Process for producing a granulate and a granulate, in particular a granulated compound of excipients

Description

1 / 17 PROCESS FOR PRODUCING A GRANULATE AND A GRANULATE, IN PARTICULAR A GRANULATED COMPOUND OF EXCIPIENTS

[001] Process for the production of a granulate, comprising the steps of a) preparing a granulation liquid, comprising the steps of i) subjecting a liquid comprising a binder, ii) adding an organic or inorganic filler to the liquid comprising a binder, iii) obtaining a granulation liquid, and b) preparing a granulation base by i) mixing an inorganic filler selected from a weight increaser, inorganic salt and an inorganic buffer material, a carrier material, a disintegrant, an inorganic filler, and an anti-caking intensifier, in particular dry mixing, and obtaining the granulation base, and c) preparing the granulation composition by i) contacting, in particular spraying or pouring, the granulation liquid with the granulation base and obtaining a granulation mixture comprising a liquid, and followed by d) sieving and / or extruding the wet granulation mixture comprising liquid,(ee) subjecting the granulation mixture comprising a liquid to a drying process and obtaining the granulation composition. Furthermore, the granulate obtained and a granulate, as well as the use and a kit comprising the granulate, are claimed.

[002] There is a need for more compounds for the production of MUPS tablets. Tablets with MUPS properties are defined, for example, in document no. WO 2020221522A1. The abbreviation MUPS refers to a Multi-Unit Pellet System. Compounds for the production of MUPS tablets may be in the form of pellets, granules or extrudates with sufficient hardness properties, wherein each pellet, granule or extrudate may be coated for a delayed or sustained release such as targeting to the colon. A matrix particle in each form described may also be used. A typical MUPS tablet comprises several compressed functional particles, here compounds in the form of a pellet, granule or extrudate. The particles may be compressed into a mixture Petition 870250087414, dated 09 / 26 / 2025, page 5 / 76 2 / 17 with powdered excipients, such as disintegrants, fillers, etc. The pellets that make up an API (active pharmaceutical ingredient) are usually coated to determine the location after swallowing the tablet, the speed and timing of the release of the active ingredient. Typically, the tablet is released in the stomach in individual pellets by digestive secretion. A particular advantage of coated pellets, in contrast to conventional coated tablet formulations, is that there is no immediate release of the entire active ingredient after possible damage to the coating.

[003] Consequently, the risk of toxic effects due to overdose is avoided. Due to the different coating options for the individual pellets and their mixing, it is possible to process functional particles with different release kinetics into one dosage form. Another advantage of the MUPS formulation is the shorter time period; several small units can reach the site of action or reabsorption in the gastric intestinal tract. Due to the disintegration of the MUPS formulation after ingestion in the stomach and release into several small functional units, passage through all stages of fat absorption is faster compared to a single unit such as a tablet.

[004] Document no. WO 2010031866A1 discloses a pellet composition and a process for its production. The pellet formulation comprises aqueous lactose as a granulation liquid sprayed onto HPMC and lactose particles. The weight ratio of lactose to HPMC is 50:50 or 40:60. The resulting pellets have a particle size of 10 mm to 25 mm. The granulate is obtained from the granulation composition after drying without further treatment. The patent application further discusses flowability, packed density, and apparent density.

[005] Document No. US 6,770,368B2 discloses spherical granules consisting of spray-dried lactose and granular starch in the ratio of 90 to 10 and 25 to 75. Friability is less than or equal to 80%, according to test A mentioned in the patent.

[006] A MUPS tablet comprises several pellets of different Petition 870250087414, dated 09 / 26 / 2025, page 6 / 76 3 / 17 compositions. Due to their good flowability, it is difficult to obtain and maintain a homogeneous composition of pellets during storage, mixing, and during compression of the composition into tablets. Therefore, there is a need for pellets, granules, or extrudates that can increase the maintenance of homogeneity after mixing, during the storage period of the process, and during compression or compaction, preventing segregation. Furthermore, a composition and a process are needed for the production of a granulate comprising pellets that can mechanically and / or chemically stabilize a homogeneous mixture after mixing.

