HU187482B - Suspension granulating process in medicine formulation - Google Patents

Abstract

The method of the invention is a new, fast, easy to implement, economical drug technology operation. With its application, it is possible to simplify production technologies, thus reducing the possibility of sources of error. Quality differences between batches of different active ingredients and the same active ingredient, such as wetting! By using the method according to the invention, the environmental contamination is less than that of the closed fluidization. It is possible to use more accessible materials, the operation can be easily integrated into the production line and does not require any particular investment. The granules of the process excipient (dicalcium phosphate and tricalcium phosphate) provide excellent simplicity and the most economical method of pharmaceutical tableting, in many cases, through their excellent properties (good fluidity, high binding force, etc.). In addition, they can be used effectively for the compression of previously granulated materials or powder mixtures containing other binders. -1-

Description

FIELD OF THE INVENTION The present invention relates to a novel process for preparing a pharmaceutical composition by slurry granulation comprising a water-miscible organic solvent-water, preferably ethyl alcohol-water 57.5: 42.5 solution containing polyvinyl ester, preferably 2-6% polyvinyl acetate in an organic solvent water mixture. suspending the particles of the water-insoluble drug or excipient in admixture with water, suitably adding it to water, aggregating the particles of the suspended drug or excipient, filtering, and dispersing through a suitable sieve.

The process of the present invention is not the same as microcapsulation! "A microcapsule is a formulation for oral use in which the particles or drops of a high dispersion solid, rarely liquid active ingredient are individually coated with gelatin or a macromolecular polymer.

The proportion of active ingredient enclosed in a microcapsule is usually between 60 and 90% of the total weight of the granule. ”(Dr. Kedvessy Gy .: Pharmaceutical Technology, Medicina Bp. 1981)

In contrast, the process I have developed yields a product having the characteristics of conventional granules.

Depending on the size of the mesh, these are conventionally sized granules of various sizes, irregularly shaped and surface-glued. An irregular aggregate of crystals and their debris.

There is no coating on the surface of the particles, with only a small fraction adhering to or with each other by the Mowilith (approximately stuck to the polyvinyl acetate particles).

The suspension granulation process of the present invention has not yet been described in the literature. Dry granulation methods are described in British Patent No. 953,960 and U.S. Patent No. 6,614,611. published Dutch patent specification. Wet granulation processes are reported, inter alia, in Lehrbuch Frost Pharmazeutischen Technologie, Berlin 1975. Manuals on Fluidization Pharmaceutical Technology Operations, with particular reference to the Arzneiformenlehre Wissenschaftliche Verlagsgesellschaft Stuttgard 1976.

The slurry granulation process of the present invention is even more productive and economical than modern fluidization technology without the use of special machine equipment.

According to the process of the present invention, a water-miscible organic solvent-water, preferably ethyl alcohol-water (51-100) :( 49-0), preferably 57.5: 42.5% is prepared, wherein 0.5% -30% polyvinyl ester, preferably 2-6% polyvinyl acetate. 1-60%, preferably 25-35%, of the drug-soluble or excipient particles having an insoluble particle size, preferably below 50 µm, are suspended in the solution.

Solids which form a stable suspension, that is to say, have little or no sedimentation or supernatant, are preferably used in the process. The suspension is admixed with water for a further 2 hours, preferably with 2 volumes of water, preferably added to water. After a brief, gentle stirring, the settled aggregates are filtered, dried to a moisture content of 4-6% and then dispersed through a sieve and then dried to a maximum of 1% moisture. The active ingredient and excipient granules thus obtained are hereinafter used as tablets or tablets. to make a dragee if the final purpose was not to produce the granulate.

The following data summarizes the factors affecting suspension granulation:

- (3,4-Dimethoxyphenyl) -5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine (hereinafter "tofisopam") and 5-chloro-7-iodo-8-quinolinol (hereinafter "iodo-chloroquinoline") for active substances.

