Controlled Delivery of Agrochemicals Ian Shirley Chemspec europe Symposium 28 June 2007 RAI Amsterdam
Controlled Delivery of AgrochemicalsIan Shirley
Chemspec europe Symposium 28 June 2007 RAI Amsterdam
2
Scheme
Scope of this talk Snapshot of the Ag industry Range of CR technologies Examples of selected technologies
3
Scope
Controlled Delivery/Release technology is used in many industries – personal care, pharmaceuticals, food, agrochemicals“Agrochemicals” include pesticides (I/F), herbicides, fertilisers (adjuvants, attractants, biocides)Agrochemicals are used for crop protection, animal and public health, materials protection, home and garden etcThis presentation
– is restricted to “agrochemicals” where cost is an important factor cf Pharma
– provides a snapshot overview of selected topics over the last 15years – not comprehensive
– is presented from a formulators point of view– focus primarily on patents reasonable reduction to practice– abbreviates Active Ingredient as “AI”
4
Agribusiness: a large, global industry
Global market 2005: $ 56 bn
9%
27%
9%
55%
ConventionalSeeds
($15 bn)Crop Protection*
($31 bn)
GMSeeds
($5 bn)
Professional Products**($5 bn)
*Includes Seed Treatment**Excludes Seed Treatment
Source: Phillips McDougall
5
Our industry family tree
CibaSandoz
ICIISK Biosciences
Monsanto
DuPont
ShellCyanamid
BASF
BayerRhone-Poulenc
HoechstSchering
DowRohm & Haas
Merck
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
Novartis
AHP
Aventis
2002
Agrevo
Zeneca
6
Six global competitors
Bayer CropScience
Monsanto
BASF
Dow
DuPont/Pioneer
25%
Significant presence
See
ds p
latfo
rm Narrow/ alliances
None
Crop Protection market share0%
Source: Phillips McDougall, Syngenta
7
2005 Sales of Major Agribusiness Companies
$m9000
Source: Phillips McDougall
Syngenta Bayer CropScience
Monsanto DuPont BASF Dow
Crop ProtectionSeeds and Traits
6,3076,917
2,9102,240
4,0973,094
1797 407
3,440
2,785270
8000
7000
6000
5000
4000
3000
2000
1000
0
8
Demand is driven by populationgrowth and scarcity of land
World population
19996 billion people
20258 billion people
2025One hectare to feed 5 people
1995One hectare to feed 4 people
19502 billion people
1960One hectare to feed 2 people
9
Controlled delivery technologies in Ag - a simplified viewpr
oces
ses
Solvent evaporation
Coacervation
Pan coating
Prilling
etc etc
Chemi-/physi-sorption
Barriers
Matrix particles, reservoir
Encapsulation – AI, bacteria
Inorganic particles
Gels / hydrogels
Imprinted polymers
Polyelectrolyte coating
Bulk polymer devices
Polymer bound (propesticides)
Coated fertilisers & granules Urea
Molecular Encapsulation
Polymer-inorganic compositions
Seed coatings
Multi-component systems
Biodegradable carriersTriggered release
CR into water, soil etc
UV protection
H B Scher, Controlled-Release Delivery systems for Pesticides Marcel Dekker 1999
10
Chemi-sorption – polymer bound AI’s
AI is covalently bonded to (polymeric) supportAfter application bond cleaved by trigger (environmental eg pH, hydrolysis) to liberate AILittle recent patent activity (primarily papers) limitations
– AI specific (ie not generic)– AI must have appropriate functional group– Environmental triggers unpredictable
