Use of sodium starch octenylsuccinate as a binder in continuous wet granulation

Abstract

The present invention relates to use of sodium starch octenylsuccinate as a binder in twin-screw granulation, in particular to use of sodium starch octenylsuccinate in pharmaceutical solid dosage forms and granules obtainable by the method.

Description

Technical Field

[0001] The present invention relates to the use of octenyl succinate starch, in particular the use of sodium octenyl succinate starch as a binder in continuous wet granulation, in particular its use in pharmaceutical solid dosage forms and granules obtainable by the method. Background Art

[0002] Wet granulation is widely used in the pharmaceutical industry due to its flexibility and reliability in achieving desired granule properties. Wet granulation can be applied to all drug substances and is considered a universal way to produce tablets.

[0003] Wet granulation is a process in which powders are agglomerated by adding a granulating liquid to form granules. Wet granulation improves flow, compactability to form tablets, content uniformity, produces uniform particle size and shape, and minimizes the effects of small variations in the properties of the drug substance and excipients.

[0004] Wet granulation was initially performed as a low shear technique in a batch process or in conjunction with fluidized bed granulation. High shear processes were then introduced and made wet granulation a much faster and more efficient continuous technique.

[0005] Research is needed to fully understand the continuous twin-screw granulation process, especially the relationship between the formulation and the process parameters that affect the properties of the granules before the technology can be applied on an industrial scale. Research on continuous twin-screw wet granulation has mainly focused on the evaluation of different process parameters. However, the type of binder may also have a major impact on the properties of the granules and the product quality of the tablets (such as friability). Therefore, extensive screening of different binders is necessary 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 studied the effect of different binder types on the properties of granules produced via continuous wet granulation. They showed that when sodium starch octenylsuccinate was used as a binder, a lower amount of granulation liquid was required to achieve good granule quality (granule friability and size). This performance can be explained by the wetting properties of the binder. The need for a lower amount of granulation liquid is beneficial for a faster drying process of the granules and the quality of the granules.

[0007] In a first embodiment, the present invention relates to a method for preparing granules containing one or more substances by continuous wet granulation, the method comprising the following steps: a) feeding a substance powder to a continuous wet granulator, b) feeding a granulation liquid to the continuous wet granulator, c) moistening the substance powder with the granulation liquid in the presence of a binder consisting of starch octenylsuccinate to obtain granules, and d) drying the granules. The continuous wet granulation is preferably extrusion granulation, more preferably twin-screw granulation. In a specific embodiment, the method comprises the following steps: a1) mixing a substance powder 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) moistening the powder mixture with the solvent to obtain the granules, and d) drying the granules. In another specific embodiment, the method comprises the following steps: a) feeding the substance powder to a continuous wet granulator, b) feeding a granulation liquid containing the binder to the continuous wet granulator, c) wetting the substance powder with the granulation liquid to obtain the granules, and d) drying the granules. Preferably, the method as previously described further comprises the step e) grinding the dried granules. In a preferred embodiment, the weight average molecular weight of the octenyl succinate is between: 10 4 with 10 7 g / mol, preferably 10 4 with 10 6 g / mol, more preferably 10 5 with 10 6 g / mol. In a first preferred embodiment, the weight-average molecular weight of the octenyl succinate is between 100,000 and 500,000 g / mol, preferably between 100,000 and 400,000 g / mol, further preferably between 100,000 and 300,000 g / mol, further preferably between 100,000 and 200,000 g / mol, yet more preferably still 150,000 g / mol. In another preferred embodiment, the weight-average molecular weight of the octenyl succinate is between 300,000 and 100,000 g / mol. 6g / mol, more preferably 400,000 to 900,000 g / mol, further preferably 500,000 to 800,000 g / mol, further preferably 550,000 to 750,000 g / mol, more preferably 600,000 g / mol. In another preferred embodiment, the octenyl succinate starch is waxy corn octenyl succinate starch. The content of the octenyl succinate starch is preferably 1% to 50% by weight, preferably 1% to 15% by weight, of the total dry weight of the granules. In a preferred embodiment, the substance is a pharmaceutically active agent.

[0008] In another embodiment, the present disclosure relates to a process for the preparation of pharmaceutical tablets, said process comprising the steps of preparing granules as previously disclosed and a final step of compressing said granules in order to obtain tablets.

