MXPA99001220A - Directly compressable stock of free flow as agglutinant, disintegrator and filler for tablets formed by compression and gelatin capsules - Google Patents

Abstract

The present invention relates to a directly compressible starch consisting of an intense white free-flowing powder which exhibits an excellent compression profile, 17 extremely good disintegration properties, said starch is specially designed to be used as a binder in direct compression processes where it produces very hard white tablets at relatively low compression forces, the tablets resulting from the compression of the aforementioned starch disintegrate in an aqueous medium at a very high speed and also show a low friability pattern, this free-flowing starch also has advantages when used as filler and binder in the filling of some hard gelatine capsules especially for those that are filled by compression of the ingredients, said starch is characterized by partially swollen regular and soft granules that can be birefringent or non-birefringent; ede prepare by spray drying a partially cooked starch

Description

DIRECTLY COMPRESSABLE STOCK OF FREE FLOW AS AGGLUTINANT, DISINTEGRATOR AND FILLER FOR TABLETS FORMED BY COMPRESSION AND HARD GELATIN CAPSULES TECHNICAL FIELD The present invention relates to a free flowing compressible processed starch powder suitable for use as a binder and as a disintegrator in tablets or capsules and to a process for producing it.

BACKGROUND OF THE INVENTION Tablets and capsules are among the most frequently used forms of supply for most medicinal preparations. This situation can be explained by the fact that said dosage forms allow a good accuracy of the dose of the active component of the medicinal formulation. In addition, since liquids are generally not involved in the process for preparing such medicinal formulations, control and packaging are much easier. Finally, the preservation and stability of these preparations are generally better than those of other formulations. The same claims also explain why tablets are often used as media for other applications such as foods, including confectionery, flavorings or sweeteners, detergents, dyes or plant protection products. Tablets can be manufactured using three main procedures: wet granulation, dry granulation and direct compression. In wet granulation, the components are typically mixed and granulated using a wet binder, the wet granulates are then screened, dried and then ground before compressing the tablets. In dry granulation, the powdered components are typically mixed before compacting, also called precompression, to form tablets that are then milled and sieved before the addition of other ingredients and the final compression. It is now considered that direct compression is the simplest and most economical economic procedure to produce tablets. This procedure requires only two steps; that is, the mixture of all the ingredients and the compression of this mixture. Hard gelatine capsules are usually filled with their ingredients according to two possible techniques. Gravity is used when these ingredients are poured into the capsule due to its natural flow. The other involves the partial compression according to which the ingredients are compressed in a calibrated die before being deposited in the capsule. A component of a tablet or capsule is usually defined as an excipient or an active ingredient. The active ingredients are usually those that activate a pharmaceutical, chemical or nutritive effect and that are present only up to the limit strictly necessary to provide this effect in the correct proportion. The excipients are chemically and pharmaceutically inert ingredients that are included to facilitate the preparation of the dosage forms or to adapt the release of the active ingredients. The excipients, when intended for direct compression, must fulfill a number of properties. They must have a high fluency; they must have a high compressibility, or a good pressure-hardness profile; they must be compatible with all types of active ingredients and not interfere with their biological capacity, they must also be stable before aging, humidity and heat. They must be colorless and tasteless. And finally they must have a proper sensation to the mouth. The excipients can be characterized according to their function during the formulation as, for example, binders, disintegrators, fillers (or diluents), sliders, lubricants and finally flavorings, sweeteners and colorants. It is intended that the lubricants improve the expulsion of the compressed tablet from the dyes of the tablet manufacturing equipment or the dies used to compress the ingredients for introduction into the capsules. Sliders are added to improve the flow of dust. They are typically used to help the mixing of all components to uniformly and regularly fill dyes before compression. Fillers are inert ingredients that are sometimes used as bulking agents to reduce the concentration of the active ingredient in the final formulation. The filler function can, in