CA2009090C - Process for producing solid pharmaceutical preparations - Google Patents

Abstract

The invention relates to the use of the air controlled granulating system (SKD) for producing solid pharmaceutical preparations.

Description

2a~~49fl ;~i, The invention relates to a process for producing solid pharmaceutical preparations such as granules, powders, pellets and crystalline active substances, which may optionally be coated.
Of the processes used in the pharmaceutical industry, the production of solid preparations of this kind for sale in this form (e.g. edible granules, dry syrup granules) and as precursors for the production of tablets is one of the most important technologies.
The process which is most frequently used in terms of its basic principle is the fluidised bed granulation process, in which all the individual production steps (mixing, wetting, granulation, drying and final mixing) can be carried out in one apparatus. In spite of this advantage, this method of production has not produced satisfactory results in a number of cases.
In addition to the problems connected with the particular recipe or with the substances used, there are major disadvantages, namely a broad spectrum of particle sizes and high contents of dust or fine dust.
These disadvantages make it particularly difficult to achieve a reproducible quality and validation.
Furthermore, certain pharmaceutical preparations require special procedures (e. g. maximum possible coating of the individual granules) in order to achieve better stability for example in the presence of heat and moisture and resistance to mechanical stresses (mixing, pneumatic conveying, compression), so that even after lengthy periods of storage under unfavourable conditions the pharmacological activity of the drug is maintained.
In addition to so-called coating, the process of granulation by the building-up method (agglomeration) has always presented problems with the processes known hitherto.
The aim of the present invention is to provide a process which makes it possible to produce solid pharmaceutical preparations, particularly for human pharmacological applications, with a narrow range of particle size distribution and a low dust content using simple methods.
According to the invention, this aim is achieved with the so-called air controlled granulating system (SKD granulation method). In the SKD method the powdered starting material is placed in an air controlled granulating system (e. g. HSP-5/10, 250 or 750 made by Huttlin, Steinen) and completely coated with a suitable costing agent. The technical apparatus is disclosed in German Patent 29 32 803. European Patent 146 680 discloses a filter arrangement which can be used for this purpose.
Using this process it is possible to produce coated particles which contain active substance and which are used as the starting material for the production of conventional pharma-ceutical preparations, e.g. for the preparation of tablets, capsules and the like, or may be used directly as a pharmaceutical preparation. The coated particles may be obtained in the form of powders, granules or pellets, depending on the starting material used. Depending on the coating material used, the coating obtained may have the function of controlling the release of active substance or may simply have flavouring or protective functions.
The process according to the invention can be used for build-up granulation. In this process a substrate is used, e.g.
small sugar pellets, which are then sprayed with a solution of active substance.
Surprisingly, it has been found that using the apparatus described in the patents referred to, solid pharmaceutical prepara-2~Q~~~~
- 3a - 27400-115 tions, e.g. including those in the form of a substrate material which contains active substance, can be prepared which have a narrower particle size distribution and a smaller dust content than similar preparations produced and coated in one of the con-ventional fluidised bed granulators.