[0009] The present disclosure also relates to a granular material and a pharmaceutical tablet comprising the granular material, wherein the granular material comprises one or more substances and octenyl succinate starch, wherein the weight average molecular weight of the octenyl succinate starch is between: 10 4 with 10 7 g / mol, preferably 10 4 with 10 6 g / mol, more preferably 10 5 with 10 6 g / mol. In a first preferred embodiment, the weight-average molecular weight of the octenyl succinate is between 100,000 and 500,000 g / mol, preferably between 100,000 and 400,000 g / mol, further preferably between 100,000 and 300,000 g / mol, further preferably between 100,000 and 200,000 g / mol, yet more preferably still 150,000 g / mol. In another preferred embodiment, the weight-average molecular weight of the octenyl succinate is between 300,000 and 10 6 g / mol, more preferably 400,000 to 900,000 g / mol, further preferably 500,000 to 800,000 g / mol, further preferably 550,000 to 750,000 g / mol, more preferably 600,000 g / mol.

[0010] In another aspect, the present disclosure relates to the use of octenyl succinate starch as a binder for continuous wet granulation. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Additional features, details, and advantages will be seen in the following detailed description and accompanying drawings, in which:

[0012] Figure 1 : Median particle size of granules produced with dry binder as a function of L / S ratio.

[0013] Figure 2 : Friability of granules produced with dry binders as a function of L / S ratio.

[0014] Figure 3 : Hardness and disintegration time of tablets obtained with different binders. DETAILED DESCRIPTION

[0015] The inventors evaluated the binder effectiveness of different modified starch types and conventional binders in continuous wet granulation. They showed that starch (particularly sodium starch octenylsuccinate) required lower amounts of granulation liquid to produce good granule quality. This performance was attributed to the wetting properties of the binder.

[0016] The present invention relates to a method for preparing granules containing one or more substances by continuous wet granulation, the method comprising the following steps:

[0017] a) feeding the material powder to a continuous wet granulator;

[0018] b) feeding a granulating liquid to the granulator,

[0019] c) wetting said substance powder with said granulating liquid in the presence of a binder comprising starch octenylsuccinate so as to obtain granules,

[0020] d) drying the granules.

[0021] The term "granulate" refers to an agglomerate made from primary particles. Granules can be obtained by different methods, in particular granulation. Granules can be obtained by wet granulation, in which a granulating liquid is used to agglomerate the powder. Unground granules can have any suitable size, preferably in the range of 0.1 to 2 mm.

[0022] The term "substance" refers to any compound of interest. The specific nature of the compound is not critical, and any substance can be used. In certain embodiments, the substance is an active substance.

[0023] Active substances as used herein include non-pharmaceuticals and pharmaceuticals. The term "active substance" is generally used to refer to any substance of interest, such as a drug, veterinary medicine, food, nutritional substance, cosmetic or agricultural chemical. Examples of such active substances are pharmaceutical active ingredients, colorants, flavorings. Preferably, the active substance of the present invention is a pharmaceutical active agent, preferably intended for use in humans. Pharmaceutical active agents can be chemical molecules, but can also be so-called "biological" active ingredients, as for example with active substances based on or derived from proteins, nucleic acids (such as those derived from DNA or RNA) cells or viruses.

[0024] The substance may be initially ground to produce a uniform distribution of the substance (referred to as a powder of the substance). The substance may also be purchased directly in powder form.

[0025] The substance powder can be homogenized with an excipient powder. The excipient is selected to ensure that a consistent amount of substance (particularly active substance) is delivered in a convenient unit dosage form and to optimize the cost, ease, and reliability of the manufacturing process. The excipient can be a filler (or diluent), a disintegrant, a lubricant, an antiadherent, a glidant, a wetting agent and a surfactant, a stabilizer, a pigment, a flavoring, a sweetener, an adsorbent, and a taste masking agent.

[0026] The binder according to the present invention is starch octenylsuccinate, preferably sodium starch octenylsuccinate.

[0027] Binders are key formulation components that provide adequate surface wetting to ensure adhesion and cohesion between the material powders in the granulate during wet granulation. The binders according to the present disclosure have high surface wettability. In a preferred embodiment, when the binder touches the surface of anhydrous dicalcium phosphate, the contact angle of the binder solution (8% w / w) with anhydrous dicalcium phosphate (CAS No. 7757-93-9) is less than 45°, preferably 40°, when the binder touches the surface of the anhydrous dicalcium phosphate, which is compacted at a pressure of 20 kN, preferably with a 10 mm diameter punch. In particular, the surface contact angle is preferably measured as described in the examples of the present disclosure.

