Aqueous polymer dispersion based on N,N-diethylaminoethyl methacrylate, its preparation and use

Abstract

The present invention relates to a process for preparing an aqueous polymer dispersion by free-radical emulsion polymerization of a monomer mixture which comprises N,N-diethylaminoethyl methacrylate, to the polymer dispersion obtainable by this process, and to the use thereof.

Claims

1. An aqueous polymer dispersion Pd) which is soluble through reduction in the pH and comprises at least one polymer which comprises a) N,N-diethylaminoethyl methacrylate, and b) at least one compound capable of free radical polymerization and selected from esters of α,β-ethylenically unsaturated mono- and dicarboxylic acids with C.sub.1-C.sub.8-alkanols, wherein monomers a) and b) are the only monomers in the copolymer, at least one emulsifier selected from anionic and nonionic emulsifiers, and water.

2. The polymer dispersion according to claim 1, comprising a polymer which comprises 43 to 47% by weight, based on the total weight of the monomers employed for the polymerization, of N,N-diethylaminoethyl methacrylate a), and 53 to 57% by weight, based on the total weight of the monomers employed for the polymerization, of at least one compound b) as only monomers in the copolymer.

3. The polymer dispersion according to claim 1, which comprises N,N-diethylaminoethanol in an amount not exceeding 2500 ppm by weight.

4. The polymer dispersion according to claim 1, which comprises N,N-diethylaminoethanol in an amount not exceeding 500 ppm by weight, methacrylic acid in an amount not exceeding 50 ppm by weight and methanol in an amount not exceeding 50 ppm by weight.

5. The polymer dispersion according to claim 1, which comprises methacrylic acid in an amount not exceeding 100 ppm by weight.

6. The polymer dispersion according to claim 1, which comprises methanol in an amount not exceeding 500 ppm by weight.

7. A coating composition comprising an aqueous polymer dispersion Pd) as defined in claim 1, or a polymer composition obtainable therefrom by drying.

8. The coating composition according to claim 7, comprising in addition at least one further polymer component.

9. A pharmaceutical composition or food product comprising A) a polymer composition obtainable by drying and/or forming a film of a polymer dispersion as defined in claim 1, B) at least one pharmaceutically acceptable active ingredient or a dietary supplement, and C) optionally at least one pharmaceutically acceptable excipient or auxiliary acceptable in the food products sector.

10. The pharmaceutical composition or food product in the form of an oral dosage form comprising a coating based on the aqueous polymer dispersion Pd) as claimed in claim 1.

11. The pharmaceutical composition or food product according to claim 1, which is in the form of coated tablets, pellets, microcapsules, granules or crystals.

12. A coating composition(s) for cosmetics, food products, veterinary medicaments, animal nutrition, seeds, and the textile, paper, printing, leather and adhesives industries which comprises the polymer as claimed in claim 1.

13. An aqueous polymer dispersion Pd) obtained by a process which comprises free-radical emulsion polymerizing a plurality of monomers in an aqueous medium at a pH of at least 8, said plurality of monomers consisting of a) N,N-diethylaminoethyl methacrylate, and b) a compound capable of free-radical polymerization selected from esters of α,β-ethylenically unsaturated mono and dicarboxylic acids with C.sub.1-C.sub.8 alkanols, and c) optionally a monomer c) selected from esters of α,β-ethylenically unsaturated mono and dicarboxylic acids with C.sub.9-C.sub.30-alkanols and C.sub.2-C.sub.30-alkanediols, amides of α,β-ethylenically unsaturated mono and dicarboxylic acids with C.sub.2-C.sub.30-amino alcohols which have a primary or secondary amino group, primary amides of α,β-ethylenically unsaturated monocarboxylic acids and theft N-alkyl and N,N diallyl derivatives, N-vinyllactams, open-chain N-vinylamide compounds, esters of vinyl alcohol and allyl alcohol with C.sub.1-C.sub.30-monocarboxylic acids, vinyl ethers, vinyl aromatic compounds, vinyl halides, vinylidene halides, C.sub.2-C.sub.8-monoolefins, unsaturated nitriles, nonaromatic hydrocarbons having at least two conjugated double bonds and mixtures thereof, and d) optionally a compound d) which is different from compound a) and has an α,β-ethylenically unsaturated double bond capable of free radical polymerization and at least one cationic group per molecule as copolymerized units.

