out under a variety of pressure conditions. For example, typical media milling is traditionally carried out under conditions of ambient pressure. Ambient processing pressures are typical of ball, attritor and vibratory mills. Processing pressures of up to about 20 psi (1.4kg/cm 2 ) are typical of conventional media milling.
  • the method according to this invention can also be practiced at elevated pressures using pressurized gasses above their critical pressure, for example see commonly owned application PCT/US02/16159 entitled High Pressure Media milling.
  • the carrier fluid can be a pressurized gas, a pressurized liquid or a supercritical fluid.
  • the present invention may also be utilized for the production of any variety of small, high surface area particles that can be used as carrier particles for liquids or as seeds for crystallization or precipitation.
  • the particles formed by the method of the present invention can, in many cases, also be concurrently or subsequently coated with moisture barriers, taste-masking agents, or other additives or encapsulating agents that enhance the attributes of the pharmaceutical, nutraceutical or diagnostic agent.
  • Particles of pharmaceuticals, nutraceuticals and diagnostic agents can also be formulated with other materials during the milling process. Most often the other material will be an inactive agent, which may include, for example, surfactants, dispersants and the like.
  • a surface modifier such as a surfactant, emulsifier, or stabilizer, can be adsorbed on the surface of the pharmaceutical, nutraceutical or diagnostic agent particle during the milling process.
  • Useful surface modifiers are believed to include those that physically adhere, as well as, those that chemically bond, to the surface of the pharmaceutical, nutraceutical or diagnostic particle.
  • Surface modifiers can be present in an amount of 0.1-90%, preferably 1-10% by weight based on the total combined weight of the respective substance and the surface modifier.
  • the preferred proportions of grinding media, the pharmaceutical, nutraceutical and/or diagnostic agent, the optional liquid dispersion medium, and the inactive agent(s) present in the grinding vessel of the mill can vary within wide limits depending, for example, on the particular pharmaceutical, nutraceutical, or diagnostic agent selected, the size and density of the grinding media, the type of mill selected, etc.
  • the process can be carried out in a continuous, batch or semi- batch mode.
  • high energy media mills it may be desirable to fill 70-90% of the volume of the grinding chamber with grinding media.
  • roller mills it is frequently desirable for 50% of the grinding chamber volume to be comprised of air, and the other 50% to be comprised of the grinding media and the liquid dispersion medium, if present. This permits a cascading effect within the vessel on the rollers, thereby enabling the solid product to be efficiently ground.
  • foaming is a problem during wet grinding, the vessel can be completely filled with the liquid dispersion medium.
  • the processing or milling time can also vary widely depending primarily on the particular mechanical means and processing conditions selected. For ball mills, processing times of up to five days or longer may be required. On the other hand, processing times of less than one day (residence of one minute to several hours) have provided the desired results using a high shear media mill.
  • the grinding media is separated from the milled particulate product (in either a dry or liquid dispersion form) using conventional separation techniques, such as by filtration, sieving through a mesh screen, and the like.
  • conventional separation techniques such as by filtration, sieving through a mesh screen, and the like.
  • the grinding fluid advantageously is separated from the grinding media and the ground particles by vaporization after the high pressure media milling process is returned to ambient pressure.
  • Cubic nylon grinding media with a size of 500 microns (Norstone Inc., Wyncote, PA, USA) was added to a 2 oz glass jar, so that 50% of the jar was filled with the cubic nylon grinding media (bulk volume).
  • a water- based dispersion containing 5wt% USP grade naproxen (Spectrum)
  • Table 1 Size of naproxen particles milled using Cubic nylon media (w/ Malvern MS2000)
  • a 1 -liter of naproxen dispersion was prepared by mixing the following ingredients as shown in Table 3.
  • Table 3 Formulation of naproxen dispersion
  • the dispersion was loaded into the feed tank of the Netzsch Labstar media mill (Netzsch Inc., Exton, PA). The mill chamber was charged with 80% Cubic nylon grinding media. The dispersion was circulated through the media mill that was operated at a speed of 3000 RPM. At fixed time points 1 g samples were taken from the mill return line for particle analyses by a Mastersizer 2000 (Malvern, England). The results are listed in table 4. The median size after 960 minutes is 230 nanometer.

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  • Chemical & Material Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Pain & Pain Management (AREA)
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  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Crushing And Grinding (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a milling method in which nonspherical grinding media is used to produce small particles useful in pharmaceuticals, nutraceuticals, and diagnostic agents.

