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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • 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
  • A61P25/24—Antidepressants

Definitions

• the invention relates to tablets containing as active ingredient citalopram hydrobromide and a process for the preparation thereof.
• 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 ⁇ m .
• citalopram hydrobromide When citalopram hydrobromide is used as a pharmaceutical, it is formulated into coated tablets, that is film-coated tablets.
• 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.
• the preparatory operations can be based on the following three principles : •powder blending technique •dry granulation technique •wet 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.
• 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.
• 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 ⁇ m measured by laser granulometry .
• 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.
• 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 ⁇ m, preferably in the range of 40-200 ⁇ m, even more preferred 45-150 ⁇ m and the most preferred 50-100 ⁇ m .
• 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 ⁇ m, preferably in the range of 4-0-250 ⁇ m, more preferred 45-200 ⁇ m and the most preferred 50-180 ⁇ m .
• citalopram hydrobromide having a;, median article .
• citalopram hydrobromide granulate is then homogenized with further excipients and compressed to tablets.
• citalopram hydrobromide having a median particle size of less -than 40 ⁇ m 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 ⁇ m, wherein the tablets meet the requirements raised by the pharmacopoeias.
• 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 ⁇ m or even less than 20 ⁇ m . 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.
• 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 ⁇ m in admixture with micro- crystalline cellulose having a median particle size in the range of 90-250 ⁇ m and other excipients conventionally applied for the preparation of tablets.
• citalopram hydrobromide namely 1- [3- (dimethylamino) - propyl ] -1 - (4 -fluorophenyl ) - 1 , 3 -dihydro -5 - isobenzofurancarboni trile hydrobromide
• citalopram hydrobromide having a median particle size in the range of 5-40
• 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 ⁇ m, optionally in the range of 5-20 ⁇ m, 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 ⁇ m, preferably 150-250 ⁇ m, 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
• 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 ⁇ i ' v optionally- 5-20 ⁇ m ' , 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 ⁇ m, preferably 150-250 ⁇ m , 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
• 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 ⁇ m, microcrystalline cellulose .having a median parrti-'cle size, in- the .range of .90-' 250 ⁇ m 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.
• 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 ⁇ m, optionally 5-20 ⁇ m, 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 ⁇ m, 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
• the term faceddirect 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 .
• 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 ⁇ m 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.
• 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 ⁇ m, that of the microcrystalline cellulose designated with 12 is in the range between 140-180 ⁇ m, while that of the micro- crystalline celluloses designated with 200 is about 180 ⁇ m .
• microcrystalline cellulose so-called silicified micro- crystalline celluloses having a median particle size of more than 90 ⁇ m 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 ) .
• 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 ⁇ m and 200 ⁇ m. . -- -'
• 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 ⁇ m .
• 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 ⁇ m .
• 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 ⁇ to ⁇ 12.495-.
• 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.
• 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 .
• 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.
• 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) .
• composition and process according to the invention is illustrated by the following Example without limiting the scope of protection to said Examples .
• fillers The following substances. suitable for direct compression are used as fillers:
• microcrystalline cellulose Emcocel 90 M, Avicel 102, Vivapur 200
• - silicified microcrystalline cellulose Prosolv SMC 90, Prosolv HD 90
• lubricant magnesium stearate 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, France.
• composition of the ci talopram homogenizates and the flowability of tlSe homogenizates are shown in the following Table :
• 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
• 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 .
• Breaking 83 73 67 strength (N) (77-90) (68-75) ; (53-80)
• the mass uniformity of the tablets meets the pharmacopoeial requirements (+/- 7,5% in case of an average mass of 180 mg) .
• 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.
• 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.
• Perlitol SD 200 mannitol
• microcrystalline cellulose Emcocel 90 M the amount of microcrystalline cellulose
• 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.
• compositions containing only micro- crystalline cellulose Vivapur 200
• lubri- • cation problems- canno-t ⁇ be experienced, but the structure " of ' - the- tablet is laminated.
• Emcocel 90 M (mg) 132.55 7.5 —
• Aerosil 200 (mg) 0.625 0.625 1.26 '
• 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 ' mass uniformity data are calculated on the basis of the individual masses of 20 tablets per lot.
• the data relating to the uniformity of content are calculated on the basis of the individual masses of 10 tablets per lot
• a coating suspension for 50,000 pieces of tablets containing 40 mg of active ingredient produced according to Example 4 are prepared as follows:
• the coating suspension 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.. - ' . " . -
• 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.
• Mass uniformity is calculated by measuring the individual masses of 20 tablets per lot for each sample.
• Uniformity of content is calculated by measuring the individual masses of 10 tablets per lot for each sample.
• 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 :
• 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) .
• 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.

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