[0028] The octenylsuccinate starch of the present disclosure is a starchy material. The expression "starchy material" conventionally refers to a material obtained from starch. It is reminded that the expression "starch" conventionally refers to starch isolated from any suitable plant source (such as corn, cassava, barley) by any technique well known to those skilled in the art. Isolated starch typically contains no more than 3% 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 matter, and fiber residues. Suitable plant sources include, for example, legumes, cereals, and tubers.

[0029] Octenyl succinate starch is well known to those skilled in the art. Octenyl succinate starch can generally be obtained by esterification, for example from the reaction of starchy material with octenyl succinic anhydride.

[0030] In a preferred embodiment, the octenylsuccinate starch according to the present disclosure is also partially hydrolyzed, preferably by alpha-amylase.

[0031] In a preferred embodiment, the octenyl succinate starch according to the present disclosure is derived from a starch containing more than 50% amylopectin, expressed as dry weight relative to the total dry weight of the starch. This amylopectin content can be conventionally determined by a person skilled in the art by potentiometric analysis of iodine uptake by amylose to form complexes. 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%, further preferably at least 80%, further preferably at least 90%, further preferably at least 95%.

[0032] In a preferred embodiment, the octenylsuccinate starch according to the present disclosure is derived from a waxy starch, even more preferably from waxy corn starch.

[0033] In a preferred embodiment, the octenyl succinate starch according to the present disclosure is sodium starch octenyl succinate.

[0034] In a preferred embodiment, the critical aggregation concentration of the octenylsuccinate starch according to the present disclosure is selected in the range of 1% to 10%, preferably in the range of 1.5% to 5%.

[0035] The critical aggregation concentration has been determined by using a tensiometer with a Wilhelmy plate K12 measures the surface tension (γ LV , mN / m) is determined. In the surface tension of logarithmic expression, there are two linear states below and above the critical aggregation concentration relative to the binder concentration. The critical aggregation concentration corresponds to the point on the curve of the surface tension relevant to the binder concentration with a sharp gradient. The extrapolation of the corresponding regression line produces the critical aggregation concentration at the intersection.

[0036] In a preferred embodiment, the octenyl succinate starch according to the present disclosure has a Brookfield viscosity selected in the range of 10 to 1000 mPa.s; the viscosity is determined at 20°C after 20 minutes using a Brookfield viscometer RVT with spindle No. 1 at 60 rpm on a solution containing 24% dry weight of the octenyl succinate starch relative to the total dry weight of the solution. More preferably, this viscosity is selected in the range of 20 to 300 mPa.s, and more preferably 50 to 150 mPa.s.

[0037] The octenyl succinate starch according to the present disclosure may undergo chemical and / or physical modifications other than the preferred modifications to which it has been previously exposed, as long as this does not interfere with the desired properties, in particular with regard to the safety and efficacy of the final powder. However, and since this does not appear to be necessary in the present invention, the octenyl succinate starch of the present invention is preferably not further modified.

[0038] Examples of suitable octenylsuccinate starches are commercially available and may be found under the name CO01, or In a preferred embodiment, having a Brookfield viscosity selected within the range of 90 to 200 mPa.s, and It has a Brookfield viscosity selected within the range of 20 to 100 mPa·s.

[0039] Octenyl succinates with a weight average molecular weight (Mw) between 10 and 20 nm used as binders produced good granular quality with only small amounts of granulating liquid. 4 with 10 7 g / mol, preferably 10 4 with 10 6 g / mol, more preferably 10 5 with 10 6 g / mol.

[0040] According to the present invention, the weight average molecular weight of the octenyl succinate starch is between: 10 4 with 10 7 g / mol, preferably 10 4 with 10 6 g / mol, more preferably 10 5 with 10 6 g / mol. In a first preferred embodiment, the weight-average molecular weight of the octenyl succinate is between 100,000 and 500,000 g / mol, preferably between 100,000 and 400,000 g / mol, further preferably between 100,000 and 300,000 g / mol, further preferably between 100,000 and 200,000 g / mol, yet more preferably still 150,000 g / mol. In another preferred embodiment, the weight-average molecular weight of the octenyl succinate is between 300,000 and 100,000 g / mol. 6g / mol, more preferably 400,000 to 900,000 g / mol, further preferably 500,000 to 800,000 g / mol, further preferably 550,000 to 750,000 g / mol, more preferably 600,000 g / mol.