The percentages given in the table are the amounts of dry matter (polyvinyl acetate and colloidal size powder) in the supernatant (filtrate) of the reconstituted suspension, based on the amount of granules weighed. Mowilith concentration data refer to the amount of active ingredient or excipient particles measured. Polyvinyl acetate (Mowilith) concentration

Material name Mowilith concentration 5% 10% 20% tofisopam Jódklóroxi- 7.8% 2.4% 2.1% quinoline 2.6% 1.3% 0.8%

Mixing speed (mixing occurs during precipitation)

Substance is called Mowilith Concentration

10% (mixing (120 (without 200 rpm) rpm)

Tofizopam 2.4% 4.7% 7.2%

Iodochloroquinoline 1.3% 2.8% 5.1%

Particle size

Substance is called Mowilith Concentration

10%

Under 63 pm Above 125 pm tofisopam 2.0% 5.2% Jódklóroxi- quinoline 1.3% -

Feed rate of precipitating water Substance is called Mowilith concentration

10% dosing time

Ά min 15 min 30 min Tofizopam 2.4% 2.5% 2.6%

Iodochloroquinoline 1.3% 1.4% 1.5%

Downtime

Substance is called Mowilith Concentration

10%

tofisopam after mixing 2.4% After 1 hour 2.5% 2.7% after 10 hours 2.9% after 20 hours Jódklóroxi- quinoline 1.3% 1.4% 1.6% 1.8%

-2187,482

The suspension is added to water

Substance is called Mowilith Concentration

10%

Tofisopam 1.4%

Iodochloroquinoline 0.7%

The present invention relates to a process for the preparation of granules of an active ingredient or excipient, and thereafter to a pharmaceutical composition for the preparation of additional excipients or active ingredients by fluidization, drum mixing and the like. blending and subsequent tabletting, or by direct tabletting, wherein a water-miscible organic solvent-water (51-100) :( 49-0) is preferably mixed with a polyvinyl ester in a 57.5: 42.5 mixture of ethyl alcohol and water. 30%, preferably 2-6%, of polyvinyl acetate is dissolved, then the drug or excipient particles having a particle size of less than 50 µm, preferably from 1 to 60%, preferably 25-35%, are suspended in the solution, and the suspension is (suitably) preferably, it is added to water, the resulting aggregates are separated, dispersed through a suitable screen and converted into pharmaceutical compositions by the addition of active ingredients and excipients conventional in pharmaceutical technology.

The process of the invention is a novel, fast, easy-to-implement, economical drug technology operation. By applying it, it is possible to simplify manufacturing technologies, thus reducing the sources of error. Quality differences between different active ingredients and batches of the same active ingredient, such as moisture uptake, mass volume, etc. they have less influence on the suspension granulation of the invention than other drug technology operations.

When using the process of the invention, the environmental contamination is also lower than in closed system fluidization. It is possible to use more readily available excipients, the operation can be easily integrated into the pharmaceutical technology line and does not require any major investment.

The excipient granules of the process (dicalcium phosphate and tricalcium phosphate plus magnesium trisilicate, etc.) are also suitable for direct tabletting due to their high binding strength and excellent fluidity.

The following examples illustrate the process of the present invention without limiting it.

Example 1

Preparation of Tablets Containing Iodine Chloroquinoline

In a mixture of 400 l of water and 575 l of ethyl alcohol (96%) is dissolved 50 kg of Mowilith DH 50% dispersion type polyvinyl acetate. To the resulting solution was added 250 kg of iodo-chloroquinoline. The resulting slurry was then quenched with double volume of water. The aggregates are filtered and dried to a moisture content of 4-6%, then dispersed (granulated) through a sieve, and the granules are then adjusted to a maximum moisture content of 1%.

