EP4695330A1

EP4695330A1 - Porous starch

Info

Publication number: EP4695330A1
Application number: EP24717233.1A
Authority: EP
Inventors: Harald Keller; Sung Min Pyo; Matthias KELLERMEIER; Karl Kolter; Felicitas Guth; Matthias Karl
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2023-04-14
Filing date: 2024-04-12
Publication date: 2026-02-18
Also published as: CN120936668A; WO2024213755A1

Abstract

Present invention is about improving flowability and compressibility (tensile strength) of starch, enhancing the porosity of the starch particles by using enzymes and using the porous starch particles for direct compression of tablets.

Description

Description Porous starch Starch has a long history of use as an excipient in pharmaceutical dosage forms. Native starch, for example corn starch, is white or off-white, odor- and tasteless and is one of the most widely used filler/ binder in tablet manufacturing. This biomaterial has unique physicochemical and functional characteristics, as well as various advantages such as low price, relative ease of isolation in pure form from plant source, non-toxicity, biodegradability, good biocompatibility, non-hygroscopicity, inert (no pharmacological activity) and no interaction with living cells. Native starch is used as filler/diluent, binder and disintegrant in tablet formulation. It has only acceptable compressibility, very poor flowability and shows elastic recovery that leads to capping and lamination of tablets. Therefore, starches are typically not used in direct compression which is the preferred route for efficient and cost- effective tablet manufacturing. Particularly for a higher content of active ingredient or when using active ingredients with poor compression properties, a wet granulation step is needed for starch-based formulations. Various physically and chemically modified starches have been presented as direct compression excipients for tablet formulation (Lawal, M.V.: Modified Starches as Direct Compression Excipients – Effect of Physical and Chemical Modifications on Tablet Properties: A Review. Starch – Stärke 2019, 71 DOI OI: 10.1002/star.201800040). WO2021195216 discloses inhibited porous granular starch products which includes hydrolyzing a granular starch feed using one or more enzymes. Lacerda et al. described the synthesis of porous rice starches and dependence of physical properties on enzymatic hydrolysis conditions. (Liziane D. Lacerda, Daiani C. Leite, Nádya P. da Silveira, Journal of Cereal Science, Volume 89, 2019, 102819.). WO2013017388-A1 discloses encapsulation of anionic or cationic pesticides with porous starch granulate. These products typically show an improved tabletability compared to native starches. One such modified starch is STARTAB® (Colorcon) a grade for direct compression and with high flowability and compressibility. For high dose formulations and difficult to formulate actives, typically additional fillers/ dry binders have to be added for an optimal performance of the formulation. Another modified starch is N-Zorbit that is manufactured by partial hydrolysis designed as plating agent with a high absorption capacity for liquid actives. N-Zorbit has a porous and granular structure and therefore an ability to carry high flavor concentrations. Another route to increase the tableting performance of native starch is to combine it with other excipients in so called “co-processed” excipient formulations. Such co-processed excipients combine individual excipients in a physical form without a significant chemical change to obtain a synergistic functional performance. An example for a starch-based excipient is StarLac® (Meggle, Germany) comprising 85% alpha-lactose monohydrate and 15% native corn starch. This excipient combines lactose (a typical filler for direct compression) with starch that contributes the binding and disintegrating property. Such co-processed excipients exhibit a performance in tableting that cannot be achieved with a simple physical mixture of the ingredients. The present invention relates to porous starch particles characterized by physicochemical parameters, which are nitrogen sorption, particle size and determination of ∆p, which is the permeability of the packed starch materials. At least one parameter should be met by the enzyme-treated starch. Preferred is a combination of two parameters, even more preferred is a combination of all three parameters which should be met by the enzyme-treated starch. The invention is further directed to the use of enzymatically hydrolyzed porous starch particles with a high inter- particulate porosity, a large specific surface area, an improved flowability and -as a result- improved tableting performance. Powder flowability is improved, by a spray drying or spray agglomeration step. The individual particles are modified by the partial enzymatic hydrolysis so that they exhibit significantly tabletability compared to the starches known from the prior art. Even though tablets made of this porous starch have a surprisingly high tensile strength, disintegration times remain low as it is common for starches. Due to that property, it is possible to formulate rapidly disintegrating tablets enabling a quick onset of action of the active ingredient without the addition of a disintegrant. Pharmaceutically dosage forms include tablets, pellets, mini tablets, lozenges and other comprimats. Usually, pharmaceutical dosage forms consist besides the active pharmaceutical active ingredient (API) of the pharmaceutical excipients: filler, binder, disintegrant, and lubricant. The porous starch according to this invention exhibits the properties of a filler, binder and disintegrant and makes simple starch-based tablet formulations accessible through direct compression. The number of excipients in the formulation can be reduced to and the direct compression route is cost effective and suitable to be integrated in continuous manufacturing lines, resulting in a very simple, directly compressed pharmaceutical dosage form. The directly compressed pharmaceutically dosage form can be manufactured without a granulation step and contains no or only low amounts of an additional filler, binder, lubricant, and disintegrant. In a further aspect the invention relates to the use of porous starches according to the invention for producing tablets, pellets and minitablet capsule fills. The porous starch is also suitable as carrier for active ingredients that can be impregnated as liquid, as solution or in the molten stage. Starch is currently used in pharmacy as a binder, disintegrating agent and film-forming material. Because of its poor flowability and compressibility the use of starch for direct tableting is not suited. Present invention is about improving tablettability, including flowability and compressibility (tensile strength of compressed tablets) of starch, enhancing the porosity of the starch particles by using enzymes, preferably Amylases, more preferably α-Amylases and to improve flowability by spray drying and agglomeration of particles. Enzymatically hydrolyzed porous starch An enzymatically hydrolyzed porous starch is a granular starch that has been hydrolyzed by one or multiple amylolytic enzymes. It can be produced through an enzymatic hydrolysis of native starch granules, which are not enzymatically or chemically processed, with one or multiple amylotic enzymes, such alpha amylase and amyloglucosidase, at a temperature inferior to the gelatinization temperature of the starch. The enzymatically hydrolyzed porous starch can be produced comprising the following steps: a) Hydrolysis of a starch by one or multiple amyllyatic enzymes, preferably an amylase b) Separation of the enzymatically hydrolyzed porous starch after hydrolysis, preferably by filtration c) Optionally washing the separated enzymatically hydrolyzed porous starch with water, preferably with de-ionized water d) Drying the enzymatically hydrolyzed porous starch, preferably by spray drying or lyophilization, more preferably by spray drying In one embodiment the enzymatically hydrolyzed porous starch particles have a relative excess specific surface area of (Sexcess) of 2 < Sexcess < 10. In a more preferred embodiment, the enzymatically hydrolyzed porous starch particles have a relative excess specific surface area of (Sexcess) of 2.5 < Sexcess < 7, more preferably 2.9 < Sexcess < 6.1. In another embodiment the enzymatically hydrolyzed porous starch particles have a polar interaction component (δP2) determined by inverse gas chromatography of δP2 < 8.8. In a more preferred embodiment, the enzymatically hydrolyzed porous starch particles have a polar interaction component (δP2) determined by inverse gas chromatography of δP2 < 8.70, more preferably δP2 < 8.66. In another embodiment the enzymatically hydrolyzed porous starch particles have a pressure difference (Δp) across GC columns packed with starch samples and purged with helium at a flow rate of 15 mL/min of 200 mbar < Δp < 800 mbar. In a more preferred embodiment, the enzymatically hydrolyzed porous starch particles have´ a pressure difference (Δp) across GC columns packed with starch samples and purged with helium at a flow rate of 15 mL/min of 200 mbar < Δp < 700 mbar, more preferably of 235 mbar < Δp < 667 mbar. The native starch granules can be based on tapioca, waxy, maize, pea, potato, waxy potato, wheat, waxy wheat, waxy maize, mung mean, ice, waxy rice, sweet potato, waxy sweet potato, millet, sago, sorghum, quinoa, arrowroot, amaranth, lotus root and buckwheat. Typically, starches for pharmaceutical applications are derived from: corn, rice, wheat, potato, millet, barley, pea and tapioca. Preferably, the native starch is derived from corn. Amylases “Amylases” according to the invention (alpha and/or beta) include those of bacterial or fungal origin (EC 3.2.1.1 and 3.2.1.2, respectively). Preferably, amylases are selected from the group of alpha-amylases (EC 3.2.1.1). Chemically modified or protein