some cases, also be provided by the binder. Disintegrators can be added to the formulations to help the tablets disintegrate when placed in a liquid environment and also to release the active ingredient. The disintegration properties, for the most part, are based on the ability of the disintegrator to swell in the presence of a fluid, such as water or gastric juice. This swelling interrupts the continuity of the tablet structure and, in this way, allows different components to enter the solution or suspension. Commonly used disintegrators include starches in their natural form, modified starches, modified celluloses, microcrystalline cellulose or alginates. The binders are used to hold together the structure of the dosage forms. They have the property of joining all the ingredients after sufficient compression force has been applied and they provide the integrity of the tablets. Compression binders commonly used include pregelatinized starches, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, sucrose, lactose, dextrose, sorbitol or mannitol. The starches are known to act in some cases as binders and in some other cases as disintegrators according to the fact that they are natural, chemically modified or physically modified. Natural granulated starches and, to a lesser extent, cooked starches (also referred to as pregelatinized starches) may show binding capabilities limited in some way when employed in direct compression. Cooked starches, even when they are satisfactory binders, are not satisfactory in terms of disintegration. Said starches do not really disperse, they show the tendency to avoid the penetration of water into the tablet, thus preventing its disintegration by forming a layer of poor quality on its surface. EP-A-0402186 describes a mixture of directly compressible starch obtained from the mixture of 1 to 20% of a starch paste with 99-80% natural starch. The starch paste is obtained by treating the natural starch at 85 ° C which results in the breaking of the starch granules. Starches that swell in partially cold water for use as binder and / or disintegrants in the manufacture of tablets by direct compression and as fillers for formulations supplied in hard gelatin capsule are described in US-A-3, 622 , 677 and US-A-4, 072, 535. The material described is essentially a precompacted starch powder obtained by subjecting a non-gelatinized granulated starch to a physical compaction between the steel rollers with the possible input of thermal energy. The compacted starch shows the presence of acute birefringent granules and non-birefringent granules as well as some aggregates of granules and dried fragments at a moisture content of 9-16%. After compaction, the starch is milled and sieved to yield a free-flowing powder. The aforementioned starch powders show a limited binding capacity in direct compression and deficient disintegration properties. Formulations of the active ingredients used by said kind of excipient are described, for example, in EP-A-0, 130, 683 for N-acetyl-p-aminophenol. Other physically modified starches that swell in cold water are described as useful disintegrators but with very poor binding properties (see US-A-4,383,111). In such a case, the granulated starch is cooked in the presence of water and possibly an organic solvent at a temperature not higher than 10 ° C higher than its gelatinization temperature. The starch that is not obtained in this way then dries resulting in non-birefringent granules. Mixtures containing cold-water swellable starch are described for food application, that is, US-A-3, 956, 515, for preparing the starch paste for suitable fragments. The chemical modification of starch has also been investigated. Cross-linked pregelatinized starches such as starch phosphates, starch adipates, starch sulfates, starch glycollates or carboxymethyl starches are useful as disintegrators although they show poor bonding capabilities (see US-A-3, 034, 911 and US- A-4, 369, 308). Hydrolyzed starches of acid and enzyme are reported as useful binders (US-A-4, 551, 177). Said compressible starches are prepared by treating a granulated starch with an acid and / or alpha-amylase enzyme at a temperature below the gelatinization temperature of the starch. Said treated starches show altered or weakened granules with discontinuous surfaces. Said starches are useful as binders for tableting as well as binders and fillers for filling capsules and show reasonable disintegration properties. Dextrinized starches (see US-A-4, 384, 005) and starch fractions such as non-granulated amylose (see US-1-3, 490, 742) are also described as having a bond and / or disintegration properties limited. These are of limited interest due to the expensive procedures necessary for their preparation. There seems to be a need for a directly flowable, directly compressible starch powder that exhibits an excellent compression profile and very good disintegration properties and that is not chemically modified or treated enzymatically and without the use of an organic solvent.

