EP1251830A1

EP1251830A1 - Continuous method for preparing pharmaceutical granules

Info

Publication number: EP1251830A1
Application number: EP01909880A
Authority: EP
Inventors: Stéphane MARTIN-LETELLIER; Jean-Claude Le Thiesse
Original assignee: Rhodia Chimie SAS
Current assignee: Rhodia Chimie SAS
Priority date: 2000-02-04
Filing date: 2001-01-24
Publication date: 2002-10-30
Also published as: FR2804603B1; FR2804603A1; US20030224057A1; WO2001056549A1; CA2399034A1; MXPA02007458A; CN1419443A; AU2001237482A1; JP2004500193A

Abstract

. The invention concerns a method for formulating in the form of granules one or several active pharmaceutical principles, characterised in that it consists in continuously introducing various ingredients to be granulated and in granulating said mixture using a device comprising a chamber and at least a rotary stirring arm, and in the presence of a sufficient amount of a binder solution until said granules are obtained.

Description

CONTINUOUS PROCESS FOR PREPARING PHARMACEUTICAL GRANULES

The field of the invention is the granulation of active ingredient (s) for pharmaceutical compositions.

Granulation is generally a technique which makes it possible to increase the granulometry of a powder. More specifically, it aims to transform pulverulent solids into aggregates of varying size more or less resistant and more or less porous, which are called granules. These granules have improved flow and mechanical properties compared to a simple dry mixing of the ingredients, and the granulation makes it possible to avoid the phenomena of demixing observable during a dry mixing operation.

There are three main granulation routes: the wet route, the melt route and the dry route. Dry granulation is generally preferred for products capable of acquiring cohesion between particles under constraint, for example by dry compaction of a mixture of ingredients. Molten granulation is generally used for thermally stable products for which granules with low porosity are sought, for example by extrusion of an active principle suspended in a molten polymer. Wet granulation requires the addition of a solution on the mixture of ingredients which is intended to act as a binder and therefore contribute to the agglomeration of the particles between them. This third route therefore generally involves carrying out a consecutive drying step.

The present invention relates more particularly to granulation in a pharmaceutical medium by the so-called wet route.

Conventionally, the formulation of pharmaceutical active principles in the form of granules is carried out in a sequenced manner. In a first step, the various active ingredients and associated excipients are mixed. The formulation of the mixture in the form of granules is carried out consecutively in a second stage, therefore carried out separately from the first stage.

In fact, continuous mode processes are developed in order to optimize in terms of cost the transformation processes proposed for obtaining a final product.

In this regard, the present invention relates to a process for formulating in the form of granules one or more active pharmaceutical ingredients, characterized in that one proceeds in continuous mode to the introduction of the various ingredients and to their granulation by means of a single device comprising an enclosure and at least one rotary stirring arm, and in the presence of an effective amount of a binder solution enabling said granules to be obtained.

For the purposes of the present invention, "continuous mode" means that there is no interruption of the transformation process of the active material. In particular, the operations of introducing the various ingredients and of granulation take place continuously.

The claimed process thus has the advantage of eliminating the operations which are usually discontinuous of a granulation process, resulting in potential economic gains. Similarly, according to a preferred variant of the invention, a drying operation of the granules obtained is also carried out in continuous mode, that is to say consecutive to the granulation step.

The process of the invention is preferably carried out by means of a mixer 10 shown in FIG. 1, of cylindrical shape in communication with a feed hopper 12 and comprising a discharge 14 for the granules obtained. It is preferably a twin screw mixer operating continuously. More specifically, the mixer 10 consists of a cylindrical tank 16, generally made of stainless steel. The tank is surrounded by a double jacket 18 containing a heat transfer fluid to ensure temperature control during the granulation step. In the tank 16, are arranged two counter-rotating stirring shafts 20 equipped with twisted stirring blades 22. These shafts are arranged parallel side by side along the axis of the tank and are driven by the same motor 24.

The mixer 10 also includes points for the injection of liquid, in particular of the binder solution, either at the bottom or at the top of the mixer.

In addition, the tank is provided, in its upstream part, with an inlet 26 for solid active materials, to which the outlet of the hopper 12 is connected.

The feed hopper 12 is introduced with the ingredient (s) to be formulated in the enclosure of the mixer.