Description

EXAMPLE 1

(1) Initial Charge:

(2) 481.75 kg of deionized water 5.59 kg of C.sub.16/C.sub.18-alkyl polyglycol ethers with about 20 ethylene oxide units, Pharma grade, 10% strength aqueous solution, 4.58 kg of sodiumlaurylsulfate GMP, 15% strength aqueous solution
Addition 1: 14.60 kg of deionized water 0.38 kg of sodium persulfate
Feed 1: 248.52 kg of deionized water 86.43 kg of C.sub.16-/C.sub.18-alkyl polyglycol ethers with about 20 ethylene oxide units, Pharma grade, 10% strength aqueous solution 71.38 kg of sodiumlaurylsulfate GMP, 15% strength aqueous solution
Feed 2: 172.00 kg of diethylaminoethyl methacrylate 258.00 kg of methyl methacrylate
Feed 3: 153.09 kg of deionized water 3.92 kg of sodium persulfate

(3) It is ensured by suitable technical measures (flushing with acetone and/or blowing dry) that the feed vessel (feed 2) is substantially free of water. Addition 1 and feed 3 are freshly made up directly, i.e. 1 hour, before the start of the polymerization (solid sodium persulfate dissolved in deionized water). The dynamic mixer (Megatron MT 3-61, Kinematica AG) is charged with water before the start of the test.

(4) The polymerization reactor (vessel volume about 2050 l) and all lines coming into contact with the polymer dispersion are flushed with a 3% strength aqueous sodium hydroxide solution before the start of the test. The polymerization reactor is then charged with the initial charge. Before starting the reaction, the initial charge is evacuated, gassed once with 5 bar of nitrogen, again evacuated and brought to atmospheric pressure with nitrogen. The initial charge is then heated to the reaction temperature of 75° C. while stirring. When an internal temperature of 70° C. is reached, addition 1 is added over the course of two minutes.

(5) Feeds 1 and 2 are metered into the reactor via the dynamic mixer (revolutions set at 5000 rpm), feed 3 is metered into the reactor via a static mixer which is located in the stretch of line between dynamic mixer and polymerization reactor.

(6) Feed 1 is started directly before feeds 2 and 3. Addition of feed 1 takes place over the course of 1.75 hours, of feed 2 over the course of 1.50 hours, and of feed 3 over the course of 3.75 hours.

(7) After feed 3 is complete, after-polymerization takes place at 75° C. while stirring for 2 hours. The reaction mixture is then cooled to room temperature and the solids content and pH are determined. The pH during the polymerization (more accurately: during the addition of the monomers) was always higher than 8.0 in Example 1 and the following Examples 2 to 6. The K values were determined on 1% strength solutions in NMP for all examples.

(8) TABLE-US-00004 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 32.7 pH 9.0

(9) The dispersion then undergoes ultrafiltration and the following characteristics are determined:

(10) TABLE-US-00005 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 30.5 Viscosity (mPas) 6 pH 9.2 Light transmission (%) 86 K value 50 Average particle size (nm) 100 (determined using an AU) Methanol (ppm) 20 Methacrylic acid (ppm) 60 N,N-Diethylethanolamine (ppm) 280 Storage stability (18 months) excellent, no sediment AU = analytical ultracentrifuge

EXAMPLE 2

(11) The procedure is as in Example 1, but only 2.2 kg of sodium persulfate are employed in feed 3, and 0.4 kg of ethylhexyl thioglycolate are included in feed 2.

(12) TABLE-US-00006 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 31.9 pH 9.1

(13) The dispersion then undergoes ultrafiltration and the following characteristics are determined:

(14) TABLE-US-00007 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 30 Viscosity (mPas) 6 pH 9.2 Light transmission (%) 87 K value 52 Average particle size (nm) 105 (determined using an AU) Methanol (ppm) 18 Methacrylic acid (ppm) 48 N,N-Diethylethanolamine (ppm) 240 Storage stability (after 18 months) excellent, minimal sediment Example 3

(15) The procedure is as in Example 1, but 193.5 kg of diethylaminoethyl methacrylate and 236.5 kg of methyl methacrylate are employed in feed 2.