BRIEF DESCRIPTION OF THE INVENTION According to the present invention there is provided a free flowing compressible directly processed starch powder characterized in that it comprises partially swollen, regular and soft starch granules, wherein the ratio of non-swollen birefringent granules to non-birefringent, swollen granules is found in the scale from 1: 5 to 5: 1 and in which it has an average particle size greater than 50 μm and a moisture content of 3 to 15% by weight. The processed starch powder according to the invention is suitable for use as a binder in direct compression processes that produce very hard tablets at relatively low compression forces and suitable for use as a binder and / or filler in the preparation of dosage forms of capsule. The tablets result from the compression of the disintegration of the aforementioned starch in an aqueous medium at a high speed and, in addition, show a low friable character.

DETAILED DESCRIPTION OF THE INVENTION The starch powder of the invention is characterized by the partially swollen regular and soft birefringent or non-birefringent granules. The relationship between birefringent granules that are not swollen and non-birefringent granules can vary from 1: 5 to 5: 1, preferably from 1: 2 to 2: 1, and it is typically preferred to be about 1: 1, as characterized by polarized optical microscopy. The particle size of the free-flowing directly compressible starch powder is markedly greater than the starch of the raw material and has an average value greater than 50 μm, typically 50 to 500 μm (approximately 95 μm in the case of corn starch). . Another agglomeration of granules is also possible to increase the size of the particular and to adapt the flow of the powder. According to the present invention, there is provided a process for preparing a free flowing compressible starch powder comprising the steps of: 1) preparing a starch paste in water 3) heating the paste to a substantially no higher temperature at the gelatinization temperature of the starch to cause partial swelling of the starch granules without causing the starch granules to be disrupted, 3) starch paste cooling to avoid any further swelling of the starch granules and 4) drying by spraying the cooled paste to produce a free-flowing starch powder having a moisture content of 3 to 15% by weight. The free flowing directly compressible starch powder can be obtained by diluting the starch base powder in demineralized water to form a paste at a concentration of 10 to 40%, calculated on the basis of the dry substance, or by using a starch paste resulting from the procedure applied to any relevant starch containing a plant (the paste of a concentration of 20% is preferred since it is a good compression between the functionality of the product and the economic viability of the process). The starch paste is then heated to a temperature close to the gelatinization temperature of the starch used such as the initial swelling of the starch granules without interruption and solubilized in water. This temperature depends on the source of the plant. For corn starch this is typically around 62 ° C, although starches from other sources will require different heating temperatures. It has been found that a part of the starch, heated to a temperature of more than 5 ° C higher than the gelatinization temperature of the starch used, results in a viscous paste which can not be further processed in an aqueous medium according to the process of the present invention. Therefore, a relatively strict temperature control within the ± 5 ° C scale of the gelatinization temperature of the starch used is important. Preferably, the temperature at which the starch paste is heated and controlled within a scale is ± 3 ° C, and most preferably within the ± 1 ° C scale, of the gelatinization temperature of the starch used. The temperature depends on the type of starch used. The objective is always to obtain a starch that is partially birefringent and partially non-birefringent. The residence time in the heating device can vary from 30 sec to 10 min and typically around 1 min. The heating device can be a heat exchanger, although a direct current injection heater is preferred because it allows better control of temperature and residence time. After heating, the partially swollen starch paste, typically at a temperature of 5-15 ° C lower than the heating temperature, is cooled to stabilize the product and prevent another swelling or explosion of the starch granules. Preferably a reduction of ß-7 ° C in the temperature is applied. The stabilized pulp is then spray dried using a spray-drying tower equipped with nozzles or turbines. The inlet and outlet temperatures are controlled in such a way that the free-flowing, directly compressible starch powder has a moisture content of 3-15%, preferably 5-10%, depending on the pharmaceutical dosage forms in which it is used. pretend said directly flowable compressible starch.

The free-flowing, directly compressible starch powder of the invention can be derived from any plant source containing starch. This includes corn (either normal corn or hybrids such as white corn, waxy corn and corn that contains high amylose content), wheat, potatoes, rice, sorghum, tapioca, cassava and any other similar plant that contains starch. White corn and high amylose starches are preferred because the best characteristics of the final products are described in the following examples. The free-flowing, directly compressible starch powder of the invention is useful as a binder and / or a disintegrator for tablets prepared by direct compression, wet granulation or dry granulation. It is also useful as a binder and a filler in the filling capsule process. Another embodiment of the present invention comprises a composition for the formulation of capsules and tablets prepared by direct compression or, to a lesser extent, by dry or wet granulation, containing the aforementioned starch powders referred to as directly compressible starch flow powders. free together with at least one active material. The free-flowing compressible processed starch described in the present invention can be used to formulate any drug usually supplied in the tablet or capsule forms. This includes, for example, analgesics, antipyretics, anti-inflammatory agents, vitamins, antibiotics, hormones, spheroids, tranquilizers or sedatives. Other active materials that can be included in the tablets can also be formulated with the free-flowing compressible processed starch described in the present invention. This activates applications such as foods, including confectionery products, flavorings or sweeteners, detergents, dyes, fertilizers or herbicidal products. The tablets obtained using the free-flowing, directly compressible starch powders of the present invention, as a binder or disintegrant, are characterized by the fact that they exhibit a very high hardness at relatively low compressive forces while also being able to disintegrate in an aqueous medium at a high speed, and additionally show a low friability pattern. The free-flowing, directly compressible starch powders of the present invention can be used as a binder-disintegrant, either alone or together, at any useful ratio, any other binder or disintegrator. The useful dose of the directly flowable, directly compressible starch powders of the invention varies depending on the active ingredients and other excipients and can be compressed from 2 to 95%. The figures are appended to help understand the nature of the treatments applied to the starch during the procedure. Figure 1 shows a partially swollen white corn starch processed at 61 ° C (by polarized optical microscopy). They show the presence of a majority of birefringent granules that are not swollen and a minority of non-birefringent granules swollen. Figure 2 shows a partially swollen white corn starch processed at 62 ° C (by polarized optical microscopy). They show the presence of a majority of birefringent granules that are not swollen and a minority of non-birefringent granules swollen. Figure 3 shows a partially swollen white corn starch processed at 63 ° C (by polarized optical microscopy). They show the presence of a majority of birefringent granules that are not swollen and a minority of non-birefringent granules swollen. Figure 4 shows granules of natural white corn starch by scanning electron microscopy. Figure 5 shows a free-flowing, directly compressible starch based on the white maize granulated starch according to the invention illustrated in Example 1 by scanning electron microscopy. The large and soft granules can be easily identified.

