Use of sodium octenyl succinate starch as a binder in continuous wet granulation

Abstract

The present invention relates to the use of starch sodium octenyl succinate as a binder in twin-screw granulation, particularly for pharmaceutical solid dosage forms, and to the granules obtained by that process.

Description

[Technical field]

[0001] The present invention relates to the use of starch octenyl succinate, in particular sodium octenyl succinate starch, as a binder in continuous wet granulation, in particular for pharmaceutical solid dosage forms, and to the granules obtained by said process. [Background technology]

[0002] Wet granulation is widely used in the pharmaceutical industry due to its versatility and reliability in obtaining desired granule properties. It can be applied to all drugs and is considered a general method for manufacturing tablets.

[0003] Wet granulation is a process in which powders are agglomerated to form granules by the addition of a granulating liquid. It improves flowability, compactibility to form tablets, content uniformity, produces uniform particle size and shape, and minimizes the effects of minor variations in drug substance and excipient properties.

[0004] Wet granulation was originally carried out in batch processes as a low shear technique or in fluid bed granulation. Then high shear processes were introduced, making wet granulation a continuous type technique, which is much faster and more efficient.

[0005] Before this technology can be applied on an industrial scale, research was required to fully understand the continuous twin screw granulation process, especially the relationship between formulation parameters and process parameters that affect granule properties. The main focus of research on continuous twin screw wet granulation has been on the evaluation of different process parameters. However, the type of binder can also have a significant effect on granule properties and tablet product quality, such as friability. Therefore, extensive screening of different binders is essential during formulation development. Therefore, there is still a need to identify good binders suitable for use in continuous wet granulation processes. Summary of the Invention

[0006] The inventors have tested the effect of different binder types on the properties of granules produced by continuous wet granulation. These tests demonstrated that when starch sodium octenyl succinate is used as a binder, less granulation liquid is required to obtain good granule quality (granule friability and size). This behavior can be explained by the wetting properties of the binder. Less granulation liquid is required is beneficial for a faster drying process of the granules and granule quality.

[0007] In a first embodiment, the present invention relates to a method for preparing granules comprising one or more raw materials by continuous wet granulation, comprising the steps of: a) feeding raw material powders to a continuous wet granulator; b) feeding a granulation liquid to the continuous wet granulator; c) wetting the raw material powders with the granulation liquid in the presence of a binder consisting of starch octenyl succinate to obtain granules; and d) drying the granules. The continuous wet granulation is preferably extrusion granulation, more preferably biaxial granulation. In a particular embodiment, the method comprises the steps of: a1) mixing raw material powders with a powder of the binder; a2) feeding the powder mixture to a continuous wet granulator; b) feeding a granulation liquid consisting of a solvent to the continuous wet granulator; c) wetting the powder mixture with the solvent to obtain the granules; and d) drying the granules. In another particular embodiment, the method comprises the steps of: a) feeding the raw powder to a continuous wet granulator; b) feeding a granulation liquid containing the binder to the continuous wet granulator; c) wetting the raw powder with the granulation liquid to obtain the granules; and d) drying the granules. Preferably, the method further comprises the step of e) milling the dried granules. In a preferred embodiment, the octenyl succinate is 10 4 ~10 7 、 Preferably 10 4 ~10 6、 More preferably 10 5 ~10 6 To In a first preferred embodiment, the octenyl succinate has a weight average molecular weight of 100,000 to 50,000. 0、 Preferably 100,000 to 40,000 0、 More preferably, it is 100,000 to 30,000 0、 More preferably, 100,000 to 20,000 0、 Even more preferably, 15,000 0 In another preferred embodiment, the octenyl succinate has a weight average molecular weight of 300,000 to 10 6 、 More preferably, 400,000 to 90,000 0、 More preferably, 500,000 to 80,000 0、 More preferably, 550,000 to 75,000 To 0 Included, more preferably 60,000 0 In another preferred embodiment, the starch octenyl succinate is waxy maize starch octenyl succinate. The starch octenyl succinate content is 1-50% by weight, preferably 1-15% by weight, of the total dry weight of the granule. In a preferred embodiment, the raw material is a medicament active agent.

[0008] In another embodiment, the present disclosure relates to a method for preparing a pharmaceutical tablet, comprising the steps of preparing granules as disclosed above and a final step of compressing the granules to obtain a tablet.

