Challenges for the PSE community in formulations

Process Systems Engineering 2003 B. Chen and A.W. Westerberg (editors) 9 2003 Published by Elsevier Science B.V.

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C H A L L E N G E S F O R THE PSE C O M M U N I T Y IN FORMULATIONS. J.L. Cordiner

Syngenta, Global Specialist Technology, T&P, Earls Road, Grangemouth. Stirlingshire. Scotland FK3 8XG

1. I N T R O D U C T I O N Process Systems and computer aided process engineering has over the last few decades very successfully tackled many of the issues from chemical processes. These range from modelling reactors, distillation columns to whole refineries and chemical manufacturing plants. Meanwhile to support this physical property models for the process fluids have been developed from SRK in the seventies through UNIFAC for predictions, Chen and Pitzer models for electrolytes. Recently with increasing computer power and improved mathematical optimisation techniques [1,2] methods have been applied to more complex problems. Rational solvent selections over whole processes [3,4,5] and computer aided molecular design [6,7] have been very successfully applied to industry problems. In addition more complex fluids, such as: associating fluids [8], polymers [9], surfactants [ 10] and electroyes [ 11,12] have been modelled by advanced property methods. Molecular dynamics, QSAR, data-mining and mathematical techniques taken from "biology" e.g. neural networks and genetic algorithms have also been used extensively in modelling complex systems. With this expanded "toolkit" the Process Systems Engineer can begin to tackle some very different types of problems. In recent years there has been much encouragement to broaden the chemical engineering discipline to meet the needs of the new industries, e.g. microprocessors, biochemical, biomedical, food etc. Along with this, academic funding is focussing on partnerships and cross-functional work [13]. Therefore the time is right to exploit the "toolkit- modelling capability and thinking" of the process systems community in these new fields.

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2. F O R M U L A T I O N S IN I N D U S T R Y The chemical process industry produces many millions of products from relatively few raw materials. Currently the PSE community is focussed on the few thousand active ingredients and bulk commodities. Final products that people use are formulated from these active ingredients and are present in all walks of life from personal care, hygiene, pharmaceuticals and agrochemicals. Formulated products use specifically chosen mechanisms to serve the customer needs by accurately exerting their desired features that can be performance related (such as crop protection, surface protection) and/or convenience (such as controlled release, ease of handling). These formulations are designed for different markets and purposes. The successful design of such formulations can have a huge impact on sales and profitability of a company. With markets tightening and growing competition many of these products need to be made more efficiently and with reduced costs. Therefore the optimisation and design of these formulations is critical to business success. This presentation will focus on the challenges for the PSE community in agrochemical formulations, though many of the issues are directly relevant to drug delivery, personal care, hygiene products and speciality/effect chemicals.

2.1 Agrochemical Market The agrochemicals market is estimated to be $40bn+/year, which is expected to grow as the world population, and pressure on food production grows as shown in figure 1.

Figure 1. The pressure on the agrochemical industry is increasing with advancing competition from Asia and much consolidation has happened as shown in figure 2.

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Figure 2. Industry is focused on finding new products and formulations that will expand their market and increase their market share. It typically takes at least 10 years of intense research and development from the discovery (- first synthesis) of an active ingredient until it's market introduction as an agro-chemical product. A new formulation can be on the market much quicker. In addition, it has become increasingly more and more difficult to find better actives, that are more user friendly, safer, cheaper to manufacture and increase the effacy of the active. Therefore the design of the formulation becomes more business critical.

3. C H A L L E N G E S IN M O D E L L I N G M A N U F A C T U R I N G PROCESSES

FORMULATION

Starting with unit operations as this is familiar to the PSE community. These unit operations for formulations, shown in figure 3, are in some part very different to active ingredient or bulk commodity manufacturing. Typical examples being of bead mills, coaters, high shear agitators as shown in figure 4. However some items are familiar to the PSE community e.g. fluid bed dryers, spay dryers, mixing tanks and agitators. The characterization of the familiar equipment though is more difficult due to high viscosity, solids, slurries and fluids such as surfactants, wetters, dispersants, polymers and complex active ingredients. Formulation manufacturing is typically more globally spread in more numerous smaller sites than active manufacture as can be seen in figures 5-6. This brings added complications of scheduling and differentiation for each market. The number of slightly different formulations may be large and therefore a system for designing formulations, their manufactures and optimising them easily for each market becomes important.