(16) TABLE-US-00008 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 30.3 pH 9.0

(17) The dispersion then undergoes ultrafiltration and the following characteristics are determined:

(18) TABLE-US-00009 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 30 Viscosity (mPas) 5 pH 9.2 Light transmission (%) 89 K value 50 Average particle size (nm) 110 (determined using an AU) Methanol (ppm) 22 Methacrylic acid (ppm) 65 N,N-Diethylethanolamine (ppm) 210 Storage stability (after 18 months) excellent, minimal sediment

EXAMPLE 4

(19) Initial Charge:

(20) 378.24 kg of deionized water 5.59 kg of C.sub.16-/C.sub.18-alkyl polyglycol ethers with about 20 ethylene oxide units, Pharma grade, 10% strength aqueous solution, 4.58 kg of sodiumlaurylsulfate GMP, 15% strength aqueous solution
Addition 1: 14.60 kg of deionized water 0.38 kg of sodium persulfate
Feed 1: 352.03 kg of deionized water 86.43 kg of C.sub.16-/C.sub.18-alkyl polyglycol ethers with about 20 ethylene oxide units, Pharma grade, 10% strength aqueous solution 71.38 kg of sodiumlaurylsulfate GMP, 15% strength aqueous solution
Feed 2: 172.00 kg of diethylaminoethyl methacrylate 258.00 kg of methyl methacrylate
Feed 3: 153.09 kg of deionized water 3.92 kg of sodium persulfate

(21) The polymerization reactor (vessel volume about 2050 l) and all lines coming into contact with the polymer dispersion are flushed with a 3% strength aqueous sodium hydroxide solution before the start of the test. The polymerization reactor is then charged with the initial charge.

(22) Before starting the reaction, the initial charge is evacuated, gassed once with 5 bar of nitrogen, again evacuated and brought to atmospheric pressure with nitrogen. The initial charge is then heated to the reaction temperature of 75° C. while stirring. When an internal temperature of 70° C. is reached, addition 1 is added over the course of two minutes.

(23) Feeds 1 and 2 are metered into the reactor via the dynamic mixer (revolutions set at 5000 rpm), feed 3 is metered into the reactor via a static mixer which is located in the stretch of line between dynamic mixer and polymerization reactor.

(24) Feed 1 is started directly before feeds 2 and 3. Addition of feed 1 takes place over the course of 1.75 hours, of feed 2 over the course of 1.50 hours, and of feed 3 over the course of 3.75 hours.

(25) After feed 3 is complete, after-polymerization takes place at 75° C. while stirring for 2 hours. The reaction mixture is then cooled to room temperature and the solids content and pH are determined.

(26) TABLE-US-00010 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 31.7 pH 9.0

(27) The dispersion then undergoes ultrafiltration and the following characteristics are determined:

(28) TABLE-US-00011 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 30 Viscosity (mPas) 6 pH 9.2 Light transmission (%) 85 K value 50.5 Average particle size (nm) 105 (determined using an AU) Methanol (ppm) 20 Methacrylic acid (ppm) 40 N,N-Diethylethanolamine (ppm) 210 Storage stability (18 months) excellent, no sediment

EXAMPLE 5

(29) The procedure is as in Example 4, but potassium persulfate is employed instead of sodium persulfate in addition 1 and in feed 3.

(30) TABLE-US-00012 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 30.8 pH 9.1

(31) The dispersion then undergoes ultrafiltration and the following characteristics are determined:

(32) TABLE-US-00013 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 30 Viscosity (mPas) 6 pH 9.2 Light transmission (%) 89 K value 51 Average particle size (nm) 110 (determined using an AU) Methanol (ppm) 15 Methacrylic acid (ppm) 55 N,N-Diethylethanolamine (ppm) 190 Storage stability (after 18 months) excellent, minimal sediment

EXAMPLE 6

(33) The procedure is as in Example 4, but ammonium persulfate is employed instead of sodium persulfate in addition 1 and in feed 3, and the pH is adjusted to pH 9 in each case with aqueous NaOH.

(34) TABLE-US-00014 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 30.7 pH 8.9

(35) The dispersion then undergoes ultrafiltration and the following characteristics are determined:

(36) TABLE-US-00015 Characteristics of the dispersion Unit Measurement or assessment Solids content (wt. %) 30 Viscosity (mPas) 7 pH 9.1 Light transmission (%) 85 K value 51 Average particle size (nm) 115 (determined using an AU) Methanol (ppm) 25 Methacrylic acid (ppm) 50 N,N-Diethylethanolamine (ppm) 210 Storage stability (after 18 months) excellent, minimal sediment

(37) In a variant of the examples indicated above it is, of course, also possible to prepare dispersions with a solids content differing from 30% by weight. For this purpose it is possible for example for deionized water to be added

(38) a) to the initial charge and/or

(39) b) to feed 1 and/or

(40) c) to feed 3

(41) (aiming at a lower solids content) or to be removed (aiming at a higher solids content).

