U.S. patent application number 12/989432 was filed with the patent office on 2011-02-17 for surface-modified nanoparticles.
This patent application is currently assigned to 3M Innovative Properties Company. Invention is credited to Neeraj Sharma, Choua C. Vu.
Application Number | 20110039947 12/989432 |
Document ID | / |
Family ID | 41137546 |
Filed Date | 2011-02-17 |
United States Patent
Application |
20110039947 |
Kind Code |
A1 |
Sharma; Neeraj ; et
al. |
February 17, 2011 |
SURFACE-MODIFIED NANOPARTICLES
Abstract
A composition comprises surface-modified nanoparticles of at
least one metal phosphate. The nanoparticles bear, on at least a
portion of their surfaces, a surface modification comprising at
least one organosilane surface modifier comprising at least one
organic moiety comprising at least about six carbon atoms.
Inventors: |
Sharma; Neeraj; (Woodbury,
MN) ; Vu; Choua C.; (Woodbury, MN) |
Correspondence
Address: |
3M INNOVATIVE PROPERTIES COMPANY
PO BOX 33427
ST. PAUL
MN
55133-3427
US
|
Assignee: |
3M Innovative Properties
Company
|
Family ID: |
41137546 |
Appl. No.: |
12/989432 |
Filed: |
May 6, 2009 |
PCT Filed: |
May 6, 2009 |
PCT NO: |
PCT/US09/43003 |
371 Date: |
October 25, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61051468 |
May 8, 2008 |
|
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61051477 |
May 8, 2008 |
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Current U.S.
Class: |
514/772 ;
428/402; 556/404; 977/773 |
Current CPC
Class: |
C01P 2004/84 20130101;
A61P 29/00 20180101; B82Y 30/00 20130101; Y10T 428/2982 20150115;
C09C 3/12 20130101; C01P 2004/64 20130101; A61K 47/02 20130101;
C01P 2006/22 20130101; A61P 11/06 20180101; A61K 9/0075 20130101;
C09C 1/02 20130101 |
Class at
Publication: |
514/772 ;
556/404; 428/402; 977/773 |
International
Class: |
A61K 47/06 20060101
A61K047/06; C07F 9/02 20060101 C07F009/02; B32B 5/00 20060101
B32B005/00 |
Claims
1. A composition comprising surface-modified nanoparticles of at
least one metal phosphate, said nanoparticles bearing, on at least
a portion of their surfaces, a surface modification comprising at
least one organosilane surface modifier comprising at least one
organic moiety comprising at least six carbon atoms.
2. The composition of claim 1, wherein the metal of said metal
phosphate is selected from transition metals, alkaline earth
metals, alkali metals, post-transition metals, and combinations
thereof
3. The composition of claim 1, wherein the metal of said metal
phosphate is divalent.
4. The composition of claim 1, wherein the metal of said metal
phosphate is selected from alkaline earth metals and combinations
thereof
5. The composition of claim 1, wherein the metal of said metal
phosphate is calcium.
6. The composition of claim 1, wherein said organosilane surface
modifier is derived from a precursor organosilane compound selected
from alkoxysilanes, halosilanes, acyloxysilanes, aminosilanes, and
combinations thereof
7. The composition of claim 1, wherein said organosilane surface
modifier comprises at least one organic moiety having from 6 to 24
carbon atoms.
8. The composition of claim 1, wherein said organosilane surface
modifier is derived from a precursor organosilane compound selected
from those represented by the following general Formula I:
(R).sub.4-ySi(X).sub.y (I) wherein y is an integer of 1 to 3; each
R is independently selected from hydrogen and organic moieties that
are linear, branched, alicyclic, aromatic, or a combination thereof
and that have from 6 to 24 carbon atoms, with the proviso that
carbon atoms in a cyclic moiety count only as half their number
toward the requisite minimum of 6 carbon atoms, and that optionally
further comprise at least one functional group selected from
heterocyclic, acryloxy, methacryloxy, cyano, isocyano, cyanato,
isocyanato, phosphino, amino, amido, vinyl, epoxy, glycidoxy,
alkyl, carbon-carbon triple bond-containing, mercapto, siloxy,
halocarbon, carbon-nitrogen double bond-containing, and
carbon-carbon double bond-containing groups, and combinations
thereof; with the proviso that at least one said R group is a said
organic moiety; and each X is independently selected from
hydrocarbyloxy, fluoroalkanesulfonate, and alkoxy groups having
from 1 to 8 carbon atoms, chlorine, bromine, iodine, acyloxy, amino
moieties --NR'R', wherein each R' is independently selected from
hydrogen and organic moieties having from 1 to 10 carbon atoms, and
combinations thereof.
9. The composition of claim 8, wherein said y is 2 or 3; wherein
said organic moiety of said R is linear, branched, or a combination
thereof wherein said organic moiety of said R has from 7 to 18
carbon atoms; and/or wherein at least one said X is independently
selected from alkoxy, acyloxy, chlorine, bromine, amino, and
combinations thereof
10. (canceled)
11. (canceled)
12. (canceled)
13. The composition of claim 1, wherein said organosilane surface
modifier is derived from a trialkoxysilane.
14. The composition of claim 1, wherein said surface-modified
nanoparticles have average primary particle diameters of 1 nm to 50
nm.
15. The composition of claim 1, wherein said surface-modified
nanoparticles comprise from 1 weight percent to 90 weight percent
of said surface modifier, based upon the total weight of said
surface-modified nanoparticles.
16. The composition of claim 1, wherein said surface-modified
nanoparticles are redispersible; and/or wherein said
surface-modified nanoparticles are substantially spherical.
17. (canceled)
18. A composition comprising surface-modified nanoparticles of
calcium phosphate, said nanoparticles bearing, on at least a
portion of their surfaces, a surface modification comprising at
least one alkoxysilane surface modifier comprising at least one
linear or branched organic moiety comprising at least seven carbon
atoms.
19. The composition of claim 18, wherein said surface-modified
nanoparticles are redispersible, substantially spherical, have
average primary particle diameters of 1 nm to 20 nm, and comprise
from 1 weight percent to 90 weight percent of said surface
modification, based upon the total weight of said surface-modified
nanoparticles.
20. The composition of claim 1, wherein said composition further
comprises at least one carrier material.
21. (canceled)
22. (canceled)
23. The composition of claim 20, wherein said composition is a
pharmaceutical formulation comprising a medicament.
24. The composition of claim 23, wherein said medicament is a
powder.
25. An article comprising the composition of claim 23.
26. An article comprising the composition of claim 24, wherein said
article is a dry powder inhaler.
Description
STATEMENT OF PRIORITY
[0001] This application claims the priorities of U.S. Provisional
Applications Nos. 61/051,468 and 61/051,477, both filed May 8,
2008, the contents of which are hereby incorporated by
reference.
FIELD
[0002] This invention relates to compositions comprising
surface-modified metal phosphate nanoparticles and, in another
aspect, to articles comprising the compositions.
BACKGROUND
[0003] Metal phosphates (for example, alkaline earth phosphates
such as magnesium phosphate and calcium phosphate) have numerous
applications. 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.
[0004] 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.
[0005] 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.sub.5(PO.sub.4).sub.3OH]), dicalcium phosphate (DCP;
[Ca(HPO.sub.4).2H.sub.2O]), tricalcium phosphate (TCP;
[Ca.sub.3(PO.sub.4).sub.2]), tetracalcium phosphate (TTCP,
[Ca.sub.4O(PO.sub.4).sub.2]), and amorphous calcium phosphate.
[0006] Of the biocompatible calcium phosphates, hydroxyapatite can
be more stable under physiological conditions. Thus, 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.
[0007] For some of these applications (for example, adjuvants for
vaccines, cores or carriers for biologically active molecules,
controlled release matrices, coating implant materials, protein
purification, and dental applications), 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.
[0008] Numerous methods have been used for the synthesis of
hydroxyapatite nanoparticles including chemical precipitation,
hydrothermal reactions, freeze drying, solgel 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.
[0009] Various additives have been used to control hydroxyapatite
particle growth and/or to alter hydroxyapatite particle morphology
but with only limited success. For example, polymers and solvent
combinations have been used in the above-described wet process to
suppress crystal growth along one axis, but only a few approaches
have provided particles with decreased aspect ratios or particles
of spherical morphology but relatively large particle size.
[0010] 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.
[0011] Generally the synthesis of spherical hydroxyapatite
nanoparticles has involved the use of either 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 powder (for example, dry powder
that can be redispersed in an appropriate solvent to provide a
non-agglomerated nanoparticle dispersion), however, has generally
not been evident.
SUMMARY
[0012] Thus, we recognize that there is a need for metal phosphate
nanoparticles (particularly, calcium phosphate nanoparticles) of
desired primary particle sizes and/or particle morphologies that
are surface-modified so as to be compatible with (and therefore
dispersible in) a variety of media (for example, solvents,
polymers, paints, coatings, cosmetic formulations, pharmaceutical
formulations, and the like). In particular, we recognize that there
is a need for very small nanoparticles (for example, having average
primary particle diameters of less than about 20 nm) that are
biocompatible and preferably of spherical morphology, which can be
effectively used in, for example, inhalable aerosol drug delivery
systems. In order to facilitate industrial use, such nanoparticles
preferably can be provided in the form of a redispersible
powder.