Environmental trigger
poly
mer
AI
Covalent bond
Cl
ClN
N
N
OHCl
Cl
O OH
O
diniconazole 2,4-dichlorophoxyacetic acid
J Materials Sci (2002), 37(21), 4677-4682
Nongyao (2005), 44(7), 309-311Internat J Polym Mat (2002), 51(8), 675-683
J Appl Polym Sci (2001), 80(3), 415-421
Reactive & Functional Polymers (1999), 39(2), 179-187
Reactive & Functional Polymers (1998), 36(1), 31-39
11
Physi-sorption
Low cost, low techPhysical bonding to organic or inorganic supports
Inorganic carrier AI DriverActivated carbon
S-methoprene Mosquito larval control
US2006/0188572
Colloidal silica, alumina
Codlemone Lepidopterapheromone
US2003/0031694
Activated carbon
isothiazolone Microbial control (coatings)
EP1142477
Org
anic
/inor
gani
c su
ppor
t
AI
physical bond
H-bonding between AI-polymer (PVOH) gives some control over rel rate (cf when no polymer is present)
SO2N CONHCO2CH3
N
N N
OCH3
CH3
Na
I
Cl
N
OO O C CO2CH2CH3
CH3
H
Fenoxaprop-p-ethylIodosulphuron-methyl Na salt
**
OAc OHn
m
WO 2001084927
http://patentorder.app.intra/patentorder/pdf/GB2418428.pdfImprinted polymers GB2418428
12
Polymer-inorganic compositions
Seed coatings
Multi-component systems
Coated Fertilisers and Granules
Twists on established generally low cost technologySignificant patent activity in JapanMany processes; vacuum coatings US6080221, latex, in situ polymerisation
Fertiliser
isocyanate (+ hormone) amine
polyol (+ hydrophobe) isocyanate
1 2
WO 99/07654
US2004/0020254 US2005/0266245
Monomers applied in sequencePolymerised in situ + mechanical agitation - minimise agglomerationPerformance depends on polymer composition (and eg hydrophobic additive)
Inorganic particle Fertiliser
1 AI (emulsion) 2 latex binder (eg PVDC-PEHA-PAA)
+1-2mm
Physi-sorption
EP 1063215A2
Inorganic-polymer composite
13
Polymer-inorganic compositions
Seed coatings
Multi-component systems
CR – seed coatings
AI + pigment + binderLatex overcoat
seed
Latex overcoats control release rate (into water) of imidacloprid
One stop ST – convenience cf spray or soil appliedMust minimise AI exposure – no dustMust release AI at chosen rateMust not inhibit germination
CH2OR
ORO O
OR
** n
plasticised ethylcellulose
SO3-
Hydrophile
**
RN+R2
latex
stepan nms
CH2OR
ORO O
OR
** n
ethylcellulose
aquacoat ecdsurelease
WO02/080675A1, US2002134012
14
MICROCAPSULE TECHNOLOGIES
FOR AGBasic concepts have been covered
– Professor Dennis Poncelet, ENITIAA (Food Engineering School), FranceMicroencapsulation: Fundamentals, Applications and Technology
– Dr Ronald J Versic, Ronald T. Dodge Co., USAUsing Mircoencapsulation to Achieve Controlled Release
Focus here is on recent work, particularly from the Ag majors, where there is strong drive for commercialisation
15
Microcapsules general
Versatile technology – high payloads, safetyFTO important Majors carve territoryMuch work outside Ag – narrow picture here of some key players
stabiliser
Polymer carrier
Core material
Options for varying parameters– Colloid stabilisers– Polymer composition/quantity and surface modification– Core materials – solvents; mixtures; eutectics, solid dispersion– Capsule sizes– Mixtures – caps + other types– Process– Presentation
