Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic 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
  • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic 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
  • A61K31/343—Heterocyclic 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds

Definitions

• the present invention relates to a novel pharmaceutical composition containing citalopram, 1 -[3-(dimethylamino)propyl]- 1 -(4-fluorophenyl)-l ,3-dihydro-5-isobenzo- furancarbonitrile.
• Citalopram is a well-known antidepressant drug that has the following structure:
• 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 used for preparing citalopram.
• the citalopram prepared was isolated in crystalline form as the oxalate, the hydrobromide and the hydrochloride salt, respectively.
• the citalopram base was obtained as an oil (B.P. 175 C/0.03 mmHg).
• the publication also outlines the manufacture of tablets containing salts of citalopram.
• Citalopram is marketed as the hydrobromide and the hydrochloride, respectively.
• crystalline citalopram base Manufacture of crystalline citalopram 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 citalopram hydrobromide.
• the publication also outlines the manufacture of tablets containing citalopram base.
• Citalopram is marketed in a number of countries as a tablet prepared by compression of granulated citalopram hydrobromide, lactose and other excipients.
• 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 ingredient either alone or in combination with a filler and/or other conventional tablet ingredients.
• One such granulation method is the "wet" granulation process.
• the dry solids active ingredients, filler, binder etc.
• water or another wetting agent e.g. an alcohol
• 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.
• melt granulation which is also known as the "thermal plastic” granulation process, where a low melting solid is used as the granulation agent. Initially, 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 forming a dry granular product.
• the citalopram tablet that is marketed, is a tablet made from granulated citalopram hydrobromide with various excipients.
• larger particles i.e. particles of a size comparable to the size of the filler, may be prepared by a new and inventive crystallisation process and that these particles are useful for the manufacture of directly compressed tablets. Accurate dosing in capsules may also be with such large particles.
• tablets with surprisingly small variation in the content of citalopram may be prepared by direct compression of citalopram hydrobromide having a significantly smaller particle size than the filler. Accurate dosing in capsules may also be achieved despite the small particle size of citalopram.
• a second object of the invention is to provide a capsule containing citalopram.
• a third object of the invention is to provide large crystals of a pharmaceutically acceptable salt of citalopram suitable for use in direct compression.
• a fourth object of the invention is to provide a method for manufacture of large crystals of a pharmaceutically acceptable salt of citalopram.
• the invention then, inter alia, comprises the following alone or in combination:
• a solid unit dosage form comprising citalopram 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.
• a method for the manufacture of crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 ⁇ m and suitable for use in a solid unit dosage form wherein 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 conventional solid/liquid separation techniques.
• 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.
• binder means an agent which is used in wet or melt granulation processes and acts as a binder in the granulated product.
• particle size distribution means the distribution of equivalent spherical diameters as determined by laser diffraction at 1 bar dispersive pressure in a Sympatec Helos equipment.
• Median particle size correspondingly, means the median of said particle size distribution.
• refluxing temperature means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
• the present invention relates to a tablet prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.
• 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.
• the present invention relates to a solid unit dosage form comprising citalopram in crystals with a median particle size below 20 ⁇ m.
• 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 ⁇ m, even more preferred 45 - 150 ⁇ m and most preferred 50 - 100 ⁇ m.
• a median particle size of at least 40 ⁇ m, preferably in the range of 40 - 200 ⁇ m, even more preferred 45 - 150 ⁇ m and most preferred 50 - 100 ⁇ m.
• 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.
• the solid unit dosage form of the invention contains 20 % w/w active ingredient calculated as citalopram base.
• the present invention relates to a solid unit dosage form wherein the active ingredient is citalopram hydrobromide or citalopram hydrochloride.
• 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 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.
• a filler selected 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.
• the solid unit dosage form of the invention does not contain lactose.
