BG109587A - Tablets of citalopram hydrobromide - Google Patents

Abstract

The invention relates to tablets and film-coated tablets containing as active ingredient citalopram hydrobromide having a median particle size of less than 40micro m in an admixture with microcrystalline cellulose having a median particle size in the range of 90-250micro m and other excipients conventionally applied for the preparation of tablets. The invention also provides a process for the preparation thereof.

Description

CITALOPROM HYDROBROMIDE TABLETS

FIELD OF THE INVENTION

The invention relates to tablets containing as active ingredient citalopram hydrobromide and a method for their preparation.

BACKGROUND OF THE INVENTION

Citalopram, called 1- [3- (dimethylamino) -propyl] -1- (4fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile hydrobromide, is a well-known antidepressant drug that has the following structure:

The substance is a white or almost white fine crystalline powder, which typically has an average particle size of less than 20 gm.

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When citalopram hydrobromide is used as a pharmaceutical, it is formulated as coated tablets, which means thin film coated tablets. As is known, in addition to the active ingredient, the tablets contain excipients (fillers, binders, decomposers, sliding agents, anti-friction agents), too. Probably, in order to maintain the uniformity of the mass and the contents of the tablets at a low value, only mixtures of the active ingredient and excipients which have good flowability and are not separable can be tableted with modern tablet machines. This is because, prior to tabletting, the active ingredients and adjuvants are converted into aggregates of granules suitable for tableting during the various operations. Detailed descriptions of these operations are provided in suitable technical books, such as Racz I. Selmeczi B.: Gyogyszer-technologia 3., Selmeczi B.: Gyogyszer-formation, Medicina, Budapest, 2001.

Basically, preparatory operations can be based on the following three principles:

• powder blending method • dry granulation method • wet granulation method.

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Through the powder blending method, the active ingredient is homogenized with easily tabletable excipients. This is because this method is also referred to as direct tableting. The disadvantage of this method is that it can only be applied to a small fraction of the active components, which is only in the case of easily tabletable or flowable per se active components, or which are used at low doses.

In the case of the dry granulation method, the active ingredient is homogenized with easily tabletable excipients and then pressed (compacted, briquetted or pre-tableted), the pressed substance is milled, sieved, further mixed with inert excipients and tableted. .

In the case of the wet granulation method, the active ingredient or optionally a mixture of the active ingredient and the tabletable excipients are wetted with a solution of the so-called granulating agent or with the solvent alone.

In this way, larger granules are formed, which are then dried, sieved, further mixed with inert fillers and compressed to tablets.

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Recently, wet granulation has been the most widely used method of pre-tabletting operations. The reason for this is that, although this method is a very complex and very expensive method among the three mentioned above, it is safer in the sense that it can probably be obtained by using tablets of the appropriate quality. Direct compression, on the other hand, is a simpler and less expensive method, but in some ways it is not possible to choose the right inert fillers. But just because this method is simple and inexpensive, there is a strict requirement in the pharmaceutical industry to replace granulation methods with direct compression methods. The dry granulation method is between direct compression and wet granulation, both of which are considered to have heavy processing and cost as methods.

According to the literature, commercially available thin-coated tablets containing the active ingredient citalopram hydrobromide are produced by wet granulation of fluidized granulate granules (IT 99MI1781, WO 01/80619, WO 02/053133). The reason for this is that citalopram hydrobromide obtained by conventional methods is a crystalline powder of fine particle size, which particles have an average size of less than 20 µm as measured by laser granulometry.

According to the prior art, two problems may arise when tableted directly by compression

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citalopram hydrobromide which has such small particle sizes. The first is that as a consequence of the small particle size of the active ingredient, the homogeneity flow of citalopram hydrobromide in combination with tablet excipients is poor, and this is because the heterogeneity of the mass does not meet the pharmacopoeial requirements. The other is that if the excipients having a slightly larger particle size are applied, probably to improve the flowability appropriately, the powder mixture may segregate during tablet compression, resulting in high fluctuation in the active ingredient content. component.

Basically, the specifications regarding the quality of the tablets are regulated by pharmacopoeia. The mentioned technical conditions are not sufficiently uniform, but mainly the technical conditions of the European and American Pharmacopoeias (respectively Ph. Eur. And USP) are respected by the pharmaceutical industry, which is becoming more and more international.