engineered mutants are included. Amylases according to the invention have “amylolytic activity” or “amylase activity” involving (endo)hydrolysis of glucosidic linkages in polysaccharides. alpha-amylase activity may be determined by assays for measurement of alpha-amylase activity which are known to those skilled in the art. Examples for assays measuring alpha-amylase activity are: alpha-amylase activity can be determined by a method employing Phadebas tablets as substrate (Phadebas Amylase Test, supplied by Magle Life Science). Starch is hydrolyzed by the alpha-amylase giving soluble blue fragments. The absorbance of the resulting blue solution, measured spectrophotometrically at 620 nm, is a function of the alpha-amylase activity. The measured absorbance is directly proportional to the specific activity (activity/mg of pure alpha-amylase protein) of the alpha-amylase in question under the given set of conditions. Alpha-amylase activity can also be determined by a method employing the Ethyliden-4-nitrophenyl-alpha-D- maltoheptaosid (EPS). D-maltoheptaoside is a blocked oligosaccharide which can be cleaved by an endo-amylase. Following the cleavage, the alpha-glucosidase included in the kit to digest the substrate to liberate a free PNP molecule which has a yellow color and thus can be measured by visible spectophotometry at 405nm. Kits containing EPS substrate and alpha-glucosidase is manufactured by Roche Costum Biotech (cat. No.10880078103). The slope of the time dependent absorption-curve is directly proportional to the specific activity (activity per mg enzyme) of the alpha-amylase in question under the given set of conditions. Amylolytic activity may be provided in units per gram enzyme. For example, 1 unit alpha-amylase may liberate 1.0 mg of maltose from starch in 3 min at pH 6.9 at 20°C. Preferred amylases are Bacillus licheniformis having SEQ ID NO:2 as described in WO 95/10603 and variants at least 95% thereto. Suitable variants are described in WO 95/10603 comprising one or more substitutions in the following positions: 15, 23, 105, 106, 124, 128, 133, 154, 156, 178, 179, 181, 188, 190, 197, 201, 202, 207, 208, 209, 211, 243, 264, 304, 305, 391, 408, and 444 which have amylolytic activity. Variants are described in WO 94/02597, WO 94/018314, WO 97/043424 and SEQ ID NO:4 of WO 99/019467. An exemplary sequence is added herein as SEQ ID NO: 1 herein. Other preferred amylases are from Aspergillus oryzae and are described for example in Brzozowski et al. Biochemistry 1997. Suitable variants are described for example in US20110159545. A suitable variant is added herein as SEQ ID NO: 2. Amylases further maybe from B. stearothermophilus having SEQ ID NO:6 as disclosed in WO 02/10355 or an amylase with optionally having a C-terminal truncation over the wildtype sequence. Suitable variants of SEQ ID NO:6 include those comprising a deletion in positions 179 and/or 181 and/or 182 and/or a substitution in position 193. TVB146 is a variant of the G. stearothermophilus (originally named B. stearothermophilus) ‘Termamyl-like’ [1]- amylase represented in PDB entry 1hvx (Suvd et al., 2001). In comparison with the most residue deletion ([1]181– 182; discussed below) and a single-point variant N193F (1hvx numbering; corresponding to Phe191 in 4uzu). In comparison with the sequence present in 1hvx, the TVB146 enzyme shows 97% sequence identity and differs, in addition to the two-residue deletion [1]181–182, at A73T, N193F, S217N, M278T, N281D, T304A and V416G. Amylases further maybe from Bacillus sp.707 having SEQ ID NO:6 as disclosed in WO 99/19467 and variants at least 95% thereto. Preferred variants of SEQ NO: 6 are those having a substitution, a deletion or an insertion in one or more of the following positions: R181, G182, H183, G184, N195, I206, E212, E216 and K269. Amylases further maybe from Bacillus halmapalus having SEQ ID NO:2 or SEQ ID NO:7 as described in WO 96/23872, also described herein as SP-722. Preferred variants are described in WO 97/3296, WO 99/194671 and WO 2013/001078. Amylases further may be from Bacillus sp. DSM 12649 having SEQ ID NO:4 as disclosed in WO 00/22103 and variants at least 95% thereto. Amylases further may be from Bacillus sp. A 7-7 (DSM 12368) having an amino acid sequence at least 95% identical to SEQ ID NO:2, in particular over the region of the amino acids 32 to 516 according to SEQ ID NO:2, as disclosed in WO 02/10356. Amylases further may be from Bacillus strain TS-23 having SEQ ID NO:2 as disclosed in WO 2009/061380 and variants thereof. Amylases further may be from Cytophaga sp. having SEQ ID NO:1 as disclosed in WO 2013/184577 and variants at least 95% thereto. Amylases further may be from Bacillus megaterium DSM 90 having SEQ ID NO:1 as disclosed in WO 2010/104675 and variants at least 95% thereto. Amylases further may be from Bacillus sp. comprising amino acids 1 to 485 of SEQ ID NO:2 as described in WO 00/60060 and variants at least 95% thereto. Amylases further may be from Bacillus amyloliquefaciens or variants thereof, preferably selected from amylases according to SEQ ID NO: 3 as described in WO 2016/092009. Amylases may have SEQ ID NO:12 as described in WO 2006/002643 or amylase variants thereof comprising the substitutions Y295F and M202LITV within said SEQ ID NO:12. Amylases may have SEQ ID NO:6 as described in WO 2011/098531 or amylase variants comprising a substitution at one or more positions selected from the group consisting of 193 [G,A,S,T or M], 195 [F,W,Y,L,I or V], 197 [F,W,Y,L,I or V], 198 [Q or N], 200 [F,W,Y,L,I or V], 203 [F,W,Y,L,I or V], 206 [F,W,Y,N,L,I,V,H,Q,D or E], 210 [F,W,Y,L,I or V], 212 [F,W,Y,L,I or V], 213 [G,A,S,T or M] and 243 [F,W,Y,L,I or V] within said SEQ ID NO:6. Amylases may have SEQ ID NO:1 as described in WO 2013/001078 or amylase variants comprising an alteration at two or more (several) positions corresponding to positions G304, W140, W189, D134, E260, F262, W284, W347, W439, W469, G476, and G477 within said SEQ ID NO:1. Amylases may have SEQ ID NO:2 as described in WO 2013/001087 or amylase variants comprising a deletion of positions 181+182, or 182+183, or 183+184, within said SEQ ID NO:2, optionally comprising one or two or more modifications in any of positions corresponding to W140, W159, W167, Q169, W189, E194, N260, F262, W284, F289, G304, G305, R320, W347, W439, W469, G476 and G477 within said SEQ ID NO:2. Amylases may be hybrid alpha-amylases from above mentioned amylases as for example as described in WO 2006/066594. Hybrid amylases may be according to WO 2014/183920 with A and B domains having at least 90% identity to SEQ ID NO:2 of WO 2014/183920 and a C domain having at least 90% identity to SEQ ID NO:6 of WO 2014/183920, wherein the hybrid amylase has amylolytic activity; preferably the hybrid alpha-amylase is at least 95% identical to SEQ ID NO: 23 of WO 2014/183920 and having amylolytic activity. Hybrid amylases may be according to WO 2014/183921 with A and B domains having at least 75% identity to SEQ ID NO: 2, SEQ ID NO: 15, SEQ ID NO: 20, SEQ ID NO: 23, SEQ ID NO: 29, SEQ ID NO: 26, SEQ ID NO: 32, and SEQ ID NO: 39 as disclosed in WO 2014/183921 and a C domain having at least 90% identity to SEQ ID NO: 6 of WO 2014/183921, wherein the hybrid amylase has amylolytic activity; preferably, the hybrid alpha-amylase is at least 95% identical to SEQ ID NO: 30 as disclosed in WO 2014/183921 and having amylolytic activity; Hybrid amylases may be according to WO 2021/032881 comprising an A and B domain originating from the alpha amylase originating from Bacillus sp. A 7-7 (DSM 12368) and a C domain originating from the alpha-amylase from Bacillus cereus; preferably, the A and B domain are at least 75% identical to the amino acid sequence of SEQ ID NO: 42 and a C domain is at least 75% identical to the amino acid sequence of SEQ ID NO: 44 – both sequences as disclosed in WO 2021/032881; more preferably, the hybrid amylase is at least 80% identical to SEQ ID NO:54 as disclosed in WO 2021/032881. Suitable amylases include also those, which are variants of the above described amylases which have amylolytic activity. In one embodiment amylase variants include variants with at least 40 to 100% identity when compared to the full length polypeptide sequence of the parent enzyme as disclosed above. In one embodiment amylase variants having amylolytic activity are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the full length polypeptide sequence of the parent enzyme as disclosed above. In another embodiment, the invention relates to amylase variants comprising conservative mutations not pertaining the functional domain of the respective amylase. Amylase variants of this embodiment having amylolytic activity may be at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% similar to the full length polypeptide sequence of the parent enzyme. In one embodiment, amylase variants have amylolytic activity according to the present invention when said amylase variants exhibit increased amylolytic activity when compared to the parent amylase. In one embodiment, amylase variants have amylolytic activity according to the present invention when said amylase variants exhibit at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% of the amylolytic activity of the respective parent amylase. In one embodiment, at least one amylase is selected from commercially available amylases which include but are not limited to products sold under the trade names Duramyl™, Termamyl™, Fungamyl™, Stainzyme™, Stainzyme Plus™, Natalase™, Liquozyme X and BAN™, Amplify™, Amplify Prime™ (from Novozymes A/S), and Rapidase™, Purastar™, Powerase^TM, Effectenz™ (M100 from DuPont), Preferenz™ (S1000, S110 and F1000; from DuPont), PrimaGreen™ (ALL; DuPont), Optisize™ (DuPont). >SEQ ID NO: 1 ANLNGTLMQYFEWYMPNDGQHWKRLQNDSAYLAEHGITAVWIPPAYKGTSQADVGYGAYDLYDLGEFHQKGTVRT KYGTKGELQSAIKSLHSRDINVYGDVVINHKGGADATEDVTAVEVDPADRNRVISGEHRIKAWTHFHFPGRGSTYSDF KWHWYHFDGTDWDESRKLNRIYKFQGKAWDWEVSNENGNYDYLMYADIDYDHPDVAAEIKRWGTWYANELQLDG