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WO2010059812A1 - Nanoparticules de phosphate métallique modifiées en surface - Google Patents

Nanoparticules de phosphate métallique modifiées en surface Download PDF

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Publication number
WO2010059812A1
WO2010059812A1 PCT/US2009/065131 US2009065131W WO2010059812A1 WO 2010059812 A1 WO2010059812 A1 WO 2010059812A1 US 2009065131 W US2009065131 W US 2009065131W WO 2010059812 A1 WO2010059812 A1 WO 2010059812A1
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phosphate
nanoparticles
metal
organocarboxylate
composition according
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Neeraj Sharma
Deivaraj Theivanayagam Chairman
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3M Innovative Properties Co
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3M Innovative Properties Co
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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/30—Alkali metal phosphates
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • C01B25/324—Preparation from a reaction solution obtained by acidifying with an acid other than orthophosphoric acid
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • C01B25/34—Magnesium phosphates
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/37—Phosphates of heavy metals

Definitions

  • compositions that include surface-modified metal phosphate nanoparticles, articles comprising said compositions, and methods of making said compositions.
  • Metal phosphates for example, alkaline earth phosphates such as magnesium phosphate and calcium phosphate
  • Alkaline earth phosphates are used in anti-rust coatings, in flame retardants, in antacids, and in producing fluorescent particles.
  • Iron phosphates find application in cathode material for lithium ion batteries.
  • Aluminum, manganese, cobalt, tin, and nickel phosphates are used in heterogeneous catalysis.
  • Zinc phosphate is commonly used as a pigment in anti-corrosion protection.
  • Zirconium phosphates are used as solid acid catalysts.
  • Various lanthanide phosphates are useful as fluorescent and laser materials.
  • Biocompatible calcium phosphates are particularly useful, however, due to their classification as biocompatible materials. Under physiological conditions, calcium phosphates can dissolve, and the resulting dissolution products can be readily assimilated by the human body.
  • Biocompatible calcium phosphates include hydroxyapatite (HAP; [Ca 5 (PO 4 )SOH]), dicalcium phosphate (DCP; [Ca(HPO 4 ).2H 2 O]), tricalcium phosphate (TCP; [Ca 3 (PO 4 ) 2 ]), tetracalcium phosphate (TTCP, [Ca 4 O(PO 4 ) 2 ]), and amorphous calcium phosphate.
  • HAP hydroxyapatite
  • DCP dicalcium phosphate
  • TCP tricalcium phosphate
  • TCP tricalcium phosphate
  • TTCP tetracalcium phosphate
  • TTCP [Ca 4 O(PO 4 ) 2 ]
  • amorphous calcium phosphate Bio
  • metal phosphates also offer interesting properties.
  • aluminum phosphate coatings are known to provide corrosion inhibition for various metallic substrates (Ni, Ti alloys)
  • zirconium phosphates are used as solid acid catalysts
  • rare earth metal phosphates find applications as luminescent probes.
  • Metal phosphate encapsulated lithium ion battery cathode materials exhibit enhanced electrochemical performances.
  • hydroxyapatite can be more stable under physiological conditions.
  • hydroxyapatite has been used for bone repair after major trauma or surgery (for example, in coatings for titanium and titanium alloys).
  • Hydroxyapatite has also been used in the separation and purification of proteins and in drug delivery systems.
  • Other calcium phosphates have been used as dietary supplements in breakfast cereals, as tableting agents in some pharmaceutical preparations, in feed for poultry, as anti-caking agents in powdered spices, as raw materials for the production of phosphoric acid and fertilizers, in porcelain and dental powders, as antacids, and as calcium supplements.
  • non-agglomerated nanoparticles of calcium phosphate can be desired.
  • the preferred sizes, morphologies, and/or degrees of crystallinity of the nanoparticles vary according to the nature of each specific application.
  • hydroxyapatite nanoparticles Numerous methods have been used for the synthesis of hydroxyapatite nanoparticles including chemical precipitation, hydrothermal reactions, freeze drying, sol- gel formation, phase transformation, mechanochemical synthesis, spray drying, microwave sintering, plasma synthesis, and the like.
  • Hydroxyapatite nanoparticles have often been synthesized by the reaction of aqueous solutions of calcium ion-containing and phosphate ion-containing salts (the so-called "wet process"), followed by thermal treatment. Nanoparticles obtained by this method generally have had a needle-like (acicular) morphology with varying degrees of crystallinity, depending upon the nature of the thermal treatment. Such acicular nanoparticles can be used as coating implant materials but have limited or no use in some of the other applications mentioned above.
  • Solid-state reaction of precursors, plasma spraying, pulsed laser deposition, and flame spray pyrolysis methods have resulted in hydroxyapatite nanoparticles of different morphologies (for example, spherical or oblong), but these have often been in the form of micron-sized agglomerates of nanoparticles that have been of limited use in certain applications.
  • Numerous researchers have carried out post- synthesis surface modification of hydroxyapatite to de-agglomerate the particles.
  • spherical hydroxyapatite nanoparticles have involved the use of either surfactants or polymers to control the morphology and the size of the resulting particles.
  • surfactants or polymers to control the morphology and the size of the resulting particles.
  • the capability of such methods to provide nanoparticles in the form of redispersible dry powders for example, dry powders that can be redispersed in an appropriate solvent to provide a non-agglomerated nanoparticle dispersions
  • Metal phosphate nanoparticles such as for example, calcium or magnesium phosphate nanoparticles and methods of making them are known.
  • cores or carriers for biologically active molecules coating implant materials and dental applications, unaggregated nanoparticles of calcium phosphate of varying composition, size, morphology and crystallinity are desired.
  • metal phosphate nanoparticles for example, calcium phosphate nanoparticles
  • metal phosphate nanoparticles for example, calcium phosphate nanoparticles
  • a variety of media for example, solvents, polymers, paints, coatings, cosmetic formulations, pharmaceutical formulations, and the like.
  • very small nanoparticles for example, having average primary particle diameters of less than about 20 nm
  • such nanoparticles typically can be provided in the form of a redispersible powder.
  • this invention provides such a composition, which comprises surface-modified nanoparticles of at least one metal phosphate (typically, calcium phosphate).
  • the nanoparticles bear, on at least a portion of their surfaces, a surface modification comprising at least one organocarboxylate surface modifier that include at least one organic moiety that has at least about six carbon atoms. Typically, the organic moiety has from about 6 to about 24 carbon atoms.
  • the provided nanoparticles can be relatively simply prepared from relatively inexpensive metal phosphate precursors (for example, from a metal cation source such as a metal salt, and a phosphate anion source such as phosphoric acid) and can be grown to average primary particle sizes (for example, average primary particle diameters of about 1 nanometers (nm) to about 50 nm).