[0009] The present disclosure also provides a method for producing a 100% aqueous 100% soluble ... 4 ~10 7 、 Preferably 10 4 ~10 6 、 More preferably 10 5 ~10 6 Toand a granule comprising starch octenyl succinate having a weight average molecular weight of 100,000 to 50,000. 0、 Preferably 100,000 to 40,000 0、 More preferably, it is 100,000 to 30,000 0、 More preferably, 100,000 to 20,000 0、 Even more preferably, 15,000 0 In another preferred embodiment, the octenyl succinate has a weight average molecular weight of 300,000 to 10 6 、 More preferably, 400,000 to 90,000 0、 More preferably, 500,000 to 80,000 0、 More preferably, 550,000 to 75,000 To 0 Included, more preferably 60,000 To 0 The weight average molecular weight is within the range of 1:1 to 1:1.

[0010] In another aspect, the present disclosure relates to the use of starch octenyl succinate as a binder for continuous wet granulation. [Brief description of the drawings]

[0011] Other features, details, and advantages are set forth in the following detailed description and drawings. [Figure 1] The median particle size of granules produced with dry binder is shown versus L / S ratio. [Diagram 2] The friability of granules made with dry binder is shown versus the L / S ratio. [Diagram 3] Hardness and disintegration time of tablets obtained with different binders. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The inventors have evaluated the binder efficiency of different modified starch types and conventional binders in continuous wet granulation. The evaluation demonstrated that starch, especially sodium octenyl succinate starch, requires less granulation fluid to obtain good granule quality. This behavior is due to the wetting properties of the binder.

[0013] The present invention provides a method for preparing a granule comprising one or more ingredients by continuous wet granulation, comprising the steps of: a) feeding raw powder into a continuous wet granulator; b) supplying a granulation liquid to the granulator; c) wetting the raw powder with a granulation liquid in the presence of a binder consisting of starch octenyl succinate to obtain granules; d) drying the granules; The present invention relates to a method comprising the steps of:

[0014] The term "granules" refers to agglomerates made from primary particles. Granules can be obtained by different methods, especially in granulation. Granules can be obtained by wet granulation, where a granulation liquid is used to agglomerate the powder. Unmilled granules may have any suitable size, preferably in the range of 0.1 to 2 mm.

[0015] The term "raw material" refers to any compound of interest. The specific nature of the compound is not important and any raw material can be used. In certain embodiments, the raw material is an active raw material.

[0016] As used herein, active ingredients include non-medicinal and pharmaceutical agents. The term "active" is typically used to refer to any ingredient of interest, such as pharmaceuticals, veterinary medicines, foods, dietary supplements, cosmetics, or pesticides. Examples of such active ingredients are pharmaceutical active ingredients, colorants, flavorings. Preferably, the active ingredient of the present invention is a pharmaceutical active agent, preferably a pharmaceutical active agent intended for human use. The pharmaceutical active agent may be a chemical molecule, but may also be a so-called "biological" active ingredient, as is the case with active ingredients based on or derived from nucleic acids, such as those derived from proteins, DNA or RNA, cells, or viruses.

[0017] The raw materials can be first milled to produce a uniform distribution of the raw materials, referred to as raw material powder, or the raw materials can be purchased directly in powder form.

[0018] Powders of additives can also be used to homogenize raw material powders. The additives are selected to ensure delivery of consistent amounts of raw materials, especially active ingredients, in a convenient unit dosage form, and to optimize the cost, ease, and reliability of the production process. The additives can be fillers (or diluents), disintegrants, lubricants, anti-adhesives, glidants, wetting and surfactants, stabilizers, pigments, flavors, sweeteners, adsorbents, and taste masking agents.

[0019] The binder according to the present invention is starch octenyl succinate, preferably sodium octenyl succinate starch.

[0020] Binders are important formulation ingredients that have adequate surface wetting to ensure adhesion and cohesion between raw powders in granules during wet granulation processes. Binders according to the present disclosure have high surface wetting. In a preferred embodiment, a binder solution (8% w / w) has a contact angle of less than 45°, preferably less than 40°, when the binder touches the surface of anhydrous dicalcium phosphate (CAS number 7757-93-9) compressed with a pressure of 20 kN, preferably with a punch of 10 mm diameter. In particular, the surface contact angle is preferably measured as described in the examples of the present disclosure.

