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Title:
DRY-BINDERS FOR TABLETS BASED ON POLYETHYLENE GLYCOL-POLYVINYL ALCOHOL GRAFT POLYMERS, THE PRODUCTION AND USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2018/234029
Kind Code:
A1
Abstract:
A finely divided binder in powder form consisting of a polyethylene glycol-polyvinyl alcohol graft polymer particles, wherein the particles have an average particle size D[4,3] in the range of from 10 to 70 µm.

Inventors:
FUSSNEGGER BERNHARD (DE)
GEBERT SILKE (DE)
GUTH FELICITAS (DE)
KOLTER KARL (DE)
Application Number:
PCT/EP2018/064730
Publication Date:
December 27, 2018
Filing Date:
June 05, 2018
Export Citation:
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Assignee:
BASF SE (DE)
International Classes:
A61K47/32; A61K47/34; A61K9/20
Domestic Patent References:
WO2000018375A12000-04-06
Foreign References:
Other References:
JANSSENS ET AL: "The use of a new hydrophilic polymer, Kollicoat IR^(R), in the formulation of solid dispersions of Itraconazole", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIEN, ELSEVIER, AMSTERDAM, NL, vol. 30, no. 3-4, 23 February 2007 (2007-02-23), pages 288 - 294, XP005901598, ISSN: 0928-0987, DOI: 10.1016/J.EJPS.2006.11.015
SANDRA GUNS ET AL: "Upscaling of the hot-melt extrusion process: Comparison between laboratory scale and pilot scale production of solid dispersions with miconazole and Kollicoat IR", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 81, no. 3, 29 March 2012 (2012-03-29), pages 674 - 682, XP028405176, ISSN: 0939-6411, [retrieved on 20120411], DOI: 10.1016/J.EJPB.2012.03.020
KARL KOLTER, AAPS ANNUAL MEETING AND EXPOSITION, 2002
Attorney, Agent or Firm:
BASF IP ASSOCIATION (DE)
Download PDF:
Claims:
Claims

1. A finely divided binder in powder form consisting of a polyethylene glycol-polyvinyl alco¬ hol graft polymer particles, wherein the particles have an average particle size D[4,3] in the range of from 10 to 70 μιτι.

2. A finely divided binder according to Claim 1, wherein the particles have an average parti¬ cle size D[4,3] in the range of from 10 to 70 μιτι and a packing fraction k of 0.15 to 0.27, and where the binder is a dry-binder for pharmaceutical tablets.

3. A finely divided binder according to Claim 1or 2, wherein the graft copolymer has a poly¬ vinyl alcohol content in the range of 75 % b.w. and a polyethylene glycol units content in the range of 25 % b.w.. 4. A finely divided binder according to any of Claims 1 to 3, wherein the average particle size D[4,3] is 10 to 60 μηη.

5. A finely divided binder according to any of Claims 1 to 4 wherein the average particle size D[4,3] is 15 to 50 μπη.

6. A finely divided binder according to any of Claims 1 to 5, containing a flowability agent.

7. A finely divided binder according to any of Claims 1 to 6, consisting of a polyethylene gly¬ col-polyvinyl alcohol graft polymer and 0.05 to 0.5 % b.w., based on the graft polymer, of a flowability agent.

8. A finely divided binder according to any of Claims 6 or 7, wherein the flowability agent is colloidal silica. 9. A process for producing a binder according to any of Claims 1 to 8 , which comprises ad¬ justing the particle properties of polyethylene glycol-polyvinyl alcohol graft polymer parti¬ cles to a volume weighted average particle size D[4,3] in the range of from 10 to 70 μιτι by milling or spray-drying. 10. A process for producing a binder according to any of Claims 1 to 8 , which comprises ad¬ justing the particle properties of polyethylene glycol-polyvinyl alcohol graft polymer parti¬ cles to a volume weighted average particle size D[4,3] in the range of from 10 to 70 μιτι and a packing fraction k of 0.15 to 0.27 by milling or spray-drying. 11. A process for producing a binder as claimed in any of claims 1 to 9, which comprises the steps of (i) providing an agueous solution of a polyethylene glycol-polyvinyl alcohol graft polymer with a polymer solids content in the range of from 1 to 35 % b.w., based on the aqueous solution, and (ii) spray drying by atomizing the solution into a spray apparatus.