  • metal phosphate precursors for example, from a metal cation source such as a metal salt, and a phosphate anion source such as phosphoric acid
  • average primary particle sizes for example, average primary particle diameters of about 1 nanometers (nm) to about 50 nm.
  • the use of relatively long-chain organocarboxylate surface modifier(s) can provide nanoparticles that are also redispersible and typically of substantially spherical morphology.
  • This can be especially advantageous for the production of calcium phosphate nanoparticles having average primary particle diameters in the range of about 1 nm to about 20 nm.
  • Such nanoparticles can be well-suited for use in various pharmaceutical, medical, and dental applications, particularly those (for example, inhalable aerosol drug delivery systems) requiring or desiring relatively small, redispersible, biocompatible nanoparticles of spherical morphology.
  • the composition of the invention can meet the above-mentioned desire for redispersible metal phosphate nanoparticles (typically, calcium phosphate nanoparticles) of desired primary particle sizes and/or morphologies that are surface-modified so as to be compatible with (and therefore dispersible in) a variety of media, and/or that can be easily tailored to fit the characteristics of a particular medium.
  • the composition can therefore further comprise, for example, at least one carrier material or medium (for example, a material or mixture of materials in the form of a gas, a liquid, a bulk solid, a powder, an oil, a gel, or a dispersion).
  • Agglomeration refers an association of primary particles, which can range from relatively weak (based upon, for example, charge or polarity) to relatively strong (based upon, for example, chemical bonding);
  • nanoparticles refers to particles having a diameter of less than 100 nm;
  • organocarboxylate(s) refer to any carboxylate or the conjugate acid of any carboxylate that include at least one organic moiety and have at least 6 and up to 24 carbon atoms in the organic moiety;
  • primary particle size or diameter refers to the size or diameter of a non-associated single nanoparticle;
  • “redispersible” refers to nanoparticles that can be “dried” or precipitated from an original dispersion of the nanoparticles in aqueous or organic solvent or a combination thereof (for example, by removal of the solvent and/or by a change in solvent polarity) to form a powder or a wet precipitate or gel that can be dispersed again in the original dispersion solvent (or a solvent of essentially the same polarity as that of the original dispersion solvent) to provide a nanoparticle dispersion (preferably, without substantial change in primary particle size (and/or average particle size as measured by dynamic light scattering) relative to the original dispersion and/or without substantial sedimentation of the nanoparticles over a period of at least four hours (for example, with size change and/or sedimentation of less than 25 percent (preferably, less than 20 percent; more preferably, less than 15 percent; most preferably, less than 10 percent), where the sedimentation percentage is by weight, based upon the total weight of nanop
  • articles that comprise the composition of the invention.
  • the articles can include a medicament and the medicament can be a powder.
  • the articles can include dry powder inhalers.
  • a process in yet another aspect, includes combining at least one metal cation source, at least one phosphate anion source, at least one organic base comprising at least one organic moiety comprising at least five carbon atoms, and at least one organocarboxylate comprising at least one organic moiety comprising at least eight carbon atoms, and allowing said metal cation source and said phosphate anion source to react in the presence of said organic base and said organocarboxylate.
  • Fig. 1 is a graph of particle size distribution determined by dynamic light scattering for Examples 1-3.
  • Fig. 2 is a graph of particle size distribution determined by dynamic light scattering for Examples 5-7 and 9-11.
  • Fig. 3 is a graph of particle size distribution determined by dynamic light scattering for Example 12.
  • Fig. 4 is a transmission electron micrograph (TEM) of Example 3.
  • Fig. 5 is a transmission electron micrograph (TEM) of Example 5.
  • Fig. 6 is a graph of a Fourier Transform Infrared Spectrum (FTIR) of Example 12.
  • the surface-modified metal phosphate nanoparticles of the provided compositions can be prepared by any of a variety of known or hereafter developed particle surface modification methods.
  • Typical preparative methods include those that can provide the desired surface modification while maintaining or producing substantially non- agglomerated nanoparticles.
  • Typical preparative methods include surface modification during nanoparticle synthesis, post-synthesis surface modification, and combinations thereof.
  • starting metal phosphate nanoparticles can be prepared by essentially any method that can provide nanosized particles (for a range of applications, having average primary particle diameters of from about 1 nm, from about 2 nm, or from about 3 nm, to about 50 nm, to about 30 nm; or to about 20 nm, where any lower limit can be paired with any upper limit of the size range) that are capable of then being surface modified with organocarboxylates.
  • Useful methods for producing such starting metal phosphate nanoparticles include those described, for example, in U. S. Pat. Appl. Publ. Nos. 2004/0170699 (Chane-ching et al), 2006/0257306 (Yamamoto et al.), and 2007/0196509 (Riman et al.).
  • the starting metal phosphate nanoparticles can be dispersed in a liquid medium (for example, alcohol, ether, or a polar aprotic solvent) and, optionally, any water residues removed.
  • a liquid medium for example, alcohol, ether, or a polar aprotic solvent
  • the organocarboxylate surface modification agent can then be added to the resulting dispersion (typically, by mixing in an organic solvent and/or water; optionally, a catalyst can be present to facilitate hydrolysis of the organocarboxylate) and the resulting mixture can be heated under reflux to a temperature between room temperature and the boiling point of the liquid medium (at atmospheric pressure).
  • any resulting water can be removed.
  • the resulting surface-modified nanoparticles can be separated (for example, by filtration or by precipitation followed by centrifugation), washed, and, optionally, dried.
  • a typical process comprises (a) combining (preferably, in at least one solvent) (1) at least one metal cation source, (2) at least one phosphate anion source, (3) at least one organic base comprising at least one organic moiety comprising at least about five carbon atoms, and (4) at least one organocarboxylate comprising at least one organic moiety comprising at least about six carbon atoms; and (b) allowing the metal cation source and the phosphate anion source to react in the presence of the organic base and the organocarboxylate (for example, to form surface-modified metal phosphate nanoparticles).
  • the metal cation source is a metal salt comprising at least one metal cation and at least one anion that is capable of being displaced by phosphate anion
  • the phosphate anion source is selected from phosphorus-containing compounds (for example, phosphoric acid or an organoammonium phosphate salt) that are capable of providing phosphate anion either directly or upon dissolution or dispersion (for example, in aqueous or non-aqueous solvent), oxidation, or hydrolysis, and combinations thereof.
  • metal phosphate precursors including an organic base and a relatively long-chain organocarboxylate can enable the preparation of substantially non-agglomerated metal phosphate nanoparticles that are redispersible and preferably of substantially spherical morphology.
  • the nanoparticles can be grown to preferred average primary particle sizes (for example, average primary particle diameters of about 1 nm to about 50 nm).
