MICELLE-COATED CRYSTALLINE PARTICLES
The present invention relates to crystalline particles [particularly organic particles or
agrochemical particles] coated with micelles of copolymers, to compositions comprising
such particles, to a process for preparing the coated particles and to uses of the particles and
the compositions [for example to produce surface coatings with high loadings of copolymer
and uses of products derived therefrom].
Effective coating of small particles such as organic crystals with a polymer is difficult to
achieve. Many techniques have been applied to coat particles, such as those based on
Wurster coating technologies for spray dry coatings wherein a fluidised bed of dry particles
has a coating solution sprayed onto the fluidised bed and solidified on the particles by either
evaporation of a volatile solvent in the coating solution or cooling to set the coating polymer
(if applied in molten form). Such techniques are notoriously variable, in that it is difficult to
avoid agglomeration of the particles into larger masses and the coating can be extremely
ineffective in coating all surfaces and edges of a particle (especially a small crystalline
particle with variable edges and sides of crystal). This limitation can be partially overcome
by employing higher quantities of coating composition but this can significantly alter the
properties of the organic particle being coated as well as having an impact on the economics
of the process and product cost.
Coating of particles in a liquid medium is highly attractive if a technique could be
identified. Work with dispersions of organic pesticides in water (WO2006/015791) in the
presence of reactive monomers produced "coated" particles as dispersions in water but these
are matrix particles where the particle is engulfed in a polymer during the polymerisation
process. Many similar techniques produce such matrix particles.
Surfactants are recognised to adsorb uniquely to interfaces such as oil/water interfaces and
solid/liquid interfaces and are employed as stabilisers to produce dispersions of particles in a
liquid medium (such as water) that remain stable to agglomeration on storage. Because of
this property of adsorbing as a monomolecular layer at an interface, surfactants in the form
of polyelectrolytes have been employed to produce layers of surfactant on a substrate such as
a solid particle. Such processes (for example, as in WO2000/077281) are slow to build up
oppositely charged single layers of polyelectrolyte (each layer being only the thickness of a
surfactant monolayer and many layers being required to build up a coating thickness of
utility). Surfactants can also aggregate into structures containing many surfactant molecules
in a single aggregate. These aggregates are called micelles. They are commonly spherical in
shape but can have a large range of shapes and structures. The number of molecules that
compose such an aggregate can be very many, often in the order of hundreds of molecules.
Micelles can be composed of relatively simple surfactant structures but can also be
composed of high molecular weight block-copolymer surfactants. Moreover, even large
complex block copolymers can form micelles. Such block copolymer micelles, when
comprised of oppositely charged micelles, have been induced to adsorb in a layer by layer
(LbL) manner onto spherical colloidal particles to produce coatings on particles such as a
latex or a spherical silica particle (NSTI-Nanotech 2007, www.nsti.org, ISBN 1420061836
Vol. 2, 2007 ppl3-16 and Adv. Mater. 2007, 19, 247-250).
We have now unexpectedly and surprisingly found that the use of complex copolymer
micelles as coating agents for crystalline particles produces surface coatings with high
loadings of copolymer in a single treatment (or very few treatments) and such products find
utility in a range of applications, particularly the agrochemical field.
In one aspect, the present invention provides a crystalline particle coated with micelles
which themselves comprise a copolymer (preferably an AB block copolymer).
WO08071957 and WO10038046 describe the chemistry of AB block copolymers that can
form micelle structures and can be employed to surface coat structures such as fabrics,
concrete structures, glass windscreens, glass structures to render them "stay-clean" by a
combination of dust- repellence and water- sheeting effects. Such structures are large (in
colloid terms). AB block copolymers mentioned in WO08071957 and WO10038046 are
suitable for use in the present invention but other AB block copolymers are also of relevance
for the present invention.
A coated crystalline particle according to the present invention may be prepared from a
coating system derived from:
(a) an AB block copolymer; and
(b) a liquid medium;
where the AB block copolymer comprises:
(i) a hydrophobic [ or substantially hydrophobic] block A; and
(ii) a hydrophobic [or substantially hydrophobic] or hydrophilic block B which has a
different affinity for, or solubility parameter in, the liquid medium to that of the block
A; where this difference between the two blocks leads to the formation of micelles.
The key difference between block A and block B is that the two blocks have different
affinities for, or solubilities in, the liquid; indeed block A and block B may even belong to
the same chemical type, provided that they are sufficiently chemically different [for example,
by virtue of different substitution patterns] such that they have different affinities for, or
solubilities in, the liquid.
The liquid medium comprises either :
(i) water; or
(ii) an organic solvent or mixture of organic solvents; or
(iii) an organic solvent free from [or substantially free from] water; or
(iv) an organic solvent and water.
The term "organic solvent" means an organic polar or apolar solvent (for example, an oil).
The liquid medium further optionally comprises one or more additives (selected from, for
example, pH modifiers, surfactants and wetting agents).
Therefore, the present invention relies upon an AB block copolymer comprising two
blocks (A and B) which have different affinities for a liquid medium such that micelles form
in the liquid medium.
Although the micelles are formed in a liquid medium, any eventual coated particles may
be present not only in not only a liquid composition but alternatively in a dry, solid
composition [for instance, due to an evaporation step or a drying step]; in one aspect the
present invention provides a composition comprising a plurality of coated crystalline
particles as described herein, where in one aspect the composition is a solid composition and
in an alternative aspect it comprises particles dispersed in a liquid [where the liquid may
comprise water or may be non-aqueous].
A preferred AB block copolymer comprises:
(i) a first hydrophobic block A, comprising a polymer selected from the group consisting
of a homopolymer of an acrylate or alkylacrylate (preferably an acrylate or Ci_4 alkylacrylate;
more preferably an acrylate or methacrylate) monomer; a copolymer comprising two or three
different monomers selected from acrylate or alkylacrylate (preferably an acrylate or
Ci_4 alkylacrylate; more preferably an acrylate or methacrylate) monomers; a homopolymer
of a styrenic derivative monomer; a copolymer comprising two different monomers selected
from styrenic derivative monomers; a homopolymer of an alkene or diene monomer; a
copolymer comprising two different monomers selected from alkene and diene monomers; a
homopolymer of a heterocyclic monomer; a copolymer comprising two different monomers
selected from heterocyclic monomers; and a random, alternating, gradient or block
copolymer comprising monomers selected from acrylate monomers, alkylacrylate
(preferably Ci_4 alkylacrylate; more preferably methacrylate) monomers, styrenic derivative
monomers, alkene monomers, diene monomers and heterocyclic monomers; and
(ii) either a second hydrophobic block B or a hydrophilic block B having a different
affinity than the block A for the liquid medium in which the AB copolymers are dispersed
such that micelles are formed.
Throughout the discussion of the present invention, references to alkyl and alkylene
groups and moieties, relate to both straight-chained and branched versions.
Preferably any acrylate or alkylacrylate monomer is, independently, of formula A'
Formula A'
wherein R is H or a Ci to C4 alkyl chain; Z is O, a phosphorous derivative [preferably
PH3] or a nitrogen derivative [preferably NH]; R' is selected from the group comprising:
Ci to Ci8 alkyl; alkylaminoalkylene containing from 1 to 18 carbon atoms (preferably
from 2 to 18 carbon atoms); alkoxyalkylene containing from 1 to 18 carbon atoms
(preferably from 2 to 18 carbon atoms); Ci to C18 dihydroxyalkyl; Ci to C18 silylalkyl; Ci
to Ci8 epoxy alkyl; phosphoryl; phosphoryl Ci to C18 alkyl; a vinyl phosphonate or
phosphoric acid monomer; and a methacrylate having at least one crosslinkable function
or one UV or thermal-responsive unit; where each alkyl or alkylene group is,
independently, fluorinated or non-fluorinated.
Preferably any styrenic derivative monomer is, independently, of formula B'
Formula B'
wherein R is H or a Ci to C4 alkyl group; and Ri, R2, R3, R4 and R are each
independently H or a Ci to C alkyl group or a halogen atom [preferably chlorine or
fluorine].
Preferably any alkene or diene monomer is, independently, of formula Ca or Cb
Formula Ca Formul,a Cb
wherein Rl R2, R 3 and R4 are each independently selected from H and Ci to C4 alkyl
(preferably Ri, R 3 and R4 are each H; and R2 is H or Ci to C4 alkyl).
Preferably any heterocyclic monomer is, independently, of formula Da, Db, Dc or Dd
Formula Da Formula Db Formula Dc
Formula Dd
wherein n is from 1 to 7, m is from 0 to 5 and p is from 1 to 7; R is H or a Ci to C8 alkyl
group; and X is O, N or S.
The ratio of the monomers in each block of block copolymer AB is such that the weight
fraction of the (hydrophobic) block A and the (hydrophobic or hydrophilic) block B agents
leads to the formation of organised aggregates, such as micelles. The number of the
monomers comprising the block copolymer AB is: preferably from 5 to 250 units of A; more
preferably from 10 to 200 units of A; and most preferably from 15 to 150 units of A; and,
likewise, preferably from 5 to 250 units of B; more preferably from 10 to 200 units of B; and
most preferably from 15 to 150 units of B.
A suitable alkylacrylic or acrylate monomer of Formula A' is when Z is O; and R' is a Ci
to Ci alkyl group (more preferably a Ci to C alkyl group); another suitable monomer of
Formula A' is provided by Formula 1:
- 6 -
Formula 1
where n is 1 to 17, more preferably 1 to 8.
A suitable fluorinated alkylacrylic or acrylate monomer of Formula A' is when Z is O;
and R' is a fluorinated alkyl group; another suitable monomer of Formula A' is provided by
Formula 2 :
F )m
H F
Formula 2
where n is 1 to 6 and the chain is linear or non-linear, more preferably 1 or 2; m is 0 to 7 and
the chain is linear or non-linear, x is 0 to 2 and y is 3-x.
A suitable alkylacrylic or acrylate monomer for Formula A' is when Z is O; and R' is
an alkylaminoalkyl group containing up to eighteen carbon atoms. Another suitable
monomer of Formula A' is provided by Formula 3 :
Formula 3
where Ri and R2 are each independently H, a Ci to C alkyl group; phenyl; benzyl or
cyclohexyl; and n is from 1 to 17; more preferably, Ri and R2 are each methyl and n is from
1 to 5.
A suitable alkylacrylic or acrylate monomer for Formula A' is when Z is O; and R' is an
hydroxyalkyl containing up to 18 carbon atoms. Another suitable monomer of Formula A' is
provided by Formula 4a or 4b:
x = 0 to 16 , y = (0 to 16) - x
Formula 4a Formula 4b
where n is 1 to 18 and the chain is linear or non-linear (more preferably n is from 1 to 4) and
x and y are each 0 to 16, more preferably 0 to 6. Suitably, for Formula 4b, x = 0 to 16; y = 0
to 16; and x + y < 16.
A suitable alkylacrylic or acrylate monomer for Formula A' is when Z is O; and R'
comprises a dihydroxyalkyl group. Another suitable monomer of Formula A' is provided
by Formula 5a or 5b:
x =0to 17, y =(0to 17) - x x =0to 16, y =(0to 16) - x
Formula 5a Formula 5b
where x and y are each 0 to 17 in Formula 5a or 0 to 16 in Formula 5b; more preferably x
and y are each 0 to 7 in Formula 5a or 0 to 6 in Formula 5b (and the chain can be linear or
non-linear). Suitably, for Formula 5a, x = 0 to 17; y = 0 to 17; and x + y < 17. Suitably, for
Formula 5b, x = 0 to 16; y = 0 to 16; and x + y < 16.
A suitable alkylacrylic or acrylate monomer for Formula A' is when Z is O; and R' is
a Ci to Ci7 silylalkyl group. Another suitable monomer of Formula A' is provided by
Formula 6a or 6b:
x = 0 to 16 , y = (0 to 16 ) - x
Formula 6a Formula 6b
where Ri is H or Ci to C4 alkyl and x and y are each from 0 to 16, preferably from 1 to 6.
Suitably, for Formula 6b, x = 0 to 16; y = 0 to 16; and x + y < 16.
A suitable alkylacrylic or acrylate monomer for Formula A' is when Z is O; and R' is an
epoxy alkyl group. Another suitable monomer of Formula A' is provided by Formula 7a or
7b:
Formula 7a Formula 7b
where x and y are each from 0 to 16, preferably from 0 to 6. Suitably, for Formula 7b, x = 0
to 16; y = 0 to 16; and x + y < 16.
