WO2003028698A2 - Method and device for producing granulates that comprise at least one pharmaceutical active substance - Google Patents

Method and device for producing granulates that comprise at least one pharmaceutical active substance Download PDF

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Publication number
WO2003028698A2
WO2003028698A2 PCT/EP2002/010743 EP0210743W WO03028698A2 WO 2003028698 A2 WO2003028698 A2 WO 2003028698A2 EP 0210743 W EP0210743 W EP 0210743W WO 03028698 A2 WO03028698 A2 WO 03028698A2
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WIPO (PCT)
Prior art keywords
granulation
gas
granules
extruder
powder
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PCT/EP2002/010743
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German (de)
French (fr)
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WO2003028698A3 (en
Inventor
Klaus-Jürgen Steffens
Rudolf Schroeder
Original Assignee
Steffens Klaus-Juergen
Rudolf Schroeder
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Priority to DE10147414 priority
Application filed by Steffens Klaus-Juergen, Rudolf Schroeder filed Critical Steffens Klaus-Juergen
Publication of WO2003028698A2 publication Critical patent/WO2003028698A2/en
Publication of WO2003028698A3 publication Critical patent/WO2003028698A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Abstract

The invention relates to a method for producing granulates that comprise at least one pharmaceutical active substance according to which the powder to be granulated is introduced into an extruder. A granulated material is formed by adding granulating liquid and is compacted by transverse forces. A gas or a gas mixture can be optionally introduced into the compacted granulated material in order to render the granulated material porous.

Description

Method and apparatus for the preparation of granules comprising at least one active pharmaceutical ingredient

The present invention relates to a method for producing granules comprehensively at least one pharmaceutical active ingredient, an apparatus for producing such granules, and granules prepared by these methods and apparatus.

Granulation is the process over cartloads of powder in Granulatkör- ner, which is particularly important for formulating dosage forms to the pharmaceutical industry, but also for the fertilizer industry and the plastics industry. In the pharmaceutical field to be granules for an as separate dosage forms, which can be taken with respect to powder mixtures better and used for other as an intermediate in the filling of pharmaceutical capsules and the tabletting, wherein flowing bulk solids are obtained by reducing the surface of the powder mixture better, which in comparison be compressed into powders to mechanically stronger compacts. Granules have the advantages of a defined rubble and flowability, reduced tendency to segregate and improved wettability of the active ingredients and auxiliary substances in the rule.

The granulation is carried out either on dry, but mostly wet route. In moist produced granules can be made between crust granulates, in which a formation of solid bridges between the Pulverpar- tikeln by crystallization partially dissolved powder ingredients or as a solution of added excipients occurs after evaporation of the granulation fluid, glue granules, in which the binder bridges formed by moistening with solutions usually macromolecular substances be, as well as sintered granules, in which solid bridges are formed by melting and subsequent solidification of ingredients of the powder mixture.

In the pharmaceutical field granulation are almost exclusively used the known to the expert in this field intensive mixer and a fluidized bed apparatus for the (wet). The quality parameters for the produced granules by means of these methods are mainly the particle size or its distribution, the particle porosity and homogeneous mass distribution. All three parameters result in the processes mentioned by the choice of the equipment and the choice of raw material and are only very limited change over the process conditions. Of particular importance for the processing of granules into tablets, the porosity of the granules, which affects both the tabletting, and the subsequent release of the drug from the granules or the tablets produced therefrom. The porosity of granules can hardly be influenced by means of prior art granulation.

Another problem arises in the wet granulation in the granulation of hydrophobic drugs that can hardly be wetted by aqueous liquids in granulation. A homogeneous mass distribution can be achieved in this case only by a good binder distribution that require significantly higher energy inputs or considerably higher amounts of liquid.

A further problem is the above two methods common batch (batch-wise) is working. This procedure carries on the one hand a great risk of inhomogeneities between batches and therefore requires a large control effort. On the other hand, it may cause difficulties in the scale-up in such a way with that arises due to the increasing size of the granulator and optionally a changed geometry change in the behavior of the granulation mixture, and thus a changed behavior of the resulting granules.