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Other advantages over the preparations made in the conventional manner are the fact that the preparation produced by the process according to the invention has a very narrow particle size distribution which can be adjusted within wide limits, the preparation has better flow properties and the odour of strong-smelling starting products is largely suppressed.
Both solid and liquid active substances are suitable for use in the process according to the invention. Liquid pharmaceutical active substances may be processed by spraying them onto a suitable substrate and then coating them as required.
Suitable active substances include inter alia pharmaceutical active substances, particularly those which are used in human drugs such as ranitidine, cimetidine, atenolol, enalapril, captopril, nifedipine, naproxene, diclofenac, sodium diclofenac, piroxicam, cefaclor, diltiazem, ketotifen, ketofifen-hydrogen fumarate, salbutamol, propranolol, amoxicillin, triamteren, norethisterone, mestranol, cefotoxamine, sodium cefotoxamine, ceftriaxon, disodium ceftriaxon, cefalexin, dipyridamole, alprazolam, cefoxitine, cyclosporin, metoprololtartrate, acyclovir, sulindac, clavulanic acid, methyldopa, nicardipin, pentoxifyllin, glyceroltrinitrate, timolol, idebenone, terfenadine, tamoxifen dihydrogen citrate, prazosine, doxorubicin, amiloride, amiloride HCl, hydrochlorothiazide, dihydroergocornin, dihydroergocornin methanesulphonate, erythromycin, erythromycinstearate, triazolam, latamoxef, cromoglicinic acid, ceftazidim, clenbuterol, bromhexine oxytetracycline, dexamethasone-21-isonicotinate, sulphadiazine, cimaterole, aditoprim, mederantil, climazolam, carprofen, caffeine, catapresan and acetylsalicyclic acid - or all vitamins permitted as drugs or foods such as Vitamin A, A1, A2, B1, B2, Ba. Bs, B1?, C (ascorbic acid), ascorbylpalmitate and other pharmacologically acceptable derivatives of ascorbic acid, D, Dl, DZ, D3, D4, E, H, K, Kl, K2, P arid Q - or active substances - such as avoparcin, flavopholipol, monensin, sodium monensin, salinomycin, carbadox, nitrovin and olaquindox, and active substances listed in the Red List 1989 (Editio Cantor Verlag fur Medizin and Naturwissenschaften GmbH and Co. KG, Aulendorf/Wurttemb.), the contents of which are hereby referred to.
Suitable coating materials include compounds such as those used as coating agents in galenic pharmaceuticals, such as polyacrylate, polysaccharides, inorganic coating agents such as silicates or carbonates provided that they are soluble or readily suspendable in water or volatile organic solvents or mixtures of solvents. Depending on the active substance involved, it is also possible to use fats, lipids, lecithin, waxes and surfactants as coating agents. The following compounds are also suitable as inorganic coating materials: bentonite, montmorillonite, calcium silicate, kaolinite clays, kieselguhr, silicic acids (precipitated and dried), sodium aluminium silicate, silicon dioxide, perlite, vermiculite. Coating agents of a basic nature which may be used include, for example, calcium hydrogen orthophosphate, calcium oxide, calcium tetrahydroorthophosphate, diammonium hydrogen orthophosphate, dicalcium diphosphate, disodium dihydrogen diphosphate, disodium hydrogen orthophosphate, potassium dihydrogen orthophosphate and/or sodium dihydrogen orthophosphate. Other coating materials include celluloses, particularly hydroxy-propylmethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose and methylcellulose.
Ethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinylacetate, polyvinylpyrrolidones, alg.inic acids, polyethylene glycols, hexadecyl alcohols and hydroxypropylcellu~.ose are also suitable. The coating material may also be made up of a mixture of the coating materials listed.
Other suitable coating materials are known compounds which bring about delayed release of the active substance. These include, for example, coatings of polyacrylates (Eudragit E 30 D, E 100 etc. made by Rohm of Darmstadt) and polyethyleneglycols.
Suitable carriers include, for example, lactose, saccharose, glucose, sugar, corn starch, calcium carbonate and all the substances listed as suitable coating materials.
The minimum possible size for the particles used as carrier material is about 0.5~ttm whilst the upper limit is about 1000~tem. The preferred size range is from 10 to 300 Vim.
Suitable solvents include all the low-boiling and pharmaceutically acceptable solvents or mixtures of solvents which are inert in the presence of the carriers and coating materials and the active substances. The preferred solvent is water.
The proportion of coating material ranges from 2.5 to 30% by weight, preferably from 4 to 20% by weight, more particularly from 5 to 7% by weight, based on the starting material used, including any carrier material present. It goes without saying that larger amounts of coating material may be used, although within the scope of the invention every effort is made to minimise the quantity of coating material. The process according to the invention proceeds as follows:
The powdered starting material, for example having a particle size of between 0.5 and 60 ~tZn, is placed in the slotted gyrodynamic filter granulating apparatus mentioned hereinbefore. The air flowing into the bed of powder through the rotating slotted gyro slots fluidises the product. Then a 3 to 10%, preferably'S to 7%
solution or suspension of the coating material, which is used as fre granulation or coating fluid, is sprayed Trade-Mark into this fluidising zone in the apparatus from below.
The individual process parameters such as the quantity of air supplied, the temperature of the air supplied, the temperature of the exhaust air and the humidity of the exhaust air, the spray nozzle diameter, spray rate, speed of slot/nozzle are dependent inter alia on the size of the apparatus used. More specific information on these parameters is given in the Examples. If desired, the process can be carried out using an inert gas such as nitrogen.
Compared with conventional granulation processes, ( e.g. fluidised bed granulation, the entire process time is much reduced. There is no need for subsequent screening in order to eliminate secondary agglomerates.
Another advantage is that the preparation is not only granulated by the build-up method but the coating completely envelopes the starting material. The difference from conventional granulation methods in which the coating is incomplete can be demonstrated by images taken with a scanning electron microscope.
Because of its very smooth surface the product according to the invention has extremely good flow properties. The granules produced by the process according to the invention exhibit a typical, relatively narrow particle size distribution. In Figure 1 the particle size distribution is illustrated using clenbuterol as an example. With conventional fluidised bed granulation, such a spectrum can only be achieved after repeated screening and mixing.
By contrast with products produced in the conventional manner the product according to the invention contains virtually no fine dust and shows no abrasion. The pharmaceutical preparations produced by means of the SKD process show no demonstrable abrasion of active substance in the Stauber-Heubach test (Fresenius; Z. Anal. Chem. 318 (1984) 522-524). This rules out the possibility of a health risk caused by fine dust containing the active substance during proper handling of the preparations produced by the process according to the invention.
A further advantage of the granules produced according to the invention is the prevention of dust explosions, which often constitute a risk when handling finely powdered substances.
The properties enumerated have major advantages in the further processing of pharmaceutical preparations, e.g. in mixing with other substances and further processing to form tablets and filling capsules.
Another advantage consists of the very homogeneous distribution of active substance in the products prepared according to the invention, thus ensuring a high degree of accuracy in dosing.
A further advantage results from the very good flow properties of the products prepared according to the invention, thus permitting problem-free packaging.
Furthermore, there is no risk of the product becoming unmixed during transportation and further processing.
A further advantage of the process according to the invention is the fact that, by contrast with the fluidised bed granulation method, micronised starting materials with particle sizes of up to 0.5 ~,cm can be used, whilst the yields achieved with the aid of a fine dust recycling system may reach almost 100%.
Furthermore, using the process according to the invention it is possible to obtain substrates having a predetermined particle size spectrum.
In addition, the process according to the invention is suitable for masking flavours.

