WO2015042334A2 - Compositions and methods for aerosol particle coating process using volatile non-flammable solvents - Google Patents

Abstract

The present teachings provide a method for coating particles containing thermally sensitive biologically active materials encapsulated by uniform thin protective moisture barrier coatings, and processes for applying such coatings efficiently, at ambient temperatures and with minimal agglomeration. The coating formulations can comprise dispersants, adhesion promoters, polymers, and plasticizers dissolved or dispersed in a non-flammable, low boiling point solvent such as methylene chloride that is delivered with an aerosol process to target particles. The present teachings also include the resulting particles.

Description

COMPOSITIONS AND METHODS FOR AEROSOL PARTICLE COATING PROCESS USING VOLATILE NON-FLAMMABLE SOLVENTS

CROSS REFERENCE TO RELATED APPLICATIONS

[001] This application claims benefit of priority from United States Provisional Application No.

61/880,742 filed on 20 September 2013, and the contents of which are incorporated herein by reference in entirety.

Field of Invention

[002] This invention pertains to particles potentially containing thermally and/or hydrolytically sensitive biologically active materials encapsulated by uniform thin protective moisture barrier coatings, and processes for applying such coatings efficiently, at ambient temperatures and with minimal agglomeration. The invention further pertains to coating formulations comprising polymers, plasticizers, dispersants, and adhesion promoters dissolved or dispersed in a nonflammable, low boiling point solvent such as methylene chloride that is delivered with an aerosol process to target particles to form specific thin coatings.

Background

[003] Enzymes, proteins, microbial cells, seeds, and other biological materials are often used in applications such as steam pelleting of animal feed, detergents, crop production, and probiotic drinks, wherein the biological material is exposed to elevated temperatures in the presence of moisture, the combination of which is known to cause a loss in potency or activity of the biological material. To prevent or minimize such losses, the biological material is often formulated as a dry granule surrounded by a moisture barrier coating, consisting of either a hydrophobic material, such as a wax, or a moisture hydrating material, such as a salt, sugar, or polysaccharide. Water vapor permeability of a coating can be directly related to enzyme stability. (Reference: Hsu et al., Pharm. Dev. Tech. 6 (2): 2000, 277-284). The coatings can be applied either (a) as "hot melt" coatings applied in a molten form by a tumbling process such as a drum granulator or high shear mixer; or (b) as an aqueous solution or suspensions, such as latex suspensions, in an atomization process, such as by a two-fluid nozzle in a fluidized bed coater.

[004] However, such existing processes suffer from a number of drawbacks. Both hot melt coatings and aqueous atomization coatings involve exposing the biological material to elevated temperatures, typically in excess of 30 degrees C, more typically in excess of 40 degrees C, which can lead to loss of activity or potency of the biological material. And both processes generally require thick coatings, built up by fusion or spreading of discrete microparticles or patches of coating solids after they are deposited and built up on a surface, in order to reduce the prevalence of pores, cracks or defects that would enable the diffusion of water vapor or condensed moisture through the coating. Such moisture diffusion is frequently destructive to biological materials, especially at storage or processing

temperatures of between 30-100 degrees C.

[005] To some extent, interparticle fusion of deposited coating microparticles or patches can be achieved by curing or annealing the coatings. However, inhomogeneities and defects in the coatings persist, and the coating permeability is generally inferior and more variable when compared that of a monolithic coating formed by equivalent polymers cast from solution. (Reference: Roulstone et al., Polymer International 27 (1992): 305-308). Thus, for example, the combined thickness of protective coatings applied to enzyme granules is typically greater than about 20 microns, often as much as 40 or 50 microns, to ensure adequate coverage and at the thinnest points in the coatings, to ensure sufficiently low water vapor permeability and water vapor uptake.

[006] While application of solvent-casting is known to produce coatings which have few or no defects, in comparison to coatings applied by atomization from aqueous solutions, latex suspensions, or melt coatings, solvent casting is not feasible as a method of coating granules or particulate solids, due to the extended time required for solvent removal and the difficulty of casting films onto particles while avoiding agglomeration. Generally, an atomization process is the preferred method of particle coating because the speed of application is compatible with the need to avoid agglomeration of coated core particles. But atomization of polymers from both latex suspensions and aqueous solutions typically results in evaporative deposition of incompletely fused particles or patches. Furthermore, even where the particles or patches exhibit some degree of fusion, defects remain and the polymer chains exhibit incomplete interpenetration, and hence an increased degree of permeability to water vapor and other gases or liquids.

[007] Coating seeds with fungicides and insecticides has become a major component of the agricultural seed producing industry. In the case of high value agricultural seeds, coating is often the critical final production step. The driving force behind the rise of such seed treatments is the need to protect high value genetically modified grain and vegetable seeds from soil borne diseases. Other advantages of seed treatments include accurate dosing and placement of pesticide as well as the cost savings associated with applying seed and pesticide in the same pass.

Functional coatings can also improve seed handling and appearance, alter surface properties and provide protection from mechanical abrasion. Furthermore, coatings can be designed to achieve protection from heat, moisture and other stresses to ensure extended shelf life during storage, combined with specific permeability to water and pesticides, assuring timely seed germination and enabling effective control over the release of pesticide into the soil.

[008] Seeds are currently treated with pesticides in mixing chambers utilizing dusts or aqueous based slurries containing polymers to improve adhesion.

[009] Dust treatments have lost popularity due to worker exposure concerns and poor seed adhesion properties. Aqueous based slurry treatments often have problems associated with nonuniform pesticide coverage, lengthy drying times and sticky coatings which require post treatment with fine particle lubricants such as talc. However, talc dust used in neonicotinoid insecticide seed treatment has been recently implicated in causing bee toxicity as a result of its dislodgement from seed during planting operations.

[0010] Liquid coating technology is often used to coat solid product forms. A

mixture of polymers, pigments and other excipients are dissolved or dispersed in water or organic solvents and sprayed onto the solid forms that are then dried with continuous exposure to heat. Rotary pan coaters are used for the larger product forms such as tablets and fluidized bed coaters are used for smaller sized product forms. One disadvantage of liquid coating technology is the necessary use of flammable solvents, the most common being ethanol, isopropanol or acetone, that require the use of explosion-proof equipment.

[0011] In order to overcome the limitations of aqueous coating technology, new efforts have been made in recent years to develop solventless (powder) coating technology. There are generally four powder coating techniques based on the use of a rotary pan coater that are currently in use. While these dry coating techniques overcome some of the disadvantages of liquid coating technology, other limitations present themselves.

[0012] One approach is the plasticizer dry coating technique where powder polymer particles are sprayed onto the product surface simultaneously with liquid plasticizer sprayed from a separate spraying nozzle. The sprayed liquid plasticizer wets the powder particles and the product surface, promoting the adhesion of particles to product surfaces. The coated products are then cured above the film forming temperature to form a continuous film. The plasticizer lowers the film forming temperature requiring additional heat to form a film.

[0013] However, a plasticizer /polymer ratio of 1/1 is normally required for the adhesion of enough particles to the product surface in order to get a coating that is thick enough for sufficient protection or proper controlled release. This high plasticizer level leads to soft or sticky films. It is often difficult to adjust the plasticizer level to get sufficient coat thickness and at the same time produce a dry coating.

[0014] Another approach is the electrostatic dry coating approach based on the attraction of charged sprayed polymer powder particles to grounded product forms. The product forms are then heated to fuse the particles to produce a continuous coating. However, the electrostatic attraction between the charged polymer particles and the solid dosages with low conductivity or high electric resistance is typically weak, leading to difficulty in producing a thick coat. This process requires heating after deposition and can be challenging when the surface to be coated is complex. Moreover, often the surface to be coated must remain stationary during coating due to the requirement that it must remain electrically neutral, even as charged particles are depositing on it; therefore, it must be actively grounded through continuous physical contact.

[0015] A further approach is heated dry coatings. Polymer powder particles are fed into a rotating bed containing the product forms. An infrared heat source mounted above the bed to provide heat to melt the polymer particles that first adhere to the product forms and then fuse to form a coating around the product forms. It is a challenge using only heat to adhere polymer particles to the product forms to achieve smooth, uniform and thick coatings.

[0016] Another approach is the plasticizer-electrostatic-heat dry coating technique that combines the electrostatic spraying of polymer powder and plasticizer onto the product form with heating to fuse the plasticized polymer powder to form a coating. This technique has the limitations of the plasticizer dry coating and electrostatic dry coating approaches with the additional complication of trying to balance the use of plasticizer, electrostatics and heat to achieve an optimum result.

[0017] These coating techniques that have been described are also used on materials other than seeds. For example, pharmaceutical solid dosage forms include tablets, granules, beads, powders and crystals. These solid dosage forms are often coated to mask odor or taste as well as provide protection from water, light, a gastric environment or air. Coatings may also provide enhanced mechanical strength to prevent attrition, control the release of active ingredients with a polymeric barrier or permit the application of pigments to the surface for improved aesthetics.

[0018] Accordingly, there is a need for a coating system that has the advantages of the aqueous coating system and powder coating systems but eliminates almost all of the limitations of those systems. There is also a need to economically provide a coating material that is stable, durable, and can be consistently applied on a large scale.

[0019] An important step towards addressing these problems in the prior art is found in

PCT/US2013/031033-"Aerosol Coating Process Based on Volatile, Non-Flammable Solvents". There, researchers provided a volatile solvent coating system. By way of example, and not of limitation, the volatile solvent coating system is a hybrid system that retains the advantages of the liquid coating systems and powder coating systems but eliminates almost all of the limitations of those systems. In one embodiment, these methods comprise simultaneously dissolving coating chemicals and adhesion promotion agents in a non-flammable, low boiling point solvent such as methylene chloride; and delivering the liquid through a gas atomization nozzle and transformative process to the target surfaces.

[0020] Because of the volatility of the solvent, the process can be tuned to allow only a trace of the solvent to arrive at target surfaces concurrently with the coating chemicals and adhesion promotion agents. By altering the elapsed time period between atomization and emission of the droplets and their subsequent impact on the target, the amount of solvent remaining, and droplet particle size, the physical properties of the in-flight droplets/particles can be controlled.

Alternatively, the relative temperature between the droplets and the ambient or atomizing gas can be tuned to control the rate of solvent vaporization. Combinations of flight times and relative temperatures can be manipulated to achieve the desired degree of solvent vaporization and particle properties.

[0021] In one embodiment, the volatile solvent coating system comprises spraying a liquid containing a polymer, particulates, active ingredients and protective agent's components dissolved/dispersed in a highly volatile, nonflammable organic solvent and forming an adhesive powder in flight as the solvent vaporizes before the spray hits the target and impacting and coating the target in a controlled manner.

[0022] The solid particles formed from the liquid droplets in flight are deformable and flatten and stick to the target surface upon impact. If any residual solvent is present, it is quickly eliminated to produce a rigid surface film on the target.

[0023] In still another embodiment, the volatile solvent coating system comprises dissolving a dispersant, adhesion promoter, coating polymers and plasticizer in a volatile, non-flammable solvent (such as methylene chloride); and dispersing solid active material particles in the solvent solution with the aid of ultrasonic energy such as a continuous wave ultrasonic bath for 10 minutes.