Description

TITLE MEDIA MILLING USING NONSPHERICAL GRINDING MEDIA
CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional Application
No: 60/427,122 filed November 18, 2002, which application is hereby incorporated by reference.
FIELD OF THE INVENTION This invention relates to a media milling method in which nonspherical grinding media are used to produce small particles that are particularly useful in the pharmaceutical, nutraceutical, and diagnostic fields.
BACKGROUND OF THE INVENTION
Methods for producing fine particles have many commercial applications, such as in the production of oral, transdermal, injected or inhaled pharmaceuticals and biopharmaceuticals, nutraceuticals, diagnostic test components and diagnostic agents. For example, it is well known that the rate of dissolution of a solid compound will increase with increasing surface area of the solid. As a result, particle dissolution rates can be increased by increasing the surface area to weight ratios of the particles that make up the solid through particle size reduction techniques. Since bioavailability is related to dissolution kinetics and membrane permeability, the bioavailability of poorly water soluble pharmaceutical or diagnostic compounds in many instances can also be increased via a reduction in the particle size. Further, in many instances it is particularly desirable to have methods of reducing the size of pharmaceutical particles, since a large portion of small molecule drugs (Class 2 and Class 4 pharmaceuticals) are poorly soluble in water or gastric fluids. Thus, successful production of small particles can result in end products having shorter dissolution times, increased bioavailability and potentially faster therapeutic onset. In the pharmaceutical and other industries, media milling is a frequently used method for producing fine and ultra fine (nano) particles. The media milling process typically involves charging grinding media to the milling chamber together with the material to be ground. In the case of wet media milling, typically the material to be ground is added to the mill as a slurry comprised of a solid suspended in a liquid. Often, a surfactant is added to stabilize the slurry. A stirring device of some form can then be used to agitate the grinding media, thereby causing the solid particles to be ground. Alternatively, the grinding media can be set in motion by either applying planetary, tumbling or vibratory motion to the milling chamber, or subjecting magnetic grinding media that has been charged to the milling chamber to an alternating/fluctuating magnetic field. Typical wet mills include colloid mills, pressure homogenizers, rotor stators, and media mills. See, for example, "Technical Aspects of Dispersion" by D. A. Wheeler, Chapter 7 "Dispersion of Powders in Liquids", edited by G.D Parfitt, 3rd edition, Applied Science Publishers hereby incorporated by reference.
The type of grinding media charged to the media mill is generally selected from any variety of dense, tough, hard materials, such as, for example, sand, stainless steal, zirconium silicate, zirconium oxide, yttrium oxide, glass, alumina, titanium, and the like. In situations involving either metal (oxide) contamination, or shifts in pH, a polymeric grinding media is utilized.
Typically, the grinding media charged to the milling chamber has consisted of spherically shaped media milling beads. Spherically shaped grinding media had been thought to be the most mechanically stable form of hard grinding media, as theoretically there are no edges to be attrited or chipped off. Traditionally, spherically shaped hard, rigid grinding media has been utilized in the milling process when chipping and attrition of the hard grinding media is sought to be avoided or reduced.
Liversidge et al, U.S. Patent No. 5,145,684, and EPO 498,492, describe dispersible particles consisting of a drug substance or an x-ray contrast agent having a surface modifier absorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400nm. The particles are prepared by dispersing a drug substance or contrast agent in a liquid dispersion medium and wet grinding in the presence of rigid spherically shaped or particulate grinding media.
Bruno, et al, U.S. Patent No. 5,518,187, describes a method for preparing particles of a drug substance or a diagnostic imaging agent that comprises grinding the drug substance or imaging agent in the presence of grinding media that consists essentially of a polymeric resin. The grinding media is characterized in the disclosure as being substantially spherical in shape.
Czekai, et al, U.S. Patent No. 5,862,999 describes a method for preparing particles of therapeutic and diagnostic imaging agents that have an average particle size of less than about 500nm by grinding the therapeutic or diagnostic imaging agent in the presence of rigid grinding media having a mean particle size less than about 100 microns. The grinding media is characterized by the disclosure as being substantially spherical in shape.
Verhoff, et al, U.S. Patent Application No 2002/0003179 A1 describes a process for preparing a dispersion of solid particles of a milled substrate comprising using together a plurality of large size media and small size media in the same milling chamber.