[0013] Briefly, in one aspect, this invention provides such a
composition, which comprises surface-modified nanoparticles of at
least one metal phosphate (most preferably, calcium phosphate). The
nanoparticles bear, on at least a portion of their surfaces, a
surface modification comprising at least one organosilane surface
modifier comprising at least one organic moiety comprising at least
about six carbon atoms. Preferably, the organic moiety has from
about 6 to about 24 carbon atoms.
[0014] It has been discovered that use of the above-described
relatively long-chain organosilane surface modifiers can enable the
preparation of substantially non-agglomerated metal phosphate
nanoparticles. The nanoparticles of the invention can be relatively
simply prepared from relatively inexpensive metal phosphate
precursors (for example, a metal cation source such as a metal
salt, and a phosphate anion source such as phosphoric acid) and can
be grown to preferred average primary particle sizes (for example,
average primary particle diameters of about 1 nm to about 50 nm).
By varying the nature of the organosilane surface modifier (for
example, the carbon chain length of its organic moiety and/or the
presence or absence of various functional groups) and/or its
amount, the surface characteristics of the nanoparticles can be
controllably tailored and their compatibility with a particular
medium can be enhanced.
[0015] Surprisingly, the use of relatively long-chain organosilane
surface modifier(s) can provide nanoparticles that are also
redispersible and preferably 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.
[0016] Thus, in at least preferred embodiments, the composition of
the invention can meet the above-mentioned need in the art for
redispersible metal phosphate nanoparticles (particularly, 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, a dispersion, and the
like).
[0017] In another aspect, this invention also provides an article
comprising the composition of the invention.
DETAILED DESCRIPTION
[0018] In the following detailed description, various sets of
numerical ranges (for example, of the number of carbon atoms in a
particular moiety, of the amount of a particular component, and the
like) are described, and, within each set, any lower limit of a
range can be paired with any upper limit of a range.
Definitions
[0019] As used in this patent application:
[0020] "agglomeration" means 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);
[0021] "nanoparticles" means particles having a diameter of less
than 100 nm;
[0022] "primary particle size or diameter" means the size or
diameter of a non-associated single nanoparticle;
[0023] "redispersible" (in regard to nanoparticles) means
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 nanoparticles in the
dispersion));
[0024] "sol" means a dispersion or suspension of colloidal
particles in a liquid phase; and "substantially spherical" (in
regard to nanoparticles) means at least a major portion of the
nanoparticles have an aspect ratio less than or equal to 2.0
(preferably, less than or equal to 1.5; more preferably, less than
or equal to 1.25; most preferably, 1.0).
Preparation of Surface-Modified Nanoparticles
[0025] The surface-modified metal phosphate nanoparticles of the
composition of the invention can be prepared by any of a variety of
known or hereafter developed particle surface modification methods.
Preferred preparative methods include those that can provide the
desired surface modification while maintaining or producing
substantially non-agglomerated nanoparticles. Preferred preparative
methods include in situ surface modification during nanoparticle
synthesis, post-synthesis surface modification, and combinations
thereof (more preferably, in situ methods).
[0026] For example, in post-synthesis surface modification,
starting metal phosphate nanoparticles can be prepared by
essentially any method that can provide nanosized particles (for a
range of applications, preferably, having average primary particle
diameters of 1 nanometer (nm) (more preferably, about 2 nm; most
preferably, about 3 nm) to about 50 nm (more preferably, about 30
nm; most preferably, 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 organosilane. Useful methods for
producing such starting metal phosphate nanoparticles include those
described, for example, in U.S. Patent Application Publication Nos.
2004/0170699 (Chane-ching et al), 2006/0257306 (Yamamoto et al.),
and 2007/0196509 (Riman et al); by Stouwdam et al. in "Improvement
in the Luminescence Properties and Processability of LaF.sub.3/Ln
and LaPO.sub.4/Ln Nanoparticles by Surface Modification," Langmuir
20, 11763 (2004); and by Mai et al in "Orderly Aligned and Highly
Luminescent Monodisperse Rare-Earth Orthophosphate Nanocrystals
Synthesized by a Limited Anion-Exchange Reaction," Chemistry of
Materials 19, 4514 (2007); the descriptions of which are
incorporated herein by reference.
[0027] The starting metal phosphate nanoparticles can then be
dispersed in a liquid medium (for example, alcohol, ether, or a
polar aprotic solvent) and optionally any water residues removed.
The organosilane surface modification agent can then be added to
the resulting dispersion (preferably, by mixing in an organic
solvent and/or water; optionally, a catalyst can be present to
facilitate hydrolysis of the organosilane) and the resulting
mixture heated under reflux to a temperature between room
temperature and the boiling point of the liquid medium (at
atmospheric pressure). Optionally, 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.
[0028] A preferred in situ 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 organosilane
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 organosilane (for example, to form surface-modified metal
phosphate nanoparticles).
[0029] Preferably, 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, and/or 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.
[0030] Use of the above-described metal phosphate precursors
including an organic base and a relatively long-chain organosilane
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.
[0031] Metal cation sources suitable for use in the preferred in
situ process 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 in situ, if desired (for example,
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 (including the lanthanides and the actinides
thorium and uranium), alkaline earth metals, alkali metals,
post-transition metals, and the like, and combinations thereof.
[0032] Preferred transition metals include titanium, vanadium,
chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium,
zirconium, niobium, molybdenum, ruthenium, cadmium, hafnium,
tantalum, tungsten, lanthanum, cerium, neodymium, samarium,
europium, gadolinium, terbium, dysprosium, erbium, ytterbium,
thorium, and combinations thereof (more preferably, titanium,
manganese, iron, cobalt, zinc, yttrium, zirconium, niobium,
tantalum, lanthanum, cerium, europium, gadolinium, terbium,
dysprosium, erbium, and combinations thereof; most preferably,
manganese, iron, zinc, yttrium, zirconium, niobium, tantalum,
lanthanum, cerium, europium, gadolinium, terbium, and combinations
thereof). Preferred post-transition metals include aluminum,
gallium, indium, tin, lead, antimony, bismuth, and combinations
thereof (more preferably, aluminum, gallium, tin, antimony,
bismuth, and combinations thereof; most preferably, aluminum).
[0033] Preferred alkaline earth metals include beryllium, calcium,
strontium, magnesium, barium, and combinations thereof (more
preferably, calcium, strontium, magnesium, barium, and combinations
thereof; even more preferably, calcium, magnesium, strontium, and
combinations thereof; most preferably, calcium). Preferred alkali
metals include lithium, sodium, potassium, rubidium, cesium, and
combinations thereof (more preferably, lithium, sodium, potassium,
and combinations thereof; most preferably, sodium, potassium, and
combinations thereof).
[0034] Preferably, the metal cation is a divalent metal cation
(more preferably, a divalent alkaline earth metal cation; even more
preferably, divalent calcium or magnesium; most preferably,
divalent calcium). Alkaline earth metals and combinations thereof
are preferred.
[0035] 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.
Preferred anions include halide, nitrate, sulfate, carbonate,
acetate, hydroxide, oxide, and combinations thereof (more
preferably, halide, nitrate, acetate, and combinations thereof;
most preferably, halide and combinations thereof).
[0036] Mixed metal salts, mixed anion salts, and/or mixtures of
salts can be utilized, if desired. The salts can comprise other
metal cations (for example, at levels up to about 10 mole percent,
based upon the total number of moles of metal cation), but
preferably all metals in the salts are selected from those
described above. Similarly, 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 preferably all anions in the
salts are selected from those described above.
[0037] Representative examples of 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 tetrahydrate,
manganese (II) bromide tetrahydrate, manganese (II) nitrate
tetrahydrate, manganese (II) acetate tetrahydrate, manganese (III)
acetylacetonate, europium (III) chloride hexahydrate, europium
(III) nitrate hexahydrate, europium (II) chloride, europium (III)
oxide, terbium (III) chloride hexahydrate, terbium (III) nitrate
hexahydrate, terbium (III,IV) oxide, and the like, and combinations
thereof. More preferred metal salts include those having anions
selected from halide, nitrate, acetate, and combinations thereof.
The halides are most preferred. Hydrated metal salts can be
preferred (for example, to facilitate hydrolysis of the
organosilane).
[0038] Such metal salts can be prepared by known methods. Many of
such salts are commercially available.