A suitable monomer of Formula A' is when Z is O; and R' is a phosphoryl or phosphoryl
alkyl group. Another suitable monomer of Formula A' is provided by Formula 8a or 8b:
Formula 8a Formula 8b
where each Ri is independently H or Ci to C alkyl, preferably H or methyl.
Suitable monomers of Formula B' are independently selected from styrene,
a-methylstyrene, 2-methylstyrene, 4-methylstyrene, 2,4-dimethylstyrene,
2,4,6-trimethylstyrene, 4-isopropylstyrene, 2-fluorostyrene, 3-fluorostyrene, 4-fluorostyrene,
2,6-difluorostyrene, 2,3,4,5,6-pentafluorostyrene, 2-chlorostyrene, 3-chlorostyrene,
4-chlorostyrene and 2,6-dichlorostyrene and other vinyl substituted aromatics.
Suitable monomers of Formula Ca or Cb are independently selected from ethylene,
propylene, butylene, butadiene and isoprene.
Suitable monomers of Formula Da or D or Dc or D are independently selected from
ethylene oxide, propylene oxide, butylene oxide and caprolactone type monomers (such as
e-caprolactone or g -butyrolactone, lactide, oxiran-2-one, 1,3-dioxolane and caprolactam).
When the Block B is hydrophobic, it may comprise one or more monomers,
independently selected from the monomers defined above. Block B is chosen to have a
different affinity to the liquid medium to Block A. The structures outlined for Block A can
be applied for Block B provided Block A and B are different to each other.
When the block B is hydrophilic, a number of chemicals may be employed for the
hydrophilic component B, all of which need to be water-soluble; examples may be selected
from the group comprising:
hydrophilic organic monomers, oligomers, prepolymers or copolymers derived from vinyl
alcohol, N-vinylpyrrolidone, N-vinyl lactam, acrylamide, amide, styrenesulfonic acid,
combinations of vinylbutyral and N-vinylpyrrolidone, methacrylic acid, acrylic acid,
vinylmethyl ether, vinylpyridylium halide, melamine, maleic anhydride/methyl vinyl ether,
vinylpyridine, ethyleneoxide, ethyleneoxide ethylene imine, glycol, vinyl acetate, vinyl
acetate/crotonic acid, methyl cellulose, ethyl cellulose, carboxymethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethyl cellulose,
hydroxypropylmethyl cellulose, cellulose acetate, cellulose nitrate, hydroxyalkyl
(alkyl)acrylate such as hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate,
alkylaminoalkyl (alkyl)acrylate, 2-(dimethyl amino) ethyl methacrylate, 2-(diethyl amino)
ethyl methacrylate, 2-(diisopropyl amino) ethyl methacrylate, 2-(N-morpholino)ethyl
methacrylate, or a derivative thereof, ethylene glycol (meth)acrylates (for example
triethylene glycol (meth)acrylate) and (meth)acrylamide), N-alkyl (meth) acrylamides (for
example N-methyl (meth)acrylamide and N-hexyl (meth)acrylamide), N,N-dialkyl
(meth)acrylamides (for example N ,N -dimethyl (meth)acrylamide and poly-N,N-dipropyl
(meth)acrylamide), N-hydroxyalkyl (meth)acrylamide polymers, such as poly-N-methylol
(meth)acrylamide and poly-N-hydroxy ethyl (meth)acrylamide, and N,N-dihydroxyalkyl
(meth)acrylamide polymers, such as poly-N,N-dihydroxyethyl (meth)acrylamide, ether
polyols, polyethylene oxide, polypropylene oxide, and poly(vinyl ether), alkylvinyl sulfones,
alkylvinylsulfone-acrylates, (alkyl)acrylate with a pendent phosphorus group such as
vinylphosphonate, vinylphosphonic acid, vinylphosphine oxide and any (alkyl)acrylate with
a ester function -COOR such as R is CxH2xP03R2 wherein x is 2 to 10, most preferably x is
2, and R is a hydrogen or an alkyl group having 1 to 4 carbon atoms, preferably methyl; and
related compounds or a combination thereof.
In accordance with the present invention the polymers comprising the AB block
copolymer comprise monomers, and the ratio of the monomers comprising each polymer of
the block copolymer AB is such that the weight ratio of the (hydrophobic) block A to the
(hydrophobic or hydrophilic) block B leads to the formation of organised aggregates. In
addition, the weight fraction of the (hydrophobic) block A and the (hydrophobic or
hydrophilic) block B leads to the formation of micelles. Certain copolymers used in the
present invention have been found to form complex and large micelles in solution.
As stated above AB Block copolymers can comprise a hydrophobic ("water hating")
block A and a second hydrophilic ("water loving") block B; or two hydrophobic blocks A
and B may be differentiated by having different solubility parameters in the same liquid
medium. Variation in the copolymer properties can be obtained by varying the monomer
types (different available chemistries), the molecular weights of the copolymer (at a fixed
ratio of the two component block sizes) and the ratio of the molecular weights of the
constituent blocks (at a fixed overall molecular weight for the copolymer).
Importantly, to form micelles (that is, aggregates formed by molecules of block
coplymer) in a liquid medium, the insoluble (or poorly soluble in the liquid medium) blocks
drive the formation of aggregates of the molecules. The structures of the aggregates are
dependent on the copolymer concentration and the exact nature of the copolymer molecules.
Schematically, micelles may be seen, for example, as a spherical aggregate having two parts;
one core composed of the copolymer block insoluble or less soluble in the liquid medium
and one corona composed of a copolymer block having affinity for the liquid medium. Other
micellar structures are possible and known to those skilled in the art.
In the present invention, once the AB block copolymers comprise a hydrophobic
("water hating") block A and a second hydrophilic ("water loving") block B, such AB block
copolymer structures will form micelles with an hydrophilic corona composed of block B in
aqueous liquid media or in polar solvents but will also form reversed micelles with a
hydrophobic corona composed of block A in more apolar solvents such as an aliphatic oil. In
aqueous liquid media, such amphiphilic copolymers are utilised that form spherical
aggregates at the concentrations employed.
In the present invention, once the AB block copolymer comprises two hydrophobic blocks
A and B differentiated by having different solubility parameters in the same liquid medium,
such structures will form micelles with a corona composed of block A in a liquid medium
where the block B is less soluble than the block A in the chosen liquid medium or micelles
with a corona composed of block B in a liquid medium where the block A is less soluble
than the block B in the chosen liquid medium.
The chemistry of the micelles (micellar aggregates) should be such that the micelles will
adsorb freely onto a wide variety of particle surfaces. Also, the composition may form
micelles preferably having a maximum dimension [diameter in the case of spherical
micelles] of from to 3 to 500nm, preferably from 3 to 300nm. The block-copolymer micelle
structures most preferably have a maximum dimension [diameter in the case of spherical
micelles] of from 10 to lOOnm.
In a preferred example, the polymers used in the composition are prepared by controlled
living radical polymerisation reactions. Preferably, the block copolymers are prepared by
means of controlled living radical polymerisation to obtain narrow molecular weight
distribution copolymers. Suitable synthetic routes include but are not limited to: Reversible
Addition - Fragmentation chain Transfer (RAFT), Group Transfer Polymerisation (GTP)
and Atomic Transfer Radical Polymerisation (ATRP), Activated Regenerated by Electron
Transfer (ARGET), Nitroxide-Mediated Polymerization (NMP), ring-opening
polymerization and ionic type of polymerization and combinations of techniques where
appropriate.
In a further aspect, the micelles may be crosslinked resulting in a more durable coating on
the substrate. In the current invention, crosslinking can be described as the physical and/or
chemical interaction between chains of the AB diblock copolymer. The crosslinking can
take place either in the core of the micelles, in the corona of the micelles and/or between the
coronas of two contiguous micelles and the crosslinking may or may not be reversible.
Chemical crosslinking requires the use of a molecule called a crosslinker or crosslinking
reagent. Three preferred chemical crosslinking strategies are: (1) crosslinking with a
multifunctional organic compound, for example via condensation or addition reactions (such
as carboxylic acids with amines; carboxylic acids with hydroxy Is; and hydroxy Is with
isocyanates); (2) ring-opening reactions (such as epoxy groups with amines); and (3) radical
initiated crosslinking of vinyl or similar chemical functions (such as those in divinyl benzene
and/or di-methacrylates); which can be introduced to the AB di-block copolymers.
A multifunctional organic compound is defined as an organic compound containing two
or more functional groups that may react with functional groups described for the AB
di-block copolymers used in this invention to form crosslinks. The functional groups in the
organic compound may be any that will react with functions described herein for the AB
di-block copolymer including but not limited to: amine, hydroxyl, carbonyls such as ketones
or aldehydes, carboxyls such as carboxylic acid, isocyanates and sulfhydryl.
Vinyl groups may be introduced to the AB di-block copolymer by using vinyl compounds
that also contain a function that will react with functional groups described in this invention
for the AB di-block copolymer. Examples of such chemistry include, but are not limited to,
amine functionalised vinyl compounds such as amino alkyl methacrylates. Following the
introduction of the vinyl chemistry, crosslinking is carried out by radical initiation via
thermal or UV curing.
Chemical covalent crosslinks are stable mechanically and thermally, so once formed are
difficult to break, whereas physical crosslinks are reversible and the physical crosslinking
process may or may not require the use of crosslinking agents. Physical crosslinking occurs
when there is the formation of a physical interaction between functional groups located
either in the AB diblock copolymer alone or between functional groups located in the AB
diblock copolymer and in the multifunctional crosslinker. Techniques include, but are not
limited to, dehydrothermal treatment, plasma treatment, hydrogen bonding, ionic interactions
and freeze thawing.
Crosslinking (physical and/or chemical) can bring many benefits including, in aqueousbased
systems or polar systems, making the hydrophilic (or hydrophobic) corona of micelles
more hydrophobic( and making corresponding changes in apolar systems). This provides
the opportunity to control the release rate of an active coated with crosslinked micelles.
In the present invention, the block copolymer comprises at least one block that adsorbs to
a target surface. The composition may further comprise an adhesion promoter (AP). An AP
will generally consist of a polyelectrolyte of opposite potential (charge) to the potential
(charge) of the crystal (crystalline particle); in this case the block copolymer micelles coat
the AP modified surface. This allows copolymer micelles of similar potential (charge) to the
crystal to be deposited on the crystal (through a crystal-AP-block copolymer arrangement).
Also in a composition used in accordance with the present invention the liquid medium
may comprise water, water and an organic solvent, an organic solvent or mixtures of solvent,
or an organic solvent free from water; wherein the block copolymer is preferably completely
dissolved in the liquid medium. To especially but not exclusively encourage reverse
micellisation the liquid medium employed will consist of two solvents, one a good solvent
for the block-copolymer and a second, less effective, solvent which will cause separation of
the block co-polymer from solution and the formation of micelles. This second solvent is
generally classed as an apolar solvent.
Generally preferred are polar solvents such as water-miscible organic solvents that can be
selected from: Ci_ alcohol (preferably, methanol, ethanol, n-propanol, iso-propanol,
n-butanol, tert-butanol or sec-butanol), alkylketones, arylalkylketones, ketoalcohols, cyclic
ketones, heterocyclic ketones, ethers (such as tetrahydrofuran), cyclic ethers (preferably
ethylene glycol or glycol ethers), esters (preferably ethyl acetate), amides (preferably
dimethylformamide) and sulfoxides (preferably dimethylsulfoxide) and combinations
thereof. Other powerful solvents, although not water miscible, are aromatic solvents - such
as toluene, xylene and the higher homologues and analogues routinely employed as solvents
in commercial products, such as Solvesso 100, Solvesso 150. Higher aromatic solvents such
as alkyl naphthalenes, for example Solvesso 200 and Solvesso 200ND may be employed as
powerful solvents for oil-soluble copolymers that may be employed to form micelles
(normal or inverse) in an oil medium. Any solvent used conventionally in agrochemical
formulations may be suitable for use in the present invention (for example, cyclohexanone,
alkyIcyclohexanones, NMP, N-octyl pyrrolidone and C8-C10 fatty acid amides).