(42) In another embodiment it is possible for example to put water from the initial charge into feed 1 and/or feed 3, in which case the solids content is then not changed. The redistribution may, however, also be effected in such a way that the water removed from the initial charge and/or feed 1 and/or feed 3 is put wholly or partly into a new feed (“feed 4”), in which case feed 4 can then be added to the polymerization in parallel, to the polymerization with a time lag or after the polymerization, continuously or all at once. This may serve for example to adapt the formulation to the sizes of vessels available, e.g. to avoid overfilling or replenishment of feed 1.

(43) It may, of course, be advantageous for the emulsifier distribution to the initial charge and feed 1 disclosed in the examples to be varied in such a way that anionic and/or nonionic emulsifier from the initial charge is put into feed 1 (or vice versa). It is, of course, also possible for anionic and/or nonionic emulsifier from the initial charge and/or feed 1 to be put into an additional feed 4 (cf. above). With all these measures it is preferred for the total amount of emulsifier to remain constant.

(44) It may, of course, also be advantageous for feeds 1 and/or feed 2 and/or feed 3 not to be metered in at a constant rate, but to be introduced at a non-constant rate. For example, the initiator feed can be metered at a higher rate during the polymerization phase (i.e. during the addition of feed 2) than after completion of feed 2.

(45) Example of Film Production

(46) A 30% strength dispersion of diethylaminoethyl methacrylate-methyl methacrylate copolymer from Example 1 was mixed while stirring with 15% triethyl citrate, based on solids, and spread on a film applicator (Erichsen Coatmaster) and dried to a film at a plate temperature of 45° C. The film thickness was 100 μm.

(47) The following properties were found:

(48) TABLE-US-00016 Elongation at break: 93% Tensile strength: 9.8 N/mm.sup.2 Water vapor permeability to DIN 53122 58 g/(m.sup.2/d)/100 μm film at 93% r.h.: Dissolution time in 0.1N HCl 2 min 50 s Dissolution time in phosphate buffer of >120 min pH 6.8 Tackiness by the Hoessel method at 0.25 (with triacetin instead of 20° C./80% r.h. triethyl citrate as plasticizer) 30° C./75% r.h. 0.25 (with triacetin instead of triethyl citrate as plasticizer)

(49) Method described in Cosmetics and Toiletries, 111(8), 73 et seq. (1996); scale from 0 (non-tacky) to 5 (tacky), r.h.=relative humidity

EXAMPLES OF COATING OF DOSAGE FORMS

Coating Example 1: Propranolol HCl 40 Mg Film-Coated Tablets

(50) TABLE-US-00017 Composition of the tablets Composition per tablet Substance [mg] Propranolol HCl 40 Ludipress 97.5 Avicel PH 105 97.5 Kollidon VA 64 12.5 Magnesium stearate 2.5 Total 250
Format: 9 mm, coated tablet form

(51) TABLE-US-00018 Composition of the spray formulation Proportion in Proportion in the film the suspension Substance [%] [%] 30% aqueous dispersion 67.83 45.22 from Example 2 Triethyl citrate 10.17 2.03 Iron oxide red 2 0.4 Talc 20 4 Water, demineralized — 48.35 Total 100 100

(52) The triethyl citrate plasticizer was added to the polymer dispersion and stirring was continued. Talc and iron oxide red were slurried in water and homogenized using a high-shear mixer. The two phases were then mixed by adding the pigment suspension to the polymer dispersion.

(53) Coating Parameters:

(54) A Manesty “Accela Cota 24” horizontal drum coater was used for coating.