12. A process for producing a spray-dried binder according to Claim 11, which comprises the steps of heating the aqueous solution provided in step (i) to 50 to 180 °C prior to atomiz¬ ing the heated solution.

13. A process according to Claim 12 wherein the aqueous solution provided in step (i) is

heated to 60 to 120 °C prior to atomizing the heated solution.

14. A process according to any of Claims 9 to 13, wherein a flowability agent is injected into the spray apparatus.

15. A method of manufacturing solid pharmaceutical dosage forms using a finely divided

binder in powder form according to any of Claims 1 to 14, as a dry-binder for direct com¬ pression mixtures.

Description:
Dry-Binders for tablets based on polyethylene glycol-polyvinyl alcohol graft polymers, the production and use thereof

Description

5

The present invention relates to binders in powder form based on polyethylene glycol-polyvi ¬ nyl alcohol graft polymer, where the polyethylene glycol-polyvinyl alcohol graft polymer bind ¬ ers have an average particle size D[4,3] in the range of from Ί0 to 70 μιτι and a packing frac ¬ tion k in the range of from 0.15 to 0.27. The invention further relates to a process for produc- Ί0 ing such binder particles and to the use thereof as a dry binder in a direct tableting process for producing tablets with high strength.

Binders are ordinarily employed in the production of compressed dosage forms in order to improve the resistance to crushing and the friability. Two tablet production processes nor-

Ί5 mally exist: wet granulation and direct tableting. Binders can be classified according to these applications into wet binders and dry binders. Application of dry binders takes place, as the name suggests, in dry form, that is no dissolving in a solvent takes place. Direct tableting is naturally the more cost-effective process because the individual components need merely to be mixed, but developments freguently fail because an efficient dry binder is not available. 0 Medicinal substances and also many other substances employed in tablets freguently have poor tableting properties, attributable in particular to the impossibility of generating any bonding between the solid particles of these materials during compression, or the materials being so elastic that the bonding is disrupted again on elastic relaxation. It would naturally be possible in principle to compensate this by a high proportion of binder in the tablet. However, 5 this is not expedient because the mass and the volume of the tablet are increased thereby, and it can then scarcely be swallowed. In addition, high proportions of binder prolong the dis ¬ integration time and dissolution of the active ingredient. Many medicinal substances therefore cannot be formulated by direct tableting. 0 The effect of dry binders is also important in roller compaction because it is necessary in this case too for a strong cohesion between the particles of the tablet ingredients to be gener ¬ ated. If this is not the case, the result of the roller compaction is mechanically unstable and disintegrates on comminution again virtually to the initial particle size, flows poorly and pro ¬ vides inadeguate resistance to crushing and friability in the subseguent tableting.

5

A problem associated with some conventional dry binders is their tendency to form peroxides. Such dry binders are unsuitable for oxidation-sensitive active ingredients.

On the other hand, the formulation of active ingredients which are both sensitive to oxidation 0 and hydrolysis is an unsolved problem. For this type of active ingredients wet-granulation is not a feasible method. At present, no dry binder for dry direct compression mixtures with adequate binder properties for solving these problems is available.

Polyethylene glycol-polyvinyl alcohol graft polymers and their use as coatings agents or bind- ers for wet granulation are described in WO 00/18375.

The use of a commercially available polyethylene glycol-polyvinyl alcohol graft polymer Kol ¬ licoat® I R as a wet binder is described by Karl Kolter, AAPS Annual Meeting and Exposition, Toronto, Canada, 2002.

However, this commercially available product is not suited for use in a dry binder direct com ¬ pression mixture since the resulting tablets are unsatisfactory with regard to tablet hardness and friability. The problem was solved by finding a binder in powder form based on a polyethylene glycol- polyvinyl alcohol graft polymer where the binder has a mean particle size D[4,3] in the range of from 10 to 70 μιτι. Preferably, the powderous binder has a packing fraction k in the range of 0.15 to 0.27. The mean particle size is the D[4,3] volume weighted mean diameter. This parameter can be measured by light scattering. Preferably, the [D4,3] is 10 -60 μιτι, more preferably 15 -60 μιτι, and particularly preferred 15 to 50 μιτι.

