DD143213A1 - PROCESS FOR GRANULATION - Google Patents

Abstract

The method of granulation is based on the invention Use of specific binders based on polyacrylate for Formulation of pharmaceutical granules containing tablets with good Decomposition, from powder mixtures of low cohesion using the usual manufacturing technologies. The binders can in solid form, as suspensions, solutions or Emulsions, preferably as finely divided aqueous dispersions for Get used. It is further demonstrated that by selecting the Type and amount of monomers to be polymerized Polyacrylatbindemittel can be made to measure with properties. With help of the method described are often occurring disadvantages of known binders with respect to their opposite effect on the Strength and disintegration of the products manufactured with them (Granules, tablets) avoided. In addition, it succeeds by the inventive method the quality fluctuations and the Microbial contamination, known in the application natural binder the reproducibility of the granular properties question almost completely.

Description

212 476

a) Title of the invention Process for granulation

b) Field of application of the invention;

The invention relates to a method for granulation, preferably for the production of pharmaceutical granules of active ingredients or Wirkstoffgemischen.King cohesion, which allows the application of the usual production technologies and leads to granules containing tablets o.a. Moldings with rapid disintegration time and optimal drug release result.

c) Characteristic of the known technical solutions

For the production of granules which give tablets with rapid disintegration time, binders are usually used when the substances to be granulated have too low cohesive forces _e serve as a binder so far mainly natural substances and only in recent years, semi-and fully synthetic adjuvants for the (see Table 1). "

Tab. 1: Overview of common granulation binders

Natural substances semi-synthetic fully synthetic adjuvants adjuvants

Proteins Cellulose derivatives Polyvinyl compounds (e.g., gelatin) (e.g., Na carboxy (e.g., polyvinylpyrrole carbohydrates, methyl cellulose, don, polyvinyl alcohol)

<zBStärke, S ^ o ^ f ¹ "polyethylene glycols Na-alginate) cellulose) (for _e B.Carbowax 6000)

Carboxyvinyl polymers (for example, polyacrylic acid, polyacrylamide, boylmethyl methacrylate)

In particular, when using ale retardants, it is also common to use polyacrylates for granulation. This results, but always products that release the active ingredients contained not immediately, but gradually and more or less delayed. For example, KALA, ERBE, KUNZE and DITTGEN describe a process which is based on the use of a polyacrylate for the formulation of sustained release forms according to the embedding principle * (DDR patent 108 456 v. 1974), which also includes the production of granules as a production step.

Although polyacrylates have not been used to a large extent to date for the production of granules which rapidly disintegrate tablets, it is known that homopolymers of acrylic or methacrylic acid, which are used as thickeners in pharmacy, are used for granulation in analogy to other swelling agents. In a Pail, moreover, a copolymer based on a methacrylate was also used for the formulation of plate granules. However, this latter case involved the use of a polyacrylate known as a retarding agent, so that the disadvantages with regard to disintegration and release of active substances mentioned in this connection are analogous , In any case, the use of said polyacrylates results in disadvantages resulting from the particular structure which, although adapted to the use as swelling agent, thickener or retarding agent, the achievement of optimum granules, the rapidly disintegrating and the drug quickly and completely releasing Tablets of good strength, but in many ways

d) Aim of the invention;

The aim of the invention, however, is to demonstrate by the use of customary production technologies by the use of specific binders based on plastic, a process for the preparation of pharmaceutical granules of active ingredients' or mixtures of low Kohäs'ion which does not include the disadvantages caused by conventional Granulierbindemittel disadvantages. It is of particular importance to avoid the difficulties, caused by conventional granulation binders, with respect to the mechanical properties and the decomposition

fallability in water or digestive juices of compacts made from the granules to avoid in such a way that the granules of the invention can be pressed into mechanically stable.Formungen with good Zerfallbarice it in water or digestive juices. · ·.