[0021] The starch octenyl succinate of the present disclosure is a starchy material. The term "starchy material" typically refers to a raw material obtained from starch. It should be noted that the term "starch" typically refers to starch isolated from any suitable plant material, such as corn, tapioca, barley, etc., by any technique known to those skilled in the art. The isolated starch typically contains 3% by weight or less of impurities. The percentage is expressed as the dry weight of the impurities relative to the total dry weight of the isolated starch. These impurities typically include proteins, colloidal materials, and fibrous residues. Suitable plant materials include, for example, legumes, cereals, and tubers.

[0022] Octenyl succinate starch is known to those skilled in the art and is typically obtained by esterification, for example from the reaction of a starchy material with octenyl succinic anhydride.

[0023] In a preferred embodiment, the octenyl succinate starch according to the present disclosure is further partially hydrolyzed, preferably with an alpha-amylase.

[0024] In a preferred embodiment, the octenyl succinate starch according to the present disclosure is derived from a starch containing more than 50% by weight of amylopectin, expressed as dry weight relative to the total dry weight of the starch. This amylopectin content can typically be determined by those skilled in the art by potentiometric analysis of iodine absorbed by amylose to form a complex. In a preferred embodiment, the octenyl succinate starch according to the present disclosure is derived from a starch exhibiting an amylopectin content of at least 60%, more preferably at least 80%, more preferably at least 90%, more preferably at least 95%.

[0025] In a preferred embodiment, the octenyl succinate starch according to the present disclosure is derived from waxy starch, even more preferably from waxy corn starch.

[0026] In a preferred embodiment, the octenyl succinate starch according to the present disclosure is sodium octenyl succinate starch.

[0027] In a preferred embodiment, the octenyl succinate starch according to the present disclosure has a critical flocculation concentration selected in the range of 1% to 10%, preferably selected in the range of 1.5% to 5%.

[0028] The critical coagulation concentration was determined by measuring the surface tension of the binder (γ LV The surface tension was determined by measuring the surface tension (mN / m) at different concentrations. The logarithmic expression of surface tension versus binder concentration has two linear regions below and above the critical coagulation concentration. The critical coagulation concentration corresponds to the point on the surface tension curve where there is an abrupt change in slope relative to the binder concentration. Extrapolation of the respective regression lines gives the critical coagulation concentration at the intersection point.

[0029] In a preferred embodiment, the starch octenyl succinate according to the present disclosure has a Brookfield viscosity selected in the range of 10 to 1000 mPa.s, determined on a solution containing 24% by dry weight of the starch octenyl succinate relative to the total weight of the solution using a Brookfield Viscometer RVT spindle no. 1 at 20° C., 60 rpm, after 20 minutes. More preferably, this viscosity is selected in the range of 20 to 300 mPa.s, even more preferably 50 to 150 mPa.s.

[0030] The octenyl succinate starch according to the present disclosure may undergo chemical and / or physical modifications other than those preferred previously subjected to, so long as they do not interfere with the desired properties, especially in terms of safety and performance of the final powder, however, this modification is not considered essential in the present invention, and therefore the octenyl succinate starch of the present invention is preferably not further modified.

[0031] Examples of suitable commercially available starch octenyl succinates include those sold under the names CLEARGUM® CO01, CLEARGUM® COA1 or CLEARGUM® CO03 (Roquette). In a preferred embodiment, CLEARGUM® CO01 has a Brookfield viscosity selected in the range of 90 to 200 mPa.s and CLEARGUM® CO03 has a Brookfield viscosity selected in the range of 20 to 100 mPa.s.

[0032] As a binder, 10 4 ~10 7 、 Preferably 10 4 ~10 6 、 More preferably 10 5 ~10 6 To Use of an octenyl succinate salt having the weight average molecular weight included results in good granule quality with only a small amount of granulation fluid.