[0039] Phosphate anion sources suitable for use in the preferred in
situ process 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.sub.3PO.sub.4); phosphorous acid
(H.sub.3PO.sub.3); hypophosphorous acid (H.sub.3PO.sub.2);
thiophosphoric acid; phosphoric acid esters; thiophosphoric acid
esters (for example, diethylchlorothiophosphate,
diethyldithiophosphate, ethyldichlorothiophosphate,
trimethylthiophosphate, and the like); phosphite esters (for
example, dimethylphosphite, trimethylphosphite,
diisopropylphosphite, diethylhydrogenphosphite,
diisobutylphosphite, dioleylhydrogenphosphite,
diphenylhydrogenphosphite, triphenylphosphite,
ethylenechlorophosphite, tris(trimethylsilyl)phosphite, and the
like); thiophosphite esters (for example,
trilauryltrithiophosphite, triethyltrithiophosphite, and the like);
phosphate salts of alkali metal cations, ammonium cation, or
organoammonium cations; thiophosphate salts of alkali metal
cations, ammonium cation, or organoammonium cations (for example,
ammonium diethyldithiophosphate, potassium diethyldithiophosphate,
sodium dithiophosphatetrihydrate, and the like); phosphite salts of
alkali metal cations, ammonium cation, or organoammonium cations
(for example, disodium hydrogenphosphite pentahydrate and the
like); hypophosphite salts of alkali metal cations, ammonium
cation, or organoammonium cations (for example, sodium
hypophosphite hydrate, potassium hypophosphite, ammonium
hypophosphite, ethylpiperidiniumhypophosphite, tetrabutylammonium
hypophosphite, and the like); phosphorus oxides (for example,
P.sub.2O.sub.5 and the like); phosphorus halides and/or oxyhalides
(for example, POCl.sub.3, PCl.sub.5, PCl.sub.3, POBr.sub.3,
PBr.sub.5, PBr.sub.3, difluorophosphoric acid, fluorophosphoric
acid, and the like); phosphorus sulfides (for example,
P.sub.2S.sub.5, P.sub.2S.sub.3, P.sub.4S.sub.3, and the like);
phosphorus halosulfides (for example, PSCl.sub.3,,PSBr.sub.3, and
the like); polyphosphoric acid; polyphosphoric acid esters;
polyphosphate salts of alkali metal cations, ammonium cation, or
organoammonium cations; and the like; and combinations thereof.
[0040] Preferred phosphate anion sources include phosphoric acid,
phosphoric acid esters, organoammonium phosphate salts, and
combinations thereof (more preferably, phosphoric acid,
organoammonium phosphate salts, and combinations thereof; most
preferably, phosphoric acid).
[0041] Useful phosphoric acid esters include alkylphosphates, and
the like, and combinations thereof. Representative examples of
useful alkylphosphates include mono-, di-, and trialkylphosphates
comprising alkyl moieties having from one to about 12 carbon atoms
such as methylphosphate, ethylphosphate, propylphosphate,
butylphosphate, pentylphosphate, hexylphosphate, dimethylphosphate,
diethylphosphate, dipropylphosphate, dibutylphosphate,
dipentylphosphate, dihexylphosphate, di-2-ethylhexylphosphate,
methylethylphosphate, ethylbutylphosphate, ethylpropylphosphate,
trimethylphosphate, triethylphosphate, tripropylphosphate,
tributylphosphate, tripentylphosphate, trihexylphosphate,
tri-2-ethylhexylphosphate, ethyl dimethylphosphate, ethyl
dibutylphosphate, and the like, and combinations thereof. Also
useful are arylphosphates such as triphenylphosphate;
alkylphosphate salts such as ammonium dilaurylphosphate;
aminoethanoldihydrogenphosphate; and the like; and combinations
thereof.
[0042] Preferred phosphoric acid esters include mono-, di-, and
trialkylphosphates comprising alkyl moieties having from one to
about four carbon atoms (for example, methylphosphate,
ethylphosphate, propylphosphate, butylphosphate, dimethylphosphate,
diethylphosphate, dipropylphosphate, dibutylphosphate,
methylethylphosphate, ethylbutylphosphate, ethylpropylphosphate,
trimethylphosphate, triethylphosphate, tripropylphosphate,
tributylphosphate, ethyl dimethylphosphate, ethyl dibutylphosphate,
and combinations thereof). More preferred phosphoric acid esters
include mono- and dialkylphosphates comprising alkyl moieties
having one to about four carbon atoms (for example,
methylphosphate, ethylphosphate, propyl phosphate, butylphosphate,
dimethylphosphate, diethylphosphate, dipropylphosphate,
dibutylphosphate, methylethylphosphate, ethylbutylphosphate,
ethylpropylphosphate, and combinations thereof). Most preferred
phosphoric acid esters include monoalkylphosphates having from one
to about four carbon atoms (for example, methylphosphate,
ethylphosphate, propylphosphate, butylphosphate, and combinations
thereof).
[0043] Useful polyphosphoric acid esters include esters of di-,
tri-, tetra-, and pentaphosphoric acid and a monohydric alcohol
and/or polyhydric alcohol, and the like, 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-, tetra-, and penta-phosphoric
acids, tetraalkyl esters of di-, tri-, tetra-, and penta-phosphoric
acids, pentaalkyl esters of di-, tri-, tetra-, and penta-phosphoric
acids, hexaalkyl esters of di-, tri-, tetra-, and penta-phosphoric
acids, and the like, and combinations thereof. Preferred
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.
[0044] 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, and the like
(including hydroxylamine phosphate), and combinations thereof.
Representative examples of useful 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 the like,
and combinations thereof.
[0045] Representative examples of useful 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 hexafluorophosphate, tetramethylammonium
hexafluorophosphate, tetraethylammonium hexafluorophosphate,
tetrapropylammonium hexafluorophosphate, tetrabutylammonium
hexafluorophosphate, tetrahexylammonium hexafluorophosphate,
phenyltrimethylammonium hexafluorophosphate,
benzyltrimethylammonium hexafluorophosphate, and the like, and
combinations thereof.
[0046] Preferred 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 (more preferably, hexyltriethylammonium phosphate,
octyltriethylammonium phosphate, dodecyltrimethylammonium
phosphate, tetrahexylammonium dihydrogen phosphate,
di-2-ethylhexylammonium hexafluorophosphate, tetrahexylammonium
hexafluorophosphate, and combinations thereof most preferably,
octyltriethylammonium phosphate, di-2-ethylhexylammonium
hexafluorophosphate, and combinations thereof).
[0047] Preferred phosphate salts include organoammonium phosphates,
and combinations thereof (more preferably, mono-, di-, tri-, and
tetraalkylammonium phosphates, and combinations thereof most
preferably, tetraalkylammonium phosphates, and combinations
thereof). Most preferably, the preferred salts comprise at least
one organic moiety comprising at least about five carbon atoms.
[0048] Such 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.
[0049] Organic bases suitable for use in the preferred in situ
process include those organic amines and organoammonium hydroxides
that comprise at least one organic moiety comprising at least about
five carbon atoms (preferably, at least about six carbon atoms;
more preferably, at least about eight carbon atoms), and
combinations thereof (preferably, 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).
Preferably, the organic moiety comprises from about 6 to about 24
carbon atoms (more preferably, from about 6 to about 18 carbon
atoms; most preferably, from about 8 to about 12 carbon atoms).
Representative examples of 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, tri-n-heptylamine, trinonylamine, N,
N-didecylmethylamine, N, N-dimethylcyclohexylamine, N,
N-dimethyldodecylamine, N, N-dimethyloctylamine, and
tris(2-ethylhexyl)amine; arylamines such as diphenylstearylamine;
polyethylene glycol mono- and diamines; and the like; and
combinations thereof.
[0050] Preferred organic amines include hexylamine, octylamine,
decylamine, dodecylamine, hexadecylamine, dihexylamine,
di-n-octylamine, bis(2-ethylhexyl)amine, di-sec-octylamine,
di-n-decylamine, trihexylamine, trioctylamine, triisooctylamine,
trinonylamine, tridodecylamine, tris(4-methylcyclohexyl)amine,
tri-n-heptylamine, N, N-didecylmethylamine, N,
N-dimethylcyclohexylamine, N, N-dimethyldodecylamine, N,
N-dimethyloctylamine, tris(2-ethylhexyl)amine, and combinations
thereof (more preferably, hexylamine, octylamine, decylamine,
dodecylamine, dihexylamine, di-n-octylamine,
bis(2-ethylhexyl)amine, di-sec-octylamine, trihexylamine,
trioctylamine, triisooctylamine, tridodecylamine,
tri-n-heptylamine, N, N-dimethyloctylamine,
tris(2-ethylhexyl)amine, and combinations thereof; most preferably,
dihexylamine, di-n-octylamine, bis(2-ethylhexyl)amine,
di-sec-octylamine, trihexylamine, trioctylamine, triisooctylamine,
tris(2-ethylhexyl)amine, and combinations thereof).
[0051] Representative examples of suitable 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, tetrapentylammonium
hydroxide, methyltriethylammonium hydroxide, tetraoctadecylammonium
hydroxide, dimethyldiethylammonium hydroxide,
methyltripropylammonium hydroxide, tetradecyltrihexylammonium
hydroxide, ethyltrimethylammonium hydroxide,
tris(2-hydroxyethyl)methylammonium hydroxide, and the like, and
combinations thereof.
[0052] Preferred 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 (more preferably,
dodecyldimethylethylammonium hydroxide, cetyltrimethylammonium
hydroxide, tetradecylammonium hydroxide, tetrahexylammonium
hydroxide, tetraoctylammonium hydroxide, tetraoctadecylammonium
hydroxide, tetradecyltrihexylammonium hydroxide, and combinations
thereof; most preferably, dodecyldimethylethylammonium hydroxide,
cetyltrimethylammonium hydroxide, and combinations thereof).
[0053] 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.
