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Experimental Design: Extruded Granule Formulation Development

Introduction: The development of wettable powder (WP) formulation technology marked the advent of modern agricultural delivery systems in which both liquid and solid technicals could be delivered to a target organism dispersed in water at the time of application. Prior to this time, agricultural products were applied primarily as "dust" formulations; that is, active ingredients were reduced in concentration in the presence of clay diluents to a target assay, processed to a small particle size using high impact equipment, and broadcast as dry powders. 

The adverse implications of the above dust applications lie in the areas of uniform distribution of active ingredient and unnecessary exposure to toxic chemicals. Wettable powders were the first delivery system developed for agricultural chemicals to begin to address these concerns by means of formulation dispersion in water at the time of application. The intent of the technology was first to improve the uniform distribution of active ingredient through the development of specific molecules which improved the wetting of the powders into water ("wetting agents") and the physical suspension of the powders once they had been wetted into water ("dispersants"). Inherent with the development of the wettable powder was reduced applicator exposure to the active ingredient once the formulation had been added to water. 

However, the applicator was still exposed to the active ingredient at the time the wettable powder was added to water.

Delivery Systems - Granulation: It was therefore desirable to develop "delivery systems" through both packaging and reformulation of WP that did not adversely affect either physical or chemical performance. Efforts to address applicator exposure through packaging involved development of a Unit Dose Delivery System. With this technology, a predetermined weight of WP is heat sealed inside a water-soluble pouch (usually composed of polyvinyl alcohol or similar polymer) and added to the spray tank at the time of application. However, there are limitations to the technology:

  1. The dissolution of the water-soluble film may be affected by water temperature: the colder the temperatures of the spray tank water, the longer it takes to dissolve the water-soluble bag. Undissolved film may then block in-line screens or spray nozzles;

  2. The packaged wettable powder may function as a desiccant for the plasticizers present in the water soluble film which will then become brittle and release powder upon handling;

  3. Being a Unit Dose Delivery System is a self imposed limitation to the applicator where variable application rates are desired;

  4. Other materials present in the spray tank at the time of application may adversely affect system performance, primarily through adverse reaction with the water-soluble film material.


In terms of reformulation, controlled addition of water to the processed wettable powder was found to form agglomerates that minimized exposure to airborne dust particles. In this technology, referred to as "Pan Granulation" the powder is fed into a rotating pan while at the same time water is misted onto the powder. The combination of rotation plus water causes agglomerated powder spheres, of variable sizes, to form. The newly formed granules literally roll off the pan as they are displaced with fresh powder to be agglomerated. The resultant granules are then directed toward a fluidized bed dryer where they are dried to predetermined residual moisture by a combination of temperature and residence time in the dryer. The controlled moisture levels in the granule introduce structural integrity while at the same time allowing the granule to disintegrate upon addition to the spray tank. Finished granules are screened to pre-select commercially particle size distribution.

However, limitations to the technology, as a delivery system for Wettable powders, were identified which came to be associated with granule hardness and a tradeoff between disintegration in the spray tank and dust formation upon handling. The harder the granule, the less airborne dust that formed upon handling, but the longer the granule took to disintegrate in water.

Efforts to balance granule dustiness and disintegration were addressed through inert selection and concentration: increased levels of wetting agent/dispersant and incorporation of disintegrants were identified which facilitated the efficient movement of water throughout the granule. Granules processed using Pan Granulation demonstrated variable hardness depending upon technical density, crystalline structure and water solubility; efforts to control granule integrity revolved around incorporation of a densification step prior to granulation and modification of the binder system at the time of agglomeration. Concerns were also expressed with the additional rework costs associated with pan agglomeration since final product is specified as to acceptable granule size distribution. Granules outside these limits had to be reduced in particle size (hammermilled) and mixed with virgin Wettable powder product at a rate that did not then negatively impact granule performance.

