CA2353693C - Pharmaceutical composition containing citalopram - Google Patents

Pharmaceutical composition containing citalopram Download PDF

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Publication number
CA2353693C
CA2353693C CA002353693A CA2353693A CA2353693C CA 2353693 C CA2353693 C CA 2353693C CA 002353693 A CA002353693 A CA 002353693A CA 2353693 A CA2353693 A CA 2353693A CA 2353693 C CA2353693 C CA 2353693C
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citalopram
crystals
range
unit dosage
dosage form
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CA2353693A1 (en
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Ken Liljegren
Per Holm
Ole Nielsen
Sven Wagner
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H Lundbeck AS
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H Lundbeck AS
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D307/00Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87Benzo [c] furans; Hydrogenated benzo [c] furans
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic macromolecular compounds

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A solid unit dosage form comprising citalopram, which is prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, or by filling of said mixture in a hard gelatine capsule. Large crystals of a pharmaceutical acceptable salt of citalopram and method for the manufacture of said large crystals.

Description

Pltarrnaceatical composition containing Citalopram The present invention relates to a novel pharmaceutical composition containing citalopram, 1-(3-(dimethylamino)propyl]-1-(4-fluoropbenyl)-1,3-dihydro-S~isobenzo furancarbonitrile.
Bsclrground of the Ynvention.
Citalopram is a well-knoww antidepressant drug that has the following structure:
N
~ H3 H
~ CH3 Tt is a selective, centrally active serotonin (S-hydroxytryptamine; 5-H~
reuptake inhibitor, accordingly having antidepressant activities.
Citalopram was first disclosed in DE 2,657,013, corresponding to US 4,136,193.
This patent publication describes the preparation of citalopram by one method and outlines a further method, which may be uscd for preparing citaloprani. The citalopram 2o prepared was isolated in crystalline fonni as the oxalate, the hydrobmmide and the hydrochloride salt, respectively. Furthermore, the citalopratn base was obtained as an oil (B.P. 175 CI0.03 nunHg). The publication also outlines the manufacture of tablets containing salts of citalopram. Citaloprarn is marketed as the hydrobromide and the hydrochloride, respectively.
Manufacture of crystalline citaloprara base is disclosed in co-pending DK 2000 00402. This patent publication describes the preparation of crystalline citalopram base and the use of crystalline citalopram base as an intermediate in the purification of crude citalopram hydrobromide into pure citalopratm hydrobmmide. The publication 3o also outlines the manufacture of tablets containing citalopram base.
2 Citalopram is marketed in a number of countries as a tablet prtpared by compression of granulated citalopram hydrobromide, lactose and other excipients.
Yt is well recognised that preparation of tablets with a reproducible composition s requires that all the dry ingredients have good flow properties. In cases, where the active ingredient has good flow properties, tablets can be prepared by direct compression of the ingredients. However, in many casts the particle size of the activo substance is small, the active substance is cohesive or has poor flow properties.
to Further, active substances with a small particle size mixed with excipients having a larger particle size will typically segregate or de-mix during the tabletting process.
The problem of small particle size and poor flowability, is conventionally solved by enlarging the particle size of the active substance, usually by granulation of the active 15 iagaredient either alone or in combination with a filler andlor other conventional tablet ingredients.
One such granulation method is the "wet" granula'on pmcess. Using this method, the dry solids (active ingredients, filler, binder etc.) are blended and moistened with water 24 or another wetting agent (e.g. an alcohol) and agglomerates or granules are built up of the moistened solids. Wet massing is continued until a desired homogenous particle size has been achieved whereupon the granulated product is dried.
An alternative to the "wet" granulation method is the "melt" granulation, which is also 25 known as the "thermal plastic" granulation process, where a low melting solid is used as the granulation agent. Tnitially, the dry solids are blended and heated until the binder melts. As the binder is liquefied and spreads over the surface of the particles, the particles will adhere to each other and form granules. The binder solidifies upon cooling fornvng a dry granular product.
Wet granulation as well as melt granulation are energy intensive unit operations requiring complicated and expensive equipment as well as technical skill.
3 The pmcess used for the preparation of citalop~ratn hydrobromide results in a product with a very small particle sire around 2-20 pm that, as many other particulate products with a small particle sixe, hae very poor flow properties. Thus, in order to achieve appropriate dosing of the citalopram during tahletting, it was cotrsiderat s necessary to make a gratrulate of citalopram with larger particle size and improved flow properties.
The citalopram tablet that is marketed is a tablet made from granulated citatopram hydmbromide with various excipiants.
to 1n view of the fact that direct compression is much simpler and cheaper than the processes involving granulation there is a desire for.a process for direct compression of citaloprsm hydrobmmide.
15 The obataclos that hitherto have hindered direct compression of citaloptam tablets have now been circunnvented after extensive laboratory research.
rt has boon found that largo particles, i.e. particles of a size eotaparable to the size of the filler, may be propared by a new and inven've cxyetallisation process ~d that 20 these particles are useful for the manufacture of directly compressed tablets. Accurate dosing in cagsulas may also be with such large particles.
It has also been found, that tablets with surprisingly small variation i>1 the content of citalopram may be preparai by direct cotrrpiession of citalopram hydrobrornido 25 having a significantly smaller particle size than the filler. Arxurate dosing in capsules may also be achieved despite iho small particle size of citalopram.
Objects olthe Iaverition 3o It is the object of the present invention to provide a novel pharmaceutical unit dosage form containing citalopram with a suitable large particle size, wherein said unit dosage form may be prepared by direct compression.
A second object of the invention ( not claimed) is to provide a capsule containing citalopram.
4 A third object of the invention is to provide large crystals of a pharmaceutically acceptable salt of eitalopram suitable for use in direct compression.
s A fourth object of the invention is to provide a method for manufacture of large crystals of a pharmaceutically acceptable salt of citaloprara.
Summary of the lrnveation 1o The invention then, inter alia, comprises the following alone or in combination:
A solid unit dosage form comprising eitalopratn prepared by direct compression of a mixture of eitalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, or by filling of said mixture in a hard gelatine 15 capsule_ Crystals of a pharmaceutically acceptable salt of citalopram suitable for use in a solid unit dosage form with a median particle site of at least 40 Nra.
2o A method for the manufacture of crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 lrm and suitable for use itt a solid unit dosage form wherein a solution of a pharmaceutically acceptable salt of citalapram in a suitable solvent system at a first temperature is first cooled down to a second temperature then seeded by addition of crystals of said citalopram salt 25 followed by a holding time at said second temperature and a controlled cooling down to a third temperature whereupon said crystals are isolated by conventional solidlliquid separation techniques.
The direct compression of citalopram, a filler and other pharmaceutically acceptable 30 excipients into tablets has the great advantage, that the granulation and a drying step is avoided. Further, as the granulation step is avoided, it is no Longer necessary to add a binding agent.