[0054] The 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). A wide range of concentrations can be useful (for
example, from about 5 to about 90 weight percent in alkanol, based
upon the total weight of the solution).
[0055] In a preferred embodiment of the preferred in situ process,
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 organosilane, and used in
the form of the resulting solution. Polar organic solvents useful
for dissolving the organic base include acetone, diethylether,
alkanols (for example, methanol, ethanol, and isopropanol),
dimethylsulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran
(THF), ethyl acetate, and the like, and mixtures thereof, with
alkanols being preferred and methanol more preferred.
[0056] When the phosphate anion source is an organoammonium
phosphate or polyphosphate comprising at least one organic moiety
that comprises at least about five carbon atoms, 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.
[0057] Organosilanes suitable for use in the preferred in situ
process include those organosilanes that comprise at least one
organic moiety comprising at least about six carbon atoms
(preferably, at least about seven carbon atoms; more preferably, at
least about eight carbon atoms), and combinations thereof. 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 six (for example, a
phenyl ring counts as three carbon atoms rather than six and must
be supplemented by, for example, an attached propyl moiety).
Preferably, the organic moiety comprises from about 6 to about 24
carbon atoms (more preferably, from about 7 to about 18 carbon
atoms; even more preferably, from about 8 to about 12 carbon
atoms). Most preferably, the organic moiety has about 8 carbon
atoms (and is preferably branched). Preferably, the organosilane is
selected from alkoxysilanes, halosilanes, acyloxysilanes, and
aminosilanes (including primary, secondary, and tertiary amines),
and combinations thereof
[0058] A class of useful organosilanes can be represented by the
following general Formula I:
(R).sub.4-ySi(X).sub.y (I)
wherein y is an integer of 1 to 3 (preferably, 2 or 3; more
preferably, 3); each R is independently selected from hydrogen and
organic moieties that are linear, branched, alicyclic, aromatic, or
a combination thereof (preferably, linear or branched) and that
have from about 6 to about 24 carbon atoms (more preferably, from
about 7 to about 18 carbon atoms; even more preferably, from about
8 to about 12 carbon atoms; most preferably, about 8 carbon atoms),
with the proviso that carbon atoms in a cyclic moiety count only as
half their number toward the requisite minimum of 6 carbon atoms
(for example, a phenyl ring counts as three carbon atoms rather
than six and must be supplemented by, for example, an attached
propyl moiety), and that optionally further comprise at least one
functional group selected from heterocyclic, acryloxy,
methacryloxy, cyano, isocyano, cyanato, isocyanato, phosphino,
amino, amido, 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; with the proviso that at least one R group is an organic
moiety; and each X is independently selected from hydrocarbyloxy,
fluoroalkanesulfonate, and alkoxy groups having from 1 to about 8
carbon atoms (preferably, 1 to about 4 carbon atoms; more
preferably, 1 to about 2 carbon atoms; most preferably, 1 carbon
atom), chlorine, bromine, iodine, acyloxy, amino moieties --NR'R',
wherein each R' is independently selected from hydrogen and organic
moieties having from 1 to about 10 carbon atoms, and combinations
thereof Preferably, at least one X is independently selected from
alkoxy, acyloxy, chlorine, bromine, amino, and combinations thereof
(more preferably, alkoxy, acyloxy, chlorine, amino, and
combinations thereof; even more preferably, alkoxy, chlorine,
amino, and combinations thereof; most preferably, alkoxy and
combinations thereof). Preferably, at least one X is a hydrolyzable
moiety.
[0059] When a functional group-containing organosilane is utilized,
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. Representative examples of
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. Representative examples of carbon-carbon
double bond-containing functional groups include alkenyl,
cyclopentadienyl, styryl, phenyl, and the like, and combinations
thereof.
[0060] Representative examples of useful organosilanes include
phenyltrimethoxysilane; phenyltriethoxysilane;
phenylethyltrimethoxysilane; diphenyldimethoxysilane;
diphenyldiethoxysilane;
N-[3-(triethoxysilyl)propyl]-4,5-dihydroimidazole;
beta-trimethoxysilylethyl-2-pyridine;
N-phenylaminopropyltrimethoxysilane; (N,
N-diethyl-3-aminopropyl)trimethoxysilane; N,
N-didecyl-N-methyl-N-(3-trimethoxysilylpropyl)ammonium chloride;
3-(N-styrylmethyl-2-aminoethylamino)propyltrimethoxysilane;
methacryloxy-propenyltrimethoxysilane;
3-methacryloxypropyltrimethoxysilane;
3-methacryloxypropyltris(methoxyethoxy)silane;
3-cyclopentadienylpropyltriethoxysilane;
7-oct-1-enyltrimethoxysilane; 3-glycidoxypropyl-trimethoxysilane;
gamma-glycidoxypropylmethyldimethoxysilane;
gamma-glycidoxypropylmethyldiethoxysilane;
gamma-glycidoxypropyldimethylethoxysilane; n-octyltriethoxysilane;
n-octyltrimethoxysilane; isooctyltrimethoxysilane;
hexyltriethoxysilane;
3-triethoxysilyl-N-(1,3-dimethyl-butyliden)propylamine;
3-acryloxypropyltrimethoxysilane;
methacryloxypropylmethyldiethoxysilane;
methacryloxypropylmethyldimethoxysilane;
glycidoxypropylmethyldiethoxysilane; 2-(3,4
epoxycyclohexyl)-ethyltrimethoxysilane;
aminophenyltrimethoxysilane;
p-chloromethyl)phenyltri-n-propoxysilane; diphenylsilanediol;
epoxyhexyltriethoxysilane; dococentyltrimethoxysilane;
1,4-bis(trimethoxysilylethyl)benzene; trimethoxysilyl-1,3-dithiane;
n-trimethoxysilylpropylcarbamoylcaprolactam;
2-(diphenylphosphine)ethyltriethoxysilane; N,
N-dioctyl-n'-triethoxysilylpropylurea;
N-cyclohexylaminopropyltrimethoxysilane;
11-bromoundecyltrimethoxysilane; 1, 2-bis(trimethoxysilyl)decane;
bis[(3-methyldimethoxysilyl)propyl]polypropylene oxide;
[(bicycloheptenyl)ethyl]trimethoxysilane;
N-(6-aminohexyl)aminopropyltrimethoxysilane;
[2-(3-cyclohexenyl)ethyl]trimethoxysilane;
(3-cyclopentadienylpropyl)triethoxysilane;
3-(1,3-dimethylbutylidene)aminopropyltriethoxysilane;
polyethyleneglycoltrialkoxysilane; n-octadecyltrichlorosilane;
isooctyltrichlorsilane; 4-phenylbutyltrichlorosilane;
4-phenylbutylmethyldichlorosilane; n-dodecyltrichlorosilane;
di-n-octyldichlorosilane; n-decyltrichlorsilane;
n-decyldimethylchlorosilane; (cyclohexylmethyl)trichlorosilane;
tridodecylbromosilane; diphenylmethylbromosilane;
tert-butylmethoxyphenylbromosilane; trioctylbromosilane;
1,3-di-n-octyltetramethyldisilazane;
phenylmethylbis(dimethylamino)silane;
1,3-bis(4-biphenyl)tetramethyldisilazane;
1,3-dioctadecyltetramethyldisilazane;
1,3-divinyl-1,3-diphenyl-1,3-dimethyldisilazane; and the like; and
combinations thereof.
[0061] Preferred organosilanes include (N,
N-diethyl-3-aminopropyl)trimethoxysilane; N,
N-didecyl-N-methyl-N-(3-trimethoxysilylpropyl)ammonium chloride;
3-(N-styrylmethyl-2-aminoethylamino)propyltrimethoxysilane;
methacryloxy-propenyltrimethoxysilane;
3-methacryloxypropyltrimethoxysilane;
3-cyclopentadienylpropyltriethoxysilane;
7-oct-1-enyltrimethoxysilane; 3-glycidoxypropyl-trimethoxysilane;
gamma-glycidoxypropylmethyldiethoxysilane; n-octyltriethoxysilane;
n-octyltrimethoxysilane; isooctyltrimethoxysilane;
hexyltriethoxysilane; 3-acryloxypropyltrimethoxysilane;
methacryloxypropylmethyldimethoxysilane; 2-(3,4
epoxycyclohexyl)-ethyltrimethoxysilane;
p-chloromethyl)phenyltri-n-propoxysilane;
epoxyhexyltriethoxysilane; dococentyltrimethoxysilane;
N-cyclohexylaminopropyltrimethoxysilane;
polyethyleneglycoltrimethoxysilane; n-octadecyltrichlorosilane;
isooctyltrichlorsilane; 4-n-dodecyltrichlorosilane;
di-n-octyldichlorosilane; n-decyltrichlorsilane;
n-decyldimethylchlorosilane; (cyclohexylmethyl)trichlorosilane;
trioctylbromosilane; tridodecylbromosilane; 1,
3-di-n-octyltetramethyldisilazane;
dioctadecyltetramethyldisilazane; and combinations thereof.