  • Preferred embodiments of the process can enable control of average primary particle size and/or particle morphology by varying, for example, the reaction temperature, time, pH, choice and/or amounts of reactants, and/or the order and/or manner of combination of reactants.
  • Metal cation sources suitable for use in making the provided nanoparticles include metal salts comprising at least one metal cation and at least one anion that can be displaced by phosphate anion. Such salts can be prepared, if desired, by the reaction of a metal hydroxide, a metal carbonate, or a metal oxide with a mineral acid. Useful metal cations include those of transition metals, alkaline earth metals, alkali metals, post-transition metals, and combinations thereof.
  • Useful transition metals include titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, ruthenium, cadmium, hafnium, tantalum, tungsten, and combinations thereof.
  • Useful post-transition metals include aluminum, gallium, indium, tin, lead, antimony, bismuth, and combinations thereof.
  • Useful alkaline earth metals include beryllium, calcium, strontium, magnesium, barium, and combinations thereof.
  • Useful alkali metals include lithium, sodium, potassium, rubidium, cesium, and combinations.
  • the metal cation can be a divalent metal cation such as a divalent alkaline earth metal cation. In some embodiments, divalent earth metal cations include divalent calcium or magnesium.
  • Useful anions include halide, nitrate, acetate, carbonate, alkanoate (for example, formate, propionate, hexanoate, neodecanoate, and the like), alkoxide, lactate, oleate, acetylacetonate, sulfate, thiosulfate, sulfonate, bromate, perchlorate, tribromoacetate, trichloroacetate, trifluoroacetate, sulfide, hydroxide, oxide, and the like, and combinations thereof.
  • Typical anions include halide, nitrate, sulfate, carbonate, acetate, hydroxide, oxide, and combinations thereof.
  • the salts can include other metal cations (for example, at levels up to about 10 mole percent, based upon the total number of moles of metal cation), but usually all metals in the salts are selected from those described above.
  • the salts can comprise other anions (for example, at levels up to about 10 mole percent, based upon the total number of moles of anion), but usually all anions in the salts are selected from those described above.
  • useful metal salts include calcium chloride hexahydrate, calcium chloride dihydrate, calcium chloride (anhydrous), calcium bromide hexahydrate, calcium nitrate tetrahydrate, calcium acetate monohydrate, calcium propionate, calcium lactate pentahydrate, calcium 2-ethylhexanoate, calcium methoxyethoxide, calcium carbonate, magnesium chloride hexahydrate, magnesium bromide hexahydrate, magnesium ethoxide, magnesium hydroxide, magnesium nitrate hexahydrate, magnesium acetate tetrahydrate, magnesium oleate, magnesium sulfate heptahydrate, zinc chloride (anhydrous), zinc acetate dihydrate, zinc carbonate hydroxide, zinc bromide dihydrate, zinc nitrate hexahydrate, zinc neodecanoate, zinc oxide, zinc sulfate heptahydrate, cobalt chloride hexahydrate, manganese (II) chloride te
  • Exemplary metal salts include those having anions selected from halide, nitrate, acetate, and combinations thereof. Hydrated metal salts can also be utilized (for example, to facilitate hydrolysis of the organocarboxylate). Useful metal salts can be prepared by known methods. Many of such salts are commercially available.
  • Phosphate anion sources suitable useful in the provided compositions include phosphorus-containing compounds that provide phosphate anion either directly or upon dissolution or dispersion (for example, in aqueous or non-aqueous solvent), oxidation, or hydrolysis, and combinations thereof.
  • Such compounds include phosphoric acid (H 3 PO 4 ); phosphorous acid (H3PO3); hypophosphorous acid (H3PO2); thiophosphoric acid; phosphoric acid esters; thiophosphoric acid esters (for example, diethylchlorothiophosphate, diethyl dithiophosphate, ethyl dichlorothiophosphate, or trimethyl thiophosphate); phosphite esters (for example, dimethyl phosphite, trimethyl phosphite, diisopropyl phosphite, diethyl hydrogenphosphite, diisobutyl phosphite, dioleyl hydrogenphosphite, diphenyl hydrogenphosphite, triphenyl phosphite, ethylenechlorophosphite, and tris(trimethylsilyl) phosphite); thiophosphite esters (for example, trilauryl trithiopho
  • Useful phosphoric acid esters include alkylphosphates.
  • Representative examples of useful alkylphosphates include mono-, di-, and trialkyl phosphates comprising alkyl moieties having from one to about 12 carbon atoms such as methyl phosphate, ethyl phosphate, propyl phosphate, butyl phosphate, pentyl phosphate, hexyl phosphate, dimethyl phosphate, diethyl phosphate, dipropyl phosphate, dibutyl phosphate, dipentyl phosphate, dihexyl phosphate, di-2-ethylhexyl phosphate, methylethyl phosphate, ethylbutyl phosphate, ethylpropyl phosphate, trimethyl phosphate, triethyl phosphate, tripropyl phosphate, tributyl phosphate, tripentyl phosphate, trihexyl phosphate,
  • polyphosphoric acid esters include esters of di-, tri-, terra-, and pentaphosphoric acid and a monohydric alcohol and/or polyhydric alcohol, and combinations thereof.
  • Representative examples of polyphosphoric acid esters include polyphosphoric acid methyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid propyl ester, polyphosphoric acid butyl ester, polyphosphoric acid pentyl ester, polyphosphoric acid dimethyl ester, polyphosphoric acid diethyl ester, polyphosphoric acid dipropyl ester, polyphosphoric acid dibutyl ester, diphosphoric acid methyethyl ester, diphosphoric acid ethybutyl ester, diphosphoric acid ethylpropyl ester, diphosphoric acid ethylhexyl ester, trialkyl esters of di-, tri-, terra-, and penta-phosphoric acids, tetraalkyl esters of di-, tri-, terra
  • polyphosphoric acid esters include those having an ester group containing one to about four carbon atoms (for example, polyphosphoric acid methyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid propyl ester, and polyphosphoric acid butyl ester), and combinations thereof.
  • Useful salts include alkali metal (for example, sodium or potassium) phosphates and polyphosphates, ammonium phosphates and polyphosphates, organoammonium (for example, mono-, di-, tri-, and tetraalkylammonium) phosphates and polyphosphates (including hydroxylamine phosphate), and combinations thereof.
  • alkali metal phosphates include sodium dihydrogen phosphate (monobasic), sodium hydrogen phosphate (dibasic), trisodium phosphate (tribasic), potassium dihydrogen phosphate, lithium dihydrogenphosphate, sodium tripolyphosphate, sodium hexametaphosphate, potassium pyrophosphate, and combinations thereof.