In contrast to Pan Granulation, extrusion eliminates the variability of granule integrity associated with technical density and crystalline structure. In this technology, Wettable powders are densified with water in a kneader to the consistency of dough which is key to granule performance prior to extrusion. Too little water and the final granule integrity is affected to the point that dust may form with abrasion; excess water and the granules form stable agglomerates after being extruded which may impact disintegration.

Granule disintegration is a function of choice/concentration of formulation excipients, extrusion screen opening diameter, and surface area/porosity of the granule 'noodle' processed. The first allows for the efficient transport of water throughout the granule. The latter two dictate the granule surface area and the depth to which the water must travel during the disintegration process.

As with Pan Granulation, finished granules are dried to predetermined residual moisture and screened to an acceptable particle size distribution. Also, granules outside this particle size range must be reworked into the initial feedstock in such a manner as to not adversely impact finished granule performance.
Powder and Granule Basics : The basic WP and Extruded Granule formulation contains the following components:

  1. Technical

  2. Wetting agent

  3. Dispersant

  4. Diluent (Clay and/or Silica)


Technical: As with the wettable powder formulations, extruded granule formulations can accommodate both liquid and solid technicals; however, their requirements in terms of diluent and processing are vastly different. The upper concentration limit of solid technicals is related to the melting point of the technical and the heat generated during processing: once the technical begins to be affected by the processing equipment (usually manifesting itself as thermoplastic), you have reached the upper formulation concentration. As a general rule, the higher the melting point of the technical, the higher the concentration at which it can be formulated. Also, processing the formulation using equipment that generates less heat should allow the formulator to increase the product active ingredient concentration.

With liquid technicals, the upper concentration limit is dictated by the amount of diluent powder necessary to isolate the individual liquid droplets. This quantity is a function of the particle size of the diluent: the smaller the particle size, the lower % (w/w) of the diluent that is required to encircle the liquid. "Impregnating a WP" is a term often used to describe the dispersion of a liquid technical into a diluent carrier; however, in many cases this is a misnomer since the liquid never enters the carrier cavities. Rather, the liquid can be viewed under the microscope as liquid spheres surrounded by diluent particles. The exceptions, technicals that can be impregnated, are those which will "wet" onto the diluent surface. Basically, the former technicals can be described as hydrophobic (water insoluble) in character and the latter as hydrophilic (water-soluble).

The water solubility of a technical and the impurities present on its surface are extremely critical to extruded granule disintegration. Hydrophobic technical surfaces require additional concentrations of wetting agent in order to facilitate the movement of water through the compacted granule.

Wetting agent: The wetting agent functions at the water/granule solid interface and aids in the incorporation of water throughout the compacted granule at the time of application. Wetting agents are surfactants, both nonionic and anionic, which orient their water soluble "end" into the water phase and their oil soluble "end" at the organic technical surface; thus serving to reduce the surface tension between the solid surface and water surface. Gravitational forces then allow the powder that is formed during the disintegration process to fall away from the granule surface and expose 'fresh' surface to be wetted. The rate at which the wetting agent aids in the transfer of water into the granule dictates its efficiency: the faster water is incorporated into the extruded granule, the more efficient the wetting agent.

Since a wetting agent functions mainly to disintegrate the extruded granule upon addition to water, its % (w/w) requirement in the formulation is dependent upon the water solubility/dispersibility of the technical and other formulation excipients. Traditionally, to more efficiently distribute the wetting agent into the WP formulation, spray-dried mixtures of wetting agent and dispersant have been developed and are commercially available. However, since a proprietary blend of wetting agent and dispersant is processed at established ratios, it is possible in this case to add an excess of dispersant in order to meet the (generally higher) wetting agent requirement of a hydrophobic technical during extruded granule development. This would unnecessarily increase formulation costs. With extruded granule formulations, fine particle size powders are the preferred wetting agent physical forms since this allows for its optimum concentration and efficient distribution throughout the wettable powder formulation prior to granulation.