Preferred apolar solvents, as opposed to polar solvents, may be selected from but are not
limited to: alkanes, preferably pentane and hexane; halogenated solvents, preferably
dichloromethane; chloroform, chlorobenzene and fluoroalkanes; and aromatic solvents and
combinations thereof. Suitable apolar solvents may also be selected from what are generally
classified as oils, such as high molecular weight alkanes, for example paraffinic oil; such as
Isopar V and Exxsol D140; alimentary oil such as olive oil, soy bean oil and castor oil and
combinations thereof. Conventional ester solvents are also suitable.
When a composition of the present invention comprises a liquid, the ratio by weight of
block copolymer to the liquid medium is preferably from 1 : 100,000 to 1 : 1 ; more
preferably from 1 : 10,000 to 1 : 2; especially from 1 : 5,000 to 1 : 5; and most preferably
from 1 : 5,000 to 1 : 10.
It will also be appreciated by one skilled in the art that the composition according to the
present invention may preferably further comprise additional components or auxiliary agents
selected from for example but not limited to dispersants, perfumes, biocides, stabilisers,
surfactants, wetting agents, emulsifiers, colouring agents, dyes, pigments, UV absorbers,
radical scavengers, antioxidants, anti-corrosion agents, optical brighteners, fluorescers,
bleaches, bleach activators, bleach catalysts, non-activated enzymes, enzyme stabilizing
systems, chelants, coating aids, metal catalysts, metal oxide catalysts, organometallic
catalysts, filmforming promoters, hardeners, linking accelerators, flow agents, levelling
agents, defoaming agents, lubricants, matte particles, rheological modifiers, thickeners,
conductive or non-conductive metal oxide particles, magnetic particles, anti-static agents, pH
control agents, preservatives, pesticides (for example, herbicides, insecticides and
fungicides), anti-fouling agents, algicides, bactericides, germicides, disinfectants, bioeffecting
agents, vitamins, drugs and therapeutic agents and a combination thereof.
We have now found that these micelle structures can be conveniently employed to coat
small particulate materials such as organic crystals. Therefore, in a further aspect, the
present invention provides a coated particle where the particle is an organic crystalline
particle. The chemistry of these applications is thereby incorporated herein. Moreover, the
technique is easy to employ and permits high coating weights to be applied over all a surface
(including corners and edges of crystals if present). The micelle structures used in the
present invention can produce a coating thickness typically up to 50nm in a single pass
treatment - very much higher than any other known technique - while maintaining complete
stability and non-agglomeration of the coated particle. Multi-coats produce even higher
coating weights and thicknesses.
The block copolymers used in the present invention form micellar aggregates typically
from 3 to 500nm in size, suitably from 3 to 300nm. Aggregation number is controlled by the
chemistry of the block copolymer in terms of absolute chemistry, charge, molecular weight
and the solution conditions under which the micelle is formed. Typical aggregation numbers
for such a block copolymer micelle can be of the order of 100 molecules. Therefore suitably
the micelles are present as micellar aggregates which each comprise from 10 to 1000
molecules. Typical molecular weights of block-copolymers used in the present invention are
from 3000 to lOOOOODalton but are specified within the chemistry.
Block copolymer micelles can be simply employed by adding to a dispersion of a particle
in a carrier liquid and allowing to equilibrate. Confirmation of coating can be obtained by
SEM observation and quantitative data by analysis of a sample for total active material
content (where an active material is coated). Other techniques to induce micelle formation
(such as pH shift, temperature, solvent exchange and dilution) can all be suitably employed.
As an alternative process, a drying technique to remove either a solvent or to induce a
chemical change - such as loss of ammonia in a drying process - can be employed.
To coat a particle, the process can be simply achieved by adding block copolymer
micelles (or inducing block copolymer micelles to form) to a dispersion of a particle in a
carrier liquid. Therefore in a further aspect, the present invention provides a process for
preparing a particle as described herein comprising the steps of (a) forming micelles of the
copolymer; and (b) mixing the micelles with the crystalline particle.
As further embodiments, we have found that if the particle dispersion is pre-treated with
an adhesion promoter, which is not a copolymer micelle, then improved deposition of block
copolymer micelles is achieved.
In one embodiment the adhesion promoter is a polyelectrolyte which is a homopolymer
selected from, but not limited to: poly(diallyldimethylammonium chloride) (PDADMAC),
poly(sodium styrene sulfonate) (PNaSS), poly(methacrylic acid sodium salt), poly(acrylic
acid sodium salt), poly(vinylpyridinium salt) and poly(alkylammonium salt). In a further
embodiment, the adhesion promoter can be a block copolymer micelle in its own right such
that a double coating of oppositely charged micelles is achieved. In a still further
embodiment, it is possible to build up significant multiple layers of micelles by sequential
treatment. It is possible to contemplate an amphiphilic block copolymer with amphoteric
properties such that by simple pH switching, several layers of the same copolymer can be
induced to be deposited. In order to modify significantly a particle surface, the number of
micelles coating an individual particle has to be large. Usually there will be at least a 10-fold
greater number of micelles per coated particle (and usually significantly greater).
Certain products of the invention comprise a particulate material covered with a coating
of block copolymer micelles (including, uniquely, edges and corners as well as faces). A key
aspect of the present invention is the ability to provide good coverage [and protection] for
sharp features such as edges and, particularly, corners of crystals. Therefore suitably a
particle according to the present invention is coated by at least 10 micelles. More preferably,
the particles according to the present invention are entirely coated by the micelles.
The copolymers according to the present invention have been found to form complex and
large micelles in solution.
The nature of the micelle (in terms of whether the core comprises a hydrophobic structure
and the corona a hydrophilic structure; or whether it is a reverse [also referred to as
'inverse'] micelle comprising a hydrophilic core and a hydrophobic corona) is dictated by
- 16 -
both the chemistry of the block copolymer and the solvent environment in which the block
copolymer is formulated. In some chemistries, the amphiphilic character can be introduced
by having two blocks wherein one block is significantly more hydrophobic than the second
block, this inducing a differential solubility in the blocks and thereby inducing an
amphiphilic structure that enables the formation of micelles. Importantly, to form micelles
(that is aggregates formed by molecules with an amphiphilic character) in a liquid medium,
one block of the copolymer should be poorly soluble in the liquid to drive the formation of
aggregates of the molecules. The structures of the aggregates are dependent on the
copolymer concentration and the exact nature of the copolymer molecules as well as the
nature of the liquid environment (for example, liquid type and temperature). In the present
invention copolymers are utilised that preferably form spherical aggregates at the
concentrations employed but other micelle shapes will also work with the present invention.
Micelles are generally composed of two defined regions within their structures; a central
"core" where all the hydrophobic parts of a surfactant are aligned together and an external
"corona" where all the hydrophilic parts of a surfactant are aligned. In a normal micelle, the
core is the more hydrophobic region and the corona is the more hydrophilic region. In a
reverse micelle, the opposite is true where the core is the more hydrophilic region and the
corona is the more hydrophobic (and in this context, a more hydrophilic region does not have
to be water soluble, just sufficiently more hydrophilic than the hydrophobic part of the
molecule to induce phase separation into such micelle structures. The coronal chemistry for
the micellar aggregates is such that the micelles will adsorb freely onto a wide variety of
particle surfaces.
The AB block copolymer may suitably take any form selected from: linear block
copolymer (diblock, triblock or multiblock), miktoarm copolymer (star copolymer), ladder
(H-shaped) copolymer, graft and comb (co)polymer; preferably it is a linear block
copolymer.
The distribution of component monomers within each copolymer block is selected from
the form of homo, random, gradient, alternative, block, graft and comb (co)polymers; that is,
any type of copolymer structure which will lead to a segregation of copolymer in the liquid
medium as organised aggregates.
It is preferred that the block copolymer is selected from the group comprising: AB blocks,
ABA blocks and ABC blocks.
In accordance with the present invention the block copolymer comprises at least one
block that absorbs to a target surface. The composition may further comprise an adhesion
promoter. Also, the composition must form micelles and the micellar aggregate structures in
the composition preferably have a maximum dimension [or diameter for spherical micelles]
of from 3 to 300nm. The block-copolymer micelles most preferably have a maximum
dimension [or diameter for spherical micelles] of from 10 to lOOnm.
In a preferred embodiment, the polymers used in the composition are prepared by a
controlled living radical polymerisation reaction.
In a composition used in accordance with the present invention the liquid medium may
comprise water, water and organic solvent, an organic solvent or mixture of solvents or an
organic solvent free from water; wherein the block copolymer is preferably completely
dissolved in the liquid medium before micelle formation.
Examples of small materials to be coated are objects that need to be protected from their
environment, for example water soluble organic crystals that may be otherwise incompatible
in an aqueous formulation and particles which may react with the other ingredients of the
formulation causing an increase of viscosity and decrease in the shelf life of the formulation.
Products of utility may be an agrochemical, laundry chemicals, cosmetics, food additives,
paint and coating additives, biocides for paints, pharmaceutical and other particles that find
utility in various fields. The novel coating, produced by micelle- forming polymers, finds
utility in a variety of ways. The coated particle can now be more effectively targeted for
adhesion to a substrate by selection of the block copolymer, as in targeting a specific
substrate in agriculture (such as an insect cuticle, leaf surface or fungal pathogen) or in
pharma (for delivery to a specific target organ or protection of an agent for delivery through
the mammalian stomach for selective and protected delivery later in the digestion system) or
in laundry (for release of an agent at the appropriate point in the wash cycle). Moreover, the
effectively coated particles confer greater colloidal stability on systems, allowing greater and
improved stability when mixed with other components.
Further suitable applications include, without limitation: sustained release and controlled
release usages, for example: in the pharmaceutical field, for example acid resistant structures
(oral delivery past low pH in the stomach), protection of labile actives, pseudo-zero order
release through the micelle layer and Ostwald-ripening resistant formulations; cosmetics;
perfumes, for example slowing down evaporation of top-notes or sustained release and
minimising overpowering odours; particles having affinity for cellulose and trapped on
textile surface during laundering; flavours, for example light stabilised to prevent oxidation;
- o -
self-healing coatings, for example particle induced to burst to release a resin that repairs
damage; carbonless copy paper; novel, double taste and texture food, for example particle
which dissolves in the mouth and releases a new taste; pressure sensitive adhesives; sealants;
nutrition (for example increased bioavailability of complex molecules and protection of
sensitive molecules such as vitamins, probiotics and other food additives); toner inks with
photosensitivity or thermal sensitivity; textile coatings, for example, for altering permeability
properties; antifouling coatings; surface protective coatings, for example, for improving
scratch or abrasion resistance; and construction materials, for example wall-boards,
plasterboards and cements.
It is well known that chemical incompatibility between different components in liquid
laundry formulations can cause instability in these formulations. In particular, laundry
bleach activation agents such as, but not limited to, tetraacetylethylenediamme (TAED) that
are widely used in powder laundry formulations are incompatible with liquid laundry
detergents. Bleach activation agents, precursors and catalysts tend to be unstable in many
liquid formulations and although the surfactants in the liquid formulation are stable they can
react with bleach or bleach activator chemicals or catalysts or derivatives of them. One
solution is to add a solid form bleach activator as a separate dose to the liquid laundry
detergent, but this is inconvenient for the consumer. The present invention provides a means
of protecting the solid bleach activator from interaction with water and other liquid detergent
components to enable a stable liquid detergent to be formulated.
The sustained release of biocides and anti-fouling agents is of commercial interest to the
paints and coatings industry and in particular for marine applications. One example of a
biocide that has been employed as an antifouling agent for marine use is DCOIT
(4,5-dichloro-2-n-octyl-3(2H)-isothiazolone). This active has a low solubility in sea water
which is extremely desirable, however in solvents used in paint formulations such as xylene,
it is extremely soluble. This means that it is likely to react with the paint binders within the
formulation and may increase the paint viscosity or induce plasticizing of the paint. Marine
paint manufacturers will benefit from a biocide that improves in-can stability of the paint
whilst incorporating sustained release of the active after application onto the marine vessel.
The present invention provides a means of protecting the biocide from the other active
ingredients in a paint formulation and provides a means of sustained release in sea water.