Weight: 265 kg

Further, the resulting granules and excipients 5 are blended by fluidization technology. The amount of excipients used is as follows:

Mowilith DH 100% 4.8 kg

Mg. Stearate 8.0 kg

Potato starch 24.1 kg

Diotylan 4.0 kg

Esma spreng 28.1 kg

Plasdone XL 8.0 kg

PEG 35,000 16.0 kg

Tartaric acid 3.2 kg

Parameters of fluidization

Inlet air velocity: 2000-5000 m ⁵ / h

Inlet air temperature: 60 'C

Exhaust air temperature at the end of operation: 20 30-32'C

Spraying size: 3 bar

Dosing rate: 1500-2000 ml / min

The resulting homogeneous powder blend is converted into a tablet having the following composition:

25 Enteroseptol 0.3000 g Mg. Stearate 0.0100 g Mowilith DH 100% 0.0360 g potato starch 0.0300 g was diethyl 0.0050 g 30 Esma spreng 0.0350 g Plasdone XL 0.0100 g PEG 35,000 0.0200 g Tartaric acid 0.0040 g

Shape: flat, flanged; Average weight: 0.4500 g; 35 Diameter: 12 mm Disintegration time: 5-9 minutes; Breaking strength: 50-70 N. Appearance: good; Friability: 0.3%; Tabletability: good; Certification: The product meets the quality standards.

Example 2 Preparation of a tablet containing 1- (3,4-dimethoxyphenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine (tofisopam)

In a mixture of 395 l of water and 575 l of ethyl alcohol (96%), 60 kg of Mowilith DH 50% dispersion type polyvinyl acetate is dissolved. To the resulting solution was added 300 kg of 1- (3,4-dimethoxyphenyl) -4-methyl-5-ethyl-7,850 dimethoxy-5H-2,3-benzodiazepine. The resulting slurry was then quenched with two volumes of water. The aggregates are filtered and dried to a moisture content of 4-6%, then dispersed (granulated) through a sieve, and the granules are then adjusted to a maximum moisture content of 1%.

Weight: 315 kg

Further, the resulting granules and excipients are homogenized in a drum mixer and directly tableted.

The amount of excipients used is as follows

Aerosil ung. R-200 2.8 kg

Mg. Stearate 11.4 kg ₆₅ Stearin 11.4 kg

187,482

Talc 11.4 kg

Ultra-amylopectin (U.S.A.) 22.8 kg Potato starch 54.4 kg

The composition of the tablet:

Tofizopam 0.1000 g

Mowilith DH 100% 0.0100 g

Aerosil ung. R-200 0.0010 g

Mg stearate 0.0040 g

Stearin 0.0040 g

Talcum 0.0040 g

Ultraamylopectin (U. A. P.) 0.0080 g

Potato starch 0.0190 g

Shape: flat, flanged; Average weight: 0.1500 g; Diameter: 8 mm; Disintegration time; 5-7 minutes; Tensile strength; 40-60 N; Appearance: good; Friability: 0.4%; Tabletability: good; Certification: The product meets the quality standards.

Comparative studies of the granules and tablets of the conventional and the new method were carried out on iodochloroquinoline and Tofizopam.

The measurement data are given below:

Sieve analysis:

Jódklóroxikinolin

Screen Size Original powder raw material %-in Ready with kneading technology. granule %-in Granulation made by suspension granulation %-in Under 10 pm - 10-20 pm 25.5 - - Between 20-30 pm 56.5 - - 30-50 µm 18.0 - -

Screen Size Original powder raw material %-in Ready with kneading technology. granule %-in % Granulation by slurry granulation Under 32 ym - 2.0 32-40 and so on - - - 40-63 and so forth - - 2.0 Between 63-90 ym - 2.0 90-125 ym - 7.0 4.0 125-250 µm - 9.0 20.0 250-500 µm - 20.0 32.0 500-1000 ym - 25.0 37.0 Over 1000 ym Average Garbage- 39.0 1.0 meadow: 25.15 etc. 673.75 et al 452.18 et al

tofisopam

Scale size Original powder raw material %-in Fluidization Tech. made of granules% Granulation made by suspension granulation %-in Under 32 ym 18.0 6.0 12.0 32-40 and so on 13.0 4.0 8.0 40-63 between 33.0 12.0 14.0 Between 63-90 ym 22.0 16.0 12.0 90-125 ym 9.0 22.0 10.0 125-250 µm 3.0 30.0 14.0 250-500 µm 2.0 8.0 14.0 Between 500-1000 ym Average grains- - 2.0 16.0 meadow: 64.18 et al 145.72 et al 230.69 et al