The packing fraction k is the constant of proportionality resulting from the ratio bulk density / true density. This constant is also known as "fractional solids content" and can also be ex ¬ pressed as a percentage.

With the constant k the percentage bed porosity can be calculated as (1- k) x 100.

The polyethylene glycol-polyvinyl alcohol graft polymer which is used for producing the bind- ers according to the invention has polyvinyl alcohol content in the range of 75 % b.w. and polyethylene glycol units content in the range of 25 % b.w.. a. The polyvinyl side chains are produced by grafting a vinyl acetate monomer on the polyethylene glycol chain (PEG 6000) with subsequent saponification of the polyvinyl acetate chain.

The mean molecular weight (weight average) of the graft polymer lies

in the range of from 15.000 to 50.000 g/mol. The molecular weight can be determined by SEC-MALLS (size exclusion chromatography-multiple angle light scattering).

A specifically preferred product is commercially available as Kollicoat® IR, Manufacturer BASF SE, Ludwigshafen, and additionally contains colloidal silica in the range of 0.3 % b.w., based on solid polymer content, being added as a flowability agent.

This commercial product has a mean particle size in the range of 120 μιτι and a bulk density of 310 g/l. The true density is 1.03 g/ml. True density is measured at 23 °C according to DIN EN 1183-3, (gas pycnometer). The solubility in water at standard conditions is more than 300 g/l. The weight average molecular weight is in the range of 20.000 g/mol. . According to a preferred embodiment of the invention the finely divided powders are ob ¬ tained by spray-drying processes.

Spray-drying processes are suitable for producing the products of the invention, and entail a 5 solution of the graft polymers being finely atomized with the aid of spraying devices and then dried in a stream of hot air. Spraying devices can be nozzles or rotating discs, with nozzles as preferred devices.

Agueous solutions are preferably processed.

Ί0

Generally, spray conditions can vary over a wide range depending of the size of the spray drying apparatus. The skilled artisan will know how to adapt specific parameters to a given operational capacity.

Ί5 It is possible to use pressure nozzles or multifluid nozzles for the atomization. Particularly suit ¬ able multifluid nozzles are two-substance nozzles. It is crucial that small droplets are achieved and that the dried particles do not stick together.

The atomization takes place at high pressure for the particular type of spraying device. On at- 0 omization through pressure nozzles, nozzle diameters of from 0.Ί to 3 mm have proved suit ¬ able, preferably 0.3 to 2 mm, particularly preferably 0.5 to 15 mm.

Pressures in the range of 1 to 50 MPa have proved to be suitable, preferably 5 to 40 MPa, particularly Ί0 to 30 MPa.

On atomization through two-substance nozzles, nozzle diameters (liguid side) of from 0.Ί to 5 mm have proved suitable, preferably 0.3 to 4 mm, particularly preferably 0.5 to 3 mm. Pres ¬ sures of the atomizing gas 0.03 to 2 MPa have proved suitable, preferably 0.05 to Ί5 Pa, par ¬ ticularly preferably 0.Ί to Ί0 M Pa. Suitable atomizing gases are the same gases as employed for drying as described below.

The solids concentrations of the solutions to be atomized are between 1 and 35% by weight, preferably between 3 and 25% by weight and particularly preferably in the range of from 5 and 15% by weight, for example 5, 7.5, 10, 12.5 and 15 % b.w.. 5 In a preferred embodiment, the spray solution is preheated to temperatures in the range of 50 - 180 °C, preferably 60 to 120°C, particularly preferably 70 to 110 °C.