[0041] In a preferred embodiment, the octenyl succinate is CO 03 (CAS N°66829-29-6; Roquette), CO 01 (CAS No. 66829-29-6) or COA1 (CAS No. 52906-93-1).

[0042] The weight-average molecular weight can be determined by one skilled in the art by dissolving a sample in an elution solvent consisting of an aqueous solution of 0.1 mol / L sodium nitrate (Merck ref.: 6546) containing 0.02% sodium azide (Aldrich ref. 19.993-1), filtering through a 0.02 μm filter (degassed HPLC-grade water), and analyzing by size exclusion chromatography equipped 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 HPLC unit is equipped with a high-pressure isocratic pump (WATERS model 515), an autosampler (WATER 717+ model), a differential diffractometer (WATERS model 2414), a column oven, and a multi-angle static light scattering (MALS) detector (DAWN HELEOS II (WYATT)). In a preferred embodiment, analysis is performed at a temperature of 40°C over a period of 110 minutes using an injection volume of 100 μL and a mobile phase output of 0.5 mL / min. The standardization step was performed by preparing a standardized sample by adding 10 mL of elution solvent to 40 mg of Pullulan P50 Shadex Standard Kit P82 (Waters - ref. WATO34207) and incubating at 100°C for 30 minutes with low temperature stirring. 100 μL of the resulting solution was analyzed by size exclusion chromatography. The sample was then prepared by adding 10 mL of elution solvent to 100 mg of the sample and incubating at 100°C for 30 minutes, and analyzed by size exclusion chromatography. Molecular weights were calculated using Astra software.

[0043] In a particular embodiment, the octenyl succinate starch is present in a concentration of 1 to 50 wt%, preferably 1 to 10 wt%, more preferably 5 wt% of the total dry weight of the granule.

[0044] In a preferred embodiment, the material is granulated using a dry-addition method of the binder. In this particular embodiment, a binder consisting of starch octenylsuccinate, as previously disclosed in powder form, is mixed with the 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 a solvent, preferably selected from the group consisting of water, organic solvents such as ethanol, isopropanol, methanol, acetone, and mixtures thereof, preferably a mixture containing at least 50% water, and more preferably the granulation liquid is water. The granulation liquid must be volatile to facilitate removal by drying. The powder mixture is moistened with the granulation liquid to obtain a granulate. Thus, in the case of a dry-addition binder, the material powder is mixed with the binder powder before feeding into the continuous wet granulator. The granulation liquid is then fed into the barrel of the continuous granulator. The material and binder powder mixture is then moistened with the granulation liquid.

[0045] In another specific embodiment, the material is granulated using wet addition of a binder. In this specific method, the material powder is fed into a continuous wet granulator. A granulation liquid is fed into the continuous wet granulator, the granulation liquid containing a binder consisting of starch octenylsuccinate as previously described. The material powder is then moistened with the granulation liquid containing the binder.

[0046] In this particular embodiment, the granulation liquid containing the binder is prepared by dissolving starch octenylsuccinate as previously described in a solvent. The solvent must be volatile to facilitate removal by drying. Preferably, the solvent is selected from the group consisting of ethanol, water, isopropanol, methanol, acetone, and mixtures thereof, preferably a mixture comprising at least 50% water, more preferably the solvent is water.

[0047] In a preferred embodiment, the Brookfield viscosity of the granulation liquid containing the octenyl succinate starch at 25°C is 50 to 300 mPa.s -1 , preferably 50 to 150 mPa.s -1 , more preferably 74 mPa.s. The viscosity is measured using a Brookfield digital viscometer DV-I at a rotation speed of 100 rpm.

[0048] The granulation is carried out in a continuous wet granulator. A continuous wet granulator combines the wet granulation process steps in a single device; preferably, the powder undergoes nucleation and wetting, consolidation and fracture, and abrasion along the length of the granulator barrel. In particular, the granulation is performed for 5 to 20 seconds. The granulator is preferably an extruder without a die at the end of the barrel.

[0049] In a preferred embodiment, the granulation is carried out in a twin-screw granulator. Typically, a twin-screw granulator comprises two co-rotating screws within a closed barrel, which are divided into different sections, in particular a feeding zone and two transition zones containing a conveying zone and a mixing zone. The powder mixture is fed through the feeder and through the barrel having various mixing and conveying zones. Coagulation occurs after the granulation liquid is added to the barrel of the granulator. The conveying zone transports the material, while densification of the material occurs in the kneading zone.