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Figure 3" Unit operations in formulation processes. Provided by Paul Bonnett Syngenta.

Figure 4 Coater, Dynomill- bead mill and high shear emulsion agitator from left to right.

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Figure 5

Figure 6

4. F O R M U L A T I O N TYPES AND ISSUES Pesticide products are split into herbicides, insecticides and fungicides. Herbicides have to penetrate deeply into the plant to kill it. Many Insecticides need to sit on the Surface of the plant leaf to contact insects attacking the plant. Contact many be by direct pick-up or ingestion. Protectant Fungicides in general form a protective layer on the wax of the leaf and therefore require slow uptake into the leaf cuticle but rapid uptake into the surface wax [ 14], although systemic fungicides require reasonable uptake for redistribution in the xylem (for example azoxystrobin). These products are split into a number of different formulation types as shown in table 1 and the characteristics of some of these formulations are shown below.

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Solid formulations Wettable Powder ( W P ) Wettable Granules ( W G ) Soluble Granules (SG) Granules (GR) Tablets (TB)

Liquid formulations Suspensionconcentrates (SC) Emulsionconcentrates (EC) Soluble liquids (SL) Emulsions in water (EW) Microemulsion concentrates (MEC) Microemulsions (ME) Capsule suspensions (CS) Suspoemulsions (SE)

Table 1: Formulation types 4.1 Solid Formulations Wettable Powders (WP) have a solid, active ingredient - or a liquid active ingredient coated on an inert carrier that is mixed up with all other formulation inerts (dispersants, surfactants, fillers). This is then dry milled (i.e. jet-stream milling) to reduce the particle size to about 2-5 microns. Redispersion upon dilution with water by the farmer results in a suspension of the active ingredient/filler particles as spray solution. Dispersants and surfactants ensure fast redispersion to single particles upon dilution in water to form the spray solution and prevent the single particles from agglomerating and/or sedimenting in the spray solution

4.2 Liquid formulations: Suspension concentrate (SC) :A solid active ingredient with the help of added dispersant and thickner is suspended in water then wet-milled to reduce the particle size to about 2 microns. Surfactants in this case protects the particles from crystal growth and agglomeration They also ensures fast redispersion to single particles upon dilution in water to form the spray solution and prevent agglomeration and/or sedimentation of particles in the spray solution. The addition of a thickener (for rhelogy and structure adjustment) prevents the sedimentation of particles during storage.

Emulsion concentrates (EC). The active ingredient is dissolved in a waterimmiscible organic solvent along with the addition of a co-solvent if not liquid already. Emulsifiers are added to ensure spontaneous emulsification of the formulation upon addition to water to form the spray solution. Emulsifiers also prevent emulsion droplets in spray solution from particle growth, agglomeration, creaming and sedimentation and prevent recrystallisation of the active ingredient upon dilution in water to form the spray solution. Capsule suspension (CS). The liquid active ingredient or solid active ingredient is dissolved in water-immiscible organic solvent and emulsified in water. Oil droplets contain an (at least bifunctional) purely oil-soluble monomer in addition of an (at least bifunctional) purely water-soluble monomer starts an interfacial polymerisation (figure 7). This reaction results in polymer capsules filled with active ingredient "Controlled release" formulation. Emulsifiers stabilise emulsion droplets before polymerisation to prevent

131 sedimentation of the polymer capsules in the suspension. This also ensures fast redispersion to single particles upon dilution in water to form the spray solution and prevents polymer capsules from agglomeration and sedimentation in the spray solution. The polymer chosen need to provide a polymer wall that is mechanically stable upon drying of spraysolution,where applicable, and allows release of active ingredient at the desired speed and amount. A cut out section of a capsule is shown in figure 8. Careful selection of the solvent system can adjust the strength and structure of the wall changing the release rates.

Figure 7 Emulsion before polymerisation and

Capsule suspension after polymerisation

Figure 8: Cut out section of a capsule showing the wall structure taken with Scan Transmission X-Ray Microscopy. Originally presented by Daryl W. Vanbesien, Harald D.H. St6ver, McMaster University, Hamilton, Canada in a internal Syngenta Presentation. Used with permission.

