Process for obtaining microcapsules

Abstract

A continuous process for preparing microcapsules containing water-insoluble active principles, comprising: (1) preparing, in a first reactor, an aqueous solution containing one or more surfactants, (2) preparing, in a second reactor, a solution comprising at least an active principle immiscible in an aqueous phase and a first component for preparing a polycondensation polymer for forming the microcapsule shell, simultaneously feeding to a tubular reactor of a stream of aqueous solution (1) and solution (2), the ratio of solution (2)/solution (1) being between 0.5 and 2.0, inletting a stream (3) of a second component for preparing the polycondensation polymer into the reactor, wherein stream (3) reacts with the first component, wherein the streams are under turbulent flow conditions in the tubular reactor, and are continuously fed to the tubular reactor, and wherein the ratio between the equivalents of the first component and second component are between 0.9 and 1.1.

Claims

1. A continuous process for preparing an aqueous dispersion of microcapsules with an encapsulation efficiency of the active principle ≧98%, the microcapsules showing an homogeneous granulometric distribution as herein below defined and encapsulating water insoluble active principles to be used in the pharmaceutical and agrochemical field, comprising: (1) preparation in a first reactor under stirring of an aqueous solution containing one or more surfactants, (2) preparation in a second reactor under stirring of a solution comprising an active principle immiscible in an aqueous phase and a first monomeric component, simultaneous feeding to a tubular reactor of a stream of the aqueous solution (1) and of a stream of solution (2), the ratio of stream solution (2)/stream solution (1) being between 0.5 and 2.0, the streams (1) and (2) being under turbulent flow conditions in the reactor, then, optionally in a time of 0-10 seconds, feeding to the reactor under turbulent flow conditions stream (3) comprising a second monomeric component, the equivalent ratio between the first monomeric component and the second monomeric component being comprised between 0.9 and 1.1, streams (1), (2) and (3) being continuously fed to the tubular reactor; wherein the substantial homogeneous granulometric distribution of the microcapsules is defined as a b)/a) ratio, wherein b) is the average diameter determined on the smallest 90% of the microcapsules and a) is the average diameter determined on the smallest 50% of the microcapsules, being comprised between 1.5 and 2.5, b) being lower than 15 μm, streams (1), (2), and (3) having separate inlets into the reactor.

2. A process according to claim 1 wherein streams (1), (2) and (3) are used.

3. A process according to claim 1 wherein as first monomeric component a mixture of isocyanates is used.

4. A process according to claim 1 wherein the solution (1) and solution (2) of the active principle and of the first monomeric component are introduced into the reactor at a temperature ranging from 10° C. up to 60° C.

5. A process according to claim 1 wherein solution (2) is prepared by mixing solution (2a) containing the active principle and optionally an organic solvent, and solution (2b) comprising the first monomeric component, optionally dissolved in organic solvent, (2a) and (2b) being continuously premixed and then fed into the tubular reactor.

6. A process according to claim 1 wherein the viscosity of solution (2), optionally diluted with an organic solvent, is in the range 400 and 1000 cps.

7. A process according to claim 1 wherein the surfactants of solution (1) are selected from anionic and nonionic surfactants.

8. A process according to claim 7 wherein the anionic surfactants are selected from the group consisting of sodium ligninsulphonates, calcium ligninsulphonates and sodium polycarboxylates, the nonionic surfactants are selected from block copolymers formed by ethoxylated and propoxylated units.

9. A process according to claim 1 wherein the active principles are selected from herbicides, acaricides, insecticides, fungicides, biocides, plant and insect growth regulators, antidotes.

10. A process according to claim 9, wherein the active principles are selected from the following classes: herbicides, selected from the following classes: dinitroanilines: pendimethalin and trifluralin chloroacetamides: alachlor, acetochlor, dimethenamide, metolachlor, pethoxamide, pretilachlor carbammates: molinates, triallates, EPTC; diphenylethers: oxyfluorfen, or flurochloridone, clomazone, dichlobenil, acaricides of the METI class, selected from fenazaquin, pyridaben, hexythiazox, insecticides, selected from those belonging to the following classes: pyrethroids: bifenthrin, α-cypermethrin, cypermethrin, deltamethrin, imiprothrin, λ-cyhalothrin, prallethrin, tetramethrin, preferably bifenthrin, α-cypermethrin, deltamethrin e λ-cyhalothrin, ethofenprox phosphoorganic compounds: phosmet, chlorpyriphos, naled, fenitrothion; neonicotinoids: imidachloprid, acetamiprid carbammates: carbosulfan, pirimicarb, aldicarb, thiodicarb, carbofuran and propoxur, preferably carbosulfan, fungicides, selected from those belonging to the following classes of imidazoles, triazoles, anilinopyrimidine.