FRLDAVKHIKFSFLRDWVNHVREKTGKEMFTVAEYWQNDLGALENYLNKTNFNHSVFDVPLHYQFHAASTQGGGYD MRKLLNSTVVSKHPLKAVTFVDNHDTQPGQSLESTVQTWFKPLAYAFILTRESGYPQVFYGDMYGTKGDSQREIPAL KHKIEPILKARKQYAYGAQHDYFDHHDIVGWTREGDSSVANSGLAALITDGPGGAKRMYVGRQNAGETWHDITGNR SEPVVINSEGWGEFHVNGGSVSIYVQR >SEQ ID NO: 2 ATPADWRSQSIYFLLTDRFARTDGSTTATCNTADRKYCGGTWQGIIDKLDYIQGMGFTAIWITPVTAQLPQTTAYGDA YHGYWQQDIYSLNENYGTADDLKALSSALHERGMYLMVDVVANHMGYDGAGSSVDYSVFKPFSSQDYFHPFCLIQN YEDQTQVEDCWLGDNTVSLPDLDTTKDVVKNEWYDWVGSLVSNYSIDGLRIDTVKHVQKDFWPGYNKAAGVYCIGE VLDGDPAYTCPYQNVMDGVLNYPIYYPLLNAFKSTSGSMDDLYNMINTVKSDCPDSTLLGTFVENHDNPRFASYTNDI ALAKNVAAFIILNDGIPIIYAGQEQHYAGGNDPANREATWLSGYPTDSELYKLIASANAIRNYAISKDTGFVTYKNWPIYK DDTTIAMRKGTDGSQIVTILSNKGASGDSYTLSLSGAGYTAGQQLTEVIGCTTVTVGSDGNVPVPMAGGLPRVLYPTE KLAGSKICSSS Tensile strength The tensile strength of a tablet is an important attribute as the tablet needs to be mechanically strong enough to withstand further handling such as film–coating, packaging, transport and end-use by the patient, but to be weak enough to break apart in the human body and so release its contents. Tensile strength refers to the ability of a material to resist breaking or becoming deformed under tension. In the case of tablets, tensile strength refers to the strength of the tablet to withstand forces applied to it during handling, packaging, and transport. Tablets with high tensile strength are less likely to break or crumble, ensuring their structural integrity and preventing the loss of their active ingredients. This is particularly important for tablets that need to be further processed, for example to apply a film coating or that are generally handled and transported extensively, such as it is common used in the pharmaceutical industry. Manufacturers use various techniques to enhance the tensile strength of tablets. These include using appropriate excipients, optimizing the compressibility and compactibility during tablet manufacturing, and incorporating binders or disintegrants to improve tablet hardness and integrity. Tensile strength testing is typically performed using equipment such as a hardness tester or a tablet tensile strength tester. This helps manufacturers assess the tablet's ability to withstand applied forces and ensure its overall quality. Overall, tablets with high tensile strength are preferred as they are less likely to break, ensuring the quality and efficacy of the medication they contain. The minimum tensile strength for tablets can vary depending on the specific tablet formulation and intended use. However, in general, tablets including active pharmaceutical ingredients (APIs) should have a tensile strength of at least 1-2 MPa (megapascals) to ensure they can withstand handling and transportation without breaking. In order to achieve this, a tablet without API, made of the excipients should have at least a tensile strength of 4 MPa. For the preparation of tablets different devices can be used, like for example a hydraulic handpress or a compactor simulator. These different devices have a different dwell time which has an impact on the tensile strength of the tablet produced by this device. The dwell time in compression is the amount of time it takes for the punches to stop moving vertically and to achieve maximum penetration in the die under the primary compression rollers. Dwell time takes place when the compression rollers make contact with the punch head flat. The punch head flat dimension divided by the turret tangential velocity will give you the tablet press dwell time calculation. As a core parameter, dwell time greatly impacts the overall quality of many tablet products and the production speed of these products. Specifically, it affects the tablet’s strength and facilitates the transfer of product between tablet presses. Subsequently, increasing or decreasing dwell time could significantly affect the results of tablet manufacturing processes. In the examples either the hydraulic hand press Specac Atlas Manual 15T from SPECAC INC having a dwell time of 10 seconds or the compaction simulator StylOne Evo (Medelpharm, Germany having a dwell time of <10ms was used. The enzymatically hydrolyzed porous starch according to the invention gives a solid dosage form having a tensile strength of >4MPa compressed with a compression pressure of 150 MPa and a dwell time of 10s. In a preferred embodiment the tensile strength is > 5Mpa. The enzymatically hydrolyzed porous starch according to the invention gives a solid dosage form having a tensile strength of >3MPa compressed with a compression pressure of 150 MPa and a dwell time of <10ms. In a preferred embodiment the tensile strength is > 4MPa. Directly compressed pharmaceutically dosage form The new porous starch is an individual excipient that provides multiple functionalities that are needed to formulate a tablet: this one ingredient unites the functionality of a filler, binder and disintegrant, making the addition of these materials obsolete. A flowing agent, such as silicon dioxide (typically used at a concentration of 0.2-1% w/w can be added optionally and a lubricant (typically used at a concentration between 0.5-3% w/w) is needed to reduce the ejection force during tablet manufacturing. The directly compressed pharmaceutically dosage form made with such new porous starch can therefore contain no or only low amounts of additional excipients, for example filler, lubricant, binder and disintegrant and thus enable very simple formulations and help to minimize the amount of inactive ingredients in tablets. In one embodiment the directly compressed pharmaceutically dosage according to the invention contains a concentration of lubricant and flowing agent based on the total weight of the dosage form is not more than 10%, preferred not more than 7.5% and even more preferred not more than 5%. In another embodiment of the invention the directly compressed pharmaceutically dosage form comprises the enzymatically hydrolyzed porous starch particles according to the invention. This dosage form can be a tablet, a pellet, a mini-tablet, a lozenge or other solid comprimat. Preferably the dosage form according to the invention, here without API or other additional excipients, shows – prepared with a compression of 150 MPa – a tensile strength of >4 MPa. In another embodiment of the invention the directly compressed pharmaceutically dosage form comprises porous starch particles present at a concentration between 1 and 98 wt.-%, preferably between 40 to 95%, more preferably 49 to 94% based on the total weight of the dosage form. In another embodiment of the invention the directly compressed pharmaceutically dosage comprises one or more active pharmaceutically ingredients present at a concentration between 1 and 80wt.-%, preferably between 10 to 80, more preferably between 25 to 50% based on the total weight of the dosage form. The following experiments (regarding relative excess specific surface area, pressure difference, and polar interaction component) were performed for the respective samples in table 1+2. Relative excess specific surface area (Sexcess) 1) Determination of specific surface areas by nitrogen sorption experiments The specific surface area of porous and non-porous starches was determined by means of the nitrogen sorption technique, which measures the amount of a test gas (here nitrogen) adsorbed on a defined quantity of solid sample in equilibrium at defined conditions. This gives an adsorption isotherm, which can be evaluated using the model of Brunauer, Emmett and Teller (BET) [1] or the Langmuir theory [2]. In both cases, values for the surface area available for adsorption per unit mass of solid material are obtained (S_BET and S_Langmuir, respectively), while the BET evaluation provides the interaction constant (C_BET, i.e. the affinity for gas molecules to adsorb on the solid surfaces) as additional parameter. For measurement, about 2.5 g solid sample were filled into glass columns (inner diameter: 9.5 mm) with known tare weight. Subsequently, the filled columns were evacuated to a pressure of 0.1 mbar and conditioned at this pressure for 48 h at 25 °C using the degassing unit of an ASAP 2420 Surface Area and Porosity Analyzer from Micromeritics (Unterschleißheim, Germany), in order to remove any volatile components (including water) from the solid sample. After conditioning, the weight of residual material in the column was determined with a precision of 0.1 mg. Then, the column was transferred to the sampling port of the ASAP 2420 instrument and the free volume in the sample container was measured by dosing non-adsorbing helium gas. After removal of the inert He, N2 adsorption isotherms were recorded at the condensation temperature of nitrogen. SBET, CBET and SLangmuir were determined from the obtained isotherms by using a five-point method implemented in the software of the supplier, covering a typical partial pressure range of 0.06 ≤ p/p0 ≤ 0.20. The described protocol is closely following procedures defined in the DIN ISO 9277:2003-05 norm. References [1] S. Brunauer, P. H. Emmett, E. Teller, J. Am. Chem. Soc.1938, 60, 309-319. [2] I. Langmuir, J. Am. Chem. Soc.1918, 40, 1361-1402. 2) Determination of particle sizes by laser diffraction measurement A Mastersizer 2000 equipped with the sample handling unit Scirocco 2000, both from Malvern Panalytical Ltd. (Worcestershire, UK), was used to determine the particle size distribution of the porous starch samples. The instrument measures the angular variation of the intensity of light scattered as a laser beam passes through a dispersed particulate sample. Larger particles predominantly scatter light at small angles relative to the laser beam, whereas smaller particles contribute more strongly to light scattered at large angles. The following detailed settings were used for the measurements: ^ Optical limit: 0.1-6.0 optical limit ^ Timeout period: 2 min ^ Result range: 0.02-2000 µm ^ Result calculation: general purpose ^ Measurement time: 60 s ^ Measurement snap: 60.000 ^ Background time: 5 s ^ Background snap: 5.000 The porous starch particles were measured in dry powder form at 0.5 bar dispersion air pressure for about 30-60 s. From the collected angular scattering intensity data, particle size distributions were calculated using the software provided by the manufacturer (version 6.00), which applies the simplified Fraunhofer approximation for evaluation [3]. The particle size was obtained as the diameter of volume-equivalent spheres and is reported as characteristic percentile values encompassing the lower 10 % (d₁₀), 50 % (d₅₀), and 90 % (d₉₀) of the entire distribution. References [3] J. Vargas-Ubera, J. F. Aguilar, D. M. Gale, Appl. Opt.2007, 46, 124-132. 