Emulsions in water (EW): Are essentially the first stage in an encapsulation. They are complex multiphase systems where the surfactant typically creates a third phase (micelles) or changes the interfacial tension sufficiently to increase the solubility of the active and increase bio-availability. The control of the water/oil or oil/water emulsion and the path to achieve the emulsion will change the droplet size distribution and the ability to form a stable emulsion as shown in fugure 9. The HLD (hydrophilic-lypophhilic deviation ) scale as described in [15] is written as a sum of the contributions of effects and therefore would lend itself to a group contribution method.

132 Small Drop Size clue to best formulation compromise Small Drop Size due to high internal phase ratio effect

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Figure 9: Reprinted from [ 16].Used with permission.

4.3 Generic issues with formulations These formulations typically need to have a shelf-life of at least 3 years which means no (or minimal within regulatory limits) chemical degradation of the active ingredient and/or formulation inerts, no change in physical appearance of the formulation i.e. lump formation in WP's, sedimentation or creaming of SC's and recrystallisation of active ingredient in EC's. There must be no change in redispersability upon dilution in water to form spray solution. And finally no agglomeration or sedimentation in the spray solution. Farmers oftern use mixtures of formulations and therefore compatability between these typical mixtures is also important. Therefore a formulation design can include wetters, emulsifiers, dispersants, polymers, surfactants as well as the active ingredient. The potential number of mixtures is vast with the choices of all the formulants possible. As was mentioned before, the design of a new formulation can be business critical and therefore formulations are often tuned to the needs of specific markets, allowing differentiation of the products to maximise sales potential. A well-designed formulation can increase the activity by a number of means, for example increased uptake from careful selection of surfactants. UV protection reduced environmental impact and reduced pytotoxicity can make the product more attractive. Increased retention and spreading characteristics can reduce usage rates. Any of these can also make the product sufficiently beneficial over a competitor's to increase sales. In addition a novel formulation can be used to extend patent coverage preventing generic competition taking over the market when the active ingredient patent runs out.

133 The current practice in designing formulations is to employ a trial and error approach based on past knowledge and expertise. Therefore, although the needs may be satisfied, there is no guarantee that the solution is optimal.

5. P L A N T S T R U C T U R E AND E F F E C T ON UPTAKE. An important step for the efficacy of an agrochemical is the uptake of the active ingredient into the target organism. Therefore building the right mixture into the formulation can enhance the speed and/or amount of uptake of the active ingredient into the target organism and therefore enhance the activity. The right mixture can enhance the chemical stability of the active ingredient, i.e. protect it against photodegradation by UV radiation and weaken the negative impact of environmental factors like heavy rainfalls on the efficacy of the agrochemical. The formulation can influence positively the toxicological profile of the agrochemical like reducing leaching,skin irritation or inhalation. Often something simple like a pH change can substantially improve the suitability of a given formulation. The pesticide, for example, needs to travel from the surface through the epicuticular wax, through the cutin and pectin layer before reaching the target cells as shown in figure 10

Figure 10: reprinted from [ 14] with permission.

This epicuticular wax is a complicated mixture which can be homogenous or show varying levels of crystallinity [ ] (figure 11) dependant on species, which slows the diffusion of the pesticide [ 17]. The intracuticular wax layer is generally accepted to be the main barrier to pesticide uptake [ 18,19,20]. Young leafs have more wax crystals possibly due to the fragile cuticles that are more permeable to water. The waxes differ between plant species. Two examples of the composition of the waxes are shown in figure 12.

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Figure 11: Pea Leaf epicuticular wax provided by Dr C Hart, Syngenta. Further information is presented in [21] This wax layer forms a 2 micron barrier that the active ingredient has to to travel through. Diffusion through the leaf wax can be improved significantly by careful selection of the surfactant [22-29]. The HLB scale [30] is used to classify and select surfactants much like solvent classifications Parker [31] and Chastrette [32] for reaction solvents [33,34]. There are several postulations about why the surfactant aids the passage of the active ingredient, for example the surfactant could be solubilizing the wax and in particular the crystalline structure reducing the tortuosity of the actives' path through to the target cells.

