EP1694321A1

EP1694321A1 - Tablets of citalopram hydrobromide

Info

Publication number: EP1694321A1
Application number: EP04798748A
Authority: EP
Inventors: Pál FEKETE; Szilvia Feikus; Zsuzsa Szlavyn Szell
Original assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Current assignee: Egis Pharmaceuticals PLC
Priority date: 2003-11-25
Filing date: 2004-11-24
Publication date: 2006-08-30
Also published as: EA010290B1; HUP0303790A2; HUP0303790A3; UA83094C2; WO2005051374A1; HU0303790D0; EA200600932A1; SK50532006A3; PL379864A1; BG109587A; HU227491B1; CZ2006376A3

Abstract

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

Description

TABLETS OF CITALOPRAM HYDROBROMIDE

Field of the invention

The invention relates to tablets containing as active ingredient citalopram hydrobromide and a process for the preparation thereof.

Technical background of the invention Citalopram, namely 1 - [ 3- (dimethylamino) - propyl ] -1 - (4 -fluorophenyl ) - 1 , 3 -dihydro -5 - isobenzofurancarboni trile hydrobromide, is a well known antidepressant drug that has the following structure:

The substance is a white or almost white fine crystalline powder usually having a median particle size of less than 20 μm . When citalopram hydrobromide is used as a pharmaceutical, it is formulated into coated tablets, that is film-coated tablets. As it is known, in addition to the active ingredient tablets contain excipients (fillers, binders, disin- tegr-ants , glidants, anti-friction agents), too. In order to keep the uniformity o^'f mass and content of the tablets at a low value, only mixtures of the active ingredient and excipients having a good flowability and not liable to segregation can be tabletted on up-to-date tabletting machines. That is why prior to tabletting the active ingredients and auxiliaries are to, be converted into an aggregate of granules suitable for tabletting in the course of different operations. Detailed descriptions of these operations are provided in appropriate technical books, such as Racz I. Selmeczi B. : Gyόgyszer- technolόgia 3. , Selmeczi B. : Gyόgyszer- formatan, Medicina, Budapest, 2001) .

Fundamentally, the preparatory operations can be based on the following three principles : •powder blending technique •dry granulation technique •wet granulation technique

By the powder blending technique the active ingredient is homogenized with readily- tab^'lettable ^' excipients.^' That^' is why this -technique is also referred to as direct tabletting (compressing) . The drawback of this .method is that it can be applied only in a small part of the active ingredients, that is only in case of active ingredients readily tablettable or flowable per se, or which are used at low doses .

In case of the dry granulation technique the active ingredient is homogenized with readily tablettable excipients, and then comp^'ressed (compacted, briquetted or pre- tabletted) , the compressed substance is ground, sieved, mixed with further excipients and tabletted.

In case of the wet granulation technique the active ingredient or optionally a mixture of the active ingredient and the tabletting excipients are wetted with a solution of the so-called granulating agent or only with the solvent. In this way larger granules are formed, which are then dried, sieved, mixed with further excipi^'e-rits and^' compressed to tablets.

Recently wet 'granulation is the most wide-' spread technique for the pre-tabletting operations. The reason of this fact is that although this is the most complicated and most expensive method among the three ones mentioned above, it is the safest one in the sense that by using it tablets in an appropriate quality can surely be prepared. On the ^• other hand,. direct compression is the simplest and cheapest method, but it is difficult - in certain cases impossible - to select appropriate excipients. But just because this method is simple and cheap, in the pharmaceutical industry there is a strong demand for replacing granulation techniques with direct compressing techniques . Dry granulation technique is between direct compressing and wet granulation considering both the cumbersome character of the method and the costs .

According to the literature the film tablets being on the market containing as active ingredient citalopram hydrobromide are produced, by wet granulation from _. a granulate . -prepared by fluidization drying (IT 99MI1781, _.WO .0.1/8.0619 ,^■ WO 02/053133) . The reason of this fact is that citalopram hydrobromide prepared by the conventional processes is a crystalline powder of a fine particle size having a median particle size of less than 20 μm measured by laser granulometry .

According to the state of the art two p.roblems may crop up. when tabletting by direct compression citalopram hydrobromide having such a small particle size. The first is that as a consequence of the small particle size of the active ingredient the flowability of the homogenizate containing citalopram hydrobromide in admixture with the tabletting excipients is poor, and that is why the mass uniformity does not meet the pharmacopoeal require- ments . The other is that if excipients having a somewhat bigger particle size are applied in order to improve an appropriate flowability, the powder mixture may segregate during compression to tablets, which results in a high fluctuation of the active ingredient content.