[0024] One advantage of the volatile solvent coating system method is that no heat is needed to cure the applied coating. This facilitates the coating of heat sensitive products and solvent sensitive products, prevent solvent interaction with the particle surface, and also improves product throughput in manufacturing settings. Additionally, the process does not require the use of high voltage electrical fields, either for atomization or deposition. This also protects sensitive bioagents and electronic products from damage. Further, by adjusting the composition of the polymers, dispersing agents and active particulates in the sprayed liquid, the physical properties of the coating can be tuned to achieve desired characteristics such as the controlled permeability of water and oxygen, the controlled release of active ingredients, mechanical integrity and an aesthetically pleasing surface.

[0025] The volatile solvent coating system can be used to provide a coating on a wide variety of objects ranging from device surface coatings to fine particulates such as seeds, tablets, granules, beads, powders and crystals as well as article surfaces. For example, the coating methods can also be used in the field of medical devices to provide a coating on a coronary stent for the controlled release of drugs to prevent restinosis. Dielectric coatings can be applied to

electro surgical devices requiring insulation or to coat printed circuit boards in the electronics industry.

[0026] In biotechnical or pharmaceutical settings, the coatings can be applied to particles or tablets to produce immediate release, extended release or delayed release characteristics. In an agricultural industry setting, seeds can be coated with a coating containing active particles for the controlled release of fungicides and insecticides. Coatings on seeds can also be applied that will provide a temperature triggered release.

[0027] According to one aspect of the volatile solvent coating system , a method is provided that combines a dispersant, an adhesion promoter, coating polymers, a plasticizer and active particles in at least one solvent that can be sprayed through the same nozzle to coat a target.

[0028] Another aspect of the volatile solvent coating system is to provide a method that can modulate the viscosity, particle adhesive properties and active materials with the use of an atomizing nozzle or pressure nozzle. According to another spect of the volatile solvent coating system , a method for coating is provided that begins with an aerosolized liquid formulation spray that is transformed to deformable solids during flight before hitting the target surface.

[0029] Another aspect of the volatile solvent coating system is to provide a system with a twin fluid or gas atomizing nozzle that is optionally configured to heat the atomizing gas or air that is delivered through the nozzle to efficiently aid in the evaporation of solvent during flight and avoid the use of heating of the surface of the coating or the ambient atmosphere surrounding the surface, as required in the art.

[0030] Another aspect of the volatile solvent coating system is to provide a system and method for coating target surfaces with a coating that has characteristic properties that are selected by the user. [0031] Further aspects of the volatile solvent coating system are provided by the present invention, and will be brought out in the following portions of the specification, wherein the detailed description is for the purpose of fully disclosing preferred embodiments of the invention without placing limitations thereon.

[0032] The present invention can be employed in any of a variety of contexts. For example, the use of active materials, such as enzymes, in dry product formulations in industrial and consumer applications, such as detergents, textile compositions, baking, foods and animal feed has become a common practice. Enzymes are known to break down stains, modify fabric colors and textures, modify the viscosity of dough and foods, and improve digestibility of food and animal feed, by improving the availability of nutrients such as soluble phosphate and reducing anti- nutritional factors such as phytic acid in food and animal feed, thereby improving animal productivity. Enzyme-containing granules made by the improved volatile solvent coating system of the present invention will advance the field of sustainable industrial biosciences.

[0033] The present invention can also be employed to protect other biologically active materials such as proteins, microbial cells, seeds, and other biological materials, which are used in applications such as crop production, and probiotic drinks, wherein the biological material is exposed to elevated temperatures in the presence of moisture, the combination of which is known to cause a loss in potency or activity of the biological material. SUMMARY OF THE INVENTION

[0034] In some embodiments, the present teachings provide a particle comprising an active ingredient surrounded by a coating, wherein the coating comprises a polymer, wherein the coating has an average thickness of less than 20 microns and a free-film water vapor

permeability of less than 500 g/m /day at 20 degrees C and 75% RH.

[0035] In some embodiments, the present teachings provide a particle comprising an active ingredients surrounded by a coating, wherein the coating comprises a polymer, wherein the coating has an average thickness of less than 20 microns and the particle has a moisture uptake rate of less than about 1% at both (a) 95 degrees C and 95% RH for 12 seconds or (b) 37 degrees C and 70%RH for 3 days.

[0036] In some embodiments, the present teachings provide a particle consisting, or consisting essentially of, an active ingredient surrounded by a coating, wherein the coating comprises a polymer, wherein the coating has an average thickness of less than 20 microns and a free-film water vapor permeability of less than 500 g/m /day at 20 degrees C and 75% RH. [0037] In some embodiments, the present teachings provide a particle consisting, or consisting essentially of, an active ingredients surrounded by a coating, wherein the coating comprises a polymer, wherein the coating has an average thickness of less than 20 microns and the particle has a moisture uptake rate of less than about 1% at both (a) 95 degrees C and 95% RH for 12 seconds or (b) 37 degrees C and 70%RH for 3 days.

[0038] In some embodiments, the present teachings provide a particle wherein the coating comprises a dispersant. In some embodiments, the present teachings provide a particle, wherein the active ingredient is an enzyme, a protein, a peptide, a seed, a spore, a nucleic acid, or a microbe. In some embodiments, the coating has an average thickness of no more than 10 microns or no more than 15 microns. In some embodiments, the coating has an average thickness of 5-10, 5-15, 5-20, or 10-15 microns. In some embodiments, the active ingredient is thermally labile, wherein thermally labile is defined as losing at least 5% of activity following exposure to lOOC for 24 hours. In some embodiments, the active ingredient is hydrolytically sensitive, wherein hydrolytically sensitive is defined as losing more than 5% of activity after 1 week when exposed either to water or to an environment with a relative humidity of 70% at 37C. In some embodiments, the active ingredient is an enzyme selected from the group consisting of phytase, amylase, protease, or cellulase.

[0039] In some embodiments, the polymer is selected from the group consisting of styrene copolymers, ethyl cellulose, hydroxyl propyl methyl cellulose, sodium carboxy methyl cellulose, poly vinyl pyrolidone, vinyl buytral copolymer and low molecular weight polyvinyl choloride. In some embodiments, the polymer is selected from the group consisting of cellulose acetate phthalate, methyl acrylic acid copolymers, hydroxyl propyl methyl cellulose phthalate, cellulose triacetate, polymethacrylates, polyphenylene sulfones, polystyrene, polycarbonate, polyether sulfone, polymethacrylate, polysiloxanes, polyurethanes and copolymers thereof, and polyvinyl acetate phytalate. In some embodiments, the plasticizer is selected from the group consisting of triethyl citrate (TEC), dibutyl sebacate (DBS), dioctyl phthalate (DOP), glycerol, triacetin and acetylated monoglycerides. In some embodiments, the dispersant is selected from the group consisting of sorbitan monooleate, sorbitan trioleate, alkyl imidazoline and ABA block copolymer where A is poly (12 hydroxy- stearic acid) and B is polyethylene oxide. In some embodiments, the particle further comprises dispersed solid particles. In some embodiments, dispersed solid particles are in the coating. In some embodiments, the median diameter of the particle prior to the application of a coating is 50-500, 100-400, or 150-300 microns and the particle further comprises an active ingredient comprising an enzyme. 16. In some embodiments, the present teachings provide a method of forming a coated particle lacking agglomeration comprising: aerosolizing a liquid formulation into a droplet, wherein the liquid formulation comprises a volatile non-aqueous solvent and a polymer; and, volatilizing the solvent from the droplet during in flight to a particle in a chamber to form a coated particle, wherein the temperature of the particles does not exceed 40 degrees C during the coating process, and wherein no more than 5% w/w of the coated particles are agglomerated during the coating process. In some embodiments, no more than 3% w/w of the coated particles are agglomerated during the coating process. In some embodiments, the temperature of the particles does not exceed 35C, or 30C, during the coating process. In some embodiments, the coating is applied to the particles without any external source of heat in the chamber other than that naturally present in the ambient environment, drying air or uncoated particles. In some embodiments, the aerosolizing comprises a nozzle to which heat is applied to counter any evaporative cooling effect. In some embodiments, the median diameter of the particle prior to the application of a coating is 50-500, 100-400, or 150-300 microns and the particle further comprises an active ingredient comprising an enzyme. In some embodiments, the volatile nonaqueous solvent consists of a single volatile non-aqueous solvent. In some embodiments, the single volatile non-aqueous solvent is methylene chloride.

[0040] In some embodiments, the present teachings provide a chamber comprising a particle and a droplet, wherein the droplet comprises a volatile non-aqueous solvent and a polymer, and wherein the particle is 50-500, 100-400, or 150-300 microns in diameter and the particle further comprises an active ingredient comprising an enzyme. In some embodiments, the particle comprises a coating arising from the polymer in the droplet.

EXEMPARY EMBODIMENTS

[0041] In some embodiments, the present invention improves the volatile solvent coating system by utilizing it to prepare particles containing thermally and/or hydrolytically sensitive biologically active materials encapsulated by uniform thin protective moisture barrier coatings. In some embodiments, the present invention can adapt the volatile solvent coating system for applying such coatings efficiently, at ambient temperatures and with minimal agglomeration. The invention can further pertain to coating formulations comprising dispersants, adhesion promoters, polymers, and plasticizers dissolved or dispersed in a non-flammable, low boiling point solvent such as methylene chloride that is delivered with an aerosol process to target particles. In some embodiments, the present teachings provide a method for coating a particle, comprising: preparing a liquid formulation of a volatile solvent, a dispersant, and adhesion promoter and particulates of an active material; aerosolizing said liquid formulation into droplets; and volatilizing said solvent from said droplets in flight to a particle. The coating process of this invention can be differentiated from conventional methylene chloride based coating processes in that it is a hybrid between a liquid coating process and a powder coating process. The process starts with the atomization of a polymer-methylene chloride solution which is converted to finely divided solid polymer particles in flight through solvent evaporation without the aid of external heating. The finely divided solid polymer particles that are formed then uniformly coat the active ingredient containing particles Since no external heating is necessary, rapid processing can be achieved. Since no liquid solvent reaches the active ingredient containing particles, there is no chemical or physical solvent interaction with the particle surface and agglomeration of the particles can be almost eliminated.

[0042] In some embodiments, the solvent comprises methylene chloride. In some embodiments, the dispersant is selected from the group of dispersants consisting of sorbitan monooleate, sorbitan trioleate, alkyl imidazoline and ABA block copolymer where A is poly(12 hydroxy- stearic acid) and B is polyethylene oxide. In some embodiments, the dispersant also functions as an adhesion promoter; wherein a separate adhesion promoter in the formulation is not needed.

[0043] In some embodiments, the active material is selected from the group of active materials consisting of a drug, an insecticide, a fertilizer, a fungicide and a pigment.

[0044] In some embodiments, the method comprises adding at least one polymer and at least one plasticizer to the liquid formulation. In some embodiments, the polymer is selected from the group of polymers consisting of ethyl cellulose, hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose, poly vinyl pyrolidone, vinyl butyral copolymer and low molecular weight polyvinyl chloride.

[0045] In some embodiments, the polymer is a styrene copolymer. In some embodiments, the polymer is a styrene copolymer, and the styrene copolymer is copolymerized with an acrylic ester.

[0046] In some embodiments, minor amounts of carnauba wax or paraffin wax or finely defined polyethylene powder is added to the polymer coating to increase water resistance. When carnauba wax or paraffin waxes are employed, typically they will be present at relatively low amounts, for example 1-5% by weight of the coating. When higher melting materials such as polyethylene powder are employed, they can be present in higher amounts, for example amounts up to 50% by weight of the coating.