135 [] n-alkanes [] iso-alkanes ~] anteiso-alkanes 9 n-alkenes 9 iso-alkenes 9 anteiso.alkenes [] n-alkanals [] n-alkanoic acids [] unsaturated alkanoic acids [] branched alkanoic acids 9 ketones 9 n-alkanols 9 secondary alkanols [] branched alkanols [] diols [] alkyl~sters [] methyl-esters [] glycerine esters [] al kyl.coum arates [] trite rpe ne esters [] triterpenes (~ constituents with basis peak 8: constituent w i ~ basis peak 123 ra constituent with basis peak 18( [] constituent w i ~ basis peak 117 [] unidentified

Figure 12 9The chemical composition as well as the chain length of the components of the cuticular wax of sunflower leaves (upper chart) and rape (lower chart) and is given in %

5.2 Cutin Composition The cutin layer is made up of an insoluble polymer matrix. This is generally whydroxy-fatty acids of chain length C16-C18 [35-37] and 1-2microns in depth.

6. M O D E L L I N G UPTAKE IN PESTICIDES. Some modelling has been attempted. Essentially the problem is a familiar one with solubility of the active chemical in the water droplet and the formulation mixture on the leaf, then a set of membranes to cross and diffuse through before reaching the target cells. Fickian diffusion can be used to model this diffusion. Foliar uptake of a pesticide has been modelled by using partition coefficients and diffusion coefficients across the plant cuticle[38,39]. This has been extended to the effect of the tortuosity of the actives through the crystallinity of the epicuticular wax [ 14]. This needs estimations for Partition Coefficients, diffusion coefficients, cuticle thickness, Solubility of Leaf Wax in Droplet and the Molar Volume of AI.

136 Whole plant models have been developed [23] which considers the cuticular membrane solubility, solute mobility and tortuosity and the driving force. Further models have been developed for adhesion [23] onto the plant leaf and retention [23] this is especially important for insecticides. Clearly the formulants selected need to aid faster diffusion through the wax in the cases of fungicides and herbicides. Insecticides ideally should diffuse very slowly into the plant and also be well retained on the surface wax. Encapsulated formulations, like microcapsules for drug delivery are being used which present some different modelling and design tasks. The solubility of the active ingredient in the polymer and the diffusivity through it becomes important. The ability to select and optimise the polymers used for efficiency, environmental and cost reasons become the objective and are very familiar to the PSE community being similar to solvent selection and design as used in the CAMD approaches. The careful selection of solvent, for encapsulation can change the release rate and structure of the capsule. This is as a result of the solubility of the monomer in the solvent and therefore the amount available for the polymerisation. A new generation of models and model-based PSE-tools would be needed. Also, formulation design problems, could in principle, be formulated as Computer Aided Mixture Design problems - the limitations at this moment are the models to predict the properties that design the mixtures.

7. CURRENT RESEARCH BY FORMULATORS, PLANT SCIENCE AND RELATED DISCIPLINES. Formulation research is focused on areas as shown in figure 3 using some new advances such as high throughput screening and combinatorial chemistry. Robots are used to rapidly generate large datasets [40] to facilitate more fundamental understanding of what processes are happening as a herbicide, insecticide or fungicide comes in contact with it's target organism. A mixture of methods is used to study the transport processes and mechanisms. Surfactant or oil/solvent enhanced uptake is studied by reconstituted or isolated waxes along with measurements of wax composition versus uptake, cuticle architecture. Clearly genomics is being exploited to build significantly new markets beyond traditional formulations of classical active ingredients. Some of these "tools" could potentially be useful for building PSE type models with high throughput screening able to generate vast quantities of data, which may be needed to build more fundamental understanding of systems or generate group contribution type methods.

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Figure 13

8. C H A L L E N G E S F R O M F O R M U L A T I O N DESIGN. As formulations can be a complicated mixture of surfactants, dispersants, emulsifiers, polymers, buffer agents, antifoams, oil concentrates and inorganic salts models for these will need to be further developed. Many of the systems are formulants such as solvents and surfactants are actually mixtures and therefore models need to capable of handling these appropriately. Models for surfactants need improvement. An understanding and representation of surfactant concentrated phase behaviour phase behaviour is required [23] e.g. liquid crystals where deposits on leaf surfaces dry, or gel phases in waxes. Models for the solubility of active ingredients in these phases are required. The solubility can change rapidly when the deposit dries. A typical surfactant structure is shown in figure 14.