Safe delivery of active pharmaceutical ingredients (APIs) to the intended target site
within a mammalian body is major area of both commercial unmet need and scientific
research. In many cases the API needs to be protected from interaction with its environment
in order to prevent unwanted chemical reaction or biological use of the active at the wrong
site within the body or at the wrong rate. One solution to this problem is to formulate the
API into a tablet and to add a protective or enteric coating to the tablet. This can be suboptimal
for a number of reasons including patient preference for non-tablet formulation and
the potential risk of over-dosing [if the enteric coating fails]. The present invention enables
individual crystals of API to be coated enabling formulation into a capsule rather than a
tablet and minimizing the risk of over-dosing [as the coating would need to fail multiple
times on individually coated API crystals rather than only once on the tablet].
Non Steroidal Anti Inflammatory Drugs (NSAIDs) such as ibuprofen and diclofenac are
limited in their administration because at higher doses, side effects such as gastric erosion,
thrombasthenia, thrombocytopenia and fluid retention may become severe.
Vitamin C is also known as ascorbic acid, ascorbate and ascorbate monoanion. It is the
enolic form of an a-ketolactone. Vitamin C works physiologically as a water soluble
antioxidant by virtue of its high reducing power. It acts as singlet oxygen quencher and it is
capable of regenerating vitamin E. Vitamin C is called an antioxidant because of its ability to
quench or stabilise free radicals that otherwise may lead over time to degenerative diseases,
including cancer, cardiovascular disease and cataracts.
Ascorbic acid properties are impaired by its high reactivity, and hence, poor stability in
solution, which can result in heavy losses during food processing. It can be degraded rapidly
in the presence of oxygen or by free-radical mediated oxidative processes. The processes are
strongly catalysed by transition metal ions, especially iron and cooper, leading to rapid
destruction of the ascorbate. Oxidation is also accelerated at neutral pH and above.
Destruction may occur due to the presence of enzymes, such as ascorbate oxidase and
ascorbate peroxidase.
The food industry may employ microencapsulation to produce foods which are more
nutritionally complete. The properties of microencapsulated nutrients will allow the food
processor greater flexibility and control in developing foods with high nutritional value.
Ascorbic acid is added extensively to many types of food products for two quite different
purposes: as a vitamin supplement to reinforce dietary intake of Vitamin C, and as an
antioxidant, to protect the sensory and nutritive quality of the food itself.
The present invention enables individual crystals of ascorbic acid or other food
supplements to be coated for application in the food industry as fortification. Coated
particles may be incorporated in dry form into cake mixes, puddings, gelatine desserts,
2 Q
chewing gum, milk powder, jellies, pet foods or breakfast cereals, in short, into products
with low water activity.
A composition according to the present invention may suitably be an agrochemical
formulation; the agrochemical formulation may comprise an agrochemical active ingredient
(such as a fungicide, herbicide, insecticide or plant growth regulator) or it may comprise an
adjuvant which is used to enhance the bioperformance of an agrochemical [either in the same
formulation as the adjuvant or to be applied from a separate formulation]. The composition
can be in the form of a concentrate which is diluted or dispersed in a spray tank prior to use,
although ready-to-use compositions can also be made. The final dilution is usually made
with water, but can be made instead of, or in addition to, water, with, for example, liquid
fertilisers, micronutrients, biological organisms, oil or solvents. The compositions may be
chosen from a number of formulation types, many of which are known from the Manual on
Development and Use of FAO Specifications for Plant Protection Products, 5th Edition,
1999. These include dustable powders (DP), soluble powders (SP), water soluble granules
(SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast
release), dispersible concentrates (DC), suspension concentrates (SC), capsule suspensions
(CS; in which case, the particle is a microcapsule) and seed treatment formulations. The
agrochemical formulation may be used to control or combat a pest [examples of agricultural
pests include unwanted plants (weeds), insects and fungi].
As further embodiments, micelles comprise a core and a corona that are chemically
different. This difference can be exploited for further benefits. The micelle core can be
selectively loaded with a component that dissolves (or can be dissolved by a suitable solvent)
in the core chemistry. For example, the application of a photostabiliser by such a technique
(by incorporating the photostabiliser into the micelle core which is then coated onto the
crystal surface) will improve the ability to stabilise sensitive chemistry against photolytic
degradation. Soil mobility of crystalline particles of a pesticide can similarly be enhanced by
coating a stable polymer micelle onto the crystal surface (optionally in combination with
added specific surfactants that can promoted improve soil mobility). In some situations,
pesticides can induce a phytotoxic response (in cotton for example) due to too rapid a
photolytic degradation. Coating crystals in this manner with a polymer micelle containing a
photostabiliser could reduce the rate of degradation.
Therefore, in another aspect, the present invention provides a crystalline particle as
described herein where the cores of the micelles contain a chemical, which may be a
photoprotectant, a biologically active compound or an adjuvant (for example an adjuvant for
improving or controlling the bioperfomance of an agrochemical).
Furthermore, the coated crystalline particle may be a biologically active compound [for
example, an agrochemical] whilst the micelle core may be loaded with a second biologically
active compound [for example, an agrochemical]. Alternatively two or more different
biologically active compounds [for example, agrochemicals] may be mixed together as
coated particles according to the present invention in such a manner that the micellar
coatings overcome any potential incompatibility problems [for example, physical or
chemical incompatibility].
In a further aspect, the ability to coat such block copolymer micelle systems onto a
substrate provides an elegant procedure to prepare mixed products by coating a polymer
micelle containing a first active onto a crystal surface of a second active (with the option of
further actives being in a dissolved or other dispersed state). Further, such coated polymer
systems could then be applied to relevant surfaces that could require protection against attack
(such as wood) or onto surfaces where a long lasting barrier might be required (such as to
prevent ingress of termites, ants or spiders or to prevent fungal growth in sensitive situations
- for example, fungicides in/on wallboards).
Further, non-limiting crop protection applications include particle coating leading to:
reduced antagonism by altering the relevant availability of two or more active ingredients,
triggered release potential - triggers may be pH, light, water, enzymes - and alteration of
release profile. These release rate alterations may be possible not only in the products of the
invention but also when subsequently applied (for example to seeds - triggered release from
seeds by coating technology - triggers can be pH, light, water or enzymes. The size range of
particles to be coated can vary enormously. Where the particle is an organic crystal, the size
range can usefully be from lOnm to 500micron, preferably 500nm to 100 micron (although
technical material greater than 500micron could be also coated and employed in some
utilities (such as pharma) in a pre-granulation stage to protect a material). The size may be
defined to be the largest dimension of the particle. Accordingly, in a further aspect of the
present invention, the largest dimension of the particle is from lOnm to 5mm. When the
crystal size is small, the micelle size chosen to coat the particle has to be even smaller.
Where the particle is a granule (or a spray-agglomerated granule) the size can vary from
about 50micron to a few millimetres.
Use of this technology can be adapted to coating poorly soluble particles such as
pharmaceutical actives including but not limited to griseofulvin, troglitazone, felodipine and
ketoconazole (which each have a very low aqueous solubility and a slow dissolution rate)
with a hydrophilic polymer system. This is a convenient method of increasing the rate of
solubility as the system benefits from a higher surface area and reduced surface/interfacial
tension.
The present invention is illustrated by the following examples.
Example 1: Preparation of Polymers and Block Copolymers.
1A. Preparation of Block Copolymers having a hydrophobic block A and a hydrophilic
block B.
The copolymers described in this example have a hydrophobic block. This block can
comprise one or more monomers, for example; styrene and styrene derivatives, methacrylate
and derivatives such as butyl methacrylate (BuMA), trifluoro ethyl methacrylate (TFEMA),
ethyl hexyl methacrylate (EHMA), methyl methacrylate (MMA) and propylene oxide (PO).
Those skilled in the art will appreciate the synthesis described in this example is not limited
to the monomers listed here.
For the polymers described in the current example, the hydrophilic block is composed of
methacrylic acid (MAA) or dimethylamino ethyl methacrylate (DMA) but those skilled in
the art will understand that other monomers leading to a hydrophilic block can also be used.
The copolymers used herein were produced according to the protocol described in the patent
applications WO08071957 and WO10038046. The block copolymers may be prepared by
means of controlled living polymerisation techniques, such as group transfer polymerisation
(GTP), atomic transfer radical polymerisation (ATRP), nitroxide mediated polymerisation
(NMP) and activated regenerated by electron transfer (ARGET) or activated generated by
electron transfer (AGET) that can synthesize well-defined homopolymers and block
copolymers. In this example, in addition to structures described in the patent applications
WO08071957 and WO10038046, new copolymer structures were produced by Reversible
Addition-Fragmentation Chain Transfer (RAFT) polymerization using the RAFT agent,
2-cyanoisopropyl dithiobenzoate (CPDB). Whilst the current example prepares the block
copolymer using the RAFT agent, CPDB, those skilled in the art will appreciate that other
RAFT agents may be used.
In addition to controlled radical polymerization, in the case of heterocyclic monomers such
as propylene oxide, ring-opening polymerisation techniques can be used. Examples of the
composition of new prepared copolymers are given in Table 1.2.
RAFT synthesis of Pol BuMA- / -MAA copolymer : P BuMA- -MAA
A series of poly[BuMA x-£-MAAy] copolymers were prepared by RAFT
polymerization using CPDB as chain transfer agent, azobisisobutyronitrile (AIBN) as
initiator, and propan-2-ol (IPA) as a solvent. The synthesis was a two step process. First, the
hydrophobic block (BuMA) was synthesised, then the synthesis of the hydrophilic block
(MAA) was initiated from the PBuMA homopolymer.
a) Synthesis of the hydrophobic block PBuMA.
BuMA (15g, 105mmol, 69eq), CPDB (0.37g, 1.51mmol, leq), AIBN (0.12g, 0.75mmol,
0.5eq), and IPA (solvent, 6.33g, 105mmol) were added in a two necked flask containing a
magnetic stirrer equipped with a cooling column. The mixture was degassed by nitrogen
bubbling and heated at 90°C in a thermostatically controlled oil bath under a nitrogen
atmosphere. The reaction was left under stirring for a minimum of 2hour 30minute (in this
example 2h45min). A sample of the crude mixture was withdrawn and analysed by size
exclusion chromatography (SEC - See Figure 1.4), and by 1H NMR (CDC13 - See Figure
1.1). A conversion of 98.3% was determined by 1H NMR in CDCI 3,hence the resultant
product was P(BuMA)x homopolymer where x = 68.
b) Synthesis of the hydrophilic blockfrom the hydrophobic block
30 minutes before the end of the first synthesis, MAA (7.78g, 90.4mmol, 59.9eq), AIBN
(0.12g, 0.75mmol, 0.5eq) and IPA (solvent, 36.2g, 603mmol) were added in another flask
containing a magnetic stirrer. The mixture was degassed by nitrogen bubbling.
At the end of the first synthesis (in the current example 2h45min), the thermostatically
controlled oil bath was removed to stop polymerisation. The mixture containing the
second monomer was then transferred into the initial two necked flask via cannula. This
flask was heated again at 85°C in the thermostatically controlled oil bath (equipped with a
cooling column) under nitrogen atmosphere to achieve the preparation of the second block
of copolymer. After a minimum of 2h30min (in this example 2h45min) a sample of the
crude mixture was withdrawn and analysed by 1H NMR (DMSO - See Figure 1.3) and
SEC (Figure 1.4).
A conversion of 93% was measured by 1H NMR in DMSO. The resultant product was
determined as P(BuMA -¾-MAAy) copolymer where x = 68 and y = 55.
Other P(BuMA -¾-MAAy) polymers were prepared with x=59 and y=54 and with x=127
and y=5 1. The generic structure of the corresponding P(BuMA -£-MAAy) copolymers is
given below in Formula 1.2:
Formula 1.2: Generic structure of the P(BuMAx-¾-MAAy) synthesised
The P(BuMA -6-MAA ) copolymers can also be prepared by NMP, ATRP, GTP or
indirect anionic polymerization. Characterisation
Size exclusion chromatography (SEC) was used to determine the number-average molar
mass (M ) and thus demonstrate the increase of molar mass due to the addition of the
second block during the RAFT polymerisation. SEC was also used to determine the
polydispersity index (PDI= Mw/M , where Mw is the weight-average molar mass) of the
polymers and copolymers, a low PDI being necessary to achieve regular micelles.