[007] The problems are solved by a process of the present invention and by the composition of the present invention. The object of the invention is therefore a process for the production of a granulate, in particular comprising excipients, preferably a placebo granulate, comprising the steps of a) preparing a granulation liquid, comprising the steps of i) subjecting a liquid comprising a binder, ii) adding an organic or inorganic filler, preferably an organic filler, in particular lactose and / or potato starch, to the liquid comprising a binder iii) obtaining a granulation liquid, b) prepare a granulation base by (i) Mixing an inorganic filler selected from a weight increaser, inorganic salt and an inorganic buffer material, in particular pentacalcium tris(orthophosphate) hydroxide or calcium sulfate, a carrier material, a disintegrant, an inorganic filler selected from metallic oxide and / or semi-metallic oxide, and an anti-caking intensifier, in particular dry mixing, and obtaining the granulation base, and optionally c) prepare the granulation composition by (i) to bring the granulation liquid into contact with the granulation base, in particular by spraying or pouring, and to obtain a granulation mixture comprising liquid, Petition 870250087414, dated 09 / 26 / 2025, page 7 / 76 4 / 17 d) sieve and / or extrude the wet granulation mixture comprising liquid, and optionally (e) subject the granulation mixture comprising a liquid to a drying process and obtain the granulation composition.

[008] The granulation liquid may be a suspension, dispersion or aqueous solution. The binder of the granulation liquid may include corn starch as an excipient. An organic filler may include lactose, in particular lactose monohydrate and anhydrous lactose, potato starch or corn starch, an inorganic filler, in particular calcium hydrogen sulfate, as excipients or a mixture comprising at least two of the above-mentioned excipients.

[009] A preferred granulation liquid a) may comprise, in particular as excipients, 2 to 15% by weight of binder, in particular corn starch, and 2 to 15% by weight of at least one organic filler, including in particular lactose, potato starch, or an inorganic filler, or comprises in particular calcium hydrogen sulfate, or a mixture including at least two of the aforementioned excipients, and a liquid, wherein the granulation liquid totals 100% by weight, and wherein the granulation base b) may comprise, in particular as excipients, 20 to 40% by weight of inorganic filler selected from a weight increaser, inorganic salt and an inorganic buffer material, preferably pentacalcium tris(orthophosphate) hydroxide synonymous with pentacalcium tris(orthophosphate) hydroxide or calcium sulfate, and 35 to 55% by weight of material carrier, in particular microcrystalline cellulose, 5 to 20% by weight of disintegrant, in particular corn starch,and 1 to 7% by weight of inorganic filler, in particular silicon dioxide, wherein the total granulation composition is 100% by weight.

[010] The inorganic salt comprises, in particular, an inorganic cation and an inorganic anion. A preferred inorganic feedstock selected from a bulking agent, inorganic salt and buffer material is pentacalcium tris(orthophosphate) hydroxide or calcium sulfate, inorganic phosphate buffer and / or carbon dioxide silicate buffer. As a carrier material, it can Petition 870250087414, dated 09 / 26 / 2025, page 8 / 76 5 / 17 Microcrystalline cellulose can be used, and corn starch can be used as the disintegrant or disintegrating material. The inorganic filler can be selected from metal oxide and / or semi-metallic oxide, such as silicates, quartz, silicon dioxide, colloidal silicon dioxide, and / or magnesium oxide. Aerosil® 200 is preferred.

[011] Microcrystalline cellulose can be used as a carrier material, as well as other cellulose materials, such as cellulose derivatives whose hydroxyl groups are independently of each other at least partially alkylated, hydroxyalkylated, sulfonated, carboxyalkylated and / or xanthogenized. In particular, the carrier material may comprise at least one cellulose derivative selected from the group consisting of hypromellose (HPMC), hypromellose phthalate, hydroxypropylcellulose (HPC), hydroxyethylcellulose, ethylcellulose (EC), carboxymethylcellulose (CMC), carboxyethylcellulose (CEC) and / or sodium and / or calcium salts thereof.

[012] The granulation composition may also include additional excipients which are selected from the group consisting of lubricants, fillers, binders, anti-adherents, flow regulators, antistatic agents, solubilizers and wetting agents.

[013] In a preferred embodiment, the inorganic charge a) ii) is different from the inorganic charge or charges b) i).