[0050] In a more preferred embodiment, the twin-screw granulation is performed at a screw speed of 100 to 1500 rpm, 200 to 900 rpm.

[0051] In another preferred embodiment, the twin-screw granulation is performed at a throughput of 5 to 20 kg / h.

[0052] In another particular embodiment, the continuous wet granulation is carried out at a temperature of 4 to 100°C, preferably 30°C.

[0053] Finally, the granules may be dried using common techniques known to those skilled in the art to an appropriate moisture content, preferably a loss on drying value of 0 to 20 wt% water, more preferably 1 to 3 wt% water.

[0054] Drying is preferably carried out in a fluidized bed within 10 to 180 minutes at a temperature of 20 to 120° C., preferably 60° C. The water content is measured using a Sartorius moisture analyzer MA150 in automatic mode at a drying temperature of 120° C.

[0055] The dried granulate can then be submitted to a grinding step to obtain a suitable particle size distribution for subsequent processing, preferably a particle size in the range of 150 to 1400 μm as measured by dynamic image analysis. The classification step is preferably achieved using a low shear screen mill such as a U5 Comil.

[0056] The dried granules can then be prepared in solid dosage forms, such as for oral administration. Solid dosage forms include tablets, capsules, pills, lozenges, cachets, and the like.

[0057] Therefore, the present disclosure also relates to a process for the preparation of pharmaceutical tablets, wherein the resulting granules obtained by the process as previously described are compressed into tablets.In another embodiment, the granules are enclosed in a capsule.

[0058] A lubricant may be added prior to the compression step to facilitate tablet ejection. As used herein, the term "lubricant" refers to any pharmaceutically acceptable agent that reduces surface friction, lubricates the surface of the granules, reduces the tendency for static electricity to accumulate, and / or reduces the friability of the granules. Preferably, the lubricant is magnesium stearate.

[0059] Preferably, the compression step is performed by a tablet press, such as a single-punch press or a rotary tablet press, preferably a rotary tablet press. Preferably, the compression step is performed using a machine that typically contains two steel punches within a steel die cavity. When pressure is applied to the dried granules by the punches within the cavity, a tablet is formed.

[0060] The present disclosure also relates to a granulate obtainable by the method for preparing a granulate as previously described. The granulate comprises one or more substances and a binder as previously described.

[0061] In another aspect, the present invention relates to a pharmaceutical tablet obtainable by the method for preparing a tablet as previously described. The pharmaceutical tablet comprises a granulate as previously described. In another embodiment, the pharmaceutical tablet comprises one or more substances and a binder as previously described.

[0062] Preferably, the pharmaceutical tablets according to the present invention have a friability of less than 5%, preferably less than 2%, and more preferably between 5 and 1%. Friability can be determined by a person skilled in the art using a friability tester as described in Eur. Ph. (PTF E Pharma Test, Hainburg, Germany) at a speed of 25 rpm for 4 minutes. The percentage weight loss is expressed as tablet friability.

[0063] Other characteristics and advantages of the invention will become clear on reading the examples given hereinafter, which illustrate the invention without limiting it.

[0064] Example

[0065] 1. Friability and particle size of granular materials

[0066] A twin-screw granulator (ConsiGma) was used for continuous powder-to-form production. TM -25 system, GEA PharmaSystems) was used to perform the granulation experiments.

[0067] The powder was fed through the feeder at a feeder rate of 20 kg / h.

[0068] The twin-screw configuration consisted of two blocks of six kneading elements separated by a conveying element (1.5 L / D) staggered at 60°. Another configuration was tested with the last kneading element in each kneading zone staggered at 90°. The processing temperature was 30°C and the screw speed was 300 rpm.