3) Calculation of relative excess specific surface areas Based on the d50 values obtained by light scattering, the envelope volume and surface area of the detected species (either single starch granules or aggregates thereof) was calculated assuming spherical geometry via the following equations: With these parameters, the theoretical specific surface area (S_Envelope) of a compact (i.e. non-porous) entity with the experimentally measured d₅₀ value can be obtained according to: where ρStarch is the density of native untreated starch (1.5301 g/cm³ at 25 °C for corn starch, as determined by helium pycnometry). Relating the calculated envelope specific surface area to the corresponding value measured experimentally for treated starches (S_BET) gives the relative excess specific surface area (S_excess): The dimensionless values obtained in this way represent the increase of surface area (and thus overall porosity) caused by pores within the granules due to prior amylase treatment as well as voids between individual granules in aggregated structures. Both of these contributions change the properties of the treated starch products and influence the final mechanical properties. Table 1 provides values of experimentally determined and calculated parameters for different types of treated and untreated starch samples, while a plot of the tensile strength as a function of S_excess is shown in Figure 1. Inverse gas chromatography (iGC), pressure difference (Δp) To investigate the surface properties of treated and untreated starch materials by iGC, samples were filled into stainless steel GC columns with an inner diameter of 4 mm and a length of 10 cm, which were closed on one end with a thin layer of silanized glass wool. Homogeneous and reproducible packing of the solid samples was achieved by vibrating the column under defined conditions. In this way, the column was filled with starch sample up to a height of ca.9.5 cm (see Table 2 for the required sample masses m) and then closed on the remaining open end with silanized glass wool. The filled columns were connected to the injector module of a GC 1310 gas chromatograph from Thermo Fisher Scientific GmbH (Dreieich, Germany) using 11wagelok fittings and placed in the oven of the GC instrument. After equilibration at a temperature of 22.7 °C, the samples in the columns were purged with helium gas (Nippon Gases, 6.0 quality) at a set inlet flow rate of 15 mL/min (as controlled by the injection module of the instrument), which was independently measured at the entrance to the injection module with a calibrated mass flow meter (Brooks SLA 5800). As a consequence of different overall porosities in the packed starch columns (due to different particle sizes and degrees of aggregation), the pressure required to maintain the targeted flow rate varied between samples and was measured at the column inlet. The difference of this pressure value to the atmospheric pressure at the column outlet (Δp) is used as a parameter describing the permeability of the packed starch materials, as listed in Table 2 and correlated to the tensile strength obtained from mechanical testing in Figure 2. Determination of the polar interaction component (δP2) After the determination of the Δp values, the packed columns were conditioned for 12 h at 27 °C in a flow of 10 mL/min dry helium, in order to remove any residual volatile compounds and thus equilibrate the starch surfaces for subsequent iGC measurements under conditions of so-called “infinite dilution” (ID) [4]. For this purpose, small amounts of different test molecules were injected at predefined times (using a PAL3 RSI Injection System) into the helium carrier gas and thus guided through the packed columns, where interactions with the starch samples occurred. The retention time t_R was measured for each probe by a flame-ionization detector (Trace 1300/1600 FID Module from Thermo Fisher Scientific GmbH) positioned at the column outlet. The following probe molecules were chosen: n-heptane, n-octane, n-nonane, n-decane, n-undecane, chloroform, acetone, 2butanone, diethyl ether, tetrahydrofuran, benzene and toluene. The dead time t0 was determined by injection of methane as a non-interacting molecule, allowing the net retention time tN to be calculated for each tested probe via tN = tR – t0. Based thereon, the specific retention volume Vg was obtained using the following equation [4]: ^ ^_^ where T is the absolute analysis temperature, D_c the corrected flow (obtained by correction of the flow rate F_out measured at the column outlet using the James-Martin coefficient j and the ambient temperature T₀ via D_c =·j·F_out·T/T₀), m the sample mass and S_BET its specific surface area determined by nitrogen sorption according to the BET theory (see Table 1). S_ref is the specific surface area of a reference state, which was arbitrarily chosen as S_ref = 1 m²/g. The V_g values obtained in this way for each probe molecule were then used to calculate the corresponding Flory-Huggins interaction parameters χ12^∞ at infinite dilution via the following equation [5]: where M1, p1, v1, ρ1 and B11 are the known molecular weight, vapor pressure, molar volume, density and second virial coefficient of the injected probe molecule, respectively. The density and molar volume of the stationary phase (i.e. the starch samples) were assumed to be ρ₂ = 1.5301 g/cm³ and v₂ = 466 cm³/mol. χ₁₂ ^∞ is linked to the squared distance D between the interaction partners in the space of the Hansen solubility parameters (HSP) according to [5,6]: where δD_i, δP_i and δH_i represent dispersive, polar and hydrogen-bonding components of the interactivity of the injected probe molecules (1) and the surfaces provided by the material in the column (2) in the framework of the HSP theory. Using the known values for δD₁, δP₁ and δH₁, the Flory-Huggins parameter can thus be calculated for each probe and a given set of assumed values for δD₂, δP₂ and δH₂. In an iterative approach [7], the correlation coefficient of linear fits to experimentally measured vs. calculated χ₁₂ ^∞ values for all studied probe molecules was maximized to extract Hansen solubility parameters for the starch samples providing the best description of the experimental data. The δD2, δP2 and δH2 values obtained for selected porous and non-porous starch materials are listed in Table 2. Although the theory outlined above was originally developed for soft matter allowing 3D interactions (e.g. liquids on a solid support or polymers above their glass transition temperature), the polar HSP component determined for the porous starch materials shows clear correlation with the tensile strength obtained from mechanical testing, as illustrated in Figure 3. References [4] E. Brendle, E. Papirer, Surface Properties Characterization by Inverse Gas Chromatography (iGC) Applications. In Powders and Fibers: Interfacial Science and Applications; CRC Press, 2006, pp.47-122. [5] https://www.stevenabbott.co.uk/practical-chromatography/hsp.php [6] C. Hansen, Hansen Solubility Parameters: A User’s Handbook; CRC Press, 2007. [7] https://www.hansen-solubility.com/HSPiP/ In a first embodiment the enzymatically hydrolyzed porous starch particles have a polar interaction component (δP2) determined by inverse gas chromatography of δP2 < 8.8. In a second embodiment the enzymatically hydrolyzed porous starch particles according to the first embodiment have a relative excess specific surface area of (Sexcess) of 2 < Sexcess < 10. In a third embodiment the enzymatically porous starch particles according to the embodiments 1 or 2 have a pressure difference (Δp) across GC columns packed with starch samples and purged with helium at a flow rate of 15 mL/min of 200 mbar < Δp < 800 mbar. In a fourth embodiment the enzymatically porous starch particles according to the embodiments 1 to 3 are enzymatically hydrolyzed by an enzyme selected from the group of amoylases. In a fifth embodiment the enzymatically porous starch particles according to the embodiments 1 to 3 are enzymatically hydrolyzed by an enzyme selected from the group of α-amoylases. In a sixth embodiment the enzymatically porous starch particles according to the embodiments 1 to 5 are selected from the group of corn, rice, wheat, potato and tapioca starch. In a seventh embodiment the enzymatically porous starch particles according to the embodiments 6 are selected from corn starch. In an eighth embodiment tablets, pellets and minitablet capsules comprise the enzymatically porous starch particles according to the embodiments 1 to 7. In a ninth embodiment the tablets, pellets and minitablet capsules according to the embodiments 8 prepared with a compression pressure of 150 MPa show a tensile strength of > 4 MPa. In a tenth embodiment a pharmaceutical formulation, pharmaceutical excipient, supplement, nutraceutical, health food or cosmetic product contains the enzymatically porous starch particles according to the embodiments 1 to 3. In an eleventh embodiment the enzymatically porous starch particles according to the embodiments 1 to 3 are used for the direct compression of tablets. Brief description of the figures: Figure 1: Plot of the tensile strength measured for tablets prepared with a compression