[014] In addition, the process may comprise the step in which the granulation liquid is sprayed or poured onto the granulation base, in particular the granulation liquid is sprayed or poured onto the granulation base in a mixing device, in particular a rotary mixing device comprising a blade, more preferably a paddle, wherein i) the mixing device comprises a mixing tool, chopper, mixing housing and a cover for the housing, wherein the mixing tool has a rotor shaft that is guided through the cover or preferably through the bottom, wherein the mixing tool further has at least one extending mixing arm, in particular Petition 870250087414, dated 09 / 26 / 2025, page 9 / 76 6 / 17 perpendicularly from the rotor axis, wherein the arm has on its outer part a blade, in particular a paddle, in particular wherein the blade, in particular the paddle, is directed upwards or ii) the mixing device comprises a mixing housing and a cover for the housing and a mixing tool, wherein the mixing tool has a rotor shaft that extends through the bottom of the housing, wherein the mixing tool has at least one mixing arm that extends, in particular perpendicularly, from the rotor axis, wherein the arm is a blade, in particular a paddle, in particular wherein the blade is on one of its long rotating edges directed upwards, in particular the device has at least three arms that are a blade, wherein each blade is on one of its long rotating edges directed upwards.Alternatively, the mixing device may comprise a rotating housing with blades or paddles fixed to the inside of the housing. The housing may preferably rotate horizontally. Alternatively, a custom-ordered horizontal mixing unit may be used.

[015] Granulation is preferably carried out with a sieve insert, which provides on the inner side of the insert a larger cross-section of the opening than the cross-section of the opening on the outer side. The cross-section of the opening on the inner side of the insert is particularly 10% larger than the cross-section on the outer side, more preferably 15% larger.

[016] According to another object of the invention, step d) may comprise the wet sieving granulation step of the granulation mixture comprising liquid, wherein the wet sieving granulation may be carried out with a sieve insert comprising a perforated insert, perforated plate, perforated cone, wherein the sieve insert has an inner side and an outer side, wherein the perforation of the outer side is not identical to the perforation of the inner side. It is preferable that the perforation of the insert comprises a triangular, semi-elliptical or triangular to semi-elliptical perforation, in particular the perforation of the insert having an inclined opening and / or Petition 870250087414, dated 09 / 26 / 2025, page 10 / 76 7 / 17 conical in the direction of passage. A sieve insert may be selected from CONIDUR®. Non-preferred sieve inserts comprise round perforation with identical inner and outer sides of the sieve insert perforation.

[017] In particular, the mesh size or cross-section of the hole is from 0.8 to 3 mm. Preferred granules may be obtained by sieving the granulation mixture comprising liquid through the sieve insert with a visual appearance comprising cylindrical granules, bar-shaped granules and / or biscuit crumb-shaped granules.

[018] The rotor speed of the wet screening granulation device, as well as the feed speed of the granulation mixture containing liquid, can be adjusted to the expected visual aspect of the particles and the specific sieve element.

[019] According to another aspect of the invention, the process may include a drying step (e) comprising fluidized bed drying or infrared drying, in particular batch drying or continuous drying. Drying may also be carried out in a cyclone mixing system, for example, from the Hüttlin company. Fluidized bed drying or infrared drying is preferred as the focus of the process to prevent the particles from being worn down into smaller particles or powder. In particular, the drying step is carried out in more than one stage, in particular the drying is carried out in a cascade control, to avoid reducing or altering the shape and / or size of the particle. The granulate of the invention may be composed, in particular in the form of a pellet with a flattened surface, more preferably in the form of a biscuit crumb.The production steps for preparing the granule according to the present invention are suitable for easy scaling up if this product is implemented for large quantities.

[020] The object of the invention is also a granulate, preferably comprising the following excipients: 3 to 15% by weight of binder, in particular corn starch, 3 to 15% by weight of organic filler, in particular containing lactose or potato starch, or an inorganic filler, in particular Petition 870250087414, dated 09 / 26 / 2025, page 11 / 76 8 / 17 calcium hydrogen sulfate, 20 to 70% by weight of inorganic filler selected from a bulking agent, inorganic salt and an inorganic buffer material, in particular pentacalcium tris(orthophosphate) hydroxide or calcium sulfate as a bulking agent, and optionally 30 to 70% by weight of carrier material, in particular microcrystalline cellulose, and optionally 5 to 25% by weight of disintegration material, in particular corn starch, and optionally 1 to 10% by weight of inorganic filler selected from metal oxide and / or semimetal oxide, in particular silicon dioxide, preferably silicon dioxide with a particle size of 10 nm to 100 nm, more preferably silanized silicon dioxide particles, the composition of the granule composition totaling 100% by weight.