Mass volume tests:

Loose (SJ Compressed (S _T )

Iodine chloroquinoline Original powder base 4.4 cm ³ / g 3.1 cm ³ / g

Mass volume tests: Compressed (S _T ) Loose (S _L ) Kneading granules 2.0 cm ³ / g 1.7 cm ³ / g Suspension. shell. granule 3.5 cm ³ / g 2.9 cm ³ / g tofisopam Original powder raw material 2.9 cm ³ / g 2.0 cm ³ / g Fluid, Tech. granule 2.3 cm ³ / g 1.8 cm ³ / g Suspension. shell. granule 3.1 cm ³ / g 2.5 cm ³ / g

Moisture content:

Jódklóroxikinolin

Original powder base 0.4%

Kneading granules 0.3%

Suspension. shell. granule 0.3%

tofisopam

Original powder base 0.2%

Fluid, Tech. granule 0.4%

Suspension. shell. granule 0.3%

Strength tests:

I subjected the granules to the same mechanical stress (200-200 g granules were run in a friability tester for 30-30 minutes, then screened again), but no significant change was observed. They were both strong enough.

Drug dissolution tests of granules:

The results are illustrated in Figure (I).

In the Figures, T _{s represents} the suspension granulation! made tofisopam, T _{f is} the fluidized tofisopam while J is represented _Case of a suspension granulation jódklóroxikinolint and _Eng J jódklóroxikinolint prepared by kneading.

Examining the sliding boundary of granules:

Jódklóroxikinolin

Kneading gra-

n ula α = 31.2 ° Suspension. graphite nul. granule α = 34.9 ° tofisopam F! Uid. techn. granule α = 33.8 ° Suspension. graphite nul. granule α = 38.1 °

I would like to note that it is not possible to develop a fluid isomerization technology of iodo-chloroquinoline because the material is highly hydrophobic and very volumetric! Production can only be achieved with time-consuming and laborious and costly kneading technology, apart from the much better suspension granulation.

-4187,482

Example 3

Niridazole: Preparation of Tablets Containing I- (5-Nitro-2-Thiazolyl) -2-Imidazolidinone

The conditions for suspension granulation and tabletting are the same as in Example 2.

The composition of the tablet:

Niridazole 0.1000 g

Mowilith DH 100% 0.0100 g

Aerosil ung. R-200 0.0006 g

Mg stearate 0.0020 g

Stearin 0.0024 g

Talcum 0.0030 g

Potato starch 0.0100 g

Esma spreng 0.0040 g

Shape: flat, flanged; Average weight: 0.1320 g; Diameter: 7 mm; Disintegration time: 4-6 minutes; Tensile strength: 30-50 N; Appearance: good; Friability: 0.5%; Tabletability: good; Certification: The product meets the quality standards.

Example 4

Preparation of Bromobenzoxaldine: Tablets containing 5,7-dibromo-2-methyl-8-quinolinylbenzoate and broxyquinoline: 5,7-dibromo-8-quinolinol

The active ingredient broxyquinoline was granulated as described in Example 2, and then homogenized with the bromobenzoxaldine active ingredient and excipients and directly tabletted.

The composition of the tablet:

Broxyquinoline 0.2000 g

Broxaldine (Bromobenzoxaldine) 0.0400 g

Mowilith DH 100% 0.0200 g

Aerosil ung. R-200 0.0030 g

Mg stearate 0.0100 g

Stearin 0.0080 g

Talkum 0.0100 g

Potato starch 0.0555 g

Diotylene 0.0035 g

Shape: flat, flanged; Average weight: 0.3500 g; Diameter: 10 mm; Disintegration time: 4-6 minutes; Tensile strength: 40-60 N; Appearance: good; Friability: 0.4%; Tabletability: good; Certification: The product meets the quality standards.

