HK1050147B - Process for preparing direct tabletting formulations or aids - Google Patents

Description

Method for preparing direct tabletting preparation and auxiliary materials

Technical Field

The invention relates to a novel granulation method for preparing a direct tabletting preparation (direct tabletting formulation) containing a pharmaceutically active ingredient or a direct tabletting auxiliary material (direct tabletting aid). This new granulation process is usually carried out by placing one or more diluents (diluents) or pharmaceutically active ingredients, binders (binders) or disintegrants (disintegrants) in a closed system under tumbling heating with low moisture or pharmaceutically acceptable solvents.

The invention further extends to tablets, capsules or granules containing such direct tabletting preparations or excipients or to a process for the manufacture of tablets, capsules or granules from such direct tabletting preparations or excipients.

Background

The relatively novel tableting step is usually associated with the use of direct tableting excipients (excipients) which, after addition of the pharmaceutical ingredient, are compressed directly into tablets. Excipients for direct tableting require good flowability, cohesive holding capacity and high holding capacity for active ingredients that are not easily tableted. The same is true of the development of direct tableting formulations containing pharmaceutical ingredients. Ideally, tablets should have low friability and high crushing strength. These requirements are somewhat relative, for example: high crushing strength is usually associated with the contact points of the excipients or active ingredients of the tablet with the binder. Such requirements can be achieved by reducing the particle size of the auxiliary materials and the binder. However, fine particles generally have poor flowability, which limits the applicability of the rapid tableting process. There have therefore been many studies aimed at improving or modifying the adjuvants (or the pharmaceutically active ingredients) and the binders so as to be able to eliminate these contradictory points while retaining the advantages.

Such direct tableting excipients, also commonly referred to as multifunctional excipients, are typically prepared by a special process involving a plurality of components, sometimes referred to as co-formulation. For example, DE-C3506276 shows the combination of alpha-lactose monohydrate (alpha-lactose monohydrate) and cellulose powder (cellulose powder) as direct tableting materials. DE-a 3505433 (USP5006345) shows that in combination with alpha-lactose monohydrate, polyvinylpyrrolidone (PVP) as binder and insoluble crosslinked polyvinylpyrrolidone (crospovidone) as disintegrant, good flowability and good disintegration without the addition of additional disintegrant are obtained, but are unsuitable for use on high-dose hard-to-tablet active ingredients, since the content of active ingredient is not so high that the mechanical properties of the resulting tablets are limited.

U.S. patent No. 5840769 (USP5840769) discloses the use of microcrystalline cellulose (MCC) as a diluent, PVP as a binder, and crospovidone (crospovidone) as a disintegrant for direct tableting. The product can be prepared by the following conventional wet granulation methods, such as mixing granulation, Shugi granulation, extrusion granulation, perforated plate granulation, or fluidized bed granulation. Wet granulation is a common method for dissolving an excipient (diluent or disintegrant) or a pharmaceutically active ingredient in water or an organic solvent using a binder such as PVP. However, although wet granulation is widely used, it has many disadvantages.

Wet granulation techniques are commonly used in the pharmaceutical industry to improve tableting properties. Wet granulation generally improves flowability by adding a binder solution to agglomerate small particles into large particles. Since the binder is uniformly distributed on the surface of the diluent or pharmaceutically active ingredient, thereby increasing the contact points, the binding efficiency of the granules and the strength of the final tablet are increased. The wet granulation method can also reduce dust in the tabletting process and improve the working environment. Another benefit of wet granulation is that it promotes uniform dispersion of the ingredients in the tablet formulation.

Wet granulation requires the addition of large amounts of liquid in appropriate tanks and control equipment. However, the water added in the wet granulation process must be removed, so a drying step is required, and thus drying equipment and a relatively complicated process are required, and energy, cost and time required in the whole process are also increased. Meanwhile, the use of a large amount of organic solvent as the granulating solution may cause damage to operators and the environment. Special precautions and equipment are therefore required to avoid explosions and to protect workers from exposure to solvents.

Wet granulation also has other disadvantages, for example, excessive moisture can negatively impact the active ingredients in a tablet formulation. For example, as discussed in U.S. patent No. 6103219 (USP6103219), exposure of microcrystalline cellulose to excessive moisture during wet granulation severely reduces its compressibility, primarily because the cellulose fibers are softened. As tablet strength decreases, more MCC needs to be added to maintain the necessary degree of compression, especially when higher active ingredients are present. Increased MCC not only increases the cost of manufacture, but more importantly increases the size of the tablet and is more difficult to swallow. The problem of the decrease in compressibility of microcrystalline cellulose by wet granulation has not been solved properly.

Examples of the use of PVP (or other binder) in a wet granulation process are numerous (e.g., WO 93/09763; WO 00/06125; USP 4968509; USP 5200193; USP 5462747). Wet granulation with a large amount of water or alcohol solution to disperse the binder is still the most common method for preparing granules for tablets or sustained release dosage form materials. To overcome the disadvantages of the over-wet granulation process, a better method is needed to improve the flowability of the formulation or excipient for direct tableting while maintaining or improving other tablet properties, such as tablet hardness, without the need to add excessive liquid.

Disclosure of Invention

It is an object of the present invention to provide a new granulation process which uses only a very low moisture or solvent content compared to conventional wet granulation processes.

It is another object of the present invention to develop a direct tableting preparation having good flowability and binding capacity, using the granulation process, which has relatively low friability and adequate hardness.

It is still another object of the present invention to develop a direct tableting auxiliary material having good flowability and binding capacity using the granulation method, which can produce tablets having relatively low friability and appropriate hardness, and also having a high capacity for active ingredients that are difficult to tableting.

Still another object of the present invention is to develop a direct tableting preparation or a direct tableting auxiliary material having good flowability and binding capacity by using the granulation method, the compressed tablet having relatively low friability and appropriate hardness, and also having appropriate disintegration ability.

Further objects and advantages of the invention will be apparent from the following discussion and examples.