The binding solution is introduced separately into the enclosure. It is introduced therein by means of one or more points for injection, and this concomitantly with that of the various solid ingredients.

The binder solution is generally introduced at room temperature, namely between 15 ° C and 40 ° C. According to a variant of the claimed process, the binder solution is introduced at a temperature above room temperature and preferably between 40 ° C and 90 ° C. Granulation is carried out rapidly by stirring all the compounds within the enclosure by means of the stirring shaft (s) and preferably at a temperature between 20 ° C. and 150 ° C. and preferably around 20 ° C to 80 ° C. Generally, the average granulation time is of the order of a few minutes.

To implement the process of the invention in particular with an apparatus as described above, it is recommended to maintain optimal granulation conditions, to ensure a feed rate of solid active materials of between 50 kg / h and 250 kg / h and preferably of the order of 60 kg / h to 180 kg / h and a speed of rotation of the order of 100 rpm to 400 rpm.

At the outlet of the mixer enclosure, the granules can be dried continuously, preferably in a fluidized bed so as to maintain a residual humidity level suitable for the subsequent use of the granules.

The granules can also, if necessary, be calibrated by forced passage through a calibration grid. Generally, the grain size is then determined by sieving.

Commonly, the particle size is defined by a coefficient of variation (CV). This CV represents the state of the particle size distribution in percent; the greater the CV, the greater the spread of the particle size distribution. This CV is assessed as follows:

2.d 50

We define - the average diameter d ₅₀ as being such that 50% by weight of the particles have a diameter greater or less than the average diameter,

- d ₁₆ as the diameter for which 16% by weight of the particles have a diameter less than this diameter, - d ₈₄ as the diameter for which 84% by weight of the particles have a diameter less than this diameter.

After the calibration step, the coefficient of variation of the products of the invention obtained at the end of the claimed process varies between 30% and 100%, preferably between 40% and 90%. Their particle size generally varies between 100 and 800 μm with a d ₅₀ which represents an average particle size generally between 300 μm and 500 μm.

It appears that the granulation state of the product obtained at the end of the claimed process is particularly satisfactory. The granulation of the product is complete because the granules contain only few fines. They are therefore not too dusty.

Advantageously, this type of granule is particularly suitable for compression and therefore is suitable for the formation of tablets.

This compression operation is of course within the competence of those skilled in the art. The galenical evaluation of the tablets thus obtained in terms of quality of cohesion, friability and disintegration time of the tablets is also satisfactory and is demonstrated in the examples given below.

The pharmaceutical active ingredients which can be formulated according to the claimed process can be highly water-soluble such as acebutolol hydrochloride or poorly water-soluble such as paracetamol.

Among the active materials which can be used in the process according to the present invention, non-limiting non-steroidal anti-rheumatic and anti-inflammatory drugs (ketoprofen, ibuprofen, flurbiprofen, indomethacin, phenometbutazone, allopurinol, nabumetone, etc.) may be mentioned, without limitation. opioid analgesics or not (paracetamol, phenacetin, aspirin .. ^' .), cough suppressants (codeine, codethyline, aiimemazine ...), psychotropics (trimipramine, amineptine, chlorpromazine and phenothiazine derivatives, diazepam, lorazepam, nitrazepam, meprobamate, zopiclone, and derivatives of the cyclopyrrolone family ...), steroids (hydrocortisone, cortisone, progesterone, testosterone, prednisolone, triamcinolone, dexamethazone, betamethazone, paramethazone) , barbiturates (barbital, allobarbital, phenobarbital, pentobarbital, amobarbital ...), antimicrobial agents (pefloxacin, sparfloxacin, and derivatives of the quinolone class, tetracylines, synergistins, metronidazole ...), drugs intended for the treatment of allergies, in particular anti-asthmatics, antispasmodics and antisecretories (omeprazole), cerebral vasodilators (quinacainol, oxprenolol, propranolol, nicergoline), cerebral protectors, hepatic protectors, therapeutic agents for gastrointestinal purposes, contraceptive agents, oral vaccines, antihypertensive agents and cardiovascular agents or cardio protectors such as beta blockers and nitrates.

The amount of active ingredient entering the pharmaceutical granules prepared according to the process of the present invention can vary within wide limits. It is more particularly between 0.001% and 98% by weight of the total composition, the complement being provided by the associated excipients.