U.S. Patent No. 3,210,016 discloses an apparatus and method for a process similar to ball milling which utilizes milling agents having planar rather than rounded surfaces.
U.S. Patent No 6,634,572 B2 discloses a process for milling a solid substrate in the presence of two or more different milling media bodies.
PCT Application International NO PCT/US02/16159 is a co-owned, co-pending application disclosing an apparatus and method for high pressure media milling.
U.S. Patent No. 5,891 ,231 relates to a grinding method for making colorants for inks wherein the grinding medium may be spherical, cylindrical or cubical. Co-owned, co-pending patent application WO 03/040245 discloses the use of cubic grinding media to produce colorant particles for the ink industry.
SUMMARY OF THE INVENTION
In accordance with this invention, there is provided a method of preparing fine particles of a pharmaceutical, nutraceutical, or diagnostic agent that comprises grinding the pharmaceutical, nutraceutical, or diagnostic agent using nonspherical grinding media. The grinding media can be made essentially of any tough resilient material. In the alternative, the grinding media can comprise particles comprising a core that has the tough resilient material adhered thereon. The type of material selected to comprise the media will be determined, in part, by the toughness and hardness required to effectively mill the particular particles to be ground.
BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a light micrograph at 80X magnification showing a 500 micron cubic nylon grinding particle purchased from Norstone Inc., Wyncote, PA, USA.
Figure 2 is a light micrograph at 80X magnification showing a 500 micron spherical polystyrene grinding particle purchased from Norstone Inc., Wyncote, PA, USA.
Figure 3 is an electron micrograph showing the starting ibuprofen used in Example 2.
Figure 4 is an electron micrograph showing the ibuprofen after grinding according to the method of Example 2.
DETAILED DESCRIPTION OF THE INVENTION All references cited in this disclosure are specifically incorporated by reference in their entirety.
The present invention is a media milling method that utilizes nonspherical shaped grinding media to produce small particles useful in many commercial applications including particularly pharmaceuticals, nutraceuticals, and diagnostic agents. As used by Applicants, the term "nonspherical" means any three- dimensional shape that is not substantially spherical. The term "spherical" is given its traditional meaning, and is defined as any three-dimensionally shaped object wherein all points as measured in straight lines from the center of the object to the surface of the object are equidistant. For example, nonspherically shaped media can include media shapes that are substantially cubic, rectangular, hexagonal, rod-like, needle-like, or ellipsoidal. Applicants point out that in their use of the term "nonspherical", the grinding media is not necessarily comprised of "perfectly shaped" cubes, rectangles, hexagons, rods, needles, etc., as such terms are classically used in the field of geometry. Furthermore, media comprised of combinations of the aforementioned nonspherical shapes are contemplated for use in the method according to the invention. A media mill, or media milling, as those terms are used by Applicants, describes generally any device or method that achieves reduction in the size of solid particulate materials through a grinding process utilizing grinding media. The media milling process practiced in the invention can be any wet or dry grinding process that uses an attritor, a tumbling ball mill, a vibratory ball mill, a planetary ball mill, a horizontal media mill, a vertical media mill, or an annular media mill. In a tumbling, vibratory, or planetary ball milling process that is dry, the carrier fluid can either be a gas, such as air or nitrogen, or an inert or reactive gas. A typical wet milling process is called slurry milling, wherein a liquid is used as the carrier fluid. Possible liquids include water, salt solutions, buffered solutions, solvents (ethanol, hexane, glycol etc.), solvent/water mixtures, solvent/solvent mixtures, and the like.
In another aspect, the carrier fluid can be either a pressurized gas, e.g., pressurized nitrogen, or a gas under supercritical pressure or temperature conditions, e.g., CO2 pressurized past its critical point. In this embodiment, the invention can be practiced in accordance with the high pressure media milling process described in commonly owned, copending patent application PCT/US02/16159 entitled High Pressure Media Milling, the disclosure of which is hereby incorporated by reference. In general, the nonspherical shaped media milling beads of the invention can be comprised of any material of greater hardness and rigidity than the material to be ground into particles. The grinding material, thus, can be comprised of almost any hard, tough material including, for example, nylon and polymeric resins, metals, and a range of naturally occurring substances, such as sand, silica, or chitin obtained from crab shells. Preferably, the nonspherical shaped grinding media of the present invention is comprised of a tough resilient material having a low rate of attrition, and therefore a low incidence of contamination of the ground material with attrited media pieces. Further, the nonspherical shaped grinding media can either consist entirely of a single material that is tough and resilient, or in the alternative, be comprised of more than one material, i.e., comprise a core portion having a coating of tough resilient material adhered thereon. Additionally, the nonspherical shaped grinding media can be comprised of mixtures of any materials that are suitable for grinding.
