CN1161660A - Encapsulated active substance and method for its preparation - Google Patents

Abstract

An active substance encapsulated in a coating material immiscible therewith is contacted with a solvent which dissolves the residual active substance on the surface of the coating material but not the coating material. The resulting encapsulates of the invention have improved stability compared to encapsulates that have not been contacted with a solvent.

Description

Encapsulated active substance and method for its preparation

The present invention relates to a method of encapsulating an active substance in a protective coating immiscible therewith and to an active substance encapsulated by the method.

Coatings or microencapsulation of active substances serve to protect these substances from the environment, or to control their release or improve their handling. A number of coating or microencapsulation techniques have been described in the prior art. For example Somerville (US Patent 3015128) describes a centrifugal encapsulator for producing large quantities of relatively small individual capsules of solid or liquid active substances having substantially uniform and predetermined properties. In a later patent (US Patent 3310612), Somerville described a method and apparatus for centrifugation to form high quality capsules of 1500 micron diameter.

Johnson et al. (Journal of Gas Chromatography, 345, (1965)) describe a method for coating glass beads with a mixture of liquid phase material and diatomaceous earth which is reproducible and improves column efficiency.

Harlowe ("Incremental Issues Concerning Microencapsulation Systems", Arden House Conference, pp. 1-2, 13-18 February 1983) describes the submerged nozzle apparatus, which can be used to produce capsules of 1200-2500 microns; And a centrifugal extruder capable of producing capsules of 500-1000 microns.

Anderson et al. (US Patent No. 4,764,317) provided a continuous collection system of microcapsules filled with liquid, which protected the capsules and reduced the rupture of the capsules, thereby solving the problem that the capsules were mostly ruptured due to collisions.

Sparks et al. (US Pat. No. 4,675,140) describe a method and apparatus for coating or microencapsulating solid particles and viscous liquid droplets, which allows the vast majority of particles to be coated individually or separately rather than in particle clusters. coating; the method also provides an improved method of separating unwanted or unutilized liquid coating material from the coated particles. This process can be adjusted to produce droplets of excess liquid coating material of an excellent predetermined size, which are smaller in diameter than the individual particles being coated.

Uratsuka (Japanese Patent Publication No. 2-292324) describes a microencapsulated urea hardening accelerator comprising a thermoplastic resin having a softening point of 40-200°C.

The coated spheres or microcapsules formed by the above method will cause the active substance to stick to the surface of the coating material, so the advantages of the coating or microcapsule method are not reflected.

It is therefore an object of the present invention to form coated spheres of active substance which are externally free of active substance.

The present invention is a method of encapsulating an active substance in a coating material immiscible therewith, the coating material having a melting point above room temperature, the method comprising the steps of: a) at a temperature sufficient to melt the coating material dispersing the active substance in the coating material under temperature; b) forming droplets of the active substance dispersed in the coating material; c) cooling the droplets to solidify the coating material; and d) allowing the droplets to dissolve the active substance but The solvent that does not dissolve the coating material is contacted to remove the active substance on the surface of the coating material.

In another aspect, the present invention relates to microspheres containing an active substance microencapsulated in a coating material, wherein the active substance is removed from the surface by contacting the surface of the coating material of the microsphere with a solvent for the active substance.

The invention solves the problem of coating and microcapsule method in the prior art by removing the active substance on the surface of the coating material.

The process of the present invention requires four steps: a) dispersing the active substance in the coating material at a temperature sufficient to melt the coating material; b) forming droplets of the active substance dispersed in the coating material; c) cooling the droplets, allowing the coating to solidify; and d) removing the active from the surface of the coating by contacting the droplets with a solvent that dissolves the active but not the coating. The four steps are described in detail below.

The first step in the process of encapsulating an active substance in a coating material is to form a heterogeneous mixture of active substance and coating material at a temperature sufficient to melt the coating material but not decompose or volatilize the coating material and active substance . The selected active substance and coating material are immiscible (immiscible) with each other.

