Thermodynamics and Kinetic Considerations of Solids State ...

Fundamentals of Solid Formulation, 11th March 2014 Dr. Neil George, Process Studies Group, Syngenta UK

Thermodynamics and Kinetic Considerations of Solids State Behaviour for the Control of Agrochemical Process and Product Design

2

Abstract

● Crystallisation in formulated products often leads to instability and poor formulation performance.

● In contrast to crystallisation for purification purposes, formulation of active compounds generally aims towards minimising crystallisation phenomena.

● Finding and manufacturing the most thermodynamically stable crystal state is key to delivering stable formulated products.

● In application of the formulation, generation of supersaturation is often inevitable due to temperature, composition changes or solid state transitions.

● Controlling rates of crystallisation is then essential but can often be challenging to measure and control.

● The application of measurement and modelling tools in an industrial context and highlight opportunities for research.

Classif ication: External Publication

3

Content

● Formulation Types ● Crystallisation in Formulation – Industrial Context: time and number ● Crystallisation Measurement and Modelling Status and Challenges ● Solid State Control ● Nucleation Control ● Growth Control ● Conclusions and Recommendations


4

Formulation Types


5

Suspension Concentrate Formulation


● 25% active ingredient ● bio-enhancing agent ● dispersant ● viscosity modifier 1 (clay) ● viscosity modifier 2 (polymer) ● Biocide & antifreeze ● Bead mill to reduce particle size.

6

Emulsifiable Concentrate Formulation


● 10% Active ingredient ● Solvents ● Emulsifiers ● Tank Mixing

7

Water Dispersible Granule Formulations


<80% active ingredient Dispersant Binder Extrusion Spray Agglomeration

8

Applied to the Field through Foliar Spray & Directly to Soil Through Coated Seeds


9

Requirements of Formulation

• Act as a convenient dispersion medium for field and soil application

• Biological activity e.g. adjuvancy, controlled delivery • Maintain homogeneity “2 year shelf life” at extremes of

temperature and cycling • Ease of pouring, dispersion rheology, fine mesh clear • Formulation manufacturing aid e.g. milling, wetting • Environmental, Safety and regulatory • Compatibility – mixtures, additives • IP Market Differentiation


10 Classif ication: External Publication

Sedimentation Gross Flocculation

Crystal Growth

Common Formulation Instability Mechanism Due to Low Energy, Slow Transformations

Fully dispersed particles

Classif ication: PUBLIC

11

Industrial Context


12

Solid State Characterisation Challenge


SOLID STATE AND PHASE CHARACTERISATION

13

Crystallisation Isolation & Purification Versus Formulation

● Isolation& Purification ● Yield, productivity, purity ● High driving forces, steep solubility,

high supersaturation, fast and complete crystallisation. Easy to measure

● Generally want large crystal size (high growth, low nucleation)

● Thermodynamics Controlled temperature and composition

● Rate - Timescale - hours ● One optimised process, well

characterised and developed over several years

● Robustness to impurities

● Formulation ● Stability, Compatibility, Activity ● Low driving forces. Slow. Hard to

Measure and predict

● Generally want little or no crystallisation

● Themodynamics Uncontrolled - variable temperature and composition in application