pressure of 150 MPa as a function of the relative excess specific surface areas obtained by combination of particle size and nitrogen sorption measurements. Empty circles: porous starch samples prepared according to the method described by the present invention in the presence of an amylase, among which tensile strengths of >4 MPa are only observed for 2 < Sexcess < 10. Filled circles: non-porous samples prepared according to the method described by the present invention in the absence of an amylase. Filled squares: reference materials as described in Table 1. Figure 2: Plot of the tensile strength measured for tablets prepared with a compression pressure of 150 MPa as a function of the pressure difference across GC columns packed with starch samples and purged with helium at a flow rate of 15 mL/min. Empty circles: porous starch samples prepared according to the method described by the present invention in the presence of an amylase, among which tensile strengths of >4 MPa are only observed for 200 mbar < Δp < 700 mbar. Filled circles: non-porous samples prepared according to the method described by the present invention in the absence of an amylase. Filled squares: reference materials as described in Table 2. Figure 3: Plot of the tensile strength measured for tablets prepared with a compression pressure of 150 MPa as a function of the polar interaction component determined by inverse gas chromatography at infinite dilution in the framework of the HSP theory. Empty circles: porous starch samples prepared according to the method described by the present invention in the presence of an amylase, among which tensile strengths of >4 MPa are only observed for δP2 < 8.8 with a more or less linear dependency of σ150 on δP2 (dashed line). Filled circles: non-porous samples prepared according to the method described by the present invention in the absence of an amylase. Filled squares: reference materials as described in Table 2. Figure 4: Scanning electron microscope (1^st row) and fluorescein microscope pictures (2^nd row) of native corn starch, N-ZORBIT and porous starch particles. Highest porosity can be observed for the porous starch. Scanning electron micrographs (3^rd row) of breakages of tablets made from corresponding particles at a compression pressure of 150 MPa. Examples Production method of porous starch particles (Examples 1 to 27) Example 1 A 4 l glass reactor is charged with 3185 g deionized water.702 g corn starch (dry weight without moisture) is added, and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 58°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 58°C for 4,8 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is cooled down to -40°C. The frozen filter cake is lyophilized for 120 h to remove the frozen water. Yield: 365g white powder. Example 2 A 4 l glass reactor is charged with 3185 g deionized water.717 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 58°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 58°C for 3 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is cooled down to -40°C. The frozen filter cake is lyophilized for 96 h to remove the frozen water. Yield: 398g white powder. Example 3 A 4 l glass reactor is charged with 3185 g deionized water.717 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 58°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 58°C for 4,6 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is cooled down to -40°C. The frozen filter cake is lyophilized for 96 h to remove the frozen water. Yield: 360g white powder. Example 4 A 4 l glass reactor is charged with 3185 g deionized water.732 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 58°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 58°C for 2 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is cooled down to -40°C. The frozen filter cake is lyophilized for 96 h to remove the frozen water. Yield: 429g white powder. Example 5 A 4 l glass reactor is charged with 3185 g deionized water.732 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 58°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 58°C for 7 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is cooled down to -40°C. The frozen filter cake is lyophilized for 96 h to remove the frozen water. Yield: 335g white powder. Example 6 A 4 l glass reactor is charged with 3185 g deionized water.732 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 58°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 58°C for 3,8 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is cooled down to -40°C. The frozen filter cake is lyophilized for 96 h to remove the frozen water. Yield: 380g white powder. Example 7 Comparative example without amylase A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred. The mixture is heated to 61°C for 2,75h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dryed at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dryed starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 592 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 8 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 1,75 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 431 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 9 A 4 l glass reactor is charged with 3185 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 3 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated and the wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 96h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 324 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 10 Comparative example without amylase A 4 l glass reactor is charged with 1585 g deionized water.360 g corn starch (dry weight without moisture) is added and the mixture is stirred. The mixture is heated to 61°C for 1h. The mixture is cooled down to ambient temperature and is spray dried. Spray drying was performed on a Büchi Mini Spray Dryer B-290 (BÜCHI Labortechnik AG) equipped with a 2.2 mm two-fluid nozzle, Inert Loop B-295, and Dehumidifyer B-296 under the following conditions: nitrogen flow rate: 30 m³/h; inlet temperature 145 °C ± 5 °C; outlet temperature 80 ± 5 °C and liquid flow rate 8-13 g/min. The product was collected using a cyclone. Example 11 A 4 l glass reactor is charged with 3170 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 0,5 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated and the wet filter cake is isolated. The washing with 2000g deionized water and filtration is repeated 2 times. Finally, the wet filter cake is mixed with 500 g deionized water and is spray dried. Spray drying was performed on a GEA Niro MM-PSR Mobile Minor Spray Dryer (GEA Process Engineering Pte. Ltd.) equipped with a 1.0 mm two-fluid nozzle: inlet temperature 145 °C ± 5 °C; outlet temperature 80 ± 5 °C; atomizing pressure 0.2 bar and liquid flow rate 25-35 g/min. The product was collected using a cyclone. Example 12 A 4 l glass reactor is charged with 3170 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 1,5 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated and the wet filter cake is isolated. The washing with 2000g deionized water and filtration is repeated 2 times. Finally, the wet filter cake is mixed with 500 g deionized water and is spray dried. Spray drying was performed on a GEA Niro MM-PSR Mobile Minor Spray Dryer (GEA Process Engineering Pte. Ltd.) equipped with a 1.0 mm two-fluid nozzle: inlet temperature 145 °C ± 5 °C; outlet temperature 80 ± 5 °C; atomizing pressure 0.2 bar and liquid flow rate 25-35 g/min. The product was collected using a cyclone. Example 13 A 4 l glass reactor is charged with 3170 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 2,5 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated and the wet filter cake is isolated. The washing with 2000g deionized water and filtration is repeated 2 times. Finally, the wet filter cake is mixed with 500 g deionized water and is spray dried. Spray drying was performed on a GEA Niro MM-PSR Mobile Minor Spray Dryer (GEA Process Engineering Pte. Ltd.) equipped with a 1.0 mm two-fluid nozzle: inlet temperature 145 °C ± 5 °C; outlet temperature 80 ± 5 °C; atomizing pressure 0.2 bar and liquid flow rate 25-35 g/min. The product was collected using a cyclone. Example 14 A 4 l glass reactor is charged with 3170 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 5 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated and the wet filter cake is isolated. The washing with 2000g deionized water and filtration is repeated 2 times. Finally, the wet filter cake is mixed with 500 g deionized and is spray dried. Spray drying was performed on a GEA Niro MM-PSR Mobile Minor Spray Dryer (GEA Process Engineering Pte. Ltd.) equipped with a 1.0 mm two-fluid nozzle: inlet temperature 145 °C ± 5 °C; outlet temperature 80 ± 5 °C; atomizing pressure 0.2 bar and liquid flow rate 25-35 g/min. The product was collected using a cyclone. Example 15 A 4 l glass reactor is charged with 3170 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 1,75 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated and the wet filter cake is isolated. Finally, the wet filter cake is mixed with 500 g deionized and is spray dried. Spray drying was performed on a Büchi Mini Spray Dryer B-290 (BÜCHI Labortechnik AG) equipped with a 2.2 mm two-fluid nozzle, Inert Loop B-295, and Dehumidifyer B-296 under the following conditions: nitrogen flow rate: 30 m³/h; inlet temperature 145 °C ± 5 °C; outlet temperature 80 ± 5 °C and liquid flow rate 8-13 g/min. The product was collected using a cyclone. Example 16 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred. The mixture is heated to 61°C for 2,75h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 550 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 17 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 58°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 58°C for 0,5 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 431 