[0062] More preferred organosilanes include (N,
N-didecyl-N-methyl-N-(3-trimethoxysilylpropyl)ammonium chloride;
3-methacryloxypropyltrimethoxysilane;
3-glycidoxypropyltrimethoxysilane;
gamma-glycidoxypropylmethyldiethoxysilane; n-octyltriethoxysilane;
n-octyltrimethoxysilane; isooctyltrimethoxysilane;
hexyltriethoxysilane; 3-acryloxypropyltrimethoxysilane; 2-(3,
4-epoxycyclohexyl)-ethyltrimethoxysilane;
epoxyhexyltriethoxysilane; N-cyclohexylaminopropyltrimethoxysilane;
polyethyleneglycoltrimethoxysilane; isooctyltrichlorosilane;
n-decyltrichlorosilane; (cyclohexylmethyl)trichlorosilane;
trioctylbromosilane; 1, 3-di-n-octyltetramethyldisilazane; and
combinations thereof
[0063] Most preferred organosilanes include
n-octyltrimethoxysilane; isooctyltrimethoxysilane;
hexyltriethoxysilane; polyethyleneglycoltrimethoxysilane; and
combinations thereof.
[0064] Such organosilanes can be prepared by known methods (for
example, from organosilane precursor compounds such as
corresponding halosilanes or hydrosilanes).
[0065] Many of such organosilanes (for example,
3-methacryloxypropyltrimethoxysilane;
3-glycidoxypropyltrimethoxysilane; n-octyltrimethoxysilane;
isooctyltrimethoxysilane; hexyltriethoxysilane;
3-acryloxypropyltrimethoxysilane; 2-(3,
4-epoxycyclohexyl)-ethyltrimethoxysilane;
N-cyclohexylaminopropyltrimethoxysilane;
polyethyleneglycoltrimethoxysilane; isooctyltrichlorosilane; and 1,
3-di-n-octyltetramethyldisilazane) are commercially available.
[0066] Solvents can be used in carrying out the preferred in situ
process, if desired. 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.
[0067] Useful solvents for dissolving or dispersing more polar
components such as the organic base and/or the phosphate anion
source include polar organic solvents (for example,
dimethylsulfoxide (DMSO), dimethylformamide (DMF), formamide,
acetonitrile, acetone, methylethylketone (MEK), alkanols (for
example, methanol, ethanol, isopropanol, 2-methoxyethanol,
1-methoxy-2-propanol, 1-methoxy-2-methyl-2-propanol, ethylene
glycol, and the like, and combinations thereof), N-methyl
pyrrolidinone (NMP), and the like, and combinations thereof.
Preferred polar organic solvents can include acetonitrile, acetone,
MEK, alkanols, and combinations thereof, due to their relatively
high polarities and relatively low boiling points. More preferred
polar organic solvents can include alkanols (most preferably,
methanol, ethanol, and combinations thereof), however, due to the
generally good solubility of reaction byproducts in these solvents
and the ease of solvent removal (along with the byproducts) during
purification.
[0068] Useful solvents for dissolving or dispersing less polar
components such as the long-chain organosilanes 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 the like,
and combinations thereof), as well as more polar solvents such as
esters (for example, ethyl acetate and the like, and combinations
thereof), ethers (for example, tetrahydrofuran (THF), diethylether,
and the like, and combinations thereof), and halocarbons (for
example, carbon tetrachloride and the like, and combinations
thereof), and the like, and combinations thereof. Preferred
non-polar organic solvents include hexane, heptane, octane,
toluene, and combinations thereof, due to their boiling points.
[0069] 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 organosilane 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.
[0070] The preferred in situ 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 organosilane comprising at least one organic moiety
comprising at least about six carbon atoms (preferably, in at least
one solvent). Generally, any order and manner of combination of the
four reaction mixture components can be utilized, although it can
sometimes be preferable 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.
[0071] Depending upon the specific chemical natures of the selected
components and the amount of water present, certain orders and
manners of combination can assist in minimizing agglomeration and
enabling the formation of nanoparticles. For example, 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 organosilane. These two
mixtures can then be combined.
[0072] 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. For
example, 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 valency of the metal. Preferably, 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).
[0073] The metal cation source (for example, a metal salt
comprising a metal cation and counteranion(s)) and the organic base
can be combined in generally stoichiometric amounts, based upon the
moles of basic groups and the moles of counteranion. For example,
these components can be combined in amounts such that the organic
base to metal molar ratio ranges from about 0.5 n/b to about 3.0
n/b, where n is the valency of the metal and b is the number of
basic groups per mole of organic base. Preferably, the molar ratio
ranges from about 0.6 n/b to about 2.0 n/b (more preferably, from
about 0.7 n/b to about 1.5 n/b).
[0074] The metal cation source and the organosilane 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 organosilane can be used in larger amounts, so as to function
as a reaction solvent.
[0075] Generally less than 100 percent of the combined organosilane
attaches (for example, physically or chemically) to the metal
phosphate nanoparticles to provide surface modification.
[0076] Mechanical agitation or stirring can be used, if desired, to
facilitate mixing. Optionally, heating can be used to facilitate
dissolution, reaction, and/or primary particle size growth. The
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).
[0077] To influence, for example, the morphology, magnetic
properties, conductivity, light absorption or emission
characteristics, and/or the crystallinity of the resulting
nanoparticles, various compounds (foreign ions) can be added
before, during, or after nanoparticle precipitation. Preferred
additive compounds include 2nd-5th main group and transition metal
compounds (more preferably, 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; most preferably, magnesium, strontium,
aluminum, tin, antimony, titanium, manganese, iron, zinc, yttrium,
zirconium, niobium, and tantalum compounds, and combinations
thereof) including lanthanide compounds (more preferably, europium,
terbium, dysprosium, samarium, erbium, praseodymium, and cerium
compounds, and combinations thereof; most preferably, cerium,
europium, terbium, and dysprosium compounds, and combinations
thereof). Such additive compounds preferably can be added to the
reaction mixture in dissolved form and/or preferably can be used in
an amount from about 0.01 to about 20 mole percent, based on the
total number of moles of metal (present, for example, in the form
of metal phosphate).
[0078] Other common additives (for example, dyes, pigments,
catalysts, and the like) can also be utilized. 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).
[0079] 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, diafiltration,
and the like, 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).
[0080] Upon solvent removal (for example, by rotary evaporation,
air or oven drying, centrifugation and decantation, a change in
solvent polarity followed by gravitational settling and
decantation, or the like), 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 organosilane). The resulting
nanoparticles can range in average primary particle diameter from
about 1 nm to about 50 nm or more (preferably, from about 1 nm to
about 30 nm; more preferably, from about 1 nm to about 20 nm; even
more preferably, from about 1 nm to about 15 nm; most preferably,
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.
[0081] 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 preferred in situ process can provide
substantially spherical nanoparticles (for example, substantially
spherical calcium phosphate nanoparticles useful in inhalable
aerosol drug delivery systems).
Composition and Articles Comprising the Surface-Modified
Nanoparticles
[0082] 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 organosilane surface modifier
comprising at least one organic moiety comprising at least about
six carbon atoms. Preferably, the organic moiety has from about 6
to about 24 carbon atoms (more preferably, from about 7 to about 18
carbon atoms; even more preferably, from about 8 to about 12 carbon
atoms; most preferably, about 8 carbon atoms (and is preferably
branched)).
[0083] The organosilane surface modifier can be derived from a
precursor organosilane compound and, when so derived, can comprise
the precursor organosilane compound or a residue thereof (that is,
a portion of the compound that remains after chemical reaction).
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). For example,
organosilane surface modifiers can be derived from alkoxysilanes
through hydrolysis of the alkoxysilane and formation of a
silicon-oxygen-metal or silicon-oxygen-phosphorus covalent
attachment to the metal phosphate nanoparticle. Preferably, the
organosilane surface modifier is derived from a precursor
organosilane compound selected from alkoxysilanes, halosilanes,
acyloxysilanes, aminosilanes (including primary, secondary, and
tertiary amines), and combinations thereof.
[0084] For use in at least some preferred applications, the
surface-modified nanoparticles preferably have average primary
particle diameters of 1 nm (more preferably, about 2 nm; most
preferably, about 3 nm) to about 20 nanometers (more preferably,
about 15 nm; most preferably, about 10 nm) and/or preferably
comprise from about 1 weight percent (more preferably, about 2
weight percent; most preferably, about 10 weight percent) to about
90 weight percent surface modifier (more preferably, about 70
weight percent; most preferably, about 50 weight percent), 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).
[0085] The 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). When the
composition is in the form of, for example, a dispersion of the
surface-modified nanoparticles in a liquid carrier, unreacted
and/or polymerized organosilane can also be present (and can be
removed, if desired, by various methods such as solvent washing
and/or dialysis).
[0086] 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.
[0087] Due to the biocompatibility of the surface modifier,
however, preferred uses for the surface-modified nanoparticles
(particularly, calcium phosphate) include use in dietary, cosmetic,
and pharmaceutical formulations. The nanoparticles can be used in
oral or dental care compositions and nutritional supplements. In
such cases, 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, emulsifiers, 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).
[0088] A particularly preferred use is in pharmaceutical
formulations comprising any of a variety of medicaments. For
example, 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.
[0089] The pharmaceutical formulations can further comprise one or
more excipients. Suitable excipients include those listed in the
Handbook of Pharmaceutical Excipients (Rowe, et al., APhA
Publications, 2003), which include 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).