It would therefore be desirable to have a process for preparing pharmaceutical granulates that allows thorough mixing to be granulated mixtures and / or allows the production of granules having a desired, pre-defined porosity.

Such a method and a device for its implementation are defined by the independent claims of the present application. The abhängi- gen claims define advantageous embodiments of the method and apparatus according to the invention.

Surprisingly, it was found that by using a - at least one pharmaceutical active ingredient by means of a method can be produced extrusion line granules comprising at which the homogeneous mass distribution can be improved over an adjustable over a wide range of energy, in particular, and in which a targeted gas introduction and - specially modified subsequent expansion, the porosity of the granules can be adjusted selectively. The inventive method for producing granules generally comprises introducing the powder to be granulated or powder mixture in an extruder, the addition of granulating liquid to form a granulation and compacting the granulation mass in the extruder. This method can further conventional process steps downstream, such as sieving, drying the like, admixture of further constituents and. According to a particularly preferred embodiment of the method a gas or gas mixture is introduced into the granulation mass, to give the granulation porosity after compaction of the granulation in the extruder.

Extruders have been used in the pharmaceutical field only in smelting processes, particularly for the processing or processing of fats, waxes or polymers, as well as in the production of pellets. have trusionsverfahren In such hazardous in the extruder, the masses to be processed entirely different physical properties than the processing by the present method to Granuliermassen. The inventive method can be performed using a per se conventional extrusion lines, but these are modified in that they comprise a device for dosage of the granulating pulverulent starting material and, in the case of the wet granulation method of the present invention, a device for metering the necessary for granulation liquid. According to a particularly preferred embodiment of the method according to the invention a gas is introduced in order to impart the porosity granulation in the granulation; in this case, the extruder further comprises a corresponding apparatus for introducing the gas and for metering the gas pressure and the gas amount. To perform the process suitable extrusion systems according to the invention are illustrated in the accompanying figures. Here shows

Figure 1 is a schematic representation of an extrusion system according to a first embodiment in which no introduction of gas takes place in the granulation;

Figure 2 is a schematic representation of an extrusion system according to the invention overall measure a second Ausführungsfoπn in which an introduction of gas takes place in the granulation;

Figure 3 is a schematic representation of an extrusion system according to a third embodiment of the invention with rotary valves for powder dosing;

Figure 4 is an illustration of a two-stage extrusion system according to the invention in a particularly preferred embodiment, in which an introduction of gas can be carried out in the granulation and

Figure 5 is an illustration of a single-stage extrusion system according to the invention in a particularly preferred embodiment in which no introduction of gas into the granulation mass.

As shown schematically in Figures 1-3, the device for execution out the method according to the invention basically comprises an extruder (D), a device for solid dosage (A) and, optionally, a device for dosing the granulating liquid (B) and a device for gas metering (C). With (E) downstream process steps are shown in FIGS meant, that is, those process steps that usually adjoin the granulation, such as sieving, drying and adding further constituents. The nature and extent of these downstream process steps are based on the requirements and the further use of the granulate. For example, a substantially uniform desired size can be obtained by press Seven granules. When marked in the figures with (A) An apparatus for solid dosage it may be a gravimetric metering screw or other suitable apparatus which enables a defined addition of the pulverulent starting substances of the granulate. The output of the Dosierwerks opens on the feed screw of an extruder or, if present, in the hopper. According to the embodiment shown in Figure 3 Ausfϊihrungsform a rotary valve is used instead of conventionally used for powder task hopper.

The device for fluid metering (B) is used, the necessary for the granulation liquid, and optionally also an adhesive solution to bring about a suitable injection device in the process. The feed point is preferably integrated directly behind the auger in the front region of the Extrusionsein-. Advantageously, they should have a recording of the quantity handled ermöglich- s. Structure and nature of the dosing unit are directed essentially to the pressure conditions within the extruder at this point and the properties of the granulation fluid, such as viscosity, tack, etc.