In order to achieve these objects, the present inventors have found that when a finely divided binder powder containing a low moisture or pharmaceutically acceptable solvent is mixed with an excipient such as: cellulose powder (cellulose powder), microcrystalline cellulose (microcrystalline cellulose), lactose (lactose), starch (starch), and calcium phosphate (dibasic calcium phosphate), or active ingredients such as acetaminophen (acetaminophen) or ascorbic acid (ascorbyl acid), and mixing and then rolling and rotating the mixture for heating, direct tableting preparations or excipients having advantageous properties not found in the starting materials can be obtained.

Therefore, the invention provides a special method for directly tabletting a preparation or an auxiliary material, which utilizes a solvent containing low water content or being acceptable in pharmacy and a finely dispersed adhesive to roll and rotate and heat with an excipient or an active ingredient in a closed container.

The present invention, named "Thermal Adhesion Granulation (TAG)", is a particular granulation method and will be described in detail below.

The invention provides a granulation method for preparing a preparation (containing pharmaceutically active ingredients) for direct tabletting or an auxiliary material (containing no pharmaceutically active ingredients) for direct tabletting. The preparation method of the invention comprises the steps of putting a mixture of the following components (A) and (B) into a closed bottle, rolling and rotating the mixture, and heating the mixture to 30-130 ℃, preferably 40-110 ℃, and most preferably 60-105 ℃; the water content or the content of the pharmaceutically acceptable organic solvent is about 0.1 to 20 percent, and the mixture is mixed, rolled and rotated in a closed system until particles are formed;

A) one or more excipients suitable for tableting comprise 5 to 99 wt%, preferably 10 to 90 wt%. The pharmaceutically active component is 0-99 wt%, preferably 10-90 wt%.

B) The binder is present in an amount of 1-95 wt%, preferably 5-50 wt%, based on the total formulation weight.

And optionally:

C) the disintegrant is 0-10 wt%, and can be added before or after granulating the mixture of (A) and (B).

According to the invention, the mixture of A), B) and optionally C) is granulated, it being necessary to obtain an initial moisture content of 0.1 to 20%, preferably 2 to 15%, most preferably 4 to 10%, in a closed system, measured with a moisture meter (for example: ohaus, Japan). Alternatively, granulation may be carried out in a medium containing a pharmaceutically acceptable organic solvent (e.g., ethanol) in an initial solvent content of 0.1 to 20%, preferably 0.1 to 10%, most preferably 0.5 to 5%.

"Rolling rotation" is defined as rotation about the horizontal axis of the container, where the powder mixture slides, rolls, flows, falls or moves in any way along the inner wall of the container.

The diluent of component A) may be selected from cellulose powder (cellulose powder), microcrystalline cellulose (microcrystalline cellulose), lactose (lactose), starch (starch), calcium phosphate dibasic (calcium phosphate), calcium phosphate tribasic (calcium phosphate), mannitol (mannitol), sorbitol (sorbitol), sucrose (sucrose), dextrose (dextrose), cellulose acetate (cellulose acetate), hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose), and others, or combinations thereof. Preferably cellulose powder, microcrystalline cellulose, lactose, starch, and calcium phosphate dibasic. According to a preferred embodiment of the invention, microcrystalline cellulose is used in a grade of 101, 90% of the particles falling in the range of 1 to 125 μm and having an average particle size of 10 to 70 μm.

The active ingredient of component A) may be selected from acetaminophen (acetaminophen), ascorbic acid (ascorbyl acid), nifedipine (nifedipine), ibuprofen (ibuprofen), aspirin (aspirin), and others, or combinations thereof. Preferred are acetaminophenol and ascorbic acid.

Although stable tablets can be obtained from dilute excipients such as cellulose powder, microcrystalline cellulose, lactose, starch, calcium phosphate dibasic, even at very low tableting forces, the flowability of these powders is poor due to the relatively small particle size. Granulation with a binder can improve the flowability of these diluent excipients by increasing the particle size.

The binder of component B) may be selected from water-soluble polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl cellulose (sodium carboxymethyl cellulose), methyl cellulose (methyl cellulose), ethyl cellulose (ethyl cellulose), sugar (sugar) and others, or may be used in combination, preferably polyvinylpyrrolidone and hydroxypropyl cellulose. Further, the binder may contain 0 to 10% (relative to the binder) of one or more anticaking agents (anticaking agents), such as dibasic calcium phosphate anhydrate (dihydrate anhydride), silica (silica dioxide) or calcium silicate (calcium silicate), preferably dibasic calcium phosphate anhydrate.

The disintegrant of component C) may be crosslinked polyvinylpyrrolidone (PVP-CL), Sodium Starch Glycolate (SSG), reticulated (crosslinked) carboxymethylcellulose (crosslinked) carbopol ethylcellulose, croscarmellose, CMC-CL), low-substituted hydroxypropylcellulose (low-subsisttedhydroxypropylmethylcellulose, L-HPC), or any other material or combination thereof, and may be mixed with the mixture during granulation (intragranular) or added after granulation (interparticle) to facilitate the final tablet or capsule disintegration.

The binder used in a preferred embodiment of the invention is a water soluble polyvinylpyrrolidone (PVP). This is a finely divided powder, whether wet granulated or directly tabletted, which is commonly used in the pharmaceutical industry as a tablet binder. In general, PVP has a K value of 12-120. The K values used according to the invention are in the range from 20 to 95, preferably from 25 to 35. The K value was determined according to the Povidone monograph of the United states Pharmacopeia USP 24/NF 19 (2000).