[0090] 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. 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.
[0091] For example, 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. Preferably, the
nanoparticles are calcium phosphate nanoparticles, and the solvent
is heptane. In an alternative method, the surface-modified
nanoparticles and the powder(s) can be dry blended, if desired.
[0092] 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 organosilane 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 organosilane 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.
[0093] The surface modifiers can be described as comprising a
headgroup (a part that interacts primarily with the nanoparticle
surface) and a tailgroup (a part that interacts with the solvent).
Useful headgroups include those that comprise alkoxy, hydroxyl,
halo, thiol, silanol, amino, ammonium, phosphate, phosphonate,
phosphonic acid, phosphinate, phosphinic acid, phosphine oxide,
sulfate, sulfonate, sulfonic acid, sulfinate, carboxylate,
carboxylic acid, carbonate, boronate, stannate, hydroxamic acid,
and/or like moieties. Multiple headgroups can extend from the same
tailgroup, as in the case of 2-dodecylsuccinic acid and
(1-aminooctyl)phosphonic acid. Useful hydrophobic and/or
hydrophilic tailgroups include those that comprise single or
multiple alkyl, aryl, cycloalkyl, cycloalkenyl, haloalkyl,
oligo-ethylene glycol, oligo-ethyleneimine, dialkyl ether, dialkyl
thioether, aminoalkyl, and/or like moieties. Multiple tailgroups
can extend from the same headgroup, as in the case of
trioctylphosphine oxide.
[0094] 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. When a processing
solvent is hydrophobic, for example, 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; when the processing solvent is hydrophilic,
one skilled in the art can select from various hydrophilic surface
modifiers; and, when the solvent is a hydrofluorocarbon, one
skilled in the art can select from among various compatible surface
modifiers; and so forth. 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.
[0095] 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). For example, 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.
[0096] 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.
EXAMPLES
[0097] Objects and advantages of this invention are further
illustrated by the following examples, but the particular materials
and amounts thereof recited in these examples, as well as other
conditions and details, should not be construed to unduly limit
this invention.
[0098] These examples are merely for illustrative purposes only and
are not meant to be limiting on the scope of the appended
claims.
[0099] All parts, percentages, ratios, etc. in the examples and the
rest of the specification are by weight, unless noted otherwise.
Solvents and other reagents used were obtained from Sigma-Aldrich
Chemical Company, St. Louis, Mo., unless otherwise noted. All
chemicals and reagents were used without further purification
unless noted otherwise.
Materials
[0100] Calcium chloride hexahydrate (98 percent (%) purity),
manganese (II) chloride tetrahydrate (99.99% purity), crystalline
phosphoric acid (99% purity; Fluka), and methyltrimethoxysilane
(98% purity) were obtained from Sigma-Aldrich Chemical Company, St.
Louis, Mo.
[0101] Zinc chloride (anhydrous; 99.99% purity), europium (III)
chloride hexahydrate (99.9% purity), terbium (III) chloride
hexahydrate (99.9% purity), isobutyltrimethoxysilane (97% purity),
n-octyltrimethoxysilane (97% purity), and tri-n-octylamine (98%
purity) were purchased from Alfa Aesar, Ward Hill, Mass.
[0102] Isooctyltrimethoxysilane (greater than 95% purity) was
purchased from Gelest Inc., Morrisville, Pa.
[0103] n-Octadecyltrimethoxysilane (95% purity) was purchased from
TCI America, Portland, Oreg.
[0104] Magnesium chloride hexahydrate (99% purity) was purchased
from EM Science, Gibbstown, N.J.
[0105] Cobalt chloride hexahydrate (99.9% purity) was purchased
from Fisher Scientific, Fairlawn, N.J.
[0106] Methanol (ACS grade; BDH) and ethanol (200 proof; absolute)
were obtained from VWR, West Chester, Pa. and AAPER, Shelbyville,
Kent., respectively.
[0107] Heptane, xylenes, hexanes, and toluene were purchased from
EMD Chemicals, Gibbstown, N.J.
[0108] .alpha.-Lactose monohydrate (100% total lactose, 4% present
as .beta.-lactose) was purchased from Sigma-Aldrich, St. Louis,
Mo., and was then micronized to a final particle size (d50) of
approximately 1.5-2.0 micrometers at Micron Technologies in Exton,
Pa.
[0109] Budesonide was purchased from OnBio, Richmond Hill, Ontario,
Canada.
TEST METHODS
X-ray Diffraction (XRD)
[0110] Reflection geometry X-ray diffraction data were collected
using a Bruker.TM. D8 Advance diffractometer (Bruker-AXS, Madison,
Wisc., USA), copper K.sub..alpha. radiation, and Vantec.TM.
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 (20) 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.
Particle Size Determination in Dispersion
[0111] Particle size distribution was measured by Dynamic Light
Scattering (DLS) using a Malvern Instruments Zetasizer-NanoZS.TM.,
Model No. ZEN3600 particle size analyzer (available from Malvern
Instruments, Malvern, U.K.). 10 weight percent (% w/w) dispersions
of sample compositions were prepared in hexane for DLS
measurements. A small (50 mg) aliquot was taken from the dispersion
and diluted with 2.5 g of hexane.
[0112] The resulting diluted sample was mixed well and then
transferred to a glass cuvette. Light scattering data was recorded
with the sample temperature set at 25.degree. C. For all
measurements, the solvent (hexane) and the dispersions were
filtered using 0.2 micrometer (p) polytetrafluoroethylene (PTFE)
filter. For transforming autocorrelation function into particle
size, standard values for the viscosity (0.294.times.10.sup.-3Pa.s;
0.294 cp) and refractive index (1.375) of hexane and the viscosity
(0.39.times.10.sup.-3Pa.s; 0.39 cp) and refractive index (1.39) of
heptane at 25.degree. C. were used. Refractive index values of 1.63
for calcium phosphate, 1.51 for magnesium phosphate, 1.59 for zinc
phosphate, and 1.61 for cobalt phosphate were used. The reported
Z-average diameter (average agglomerated particle diameter, d, in
nm) was based upon an intensity weighted distribution. Particle
size distribution was also measured as a function of time in order
to study the stability of the dispersion and the agglomeration of
the particles by collecting the DLS data over a period of 18 hours
with a time delay of 2 hours between measurements. All results are
reported in terms of particle size, d (nm), and polydispersity
index (PdI).
Transmission Electron Microscopy (TEM)
[0113] Samples were prepared by placing a drop of a 2 weight
percent heptane or hexane colloidal suspension onto the carbon side
of a carbon grid sample holder (type 01801, from Ted Pella Inc.,
Redding Calif., USA). Excess solvent was wicked from the sample
holder, and the remaining slurry was air dried for 5 minutes before
use. The samples were examined in a JEOL.TM. JSM 200CX transmission
electron microscope (TEM) (JEOL, Tokyo, Japan) at 200 KV. Pictures
of the particulate material were imaged at 50 and 100 Kx and
Selected Area Diffraction (SAD) was used to determine crystal type
and size. Some dark field imaging was conducted to illuminate the
crystal phases and again determine crystal size. The images and SAD
patterns were captured and digitized for image analysis.
Pharamaceutical Performance
[0114] A small amount (nominally 2 mg) of powder was weighed into a
size three Shionogi Quali-V.TM. hydroxypropyl methylcellulose
capsule (Shionogi Qualicaps, Madrid, Spain) and loaded into an
Aerolizer.TM. device ("DPI" device, commercially available as a
Foradil.TM. Aerolizer.TM. product, available from Schering Plough
Co., Kenilworth, N.J.), which was tested for pharmaceutical
performance using a Next Generation Pharmaceutical Impactor ("NGI")
(MSP Corporation, Shoreview, Minn.). Samples of micronized lactose
and micronised budesonide powder were tested in addition to testing
samples of nanoparticle-modified lactose and nanoparticle-modified
budesonide powders. The NGI was coupled with a USP throat (United
States Pharmacopeia, USP 24 <601>Aerosols, Metered Dose
Inhalers, and Dry Powder Inhalers) and operated at a volumetric
flow rate of 60 liters per minute (lpm) for a collection time of
four seconds. A suitable coupler was affixed to the USP throat to
provide an air-tight seal between the DPI device and the throat.
For all testing, the stage cups of the NGI were coated with a
surfactant to prevent particle bounce and re-entrainment.
[0115] The amount of lactose or budesonide collected on each
component of the NGI testing apparatus was determined by rinsing
the component with a measured volume of an appropriate solvent and
subjecting the rinsed material to high pressure liquid
chromatography (HPLC) analysis with charged aerosol detection to
determine lactose or budesonide concentration. Data that was
returned from HPLC analysis was analyzed to determine the average
amount of drug collected on the DPI and capsule, the USP throat,
and on each component of the NGI per delivered dose.
[0116] Using the individual component values, the respirable
fraction and delivery efficiency were calculated for each powder
sample. Respirable mass is defined as the percentage of the total
delivered dose that is measured to be smaller than the respirable
limit of 4.5 micrometers in aerodynamic diameter. Respirable
fraction is defined as the percentage of a delivered dose that
reaches the entry of the throat and is smaller than the respirable
limit. Delivery efficiency is defined as the respirable mass
divided by the total delivered dose. When using the NGI, respirable
mass is collected in cups 3, 4, 5, 6, and 7, and on the filter.