Examt~le 1 Composition Ingredients: g/100 g g/10 kg (O1)Clenbuterol 0.0016 0.160 (02)Mannitol 0.3184 31.840 (03)Fine lactose (D 80) 60.000 6 000.000 (04)Corn starch, dried* 33.680 3 368.000 (05)Collidone*25 (PVP**) 1.000 100.000 (06)Soluble starch 5.000 500.000 100.000 10.000.000 * If undried corn starch is used, an additional weight of 7% must be included in the calculation ** PVP = polyvinylpyrrolidone Starting material in the SKD process 6.000 g lactose, coarse (specification D 20) 3.368 g corn starch, dried Preparation of the granulating solution for a 10 ks batch Solution 1:
0.160 g of clenbuterol are dissolved in 50 ml of H20 .
Solution 2:
800 ml of HZO are placed in a thermostatically controlled vessel at ambient temperature and 500 g of soluble starch are suspended therein with stirring.
Trade-Mark 20ososo Solution 1 is stirred into this suspension.
Solution 3:
2.500 ml of H20 are placed in a 5 litre beaker.
31.84 g of mannitol are dissolved therein with stirring and the solution is heated to boiling point.
Solution 4:
The hot mannitol solution is added to solution 2 with stirring, whereupon the soluble starch immediately clumps together visibly (swells).
Solution 5:
650 ml of H20 are heated in a glass beaker to boiling point and 100 g of collidone 25 are dissolved therein with stirring.
Granulating solution:
Solution 5 is then stirred into Solution 4 (in the thermostatically controlled vessel). The temperature of 50°C required for spraying is adjusted.
Granulation in the SKD*:
Preparation: The SKD is preheated to about 60°C. Then the previously prepared fillers, unscreened, are put in and mixed together for about 2 to 3 minutes (about 50 Nm3Nz/h). In the meantime the SKD is heated further (temperature for air supplied is adjusted to 100°C). After mixing, the granulating solution is sprayed on at a temperature of about 50°C.
After all the granulating solution has been sprayed in, the thermostatically controlled vessel is rinsed out twice with ml. of H;O, which is also sprayed in.