In view of the heterogeneity of the contents of the tablets, the specifications concerning the critical parameters are as follows:

ο

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parameter Ph. Eig. technical condition ¹ USP Specification ² heterogeneity of mass of there is no tablets (measured on 20 tablets) below 80 mg average +/- 10% between 80-250 mg average +/- 7.5% more than 250 mg average +/- 5% heterogeneity of content. face value of tablets (measured average +/- 15% +/- 15% 10 tablets) RSD *: max. 6%

* RSD: Relative standard deviation

1. / European Pharmacopeia, Ed. 4, 2002, pp. 199-200. Council of Europe, Strasbourg,

2. / The United States Pharmacopeia, Ed. 26, 2003, p.2227 United States Pharmacopeial Convention, Inc. Rockville

In order to respond to the general trend of tablet production, the refinement of the direct compression method in the case of citalopram hydrobromide was also refined. In accordance with international patent application No. WO 01/80619 solid pharmaceutical dosage form containing citalopram hydrobromide can be obtained by direct compression if the average particle size of citalopram hydrobromide is at least 40 µm, preferably in the order of 40-200 µm, even more preferably 45-150 mm and

PCT / HU2004 / 000110 and most preferably 50-100 µm. Since citalopram hydrobromide with such a particle size cannot be obtained by conventional methods, said patent application also provides a method for producing citalopram hydrobromide with a larger particle size required for direct compression. It is easy to implement this method since no real solution is created, since in practice the cost reduction is achieved by applying the direct compression method, thus losing some time for recrystallization of the active component.

Probably to overcome the above problem, the same inventors provide another method in WO 01/80619 for increasing the particle size of citalopram hydrobromide by applying dry granulation. In accordance with this method, citalopram hydrobromide alone or in admixture with one or more excipients is converted by compression into a rotating cylinder into granules having at least 40 µm, preferably in the order of 40-250 µm, more preferably 45200 µm and most preferably 50-180 µm. For the granulation method applied according to said patent application, citalopram hydrobromide having an average particle size of less than 20 µm, preferably less than 15 µm, is used. The citalopram hydrobromide granulate thus obtained is then further homogenized with excipients and compressed into tablets.

Thus, according to the prior art, citalopram hydrobromide having an average particle size of less than ppm cannot be compressed by direct compression into tablets that meet the pharmacopoeial requirements.

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It is an object of the present invention to provide a direct compression method enabling the preparation of tablets of citalopram hydrobromide particles with an average size of less than 40 µm in which the tablets meet the requirements collected in the pharmacopoeia.

SUMMARY OF THE INVENTION

The invention is based on the recognition that by using suitably selected excipients, the direct compression method is also suitable for the preparation of tablets, of a quality that meets even the strictest pharmacopoeial requirements, of citalopram hydrobromide having an average particle size of less than 40 ppm or even less than 20 ppm. It has also been recognized that the stability and other advantageous parameters of the tablets provided according to the invention are expected to be usable as tablet cores, suitably coated with substances and in accordance with generally accepted methods used in the pharmacological industry. The coated tablets thus obtained can be advantageously used in therapy.

It was surprisingly discovered that despite the fact that

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citalopram hydrobromide has poor flow properties due to the small size of its particles, and by suitable selection of excipients it is possible to obtain a composition exhibiting good flow properties. The composition obtained in accordance with the invention does not segregate under the conditions of the manufacturing process, although there is a significant difference between the particle size of the active component and that of the excipients. Thus, it is possible to produce citalopram tablets by the method of direct compression, and the stability, heterogeneity of the mass, the heterogeneity of the content, the disintegration time and the dissolution of the tablets thus obtained meet the strict pharmacopoeial requirements.

Mixtures of substances are known to have

significantly different particle sizes are segregated as they are processed, separated by particle sizes. Separation makes it impossible to equally distribute the active ingredient in the individual tablets, which is a basic requirement in tablet production.

Details of the invention

In accordance with one aspect of the present invention, direct compression tablets are provided containing the active ingredient citalopram hydrobromide,

PCT / HU2004 / 000110 called 1- [3- (dimethylamino) -propyl] -1- (4-fluorophenyl) -1,3-dihydro-5 isobenzofurancarbonitrile hydrobromide, which include citalopram hydrobromide, which has an average particle size of 5 -40 µm in admixture with microcrystalline cellulose having an average particle size of the order of 90 - 250 µm and other excipients commonly used for the preparation of tablets.

In particular, tablets containing as active ingredient citalopram hydrobromide are provided, which include 5-50% by weight, preferably 10-30% by weight of citalopram hydrobromide, which has an average particle size of the order of 5-40 µm, optionally from in the range of 5-20 µπι, 5-85% by weight, preferably 50-80% by weight, more preferably 70-80% by weight of microcrystalline cellulose having an average particle size of the order of 90 - 250 µm, preferably 150 - 250 μπτ, as an excipient of 5-85% by weight, preferably 5-20% by weight, more preferably 5-10% by weight of sugar suitable for direct compression, 0.3-3.0% by weight, preferably 0.5-2.5% by weight, more preferably 1.0-2.0% by weight of magnesium stearate and optionally 0.1-2.0% by weight, preferably 0.5 - 1.5 % by weight, more preferably 0.5-1.0% by weight colloidal or optionally micronized silica.