The coating material preferably has a melting point between 40-200°C. More preferred coating materials are petroleum derived paraffin waxes, polyethylene waxes, polyethylene-olefin copolymers, oxidized hydrocarbon waxes containing hydroxyl or carboxyl groups, polyesters, polyamides or mixtures thereof. The most preferred coating materials are petroleum derived alkane waxes, polyethylene-olefin copolymers, or polyethylene waxes. The most preferred coating material is polyethylene wax. Preferably the average molecular weight of the polyethylene wax is preferably in the range of 500, more preferably 1000 to 3000, especially preferably 2000 Daltons. Examples of these waxes include Polywax ^™ 500, Polywax ^™ 1000 and Polywax ^™ 2000, or mixtures thereof, more preferably a 75:25 mixture of Polywax ^™ 1000 and Polywax ^™ 2000 (Polywax is a registered trademark of Petrolite Corporation).

The active substance may be liquid or solid at room temperature, but is preferably solid at room temperature. More preferably the active substance has a melting point above room temperature but below the decomposition or volatilization temperature of the coating material. Thus, the melting point of the active substance may be higher, lower or equal to the melting point of the coating material. In any case, the active substance is dispersed in the coating material in the first step of the process, preferably at a temperature above the melting point of the coating material and the active substance, but at which the coating material and the active substance do not decompose.

The active substance can be any substance that forms a non-uniform slurry with the coating material and dissolves in a solvent that does not dissolve the coating material. Active substances can be, for example, drugs for slow-release application, insecticides, herbicides, aroma compounds, dyes, catalysts or curing agents.

The active substance is preferably a curing agent, more preferably a hardening accelerator having a melting point or glass transition temperature ( _Tg ) between 70-200°C.

The hardening accelerator is preferably urea or imidazole. Preferred ureas include 3-phenyl-1,1-dimethylurea; 3-(4-chlorophenyl)-1,1-dimethylurea; 3-(3,4-dichlorophenyl)- 1,1-dimethylurea; 1,1'-(4-methyl-m-phenylene)bis(3,3'-dimethylurea); 3-isomethyldimethylurea-3, 5,5-trimethylcyclohexyldimethylurea; or 4,4'-methylenebis(phenyldimethylurea). A more preferred urea is 3-phenyl-1,1-dimethylurea (PDMU).

Preferred imidazoles include alkyl or aryl imidazoles, such as 2-methylimidazole, 2-undecylimidazole, 2-heptadecylimidazole, 2-phenylimidazole, 2-ethylimidazole, 2-isopropylimidazole imidazole and 2-phenyl-4-methylimidazole; 1-cyanoethyl derivatives such as 1-cyanoethyl-2-methylimidazole, 1-cyanoethyl-2-phenylimidazole, 1-cyanoethyl Ethyl-2-undecylimidazole and 1-cyanoethyl-2-isopropylimidazole; and carboxylates such as 1-cyanoethyl-2-ethyl-4-methylimidazole-trimellitidine salt. A more preferred imidazole is 2-methylimidazole.

The hardening accelerator can also be a urea-imidazole conjugate, such as 2-methyl-N-phenyl-1H-imidazole-1-carboxamide, which can be prepared by reacting imidazole with an organic cyanate.

As noted above, a heterogeneous slurry is formed at elevated temperatures. For the purposes of the present invention, the elevated temperature should be above room temperature sufficiently to dissolve the coating material, more preferably the coating material and the active substance; but low enough to prevent thermal decomposition of the coating material or the active substance or volatile.

The concentration of active substance is preferably from 1wt.%, more preferably from 10wt.%, most preferably from 25wt.%, preferably to 60wt.%, more preferably to 45wt.%, most preferably to 35wt.%, with active substance and coating material total weight calculation.

The second step of the method of the present invention entails the formation of droplets. While droplets of any size can be used, the present invention is preferably used with microspheres of the active substance dispersed in a coating material. For the purposes of the present invention, microspheres are spherical particles having a diameter of 500 microns or less. The preferred particle size may vary depending on the application, but is preferably from 300 microns, more preferably from 200 microns, most preferably from 150 microns preferably to 10 microns, more preferably to 30 microns, most preferably to 50 microns. Similarly, the terms "microencapsulation" and "microencapsulation" are used to describe the encapsulation of active substances in a coating material to form microspheres.

As mentioned above, the formation of microspheres of the active substance dispersed with the coating material can be accomplished in different ways. The method of forming the microspheres of the active substance dispersed with the coating material is preferably at an elevated temperature sufficient to melt the coating material, more preferably at a temperature sufficient to melt the coating material and the active substance by disintegrating the first step formed without The homogeneous slurry is poured on the turntable. The rotation throws the coating material/active substance dispersion off the turntable into microspheres, which are solidified by air cooling (step 3). The speed of the turntable, the temperature, the rate at which the slurry is poured onto the turntable and the type of apparatus used determine the size of the microspheres formed.