In the extruder (D), the added ingredients are processed to a granular adhesive or any other process capable of mass. The extruder must be transferred to the mixture a minimum level of shear forces in order to achieve a sufficient dispersion power. To enable a defined dosage of ingredients must also prevail certain pressure conditions within the extruder, especially in the embodiment, in addition a gas is introduced into the granulation to give the granulation porosity. The pressure conditions in the extruder are indicated by the wedges below the figures. Between the marked (1) and (2) points (see Figure 2) must be a pressure gradient with increasing pressure in the direction of point (2) are generated in order on the one hand to increase the dispersion of the mixture, on the other hand, a Rückströ- men of the gas which is added immediately after the point with the highest pressure at point (2) to prevent. This also results in that a gas-tight seal of the extruder must consist of material immediately before the addition point. Immediately behind the mass pressure must again be low, a gas conditioning would allow. Towards the end of the extrusion line of the ground pressure increases naturally to back, as there is a nozzle or other suitable form unit is purposed to prevent leakage unprocessed gas and to increase the contact time between gas and granulation. Advantageously, the extruder can be cooled, so that an extrusion below the critical raw materials for the

Temperatures is possible. Advantageously, the speed of the extruder and the extruder output are measured by suitable means.

In a particularly preferred embodiment, a gas is in the overall formed in the extruder granulation introduced, preferably nitrogen, to give the granulation porosity. In this embodiment, a device for gas metering (C) is required, by means of which the gas is introduced into the process. Both the gas pressure and the gas quantities are advantageously controlled by means of suitable equipment such as pressure reducers, or volume flow meter. The required Liehe maximum gas pressure depends on the mass pressure of the mixture within the extruder at the point of the object gas, and immediately before and at the nozzle of the extruder. The range of the volume flow meter is based on the flow rate of the extruder and the desired porosity. As gas is nitrogen offers, but any other gas is conceivable that does not adversely affect the quality of the product and from other non-process-related reasons, in particular aspects of the environmental impact is acceptable.

Depending on the requirements of the raw materials and the demands on the product and the apparatuses shown in Figures 1 and 3 may be used.

In Figure 1, a single stage extrusion system is shown schematically, is worked for the introduction of gas and without in aforesaid pressure gradient. This configuration is advantageous for very pressure / shear sensitive mixtures whose granulation-regulation without gas dispersion results in a product with adequate properties. In Figure 3, an apparatus is schematically shown in which, instead of the conventionally used for powder hopper object a cellular wheel sluice is used. A fumigation of the granulation mass may then be carried out in spite of the one-stage rotary valve assembly between and auger of the extruder. To the Stickstoffaus- occurs in the product side of the extruder to prevent, can be used for preventing means of an appropriate seal leakage of the gas or, if intended to be dispensed with a nozzle either a nozzle instead a further rotary valve can be integrated therein , a pressure balance between the region of the auger and the range needs to be created immediately downstream of the nozzle at the same time using a die and a second rotary valve in dependence on the material properties and the requirements.

Using one of the previously discussed devices, the erfindungsge- Permitted preparation of granules is carried out by the powder to be granulated or powder mixture on the dosage unit (A) is introduced into the extruder. The extruder, in one particularly preferred embodiment, a planetary roller extruder. a granulation mass is then formed in the extruder, the like, either by introducing an appropriate granulation liquid, such as water, ethanol, isopropanol or the like, or mixtures of these, or by introducing a solution of suitable adhesives, such as povidone, gelatine, cellulose derivatives and the like. The above-mentioned granulating and adhesives are only exemplary of a variety of other substances which are familiar to the expert. After fumigation the optional granulation this occurs as a mass se with kuchenteigartiger consistency from the extruder and can be subsequently processed; it may for example sieved, dried and / or mixed with further ingredients. The granules thus prepared can be used directly as the final dosage form or it may be then filled into capsules or compressed into tablets.

The granulating of the particularly preferred planetary-gear extruder consisting of a helical central spindle (4) which is connected directly to the only part of the process with the drive and supported only at the driving point. About the central mandrel up to 7 planetary spindles (5) are arranged 3, having a contra-rotating toothing and overlap to a high degree with the toothing of the central spindle. The planetary spindles in turn are mounted to the outside in the toothing of the jacket (6). Thus, this system front panel view very similar to a planetary gear.