[0047] In some embodiments, the polymer in water soluble, for example water soluble of at least 1 gram/liter. In some embodiments, the polymer is swellable in the solvent, as measured for example by the acquisition of greater size upon exposure to the polymer. [0048] In some embodiments, the polymer is selected from the group of polymers consisting of cellulose acetate phthalate, methyl acrylic acid copolymers, hydroxy propyl methyl cellulose phthalate and polyvinyl acetate phthalate. In some embodiments, the plasticizer is selected from the group of plasticizers consisting of triethyl citrate (TEC), dibutyl sebacate (DBS), dioctyl phthalate (DOP), triacetin and acetylated monoglycerides.

[0049] In some embodiments, the present teachings provide a coating method comprising spraying a liquid formulation of at least one polymer and at least one plasticizer

dissolved/dispersed in a highly volatile, nonflammable solvent; vaporizing solvent from the spray to form deformable solid particles in flight; and impacting and coating the target with the deformable particles. In some embodiments, the solvent comprises methylene chloride. In some embodiments, the polymer is selected from the group of polymers consisting of ethyl cellulose, hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose, poly vinyl pyrolidone, vinyl butyral copolymer and low molecular weight polyvinyl chloride.

[0050] In some embodiments, the polymer is selected from the group of polymers consisting of cellulose acetate phthalate, methyl acrylic acid copolymers, hydroxy propyl methyl cellulose phthalate and polyvinyl acetate phthalate.

[0051] In some embodiments, the plasticizer is selected from the group of plasticizers consisting of triethyl citrate (TEC), dibutyl sebacate (DBS), dioctyl phthalate (DOP), triacetin and acetylated monoglycerides. In some embodiments, the plasticizer is an oil selected from the group consisting of triglycerides, diglycerides and monoglycerides. In some embodiments the triglyceride is corn oil, soybean oil, sunflower oil, sesame oil or cottonseed oil. In some embodiments, the plasticizer is corn oil. In some embodiments, the method further comprises adding at least one dispersant and at least one active material to the liquid formulation.

[0052] In some embodiments, the method further comprises adding at least one adhesion promoter to the liquid formulation.

[0053] In some embodiments, the present teachings provide a method for coating a surface, comprising: preparing a liquid formulation of a volatile solvent, a dispersant, an adhesion promoter, a polymer, a plasticizer and particulates of an active material; aerosolizing the liquid formulation into droplets with a gas atomization nozzle operably coupled to a gas source and a liquid source; controlling the temperature of the gas source; vaporizing solvent from said droplets to form deformable solid particles in flight; and impacting and coating the target with the deformable particles; wherein gas temperatures are manipulated to accelerate or decelerate the evaporation of solvent on the particles in flight to the target. In some embodiment, the method further comprises controlling the liquid formulation temperature. In some embodiments, the ratio of dispersant to active material is within the range of 0.3 to 100 to 3 to 100.

[0054] In some embodiments, the ratio of plasticizer to polymer is within the range of 0.5 to 9.5 to 1 to 3.

[0055] In some embodiments, the average coating thickness of the applied layer is 10 microns. In some embodiment the average coating thickness is 5-10, 5-15, 5-20, or 10-15.

[0056] In some embodiments, the granules of the present teachings are subjected to a moisture uptake test. In some embodiments, the coated granules of the sample absorb less than 1% w/w moisture uptake, measured as percent weight gain. In some embodiments it is less than .9%, .8%, .7%, .6%, .5%, or .4%. In some embodiments, the sample absorbs between .99% and .4%, between .99% and .5%, .99% and .6%, or .99% and .7%.

[0057] In some embodiments, the granule of the present teachings are subjected to a free-film water vapor transmission rate test to provide a WVTR. In some embodiments, the free film has a WVTR of less than 500 g/m7day. In some embodiments, the free film has a WVTR of less than 400 g/m 2 /day, less than 300 g/m 2 /day, or less than 250 g/m 2 /day. In some embodiments the free film has a WVTR of 500 g/m²/day-250 g/m²/day, 500 g/m²/day-300 g/m²/day, 500 g/m²/day-400 g/m²/day, or 500-100 g/m²/day.

[0058] In some embodiments, the volatile solvent has a boiling point of less than 40C.

[0059] In some embodiments the volatile solvent has a boiling point of less than 35C, less than 30C, or less than 28C.

[0060] In some embodiments, the volatile solvent has a boiling point of 25-40C, 30-40C, or 35- 40C.

[0061] In some embodiments, the volatile solvent has a surface tension measured at 20C of 20- 25, 20-35, or 20-30 dynes/cm.

[0062] In some embodiments, the volatile solvent is non-flammable. In some embodiments, the volatile solvent has a low heat of vaporization, for example less than 0.1 kcal/gram.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood by reference to the following drawings which are for illustrative purposes only:

[0063] FIG. 1 is a flow diagram of a method for a hybrid film coating with an active material according to one embodiment of the invention. [0064] FIG. 2 is a graph of Measured Water Vapor Transmission Rate (G Hr -^"1 M -^"2 ) for sprayed 3.7 mil thick polymer film of ethyl cellulose with (TEC) as the plasticizer according to the invention.

[0065] FIG. 3 is a graph of Measured Water Vapor Transmission Rate (G Hr -^"1 M -^"2 ) for sprayed 3.7 mil thick polymer film of ethyl cellulose with (DBS) as the plasticizer according to the invention.

[0066] FIG. 4 is an image of corn coated according the present teachings as performed in Example 9.

[0067] Fig. 5 is an image of a particle according to the present teachings.

[0068] Fig. 6 is an image of a particle according to the present teachings.

[0069] Fig. 7 is an image of a particle according to the present teachings.

[0070] Fig. 8 is an image of a particle according to the present teachings.

[0071] Fig. 9 is an image of a particle according to the present teachings.

[0072] Fig. 10 is an image of a particle according to the present teachings.

[0073]

DETAILED DESCRIPTION OF THE INVENTION

[0074] Referring more specifically to the drawings, for illustrative purposes several embodiments of the materials and methods for coating of the present invention are depicted generally in FIG. 1 through FIG. 4. It will be appreciated that the methods may vary as to the specific steps and sequence and the formulations may vary as to structural details, without departing from the basic concepts as disclosed herein. The method steps are merely exemplary of the order that these steps may occur. The steps may occur in any order that is desired, such that it still performs the goals of the claimed invention.

[0075] By way of example, and not of limitation, FIG. 1 illustrates schematically one method 10 for coating target surfaces according to the invention. At block 12, the components of the spray formulation are selected. The selection of components at block 12 will be directed by the nature of the surfaces that are to be coated, the desired characteristics of the coating and the intended use of the coated targets. For example, surface sensitivities of the target as well as toxicity, permeability and active material release characteristics can be controlled in part by the selection of components at block 12.

[0076] In the embodiment shown in FIG. 1, a dispersant is selected at block 14; an adhesion promoter is selected at block 16; a polymer is selected at block 18; a plasticizer is selected at block 20; at least one active material is selected at block 22 and a solvent is selected at block 24. In another embodiment, the components of the formulation selected at block 12 did not include a plasticizer or a polymer.

[0077] The dispersant that is selected at block 14 is preferably an oil soluble material that is capable of dispersing polar particles in the solvent. A dispersant with a low hydrophilic- lipophilic balance (HLB) number (<5) is preferred. Preferred dispersants selected at block 14 include sorbitan monooleate, sorbitan trioleate, alkyl imidazoline and ABA block copolymer where A is poly (12 hydroxy-stearic acid) and B is polyethylene oxide.

[0078] The adhesion promoters that are selected at block 16 help to adhere particles to the target substrate after the solvent evaporates in flight. The dispersants listed above are inherently adhesion promoters as well. Therefore, in some settings an additional adhesion promoter may not be necessary. However, if a dispersant selected at block 14 does not promote adhesion, then an adhesion promoter such as paraffin wax (melting point = 55 °C) can be selected and used at block 16.

[0079] One or more polymers can be selected at block 18 to give further structural integrity and predictable characteristics to the overall coating. For example, polymers can be selected to give extended release characteristics to the coating. Suitable polymers for this purpose include ethyl cellulose, hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose, poly vinyl pyrolidone, vinyl butyral copolymer and low molecular weight polyvinyl chloride.

[0080] Other polymers can be selected at block 18 to provide delayed release characteristics to the overall coating. For example, enteric polymers that do not dissolve in the stomach at pH = 1.5 but do dissolve in the intestine at pH = 5-6 can be selected. Examples of suitable polymers include: cellulose acetate phthalate; methyl acrylic acid copolymers; hydroxy propyl methyl cellulose phthalate and polyvinyl acetate phthalate.

[0081] A plasticizer can be selected at block 20 that is generally used to make the polymers less brittle. The plasticizer can also lower the film forming temperature of the polymer. Preferred plasticizers selected at block 20 include: triethyl citrate (TEC); dibutyl sebacate (DBS); dioctyl phthalate (DOP); triacetin and acetylated monoglycerides. If it is desirable to coat particles without polymers, for example, the formulation can be used without the polymer and without the plasticizer.

[0082] The selection of an active material at block 22 is governed by the ultimate use of the target and is optional. The active material can be any preferably fine particulate that provides some desirable function to the coating. For example, fungicides, insecticides, fungicides, anti- mold and similar agents can be used in seed coatings. Coatings of medical devices may have drugs that have a desired physiological effect such as drugs to prevent restenosis in coronary stents. However, the active material does not need to be biologically active. The active material could be a colorant such as titanium dioxide, aluminum oxide, zinc oxide or carbon. The selection of the active material will influence the selection of the dispersant and adhesion promoter as well as the polymer.

[0083] The selection of the solvent at block 24 is based on boiling point because of the flash evaporation of the solvent aspect of the process. The preferred solvent is methylene chloride. However, other solvents could be used, such as low boiling point cholor-fluoro hydrocarbons where their boiling point is on the order of the boiling point of methylene chloride.

[0084] Once the components of the formulation have been selected at block 12, the formulation solution for spraying is assembled at block 26 of FIG. 1. The quantity of each component in the final formulation is also influenced by the ultimate use of the coating and the characteristics of the selected individual components. For example, if the ratio of plasticizer to the other components in the final solution is too large, then the coated particles will stick together and will not disperse. Likewise, if the ratio of polymers to the solvent is too large then the spray solution becomes too viscous and will not spray properly.

[0085] Accordingly, at block 26, the spray formulation is assembled with the selected components in the proper proportions. The proportions of each selected component can also be adjusted to optimize the coating procedure and the characteristics of the resulting coating.

[0086] The dispersant, adhesion promoter, coating polymers and plasticizer are dissolved in a volatile, non-flammable solvent, preferably methylene chloride, in selected proportions. The preferred ratio of dispersant to active material is within the range of approximately 0.3 to 100 to approximately 3 to 100. The ratio of 1 to 100 of dispersant to active material is particularly preferred.

[0087] The ratio of polymer to plasticizer will vary with the selection of polymers and plasticizers. Complete elimination of the plasticizer greatly reduced the quality of the coating and is not preferred. The preferred range of plasticizer to polymer is a ratio of 0.5 to 9.5 to 1 to 3 and the range of 1 to 9 to 1 to 3 is particularly preferred.