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 18 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added.14,1 g Termamyl is added and the mixture is stirred at 61°C for 5 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 344 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 19 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 6 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 336 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 20 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 6 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 302 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 21 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 58°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 58°C for 0,5 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 572 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 22 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 1,8 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 442 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 23 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred. The mixture is heated to 61°C for 2,75h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 610 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 24 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 1,8 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, the wet filter cake stored at 40°C for 24h. The wet filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated to separate the starch particles. The wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 588 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 25 A 4 l glass reactor is charged with 3160 g deionized water.720 g corn starch (dry weight without moisture) is added and the mixture is stirred.1,23 g Calcium acetate monohydrate is added, and the mixture is heated to 61°C for 1h. 14,1 g Termamyl is added and the mixture is stirred at 61°C for 1,8 h. The mixture is cooled down to ambient temperature and filtrated to separate the starch particles. The wet starch filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated, and the wet filter cake stored at 40°C for 24h. The wet filter cake is charged into a 4 l glass reactor containing 2000g deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C). The mixture is filtrated to separate the starch particles. The washing with 2000g deionizied water and filtration is repeated 2 times. The wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size. The wet starch is transferred to a vacuum dryer and dried at 40°C with a reduces pressure of 40 – 60 mbar for 24h. The dried starch particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and 324 g starch particles with a particle size fraction of 50 – 1000 µm are collected. Example 26 Native corn starch purchased from Sigma-Aldrich was dispersed in deionized water at a ratio of 4:6, respectively. Spray drying was performed on a Büchi Mini Spray Dryer B-290 (BÜCHI Labortechnik AG) equipped with a 2.2 mm two-fluid nozzle, Inert Loop B-295, and Dehumidifyer B-296 under the following conditions: nitrogen flow rate: 30 m³/h; inlet temperature 140 °C ± 5 °C; outlet temperature 80 ± 5 °C and liquid flow rate 8-13 g/min. The product was collected using a cyclone. Example 27 A 4 L glass reactor is charged with 2570 g deionized water.1227 g corn starch (dry weight without moisture) is added, and the mixture is stirred and heated to 61°C for 1h.1,85 g Calcium acetate monohydrate is added solved for 5min.21,1 g amylase (Termamyl 120L) or 5,3 g (Termamyl 2X) is added, and the mixture is stirred at 61°C for 2 h. The mixture is cooled down to ambient temperature, filtrated and washed with 1000 g of de-ionized water. Spray drying is performed in a GEA Niro MM-PSR with an inlet temperature of 150°C and an outlet temperature of 75°C. The sugar content (<5%, w/w) of the dried product is finally determined. Yield: approx.550 g white powder. Reference N-Zorbit: N-Zorbit was purchased from Ingredion N-Zorbit has a sugar content of 20% which results in high disintegration times. N-Zorbit was either used as purchased or in a washed form as described below. 100g N-Zorbit is charged into a 1 l beaker containing 250mL deionized water and the mixture is stirred for 1 h at ambient temperature (20 – 25°C) and then separated with a nutsche Suction filter. The resulting wet solid was washed again three times with 250mL of deionized water each time and separated with a nutsche. The wet filter cake is crushed by being pushed through a sieve with 4000 µm mesh size and stored at 40°C or 20-25°C for 24h. The wet product is transferred to a vacuum dryer and dried at 40°C with a reduced pressure of 40 – 60 mbar for 24h. The dried particles are first pushed through a sieve with 2000 µm mesh size and then through a sieve with 1000 µm mesh size. Fine particles are removed by a sieve with 50 µm mesh size and the product with a particle size fraction of 50 – 1000 µm are collected. Physicochemical characterization of porous starch particles for the respective samples in table 1+2 and figure 1 The relative excess specific surface area (Sexcess), δP2 , Δp and other parameters were determined as described before. Scanning electron microscopy The starch particles were then mounted onto a stub by using Leit-C (conductive carbon cement). After sputtering of a 9 nm thick platinum layer on the surface of the granules, the sample was transferred into a scanning-electron microscope (Zeiss Gemini 500). By using 5kV acceleration voltage images of the starch particles were taken using the secondary electron contrast (based on the Everhart–Thornley detector). Fluorescence microscopy The starch particles were dispersed into water and 100 ppm Fluorescein sodium salt was added. After about one hour image stacks of the fluorescence of Fluorescein, staining the starch structure, were taken for an excitation wavelength at 488 nm. The emission was integrated between 500 nm and 600 nm using a confocal laser-scanning microscope (Leica, SP8). Production of tablets a) Production of tables with a hand press (dwell time of 10 s) For the preparation of tablets, a hydraulic hand press Specac Atlas Manual 15T from SPECAC INC. was used. The hand press was equipped with a biplane punch of 10 mm diameter. Prior the compression step, all powders were conditioned to the same moisture content as the native starch (8.2 ± 0.8 %). The matrix was filled with 300 mg of so prepared powder. At compression force of 400, 800, 12001600 and 2000 kg corresponding to 50, 100, 150, 200 and 250 MPa compression pressure and a retention time of 10 seconds. For each compression pressure, 11 tablets were prepared at identical manner. Characterization of tablets For characterizing the tablets, a Sotax ST 50 from Sotax AG with the pre-installed software q-doc i was used. Following 5 physical parameters were analyzed by Sotax ST 50: tablet hardness, diameter, thickness, and mass. The measured tablet hardness was converted in tensile strength by applying following equation: One sample, corresponding to one powder at produced at one compression pressure, was examined five times. The calculated mean value was used as the result. Scanning electron microscopy of cross section of tablets Tablets were broken into two halves by hand. The cross sections were then mounted onto a stub by using Leit-C (conductive carbon cement). After sputtering of a 12 nm thick platinum layer on the surface of the cross-section, the sample was transferred into a scanning-electron microscope (Zeiss Gemini 500). By using 5kV acceleration voltage images of the cross-section were taken using the secondary electron contrast (based on the Everhart–Thornley detector). Overview of all measured values for the respective examples Dry- d₅₀ S_BET C_BET S_Langmuir S_Envelope S_excess σ₁₅₀ Example No Comment ing [µm] [m²/g] [] [m²/g] [m²/g] [] [MPa] Reference Native n/a 15 0.43 78.3 0.61 0.261 1.6 1.28 Native Reference n/a 16 0.47 36.5 0.68 0.245 1.9 0.95 Meritena N-Zorbit Reference n/a 735 0.80 61.9 1.13 0.005 149.7 1.90 (washed) N-Zorbit Reference n/a 602 0.84 40.8 1.21 0.007 129.0 2.17 (washed) 1 Lyo 10 1.53 51.9 2.17 0.392 3.9 6.36 2 Lyo 13 1.69 43.1 2.42 0.302 5.6 4.67 3 Lyo 13 1.64 29.6 2.41 0.302 5.4 5.31 4 Lyo 13 1.85 56.7 2.60 0.302 6.1 6.10 5 Lyo 13 1.54 28.0 2.27 0.302 5.1 4.99 6 Lyo 13 1.56 30.1 2.29 0.302 5.2 4.89 No 7 Vac 236 0.39 87.1 0.54 0.017 23.4 1.24 amylase 8 Vac 280 0.97 29.6 1.44 0.014 69.6 2.36 9 Vac 334 1.45 20.0 2.26 0.012 123.5 3.36 No 10 Spray 14 0.46 290.7 0.63 0.280 1.6 2.48 amylase 11 Spray 20 0.98 87.1 1.36 0.196 5.0 7.08 12 Spray 17 1.19 75.1 1.65 0.231 5.2 5.99 13 Spray 17 1.20 82.5 1.67 0.231 5.2 7.38 14 Spray 17 1.25 37.5 1.81 0.231 5.4 6.06 15 Spray 15 0.75 25.7 1.12 0.261 2.9 9.27 No 16 Vac 340 0.42 76.2 0.60 0.011 39.6 1.11 amylase 17 Vac 29 1.34 36.0 1.98 0.135 9.9 2.41 18 Vac 306 1.10 28.4 1.66 0.013 85.8 1.94 19 Vac 300 1.25 24.7 1.86 0.013 95.3 1.94 20 Vac 287 1.28 24.7 1.92 0.014 93.7 2.06 21 Vac 274 0.93 32.3 1.39 0.014 65.0 1.54 22 Vac 322 1.08 27.6 1.60 0.012 88.9 1.90 No 23 Vac 227 0.39 71.7 0.55 0.017 22.7 1.03 amylase 24 Vac 742 1.34 25.1 2.00 0.005 253.0 3.59 25 Vac 742 1.52 24.8 2.28 0.005 287.6 2.87 No 26 Spray 14 0.42 134.9 0.58 0.280 1.5 1.57 amylase 27 Spray 18 4.8 5.42 Table 1: Properties of treated and untreated starch products determined by particle size measurements (median diameter d₅₀), nitrogen sorption experiments (specific surface areas according to BET and Langmuir theory, S_BET and S_Langmuir, and interaction constants from BET theory, C_BET) and mechanical testing (tensile strength after compression at 150 MPa, σ₁₅₀). The envelope specific surface area (S_Envelope) was calculated from the d₅₀ values assuming spherical geometry, while the relative excess specific surface area (S_excess) is given as the ratio of S_BET and S_Envelope. m Δp δD₂ δP₂ δH₂ σ₁₅₀ Example No Comment Drying [g] [mbar] [] [] [] [MPa] Reference Native n/a 0.928 732 13.57 8.30 3.15 1.28 Native Reference n/a 0.993 