EXAMPLE 1 This example describes the production of a free-flowing, directly compressible starch powder based on a hybrid of granulated white corn starch. The powder of granulated white corn starch is diluted in demineralized water to form a paste at a concentration of 20% calculated on the dry substance resulting in a paste with a relative density of 1.085 compared to water. The starch paste is then heated in a direct current injection heat exchanger at a temperature of 62 ° C with a variation of not more than ± 1 ° C. If the temperature reaches 64 ° C, a viscous paste is obtained, which could no longer be processed. The microscopic examination of said paste reveals the absence of birefringent granules. The heating time is maintained for 1 minute. The partially swollen starch paste is then cooled to a temperature of 55-57 ° C by cold water. The drying of the partially swollen cold starch paste is carried out using an Alfa-Laval spray-drying tower equipped with a turbine rotating at a maximum speed of 13,000 rd / min and supplied at 2.7-3.1 rrr / h. The inlet temperature is set at 252 ° C and the outlet temperature is set at about 81 ° C to obtain a product with a final dry substance of about 91%. The intense white free-flowing powder obtained as described above shows an average particle size of 96 μm compared to 20 μm for the initial granulated white corn starch as shown in table 1.

TABLE 1 Starch 1-10 10-25 25-50 50-75 75-100 100-125 125-150 150-200 200-300 Density of loose product p jim jip μm μi μm μm μm Native (ti 12.5 80.1 6.5 0.7 0.2 0 0 0 0 500 g / 1 Processed 0.3 8.3 18.2 16.3 19.4 10 12.5 9 6.0 510 g / 1 As shown in Table 1, the free-flowing, directly compressible starch described above is characterized by a particle size markedly greater than crude material starch typically centered at 95 microns. As observed by polarized microscopy (see Figures 1 to 3), the swelling of the starch granules depends to a large extent on the heating temperature of the pulp. A heating temperature of 61-62 ° C produces granules with a typical ratio of birefringent granules that are not swollen and swollen non-birefringent granules of about 50/50 (Figures 1 and 2). A heating temperature of 63 ° C results in a product that shows a much smaller proportion of non-birefringent, swollen granules (Figure 3).

EXAMPLE 2 This example describes the production of a free-flowing, directly compressible starch powder based on a hybrid of high amylose corn starch. The high amylose corn starch powder is diluted in demineralised water to form a paste at a concentration of 20% calculated on the dry substance resulting in a paste with a relative density of 1.050 compared to water. The starch paste is then heated in a direct current injection heat exchanger at a temperature of 78 ° C with a variation of not more than ± 2 ° C. The heating is maintained for 1 minute. The partially swollen starch paste is then cooled to a temperature of 50 ° C by cold water. The drying of the cold partially swollen starch paste is carried out using a Niro FSD 4 spray drying tower equipped with a nozzle and supplied at 10 liters / h. The inlet temperature is set at 200 ° C and the outlet temperature is set at about 80 ° C to obtain a product with a final drying substance of about 91%. The high amylose starch free flowing powder obtained as described shows an average particle size of 85 μm compared to 20 μm for the initial high granulated amylose corn as shown in table 2.

TABLE 2 Starch 1-10 10-25 25-50 50-75 75-100 100-125 125-150 150-200 200-300 Density of loose product Native (t) 12.5 80.1 6.5 0.7 0.2 0 0 0 0 500 g / 1 Processed 0.9 6.9 18.1 20.6 25.2 10.9 7.4 6.3 3.7 300 g / 1 As shown in Table 2, the free-flowing, directly compressible starch described above is characterized by a particle size remarkably larger than that of raw material starch typically centered at 85 microns.

EXAMPLE 3a This example demonstrates the advantages of the directly compressible free-flowing starches obtained as described in Example 1 and Example 2 compared to conventional compressible starches when used for the production of tablets by direct compression. The tablets are formulated with 98.8% starch, 1% magnesium stearate Ph. Eur. III (Tramedic) and 0.2% silicon dioxide (Aerosil 200) -Degussa). The starch is sieved in a 0.8 mm sieve and mixed with silicon dioxide for 15 minutes at 12 rpm in a cutting drum mixer. The magnesium stearate is added to the mixture and mixed for 3 minutes at 12 rpm. All tableting tests are carried out on a rotating triple press die Korch of tableting press at a speed of 40 rpm to produce a flat-faced tablet of lcm weighing .50 mg. The hardness and dimensions of the tablets are measured in a test unit of the Pharma Test PTB-311 tablet; the disintegration time of the tablets is determined in a Pharma Test PTZ-E in water at 37 ° C. The friable character is measured in a friabilador Pharma Test PTF-E friabilador. All the tests are carried out in accordance with the procedures described in the European Pharmacopoeia 3rd edition. The tensile strength (TS) is calculated from the hardness according to the formula TS = 2.H / II.D. T is the hardness of the tablet, D is the diameter and T is the thickness. The results are summarized as shown in tables 3 to 5.