According to another aspect of the present invention, tablets containing as active ingredient citalopram hydrobromide are provided, which include 5-50% by weight, preferably 10-30% by weight of citalopram hydrobromide, which

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has an average particle size of the order of 5-40 µm, optionally 5-20 µm, 5-85% by weight, preferably 50-80% by weight, more preferably 70-80% by weight of microcrystalline cellulose, which has an average size of particles in the order of 90 - 250 µm, preferably 150 - 250 µπι, as an excipient of 5-85% by weight, preferably 5-20% by weight, more preferably 5-10% by weight of sugar suitable for direct compression, 0.3-3.0 % by weight, preferably 0.5 - 2.5% by weight, more preferably 1.0 - 2.0% by weight of magnesium stearate and optionally 0.1 - 2.0% by weight, preferably 0.5-1.5% by weight, more preferably 0.5-1.0% by weight colloidal or micronized silica, and a coating on the surface of the tablet core obtained from substances and according to the method commonly used in the pharmacological industry.

In accordance with a still further aspect of the present invention there is provided a method for the preparation of tablets containing, as an active ingredient, citalopram hydrobromide, which comprises solid-state mixing of citalopram hydrobromide having an average particle size in the order of 5 - 40 µm, microcrystalline cellulose having an average particle size of the order of 90 - 250 cm and one or more other excipients suitable for the preparation of tablets and compressing the thus obtained homogenisate of tablets containing citalopram hydro bromide in an amount corresponding to 10-40 mg of citalopram base.

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In particular, there is provided a method for the preparation of tablets containing citalopram hydrobromide, which involves mixing in solid form 5 - 50% by weight, preferably 10-30% by weight, of citalopram hydrobromide having an average particle size of the order of 5- 40 µm, optionally 5-20 µm, 5-85% by weight, preferably 50-80% by weight, more preferably 70-80% by weight, microcrystalline cellulose having an average particle size of the order of 90 - 250 µm, 5 -85% by weight, preferably 5-20% by weight, more preferably 5-10% by weight of sugar suitable for direct compression, 0.3-3.0% by weight, preferably 0.5 - 2.5% by weight, more preferably 1.0 - 2.0% by weight of magnesium stearate and optionally 0.1 - 2.0% by weight, preferably 0.5 -1.5% by weight, more preferably 0.5 -1.0 % by weight colloidal or micronized silica, compression of the homogenisate thus obtained into tablets containing citalopram hydrobromide in an amount corresponding to 10-40 mg citalopram base, and application to the tablet core of one or more layers, Including substances conventionally applied thereto farm isation industry in accordance with methods known per se.

The term "direct compression tableting methods" means that the active ingredient and excipients are homogenized at room temperature without adding liquid to the mixture and without altering the particle size of the components, and compressing the homogenization into tablets.

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The term "average particle size" refers to the particle size that divides the frequency of distribution by half. 50% of the particles have a larger particle size and the remaining 50% have a smaller one. This value is referred to as d ₅₀ .

As microcrystalline cellulose used in citalopram hydrobromide tablets according to the invention, microcrystalline cellulose used for direct compression having an average particle size of more than 90 µm can be applied. These microcrystalline celluloses differ in the numbers 102, 200, 90 or 12 marked with the trademark. Such substances are, for example, Avicel PH 102, Avicel 102 SCG, Avicel 200, Vivapur 102, Vivapur 200, Vivapur 12, Microcel 102, Emcocel 90 M, Emcocel 90 HD, Emcocel LP 200 and others. Among these substances, the microcrystalline cellulose, designated no. 200 having a larger particle size has the most favorable flowability. The average particle size of microcrystalline cellulose indicated by 102 and 90 was in the range between 90-110 µm, that of microcrystalline cellulose indicated by 12 was in the range between 140 and 180 µm, while that of microcrystalline cellulose indicated by 200 was about 180 µm. As microcrystalline cellulose, the so-called microcrystalline cellulose containing silicon, which has an average particle size of more than 90 µm and which contains 2 - 3% by weight of silica, can also be used. In this case, it is not necessary to add silica to the homogenisation. Such products are for example Prosolv SM CC 90 or Prosolv HD 90 (trademarks).

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Kamo Suitable for Direct Compression Any sugar based on product obtained for the purpose of direct compression can be used. Such products include, for example, spray dried or specially crystallized lactose, maltose or sucrose. The average particle size of these sugar-based products obtained for direct compression is typically in the range of 100 µm to 200 µm.

As magnesium stearate, any magnesium stearate product that meets the pharmacopoeial requirements may be used. The average particle size of these products is typically less than 10 µm.

As colloidal or micronized silica, any colloidal or micronized silica product that meets the pharmacopoeial requirements may be administered. The average particle size of colloidal micronized silicone dioxide products is generally in the range of 4-20µm. Silica products can also be used in mixtures formed with microcrystalline cellulose such as so-called microcrystalline cellulose containing silicon.