16
Matrix microparticles – solvent evaporation process
AIsolvent
waterMatrix particle
polymer AI-polymer matching Solvent use & recovery (manufacture)
Lignin acetateMonsanto US2003 0013612
ImidaclopridSilthiopham
UV photostabilisation
matrix AICyproconazole
Poly(lactic Acid)Cellulose acetate butyratePoly(styrene) Monsanto US7070795
Phytotox reduction
PMMA, PS-co-MAn, PVAcPhthalic anhydride, Dibutylphthalate
Tebuconazole
Monsanto WO02/21913
Plasticiser controls release rate
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Bayer capsule technology - 1
Ag applications illustrated here – does not include uses in perfumes, carbonless copy paper etc
2003 penetrant aid + non-encapsulated AI SC WO2003099005, US2005221991
2002 isocyanurate + guanidine US6797670B2 EP1199100 –mainly carbonless paper copying
2001 protein hydrolysates – EP1151789 US2002009495 – mainly carbonless paper copying
2001 * PU 2 phase wall + dispersed solid encapsulated in non-solvent + external SC WO2001068234, US6730635
2001 *PU 2 phase + dispersed solid encapsulated in non-solvent strengthened by vinyl polymerisation 2001 DE19947147, CA2385991 –ST CS strength
2000 *oxadiazinetrione (+TDI) + poly-ol/amine DE19840583, US6566306 DE19840582, US6653256
Aqueous endosulfan microcapsule dispersion DE19646880 Hoechst
BayerBayerRhone-PoulencHoechstSchering
Aventis
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
Representative patents listed here
18
Bayer capsule technology - 2
wall
AI
WO2001068234
PU 2 phase wall + dispersed solid encapsulated in non-solvent + external SC
Controlled release + formulation stability Multi-component system
PU wall
Vinyl polymer
Non-solvent
DE19947147 stearyl methacrylate
AI PU 2 phase wall + dispersed solid encapsulated in non-solvent strengthened by vinyl polymerisation
Enhancing capsule strength for seed treatment
N
N
N
O
OO
R N
R N
RN O
O
O
R = -(CH2)6-
oxadiazinetrioneisocyanurate
DE19840583, US6566306DE19840582, US6653256
oxadiazinetrione (+TDI) + poly-ol/amineRelease rate via wall composition
19
BASF capsule technology - 1
Ag applications here do not include uses in leather, pressure sensitive recording materials, vitamin, printing, coatings, copying, laundry, detergents, dyes, adhesives (except latent heat storage)
1993 Gelatin-glutaraldehyde coacervate on diazinoncontaining feeding deterrent DE4309756 (Micro Flo Co)
2007 *polymer particle film formation from Pickering emulsion WO07033931
2006 *WO2006/092409 H2O absorbinginclusion PU 2 phase wall release
2004 PU 2 phase wall Pendimethalin – WO2004/008852
BASF
ShellCyanamidBASF
AHP
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
Shell & Cyanamid activity predates the present 15 year analysis.
20
BASF Capsule Technology - 2
Chlorpyrifos
octanolEcoflex
heat
WO07033931
Polymer particles SDS polymer particle film formation of
pickering emulsionPotential for variation of polymer
compositions
PU 2 phase wall encapsulating AI & H2O absorbing inclusion
Objective – fast release, and seed treatment for fungicide or insecticide
Technical - Osmotic balance? Dry vs wet? Release in spray tank?
