Controlled Delivery of Agrochemicals

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


2025One hectare to feed 5 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


Seed coatings


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


Seed coatings


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

17

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

31

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

Documents

Controlled Delivery of Agrochemicals