Mass collected in the throat and cups 1 and 2 are considered
non-respirable.
Examples 1-16 and Comparative Examples C1-C3
Surface-Modified Nanoparticles
[0117] In a 3-neck round bottom reaction flask connected to a
condenser via a Dean-Stark receiver, Component Mixture 1 was mixed
with Component Mixture 2 as specified in Table 1 below, and the
resulting reaction mixture was stirred at Reaction Condition A of
Table 1 in a stream of nitrogen until one cloudy and one clear
layer were observed in the reaction flask. At this temperature,
Component Mixture 3 was added as specified in Table 1. The reaction
mixture was then maintained under Reaction Condition 2 as indicated
in Table 1. To the warm reaction mixture was added a four-fold
excess of methanol (by volume) leading to the precipitation of
white solid. Centrifugation of the mixture, followed by subsequent
washes of the solid with ethanol, provided clean powder of metal
phosphate. The powder was dried in an oven (200.degree. C.) for 15
minutes to give dried metal phosphate powder. The redispersibility
characteristics of the dried powder were determined, as shown in
Table 1. The dried powder was further characterized by XRD, DLS,
and TEM as appropriate, and the results are reported in Table
1.
[0118] Generally, the dried powder was easily redispersed in
solvents such as toluene, xylene, hexane, and heptane at ambient
temperature to yield optically clear and stable dispersions. In
many cases, the dried powder was stored in a vial for several
months and then redispersed in the above solvents to yield
optically clear and stable dispersions.
[0119] In Example 1, the redispersibility characteristics were
somewhat different. To the warm reaction mixture of Example 1 was
added 160 g of methanol, and the mixture was centrifuged at 3500
rpm (revolutions per minute) for 10 minutes. The resulting
supernatant was discarded, another 160 g of methanol was added to
the resulting gel-like precipitate, and the resulting mixture was
centrifuged again. 35 g of hexane was added to precipitate that was
isolated by removing the resulting supernatant, and the resulting
mixture was centrifuged to remove any residues which settled at the
bottom. The resulting supernatant was washed with 320 g methanol
and 160 g ethanol. The solvent was removed using a rotary
evaporator to provide a sticky gel, which on drying yielded a
glassy solid. This glassy solid could not be redispersed to give a
stable dispersion in heptane, hexane, or xylene, but the sticky gel
was redispersed in heptane, hexane, and xylene to give optically
clear and stable dispersions.
[0120] For Examples 14 and 15, the resulting dried powders were
stored for 8 weeks, dispersions of each were prepared, and the
particle size distributions of each were then measured by DLS as a
function of time. The resulting data (reported in Table 2) showed
essentially no change in Z-average particle diameter with
progression of time and, when averaged, showed the mean average
particle sizes reported in Table 3. This data indicated that there
had been essentially no loss of redispersibility upon storage.
TABLE-US-00001 TABLE 1 Example Reaction No. Component Mixture 1
Component Mixture 2 Condition A Component Mixture 3 C1 Calcium
Chloride Tri-n-octylamine (7.6 g) 130.degree. C. for Phosphoric
acid (2 g) & Hexahydrate (4.4 g) 20 Tri-n-octylamine (7 g) in
minutes methyl alcohol (2 g) C2 Calcium Chloride
Methyltrimethoxysilane 130.degree. C. Phosphoric acid (1.8 g) &
Hexahydrate (4 g) (7.45 g) until one Tri-n-octylamine (12.9 g)
cloudy in methyl alcohol (6 g) and one clear layer observed C3
Calcium Chloride Isobutyltrimethoxysilane 130.degree. C. Phosphoric
acid (2 g) & Hexahydrate (4.4 g) (12.5 g) until one
Tri-n-octylamine (14.2 g) cloudy in methyl alcohol (g) and one
clear layer observed 1 Calcium Chloride n-Octyltrimethoxysilane
130.degree. C. Phosphoric acid 1.8 g) & Hexahydrate (4 g) (12.8
g) until one Tri-n-octylamine (12.9 g) cloudy in methyl alcohol (6
g) and one clear layer observed 2 Calcium Chloride
Isooctyltrimethoxysilane 130.degree. C. Phosphoric acid (8.8 g)
& Hexahydrate (19.7 g) (50 g) until one Tri-n-octylamine (63.6
g) cloudy in and one Isooctyltrimethoxysilane clear layer (50 g)
observed 3 Calcium Chloride Isooctyltrimethoxysilane 130.degree. C.
Phosphoric acid (6.2 g) & Hexahydrate (13.8 g) (35 g) until one
Tri-n-octylamine (44.6 g) cloudy in and one
Isooctyltrimethoxysilane clear layer (35 g) observed 4 Calcium
Chloride Isooctyltrimethoxysilane 130.degree. C. Phosphoric acid
(1.8 g) & Hexahydrate (4 g) (10.2 g) until one Tri-n-octylamine
(12.9 g) cloudy in and one Isooctyltrimethoxysilane clear layer
(10.2 g) observed 5 Calcium Chloride Isooctyltrimethoxysilane
130.degree. C. Phosphoric acid (1.2 g) & Hexahydrate (4 g)
(10.1 g) until one Tri-n-octylamine (12.9 g) cloudy in and one
Isooctyltrimethoxysilane clear layer (10.1 g) observed 6 Calcium
Chloride Isooctyltrimethoxysilane 130.degree. C. Phosphoric acid
(1.8 g) & Hexahydrate (4 g) (10.2 g) until one Tri-n-octylamine
(12.9 g) cloudy in methyl alcohol (2 g) and one clear layer
observed 7 Calcium Chloride Isooctyltrimethoxysilane 130.degree. C.
Phosphoric acid (2 g), Tri- Hexahydrate (4.4 g) (14 g) until one
n-butyl amine (2 g) & Tri- cloudy n-octylamine (10.4 g) in and
one methyl alcohol (5 g) clear layer observed 8
Isooctyltrimethoxysilane Phosphoric acid (1.8 g) & 110.degree.
C. for Calcium Chloride (12.8 g) Tri-n-octylamine (12.9 g) 10
Hexahydrate (4 g) minutes 9 Calcium Chloride
Octadecyltrimethoxysilane 130.degree. C. Phosphoric acid (0.9 g),
Hexahydrate (2.5 g) (8.2 g) until one Tri-n-octylamine (6.5 g)
& cloudy n- and one Octadecyltrimethoxysilane clear layer (8.2
g) observed 10 Magnesium Chloride Isooctyltrimethoxysilane
130.degree. C. Phosphoric acid (1.8 g) & Hexahydrate (3.7 g)
(10.1 g) until one Tri-n-octylamine (12.9) in cloudy
Isooctyltrimethoxysilane and one (10.1 g). clear layer observed 11
Calcium Chloride Isooctyltrimethoxysilane 130.degree. C. Phosphoric
acid (1.8 g) & Hexahydrate (3.8 g) and (10.8 g) until one
Tri-n-octylamine (12.9 g) EuCl.sub.3.cndot.6H.sub.2O (0.33 g)
cloudy in and one Isooctyltrimethoxysilane clear layer (10.8 g)
observed 12 Calcium Chloride Isooctyltrimethoxysilane 130.degree.
C. Phosphoric acid (1.8 g) & Hexahydrate (3.8 g) and (10.2 g)
until one Tri-n-octylamine (12.9) in TbCl.sub.3.cndot.6H.sub.2O
(0.34 g) cloudy Isooctyltrimethoxysilane and one (10.2 g). clear
layer observed 13 Zinc Chloride (2.7 g) in Isooctyltrimethoxysilane
130.degree. C. Phosphoric acid (1.9 g) & water (2.2 g) (14 g)
until one Tri-n-octylamine (14.1 g) cloudy in methyl alcohol (2 g)
and one clear layer observed 14 Cobalt (II) Chloride
Isooctyltrimethoxysilane 130.degree. C. Phosphoric acid (1.9 g)
& (4.7 g) (14 g) until one Tri-n-octylamine (14.1 g) cloudy in
methyl alcohol (2 g) and one clear layer observed 15 Zinc Chloride
(4.9 g) Isooctyltrimethoxysilane 130.degree. C. Phosphoric acid
(3.9 g) & and Manganese (II) (28.1 g) until one
Tri-n-octylamine (28.2 g) Chloride (0.79 g) in cloudy in methyl
alcohol (5 g) water (4 g) and one clear layer observed 16 Calcium
Chloride Isooctyltrimethoxysilane 120.degree. C. Phosphoric acid
(9.0 g) & Hexahydrate (20 g) (64.2 g) until one
Tri-n-octylamine (64.6 g) cloudy in methyl alcohol (16 g) and one
clear layer observed Example Reaction d No. Condition B (nm) PdI
XRD TEM Redispersibility C1 Added No redispersion heptane (35 g);
110.degree. C. for 2 hours C2 Added No redispersion heptane (35 g);
100.degree. C. for 0.5 hour C3 Added Broad Redispersible heptane
peaks; but unstable (30 g); nanosized 110.degree. C. for material
15 minutes 1 Added 40.84 0.259 Redisperible heptane from gel only
(2 (35 g); months) prior to 110.degree. C. for complete drying 2.5
hours 2 110.degree. C. for 21.93 0.218 Broad Redispersible 3 hours
peaks; even after nanosized storage as material powder for 5 months
3 110.degree. C. for 27.43 0.25 Broad Unagglomerated; Redispersible
3 hours peaks; primary particle even after nanosized size 2-10 nm
storage as material powder for 5 months 4 110.degree. C. for 38.69
0.085 Broad Unagglomerated; Redispersible 3 hours peaks; primary
particle even after nanosized size 2-8 nm storage as material
(average = 4.7 nm powder for 3 based on 89 months particles) 5
110.degree. C. for 61.31 0.104 Redispersible 2 hours even after
storage as powder for 3 months 6 Added 47.66 0.453 -- Redispersible
heptane even after (33 g); storage as 110.degree. C. for powder for
3 15 hours months 7 Added 23.79 0.448 Broad Redispersible heptane
peaks; even after (20 g); nanosized storage as 110.degree. C. for
material powder for 2 2 hours weeks 8 Added n- -- -- Broad
Redispersible octane (50 g); peaks; even after 110.degree. C.