TABLE 3 STRENGTH OF TENSION RESISTANCE (N / mm2) COMPRESSION 15 20 25 30 White corn 0.4 1.6 2.6 3.2 3.5 3.6 processed TABLE 3 (CONTINUED) Amylose high 1.7 4.1 5.6 6.5 6.8 7 processed Starch 0.2 0.5 1 1.3 1.5 1.6 * Free-flowing white corn starch produced as described in Example 1 ** Free flowing high amylase corn starch produced as described in example 2 *** Standard moisture starch 1500 ™ (high) Colorcon Company Table 3 clearly shows that the hardness, directly indicated through the tensile strength measurements, of the tablets obtained by direct compression of the free-flowing white corn starch produced according to the procedure described in example 1 and, in a greater extension, the hardness of the tablets obtained by direct compression of the free-flowing high amylose corn starch produced according to the procedure described in example 2, are much more significantly superior than the standard compressible starch to any of the compression forces. This fact, which results directly from the high bonding capacity of the aforementioned starches, allows the manufacture of tablets of similar hardness at lower compression strength which result in significant advantages in the course of the tabletting process.

TABLE 4 Disintegration time (mm) Compression force 10 15 20 25 30 (KN) White corn 1.8 3.8 5.9 6.6 7.1 7.1 processed * High amylose 1.5 3.5 6.5 processed ** Starch 1500 TM 10.7 15 25 30 no no (Colorcon) *** desint. desint * Free-flowing white corn starch produced as described in the example ** Free-flowing high amylase corn starch produced as described in Example 2 *** Color (standard) 1500 ™ high humidity starch Company Table 4 clearly shows that the disintegration times of the tablets obtained by direct compression of the free-flowing white corn starch produced according to the procedure described in example 1 and the tablets obtained by direct compression of the high amylose corn starch free flowing produced according to the procedure described in example 2, are on the scale five times lower than the standard compressible starch at any compression force. The foregoing results in significant disadvantages for the supply of the active ingredients formulated with the aforementioned starches.

TABLE 5 Friability Compressive force 10 15 20 25 30 (KN) White corn 2.5 0.3 0.2 0.1 0.1 0.1 processed * High amylose 0.3 0.1 < 0.1 < 0.1 < 0.1 < 0.1 processed ** Starch 1500 TM 4.5 3.2 1.2 0.8 0.7 (Colorcon) *** * Free-flowing white corn starch produced as described in example 1 ** High-flow free amylase corn starch produced as described in example 2 *** Color (Standard) 1500 ™ high humidity starch Company Table 5 shows that although they have much better disintegration times, at any compression force, the tablets obtained by direct compression of the free-flowing white corn starch produced according to the procedure described in example 1 and the tablets obtained by compression Directly from the free-flowing high amylose corn starch produced according to the procedure described in example 2, they have significantly lower friability standards than the standard compressible starch. Therefore, the control and processing of the tablets obtained using the aforementioned starches are much easier and safer. In conclusion, it can be stated that the tablets obtained using directly compressible free-flowing starches produced according to examples 1 and 2 as binders and disintegrators are characterized by their high hardness in relatively low compression forces while also being able to disintegrate in an aqueous medium at a very high speed and additionally show a low friability pattern.

EXAMPLE 3b This example reproduces the same experiments as in example 3a using a different formulation for the tablets. The tablets are formulated with 99.25% starch, 0.5% magnesium stearate Ph. Eur. III (Tramedic) and 0.25% silica dioxide (Aerosil 200-Degussa). The hardness and dimensions of the tablets are measured in an Erweka TBH 30 MD tablet test unit. The disintegration time of the tablets is determined in a PharmaTest PTZ-E in water at 37 ° C. The friability is measured in a PharmaTest PTZ-E friabilator. All tests are carried out with the procedures described in the European Pharmacopoeia 3rd edition. The tensile strength (TS) is calculated from the hardness according to the formula TS = 2.H / II.D.T. where H is the hardness of the tablet, D is the diameter and T is the thickness. The results are summarized as shown in tables 6 to 8.