871 0.95 Meritena N-Zorbit Reference n/a 0.628 <50 13.50 9.06 3.37 1.90 (washed) N-Zorbit Reference n/a 0.739 78 13.53 8.62 3.53 2.17 (washed) 1 Lyo 0.590 581 13.43 8.34 3.07 6.36 2 Lyo 0.577 533 13.16 8.66 2.34 4.67 3 Lyo 0.562 595 13.09 8.58 3.63 5.31 4 Lyo 0.620 642 6.10 5 Lyo 0.551 639 4.99 6 Lyo 0.619 667 13.72 8.51 1.75 4.89 No 7 Vac 0.652 <50 13.36 8.95 3.63 1.24 amylase 8 Vac 0.415 <50 2.36 9 Vac 0.599 124 3.36 No 10 Spray 0.897 813 13.66 7.89 4.29 2.48 amylase 11 Spray 0.680 373 13.63 7.59 3.70 7.08 12 Spray 0.636 476 13.46 7.75 3.32 5.99 13 Spray 0.630 552 13.54 7.99 3.71 7.38 14 Spray 0.588 508 13.21 8.48 3.20 6.06 15 Spray 0.490 235 13.37 7.43 3.51 9.27 No 16 Vac 0.654 <50 1.11 amylase 17 Vac 0.843 1045 13.02 9.09 2.28 2.41 18 Vac 0.550 77 1.94 19 Vac 0.454 <50 12.56 9.06 1.05 1.94 20 Vac 0.455 <50 2.06 21 Vac 0.651 83 1.54 22 Vac 0.566 77 1.90 No 23 Vac 0.558 <50 1.03 amylase 24 Vac 0.389 <50 12.83 8.91 1.43 3.59 25 Vac 0.415 <50 2.87 No 26 Spray 0.973 1017 13.77 7.93 3.23 1.57 amylase 27 Spray 529 13.58 7.47 3.62 5.42 Table 2: Selected properties of treated and untreated starch products determined by inverse gas chromatography: sample mass m required for filling of the columns to a height of ca.9.5 cm; pressure difference Δp measured across packed columns in a flow of helium at 15 mL/min; Hansen solubility parameters (HSP) representing dispersive (δD₂), polar (δP2) and hydrogen-bonding (δH2) components of the interactivity of the surfaces provided by the material in the column under conditions of infinite dilution. For comparison, the corresponding values for the tensile strength for tablets prepared with a compression pressure of 150 MPa (σ150) are also shown. The following experiments were performed with the porous starch of example 27: Sugar content determination of dried porous starch: Determine solid content of porous starch sample (example: solid content of the sample is 95%, that means the sample consists of 9.5g of product and 0.5g of water). Present 25g of water in a beaker and add 10g of the porous starch sample while stirring, considering the solid content of the sample. Stir at room temperature for 1h and vacuum via blue band filter. Determine the solid content of filtrate for 2h at 120°C (vacuum). Tableting experiments (starch) w/o active ingredient, (dwell time of <10 ms) Tableting experiments were performed using a fully instrumented compaction simulator StylOne Evo (Medelpharm, Germany) equipped with a round, flat punch (10 mm) diameter. Each tablet had 300 mg and were compressed at a compression force of 4, 8, 12, 16, and 20 kN. Tablet weight, dimensions and hardness was measured using a Sotax Tablet Hardness Tester (Sotax, Switzerland). 1) The compression pressure was calculated using the following formula: 2) The tablet tensile strength was calculated using the following formula: 3) Determination of particle size by laser diffraction measurement A Mastersizer 2000 equipped with the sample handling unit Scirocco 2000, both from Malvern Panalytical Ltd. (Worcestershire, UK), was used to determine the particle size distribution of the samples. The instrument measures the angular variation of the intensity of light scattered as a laser beam passes through a dispersed particulate sample. Larger particles predominantly scatter light at small angles relative to the laser beam, whereas smaller particles contribute more strongly to light scattered at large angles. The following detailed settings were used for the measurements: • Optical limit: 0.1-6.0 optical limit • Timeout period: 2 min • Result range: 0.02-2000 µm • Result calculation: general purpose • Measurement time: 60 s • Measurement snap: 60.000 • Background time: 5 s • Background snap: 5.000 The porous starch particles were measured in dry powder form at 0.5 or 1.0 bar dispersion air pressure for about 30- 60 s. From the collected angular scattering intensity data, particle size distributions were calculated using the software provided by the manufacturer (version 6.00), which applies the simplified Fraunhofer approximation for evaluation [1]. The particle size was obtained as the diameter of volume-equivalent spheres and is reported as characteristic percentile values encompassing the lower 10 % (d10), 50 % (d50), and 90 % (d90) of the entire distribution. References [3] J. Vargas-Ubera, J. F. Aguilar, D. M. Gale, Appl. Opt.2007, 46, 124-132. 4) Determination of loss on drying To determine the loss on drying the IR moisture analyzer MA 150 from Sartorius (Sartorius, Germany) was used.5-6 g sample was evenly distributed over the sample tray and dried at 105°C until mass constancy. Table 3: Results of tableting experiments (starch) w/o active ingredient) Example Excipient Tensile Tensile Tensile Tensile Tensile d(0.5) Loss on strength strength at strength strength strength drying at 50 100 MPa at 150 at 200 at 250 [µm] [%, w/w] MPa MPa MPa MPa 1 Native corn 0.10 0.51 1.27 1.61 1.67 14 11.5 starch 2 StarTab 0.00* 0.24 0.72 1.32 1.83 80 10.5 3 N-Zorbit 0.58 0.66 1.43 2.81 4.44 51 8.4 (purchased) 4 StarLac 0.40 1.15 2.01 2.93 3.80 106 1.9 5 New porous 0.77 3.09 5.42 6.73 7.24 18 8.6 starch (sugar <1 %, w/w) (example 27) * No tableting possible Tableting experiments with active ingredient Propranolol hydrochloride, paracetamol, and diclofenac-Na were used as model active ingredients to demonstrate the performance of the new porous starch as multifunctional tableting excipient. The composition of the formulation was (Table 4): Ingredient Content [%, w/w] Content [%, w/w] Content [%, w/w] Active ingredient 5.0 25.0 50.0 Starch-based 94.0 74.0 49.0 excipient Sodium stearyl 1.0 1.0 1.0 fumarate Active ingredient and starch-based excipients were sieved (800µm sieve) and mixed for 8 minutes in a Turbula mixer. Sodium stearyl fumarate (previous sieving by 800 μm) is added to the mixture and the mixture is mixed for another 2 minutes. Tableting experiments were performed using a fully instrumented compaction simulator StylOne Evo (Meldelpharm, Germany) equipped with a round, flat punch (10 mm) diameter. Each tablet had 300 mg (include, for example (50% API formulation): 150 mg of active ingredient, 147 mg starch-based excipient and 3 mg sodium stearyl fumarate). Tablets were compressed at a compression force of 4, 8, 12, 16, and 20 kN (dwell time of <10 ms) The compression pressure was calculated using the following formula: The tablet tensile strength was calculated using the following formula: Disintegration time (minutes) was measured according to the United States Pharmacopoeia Chapter 701 Disintegration using a Sotax ST50 disintegration tester. Six tablets were tested in water at a temperature of 37°C. Table 5: Results 50% (w/w) active ingredient Formulation Tensile Tensile Tensile Tensile Tensile Disintegratio strength at strength at strength at strength at strength n time at 50 MPa 100 MPa 150 MPa 200 MPa at 250 150 MPa MPa 5.1 Propranolol HCl 0.09 0.37 0.84 1.31 1.65 0:57 StarTab 5.2 Propranolol HCl 0.11 0.65 1.35 2.01 2.41 2:12 N-Zorbit (as purchased) 5.3 Propranolol HCl 0.22 0.93 1.70 2.20 2.54 1:39 New porous starch (example 27) 5.4 Paracetamol -* 0.27 0.62 0.93 1.05 0:37 StarTab 5.5 Paracetamol -* -* -* -* -* - N-Zorbit (as purchased) 5.6 Paracetamol 0.22 0.89 1.77 2.44 2.93 0:30 New porous starch (example 27) 5.7 Diclofenac-Na -* 0.21 0.57 1.08 1.54 > 20 StarTab 5.8 Diclofenac-Na -* -* -* -* -* - N-Zorbit (as purchased) 5.9 Diclofenac-Na 0.15 0.64 1.45 2.21 2.81 5:32 New porous starch (example 27) Table 6: Results 25% (w/w) active ingredient Formulation Tensile Tensile Tensile Tensile Tensile Disintegratio strength at strength at strength at strength at strength n time at 50 MPa 100 MPa 150 MPa 200 MPa at 250 150 MPa MPa 6.1 Propranolol HCl 0.11 0.22 0.69 1.19 1.62 0:39 StarTab 6.2 Propranolol HCl 0.14 0.58 1.30 1.94 2.44 4:23 N-Zorbit (as purchased) 6.3 Propranolol HCl 0.27 1.32 2.53 3.24 3.61 2:06 New porous starch 6.4 Paracetamol 0.00 0.23 0.63 1.09 1.44 1:44 StarTab 6.5 Paracetamol 0.13 0.59 1.44 2.21 2.99 3:32 N-Zorbit (as purchased) 6.6 Paracetamol 0.39 1.57 2.79 3.67 4.13 0:44 New porous starch 6.7 Diclofenac-Na 0.00 0.16 0.47 0.94 1.35 2:26 StarTab 6.8 Diclofenac-Na 0.11 0.42 1.01 1.76 2.52 4:22 N-Zorbit (as purchased) 6.9 Diclofenac-Na 0.32 1.23 2.38 3.31 4.03 3:27 New porous starch Table 7: Results 5% (w/w) active ingredient Formulation Tensile Tensile Tensile Tensile Tensile Disintegratio strength at strength at strength at strength at strength n time at 50 MPa 100 MPa 150 MPa 200 MPa at 250 150 MPa MPa 7.1 Propranolol HCl 0.00* 0.24 0.64 1.02 1.39 0:28 StarTab 7.2 Propranolol HCl 0.17 0.81 1.91 2.89 3.54 2:12 N-Zorbit (as purchased) 7.3 Propranolol HCl 0.59 2.46 4.30 5.24 5.89 1:21 New porous starch 7.4 Paracetamol 0.00 0.25 0.62 1.05 1.51 0:53 StarTab 7.5 Paracetamol 0.13 0.59 1.45 2.49 3.28 4:24 N-Zorbit (as purchased) 7.6 Paracetamol 0.67 2.62 4.30 5.22 5.79 1:10 New porous starch 7.7 Diclofenac-Na 0.00 0.25 0.64 0.99 1.41 1:00 StarTab 7.8 Diclofenac-Na 0.11 0.48 1.22 2.20 3.11 5:04 N-Zorbit (as purchased) 7.9 Diclofenac-Na 0.67 2.58 4.39 5.44 6.10 2:06 New porous starch Additional tableting experiments (starch) w/o active ingredient using different dwell times N-Zorbit was purchased from Ingredion N-Zorbit has a sugar content of 20% which results in high disintegration times. In the following examples N-Zorbit was used as purchased (N-Zorbit-W0). 