[0033] According to the present invention, the octenyl succinate starch is 10 4 ~10 7 、 Preferably 10 4 ~10 6 、 More preferably 10 5 ~10 6 To In a first preferred embodiment, the octenyl succinate has a weight average molecular weight of 100,000 to 50,000. 0、 Preferably 100,000 to 40,000 0、 More preferably, 100,000 to 30,000 0、 More preferably, 100,000 to 20,000 0、 Even more preferably, 15,000 0 In another preferred embodiment, the octenyl succinate has a weight average molecular weight of 300,000 to 10 6 、 More preferably, 400,000 to 90,000 0、 More preferably, 500,000 to 80,000 0、 More preferably, 550,000 to 75,000 To 0 Included, more preferably 60,000 0 It has a weight average molecular weight.

[0034] In a preferred embodiment, the octenyl succinate is CLEargum® CO03 (CAS N° 66829-29-6, Roquette), CLEargum® CO01 (CAS N° 66829-29-6), or CLEargum® COA1 (CAS N° 52906-93-1).

[0035] The weight average molecular weight can be determined by the skilled artisan by dissolving the sample in an elution solution consisting of 0.1 mol / L aqueous sodium nitrate (degassed HPLC grade water) solution (Merck ref:6546) containing 0.02% sodium azide (Aldrich ref.19.993-1) filtered through a 0.02 micrometer filter and analyzing by size exclusion chromatography with a MALS detector. The MW distribution is recorded and the average value of the complete weight distribution is calculated. As a non-limiting example, the high performance liquid chromatography unit is equipped with a high pressure isocratic pump (WATERS515 type), an autosampler (WATER717+ type), a differential refractometer (WATERS2414 type), a column oven, a multi-angle static light scattering (MALS) detector (DAWN HELEOS II (Wyatt)). In a preferred embodiment, the analysis is carried out for 110 minutes with an injection volume of 100 μL and a mobile phase output of 0.5 mL / min at a temperature of 40° C. A normalization step is performed by preparing a normalization sample by adding 10 mL of dissolution solvent to 40 mg of Pullulan P50 Shadex Standard Kit P82 (Waters-ref.WATO34207) and incubating at 100°C for 30 minutes with gentle stirring. 100 μL of the resulting solution is analyzed by the size exclusion chromatography. Samples are then prepared by adding 10 mL of dissolution solvent to 100 mg of sample and incubating at 100°C for 30 minutes and analyzed by the size exclusion chromatography. Molecular weights are calculated with the Astra software.

[0036] In a particular embodiment, the starch octenyl succinate is present in a concentration comprised between 1 and 50% by weight, preferably between 1 and 10% by weight, more preferably 5% by weight of the total dry weight of the granule.

[0037] In a particular embodiment, the raw materials are granulated using the dry addition method of the binder. In this particular embodiment, the binder in powder form consisting of starch octenyl succinate as disclosed above is mixed with the raw material powder. The resulting powder mixture is then fed into a continuous granulator. A granulation liquid is fed into the continuous granulator. In this case, the granulation liquid is preferably a solvent selected from the group consisting of water, organic solvents such as ethanol, isopropanol, methanol, acetone, and mixtures thereof, preferably mixtures containing at least 50% water, more preferably the granulation liquid is water. The granulation liquid should be volatile so that it can be easily removed by drying. Granules are obtained by wetting the powder mixture with the granulation liquid. Thus, in the case of dry addition of the binder, the raw material powder is mixed with the binder powder and then fed into a continuous wet granulator. The granulation liquid is then fed into the barrel of the continuous granulator. The raw material and binder powder mixture is then wetted with the granulation liquid.

[0038] In another specific embodiment, the raw material is granulated using wet addition of a binder. In this specific method, the raw material powder is fed into a continuous wet granulator. A granulation liquid containing the binder, which is made of starch octenyl succinate, is fed into the continuous wet granulator. The raw material powder is then moistened with the granulation liquid containing the binder.

[0039] In this particular embodiment, the granulation liquid containing the binder is prepared by dissolving starch octenyl succinate in a solvent as described above. The solvent should be volatile so that it is easily removed by drying. Preferably, the solvent is selected from the group consisting of ethanol, water, isopropanol, methanol, acetone, and mixtures thereof, preferably mixtures containing at least 50% water, more preferably the solvent is water.

[0040] In a preferred embodiment, the granulation liquid containing the starch octenyl succinate has a viscosity of 50 to 300 mPa.s -1 , preferably 50 to 150 mPa.s -1and more preferably has a Brookfield viscosity at 25° C. comprised within the range of 74 mPa.s. The viscosity is measured with a Brookfield digital viscometer DV-I at a rotation speed of 100 rpm.