[021] A preferred granulate, more preferably a final granulate, may comprise granules with at least two different diameters, in particular with three different diameters. Diameter a) may be from 500 pm to 800 pm, diameter b) may be from 1000 pm to 1300 pm and, optionally, diameter c) may vary from 1500 pm to 2000 pm, wherein all diameters are perpendicular to all other diameters.

[022] The granules may also consist of granules with a visual appearance of elliptical granules, bar-shaped granules and / or bicuspid granules. Particularly preferred is a granule comprising surface-modified granules. It is particularly preferred that the surface of the granules be coated with at least one polymer, in particular with a polymer containing HO-, N-, NH-, CO- and / or COO- groups, or modified with at least one surfactant or at least one other polymer capable of polycondensation and / or polymerization. The polymer may include olefinic cellulose derivatives, methacrylic and / or acrylic derivatives. The surface polymer comprising HO-, N-, NH-, CO-, and / or COO- groups of the granules can bind to other HO-, N-, NH-, CO-, and / or COO- groups of polymers in neighboring granules, forming strong hydrogen bonds in a preferred supramolecular network that stabilizes the obtained position of the specific granules in a composition. Petition 870250087414, dated 09 / 26 / 2025, page 12 / 76 9 / 17 homogeneous granules. Therefore, the homogeneity of a composition can be chemically stabilized by a surface coating of the granules with polymers that are capable of forming hydrogen bonds with polymers that are a surface coating on neighboring granules in a composition.

[023] After the drying process, dry sieving can be carried out to select the particle sizes. A preferred sieve comprises a rotating or oscillating horizontal sieve, in particular a pressure sieve or a screen.

[024] The surface of the granules with a rough surface remains after the drying process, which can be seen in Figure 1. The rough surface of the granules results from the specific wet sieving process. Furthermore, the object of the invention may also be a granulate comprising, in particular, the following excipients: 5 to 10% by weight of binder, in particular corn starch, 5 to 10% by weight of organic filler, in particular including lactose or potato starch or an inorganic filler, in particular calcium hydrogen sulfate, 20 to 50% by weight of inorganic filler selected from a bulking agent, inorganic salt and an inorganic buffer material, in particular pentacalcium tris(orthophosphate) hydroxide or calcium sulfate as a bulking agent, and optionally 30 to 50% by weight of carrier material, in particular microcrystalline cellulose, and optionally 5 to 20% by weight of disintegrant material, in particular corn starch,and optionally 1 to 10% by weight of inorganic filler selected from metal oxide and / or semimetal oxide, in particular silicon dioxide, preferably silicon dioxide with a particle size of 10 nm to 100 nm, more preferably silanized silicon dioxide particles, the total granule composition being 100% by weight. Suitable silicon dioxides are commercially available under the trade names Aerosil 200® and Sipernat® FP 244. The particle size can be determined by sieving.

[025] According to another aspect of the invention, the use of granules obtained according to the process or granules is claimed, wherein the granules Petition 870250087414, dated 09 / 26 / 2025, page 13 / 76 10 / 17 are used as an excipient compound for tablet compression, in particular as an excipient compound for direct tablet compression, preferably among other universal applications for rapid disintegration and / or oral dispersion dosages, application to waxy and oily substrates and controlled-release formulation or matrix formulation, most preferably in pharmaceutical compositions, food compositions, beverage compositions, supplement compositions, hygiene compositions, dental cleaning or pool compositions as a tablet compression compound.

[026] In addition, a kit is claimed comprising the granules obtained according to the process of the invention or granules of the invention in a container, wherein the container comprises a measuring element that allows the dispensing of a predefined quantity of granules from the container. MODALITIES OF MEASURING DEVICES AND TECHNIQUES:

[027] A Heittlin Mixing-Granulation or a Glatt System comprises a mixing device, a mixing housing and a cover for the housing, wherein the mixing tool has a rotor shaft that is guided through the cover or bottom, wherein the mixing tool further has at least one mixing arm that extends perpendicularly to the rotor shaft, wherein the arm has on its outer part a blade, wherein the blade is directed upwards. In addition, a chopper is preferably installed through the wall of the mixing housing.