11. A process according to claim 10 wherein the herbicide is pendimethalin.

12. A process according to claim 1 wherein the polymeric shell of the microcapsule is obtainable by polycondensation or by reacting the second monomeric component formed in situ with the first monomeric component.

13. A process according to claim 12 wherein the polymer shell is selected from the group of polyamides, polyesters, polyurethanes, polyureas.

14. A process according to claim 12 wherein the polymer is a polyurea or a polyurethane and the first monomeric component is selected between di- and tri-isocyanates wherein the isocyanate groups are linked to an aliphatic or aromatic group and the second component is an aliphatic diamine having C.sub.2-C.sub.7 carbon atoms.

15. A process according to claim 1 wherein during the preparation of the microcapsule or after the microcapsule formation, ammonium salts, or inorganic alkaline metal salts selected from the following ones are added: lithium chloride, sodium chloride, potassium chloride, lithium nitrate, sodium nitrate, potassium nitrate, lithium sulphate, sodium sulphate, potassium sulphate, sodium monohydrogen-phosphate, potassium monohydrogen phosphate, sodium dihydrogen-phosphate, potassium dihydrogen-phosphate; alkaline-earth metal salts selected from magnesium chloride, calcium chloride, magnesium nitrate, calcium nitrate, magnesium sulphate; and alkaline metal salts of acetic acid.

16. A process according to claim 15 wherein the salt is calcium nitrate.

17. The process of claim 15, wherein the ammonium salts are selected from the group consisting of: ammonium chloride, ammonium sulphate, ammonium monohydrogen phosphate, and ammonium dihydrogen-phosphate.

Description

EXAMPLES

(1) Methods

(2) Microcapsule Granulometry

(3) The distribution of the microcapsule sizes is measured by a infrared rays Malvern Mastersizer. By this instrument the volumetric distribution of the microcapsules (particles) is determined and the average diameters of the microcapsule fractions corresponding respectively to 50% and 90% of the total microcapsule volume are evaluated.

(4) Viscosity of the Microcapsule Suspension

(5) It is measured at the temperature of 25° C. on the microcapsule suspension as such by a LVT model Brookfield viscosimeter in 2×12 modality.

(6) Encapsulation Efficiency

(7) The encapsulation efficiency is evaluated by contacting a sample of the microcapsule formulation with hexane. This solvent has the property to solubilize the free active principle (a.i.) (not encapsulated) but it is not able to dissolve the polyurea polymer of the microcapsule.

(8) The a.i. extracted with hexane was determined by the analytical methods herein below reported at the following different contact times (minutes) with the solvent: 1,5, 15, 30, 60. A plot was made by reporting in a graph on one axis the time intervals and on the other the amounts of a.i. found in hexane. The value at t=0 gives the amount of a.i. non encapsulated.

(9) The encapsulation efficiency is evaluated by means of the following equation:

(10) $\frac{\left(\mathrm{total}\mathrm{amount}\mathrm{of}a.i.\right)-\left(\mathrm{amount}\mathrm{of}a.i.\mathrm{at}t=0\right)}{\left(\mathrm{total}\mathrm{amount}\mathrm{of}a.i.\right)}\times 100$
wherein the total amount of a.i. is the quantity of a.i. added in the microecapsulation process.

(11) The encapsulation efficiency is ≧96%, preferably ≧98%, more preferably ≧99%.

(12) Density

(13) It is measured on the microcapsule suspension by using a DMA 100M densimeter (Mettler Toledo). The determination is carried out in a thermostated cell at 20° C.

(14) Alachlor Determination

(15) The compound is determined according to the CIPAC MT 204/TC/M/3 method by gaschromatographic analysis.

(16) Pendimethalin Determination

(17) The compound is determined according to the CIPAC MT 357/TC/M/3 method by using HPLC analysis.

(18) Acetochlor Determination

(19) The determination is carried out by gaschromatography, by using as internal standard a sample of the compound having a purity of at least 99.9%.

(20) Suspendability

(21) The suspendability is evaluated by the official CIPAC MT 161 method. The microcapsule suspension is diluted with water at 1% w/w and kept in a thermostated bath at 20° C. for 30 minutes. The supernatant is removed by suction and the residue on the bottom of the vessel is dried and weighed. The weight of the residue must be lower than 30% by weight with respect to the starting weight of the microcapsule suspension.