Fundamentally, 'the specifications relating to the quality of the tablets are regulated by pharmacopeias . Said specifications are not quite uniform, but mainly the specifications- of the European and American pharmacopoeias (Ph. Eur. and USP, respectively) are to be respected by the pharmaceutical industry becoming more and. more international .

In respect of the content uniformity of the tablets the specifications relating to the crucial parameters are as follows:

*RSD : relative standard deviation

1 . / E uropean Pharmacopei a , E d . 4 , 2002 , p .

1 99 -200 .

Council of Europe, Strasbourg,

2./ The United States Pharmacopeia, Ed.

26, 2003, p. 2227

United States Pharmacopeial Convention,

Inc, Rockville

Corresponding to a general trend in the manufacture of tablets the elaboration of a direct compression method has been tried in case of citalopram hydrobromide, too. According ^' to the International patent application No. WO01/80619 a solid pharmaceutical dosage form containing citalopram hydrobromide can be prepared by direct compression if the median particle size of the citalopram hydrobromide is at least 40 μm, preferably in the range of 40-200 μm, even more preferred 45-150 μm and the most preferred 50-100 μm . As citalopram hydrobromide with such a particle size cannot be prepaEβ by^J.the conventional ■ ^'.methods ₇ , said patent application ^"provides alsσ^: a process --for- the preparation of citalopram hydrobromide with an enlarged particle size necessary for direct compression. It is easy to realise that this process does not constitute a real solution, because in the practice the reduction in the costs achieved by the application of the .direct compression method is lost several times by the . recrys tallization of the .active ingredient.

In order to overcome the above problem the same inventors provide another method in WO 01/80619 for the enlargement of the particle size of citalopram hydrobromide by applying dry granulation. According to this method citalopram hydrobromide alone or in admixture with one or more ex^'ci- pient(s) is converted by roller compaction into granules having a median particle size of at least 40 μm, preferably in the range of 4-0-250 μm, more preferred 45-200 μm and the most preferred 50-180 μm . For the granulation method applied, according to said patent specification citalopram hydrobromide having a;, median article . size smaller than 20^: μm^1",^' preferably-.-'- smallerthan 15 μm is used. The -thus-obtained citalopram hydrobromide granulate is then homogenized with further excipients and compressed to tablets.

Thus, according to the state of the art citalopram hydrobromide having a median particle size of less -than 40 μm cannot -fae compressed - by direct compression to tablets meeting the - pharmacopoeial requirements .

The aim of the present invention was to elaborate a direct compression method enabling the preparation of tablets from citalopram hydrobromide particles with a median particle size of less than 40 μm, wherein the tablets meet the requirements raised by the pharmacopoeias. Summary of the invention -

The invention is based on the recognition that by using appropriately chosen excipients direct compression method is also suitable for the preparation of tablets in a quality meeting even the strictest pharmacopoeial requirements from citalopram hydrobromide having a median particle size of less than .40 μm or even less than 20 μm . It has also been recognised that due to the stability and other favourable parameters of the tablets ■ provided according to the invention they can be used as tablet cores, that is they are suitable to be coated with substances and- according . to methods conventionally'^ applied in the pharmacological industry. The thus-obtained coated tablets can be- used to advantage in the therapy.

Surprisingly it has been found that in spite of the fact that citalopram hydrobromide has poor flow properties due to its small particle size, by the appropriate selection of the excipients it is possible to prepare a composition exerting good flow properties. The compo- sition prepared according to the invention does not segregate under the conditions of the manufacturing process, in spite of that there is a considerable difference between the particle size of the active ingredient and that of the excipients. Thus it is p.ossible- to produce citalopram tablets by di-rect compression method, and the stability, • mass uniformity, content uniformity, disintegration time and dissolution of the thus-obtained tablets meets the strict pharmacopoeial requirements .

It is known that the mixtures of substances having considerably different particle sizes segregate while they are processed, that is they separate by particle sizes. The separation renders impossible the uniform distribution of the active ingredient in the individual tablets, which is a fundamental requirement in the production of tablets .