The atomization can take place in any spray tower of conventional design. Drying gases which can be used are air or inert gases such as nitrogen, argon or helium, which can be passed 0 through the drying tower co-currently or counter-currently to the liguid droplets. The drying gas is preferably employed co-currently. The tower inlet temperature of the drying gas is from 100 to 200 °C, preferably 110 to 180 °C particularly preferably 120 to 170 °C. The tower outlet temperature is from 50 to 120 °C, preferably 60 to 110 °C, particularly preferably 70 to 100 °C . The resulting powder can be removed from the gas stream for example via a cyclone or a fil ¬ ter.

The flow-rate of the polymer solution can range from 300 kg/h to 2500 kg/h. The flow of the drying gas can be 10.000 m 3 /h to 80.000 m 3 /h

According to a specific embodiment of the spray-drying process, a flowability agent can be injected into the spray tower. Suitable flowability agents are finely divided silica or Mg-AI- silicate, Na-AL-silicate, Mg-silicate, Ca-silicate or starches.

The amounts for such agent can be 0.01 to 1 % b.w., preferably 0.05 to 0.5% b.w. based on the polymer content of the resulting powder product.

According to another specific embodiment for the process the particle size of the binders of the invention before processing, it is possible for products sprayed in this way to be sieved to even finer average particle sizes. Suitable sieve sizes are 40 μιτι, 60 μιτι or 80 μιτι.

According to another embodiment of the invention to change the particle morphology of the binders, it is possible for products sprayed in this way to be ground using conventional mills such as, for example, air jet mills, pinned-disk mills. Particle sizes can be further adjusted by additional sieving.

According to yet another embodiment commercially available material can be ground using conventional mills such as, for example, airjet mills, pinned-disk mills. Particle sizes can be further adjusted by additional sieving.

In order to produce the dry compression mixture the products of the invention are ordinarily used by mixing with the other ingredients of the formulation and subseguently compressing to a tablet or a compact. The decisive point in this connection is that the dry binder is uni ¬ formly distributed in the mixture. In a particular embodiment, it is also possible after the mix- ing to add water, steam or an organic solvent, thus partly dissolving the small particles and leading to a high strength of the tablet or the compact.

Customary pharmaceutical auxiliaries may optionally be processed at the same time. These take the form of substances of the class of fillers, softeners, solubilizers, additional binders, sili- cates and also disintegrants and adsorbents, lubricants, flow agents, dyes, stabilizers such as antioxidants, wetting agents, preservatives, release agents, flavorings or sweeteners, prefera ¬ bly fillers, softeners and solubilizers.

The fillers added can be e.g. inorganic fillers such as oxides of magnesium, aluminum or sili ¬ con, titanium carbonate or calcium carbonate, calcium phosphates or magnesium phosphates or organic fillers such as lactose, sucrose, sorbitol or mannitol. Suitable softeners are, for example, triacetin, triethyl citrate, glycerol monostearate, low mo ¬ lecular weight polyethylene glycols or poloxamers.

Suitable solubilizers are surface-active substances having an H LB value (Hydrophilic Lipophilic Balance) greater than 11, for example hydrogenated castor oil ethoxylated with 40 ethylene oxide units (Kolliphor® RH 40), castor oil ethoxylated with 35 ethylene oxide units (Kolliphor EL), polysorbate 80, poloxamers or sodium lauryl sulfate.

The lubricants used may be stearates of aluminum, calcium, magnesium and tin and also magnesium silicate, silicones and the like.

The flow agents used may be, for example, talc or colloidal silicon dioxide. Suitable additional binders are, for example, microcrystalline cellulose.

A tablet is normally produced in a tablet press, and a compact is produced in a roll com ¬ pactor. For further processing, the compact is comminuted again to granules which can be mixed with further additives and can for example be compressed to a tablet. The process of roller compaction is also referred to as dry granulation.

The compression to tablets can take place under compressive forces in the range of from 3 to 50 kN, preferably 5 to 40 kN, particularly preferable 5 to 20 kN. . The tablets obtained with the aid of the binders of the invention show a high hardness. The resulting hardness can range from 10 to 500 N, preferably 30 to 300 N, more preferably 50 to 200 N.

The proportion of the dry binder in the formulation can be 0.5 - 20% by weight, preferably 1 - 15% by weight and particularly preferably 5 - 15 % by weight.