  • organoammonium phosphates and polyphosphates include ethylammonium phosphate, diethylammonium phosphate, trimethylammonium phosphate, triethylammonium phosphate, tributylammonium pyrophosphate, methyltriethylammonium dibutylphosphate, pentyltriethylammonium phosphate, hexyltriethylammonium phosphate, octyltriethylammonium phosphate, dodecyltrimethylammonium phosphate, hexadecyltrimethylammonium dihydrogen phosphate, tetramethylammonium dihydrogen phosphate, tetraethylammonium dihydrogenphosphate, tetrabutylammonium phosphate, tetrahexylammonium dihydrogen phosphate, di-2-ethylhexylammonium
  • organoammonium phosphate salts include pentyltriethylammonium phosphate, hexyltriethylammonium phosphate, octyltriethylammonium phosphate, dodecyltrimethylammonium phosphate, hexadecyltrimethylammonium dihydrogen phosphate, tetrahexylammonium dihydrogen phosphate, di-2-ethylhexylammonium hexafluorophosphate, tetrahexylammonium hexafluorophosphate, phenyltrimethylammonium hexafluorophosphate, benzyltrimethylammonium hexafluorophosphate, and combinations thereof.
  • Useful phosphate salts include organoammonium phosphates, and combinations thereof. In some embodiments, useful salts comprise at least one organic moiety comprising at least about five carbon atoms.
  • phosphate anion sources can be prepared by known methods. Many of such sources (for example, phosphoric acid, alkylphosphates, and polyphosphoric acid esters) are commercially available.
  • Organic bases suitable for use in making the provided nanoparticles compositions include those organic amines and organoammonium hydroxides that include at least one organic moiety comprising at least about five carbon atoms, at least about six carbon atom, or even at least about eight carbon atoms, and combinations thereof (typically, an organic amine).
  • the organic moiety can be linear, branched, alicyclic, aromatic, or a combination thereof (preferably, linear or branched), with the proviso that carbon atoms in a cyclic moiety count only as half their number toward the requisite minimum of five (for example, a phenyl ring counts as three carbon atoms rather than six and must be supplemented by, for example, an attached ethyl moiety).
  • suitable organic amines include monoalkylamines such as hexylamine, heptylamine, octylamine, nonylamine, decylamine, dodecylamine, hexadecylamine, and octadecylamine; dialkylamines such as dihexylamine, di-n-heptylamine, di-n-octylamine, bis(2- ethylhexyl)amine, di-sec-octylamine, di-n-nonylamine, di-n-decylamine, di-n- undecylamine, di-n-tridecylamine, and dicyclooctylamine; trialkylamines such as trihexylamine, triheptylamine, triisooctylamine, trioctylamine, tridodecylamine, tris(4- methylcyclohexyl)amine,
  • organoammonium hydroxides include benzyltriethylammonium hydroxide, benzyltrimethylammonium hydroxide, hexane-1,6- bis(tributylammonium)dihydroxide, 3-(trifluoromethyl)phenyltrimethylammonium hydroxide, dodecyldimethylethylammonium hydroxide, phenyltrimethylammonium hydroxide, cetyltrimethylammonium hydroxide, triethylphenylammonium hydroxide, tetradecylammonium hydroxide, tetrabutylammonium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrahexylammonium hydroxide, tetraoctylammonium hydroxide, tetrapentylammoni
  • organoammonium hydroxides include benzyltriethylammonium hydroxide, benzyltrimethylammonium hydroxide, dodecyldimethylethylammonium hydroxide, cetyltrimethylammonium hydroxide, triethylphenylammonium hydroxide, tetradecylammonium hydroxide, tetrahexylammonium hydroxide, tetraoctylammonium hydroxide, tetrapentylammonium hydroxide, tetraoctadecylammonium hydroxide, tetradecyltrihexylammonium hydroxide, and combinations thereof.
  • Such organic bases can be prepared by known methods. Many of such bases (for example, dodecyldimethylethylammonium hydroxide, cetyltrimethylammonium hydroxide, tetradecylammonium hydroxide, tetrahexylammonium hydroxide, and tetraoctylammonium hydroxide) are commercially available.
  • bases for example, dodecyldimethylethylammonium hydroxide, cetyltrimethylammonium hydroxide, tetradecylammonium hydroxide, tetrahexylammonium hydroxide, and tetraoctylammonium hydroxide
  • organic bases (as well as the phosphate anion sources) can be used in neat solid or liquid form or can be used in the form of a solution in organic solvent (for example, an alkanol such as methanol).
  • organic solvent for example, an alkanol such as methanol.
  • concentrations can be useful (for example, from about 5 to about 90 weight percent in alkanol, based upon the total weight of the solution).
  • the organic base can be combined with the phosphate anion source (for example, phosphoric acid), dissolved in a polar organic solvent or in at least a portion of the organocarboxylate, and used in the form of the resulting solution.
  • Polar organic solvents useful for dissolving the organic base include acetone, alkanols (for example, methanol, ethanol, and isopropanol), dimethylsulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), and mixtures thereof.
  • the organic solvent includes alkanols and methanol.
  • the organoammonium phosphate or polyphosphate can serve as both the phosphate anion source and the organic base, without the need for addition of a separate organic base.
  • Such dual functionality is not limited to these components, however, as other materials can simultaneously serve as more than one of the four reaction mixture components.
  • Organocarboxylates suitable for use in the preferred in situ process include those organocarboxylates that comprise at least one organic moiety comprising at least about 6 carbon atoms, at least about 8 carbon atoms, at least about 12 carbon atoms, at least about 14 carbon atoms, at least about 16 carbon atoms, or even at least about 18 carbon atoms, and combinations thereof.
  • the organic moiety can be linear, branched, alicyclic, aromatic, or a combination thereof, with the proviso that carbon atoms in a cyclic moiety count only as half their number toward the requisite minimum of 6 (for example, a phenyl ring counts as three carbon atoms rather than six and must be supplemented by, for example, an attached propyl moiety).
  • the organic moiety comprises from about 6 to about 24 carbon atoms, from about 12 to about 20 carbon atoms; or even from about 16 to about 18 carbon atoms. In some embodiments, the organic moiety has about 18 carbon atoms and can be straight-chained, branched, saturated, monounsaturated, polyunsaturated or a combination thereof. In some embodiments the organocarboxylate can include more than one carboxyl group.
  • organocarboxylates include straight-chain organomonocarboxylates that have from about 8 to about 24 carbon atoms. These organomonocarboxylates include the conjugate base of organomonocarboxylic acids such as, for example, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, anachidic acid, and eicosonoic acid. In some embodiments, organomonocarboxylates include the conjugate bases of unsaturated straight chain organic acids such as, for example, palmitoleic acid, oleic acid, linoleic acid, and trilinolenic acid.