Details of the invention

According to an 'aspect of the present invention there are provided tablets prepared by direct compression containing as active ingredient citalopram hydrobromide, namely 1- [3- (dimethylamino) - propyl ] -1 - (4 -fluorophenyl ) - 1 , 3 -dihydro -5 - isobenzofurancarboni trile hydrobromide , which comprise citalopram hydrobromide having a median particle size in the range of 5-40 μm in admixture with micro- crystalline cellulose having a median particle size in the range of 90-250 μm and other excipients conventionally applied for the preparation of tablets.

More specifically, there are provided tablets containing as active ingredient citalopram hydrobromide comprising 5-50% by weight, preferably 10-30% by weight of citalopram hydrobromide having a median particle size in the range of 5-40 μm, optionally in the range of 5-20 μm, 5-85% by weight, preferably 50-80% by weight, more preferred 70-80% by weight of micro- crystalline cellulose having a median particle size in the range of 90-250 μm, preferably 150-250 μm, as excipient 5-85% by weight, preferably 5-20% by weight, more preferred 5-10% by weight of sugar 74

suitable for direct compression, 0.3-3.0% by weight, preferably 0.5-2.5% by weight, more preferred 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 preferred 0.5-1.0% by weight of

- colloidal -ox^' optionally nτic.ronized"S-ilicon

'•dioxide .

According to another aspect of the present invention there are provided tablets containing as active ingredient citalopram hydrobromide, which comprise 5-50% by weight, preferably 10-30% by weight ' of citalopram hydrobromide having a' median particle size ^"in the^" range of^' 5-40 μi^'v optionally- 5-20 μm^', 5-85% -by' weight, preferably ^■ 5.Q-8^;0% by weight, -more preferred 70-80% by weight of micro- crystalline cellulose having a median particle size in the range of 90-250 μm, preferably 150-250 μm , as excipient 5-85% by weight, preferably 5-20% by weight, more preferred 5-10% by weight of sugar suitable for direct- compression, 0.3-3.0% by weight, preferably 0.5-2.5% by^' weight, more preferred 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 preferred 0.5-1.0% by weight of colloidal or micronized silicon dioxide, and on the surface of the tablet core a coating prepared from substances and according „- to methods generally...-applied in- the pharmacological industry. -^{; " ;';}

According to a still further aspect of the present invention there is provided a process for -the -preparation of tablets containing as active ingredient citalopram hydrobromide, which comprises admixing in solid form- citalopram hydrobromide having a median particle size in the -range of 5- 40 μm, microcrystalline cellulose .having a median parrti-'cle size, in- the .range of .90-' 250 μm and one or more other excipient(s) suitable for the preparation of tablets', and compressing the thus-obtained homo- genizate to tablets containing citalopram hydrobromide in an amount corresponding to 10-40 mg of citalopram base.

More particularly, there is provided a process for the preparation of tablets containing citalopram hydrobromide, which comprises admixing in solid form 5-50% by weight, preferably 10-30% by weight of citalopram hydrobromide having a median particle size in the range between 5-40 μm, optionally 5-20 μm, 5-85% by weight, preferably^' 50-80-% by weight, more preferred 70-80% .' by weight of micro- crystalline cellulose' having a median particle size in the range of 90-250 μm, 5-85% by weight, preferably 5-20% by weight, more preferred 5-10% by weight of sugar suitable for direct compression, 0.3-3.0% by weight, preferably 0.5-2.5% by weight, more preferred 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 preferred 0.5-1.0% by weight of colloidal or micronized silicon dioxide, compressing the thus- obtained homogenizate to tablets containing citalopram hydrobromide in an amount corresponding to 10-40 mg of citalopram base, and applying to the tablet core one or more layers comprising substances conventionally applied for this purpose- in the pharmaceutical industry according to methods known per se .

The term „direct compression tabletting methods" means that the active ingredient and the excipients are homogenized at room temperature without adding a liquid to the mixture and without changing the particle size of the components, and compressing the homoge-nizate to tablets.

The term "median particle size" relates to the particle size that divides the frequency distribution in half. 50% of the particles have a larger particle size and the other 50% have a smaller one. This value is referred to as dso .