The polymeric resins suitable for use herein as grinding media are chemically and physically inert, preferably substantially free of metals, solvents and monomers, and of sufficient hardness and friability to avoid being chipped and crushed during grinding. Suitable polymeric resins include, but are not limited to, crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polycarbonates, polyacetals, such as Delrin™, vinyl chloride polymers and copolymers, polyurethanes, polyamides, poly(tetrafluoroethylenes), e.g., Teflon™, and other fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers and esters such as cellulose acetate, polyhydroxymethacrylate, polyhydroxyethyl acrylate, silicone containing polymers such as polysiloxanes and the like.
Biodegradable polymeric resins are also suitable for use herein. Exemplary biodegradable polymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino carbonates), poly(N-acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes).
In the case of biodegradable polymers, media contaminants can be advantageously metabolized in vivo to biologically acceptable products that can be eliminate from the body. Additional grinding media materials include digestible ingredients having "GRAS" (generally recognized as safe) status. For instance, starch based materials or other carbohydrates, protein based materials, and salt based materials, e.g., cubic sodium chloride crystals. In grinding media that comprise a core of one or more materials, the core material(s) preferably can be selected from materials known to be useful as grinding media when fabricated as spheres or particles. Suitable core materials include, but are not limited to, zirconium oxides (such as 95% zirconium oxide stabilized with magnesia or yttrium), zirconium silicate, glass, stainless steel, titania, alumina, ferrite, and the like. The core material(s) can also be magnetic.
Particle sizes produced according to the method of the invention can vary widely, depending upon the desired application. However, with regard to many pharmaceutical, nutraceutical and diagnostic applications, the desired size will range from 100 μm down to the nanometer range. Often, a useful size range in the pharmaceutical field, especially, will be approximately 500 nm or less.
Surprisingly, nonspherically shaped grinding media may enable small particles of pharmaceuticals, nutraceuticals, and diagnostic agents to be produced on a large-scale. In addition, the nonspherically shaped grinding media may reduce mill processing times, particularly when there is a need to produce ultra fine particles. Applicants have noted, as demonstrated in Example 1 , that when grinding conditions and grinding materials are the same, grinding can progress faster with nonspherical shaped grinding media than with spherical shaped grinding media.
Specifically, it was found that when the same volume of cubic polysterene grinding and spherical polystyrene grinding media are utilized in the same milling process under the same milling conditions, grinding progresses at a quicker rate with the cubic polystyrene grinding media than with the spherical polystyrene grinding media.
Any size of grinding media suitable to achieve the desired particle size can be utilized. However, in many applications the preferred size range of the grinding media will be in the 15 mm to 20 micron range for continuous media milling with media retention in the mill. For batch media milling (in attritors) or circulation milling in which slurry and grinding media are circulated, smaller nonspherical grinding media can be often utilized. A variety of manufacturing processes can be employed to produce the nonspherical grinding media used according to the method of the present invention. For example, the media material can be cryogenically ground and then subjected to screening or air classification techniques to obtain the size class/fraction desired. Additionally, nonspherical grinding media can be formed by being 1 ) extruded through different die designs, 2) subjected to various cutting techniques, or 3) cast via available casting processes. In many instances, nonspherical grinding media having the desired size and material characteristics can be purchased commercially.