Thermo-adhesive granulation is essentially a dry process in which the binder is mixed with the mixture by dry agitation and not added after dissolving in solution. To maximize the effectiveness of the bond, it is necessary to use finely dispersed binder powders to maximize the contact point of the binder with the diluent or active ingredient. Generally, these binders, such as PVP, have a strong water absorption and tend to stick and cake after absorbing water. Finely powdered PVP is the most common problem during storage as it absorbs atmospheric moisture and agglomerates. To help promote or maintain homogeneity in the mixing of the finely divided binder (composition B) with the diluent or active ingredient (composition A), the binders used in the present invention may be supplemented with 0 to 10%, preferably 0.01 to 10%, and most preferably 2 to 4% (relative to the binder) of an anticaking agent (anticaking agent) prior to use. A preferred method of using the anti-caking agent is to mix the binder and anti-caking agent together, grind them into a fine powder in a mixer, and then pass through a 200 mesh screen. This binder/anticaking agent mixture may be granulated with composition a or optionally composition C.

The TAG system can be pelletized at low water or low solvent levels because the pelletization is performed in a closed system. Because it is possible to avoid the escape of vapours (from the added solution plus the moisture contained in the powder) from the system during heating, the use of granulation liquid can be maximized, and thus granulation can be accomplished with a minimum addition of moisture or solvent. Generally, the process of heating can cause moisture within the diluent to transfer to the binder. A more detailed observation of the TAG system is that the heat distribution over the granulation vessel is not very uniform, which can cause moisture to condense on the inner walls of the vessel in relatively cool areas as the powder is heated. Binders, such as PVP, are generally highly hygroscopic, and any moisture present in the system, particularly moisture in the condensed state, is totally absorbed by the binder, rendering the binder tacky. Because the binder is uniformly dispersed in the form of fine powder between the diluent and the active ingredient before granulation, the increased viscosity of the binder causes adjacent particles to stick together, and finally the granules are rolled in a closed container to form the granules. The optimal temperature range for the TAG system varies with the type and amount of diluent, binder, and granulating solution. For example, the temperature required for using an organic solvent may be lower than for using water.

The technique of mixing or tabletting the active ingredient with microcrystalline cellulose, crosslinked PVP and water-soluble PVP is compared with other known techniques, such as: EP-A273209 or USP5840769, the greatest difference in tableting with the direct tableting aid of the present invention is the use of lower energy, minimal contamination and wide application. The present invention requires less moisture or organic solvent than previously known techniques, yet the resulting particle characteristics are comparable or better.

The "hot-tack granulation" process of the present invention differs from the conventional wet granulation process in many ways:

1) in the hot-tack granulation method, only a small amount of water is added to a mixture already containing a diluent and a binder, whereas in the conventional wet granulation method, the binder is dissolved in a granulation liquid and then mixed with a diluent excipient.

2) Thermal granulation can be defined as a dry process because the liquid (water or organic solvent) required for granulation is significantly lower than that required for conventional wet granulation.

3) Wet granulation processes generally operate at room temperature, except for the drying step, whereas hot-tack granulation processes require heating to promote particle formation.

4) In wet granulation, the mixing step is usually performed by using paddles, arms, propellers, cutters or other mechanical stirring devices (for example: planetary mixer for shear granulation, high-speed mixing granulator), by directly stirring a mixture of powder and liquid or a lump. Or by suspending the powder in a hot gas stream and spraying with a solution of the binder (fluidized bed granulation). The former granules are formed by sieving a moist mass and the latter granules are formed by coating the granules with a binder solution. In the hot-tack granulation method, the moist powder is continuously heated in a container and rotated by rolling, and the powder is slowly aggregated with the aid of a binder to form granules.

5) Wet granulation requires drying and grinding steps after granulation to achieve the desired particle size. These steps are not required in the present invention because the moisture content of the mixture is low.

6) The conventional granulation method is usually carried out in an open system, and the thermal bonding granulation method of the present invention is carried out in a closed system.

The advantage of granulation in a closed system is that the conditions of the whole system can be controlled to a higher specific state, depending on the reactor configuration. For example, in a mixer that can be heated and dried, the space can be completely evacuated or partially evacuated, or filled with an inert or non-reactive gas (e.g., nitrogen or helium). The absence of oxygen increases the stability of the particles in the system and reduces the chance of explosion of the organic solvent even with the supply of heat. In the same reactor, a vacuum drying step after granulation may also be used to increase solvent recovery.

Another advantage of granulation in a closed system is to minimize dust generation of the powder during the process. This technique can be applied to certain finely powdered pharmaceutically active ingredients that are not desired to leak out of or be lost from the system during processing, because they are expensive or biologically active. Furthermore, the TAG approach can also be applied in other industries, such as: nutraceutical manufacture, food or animal feed, and the like.

The use of TAG can be further extended to the granulation of other industrial or agricultural products, such as powders, granules or granules of fertilizers or pesticides. Granulation in a closed system can help reduce toxic or hazardous dust generation.

The invention also relates to a powder mixture of soluble polyvinylpyrrolidone containing 0.01 to 10 wt% (relative to the polyvinylpyrrolidone) of dibasic calcium phosphate anhydride.

The present invention further relates to a direct tableting formulation or excipient comprising:

1) from 5 to 99% by weight of cellulose powder (cellulose powder), microcrystalline cellulose (microcrystalline cellulose), lactose (lactose), starch (starch), or calcium phosphate dibasic (calcium phosphate);

2) from 0 to 99% by weight of acetaminophen or ascorbic acid;

3) from 1 to 95% by weight of a soluble polyvinylpyrrolidone (polyvinylpyrrolidone) which contains 0.01 to 10% by weight (relative to the polyvinylpyrrolidone) of calcium phosphate dibasic anhydride; and

4) from 0 to 10% by weight of crosslinked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, reticulated carboxymethyl cellulose (carboxymethylcellulose), or low-substituted hydroxypropyl cellulose (low-substistuted dihydroxypropylcellulose).

The present invention may further relate to tablets, capsules, or granules prepared using the direct tableting preparation or the auxiliary prepared by the present invention, and a method of preparing the tablets, capsules, or granules.

The invention is described in more detail by the following examples. The following examples are intended to illustrate the invention in more detail and are not intended to limit the scope of the invention.