The active ingredient content of citalopram hydrobromide tablets according to the invention is in the range of 10-30% by weight. Given that the lower single dose of citalopram hydrobromide is 10 mg of citalopram base corresponding to 12.495 mg of citalopram hydrobromide, and taking into account the explanation that the tablet weight is

PCT / HU2004 / 000110 at least 50 mg, presumably to be physically controlled, content of the active ingredient in the range of 10-30% by weight is considered optimal. Tablets with a higher active ingredient content but having the same composition, probably to provide bioequivalence, are usually prepared by repeatedly incorporating the tablet weight (proportional formulations). The ratio of microcrystalline cellulose to sugar suitable for direct compression may vary over a wide range of 5-85% by weight. Based on the flowability of the powder mixture and the physical parameters of the tablets, the advantageous amount of microcrystalline cellulose is in the range of 50-80% by weight, while the amount of sugar suitable for direct compression is in the range of 5-20% by weight. Particularly advantageous amounts of macrocrystalline cellulose are in the range between 70-80% by weight, while that of sugar suitable for direct compression is in the range between 5-10% by weight. The amount of magnesium stearate and colloidal or micronized silica corresponds to the conventional amount applied for the manufacture of tablets. In the case of magnesium stearate, this amount is in the range of 0.3 - 3.0% by weight, preferably 0.5-2.5% by weight, more preferably 1.0-2.0% by weight, while in the case of colloidal or micronized silica it is in the range of 0.1 - 2.0% by weight, preferably 0.5-1.5% by weight, even more preferably 0.51.0% by weight.

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Tablets containing citalopram hydrobromide according to the invention have adequate mechanical strength and are particularly suited for thin-film coating operations with high mechanical performance. Thin film coating may be carried out according to methods known in the literature. Hydroxypropyl-methyl cellulose together with polyethylene glycol as a plasticizer and optionally titanium dioxide as a coloring agent may be used as a thin film forming agent, for example. Finished fabricated coating systems such as Opadry (trademark) may also be applied. These substances contain polymer hydroxypropyl-methyl cellulose (Opadry I and Opadry II) or polyvinyl alcohol (Opardry II HP) as a thin film.

The composition and method of the invention are illustrated by the following examples without limiting the scope of protection to the aforementioned examples.

u Example 1

Effect of fillers having different particle sizes on flowability and tableting ability

The following substances suitable for direct compression are used as fillers:

- spray - dried lactose monohydrate (Lactose

DCL 11),

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- microcrystalline cellulose (Emcocel 90 M, Avicel 102,

Vivapur 200),

- microcrystalline cellulose containing silicon (Prosolv

SMC 90, Prosolv HD 90).

Magnesium stearate is used as a lubricant and colloidal silica (Aerosil 200) as a sliding agent.

u The components used in the amount given in the following table are homogenized in a Turbula mixer. The fluidity of the homogenates is determined according to the method provided in European Pharmacopeia, Ed. 4, 2002, pp. 208-209., Council of Europe, Strasbourg.

The composition of citalopram homogenates and the flowability of the homogenates are shown in the following table:

F.

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experiment components (g) US CI61 CI63 CI64 CI65 CI66 citalopram HBr * 24.99 24.99 24.99 ΐ 24.99 24.99 24.99 lactose DCL 11 14.4 14.4 14.4 14.4 14.4 14.4 vivapur 200 136.8 - - - - - avicel 102 - 136.8 - - - - emotional - - 136.8 - - - vivapur 102 - - - 136.8 - prosolv SM CC 90 - - - - 138.06 - prosolv HD 90 - - - - - 138.06 aerosil 200 1.26 1.26 1.26 1.26 - - magnesium stearate 2.55 2.55 2.55 2.55 2.55 2.55 total: 180.0 180.0 180.0 180.0 180.0 180.0 flowability (s / 50g) 6.2 33.9 30 17 29.3 14.2

* d ₅₀ : 13.8 pm

As can be seen, the best flowability of homogenization can be achieved by using Vivapur 200, which is the microcrystalline cellulose that has the largest particle size.

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The homogenates are compressed into tablets weighing

180 mg per Fette EXI tabletop machine using 8 mm diameter concave molds. In the course of the tableting procedure, no adhesion was observed at one of the two sites, on the die or on the surface of the tablets. When the tablets are torn in two, the inner surface is homogeneous, devoid of coating.

The average mass and uniformity of mass of the tablets obtained according to the invention are also determined at 20 tablets.

experiment parameter CI11 CI61 CI63 CI64 CI65 C166 average mass (mg) 181.4 183.1 180.1 179.0 180.0 179.9 individual mass, minimum 178.7 182.5 179.3 178.5 178.8 179.4 individual mass, maximum 183.3 183.8 181.0 179.7 181.3 180.4 mass deviation, (%) <1.5% <0.4% <0.5% <0.4% <0.8% <0.3%

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The above table shows that the uniformity of tablet weight meets the pharmacopoeial requirements (+/- 7.5% in the case of an average weight of 180 mg).

Example 2

Effect of sugar to microcrystalline cellulose ratio on tabletability and on tablet properties

The components used in the amount given in the following table are homogenized in a Turbula mixer. The fluidity of the homogenates is determined according to the method provided in European Pharmacopeia, Ed. 4, 2002, pp. 208-209., Council of Europe, Strasbourg.

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experiment components (g) CI11 CI59 CI60 citalopram HBr, | 24.99 24.99 24.99 d ₅₀ : 13.8 ppm vivapur 200 136.8 75.6 14.4 lactose DCL11 14.4 75.6 136.8 aerosil 200 1.26 1.26 1.26 magnesium 2.55 2.55 2.55 stearate total 180.0 180.0 180.0 flowability 6.2 10.1 14.0 (s / 50 g)

As can be seen from the table above, the best flowability of homogenization can be achieved when the Vivapur 200 microcrystalline cellulose is applied in the highest amount.