The dispersion of the components is accomplished by constant rolling between the planetary spindles and central spindle of a hand, and by planetary spindles and coat the other hand. These surfaces are preferably heatable so that the occurring process heat is dissipated directly where they occur, what an excellent temperature control allowed. The entire structure of the granulating unit can be seen from FIG. 4 The granulation system shown in Figure 4 has a two-stage structure, ie, there are two more or less independent process steps of the structure described above, which are connected only by a gap from a few millimeters in width, formed by a stop ring and of the central spindle, with each other. Thus, here the possibility to meter gas between the first and second part of the process to the product features to further influence regarding porosity results. The gas is incorporated within the means of being extruded material and causes an increase in the porosity of the product. Of course, further liquid can be added at this point.

There is also the opportunity to build the granulation system stage, as shown in FIG. 5 This is achieved by omitting the first granulation and thus the central thrust ring, which in turn rules out gassing of the granulate mixture with for example nitrogen. The properties of the granules with respect to the two-step process thereby does not change significantly as long as the two-stage comparison process is also operated without gas.

The invention is further described by the following non-limiting examples. methods:

granulation

Analogous to the usual steps in the granulation in the intensive mixer made weighing, granulation, drying and sieving sequentially. The continuous method requires tight integration of the powder and liquid dosage and the granulating unit, whereas the subsequent process steps can be done spatially but also temporally separated.

Granulate

The granulating unit consisted of a specially modified planetary roller extruder (L-WE 50, Entex Rust + Mitschke GmbH, Bochum, Germany) with a one- or two-stage structure and a length / diameter ratio (LD) of 8 and 16. the powder mixture was introduced by an auger length of 4D in the extrusion or Granulierbereich where the granulation liquid was added via an injection channel. Moreover, the two-stage structure, it was possible to bring to 8D a special stop ring gas into the system. The ring also prevented by sealing material inflow of the gas counter to the extrusion direction. The Austrittsöff ung the extruder resulted in a tube-shaped strand having a wall thickness of 1.5 mm and a diameter of about 30 mm.

The powder dosing was performed by a Einschneckendosierers (Brabender, Duisburg, Germany), the granulation was promoted with a peristaltic pump changed (Ismatec, Zurich, Switzerland). The gas in the two-stage structure of nitrogen was used. The total granulation was cooled with water.

dry

The drying of the granulated mass was carried out in a vacuum drying cabinet at 30 ° C. but it can be used on microwave technology and a continuously operating dryer. seven

All granules were strands after drying in the BTS 100 (LB Bohle Maschinen and methods, Ennigerloh, Germany) sieved (sieve 1.0 mm rasp, impeller Blechausfuhrung, 1,500 revolutions per minute)

Measurement of Porosity

The porosity determination of granule strands carried on the relationship between true volume to apparent volume. The true volume was measured in Gaspykno- meter. The apparent volume was determined by the sample was coated with egg nem gas-impermeable coating of known density and the buoyancy of the sample so prepared was determined in silicone oil of known density. Assuming that the resist remains only at the surface of the sample and has no air pockets, the apparent volume results Vs to Vs = mp - ιn _ m k Ql ({)

Ps PL wherein m P represents the mass, pp true density of the sample, m L, the true density, p L, the true density of the paint, ms, the density of the silicone oil is the determined weight in silicone oil and ps. Thus, the porosity results in ε to:

ε = l - - ^ - Eq. (2) m P V s

pellet production

All solid components were dosed as a premix in the catchment area.

Granulation was carried out with water only.

To find parameters of granulation about 50% of the maximum allowable powder entry was determined initially required at a high water entry and then limits the amount of water to a specific product by temperature and power level. The product temperature should not exceed 60 ° C and the power consumption should not exceed 80% of the permissible maximum limit. The speed of the granulator was set at 150 and 200 revolutions per minute. This was followed by drying the product to a residual moisture content of about 2.5%.