The samples were injected in the SEC equipment. (2 PL gel 5 Micron Mixed-c columns)
Analysis was performed as described below
The eluent was composed of THF (elution flow rate: 1 mL/min, run time: 30 min).
The calculation (for data analysis) was made with a calibration curve based on
poly(methyl methacrylate).
Before injecting the polymer samples containing methacrylic acid units, a
methylation reaction was performed to convert the acid groups into methyl esters,
using trimethylsilyldiazomethane as methylating agent, in order to solubilise the
polymers in THF to perform the analysis.
- The samples (20mg) were dissolved in the eluent and then filtered with a 0.2mih
PTFE filter into the SEC vials.
An example of a SEC chromatogram is given in Figure 1.4. The SEC chromatogram of the
first block of P(BuMA) and the chromatogram of the copolymer P(BuMA-^-MAA) are
represented. The observed shift of the chromatogram is consistent with an extension of
chains between both steps.
Table 1.1 : Indication of polydispersity index (PDI) obtained by SEC for some copolymers
described in Table 1.2 and 1.3.
Copolymer PDI - block 1 PDI - block 2
P(BuMA5 -b-MAA55) 1.13 1.21
P(BuMAi 2v-b-MAA5i) 1.17 1.28
P(BuMA30-b-DMAioo) 1.16 1.42
P(MMAi 5-b-DMA55) 1.32 1.20
P(TFEMA 52-b-MAA2 9) 1.23 1.50
Proton Nuclear Magnetic Resonance (1H NMR) was used to determine the conversion of
each polymerisation and accordingly the calculated degree of polymerisation (in number:
DP ) for each block.
1H NMR was performed with a 500MHz apparatus (Bruker), in CDC13 for the
homopolymer, and in DMSO for the copolymer.
NMR spectra, with the location of the monomer and polymer peaks, are given in Figures
1.1 and 1.3.
Preparation of other copolymers by RAFT synthesis.
Various block copolymers were synthesised. The hydrophobic block was obtained from
styrene and various methacrylate based monomers such as TFEMA and EHMA. The
hydrophilic block was composed each time of MAA, HEMA or DMA units.
The method described above for the synthesis of P(BuMAx-¾-MAAy) was used, which led to
the successful synthesis of P(TFEMA x-6-MAA ), P(EHMAx-6-MAA ), P(MMAx-6-DMA ),
and P(BuMA -¾-DMAy) . The conversion rates, block sizes and reaction times are given in
Table 1.2:
Table 1.2
Table 1.2: Synthesis and composition data according to H NMR BuMA: buty
methacrylate; MAA: methacrylic acid; TFEMA: trifluoro ethyl methacrylate; DMA:
N,N-dimethylaminoethyl methacrylate; MMA: methyl methacrylate; EHMA: 2-ethyl
hexyl methacrylate; Sty: styrene; HEMA: 2-hydroxyethyl methacrylate; Conv. :
conversion given in %; DPn th: degree of polymerisation targeted; DPn exp: degree
of polymerisation calculated;
i) Copolymers with a DMA block can be classified as well as amphiphilic copolymers
when they are dispersed in low pH aqueous solution.
ii) Synthesis performed in DMF instead of IPA.
l b :Preparation of Block Copolymers having two hydrophobic blocks A and B.
Block copolymers having two hydrophobic blocks were prepared following the same
procedure as used for the preparation of P(BuMA -£-MAAy) copolymers as described in the
Example 1 section la. Examples of the structures prepared by this method are listed in Table
1.3:
Table 1.3
Table 1.3: Synthesis and composition data according to 1H NMR; EHMA: 2-ethyl
hexyl methacrylate; LMA: lauryl methacrylate; ODMA: octadecyl methacrylate;
Conv.: conversion given in %; DPn th: theoretical degree of polymerisation; DPn
exp: the-experimental degree of polymerisation measured;
(i): Synthesis performed using RAFT in toluene
Example 2 : Demonstration of micelle formation in an aqeous system or polar solvent
Micellar aggregates can be formed from the copolymers of Example 1 by a number
or routes. One such route is described below. Size distribution measurements using a
Malvern Nano Zetasizer were performed to demonstrate micelle formation for solutions of
copolymers in water-based mixtures or in organic solvents such as toluene, ethyl acetate,
dodecane, hexane, Exxsol D140, Solvesso 200ND and Isopar V.
Production and characterisation of micelles
1. The copolymer was dissolved in a good solvent with the assistance of gentle
agitation (for example using a magnetic stirrer set on low for 1 hour).
2. When the polymer had dissolved, a second solvent was added drop-by-drop until it
reached a large enough quantity that it became the continuous phase. The second
solvent was chosen to be a poor solvent for one of the copolymer blocks and a
good solvent for the other block, thus inducing the formation of micelles.
3. To ensure equilibrium was reached, the mixture was gently agitated for 2 hours,
using a magnetic stirrer set on low. At the conclusion of this period, stable
micelles were formed. The following sections detail the precise conditions used to
form micelles from the copolymers of Example 1 in a range of solvents.
Table 2.1 shows the structures of the copolymers used for this experiment, the concentration
of the micellar solutions and recorded micelle size in solution.
Aqueous systems and polar solvents
1. The copolymer was dissolved as a lwt% solution in either water or ethanol. As
described in patent applications WO08071957 and WO10038046, ethanol was used
(at 8wt%) if the copolymer did not dissolve directly in water or other organic
solvents.
2. A second solvent, in this case water, methanol or ethyl acetate was added in a drop by
drop manner until a concentration of 0.05- lwt% was reached.
3. The solution was gently agitated for at least 2 hours using a magnetic stirrer set on
low in order to allow the micelles to stabilise in solution.
To ensure an accurate measurement, using the Malvern Nano Zetasizer it is important to
have the correct concentration for a given copolymer solution. The optimum
concentration range for the examples herein was shown to be 0.05- lwt%. The size
distribution measurements in Table 2.1 shows that the copolymers form micelles, since
the minimum diameter is 6 - 1lnm and if the copolymers were present as unimers, the
diameter would be less than 5 nm.
Table 2.1
Table 2,1 Zeta sizer data obtained from copolymers dispersed in water-based and polar media
i)_Measurements made from aqueous solution; ii) Measurements made from methanol solution;
iii) Measurements made from ethyl acetate solution. Measurements collected using a Malvern
Zetasizer.
The data in Table 2.1 demonstrate that copolymer micelles can be formed in a range of polar
solvents, with the size of the micelles ranging from 6 to 108nm.
Example 3. Coating Crystal in a aqueous system
3.a. Layer by Layer Coating of a crystal, with one layer of homopolymer containing
cationic charges, and one layer of negatively polarised copolymer
Thiamethoxam crystals (TMX) with a size distribution of approximately 2.5 - 5mih
(Figure 3.1) were coated with two layers of copolymers.
First, a layer of poly(diallyldimethylammonium chloride) (PDADMAC) homopolymer
containing cationic charges was applied on the crystal. Then, a layer of negatively polarised
copolymer, P(BuMA(15)-£-MAA(120)) was applied following the protocol described below.
The coating protocol required that the crystal to be coated remained dispersed in the liquid
medium. In this example, TMX was coated in water. As TMX is soluble in water up to
4.1g/litre, a saturated stock solution of TMX was prepared at a concentration much higher
than 4.1 g/litre. The experimental procedure is detailed below:
1. l g of negatively charged TMX particles was placed in 10ml of TMX saturated stock
solution.
2. A 10ml PDADMAC solution (0.35wt%) was added to the TMX solution.
3. The sample was tumbled for 30minutes.
4. The sample was then centrifuged for 2minutes at 2000rpm in order to deposit the
particles onto the bottom of the tube.
5. Following centrifugation 15ml of the supernatant was removed.
6. This was replaced by 15ml of TMX saturated stock solution.
7. The sample was tumbled for 30 minutes.
8. The sample was then centrifuged for 2 minutes at 2000rpm in order to deposit the
particles onto the bottom of the tube.
9. Following centrifugation, 15ml of the supernatant was removed
10. The solution concentration was then brought back up to 10ml by adding 5ml of TMX
saturated stock solution.
11. 10ml of a lwt % solution of P(BuMA(15)-6-MAA(120)) was added to the TMX
solution.
12. The sample was tumbled for 30 minutes.
Q
13. The sample was then centrifuged for 2 minutes at 2000rpm in order to deposit the
particles onto the bottom of the tube.
14. Following centrifugation 15ml of the supernatant was removed.
15. This was replaced with 15ml of TMX saturated stock solution.
16. The sample was tumbled for 30 minutes.
17. The sample was then centrifuged for 2 minutes at 2000rpm in order to deposit the
particles onto the bottom of the tube.
18. Following centrifugation 15ml of the supernatant was removed.
19. The solution concentration was then brought back up to 10ml by adding 5ml of TMX
saturated stock solution.
Note: The pH of each solution was adjusted to, and maintained at pH9 using a 35wt%
ammonia solution or a 0.1M potassium hydroxide (KOH) solution in water.
A sample of the mixture in step 8 was withdrawn and analysed by Scanning Electron
Microscopy. Pictures of this final coating are shown in Figure 3.2(a & b)
Figure 3.2 clearly shows micellar deposits on all faces, corners and edges of the TMX
crystals as indicated by the uneven topography and rounded edges in comparison to the
uncoated TMX crystals shown in Figure 3.1.
3.b. Layer by Layer Coating of a crystal, with one layer of copolymer containing
cationic charges, and one layer of negatively polarised copolymer
The adhesion promoter PDADMAC of example 3a can be replaced by cationically charged
copolymers and by repeating the process of 3a in order to deposit a double layer of
copolymer micelles. In this example a first layer of a cationic copolymer PDEA(26)-b-
PDMA(74 non quaternized units and + 22 quaternized units) was deposited before a second
layer of an anionic copolymer PDPA(90)-b-PMAA(50); PDEA meaning poly(N,N'-
diethylaminoethyl methacrylate), PDMA meaning poly(N,N'-dimethylaminoethyl
methacrylate), PDPA meaning poly(diisopropylaminoethyl methacrylate) and PMAA
meaning polymethacrylic acid. Figure 3.3 shows that the coating covers all crystal faces,
corners and edges.
The presence of micelles all over the surface of the TMX crystals is clearly illustrated in
Figure 3.3a and comparison of Figure 3.3b and 3.1b illustrates the crystal surface has been
significantly modified by surface coating.
Zeta potential measurements of the coated TMX particles
The deposition of sequential copolymer layers on the surface of the TMX crystals can be
demonstrated by Zeta potential measurements as each layer has a different charge,
(PDEA(26)-b-PDMA(74+22) has a positive charge and PDPA(90)-b-PMAA(50) a negative.
Using Zeta potential measurements it is possible to track the deposition of at least 5
alternatively charged layers, as shown in Figure 3.4.
The coating procedure, either using a homopolymer or a copolymer layer as an adhesion
promoting pre-treatment for the subsequent deposition of a second copolymer layer, was
carried out on TMX and tetraacetylethylene diamine (TAED). In addition, several types of
copolymers were involved in this coating procedure demonstrating that this procedure is
flexible and easily adaptable. Table 3.1 summarises a range of systems prepared using the
coating procedure previously outlined. Figures 3.5-3.7 demonstrate the deposition of
micelles onto all faces of TMX and TAED.
Table 3.1
TMX: Thiamethoxam; TAED: tetraacetylethylene diamine; PBuMA: polybutyl
methacrylate; PDAMAC: poly(diallyldimethylammonium chloride); PDEA: poly(N,Ndiethylaminoethyl
methacrylate); PDMA: poly(N,N-dimethylaminoethyl methacrylate);
PDPA: poly(N,N'-diisopropylaminoethyl methacrylate); PMAA: polymethacrylic acid;
PTFEMA: poly(trifluoroethyl methacrylate).
Table 3.1: Description of crystals coated according to the procedure described in
present invention.
Example 4 : Crosslinking and alteration of dissolution profiles
Crosslinking is described as the physical and/or chemical interaction between chains of the
AB diblock copolymer. The crosslinking can take place either in the core of the micelles, in
the corona of the micelles and/or between the coronas of two contiguous micelles.