Detailed Description

The diluent (filler) excipients used in the examples of the present invention include microcrystalline cellulose 101(MCC101), lactose (lactose anhydrate, Borculo), starch (starch 1500, Colorcon), and dibasic calcium phosphate anhydrate (DCP, Fujicalin SG, Fuji Chemical). These excipients are chosen because they are most commonly used in tableting diluents. The choice of these excipients is intended to demonstrate the broad utility of the invention and is not intended to limit the scope of the invention. The basic physical and tableting properties of these excipients include Ludipress^®(containing 93% lactose, 3.5% Kollidon)^®30，3.5％Kollidon^®CL, BASF) and Avicel^®The pH200, a microcrystalline cellulose (FMC Corporation), is listed in Table 1. All examples of the invention will incorporate 3% by weight (relative to the binder) of anhydrous divalent calcium phosphate (Fujic) in the binderalin^®Fuji Chemical, Japan) as an anti-caking agent. Thus, the percentage of binder in the examples is a nominal percentage, with some minor amounts of anhydrous calcium phosphate.

In order to determine the powder properties of the excipients, granules and direct tableting excipients of the present invention, we examined the following parameters: average particle size (mean particle size) size (sieved using a 37 to 800 μm sieve size), repose angle (repose angle) of the powder, bulk density (bulk density) of the powder, and tapped density (tapped density) of the powder (using a.b. d. fine particles characteristics measurement Instrument, tsutsutsui, japan). The flowability of the powder is expressed in terms of the angle of repose and the Carr's Index, which is calculated from the following formula:

the kappa number (%) - (oscillation density-bulk density)/oscillation density × 100%

Lower values of repose angle and Cascade number indicate better flowability. In order to measure the characteristics of tablets made of excipients, granules and excipients for direct tableting according to the present invention, tablets (diameter 11.3mm, 0.5g) were made using a Sankyo Pio-Tec SK-02tablet stability Tester (manufactured by Japan) with a compression force of 49MPa (500 Kg). The hardness (tensile strength in the diametrical direction) of the tablets was measured on the same machine. The tablet disintegration degree (friability) and disintegration time (disintegration time) were measured on an Aikho AE-20 Roche disintegration tester (20 rpm; 5 min; n.10) and a Xinguan (Taiwan) SK-0004 tablet disintegration tester (n.6), respectively.

TABLE 1

Characteristics of	MCC101	Lactose	Starch	DCP	Ludipress®	Avicel®PH200
							Average particle Size (. mu.m) Repose Angle of Repose (deg.)aBulk Density (Bulk Density, g/ml)aOscillating Density (Tapped Density, g/ml)aCascade coefficient (Carr's Index,%)aTensile Strength (Tensil Strength, MPa)bFriability (percent) Disintegration time (sec)	5054.33±1.530.256±0.0020.397±0.00235.58±0.712.677±0.4930.20＞900	9040.33±0.580.635±0.0060.811±0.01121.63±0.34NTcNTcNTc	8040.68±0.580.623±0.0070.784±0.00620.560.210.191±0.0171.03＜420	11341.33±0.580.387±0.0020.455±0.00214.94±0.14NTcNTcNTc	17035.67±0.580.527±0.0020.600±0.00212.20±0.530.302±0.0432.99＜40	18046.00±1.000.324±0.0010.411±0.00121.04±0.353.154±0.3730.20＜440

^aMean ± SD, n ═ 3;^bthe mean value ± SD, n is 10,^cNT: no tablets could be formed under the test conditions of 500kg (49MPa)

Example 1

Preparation of direct tabletting auxiliary materials with different excipients

The direct tabletting excipient is prepared by the following method, namely a thermo-adhesive granulation method. First, a water-soluble PVP (Kollidon) having a K value of 30 was taken^®30 BASF), hereinafter referred to as "PVP K30", contains 3% of calcium phosphate dibasic anhydride and is mixed with microcrystalline cellulose 101 (granule a), lactose (granule B), starch (granule C) or calcium phosphate dibasic (granule D) in an amount of 10% by weight. This mixture of binder and diluent is added in the form of a spray with 5% (relative to the total weight of the mixture) of water vapor and stirred uniformly. Then put into a preheated glass bottle, sealed, and then put under an infrared lamp to be heated to 90-105 ℃, and rolled and rotated for 3-20 minutes until particles are formed. In the process of granulation, the bottle is vibrated discontinuously, so that the powder is prevented from adsorbing excessive condensed moisture and attaching to the inner wall of the glass bottle. The resulting granules were immediately passed through a No. 24 sieve (800 μm). Finally the granules can be used directly after cooling to room temperature or, if necessary, can be further dried under infrared lamps or other available equipment. The particle composition and characteristics of this process are listed in table 2A. It is clear that the particle size, density, flowability, tablet strength and disintegration time of particles a to D are all significantly improved compared to the starting materials in table 1. In addition to the diluents used in particles a to D, the TAG process can also be applied to other diluents, or to granulation of other grades of MCC, lactose, starch or DCP. For example, larger particles can be obtained by using as the starting material microcrystalline cellulose of a relatively large particle size grade (e.g., 102 grade, average particle size of 90 μm).