In the fourth step, solidified droplets, preferably solidified microspheres of the active substance dispersed in the coating material, are pooled and contacted with a solvent that dissolves the active substance but not the coating material.

Preferred solvents are polar, as preferred coating materials are non-polar polymeric waxes and preferred actives are more polar. More preferred solvents are volatile, ie are readily removed by evaporation. Solvents with a melting point below 100°C are most preferred.

Examples of preferred solvents include water; alcohols, such as methanol, ethanol, and isopropanol; ketones, such as acetone and methyl ethyl ketone; chlorinated hydrocarbons, such as methylene chloride; and polar aprotic solvents, such as acetonitrile. More preferred solvents are water, methanol, ethanol, isopropanol and acetone. The most preferred solvents are acetone and methanol.

The amount of active substance encapsulated in the coating material after solvent washing was determined by thermogravimetric analysis (TGA), assuming that the active substance and the coating material evaporate at different temperatures. In the TGA method, a sample is placed on a platinum pan attached to a microbalance and heated to volatilize the active and coating materials. Since the active substance and coating material volatilize at different temperatures, the composition is conveniently determined by measuring the weight as a function of temperature.

The method of the present invention provides active substance droplets encapsulated in a coating material, preferably active substance microspheres encapsulated in a coating material, which exhibit long-term stability in the adhesive formulation, and Also exhibits high reactivity ("cook-on-demand") under moderate heat conditions. In a preferred application, urea or imidazole microencapsulated in polyethylene wax in the form of a composition comprising epoxy resin and dicyandiamide is storable for several months at 40°C or below. However, when the composition is heated to a high temperature high enough to melt the wax, the hardening accelerator is released and accelerates the reaction of the epoxy resin with dicyandiamide. (See Japanese Patent Publication 2-2923324, December 3, 1990)

Example 1 Solvent rinsed PDMU microcapsule beads coated with low molecular weight polyethylene wax

preparation

3-Phenyl-1,1-dimethylurea (PDMU) (300 g) was dispersed into molten 75/25 Polywax ^™ 1000/Polywax ^™ 2000 (75:25 weight percent of Polywax ^™ 1000 and Polywax ^™ 2000 mixture) (700g). The mixture was then heated until the PDMU was molten and poured at a rate of 500 g per minute onto the center of a turntable maintained at 140°C rotating at 650 rpm. The PDMU microspheres dispersed in ^PolywaxTM were thrown off the turntable and collected in the cone. The diameter of gained solid microsphere (1000g) is between 50-300 micron, makes them soak in acetone (1000ml) 5 minutes, then rinses with acetone 4 times (each time 500ml) with the PDMU of Polywax ^TM surface. The beads are air dried and stored until required for formulation into an adhesive. Example 2 Comparison of the stability of solvent-washed microspheres and non-encapsulated microspheres

The solvent washed microspheres of Example 1 were mixed into DER ^™ 331 (registered trademark of Dow Chemical Company) liquid epoxy resin at a ratio of 2 parts active material (PDMU) per 100 parts epoxy resin and stored at 110°F. The formulation was kept in a fluid state for six months. For comparison, formulations containing non-encapsulated PDMU were allowed to gel within 10 days. Example 3 Adhesive prepared using solvent washing microspheres

The adhesive was prepared as follows: Tactics ^™ 123 liquid epoxy resin (247.5 g); DER™ 755 liquid epoxy resin (247.5 g); acrylic rubber modified epoxy resin (495 g); aluminum powder (310 g, Reynolds A-200 ), Cab-O-Sil ^™ M-5 mist silica gel (50g); Byk ^™ R-605 polycarboxylic acid amide (polycarboxylic acid amide) (15g); Dicyandiamide (50g) and the solvent prepared in Example 1 Wash microspheres (70 g) were mixed in a heavy duty blender to form a paste binder. The adhesive was added to a 32 mil thick cold rolled steel coupon at a 5 mil adhesive thickness and aged at 177°C for 30 minutes. The adhesive was found to have a lap shear tensile strength of greater than 2000 psi and a T-peel strength of greater than 20 pounds per inch of length.