[028] Alternatively, the mixing device (Dinosa) comprises a mixing housing and a cover for the housing and a mixing tool, wherein the mixing tool has a rotor shaft at the bottom of the housing, wherein the tool has three mixing arms extending perpendicularly from the rotor shaft, wherein the arm is a paddle, which is on one of its long rotating edges directed upwards. In addition, a chopper is preferably installed through the wall of the housing. Petition 870250087414, dated 09 / 26 / 2025, p. 14 / 76 11 / 17 mixture. SYNTHESIS OF GRANULE SAMPLES GRANULE SYNTHESIS EXAMPLE 1: PREPARATION OF THE GRANULATION COMPOUND COMPOSITION OF GRANULES FOR RAPIDLY DISINTEGRATING TABLETS: 6.41% by weight of corn starch 5.13% by weight of filler comprising lactose or potato starch. 29.61% by weight of pentacalcium tris(orthophosphate) hydroxide or calcium sulfate as a bulking agent. 46.16% by weight of microcrystalline cellulose as carrier material, 10.97% by weight of corn starch as disintegrant material, 1.74% by weight of Aerosil 200® GRANULATION LIQUID:

[029] A liquid comprising 10% by weight of corn starch in water was prepared (C* PharmaGel 03406, 10% aqueous). To this liquid, 8.0% by weight of a filler comprising lactose or potato starch was added. The resulting granulation liquid comprises 10.0% by weight of corn starch, 8.0% by weight of potato starch or lactose, and water to 100% by weight of the granulation liquid composition.

[030] In the case of corn starch, a pregelatinized version of the starch type may be used. Granulation base:

[031] The granulation base contains 29.61% by weight of pentacalcium tris(orthophosphate) hydroxide or calcium sulfate as a weight increaser and 46.16% by weight of microcrystalline cellulose in parts of Avicel PH 105 and PH 102 as carrier material, 10.97% by weight of corn starch as a disintegration / filler material and 1.73% by weight of Aerosil 200®.

[032] The granulation liquid and the granulation base were mixed 1:1 by weight. Petition 870250087414, dated 09 / 26 / 2025, page 15 / 76 12 / 17 EXAMPLE 2: PREPARATION OF THE GRANULATION COMPOUND COMPOSITION OF GRANULES FOR ORAL DISPERSIBLE TABLETS: 6.27% by weight of corn starch 5.01% by weight of filler comprising lactose or potato starch. 28.93% by weight of pentacalcium tris(orthophosphate) hydroxide or calcium sulfate as a bulking agent. 45.13% by weight of microcrystalline cellulose as carrier material, 10.72% by weight of corn starch as disintegrant material, 3.95% by weight of Aerosil 200® GRANULATION LIQUID:

[033] A liquid comprising 10% by weight of corn starch in water was prepared (C* PharmaGel 03406, 10% aqueous). To this liquid, 5.0% by weight of a filler comprising lactose or potato starch was added. The resulting granulation liquid comprises 10.0% by weight of corn starch, 8.0% by weight of potato starch or lactose and water, and 100% by weight of the granulation liquid composition. In the case of corn starch, a pre-gelatinized version of the starch type may be used. GRANULATION BASE:

[034] The granulation base contains 28.93% by weight of pentacalcium tris(orthophosphate) hydroxide or calcium sulfate as a weight increaser and 45.13% by weight of Avicel PH 105 microcrystalline cellulose as a carrier material, 10.72% by weight of corn starch as a disintegration / filler material and 3.95% by weight of Aerosil 200®. The granulation liquid and the granulation base are mixed 1:1 by weight. COMPARATIVE EXAMPLE 1: PREPARATION OF THE GRANULATION COMPOUND GRANULE COMPOSITION FOR FORMULATING DIRECTLY COMPRESSIBLE COMPRESSED MATRIX: 81.63% by weight of the composition of granules for disintegrating tablets Petition 870250087414, dated 09 / 26 / 2025, page 16 / 76 13 / 17 quick: 6.12% by weight of non-stick talc 12.25% by weight of methacrylic ester copolymer or dry ammonium alkyl methacrylate copolymer. The application of the polymer may be increased / decreased depending on the solubility of the API and / or the delay time. EXAMPLE 3:

[035] 81.63 % by weight of final granules from example 1 with a particle size of 500 µm are used to apply the functional polymer in a fluidized bed coating apparatus. Coating Liquid

[036] 12.25% by weight of methacrylic ester copolymer dry polymer (EUDRAGIT® NM 30 D) 6.125% by weight of talc

[037] Water adds 20% of the solid content of the spray suspension. COMPARATIVE EXAMPLES

[038] Formulation tests for comparison of manufacturing and properties of the final tablet.