[0088] The polymer preferably dissolves completely in the solvent. For example, ethyl cellulose will dissolve in methylene chloride but many polymers will not. Some polymers, such as low molecular weight PVC, will only swell in some solvents. The polymer does not have to dissolve so long as it swells to be used in the formulation. However, if the polymer does not dissolve or swell, then a different polymer should be selected to form a coating. A polymer that only disperses in the solvent can be used to modify a coating. [0089] Methylene chloride is the preferred solvent because it is nonflammable and volatile, and has low surface tension so that it is easier to atomize particles. A greater number of smaller particles will yield greater surface area for faster evaporation. The preferred range of polymer in solvent is approximately 5% to approximately 20%. At 20% polymer in solvent, the solution becomes very viscous. However, the higher viscosity solutions can still be atomized by an air atomization or twin-fluid nozzle.

[0090] At block 28 of FIG. 1, the assembled liquid formulation is preferably

atomized and applied to a target surface. One important feature of the hybrid coating process of the invention is that it starts with the atomization of a liquid solution/dispersion (like a liquid coating process) and the solvent evaporates without heating during flight producing solid particles that impact, adhere and coat the target so that it ends as a powder coating process. This hybrid process therefore overcomes the inherent difficulties associated with the liquid and powder coating processes and extended heating of the coating is not necessary.

[0091] Immediately after the droplets of solvent-component formulation are formed from the nozzle, the solvent evaporates very quickly in flight to produce a much smaller solid particle containing a very high polymer concentration at the surface since the diffusing solvent carries polymer to the surface. This solid particle appears dry, but the core of the particle may still contain trace amounts of solvent since evaporation can be inhibited by the surface polymer membrane. As soon as these deformable particles impact a surface, they flatten and stick. The flattened particle has an increased surface area and shortened diffusion distances and therefore loses any residual solvent very quickly to produce a non-tacky rigid surface film.

[0092] Without wishing to be bound by theory, it is believed that a homogeneous integral coating with reduced permeability, and few or no defects, results from the rapid transition of the polymer from a solvated state in the particle-in-flight to a solvent-depleted, rigid, non-tacky state in the flattened droplet after it has contacted the target surface and fused with adjoining deposited coating material.

[0093] In some embodiments, the present invention provides a method for coating particles by an atomization process that in effect represents a solvent casting process, yet avoids causing significant microparticle agglomeration. Agglomeration, in the context of this invention, is understood to be the bridging of two or more coated particles with single cores into a solid mass containing multiple cores. Agglomeration can be quantitatively defined as the weight percentage of particles retained on a sieve screen with an opening that is 20% larger than the D90 (ninetieth mass percentile diameter) of coated single core particles that pass through such a sieve. For example, a batch of coated particles 90% of whose coated single cores are smaller than 400 microns, can be passed through a sieve that is approximately 480 microns (i.e. a 35 mesh US standard screen is 500 microns, the closest choice). The percent agglomeration would be the weight percent of the batch that is retained on the 500 micron screen. In one

embodiment of the invention, the agglomeration of the batch of coated cores is less than 3% w/w. In some embodiments, the agglomeration is less than 15, 10, or 5.%. In some

embodiments, the agglomeration is 15-.5, 10-.5, 5-.5, 3-.5, 15-.1, 10-.1, 5-.1 or 3-. l w/w.

[0094] The hybrid coating process of the invention can be contrasted with aqueous atomization of solutions or latex suspensions, both of which deposit dried solids onto particles which do not completely fuse, at least without additional processing. For example, Roulstone (1992) compares the properties of film coatings prepared by producing water based latex films with solvent-cast films. Latex films typically have much higher permeability and water vapor transmission rates than do solvent cast films of equivalent chemical composition. Furthermore, unlike solvent-cast films, latex films are very much dependent on conditions of film formation, exhibit a great dependence on film orientation, and show considerable evidence of aging effects. In short, solvent cast films are not only less permeable, but are more stable and less variable than equivalent films prepared from latex suspensions.

[0095] This transition from liquid particles to solid particles in flight without heating is accomplished by the contribution of several factors. One factor is the selection of a solvent such as methylene chloride that is highly volatile (Boiling Point = 39°C) and has a very low heat of vaporization (0.089 Kcal/g). Another factor is the inclusion of an adhesion agent (low

Hydrophile-Lipophile Balance (HLB) surfactants) in the formulation that aids in adhesion of the solid particles on the target surface.

[0096] A further factor may be the use of a gas atomization nozzle that combines high gas flow with low liquid flow that can create very fine liquid particles even with concentrated viscous solutions/dispersions. For example, methylene chloride has a very low surface tension (26.5 dynes/cm at 20°C) which also promotes the formation of very fine liquid particles with very high surface area resulting in very rapid methylene chloride evaporation.

[0097] The gas atomization technique is a highly convective process in which a carrier gas is used to atomize, or create spray droplets from, a bulk of liquid. The liquid flows into the nozzle (either by pumping or a siphon action) where it is mixed with a high velocity jet of carrier gas, the gas then shatters the liquid flow and creates droplets; it also carries the droplets outward in a high speed jet of gas.

[0098] The advantages of gas atomization include: 1) the ability to atomize highly viscous fluids and slurries, such as a high solid concentration solution or suspension; 2) the ability to use large nozzle openings to prevent clogging; 3) the ability to control spray droplet size independently of liquid flow rate; and 4) the ability to manipulate the relative temperature between the liquid to be atomized and the atomizing and carrier gas supplied to the nozzle.

[0099] By manipulating the relative temperature, the rate of vaporization of the liquid solvent can be controlled. For example, supplying heated gas to the gas atomizing nozzle would increase the evaporation rate of the solvent while supplying chilled liquid would decrease the rate of evaporation. Depending on the boiling point of the solvent, the solvent could be kept at a desired temperature below boiling point in order to maintain a concentration or for a safety factor prior to atomization and then the atomizing gas could be heated to a level to cause rapid evaporation. Finally, by optimizing the distance of the nozzle from the target (effectively, the elapsed time between droplet creation/emission and subsequent impact), complete solvent evaporation occurs before particles impact the target while still allowing maximum capture of particles by the target surface. For pressure nozzles, the pressure determines droplet size and velocity. With gas atomization, the temperature and flow rates of the liquid and gas control the characteristics of the deposit. Accordingly, the atomization pressure can also be optimized.

[00100] In another embodiment, the evaporated methylene chloride solvent is captured, condensed and recycled. Compact solvent recovery units are commercially available and could be easily coupled to the spray system.

[00101] Accordingly, a powder coating is created as a result of the flash evaporation of the solvent. It is important to note that heat is not required to evaporate the solvent from the surface being coated, so the coating process time is shortened and the coatings can be applied to heat sensitive targets. Furthermore, solvent sensitive target surfaces will not be exposed to solvents since the solvent has evaporated prior to impact of the spray with the surface.

[00102] The spray process can also be controlled to prevent any condensation of ambient water or other contaminants in the atmosphere surrounding the target to be coated. By knowing the mass flow rate of solvent through the nozzle and the heat of vaporization of the solvent, the carrier gas supplied to a gas atomizing nozzle can be heated to a sufficient temperature such that no net temperature depression occurs in the coating arena. In essence, the inherent chilling that would occur due to solvent evaporation is offset by a higher temperature (depending on specific heat of the gas, the gas density and gas flow rate). By monitoring the flow rates of the liquid and carrier gas and knowing the heat of vaporization of the solvent and the thermal properties of the gas, the requisite gas temperature can be calculated and an in-line heater used to heat the gas. [00103] The atomization of the formulation at block 28 can be accomplished with hydraulic or pressure nozzles, the energy for atomization (i.e. the creation of droplets from a mass of fluid) is supplied via the liquid to be atomized. The spray characteristics (e.g., flow rate, droplet size, spatial distribution, etc.) are all limited by the geometry of the nozzle and the fluid properties. Gas atomization nozzles are preferred because they can atomize "difficult" fluids such as slurries or suspensions with high solids and are resistive to clogging and wear.

[00104] In typical systems, the liquid and gas streams are combined at the nozzle. The air or gas inlet normally has an air shut off valve, air filter and air pressure regulator in the line that is coupled to the nozzle. The liquid inlet typically includes a liquid shut off valve, liquid strainer or filter and liquid pressure regulator in the liquid line coupled to the nozzle. Thus, the gas and liquid flows can be controlled independently. With external mix nozzles, the liquid and gas streams are mixed outside of the nozzle.

[00105] In one particularly preferred embodiment, the formulation is atomized at block 28 with a twin fluid gas atomizing system that has temperature control elements in the gas inlet line. The temperature control element allows the inlet gas to be heated to a desired temperature above the ambient temperature. The heated inlet gas flowing out of the nozzle assists in the vaporization of the solvent of the liquid. In another embodiment, the liquid inlet also has a temperature control element that heats or cools the liquid delivered to the nozzle. In this embodiment, the apparatus has a control system that is configured to monitor the temperature of the surface to be coated as well as the in flight spray with a non-contact IR temperature sensor and the temperatures of the carrier gas and the liquid feed are manipulated to maintain a desire temperature. The temperature is an accurate indicator of the degree of solvent evaporation.

[00106] Accordingly, in one embodiment, an atomization process is provided

that utilizes a gas atomization nozzle in which the liquid to the atomized and the atomizing gas temperatures are manipulated to accelerate or decelerate the evaporation of solvent so as to achieve a desired fraction of solvent remaining on the particles at the time of impact on the target surface. In addition, condensation of ambient liquids in the atmosphere surrounding the deposition target can be prevented by heating the atomization / carrier gas so as to balance the heat of vaporization of the solvent in the spray liquid.

[00107] The invention may be better understood with reference to the accompanying examples, which are intended for purposes of illustration only and should not be construed as in any sense limiting the scope of the present invention as defined in the claims appended hereto.

Example 1A [00108] In order to demonstrate the coating process, two types of liquid spray formulations were produced. The first type was a combination of a methylene chloride solvent, a

dispersant/adhesion promoter and an engineered particulate with highly specific electrical properties as an active material. The second type of spray formulation was a combination of a dispersant, an adhesion promoter, coating polymers and a plasticizer that were dissolved in methylene chloride and then solid titanium dioxide pigment particles were dispersed in the methylene chloride solution with the aid of ultrasonic energy.

[00109] Methylene chloride (BP = 39.8°C) was chosen as the dispersion solvent as it is sufficiently volatile at room temperature so that when sprayed the solvent evaporates prior to the arrival of the other formulation components at the surface of the target and the composite powder is formed in flight.

[00110] The spray formulations were delivered through a custom-developed, electrically- neutral, gas atomization and handling system that, in combination with the spray formulation, produced highly mobile, coating particles.

[00111] The first type of liquid spray formulation allowed an enclosure containing complex spray targets to be treated nonintrusively from a single entry point and allowed all surfaces within the enclosure to be coated with particles. Surface coating experiments with the first type of liquid spray formulations produced coatings with good adherence even without the polymer which was unexpected. This was accomplished by including a dispersant/adhesive promoter. This coating adhered but could be removed by abrasion.