  • Organocarboxylates derived from branched monocarboxylates such as, for example, 3,5,5-trimethylhexanoic acid, 3-methylhexanoic acid, 3-ethyl5-methylhexanoic acid, 3,3-dimethylhexanoic acid, 5,5-dimethylhexanoic acid, 2-ethylhexanoic acid, 6-methylheptanoic acid, 2-butyloctanoic acid, 7,7-dimethyloctanoic acid can also be useful to make the provided nanoparticle compositions.
  • useful organocarboxylates can further comprise at least one functional group selected from heterocyclic, acryloxy, methacryloxy, cyano, isocyano, cyanato, isocyanato, phosphino, amino, amido, hydroxyl, vinyl, epoxy, glycidoxy, alkyl, carbon-carbon triple bond-containing, mercapto, siloxy, halocarbon (for example, fluorocarbon), carbon-nitrogen double bond-containing, and carbon-carbon double bond-containing groups, and combinations thereof.
  • these organocarboxylates include biotin, abeitic acid, cholic acid, to name a few.
  • the particular functional group can be selected so as to be compatible with a material to which the resulting metal phosphate nanoparticles are to be added.
  • heterocyclic functional groups include substituted and unsubstituted pyrroles, pyrazoles, imidazoles, pyrrolidines, pyridines, pyrimidines, oxazoles, thiazoles, furans, thiophenes, dithianes, isocyanurates, and the like, and combinations thereof.
  • Representative examples of acryloxy functional groups include acryloxy, alkylacryloxy groups such as methacryloxy, and the like, and combinations thereof.
  • solvents can be used in making the provided nanoparticle compositions. Suitable solvents include those in which the various metal phosphate precursors or reaction mixture components can be substantially soluble or dispersible. Most preferably, the solvent will be capable of dissolving the reactants and products of the process, while keeping the desired metal phosphate nanoparticles well-dispersed.
  • Useful solvents for dissolving or dispersing less polar components such as the long-chain organocarboxylates include non- polar organic solvents such as alkanes (for example, hexane, heptane, octane, and the like, and combinations thereof) and aromatic hydrocarbons (for example, toluene, benzene, xylene, and combinations thereof), as well as more polar solvents such as esters (for example, ethyl acetate and combinations thereof), ethers (for example, tetrahydrofuran (THF), diethylether, and combinations thereof), and halocarbons (for example, carbon tetrachloride and combinations thereof), and combinations thereof.
  • Useful non-polar organic solvents include hexane, heptane, octane, toluene, and combinations thereof, due to their boiling points.
  • Mixtures of the polar and non-polar solvents can advantageously be utilized to facilitate separation of the resulting metal phosphate nanoparticles from reaction byproducts.
  • Water in relatively small amounts can speed the kinetics of growth of the metal phosphate nanoparticles and/or facilitate hydrolysis of the organocarboxylate surface modifier, but the presence of water in relatively larger amounts (for example, a water to metal ratio of greater than about 25) can cause nanoparticle agglomeration and/or loss of substantially spherical morphology.
  • a process is provided to make metal phosphate nanoparticles according to this disclosure.
  • the process can be carried out by combining at least one metal cation source, at least one phosphate anion source, at least one organic base comprising at least one organic moiety comprising at least about five carbon atoms, and at least one organocarboxylate comprising at least one organic moiety comprising at least about six carbon atoms (typically, in at least one solvent).
  • the metal cation source and the organocarboxylate are commercially available as a salt and can be added as such. Examples of these organocarboxylate salts are calcium stearate, calcium 2-ethylhexanoate, and magnesium stearate.
  • the salts When the salts are utilized as a combination of the metal cation source and the organocarboxylate it is typical to an additional amount of the conjugate organocarboxylic acid to the process mixture.
  • an additional amount of the conjugate organocarboxylic acid For example, when calcium stearate is used as the metal source, typically additional stearic acid is included in the reaction mixture.
  • any order and manner of combination of the reaction mixture components can be utilized, although in some embodiments it is useful to dissolve or disperse one or more components (for example, the phosphate anion source and the organic base) separately in solvent prior to combination with the other components.
  • certain orders and manners of combination can assist in minimizing agglomeration and enabling the formation of nanoparticles.
  • it can be preferable (for example, when using relatively more reactive phosphate anion sources such as phosphoric acid) to separately form a mixture of the phosphate anion source and the organic base and a mixture of the metal cation source and the organocarboxylate. These two mixtures can then be combined.
  • the metal cation source and the phosphate anion source can be combined in generally stoichiometric amounts, based upon the moles of metal cation and the moles of phosphate anion.
  • these components can be combined in amounts such that the metal to phosphorus molar ratio ranges from about 0.8/n to about 6.0/n, where n is the valence of the metal cation.
  • the molar ratio ranges from about 1.0/n to about 4.0/n (more preferably, from about 1.4/n to about 3.4/n).
  • the metal cation source for example, a metal salt comprising a metal cation and counter anion(s)
  • the organic base can be combined in generally stoichiometric amounts, based upon the moles of basic groups and the moles of counter anion.
  • these components can be combined in amounts such that the organic base to metal molar ratio ranges from about 0.5n/b to about 3.0n/b, where n is the valance of the metal and b is the number of basic groups per mole of organic base.
  • the molar ratio ranges from about 0.6n/b to about 2.0n/b (typically, from about 0.7n/b to about 1.5n/b).
  • the metal cation source and the organocarboxylate can be combined in amounts such that the molar ratio of metal to silicon ranges from about 0.1 to about 20 (preferably, from about 0.2 to about 15; more preferably, from about 0.3 to about 10). If desired, however, the organocarboxylate can be used in larger amounts, so as to function as a reaction solvent. Generally less than 100 percent of the combined organocarboxylate attaches (for example, physically or chemically) to the metal phosphate nanoparticles to provide surface modification.
  • reaction mixture components can be combined in a pressure vessel, if desired (for example, this can be useful for reactions carried out at temperatures above the boiling point of a selected solvent).
  • An inert atmosphere for example, nitrogen
  • can optionally be utilized for example, to minimize the presence of moisture or air).
  • various compounds foreign ions can be added before, during, or after nanoparticle precipitation.
  • Typical additive compounds include 2nd-5th main group and transition metal compounds (typically, magnesium, strontium, barium, aluminum, indium, tin, lead, antimony, bismuth, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, zinc, yttrium, zirconium, niobium, molybdenum, cadmium, hafnium, tantalum, and tungsten compounds, and combinations thereof; typically, magnesium, strontium, aluminum, tin, antimony, titanium, manganese, iron, zinc, yttrium, zirconium, niobium, and tantalum compounds, and combinations thereof) including lanthanide compounds (typically, europium, terbium, dysprosium, samarium, erbium, praseodymium, and cerium compounds, and combinations thereof; most preferably, cerium, europium, terbium, and dysprosium compounds, and combinations thereof).