Examination of the granules The granules were further characterized by flow rate, rubble and tapped density and Hausner Ratio. The flow rate was measured using a round outlet funnel with an opening width of 11 mm and debris and tapped density according to Ph.Eur. certainly.

tablet production

The granules were mixed for 10 and 2 minutes at 90 revolutions per minute under the addition of disintegrating agents and flow control agents and lubricants in a Turbula mixer (T2C, Willy A. Bachofen, Basel, Switzerland). The granular mass was 400 g, the volume of the mixing vessel 1250 ml of the compression of the final mix was carried out on an instrumented eccentric of biconcave die set, the target weight was 400 -. 430 mg.

Examination of the tablets

It was the creation of a pressing force - breaking strength (tensile strength) - Pro fils for press forces in the range of 6 - 18 kN. Furthermore, the tablets were tested for disintegration time and drug release. This was carried out with tablets of a breaking strength of 100 N, regardless of the pressing force.

Equipment analytical balance BP 150 and drying balance (Sartorius, Goettingen, Germany), eccentric press Korsch EK0 (Korsch, Berlin, Germany) with stamp set 10 mm biconcave with embossing (Ritter, Hamburg, Germany), fracture resistance tester (Schleuniger, Solothurn, Switzerland), disintegration tester ZT 6 (Erweka, Heusenstamm, Germany), Ultrapyknometer® 1000 (Quantachrome, Odelzhausen, Germany), scanning electron microscope Hitachi S 2460 (Nissei Sangyo, Ratingen, Germany). Experiment examples:

Granulation poorly wettable active substances

The following tests were carried out without gassing. Three different poorly wettable substances were processed in high concentrations with small amounts of povidone. The substances of the final mixture of the weighed quantity of dried granules were added except the magnesium stearate and blended for 5 minutes in a Turbula mixer at 90 rotations per minute. Then, the admixture of the lubricant for 2 minutes done. The percentages of the final mixture should be regarded as shares of the total mass of the granule mixture.

formulation I

Caffeine anhydrous 97.5%

1 O polyvidone 2.5%

a povidone, cross-linked 3.0%

Magnesium stearate 1.0%

Ö

W silicon dioxide 0.5%

Caffeine is relatively uncritical in the granulation because up to very high temperatures, it is stable. Insofar granulation from a quantity of water of 8% could be realized. The granulation was carried out at 12% addition of water and a resulting product temperature of 51 ° C.

The granulate was mixed with 10 g / s quite readily flowable and easily tabletted at a residual moisture content of 1.4%, as the breaking strength press force profile (Figure 6) occupied.

The disintegration time was 8 minutes immediately after tableting quite short, the release profile of these tablets is shown in FIG 7. However, the tablets tended extremely to post-curing. After two weeks of storage, the release time increased by about 60 times, the disintegration time increased to 56 minutes. Therefore, a way had to be found to prevent this post-cure or at least alleviate. By the addition of 5% cellulose, this problem could be solved. In this way could be brought about a disruption of the granular structure, the sub-band post-curing reliable. The tableting and release behavior was almost identical to that already determined. The technological stability was confirmed analytically up to a storage period of six months. A review after that period has not been carried out.

An almost identically constructed granules were prepared on the basis of ibuprofen.

formulation II

Ibuprofen 92.0%

1 Cellulose 5.0%

Ü

Polyvidone 3.0%

Povidone, cross-linked 3.0% υ

Magnesium stearate 0.5% α W silicon dioxide 0.5%

ibuprofen has a relatively low melting point 75-78 ° C, so that a maximum allowable product temperature was set at 40 ° C.

The granulation required 14% water, and ran completely stable over a test period of 4 hours. The good flowability of the granules was advertising confirms, as does the simple tabletting. The residual moisture of the granules prior to preparation of the final mixture was 1.4%. The release profile was also confirmed as the stability of the dosage form over 6 months. The disintegration time was 1, 7 minutes, which is not surprising due to the poor solubility of the drug in water. For direct comparison, mefenamic was granulated with the addition of the identical excipients.

formulation III

Mefenamic 92.0%

1 Cellulose 5.0% α

Polyvidone 3.0%

Povidone, cross-linked 3.0%

Magnesium stearate 0.5%

Figure imgf000015_0001
Silica 0.5%

Mefenamic is an almost non-wettable agent. Yet almost complete wrapping of the active ingredient could be seen analogous formula II. The granulation required much more water because of the poorer wettability. At a water addition of 22% product temperatures were 75 ° C measured, but this is no risk of mefenamic acid.