TABLE 2A

% of	Particle A	Particle B	Particle C	Particles D	Particles E	Granule F	Particle G
								MCC101 lactose starch DCPVP K30	90.010.0	90.010.0	90.010.0	90.010.0	95.05.0	90.010.0	85.015.0
Added water (%)	5	5	5	5	5	5	5
								Average particle Size (. mu.m) Repose Angle of Repose (deg.)aBulk Density (Bulk Density, g/ml)aOscillating Density (Tapped Density, g/ml)aCascade coefficient (Carr's Index,%)aTensile Strength (Tensile Str)ength，MPa)bFriability (percent) Disintegration time (sec)	212.442.67±0.580.205±0.0030.255±0.00119.69±0.883.077±0.3290＞900	326.035.00±1.000.524±0.0040.561±0.0056.52±0.082.234±0.8020.60＜375	515.238.33±0.580.443±0.0030.458±0.0013.17±0.691.077±0.1610.81＜190	200.732.00±1.530.454±0.0020.505±0.00310.08±0.861.162±0.1241.42＜180	123.049.33±1.530.216±0.0010.291±0.00125.58±0.233.324±0.4690.20＞900	239.943.00±1.000.213±0.0020.253±0.00215.59±0.293.125±0.2050.40＞900	419.041.33±1.000.223±0.0040.245±0.0049.11±0.743.529±0.2640＞900

^aMean ± SD, n ═ 3;^bthe mean value ± SD, n is 10,

example 2

PVP (polyvinyl pyrrolidone) with different proportions is used for preparing direct tabletting auxiliary materials

Direct tableting aids were prepared in analogy to example 1, with the only difference that in this example PVP K30 was mixed in different proportions (5% (granule E), 10% (granule F), and at 15% (granule G)) with microcrystalline cellulose 101, followed by granulation by hot-melt granulation. The overall moisture increase was 5%. The results for this composition are listed in table 2A. It is clear that the particle size and flowability can be increased with increasing amount of PVP. There was no statistical difference in tablet tensile strength between the three.

Example 3

Preparing the direct tabletting auxiliary material by using PVP with larger proportion

Direct tableting excipients were prepared in analogy to example 1, with the only difference that in this example PVP K30 was mixed in a proportion of 50% with microcrystalline cellulose 101 (granule H), lactose (granule I), starch (granule J) or calcium phosphate dibasic (granule K), followed by granulation in a hot-melt granulation process. The overall moisture increase was 5%. The results for this composition are listed in table 2B. It is clear that the use of 50% PVP reduces the particle size of the particles compared to particles A, B, C and D which use 10% PVP.

Example 4

Direct tabletting auxiliary material prepared from PVP (polyvinyl pyrrolidone) with different water contents

Direct tableting aids were prepared in analogy to example 1, with the only difference that in this example PVP K30 was mixed in a fixed ratio (10%) with microcrystalline cellulose, but with the addition of different moisture (5% (granule L), 10% (granule M), 15% (granule N)), followed by granulation by hot-tack granulation. The results for this composition are listed in table 2B. Comparing the three different moisture contents, it is clear that the largest and best flowability granules were made with 5% moisture addition. It is also evident that increasing the moisture content reduces the formation of particles. The most obvious difference between the present invention and the conventional wet granulation method is that the present invention can have a better state at a lower moisture content. Further, the characteristics of pellets A, F and L having the same composition are also similar, and the reproducibility of the thermo-viscous granulation method can be also seen.

TABLE 2B

% of	Particles H	Granule I	Granule J	Particle K	Particles L	Particles M	Particle N
								MCC101 lactose starch DCPVP K30	50.050.0	50.050.0	50.050.0	50.050.0	90.010.0	90.010.0	90.010.0
Added water (%)	5	5	5	5	5	10	15
								Average particle Size (. mu.m) Repose Angle of Repose (deg.)aBulk Density (Bulk Density, g/ml)aOscillating Density (Tapped Density, g/ml)aCascade coefficient (Carr's Index,%)aTensile Strength (Tensil Strength, MPa)bBrittleness (% Disintegration time (sec)))	162.649.00±1.000.296±0.0020.385±0.00123.08±0.566.931±0.9410＞900	204.744.66±3.510.430±0.0010.523±0.00117.82±0.076.470±1.0870.20＞900	151.438.67±1.160.425±0.0010.531±0.00119.97±0.214.362±0.9070.20＞900	195.138.33±0.580.415±0.0010.495±0.00116.12±0.171.284±0.3220.40＞900	196.144.67±0.580.209±0.0020.258±0.00119.17±0.583.277±0.3980.20＞900	156.650.00±1.000.234±0.0010.301±0.00122.31±0.172.761±0.2120＞900	144.856.33±0.580.239±0.0020.294±0.00118.61±0.233.197±0.2920＞900

^aMean ± SD, n ═ 3;^bthe mean value ± SD, n is 10,

example 5

Direct tabletting auxiliary materials prepared from different adhesives, wetting solutions and system states

This example demonstrates the preparation of direct tableting excipients with different binders, wetting solutions and system states. The hot-tack granulation method in this example was substantially the same as that described above, and some modifications are listed below. Microcrystalline cellulose 101 was used in an amount of 90% in all granules. The composition and characteristics of the particles, including particle a in example 1, can be found in table 3. Granule a' has a similar composition to granule a except that 3.5% cross-linked polyvinylpyrrolidone (crospovidone) is added as an intragranular disintegrant (the cross-linked polyvinylpyrrolidone is mixed with MCC and PVP K30 prior to hot-melt granulation). In granule Q, 10% PVP K30 was mixed with MCC, but a small amount of ethanol (about 1.5%) was substituted for waterAs a wetting solution. When ethanol is used as the granulating solution, the heating temperature is about 70-90 ℃. As is apparent from table 3, ethanol can be regarded as a wetting solution in the hot-tack granulation method, although the formed particles (particles Q) are a little smaller than those with water as a wetting solution (particles a). In granule R, 10% of hydroxypropyl cellulose (HPC, Klucel)^®EXF, Aqualon) is mixed with microcrystalline cellulose. 1.5% ethanol was again used as the wetting solution. It is clear that the use of HPC also produces very good granules, demonstrating that hot-tack granulation can be used on tableting mixes containing different binders.

To demonstrate the necessity of a closed system in the hot-melt granulation process, two series of granules (group T, with 5% water added; group U, with 1.5% ethanol added), both containing 10% PVP K30 and 90% MCC101, were granulated in an open system. Comparing the granules A and Q in groups T and U and in the closed system, respectively, it is clear that the thermal bonding granulation process of the present invention could not be carried out in an open system. This result also demonstrates that TAGs are not only wet granulated at low moisture levels. Groups T and U do not form granules and also distinguish the present invention from moisture-activated dry granulation (MADG) granulation. The thermal bonding granulation method must be described in a closed system, which is unique to the present invention, because the conventional wet granulation method is performed in an open system.