[00112] Trial spray coating experiments using the second type of spray formulation that were conducted using corn seed in a one quart baffled rotating drum resulted in a thin uniform seed coating with respect to polymer and titanium dioxide pigment. The pigment was firmly anchored in the instantly dry polymer coating and hence no fine solid particle lubricant was required. There was no clumping of seeds and there was no dust produced. The process time was very rapid as no time was required for drying.

[00113] The applied surface coatings were evaluated for adhesion, agglomeration, and coverage. All of the formulations produced coatings with good adhesion and coverage with little agglomeration. The addition of polymer formed coatings that could not be abraded easily. Example IB

[00114] In order to demonstrate the coating process, a spray formulation was prepared from a combination of a dispersant, an adhesion promoter, coating polymers and a plasticizer that were dissolved in methylene chloride and then solid titanium dioxide pigment particles were dispersed in the methylene chloride solution with the aid of ultrasonic energy.

Methylene chloride (BP = 39.8°C) was chosen as the dispersion solvent as it is sufficiently volatile at room temperature so that when sprayed the solvent evaporates prior to the arrival of the other formulation components at the surface of the target and the composite powder is formed in flight.

[00115] The spray formulations were delivered through a custom-developed, electrically- neutral, gas atomization and handling system that, in combination with the spray formulation, produced highly mobile, coating particles.

[00116] Trial spray coating experiments using the spray formulation that were conducted using corn seed in a one quart baffled rotating drum resulted in a thin uniform seed coating with respect to polymer and titanium dioxide pigment. The pigment was firmly anchored in the instantly dry polymer coating and hence no fine solid particle lubricant was required. There was no clumping of seeds and there was no dust produced. The process time was very rapid as no time was required for drying.

[00117] The applied surface coatings were evaluated for adhesion, agglomeration, and coverage. All of the formulations produced coatings with good adhesion and coverage with little agglomeration. The addition of polymer formed coatings that could not be abraded easily.

Example 2

[00118] In order to apply uniform coatings on a substrate support for mechanical analysis and determination of water vapor transmission rate (WVTR) and oxygen transmission rate (OTR), a rotating drum was utilized. A handheld compressed gas sprayer was modified to produce a narrow fan spray of small volumes of test mixtures and suspensions. A rotating drum was constructed that allowed a substrate material (e.g., vulcanized cotton sheet) to be attached to the drum and treated with the hybrid polymer coatings.

[00119] The cardboard drum was 40.6 cm (16 inches) tall and 10.2 cm (4 inches) in diameter. A DC motor was used to rotate the drum. The drum rotational velocity was varied with a DC motor speed controller. The motor was held upright using a ring stand. The driveshaft of the motor was connected to the drum with a threaded rod and a shaft collar. The drum rotation device was placed on the left side of a three meter (nine foot) wide fume hood.

[00120] A pressurized sprayer bottle was used that had a maximum volume of 0.946 liters (32 oz). A 40° flat fan nozzle with a flow rate of 64.4 ml min ¹ (0.017 GPM) at 275.8 kPa (40 psi) was mounted on the spray bottle. The spray bottle was charged with compressed air to 620.5 kPa (90 psi) giving the spray bottle a flow rate of 96.5 ml min^"1 (0.0255 GPM). Samples (200 ml) took on average about 2.5 minutes to spray.

[00121] The spray bottle was hand held on the right side of the fume hood 75 cm (29.5 in) away from the rotating drum. The spray bottle was modulated in an up and down sweeping motion. The focus of the spray was at the center of the drum vertically and the modulation was +/- 10 cm. All spray trials were conducted at 5 rpm for the drum. This rotational velocity is equivalent to 159.6 cm min^"1 (62.8 in min^"1). At this rpm, it took 12 seconds for a sprayed location to rotate all the way around and get sprayed again.

[00122] The coatings and substrate were removed from the drum and their transmission properties measured. The substrate itself was selected because of its high water vapor transmission rate. Therefore, when the transmission rate of the polymer-coated substrate was measured, the water vapor transmission rate of the polymer film could be determined by subtracting the relatively low barrier properties of the substrate. The thickness of each of the sprayed polymer films was also measured.

Example 3

[00123] The Water Vapor Transmission Rate (WVTR) and Oxygen Transmission Rate (OTR) of polymeric films are important properties for many different applications. However, in order to determine these transport rates,isolated films must be produced. This can often be done by casting solutions of the polymer onto low energy surfaces such as Teflon, allowing the solvent to evaporate and then peeling the intact film off the surface. However, in many cases this technique is not successful either because the polymer film adheres too strongly even on Teflon or the film is too fragile and is shattered in the process of removal.

[00124] To avoid these issues, an alternative technique was used. A methylene chloride solution of the polymer was sprayed onto a very thin substrate film where the substrate film has a much higher WVTR or OTR than the applied film and hence the WVTR or OTR of this double layer film really represents the WVTR or OTR of the applied film. Since the solvent evaporates before it reaches the substrate film, the substrate film is not physically compromised.

[00125] This technique allows the WVTR or OTR of the applied film to be quantitatively measured as a function of film composition. If the WVTR or OTR of the substrate film is only slightly higher or equal to the WVTR or OTR of the applied film, only qualitative rankings of WVTR or OTR can be determined as a function of film composition. [00126] Several different films were produced using different mixtures of polymer, plasticizer and active particle to evaluate the contributions of component concentrations on the WVTR or OTR of the final product. The coatings were deposited on substrates producing composite coating-substrate films using the apparatus described in Example 2. This allowed evaluation of the absolute WVTR for EC coatings as a function of plasticizer and Ti02 concentrations and the relative OTR for VBCP and PVC coatings as a function of plasticizer concentration.

[00127] Films were produced using mixtures of ethyl cellulose, titanium dioxide and a plasticizer (triethyl citrate or dibutyl sebacate). The spray solvent was dichloromethane and spraying was done in a fume hood. The ratios of ethyl cellulose, titanium dioxide and triethyl citrate (TES) or dibutyl sebacate (DBS) were varied over an experimental range and the molecular weight of the ethyl cellulose was varied using commercial products (Ethocel

StandardsTM 100, 20 and 4; Dow Chemical, Inc.). Water vapor transmission rates were measured using standard methods over a multiday stabilization period.

[00128] For WVTR (Water Vapor Transfer Rate) measurements, formulations

were made with different ratios of plasticizer to polymer and polymer to active material for evaluation. For example, one formulation was prepared by weighing out 3.52 gm dibutyl sebecate and placing it into 250 ml Pyrex^® media bottle. Then 180 ml methylene chloride was added and mixed at high speed until solids were dissolved. Slowly, 10.56 gm Ethocel 4 was added, giving it time to dissolve, and 6 ml of Atlox 4912 in methylene chloride solution (Atlox concentration = 0.008g/ml) was added. Finally, 1.76 gm Ti02 titanium dioxide was added stirring continuously until it was time to spray. The resulting formulation had a dibutyl sebacate/Ethocel 4 ratio of 1/3 and an Ethocel 4/titanium dioxide ratio of 6/1.

[00129] Another formulation was produced having a triethyl citrate/ethyl

cellulose 20 ratio of 1/4 and Ethocel 20/titanium dioxide ratio of 6/1. This was produced by weighing out 2.64 gm TEC and introducing it to a 250 ml Pyrex^® media bottle. A 180 ml volume of methylene chloride was added and stirred with a stir bar until dissolved for about 20 minutes at 700 rpm. Over a span of 20 minutes, 10.56 gm Ethocel 20 was added slowly until it dissolved followed by the addition of 6 ml Atlox 4912 dispersant in methylene chloride solution (Atlox concentration 0.008 g/ml) and 1.75 gm Ti02 and stirred until time to spray.

[00130] A hard rubber- fiber sheet (5.0 mil thick) known as vulcanized cotton fabric was chosen as the substrate for coating Ethyl cellulose (EC) films because of its low resistance to water vapor (Water absorption equals 63- 66%) compared to EC. One of the functions of an EC coating is to act as a water vapor barrier. Therefore, the water vapor transmission rate (WVTR) is an important property of EC coatings.

[00131] Various films were created to evaluate the WVTR of the EC films as a

function of EC Molecular Weight, plasticizer type (Dibutyl Sebecate (DBS) and Triethyl Citrate (TEC)) and level and Ti02 particulate level. Four replicates were run for each sample.

[00132] The films were measured, cut and preconditioned prior to evaluation. Sections of the films that were free from defects such as cracks or pinholes were cut by gently tapping the top portion of a 4 cm or 6 cm diameter circular die cutter with a mallet for oxygen permeability (OP) or Water Vapor Permeability (WVP) testing, respectively. Preconditioning was performed to standardize all samples prior to subjecting them to oxygen and moisture permeability tests according to the Standard method, D 618-00 (2000), due to the fact that the barrier properties may be affected by relative humidity and temperature. An environmental chamber at 50 + 5%RH over a saturated solution of magnesium nitrate, Mg(N03)2-6H20 was placed in a 23 + 2°C controlled temperature room. The samples were preconditioned by keeping them in the chamber at least for 48 hours before the tests. In order to prevent interactions of the samples, smooth- surfaced release papers with a silicone finish were used to place the samples in the environmental chamber in accordance with ASTM D2370-98 (2010).

[00133] Film thickness was measured by a caliper micrometer to the nearest 2.5 μιη at four and five random positions on each testing specimen used for OP and WVP tests, respectively. Mean thickness values for each sample were calculated and used in oxygen transmission rate (OTR) and water vapor transmission rate (WVTR) calculations.

Example 4

[00134] Prepared samples of the various films were tested for water vapor permeability. The water vapor transmission rate for a 3.7 mil thick low, medium and high molecular weight ethyl cellulose films with varying ratios of TEC/EC and EC/Ti02 is shown in FIG. 2. The water vapor transmission rate for a 3.7 mil thick low, medium and high molecular weight ethyl cellulose films with varying ratios of DBS/EC and EC/Ti02 is shown in FIG. 3. In addition, the vertices of the plane shown in FIG. 2 and FIG. 3 are ratios of plasticizer to ethyl cellulose on one edge and the ratio of ethyl cellulose to active particles on the other.

[00135] Water vapor transmission rate (WVTR) was determined in accordance

with the WVP modified cup method correcting for the resistance of the stagnant air gap in the test cups. It was assumed that the relative humidity under the sample was 100%, however, the RH is less than 100% since there is a stagnant air layer just below the sample surface.

Therefore, the calculations that were used account for the stagnant layer.

[00136] The sprayed and non-sprayed samples were mounted on plexiglass plastic cups with wide rims containing 6 grams of distilled water. The samples were then sealed on the cups with plastic rings that were screwed into the cup rim with aid of silicone high vacuum grease as a sealant. The spray-coated sides of the samples were facing the high RH environment (facing down) in all experiments consistently.

[00137] After taking the initial weight of the test cups, the cups were placed in an

environmental chamber at 0%RH and 23 + 2°C. For the 0%RH condition in the environmental chamber, anhydrous calcium sulfate desiccant was placed into trays and then the trays were immediately placed into the chamber. In order to check that the chamber was at 0%RH, a hygrometer probe was placed into the chamber and %RH in the chamber was monitored. A fan was used in the chamber to ensure uniform %RH over the surface of the samples at a velocity of more than 152 m/min. The cups were weighed at certain intervals after steady state was achieved to measure water vapor lost though the samples from the cups. A linear regression analysis of water weight loss versus time was performed to obtain WVTR of the samples. Then, WVP was calculated from WVTR by the equation: WVP = WVTR x thickness/water vapor partial pressure (where WVTR is in g h — 1 m—2 , thickness is in millimeters and partial pressure is in kilopascals). Four replicates of each sample were evaluated.