e) Presentation of the essence of the invention

A process has been developed for granulation which is based on the use of physiologically indifferent plastics as granulation binders which are used in dry form, as a suspension, emulsion or solution, but preferably as a finely divided aqueous dispersion. These plastics are oxygen-functional copolymers, for example, carboxyl, glycidyl, hydroxyl and / or carboxyvinyl copolymers, preferably copolymers of one or more acrylic and / or methacrylic esters with unsaturated acids. The Copolymer ^ sate of one or more acrylic and / or methacrylic acid ester]! Acrylic acid, methacrylic acid, itaconic acid, crotonic acid, maleic acid or fumaric acid are preferred. However, copolymers of acrylic and / or methacrylic acid esters with C ₁ - to C. alcohols and acrylic and / or methacrylic acid are used

It can in principle also other, the copolymer harder or softer vinyl compounds to be set be used with, for example, vinyl acetate, styrene, vinyl ethers "However, it is more advantageous, these properties through the various acrylic and / or methacrylic esters, for _e B 'methyl, ethyl , Butyl and 2-ethylhexyl acrylate, methyl and butyl methacrylate. ,

The swelling ability of the binder, which is required in different ways in a wide variety of practical drug formulations, can be adjusted by the acrylates and / or methacrylates of different hydrophiles depending on the use of acrylic acid or methacrylic acid. In special cases, you must also work with a mixture of acrylic and methacrylic acid. , , The acid content of the copolymers can vary within wide limits (2 to 45 %, preferably 12 to 25 %) , thus leaving room for each specific pharmaceutical preparation desired in the context of the invention.

The use of favorable from an application point of view partial and full synthetic are opposed to the poorer disintegration times of the resulting tablets, so that the natural products in many cases still get the advantage. Among the binder-containing preparations, the products formulated with partial and full synthetic products are clearly superior to natural products due to their lower microbial susceptibility and their uniform quality. In particular, the quality fluctuations of the natural substances influence the reproducibility of the granule properties. In addition to these considerations, processing and compatibility issues should also be considered to assess the suitability of a binder. For example, Gelatineknetmassen to plastic flow, which complications in the granule formation may be due «for this difficulty can already give rise to increased air humidity,. , '

The processing of starch pastes is also deficient, with the risk of poor disintegration and drug release of the drug forms prepared with this binder is mainly.

For granule forming various technologies are known. The most common is wet granulation, wherein a suitable binder is used in dissolved form for agglomeration of the powder particles. The usual concentrations of the binder solutions are between 1 and 10 percent. The application of the binder solutions takes place mainly according to the kneader or veiling layer technology. The granules produced using binder-containing liquids can usually be further processed without complications, zeZe compressed into tablets or fill in pharmaceutical capsule preparations. In this case, the binder must on the one hand ensure the desired mechanical properties, on the other hand, however, an optimal drug release.

(Hereafter referred polyacrylates) carboxyvinyl polymers and especially co-esters of acrylic and / or methacrylic acid with their alky! Esters have proved themselves as auxiliaries in pharmaceutical technology of solid peroral in numerous application purposes, eg as Dragierhilfsstoffe, retarding etc ₀

However, it is not possible to use homopolymers of acids or copolymers of acid mixtures alone since they do not ensure rapid release of active ingredient in the sense of the invention due to their strong swelling. The binder can be present both in solid form and in a suitable solvent, emulsified or suspended. the solution polymers can be produced in a variety of solvents, but preferably in ethanol, isopropanol, butanol, toluene, chloroform, methylene chloride, acetone or mixtures thereof ₀ Den advantages, such as the absence of any kind of emulsifiers are the known processing technical disadvantages, such as flammability , expensive solvents, high viscosity with high plague content, compared. The desired copolymers can also be used as suspension polymers.

As low on all sides, the use of the copolymers has a. Form of emulsion polymers proven "talk For u _e a" low viscosity at high .Festkörpergehalt, the known advantages of the solvent water, the favorable and reproducible control of the polymerization. In order to avoid unfavorable side effects, these polymers are oriented to the lowest possible emulsifier content. Thus, it is characteristic that the above-mentioned copolymers are only anionic emulsifiers based at levels below 0.5% _t in aqueous phase, prepared and used for the pharmaceutical preparation. Preferred anionic emulsifiers are alkyl sulfonates and sulfates, z "B, sodium alkyl sulfonate having an average carbon number of 14 or sodium lauryl sulfate.