TABLE 6 Tension strength (N / mn) Compression force 5 10 15 20 25 30 (KN) White corn 0.5 2.4 4.2 5.5 6.2 6.6 processed * High amylose 1.9 4.4 6.9 8.8 10.3 processed ** Starch 1500 ™ - 0.7 1.2 1.9 2.3 2.5 (Colorcon) *** * Free-flowing white corn starch produced as described in example 1 ** Free-flowing high-amylase corn starch produced as described in example 2 *** Starch 1500 TM Standard (high) humidity of Colorcon Company TABLE 7 Disintegration time (min) Compression force 10 15 20 25 30 (KN) White corn 1.5 7.5 processed * High amylose 6.5 processed ** Starch 1500 TM 17 25 30 40 Colorcon) *** * Free-flowing white corn starch produced as described in example 1 ** Free-flowing high-amylase corn starch produced as described in example 2 *** Colorcon standard (high) moisture starch 1500 Company TABLE 8 Friability% Compression force 10 15 20 25 30 (KN) White corn 1.58 0.17 0.09 0.06 0.06 0.06 processed * High amylose 0.19 0.08 0.04 0.06 0.02 0.04 processed ** TABLE 8 (CONTINUED) Starch 1500 ™ - 2.73 1.07 0.55 0.4 0.28 (Colorcon) *** * Free-flowing white corn starch produced as described in example 1 ** Free-flowing high-amylase corn starch produced as described in example 2 *** Standard moisture starch 1500 ™ (high) Colorcon Company This example shows that when the formulation is optimized, compared to Examples 3a, the increase in the development in terms of tensile strength is even better with the directly compressible starch than with the directly compressible standard starch.

EXAMPLE 4 This example describes the behavior of the directly compressible free-flowing white corn starch powder obtained as described in example 1 when it is used for the preparation of tablets by wet granulation. The granulation of the starch is carried out in a Collette GRAL 75 high-cut mixer. 16 kg of starch are granulated with 3 kg of water for 10 minutes. The granules are dried in a fluid bed dryer at 10% humidity. The tablets are formulated with 99.25% granulated starch, 0.25% magnesium stearate Ph. Eur. III (Tramedic) and 0.25% silicon dioxide (Aerosil 200 - Degussa). The granulated starch is mixed with silicon dioxide for 15 minutes at 12 rpm in a low-cut drum mixer. The magnesium stearate is added to the mixture and mixed for 3 minutes at 12 rpm. The tableting tests are carried out in a Korsch rotary triple press tabletting press at a speed of 40 rpm to produce 1 cm of flat face tablets weighing 350 mg. The hardness and dimensions of the tablets are measured in an Erweka TBH 30 MD tablet test unit. The disintegration time of the tablets is determined in a PharmaTest PTZ-E in water at 37 ° C. The friability is measured in a PharmaTest PTZ-E friabilator. All tests are carried out according to the procedures described in the European Pharmacopoeia 3rd edition. The tensile strength (TS) is calculated from the hardness according to the formula TS = 2.H / II.D.T. where H is the hardness of the tablet, D is the diameter and T is the thickness. The results are summarized as shown in table 9.

TABLE 9 Compression force 10 15 20 25 30 (KN) Resistance of 0.45 2.2 5.5 6.5 tension Disinction time 2.5 2.5 4.2 4.2 5.2 Tegration (min) Friability (%) 0.22 0.17 0.17 0.12 0.1 (Colorcon) *** * Free-flowing white corn starch produced as described in example 1 ** Free-flowing high-amylase corn starch produced as described in example 2 *** Colorcon standard (high) moisture starch 1500 Company The results show that the tensile strengths of the tablets obtained after the wet granulation are very similar to those of the tablets obtained by direct compression as enlisted in the 3d example. This demonstrates the property of the directly compressible starch described in this invention for the preparation of tablets by wet granulation.

EXAMPLE 5 This example demonstrates the advantage of the directly compressible free-flowing white corn starch powder obtained as described in Example 1 compared to a conventional compressible starch when used for the production of aspirin tablets (Merck USP) by direct compression. Tablets are formulated with 19.3% starch, 80% aspirin, 0.5% magnesium stearate Ph. Eur. III (Tramedic) and 0.2% silicon dioxide (Aerosil 200-Degussa). The starch and aspirin are sieved in a 0.8 mm sieve and mixed with the silicon dioxide and magnesium stearate for 15 minutes at 12 rpm in a lower cut drum mixer. All tableting tests are carried out on a Korch triple rotary press tabletting press at a speed of 40 rpm to produce 1 cm2 tablets weighing 450 mg. The hardness and dimensions of the tablets are measured on a PharmaTest PTB-311 tablet test instrument. The disintegration time of the tablets is determined in a PharmaTest PTZ-E in water at 37 ° C. The friability of the tablets is measured in a Fridabilator PharmaTest PTF-E friabilator. All tests are carried out in accordance with the procedures described in the European Pharmacopoeia 3rd edition. The tensile strength (TS) is calculated from the hardness according to the formula TS = 2.H / II.D.T. where H is the hardness of the tablet, D is the diameter and T is the thickness. The results are summarized as shown in table 10.