nanosized storage as for 15 material powder for 3 hours weeks 9
Added -- -- Redispersible heptane even after (26.6 g); storage as
110.degree. C. for powder for 2 hours 3 months 10 110.degree. C.
for 92.59 0.15 Broad Unagglomerated; Redispersible 2 hours peaks;
primary particle even after nanosized size 2-15 nm storage as
material powder for 3 months 11 110.degree. C. for 31.9 0.328 Broad
Redispersible 2 hours peaks; even after nanosized storage as
material powder for 3 months 12 110.degree. C. for 69.29 0.176
Broad -- Redispersible 2 hours peaks; even after nanosized storage
as material powder for 3 months 13 Added 57.82 0.403 Broad
Unagglomerated; Redispersible heptane peaks; primary particle even
after (75 g); nanosized size 2-10 nm storage as 110.degree. C. for
material powder for 2 2 hours months 14 Added 36.55 0.398 Broad
Unagglomerated; Redispersible heptane peaks; primary particle even
after (75 g); nanosized size 2-10 nm storage for 2 110.degree. C.
for material months as 2 hours powder 15 Added 75.87 0.186 Broad
Redispersible heptane peaks; even after (75 g); nanosized storage
for 2 110.degree. C. for material months as 2 hours powder 16 Added
-- -- Broad Redispersible heptane peaks; even after (140 g);
nanosized storage for 2 110.degree. C. for material months as 1.5
hours powder
TABLE-US-00002 TABLE 2 Example Example Example Example Time 14 14
15 15 (hours) d (nm) PdI d (nm) PdI 0 34.45 0.309 62.62 0.214 2
34.35 0.297 58.51 0.175 4 33.96 0.297 59.23 0.171 6 34.31 0.304
59.08 0.199 8 34.49 0.303 59.85 0.213 10 34.35 0.302 59.56 0.207 12
34.53 0.290 60.62 0.211 14 34.42 0.299 59.37 0.198 16 34.31 0.300
58.66 0.187 18 34.64 0.303 59.85 0.199
TABLE-US-00003 TABLE 3 Example Mean d Standard Mean Standard No.
(nm) Deviation PdI Deviation 14 34.38 0.1817 0.301 0.005 15 59.74
1.187 0.197 0.015
Examples 17-19 and Comparative Examples C4 and C5
Pharmaceutical Compositions Comprising Surface-Modified
Nanoparticles
Example 17 and Comparative Example C4
[0121] A stock dispersion of the surface-modified calcium phosphate
nanoparticles of Example 2 above (5 nm nominal size,
isooctyltrimethoxysilane surface-modified) with a concentration of
0.002 g/mL was prepared by adding the surface-modified
nanoparticles (1.0 g) to a 500 mL volumetric flask and filling the
remainder of the volume with heptane. A stir bar was placed in the
flask, and the mixture was stirred on a stir plate until the
nanoparticles became fully dispersed based on visual
appearance.
[0122] Micronized lactose powder (10.0 g) and the stock
nanoparticle dispersion (approximately 220 mL) were added to a
round bottom flask (1.0 L). The flask was sealed with a rubber
stopper, and the mixture was deagglomerated by sonication and hand
swirling for approximately 3 to 5 minutes and until no agglomerated
material could be seen sticking on the sides of the flask. The
flask was then placed on a rotary evaporator to remove the solvent.
The rotary evaporator was set to a nominal temperature of
50.degree. C. and operated under vacuum. After removal of
essentially all of the solvent, the remaining powder was caked on
the flask sides. The flask was then placed in a vacuum oven
(508-635 torr) at 45.degree. C. for approximately 1 hour to further
remove any residual solvent. A stiff bristle brush was used to
remove the caked powder from the walls of the flask, and the powder
was subsequently forced through a 400 mesh sieve to break up the
caked material. The sieved material was then collected and placed
in a container for later use. The resulting nanoparticle-modified
lactose powder composition had a nominal concentration of
surface-modified nanoparticles of 4 weight percent. The respirable
fractions and delivery efficiencies of the lactose powder
(Comparative Example C4) and the nanoparticle-modified lactose
powder (Example 17) were measured by the above procedure, and the
results are set forth in Table 5 below.
Example 18 and Comparative Example C4
[0123] Another blend of lactose with 4 weight percent
isooctyltrimethoxysilane surface-modified calcium phosphate
nanoparticles was prepared essentially as described above, except
that the surface-modified nanoparticles of Example 3 above were
utilized. The respirable fractions and delivery efficiencies of the
lactose powder (Comparative Example C4) and the
nanoparticle-modified lactose powder (Example 18) were measured by
the above procedure, and the results are set forth in Table 5
below.
Example 19 and Comparative Example C5
[0124] A series of budesonide powders with varying surface-modified
nanoparticle content, ranging from nominal concentrations of 0.5 to
2.0 weight percent, were prepared. A stock dispersion of
surface-modified nanoparticles (5 nm nominal size,
isooctyltrimethoxysilane surface-modified) was prepared by adding
the surface-modified calcium phosphate nanoparticles of Example 16
above to a volumetric flask and filling the remainder of the volume
with heptane. The powder blending parameters are summarized in
Table 4 below.
[0125] Micronized budesonide powder, heptane, and the stock
nanoparticle dispersion were added to a round bottom flask (0.25
L). A small amount of heptane was used to rinse the graduated
cylinder used to measure the stock nanoparticle dispersion and to
provide a quantitative transfer of nanoparticles to the round
bottom flask. The flask was sealed with a glass stopper, and the
mixture was deagglomerated by sonication and hand swirling for
approximately 3 to 5 minutes and until no agglomerated material
could be seen sticking on the sides of the flask. The flask was
then placed on a rotary evaporator to remove the solvent. The
rotary evaporator was set to a nominal temperature of 60.degree. C.
and operated under vacuum. After removal of essentially all of the
solvent, the remaining powder was caked on the flask sides. The
flask was then placed in a drying oven for approximately one hour
to further remove any residual solvent. After cooling to room
temperature, the flask containing the dry powder was sonicated to
break up the caked material. The powder was subsequently forced
through a 60 mesh sieve to further break up the caked material. The
sieved material was then collected and placed in a container for
later use. The respirable fractions and delivery efficiencies of
the budesonide powder (Comparative Example C5) and the
nanoparticle-modified budesonide powder (Example 19) were measured
by the above procedure, and the results are set forth in Table 5
below.
TABLE-US-00004 TABLE 4 Example 19A: Example 19B: Example 19C:
Budesonide/0.5% Budesonide/1.0% Budesonide/2.0% Blending Calcium
Phosphate Calcium Phosphate Calcium Phosphate Parameter Blend Blend
Blend Mass of budesonide 3.98 3.96 2.94 powder (g) Volume of
heptane 120 120 50 (mL) Concentration of stock 0.005 0.005 0.001
nanoparticle dispersion (1 gram powder (1 gram powder (0.10 gram
(g/mL) in 200 mL in 200 mL in 100 mL heptane) heptane) heptane)
Volume of stock 4 8 60 nanoparticle dispersion added to budesonide
powder (mL) Total volume of 124 128 110 heptane [from stock
nanoparticle dispersion + additional heptane] (mL) Oven 120 120 85
temperature (.degree. F.)
TABLE-US-00005 TABLE 5 Example No. % Respirable Fraction % Delivery
Efficiency C4 63 34 17 71 62 18 78 70 C5 55 34 19A 84 68 19B 86 68
19C 82 70
[0126] The referenced descriptions contained in the patents, patent
documents, and publications cited herein are incorporated by
reference in their entirety as if each were individually
incorporated. Various unforeseeable modifications and alterations
to this invention will become apparent to those skilled in the art
without departing from the scope and spirit of this invention. It
should be understood that this invention is not intended to be
unduly limited by the illustrative embodiments and examples set
forth herein and that such examples and embodiments are presented
by way of example only, with the scope of the invention intended to
be limited only by the claims set forth herein as follows:
* * * * *