[00138] The WVTR results shown graphically in FIG. 2 and FIG. 3 are average value with standard deviation and have been normalized to 3.7 mils. For example, in FIG. 2 the Medium MW EC film with TEC/EC = 1/4 and EC/Ti02 = 6/1 had a thickness of 4.5 mil. The WVTR for this 4.5 mil coating was 12.1 g/hr-m that was normalized to 3.7 mil. Therefore, the WVTR for this coating reported in FIG. 2 was based on the calculations: (3.7 mil) = 12.1(4.5/3.7) = 14.7 g/hr-m with Standard Deviation = 1.64.

[00139] Similarly, the WVTR and associated standard deviations shown in FIG. 3 for films with the DBS plasticizer were also normalized to 3.7 mils. For example, the Low MW EC film with DBS/EC = 1/3 and EC/Ti02 = 6/1 was 4.0 mil thick. The observed WVTR for this coating was (4.0 mil) = 11.9 g/hr-m . Therefore, the WVTR for the coating was normalized to 3.7 mil and plotted in FIG. 3. The reported WVTR for the 4.0 mil coating was (4.0) = 11.9 (4.0/3.7) = 12.9 g/hr-m². Standard Deviation = 0.585(4.0/3.7) = 0.63.

[00140] The results shown in FIG. 2 and FIG. 3 clearly show that the water vapor

transmission rates can be adjusted over a 2: 1 range (from 11.5 to 23.6 g hr -^"1 m -^"2 ) through the manipulation of the spray properties and that continuous films can be produced by the spray methods.

[00141] As shown in the TEC plasticizer results in FIG. 2, when the ratio of plasticizer to Low MW EC (1/4) is constant, the WVTR values increased as the Ti02 was reduced with respect to the Low MW EC. This indicated that the Ti02 had greater water vapor transmission resistance than the plasticized (TEC) EC coating.

[00142] It can also be seen in the results of FIG. 2 that when the ratio of polymer/active particles (e.g. Low MW EC to Ti02 at 6/1) is held constant, the WVTR increases as the plasticizer ratio was increased. This result can be explained by the fact that TEC has appreciable water solubility (65 grams/liter). In addition, at a constant ratio of plasticizer to EC (e.g. 1/4) and constant ratio of EC to Ti02 (e.g. 6/1), the WVTR is reduced as the molecular weight (MW) of the EC increases.

[00143] By comparison, it can be seen in the DBS plasticizer results in FIG. 3 that when the ratio of plasticizer to Low MW EC (e.g. 1/3) is held constant, the WVTR decreases as the Ti02 is reduced with respect to Low MW ethyl cellulose polymer. This indicated that the Ti02 had less water vapor transmission resistance than the plasticized (DBS) EC coating.

[00144] FIG. 3 also shows that at a constant ratio of Low MW EC to Ti02 (e.g. 6/1), the WVTR decreased as the plasticizer quantity increases. This result can be explained based on the fact that DBS has very low water solubility (0.04 grams/liter) and hence water has very low solubility in DBS. It can also be seen in FIG. 3 that when that ratio of plasticizer to EC (e.g. 1/3) and the ratio of EC to Ti02 (e.g. 6/1) are constant, the WVTR increases as the molecular weight of the EC polymer increases.

Example 5

[00145] In order to evaluate oxygen permeability, coatings formed from different

formulations were created. In addition to ethyl cellulose coatings, formulations using other polymers and plasticizers were produced both with and without active materials. To illustrate permeability characteristics of coatings without active materials, formulations with vinyl butyral copolymer (VBCP) and low molecular weight PVC (LMWPVC) were assembled and sprayed.

[00146] Formulations using different percentages of Triethyl Citrate (TEC) and different percentages of Dioctyl Phthalate (DOP) with the VBCP and LMWPVC polymers were evaluated for oxygen transmission rate (OTR). [00147] For example, a vinyl butyral copolymer with 25% DOP formulation was produced by placing 21 grams of copolymer in a 500 ml media bottle and adding 400 ml of methylene chloride and stirring with stir bar. Then 7 grams of DOP (dioctyl phthalate) was added slowly and stirred until the Copolymer is dissolved.

[00148] Similarly, a vinyl butyral copolymer with 12.5% TEC formulation was produced by placing 21 grams of copolymer in a 500 ml media bottle and adding 400 ml of methylene chloride and stirring with stir bar. Then 3 grams of triethyl citrate (TEC) was added slowly and stirred until the Copolymer is dissolved and stirred continuously until it was time to spray. All the other Samples were prepared using the same procedures.

[00149] A Low Density Polyethylene (LDPE) (0.6 mil thick) was chosen as the substrate for coating Vinyl Butyral Copolymer (VBCP)and Low MW PVC (LMWPVC) because its resistance to oxygen was the same order of magnitude as that of VBCP and LMWPVC. Even though the absolute value of OTR for these plasticized polymer coatings could not be evaluated from the OTR of the composite films, the trends in OTR as plasticizer level was varied could be determined.

[00150] Oxygen transmission rate (OTR) is a procedure for determining steady-state rate of transmission of oxygen gas through the samples. The OTR characteristics of the coatings were measured with an Ox-Tran 2/20 ML modular system in accordance with ASTM standard method D 3985-95 (1995).

[00151] The sprayed film samples were preconditioned at 23 + 2°C and 50 + 5%RH for a minimum of 48 hours and were double-masked with strong adhesive aluminum foil tapes leaving a circular uncovered testing area of 0.42 cm . Then, the films were sealed in the Oxtran test cells. The test cells were sealed to prevent outside air from entering by the use of rubber O- rings and the application of Apiezon type T vacuum grease to the metal surfaces, O-rings and foil masks. The films were masked and placed between stainless steel plates. The outer half of the test cell (one side of the film) was purged by flowing 100% oxygen and the inner half of the test cell (another side of the film) was purged by flowing carrier gas, which consist of 98% nitrogen and 2% hydrogen. Oxygen molecules diffusing through the films to the inner side of the test cell were conveyed to the sensor by the carrier gas. The sprayed side of the films was faced with oxygen gas in the test cells. OP was calculated by multiplying OTR (cm3 m —2 day 1 ) by the average film thickness (μιη) and dividing by partial pressure of 02 at 100% oxygen (kPa). Four replicates were made for each sample formulation. [00152] The OTR of the prepared VBCP coatings were evaluated as a function of plasticizer type and concentration. The relative OTR for VBCP composite coatings were normalized to 3.1 mil thickness. For example, the TEC/VBCP = 1/3 composite coating thickness was 3.1 mil. The

OTR for this coating was (3.1 mil) = 513.5 cm 3 /m 2 -day with a standard deviation = 29.9. The OTR results for the TEC/VBCP formulations showed a minimal resistance to oxygen at 6.25% TEC. The coating with 12.5% TEC had an OTR of 387.5 (24.4) and the 25.0% TEC coating had an OTC of 513.5 (29.9). The 37.5% TEC formulation produced a sticky film with an OTC of 596.6 (27.2).

[00153] The coatings from the DOP/VBCP formulations had OTC that were similar. The 12.5% DOP coating had an OTC of 502.6 (18.8). The 25.0% DOP coating had an OTC of 398.3 (13.5) and the 37.5% DOP coating had an OTC of 599.6 (34.6).

[00154] For the VBCP-TEC coating system, the 12.5% TEC coating gives the greatest oxygen resistance and for the VBCP-DOP coating system, 25.0% DOP gives the greatest oxygen resistance. For both plasticizers, the 37.5% formulation produced sticky coatings. For the 6.25% TEC, there was minimal oxygen resistance.

[00155] The OTR of the prepared LMWPVC coatings were also evaluated as a function of plasticizer type and concentration. The relative OTR for the PVC composite coatings were also normalized to a 3.1 mil thickness. For example, the DOP/PVC = 1/3 composite coating thickness was 7.0 mil. The OTR for this coating normalized to (3.1 mil) = 226.6 (7.0/3.1)= 511.7 cm 3 /m 2 -day with a standard deviation = 51.5.

[00156] The PVC did not completely dissolve in methylene chloride containing the DOP plasticizer; however the PVC did swell in the methylene chloride containing DOP plasticizer. The spray was a dispersion rather than a solution. However a uniform coating was achieved nevertheless.

[00157] The 12.5% DOP/PVC composite coating normalized to 3.1 mil had an OTC of 502.5 (18.8). The 25.0% DOP/PVC coating had an OTC of 511.7 (51.5). The 37.5% DOP/PVC coating had an OTC of 763.3 (12.4) and the 50.0% DOP/PVC coating had an OTC of 1284.7 (92.3). For the PVC - DOP system, 12.5 % DOP gives the greatest oxygen resistance and the 6.25% DOP/PVC showed minimal resistance to oxygen.

Example 6. Enzyme granule with cellulosic coating applied in pan coater

[00158] A fluid-bed coated phytase granule is prepared using a Vector FL1 fluid bed coater. 1000 grams of sodium sulfate cores, with a particle size range of 150-300 microns and a mean diameter of 200 microns, are charged into the coater and fluidized while spraying a solution of phytase containing 25% phytase enzyme solids and 3% polylvinyl alcohol onto the granules until 5% solids are added to the cores. The bed temperature is maintained at 40 degrees C, and the particles are dried until the water activity is between 0.1 and 0.3. From the fluid bed coater, 1050 grams of enzyme coated cores are harvested.

[00159] The enzyme coated cores are charged into a rotary pan coater. The pan coater is tumbled at 60 rpm, in ventilated hood designed to capture, condense and collect solvent, without any heating applied to the fluidization air, the pan coater, or the enzyme coated cores.

[00160] A coating formulation is prepared having a triethyl citrate/ethyl cellulose 20 ratio of 1/4 and Ethocel 20/titanium dioxide ratio of 6/1. This is produced by weighing out 52.8 gm TEC and introducing it to a 5 liter cap-able bottle to minimize loss. A 3.6 liter volume of methylene chloride is added and stirred with a magnetic stir bar at 700 rpm until the TEC is dissolved. Over a span of 20 minutes, 211.2 gm Ethocel 20 is added slowly until it dissolved followed by the addition of 120ml Atlox 4912 dispersant in methylene chloride solution (Atlox concentration 0.008 g/ml) and 35.0 gm Ti02 and stirred until time to spray.

[00161] The above coating formulation is sprayed onto the enzyme cores in the pan coater using an 150-017 nozzle (15 degree angle-.017 gal/min), until 10% w/w solids were added to the 1050 grams of enzyme cores, bringing the total mass to 1155 grams. The coated particles are harvested and analyzed.

[00162] In general, any nozzle can be employed according to the present teachings, as will be appreciated by one of skill in the art. In some embodiments, a twin fluid or gas atomization nozzle is employed. In some embodiments, a pressure atomization nozzle is employed.

[00163] An scanning electron microscope is prepared of five sectioned Ethocel /Ti02 coated cores Measurements are taken of the coatings of 5 particles are then made at the thickest and thinnest points, and averaged.