[0069] Use the dry adding (as the dry powder in premix) and wet adding (as aqueous solution) of binding agent to make dicalcium phosphate (DCP) granulation.The concentration of dry binding agent is 5 dry weight% of the total dry weight of described powder mixture.By wet adding, the concentration of binding agent in granular object is 1.44 dry weight% of the total dry weight of described granular object.In addition, depending on the viscosity of binding agent solution, higher concentration (3 and / or 5%) can be realized for specific binding agent.For granular object characteristic (granular object friability and particle size distribution), evaluate the effect of adding method (wet and dry) and different binding agents (cleargum CO 01 (600 000g / mol), cleargum CO 03 (150 000g / mol), Glucidex 2, Glucides 6, HPMC E5, HPMC E15, LycatabDSH, Lycatab PGS, Lycoat RS720, PVP K12, PVP K30 and PVP K90). The friability of the granules was determined using a friability tester equipped with an abrasive roller (PTFE Pharmatest).The particle size of the granules was analyzed by dynamic image analysis using a QICPIC particle size analyzer (Sympatec, Germany).

[0070] Typically, the water or liquid content is expressed as a liquid to solid ratio (L / S). The liquid to solid ratio (L / S) varied from 0.105 to 0.225. The granules were tray dried until a loss on drying of 1 to 3 wt % was obtained.

[0071] Dry addition method

[0072] Using the dry addition method with a fixed binder concentration of 5%, the particle size distribution was significantly affected by the L / S ratio, as higher L / S ratios resulted in larger granules. Compared to the other binders, Cleargum CO 01 produced granules with a very large median particle size (d50) (4026 μm) at a low L / S ratio (0.155), which can be attributed to the amphiphilic nature of this binder. Figure 1 The d50 values ​​of the granules obtained with dry-added binder are shown in FIG.

[0073] The L / S ratio also strongly affects friability, as higher L / S ratios result in more fragile granules per binder. If a higher amount of granulating liquid is added, a larger fraction of binder can contribute to the interaction, as more binder is in contact with the fluid. Figure 2 The friability of granules produced using dry binders is shown in FIG.

[0074] Since Cleargum can be processed at a lower L / S ratio, less water is required to activate the binder properties of this binder. Therefore, it can be said that the inherent binder capacity of Cleargum is considered to be higher in a continuous process when compared with other binders that require more liquid. The friability of the resulting granules is low (<30%).

[0075] Wet addition method

[0076] The particle size distribution of the wet-added binder depends on the L / S ratio and the binder content in the dry granules. Larger granules are produced at higher L / S ratios and higher binder concentrations in the dry granules. However, when operating at the highest L / S ratio of Cleargum CO 03, over-wet granules with particularly high median particle sizes (>10,000 μm) are observed.

[0077] It is noteworthy that Cleargum CO 03 and Cleargum CO 01 can be processed in a lower range of L / S ratios compared to the other binders, indicating that less granulation liquid is required for the activation of these binders.

[0078] 2. Description of adhesive properties: Wettability of adhesive

[0079] The sessile drop method was used and the drop shape analyzer (DSA 30, GmbH, Hamburg, Germany) to determine the wettability of the binder via surface contact angle measurements. Two different types of experiments were performed. (i) Anhydrous dicalcium phosphate (DCP) ( A, obtained from Innophos, Chicago Heights, USA). Since the tableting of pure DCP results in high ejection forces, high output forces are not applied. This results in high tablet porosity. Aqueous binder dispersions (8% w / w) were prepared and 5 μl of each dispersion was placed on a DCP tablet. The contact angle (°) was measured when the droplet touched the tablet surface (CADCP). Due to the high porosity, the angle could not be obtained at 30 s. Five repeated measurements were performed. (ii) A droplet of each binder dispersion (8% w / w) was also placed on a polytetrafluoroethylene (PFTE) surface. Since PFTE is an inert substance, no angle difference was seen over time. Therefore, the contact angle (°) was measured only when the droplet touched the surface (CAPFTE). The measurements were performed in triplicate.

[0080]

[0081] Table 1: Contact angles (°) of different adhesives measured when a droplet touches the surface (CADCP and CAPFTE) .

[0082] The lowest contact angle was obtained when the hydrophobic polytetrafluoroethylene (PFTE) surface was wetted with the octenyl succinate starch solution. Thus, the octenyl succinate starch exhibited good wetting properties of PFTE (Table 1).

[0083] These values ​​were confirmed using a specific model based on compacted anhydrous dicalcium phosphate tablets (CADCP). The inventors found significant differences between all tested binders. The binder with starch octenylsuccinate exhibited a contact angle of 32.8° (Table 1).

[0084] The characterization of dry and wet binders shows that Cleargum has specific wetting properties. When Cleargum solutions (octenyl succinate starch) were measured against DCP, low contact angles were observed. This can be attributed to processability at lower L / S ratios when compared to other binders.