1. Production of Porous Starch Example H202-24) A 4 L glass reactor is charged with 2570 g deionized water.1227 g corn starch (dry weight without moisture) is added, and the mixture is stirred and heated to 61°C for 1h.1.85 g Calcium acetate monohydrate is added solved for 5min.21.1 g amylase (Termamyl 120L) or 5.3 g (Termamyl 2X) is added, and the mixture is stirred at 61°C for 2 h. Set the product medium to pH 3 with 1 N sulfuric acid and stir for another 30 minutes, then set to pH 6.5 with 1 N NaOH (H202-24-01-W0). The mixture is cooled down to ambient temperature, filtrated and washed with 1000 g of de-ionized water for 30 minutes (with one, with three wash steps). Spray drying is performed in a B290 Advanced Büchi with an inlet temperature of 135°C and an outlet temperature of 75°C. Yield: approx.110 g white powder. H202-24-01-W1 (with one wash step) H202-24-03-W3 (with three wash step) 2. Production of tablets with a hand press (dwell time of 10 s) For the preparation of tablets, a hydraulic hand press Specac Atlas Manual 15T from SPECAC INC. was used. The hand press was equipped with a biplane punch of 10 mm diameter. Prior the compression step, all powders were conditioned to the same moisture content as the native starch (8.2 ± 0.8 %). The matrix was filled with 300 mg of so prepared powder. At compression force of 400, 800, 12001600 and 2000 kg corresponding to 50, 100, 150, 200 and 250 MPa compression pressure and a retention time (dwell time) of 10 seconds. For each compression pressure, 11 tablets were prepared at identical manner. Characterization of tablets For characterizing the tablets, a Sotax ST 50 from Sotax AG with the pre-installed software q-doc i was used. Following 5 physical parameters were analyzed by Sotax ST 50: tablet hardness, diameter, thickness, and mass. The measured tablet hardness was converted in tensile strength by applying following equation: ^^ = ^^^^^^^ ^^^^^^ℎ^ ⁽^^^⁾; ^ = ^^^^^^ ℎ^^^^^^^ ⁽^⁾; ^ = ^^^^^^^^ ⁽^^⁾; ℎ = ^ℎ^^^^^^^ (^^) One sample, corresponding to one powder at produced at one compression pressure, was examined five times. The calculated mean value was used as the result. 3. Production of tablets with a compaction simulator (dwell time of <10 ms) Tableting experiments were performed using a fully instrumented compaction simulator StylOne Evo (Medelpharm, Germany) equipped with a biplan punch of 10 mm diameter. Prior the compression step, all powders were conditioned to the same moisture content (8.2 ± 0.8 %). Each tablet had 300 mg and were compressed at a compression force of 4, 8, 12, 16, and 20 kN corresponding to 50, 100, 150, 200 and 250 MPa and a dwell time of <10ms. For each compression pressure, 10 tablets were prepared at identical manner. Tablet weight, dimensions and hardness was measured using a Sotax Tablet Hardness Tester (Sotax, Switzerland). 1) The compression pressure was calculated using the following formula: 2) The tablet tensile strength was calculated using the following formula: Dryin d50 SBET CBET SLangmuir SEnvelope Sexcess σ150 Example No Comment g [µm] [m²/g] [] [m²/g] [m²/g] [] [MPa] N-Zorbit-W0 Hand press 67 0.529 46.2 0.757 0.059 9.039 4.08 H202-24-01-W1 Hand press Spray 16 0.902 71 1.268 0.245 3.681 6.87 H202-24-03-W3 Hand press Spray 16 1.073 77 1.503 0.245 4.379 7.23 N-Zorbit-W0 StylOne 67 0.529 46.2 0.757 0.059 9.039 1.68 H202-24-01-W1 StylOne Spray 16 0.902 71 1.268 0.245 3.681 4.29 H202-24-03-W3 StylOne Spray 16 1.073 77 1.503 0.245 4.379 4.61 Table 8: Properties of treated and untreated starch products determined by particle size measurements (median diameter d50), nitrogen sorption experiments (specific surface areas according to BET and Langmuir theory, SBET and S_Langmuir, and interaction constants from BET theory, C_BET) and mechanical testing (tensile strength after compression at 150 MPa, σ₁₅₀). The envelope specific surface area (S_Envelope) was calculated from the d₅₀ values assuming spherical geometry, while the relative excess specific surface area (S_excess) is given as the ratio of S_BET and S_Envelope. m Δp δD2 δP2 δH2 σ150 Example No Comment Drying [g] [mbar] [] [] [] [MPa] N-Zorbit-W0 Hand press 0.720 106 13.46 4.58 3.92 4.08 H202-24-01-W1 Hand press Spray 0.656 328 13.56 7.04 3.58 6.87 H202-24-03-W3 Hand press Spray 0.710 479 13.53 7.58 3.52 7.23 N-Zorbit-W0 StylOne 0.720 106 13.46 4.58 3.92 1.68 H202-24-01-W1 StylOne Spray 0.656 328 13.56 7.04 3.58 4.29 H202-24-03-W3 StylOne Spray 0.710 479 13.53 7.58 3.52 4.61 Table 9: Selected properties of treated and untreated starch products determined by inverse gas chromatography: sample mass m required for filling of the columns to a height of ca.9.5 cm; pressure difference Δp measured across packed columns in a flow of helium at 15 mL/min; Hansen solubility parameters (HSP) representing dispersive (δD2), polar (δP₂) and hydrogen-bonding (δH₂) components of the interactivity of the surfaces provided by the material in the column under conditions of infinite dilution. For comparison, the corresponding values for the tensile strength for tablets prepared with a compression pressure of 150 MPa (σ₁₅₀) are also shown.

Claims

Claims 1. Enzymatically hydrolyzed porous starch particles having a relative excess specific surface area of 10. 2. Enzymatically hydrolyzed porous starch particles having a polar interaction component (δP₂₎ determined by inverse gas chromatography of δP₂ < 8.8. 3. Enzymatically hydrolyzed porous starch particles having a pressure difference (Δp) across GC columns packed with starch samples and purged with helium at a flow rate of 15 mL/min of 200 mbar < Δp < 800 mbar. 4. Enzymatically hydrolyzed porous starch particles having a relative excess specific surface area of < 10 and having a polar interaction component (δP2) determined by inverse gas chromatography of δP2 < 8.8. 5. Enzymatically hydrolyzed porous starch particles having a relative excess specific surface area of < 10 and having a pressure difference (Δp) across GC columns packed with starch samples and purged with helium at a flow rate of 15 mL/min of 200 mbar < Δp < 800 mbar. 6. Enzymatically hydrolyzed porous starch particles having a relative excess specific surface area of < 10 and having a polar interaction component (δP2) determined by inverse gas chromatography of δP2 < 8,8 and having a pressure difference (Δp) across GC columns packed with starch samples and purged with helium at a flow rate of 15 mL/min of 200 mbar < Δp < 800 mbar. 7. Enzymatically hydrolyzed porous starch particles according to claims 1 to 6, wherein the particles have a relative excess specific surface area of < 7. 8. Enzymatically hydrolyzed porous starch particles according to claims 1 to 7, wherein the enzyme is selected from the group of amylases. 9. Enzymatically hydrolyzed porous starch particles according to claim 8, wherein the enzyme is selected from the group of α-amylases. 10. Enzymatically hydrolyzed porous starch particles according to claims 1 to 9, wherein the porous starch is selected from the group of corn, rice, and potato starch. 11. Enzymatically hydrolyzed porous starch particles according to claim 10, wherein the starch selected is corn starch. 12. Enzymatically hydrolyzed porous starch particles according to claim 1 to 11 having preferred not more than 5%-by weight, more preferred not more than 1.5%-by weight and even more preferred not more than 0.5%-by weight of sugar and oligosaccharide content in the porous starch particles. 13. Enzymatically hydrolyzed porous starch particles according to claims 1 to 12, giving compressed with a compression pressure of 150 MPa, a solid dosage form having a tensile strength of >4 MPa. 14. Enzymatically hydrolyzed porous starch particles according to claims 1 to 13, giving compressed with a compression pressure of 150 MPa and a dwell time of 10 s, a solid dosage form having a tensile strength of >4 MPa. 15. Dosage form comprising enzymatically hydrolyzed porous starch particles according to anyone of claims 1 to 14. 16. A directly compressed pharmaceutically dosage form according to claim 15, wherein said dosage form is a tablet, a pellet, a mini-tablet, a lozenge or other solid comprimat. 17. A directly compressed pharmaceutically dosage form according to claim 16 comprising porous starch particles present at a concentration between 1 and 98 wt.-% based on the total weight of the dosage form. 18. A directly compressed pharmaceutically dosage form according to claim 15 to 17 comprising one or more active pharmaceutically ingredients present at a concentration between 1 and 80wt.-% based on the total weight of the dosage form. 19. A directly compressed pharmaceutically dosage form according to claim 17, whereby the one or more active pharmaceutically ingredients, is/are in admixture with and/or loaded into said enzymatically hydrolyzed porous starch particles. 20. A directly compressed pharmaceutically dosage form according to claim 16 to 19, whereby the concentration of lubricant and flowing agent based on the total weight of the dosage form is not more than 10%, preferred not more than 7.5% and even more preferred not more than 5%. 21. A pharmaceutical formulation, food formulation, feed formulation, agrochemical formulation or cosmetic formulation comprising the enzymatic hydrolyzed porous starch particles according to anyone of claims 1 to 15. 22. A directly compressed pharmaceutically dosage form according to claim 15 to 20, having the following characteristics: A directly compressed pharmaceutically dosage form according to claim 16 to 20, having the following characteristics: Active pharma ingredient (API) content of 10 to 80 wt%, tensile strength of tablets (compressed at 150 MPa) of >1.5 MPa and a disintegration time of <5 minutes, but does not comprise a disintegrant. 23. A directly compressed pharmaceutically dosage form according to claim 22, wherein the API content is 25% to 50 wt%, preferably 25 wt%. 24. A directly compressed pharmaceutically dosage form according to claim 15 to 20, having the following characteristics: A directly compressed pharmaceutically dosage form according to claim 16 to 20, having the following characteristics: API content of 10 to 80 wt-%, preferably 25 to 50 wt%, more preferably 25 wt %, tensile strength of tablets (compressed at 150 MPa and a dwell time of < 10 ms) of >1.5 MPa and a disintegration time of <5 minutes, but does not comprise a disintegrant. 25. Use of enzymatically hydrolyzed porous starch particles according to claim 1 to 14 for direct compression of tablets, pellets, mini tablets, lozenges and other comprimats.