Dispersant: Once the powder or granule has been added to the water phase (with the aid of the wetting agent), the dispersant now functions to isolate the individual particles and maintain them in suspension upon agitation. Dispersants useful in powder and granulated products are, for the most part, anionic surfactants which function at the water/particle interface and, by means of surface charge (electrostatic stabilization), prevent the individual particles from forming stable agglomerates. 
Dispersant performance is affected by:

  • Concentration: Since dispersants partition between the water phase and the solid surface, there must be sufficient dispersant present to accommodate the desired equilibrium concentration at the water-solid interface.

  • Temperature: Dispersants are surfactants; as such, their solubility in water (or, partitioning at the water/solid interface) is affected by changes in temperature. Therefore, physical suspension performance at one temperature may not speak for performance at a different temperature.

  • Water Hardness: The presence of ions in water may adversely affect the solubility of the dispersant in the water phase. Therefore, it may be necessary to either determine the % (w/w) dispersant required to accommodate a range of water hardnesses or select the specific dispersant composition which performs optimally in the desired water hardnesses.

Diluent: The role of the clay or silica diluent, whether the technical is solid or liquid, is to reduce the active ingredient assay to a targeted concentration and to isolate the individual organic particles. This isolation serves two purposes:

  1. Minimizing the impact of processing heat of shear upon the technical and other formulation components;

  2. Facilitating technical dispersion upon addition to water;


However, with extruded granules, the diluent serves an additional function: it aids in granule disintegration. Therefore, as the extruded granule active ingredient concentration increases, the choice/concentration of the selected wetting agent becomes increasingly more critical to formulation performance upon application. 

In general, the smaller the particle size of the diluent the higher the concentration of a technical that can be formulated. However, with reduced diluent particle size comes reduced formulation bulk density, which may impact commercial packaging and delivery requirement. When considering reduction of the diluent particle size to improve formulation physical suspension upon dilution, it must also be determined whether for wettable powders the same weight of formulated product will still fit into the current commercial container and whether the same volume unit dose applicators (scoops) are still appropriate. Small particle size diluent may also raise the wetting agent requirement in extruded granule formulations, especially with hydrophobic technical surfaces, due to increased surface area and reduction of 'channels' for water penetration throughout the granule.

With liquid technicals, in order to facilitate dispersion in water, it is desirable that the silica be hydrophilic. Although higher concentrations of organic liquid technical active ingredients (through true impregnation) can be formulated using hydrophobic silicas, it is extremely difficult to wet and disperse these formulated powders into water without addition of high concentrations of wetting agent.

Isolation of the individual technical particles is extremely important with those low melting technicals that are solid under normal storage conditions but are melted and processed as liquids. Once processed as wettable powder, the liquid technicals will revert to their preferred physical state, as solids, upon storage. This change in physical states will significantly affect physical performance at the time of application. The wettable powder, which at the time of production was free-flowing and readily dispersed in water to its primary particle size, may have formed physically stable agglomerates upon aging that will adversely affect flowability and physical suspension upon dilution.

Other excipients may be added to the formulation to address concerns associated with chemical stability, odor, surface adhesion, etc. For liquid and low melting point technicals, the issues related to formulation disintegration and suspension performance at higher technical concentrations would likely be exacerbated by conditions encountered in the extrusion process.

Wettable Powder (WP) and Water-Dispersible Granule (WG) Development: To develop a wettable powder involves a series of steps:

  1. Establishment of performance criteria

  2. Selection of formulation inerts

  3. Formulation processing

  4. Establishment of test procedures

  5. Determination of a development methodology


Establishment of performance criteria: It is important to establish up front how the formulation is expected to perform since this may dictate choice/concentration of inerts.

  1. Concentration: dictates formulation composition. Assuming that the optimum concentrations of the wetting agent and dispersant have been experimentally determined, the % (w/w) of clay or silica in the formulation is adjusted to accommodate changes in technical concentration.

  2. Chemical/Physical stability: is important to the applicator since efficacy is a function of the quantity of active ingredient added to the spray tank and its uniform distribution in the water phase over the time frame of application.