The fact that the dry binders of the invention have excellent binding properties makes it possi ¬ ble also for poorly compressible active ingredients and excipients to be compressed, espe- daily when they are also present in high concentration.

Normally, powders consisting of fine particles show relatively lower flowability because How ¬ ever, surprisingly, for binders of the invention flowability and angle of repose prove to be un ¬ expectedly good.

It was also surprising that the binders according to the invention do not build up electrostatic charge something which normally expected with small particle sizes. Binders are frequently tacky substances which increase the ejection force during tableting, thus possibly causing numerous problems such as, for example, reduced strength of the tab ¬ let, capping, large rise in temperature of the compression tools and of the die wall, increased wear of the press etc. Entirely unexpectedly, the binders of the invention show a lubricant ef- 5 feet, since the residual and ejection forces during tableting are distinctly lower than without use of a binder or with use of a conventional binder.

The combined properties of average particle size and fractional solids content is important for the desired properties of the tablets as crushing strength or friability.

Ί0

In summary, the binders of the invention lead to tablets with exceptional mechanical proper ¬ ties, they make it possible to compress medicinal substances which are compressible with dif ¬ ficulty or not at all, they make it possible to reduce the total tablet mass or the tablet volume, and they ensure that the tableting process proceeds without impediment.

Ί5

The binders of the invention are particularly suitable for producing tablets of the following ac ¬ tive pharmaceutical ingredients which are normally difficult to compress: paracetamol, carbamazepine, acetylsalicylic acid, ascorbic acid, metoprolol tartrate, ibuprofen, 0 pseudoephedrine HCI, diphenhydramine HCI, dimenhydrinate, indometacin, diclofenac so ¬ dium, N -acetylcysteine, albendazole, alpha-methyldopa, aluminum hydroxides, magnesium silicate, ampicillin, atenolol HCI, captopril, cimetidine, diltiazem, griseofulvin, levamisole, magaldrate, magnesium carbonate, mebendazole, meprobamate, metamizole, metronida ¬ zole, neomycin sulfate, oxytetracycline HCI, nitrofurantoin, nystatin, nicotinic acid, phenytoin, 5 piroxicam, pyrazinamide, ranitidine, tetracycline, amoxicillin, chloroquin diphosphate, etham- butol, gemfibrozil, mefenamic acid, metformin HCI, nalidixic acid, naproxen, probenecid, ri- fampicin, sulfadiazine, sulfadimidine, sulfadoxine, sulfamethoxazole, sulfathiazole, valproic acid, verapamil, aciclovir, allopurinol, bezafibrate, carbidopa, cefuroxime, cephachlor, ciprof ¬ loxacin, fenofibrate, alpha-lipoic acid, pentoxyfylline, piracetam, propafenone HCI, roxithromy- 0 cin, sotalol, sulpiride, tramadol, tilidine.

The binder according to the invention where the binder is a dry-binder for pharmaceutical tablets is particularly characterized by the following preferred embodiments: 5 Embodiment 1: A finely divided binder in powder form consisting of a polyethylene glycol- polyvinyl alcohol graft polymer particles, wherein the particles have an average particle size D[4,3] in the range of from Ί0 to 70 μιτι and a packing fraction k of 0.15 to 0.27, and.

Embodiment 2: A finely divided binder according to Embodiment 1, wherein the average par ¬ ticle size D[4,3] is Ί0 to 60 μιτι.

0 Embodiment 3: A finely divided binder according to Embodiment 1 , wherein the average par ¬ ticle size D[4,3] is Ί5 to 50 μιτι. Embodiment 4: A finely divided binder according to Embodiments 1 to 3, wherein the graft copolymer has a polyvinyl alcohol content in the range of 75 % b.w. and a polyethylene glycol units content in the range of 25 % b.w..

Embodiment 5: A finely divided binder according to any of the Embodiments 1 to

4, wherein the mean molecular weight (weight average) of the graft polymer lies

in the range of from 15.000 to 50.000 g/mol.

Embodiment 6 : A finely divided binder according to Embodiments 1 to 5, wherein the poly ¬ ethylene glycol chain of the graft copolymer is a polyethylene glycol with an average molecu ¬ lar weight Mn 6000.