● Timescale days to years ● Multiple formulation compositions,

region, crop and time specific ● Robustness to impurities and physical

quality


14

The Role of Modelling& Measurement in Solid State Discovery & Characterisation


Measurement Dominated

Mod

ellin

g

Measurement

Easy/Fast

Eas

y/Fa

st

Difficult/Slow

Diff

icul

t/Slo

w

Model Based Formulation Insights

Challenging Quantification/ Limited Utility

Rapid, Precise Validated Quantification Extrapolation & Innovation

15 Classif ication: External Publication

Mod

ellin

g

Measurement

Easy/Fast

Eas

y/Fa

st

Difficult/Slow

Diff

icul

t/Slo

w

Polymorphism & Solid State

Nucleation

Crystal Growth & Dissolution

Solubility & Melting

Solid State Thermodynamic Stability

Colloidal stability/Gels /Sedimentation& Rheology

Powder & Granule Flow Behaviour

Solid State Complexes

Crystal Habit

Population Balance – Size Distribution

XRD Crystal Structure Determination

Surfaces, Adsorption, & Wetting

Thermodynamic Solutions Preferable

Thermodynamic

Kinetic

Key

Kinetic opportunities but risky and empirical

16

Defining and Controlling The Solid State


17

Rapid automated polymorphism discovery aided with modelling and targeting screen

Form Identification -Experimental

-4

-3

-2

-1

0

1

2

3

4

5

6

-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11

t[2]

t[1]

CoX Solvent list_b.M10 (PCA-X), with all JF suggested variablest[Comp. 1]/t[Comp. 2]Colored according to value in variable CoX Solvent list_b(MWt)

R2X[1] = 0.42191 R2X[2] = 0.257796 Ellipse: Hotelling T2 (0.95)