EXAMPLE 1

(22) In a tubular reactor, having the following dimensions: length 11 cm, inner diameter 7.5 cm, by means of pumps and by aid of flowmeters, the following components/solutions are fed: (1) aqueous solution at 2.6% w/w of sodium ligninsulphonate (Reax® 88B): 1,060 kg/h kept at the temperature of about 50° C., (2a) Alachlor, purity 94%: 1,358 kg/h fed as such, at the temperature of about 50° C., (2b) hydrophobic monomer mixture polymethylene polyphenyl isocyanate+MDI (PAPI 60%, MDI 40%, average functionality 2.7) (Voronate® M220): 95 kg/h.

(23) The feeding solutions (2a) and (2b) are united in continuous into one stream inletting the tubular reactor, (3) aqueous solution at 40% w/w of hexamethylendiamine, hydrophilic monomer: 91 l/h-7,

(24) Feeding solution (3) inlets the tubular reactor at a position located 2 seconds downstream from the inlet (2a)+(2b).

(25) The ratio by weight between streams (2a)+(2b)/(1) is of 1.37.

(26) The feeding solutions inletting the reactor are subjected to a turbulent flow.

(27) The formation of the microcapsules is almost instantaneous. After about 4 hours of run 12,296 kg of aqueous microcapsule suspension were obtained.

(28) The obtained suspension was collected in a tank.

(29) The formulation of the microcapsule suspension is completed by adding the following components, under a mild stirring, in the same tank wherein the subsequent maturation step will take place:

(30) TABLE-US-00001 CaCl.sub.2 922 kg NaCl 494 kg dimethylpolysiloxane (Defomex ® 1510) 30 kg dispersion in water of xanthan rubber Rhodopol ® 23 (pregel in water at 2.7%) 425 kg

(31) The maturation step has been carried out by maintaining the so obtained formulation under mild stirring at the temperature of about 50° C. for about 3 hours. Then it is cooled to room temperature and on the suspension the following analytical parameters are evaluated:

(32) TABLE-US-00002 Alachlor 475 g/L density 1.13 g/mL granulometry a)average diameter of 50% of the particles: 4.8 μm (microcapsules) b)average diameter of 90% of the particles 9.7 μm Ratio b)/a) 2.sup.  pH 5.5 suspendability 85% viscosity 1600 cps encapsulation efficiency 99%

EXAMPLE 2

(33) In the same tubular reactor of example 1, by using pumps and flowmeters, the following components/solutions are fed: (1) aqueous solution at 2.4% w/w of calcium ligninsulphonate (Borrement® CA): 1,080 kg/h, kept at a temperature of about 50° C., (2a) 82,5% w/w of pendimethalin (purity 95%) in Solvesso® 200 ND solvent): 1,040 kg/h, the solution kept at a temperature of about 50° C., (2b) hydrophobic monomer mixture polymethylene polyphenyl isocyanate+MDI (Voronate® M220): 73 kg/h,

(34) The feeding solutions (2a) and (2b) are united in continuous into one stream inletting the tubular reactor, (3) aqueous solution at 20% w/w of hexamethylendiamine, hydrophilic monomer: 91 l/h,

(35) Feeding solution (3) inlets the tubular reactor at a position located 2 seconds downstream from the inlet of (2a)+(2b).

(36) The stream ratio by weight (2a)+(2b)/(1) is of 1.0.

(37) The feeding solutions inletting the reactor are subjected to a turbulent flow.

(38) After about 3 hours of run 9,000 kg of aqueous suspension of microcapsules were obtained.

(39) The obtained suspension was collected in a tank.

(40) The maturation step is then carried out by heating the obtained suspension in a tank at a temperature of 50° C. under mild stirring for 3 hours. The formulation is then completed by adding the following components:

(41) TABLE-US-00003 Ca(NO.sub.3).sub.2 50 kg Amebact ® C 17 kg Defomex ® 1510 18 kg Rhodopol ® 23 (pregel in water at 2.7%) 380 kg dimethylpolysiloxane (Defomex ® 1510) 30 kg dispersion in water of xanthan rubber Rhodopol ® 23 (pregel in water at 2.7%) 425 kg

(42) It is then cooled down to room temperature and on the suspension the following analytical parameters are then evaluated:

(43) TABLE-US-00004 pendimethalin 365 g/l density 1.13 g/ml granulometry a)average diameter of 50% of the particles: 5.8 μm b)average diameter of 90% of the particles: 9.8 μm ratio b)/a) 1.7 pH 8.sup.  suspendability 86% viscosity 1700 cps encapsulation efficiency 99%