[00164] Moisture uptake test. Samples of 1-2 grams each of the coated particles are placed into humidity chambers at the following two Test conditions and times:

Temperature %RH Time

A. 37C 70% l day

B. 95C 95% 12 seconds

[00165] The samples are weighed before and after incubation in the humidity chambers, and a % w/w moisture uptake determined, measured as percent weight gain. Example 7. Enzyme granule with vinyl copolymer coating applied in pan coater

[00166] A fluid-bed coated phytase granule is prepared using a Vector FL1 fluid bed coater. 1000 grams of sodium sulfate cores, with a particle size range of 150-300 microns and a mean diameter of 200 microns, are charged into the coater and fluidized while spraying a solution of phytase containing 25% phytase enzyme solids and 3% polylvinyl alcohol onto the granules until 5% solids are added to the cores. The bed temperature is maintained at 40 degrees C, and the particles are dried until the water activity is between 0.1 and 0.3. From the fluid bed coater, 1050 grams of enzyme coated cores are harvested.

The enzyme coated cores are charged into a rotary pan coater. The pan coater is tumbled at 60 rpm, in ventilated hood designed to capture, condense and collect solvent, without any heating applied to the air, the pan coater, or the enzyme coated cores.

[00167] A coating formulation is prepared having a dibutylphalate (placticizer)/ vinyl butyral copolymer (Butvar B-79 from Solutia) ratio of 1/7. This is produced by weighing out 30 g of dibutylphalate and introducing it into a 5 liter bottle.

[00168] A 4 liter volume of methylene chloride is added to the bottle and agitated briefly with a magnetic stirring bar. 210 g of Butvar 79 is next added slowly to the bottle, the bottle capped and the contents agitated for one hour until the polymer is completely dissolved.

[00169] The above coating formulation is sprayed onto the enzyme cores in the pan coater using an 150-017 nozzle (15 degree angle-.017 gal/min) until 10% w/w solids were added to the 1050 grams of enzyme cores, bringing the total mass to 1155 grams. The coated particles are harvested and analyzed.

[00170] A scanning electron microscope is prepared of five sectioned vinylbutyral copolymer coated cores Measurements are taken of the coatings of 5 particles made at the thickest and thinnest points, and averaged.

[00171] Moisture uptake test. Samples of 1-2 grams each of the coated particles are placed into humidity chambers at the following two Test conditions and times:

Temperature %RH Time

A. 37C 70% l day

B. 95C 95% 12 seconds

[00172] The samples are weighed before and after incubation in the humidity chambers and moisture uptake determined. A free-film water vapor transmission rate test can also be performed. Example 8. Enzyme granule with cellulosic coating applied in fluid bed spray coater

[00173] Phytase-coated sodium sulfate cores are produced using a Vector FL1 fluid bed coater using the exact protocol described in Example 6, up until the polymer coating step. From the fluid bed coater, 1050 grams of enzyme coated cores are harvested. The enzyme coated cores are charged back into the Vector FL1 fluid bed coater. The cores are fluidized at an inlet air temperature of 25 degrees C, in ventilated hood designed to capture, condense and collect solvent from the exhaust, without any heating applied to the fluidization air, the fluid bed coater, or the enzyme coated cores.

[00174] A coating formulation is prepared having a triethyl citrate/ethyl cellulose 20 ratio of 1/4 and Ethocel 20/titanium dioxide ratio of 6/1, by the same method described in Example 6, except that twice as much coating solution is prepared as that described in Example 6. The above coating formulation is sprayed onto the enzyme cores in the fluid bed coater using a Schlick two-fluid nozzle, until 20% w/w solids were added to the 1050 grams of enzyme cores, bringing the total mass to 1260 grams. The coated particles are harvested and analyzed.

[00175] A scanning electron microscope is prepared of five sectioned Ethocel /Ti02 coated cores Measurements are taken of the coatings of 5 particles were made at the thickest and thinnest points, and averaged.

[00176] Moisture uptake test. Samples of 1-2 grams each of the coated particles are placed into humidity chambers at the following two Test conditions and times:

Temperature %RH Time

A. 37C 70% l day

B. 95C 95% 12 seconds

[00177] The samples are weighed before and after incubation in the humidity chambers and moisture uptake determined. A free-film water vapor transmission rate test can also be performed.

Example 9 Coated corn seeds

[00178] 9.75 g of dibutylsebecate plasticizer was weighed into a one liter bottle. Next 720 ml of methylene chloride was added to the bottle, the bottle capped and the contents agitated briefly with a magnetic bar. 39.0 g of Ethyl Cellulose Standard 4 Premium polymer (Dow

Chemical Co.) was then added, the bottle capped and agitated with a magnetic bar for one hour to completely dissolve the Ethyl Cellulose. Next 0.59 g of Atlox 4912 (Croda) dispersant dissolved in one ml of methylene chloride was added, followed by the addition of 6.5 g of TiO pigment. (TheTiO tracer was black in color with an average particle size of 4 microns). The total volume of the resulting dispersion was about 750 ml.

[00179] 908 g of corn seed was loaded into a 5 gal. stainless steel bucket with four equally spaced baffles. The bucket at a raised angle was rotated at about one revolution per second to cause the corn seed to be lifted up by the baffles and fall in a curtain. 500 ml of the above methylene chloride dispersion was sprayed into the falling curtain of seeds from a pressurized (80 psig) metal container using a 150-017 nozzle (15 degree angle-.017 gal/min). The spray nozzle was positioned 34 inches from the bottom of the bucket and the spray duration was for about 8 minutes.

[00180] The resulting coated seed was immediately dry and as such there was minimal agglomeration. By visual observation of the coated seeds (With the black TiO tracer in the coating) we were able to conclude that the seeds were completely coated (No bare spots). By examining the coated seeds using an electron microscope (Electronmicrograph shown in Fig. 4) we were able to confirm that indeed the coating was continuous and that it was also nonporous and uniform with an average thickness of about 20 microns.

Example 10 Enzyme granule with enzyme and salt coating applied in fluid bed spray coater

[00181] A fluid-bed coated phytase enzyme granule was prepared using a 150 kilogram capacity pilot scale top spray fluid-bed spray coater, into which was charged 65 kg of sodium sulfate cores with a particle size between 200 - 500 microns and a mean particle size of 290 microns. An enzyme solution was prepared by combining 34.7 kg of a 24.1% w/w Axtra PHY ™ (BP17ETD) phytase ultrafiltration concentrate with 19.3 kg of a 20% w/w solution of partially hydrolyzed PVA (Celvol 5-88) and 2.2 kg of a 35.4% solution of sodium phytate (An Kang Shi Mao, CAS #14306-25-3). The enzyme solution/suspension was sprayed onto the fluidized cores, with a bed temperature of 42 degrees C. A sodium sulfate solution was prepared by dissolving 60 kg of sodium sulfate into 140 kg water. The sodium sulfate solution was sprayed onto the enzyme-coated cores at a bed temperature of 44 degrees C. , keeping the bed temperature between 40-50 degrees C, and avoiding agglomeration. A total of 141.5 kg of enzyme- and salt-coated cores was harvested from the coater and sieved to remove

agglomerates and fines. This material is designated as Granule 10, shown in Figures 5 and 6.

[00182] Example 11 Enzyme granule with cellulosic coating applied in fluid bed spray coater One kilogram of enzyme- and salt-coated sodium sulfate cores from Example 10 were charged into a Uniglatt fluid bed spray coater, in the Wurster (bottom spray) configuration. A 3.40% w/w solution of ethycellulose, combined with 1.15% corn oil as plasticizer, in methylene chloride. The ethylcellulose / corn oil solution had a viscosity of 2 centipoises and was prepared and sprayed onto the enzyme- and salt-coated cores, at a spray rate of 12.5 ml/min, with 40 psig atomization air pressure, and an inlet temperature of 48C, and outlet temperature of 37 C, with the flap set at 45% open. Samples were removed from the upper port after 30 min and 72 minutes of coating. These are designated Granules 11 A (shown in Figures 7 and 8 and 1 IB (shown in Figures 9-10). No agglomeration was apparent during the run or in Granules 11A and 11B. Scanning electron micrographs of

Scanning electron micrographs of Granules 10, 11A and 1 IB and their coating layers are shown in Figures 5-10. These figures illustrate the continuity, uniformity and non-porous nature of the ethylcellulose coatings The coating thicknesses of the ethylcellulose coatings, calculated as an average of 5 measurements, were 6.2 microns and 11.4 microns for Granules 11A and 11B, respectively.

[00183] Example 12 Steam resistance of ethylcellulose coated enzyme samples

One gram samples of Granules 10, 11A and 1 IB were placed onto a porous mesh screen and exposed to gently flowing unpressurized steam for 12 seconds before being immediately removed from the steam and allowed to cool, drain and air dry. The samples were subsequently analyzed for remaining phytase activity by grinding with a mortar and pestle and extracting in buffer using the Malachite Green activity assay and reported as FTU units per gram of granule. Samples were also analyzed for extractable soluble protein using HPLC. Specific activity of the extracted protein was calculated as the ratio of the phytase activity concentration in the granule (FTU/g granule) to the soluble protein activity in the granule (mg protein/g granule) Duplicate analyses were performed for each sample and averaged. The results are summarized in Table 1, indicating that ethylcellulose coating applied in Granules 11A and 1 IB led to a significant increase relative to Granule 10 in both the amount and specific activity of the phytase extracted from the granule after exposure to steam.

Table 1. Retention of enzyme activity by ethyl cellulose coated enzyme granules after steam exposure

Phytase Activity Specific Activity

(FTU/mg granule) (FTU/ mg protein)

Granule Average Before After Percent Before After Percent

Ethylcellulose Steam Steam Retained Steam Steam Retained

Coating thickness (um)

10 0 15,661 871 6% 474 149 31%

11A 6.2 16,374 7258 44% 465 421 91%

11B 11.4 16,602 7455 45% 476 475 100%

Enzymes as Active Materials

[00184] In addition to the foregoing, the active material of the present invention may be any material that is to be added to a granule to provide the intended functionality for a given use. The active agent may be a biologically viable material, a food or feed ingredient, an

antimicrobial agent, an antibiotic replacement agent, a prebiotic, a probiotic, an agrochemical ingredient, such as a pesticide, fertilizer or herbicide; a pharmaceutical ingredient or a household care active ingredient, or combinations thereof. In a preferred embodiment, the active ingredient is a protein, enzyme, peptide, polypeptide, amino acid, carbohydrate, lipid or oil, vitamin, co-vitamin, hormone, or combinations thereof.