[039] Competing market products for easy use or direct formulation by mixing with an API were tested in comparison with the granules of Examples 1 and 2.

[040] The ready-to-use products were mixed with 50% caffeine as a model substance.

[041] Caffeine was chosen because it is a micronized powder with high solubility in acid and buffers to indicate one of the worst cases.

[042] The competing products used for comparison testing were: • Firmapress from LFA company • Combilac from Meggle company (patented under document no. EP 1175899 B1) • Prosolv from JRS company

[043] All examples and comparative examples were compressed in a single-puncture tablet compression machine (Korsch XP1). Petition 870250087414, dated 09 / 26 / 2025, page 17 / 76 14 / 17

[044] The compressive strength differs from product to product between 12-25 kN to achieve adequate hardness.

[045] The compression speed was adjusted to 10000 tablets / h.

[046] The punch size is 10 mm.

[047] The resulting tablet height with the different products differs when comparing products, depending on the product supplier and the required compression force of 0.205 mm.

[048] The target weight was the same. ANALYTICAL EQUIPMENT:

[049] Texture Analyzer. This equipment was chosen in comparison with a disintegration tester. The Texture Analyzer provides more reliable data for comparing rapidly disintegrating tablets. The results are documented with a decomposition diagram and video documentation for visual comparison of test takers. TEST RESULTS: 1) FIRMAPRESS FROM LFA COMPANY

[050] It is relatively compressible, but the tablet does not disintegrate for very long.

[051] Therefore, it is not intended for rapid disintegration without adding a rapidly disintegrating excipient. 2) COMBILAC FROM THE COMPANY MEQQLE (PATENTED IN DOCUMENT NO. EP 1175899 B1)

[052] It disintegrates as quickly as the granules of Example 1 in 60 ml of warm water, but has a strong tendency to stick to the punches and would therefore be unsuitable for production without modification. Therefore, there are no ready-to-use tablet granules. Furthermore, this mixture flows poorly in the tablet press and therefore causes weight deviations. The tablets accumulate on the tablet chute of the tablet press due to poor sliding properties. 3) PROSOLV OF THE COMPANY JRS Petition 870250087414, dated 09 / 26 / 2025, page 18 / 76 15 / 17

[053] It flows very poorly in the tablet press and the tablet hardness is not sufficient for acceptable further processing, i.e. possibly coating, packaging, etc. The pressed tablets disintegrate very quickly, they would be usable for an ODT. 4) Granules from Example 1

[054] The granule in Example 1 provides a rapidly disintegrating tablet. The flowability in the tablet press is stable. The granule is easily compressible with low compression forces.

[055] The granules from example 1 can be used ready for use by future customers. 5) Granules from Example 2

[056] The granule of Example 2 provides a tablet that disintegrates rapidly in about 10 seconds, which is suitable for ODT formulation. The fluidity in the tablet press is kept constant by the addition of 0.5% Mg stearate. The granule is easily compressible with low compression forces. 6) Granules from Example 3 Production Equipment

[057] The product was compressed in a single-puncture tablet compression machine (Korsch XP1).

[058] The compression speed was adjusted to 10000 tablets / h.

[059] The punch size is 10 mm ANALYTICAL EQUIPMENT:

[060] Dissolution Test Apparatus DESCRIPTION OF THE TEST:

[061] The granule of Example 3 is a further evolution of the granules of Example 1 by an additional process step in which the granules are processed with a sustained-release polymer to obtain a matrix granule that can be used for matrix tablets simply by adding an arbitrary API. The granule contains 15% functional polymer by weight of the granule. In the compression test of a tablet, caffeine was used as Petition 870250087414, dated 09 / 26 / 2025, page 19 / 76 16 / 17 model substance with 50% caffeine content in the final pharmaceutical form. This resulted in a polymer content of 7.5% in the final pharmaceutical form.