The claimed process is particularly advantageous for granulating paracetamol (acetyl-para-amino-phenol). In this particular case, the use of a raw material is preferred, paracetamol having an overall particle size varying between 2 μm to 200 μm with a size d ₅₀ of 20 μm to 70 μm and whose CV is range from 60% to 150%.

The active pharmaceutical ingredients can be formulated with excipients which make it possible to obtain the desired use properties of the granules. These excipients can be diluents, such as lactose, sucrose, calcium phosphates; agents of cohesion, such as hydrophilic polymers such as poly-vinyl-pyrrolidone cellulose, cellulose derivatives (hydroxy-methyl-propyl-cellulose, ethyl-cellulose), natural, natural or modified gums (gelatin, carob gums, gums guar, xanthan gums, alginates, carrageenans), native or pre-cooked starches; disintegrating agents, such as native starches, super-disintegrants such as sodium starch glycolate; flow agents, such as silica, talc; lubricating agents, such as stearic acid, magnesium stearate, calcium stearate; preservatives, such as potassium sorbate, citric acid, ascorbic acid. All of these components are generally introduced into the device with the active ingredients to be granulated. However, these excipients can be wholly or partly incorporated into the binding solution.

As regards more particularly the binder solution, it is generally water. This binder solution can incorporate a material which, by its nature, promotes the agglomeration of the particles of active materials to be formulated to form granules. Particularly suitable for this type of function are binding agents such as polyvinylpyrrolidone cellulose, cellulose derivatives (hydroxy-propyl-methyl-cellulose, hydroxy-propyl-cellulose), natural, modified or synthetic natural gums (gelatin , carob gums, guar gums, xanthan gums, alginates, carrageenans), native or precooked starches.

The binder solution is generally used in an amount of 40% to 100% by weight of active materials to be granulated. In fact, its quantity is very variable and in particular linked to the characteristics of the ingredients to be formulated (solubility, hygroscopy, particle size distribution, rheology) and to the desired use properties (mechanical properties, particle size distribution). Adjusting this amount is primarily a skill in the art. The present invention also relates to the use of a device comprising a cylindrical tank 16, generally made of stainless steel, surrounded by a double jacket 18 containing a heat transfer fluid to ensure the control of the temperature of the mixture during granulation. and in which are arranged parallel and side by side along the axis of the tank and driven by the same motor 24, two counter-rotating stirring shafts 20 fitted with twisted stirring blades 22, for granulating at least one pharmaceutical active material .

The examples and figure which follow are presented by way of illustration and without limitation of the present invention.

FIGURE

Figure 1: Schematic representation of the installation for granulation.

MATERIAL AND METHOD

For all the tests carried out (residence time measurements, granulation tests, etc.), the procedure is identical. A device as shown in FIG. 1 is used.

The granulation device is the continuously operating twin screw mixer described above (CLEXTRAL 150 I pre-conditioner).

The drive motor of the mixer shafts has a power of 5.5 kW. The rotation speed of the shafts is from 80 rpm to 420 rpm. A thermostated circulation bath is used at its double jacket. A weight loss dosing hopper regulates a constant feed rate in the mixer. The product outlet from the mixer is located on the lower level.

The tests used as active ingredient paracetamol or acetyl-para-amino-phenol (Rhodapap Pulverized Dense NP, Rhodia), the feed rate of which varied between 60 kg / h and 120 kg / h. The binder solution, for its part, is composed of demineralized water and corn starch (Extra White Corn Starch, Food Grade, Roquette Frères) in a proportion of 20 kg of water per 3 kg of starch. This solution is cooked in a double-wrapped stirred tank between 80 ° C and 85 ° C for at least 20 minutes to allow the gelatinization of the starch, then injected into the mixer at a rate varying between 20 kg / h and 60 kg / h.

EXAMPLE 1

During this test, the feed rate of the paracetamol was set at 90 kg / h and that of the binder solution at 30 kg / h, for a speed of rotation of the shafts of the mixer of 290 rpm. Two samples of granules were taken from the mixer, then were dried to a residual humidity between 2.0% and 2.5%. They are finally calibrated through an 800 μm grid. Table I below shows the results of the particle size distribution measured on the granules obtained after calibration.