TABLE 10 Compression force 15 20 25 30 (KN) Tension resistance (N / mm) Aspirin + corn 1.25 1.5 1.6 1.65 processed white * Aspirin + starch 0.7 0.8 0.9 0.95 i15cn0n0 ™! (Colorcon) ** Disintegration time (min) Aspirin + corn 1.25 2.9 processed white * í Si? íina + starch 10 11 12.5 1500 ™ (Colorcon) ** Friability (%) Aspirin + corn 0.8 0.62 0.55 0.52 processed white * Aspirin + starch 1.75 1.4 1.2 1.25 i15 c n0n01 ™. (Colorcon) ** ** Free-flowing white corn starch produced as described in example 1 *** Standard moisture starch 1500 ™ (high) Colorcon Company Table 6 clearly shows that the hardness, directly indicated by the tensile strength, of the tablets obtained by the direct compression of the aspirin, plus the free-flowing white corn starch produced according to the procedure described in example 1 as Binder-binder is significantly higher than that of standard compressible starch at any compression force. This fact, which results directly from the high binding capacity of the aforementioned starches, allows the manufacture of tablets of similar hardness in lower compression strength that result in a significant advantage in the course of the tabletting process. It is also clearly demonstrated that the disintegration times are on the scale of 4 to 5 times lower, resulting in significant advantages for the supply of aspirin formulated in this way Another advantage of the formulation of aspirin with the free-flowing white corn starch produced according to the procedure described in example 1 as a binder-binder is summarized in a significantly lower friability resulting in easier and safer handling and processing of the tablet. In conclusion it can be affirmed that the active ingredients of formulation such as aspirin in the tablets by direct compression using directly free-flowing compressible starch produced according to example 1, the binder-disintegrant results in tablets of higher hardness, lower disintegration and lower friability profiles in relatively lower compression forces.

EXAMPLE 6 This example describes the behavior of the directly compressible free-flowing white corn starch powder obtained as described when it is used for the production of ibuprofen (knoll) tablets by direct compression. The tablets are formulated with 59.25% starch, 40% ibuprofen. 0.05% magnesium stearate Ph. Eur. III (Tramedic) and 0.25 silicon dioxide (Aerosil 200 Degusta). The starch and ibuprofen are sieved in a 0.8 mm sieve and mixed with the silicon dioxide and magnesium stearate for 15 minutes at 12 rpm in a lower cut drum mixer. All tableting tests are carried out on a Korsh rotary triple tableting pressure die at a speed of 40 rpm to produce lcm tablets weighing 450 mg. The hardness and dimension of the tablets are measured in an Erwka TBH 30 MD tablet test unit. The disintegration time of the tablets is determined in a Pharma Test PTZ-E in water at 37 ° C. Friability is measured in a Pharma Test PTF-E friabilator. All tests are carried out according to the procedures described in the Eurepea pharmacopoeia 3rd edition. The tensile strength (TS) is calculated from the hardness according to the formula TS = 2.H / IT.D.T, where H is the hardness of the tablet, D is the diamer and T is the thickness. The properties of the tablets containing 40% ibuprofen formulated with free-flowing white corn starch produced as described in example 1 are summarized in table 11.

TABLE 11 Compression force 5 10 15 20 25 30 (kN) Stress resistance 0.45 1.25 1.6 1.75 1.7 1.7 (n / mm) Disintegration time- 1.1 3.8 - 4.9 - 6.1 tion (min.) Friability (%) 2.4 0.9 0.7 0.8 0.8 0.8 EXAMPLE 7 This example describes the behavior of the directly compressible free-flowing white corn starch powder obtained as described when it is used in the production of aceptamolam tablets (Merck USP) by direct compression. The tablets are formulated with 59.25% starch, 40% acephatamol, 0.5% magnesium stearate Ph. Eur. III (Tramedicum and 0.25% silicon dioxide (Aerosil 200 - Degussa).) The starch and the sememol are screened with a sieve of 0.8 mm and mixed with the silicon dioxide and the magnesium stearate for 15 minutes at 12 rpm in a lower cut drum mixer.

All tableting tests are carried out on a Korch triple rotary press tabletting press at a speed of 40 rpm to produce tablets of an age of 450 mg weight. The hardness and dimensions of the tablets are measured in an Erweka TBH-30 MD tablet test unit. The disintegration time of the tablets is determined in a Parma Test PTZ-E in water at 37 ° C. The friability is measured in a Parma Test PTF-E friabilator. All tests are carried out in accordance with the procedures described in the European Pharmacopoeia 3rd. edition. The tensile strength (TS) is calculated from the hardness according to the formula TS = 2.H / II.D.T, where h is the hardness of the tablet, D is the diameter and T is the thickness. The properties of the tablets containing 40% ibuprofen formulated with the free flowing white corn starch produced as described in Example 1 are summarized in Table 12.