H2O absorber salt soln
Pendimethalinin Ar-200
WO2006/092409
Salt aqueous phase
Vinyl monomer
[In] silica particles
US200311822
in situ vinyl monomer polymerisation via pickering emulsion(Not Ag but neat – heat storage)
21
Ag Industries - capsule technology
2004 *Pesticide microcapsules with amine-adjusted release rates WO2004054362
2002 *microcapsules containing agrochemicals having a high melting point WO2002082901
1999 *Safened herbicide microcapsules with readily-adjustable release rates WO9911122
1998 Herbicidal aqueous microcapsule dispersion PU clomozone cap to reduce volatility WO9824317
1994 Water-based pesticidal flowable formulations EP619073 pourability enhancing additives
1996 Encapsulation by complex coacervation using gelatin and polyaspartic acid –model compounds only WO9632191
MonsantoMonsanto1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
DowDowRohm & Haas
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
1998 Storage-stable pesticide microcapsule dispersions super-cooled melt <6um, non-micelle surfactants WO9803065 A1
1996 Microencapsulation of pesticides (PVOH stabilised spray dried) WO9622159
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
DuPontDuPont
1994 PVP-DMAEMA-PU-two phase, high loading, good dispersibility WO9413139
1993 CMC gel-PU-two phase – thiotropic gel WO9321764
22
Monsanto reservoir capsule technology
capsules with amine-adjusted release rates•Combination of amines gives good control over release rate
n
NH2
OO
NH2Et
(PO)nNH2
(PO)nNH2
(PO)nNH2
CH2NH2
CH2NH2
(CH2)6
(CH2)6
NCONH
(CH2)6
CONH
N=C=O N=C=O N=C=O
NCO
NCOOCN H-NH-[CH2CH2NH]-CH2CH2-NH2
WO2004054362
Jeffamine EDR148 Jeffamine T403
Desmodur N3200
AI-melting point depression silthiopham (86oC) + tebuconazole (100oC) 50oC eutectic or
depressed by acetyl tri-n-butylcitrateDesmodur N3200+TMXDI TETA/Jeffamine T404 Low odour; process at manageable temps for high mp AI;
differential rel rate of diff AI’s; different isocyanate feedstocks
WO2002082901
adjustable rel rate safened herbi caps Blends of di-/tri-NCO’s cured (TETA or
DETA) release rates days to years.Differential rel of co-encapsulated AIs.Carves out wall composition IP
(CH2)6
(CH2)6
NCONH
(CH2)6CONH
N
N
N
O
OO
(CH2)6
(CH2)6
(CH2)6
Me
Me
MeMe
NCOOCN
Desmodur N3200
NCO
OCN NCO
NCODesmodur N3300
NCO
NCO
WO9911122
23
Syngenta capsule technology
*Triggered release disulphide capsules WO2001019509
*Acid triggered release WO2000005952
*Triggered release ester capsules WO2000005951
*Particulate Ultraviolet protectant US5846554
*microcaps in water dissolvable tapes WO9720627
UV protectant and dispersed AI WO9633611Microcapsules bound to fabric WO2007036710
*Reactive polymeric surfactants WO2002100525
Nano-capsules by phase inversion WO2002068111
*Surface modified capsules WO2001094001
*Co-encapsulated organic photoprotectants WO2006089747
*Fast release by monomer composition WO97/44125
*CS of Oil Dispersion WO 95/13698
Encapsulated adjuvants WO 2004/017734
Nucleation promoter for microcrystal formation WO9603039
non-ionic surfactant -PU-two phase EP611253
S-MA surfactant-PU-two phase US5310721, EP551796
U-F coacervation EP532463
Urea-dialdehyde EP532462
melamine-formaldehyde coacervate WO2000062612
PVOH-PVEMA -polyester EP517669
Novartis
Syngenta
CibaSandoz
ZenecaISK Biosciences
Merck
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
24
Encapsulated dispersions
High mp ‘low solubility’ AI is dispersed in non-solvent & dispersion is encapsulated.Formulation stability, benefits some AI’sRequires careful selection of oil dispersant and capsule stabilisersLoad capacity is a limitation
Similar technology can be used to co-encapsulate particulate photoprotectants such as TiO2
Cap wall
AI-solvent
TiO2 particle
US5846554
Cap wall
Non-solvent
Dispersed solid AI particle
WO 95/13698
25
Triggered release
Chemical Acid or base sensitive groups are built into the capsule wall