TABLE 3

% of	Closed system open system
				Granular particles A A' Q	Particle R	Particulate pellets T U
	MCC101 PVP K30HPC disintegrant (crospovidone)	90 86.85 9010 9.65 103.5	9010				90 9010 10
Wetting method				5% 5% 1.5% aqueous ethanol	1.5% ethanol	5% 1.5% aqueous ethanol
	Average particle Size (. mu.m) Repose Angle of Repose (deg.)aBulk Density (Bulk Density, g/ml)aOscillating Density (Tapped Density, g/ml)aCascade coefficient (Carr's Index,%)aTensile strength	212.4 139.8 76.542.67 45.33 47.67±0.58 ±0.58 ±0.580.205 0.199 0.231±0.003 ±0.002 ±0.0010.255 0.241 0.320±0.001 ±0.001 ±0.00219.69 17.41 27.77±.088 ±0.43 ±0.183.077 3.787 2.457	98.351.00±1.000.216±0.0010.287±0.00124.70±0.232.535				56.3 53.847.67 49.67±0.58 ±0.580.250 0.292±0.002 ±0.0030.329 0.400±0.002 ±0.00423.88 27.01±0.28 ±0.261.846 2.139

(Tensile Strength，MPa)bFriability (percent) Disintegration time (sec)

±0.329 ±0.192 ±0.1680 0.2 1.02＞900 ＜180 ＞900

±0.1500＞900

±0.457 ±0.3880.40 0＞900 ＞900

^aMean ± SD, n ═ 3;^bmean ± SD, n ═ 10, a': + 3.5% of an intra-granular disintegrating agent.

Example 6

Preparation of direct tabletting preparation from pharmaceutically active ingredients

A direct tableting preparation containing only the pharmaceutically active ingredient without adding a diluent was prepared in the above manner. PVP K30 was mixed with acetaminophen (fine powder, BASF) and either (granule O) or no (granule P) disintegrant. Then, the mixture was pelletized by a thermal bonding method. The overall moisture increase was 5%. The particle composition and results of the process are given in table 4. Prior to granulation, the acetamidophenol was present in the form of a very fine powder (< 400 mesh, 37 μm), the flowability was very poor and tablets could not be formed under a tabletting force of 500Kg (49 MPa). It is obvious that the acetaminophen particles made of TAG can effectively improve the particle size and the flowability, and the tablet strength and the disintegration property are better.

TABLE 4

% of	Particle O	Particle P
			PVP K30 disintegrant (crospovidone) acetaminopher	9.653.586.85	1090
Average particle Size (. mu.m) Repose Angle of Repose (deg.)aBulk Density (Bulk Density, g/ml)aOscillating Density (TappedDensity, g/ml)aCascade coefficient (Carr's Index,%)aTensile Strength (Tensil Strength, MPa)b	177.248.00±1.000.247±0.0030.303±0.00218.36±0.520.481±0.057	165.053.00±1.000.283±0.0020.319±0.00211.42±0.010.808±0.094

Friability (percent) disintegration time (separation. sec)

1.05＜35

1.38＜55

^aMean ± SD, n ═ 3;^bthe mean value ± SD, n is 10,

example 7

Directly tabletting auxiliary materials and active ingredients

The tableting mixture in this example was prepared by first sieving the active ingredients (test 1: ascorbic acid (ascorbyl acid), hydrophilic drug, and test 2: acetaminophen, hydrophobic drug) through a 24 mesh (800 μm) followed by thorough mixing with the direct tableting excipients prepared by the thermal bonding granulation method in example 1. The mixture was thoroughly mixed for at least 10 minutes before granulation. Formulations (pellets A, B, C and D) made according to the invention and using Ludipress^®(containing 93% lactose, 3.5% Kollidon)^®30 and 3.5% Kollidon^®CL) and Avicel^®The results after tableting at pH200 (a microcrystalline cellulose) are shown in tables 5 and 6, together with a comparison.

In MCC based products, the formulation of ascorbic acid (ascorbyl acid) and acetaminophen (acetaminophen) is clearly visible, using granule A at least as good as Avicel in terms of tablet strength, disintegration time and friability^®The pH200 is comparable (tables 5 and 6). However, the flowability ratio of particle A is Avicel^®The pH200 was much better (tables 1 and 2A). In lactose-based products, it is evident that the formulation containing granule B is in many ways comparable to Ludipress^®The preparation is good.

Tabletting test 1 (with ascorbic acid)

Ascorbic acid crystal direct tabletting adjuvant disintegrating agent (Croospovidone)

40.0% (by weight) 56.5% (by weight) 3.5%, (Weight percent)

TABLE 5

Auxiliary material for direct tabletting	Tensile Strength (Tensil Strength, MPa) (mean + -SD; n ═ 10)	Disintegration time (DisintegationTime, sec)	Brittleness (Friability,%)
				Particles A particles B	1.296±0.1120.532±0.135	＜20＜20	01.21

Granule C granule DAvicel®PH200 (comparative) Ludipress®(comparison)

0.369±0.0370.240±0.0381.325±0.1200.183±0.043

＜150＜45＜20＜40

1.955.490.4110.85

Tabletting test 2 (with acetaminopher)

Acetamidophenol powder for directly preparing tablet and disintegrating tablet (Croospovidone)

30.0% (weight percent) 66.5% (weight percent) 3.5% (weight percent)

TABLE 6

Auxiliary material for direct tabletting	Tensile Strength (Tensil Strength, MPa) (mean + -SD; n ═ 10)	Disintegration time (DisintegationTime, sec)	Brittleness (Friability,%)
				Granule A granule B granule C granule DAvicel®PH200 (comparative) Ludipress®(comparison)	1.287±0.1150.457±0.0900.258±0.0250.321±0.0500.826±0.0580.173±0.045	＜26＜37＜205＜45＜17＜60	01.621.034.450.815.98

Example 8

Direct tabletting auxiliary material containing active ingredients prepared by hot sticking granulation method

In the previous example 7, the active ingredient and disintegrant were directly tabletted after being mixed completely with the direct tabletting excipients produced by the TAG method. The TAG method can also be used to granulate all the ingredients together into a direct tableting formulation, so that no additional ingredients are requiredThe tablet can be directly prepared by using things or modification. In this example, the following mixture of formulations would be subjected to hot-tack granulation (with the addition of 5% moisture) followed by direct compression into tablets. This composition is comparable to the particle a series in table 6.