Example 5

A process for preparing a tablet containing granular dicalcium phosphate excipient

In a mixture of 372.51 water and 5751 ethyl alcohol (96%), 105 kg of Mowilith DH 50% dispersion polyvinyl acetate are dissolved. To the resulting solution was added 350 kg of anhydrous dicalcium phosphate. The resulting suspension is then quenched with twice the volume of water. The aggregates are filtered and then dried to a moisture content of 4-6%, dispersed through a sieve, and the granules are then adjusted to a maximum moisture content of 1%.

Weight: 385 kg

Further, the granules and excipients obtained are homogenized in a drum mixer and directly tableted. The nature and amount of the granulate is determined by the properties of the active ingredient (s) in question.

The composition of the tablet:

Peritol HCl: 4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1-methylpiperidine = HCl 0.0040 g

Mg stearate 0.0010 g

Talcum 0.0025 g

Aerosil ung. R-200 0.0005 g

Stearin 0.0020 g

Primojel 0.0030 g

Potato starch 0.0070 g

Dicalcium phosphate 0.0800 g (granular) _

Shape: flat, flanged; Average weight: 0.10 g; Diameter: 7 mm; Disintegration time: 5-7 minutes; Tensile strength: 30-50 N; Appearance: good; Friability: 0.8%; Tabletability: good; Certification: The product meets the quality standards.

Example 6

A process for preparing a tablet containing granular tricalcium phosphate excipient

The conditions for suspension granulation and tabletting are the same as in Example 5.

The composition of the tablet:

Ta Chemical: 1-Methyl-2- [2- (a-methyl-p-chlorobenzhydryloxy) ethyl] pyrrolidine 0.0010 g

Mg stearate 0.0010 g

Talcum 0.0025 g

Aerosil ung. R-200 0.0005 g

Stearin 0.0020 g

Primojel 0.0030 g

Potato starch 0.0100 g tricalcium phosphate 0.0800 g (granular), pore thickness: 7 mm; Disintegration time: 4-5 minutes; Tensile strength: 30-50 N; Appearance: good; Friability: 0.7%; Tabletability: good; Certification: the quality of the preparation; meets the requirements.

-5187482

Examination of tablets:

Breaking strength: N

Iodochloroquinoline Tofizopam

leave slurry. granny gran. 50-70 50-70 traditions agent 40-60 suspensions. gran. 40-60 Average weight: g Jódklóroxikinolin tofisopam leave slurry. traditions suspensions. granny gran. agent gran. 0.45 0.45 0.18 0.15 appearance: Jódklóroxikinolin tofisopam leave slurry. traditions suspensions. granny gran. agent gran. yo-yo good good Wear resistance:% Jódklóroxikinolin tofisopam leave slurry. traditions suspensions. granny gran. agent gran. 0.3 0.3 0.6 0.4 Diameter: mm Jódklóroxikinolin tofisopam leave slurry. traditions suspensions. granny gran. agent gran. 12 12 8 8 Batch size: million pieces Jódklóroxikinolin tofisopam leave slurry. traditions suspensions. granny gran. agent gran. 0.26 '0.53 1.50 2.00 Disintegration time: minutes Jódklóroxikinolin tofisopam leave slurry. traditions suspensions. granny gran. agent gran. 11-13 5-9 8-10 5-7 Production method: Jódklóroxikinolin tofisopam leave slurry. traditions suspensions. granny gran. agent gran. kneading fluid fluid direct technology technology technology tabl.

From Perit Tavegyl

traditions agent 40-50 suspensions. gran. 30-50 traditions agent 30-40 suspensions. gran. 30-50 Peritol Tavegyl traditions suspensions. traditions suspensions. agent gran. agent gran. 0.20 0.10 0.12 0.10 Peritol Tavegyl traditions suspensions. traditions suspensions. agent gran. agent gran. good good good good Peritol Tavegyl traditions suspensions. traditions suspensions. agent gran. agent gran. 1.0 0.8 0.9 0.7 Peritől Tavegyl traditions suspensions. traditions suspensions. agent gran. agent gran. 8 7 7 7th Peritol Tavegyl traditions suspensions. traditions suspensions. agent gran. agent gran. 1.25 3.00 2.00 3.00 Peritol Tavegyl traditions suspensions. traditions suspensions. agent gran. agent gran. 10-11 5-7 8-10 4-5 Peritől Tavegyl traditions suspensions. traditions suspensions. agent gran. agent gran. fluid direct fluid direct technology tabl. technology tabl.