As used herein, "direct compression" means that the solid unit dosage form is prepared by compression of a simple mixture of the active ingredient and excipients, without the active ingredient having been subjected to an intermediate granulation process in order to embed it in a larger particle and improve its fluidity properties.
As used herein, "binder" means an agent, which is used in wet or melt granulation processes and acts as a binder in the granulated product.
As used herein, "particle size distribution" means the distribution of equivalent spherical diameters as determined by laser diffraction at Z bar dispersive pressure in a Sympatec Helos* equipment. "Median particle size", correspondingly, means the median of said particle size distribution.
As used herein, "refluxing temperature" means the tempera-ture at which the solvent or is solvent system refluxes or boils at atmospheric pressure.
Thus in one embodiment of the invention, the present invention relates to a tablet prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof in the form of crystals with a medium particle size of at least 40~,m and pharmaceutically acceptable excipients.
* (trademarks) 5a In another embodiment not claimed, the present invention relates to a capsule prepared by filling a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients in a hard gelatine capsule.
In a further embodiments not claimed, the present invention relates to a solid unit dosage form comprising citalopram in crystals with a median particle size below 20 ,um.
In another embodiment, the present invention relates to a solid unit dosage form comprising citalopram in crystals with a median particle size of at least 40 ~.m, preferably in the range of 40 - 200 ~Cm, even more preferred 45 - 150 ~m and most preferred 50 - 100 ~.m.