pH trigger is activated on demand punctures reduce wall thickness to zero fast release
Physical Wall composition / quantity robust for processing
Fast release by burst on drydownand/or high surface area of small capsules
Operator safety
triggerrupturesweak linkallowingfast release
WO2000005952 WO2000005951 WO2001019509
26
Triggered release – contact and feeding activity
Incorporation of photostabilisers in capsules affords UV protection to the mectin
Triggered release targets specific pests - affords protection for beneficial insects (safened ≥ x10) for
Typhlodromus pyri(mite predator)Apis mellifera
Emamectin benzoate is a potent lepidoptericide
WO2006089747
Formulation type Feeding activity % mortality at 2ppm AI
Contact activity% mortality at 33ppm AI
SG 1009096
80CS w/o photostabiliser 5CS with photostabiliser 0
Gut pH ~8.7
Spodoptera littoralis
27
Surface modified capsules
Surface modification enables enhanced stability by non-detachable stabiliser
Modifiers (reacted into the polymer wall) may be
– small molecules or polymers– anionic, or cationic or neutral
(steric)
XXX
monomer
Surface modifier
WO2001094001 WO2002100525
28
Measuring adhesion
pH
2 4 6 8 10
F/R
nN
/µm
-2
0
2
4
6
8
10
12alkyl modified microcapsuleanionic modified microcapsuleunmodified microcapsulecationic modified microcapsule
Characterise attraction between individual surface modifiedparticles and substrates by AFM
AFM cantilever
capsule
Adhesion steric > anionic >> cationic ~ non-modified capsules on SAM surfacecontaining OH groups
SAM surface containing OH groups
29
Measuring strength (1)
Incident beam
Microcapsule
Deflected beam
Probe
Deformation
FPressCompression
AFM-SEM is used to characterise the compressive strength of individual microcapsules
30
Measuring strength (2)
F
Scrape – bare probe or attached cap
Shear
0
50
100
150
200
250
0 20 40 60 80 100 120
Before application of capsule probe shear force
After application of capsule probe shear force
Comparative profile scan
Capsule attached to AFM Tip
Intact capsules
Bare AFM Tip
Removal of shear force
High level shearing destruction of
capsule integrity
Capsule integrity intact
The applied shear force is a function of the speed of raster and the normal force (N) applied
As the probe is raster-scanned across the surface, torsional forces are realised in the AFM cantilever
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Measuring composition
PMPPI / IPDI
Epoxy resin
An understanding of the morphology of mixed monomer wall compositions can help in product design.Model capsules made by differential reaction of IPDI and PMPPI (DETA)Scanning Transmission X-ray Microscopy profiles chemical gradients across microcapsule wallCan be much more complex!!
Journal of Electron Spectroscopy and Related Phenomena (2007), 156-158
32
Soft X-ray Spectromicroscopy withScanning Transmission X-ray Microscopy
e-
ALSbendingmagnet
Soft X-rays
Fresnelzone plate
Order sortingaperture
Detector
Scannedsample
Advanced Light Source
Chemical speciation through X-ray absorption spectra (NEXAFS) Spatial resolution ~30 nm; Energy resolution < 0.1 eV
Beamline 5.3.2 at the Advanced Light Source, Berkeley, USABeamline 10ID1 at the Canadian Light Source, Saskatoon, CanadaTransmission requires thin samples ⇒ microtomed sections (~100 nm thick)
Quantitative chemical mapping in 2d and 3dQuantitative molecular orientation mapping
Acknowledgement – Adam Hitchcock, McMaster University
33
Comparison of spectro-microscopy techniques
GOAL: QUANTITATIVE CHEMICAL ANALYSIS at relevant spatial resolution
X-ray microscopy ~ 30 nm excellentSTXM radiation damage 103 less than TEM-EELS
Technique Spatial Resolution Speciation Capabilitynmr > 1 µm excellentIR > 1 µm excellentRaman ~0.3 µm excellentoptical ~0.5 µm needs chromophoresscanning probe 0.2-10 nm variableTOF-SIMS ~ 1 µm excellentEELS - (S)TEM < 1 nm good;
BUT radiation damage !