In this example, crosslinking of copolymer micelles is used to decrease the solubility of a
coated crystalline material in water. Micelles comprising AB di-block copolymers were
deposited on the surface of crystals of a crystalline material (for example a pharmaceutical or
an agrochemical) in aqueous and oil based liquid media. Addition of linear and cyclic
diamine molecules to this system led to the modification of the topology of the micellar
coating. This also resulted in a decrease in the release rate of the crystalline material in
water.
A) Example of crosslinking in water based system.
TMX was coated with Poly(BuMA5 -b-MAA54 ) using the protocol described in Example 3a.
Following coating the sample was crosslinked following the procedure described below.
1. A diamine compound (see Table 4.1 for mass and molar ratio compared to MAA
functions in the copolymer) was added to the solution (lg coated TMX in 10ml TMX
saturated stock solution) and tumbled for 48 hours.
2. The mixture was then centrifuged for 2 minutes at 2000rpm and approximately 8ml
of the supernatant liquid was removed. The same quantity of TMX saturated stock
solution was added, and the mixture tumbled again for 30 minutes.
3. The mixture was then centrifuged for 2 minutes at 2000rpm and 8ml the supernatant
liquid was removed, 8ml of TMX saturated stock solution was added.
4. The sample was dried under vacuum at 50°C for 8 hours thus removing all solvents.
A visual release test (i.e. observation of the speed and extent of dissolution) was performed
on the coated particles before and after crosslinking. It was found that the crosslinked
samples dissolved at a slower rate compared to the uncrosslinked samples.
Crosslinked and uncrosslinked samples were weighed before and after 8 hours in water in
order to measure the percentage weight loss. Results are shown in Table 4.1. They confirm
the visual release rate observation: TMX samples coated with crosslinked copolymers show
less weight loss, in other words less dissolution, than samples coated with un-crosslinked
copolymer.
Table 4.1
Molar ratio of
carboxylic acid Mass of
% of
Cross-linker functions crosslinker
weight loss
compared to amine used (g)
functions
Control (coated but not crosslinked) - 0.0000 84
Methylene bis(cyclohexylamine) 1 : 1.0 0.0715 54
Methylene bis(cyclohexylamine) 1 : 2.1 0.1454 35
Methylene bis(cyclohexylamine) 1 : 3.1 0.2170 38
Hexamethylene diamine 1 : 2 0.0348 4 1
Hexamethylene diamine 1 : 2.4 0.0708 36
Hexamethylene diamine 1 : 3.6 0.1057 34
Table 4.1 : Percentages weight loss of the coated TMX particles
To perform release rate analysis, 45-55mg of each sample was accurately weighted into a
60ml powder jar and 50ml of dispersant solution (0.1%w/w Aerosol OTB, 0.5%w/w Morwet
D425 in DI water) added at time zero. The samples were then placed on a roller moving at
20rpm. A time point measurement of TMX in solution was made by extracting 3ml of
solution and passing it through a 0.45 mih syringe filter. The filtrate was then analysed by
HPLC to determine the concentration of TMX. The analysis was carried out by HPLC using
an Agilent 1100 (equipped with an auto-injector), a 50 X 3.0 MM ACE 3mM C18 COLUMN
FROM ACE, PART NUMBER ACE-1 11-0503 and mobile phases of (A) Acetonitrile +
0.1% Formic acid and (B) ASTM II Water + 0.1% Formic acid. Analysis was carried out
with an injection load of 5m1and column temperature of 40°C. Data were collected at a
range of time points.
Total TMX content of the samples was determined by weighing 30-50mg of each dry
powder accurately weighted into an aluminium weighting boat. The weighing boat was then
placed in a volumetric flask and 50ml acetonitrile added. The flask was gently swirled until
a colourless solution was formed. This solution was analysed using the HPLC conditions
described previously.
Table 4.2 shows the quantity of TMX release after 1, 8 and 24 hours as a percentage of the
total TMX concentration as measured by the method described previously.
Table 4.2
Table 4.2: Quantity of thiamethoxam released over time periods 1, 4, and 24 hours as a
percentage of the measured total content. Both crosslinkers were present in a molar ratio of
1:1.5 COOH functions to diamine.
Example 5: Demonstration of increased polymer deposition using copolymer micelles
The coating procedure described in Example 3 was used to deposit 4 layers of homopolymer
electrolyte (PDADMAC / PNaSS / PDADMAC / PNaSS) onto TMX crystals, sample 5.1;
and 4 layers of copolymer micelles (P(BuMA26-DMAEMA 5 (50% quaternized)/P(BuMAi 5-
MAA120)/ (P(BuMA2 6-DMAEMA 5 (50% quaternized)/ P(BuMAi 5-MAAi20) onto TMX
crystals, sample 5.2.
The samples were then dried in at 40°C in a vacuum oven at (lOOOmbar below atmospheric
pressure) overnight. After this period the liquid was observed to have been removed and dry
coated particles of TMX remained. 30-50mg of each dry powder was accurately weighted
into an aluminium weighting boat. The weighing boat was then placed in a volumetric flask
and 50ml acetonitrile added. The flask was gently swirled until a colourless solution was
formed. This solution was analysed to determine the total content of TMX present. The
analysis was carried out by HPLC using an Agilent 1100 (equipped with an auto-injector), a
50 X 3.0 MM ACE 3mM C18 COLUMN FROM ACE, PART NUMBER ACE-1 11-0503
and mobile phases of (A) Acetonitrile + 0.1% Formic acid and (B) ASTM II Water + 0.1%
Formic acid. Analysis was carried out with an injection load of 5m1and column temperature
of 40°C. Table 5.1 details the mobile phase ratios used during analysis.
Table 5.1
Table 5.1: Mobile phase ratios for the total content analysis of TMX.
The total content of the TMX samples is shown in Table 5.2
Table 5.2
Table 5.2 Total Thiamethoxam (TMX) content of samples coated by 4 layers of (a)
homopolymer; and (b) 4 layers of copolymer micelles
Table 5.2 clearly demonstrates that more than 6 times the weight of polymer has been
deposited using copolymer micelles rather than homopolymer.
Example 6: Increasing micelle size by chemical addition
It is well established that micelle size can be increased by adding chemicals which partition
into the micelle core. In this example we demonstrate that the micelles from the copolymers
in Example 1 can be loaded with chemicals such that a particle size increase is observed.
Observation of size alteration in the presence of such chemicals is further demonstration of
the presence of micelles.
In a 120 ml screw-top jar, the copolymer (O.lg, 0.5wt%) was dissolved in ethanol (1.6g,
8wt%), under stirring. Water (18.5g, 91.5wt%) was added drop by drop onto this mixture,
always under stirring. When the mixture became cloudy, the stirring was stopped. Finally,
styrene (40g, twice the mass of the aqueous solution) was poured above the aqueous phase.
The two-phase system was left to equilibrate for two days. The lower phase, containing the
loaded micelles, was extracted using a pipette and stored for further analysis and/or use.
(Weight Percentages are given compared to water.)
A Malvern Nano Zetasizer was used to monitor the size of copolymer micelles after the
addition of chemicals. In the first instance, styrene was added to copolymer micelles of
P(BuMAi5-b-MAAi2o). Size distribution measurements shown in Table 6.1 show that the
minimum micelle diameter increased from 20 to 30nm.
As expected, a greater increase in micelle size can be obtained by using micelles with a
larger hydrophobic core, for example those formed from copolymer P(BuMAi27-b-MAA i).
In this case, size distributions measurements shown in Table 6.1 demonstrate a 29% increase
in the average size of the micelles.
Table 6.1
P(BuMAi5-b-MAAi2o) P(BuMAi2v-b-MAA5i)
Before the loading 20 - 70nm 20 - 50nm
After the loading 30 - 70nm 30 - 60nm
Table 6.1 Size distribution measurement before and after the oading of copolymer micelles
with styrene.
The increase in micelle size in the presence of styrene is further evidence that micelles have
been formed.
Example 7: Coating of Griseofulvin Crystals
Griseofulvin crystals were coated with two layers of copolymer using the protocol as
described in section 3a .
The copolymers used were Poly(BuMA6o-b-MAA55) and Poly(BuMai 5-b-MAAi2o) at 0.4,
1, 2.5 and 5wt%.
A SEM image demonstrating the coating of Griseofulvin with PDADMAC at 0.35wt%
and Poly(BuMAi5-b-MAAi2o) at 1wt% can be seen in Figure 7.1.
Example 8 - Targeted delivery of photoprotectants to the crystal interface
The micelle core can be loaded swollen as demonstrated in Example 6. In this example the
micelle size was increased by addition of a photoprotectant and the impact on photostability
of an agrochemical coated with such loaded micelles was demonstrated. The addition of the
photostabiliser can be before or after coating the active ingredient with the copolymer
micelles.
To load the micelle prior to coating a Poly(BuMAi5-b-MAAi2o) solution in ethanol was
prepared (lg polymer, 8g ethanol,) to which 0.5g of 2,6-di-butyl-4-methyl-phenol was
added. After complete dissolution water and ammonia solution (35%wt) are added to make
a l%wt copolymer solution at pH 9. This micellar solution was then used to coat 0.86 g of
emamectin benzoate particles using the method below.
1. l g of emamectin benzoate particles was placed in 10ml of deionised water and gently
vortexed to disperse the particles.
2. 10ml o f the P(BuMA(15)-6-MAA(120))/ 2,6-di-butyl-4-methyl-phenol solution
described above was added to the emamectin benzoate dispersion.
3. The sample was tumbled for 30 minutes.
Those skilled in the art will recognize that an adhesion promoter can be optionally added.
Those skilled in the art will also recognize that the loading of the micelles was not optimized
for this example and further swelling of the micelles is possible.
The post loading approach is described below.
1. A l%wt Poly(BuMAi5-b-MAAi2o) micellar solution at pH 9 was prepared in water (l%wt
polymer, 8%wt ethanol, 91%wt water/ammonia solution).
2. 0.86g of emamectin benzoate was weighed out and placed in a centrifuge tube and 8.6ml
of water was added.
3. The sample was then gently vortexed in order to slowly disperse the active.
4. 8.6ml of 1% micellar solution was added and the sample tumbled for 30 mins.
5. 0.22g of 2,6-di-butyl-4-methyl-phenol and 1.72g of lignin sulphonate [Polyfon™ H] were
then added and the dispersion was tumbled until homogenous (in this example the sample
was tumbled for 1 hour).
- o -
SEM characterisation of the coated sample demonstrates the association of the loaded
copolymer micelles with the emamectin benzoate crystal particles, Figure 8.1
The photostability of the coated samples was assessed by irradiating samples and
measuring the remaining concentration of emamectin benzoate, by gathering data for a
number of time points the half-life for emamectin benzoate under irradiation can be
determined.
50ppm dilutions of the emamectin benzoate dispersions were prepared in ultra-pure
water. 8 x 2m1drops of these dilutions were applied to glass microscope slides and irradiated
at 750W/m2 with samples taken after 0, lh, 3h, 6h, 17h and 25hour irradiation. Deposits
removed from slides using 40/50/10 MeCN/0.1% H3P04/THF solvent and analysed by
reverse-phase LC with MS detection. Standards were prepared as follows:
- 8 x 2m1drops of application solution were added directly into liquid chromatogrpahy
vials and immediately the solvent was added before storing at 4°C until analysis.
- Time zero samples were prepared by dispensing 8 x 2m1 drops of application solution
onto a glass microscope slide, allowing the solvent to evaporate and immediately
removing the deposit by immersion into the wash-off solvent.
Table 8.1 demonstrates the impact of photoprotectants in the micellar core on the half-life of
emamectin benzoate.
Emamectin Ratio of Emamectin
Poly(BuMAi 2,6-di-butyl-4- lignin
Benzoate Benzoate sun
description 5-b-MAAi2o) methyl-phenol sulfonates to
concentratio test half-life
(%w/w) (%w/w) Emamectin
n (%w/w) (hours)
Benzoate
uncoated
Emamection 4.8 2.4 - - 8
Benzoate
Emamectin
Benzoate
4.8 2.4 - - 6
coated with co
polymer
Emamectin
Benzoate
coated with co 4.4 2.2 - 2:1 8
polymer and
lignin
sulfonates
Table 8.1 The effect of copolymer micelles and photoprotectants on the half-life of
Emamectin Benzoate
Example 9: Preparation of Polymers and Block Copolymers for micelle formation in
apolar liquids
The surface treatment of the present invention is hydrophobic. The copolymers described in
this example are AB block copolymers comprising a substantially hydrophobic block A, and
a substantially hydrophobic or hydrophilic block B which has a different affinity for or
solubility parameter within the liquid media where the copolymers are dispersed compared to
block A, such that micelles form in the liquid medium.