Flow, segregation and demixing properties and, hence, the suitability of the citalopram crystals for direct compression depend, besides the median particle size, on the particle side distribution.
s Preferably, the solid unit dosage forms according to the invention do not contain a binder.
The solid unit dosage form according to the invention may contain 2-60 % w/w active ingredient calculated as citalopram base, preferably 10-40 % w/w active ingredient calculated as citalopram base, and more preferred 15-25 % w/w active ingredient calculated as citalopram base. Suitably, the solid unit dosage form of the invention contains 20 % w/w active ingredient calculated as citalopram base.
In particular, the present invention relates to a solid unit dosage form wherein the active ingredient is citalopram hydrobromide, or citalopram hydrochloride.
Preferably the active ingredient contained in the solid unit dosage form of the invention is citalopram hydrobromide.
The solid unit dosage form according to the invention may contain a filler selected 2o from lactose, or other sugars e.g. sorbitol, mannitol, dextrose and sucrose, calcium phosphates (dibasic, tribasic, hydrous and anhydrous), starch, modified starches, microcrystalline cellulose, calcium sulphate and/or calcium carbonate. In a preferred embodiment, the solid unit dosage form of the invention does not contain lactose.
Suitably the filler is a microcrystalline cellulose such as ProSolv SMCC90*
manufactured by Penwest Pharmaceuticals or Avicel PH 200 manufactured by FMC
Corporation.
Besides the active ingredient and filler, the solid pharmaceutical unit dosage forms may include various other conventional excipients such as disintegrants, and optionally minor amounts of lubricants, colorants, and sweeteners.
* (trademarks) Lubricants used according to the invention may suitably be one or more of the follovcring metallic stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica.
Suitably the lubricant ie magnesium stearate or calcium stearate Disintegrants include sodium starch glycolate, croscarmellose, crospovidone, lover substituted hydmxypropylccllulose, modified cornstarch, pregelatizined starch and natural starch.
to The solid, pharmaceutical unit dosage form of the invention may be prepared by conventional methods using a tablet press with forced feed capability.
?he filled, hard gelatine capsule of the invention may be prepared by conventional ~ s methods using a capsule filler suitable for powder filling.
In one embodiment of the present invention the crystals of a pharmaceutically acceptable salt of citalopram have a median particle size in the range of 40 -200 p.m, preferably 45 -150 pro and even more preferred 50 -120 pro.
In a preferred embodiment of the present invention the crystals are of citalopram hydrobromide or citalopram hydrochloride, preferably citalopram hydrobmmide.
xn yet another embodiment of the present invention crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 itm and suitable for use in a solid unit dosage form are crystallised from a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system.
Said solvent system may comprise one or more alcohols and optionally water, preferably the solvent system is a mixture of methanol and water, wherein the methanol:water 3o weight ratio preferably is in the range of S:1 to 50:1; even more preferred 10:1 to 30:1 and most preferred 15:1 to 25:1. Said pharmaceutically acceptable salt of citaloprarn is preferably dissolved in the solvent system at a temperature in the range between 50 °C and the refluxing temperattue of the solvent system, preferably between 60 °C and B
the refluxing temperature and more preferred between 64 °C and the refluxiirg temperature. The amounts of pharmaccudcally acceptable salt of citaloprarn and solvent used are preferably corresponding to a sol~rentaolute weight ratio in the range of 0.5:1 to 5:1, more preferred 0.7:1 to 2:1 arid most preferred 0.9:1 to 1.5:1. The solution of a pharmaceutically acceptable salt of citalopram is cooled down to a temperature, the seeding temperature, in the range of 20-40 °C, preferably 25-35 °C, whereupon it is seeded with citalopraJn crystals and kept at said seeding temperature for a holding time for crystal grnwth in the range of 30 minutes to 7 days, prefcrebly 1 hour to 4 days and more preferred 12 to 36 hours. After said holding time, the to crystallisation batch is gradually cooled down in a controlled way from the seeding temperature to the temperature at which the crystals will be isolated from the mother liquor wherein said gradual cooling down is done over a time span in the range of 5 minutes to 6 hours, preferably 1 S minutes to 4 hours aad more preferred 30 minutes to 2 hours_ 'Ihe crystals of said pharmaceutically acceptable salt of citalopram are preferably isolated from the mother liquor at a temperature in the range of 0-20 °C, more preferred 5-15 °C, using conventional separation techniques, e.g.
filtration.
The small crystals of a pharmaceutically acceptable salt of citalopram used ip one embodiment of the invention may be produced according to methods described in US
4,136,193.
The crystals of citalopram base used in one embodiment of the invention may be producod according to metbods described in NL patent No. 1016435.
xn the following, the invention is illustrated by way of examples. However, the examples are merely intended to illustrate the invention and should not be constnred as limiting.