The homogenizates were compressed to 180 mg tablets on a Fette EXI tabletop machine using 8 mm lenticular molds. In the course of the tableting procedure, adhesion may not be observed at one of the two sites, on the matrix or on the surface of the tablets. When the tablets are broken into two parts, the inner surface is homogeneous, devoid of layered structure.

The average mass and uniformity of mass of the tablets obtained according to the invention were also determined on 20 tablets.

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Other physical parameters of the tablets and the rate of dissolution of the active ingredient are determined on the basis of appropriate pharmacopoeial procedures.

experiment parameter US CI59 CI60 average 181.4 179.2 183.6 mass (mg) individual 178.7-183.3 178.8-179.7 182.8-184.8 mass (mg) diversion on the table (%) <1.5% <0.3% <0.7% quality 83 73 67 destruction ¹ (N) (77-90) (68-75) (53-80) time of breakup ² (minutes) 2'53 ”-4'47” 3'58 ”-539” 737 ^ -8'21 ” dissolution ³ (%) 5 minutes 81.19 65.66 27.34 10 minutes 96.63 96.97 51.62 20 minutes 100.21 97.83 99.97 30 minutes - 97.95 101.67

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1, 2, 3,: 1. / European Pharmacopeia, Ed. 4, 2002, p. 191, 194 and 201.

Council of Europe, Strasbourg

The uniformity of the weight of the tablets meets the pharmacopoeial requirements (+/- 7.5% in the case of an average weight of 180 mg).

All other tablet parameters meet strict pharmacopoeial requirements. The most advantageous result can be achieved in the case of a homogenate containing the highest amount of microcrystalline cellulose. In this case, the rupture strength of the tablet is highest, the dissolution of the active ingredient is the fastest, and the disintegration time of the tablet is the shortest.

Example 3 (Comparative Experiment) Preparation of sugar deprived tablets

The components listed in the following table are homogenized in a Turbula mixer. The homogenizates were compressed to 180 mg tablets in a Fette EXI tabletop machine using 8 mm-diameter concave matrices. During the tableting process, there are lubrication problems in the case of homogenizates containing spray-dried mannitol (Pearlitol SD 200), "friction" can be established on the inner surface of the matrices and the strength of the

PCT / HU2004 / 000110 tablet rupture is inappropriate (low rupture strength with high deviation). Lubrication problems can be reduced by gradually reducing the amount of Perlitol SD 200 (mannitol) and gradually increasing the amount of microcrystalline cellulose Emcocel 90 M, but the tablets become more and more multilayered. In the case of formulations containing only microcrystalline cellulose (Vivapur 200), lubrication problems cannot be experienced but the structure of the tablets is multilayered.

In the case of the compositions given in the following table, tablets containing the active ingredient citalopram hydrobromide cannot be obtained in an appropriate quality.

experiment components (g) CI010401 CI130401 CI580103 citalopram HBr (mg) 24.99 24.99 24.99 d ₅₀ : 13.8 pm vivapur 200 (mg) - - 151.2 emcocel 90 M (mg) 132.55 7.5 - mannitol 17.885 142.96 - (perlitol SD 200) (mg) aerosil 200 (mg) 0.625 0.625 1.26 magnesium 3.95 3.925 2.55 cmeapam (mg) total 180.0 180.0 180.0

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Example 4

A tablet containing 40 mg of citalopram

The components in the following table are homogenized in a Pharmatech 400 drum mixer.

substance quantity citalopram hydrobromide particle size: d ₅₀ : 15.5 it 5.00 kg microcrystalline cellulose particle size: 27.40 kg d ₅₀ : about 180 µm lactose (spray dried) 2.88 kg magnesium stearate 510.0 g colloidal silica 252.0 g

Homogenization tableting was performed in a 16-seat Manesty Betapress rotary press at a rate of 750 tablets / minute. 100,000 pieces of biconvex tablets were compressed and each contained 40 mg of citalopram base. By dividing the production time into separate intervals, 8 batch samples were taken and the uniformity of mass and contents of the tablets was determined.

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The data relating to the tablets obtained according to the example are summarized in the following tables.

Uniformity of the table

Mass uniformity data are calculated on the basis of the individual masses of 20 tablets per batch.

Citalopram 40 mg tablet

sample 1 2 3 4 5 6 7 8 on average 363.5 362.0 359.7 360.9 361.1 362.6 364.4 363.9 (mg) min 357.9 357.9 353.7 355.9 355.9 355.1 360.1 357.7 mg max 368.7 369.2 367.3 366.1 365.8 369.6 368.8 371.3 mg RSD (%) 0.75 0.79 0.87 0.88 0.75 1.13 0.60 1.04

Based on the above data, the uniformity of the tablet weight completely meets the pharmacopoeial requirements.