The granulate was generally finer than II in formulation: fine gaps between active substance and binder by drying, had shown, so that the amic acid Mefen- crystals were loosely incorporated into the binder backbone and thus the extruder dat was also considerably more brittle. Nevertheless, after drying to a residual moisture of 1.1% tableting was no problem.

It has been found a lower resistance and a prolonged release tablets than Formulation II, which, however, due to the lower wettability and low solubility of ibuprofen and mefenamic acid compared with due their different physical properties. Thus, it was shown that the presented system for the granulation of formulations suitable verschiedenster kind.

Granulation using nitrogen

In Table 1, the formulations are given, which were granulated under nitrogen. The constituents of the outer phase are percentages of the granular mass. All figures in% (m / m)

Table 1

IV V VI VII VIII IX

granules

Caffeine Anhydrous

Lactose monohydrate 82.5 80.0 70.0 82.0

Mannitol 72.0 80.0

Corn starch 14.6 15.0 15.0 5.0 10.0

Cellulose 15.0 10.0 15.0 15.0

Povidone 2.9 3.0 3.0

HPMC 5.0

Polyvidone, 5.0 * outer phase qv

Magnesium stearate 0.5 0.5 0.5 0.5 1.0 1.0

Silicon dioxide highly dispersed

Polyvidone, qv * 5.0 2.0 5.0 5.0 5.0

Carboxymefhylcellulose,

3.0 qv *

* Cross-linked formulation IN gave an easily expandable moist granules depending on the viscosity of the product. This can be controlled, as expected, on the amount of water used. The lower the amount of water is, the higher the viscosity, and the better can be incorporated gas. The porosity of the granulate strands as a function of the gas pressure is shown in FIG. 8

The total porosity of the mixture appears compared to existing literature data of granules very low, but it must be remembered here is that this is the porosity of a granulate strand, and this is also determined differently here than the porosity of an accumulation, which is usually the ratio of true density tap density results and thus includes the interparticle voids. These arise in the present granulate strands only through the screening.

The porosity of the mixture increases with the gas pressure, since the pressure difference between the gas pressure and melt pressure of the mixture decreases immediately before the Austrittsöff ung the granulation and thus is facilitated by the outlet channel, a transport of the disperse system. The decrease of the porosity at a gas pressure of 10 bar is explained by the fact that the gas is more or less uncontrollably leaking and thus no longer available for the Porositätssteigerung for disposal. Here, the upper gas retention limit of the system is achieved, the results from the ground pressure, and the "tightness" of the granule mixture and the cross-sectional area of ​​the outlet opening. Since just before the Begasungskanal to passing cross-sectional area of ​​the granulating unit is lower than at the outlet opening, hereby, a gas - resounding avoided counter to the extrusion direction.

The residual water content of the granulate immediately following granulation strands is about 10%, the product temperature increases with increasing gas pressure (from 56 to 50 ° C). As expected, the product temperature correlates primarily with the amount of water used.

By thus adjustable porosity influencing the fracture strengths revealed. This is shown in FIG 9, the pressing force is 5, 10 or 15 Kv. Clearly visible is an increase in fracture strength, which, however, would not be as expected, increases with increasing porosity, but from a gas pressure of 4 - 6 bar drops again. As an explanation for this may serve that the number increases with increasing gas pressure of nitrogen generated by cavities within the granules. Germany nerhalb this can be seen in the electron microscope virtually unwetted powder components which can then be responsible for the deteriorating tableting properties.

The disintegration time of the tablets was 10-12 minutes for a breaking strength of 100 N, wherein the value is quite independent of the gas pressure and primarily correlated with the resistance to breaking.