As microcrystalline cellulose- used in the citalopram hydrobromide tablets according to the invention microcrystalline celluloses applied for direct compressing having a median particle size of more than 90 μm can be applied. These micro- crystalline celluloses are distinguished by numbers 102, 200, 90 or 12 indicated together with the trade name. Such substances are e.g. 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 etc. Among these substances the microcrystalline cellulose designated with No. 200 having the biggest particle size possesses the most favourable flowability. The median particle size of the micro- crystalline celluloses designated wi th 102 and 90 is in the range between 90-110 μm, that of the microcrystalline cellulose designated with 12 is in the range between 140-180 μm, while that of the micro- crystalline celluloses designated with 200 is about 180 μm . As microcrystalline cellulose so-called silicified micro- crystalline celluloses having a median particle size of more than 90 μm can also be applied, which contain 2-3% by weight of silicon dioxide. In such a case it is not necessary to add silicon dioxide to the homogenizate . Such products are e.g. Prosolv SM CC 90 or Prosolv HD 90 (trade names ) .

As sugar suitable for direct compression any sugar-based product prepared for the purpose of direct compression can be used. Such products involve e.g. spray-dried or specially crystallized lactose, maltose or saccharose. The median particle size of these sugar-based products prepared for the purpose of direct compression is usually .in the ran.ge ,-between- • 100 μm and 200 μm. . -- -'

As magnesium stearate any magnesium stearate product meeting the pharma- copoeial requirements can be used. The median particle size of these products is usually less than 10 μm .

As colloidal or micronized silicon dioxide any . colloidal or micronized silicon- dioxide product meeting .the." pharmacbpoeial requirements can be applied. The median particle size of the colloidal micronized silicon dioxide products is a few nm, while that of the micronized silicon dioxide products is usually in the range between 4-20 μm . Silicon dioxide products may also be used in mixtures formed with microcrystalline cellulose as so-called silicified microcrystalline cellulose. The active ingredient content of the citalopram hydrobromide tablets according to the invention is in the range between 10-30% by weight. Considering that the smallest single dose of the citalopram hydrobromide is 10 mg of citalopram base corresponding ι to ^■ 12.495-. mg ^"of ^'"'citalopram- hydrobromide ,-' ^" taking into, .-account that- the mass ' of a tablet is at least 50^' -mg -in order to be physically manageable, an active ingredient content in the range between 10-30% by weight is considered optimal. Tablets with higher .active ingredient content but having the same composition in order to . ensure bio- equivalency - are usually prepared by multiplying..- the tablet weight (proportional . ompositions) . The ratio of the microcrystalline cellulose and the sugar suitable for direct compression may be varied in a wide range between 5-85% by weight. On the basis of the flowability of the powder mixture and the physical parameters of the tablets the advantageous amount of the microcrystalline cellulose is in the range between 50-80% by weight, while the amount of the sugar suitable for direct compression is in the range between 5-20% by weight. A particularly advantageous amount of the micro- crystalline cellulose is in the range between 70-80% by weight, while that of the sugar suitable for direct compression is in , .the ,. range, between 5-10% by weight; The .amount of- -the magnesium- stearate and colloidal or -micronized silicon dioxide corresponds to the amount conventionally applied or the manufacture of tablets . In case of magnesium stearate this amount is in the range between 0.3-3.0% by weight, preferably 0.5-2.5% by weight, more preferred 1.0-2.0% by weight, while in case of colloidal or micronized silicon dioxide it is in the range between 0..1-2.0% by weight, preferably 0.5-1.5% by weight, even more preferred 0.5-1.0% by weight.

The tablets containing citalopram hydrobromide according to the invention have a suitable mechanical strength and are particularly suitable for film coating operations constituting strong mechanical effects . Film coating may be carried out according to methods known from the literature. As film-forming substance e.g. a hydroxypropyl -methyl cellulose can be used together with polyethylene glycol as plasticizer and optionally titanium dioxide as pigmenting substance. Ready- made coating systems, such as Opadry (trade name) may also be applied. These substances contain as film-forming polymer hydroxypropyl -methyl cellulose (Opadry I and Opadry II) or polyvinylal cohol (Opardry II HP) .

The composition and process according to the invention is illustrated by the following Example without limiting the scope of protection to said Examples .

Example 1

Effect of fillers having different particle sizes on the flowability and tablettabili ty

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

- spray-dried lactose monohydrate (Lactose DCL 11) ,

- microcrystalline cellulose (Emcocel 90 M, Avicel 102, Vivapur 200) , - silicified microcrystalline cellulose (Prosolv SMC 90, Prosolv HD 90). As lubricant magnesium stearate, as glidant colloidal silicon dioxide (Aerosil 200) is applied.

The ingredients used in an amount given in the following Table are homogenized in .a Turbula mixer. The flowability of the homogenizates is determined according to the method provided in European Pharmacopeia, Ed. 4, 2002, p. 208-209., Council of Europe, Strasbourg.