(55) The following conditions were set or resulted from the settings:

(56) TABLE-US-00019 Spray nozzle Schlick 937 with 1 mm liquid insert Number of spray nozzles 1 Charge 10 kg of propranolol HCl cores Core bed-nozzle distance 20 cm Spraying pressure 1.5 bar Pattern air pressure 0.5 bar Inlet air temperature 60° C. Outlet air temperature 36° C. Drum speed 15 rpm Spraying rate 40 g/min. Spraying time 55 min. Drying approx. 5 min. Application rate 6 mg/cm.sup.2
Properties of the Film-Coated Tablets
Release
Paddle, 50 rpm, 37° C., 1000 ml

(57) TABLE-US-00020 0.08N HCl Phosphate buffer pH 6.8 after 45 min. >90% <5%
Disintegration Time
Erweka type ZT 74 disintegration tester, 37° C., 800 ml

(58) TABLE-US-00021 0.08N HCl (min:s) Phosphate buffer pH 6.8 (min:s) 4:30 >45 min

Coating Example 2: Enalapril 10 Mg Film-Coated Tablets

(59) TABLE-US-00022 Composition of the tablets Composition per tablet Substance [mg] Enalapril 10 Avicel PH 102 120 Di-Tab 60 Kollidon CL 8 Magnesium stearate 2 Total 200 Format: 7 mm, coated tablet form

(60) TABLE-US-00023 Composition of the spray formulation Proportion in Proportion in the film the suspension Substance [%] [%] 30% aqueous dispersion 62.4 41.60 from Example 3 Tributyl citrate 9.36 1.87 Polyvinyl alcohol 5-88 6.24 1.25 Water, demineralized — 30.88 Titanium dioxide 2.00 0.40 Talc 20.00 4.00 Water, demineralized — 20.00 Total 100.00 100.00

(61) The tributyl citrate plasticizer was added to the polymer dispersion and stirring was continued. Talc and titanium dioxide were slurried in water and homogenized using a high-shear mixer. Polyvinyl alcohol is heated to 85° C. in water and dissolved. The cooled solution is stirred into the polymer dispersion. The pigment suspension was then added with stirring.

(62) Coating Parameters

(63) A Manesty “Accela Cota 24” horizontal drum coater was used for coating.

(64) The following conditions were set or resulted from the settings:

(65) TABLE-US-00024 Spray nozzle Schlick 937 with 1 mm liquid insert Number of spray nozzles 1 Charge 12 kg of enalapril cores Core bed-nozzle distance 20 cm Spraying pressure 1.5 bar Pattern air pressure 0.5 bar Inlet air temperature 65° C. Outlet air temperature 38° C. Drum speed 15 rpm Spraying rate 45 g/min. Spraying time 50 min. Drying approx. 5 min. Application rate 5 mg/cm.sup.2
Results
Release: Paddle, 50 rpm, 37° C., 1000 ml

(66) TABLE-US-00025 0.08N HCl Phosphate buffer pH 6.8 After 45 min. >90% <10%
Disintegration time: Erweka type ZT 74 disintegration tester, 37° C.

(67) TABLE-US-00026 0.08N HCl (min:s) Phosphate buffer pH 6.8 (min:s) 3:59 >45
Stability: Storage at 30° C./70% r.h. for 1 year

(68) TABLE-US-00027 Enalapril content (%) Enalapril content (%) 0 months 12 months Core 100.2 92.3 Film-coated tablet 100.7 100.1

Coating Example 3: Coated Ibuprofen Minipellets

(69) TABLE-US-00028 Composition of the pellets Composition per pellet Substance [%] Ibuprofen 100
Pellet size 200 to 400 μm

(70) TABLE-US-00029 Composition of the spray formulation Proportion in film Proportion in suspension Substance [%] [%] 30% aqueous dispersion 65.42 43.61 from Example 4 Triacetin 13.08 2.62 Talc 21.5 4.3 Water, demineralized — 49.47 Total 100 100

(71) The triacetin plasticizer was added to the polymer dispersion and left to stir. Talc was slurried in water and homogenized using a high-shear mixer. The two preparations were then mixed.

(72) Coating Parameters

(73) A “Glatt GPCG 3.1” fluidized bed granulator from Glatt was used for coating.

(74) TABLE-US-00030 Spray nozzle 1 mm diameter Number of spray nozzles 1 Charge 2.5 kg of ibuprofen pellets 200-400 μm Process Bottom spray (Wurster) Spraying pressure 1.0 bar Inlet air temperature 60° C. Outlet air temperature 46° C. Spraying rate 12 g/min. Spraying time 4 h Drying approx. 5 min. Application rate/weight gain 20%
Tabletting to MUPS Tablets

(75) It is possible by mixing and compressing the coated pellets produced above with microcrystalline cellulose of type 102 to produce a tablet which disintegrates into pellets again on disintegration.