  3. Formulation flowability: is a function of Extruded Granule particle size. The more rounded the granule, the greater the ease of flowability. Far less important is the performance of the Wettable powder. For the Wettable powder, the less dense the formulation or the more air is maintained in the powder, the better a wettable powder flows. Incorporation of desiccants, or hydrophobic silicas, will adversely affect extruded granule performance.

  4. Granule disintegration: is a function of extruded granule composition and processing. In terms of composition, it is necessary to incorporate sufficient wetting agent into the formulation to properly wet the technical into water. With hydrophobic technical surfaces, this implies a higher formulation requirement than with hydrophilic technical surfaces. When processing extruded granules, the greater the surface area generated (through controlled granule length and diameter), the faster the granule will disintegrate.

  5. Physical suspension upon dilution: is a function of granule disintegration, which is a function of small particle size and choice/ concentration of dispersant. Water hardness and water temperature as well as the presence of another formulation (WP, SC, EC, or adjuvant) may impact physical suspension in the spray tank at the time of application.

  6. Dust: is a function of granule processing integrity and Wettable powder fine particle size/composition and may be minimized through proper selection of formulation excipients (wetting agent concentration and diluent), active ingredient concentration and adequate water addition during the granulation process.

 

Selection of formulation inerts: Formulation inerts should be selected on a cost/performance basis: if you don't get the performance, then it doesn't matter what the cost. Where possible, formulation components should also be dry powders since liquids may be problematic both in their uniform distribution and stability within the formulation.

One of the major issues associated with clay/silica diluent selection relates to chemical degradation of the active ingredient and appears to be a problem mainly with technicals processed as liquids or wettable powder formulations which contain a liquid inert which solubilizes the active ingredient. Although in its simplest terms the degradation process is associated with diluent pH, this may not be a completely accurate description since chemical degradation may occur in the absence of water. Also, carriers of the same pH may demonstrate diametrically opposed chemical stability profiles. Rather it appears that chemical degradation may be related to the specific composition of the carrier or specific sites on the carrier surface.

Beyond this, issues with chemical stability during processing may be related to the increased surface area of the technical which, in the case of carrier dependent degradation, may relate to increased contact between the carrier and the technical active ingredient. In general, the more severe the milling process (hammermill > > airmill) the greater the degradation.

One factor that is often overlooked during formulation development is the interaction between wetting agent/dispersant and technical, which results in stable agglomerate formation. There are solid technicals that demonstrate variable water solubility as a function of pH. It is necessary to determine whether choice of wetting agent/dispersant could contribute to the establishment of such an environment. Although not an issue at the time of production, the change in solubility could affect formulation performance under storage conditions which would encourage increased technical solubility followed by decreased technical solubility; specifically, a hot Midwestern United States summer followed by a cold Midwestern winter. The agglomerate formation issue can only be exacerbated when the wettable powder is not treated as an end-use product but rather serves as an intermediate in the processing of a Water-Dispersible Granule (WG) formulation where additional water is intentionally added and removed. 

Dispersants should be selected based upon physical suspension stability over a range of water hardnesses and temperatures. Effective dispersant weight percentages in a formulation may range from 3-13 % (w/w) depending upon the chemistry involved.

Wetting agents serve to efficiently distribute the water throughout the Extruded Granule upon addition to the spray tank and are effective at formulation weight percentages of 1-8 % (w/w) depending upon the surface properties of the formulation components.

 

Formulation processing: Since extruded granules are considered as delivery systems for wettable powders, it is necessary that the technology associated with Wettable powder development be understood before advancing to the next step of granulation.

Wettable Powders:

  1. Blender #1  

  2. Hammermill  

  3. Blender #2 

  4. Airmill

  5. Blender #3

  6. Pack-Out

Traditionally, wettable powder processing begins with the addition of formulation components to a blender, with the most widely used being a ribbon blender. However, choice of blender will affect ultimate formulation performance, especially with liquid technicals, since they dictate the degree to which agglomerates are broken down to their primary particles. The amount of shear the equipment places upon the formulation in combination with the resistance to shear the formulation places upon the equipment will determine the efficiency to which the formulation components are mixed. In other words, in order to mix adequately the formulation components, the shear energy of the equipment must exceed the attractive forces holding the primary particles together. In general, the smaller the primary particle size of any formulation component, the more energy required to fully deagglomerate it.