The composition of the ci talopram homogenizates and the flowability of tlSe homogenizates are shown in the following Table :

As it can be seen, the best flowability of the homogenizates can be achieved by using Vivapur 200, that is the microcrystalline cellulose having the largest particle size .

The homogenizates are compressed to tablets of mass of 180 mg on a tabletting machine of Fette EXI type using concave dies of 8 mm in diameter. In the course of the tabletting procedure adhesion could 4

24

not be observed either on the punch or on the surface of the tablets . When breaking the tablets in two parts the inner surface is homogeneous, devoid of lamination.

The average mass and mass uniformity of tJ-β'. .?.tablets prepared . according to the -invention: were -also determined on"' 20- tablets . ^' -^{' ■} '.

From the above Table it can be seen that the mass uniformity of the tablets meets the pharmacopoeial requirements (+/- 7,5% in case of an average mass of 180 mg) . Example 2

Effect of the ratio of the sugar and microcrystalline cellulose on the tab- lettability and on the properties of the tablets

The ingredients used in -.-an amount given in the, following. Table are homogenized in a Turbula -mixer. .The flowability of the homogenizates is determined according to the method provided in European Pharmacopeia, Ed. 4, 2002, p. 208-209., Council of Europe, Strasbourg) .

Experiment cm CI59 CI60

Components (g)

Citalopram HBr, 24.99 24.99 24.99 d_50: 13,8μm

Vivapur 200 Ϊ36Ϊ8 75.6^" 14.4

Lactose DCL 11 14.4 ^"75.6^" 136.8

Aerosil 200 1.26 1.26 1.26

Magnesium 2.55 2.55^" 2.55 stearate

Total ^"l80^~.θ^" 180.0 180.0

Flowability 6.2 10.1 14.0

(s/50 g) As it can be seen from the above Table the best flowability of the homogenizate can be achieved when the microcrystalline cellulose Vivapur 200 is applied in the highest amount.

The homogenizates are compressed to tablets off mass of 180 mg on a tabletting machine of Fette^' EXI type using lentiform dies of 8 mm in diameter. In the course of the tabletting procedure adhesion could not be observed either on the punch or on the surface of the tablets. When breaking the tablets into two parts the inner surface is homogeneous, devoid of lamination .

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

Other physical parameters of the tablets and the dissolution rate of the active ingredient were determined on the basis of the appropriate pharmacopoeial procedures . 4

27

Experiment cm CI59 ! CI60

Parameter

Average mass 181.4 179.2 183.6

(mg)

Individual mass 178.7-183^".3^' 178.8-179.7 - 182.8-184.8

(mg) ) ,L_.

Mass deviation 1

(%) < 1.5% . < 0.3% < 0.7%

Breaking 83 73 67 strength (N) (77-90) (68-75) ; (53-80)

Disintegration time² (minute) 2'53"-4'47" 3'58"-5'39" j 7'37"-8'21"

Dissoluti Dn³ (%)

5 minutes 81.19 65.66 27.34 -'

10 minutes 9^*6.63 96.97 51.62 ^■''^'

20 minutes 100.21 97.83 99.97

30 minutes - 97.95 101.67 -v

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

Council of Europe, Strasbourg

The mass uniformity of the tablets meets the pharmacopoeial requirements (+/- 7,5% in case of an average mass of 180 mg) .

All other parameters of the tablets meet the strict pharmacopoeial requirements. The most favourable result can be achieved in case of the homogenizate containing the highest amount of microcrystalline cellulose. In this case the breaking strength of the tablet is the highest, the dissolution of the active ingredient is the quickest and the disintegration time of th-^'e tablet ^'-is the shor-te^'str"'-' "^{• • . .} --

Example 3 (comparative experiment) Preparation of tablets devoid of sugar

The ingredients enumerated in the following Table are homogenized in a Turbula mixer. The homogenizates are compressed to tablets of 180 mg on' a tab- letting machine of Fette EXI type using concave dies of 8 mm in diameter. In .the course of the tabletting procedure, lubrication problems occur in case of the homogenizates containing spray-dried mannitol (Pearlitol SD 200) , ,, friction" can be experienced on the inner surface of the dies and the breaking strength of the tablets is unsuitable (a low breaking strength with high deviation) . The lubrication problems can be diminished by gradually decreasing 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 laminated. In case of compositions containing only micro- crystalline cellulose (Vivapur 200) lubri- • cation problems- canno-t ^■ be experienced, but the structure^" of^' - the- tablet is laminated.^"

In case of the compositions given in the following ^' Table tablets containing as active ingredient citalopram hydrobromide cannot be prepared in a suitable quality.