Tablet content uniformity

Content uniformity data were calculated based on the individual masses of 10 tablets per batch.

....... I

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Citalopram 40 mg tablet

sample 1 2 3 4 5 6 7 8 on average 98.72 99.70 98.51 98.76 100.11 99.55 98.42 99.56 (%) min 96.55 98.26 96.84 95.14 97.09 96.56 95.10 97.80 (%) max 101.45 101.83 101.39 102.39 103.32 101.00 100.93 102.28 (%) RSD (%) 1.46 1.05 1 1.45 ί 2.21 2.14 1.45 _ 1.98 _ 1.43

Based on the above data, the uniformity of the content fully meets the pharmacopoeial requirements. The relative deviation of the content of the active ingredient is about 1-2% during the tabletidaid procedure, which is a separation that does not occur during production.

Example 5

Preparation of a thin film coated tablet containing 40 mg of citalopram

A coating suspension for 50,000 pieces of tablet containing 40 mg of active ingredient produced according to Example 4 was prepared as follows:

2.8 kg of purified water was measured in a stainless steel vessel, with continuous stirring, 262.8 g of hydroxypropyl methyl cellulose (HPMC) was added, which had a viscosity of 5-6 cP, and the mixture was stirred until complete dissolution. 150 g of purified water is measured in a stainless steel vessel, 63.6 g of Macrogol are added to it with continuous stirring.

6000 and the mixture was stirred until complete dissolution.

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To 1 liter of HPMC solution was added at

stirring 105.6 g of titanium dioxide. The suspension was passed through a Fryma-type colloid mill and the colloid mill was washed with 0.4 kg of purified water. The slurry was passed through the mill and a solution of Macrogol 6000 was added to the residual HPMC solution, the mixture was stirred for 1 hour using an IKA stirrer at average rpm (s), finally filtered with a sieve having mesh size. 0.36 mt in tare acid-resistant container. The slurry was continuously stirred during the coating procedure. The tablets are coated in Driacoater 500/600 Vario coating equipment.

The tablets are fed into the apparatus and heated

advance until the outlet air temperature reaches 42 ° C (~ 10 minutes).

When the preheating is complete, the coating suspension is sprayed. The intake and drying parameters are set so that the outlet air temperature remains between 38-45 ° C.

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During spreading, the total mass of 50 pieces of tablets is determined every 10 minutes to the nearest mg. The spreading was continued until the mass increased to reach 360 mg / 50 tablets. The dispersion is then complete and the thin film tablets are further dried for 5 minutes with air at 30 ° C with continuous rotation.

Example 6

Tablets containing 10 or 20 mg of citalopram

The components in the following table are homogenized in a Pharmatech 400 drum mixer.

substance quantity citalopram hydrobromide particle size: d ₅₀ : 10.8 µm 5.00 kg microcrystalline cellulose particle size: d ₅₀ : about 180 µm 27.40 kg lactose (spray dried) 2.88 kg magnesium stearate 510.0 g colloidal silica 252.0 g

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The homogenate is divided into two parts. One part is compressed into 100,000 pieces of lenticular tablets with a diameter of 8 mg weighing 180 mg and containing 20 mg of citalopram base, the other part is used to prepare 200,000 pieces of lenticular tablets with a diameter of 90 mg weighing 90 mg containing 10 mg of citalopram base. The tableting was performed in a 16-seat Manesty Betapress rotary press at a rate of 750 tablets / minute. By dividing the production time into equal intervals, 8 samples were taken per batch of tablets containing 20 mg of citalopram base and 16 samples per batch of tablets containing 10 mg of citalopram base. The uniformity of mass and content of the tablets is determined. The results are summarized in the following table.

Uniformity of the table

Mass uniformity was calculated by measuring the individual masses of 20 tablets per batch for each sample.

A.) The mass uniformity data of citalopram tablets are obtained according to the example containing 20 mg of active agent:

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sample 1 2 3 4 5 6 7 8 on average 179.6 180.3 180.4 181.2 180.4 181.9 180.1 180.7 (mg) min 177.0 178.2 176.8 179.0 177.2 179.0 175.9 178.5 mg max 183.5 184.2 183.0 184.0 182.7 185.0 182.5 183.5 mg RSD (%) 0.88 0.87 0.82 0.81 0.89 0.88 0.92 0.77

C.) Mass uniformity data of citalopramob tablets are obtained according to the example containing 10 mg of active agent:

sample 1 2 3 4 5 6 7 8 on average 91.0 91.1 89.9 89.7 91.6 91.0 91.1 90.6 (mg) min 90.0 90.1 88.6 88.3 90.0 89.3 90.1 89.2 mg max 92.3 92.1 90.7 90.6 92.9 92.1 91.9 91.6 mg RSD (%) 0.74 0.70 0.71 0.68 0.80 0.60 0.60 0.81

PCT / HU2004 / 000110

sample 9 10 11 12 13 14 15 16 on average 90.9 91.6 91.4 91.5 91.3 91.7 92.2 91.9 (mg) min 89.8 89.8 90.0 89.5 90.0 90.7 90.6 90.3 mg max 92.5 92.6 93.1 92.9 92.5 92.6 93.4 93.3 mg RSD (%) 0.94 0.81 0.73 0.90 0.76 0.65 0.88 0.91

According to the above data, the uniformity of the tablet weight completely meets the pharmacopoeial requirements.