Form:

Each tablet had the same shape - flat, bevelled.

The results and the essence of the suspension granulation are shown very clearly in Figures II and III (scanning electron microscope images). Magnification: 1000x.

Figure (II) represents iodo-chloroquinoline and Figure (III) represents the result for Tofizopam.

They clearly illustrate why drug dissolution was the fastest in suspension granulation, even when I performed the suspension granulation process with the drug itself. More homogeneous dissolution and improved bioavailability is due to the absence of a binder for each individual particle liner ⁵⁵ as with other wet granulation.

In this case, the active ingredient crystals or their debris adhere only to a small part to the Mowihth (polyvinyl acetate) droplets. Most of them are 60 free, easily accessible to the environment. Compared to the smaller tablet size (10-20% reduction) and weight (20-50% reduction), the fracture strength was greatly increased compared to conventional tablets, but the disintegration time was reduced.

-6187482

Harder tablets cause less dusting and less chance of fragmentation. These features facilitate tabletability as well as machine packaging, shipping and accurate dosing, resulting in a more pronounced therapeutic effect.

The small size allows easy handling and increases productivity by a factor of 2-3.

The use of packaging material is also improving. In the case of dragees, this leads to significant savings in coating. Transport and storage become more economical.

The process can process a plurality of excipients such that direct tabletting can be introduced without the need for much more costly and complicated processes to produce excipients.

Tablet release test:

The measured results are summarized in Figure IV.

In the figures, TV _{SZ is} a Tavegyl tablet made by suspension granulation, TV _f is a Tavegyl tablet made by fluidization, and P _{sz is} a suspension granule. P _{f is} a fluidized bed Peritol tablet, T _{sz is} a suspension granulate. tablets made tofisopam, T _f in the fluidization means tofisopam tablets, J _Case slurry gran. jódklóroxikinolin made, and the J _ring jódklóroxikinolin tablets are prepared by kneading.

Claims (11)

CLAIMS 1. A process for the preparation of granules of an active ingredient or excipient and formulation of the pharmaceutical composition therefrom by adjuvanting additional excipients or active ingredients by fluidisation or subsequent tabletting following direct drum mixing, characterized in that the organic solvent or water is miscible with water. 51-99) :( 49: 1), preferably in ethyl alcohol-water 57.5: 42.5, a polyvinyl ester of 0.5% to 30%, preferably polyvinyl acetate The solution is dissolved in an amount of 2 to 6%, and the particles of the drug or excipient in the above-mentioned mixture of organic solvent-water and water-insoluble particles of a particle size of 1-60%, preferably 25-35%, preferably less than 50 µm are suspended. a suitable amount, preferably twice It is decomposed with 10 volumes of water, preferably added to water, and the resulting aggregates are separated, dried, dispersed, and converted to pharmaceutical compositions by the addition of active ingredients and excipients conventional in pharmaceutical technology. 2. A process according to claim 1 wherein the active ingredient is a benzodiazepine derivative. 3. A process according to claim 2 wherein the active ingredient is 1- (3,420 dimethoxyphenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine. 4. The process of claim 1 wherein the active ingredient is a quinolinol derivative. 25 5. The process of claim 4 wherein the active ingredient is 5-chloro-7-iodo-8-quinolinol. 6. A process according to claim 4 wherein the active ingredient is 5,730 dibromo-8-quinolinol. 7. A process according to claim 4 wherein the active ingredient is 5,7-dibromo-2-methyl- 8-Quinolinol benzoester is used. 8. A process according to claim 1 wherein the active ingredient is 1- (5-nitro-2-thiazolyl) -2-imidazolidinone. 9. The process of claim 1 wherein the calcium salt is an excipient. 10. A process according to claim 9 wherein the excipient is dicalcium phosphate. 11. The process according to claim 9, wherein the excipient is tricalcium phosphate.