Example 1 Crystallisation of citalopram hydrobromide into large crystals Citalopram hydrobromide (200 g) is dissolved in a mixture of methanol (200 g) and water (20 g) at 69 °C. The solution is cooled down to 30 °C, seeded with citalopram hydrobromide crystals and kept at 30 °C for 24 hours, whereupon it is cooled down to °C within 1 hour. The cry. stals are isolated by filtration, washed with cold methanol and dried. The particle size distribution for the resulting crystals is listed in table 1.
io Ezamplc 2 Crystallisation of citalopram hydrobromide into large crystals 1s CitaJopram hydrobromide (12.0 kg) is dissolved in a mixture of methanol (12.5 kg) and water (1.2 kg) at reflux. The solution is cooled down to 30 °C, seeded with citalopram hydrobromide crystals (27 g) and kept at 30 °C for 16 hours, whereupon it is cooled down to 10 °C within 1 hour. The crystals are isolated by filtration, washed with cold (10 °C) methanol (3.5 kg) and dried. The particle size distribution for the 2o resulting crystals is listed in table 1.
Example 3 Crystallisation of citalopram Lydrobromide Into small crystals Citalopram hydrobromide (Z00 kg) is dissolved in a mixture of methanol (170 L) and acetone (680 L) at 56 °C. The solutioa is cooled down to 1 S °C, seeded with citalopram hydrobromide crystals (50 g), hexane (1600 L) is gradually added within 60 minutes, whereupan the suspension is left standing with moderate stirring and 3o cooling for 8 boors. The crystals are isolated by filtration, washed fast with a cold (10 °C) mixture of acetone (s0 L) and hexane then with cold (10 °C) hexane (220 L) and dried. The particle size distribution far the resulting crystals is listed in table 1 to Example 4 Crystallisation of citalopram as the free base.
Citalopram hydrobromide (101 g) is suspended in water (500 mL) and toluene (500 mL). NaOH (60 mL, 5 N (aq)) is added and the mixture (pH>10) is stirred for 15 min before the phases are separated. The organic phase is washed with water (2 x100 mL) and filtered through a pad of filter help. The volatiles are removed in vacuo and the title compound is obtained as an oil. n-Heptane (400 mL) is added and the mixture is heated to 70 °C. On cooling, crystals forms. The white crystals of citalopram base are f ltered off and dried at ambient temperature over night in vacuo.
Table 1: Particle size distribution (Sympatec Helos) for citalopram hydrobromide crystals and ProSolv SCMC90*
Quartile Example 1 Example Example ProSolv SCMC90 (%) (um) 2 3 (wm) (um) (!gym) 95 465.43 549.42 96.96 279.94 90 342.89 352.23 72.27 231.66 50 96.87 52.70 14.04 114.17 10 16.54 11.97 1.19 32.10
5 8.23 6.67 0.82 20.56 Example 5 Tablet prepared by direct compression of small citalopram hydrobromide crystals.
Tablet ingredients:
Citalopram, HBr 58_ 00 g (20 % w/w) ProSolv SMCC90* 23055 g (79.5 % w/w) Magnesium stearate 145 g (0.5 % w/w) * (trademarks) Citalopram hydrobromide crystals from example 3 and ProSolv SMCC90 Were blended at 7 rpm for 10 min in a 100 litre Bohle PTM 200 mixer. Magnesium stearate was added and blending continued for 3 min.
25 kg of the resulting mixture was tabletted (125.000 tablets/hour) on a 30 station Fette P 1200/IC# tablet press fitted with oblong, embossed, scored 5,5 x 8 mm punches. Tablet core weight was set to 125 mg. The nominal yield was 200.000 tablets. The tablet press was run until the mixture level was just above the forced feeder, i.e. the tabletting was continued as long as possible in order to identify 1o possible segregation tendencies in the last quantities of mixture.
Tablet properties:
Diametrical crushing strength: 70 N
Disintegration time: 30 seconds Friability: NA
Weight variation: 0.84% relative standard deviation (measured on 20 tablets) Punch adhesion: None observed Citalopram content in the composition during compression.
Tablets were sampled throughout the compression in order to measure segregation tendency. Since there is a significant size difference between the active ingredient, citalopram hydrobromide, and the inert filler, ProSolv SMCC90, as seen in table 1, it would be expected that the unequally sized components would segregate; i.e. de-mix, during transfer from blending vessel to tablet press hopper or sitting in the tablet press hopper during tabletting.
Sampling was performed 50 times at regular intervals during tabletting, corresponding to sampling at every 4000 tablets produced. Two tablets were withdrawn for each sample.
* (trademarks) The tablets were assayed by a validated method using UV-absorption in an aqueous solution, thus analysing in total 100 tablets. The relative standard deviation in citalopram content was 1.6%
The variability in tablet strength is surprisingly low in view of the small particle size of citalopram hydrobromide as compared to the inert filler.
One possible explanation for this surprising and beneficial result may be that the tendency to segregation between small citalopram crystals and larger filler particles is to uniquely balanced by the poor flow properties of the small crystals.
Example 6 Tablet prepared by direct compression of large citalopram hydrobromide 1s crystals.
Tablet ingredients:
Citalopram, HBr (20 % w/w) 2o ProSolv SMCC90* (79.5 % w/w) Magnesium stearate (0.S % w/w) Citalopram hydrobromide crystals from example 2 and ProSolv SMCC90 were blended. Magnesium stearate was added and blending continued.