TEMEELS
100 µm 1 µm 10 nm 1 Å
Spatial Resolution
Che
mic
al In
form
atio
n C
onte
nt
Low
HighIR
RM
XPS
FMEDS
OMSEM
TEMSTMAFM
NSOM
NMR
STXM
Acknowledgement – Adam Hitchcock, McMaster University
34
Hydrogels
Micro-irrigation, mulching, plant tissue culture, seed coatingsCross-linked hydrophilic monomers bulk polymer or microparticles loaded with AI
carrier AI DriverMBAm-AA; MBAm-AMPSAA-MAc
HCO2Na Mite control in bee hives
WO 2006/017310A1
Aqualon aquasorb (CMC)Aridall superabsorber(acrylics)
TriticonazoleImidacloprid
Seed treatment -enhanced AI uptake(phyto?)
WO 02/21914Monsanto
Carageenan; Na-alginate CH2FCO2Na Possums etc WO 00/02447
Rudzinski et al Designed Monomers & Polymers (2002) 5 (1) 39-65 Hydrogels as controlled release devices in agriculture
35
Biodegradable carriers
AI + biodegradable polymer melt extruded with optional additives(synthetic polymer, plasticiser, fillers) to lace, rod, ribbon (chopped)Morphology depends on composition – homo-/hetero-geneousAimed primarily at soil/water – release rate control by diffusion and biodegradation
Carrier AI UseAliphatic polyester Imidacloprid aphid control; 16-
100% biodeg 5 mthsEP0843963A1
PLA + p(butyleneadipate terephthalate)
ClothianodinStrobilurin*Tetrafuranitdine
Disease and insect control
US2004/0259736BASF
(modified) starch (+synthetic EVA, PVC)
ChlorpyrifosCarbosulfan
Wireworm and bloodworm control
US5741521
Cellulose acetate; starch
FipronilChlorpyrifos
Termite control (implanted rods)
US 6337079 (2002)
*Mitsui neonic
36
Water Dispersible Tapes
Water-soluble polymermicrocapsule
cast
dry
Spray tank
Use ‘dry’
Flat flexible water dispersible sheet that may be cut or shaped
Dissolves in spray tank to release CS
Advantages– reduced operator contact
– measurable/unit doses
– mixed product compatibilityWO 97/20627
37
Controlled release from bulk polymers by diffusion
Polymer
A.I. Release rate depends on compatibility of AI with polymer
Polymer 1Polymer 2
Release rate depends on compatibility of AI with polymers 1 and 2Polymer 2 matrix or reservoir
PolymerParticle
Release rate depends on adsorption of AI to particle and compatibility with polymer
Variables•Polymer types (tp or ts, x-link density, water permeability, biodegradability; photostability; hydrolysable)
•Processes - melt extrusion and lamination, in situ polymerisation egurethane coatings
•Adsorption equilibrium for particles
38
Controlled delivery from bulk polymers
Railroad tie
Controlled Release Device
Polymer-AI strip melt bonded on support film
deltamethrin
Bayer
Polymer-AI coating on pole
Controlled release device in railroad tie
US6852328
Pyrethroid ear tags
39
And …
casing AI~45o mp waxy carrier containing deltamethrin
Gelatin-gum arabic (breakable) coating
EP 1163846 (2001)
AI macro-capsule attached to flat head of pellet
Fired from air-rifle at processionary pine moth nests
Two shots for large nests
40
Targeted delivery in action
Marijuana is eradicated on inaccessible terrain by targeted delivery of an herbicide, preferably glyphosate, from a helicopter. The herbicide is packed into balls made of frangible skins and shot from the helicopter, using a gun. US5174807
http://patentorder.app.intra/patentorder/pdf/US5174807.pdf
41
Acknowledgements
Colleagues at Syngenta too numerous to list Warwick University (P Unwin, J MacPherson, I Lee, S Dale)McMaster University (H Stover, A Hitchcock, P Foley, S Reijerkerk, J Li)To the organisers for the invitation to speak at this meetingTo the audience for your attention