acetaldehy

acetonitri

acetylene

ethane

ethanol

ethylenefluorometh

formaldehy

formamide

formic aci

methane

methanol

n-propane

propene

propyne

w ater

dibutyl st

triethylen1,2-dichlo

1,2-dichlo

1,3-butane

1,4-dioxan

1-butanol

1-butene1-butyne

1-chlorobu1-chloropr

1-methyl p

1-pentanol

1-propanol2-butanol2-butanone

2-chlorobu

2-methyl b

2-methyl-12-methyl-12-methyl-22-methyl-2

2-nitropro

2-pentanol2-pentanon2-propanol

2-pyrrolid

3-methyl p

3-methyl-13-pentanol3-pentanon

acetic aci

acetol

acetone

acetone cy

acetyl chlacrolein

acrylic ac

acrylonitrallyl alco

aniline

benzene

bromometha

butyraldeh

butyronitr

carbon dischlorodif l

chloroethachlorometh

cyclohexan

cyclohexan

cyclohexyl

cyclopenta

cyclopentacyclopenta

diethyl etdiethyl su

diethylami

dimethyl s

dimethyl s

ethanethio

ethanolami

ethyl acet

ethyl formethylene c

ethylene g

ethylene gethylene g

ethylenedi

f luorobenz

furan

furfural

gamma-buty

glycerol

isobutane

lactic aci

methacrylimethyl ace

methyl cyc

methyl for

methyl promethylal

methylene

morpholine

N,N-dimeth

N,N-dimeth

N,N-dimeth

n-butane

n-butyl amn-butyric

n-hexane

nitroethannitrometha

N-methyl p

N-methyl p

n-pentane

n-propylam

phenol

piperazine

piperidine

propionitr

propylene

pyridine

tetrahydrotetrahydro

toluene

vinyl acet

vinyl chlo 1,1,1-tric

1,1,3,3-te

1,2-dimeth

1-chlorope

1-heptanol1-hexanol

1-methyl n

1-nonanol1-octanol2,2-dimeth2,2-dimeth2-acetylcy

2-acetylcy

2-acetylpy2-acetylth2-ethoxyet

2-ethyl-1-2-heptanol2-heptanon

2-hexanol2-hexanone

2-methyl-12-methyl-22-methyl-22-methyl-22-methyl-3

2-nitroben

2-octanol

2-octanone

3,3-dimeth

3-acetylpy3-heptanol3-hexanol

3-methyl h

3-methyl-23-methyl-33-methyl-33-methyl-3

4-acetylbu4-acetylpy

4-heptanol4-methyl-14-methyl-25-methyl-2

acetal

acetic anh

acetonylacacetopheno

acetyltrimallyl acet

allylbenze

allyltrimealpha pine

amyl acetaanisole

benzaldehybenzoic acbenzonitribenzyl alc

benzyl chlbromochlor

bromoethan

bromotrif l

chlorobenzchloroform

cyclohexan

cyclohexyl

decalin

dibutyl et

dichlorodi

dichlorofl

diethanola

diethyl ca

diethylene

diethylenediethylene

diethylene

diisobutyl

diisopropydi-n-propydipropyl e

dipropylen

dipropylen

ethyl phen

ethyl prop

ethylbenze

ethylene g

ethylphenyhexanal

hexylene ghydrocinna

iodomethan

isoamyl acisobutyl aisobutyl i

isooctane

isophorone

mesitylene

methyl hex

methyl isomethyl isomethyl met

m-xylene

N,N-diethy

N,N-diethyN,N-dimeth

N,N-dimeth

N,N-dimethnaphthalen

n-butyl ac

n-decanen-heptane

nitrobenze

n-nonanen-octane

o-cresol

octanoic ao-dichloro

o-methoxyp

o-xylenep-diethylb

p-fluorotophenylproppropyl ace

p-xylene

tetrahydro

tetralintrichloroe

trichlorof

triethylam

trif luorom

tripropyla

1,1,2,2-te

1,1,2-tric

1,2-dibrom

1,2-dichlo

2-Undecano

3-decanone

benzopheno

benzyl ace

benzyl eth biphenyl

bromobenze

carbon tet

diethyl fu

diethylenedimethyl p

dodecane

ethyl cinn

ethyl hept

ethyl hydrethylbenzo

hexamethyl

methyl oct

methyl phe

methyl phen-decyl al

n-octyl py

phenethyl Phenyl(CH2

Phenyl(CH2Phenyl(CH2

PhenylOCH2triethyl ptriethylen

triethylen benzyl ben

DBNPA

diethyl ph

hexadecane

iodobenzen nonylpheno

pentachlor

PhenylC(CO

bromoform

butyl benz

dibutyl ph

diiodometh

dodecylpyr

eicosane

isopropyl methyl ole

nonoxynol-

oleic acid

Tektamer 3tributyl p

1,1,2,2-te

dibutyl se

dioctyl ph

SIMCA-P+ 12 - 2010-07-27 09:16:15 (UTC+1)

Solid state analysis: HTPXRD DSC Raman TGA / GVS

High-throughput screening Diverse Solvent Screening Emerging Propensity Statistical Modeling Polymorphism Prediction ?

Screen individual isomers and phase behaviour can add greatly to work load

Identify stable forms -Experimental

DSC and Van’t Hoff Relative Polymorphism Stability Slurrying Temperature Sensitivity

Conversion to stable form

Slurry known forms


TTR

Hax

m

fus 11ln

18

Solid State Stability – Minimising Formulation Supersaturation


Integral -452.72 mJ normalized -82.24 Jg -1Peak Height 20.82 mWPeak 139.71 °CExtrapol. Peak 139.64 °CPeak Width 2.81 °C

$520453-0510-29520453-0510-29, 5.5050 mg



520453-SMU6AP008-6, 27.02.2006 14:21:47520453-SMU6AP008-6, 5.9720 mg

520453-SMU5LP001-6, 27.02.2006 14:42:40520453-SMU5LP001-6, 8.0940 mg

mW

10

°C40 50 60 70 80 90 100 110 120 130 140 150

^exo

STARe SW 9.00Syngenta Huddersfield: Ian Jones

19

Stereo Isomers: Mapping Complex Phase Behaviour Defining the Stable States of the Pure Components and of Complex (can be the rate limiting step)