Experiment CI010401 CI130401 CI580103

Components (g)

Citalopram HBr (mg) 24.99 24.99 24.99 d_50: 13,8μm -

Vivapur 200 (mg) -- — 151.2

Emcocel 90 M (mg) 132.55 7.5 —

Mannitol IT.^"885 142.96 —

(Perlitol SD 200)

(mg)

Aerosil 200 (mg) 0.625 0.625 1.26^'

Magnesium stearate ^"3.95 3.925 2.55

(mg)

Total 180.0 180.0 180.0 Example 4

Tablet containing 40 mg of citalopram

The ingredients given in the following Table are homogenized in a drum blender of Pharmatech 400 type.

^{* '} Substance - Quantity

Citalopram hydrobromide

Particle size: dso_: 15.5 μm 5.00 kg

Microcrystalline cellulose

Particle size: 27.40 kg d₅o: about 180 μm

Lactose (spray-dried) 2.88 kg

. Magnesium stearate 510.0 g

Colloidal silicon dioxide 252.0 g

Tabletting of the homogenizates is carried out on a Manesty Betapress 16 station rotary press at a speed of 750 pieces of tablet/minute. 100,000 pieces of biconvex tablets 10 mm in diameter weighting 360 mg and containing 40 mg of citalopram base each are compressed. By dividing the manufacture time into identical intervals 8 samples per lot were taken and the uniformity of mass and content of the tablets are determined.

The data relating to the tablets prepared according to the Example are summarized in the following Tables.

Mass uniformity

The ^'mass uniformity data are calculated on the basis of the individual masses of 20 tablets per lot.

Citalopram 40 mg tablet

On the basis of the above data the mass uniformity of the tablets fully meets the pharmacopoeial requirements .

Uniformity of content of tablets

The data relating to the uniformity of content are calculated on the basis of the individual masses of 10 tablets per lot

Citalopram 40 mg tablet

On the basis of the above data the content uniformity fully meets the pharmacopoeial requirements . The relative deviation of the active ingredient content is about 1- 2% in the course of the tabletting procedure, that is segregation does not occur during the manu acture. Example 5 Preparation of film-coated tablets containing 40 mg of citalopram

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

2.8 kg of purified water is measured into a stainless steel vessel, 262.8 g of hydroxypropyl -methyl . cellulose (HPMC) having a viscosity of 5-6 cP are added to it under continuous stirring, and the mixture, is stirred until complete dissolution. 150 g of purified water is measured into a stainless steel vessel, 63.6 g Macrogol 6000 are added to it under continuous stirring, and the mixture is stirred until complete dissolution.

To about 1 litre of the . HPMC solution 105.6 g of titanium dioxide are added under stirring. The suspension is passed through a colloid mill of Fryma type and the colloid mill is washed with 0.4 kg of purified water. The suspension passed through the mill and the Macrogol 6000 solution are added to the residual HPMC solution, the mixture is stirred for 1 hour using an IKA stirrer at a medium rpm, finally filtered with a sieve having a mesh size of 0.36 mm into a tarated acid- proof vessel. During the coating procedure the suspension is continually stirred. The tablets are coated in a coating apparatus of Driacoater 500/600 Vario type. . ..

-The .-table.t.s are fed. into _; the apparatu-s and they .are pre-warmed until the- temperature' of ^• the outgoing air has achieved 42 °C (~ 10 minutes ) .

When pre-warming has been finished the coating suspension is sprayed. The parameters of ■ the- introduction and drying are set so that the temperature of the outgoing- air remains in the ran.ge between 38- 45°C.. - ^' . " . -

During •^■spraying the total mass of" :50, pieces of tablets are determined in every 10 minutes with an accuracy of "mg" . Spraying is continued until a mass increase of 360 mg / 50 pieces of tablets has been achieved. Then spraying is finished and the film-tablets are dried further for 5 minutes with 30°C air under discontinuous rotation. Example 6

Tablets containing 10 and 20 mg of citalopram

The ingredients given in the following Table are ' homogenized in a drum blender of Pharmateeh 400- type. 7

The homogenizate is divided into two parts. One part is compressed to 100,000 pieces of lentiform tablets 8 mm in diameter weighting 180 mg and containing 20 mg of citalopram base, the other part is used for the preparation of 200,000 pieces of lentiform tablets 6 mm in diameter weighting 90 mg and containing 10 mg of citalopram base. Tabletting is carried out on a Manesty Betapress 16 station rotary press at a speed of 750 pieces of tablet/minute. By dividing the manufacture time into identical intervals 8 samples per lot were taken from tablets containing 20 mg of citalopram base and 16 samples per lot from tablets containing 10 mg of citalopram base. The uniformity of mass and content of the tablets are determined. The results are summarized in the following Table.