Acetaminophen powder MCC101

30.3％by wt59.85％by wt

PVP K30 disintegrating agent (crospovidone)

6.65％by wt3.5％by wt

The results are as follows: tensile strength is 1.088 plus or minus 0.167 MPa; the disintegration time is less than 10 seconds; the brittleness was 0%. The results are comparable to the tablets made with granule a (granule plus active ingredient and disintegrant) in table 6.

Example 9

Determining the amount of active ingredient contained in the direct tableting preparation

The holding capacity (loading) of the particles A for the active ingredient will be compared with the Ludipress^®And (6) comparing. Acetaminophen (acetaminophen) was used as the active ingredient sample in this example. The tableting mixture was prepared in the same manner as described in example 8 (3.5% crosslinked polyvinylpyrrolidone (crospovidone) as the extragranular disintegrant + acetamidophenol content shown in table 7 + Ludipress)^®Or particles a up to 100%). The results after tableting are listed in table 7. It is evident that the particles a are contained in a better quantity.

TABLE 7

	Tensile Strength (Tensil Strength, MPa) (mean + -SD; n ═ 10)	Disintegration time (DisintegationTime, sec)	Brittleness (Friability,%)
				Ludipress®10% acetamidophenol, 20% acetamidophenol, 30% acetamidophenol, 40% acetamidophenol, No active ingredient particles A, 10% acetamidophenol, 20% acetamidophenol, 30% acetamidophenol, 40% acetamidophenol, and 50% acetamidophenol	0.302±0.0430.318±0.0700.251±0.0660.226±0.0550.198±0.0353.355±0.3762.736±0.3432.010±0.3191.379±0.1080.909±0.0980.529±0.046	＜50＜55＜60＜45＜45＜6＜45＜30＜20＜20＜40	2.994.064.523.888.3900.400.401.411.842.67

Example 10

Use of other disintegrating agents in combination with direct tableting preparations

Other commonly used disintegrants, for example Sodium Starch Glycolate (SSG), reticulated carboxymethyl cellulose (croscarmellose ), and low-substituted hydroxypropyl cellulose (L-HPC) may be used in place of the crosslinked polyvinylpyrrolidone (crospovidone) of examples 5 to 9, with comparable results. The optimum concentration range for SSG is 4 to 8%, while the range for croscarmellose and L-HPC is 3 to 6%. The timing of adding the disintegrant may be completely intragranular (before granulation), completely extragranular (after granulation) or partially before and after granulation. The advantage of the third method is that the extragranular disintegrant first breaks up the tablet into granules, thereby increasing the surface area so that the intragranular disintegrant completely breaks up the granules.

Comparative example

Comparison of tablet characteristics between TAG-process granules and physical blends of MCC101, PVP K30 and 3.5% crosslinked polyvinylpyrrolidone (crospovidone)

In this comparative example, 3.5% of crosslinked polyvinylpyrrolidone (crospovidone) was added to granule a as an extragranular disintegrant to make the composition the same as that of the physically mixed preparation. Cross-linked polyvinylpyrrolidone (crospovidone) was not added to particles A' and Ludipress^®Because they already contain disintegrants. The results of this comparison are listed in table 8. The physical mixture MCC/PVP K30/crospovidone is not suitable for tableting because of the very poor flowability (angle of repose 54.67 °, bulk density 0.293g/ml, oscillation density 0.427g/ml, kappa number 31.27%), in particular in comparison with the granules a (angle of repose 42.67 °, bulk density 0.205g/ml, oscillation density 0.255g/ml, kappa number 19.69%), the granules of the TAG method having a significantly better flowability. Tablets made from the physical blend also had a standard deviation of tablet strength that was much greater than tablets made from the TAG particles. In addition, even if crosslinked polyvinylpyrrolidone (crospovidone) is added to aid disintegration, tablets made with a physical mixture containing acetaminophen have disintegration times of much greater than 15 minutes. In contrast, particles a with the addition of crosslinked polyvinylpyrrolidone (crospovi done) as a disintegrant showed a significantly faster disintegration time. The tablet disintegration time of granule A' is a little slower than that of granule A, that is, the disintegration time using the intra-granular disintegrant is a little longer than that using the inter-granular disintegrant because the extra-granular disintegrant can disintegrate the tablet into small granules quickly. These comparisons demonstrate that granule a has better tabletting properties than MCC101 (or granules of other excipients compared to the respective starting materials), not just as a result of the addition of PVP. These excipient improvements are due to the TAG granulation process. The invention proposesThe thermal-bonding granulation method can improve the flowability of the excipient and does not deteriorate the strength, the anti-brittleness capability and the disintegration time of the tablet.

TABLE 8

	Tensile Strength (Tensil Strength, MPa) (mean + -SD; n ═ 10)	Disintegration time (DisintegationTime, sec)	Brittleness (Friability,%)
				Physical mixing active ingredient-free physical mixing of a powder containing 30% acetaminophenol	3.754±0.5881.495±0.195	＜150＞900	0.200.81
Granule A active ingredient free granule A30% acetaminopher powder	3.355±0.3761.379±1.108	＜60＜20	01.41
				Granules A 'without active ingredient granules A' contained 30% acetaminopher powder	3.787±0.1921.548±0.123	＜180＜40	0.200.40
Ludipress®Is free of living thingsSex ingredient Ludipress®Containing 30% acetaminophenol powder	0.302±0.0430.226±0.055	＜50＜35	2.993.88

Conclusion, differentiation and scope

From the above examples and discussion, it can be seen that the present invention is a simple but effective and unique method for preparing direct tableting formulations and excipients. The thermal-bonding granulation method can be widely used in various diluents, binders and pharmaceutically active ingredients, and can utilize water or organic granulating solutions. The present process is a good alternative to the wet granulation process and offers several advantages:

● TAG does not reduce the tabletting properties of MCC due to the addition of very small amounts of water, a problem often encountered in wet granulation.