Integral -313.92 mJ

normalized -59.48 Jg^-1

Onset 88.87 °C

Peak 93.98 °C

Integral -352.81 mJ


Onset 86.92 °C

Peak 92.79 °C

Integral -83.88 mJ


Onset 83.54 °C

Peak 90.24 °C

Integral -5.55 mJ


Onset 84.26 °C

Peak 87.93 °C

Integral -352.13 mJ


Onset 68.36 °C

Peak 79.64 °C

Integral -372.30 mJ


Onset 67.27 °C

Peak 76.48 °C

Integral -175.34 mJ


Onset 70.79 °C

Peak 78.66 °C

Integral -430.60 mJ


Onset 73.41 °C

Peak 78.94 °C

Integral -361.98 mJ


Onset 71.24 °C

Peak 78.56 °C

49% R 51% S of NOA446510 ground, 02.04.2004 13:10:36

49% R 51% S of NOA446510 ground, 5.2780 mg

89% R 11% S of NOA446510 ground, 02.04.2004 14:26:27


79% R 21% S of NOA446510 ground, 02.04.2004 14:43:33


60% R 40% S of NOA446510 ground, 02.04.2004 15:39:31


70% R 30% S of NOA446510 ground, 02.04.2004 15:56:34


mW

10

min

°C40.0 45.0 50.0 55.0 60.0 65.0 70.0 75.0 80.0 85.0 90.0 95.0 100.0 105.0 110.0 115.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5

exo

Syngenta, Huddersfield: Cath Taylor SystemeRTAMETTLER TOLEDO S

Integral -456.74 mJ


Onset 76.95 °C

Peak Height 15.22 mW

Peak 80.64 °C

Extrapol. Peak 80.77 °C

Endset 83.89 °C

Peak Width 3.88 °C

Left Limit 55.71 °C

Right Limit 90.38 °C

Left bl Limit 55.71 °C

Right bl Limit 90.38 °C

Heating Rate 10.00 °Cmin^-1

Baseline Type line

R-enantiomer of NOA446510, 02.04.2004 09:43:05

R-enantiomer of NOA446510, 5.0690 mg

mW

10

min

°C40 50 60 70 80 90 100 110 120 130 140

0 1 2 3 4 5 6 7 8 9 10

exo R-enantiomer of NOA446510 16.04.2004 14:34:45

Syngenta, Huddersfield: Cath Taylor SystemeRTAMETTLER TOLEDO S

Meta Stable Conglomerate Eutectic

Stable Racemic Crystal

20

Diastereoisomer Polymorphism Detection Challenges


Pure Racemate ANTI

Pure Racemate SYN F1 Pure Racemate SYN F2

Syn:Anti

21

Generation of Supersaturation within Formulations is Inevitable !

● Solid State Transitions Within the Formulation Storage Temperature Range (Solid-Solid, Solvate-Non Solvate, Liquid –Solid)

● Temperature Changes ● Composition Changes


22

Low Temperature Solid State Phase Transitions

Temperature 0°C 50°C

Low Temperature Phase Transition


23

0123456789

10

0 10 20 30 40 50 60

Temperature (°C)

% P

rodu

ct

Liquid-Liquid - Emulsion

Solution

Meta-stable liquid

Crystals + Solution

Melting Point

Emulsion Phase Stability – Low Melting Active


24

Solid State Thermodynamic Solutions to Phase Transitions


(a)

(b)

(c)

Propiconazole Dihydroxybiphenol Co-crystal

Cyprodinil–Succininc Acid Co-crystal

Patent: PCT2008/117037 N.George, J. Forrest, P.Bonnett, P Gavin Patent PCT 2008/107060 N.George, J.Forrest, P. Gavin, R. Burton,L. Gregory

25

Formulation Thermodynamic Challenges

● Temperature ● In Manufacture ● Storage and Application -20’C to 50’C

● Composition ● In Application ● Dilution – spray tank ● Drying – leaf deposit drying ● Mixing - formulation mixtures and additives


26

Minimising Nucleation


27

Solu

bilit

y (w

t %)

Temperature ( C)

Nucleation Temperature: Formulation Loading Below Minimum Solubility for Storage

27 27

----10°C 50°C

Maximum Thermodynamic Loading

Maximum Kinetic Loading Risk of Nucleation – but what is the risk ?