Uniformity of mass

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

A.) Mass uniformity data of the citalopram tablets prepared according to the .Example containing 20 mg of active agent:

Sample l I 2 ; 3 ! ! 5 ; 6 7 8

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^" ; 1797 o^"; ^' 175^'.9 ^' 178.5

(mg) !

. ^„_ --I---- _Q .

Max. ^"183.5.^'i84.2 183.0^' : 184.0 182.5 ^; Ϊ8375~

(mg) RSD (%) 0.88 ; 0.87 0^".82 , ^"δ^". όi 0.89 0.88 0.92 0.77 B.) Mass uniformity data of the citalopram tablets prepared according to the Example containing 10 mg of active agent:

According to the above data the uniformity of mass of the tablets fully meets the pharmacopoeial requirements .

Uniformity of content

Uniformity of content is calculated by measuring the individual masses of 10 tablets per lot for each sample. A.) Uniformity of content of citalopram tablets containing 20 mg of active ingredient prepared according to the Example :

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

According ^'t^'o⁼ the above^' data the uniformity of content -of ^"the tablets- fully meets^' the pharmacopoeial requirements. In the course of the tabletting procedure segregation could not be observed.

Example 7

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

Coating suspensions for 100,000 pieces of tablets containing 20 g of active ingredient and for 200,000 pieces of tablets containing 10 mg of active ingredient are prepared as follows :

2.8 kg of purified water is measured into a stainless steel vessel, 262.8 g of hydroxypropyl -methyl cellulose (HPMC) having a viscosity of 5-6 cP are added to it under continuous stirring, and the mixture is stirred until complete dissolution. 150 g of purified water is measured into a stainless steel vessel, 63.6 g of- Macrogol ιβ^'000 are added, to it under ^' continuous stirring, and the mixture is stirred until complete dissolution.

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

The coating of the tablets is carried out in a coating apparatus of Driacoater 500/600 Vario type. The tablets are filled into the apparatus and pre-warmed until the temperature of the outgoing air has achieved 42°C (~ 10 minutes) . When pre- warming has been finished the coating suspension is sprayed. The parameters of the introduction and drying are set so that the temperature of the outgoing air remains in the range between 38-45°C.

A.) Tablets containing 10 mg of active ingredient

During spraying the total mass of 50 pieces of tablets are determined in every 10 minutes with an accuracy of "mg" . Spraying is continued until a mass increase of 90 mg / 50 pieces of tablets has been achieved. Then spraying is finished and the film-tablets are dried further for 5 minutes with 30°C air under discontinuous rotation. B.) Tablets containing 20 mg of active ingredient

During spraying the total mass of 50 pieces of tablets are determined in every 10 minutes with an accuracy of "mg" Spraying is¹ continued until.,- a mass increase, of 180 mg / .50 pieces of tablets has been achieved. Then spraying ._.. is- finished and the film-tablets are dried further for 5 minutes with 30°C air u der discontinuous rotation.

Claims

What we claim is:

1. Tablets prepared by direct compression containing as active ingredient citalopram hydrobromide, namely 1- [3- (dimethylamino) propyl ] -1 - (4 -fluorophenyl ) -

-, -. -1-, 3-.dihyd.r.o-5 -i s.o-b,en,zofuj,ancarb.oni tril.e.._. . ydrobromide, which, comprise . .citalopram hydrobromide having a median particle size in the range' of 5-40 μm in admixture with microcrystalline cellulose having a median particle size in the range of 90-250 μm and other excipients conventionally applied f;br the preparation of tablets.

2. Tablets containing as active ingredient citalopram as claimed in claim 1, which comprise 5-50% by weight of citalopram hydrobromide having a median particle size in the range of 5-40 μm, 5-85% by weight of microcrystalline cellulose having a median particle size in the range of 90-250 μm, as excipient 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 silicon dioxide.