● the stability of the drug can be increased by using a small amount of granulating liquid and granulating under a controlled oxygen-free environment (because of the closed system).

● the time required to dry and grind the particles after sieving can be avoided in TAG.

● the process is simplified and the manufacturing time is shortened by using a small amount of granulating liquid. Thus, a large production amount and a reduced production cost can be obtained.

● because the organic solvent is required in a very low amount and is manufactured in a closed system, occupational safety and environmental protection can be increased.

While the above description and examples contain some uniqueness, this is not intended to limit the scope of the invention, but rather is a preferred embodiment. Many other variations of TAG are possible. For example, the diluent may be mixed in different proportions before or after thermal-adhesive granulation, thereby forming a combined direct tableting aid of different properties. An example of such a combination is the mixing of MCC and lactose to form a tableting excipient, which has both water soluble and water insoluble fractions. Other possibilities are to add other excipients before and after the thermoadhesive granulation, for example: colorants, fragrances or glidants (glidants) (e.g., silicon dioxide or calcium silicate). Furthermore, thermal bonding granulation can be used in many different industries where granulation is required, not just the pharmaceutical industry.

Claims (27)

1. A thermal bonding granulation method for preparing a direct tabletting preparation or an auxiliary material, which is characterized by using a mixture containing the following components:

A)5 to 99% by weight of one or more dilution excipients and/or 0 to 99% by weight of a pharmaceutically active ingredient,

B)1 to 95% by weight of a binder, and

in the alternative, the first and second substrates are,

C)0 to 10% by weight of a disintegrant,

heating to a temperature in the range of 30 to 130 ℃ under conditions of an initial moisture or an initial content of pharmaceutically acceptable organic solvent of 0.1 to 20%, and rotating by rolling in a closed system until granules are formed.

2. The method of claim 1, wherein the temperature ranges from 40 to 110 ℃.

3. The method of claim 1, wherein the temperature ranges from 60 to 105 ℃.

4. The method of claim 1, wherein the initial moisture content is from 2 to 15%.

5. The method of claim 1, wherein the initial moisture content is from 4 to 10%.

6. The process as claimed in claim 1, characterized in that the initial organic solvent content is from 0.1 to 10%.

7. The process as claimed in claim 1, characterized in that the initial organic solvent content is from 0.5 to 5%.

8. The method of claim 1, wherein the diluent excipient is cellulose powder, microcrystalline cellulose, lactose, starch, or calcium phosphate dibasic.

9. The method of claim 1, wherein the pharmaceutically active ingredient is acetamidophenol or ascorbic acid.

10. The method of claim 1, wherein the binder is soluble polyvinylpyrrolidone or hydroxypropyl cellulose.

11. The method of claim 1, wherein the disintegrant is crosslinked polyvinylpyrrolidone, sodium starch glycolate, reticulated carboxymethyl cellulose, or low-substituted hydroxypropyl cellulose.

12. The method of claim 1, wherein the diluent excipient is microcrystalline cellulose.

13. The method of claim 12, wherein the microcrystalline cellulose has 90% of its particles ranging from 1 μm to 125 μm and an average particle size ranging from 10 μm to 70 μm.

14. The method of claim 1, wherein the binder is a soluble polyvinylpyrrolidone.

15. The method of claim 14, wherein the soluble polyvinylpyrrolidone has a K value of from 12 to 120.

16. The method of claim 14, wherein the soluble polyvinylpyrrolidone has a K value of from 20 to 95.

17. The method of claim 14, wherein the soluble polyvinylpyrrolidone has a K value of from 25 to 35.

18. The method of claim 1, wherein the adhesive further comprises 0 to 10% by weight of an anti-caking agent relative to the adhesive.

19. The method of claim 18, wherein the adhesive further comprises 0.01 to 10% by weight of an anti-caking agent relative to the adhesive.

20. The method of claim 18, wherein the adhesive further comprises 2 to 4% by weight of an anti-caking agent relative to the adhesive.

21. The method of claim 18, wherein the anticaking agent is an anhydrous calcium phosphate dibasic.

22. A product obtained by the thermal bonding granulation method for directly tableting preparations or accessories as claimed in claim 1.

23. A powder mixture of soluble polyvinylpyrrolidone, characterized by comprising 0.01 to 10% by weight of calcium phosphate dibasic anhydrate relative to polyvinylpyrrolidone.

24. A direct tableting preparation or an adjuvant characterized by comprising:

i)5 to 99% by weight of cellulose powder, microcrystalline cellulose, lactose, starch or dibasic calcium phosphate,

ii)0 to 99% by weight of an acetamidophenol or ascorbic acid,

iii)1 to 95% by weight of a soluble polyvinylpyrrolidone comprising 0.01 to 10% by weight of a dibasic calcium phosphate anhydrate relative to the polyvinylpyrrolidone, and

iv)0 to 10% by weight of crosslinked polyvinylpyrrolidone, sodium starch glycolate, reticulated carboxymethyl cellulose, or low-substituted hydroxypropyl cellulose.

25. A tablet comprising the product of claim 22, the powder blend of claim 23, or the direct tableting formulation or excipient of claim 24.

26. A capsule comprising the product of claim 22, the powder blend of claim 23, or the direct tableting formulation or excipient of claim 24.

27. A microparticle comprising a product according to claim 22, a powder blend according to claim 23, or a direct tabletting formulation or adjuvant according to claim 24.