Metastable liquid formulation – high risk of nucleation

Understanding of solubility & Nucleation Kinetics – Assessment Of Risk Impurities and Scale Important

28 28

Nucleation Composition : Solubility for Spray Tank Dilution

Decreasing [water]

conc

entr

atio

n (w

/w%

)

tstart tend

cend

cstart

SolubilityCurve Polar Solvent

Dilution Curve

Supersaturation

Formulation Loading

29

Nucleation Time

● Induction time experiments

are a feasible estimation of acceptable stability

● Extrapolation over long time scales questionable

● But sensitive to impurities, scale, variation in temperature conditions


0

0

1

10

100

1000

0 100 200 300 400 500

Indu

ctio

n tim

e da

ys

Concentration of EC

Shelf Life Predicition

Acceptable Application Time Stability

Acceptable Storage Stability

30 30

Monotropic Polymorph Transformation on Storage – Nucleation at Low Supersaturation

31

Polymorph Transition Within a Suspension concentrate


!&2006-11-22 1-SMU6AP0082006-11-22 1-SMU6AP008, 8.2760 mg

!&2007-03-01 1-8w 35C J4972/28/1 4900902007-03-01 1-8w 35C J4972/28/1 490090, 4.8880 mg

Wg -1

1

°C80 90 100 110 120 130 140 150 160 170 180 190 200

^ e xo

S T A R e S W 9 . 1 0L a b : M E T T LE R

8 weeks

Slow Polymorph Transitions in Suspension Concentrates Early Crystal Nucleation & Growth

32

!&2007-4-2 1-16w 35C J4972/28/1b2007-4-2 1-16w 35C J4972/28/1b, 5.7410 mg

!&2007-03-01 1-8w 35C J4972/28/1 4900902007-03-01 1-8w 35C J4972/28/1 490090, 4.8880 mg

Wg -1

1

°C90 100 110 120 130 140 150 160 170 180 190 200

^ e xo



8 weeks 16 weeks

Crystal Growth Through Polymorph

Slow Growth

33

!&2007-5-31 1-24w 35C J4972/28/1b2007-5-31 1-24w 35C J4972/28/1b, 5.1800 mg

!&2007-4-2 1-16w 35C J4972/28/1b2007-4-2 1-16w 35C J4972/28/1b, 5.7410 mg

!&2007-03-01 1-8w 35C J4972/28/1 4900902007-03-01 1-8w 35C J4972/28/1 490090, 4.8880 mg

Wg -1

1

°C90 100 110 120 130 140 150 160 170 180 190 200

^ e xo



8 weeks 16 weeks 24 weeks Nucleation

after 6 months !

Nucleation

Slow Nucleation

34

!&2008-01-23 1-57w 35C J4972/28/1b2008-01-23 1-57w 35C J4972/28/1b, 5.5530 mg

!&2007-5-31 1-24w 35C J4972/28/1b2007-5-31 1-24w 35C J4972/28/1b, 5.1800 mg

!&2007-4-2 1-16w 35C J4972/28/1b2007-4-2 1-16w 35C J4972/28/1b, 5.7410 mg

!&2007-03-01 1-8w 35C J4972/28/1 4900902007-03-01 1-8w 35C J4972/28/1 490090, 4.8880 mg

Wg -1

1

°C90 100 110 120 130 140 150 160 170 180 190 200

^ e xo



Batch 2 8 weeks 16 weeks 24 weeks 57 weeks

Product Instability – Sedimentation of Field Nozzle Blockage

35

Early Thermodynamic Resolution of Solid State Stability Isolation Crystallisation Optimised to Deliver this Form