Tablets containing as active ingredient citalopram as claimed in claim 1, which comprise 10-30% by weight of citalopram • Hydrobromid^'e-; * h-av-i-hg ^" a median --particle size in the-'-range- of 5-40.- --ιi^{' '}5O~8Q% by, weight of' "microcrystalline ^" cellulose having a median particle size in the range of 90-250 μm , as excipient 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 silicon dioxide,

Tablets containing as active ingredient citalopram as claimed in claim 3, which comprise, in addition to the active ingredient, 70-80% by weight of micro- crystalline cellulose having a median particle size in the range of 90-250 μm, as 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 silicon dioxide.

5. Tablets containing as active ingredient citalopram hydrobromide as claimed in any of claims 1 to 4 , wherein on the surface of the tablet core there is a coating- prepared- from substances and according to methods conventionally applied in the pharmaceutical industry.

6. Tablets containing as active ingredient citalopram hydrobromide as claimed in any of claims 1 to 5, wherein the citalopram hydrobromide has a median particle size in the range of 5-20 μ .

7. Tablets containing as active ingredient citalopram hydrobromide as claimed in any of claims 1 to 5, wherein the micro- crystalline cellulose has a median particle size in the range of 150-250 μm.

8. Tablets containing as active ingredient citalopram hydrobromide as claimed in any of claims 1 to 5, wherein the sugar suitable for direct compression is spray-dried lactose.

9. A process for the preparation of tablets containing as active ingredient citalopram hydrobromide as claimed in claim 1, which comprises . admixing in solid • form citalopram- hydrobromide having a median particle size in. the range of 5-40 μm, microcrystalline cellulose having a median particle size in the range of 90-250 μm and one or more other excipien (s) conventionally applied for the preparation of tablets-, and compressing the homogenizate to tablets containing citalopram hydroj- bromide in an amount corresponding,- fop- 10-40 mg of citalopram base.

10. A process for the preparation of tablets containing as active ingredient citalopram hydrobromide as claimed in claim 2, which comprises admixing in solid form 5-50% by weight of citalopram hydrobromide having a median particle size In the range^" of^" 5-40 -μm, 5-85% by weight of microcrystalline cellulose having a median particle size in the range of 90-250 μm , 5-85% by weight of sugar 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 silicon dioxide, and compressing the homogenizate to tablets containing citalopram -hydrobromide in an amount corresponding 10-40 mg of citalopram base .

11. A process for the preparation of tablets containing as active ingredient citalopram hydrobromide as claimed in claim 3, which comprises admixing in solid state 10-30% by weight of citalopram hydrobromide having a median particle size in the range of 5-40 μm, 50-80% by weight of microcrystalline cellulose having a median particle size in the range of 90-250 μm, 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 micronized silicon dioxide, and compressing the homogenizate to tablets containing citalopram hydrobromide in an amount corresponding to 10-40 mg of citalopram base .

12. A process for the preparation of tablets containing as active ingredient

.citalopram ^'• hydrobromide as claimed -in- claim 4-, -which comprises ■•^" admixing, in solid state- 10-30% by-weight of- citalopram hydrobromide having a median particle size of 5-40 μm, 70-80% by weight of microcrystalline cellulose having a median particle size in the range of 90-250 μm, 5-10% by weight of^' ^' sugar suitable for direct compression'^ 1.0-2.0% by weight^' of .magnesium stea-l; rate and- optionally 0.5-1.0% by weight of colloidal or micronized silicon dioxide, and compressing the homogenizate to tablets containing citalopram hydrobromide in an amount corresponding to 10-40 mg of citalopram base.

13. A process 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 prepared from substances and according to methods conventionally applied in the pharmaceutical industry.

14. A process as claimed in any of claims • -9"-.-to -₅I.3-- fo:. th-e.'-_;.preparation of -table.ts containing-, as.-actiye ingredient citalopram hydrobromide ,..which- comprises u-sing citalopram hydrobromide having a median particle size in the range between -5-20 μm.

15. A process as claimed in any of claims 9 to. 13 for- .the preparation of tablets

.containing as active ingredient citalopram hydrobromide, which comprises using microcrystalline cellulose having, -a median particle size in the range of 150-250 μm.

16. A process as claimed in any of claims 9 to 13 for the preparation of tablets containing as active ingredient citalopram hydrobromide, which comprises using as sugar ready for direct compression spray-dried lactose.