[0041] The granulation is carried out in a continuous wet granulator, which is capable of combining the wet granulation process steps in one machine, and preferably the powder undergoes nucleation and wetting, compaction and breakage along the length of the granulator barrel. In particular, the granulation is carried out within 5 to 20 seconds. The granulator is preferably an extruder without a die located at the end of the barrel.

[0042] In a preferred embodiment, the granulation is carried out in a twin-shaft granulator. In general, a twin-shaft granulator has two co-rotating shafts inside a closed barrel, which is divided into different parts, in particular a feeding zone and two transfer zones, including a conveying zone and a mixing zone. The powder mixture is fed through a feeder and passes through a barrel with various mixing and conveying zones. Agglomeration occurs after adding the granulation liquid to the barrel of the granulator. The conveying zone transports the material, while the kneading zone densifies the material.

[0043] In a more preferred embodiment, the twin-screw granulation is carried out at a shaft speed comprised between 100 and 1500 rpm, between 200 and 900 rpm.

[0044] In another preferred embodiment, the twin-screw granulation is carried out with a throughput comprised between 5 and 20 kg / h.

[0045] In another particular embodiment, the continuous wet granulation is carried out at a temperature between 4 and 100°C, preferably at 30°C.

[0046] Finally, the granules can be dried using common techniques known to those skilled in the art to an appropriate moisture content, preferably to a loss on drying value of 0-20% by weight of water, more preferably 1-3% by weight of water.

[0047] Drying is preferably carried out in a fluidized bed for 10 to 180 minutes at a temperature comprised between 20 and 120° C., preferably at 60° C. The water content is measured using a Sartorius moisture analyzer MA150 in automatic mode at a drying temperature of 120° C.

[0048] The dried granules can then be subjected to a milling step to obtain a particle size distribution suitable for further processing, preferably to obtain a granule size in the range of 150-1400 μm as measured by dynamic image analysis. Preferably, the sizing step is performed using a low shear screening mill, e.g. U5Comil.

[0049] The dried granules can then be prepared, for example, for oral administration in solid dosage forms including tablets, capsules, pills, troches, cachets and the like.

[0050] Therefore, the present disclosure also relates to a method for preparing a pharmaceutical tablet, wherein the granules obtained by the aforementioned method are compressed into a tablet. In another embodiment, the granules are encapsulated in a capsule.

[0051] A lubricant can be added before the compression step to facilitate tablet ejection. As used herein, the term "lubricant" refers to any pharma- ceutically acceptable agent that reduces surface friction, lubricates the surface of granules, reduces the tendency for static buildup, and / or reduces wear and tear of granules. Preferably, the lubricant is magnesium stearate.

[0052] Preferably, the compression step is carried out by a tablet press, for example by a single punch press or a rotary tablet press, preferably by a rotary tablet press, and preferably the compression step is carried out in a machine that typically comprises two steel punches in a steel die cavity. In forming a tablet, the dried granules are subjected to pressure by the punches in the cavity.

[0053] The present disclosure also relates to granules obtainable by the process for preparing the granules described above, the granules comprising one or more ingredients and a binder as described above.

[0054] In another aspect, the present invention relates to a pharmaceutical tablet obtained by the method for preparing a tablet as described above. The pharmaceutical tablet comprises the granules as described above. In another embodiment, the pharmaceutical tablet comprises one or more ingredients and a binder as described above.

[0055] Preferably, the pharmaceutical tablet according to the present invention has a friability of less than 5%, preferably less than 2%, more preferably 5-1%. The friability can be measured by a person skilled in the art according to the method described in Eur.Ph. (PTF E Pharma Test, Hainburg, Germany) at a speed of 25 rpm for 4 minutes. The percentage of weight loss was expressed as the friability of the tablet.

[0056] Other characteristics and advantages of the invention will emerge more clearly from a reading of the examples which follow, which are intended to illustrate but not limit the invention. EXAMPLES

[0057] 1. Granule friability and particle size Granulation experiments were carried out using a powder-to-tablet line continuous twin screw granulator (ConsiGma™-25 system, GEA Pharma Systems).

[0058] The powder was fed through a feeder at a feeder rate of 20 kg / hr.