  • Monomer(s), oligomer(s), and/or polymer(s) of various types can be present in the reaction mixture (for example, in order to form a polymeric composite comprising the resulting metal phosphate nanoparticles).
  • the resulting nanoparticles can be isolated (for example, from a resulting sol) and/or purified by using standard techniques such as decantation (for example, following centrifugation or settling optionally induced by cosolvent addition), filtration, rotary evaporation for solvent removal, dialysis, diaf ⁇ ltration, and combinations thereof.
  • the characteristics of the resulting product can be evaluated by ultraviolet- visible spectroscopy (absorption characteristics), X-ray diffraction (crystalline particle size, crystalline phase, and particle size distribution), transmission electron microscopy (particle sizes, crystalline phase, and particle size distributions), and dynamic light scattering (degree of agglomeration).
  • the resulting nanoparticles can be in the form of a powder or gel that can be re-dispersed in solvent (for example, a polar or a non-polar solvent, depending upon the specific chemical nature of the organocarboxylate).
  • solvent for example, a polar or a non-polar solvent, depending upon the specific chemical nature of the organocarboxylate.
  • the resulting nanoparticles can range in average primary particle diameter from about 1 nm to about 50 nm or more, from about 1 nm to about 30 nm, from about 1 nm to about 20 nm, from about 1 nm to about 15 nm, or even from about 2 nm to about 10 nm, where any lower limit can be paired with any upper limit of the size ranges as explained above.
  • the nanoparticles can be used in various different applications (for example, calcium phosphate nanoparticles can be used in various pharmaceutical, medical, and dental applications).
  • Preferred embodiments of the provided process can provide substantially spherical nanoparticles (for example, substantially spherical calcium phosphate nanoparticles useful in inhalable aerosol drug delivery systems).
  • the above-described preparative methods can produce metal phosphate (most preferably, calcium phosphate) nanoparticles bearing, on at least a portion of their surfaces, a surface modification comprising at least one organocarboxylate surface modifier comprising at least one organic moiety comprising at least about six carbon atoms.
  • the organic moiety has from about 6 to about 24 carbon atoms, from about 12 to about 20 carbon atoms; or even from about 16 to about 18 carbon atoms.
  • the surface modifier can be attached or bonded to the surface of the nanoparticle by a relatively strong physical bond or by a chemical bond (for example, a covalent or ionic bond).
  • organocarboxylate surface modifiers can be derived from organocarboxylate esters through hydrolysis of the organocarboxylate ester and formation of a carbon-oxygen-metal or carbon-oxygen-phosphorus covalent attachment to the metal phosphate nanoparticle.
  • the organocarboxylate surface modifier is derived from a precursor organocarboxylate compound selected from straight-chain carboxylic acids that are saturated, or unsaturated.
  • the surface-modified nanoparticles preferably have average primary particle diameters of from about 1 nm, from about 2 nm, from about 3 nm, to about 20 nanometers, to about 15 nm, or even to about 10 nm, and/or preferably comprise from about 1 weight percent, from about 2 weight percent, or from about 10 weight percent to about 90 weight percent, to about 70 weight percent, or even to about 50 weight percent of surface-modifier, based upon the total weight of the surface-modified nanoparticles (where any lower limit of a range can be paired with any upper limit of the range).
  • composition of the invention can consist or consist essentially of the surface- modified nanoparticles or can further comprise a carrier material or medium (for example, a material or mixture of materials in the form of a gas, a liquid, a bulk solid, a powder, an oil, a gel, a dispersion, and the like).
  • a carrier material or medium for example, a material or mixture of materials in the form of a gas, a liquid, a bulk solid, a powder, an oil, a gel, a dispersion, and the like.
  • a carrier material or medium for example, a material or mixture of materials in the form of a gas, a liquid, a bulk solid, a powder, an oil, a gel, a dispersion, and the like.
  • the nature (and amount) of the carrier material can vary widely, depending upon the particular application, as is known in the art.
  • the surface-modified nanoparticles can be used, for example, in biomedical applications (including as adjuvants or excipients for drugs and vaccines, as carriers for various proteins and other growth factors, as components of dental hygiene agents such as mouthwashes and toothpastes, as artificial prosthetic fillers, as drug delivery and gene therapy vectors, and the like), as adsorption materials for chromatography columns, as catalysts, in fluorescent materials, in flame retardants, and in anti-corrosion coatings.
  • Preferred embodiments can be useful, for example, in making dental hygiene products and cements, as carriers and/or aerosolization aids for drugs, in dietary formulations, and in fluorescent materials.
  • exemplary uses for the surface-modified nanoparticles include use in dietary, cosmetic, and pharmaceutical formulations.
  • the nanoparticles can be used in oral or dental care compositions and nutritional supplements.
  • useful carrier materials can include water, water-based liquids, oils, gels, emulsions, microemulsions, dispersions, and the like, and mixtures thereof.
  • the compositions can further comprise, for example, additives commonly used in cosmetics and/or dietary formulations such as fragrances, emulsif ⁇ ers, thickeners, flavorings, solubilizers, dyes, antibiotics, moisturizers, and the like, and mixtures thereof.
  • the formulation can be borne on a paper or fabric carrier (for example, a woven or non-woven material) to provide a means of delivery other than by application of a powder or dispersion (for example, in the form of a wipe, an adhesive tape, or a flame-retardant web).
  • a paper or fabric carrier for example, a woven or non-woven material
  • a powder or dispersion for example, in the form of a wipe, an adhesive tape, or a flame-retardant web.
  • the provided nanoparticle compositions can find use in pharmaceutical formulations comprising any of a variety of medicaments.
  • the surface-modified nanoparticles can be used to enhance the mixing and/or delivery of medicaments including antiallergics, analgesics, glucocorticoids, bronchodilators, antihistamines, therapeutic proteins and peptides, antitussives, anginal preparations, antibiotics, anti-inflammatory preparations, diuretics, hormones, and combinations of any two or more of these.
  • Noted categories include beta-agonists, bronchodilators, anticholinergics, anti-leukotrienes, mediator release inhibitors, 5-lipoxyoxygenase inhibitors, and phosphodiesterase inhibitors.
  • the pharmaceutical formulations can further comprise one or more excipients.
  • Suitable excipients include those listed in the Handbook of Pharmaceutical Excipients
  • microcrystalline cellulose dicalcium phosphate, lactose monohydrate (a preferred sugar), mannose, sorbitol, calcium carbonate, starches, and magnesium or zinc stearates.
  • the surface-modified nanoparticles can aid in the preparation of excipient/medicament blends (for example, by reducing mixing times, reducing attrition during processing, and improving the homogeneity of the blends).