Tablets (12S mg nominel weight) were produced.
The tablets had satisfactory technical properties.
* (trademarks) Example 6 Tablet prepared by direct compression of citalopram crystals.
Tablet ingredients:
Citalopram base (16 % w/w) ProSolv SMCC90* . (83.3 % w/w) Magnesium stearate (0.7 % w/w) to Citalopram base crystals from example 4 were sieved through sieve aperture of 0.3 mm and mixed with ProSolv SMCC90*for 3 minutes in a Turbula mixer. Magnesium stearate was added and blending continued for 30 seconds.
Tablets were produced on a single punch tabletting machine Korsch EKO*
Tablet properties:
Tablet strength, mg: 20 Nominel tablet weight, mg: 125 2o Tablet diameter, mm: 7 Tablet shape: Film coating, special doomed Diametrical crushing strength: 61.6 N
Disintegration time, min: < 1 Friability: 0.1 Mean tablet weight: 125.4 Weight variation: 0.22 % relative standard deviation The tablets produced had satisfactory technical properties.
* (trademarks)

Claims (54)

14
1. A solid unit dosage form comprising citalopram, characterized in that it is in the form of a tablet prepared by direct compression of a mixture of citalopram or a pharmaceutically acceptable salt thereof in the form of crystals with a median particle size of at least 40 µm, and pharmaceutically acceptable excipients.
2. The solid unit dosage form according to claim 1, characterized in that it does not contain a binder.
3. The solid unit dosage form according to claim 1 or 2, characterized in that it contains 2 to 60% w/w of active ingredient calculated as citalopram.
4. The solid unit dosage form according to claim 3, characterized in that it contains 10 to 40% w/w of active ingredient calculated as citalopram.
5. The solid unit dosage form according to claim 4, characterized in that it contains 15 to 25% w/w of active ingredient calculated as citalopram.
6. The solid unit dosage form according to any one of claims 1 to 5, characterized in that it contains a filler selected from the group consisting of lactose, sugars, calcium phosphates, starch, modified starches, microcrystalline cellulose, calcium sulfate and calcium carbonate.
7. The solid unit dosage form according to claim 6, characterized in that the filler is a sugar selected from the group consisting of sorbitol, mannitol, dextrose and sucrose.
8. The solid unit dosage form according to claim 6, characterized in that the filler is a calcium phosphate selected form the group consisting of dibasic, tribasic, hydrous and anhydrous calcium phosphates.
9. The solid unit dosage form according to claim 6, characterized in that the filler is a microcrystalline cellulose.
10. The solid unit dosage form according to claim 9, characterized in that the microcrystalline cellulose is ProSolv SMCC90* or Avicel PH 200*.
11. The solid unit form according to any one of claims 1 to 10, characterized in that it contains a lubricant selected from the group consisting of metallic stearates, stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica.
12. The solid unit dosage form according to claim 11, characterized in that the lubricant is magnesium stearate or calcium stearate.
13. The solid unit dosage form according to any one of claims 1 to 12, characterized in that it is substantially free of lactose.
* (trademarks)
14. The solid unit dosage form according to any one of claims 1 to 13, characterized in that the active ingredient is citalopram.
15. The solid unit dosage form according to any one of claims 1 to 13, characterized in that the active ingredient is citalopram hydrobromide or citalopram hydrochloride.
16. The solid unit dosage form according to claim 15, characterized in that the active ingredient is citalopram hydrobromide.
17. The solid unit dosage form according to any one of claims 1 to 16, characterized in that the median particle size of the crystals is in the range of 40 to 200µm.
18. The solid unit dosage form according to claim 17, characterized in that the median particle size of the crystals is in the range of 45 to 150 µm.
19. The solid unit dosage form according to claim 18, characterized in that the median particle size of the crystals is in the range of 50 to 100 µm.
20. Crystals of a pharmaceutically acceptable salt of citalopram suitable for use in a solid unit dosage form according to claim 1, characterized in that said crystals have a median particle size of at least 40 µm.
21. Crystals according to claim 20, characterized in that the crystals are of citalopram hydrobromide or citalopram hydrochloride.
22. Crystals according to claim 21, characterized in that the crystals are of citalopram hydrobromide.
23. Crystals according to any one of claims 20 to 22, characterized in that the median particle size of the crystals is in the range of 40 to 200 µm.
24. Crystals according to claim 23, characterized in that the median particle size of the crystals is in the range of 45 to 150 µm.