Embodiment 7: A finely divided binder according to any of Embodiments 1 to 6 containing a flowability agent.

Embodiment 8: A finely divided binder according to any of Embodiments 1 to 7, consisting of a polyethylene glycol-polyvinyl alcohol graft polymer and 0.05 to 0.5 % b.w., based on the graft polymer, of a flowability agent.

Embodiment 9: A finely divided binder according to any of Embodiments 7 or 8, wherein the flowability agent is colloidal silica.

Embodiment 10: A finely divided binder according to any of Embodiments 1 to 8, containing a polyethylene glycol-polyvinyl alcohol graft polymer with a true density in the range of 1.03 g/ml +/- 0.02 g /ml.

Embodiment 11: A process for producing a binder according to any of Embodiments 1 to 10 , which comprises adjusting the particle properties of polyethylene glycol-polyvinyl alcohol graft polymer particles to a volume weighted average particle size D[4,3] in the range of from 10 to 70 μιτι and a packing fraction k of 0.15 to 0.27 by milling or spray-drying.

Embodiment 12: A process for producing a binder according to any of Embodiments 1 to 11, which comprises the steps of (i) providing an agueous solution of a polyethylene glycol-poly ¬ vinyl alcohol graft polymer with a polymer solids content in the range of from 1 to 20 % b.w., based on the agueous solution, and (ii) atomizing the solution into a spray apparatus and drying of the atomized solution to a powder using a drying gas. Embodiment 13: A process for producing a spray-dried binder according to Embodiment 12, which comprises the steps of heating the agueous solution provided in step (i) to 50 to 180 °C prior to atomizing the heated solution.

Embodiment 14: A process according to Embodiments 12 and 13, wherein the agueous solu ¬ tion provided in step (i) is heated to 60 to 120 °C prior to atomizing the heated solution.

Embodiment 15: A process according to any of Embodiments 12 to 14, wherein the agueous solution provided in step (i) is heated to 70 to 110 °C prior to atomizing the heated solution. Embodiment 16: A process according to any of Embodiments 12 to 15, wherein a flowability agent is injected into the spray apparatus.

Embodiment 17: A process according to any of Embodiments 12 to 16, wherein the polymer solids content of the spray solution is in the range of from 3 to 25 % b.w..

Embodiment 18: A process according to any of Embodiments 12 to 16, wherein the polymer solids content of the spray solution is in the range of from 5 to 15 % b.w.. Embodiment Ί9: A process according to any of Embodiments 12 to Ί8, wherein the polymer solids content of the spray solution is in the range of from 5 to Ί2.5 % b.w..

Embodiment 20: A process according to any of Embodiments Ί2 to Ί9, wherein the atomiza- tion step (ii) is carried out using pressure nozzles.

Embodiment 2Ί: A process according to any of Embodiments Ί2 to Ί9, wherein the atomiza- tion step (ii) is carried out using two-substance nozzles.

Embodiment 22: A process according to any of Embodiments Ί2 to 2Ί, wherein the tower inlet temperature of the drying gas is in the range of from 100 to 200 °C.

Embodiment 24: A process according to any of Embodiments 12 to 22, wherein the tower outlet temperature of the drying gas is in the range of from 50 to 120 °C.

Embodiment 25: A process to any of Embodiments 11 to 24, wherein the particle size is further adjusted by a sieving step.

Embodiment 26 : A method of manufacturing solid pharmaceutical dosage forms using a finely divided binder in powder form according to any of Embodiments 1 to 24, as a dry- binder for direct compression mixtures.

Embodiment 27: A method of manufacturing solid pharmaceutical dosage forms according to any of Embodiments 1 to 26 wherein the solid pharmaceutical dosage form is a tablet.

Embodiment 28: A method of manufacturing solid pharmaceutical dosage forms according to any of Embodiments 1 to 26 wherein the solid pharmaceutical dosage form is a roller com- pact.