  • the surface-modified nanoparticles can be particularly useful in pharmaceutical inhalation powder formulations (for example, comprising a medicament and optional excipient(s) such as sugar(s) for use in nasal or oral inhalation drug delivery) to enhance the flow characteristics of the powder.
  • pharmaceutical inhalation powder formulations for example, comprising a medicament and optional excipient(s) such as sugar(s) for use in nasal or oral inhalation drug delivery
  • the nanoparticles can be present in the formulations in an amount that is at least sufficient to improve the flowability or floodability of the powder relative to corresponding powder that is substantially free of the nanoparticles (for example, the nanoparticles can be used in an amount less than or equal to about 10 weight percent, less than or equal to about 5 weight percent, less than or equal to about 1 weight percent, less than or equal to about 0.1 weight percent, or even less than or equal to about 0.01 weight percent (such as 0.001 weight percent), based upon the total weight of the formulation).
  • Such formulations can generally be prepared by mixing one or more powders (for example, having an average particle size, generally measured as an effective diameter, of less than or equal to about 1,000 microns, more typically less than or equal to about 100 microns) with the surface-modified nanoparticles using any suitable, conventional mixing or blending process.
  • powders for example, having an average particle size, generally measured as an effective diameter, of less than or equal to about 1,000 microns, more typically less than or equal to about 100 microns
  • the surface-modified nanoparticles can be added to an organic solvent so as to form a dispersion, and the powder(s) can be added to the dispersion and the resulting combination stirred or agitated for a period of time to facilitate mixing.
  • the solvent can then be removed by evaporation, with or without the aid of vacuum.
  • Useful solvents include toluene, isopropanol, heptane, hexane, octane, and the like, and mixtures thereof.
  • the nanoparticles are calcium phosphate nanoparticles, and the solvent is heptane.
  • the surface-modified nanoparticles and the powder(s) can be dry blended, if desired.
  • the surface-modified nanoparticles can be selected to provide the pharmaceutical inhalation powder formulations with a degree of flowability.
  • the hydrophobic or hydrophilic character of the organocarboxylate surface modifier can be varied (for example, by varying the length of the carbon chain of the organic moiety and/or by varying the chemical nature of other moieties present). If desired, the organocarboxylate surface modifiers can also be used in combination with other hydrophobic or hydrophilic surface modifiers, so that, depending upon the character of the processing solvent or the powder(s), the resulting formulation can exhibit substantially free-flowing properties.
  • Suitable surface modifiers can thus be selected based upon the nature of the processing solvents and powder(s) used and the properties desired in the resulting formulation.
  • a processing solvent is hydrophobic
  • one skilled in the art can select from among various hydrophobic surface modifiers to achieve a surface- modified nanoparticle that is compatible with the hydrophobic solvent
  • the processing solvent is hydrophilic
  • the solvent is a hydrofluorocarbon
  • the nature of the powder(s) and the desired final properties can also affect the selection of the surface modifiers.
  • the nanoparticle can have a plurality of different surface modifiers (for example, a combination of hydrophilic and hydrophobic modifiers) that combine to provide nanoparticles having a desired set of characteristics.
  • the surface modifiers can generally be selected to provide a statistically averaged, randomly surface-modified nanoparticle.
  • the surface modifiers can be present on the surface of the nanoparticles in an amount sufficient to provide surface-modified nanoparticles with the properties necessary for compatibility with the powder(s).
  • the surface modifiers can be present in an amount sufficient to form a discontinuous or continuous monolayer on the surface of at least a portion (preferably, a substantial portion) of the nanoparticle.
  • the resulting pharmaceutical inhalation powder formulations can be stored in a storage article or device (preferably, a dry powder inhaler comprising a mouthpiece and a powder containment system) prior to dosing.
  • This storage article or device can comprise, for example, a reservoir, capsule, blister, or dimpled tape and can be a multi-dose or single-dose device.
  • Calcium hydroxide (95% percent (%) purity), zinc acetate, tris [2-(2-methoxy ethoxy)-ethyl] amine and crystalline phosphoric acid (99 % purity; Fluka) were obtained from Sigma-Aldrich Chemical Company, St. Louis, MO.
  • Magnesium stearate, Oleic acid (90 % purity), and tri-n-octylamine (98 % purity) were obtained from Alfa Aesar, Ward Hill, Massachusetts.
  • Calcium stearate (95 % purity) and 3,5,5-Trimethylhexanoic acid were obtained from TCI America, Portland, Oregon.
  • Magnesium stearate chloride hexahydrate (99 % purity) was obtained from EM Science, Gibbstown, NJ.
  • Calcium Acetate and Calcium acetate monohydrate were obtained from MP Biomedicals LLC Aurora, OH.
  • Methanol (ACS grade; BDH) was obtained from VWR, West Chester, PA. Stearic acid, Heptane and hexanes were obtained from EMD Chemicals, Gibbstown, NJ.
  • Calcium hydroxide (1.48 g) was mixed with deionized water (1 g), oleic acid (16.92 g) and heptane (50 g). the mixture was heated at 120 0 C under a stream of nitrogen in an oil bath for 20 minutes. At this temperature a previously made solution of phosphoric acid (1.16 g) and 11.1 tri-n-octylamine (11.1 g) in methanol (3 g) prepared using a vortex mixer was added. Additional heptane (75 g) was added to the reaction flask. The reaction mixture was heated under stirring at 120 0 C under nitrogen atmosphere for 16 hours.
  • the heating was stopped and the warm reaction mixture was poured in polypropylene bottles, to which a three-fold excess of methanol was added leading to the precipitation of a white solid. Centrifugation of this solution followed by subsequent washes with methanol led to a wet precipitate which was dried under flowing air. The dried precipitate was dispersed in heptane using a vortex mixer. The resulting mixture was centrifuged to remove any solid which did not disperse in heptane. The precipitate was discarded and the supernatant was an optically clear stable dispersion. The dispersion was characterized by Dynamic Light Scattering and Transmission Electron Microscopy (TEM).
  • TEM Dynamic Light Scattering and Transmission Electron Microscopy
  • Calcium hydroxide (1.48 g) was mixed with deionized water (1 g), 3,5,5- trimethylhexanoic acid (31.6 g), and heptane (50 g). The mixture was heated at 120 0 C under a stream of nitrogen in an oil bath for 20 minutes. At this temperature a previously made solution of phosphoric acid (1.34 g) and tri-n-octylamine (9.52 g) in methanol (3 g) prepared using a vortex mixer was added. Additional heptane (75 g) was added to the reaction flask. The reaction mixture was heated under stirring at 120 0 C under nitrogen atmosphere for 16 hours.