(Note: Tactics is a registered trademark of Dow Chemical Company; Cab-O-Sil is a registered trademark of Cabot Company; Byk is a registered trademark of BykChemie) Example 4 Preparation of 2-methylimidazole and low molecular weight polyethylene wax solvent rinse microbe Capsule small

beads

2-Methylimidazole (2-MI) (900 g) was dispersed into molten 75/25 Polywax ^™ 1000/Polywax ^™ 2000 (75:25 weight percent mixture of Polywax ^™ 1000 and Polywax ^™ 2000) (525 g). The mixture was then heated until the 2-MI was molten (180°C) and poured at a rate of 300 g per minute onto the center of a turntable maintained at 150°C rotating at 10,000 rpm. The 2-MI microspheres dispersed in Polywax ^™ were thrown off the turntable and pooled into the collection chamber. Unwashed microspheres (90 g) were kept in containers and compared to washed microspheres.

Microspheres (2500 g) with a diameter of 50-300 microns were soaked in isopropanol (3000 ml) for 5 minutes and then rinsed 4 times with acetone (1500 ml each) to remove 2-MI from the Polywax ^™ surface. The final washed beads (approximately 2300 g) were air dried and then stored until needed for formulation. Example 5 The stability comparison of solvent-washed microspheres and unwashed microspheres

The solvent-washed microspheres of Example 4 were mixed into DER ^™ 331 (registered trademark of Dow Chemical Company) liquid epoxy resin at a ratio of 1 part active 2-MI per 100 parts liquid epoxy resin and stored at room temperature (usually 70°F). The formulation was kept in a fluid state for more than six months. For comparison, formulations containing non-encapsulated 2-MI and unwashed microspheres were allowed to gel within 2 and 3 weeks, respectively.

Claims (12)

1. A method of encapsulating an active substance in a coating material immiscible therewith, the coating material having a melting point higher than room temperature, the method comprising the steps of: a) at a temperature sufficient to melt the coating material dispersing the active substance in the coating material; b) forming droplets of the active substance dispersed in the coating material; c) cooling the droplets to solidify the coating material; and d) mixing the droplets with the dissolved active substance but not Contact with a solvent that dissolves the coating material to remove the active substance from the surface of the coating material. 2. The method of claim 1, wherein step a) is dispersing the active substance in the coating material at a temperature sufficient to melt the active substance; and the droplets in steps b), c) and d) are microspheres. 3. The method of claim 1 or 2, wherein the coating material is a petroleum derived alkane wax, polyethylene wax, polyethylene-olefin copolymer wax, oxidized hydrocarbon wax containing hydroxyl or carboxyl groups, polyester or polyamide. 4. A method according to any one of claims 1-3, wherein the active substance is urea or imidazole having a melting point between 70-200°C. 5. A process according to any one of claims 1-4, wherein the solvent is water, an alcohol or a ketone having a melting point below 100°C. 6. The method of any one of claims 1-5, wherein the active substance is 3-phenyl-1,1-dimethylurea; 3-(4-chlorophenyl)-1,1-dimethylurea ; 3-(3,4-dichlorophenyl)-1,1-dimethylurea; 1,1'-(4-methyl-m-phenylene)bis(3,3'-dimethylurea ); 3-isomethyldimethylurea-3,5,5-trimethylcyclohexyldimethylurea; or 4,4'-methylenebis(phenyldimethylurea); 2-methyl Base-N-phenyl-1H-imidazole-1-carboxamide or 2-methylimidazole. 7. The method of any one of claims 1-6, wherein the hardening accelerator is 3-phenyl-1,1-dimethylurea or 2-methylimidazole. 8. The method of any one of claims 1-7, wherein the coating material is a polyethylene wax having a molecular weight between 1000-2000 Daltons. 9. The method of any one of claims 1-8, wherein the solvent is water, acetone, methanol, ethanol or isopropanol. 10. The method of any one of claims 1-9, wherein the solvent is acetone. 11. A microsphere containing an active substance encapsulated in a coating material, wherein the surface of the coating material of the microsphere is contacted with a solvent of the active substance, so that the active substance is not contained. 12. The microsphere according to claim 11, wherein the active substance is 3-phenyl-1,1-dimethylurea or 2-methylimidazole, and the coating material is a polymer with molecular weight between 1000-2000 Daltons. vinyl wax.