[062] This tablet granule / caffeine mixture is easy to compress with low compression forces.

[063] In this form of formulating a matrix tablet, there is no need to treat the API with a functional polymer first, potentially with the tablet mass, before it is formulated into a matrix system. This system preserves potentially sensitive API against impacts from water or organic liquid.

[064] The result of the dissolution can be seen in Figure 2. 7) Formulation of Granules from Example 1 for Available Tablet Production Equipment

[065] The product was compressed in a single-puncture tablet compression machine (Korsch XP1).

[066] The compression speed was adjusted to 10000 tablets / h.

[067] The punch size is 10 mm. TEST OBJECTIVE

[068] The need to compress solidified omega-3 acids is to avoid oily surfaces and obtain easy compression processes. Due to the seams of the product upon reliquefaction, which impact compression forces in tablet presses, there is a need to use a tablet mass that is able to adsorb the liquefied portion without significantly affecting the active content upon release. DESCRIPTION OF THE TEST:

[069] The granules from Example 1 are blended with AvailOM in a weight ratio of 1:1. This is compacted in a single punch tablet press.

[070] The tablets do not have significant oily surfaces. The mixture is easy to compress with low compression force. Petition 870250087414, dated 09 / 26 / 2025, page 20 / 76 17 / 17 ANALYTICAL RESULTS:

[071] The tablets disintegrate within 30 minutes in 1 N HCl. THEORY ANALYSIS

[072] Storage time of fresh tablets 1 month under room conditions.

[073] 6 samples tested.

[074] EPA content: 11.98% (12.07% / 12.15% / 11.92% 11.85% / 11.81% / 12.08%)

[075] DHA content: 9.17% (9.24% / 9.30% / 9.13% / 9.06% / 9.04% / 9.26%) DESCRIPTION OF THE FIGURES Figure 1: Image of the granules after drying. Figure 2: Results of the dissolution of the granules from Example 3 Petition 870250087414, dated 09 / 26 / 2025, page 21 / 76

Claims

1 / 5 CLAIMS 1. PROCESS FOR THE PRODUCTION OF A GRANULATE comprising the steps a) preparing a granulation liquid, comprising the steps i) subjecting a liquid comprising a binder, ii) adding an organic or inorganic filler or a mixture thereof to the liquid comprising the binder, iii) obtaining a granulation liquid, b) preparing a granulation base i) mixing - an inorganic filler selected from a weight increaser, inorganic salt and an inorganic buffer material, - a carrier material; - a disintegrant, and - an inorganic filler selected from metal oxide and / or semi-metallic oxide and obtaining the granulation base, c) preparing the granulation composition i) contacting the granulation liquid with the granulation base and obtaining a granulation mixture comprising liquid, d) sieving the granulation mixture comprising liquid,(ee) subjecting the granulation mixture comprising liquid to a drying process and obtaining the granulation composition, characterized in that the granulation liquid a) comprises 2 to 15% by weight of corn starch as a binder and 2 to 15% by weight of lactose or potato starch as an organic filler or calcium hydrogen sulfate as an inorganic filler or a mixture comprising at least two of the aforementioned excipients, and a liquid, in which the granulation liquid totals 100% by weight, and the granulation base b) comprises 20 to 40% by weight of hydroxide. Petition 870250087414, dated 09 / 26 / 2025, page. 22 / 76 2 / 5 tris(orthophosphate) pentacalcium or calcium sulfate as inorganic filler, 35 to 55% by weight - 30% microcrystalline cellulose as carrier material and 5 to 20% by weight corn starch as disintegrant, and 1 to 7% by weight silicon dioxide as additional inorganic filler, wherein the granulation composition is 100% by weight.