The present invention can be practiced to produce a wide variety of particle sizes, particularly in the pharmaceutical, nutraceutical, and diagnostic fields. In the case of dry milling, the pharmaceuticals, nutraceuticals, and diagnostic agents must be capable of being formed into solid particles. In the case of wet milling, the pharmaceuticals, nutraceuticals, and diagnostic agents are preferably dispersible and poorly soluble in at least one fluid medium. By "poorly soluble", is meant that the pharmaceutical, nutraceutical, or diagnostic agent has a solubility in the liquid dispersion medium, e.g., water, of less than about 10mg/ml, and in most instances less than about 1mg/ml, at room temperature. However, compounds that are not poorly soluble can still be milled by utilizing a fluid that is saturated with the compound. The term "fluid" as used by Applicants in the context of wet milling means that the continuous phase may be a liquid, a gas, a pressurized gas, a liquefied gas, a supercritical fluid, a subcritical fluid, or any combination thereof. Suitable water soluble and water insoluble pharmaceuticals for use " in the" invention include, but are not limited to, anabolic steroids, analeptics, analgesics, anesthetics, antacids, anti-arrthymics, anti- asthmatics, antibiotics, anti-cariogenics, anticoagulants, anticolonergics, anticonvulsants, antidepressants, antidiabetics, antidiarrheals, anti- emetics, anti-epileptics, antifungals, antihelmintics, antihemorrhoidals, antihistamines, antihormones, antihypertensives, anti-hypotensives, anti- inflammatories, antimuscarinics, antimycotics, antineoplastics, anti-obesity drugs, antiplaque agents, antiprotozoals, antipsychotics, antiseptics, anti- spasmotics, anti-thrombics, antitussives, antivirals, anxiolytics, astringents, beta-adrenergic receptor blocking drugs, bile acids, breath fresheners, bronchospasmolytic drugs, bronchodilators, calcium channel blockers, cardiac glycosides, contraceptives, corticosteriods, decongestants, diagnostics, digestives, diuretics, dopaminergics, electrolytes, emetics, expectorants, haemostatic drugs, hormones, hormone replacement therapy drugs, hypnotics, hypoglycemic drugs, immunosuppressants, impotence drugs, laxatives, lipid regulators, mucolytics, muscle relaxants, non-steroidal anti-inflammatories, nutraceuticals, pain relievers, parasympathicolytics, parasympathicomimetics, prostagladins, psychostimulants, psychotropics, sedatives, sex steroids, spasmolytics, steroids, stimulants, sulfonamides, sympathicolytics, sympathicomimetics, sympathomimetics, thyreomimetics, thyreostatic drugs, vasodialators, vitamins, xanthines, and mixtures thereof.
Suitable biopharmaceutical substances include, but are not limited to, any therapeutic compound being derived from a biological source or chemically synthesized to be equivalent to a product from a biological source, for example, a protein, a peptide, a vaccine, a nucleic acid, an immunoglobulin, a polysaccharide, cell product, a plant extract, a phytochemical, an animal extract, a recombinant protein, an enzyme or combinations thereof.
Suitable pharmaceutical and biopharmaceutical substances are intended to include those delivered via a pulmonary delivery mechanism, a parenteral delivery mechanism, a transdermal delivery mechanism, an oral delivery mechanism, an ocular delivery mechanism, a suppository or vaginal delivery mechanism, an aural delivery mechanism, a nasal delivery mechanism and an implanted delivery mechanism.
Suitable diagnostic agents include, but are not limited to, ethyl-3,5- bisacetoamido-2,4,6-triiodobenzoate (WIN 8883), ethyl(3,5- bis(acetylamino)-2,4,6-triiodobenzoyloxy)acetate(WIN 12901 ), ethyl-2- (bis(acetylamino)-2,4,6- triiodobenzoyloxy)butyrate (WIN 16318), 6- ethoxy-6-oxohexyl-3,5-bis(acetylamino)-2,4,6- triiodobenzoate (WIN 67722). Other suitable imaging agents are described in EPO 498, 482, the disclosure of which is hereby incorporated by reference. Diagnostic agents also include any other particulate material that is useful in vivo or in vitro in the detection or quantification of health or disease.
Suitable nutraceuticals may include, but are not limited to, dietary supplements, such as vitamins and minerals, herbal remedies, such as Asian ginseng, bilberry, black cohash, cascara, cat's claw, cayenne, cranberry, devil's claw, dong quai, echinacea, evening primrose oil, feverfew, garlic, ginger, ginkgo biloba, ginseng, golden seal, gotu kola, grape seed, green tea, hawthorn, kava, licorice, milk thistle, saw palmetto, Siberian ginseng, St. John's wort, valerian root, probiotics, and functional foods, such as Yakult, calcium-enriched milk, and high fiber bread. In addition, any matter that is normally ingested by humans or animals for sustenance, growth and maintenance of optimal health is considered a food or food substance that can be used as a source of nutraceuticals. A skilled practitioner will be capable of identifying other fields and applications in which many other types of articles can be milled according to the method of the invention.