The other parameters of the granules are shown in Table 2:

table 2

Gas pressure [bar] 0 2 4 6 8 10

Bulk density [g / cm 3] 0.65 0.63 0.63 0.61 0.60 0.58

Tamped density [g / cm 3] 0.77 0.75 0.70 0.72 0.69 0.69

Hausner Ratio 1.189 1.179 1.108 1.184 1.143 1.195

Flow rate 9.46 10.73 9.48 10.10 10.13 10.17

[Gs]

In the case of formulation C the parameters and in particular the disintegration times were largely in the range of formula IV at 0 bar. Thus, the use of povidone quervemetztem brought in this pelletizing first no advantage for the disintegration time.

Formulation VI showed significantly shorter disintegration times of 6.5 minutes, which was to be expected due to the high cellulose content of 15%. However, this mixture required about twice the amount of water compared with formula IN. A change of the powder fraction used for the same water supply gave an influencing of the pressing force - breaking strength - profile and - as expected - the product temperature. The disintegration time remained almost unaffected.

From these points of formula VII gave a granulate with satisfactory stellen- the tableting and disintegration properties, as well as a sufficient gas retention.

The formulas VIII and IX illustrate the use of other fillers and binders. Here, however, a different effect than in previous formulations showed. In formula VIII showed up with increasing gas pressure is first a decrease in tablet hardness, but at 6 bar, they increased again.

In formula IX, the expected increase in fracture toughness with increasing gas pressure was found after an initial drop in the tableting properties. but the disintegration time was significantly shorter than expected.

Thus, it was shown that the injection of nitrogen during the granulation had an impact on the tabletting of the granules.

It was further investigated to what extent the nitrogen pressure affected the properties of the granules and tablets. For this purpose, two ibuprofen Mischun- were chosen gene, wherein a combination of HPMC and amylomaize starch or cellulose were used as an auxiliary additive. Were added and subjected to 1.5 and 3.0 bar of nitrogen per 4% binder and 8% disintegrant. As a reference an identical granulate was produced without addition of nitrogen. The IBU used profen-Charge (IBU) was FBI J584, BASF, Ludwigshafen, Germany. the sealing boundary of the mass to be granulated was exceeded for gas additives than 3 bar.

As Table 3 shows, massive influences on the disintegration and release behavior were observed: Table 3

IBU + HPMC + cellulose

Nitrogen pressure of 1.5 bar to 3.0 bar without

Disintegration time [min] 33.0 47.9 61.6

MDT [min] 20.71 34.43 46.61

IBU + HPMC + Strength

Nitrogen pressure of 1.5 bar to 3.0 bar without

Disintegration time [min] 17.9 45.2 52.2

MDT [min] 25.6 27.4 31.6

It is surprising that the disintegration time partly substantially greater than the determined mean dissolution time (Mean Dissolution Time: MDT) was what was due to gradual dissolution of the dosage form without a preceding complete disintegration. The reasons these influences provided the scanning electron microscopy images, on the one hand auswiesen an increase in number and size of visible Gaskavitäten under increasing gas pressure, which in turn allowed the Porositätmessungen little plausible. On the other hand was also recognized that within the cavities existed almost unwetted drug particles. At first, this seemed unlikely, as even with the passing of the average start-up ring and before the onset of the nitrogen granulation had been completed and the

had drug particles with binders must be enclosed. However, it concerned with used herein ibuprofen is a highly lipophilic substance, which thus could rather interact with the non-polar gas and contact with the hydrophilic binder, which nitrogen offset in the location was to displace the HPMC used by the active ingredient.

This has far-reaching consequences for the use of gas, which definitely is thus in this granular type to be disadvantageous in the production of fast disintegrating tablets. Nevertheless, a controllability of drug release is given, without changing the tablettability significantly or to extend, so that the use of nitrogen should not be generally considered uninteresting. Rather, here an instrument is provided, which allows users to control the release of active ingredient may of highly concentrated sustained-release pharmaceutical without changing the basic formulation.