TABLE 12 Compression force 5 10 15 20 25 30 (kN) Stress resistance - 0.6 1.2 1.6 1.9 2.1 (n / mm2) Disintegration time- 0.85 1.2 - 21 - 2.9 tion (min.) Friability (%) - 2 0.76 0.48 0.38 0.32 EXAMPLE 8 This example describes the behavior of the directly compressible free-flowing white corn starch powder obtained as described when used for the production of ascorbic acid tablets (Merck USP) by direct compression. The tablets are formulated with 59.25% starch, 40% ascorbic acid, 0.5% magnesium stearate Ph. Eur. III (Tramedic) and 0.25% silicon dioxide (Aerosil 200 Degussa). The starch and the semetamol are sieved in a 0.8 mm sieve and mixed with silicon dioxide and magenation stearate for 15 minutes at 12 rpm in a lower cut drum mixer. All the tableting tests are carried out in Korsh rotary triple pressure tableting press at a speed of 40 rpm to produce lrrr tablets and a weight of 450 mg. The hardness and dimensions of the tablets are measured in an Erweka TBH 30 MD tablet test unit. The disintegration time of the tablets in a Pharma Test PTZ-E in water at 37 ° C. The friability is measured in friabilidor Pharma Test PTE-E. All the tests were carried out according to the procedures described in the 3rd European Pharmacopoeia. Edition. The tensile strength (TS) was calculated from the hardness according to the formula TS = 2.H / II.D.T where H is the hardness of the tablet, D is the diameter and T is the thickness. The properties of the tablets containing 40% ibuprofen formulated with the free-flowing white corn starch produced as described in Example 1 are summarized in Table 13.

TABLE 13 Compression force 5 10 15 20 25 30 (kN) Stress resistance - 0.5 1.3 1.8 2.2 2.5 (n / mm) Disintegration time- 0.75 1.5 - 3.8 - 5.6 tion (min.) Friability (%) - - - - 0.34 -

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A directly flowable compressible processed starch powder characterized in that it comprises regular and soft partially swollen granules of starch wherein the ratio of birefringent granules that are not swollen to non-birefringent and swollen granules are in the range of 1: 5 to 5 : 1 in which it has an average particle size greater than 50 microns and a moisture content of 3 to 15% by weight.

2. - A free flowing compressible processed starch powder according to claim 1, further characterized in that the ratio of birefringent granules that are not swollen to non-birefringent, swollen granules is found on the scale of 1: 2 to 2: 1.

3. A free flowing compressible processed starch powder according to claim 2, further characterized in that the ratio of birefringent granules that are not swollen to non-birefringent, swollen granules is about 1: 1.

4. A free flowing compressible processed starch powder according to any of claims 1 to 3, further characterized in that at least 50% of the particles have a particle size of 50 microns or more, preferably 75 microns.

5. - A free flowing compressible processed starch powder according to any of claims 1 to 4 which when compressed into a tablet under a compression force of 10 kN gives a tablet having a tensile strength of at least 1N / mm and preferably at least 2N / mm.

6. - A process for preparing a free-flowing compressible starch powder comprising the steps of; 1) prepare a starch paste in water, 2) heat the paste to a temperature substantially no higher than the gelatinization temperature of the starch to cause partial swelling of the starch granules without causing the starch granules to be disrupted, 3) cooling the starch paste to avoid any further swelling of the starch granules; and 4) sprinkling the cold paste to produce a free-flowing starch powder having a moisture content of 3 to 15% by weight.

7. - A method according to claim 6, further characterized in that the dough is heated to a temperature which is ± 5 ° C of the gelatinization temperature of the starch, preferably ± 3 ° C, and most preferably ± 1 ° C , of the gelatinization temperature of the starch.

8. A process according to claim 6 or 7, further characterized in that the starch paste, after the heating step, is cooled to a temperature which is 5 ° C to 15 ° C lower than the temperature used in the step of heating.

9. A composition for forming a tablet or other form of unit dose comprising at least one active material and, as a binder or filler, a directly flowable compressible processed starch powder of any of claims 1 to 5. A composition according to claim 9 further characterized in that the active material is selected from the group consisting of pharmaceutically active materials, foods, including confectionery products, flavors or sweeteners, detergents, enzymes and other proteases, dyes, fertilizers and herbicide products. 11. A dry compressed tablet comprising at least one active material and, as a binder or filler, processed starch, said processed starch comprises regular and soft partially swollen granules of starch wherein the ratio of birefringent granules that are not swollen to birefringent granules Puffs are on a scale of 1: 5 to 5: 1 which has an average particle size greater than 50 microns and a moisture content on the scale of 3 to 15% by weight, said tablet when formed under a force of kN compression has a tensile strength greater than 2 N / mm, preferably greater than 3 N / mm and most preferably greater than 4 N / mm, a disintegration time in water at 37 ° C of less than 6 minutes and percent of fribidity of less than 1%.