The substance to be ground by means of the invention will often be milled at a temperature that does not cause the substance to significantly degrade or lose efficacy. Processing temperatures of less than about 30° to 40° C. are ordinarily preferred if the ground substance is a pharmaceutical. Toward this end, the processing equipment can be cooled using conventional cooling equipment. Super cooling conditions can also be employed if the fluid selected is a gas at ambient temperature. Media milling methods can be carried out under a variety of pressure conditions. For example, typical media milling is traditionally carried out under conditions of ambient pressure. Ambient processing pressures are typical of ball, attritor and vibratory mills. Processing pressures of up to about 20 psi (1.4kg/cm2) are typical of conventional media milling.
The method according to this invention can also be practiced at elevated pressures using pressurized gasses above their critical pressure, for example see commonly owned application PCT/US02/16159 entitled High Pressure Media milling.
The carrier fluid can be a pressurized gas, a pressurized liquid or a supercritical fluid.
The present invention may also be utilized for the production of any variety of small, high surface area particles that can be used as carrier particles for liquids or as seeds for crystallization or precipitation.
The particles formed by the method of the present invention can, in many cases, also be concurrently or subsequently coated with moisture barriers, taste-masking agents, or other additives or encapsulating agents that enhance the attributes of the pharmaceutical, nutraceutical or diagnostic agent.
Particles of pharmaceuticals, nutraceuticals and diagnostic agents can also be formulated with other materials during the milling process. Most often the other material will be an inactive agent, which may include, for example, surfactants, dispersants and the like. Thus, in the method of the present invention, a surface modifier, such as a surfactant, emulsifier, or stabilizer, can be adsorbed on the surface of the pharmaceutical, nutraceutical or diagnostic agent particle during the milling process. Useful surface modifiers are believed to include those that physically adhere, as well as, those that chemically bond, to the surface of the pharmaceutical, nutraceutical or diagnostic particle. Surface modifiers can be present in an amount of 0.1-90%, preferably 1-10% by weight based on the total combined weight of the respective substance and the surface modifier. The preferred proportions of grinding media, the pharmaceutical, nutraceutical and/or diagnostic agent, the optional liquid dispersion medium, and the inactive agent(s) present in the grinding vessel of the mill can vary within wide limits depending, for example, on the particular pharmaceutical, nutraceutical, or diagnostic agent selected, the size and density of the grinding media, the type of mill selected, etc.
The process can be carried out in a continuous, batch or semi- batch mode. In high energy media mills, it may be desirable to fill 70-90% of the volume of the grinding chamber with grinding media. On the contrary, in roller mills it is frequently desirable for 50% of the grinding chamber volume to be comprised of air, and the other 50% to be comprised of the grinding media and the liquid dispersion medium, if present. This permits a cascading effect within the vessel on the rollers, thereby enabling the solid product to be efficiently ground. However, when foaming is a problem during wet grinding, the vessel can be completely filled with the liquid dispersion medium.
The processing or milling time can also vary widely depending primarily on the particular mechanical means and processing conditions selected. For ball mills, processing times of up to five days or longer may be required. On the other hand, processing times of less than one day (residence of one minute to several hours) have provided the desired results using a high shear media mill.
After milling is completed, the grinding media is separated from the milled particulate product (in either a dry or liquid dispersion form) using conventional separation techniques, such as by filtration, sieving through a mesh screen, and the like. When using a high pressure media mill containing a supercritical fluid, the grinding fluid advantageously is separated from the grinding media and the ground particles by vaporization after the high pressure media milling process is returned to ambient pressure.
EXAMPLES The present invention is further defined in the following Examples, in which all parts and percentages are by weight. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these Examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions.
EXAMPLE 1 Grinding of Naproxen on SPEX mill using Cubic Polymeric Grinding Media
Cubic nylon grinding media with a size of 500 microns (Norstone Inc., Wyncote, PA, USA) was added to a 2 oz glass jar, so that 50% of the jar was filled with the cubic nylon grinding media (bulk volume). A water- based dispersion containing 5wt% USP grade naproxen (Spectrum
Chemicals) and 3wt% pluronics (VWR Scientific) was formed. 8 grams of this dispersion was then added to the 2 oz glass jar containing the grinding media, and the jar was placed in a holder in the SPEX 8000 mixer/mill (SPEX, Rexton, VA, USA). The dispersion was milled at the default mill speed (60Hz). A
Malvern Mastersizer 2000 (Malvern Instruments, Worcestershire, UK) was used to measure the size of the naproxen particles at 8hrs and 18hrs time intervals. The results are listed herein below in Table 1. After 8 hours of milling the cubic Nylon grinding media produced particles 2,986 nm in size. After 18 hours of milling that the cubic nylon, produced the fine naproxen particles with a median size of 363 nm. The end product produce was a milky white substance with no noticeable discoloration.