2. PROCESS, according to claim 1, wherein the granulation liquid is sprayed or poured onto the granulation base, in particular the granulation liquid is sprayed onto the granulation base in a mixing device, characterized by i) the mixing device comprising a mixing tool, chopper, mixing housing and a cover for the housing, wherein the mixing tool has a rotor shaft that is guided through the cover or bottom, wherein the mixing tool further has at least one mixing arm extending, in particular perpendicularly, from the rotor shaft, wherein the arm has on its outer part a blade, in particular a paddle, wherein the blade, in particular the paddle, is directed upwards or ii) the mixing device comprises a mixing housing and a cover for the housing and a mixing tool, wherein the mixing tool has a rotor shaft extending through the bottom of the housing,wherein the mixing tool has at least one mixing arm extending, in particular perpendicularly, from the rotor axis, wherein the arm is a blade, in particular a paddle, in particular wherein the blade is facing upwards on one of its long rotating edges, in particular the device has at least three arms that are blades, wherein each blade is facing upwards on one of its long rotating edges.

3. PROCESS, according to any one of claims 1 or 2, characterized by step d) comprising the wet sieving granulation step of the granulation mixture comprising liquid, wherein the wet sieving granulation is carried out with a sieve insert comprising a perforated insert, perforated plate, perforated cone, wherein Petition 870250087414, dated 09 / 26 / 2025, page 23 / 76 3 / 5 the sieve insert has an inner side and an outer side, wherein the perforation of the outer side is not identical to the perforation of the inner side, in particular the perforation of the insert comprises a triangular, semi-elliptical or triangular to semi-elliptical perforation, in particular having an inclined and / or conical opening in the direction of passage.

4. PROCESS, according to any one of claims 1 to 3, characterized in that, in step (e), the drying process comprises the fluidized bed drying or infrared drying step, in particular batch drying or continuous drying, cascade drying more preferably.

5. GRANULES characterized by being produced, in particular, as defined in any one of claims 1 to 4, comprising 3 to 15% by weight of corn starch as a binder, and 3 to 15% by weight of lactose or potato starch as an organic filler or calcium hydrogen sulfate as an inorganic filler or a mixture thereof, and 20 to 70% by weight of pentacalcium tris(orthophosphate) hydroxide or calcium sulfate as an inorganic filler, and 30 to 70% by weight of microcrystalline cellulose as a carrier material and 5 to 25% by weight of corn starch as a disintegrating material, and 1 to 10% by weight of silicon dioxide as an inorganic filler, wherein the composition of the granule composition is 100% by weight.

6. Granulated, according to claim 5, characterized in that the silicon dioxide has a particle size of 10 nm to 100 nm.

7. Granulated, according to any one of claims 5 or 6, characterized in that the silicon dioxide particles are silanized.

8. Granules, according to any one of claims 5 to 7, characterized in that the granules comprise granules with at least two different diameters, in particular with three different diameters.

9. GRANULATED PRODUCT, according to any one of claims 5 to 8, Petition 870250087414, dated 09 / 26 / 2025, page 24 / 76 4 / 5, characterized in that the granulated product comprises granules that have a visual appearance of cylindrical granules, bar-shaped granules and / or biscuit crumb-shaped granules.

10. GRANULES, according to any one of claims 5 to 9, characterized in that the granules comprise surface-modified granules, in particular the surface of the granules is coated with at least one polymer, in particular with a polymer comprising HO-, N-, NH-, CO- and / or COO- groups, or modified with at least one surfactant or at least one other polymer capable of polycondensation and / or polymerization.

11. GRANULES, according to any one of claims 5 to 9, characterized in that the granules comprise 5 to 10% by weight of corn starch and 5 to 10% by weight of lactose or potato starch or calcium hydrogen sulfate or a mixture thereof, and 20 to 50% by weight of pentacalcium tris(orthophosphate) hydroxide or calcium sulfate, and 30 to 50% by weight of microcrystalline cellulose and 5 to 20% by weight, namely corn starch, and 1 to 10% by weight of silicon dioxide, wherein the composition of the granule composition is 100% by weight.

12. USE characterized by being of the obtainable granules, as defined in any one of claims 1 to 4, or of the granules, as defined in any one of claims 5 to 11, as an excipient compound for compression, in particular as an excipient compound for direct compression, most preferably in pharmaceutical compositions, food compositions, beverage compositions, supplement compositions, hygienic compositions, compositions for dental or pool cleaning as a compression compound.

13. A KIT characterized by comprising obtainable granules, as defined in any one of claims 1 to 4, or granules, as defined in any one of claims 5 to 11, in a container with a measuring element that allows the dispensing of a predefined quantity of granules from the container.

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