(76) TABLE-US-00031 Composition per tablet Substance [mg] Coated ibuprofen minipellets 120 Microcrystalline cellulose, type 102 258 Kollidon CL 20 Magnesium stearate 2 Total 400 Format: 11 mm, flat, bevelled
Tablet and Pellet Properties:
Release, pellets, paddle, 50 rpm, 37° C., 1000 ml, weight 250 mg

(77) TABLE-US-00032 Acetate buffer pH 4.5 Acetate buffer pH 6.8 After 45 min. >90% <10%
Tablets:
Paddle, 50 rpm, 37° C., 1000 ml

(78) TABLE-US-00033 Acetate buffer pH 4.5 Acetate buffer pH 6.8 After 45 min. >90% <15%
Tablet Disintegration:
Erweka type ZT 74 disintegration tester, 37° C.

(79) TABLE-US-00034 Acetate buffer pH 4.5 Acetate buffer pH 6.8 2:29 2:45

Coating Example 4: Coated Caffeine Pellets

(80) TABLE-US-00035 Composition of the pellets Composition per pellet Substance [%] Caffeine, fine powder 20 Avicel PH 101 (MCC) 38.75 Granulac 230 (Lactose) 38.75 Kollidon VA 64 2.5
Production by extrusion, pellet size 0.7-1.4 mm

(81) TABLE-US-00036 Composition of the spray formulation Proportion in film Proportion in suspension Substance [%] [%] 30% aqueous dispersion 62.61 41.74 from Example 5 Acetyl triethyl citrate 9.39 1.88 Iron oxide yellow 3 0.6 Kaolin 25 5 Water, demineralized — 50.78 Total 100 100

(82) The acetyl triethyl citrate plasticizer was added directly to the cationic polymer dispersion and left to stir. Talc and iron oxide yellow were slurried in water and homogenized using an Ultraturrax. The two phases were then mixed by adding the pigment suspension to the polymer dispersion.

(83) Coating Parameters:

(84) A “Glatt GPCG 3.1” fluidized bed granulator from Glatt was used for the coating.

(85) The following conditions were set or resulted from the settings:

(86) TABLE-US-00037 Spray nozzle 1 mm diameter Number of spray nozzles 1 Charge 2.5 kg of caffeine pellets 0.7-1.4 mm Process Top spray Spraying pressure 1.0 bar Inlet air temperature 60° C. Outlet air temperature 43° C. Spraying rate 14 g/min. Spraying time 135 min. Drying approx. 5 min. Application rate/weight gain 15%
Release:
Paddle, 50 rpm, 37° C., 1000 ml, weight 300 mg

(87) TABLE-US-00038 0.08N HCl Phosphate buffer pH 6.8 After 45 min. >95% <10%

Coating Example 5: Coated Quinine Sulfate Minipellets

(88) TABLE-US-00039 Composition of the pellets Composition per pellet Substance [%] Quinine sulfate * 2H.sub.2O 10 Avicel PH 101 (MCC) 46.75 Granulac 230 (Lactose) 40.75 Kollidon VA 64 2.5
Pellet size 125-300 μm

(89) TABLE-US-00040 Composition of the spray formulation Proportion in film Proportion in suspension Substance [%] [%] 30% aqueous dispersion 68.26 45.51 from Example 6 Triacetin 10.24 2.05 Indigotine lake 1.5 0.3 Talc 20 4 Water, demineralized — 48.14 Total 100 100

(90) The triacetin plasticizer was added directly to the polymer dispersion and left to stir. Talc and indigotine lake were slurried in water and homogenized using an Ultraturrax. The two preparations were then mixed by adding the pigment suspension to the polymer dispersion.

(91) Coating Parameters:

(92) A “Glatt GPCG 3.1” fluidized bed granulator from Glatt was used for the coating.

(93) The following conditions were set or resulted from the settings:

(94) TABLE-US-00041 Spray nozzle 1 mm diameter Number of spray nozzles 1 Charge 1.5 kg of quinine sulfate pellets 125-300 μm Process Bottom spray (Wurster) Spraying pressure 1.0 bar Inlet air temperature 60° C. Outlet air temperature 47° C. Spraying rate 10 g/min. Spraying time 225 min. Drying approx. 5 min. Application rate/weight gain 30%
Release:
Paddle, 50 rpm, 37° C., 1000 ml, weight 1000 mg

(95) TABLE-US-00042 0.08N HCl Phosphate buffer pH 6.8 After 45 min. >90% <10%