[0085] 3. Tablet characteristics

[0086] Mannitol was granulated using dry addition of a binder. The dry binder concentration was 5% dry weight of the total dry weight of the powder mixture. Prior to tableting, the milled granules were blended with 1.2% w / w magnesium stearate in a tumble blender (T2F, WA Bachofen, Basel, Switzerland). Tablets were prepared using a Styl'One compaction simulator equipped with a 10 mm punch. Tablets were compressed at 5 different main compression forces (5, 10, 15, 20, 25 kN) and the disintegration time of these tablets (n=5) was tested in 900 ml of demineralized water at 37±0.1°C (PharmaTest, Hainburg, Germany). The hardness of the tablets (n=5) was also determined using a hardness tester (Type HT 10, Sotax, Basel, Switzerland).

[0087] Tablets of mannitol granulated with Cleargum CO 01 exhibited high hardness and low disintegration time ( Figure 3 ).

[0088] in conclusion

[0089] The effects of different binder types and addition methods on the quality of pellets produced via twin-screw pelletizing were evaluated. This study demonstrated that different binder types and addition methods affect pellet properties differently. According to industry opinion, dry addition of binders is preferred due to its ease of manufacture.

[0090] Cleargum CO 01 and Cleargum CO 03 binders require a lower L / S ratio to produce good granule quality. The lower amount of granulation liquid required to achieve good granule quality is beneficial for granule drying. The lower L / S ratio can be explained by the effective wetting of the powder bed by these binders.

Claims

1. A method for preparing a granular material comprising one or more substances by continuous wet granulation, the method comprising the following steps: a1) mixing the substance powder with a binder powder consisting of partially hydrolyzed waxy maize octenyl succinate starch having a weight average molecular weight between: 10 5 with 10 6 g / mol, a2) feeding the powder mixture to a continuous wet granulator, b) feeding a granulation liquid consisting of a solvent selected from the group consisting of water, ethanol, isopropanol, methanol, acetone and mixtures thereof to the continuous wet granulator, c) moistening said powder mixture with said solvent in order to obtain said granules, d) drying the granules, wherein the content of the partially hydrolyzed waxy corn octenyl succinate starch is 1 wt % to 15 wt % of the total dry weight of the granules, The Brookfield viscosity of the partially hydrolyzed waxy maize octenyl succinate starch is selected to be in the range of 10 to 300 mPa.s, as determined at 20° C. using a Brookfield viscometer RVT with spindle No. 1 running at 60 rpm for 20 minutes and based on a solution containing 24% dry weight of the partially hydrolyzed waxy maize octenyl succinate starch relative to the total dry weight of the solution.

2. A method for preparing granules containing one or more substances by continuous wet granulation, the method comprising the following steps: a) feeding the material powder to a continuous wet granulator, b) feeding a granulation liquid comprising a binder consisting of partially hydrolyzed waxy maize octenyl succinate starch having a weight average molecular weight between 10 and 20 to the continuous wet granulator, the granulation liquid having a solvent selected from the group consisting of water, ethanol, isopropanol, methanol, acetone and mixtures thereof. 5 with 10 6 g / mol, c) wetting said substance powder with said granulating liquid so as to obtain said granulate, d) drying the granulated material, wherein the content of the partially hydrolyzed waxy corn octenyl succinate starch is 1 wt % to 15 wt % of the total dry weight of the granules, The Brookfield viscosity of the partially hydrolyzed waxy maize octenyl succinate starch is selected to be in the range of 10 to 300 mPa.s, as determined at 20° C. using a Brookfield viscometer RVT with spindle No. 1 running at 60 rpm for 20 minutes and based on a solution containing 24% dry weight of the partially hydrolyzed waxy maize octenyl succinate starch relative to the total dry weight of the solution.

3. The method according to any one of claims 1-2, wherein the continuous wet granulation is extrusion granulation.

4. The method according to any one of claims 1 to 2, wherein the continuous wet granulation is twin-screw granulation.

5. The method according to any one of claims 1 to 2, wherein the weight average molecular weight of the partially hydrolyzed waxy maize octenylsuccinate starch is between 100 000 and 500 000 g / mol.

6. The method according to any one of claims 1 to 2, wherein the weight average molecular weight of the partially hydrolyzed waxy maize octenylsuccinate starch is between 100 000 and 400 000 g / mol.