[0059] In the twin shaft configuration there are two blocks of 6 kneading elements separated by a conveying element (1.5 L / D) with a stagger angle of 60°. In another configuration, the last kneading element in each kneading zone is staggered at an angle of 90° and tested. The processing temperature is 30°C and the shaft speed is 300 rpm.

[0060] Dicalcium phosphate anhydrous (DCP) is hmm Granulation was performed using both dry (as dry powder in a pre-blend) and wet (as aqueous solution) addition of binders. The concentration of dry binder was 5% by dry weight of the total dry weight of the powder mixture. With wet addition, the concentration of binder in the granules was 1.44% by dry weight of the total dry weight of the granule. In addition, depending on the viscosity of the binder solution, higher concentrations (3% and / or 5%) could be achieved for certain binders. The addition methods (wet and dry) and different binders (clearg The effect of umCO01 (600000 g / mol), cleargumCO03 (150000 g / mol), Glucidex2, Glucides6, HPMC E5, HPMC E15, Lycatab DSH, Lycatab PGS, Lycoat RS720, PVP K12, PVP K30, PVP K90 on granule properties (granule friability and particle size distribution) was evaluated. Granule friability was evaluated using an abrasive drum equipped abrasion tester (PTFE Pharmatest). Granule particle size was analyzed by dynamic image analysis using a QICPIC particle size analyzer (Sympatec, Germany).

[0061] Generally, the water or liquid content is expressed as the liquid to solid ratio (L / S). The liquid to solid (L / S) ratio was varied from 0.105 to 0.225. The granules were tray dried until a loss on drying of 1-3 wt% was obtained.

[0062] Dry addition method For the dry doping method with a constant binder concentration of 5%, the particle size distribution was significantly affected by the L / S ratio, with the higher the L / S ratio the larger the granules. CleargumCO01 produced granules with a very large median particle size (d50) (4026 μm) at a lower L / S ratio (0.155) compared to the other binders. This can be attributed to the amphiphilic properties of this binder. The d50 values ​​of the granules obtained with the dry doped binders are shown in Figure 1.

[0063] The L / S ratio also had a strong effect on friability, as higher L / S ratios resulted in less friable granules for each binder. When more granulation liquid was added, more binder was in contact with the fluid, and therefore a larger proportion of the binder was available to participate in the interaction. The friability of granules made with dry binders is shown in Figure 2.

[0064] Since Cleargum can be processed at lower L / S ratios, less water is required to activate the binder properties of this binder. Therefore, it can be said that the inherent binder performance of Cleargum in a continuous process is considered to be higher compared to other binders that require more liquid. The friability of the resulting granules is low (<30%).

[0065] Wet addition method The granule size distribution of the wet-added binder varied depending on both the L / S ratio and the binder content in the dried granules. Increasing the L / S ratio and increasing the binder concentration in the dried granules resulted in larger granules. However, over-wet granules with particularly high median particle size were observed (>10,000 μm) when operating with Cleargum CO03 at the highest L / S ratio.

[0066] Notably, the L / S ratio range in which Cleargum CO03 and Cleargum CO01 can be processed is lower compared to the other binders, indicating that less granulation fluid is required for activation of these binders.

[0067] 2. Binder characterization: Binder wettability The Sessile Drop Method was applied to measure the wettability of the binders by surface contact angle measurements using a Drop Shape Analyzer (DSA30, KRUSS GmbH, Hamburg, Germany). Two different types of experiments were performed: (i) Anhydrous dicalcium phosphate (DCP) (Calipharm® A, obtained from Innophos, Chicago Heights, USA) was compressed with a 10 mm diameter punch at a pressure of 20 kN using a compression simulator (Styl'One Evolution, Medelpharm, Lyon, France). Tabletting of pure DCP resulted in high ejection forces without high force application. This resulted in high tablet porosity. Aqueous binder dispersions were prepared (8% w / w) and 5 μL of each dispersion was placed on a DCP tablet. The contact angle (°) was measured when the drop touched the surface of the tablet (CADCP). Due to the high porosity, it was not possible to obtain an angle of 30 seconds (30 s). Five repeated measurements were performed. (ii) A drop (8% w / w) of each binder dispersion was also placed on a polytetrafluoroethylene (PFTE) surface. As PETE is an inert material, no difference in angle over time was observed. Therefore, the contact angle (°) was measured only when the drop touched the surface (CAPFTE). Measurements were performed in triplicate.