The inventive method enables the thorough mixing of the substances to be granulated, which results in a particularly homogeneous distribution of the ingredients in the resulting granules result. By the present invention superiors provided for introduction of gas into the formed granulate mass, a desired porosity can this be imparted, so that it becomes possible with the inventive process, to affect the release of contained in the granules active pharmaceutical ingredients of the final dosage forms, for example tablets, ,

Claims

1. A process for the preparation of granules comprising at least one pharmaceutically active agent, comprising the introduction of the powder to be granulated or powder mixture in an extruder, the addition of granulating liquid to form a granulation and compacting the granulate mass.
2. The method of claim 1, characterized in that a gas or gas mixture is introduced into the granulation mass after the compaction of the granulation mass.
3. The method of claim 1 or 2, characterized in that for metering the powdery raw material, a gravimetric dosing screw is used.
4. The method according to any one of the preceding claims, characterized in that is used for introduction of the powder into the extruder a cellular wheel sluice.
5. The method according to any one of claims 2-4, characterized in that the gas introduced into the granulation gas is nitrogen.
6. The method according to any one of the preceding claims, characterized in that the granules produced further sieved and / or dried and / or is mixed with other ingredients.
7. An apparatus for the preparation of granules comprising at least one pharmaceutically active agent, comprising an extruder and means for dosing the powder to be granulated or powder mixture.
8. The apparatus of claim 7, further comprising means for introducing required for granulation liquid.
9. Device according to claim 7 or 8, further comprising a device for introducing a gas into the granulation mass.
10. Granules comprising at least one active pharmaceutical ingredient, prepared by a process according to any one of claims 1-6.
11. A pharmaceutical composition comprising a granulate according
Claim 10th
PCT/EP2002/010743 2001-09-26 2002-09-25 Method and device for producing granulates that comprise at least one pharmaceutical active substance WO2003028698A2 (en)

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023215A2 (en) * 2003-09-10 2005-03-17 Janssen Pharmaceutica N.V. Particles shaped as platelets
US8114383B2 (en) 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
US9486412B2 (en) 2006-08-25 2016-11-08 Purdue Pharma L.P. Tamper resistant dosage forms
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WO2018054577A1 (en) * 2016-09-21 2018-03-29 Robert Bosch Gmbh Production module and method for producing solid medicaments
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US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
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US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2723438C (en) 2008-05-09 2016-10-11 Gruenenthal Gmbh Process for the preparation of an intermediate powder formulation and a final solid dosage form under usage of a spray congealing step
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
JP2017518980A (en) 2014-05-12 2017-07-13 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Containing tapentadol, modified prevent immediate release capsule formulation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1629423A1 (en) * 1966-04-02 1971-01-14 Gruenzweig & Hartmann A process for producing synthetic resin foams and the use of a fabricated by this process pipe
US3922339A (en) * 1974-06-20 1975-11-25 Kv Pharm Co Sustained release medicant
US5496865A (en) * 1993-12-08 1996-03-05 Brugg Kabel Ag Additive-charged porous carrier material

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07184550A (en) * 1993-12-24 1995-07-25 Lotte Co Ltd Production of chewing gum having reduced specific gravity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1629423A1 (en) * 1966-04-02 1971-01-14 Gruenzweig & Hartmann A process for producing synthetic resin foams and the use of a fabricated by this process pipe
US3922339A (en) * 1974-06-20 1975-11-25 Kv Pharm Co Sustained release medicant
US5496865A (en) * 1993-12-08 1996-03-05 Brugg Kabel Ag Additive-charged porous carrier material

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 1995, no. 10, 30. November 1995 (1995-11-30) & JP 07 184550 A (LOTTE CO LTD), 25. Juli 1995 (1995-07-25) *
SCHROEDER R ET AL: "A new system for continuous wet granulation" PHARMAZEUTISCHE INDUSTRIE 2002 GERMANY, Bd. 64, Nr. 3, 2002, Seiten 283-288, XP009012069 ISSN: 0031-711X *
See also references of EP1429735A2 *

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WO2005023215A3 (en) * 2003-09-10 2005-12-01 Albertina Maria Eduarda Arien Particles shaped as platelets
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US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
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US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
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