[00185] In another embodiment, the active ingredient is an enzyme, bleach, bleach activator, perfume, or other biologically active ingredient. Inherently thermostable active agents are encompassed by the present teachings and can exhibit enhanced thermostability in the granules. Most preferred active ingredients for food and feed applications are enzymes, peptides and polypeptides, amino acids, antimicrobials, gut health promoting agents, vitamins, and combinations thereof. Any enzyme may be used, and a nonlimiting list of enzymes include phytases, xylanases, β-glucanases, phosphatases, proteases, amylases (alpha or beta or glucoamylases) cellulases, lipases, cutinases, oxidases, transferases, reductases, hemicellulases, mannanases, esterases, isomerases, pectinases, lactases, peroxidases, laccases, other redox enzymes and mixtures thereof. Particularly preferred enzymes include a xylanase from

Tnchoderma reesei and a variant xylanase from Tnchoderma reesei, both available from DuPont Industrial Biosciences or the inherently thermostable xylanase described in

EP1222256B1, as well as other xylanases from Aspergillus niger, Aspergillus kawachii, Aspergillus tubigensis, Bacillus circulans, Bacillus pumilus, Bacillus subtilis, Neocallimastix patriciarum,Penicillium species, Streptomyces lividans, Streptomyces thermoviolaceus, Thermomonospora fusca, Trichoderma harzianum, Tnchoderma reesei, Trichoderma viride. Additional particularly preferred enzymes include phytases, such as for example Finase L^®, a phytase from Aspergillus sp., available from AB Enzymes, Darmstadt, Germany; Phyzyme XP, a phytase from E. Coli, available from DuPont Nutrition and Health, and other phytases from, for example, the following organisms: Trichoderma, Penicillium, Fusarium, Buttiauxella, Citrobacter, Enterobacter, Penicillium, Humicola, Bacillus, and Peniophora, as well as those phytases described in US patent applications 61/595,923 and 61/595,941, both filed February 12, 2012 . An example of a cellullase is Multifect^® BGL, a cellulase (beta glucanase), available from DuPont Industrial Biosciences and other cellulases from species such as Aspergillus, Trichoderma, Penicillium, Humicola, Bacillus, Cellulomonas, Penicillium, Thermomonospore, Clostridium, and Hypocrea. The cellulases and endoglucanases described in

US20060193897A1 also may be used. Amylases may be, for example, from species such as Aspergillus, Trichoderma, Penicillium, Bacillus, for instance, B. subtilis, B. steawthermophilus, B. lentus, B. licheniformis, B. coagulans, and B. amyloliquefaciens. Suitable fungal amylases are derived from Aspergillus, such as A. oryzae and A. niger. Proteases may be from Bacillus amyloliquefaciens, Bacillus lentus , Bacillus subtilis, Bacillus licheniformis, and Aspergillus and Trichoderma species. Phytases, xylanases, phosphatases, proteases, amylases, esterases, redox enzymes, lipases, transferases, cellulases, and β-glucanases are enzymes frequently used for inclusion in animal feed. Enzymes suitable for inclusion into tablets for household care applications are similar, particularly proteases, amylases, lipases, pectate lyases, mannanases, hemicellulases, redox enzymes, peroxidases, transferases, and cellulases. In particularly preferred aspects of the present teachings, the enzymes are selected from phytases, xylanases, beta glucanases, amylases, proteases, lipases, esterases, and mixtures thereof. In one embodiment of the present invention, two enzymes are provided in the granule, a xylanase and a beta-glucanase. In another embodiment of the present invention, two enzymes provided in the granule are a protease and amylase. The enzymes may be mixed together or applied to the granule separately.

[00186] In another embodiment, three enzymes are provided in the granule, namely beta- glucanase, xylanase and phytase. The above enzyme lists are examples only and are not meant to be exclusive. Any enzyme may be used in the granules of the present teachings, including wild type, recombinant and variant enzymes of bacterial, fungal, yeast, plant, insect and animal sources, and acid, neutral or alkaline enzymes. It will be recognized by those skilled in the art that the amount of enzyme used will depend, at least in part, upon the type and property of the selected enzyme and the intended use.

Dispersed solid particles

[00187] In some embodiments, the coatings of the present teachings can comprise dispersed solid particles, at a level between 1-80%. The dispersed solid particles can be water insoluble, but can form a dispersion or solid solution with the polymer. These dispersed solid particles can be fillers, pigments, anti-tack agents, lubricants, permeability reducers and the like.

Specific examples include: titanium dioxide, calcium carbonate, talc, kaolin, montmorillonite, silica, starch, powdered or fibrous cellulose, or waxes, such as carnauba wax, beeswax, candellila wax, paraffin wax, or polyethyene wax.

Processing Aspects

[00188] In some embodiments, the coating process may be deployed in a manner such that the particles and process air are maintained at a constant, desired temperature. In some

embodiments, no supplemental heating is required for the evaporation of the solvent, given the relatively low boiling point. However, the evaporation of the solvent and the expansion of the atomizing gas as it transits and exits the twin-fluid atomizing nozzle can result in a temperature depression, potentially affecting coating quality. It should be noted that heating the atomizing air constitutes a negligible amount of air volume and heating in comparison to what is typically required to heat the mass of air used to suspend, convey, or dry the target particles in the chamber. Accordingly, in some embodiments heating of the atomizing gas, the spray liquid or both can be used to maintain the desired temperature of the coating process. In one

embodiment, the flowrate and heat of vaporization of the solvent are used to calculate the required heat to be added in order to balance the temperature depression from evaporation. In another embodiment, the temperature of the process environment is sensed and the heat applied to the atomizing gas or spray liquid in a feedback controlled process.

[00189] Although the description above contains many details, these should not be construed as limiting the scope of the invention but as merely providing illustrations of some of the presently preferred embodiments of this invention. Therefore, it will be appreciated that the scope of the present invention fully encompasses other embodiments which may become obvious to those skilled in the art, and that the scope of the present invention is accordingly to be limited by nothing other than the appended claims, in which reference to an element in the singular is not intended to mean "one and only one" unless explicitly so stated, but rather "one or more." All structural, chemical, and functional equivalents to the elements of the above- described preferred embodiment that are known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the present claims. Moreover, it is not necessary for a device or method to address each and every problem sought to be solved by the present invention, for it to be encompassed by the present claims.

Furthermore, no element, component, or method step in the present disclosure is intended to be dedicated to the public regardless of whether the element, component, or method step is explicitly recited in the claims. No claim element herein is to be construed under the provisions of 35 U.S.C. 112, sixth paragraph, unless the element is expressly recited using the phrase "means for."

Claims

1. A particle comprising an active ingredient surrounded by a coating, wherein the coating comprises a polymer, wherein the coating has an average thickness of less than 20 microns and a free-film water vapor permeability of less than 500 g/m /day at 20 degrees C and 75% RH.

2. A particle comprising an active ingredient surrounded by a coating, wherein the coating comprises a polymer, wherein the coating has an average thickness of less than 20 microns and the particle has a moisture uptake rate of less than about 1% at both (a) 95 degrees C and 95% RH for 12 seconds or (b) 37 degrees C and 70%RH for 3 days.

3. A particle consisting, or consisting essentially of, an active ingredient surrounded by a coating, wherein the coating comprises a polymer, wherein the coating has an average thickness of less than 20 microns and a free-film water vapor permeability of less than 500 g/m /day at 20 degrees C and 75% RH.

4. A particle consisting, or consisting essentially of, an active ingredient surrounded by a coating, wherein the coating comprises a polymer, wherein the coating has an average thickness of less than 20 microns and the particle has a moisture uptake rate of less than about 1% at both (a) 95 degrees C and 95% RH for 12 seconds or (b) 37 degrees C and 70%RH for 3 days.

5. The particle of any of the preceding claims, wherein the coating comprises a dispersant.

6. The particle of any of the preceding claims, wherein the active ingredient is an enzyme, a protein, a peptide, a seed, a spore, a nucleic acid, or a microbe.

7. The particle of any of the preceding claims, wherein the coating has an average thickness of no more than 10 microns or no more than 15 microns.

8. The particle of any of the preceding claims, wherein the coating has an average thickness of 5-10, 5-15, 5-20, or 10-15 microns.

9. The particle according to any of the preceding claims wherein the active ingredient is thermally labile, wherein thermally labile is defined as losing at least 5% of activity following exposure to lOOC for 24 hours.

10. The particle according to any of the preceding claims wherein the active ingredient is an enzyme selected from the group consisting of phytase, amylase, protease, or cellulase.

11. The particle according to any of the preceding claims wherein the polymer is selected from the group consisting of styrene copolymers, ethyl cellulose, hydroxyl propyl methyl cellulose, sodium carboxy methyl cellulose, poly vinyl pyrolidone, vinyl buytral copolymer and low molecular weight polyvinyl choloride.

12. The particle according to any of the preceding claims wherein the polymer is selected from the group consisting of cellulose acetate phthalate, methyl acrylic acid copolymers, hydroxyl propyl methyl cellulose phthalate, cellulose triacetate, polymethacrylates,

polyphenylene sulfones, polystyrene, polycarbonate, polyether sulfone, polymethacrylate, polysiloxanes, polyurethanes and copolymers thereof, and polyvinyl acetate phytalate.

13. The particle according to any of the preceding claims wherein the plasticizer is selected from the group consisting of triethyl citrate (TEC), dibutyl sebacate (DBS), dioctyl phthalate

(DOP), glycerol, triacetin and acetylated monoglycerides.

14. The particle according to any of the preceding claims wherein the plasticizer is selected from the group consisting of triglycerides, diglycerides and monoglycerides

15. The particle according to any of the preceding claims wherein the plasticizer is corn oil, soybean oil, sunflower oil, sesame oil or cottonseed oil.

16. The particle according to any of the preceding claims wherein the plasticizer is corn oil.

17. The particle according to any of the preceding claims wherein the dispersant is selected from the group consisting of sorbitan monooleate, sorbitan trioleate, alkyl imidazoline and ABA block copolymer where A is poly (12 hydroxy- stearic acid) and B is polyethylene oxide.

18. The particle according to any of the preceding claims further comprising dispersed solid particles.

19. The particle according to any of the preceding claims further comprising dispersed solid particle in the coating.

20. The particle of any of the preceding claims wherein the median diameter of the particle prior to the application of a coating is 50-500, 100-400, or 150-300 microns and the particle further comprises an active ingredient comprising an enzyme.

21. A method of forming a coated particle lacking agglomeration comprising: aerosolizing a liquid formulation into a droplet, wherein the liquid formulation comprises a volatile non-aqueous solvent and a polymer; and, volatilizing the solvent from the droplet in flight to a particle in a chamber to form a coated particle, wherein the temperature of the particles does not exceed 40 degrees C during the coating process, and wherein no more than 5% w/w of the coated particles are agglomerated during the coating process.

22. The method of claim 21 wherein no more than 3% w/w of the coated particles are agglomerated during the coating process.

23. The method of any of claims 21-22 wherein the temperature of the particles does not exceed 35C, or 30C, during the coating process

24. The method of any of claims 21-23 wherein the coating is applied to the particles without any external source of heat in the chamber other than that naturally present in the ambient environment, drying air or uncoated particles.

25. The method of any of claims 21-24 wherein the aerosolizing comprises a nozzle to which heat is applied to counter any evaporative cooling effect.

26. The method of any of claims 21-25 wherein the median diameter of the particle prior to the application of a coating is 50-500, 100-400, or 150-300 microns and the particle further comprises an active ingredient comprising an enzyme.

27. The method of any claims 21-26 wherein the volatile non-aqueous solvent consists of a single volatile non-aqueous solvent, and wherein the single volatile non-aqueous solvent is methylene chloride.

28. A particle according to any of claims 1-20, formed by the method according to any of claims 21-27.

29. A chamber comprising a particle and a droplet, wherein the droplet comprises a volatile nonaqueous solvent and a polymer, and wherein the particle is 50-500, 100-400, or 150-300 microns in diameter and the particle further comprises an active ingredient comprising an enzyme.

30. The chamber according to claim 29, wherein the particle comprises a coating arising from the polymer in the droplet.

31. Use of a particle according to any of claims 1-20 as a detergent.

32. Use of a particle according to any of claims 1-20 as an animal feed.