It is known that in the production of acid-containing Acrylatkopolymerisaten especially with a high acid content, the use of nonionic Emulgaioren or, mixtures of nonionic and anioactive emulsifiers with a total content of emulsifier from 3 to 7 % _t based on aqueous phase can be expected «

It is recognized that it is difficult to use the acrylate- and / or methacrylate-based stable dispersion having a high acid content (up to 45%), a high content

Pestkörpergehalt and only anionic emulsifiers with a content of less than 0.5% to produce.

However, the use of such a binder is characteristic of the pharmaceutical preparations according to the invention. It is also necessary to make the requirement that the dispersion to be used as binder contains as little as possible further foreign substances, activator components, regulators, defoamers, antifreeze agents, stabilizers and / or their decomposition products from the application point of view. Thus, a binder is used, which was prepared using at most 0.06 % _t based on the aqueous phase, an activator, z _{o '} ammonium or potassium peroxide sulfate is in special pharmaceutical preparations, this very small proportion of decomposed activator disturbing the binder can also be prepared with the same small amount of hydrogen peroxide ₀

f) embodiments

The invention will be explained in more detail below on some embodiments

 For this purpose, two basic formulations are used:

A '

285.8 parts Phenazetin 214.2 parts lactose 500.0 parts potato starch

'50 parts aminophenazone 87 parts lactose 203 parts potato starch

The components of the mixtures have a particle size of less than 0.160 mm.

Binder I

A one-part aqueous dispersion of a copolymer of methyl acrylate, styrene and acrylic acid in a ratio of 73:17:10, prepared by emulsion polymerization.

Binder II ", ..

^ one-part aqueous dispersion of a copolymer of acrylic acid ester and acrylic acid in the ratio 80:20, prepared by emulsion polymerization.

The test results of some properties of the granules and the tablets made from these are tabulated.

example 1

a) Preparation of granules according to the kneader technology: 1000.0 g of the powder mixture A with 250.0 g of a

10 fo-iger dispersion of the binder I kneaded well. The moist kneaded material is pressed through a sieve of mesh size 1 mm (sieve V of the 2 _e AB-GDR) and the resulting granules are dried at room temperature of the obtained by sieving granular fraction with a grain size of 0.5 to 0.8 mm then each 350 mg at a pressure of 100 MPa to biplane tablets of

11 mnihdiameter pressed.

b) Production of a Granulate by Fluid Bed Technology: 500.0 g of Powder Mixture A are granulated with 125.0 g of a 10% dispersion of Binder I in the Uni-Glatt laboratory apparatus and then dried. The following operational data are observed during the granulation process:.

Supply air: position 30

Supply air temperature: 40 ° 0

Nozzle height: middle position.

Spray pressure: 2at. '

Inflow rate of

Granulating liquid: 8-10ml / min ·

The operation of the vibrating device on the exhaust air filter is about 5 seconds per 30 see when the Granulierflüssigkeitszufuhr and interruption of supply air (throttle valve: position 5). During drying, the following operational data are adhered to: Supply air: Position 40

Supply air temperature: 4o ° C.

The operation of the vibrating device at the exhaust air filter is about 5 see per 3o see reduction of the supply air (throttle: position 5) ·

The fluidized-bed spray granules are processed at a pressing pressure of MPa into 350 mg biplane tablets of 11 mm diameter.

Example 2

a) and b) The formulation of the granules and tablets with the binder II is carried out analogously as in Example 1a) and 1b).

Example 3

68.0 g of the powder mixture according to the basic formulation B are thoroughly moistened with 17.5 g of an 11.43% dispersion of the binder I. The moist mass is subsequently filtered through a sieve of mesh size 1 mm (sieve V of 2.AB -DDR) and dried for 24 h at 40 ⁰ C in a drying oven. Each 350 mg amounts of by

Seven recovered dry granules fraction with the grain size of 0.5 to 0.8 mm are pressed under a pressure of 100 MPa to biplane tablets of 11mm diameter.

For the characterization of the granules and tablets after Bei-. play 1 to 3, some parameters are used, the determination of which is carried out as follows,.