~O~o~O~o~O~o~O~o/~/O~o'~O',H 0 Figurel4: Typical surfactant: "Akypo RML 100" surfactant molecule: C12, EO l0 COOH. Alkyl chain ranges, EO number typically gaussian distribution with mean at 10. Below pH 3.65 effectively non-ionic but anionic above pka of acid group Control of the rheology and interfacial properties can be the key to size control of particles, stability of emulsions and process ability. As mentioned above, the solubility of complicated actives in polymers along with the solubility of the polymers in solvents are also required. Solubilities of the complex actives in the surfactant and in the leaf wax are required. Even solubility of the complex actives in water is important and at the bounds of

138 what is currently possible. Improved models for solubility of complex multi-functional molecules would be very beneficial in development of active ingredients purifications and separations as well as formulation design. Many of the systems are electrolytic, as are many active ingredient processes. However no reasonable predictive models exist for such systems. Such predictive models would be extremely useful in Active process optimisation [34]. Predictive models are needed for all the systems m e n t i o n e d - current models are unable to handle interfacial phenomena and the properties related to this. Models need to consider the phenomena as well as the physics and chemistry (that is, thermodynamic properties, molecular structural properties as well as mass transport, interfacial phenomena with or without reactions - in the case of electrolytes, there are reactions). Without suitable models, development of PSE or CAPE tools would not be possible (these tools can contribute by providing the means to investigate solutions that otherwise would not be possible - but, they require models, which are not available, currently). The interaction between the species and a fundamental understanding on how they affect the active ingredients joumey to the target organism is required. How does the surfactant and other additives really affect uptake. The PSE toolkit allows for rationalization of large datasets and to fit models to the data. Perhaps this can be used to generate more fundamental understanding of the systems in formulation or the effect on the target organism. The ability to model the effect of the different formulants is necessary in-order to be able to optimise and generate and handle the large amount of data required. Models are required for partition coefficients and diffusivity from the drop into the wax and from the wax into the cutin, through the pectin. Models are also required for retention on the leaf surface, spreading and loss, to allow optimisation of formulations and conditions to maximise active ingredient uptake and beneficial bio-availability. If such models can be developed or approximated from analysis of large data sets potentially available from high throughput experiments, then the ability to optimise formulation design and design like the CAMD approach for solvents would be feasible. However, what's needed in this case is computer aided mixture design and has a much higher potential benefit than CAMD, as the composition space is much larger than for solvent selection. Global optimisation techniques may well be appropriate to rapidly assess such large composition spaces for optimal solutions. Empirical models and geometrical techniques [41,42 and 34] have proven very useful in design of active ingredient plant design. Perhaps there is an opportunity to use these types of models to develop our understanding and selection of formulation mixtures. Clearly developing understanding of the effect of formulants in the mixture and the ability to select as required in a Computer aided formulation mixture design tool would also lead to better understanding of the impact of the Active ingredient design and manufacture. Typically active ingredients are made to a specification and designed for the best process for the active. However, this artificial boundary between the active and

139 formulation manufacture can lead to less than optimal designs. The boundary must be removed and any designs need to take into account the formulation ability of the product and optimise across this wider whole process. An understanding of the properties that are important in an active to ensure successful formulation is required.

9. C O N C L U S I O N S . A series of challenges for the PSE community have been presented showing the need for more fundemental understanding of the impact of each formulant on uptake, effacy and the ability to model the systems. The critical need to develop physical property models to handle the complex mixtures was highlighted. The aim being to be able to use PSE models to design and optimise formulations and invent new formulation types. A rational selection tool or computer aided formulation mixture design tool being the goal to radically improve formulation design. Such tools and the ability to tune formulations specifically, optimising their design will reduce costs, reduce environmental impact and allow product differentiation giving potential for sales growth. Given the increasing difficulty to find new agrochemicals that show advantages over those currently available. The ability to design new and improved and cost effective formulations will be the key to business growth and therefore critically important. The PSE community needs to work in partnership with plant scientists, surface scientists and those working in formulation development to build understanding of the systems bringing their toolkits and thinking together.

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ACKNOWLEDGEMENTS Permission to publish from Syngenta is gratefully acknowledged. Thanks to a great many friends and colleagues for advice and information, especially: Dr Gordon Bell, Dr Alan Hall, Kenneth McDonald, Brian Lauder, Paul Bonnett, Dr Adrian Friedmann, Dr Cliff Hart and Dr Stefan Haas of Syngenta Dr Claire Adjiman of Imperial College and Prof Rafiqul Gani of Danish Technical University, Denmark.