!$520453-SMU6AP007-6

520453-SMU6AP007-6, 6.3130 mg

!$520453-SMU6AP005-6

520453-SMU6AP005-6, 4.4030 mg

Integral -86.38 mJ


Peak 138.81 °C

Heating Rate 10.00 °Cmin^-1

!$1-A15149G crystals from EC

1-A15149G crystals from EC, 0.9750 mg

Wg^-1

5

°C20 40 60 80 100 120 140 160 180

^ e xo

S T A R e S W 1 0 . 0 0L a b : B e t h Sh i r l e y

F2F1

New form?Form 3

36

Nucleation Composition: Water Activity and Anhydrous to Hydrate Transformation


Spray Tank

Field

37

0

10

20

30

40

50

60

70

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

T /°

C

aw

Field Application

Hydrate Stability In Processing and Application Traversing The Phase Diagram – Nucleation at Low Supersaturation


Dispersion & Milling

Granule Drying Agglomeration

Granule Storage

Spray Tank

AI Powder

38

y = 295.83e0.0149x

y = 21.715e0.0544x

0

100

200

300

400

500

600

700

800

900

1000

0 10 20 30 40 50 60 70

Co

nce

ntr

atio

n µ

g/m

l

Temperature /°C

SC F1 µg/ml

SC F2A µg/ml

Nucleation Times: Anhydrate Nucleates More Rapidly

Classif ication: INTERNAL USE ONLY

N’= 7days N’12 days N’ 40 days

N’ 40 days N’ 77 days >100days

Hydrate Solubility Anhydrate Solubility

[Sol

utio

n] g

/L

39

Minimising Crystal Growth


40

0

100

200

300

400

500

600

700

0.01 0.1 1 10 100 1000

SYN5

4519

2 con

cent

ratio

n /pp

m

Time /h

F2A solubility

F1 solubility

Std F1+F2A

Solvias F1+F2A

Solo F1

Crystal Growth: Isothermal Anhydrate to Hydrate Transformation Rate – Hydrate Crystallisation Rate Limited


Log Time

[Sol

utio

n] g

/L

Anhydrous solubility

Hydrate solubility

41

Rate of Transformation in Anhydrous SC With Hydrate Contamination – Robust Processing Dry Granule Formulation


[Sol

utio

n] g

/L

Time (hours)

42

Low Supersaturation Growth Inhibition: Zero Growth Zone If overall ZGZ > (C-C*) gives stability Face Specific ZGZ = anisotropic growth

Dry samples, slow

Wet samples, fast recrystallisation


ZGZ Process Impurities

ZGZ Formulation Additives

[Sol

utio

n] g

/L

43

Solid Solutions – Molecular analogues

Poornachary, S. K.; Lau, G.; Chow , P. S.; Tan, R. B. H.; George, N. The Effect and Counter-Effect of Impurities on Crystallization of an Agrochemical Active Ingredient: Stereochemical Rationalization and Nanoscale Crystal Grow th Visualization. Cryst. Grow th Des., 2011, 11, 492-500.

44

Summary – solid state information for maximum impact

● Generally we aim to minimise crystallisation in formulations ● Defining solid state stability is central to stable formulations – minimises

supersaturation ● Automation of solid state screening for rapid and early discovery of solid state has

become established over the last decade able to cope with the rising complexity of active ingredients and formulations. Emerging solid state modelling will help streamline experimentation.

● Supersaturation generation in formulation is inevitable due to phase transitions, composition and temperature variation.

● Rapid and precise determination of crystallisation kinetics in formulations is challenging but can be very helpful in minimising formulation risk

● Measurement and prediction of crystal nucleation particularly at low supersaturations is challenging. There are great opportunities here for improved formulations and enhanced formulation performance – including metastable phases

● Measurement of crystal growth is most cases is achievable and a means of modelling modification of crystal growth is emerging. The link between surface properties and crystal growth requires more study.


45

Acknowledgments

● Particle Science Team Syngenta ● John Hone, James Forrest, Rhea Brent, Ian Jones and others ● Academic collaborations with Manchester & Leeds Universities


Thermodynamics and Kinetic Considerations of Solids State ...

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