Optimally, 95% of the mixing should be accomplished in the blender and the remaining 5% upon passage through a hammermill and/or airmill. Conversely, the more that blending takes place in the hammermill, the more inconsistent the mixture that will be processed. There is a volume range over which a blender operates (mixes) most efficiently; formulating either above or below this volume may result in adequate mixing.
With viscous liquid technicals, warming the technical to reduce its viscosity reduces resistance to the shear forces of the mixer. However, as the warm technical comes in contact with the diluent carrier, the heat of the liquid is rapidly dissipated. The carrier/adsorbent acts as a "heat sink" in this example. The result of this heat loss being that the particle size of technical can not be reduced to the extent obtained upon initial addition to the mixer: the technical is demonstrating increasing resistance to the shear of the mixer as the temperature decreases. It is possible to lessen the resistance of the technical to the shear of the mixer by use of a heat-jacketed blender. In this case, the technical will remain lower in viscosity throughout the dispersion process. However, if the diluent carrier can chemically degrade the active ingredient, the effect can be exaggerated by use of the heat-jacketed blender.

With liquid technicals, if optimum dispersion is accomplished in the blender and a small particle size diluent carrier is used it should not be necessary to continue processing beyond hammermilling/ Blend #2 Stage. The role of the hammermill should be to complete the blending operation by means of breaking and redispersing the agglomerates that were too small to be separated in the blender. However, if a large particle size diluent carrier is used (which requires actual particle size reduction in order to accomplish the desired physical suspension performance) it may have the undesired effect of smearing the liquid technical onto the solid formulation component surfaces. This will cause agglomeration and/or reduced physical/chemical stability on aging. Choice of hammermill screen design (herringbone, pinhole) and screen size opening dictate residence time in the hammermill. Selecting screen openings that are too small leads to extended residence time and technical smearing; too large leads to minimum residence time and poor deagglomeration.

With solid technicals, the goal is to minimize the impact of processing heat upon the technical surface. Therefore, the higher the melting point of the technical, the higher active ingredient concentration (granule "assay") that can be formulated. As with liquid technicals, residence time in the hammermill will affect formulation performance. However, the hammermill can be used as part of a stepwise processing operation with low melting solid technicals to deagglomerate and perform minimal particle size reduction. Here, actual milling is performed in the airmill, which rapidly dissipates heat upon generation.

This does not mean that the airmill will not affect wettable powder performance: the heat generated at the moment of impact inside the airmill may be sufficient enough to allow the undesired incorporation of formulation components into the softened technical surface. Adverse performance attributable to processing equipment can be mitigated by choice of smaller particle size diluent carrier and/or reduced formulation concentration.

Use of a Blender #2 after the hammermill serves two functions: (1) Uniform blending of the deagglomerated Wettable powder either prior to pack-off or airmilling, and (2) if at least twice the size of Blender #1, it converts the manufacturing process from a batch operation to a continuous process.

As stated above, the role of the airmill is to reduce the primary particle size where improved physical suspension is the desired performance criteria being addressed. However, it should be noted that along with the improved physical suspension comes reduced bulk density due to air incorporation.

As with Blender #2, use of Blender #3 after the airmill allows for the uniform mixing of the Wettable powder prior to pack-off. There is pack-off equipment that will remove air incorporated during processing from the Wettable powder prior to packaging by means of a vacuum placed at the point of discharge. This negates the need for oversized commercial containers at the time of pack-out.