Block A can comprise of one or more monomers, for example; styrene (S) and styrene
derivatives, methacrylate and derivatives such as 2-ethyl hexyl methacrylate (EHMA), lauryl
methacrylate (LMA), octadecyl methacrylate (ODMA), glycidyl methacrylate (GMA) and
propylene oxide (PO). Those skilled in the art will appreciate the synthesis described in this
example is not limited to the monomers listed here.
In the current example, the hydrophobic or hydrophilic block B was composed of
methacrylic acid (MAA), 2-hydroxyethyl methacrylate (HEMA) or 2-ethyl hexyl
methacrylate but those skilled in the art will understand that other monomers leading to a
hydrophilic block can also be used.
The copolymers used herein were produced by Reversible Addition-Fragmentation Chain
Transfer (RAFT) according to the protocol described in the patent applications
WO08071957 and WO10038046 or by nitroxide mediated polymerisation (NMP) according
to the protocol described in WO2007/057620A1. Therefore the block copolymers may be
prepared by means of controlled living polymerisation techniques, such as group transfer
polymerisation (GTP), atomic transfer radical polymerisation (ATRP), and activated
regenerated by electron transfer (ARGET) or activated generated by electron transfer
(AGET) that can synthesize well-defined homopolymers and block copolymers.
Examples of the composition of new prepared copolymers are given in Table 9.2.
A) Use of RAFT to synthesise copolymers
In this example, in addition to structures described in WO08071957 and WO10038046, new
copolymers structures were produced by RAFT polymerization using the RAFT agent,
2-cyanoisopropyl dithiobenzoate (CPDB). Whilst the current example prepares the block
copolymer CPDB, those skilled in the art will appreciate that other RAFT agents may be
used.
RAFT synthesis of Polv(EHMA-6/ocfc-MAA' copolymer : P(EHMA-6-MAA)
A series of poly[EHMA -£-MAAy] copolymers were prepared by RAFT polymerization
using CPDB as chain transfer agent, azobisisobutyronitrile (AIBN) as initiator and
propan-2-ol (IPA) as a solvent. The synthesis was a two step process: First, the
hydrophobic block (EHMA) was synthesised, then the synthesis of the hydrophilic block
(MAA) was initiated from the PEHMA homopolymer.
a) Synthesis of the block A: PEHMA.
EHMA (15g, 75.7mmol, 60eq), CPDB (0.31g, 1.26mmol, leq), AIBN (0.10g, 0.63mmol,
0.5eq) and IPA (solvent, 6.82g, 114mmol) were added in a two necked flask containing a
magnetic stirrer equipped with a cooling column. The mixture was degassed by nitrogen
bubbling and heated at 90°C in a thermostatically controlled oil bath under a nitrogen
atmosphere. The reaction was left under stirring for a minimum of 2hours 30minutes (in
this example 3hl5min). A sample of the crude mixture was withdrawn and analysed by
size exclusion chromatography (SEC - See Figure 9.4), and by Proton Nuclear Magentic
Resonance (Ή NMR). A conversion of 98% was determined by Ή NMR in CDCl3 hence
the resultant product was P(EHMA)Xhomopolymer where x = 59.
b) Synthesis of block Bfrom block A
30 minutes before the end of the first synthesis, MAA (6.54g, 76.0mmol, 60 q), AIBN
(0.10g, 0.64mmol, 0.5eq) and IPA (solvent, 45.39g, 757mmol) were added in another
flask containing a magnetic stirrer. The mixture was degassed by nitrogen bubbling.
At the end of the first synthesis (in the current example 3hl5min), the thermostatically
controlled oil bath was removed to stop polymerisation. The mixture containing the
second monomer was then transferred into the initial two necked flask via a cannula. This
flask was heated again at 85°C in the thermostatically controlled oil bath (equipped with a
cooling column) under nitrogen atmosphere to achieve the preparation of the second block
of copolymer. After a minimum of 2h30min (in this example 2h35min), a sample of the
crude mixture was withdrawn and analysed by H NMR and SEC (Figure 9.4).
A conversion of 88% was measured by NMR in DMSO. The resultant product was
determined as P(EHMA x-Z>-MAA ) copolymer where x = 59 and y = 53.
Other P(EHMA -6-MAAy) polymers were prepared with x=68 and y=25 and with x=33
and y=21. The generic structure of the corresponding P(EHMA -6-MAA y) copolymers is
given below.
Formula 9.1: Generic structure of the P(EHMA - -MAA ) synthesised by RAFT
The P(EHMA x-6-MAA ) copolymers can also be prepared by NMP, ATRP, GTP and
indirect anionic polymerization.
Preparation of other copolymers by RAFT synthesis.
Various block copolymers were synthesised. Block A was obtained from various
methacrylated based monomers such as EHMA, LMA, ODMA and TFEMA. Block B was
composed of hydrophilic units such as MAA and HEMA, or hydrophobic monomers such as
EHMA. In this case, toluene was the solvent used for the synthesis instead of isopropanol.
The method described above for the synthesis of P(EHMAx-b-MAAy) was used, which led
for example to the successful synthesis of P(LMAx-b-EHMA ) and P(ODMAx-b-MAA ) .
The conversion rates, block sizes and reaction time are given in Table 9.2.
For the synthesis of (PEHMA5i-r-PGMA22)-b-PMAA47 the following protocol was used:
a) Synthesis of the blockA: PGMA and EHMA
GMA (3.29g, 23.2mmol, 25.6eq), EHMA ( l l.Olg, 55.6mmol, 61.3eq), CPDB (0.22g,
lmmol, eq), AIBN (0.08g, 0.5mmol, 0.5eq) and IPA (solvent, 24.32g, 407mmol) were
added in a two necked flask containing a magnetic stirrer equipped with a cooling
column. The mixture was degassed by nitrogen bubbling and heated at 82°C for 5 hours
in a thermostatically controlled oil bath under a nitrogen atmosphere and then reduced to
70°C for another 16 hours. A sample was removed for NMR analysis. A conversion of
93% GMA and 89% EHMA was measured by 1H NMR in CDC13.
b) Synthesis of block Bfrom blockA
30 minutes before the end of the first synthesis, MAA (4.7882g, 55.6mmol, 56.4eq),
AIBN (0.0771g, 0.5mmol, 0.5eq) and IPA (solvent, 24.5034g, 408.7mmol) were added in
another flask containing a magnetic stirrer. The mixture was degassed by nitrogen
bubbling.
At the end of the first synthesis, the thermostatically controlled oil bath was removed to
stop polymerisation. The mixture containing the second monomer was then transferred
into the initial two necked flask via a cannula. This flask was heated again at 82°C for 4
hours in the thermostatically controlled oil bath (equipped with a cooling column) under
nitrogen atmosphere and then reduced to 70°C for 16 hours to achieve the preparation of
the second block of copolymer. Polymers were precipitated out in diethyl ether and dried
in a vacuum oven at 40°C.
A conversion of 82% for the MAA was measured by 1H NMR in DMSO. The resultant
product was determined as (PEHMAx-r-PGMA )-b-PMAA copolymer where x = 51, y = 22
and z = 47.
Formula 9.2: Generic structure of the (PEHMAx-r-PGMA )-b-PMAA synthesised by RAFT
B) Use of NMP to synthesise copolymers
In this example, according to the protocol described in the patent WO2007/057620A1, new
copolymers structures were produced by NMP polymerization using the NMP agent
Blocbuilder®. Whilst the current example prepares the block copolymer using Blocbuilder®,
those skilled in the art will appreciate that other NMP agents may be used.
NMP synthesis of PS b- HEMA -r-PS
In the first step, the following conditions were used for the synthesis of PS with a targeted
polymerisation degree of 55. Styrene (15.00g, 0.14mol) and Blocbuilder® (l.OOg, 2.62mmol)
were added to a 100ml round bottom flask equipped with a magnetic stirrer. The reaction
flask was degassed by nitrogen bubbling for 20 minutes and then heated at 90°C in a
thermostatically controlled oil bath under a nitrogen atmosphere. After 78hr40 min of
polymerization, a sample was withdrawn and analysed by 1H NMR (CDC13) . A conversion
of 76.9% was determined by 1H NMR in CDCI 3, hence the resultant product was PSX
homopolymer where x = 42.
At the end of this step 15g chloroform was added to solubilise PS. The reactive mixture was
precipitated drop by drop in 300ml cold methanol and then filtered on paper. The product
was dried down in a vacuum oven.
In a second step, newly synthesised PS (l.OOg, 0.23mmol), styrene (0.24g, 2.32mmol),
HEMA (2.95g, 22.7mmol) and dimethylformamide (DMF, 4.02g, 0.55mmol) were added to
a 50ml round bottom flask equipped with a magnetic stirrer. PS was solubilised in DMF by
using a sonic bath (20min). The reaction flask was degassed by nitrogen bubbling for 20
minutes and then heated at 90°C in a thermostatically controlled oil bath under a nitrogen
atmosphere. After 18 hours of polymerization, a sample was withdrawn and analysed by 1H
NMR (DMSO). A conversion of 90.0% for HEMA and 8.0% for styrene was determined by
1H NMR in DMSO, hence the resultant product was PSx-b-(HEMA -r-PS ) diblock
copolymer, where x = 42, y = 90 and z = 8.
At the end of this step, 7mL DMF was added to solubilise the copolymer. The reactive
mixture was precipitated drop by drop in 300ml cold ether and then filtered on paper. The
product was dried down in a vacuum oven.
Other PSx-b-(HEMAy-r-PS ) were prepared with x=86, y=57 and z = 0 and with x=74, y=30
and z=10. The generic structure of the corresponding PSx-b-(HEMAy-r-PS ) copolymers is
given below.
Formula 9.3: Generic structure of the PSx-b-(HEMAy-r-PS ) synthesised
C) Characterisation
SEC was used to determine the number-average molar mass (M ) and thus demonstrate the
increase of molar mass due to the addition of the second block during the polymerisation.
SEC was also used to determine the polydispersity index (PDI= Mw Mn, where Mw is the
weight-average molar mass) of the polymers and copolymers, a low PDI being necessary to
achieve regular micelles.
The samples were injected in the SEC equipment (2 PL gel 5 Micron Mixed-c columns) and
analysis was performed as described below
- The eluent was composed of tetrahydrofuran (THF) for P(EHMA -Z»-MAA )
copolymers and DMF for PS -b-(HEMA -r-PS ) copolymers (elution flow rate:
lml/min, run time: 30 min).
- The calculation (for data analysis) was made with a calibration curve based on
poly(methyl methacrylate).
- Before injecting the polymer samples containing methacrylic acid units, a
methylation reaction was performed to convert the acid groups into methyl esters,
using trimethylsilyldiazomethane as the methylating agent, in order to solubilise the
polymers in THF to perform the analysis.
- The samples (20mg) were dissolved in the eluent and then filtered with a 0.2um
PTFE filter into the SEC vials.
An example of SEC chromatogram is given in Figure 9.4. The SEC chromatogram of the
first block of P(EHMA) and the chromatogram of the copolymer R(EHMA- -MAA) are
represented. The observed shift of the chromatogram is consistent with an extension of
chains between both steps.
Table 9.1
Copolymer PDI - block 1 PDI -block 2
P(EHMA 9-b-MAA 5 3) 1.68 1.85
P(S 2-b-[HEMA9o-r-S8J) 1.31 2.03
P(S -b-HEMA 7) 1.65 1.58
P(S 4-b-[HEMA 3o-r-S,o]) 1.43 1.84
P(LMA3 3-b-EHMA ,o6) 1.23 1.62
.
- 46 -
Table 9.1 : Indication of PDI obtained by SEC for some copolymers described in Table 9.2
1H NMR was used to determine the conversion of each polymerisation and the degree of
polymerisation (in number: DP ) calculated accordingly for each block.
1H NMR was performed with a 500MHz apparatus (Bruker), in CDCI 3 for the
homopolymer, and in DMSO for the copolymer.