Embodiment 29: A method of manufacturing solid pharmaceutical dosage forms according to any of Embodiments 1 to 27, wherein the resulting tablets show a hardness of 50 to 200 N. Embodiment 30: A method of manufacturing solid pharmaceutical dosage forms using a finely divided dry binder in powder form according to any of Embodiments 1 to 27, as a dry- binder for direct compression mixtures, wherein the proportion of the dry-binder in the direct compression mixture is 5 -15 % b.w..

Examples

Commercial Kollicoat® I R was used as a starting material with weight average molecular weight in the range of 20.000 g/mol (determined by SEC-MALLS, mobile phase: 0,08 mol/l TRIS -buffer pH 7 in water (+0,15 mol/L NaCI); stationary phase: TSK Gel; standard: pullu- lan;Detektor: DRI Agilent 1100)

True density was measured at 23 °C, according to EN ISO 1183-3 (gas pyknometer):

Gas Pyknometer: Micromeritics, Accu Pyc 1340; volume metering chamber 10 cm 3 ; calibration with steel balls.

Prior to the measurement the samples were dried overnight in a vacuum oven (Fa. Heraeus) at 23 °C and 5 hPa.

Measurement was carried out at 23 +/- 0.1 °C and 1.35 MPa, using argon as measurement gas. N umber of specimens tested: three (mass: 2.9782 g; 3.3450 g; 3.2190 g);

Arithmetic mean density: 1.03030 g/ml; standard deviation +/- 0.5 % True density of the graft copolymer known as commercial Kollicoat® I R: 1.03 g/ml, true densi ¬ ties of the inventive products:103 g/ml .

5 Particle sizes: volume averaged particle sizes D[4,3] and the respective median d50 were

measured using a Malvern Mastersizer 2000.

Bulk densities were measured according to EN ISO 60 using a normed funnel.

Ί0 Tablet hardness was measured in accordance with Chapter 2.9.8. of the European Pharmaco ¬ peia 9 using a Sotax HT 100 tablet tester, the tablet hardness being determined successively on 20 tablets with a speed of the test jaw of Ί20 mm/min.

Tablet Disintegration was measured according to Chapter 2.9.Ί. of the European Pharmaco- Ί5 peia 9, Test Method A.

Spray Apparatus:

Products A-D: Niro/Gea Spray Apparatus, Pressure nozzle, diameter 1.2 mm

Product E. Niro Minor, Two-substance nozzle, diameterlO mm

Commercial Kollicoat IR material was used to prepare aqueous solutions with a polymer con ¬ tent of 5, 7.5, Ί0 and 12.5% bw. respectively. 5 Table !:

Products A -D:

The aqueous solutions were heated to 80°C and atomized via three nozzles with a pressure of 0 20 MPa. The throughput of the spray solution was in the range of 800 kg/h. The inlet temper ¬ ature of the drying gas (air) was115 °C, the outlet temperature60 °C.

Product E: The particle characteristics of the resulting powders are listed in Table 2.

Two-substance nozzle diameter 10 mm; Inlet air: Ί20 °C; outlet air 65 °C; feed rate Ί7 g/min; 5 nozzle pressure: 0.4 M Pa Table 2: Powder particle characteristics

Tableting experiments

Table 3: Direct compression mixtures with inventive binders

Dicafos A60: direct compressible anhydrous dicalcium phosphate, bulk density 1300- 1400 g/l, Chemische Fabrik Budenheim

Kollidon ® CL-F: Crospovidone, BASF SE, bulk density 0.18-0.28 g/ml; Particle size sieve frac ¬ tion: more than 95 % < 250 μιτι

In addition, spray product A was sieved to a median particle size d50 of 22 μιτι. and used for the tableting experiments described below. Also , Kollicoat I R powder was milled to the particle size listed in Table 2 and used in a tablet- ing mixture. Milling was carried out using a countercurrent fluidized bed mill AFG 100 (Alpine). Mill settings: 3 nozzles of 1.9 mm diameter; grinding gas pressure of 0.6 Pa; gas throughput 55.0 m 3 /h; 50 mm diameter deflector wheel; rotational speed 8000 rpm; 21 m/s tip speed; 0.7 kg/h product throughput, trial time 20 min; amount of ground product: 5 kg