[0068] [Table 1]

[0069] Table 1: Contact angles (°) of different binders measured when a droplet touched the surfaces of CADCP and CAPFTE.

[0070] Wetting of hydrophobic polytetrafluoroethylene (PFTE) surfaces with starch octenyl succinate solutions yielded the smallest contact angles, thus indicating good wetting properties of PFTE (Table 1).

[0071] These values ​​are confirmed by using a concrete model based on densified anhydrous dicalcium phosphate tablets (CADCP). We find large differences between all binders tested. The binder based on starch octenyl succinate shows a contact angle of 32.8° (Table 1).

[0072] Dry and wet binder characterization showed that Cleargum has a specific wetting behavior: when Cleargum solution (starch octenyl succinate) was measured against DCP, a low contact angle was observed, which may indicate processability at lower L / S ratios compared to other binders.

[0073] 3. Tablet Characterization Mannitol was granulated with dry addition of binder. The concentration of dry binder was 5% by dry weight of the total dry weight of the powder mixture. The milled granules were mixed with 1.2% w / w magnesium stearate in a tumble blender (T2F, W, A. Bachofen, Basel, Switzerland) before tableting. Tablets were prepared with a 10 mm punch using a Styl'One compression simulator. Tablets were compressed with five different main compression forces: 5 kN, 10 kN, 15 kN, 20 kN, 25 kN and tested for disintegration time in 900 mL demineralized water at 37 ± 0.1 °C, n = 5 (Pharmatest, Hainburg, Germany). Tablet hardness (n = 5) was also measured using a hardness tester (Type HT10, Sotax, Basel, Switzerland).

[0074] Mannitol tablets granulated with Cleargum CO01 exhibit high hardness and short disintegration time (Figure 3).

[0075] conclusion The effect of different binder types and addition methods on the quality of granules produced by twin screw granulation was evaluated. The study demonstrated that different binder types and addition methods had different effects on granule properties. From an industrial point of view, dry addition of binder is preferred due to ease of production.

[0076] The Cleargum CO01 and Cleargum CO03 binders required a low L / S ratio to obtain good granule quality. Less granulation liquid was required to obtain good granule quality, which favors drying of the granules. This low L / S ratio can be explained by the efficient wetting of the powder bed by these binders.

Claims

1. 1. A method for preparing a granule comprising one or more ingredients by continuous wet granulation, comprising: a) feeding raw powder into a continuous wet granulator; b) supplying a granulation liquid to the continuous granulator; c) wetting the raw powder with the granulation liquid in the presence of a binder consisting of starch octenyl succinate to obtain the granules; d) drying the granules; Including, The method wherein the granulation liquid is water or a mixture comprising at least 50% water and an organic solvent.

2. The method of claim 1 , wherein the continuous wet granulation is extrusion granulation.

3. Step a) comprises: a1) mixing a raw material powder with a powder of the binder to obtain a powder mixture; a2) feeding the powder mixture into a continuous wet granulator; The method of claim 1 or 2, comprising:

4. A method as described in claim 1 or 2, wherein in step b), the granulation liquid and the binder are supplied to the continuous granulator.

5. The octenyl succinate is 10 ４ The method according to any one of claims 1 to 4, having a weight average molecular weight comprised between 107 and 107.

6. 6. The method of claim 5, wherein the octenyl succinate has a weight average molecular weight comprised between 100,000 and 500,000.

7. The method of claim 5, wherein the octenyl succinate has a weight average molecular weight comprised between 300,000 and 106.

8. The method of any one of claims 1 to 7, further comprising the step of: e) milling the dried granules.

9. The method according to any one of claims 1 to 8, wherein the octenyl succinate starch is waxy corn octenyl succinate starch.

10. 10. The method according to any one of claims 1 to 9, wherein the starch octenyl succinate content is from 1 to 50% by weight of the total dry weight of the granules.

11. The method according to any one of claims 1 to 10, wherein the ingredient is a pharma- ceutical active agent.

12. A method for preparing a pharmaceutical tablet, comprising the steps of preparing granules according to the method of any one of claims 1 to 11, and a final step of compressing said granules to obtain a tablet.

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