The granules are dried until the product temperature is 60°C. (The residual moisture is then about 4.5 to 6% according to the Karl Fischer Method.) *SKD = air controlled granulating system.
Example 2 Composition: 95.0 g active substance 5.0 g methylcellulose 100.0 g active substance granules Method: The powdered starting material, the active substance, with a particle size of 1 to 40 um (main fraction: 10 to 15 um) is placed in the SKD. A 5o methylcellulose solution is prepared, which is used as the granulat-ing liquid. The air flowing into the powder bed through the rotating slotted gyro slots fluidises the product and the granulating liquid is then sprayed into these fluidising zones from below.
Process parameters: Quantity of air fed in: 150 to 250 m3/h Temperature of incoming air: 60 to 70°C
Spray nozzle diameter: 1.2 mm Average spray rate: 18 ml/min Speed of slot/nozzle: 3 rpm ~ lla 2 0 0 9 0 9 0 The total spraying time is about 155 minutes and the drying phase about 25 minutes. The entire process time is therefore about 180 minutes. Compared with this, the total process time for _u ~ X009090 granules of active substance produced in a conventional fluidised bed granulator (e. g. WSG 200 made by Glatt) is more than 8 hours, whilst additional screening and mixing are also required because of the large secondary agglomerates and the broad spectrum of particle size distribution.
After only 15 minutes, the formation of granules is apparent. The granulation phase merges, apparently smoothly, into a coating phase, in which the granules initially formed are gradually coated with methylcellulose. Images taken using a scanning electron microscope 600/1800 x magnification show different smooth surfaces in two samples which were coated with 5.14 and 9.48% of methylcellulose, respectively, the higher coating concentration producing the smoother surface.
The end product produced by means of the SKD contains virtually no fine dust (particles smaller than 45 ~tm = 0%) and has a narrow particle size distribution spectrum (particles 200 to 400 ~Gm = 92%).
This is accompanied by good flow properties of the granules (angle of slope: 33.6°, nozzle opening 6 mm, flow time for 200 ml: about 75 seconds).

Claims (6)

1. Process for producing a solid pharmaceutical preparation with a narrow particle size distribution of between 0.5 to 1000 µm, characterised in that the pharmaceutical preparation is produced from - a powdered starting material comprising a solid or liquid active substance and - a coating agent in the form of a solution or suspension to completely cover the starting material by build-up granulation using an air controlled granulation method.

2. Process according to claim 1, characterised in that the pharmaceutical preparation is provided with the coating using the air controlled granulating system.

3. Process according to claim 2, characterised in that the coating material is a physiologically acceptable polymer.

4. Process according to claim 2, characterised in that the coating material is a physiologically acceptable inorganic excipient.

5. Process for preparing particles which contain active substance, in the form of powders, granules or pellets, characterised in that carrier particles are sprayed with a solution or suspension which contains the active substance using an air controlled granulating system.

6. Process for preparing coated particles containing active substance according to claim 5, characterised in that the carrier particles containing active substance are sprayed with a solution which forms a coating using an air controlled granulating system.