Content uniformity

Content uniformity was calculated by measuring the individual masses of 10 tablets per batch for each sample.

A.) Uniformity of the content of citalopram tablets containing 20 mg of active ingredient prepared according to the example:

PCT / HU2004 / 000110

sample 1 2 3 4 5 6 7 8 on average 98.77 100.29 99.74 99.82 99.76 99.98 101.33 100.01 (%) min 97.20 98.09 97.15 97.38 97.18 97.49 99.09 97.80 (%) max 100.42 102.20 102.40 101.95 101.26 103.42 103.79 102.02 (%) RSD (%) 1.03 1.48 1.76 1.34 1.20 1.63 1.48 1.32

C.) Uniformity of the content of citalopram tablets containing 10 mg of active ingredient prepared according to the example:

sample 1 2 3 4 5 6 7 8 on average 98.77 99.29 99.09 99.97 99.67 99.58 99.31 101.15 (%) min 96.51 97.48 96.59 97.30 97.64 97.53 96.89 98.77 (%) max 100.75 101.04 102.70 103.09 101.15 103.18 101.38 103.29 (%) RSD (%) 1.33 1.08 1.78 2.03 1.13 1.67 1.51 1.55

PCT / HU2004 / 000110

sample 9 10 11 12 13 14 15 16 on average 99.67 101.25 100.83 101.88 101.28 100.53 100.98 101.29 (%) min 95.91 98.36 97.76 100.09 99.85 98.36 98.66 97.90 (%) max 102.40 103.20 103.87 103.47 103.12 102.68 103.18 103.96 (%) RSD (%) 1.95 1.51 1.89 1.17 0.86 1.57 1.37 1.94

According to the above data, the uniformity of the contents of the tablets fully meets the pharmacopoeial requirements. During the tabletting procedure, delamination could not be observed.

Example 7

Preparation of thin film coated tablets containing 20 mg and 10 mg of active ingredient

The coating suspensions for 100,000 pieces of tablet containing 20 mg of active ingredient and for 200,000 pieces of tablet containing 10 mg of active ingredient are obtained as follows:

2.8 kg of purified water is measured in a stainless steel vessel, with 262.8 g of hydroxypropyl methyl cellulose (HPMC) having a viscosity of 5-6 are added to it with continuous stirring.

PCT / HU2004 / 000110 cP, u the mixture was stirred until dissolution was complete. 150 g of purified water is measured In a stainless steel vessel, 63.6 g of Macrogol are added to it with continuous stirring.

6000 and the mixture was stirred until complete dissolution.

105.6 g of titanium dioxide are added with stirring to about 1 liter of HPMC solution. The suspension was passed through a Fryma-type colloid mill and the colloid mill was washed with 0.4 kg of purified water. The suspension was passed through the mill and a solution of Macrogol 6000 was added to the residual HPMC solution. The mixture was stirred for 1 hour using an IKA stirrer at medium rpm (rpm) and filtered into a tared acid-resistant vessel through a stainless steel sieve having a mesh size of 0.36 mm. During the coating, the suspension is continuously stirred.

The tablets are coated in Driacoater 500/600 Vario coating equipment. The tablets were fed into the apparatus and preheated until the outlet air temperature reached 42 ° C (~ 10 minutes). When the preheating is complete, the coating suspension is sprayed. The intake and drying parameters are set so that the outlet air temperature remains between 38-45 ° C.

PCT / HU2004 / 000110

A.) Tablets containing 10 mg of active ingredient

During spreading, the total mass of 50 pieces of tablets is determined every 10 minutes to the nearest mg. The spreading was continued until the mass increased to reach 90 mg / 50 tablets. The dispersion is then complete and the thin film tablets are further dried for 5 minutes with air at 30 ° C with continuous rotation.

C.) Tablets containing 20 mg of active ingredient

During spreading, the total mass of 50 pieces of tablets is determined every 10 minutes to the nearest mg. The spreading was continued until the mass increased to reach 180 mg / 50 pieces of tablet. The dispersion is then complete and the thin film tablets are further dried for 5 minutes with air at 30 ° C with continuous rotation.