TABLE I The two samples were taken respectively 26 min and 42 min after the start of injection of the binder solution into the mixer. The particle size analysis by sieving (RETSCH AS 200 vibrated sieve, 100 g sample, 1.5 mm vibrations, 10 min duration) shows that the granules after the calibration step have a tight size distribution illustrated by a low CV, and that the granulation is complete as illustrated by a high value of d ₁₀ , the active principle initially having a d ₅₀ between 20 μm and 80 μm. The granules obtained are therefore very little dusty.

EXAMPLE 2

During this new test, the feed rate of the paracetamol was set at 90 kg / h and that of the binder solution was increased to 42 kg / h, for a speed of rotation of the shafts of the mixer maintained at 290 rpm. / min. Three samples of granules were taken from the mixer, then were dried to a residual humidity between 2.0% and 2.5%, and finally calibrated through a grid of 800 μm. Table II below presents the results of residual humidity of the granules leaving the mixer and of the paracetamol titer of the granules obtained after calibration.

TABLE II Residual humidity is measured by weight loss on METTLER PM460 thermobalance (sample of 3 g to 4 g, temperature of 105 ° C, duration of 15 min), while the titer of paracetamol is obtained by completely dissolving the granules after drying and calibration and comparing the absorption at 240 nm with a reference sample using a PERKIN ELMER Lambda 20 UV spectrometer.

The results obtained show that the process is stable, the samples of granules leaving the mixer on different dates having similar levels of residual humidity. This stability is confirmed by the comparable paracetamol contents obtained on these same samples. In addition, the homogeneity of composition of the granules shows the advantage of this granulation process in continuous mode to fix a composition on the scale of the granules and to avoid the phenomena of demixing observable during a simple dry mixing of the ingredients.

EXAMPLE 3

One of the aims sought through a granulation process is the improvement of the properties of use of the starting active ingredients or of their simple mixing with excipients. In the case of paracetamol, one of the essential properties desired is the compressibility of the granules.

In this example, are added to the granules produced by means of this invention a disintegrating agent, namely corn starch (Extra White Corn Starch, Food Grade, Rocket Brothers) and a lubricating agent, magnesium stearate ( Magnesium stearate, Propharm). These excipients are added in a dry mixing device (RETSCH Bicone, rotation speed of 40 rpm, mixing time of 20 min). The mixture thus obtained is fed into a rotary press (MANESTY Betapress 16 station press, fed by double pallet) where flat tablets, with chamfer, with a diameter of 12.5 mm are produced.

The tablets are characterized by their geometric properties (diameter, thickness), their mass and their mechanical properties (breaking strength, friability). These measurements are carried out by means of a CONTESTAR automaton and an ERWEKA TA 20 friability bench coupled to an electronic METTLER PM 400 balance. The cohesion of the tablets, expressed in MPa, is a quantity calculated from the resistance to break and geometric data according to the following formula:

2 x breaking strength

Cohesion = π x Diameter x Thickness

Tables III and IV below show the results of the measurements carried out on tablets of different formulations made from the granules obtained according to the operating conditions described in Example 2.

BOARD

Formulation: 1000.0 g granules example 2 + 61.5 g starch + 2.0 g stearate Mg TABLE IV

Formulation: 1000.0 g granules example 2 + 27.3 g starch + 2.0 g stearate Mg

These results were obtained from tablets manufactured at a tableting speed of 45,000 tablets / min, with the application of a pre-compression force of 0.5 t. Granulation significantly improves the flow properties of the simple mixture of ingredients, as illustrated by the small standard deviation obtained on the mass of the tablets (standard deviation less than 1.0%, generally of the order of 0.6%).

Furthermore, the tablets produced have satisfactory mechanical properties, as illustrated by the cohesion and friability data, knowing that the level of friability generally required by the European and American Pharmacopoeias, in particular, is 1.0% maximum.

In general, the good progress of a pelletizing step of granulated active ingredients is very much linked to the water content of these granules, the water in fact providing the granules with the ability to deform plastic necessary during of the pelletizing step. The good behavior of granules produced with the present invention during pelletizing step is very closely related to the residual _moisture of the granules and the good control of this parameter in this continuous granulation process. On the other hand, the measurement of the paracetamol titer (according to the method described above, see § Example 2) on tablets obtained from the formulation "1000.0 g granules example 2 + 27.3 g starch + 2.0 g stearate Mg "gives values equal to 88.6% ± 0.5%. This confirms the homogeneity of the granules obtained according to the granulation process in continuous mode as described here.