Table 9.2
Table 9.2: Synthesis and composition data according to 1H NMR; EHMA: 2-ethyl
hexyl methacrylate; HEMA: 2-hydroxyethyl methacrylate ; MAA: methacrylic acid;
S : styrene; LMA: lauryl methacrylate; ODMA: octadecyl methacrylate; Conv.:
conversion given in %; DPn th: degree of polymerisation targeted; DPn exp: degree
of polymerisation calculated;
i) Synthesis performed using RAFT in IPA
ii) Synthesis performed using NMP in DMF
iii) Synthesis performed using RAFT in toluene
Example 10: Demonstration of micelle formation in apolar liquid media
Micellar aggregates can be formed from the copolymers of Example 9. Size
distribution measurements using a Malvern Nano Zetasizer were performed on solutions of
in apolar solvents such as dodecane, hexane, Exxsol D140, Solvesso 200ND and Isopar V.
1. To demonstrate the formation of micelles in apolar solvent, a solution (10 to 20ml) of
copolymer was prepared by dissolving the copolymer powder in -THF (Sigma-
Aldrich) (lwt%).
2. When the polymer had dissolved, a second solvent as indicated in Table 10.1 was
added drop-by-drop until it reached a large enough quantity that it became the
continuous phase. For size distribution measurements, this was when the
concentration of copolymer reached -0.01 wt%.
3. To ensure that equilibrium was reached the mixture was gently agitated for over one
hour (mixing with a magnetic stirrer set on low).
To ensure an accurate measurement by the Malvern Nano Zetasizer, concentrations of the
copolymer solution were varied so the sample was in the optimum detection range of the
instrument for the polymer being examined. The size distribution measurements shown in
Table 10.1 shows that the copolymers form micelles, since the minimum diameter measured
was 20nm and if copolymers were present as unimers, the diameter would have been less
than 5nm. In all cases a clear solution was formed following stage 1. The results in Table
10.1 demonstrate that in each case micelles were formed following stage 3.
Examples of hydrophobic copolymer micelles solutions which were prepared according to
the general procedure are described in Table 10.1.
size distribution following stage 3
(nm)
Exxsol Solvesso
Dodecane Hexane Isopar V
D140 200ND
230 - 240 100 - 110 95 - 105 20 - 80 25 - 70
Table 10.1: Micelle size measurements of copolymer P(Ethyl Hexyl MA(29)-b-MAA(48)) in
apolar liquid media. Measurements collected using a Malvern Nano Zetasizer.
Example 11 - Coating of a crystalline particle
A copolymer solution was prepared by dissolving the copolymer in a good solvent (toluene /
THF) under gentle agitation. Once a homogeneous solution was obtained a second solvent
(for example hexane / Isopar V) was added to the mixture using drop-by-drop addition. The
final concentration of the copolymer in solution was 0.4wt%. The second solvent was
- 4 -
selected to be a poor solvent or non-solvent for one of the blocks and a good solvent for the
other block. The mixture was gently stirred and left for more than 2 hours in order to allow
the copolymers to equilibrate into micelles. When the micelle system had reached
equilibrium, l g of TMX air milled crystals was added to the mixture. The sample was then
allowed to tumble for at least 2 hours in order to ensure complete mixing and thus allow time
for the micelles to coat the individual TMX crystals. Table 11.1 shows possible but not
limiting combinations of copolymers and organic solvents which form micelles and can be
used to coat crystals.
Table 11.1
Table 11.1: Composition of copolymers solutions in apolar hexane and in Isopar V
The copolymer solutions in Table 11.1 were used to coat TMX particles using the
methodology outlined previously. Figures 11.1 and 11.2 demonstrate that micelles have
been deposited from the organic solutions.
Figures 11.1 and 11.2 clearly illustrate the deposition of micelles from a range of organic
solvents on all crystal faces, including corners and edges of TMX.
Example 12: Crosslinking of copolymer micelles
Crosslinking is described as the physical and/or chemical interaction between chains of the
AB diblock copolymer. The crosslinking can take place either in the core of the micelles, in
the corona of the micelles and/or between the coronas of two contiguous micelles.
In this example, crosslinking of copolymer micelles was used to decrease the solubility of a
coated crystalline material in water. Micelles comprising AB di-block copolymers were
deposited on the surface of crystals of a crystalline material (for example a pharmaceutical or
an agrochemical) in oil based liquid media. Addition of either linear or cyclic diamine
molecules to this system led to the modification of the topology of the micellar coating. This
also resulted in a decrease in the release rate of the crystalline material in water compared to
crystalline material coated with un-crosslinked copolymer micelles.
Example of crosslinking in oil based system
TMX was coated by using the same protocol as example 11.
A copolymer solution (lOg) was prepared by dissolving (PEHMA 5i-r-PGMA 22)-b-PMAA47
copolymer in a good solvent (THF) under gentle agitation. Once a homogeneous solution
was obtained a second solvent (hexane) was added to the mixture using drop-by-drop
addition. The final concentration of the copolymer in solution was 0.4wt%. The second
solvent was selected to be a poor solvent or non-solvent for one of the blocks and a good
solvent for the other block. The mixture was gently stirred and left for 24 hours in order to
allow the copolymers to equilibrate into micelles. When the micelle system had reached
equilibrium, l g of TMX air milled crystals was added to the mixture. The sample was then
allowed to tumble for 24 hours in order to ensure complete mixing and thus allow time for
the micelles to coat the individual TMX crystals.
Crosslinking was then performed.
5. A diamine compound (see Table 12.1 for mass and molar ratio compared to MAA
functions in the copolymer) was added to the solution and tumbled for 24 hours.
6. The mixture was then centrifuged for 2 minutes at 2000rpm and approximately 9ml
of the supernatant liquid was removed. The same quantity of water based TMX
saturated stock solution was added, and the mixture tumbled again for 30 minutes.
7. The mixture was then centrifuged for 2 minutes at 2000rpm and 9ml the supernatant
liquid was removed.
8. The sample was then dried under vacuum at 50°C for 8 hours thus removing all
remaining solvents.
Table 12.1
Molar ratio of
(carboxylic acid + Mass of crosslinker
Cross-linker
epoxy) functions used (g)
compared to amine
Control (coated but not crosslinked)
Hexamethylene diamine (0.4 wt%) 1 : 3.8 0.0348
Hexamethylene diamine (5 wt%) 1 : 1.1 0.1566
Table 12.1 Percentages weight loss of the coated TMX particles
To perform release rate analysis 45-55mg of each sample was accurately weighted into a
60ml powder jar and 50ml of dispersant solution (0.1%w/w Aerosol OTB, 0.5%w/w Morwet
D425 in deionised water) added at time zero. The samples were then placed on a roller
moving at 20rpm. A time point measurement of TMX in solution was made by extracting
3mls of solution and passing it through a 0.45 mih filter. The filtrate was then analysed by
HPLC to determine the concentration of TMX. The analysis was carried out by Highperformance
liquid chromatography (HPLC) using an Agilent 1100 (equipped with an autoinjector),
a 50 X 3.0 MM ACE 3mM CI 8 COLUMN FROM ACE, PART NUMBER ACE-
111-0503 and mobile phases of (A) Acetonitrile + 0.1% Formic acid and (B) ASTM II
Water + 0.1% Formic acid. Analysis was carried out with an injection load of 5m1and
column temperature of 40°C. Data was collected at a range of time points
Total TMX content of the samples was determined by weighing 30-50mg of each dry
powder accurately weighted into an aluminium weighting boat. The weighing boat was then
placed in a volumetric flask and 50 ml acetonitrile added. The flask was gentle swirled until
a colourless solution was formed. This solution was analysed using the HPLC conditions
described previously.
Table 12.2 shows the quantity of TMX released after 1 and 4 hours as a percentage of the
total TMX concentration as measured by the method described previously.
Table 12.2
Example 13: Use of micelles from an apolar solution to coat -actives used in the field of
laundry.
Sodium percarbonate crystals were coated by adding a copolymer micellar solution of
Poly(PS42-b-HEMA6 ) at 0.4 and 5wt% in DMF/Solvesso.
The protocol described in Example 11 was used to coat sodium percarbonate - see Figure
13.1.
The protocol described in Example 11 was used to coat sodium carbonate crystals with
micelles of Poly(PS42-b-HEMA4 ) via a DMF/Solvesso™ 200 liquid medium - see Figure
13.2.
Example 14: Use of oil-based micelles to coat - actives used in the field of taste masking
Bitrex was chosen as it is the bitterest chemical known to man, and has similar physical and
chemical characteristics to many pharmaceuticals.
The protocol described in Example 11 was used to coat Bitrex, denatonium benzoate, with
copolymer micelles of Poly(EHMA 6o-b-MAA55) via DMF/Solvesso™ 200 liquid medium -
see Figure 14.1.
Visual release rate test
Release rate was monitored visually in order to compare the uncoated Bitrex with the 5wt%
coated Bitrex particles. 0.4mg of sample was agitated in 10ml of water and observed over 8
hours. After 15 minutes the uncoated Bitrex was fully dissolved but after 8 hours the coated
particles were still present - see Figure 14.2.
UV/Vis release rate measurement
lOOmg in 40ml water of uncoated Bitrex and 5wt% coated Bitrex was shaken for a period of
10 minutes and sampled at various time intervals. 2ml of the mixture was removed at each
time interval for analysis.
Total content of the samples was determined by the accurately weighing 17.5mg of 5wt%
coated Bitrex particles was sonicated until the coated particles had fully dissolved in 25ml of
water and analysed by UV/Vis. A total content measurement of 57.75% was obtained - see
Figure 14.2.
Table 14.1
Table 14.1 % release of micelle coated and uncoated Bitrex relative to the total content
determined by UV/vis measurements.
CLAIMS
1. A crystalline particle coated with micelles which themselves comprise an AB
block copolymer.
2. A crystalline particle as claimed in claim 1 where the particle is an organic
crystalline particle.
3. A crystalline particle as claimed in claim 1 or 2 where the particle is or
comprises a biologically active compound.
4. A crystalline particle as claimed in claim 3 where the biologically active
compound is an agrochemical or pharmaceutical.
5. A crystalline particle as claimed in any one of the preceding claims where the
largest dimension of the particle is from 5mm to lOnm.
6. A crystalline particle as claimed in any one of the preceding claims where the
polymer has a molecular weight of from 3000 to lOOOOODalton.
7. A crystalline particle as claimed in any one of the preceding claims where the
micelles have a largest dimension of from 3 to 500nm.
8. A crystalline particle as claimed in any one of the preceding claims where the
micelles each comprise from 10 to 1000 copolymer molecules.
9. A crystalline particle as claimed in any one of the preceding claims where the
micelles are crosslinkable and are optionally crosslinked.
10. A crystalline particle as claimed in any one of the preceding claims where the
particle is coated by at least 10 micelles.
11. A crystalline particle as claimed in any one of the preceding claims where the
particle is entirely coated by the micelles.
12. A crystalline particle as claimed in any one of the preceding claims where the
cores of the micelles contain a chemical.
13. A crystalline particle as claimed in claim 12 where the chemical contained in
the cores of the micelles is a photoprotectant.
14. A crystalline particle as claimed in claim 12 where the chemical contained in
the cores of the micelles is a biologically active compound.
15. A crystalline particle as claimed in claim 12 where the chemical contained in
the cores of the micelles is an adjuvant.
16. A composition comprising a plurality of coated crystalline particles where
each of those particles is a particle as claimed in any one of the preceding
claims.
17. A composition as claimed in claim 16 where the composition is a solid
composition.
18. A composition as claimed in claim 16 where the particles are dispersed in a
liquid.
19. A composition as claimed in claim 18 where the ratio by weight of the
copolymer to the liquid is from 1:100000 to 1:1.
20. A composition as claimed in claim 18 or 19 where the liquid comprises water.
21. A composition as claimed in claim 18 or 19 where the liquid is non-aqueous.
22. A composition as claimed in claim 2 1 where the micelle is a reverse micelle.
23. A process for preparing a particle as claimed in any one of claims 1 to 15
comprising the steps of
(a) forming micelles of the copolymer; and
(b) mixing the micelles with the crystalline particle.
24. A process as claimed in claim 23 where the micelles are crosslinked before,
during or after mixing the micelles with the crystalline particle.
25. Use of a particle as claimed in any one of claims 1to 15 or use of a
composition as claimed in any of claims 16 to 22 to combat or control an
agricultural pest.