7. The method according to any one of claims 1 to 2, wherein the weight average molecular weight of the partially hydrolyzed waxy maize octenylsuccinate starch is between 100 000 and 300 000 g / mol.

8. The method according to any one of claims 1 to 2, wherein the weight average molecular weight of the partially hydrolyzed waxy maize octenylsuccinate starch is between 100,000 and 200,000 g / mol.

9. The method according to any one of claims 1 to 2, wherein the partially hydrolyzed waxy maize octenylsuccinate starch has a weight average molecular weight of 150 000 g / mol.

10. The method according to any one of claims 1 to 2, wherein the partially hydrolyzed waxy maize octenyl succinate starch has a weight average molecular weight between 300,000 and 10 6 g / mol.

11. The method according to any one of claims 1 to 2, wherein the partially hydrolyzed waxy maize octenylsuccinate starch has a weight average molecular weight between 400 000 and 900 000 g / mol.

12. The method according to any one of claims 1-2, wherein the weight average molecular weight of the partially hydrolyzed waxy maize octenylsuccinate starch is between 500 000 and 800 000 g / mol.

13. The method according to any one of claims 1 to 2, wherein the weight average molecular weight of the partially hydrolyzed waxy maize octenylsuccinate starch is between 550 000 and 750 000 g / mol.

14. The method according to any one of claims 1-2, wherein the partially hydrolyzed waxy maize octenylsuccinate starch has a weight average molecular weight of 600 000 g / mol.

15. The method according to any one of claims 1 to 2, further comprising the step e) grinding the dried granules.

16. The method according to any one of claims 1 to 2, wherein the substance is a pharmaceutically active agent.

17. The process according to any one of claims 1 to 2, wherein the granulation liquid comprises at least 50% water.

18. A process for preparing pharmaceutical tablets, comprising the steps of preparing a granulate according to any one of claims 1 to 17 and a final step of compressing the granulate in order to obtain a tablet.

19. A granular material comprising one or more substances and partially hydrolyzed waxy maize octenyl succinate starch having a weight average molecular weight between 300,000 and 10 6 g / mol, wherein the content of the partially hydrolyzed waxy corn octenyl succinate starch is 1 wt % to 15 wt % of the total dry weight of the granules, The Brookfield viscosity of the partially hydrolyzed waxy maize octenyl succinate starch is selected to be in the range of 10 to 300 mPa.s, as determined at 20° C. using a Brookfield viscometer RVT with spindle No. 1 running at 60 rpm for 20 minutes and based on a solution containing 24% dry weight of the partially hydrolyzed waxy maize octenyl succinate starch relative to the total dry weight of the solution.

20. The granulate according to claim 19, wherein the partially hydrolyzed waxy maize octenylsuccinate starch has a weight average molecular weight of between 400,000 and 900,000 g / mol.

21. The granulate of claim 19, wherein the partially hydrolyzed waxy maize octenylsuccinate starch has a weight average molecular weight of between 500,000 and 800,000 g / mol.

22. The granulate of claim 19, wherein the partially hydrolyzed waxy maize octenylsuccinate starch has a weight average molecular weight of between 550,000 and 750,000 g / mol.

23. The granulate of claim 19, wherein the partially hydrolyzed waxy maize octenyl succinate starch has a weight average molecular weight of 600,000 g / mol.

24. A pharmaceutical tablet comprising the granulate according to any one of claims 19 to 23.

25. Use of partially hydrolyzed waxy maize octenyl succinate starch as a binder for continuous wet granulation to obtain granules, the partially hydrolyzed waxy maize octenyl succinate starch having a weight average molecular weight between: 10 5 with 10 6 g / mol, wherein the granulation liquid of the continuous wet granulation has a solvent selected from the group consisting of: water, ethanol, isopropanol, methanol, acetone and mixtures thereof, wherein the content of the partially hydrolyzed waxy corn octenyl succinate starch is 1 wt% to 15 wt% of the total dry weight of the granules, and wherein the Brookfield viscosity of the partially hydrolyzed waxy corn octenyl succinate starch is selected in the following range: 10 to 300 mPa.s, the Brookfield viscosity being determined at 20°C based on a solution containing 24% dry weight of the partially hydrolyzed waxy corn octenyl succinate starch relative to the total dry weight of the solution using spindle No. 1 of a Brookfield viscometer RVT running at 60 rpm for 20 min.

26. The use of claim 25, wherein the granulation liquid comprises at least 50% water.

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