25. Crystals according to claim 24, characterized in that the median particle size of the crystals is in the range of 50 to 100 µm.
26. Method for the manufacture of crystals of a pharmaceu-tically acceptable salt of citalopram that have a median particle size of at least 40 µm and are suitable for use in a solid unit dosage form according to claim 1, characterized in that a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system at a first temperature is first cooled down to a second temperature then seeded by addition of crystals of said citalopram salt followed by a holding time at said second temperature and a controlled cooling down to a third temperature whereupon said crystals are isolated by solid/liquid separation techniques.
27. The method according to claim 26, characterized in that the median particle size of the crystals is in the range of 40 to 200 µm.
28. The method according to claim 27, characterized in that the median particle size of the crystals is in the range of 45 to 150 µm.
29. The method according to claim 28, characterized in that the median particle size of the crystals is in the range of 50 to 100 µm.
30. The method according to any one of claims 26 to 29, characterized in that the dissolved substance is citalopram hydrobromide or citalopram hydrochloride.
31. The method according to claim 30, characterized in that the dissolved substance is citalopram hydrobromide.
32. The method according to any one of claims 26 to 31, characterized in that the solvent system comprises one or more alcohols.
33. The method according to claim 32, characterized in that the solvent system also comprises water.
34. The method according to claim 33, characterized in that the solvent system is a mixture of methanol and water.
35. The method according to claim 34, characterized in that the methanol water weight ratio is in the range of 5:1 to 50:1.
36. The method according to claim 35, characterized in that the methanol water weight ratio is in the range of 10:1 to 30:1.
37. The method according to claim 36, characterized in that the methanol water weight ratio is in the range of 15:1 to 25:1.
38. The method according to any one of claims 26 to 37, characterized in that the sovent:solute weight ratio is in the range of 0.5:1 to 5:1.
39. The method according to claim 38, characterized in that the sovent:solute weight ratio is in the range of 0.7:1 to 2:1.
40. The method according to claim 39, characterized in that the sovent:solute weight ratio is in the range of 0.9:1 to 1.5:1.
41. The method according to any one of claims 26 to 40, characterized in that said first temperature is in the range between 50°C and the refluxing temperature of the solvent system.
42. The method according to claim 41, characterized in that said first temperature is in the range between 60°C
and the refluxing temperature of the solvent system.
43. The method according to claim 42, characterized in that said first temperature is in the range between 64°C
and the refluxing temperature of the solvent system.
44. The method according to any one of claims 26 to 43, characterized in that. said second temperature is in the range of 20 to 40°C.
45. The method of claim 44, characterized in that said second temperature is in the range of 25 to 35°C.
46. The method according to any one of claims 26 to 45, characterized in that said holding time is in the range of 30 minutes to 7 days.
47. The method according to claim 46, characterized in that said holding time is in the range of 1 hour and 4 days.
48. The method according to claim 47, characterized in that said holding time is in the range of 12 to 36 hours.
49. The method according to any one of claims 26 to 48, characterized in that said third temperature is in the range of 0 to 20°C.
50. The method according to claim 49, characterized in that said third temperature is in the range of 5 to 15°C.
51. The method according to any one of claims 26 to 50, characterized in that said controlled cooling down is a gradual cooling down over a time span in the range of 5 minutes to 6 hours.
52. The method according to claim 51, characterized in that said controlled cooling down is a gradual cooling down over a time span in the range of 15 minutes to 4 hours.
53. The method according to claim 52, characterized in that said controlled cooling down is a gradual cooling down over a time span in the range of 30 minutes to 2 hours.
54. The method according to any one of claims 26 to 53, characterized in that said isolation of the crystals of a pharmaceutically acceptable salt of citalopram from the mother liquor is performed by filtration.
CA002353693A 2000-08-10 2001-07-24 Pharmaceutical composition containing citalopram Expired - Lifetime CA2353693C (en)

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