  • Calcium acetate monohydrate (3.52 g) was mixed with oleic acid (68.2 g) and heptane (50 g). The mixture was heated at 120 0 C under a stream of nitrogen in an oil bath for 20 minutes. At this temperature a solution of phosphoric acid (1.34 g) and tri-n- octylamine (9.52 g) in methanol (3 g) prepared using a vortex mixer was added.
  • Example 1 To obtain a dry powder of calcium phosphate nanoparticles modified by trimethylhexanoate groups a workup similar to that in Example 8 was followed.
  • Magnesium stearate (17.72 g) was mixed with stearic acid (22.45 g) and heptane (50 g). The mixture was heated at 120 0 C under a stream of nitrogen in an oil bath for 20 minutes. At this temperature a solution of phosphoric acid (2.1 g) and of tri-n-octylamine (14.83 g) in methanol (3 g) prepared using a vortex mixer was added. Additonal heptane (75 g) was added to the reaction flask. The reaction mixture was heated under stirring at 120 0 C under nitrogen atmosphere for 3 hours. The rest of the workup of the reaction was the same as Example 1. To obtain a dry powder of magnesium phosphate nanoparticles modified by stearate groups a workup similar to that in Example 8 was followed.
  • Zinc acetate dihydrate (1.10 g) dissolved in methanol (10 mL) was mixed with oleic acid (14.4 g) in hexane. The mixture was heated at 120 0 C under a stream of nitrogen in an oil bath. After 30 minutes a premixed solution of phosphoric acid (0.32 g) and tris- [2-(2-methoxy ethoxy)-ethyl] amine (3.2 g) were dissolved in methanol (4 g) and hexane (20 g) was added to the aforementioned reaction mixture and the heating was continued at 120 0 C for another 2 hrs. Zinc phosphate nanoparticles dispersed in hexane were obtained from this reaction mixture using a similar workup described in Example 1.
  • Reflection geometry X-ray diffraction data were collected using a BRUKER D8 Advance diffractometer (Bruker-AXS, Madison, Wisconsin, USA), copper IQ x radiation, and VANTEC detector registry of the scattered radiation.
  • the diffractometer was fitted with variable incident beam slits and fixed diffracted beam slits.
  • the survey scan was conducted in coupled continuous mode from 5 to 80 degrees (2 ⁇ ) using a 0.015 degree step size and 2 second dwell time.
  • X-ray generator settings of 40 kV and 40 mA were employed. Tested samples were first milled to produce a fine powder and applied as dry powders to specimen holders containing glass inserts.
  • X-ray diffraction patterns for Example 7 show that the materials shows broad peaks indicative of nanocrystalline nature of the material. The peaks are too broad to attribute to any crystalline calcium phosphate. The material is indeed X-ray amorphous.
  • PTFE polytetrafluoroethylene
  • Figs. 1 and 2 show the particle size distribution by volume for Examples 1, 2, 9-1 l(heptane) and 3, 5-7 (hexane) in dispersion.
  • the Z-average diameters for Example 1, 2 and 3 are 99nm, 76nm and 86nm respectively. Nearly all the particles have size less than lOOnm.
  • the Z-average sizes for the calcium phosphate nanoparticles functionalized with stearate groups is 33 nm, 16 nm and 44 nm respectively (see Examples 5-7).
  • Example 11 For Magnesium phosphate nanoparticles functionalized with stearate molecules Example 11 the Z-average size is 54nm. The Z-average diameter for the zinc phosphate nanoparticles surface modified with oleic acid (example 12) was found to be 91 nm (Fig. 4).
  • TEM Transmission Electron Microscopy
  • TEM images for Examples 3 and 5 shown in Figs. 4 and 5 respectively show that nearly all the nanoparticles are less than 20 nm in size with most of the nanoparticles sizes are between 3-5 nm.
  • the FTIR measurements were performed using a Thermo Nicolet Avatar 370 durascope instrument in the reflectance mode (64 scans and resolution at 8 cm “1 ).
  • the FTIR spectrum of the zinc phosphate nanoparticles shows characteristic peaks due to (PO 4 ) 3" at 1010 cm “1 , and peaks due to the C-H stretching (2921, 2851 cm “1 ), carboxylate anion (peaks at 1547, 1526 and 1455, 1396 cm “1 ) of oleic acid could be observed.

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Abstract

L'invention porte sur des compositions qui comportent des nanoparticules modifiées en surface d'au moins un phosphate métallique. Les nanoparticules portent, sur au moins une partie de leurs surfaces, une modification de surface comportant au moins un modificateur de surface organo-carboxylate qui comporte au moins une fraction organique comportant au moins environ six atomes de carbone. L'invention porte également sur des procédés de fabrication desdites compositions et d’articles qui en sont issus.
PCT/US2009/065131 2008-11-24 2009-11-19 Nanoparticules de phosphate métallique modifiées en surface Ceased WO2010059812A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN114451423A (zh) * 2021-12-27 2022-05-10 杭州同晨环保科技有限公司 一种边缘有机修饰的磷酸锆载铜抗菌剂及其制备方法
CN117534050A (zh) * 2023-12-25 2024-02-09 广东惠云钛业股份有限公司 一种粒径小且均匀的磷酸铁及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040242729A1 (en) * 2003-05-30 2004-12-02 3M Innovative Properties Company Stabilized particle dispersions containing surface-modified inorganic nanoparticles
WO2008033718A1 (fr) * 2006-09-15 2008-03-20 3M Innovative Properties Company Procede de modification de surface de nanoparticules
WO2009137592A2 (fr) * 2008-05-08 2009-11-12 3M Innovative Properties Company Nanoparticules modifiées en surface

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040242729A1 (en) * 2003-05-30 2004-12-02 3M Innovative Properties Company Stabilized particle dispersions containing surface-modified inorganic nanoparticles
WO2008033718A1 (fr) * 2006-09-15 2008-03-20 3M Innovative Properties Company Procede de modification de surface de nanoparticules
WO2009137592A2 (fr) * 2008-05-08 2009-11-12 3M Innovative Properties Company Nanoparticules modifiées en surface

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114451423A (zh) * 2021-12-27 2022-05-10 杭州同晨环保科技有限公司 一种边缘有机修饰的磷酸锆载铜抗菌剂及其制备方法
CN114451423B (zh) * 2021-12-27 2023-04-14 杭州同晨环保科技有限公司 一种边缘有机修饰的磷酸锆载铜抗菌剂
CN117534050A (zh) * 2023-12-25 2024-02-09 广东惠云钛业股份有限公司 一种粒径小且均匀的磷酸铁及其制备方法
CN117534050B (zh) * 2023-12-25 2024-04-30 广东惠云钛业股份有限公司 一种粒径小且均匀的磷酸铁及其制备方法

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