SiebanaIyset

The sieves IV to IX of the 2, AB-DDR are with increasing mesh size on each other and then on the bottom plate di; closed. Subsequently, in each case 100 g of a granule sample are placed on the top sieve of the sieve.

The sieve set is closed with the lid, mounted on a vibrating sieve sieve type THYR and shaken for 2 min. At the strongest vibration setting. Afterwards the residues are weighed on each sieve,

Strength percentage:

100 g of a granule sample of grain size fraction 0.8 to 1.0 mm are placed in a granulated Friabilator KÖHLER, "This is sealed with the lid, placed on the roller block of a ball mill type KM 25 and at a speed of 25 U / min. 4 minutes in a rotating motion.,., Held. Subsequently, the granulate sample thus subjected to the sieve analysis described above The strength percentage is calculated from the percentage of residues of the granulate fraction read on the sieve of mesh size 0.8 mm _o

Tamping bulk volume ratio:

Each 5o g of a granular sample are from a smooth paper sheet using a Pulvertrichters in the measuring cylinder. of the tamping volumeter according to DIN "gently and filled 53,194. The powder funnel was removed and the sample surface smoothed without applying pressure ,, the at Meßzylinderskala in 1 ml accurately read off volume of the sample corresponds to the debris volume. Then, the measuring cylinder with the sample 1250 will times mashed »The volume of the mashed granule sample read on the graduated cylinder scale corresponds to the tamping volume, Table 2 shows the quotient of tamping volume and bulk volume,

Compressive strength of the tables: ~

The radial compressive strength of the tablets is determined using the PFIZER Tablet Hardness Tester (Chas, Pfizer & Co. Inc., Brooklyn, N.Y.) ο

Disintegration time of the tablets;

To determine the decay time of the Erweka digestible. keits- and Zerfallbarkeitsmesser VZ 4 '(Erweka G.m.b.H ",, Prankfurt / Main) used. The test medium used for example 1 and 2 was artificial gastric juice without enzymes (according to MOTZEL) and distilled water for example 3.

Tab., 2: Test results of the granules according to Example 1 and 2

Granules Parameter Example 1. Example 2

a b a b

Sieve Analysis

(Results in .%) 0.150mm

0.160-0.315 mm 0.315-0.500 mm 0.500-0.800 mm 0.800-1.000 mm 1.000-1.600 mm

1,600 mm ~ «0.7

Festigkeitsprozent-

set ffoj - - 93,5

Tamping Schüttvolu-

meri ratio 0.657 0.793 0.823 0.717

45.8 94.7 4.1 94.4 14.1 2.8 2.3 4.6 8.4 0.9 1 * 4 0.4 14.6 0.7 3.6. 0.2 16.6 0.9 52.1 0.1 0.5 35.8 0.3

Tab ο: 3: Test results Example 1 - 3 of the tablets 7.6 127 out Granules after 8.2 193 Example a 3 b tablets temperature Example 1 a b Example 2 a b 3,1 55 • Compressive strength f kg / decay time / see / 7.0 49 6.9 127

Claims (2)

212 476 invention claim 1, A method of granulation, characterized in that a physiologically indifferent, oxygen functional, swellable, polymeric binder, for example, a carboxyl, glycidyl, hydroxyl and / or carboxyvinylhaltiges copolymer, preferably a copolymer of one or more acrylic and / or Methacrylic esters with acrylic, methacrylic, itaconic, crotonic, maleic or fumaric acid, with a maximum impurity content of 0.56 wt .-%, which using a maximum of 0.5 wt .- # of an anionic emulsifier and a maximum 0.06 wt -.% of an initiator, such as a persalt or hydrogen peroxide is produced gelangt.- in solid form, as a suspension, solution or emulsion, preferably as a finely divided aqueous dispersion for use 2. The method according to item 1, characterized in that copolymers of one or more acrylic and / or methacrylic esters with C ₁ - to C - alcohols with 2 to 45 wt .-%, preferably 12 to 25 wt - . %> Acrylic and / or methacrylic acid, if appropriate with a proportion of a further, the hardness of the copolymer affecting vinyl compound, preferably from 2.2 to 28.8 wt .-% of styrene, a styrene derivative, a glycidyl and / or a Hydroxyäthy!