Extruded Granules :

  1. Wettable powder  

  2. Hobart Mixer  

  3. Granule Extruded

  4. Granule Dried

  5. Granule Screened

  6. Granule Packed Off

Once an acceptable WP formulation has been developed, continuation of the product development as an extruded granule is relatively straightforward. Water (or water + surfactant) is added to the WP incrementally in a Hobart Mixer until the powder has the consistency of bread dough. It is important that each water addition be thoroughly mixed with the wettable powder before further addition of water since excess water will adversely affect granule integrity. The presence of excess water may not appear until the dough is passed through the extrusion equipment where additional mixing (compaction) makes more effective use of the water present in the formulation.

Granule particle size, both diameter and length, should be optimized in order to facilitate formulation disintegration in the spray tank and to minimize product segregation in combination with other granule formulations in commercial packaging. They should be dried uniformly, by means of a fluidized bed dryer, in order to prevent surfactant migration through the granule. Granule disintegration may be aided by maintaining a minimum residual moisture; however, the need and concentration should be determined since the presence of water may adversely affect granule integrity (friability and flowability).

Since extruded granules are viewed as delivery systems for wettable powders and as such are intended to minimize exposure to dust, it is necessary to identify an appropriate sieve distribution that supports the above objectives of granule disintegration and non-segregation in commercial packaging. Those granules and powder outside the targeted particle size distribution range may be reworked through a combination of micro-milling (and blended with virgin production) and macro-milling (and passage again over the desired sieve distribution).

Establishment of test procedures: Aside from those tests related to product registration, it is important that the tests established in the laboratory ultimately speak for the performance of the formulation under actual field conditions. Such performance test procedures generally fall into three (3) basic categories:

  1. Storage conditions 

  2. Screening methods  

  3. Application methods

In very few regions of the world will a formulation experience a constant temperature environment with no variation. Therefore, extended storage at one temperature, for instance 50°C, may not be predictive of the formulation's long term physical stability. In the real world, most formulations will experience cyclic temperature conditions: cold winter, moderate spring and fall, and hot summers. In order to understand more fully product physical limitations, it is necessary to evaluate the formulation performance under both static and dynamic storage conditions.

Tied into formulation storage conditions are screening test methods for easily distinguishing the obviously good from the obviously bad formulations. These methods could include, but not be limited to, granule disintegration, physical suspension in a series of water hardnesses and chemical stability. Formulations that pass the screening methods hurdle can now be evaluated in terms of their interaction with application equipment. Here, concerns fall into the areas of equipment shear, equipment hose and seal compatibility, application dilution range, and tank mix compatibility with other formulations.

Determination of a development methodology: There are two approaches that can be taken to expeditiously develop an extruded granule formulation where the active ingredient concentration has been established:

  1. Select a dispersant product and then determine its requirement in the formulation 

  2. Establish an dispersant requirement and then determine which dispersant meets that requirement

     

With the first approach, the development methodology becomes one of blending three components where one of the components is the dispersant of interest, another is the wetting agent, and the last component would the diluent carrier. As stated above, there are minimum concentration requirements for dispersant (3 - 13 % w/w) and wetting agent (1 - 8 % w/w) in an extruded granule that are dependent upon the respective chemistries involved and the properties of the technical and diluent carrier. The actual requirement can be determined by means of Experimental Design approaches; specifically reference the Uniqema Technical Bulletin entitled "Experimental Design: EC Formulation Development" For additional guidance in the application of this approach.

With the second approach, the basic dispersant requirement has been established and each dispersant is substituted directly into the formula. Whereas the first approach allows for the evaluation of individual component interaction, the second approach does not. However, the first approach may require a significantly greater time/resource commitment due to the number of sample preparations required. The second approach may be accomplished in a relatively short time frame if the "right" dispersant has already been identified and the Wetting agent requirement of the formulation has been addressed. It is important to realize that an Experimental Design approach does not guarantee the successful development of an extruded granule formulation. It still falls upon the formulation chemist to select the excipients to be evaluated, to determine the impact of the processing equipment upon the formulation, and whether the application equipment impacts formulation performance.

What Experimental Design does is to provide the formulation chemist with a "road map" to monitor whether the changes in formulation inerts, processing equipment, and application equipment are taking him/her closer to their target: a commercially viable formulation.