EXAMPLE 3

Comparative

(44) In a vessel equipped with stirrer 473.0 g of technical Acetochlor 95% purity are charged under stirring while heating at 50° C. Then, always under stirring, 34.2 g of Voronate® M 220 are added. In the meantime 11 g of dispersant Reax™100M are dispersed in 323 g of water. The organic mixture Acetochlor+Voronate® M 220 is added to the aqueous solution of the dispersant by stirring by a Turrax equipment at 10,000 rpm for about 5 seconds. Then to the so obtained dispersion 14.8 g of an aqueous solution containing 85% by weight of hexamethylendiamine are added.

(45) The mixture is transferred into a reactor kept at 50° C. and added of 50 g of a thickener (pregelled Rhodopol® 23 at 2.7% by weight in water and containing 1 g of Proxel® GXL as antimould agent), 2 g of an antifoam agent Defomex® 1510 and 90 g of calcium nitrate and then the suspension let mature at 4 h at 50° C., as described before.

(46) 1 Kg of of microcapsule suspension is obtained.

(47) The suspension is cooled at room temperature and the following analytical parameters are then evaluated:

(48) TABLE-US-00005 Acetochlor 495 g/l density 1.10 g/ml granulometry a)average diameter of 50% of the particles: 8.90 μm b)average diameter of 90% of the particles: 19.03 μm ratio b)/a) 2.14 pH 6.5  suspendability 86% viscosity 1500 cps

(49) This comparative example shows that by operating in a batch process and maintaining among the reactants the same weight ratios as in the continuous process, the same temperature conditions, with a mixing time of 5 s between the organic mixture Acetochior+Voronate® (corresponding to stream (2) of the continuous process) and the aqueous solution of the dispersant (corresponding to solution (1) of the continuous process), 90% of the microcapsules shows an average diameter larger than that of the microcapsules of the present invention.

(50) Therefore by operating in batch process under high productivity conditions, using mixing times comparable with those of the examples of the continuous process of the invention, it is not possible to obtain microcapsules having the same characteristics.

EXAMPLE 4

Comparative

(51) Example 3 is repeated but increasing the mixing time of the organic mixture with the aqueous solution of the dispersant in water from 5 seconds to 5 minutes.

(52) 1 kg of microcapsule suspension is obtained.

(53) The suspension is cooled at room temperature and analyzed for determining the parameters reported hereunder:

(54) TABLE-US-00006 Acetochlor 495 g/l density 1.10 g/ml granulometry a)average diameter of 50% of the particles: 4.75 μm b)average diameter of 90% of the particles: 9.96 μm ratio b)/a) 2.14 pH 6.5  suspendability 86% viscosity 1550 cps

(55) Example 4 comparative shows that with a batch process it is possible to obtain microcapsules having a granulometric distribution and an average size of 90% microcapsules comparable with those obtained with the continuous process of examples 1 and 2 of the present invention, but using a mixing time much longer than that of the examples of the invention, therefore with reduced productivity compared with the claimed continuous process.

EXAMPLE 5

(56) In a tubular reactor having the same dimensions as that used in example 1, by means of pumps and by the aid of flowmeters, the following components/solutions are fed: (1) aqueous solution at 2.6% w/w of sodium ligninsulphate (Reax® 88B/:1,060 kg/h kept a a temperature of about 50° C. (2a) Alachlor, purity 94%: 1,358 kg/h, fed as such at a temperature of about 50° C. (2b) hydrophobic monomer mixture PAPI+MDI (Voronate® M 220: TDI 1:1 w/w: 130 kg/h.

(57) The feeding solutions (2a) and (2B)M are united in continuous into one stream inletting the tubular reactor.

(58) The ratio by weight between streams (2a)+(2b)/(1) is 1.40.

(59) The feeding solutions inletting the r3eactor are subjected to a turbulent flow.

(60) The formation of microcapsules is almost instantaneous. After about 4 hours of run, 12,240 kg of microcapsule aqueous suspension are obtained.

(61) The formulation is then completed and heated as described in example 1.

(62) Analysis on the final microcapsule suspension has given the following results:

(63) TABLE-US-00007 Alachlor 472 g/l Density 1.13 g/ml Granulometry a) average diameter of 50% of the microcapsules: 4.5 μm b) average diameter of 90% of microcapsules: 9.6 μm ratio b)/a) 2.1 pH 5.5 viscosity 1590 cps encapsulation efficiency 99%.