Table 1 : Size of naproxen particles milled using Cubic nylon media (w/ Malvern MS2000)
EXAMPLE 2 Milling of Ibuprofen on a High Pressure Media Mill
Cubic nylon grinding media with a size of 500 microns (Norstone
Inc., Wyncote, PA, USA) was added to a 1L High Pressure Media Mill (Dupont, WO 02/094443 A2). 72% of the grinding chamber was filled with the cubic nylon grinding media (bulk volume). 150 grams of ibuprofen (Spectrum Chemicals) was charged to the grinding chamber. The mill was then pressurized with carbon dioxide under supercritical conditions. The mill was operated for four hours at a pressure of 1450 psi and a temperature of 35 degrees Celsius. The mill speed was kept constant at 1750 RPM . After completion of the run product was recovered from the mill. The particle size of the feedstock and milled product were measured by forward light scattering (Mastersizer2000, Malvern Instruments, England). Particle size data is listed in Table 2. Particle Scanning micrographs (SEM, Hitachi S-4700, San Jose, CA) of the feedstock (Figure 3) and milled product (Figure 4) were taken. The particle size of the milled product had increased. However, the scanning electron micrographs show that the milled product was agglomerated and consisted of fine primary crystals.
Table 2: Cumulative undersize of feedstock and milled ibuprofen
EXAMPLE 3 Grinding of Naproxen on Netzsch high speed media mill
A 1 -liter of naproxen dispersion was prepared by mixing the following ingredients as shown in Table 3. Table 3: Formulation of naproxen dispersion
The dispersion was loaded into the feed tank of the Netzsch Labstar media mill (Netzsch Inc., Exton, PA). The mill chamber was charged with 80% Cubic nylon grinding media. The dispersion was circulated through the media mill that was operated at a speed of 3000 RPM. At fixed time points 1 g samples were taken from the mill return line for particle analyses by a Mastersizer 2000 (Malvern, England). The results are listed in table 4. The median size after 960 minutes is 230 nanometer.
Table 4: Particle size distribution of milled Naproxen on Netzsch Labstar

Claims

CLAIMS We Claim:
1. A method of grinding pharmaceutical, nutraceutical, or diagnostic substances, comprising grinding said substance in the presence of nonspherical grinding media, wherein said grinding is performed using a media mill.
2. The method of claim 1 , wherein the media mill is a dry media mill.
3. The method of claim 1 , wherein the media mill is a wet media mill.
4. The method of claim 1 , wherein the media mill contains a fluid pressurized above the fluid's critical pressure.
5. The method of claim 4, wherein the nonspherical grinding media is cubic.
6. The method of claim 5, wherein the cubic nonspherical grinding media comprises a polymeric material.
7. The method of claim 6, wherein the substance is a pharmaceutical.
8. The method of claim 7, wherein the pharmaceutical is ibuprofen or naproxen.
9. The method of claim 1 , wherein the media mill contains at least one fluid selected from the group consisting of liquids, gases, liquefied/cooled gases, supercritical fluids and subcritical fluids.
10. The method of claim 1 , wherein the nonspherical grinding media is cubic.
11. The method of claim 10, wherein the cubic nonspherical grinding media comprises material selected from the group consisting of polymeric material, ceramic material, and mixtures thereof.
12. The method of claim 11 , wherein the substance is a pharmaceutical.
13. The method of claim 11 , wherein the polymeric material is polystyrene.
14. The method of claim 13, wherein the substance is a pharmaceutical.
15. The method of claim 11 , wherein the polymeric material is nylon.
16. The method of claim 15, wherein the substance is a pharmaceutical.
17. The method of claim 1 , wherein the substance is a pharmaceutical.
18. A method of increasing the solubility of a poorly soluble pharmaceutical, nutraceutical or diagnostic substance comprising grinding said substance in the presence of nonspherical grinding media, wherein said grinding is performed using a media mil.
19. A pharmaceutical, nutraceutical, or diagnostic imaging agent preparation comprising particles ground according to the method of claim 1.
20. Naproxen or ibuprofen comprising particles ground according to the method of claim 1.
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