Claims (16)

Patent Claims 1. Direct compression tablets containing citalopram hydrobromide, called 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5isobenzofurancarbonitrile hydrobromide, which include citalopram hydrobromide, as an active ingredient which has an average particle size in the range of 5-40 µm in admixture with microcrystalline cellulose, which has an average particle size in the range of 90-250 µm and other excipients commonly used for the preparation of tablets. Tablets containing citalopram as the active ingredient as claimed in claim 1, comprising 5-50% by weight of citalopram hydrobromide having an average particle size in the range of 5-40 µm, 5-85% by weight of microcrystalline cellulose having average particle size in the range of 90250 µm, as an inert filler of 5-85% by weight of sugar suitable for direct compression, 0.3-3.0% by weight of magnesium stearate and optionally 0.1-2.0% by weight of colloidal or optionally micronized silica. Tablets containing citalopram as the active ingredient as claimed in claim 1, comprising 10-30% by weight of citalopram hydrobromide having an average particle size in the range of 5-40 µm, 50-80% by weight of microcrystalline cellulose having average particle size in the range of 90-250 gm, as an excipient of 5-20% by weight of sugar suitable for direct compression, 0.5-2.5% by weight of magnesium stearate and optionally 0.5-1.5% by weight of colloidal or optionally micronized silica. PCT / HU2004 / 000110 Tablets containing citalopram as the active ingredient as claimed in claim 3, which include, in addition to the active ingredient, 70-80% by weight microcrystalline cellulose having an average particle size in the range of 90-250 µm, such as an excipient 5 -10% by weight of sugar suitable for direct compression, 1.0-2.0% by weight of magnesium stearate and optionally 0.5-1.0% by weight of colloidal or micronized silica. Tablets containing as an active ingredient citalopram hydrobromide as claimed in any one of claims 1 to 4, wherein on the surface of the tablet core there is a coating obtained from substances and in accordance with methods commonly used in the pharmaceutical industry. Tablets comprising as an active ingredient citalopram hydrobromide as claimed in any one of claims 1 to 5, wherein the citalopram hydrobromide has an average particle size in the range of 5-20 µm. Tablets containing as an active ingredient citalopram hydrobromide as claimed in any one of claims 1 to 5, wherein the microcrystalline cellulose has an average particle size in the range of 150-250 µm. PCT / HU2004 / 000110 Tablets containing citalopram hydrobromide as the active ingredient as claimed in any one of claims 1 to 5, wherein the sugar suitable for direct compression is spray dried with lactose. A method for the preparation of tablets containing, as an active ingredient, citalopram hydrobromide as claimed in claim 1, which comprises solid-state mixing of citalopram hydrobromide having an average particle size in the order of 5 - 40 µm, microcrystalline cellulose, which having an average particle size of the order of 90 - 250 cm and one or more other excipients commonly used for the preparation of tablets, and compressing the homogenization of tablets containing citalopram hydrobromide in an amount corresponding to 10 - 40 mg cy talopram base. A method for the preparation of tablets containing as active ingredient citalopram hydrobromide as claimed in claim 2, which comprises mixing in solid form 5-50% by weight citalopram hydrobromide having an average particle size in the order of 5 - 40 µm , 5-85% by weight microcrystalline cellulose having an average particle size of the order of 90 - 250 µm, 5-85% by weight of sugar PCT / HU2004 / 000110 ready for direct compression, 0.3-3.0% by weight of magnesium stearate and optionally 0.1-2.0% by weight of colloidal or micronized silica and compression of the homogenization of tablets containing citalopram hydrobromide in an amount equivalent to 10 mg of ppr base. A method for the preparation of tablets containing as active ingredient citalopram hydrobromide as claimed in claim 3, which comprises solid-state mixing of 10-30% by weight of citalopram hydrobromide having an average particle size in the order of 5 - 40 µm , 50-80% by weight microcrystalline cellulose having an average particle size of the order of 90 - 250 µm, 5-20% by weight of sugar suitable for direct pressing, 0.5-2.5% by weight of magnesium stearate and optionally 0.5-1.5% by weight of colloidal or micronized silica and homo pressing enizata of tablets containing citalopram hydrobromide in an amount corresponding to 10 -40 mg citalopram base. A method for the preparation of tablets containing as active ingredient citalopram hydrobromide as claimed in claim 4, which comprises solid-state mixing of 10-30% by weight of citalopram hydrobromide having an average particle size in the order of 5 - 40 µm , 70-80% by weight microcrystalline cellulose having an average particle size of the order of 90 - 250 µm, 5-10% by weight of sugar PCI7HU2004 / 000110 suitable for direct compression, 1.0-2.0% by weight of magnesium stearate and optionally 0.5-1.0% by weight of colloidal or micronised silica, and compression of the homogenization of tablets containing citalopram hydrobromide in an amount corresponding to 10 mg per milligram. A method for the preparation of tablets containing as active ingredient citalopram hydrobromide as claimed in claim 5, which comprises applying to the tablet core a coating obtained from substances and in accordance with methods commonly used in the pharmaceutical industry. A method as claimed in any one of claims 9 to 13 for the preparation of tablets containing as active ingredient citalopram hydrobromide, which involves the use of citalopram hydrobromide having an average particle size in the range of 5-20 µm. The method as claimed in any one of claims 9 to 13 for the preparation of tablets containing as active ingredient citalopram hydrobromide, which involves the use of microcrystalline cellulose having an average particle size of the order of 150 - 250 µm. PCT / HU2004 / 000110 The method as claimed in any one of claims 9 to 13 for the preparation of tablets containing, as active ingredient, citalopram hydrobromide, which includes use as a lactose-dried direct compressed sugar.