Claims

1. Method for formulating in the form of granules one or more active pharmaceutical ingredients, characterized in that one proceeds in continuous mode to the introduction of the various ingredients and to their granulation by means of a single device comprising an enclosure and minus a rotary stirring arm, in the presence of an effective amount of a binding solution allowing the production of said granules.

2. Method according to claim 1, characterized in that one can proceed in continuous mode to a drying operation of said granules following the granulation step.

3. Method according to claim 1 or 2, characterized in that the pharmaceutical materials are introduced at the level of the enclosure with a feed rate of between 50 kg / h and 250 kg / h.

4. Method according to one of the preceding claims, characterized in that the rotary stirring arm (s) is (are) subjected to a speed of rotation of the order of 100 rpm to 400 rpm min.

5. Method according to one of the preceding claims, characterized in that the enclosure is maintained at a temperature between 20 ° C and 150 ° C during the granulation operation.

6. Method according to one of the preceding claims, characterized in that the binder solution is introduced at ambient temperature or at a temperature higher than ambient temperature.

7. Method according to one of the preceding claims, characterized in that the binder solution is introduced separately, at the level of the enclosure.

8. Method according to one of the preceding claims, characterized in that the coefficient of variation of the granules obtained after the calibration step varies between 30% and 100%, preferably between 40% and 90%.

9. Method according to one of the preceding claims, characterized in that the average size d ₅₀ of the granules obtained after the calibration step is between 300 μm and 500 μm.

10. Method according to one of the preceding claims, characterized in that the active substances are chosen from non-steroidal antirheumatic and anti-inflammatory drugs (ketoprofen, ibuprofen, flurbiprofen, indomethacin, phenylbutazone, allopurinol, nabumetone ...), analgesics opiates or not (paracetamol, phenacetin, aspirin ...), cough suppressants (codeine, codethyline, alimemazine ...), psychotropics (trimipramine, amineptine, chlorpromazine and derivatives of phenothiazines, diazepam, lorazepam, nitrazepam, meprobamate, zopidone and derivatives of the cyclopyrrolone family ...), steroids (hydrocortisone, cortisone, progesterone, testosterone, prednisolone, triamcinolone, dexamethazone, betamethazone, paramethazone, fluocinolone, beclomethazone ...), barbiturates, barbital, phenobarb pentobarbital, amobarbital ...), antimicrobial agents (pefloxacin, sparfloxacin, and clas derivatives se of quinolones, tetracylines, synergistins, metronidazole ...), drugs intended for the treatment of allergies, in particular anti-asthmatic, antispasmodic and antisecretory (omeprazole), cerebral vasodilators (quinacainol, oxprenolol, propranolol, nicergoline), brain protectors, hepatic protectors, gastrointestinal therapeutic agents, contraceptive agents, oral vaccines, antihypertensive agents- and cardiovascular or cardioprotective agents such as beta-blockers and nitrates.

11. Method according to one of the preceding claims, characterized in that the active material is paracetamol (acetyl-para-amino-phenol).

12. Method according to claim 11, characterized in that the starting active material has an overall particle size of between 2 μm and 200 μm with a size d ₅₀ of 20 μ to 70 μm and a CV of the order of 60 % to 150%.

13. Method according to one of the preceding claims, characterized in that the device is in communication with a feed hopper 28 and consists of a cylindrical tank 16 surrounded by a jacket 18 containing a heat transfer fluid to ensure control of the temperature of the mixture during granulation and in which are arranged, parallel and side by side along the axis of the tank and driven by the same motor 24, two counter-rotating stirring shafts 20 equipped with stirring blades 22 twists.

14. Use of a device comprising a cylindrical tank 16, generally made of stainless steel, surrounded by a double jacket 18 containing a heat transfer fluid to ensure control of the temperature of the mixture during granulation and in which are arranged parallel and side by side along the axis of the tank and driven by a single motor 24, two counter-rotating stirring shafts 20 fitted with twisted stirring blades 22, for granulating at least one pharmaceutical active material.