For comparison: Direct compression mixtures without inventive binder:

Comparative Ex. I:

Dicafos A60 97.0 %

Kollidon CI-F 2.5 %

Mg -stearate 0.5 %

Comparative Ex. I I

Dicafos A60 87.0 %

Kollidon Cl-F 2.5 %

Mg -stearate 0.5 %

Kollicoat® IR 10 %

The direct compression mixtures were pressed to tablet under the following conditions:

The individual components were sieved through a 0.8 mm sieve and then blended in ab tur- bula mixer (T10B) for 8 min. After addition of magnesium stearate the powders were blended for a further 2 min. The resulting powder blends were compressed into tablets on a single punch press (EKO, Korsch) with a punch diameter of 10 mm (biplanar) applying 5, 7.5, 10, 12.5 and 15 kN, respectively.

The tablets were tested for hardness as described above. The results are listed in Table 4.

Table 4

DCM No. Tablet Hardness [N] at different compression forces [kN]

/Spray Prod ¬ 5 kN 7.5 kN 10 kN 12.5 kN 15 KN uct, Particle

Size Distr.

Comp. DCM 1/ n/m n/m 9 13 17

0 %

DCM1, Product 7 18 24 38 50

A, d50 =33μιτι

DCM2, Prod ¬ 12 28 43 62 76 uct A, sieved,

d50=22μm

DCM2, Prod ¬ 10 23 36 51 65 uct A, d50

=33μιτι

DCM3, Prod ¬ 16 34 52 73 91 uct A, sieved,

d50= 22μιτι

DCM3, Prod ¬ 14 35 55 79 104 uct A, d50

=33μιτι

DCM 4, Prod ¬ 22 50 80 107 138 uct A sieved,

d50= 22μιτι

DCM 4, Prod ¬ 15 41 68 82 109 uct A,

d50=33μm

DCM 4, Prod ¬ 14 38 60 90 114 uct B, d50 =

45μιτι

DCM 4, Prod ¬ 22 47 62 71 92 uct C, d50 =

54μιτι

DCM 4, Prod ¬ 17 36 62 97 125 uct D, d50 =

60μιτι

DCM,5 Prod ¬ 35 72 126 155 183 uct A, d50 =

33μιτι

DCM 6, Prod ¬ 63 - 143 - 213 uct A, d50 =

33μιτι DCM 4, Prod ¬ 25 40 68 91 122 uct E, d50 = 6

μηι

Comp. Ex. II / n/m n/m 8 26 37 ά50=106μηη

n/m : not measurable, due to insufficient stability

DCM No. /Spray Disintegration time [s] obtained at different compression forces Product, Particle [kN]

Size Distr. 5 kN 7.5 kN 10 kN 12.5 kN 15 KN

Comp. DCM I/ O n/m n/m 2 3 2

%

DCM1, Product 3 2 6 4 5 A, d50 =33μιτι

DCM2, Product 9 14 12 10 11 A, sieved,

d50=22μm

DCM2, Product 6 9 10 11 9 A, d50 =33μιτι

DCM3, Product 25 21 21 21 25 A, sieved, d50=

22μιτι

DCM3, Product 18 15 11 14 20 A, d50 =33μιτι

DCM 4, Product A 56 52 83 127 228 sieved, d50=

22μιτι

DCM 4, Product 20 25 21 23 40 A, d50=33μm

DCM 4, Product 16 17 14 18 23 B, d50 = 45μΓη

DCM 4, Product 13 13 16 13 15 C, d50 = 54μΓΠ

DCM 4, Product 9 7 12 15 18 D, d50 = 60μΓη

DCM4,Product E, 11 14 15 13 17 d50= 58μm

DCM 5, Product 53 96 258 269 466 A, d50 = 33μm

DCM 6, Product 279 nd 600 nd 749 A, d50 = 33μιτι

DCM 4, Product 23 29 25 23 31 E, d50 = 6 μm DCM 4, Kollicoat 27 33 21 22 31 IR milled, d50=15

μιτι

Comp. Ex. II / nd nd 5 4 5 ά50=106μηη

Nd: not determined, tableting not possible