• the filler is a microcrystalline cellulose such as ProSolv SMCC90 manufactured by Penwest Pharmaceuticals or Avicel PH 200 manufactured by FMC Corporation.
• the solid pharmaceutical unit dosage forms may include various other conventional excipients such as disintegrants and optionally minor amounts of lubricants, colorants and sweeteners.
• Lubricants used according to the invention may suitably be one or more of the following metallic stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica.
• the lubricant is magnesium stearate or calcium stearate
• Disintegrants include sodium starch glycolate, croscarmellose, crospovidone, low substituted hydroxypropylcellulose, modified cornstarch, pregelatizined starch and natural starch.
• the solid, pharmaceutical unit dosage form of the invention may be prepared by conventional methods using a tablet press with forced feed capability.
• the filled, hard gelatine capsule of the invention may be prepared by conventional methods using a capsule filler suitable for powder filling.
• the crystals of a pharmaceutically acceptable salt of citalopram have a median particle size in the range of 40 - 200 ⁇ m, preferably 45 - 150 ⁇ m and even more preferred 50 - 120 ⁇ m.
• the crystals are of citalopram hydrobromide or citalopram hydrochloride, preferably citalopram hydrobromide.
• crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 ⁇ m 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 weight ratio preferably is in the range of 5 : 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 citalopram is preferably dissolved in the solvent system at a temperature in the range between 50 °C and the refluxing temperature of the solvent system, preferably between 60 °C and the refluxing temperature and more preferred between 64 °C and the refluxing temperature.
• the amounts of pharmaceutically acceptable salt of citalopram and solvent used are preferably corresponding to a solvent:solute weight ratio in the range of 0.5:1 to 5:1, more preferred 0.7:1 to 2:1 and 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 citalopram crystals and kept at said seeding temperature for a holding time for crystal growth in the range of 30 minutes to 7 days, preferably 1 hour to 4 days and more preferred 12 to 36 hours.
• the 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 15 minutes to 4 hours and more preferred 30 minutes to 2 hours.
• the 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 in one embodiment of the invention may be produced according to methods described in US 4,136,193.
• crystals of citalopram base used in one embodiment of the invention may be produced according to methods described in NL patent No. 1016435.
• Example 1 In the following, the invention is illustrated by way of examples. However, the examples are merely intended to illustrate the invention and should not be construed as limiting. Example 1
• 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 10 °C within 1 hour. The crystals are isolated by filtration, washed with cold methanol and dried. The particle size distribution for the resulting crystals is listed in table 1.
• Citalopram 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 resulting crystals is listed in table 1.
• Citalopram hydrobromide (200 kg) is dissolved in a mixture of methanol (170 L) and acetone (680 L) at 56 °C. The solution is cooled down to 15 °C, seeded with citalopram hydrobromide crystals (50 g), hexane (1600 L) is gradually added within 60 minutes, whereupon the suspension is left standing with moderate stirring and cooling for 8 hours. The crystals are isolated by filtration, washed first with a cold (10 °C) mixture of acetone (50 L) and hexane then with cold (10 °C) hexane (220 L) and dried. The particle size distribution for the resulting crystals is listed in table 1.
• 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 x 100 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 filtered off and dried at ambient temperature over night in vacuo.
• Table 1 Particle size distribution (Sympatec Helos) for citalopram hydrobromide crystals and ProSolv SCMC90
• 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 possible segregation tendencies in the last quantities of mixture.
• 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.
• the variability in tablet strength is surprisingly low in view of the small particle size of citalopram hydrobromide as compared to the inert filler.
• Tablet prepared by direct compression of large citalopram hydrobromide crystals Tablet prepared by direct compression of large citalopram hydrobromide crystals.
• Magnesium stearate (0.5 % w/w)
• Citalopram hydrobromide crystals from example 2 and ProSolv SMCC90 were blended. Magnesium stearate was added and blending continued.
• Tablet prepared by direct compression of citalopram crystals Tablet prepared by direct compression of citalopram crystals.
• Citalopram base (16 % w/w)
• Magnesium stearate (0.7 % w/w)
• 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 shape Film coating, special doomed
• the tablets produced had satisfactory technical properties.

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• 2001
  • 2001-07-24 IE IE20010693A patent/IES20010693A2/en not_active IP Right Cessation
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