Classifications

• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants

Definitions

• the present invention relates to crystalline preparations of the oxalate salt of the compound escitalopram (LNN-name), which is the S-enantiomer of the well-known antidepressant drug citalopram, i.e. (S)-l-[3-(dimethylamino)propyl]- 1 -(4-fluorophenyl)- 1 ,3-dihydro-5-isobenzofurancarbonitrile oxalate.
• escitalopram LNN-name
• 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.
• Escitalopram the pharmaceutical activity thereof and crystalline escitalopram oxalate are disclosed in US Patent No 4,943,590. Methods for preparation of pharmaceutical preparations of escitalopram are outlined.
• Citalopram is marketed in a number of countries as a tablet prepared by compression of granulated citalopram hydrobromide, lactose and other excipients. It is well recognised that preparation of tablets with a reproducible composition 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 cases the particle size of the active substance is small, the active substance is cohesive or has poor flow properties.
• 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.
• melt granulation as well as melt granulation are energy intensive unit operations requiring complicated and expensive equipment as well as technical skill.
• the granulation step can be avoided and tablets may be prepared by direct compression, which is a cheaper production method.
• the process used for the preparation of citalopram hydrobromide results in a product with a very small particle size around 2-20 ⁇ m that, as many other particulate products with a small particle size, has very poor flow properties.
• the citalopram tablet that is marketed is a tablet made from granulated citalopram hydrobromide with various excipients.
• escitalopram has significantly different solubility and salt formation properties from the citalopram racemate.
• the only pharmaceutically crystalline salt known so far is the oxalate, whereas the citalopram racemate forms crystalline hydrobromide and hydrochloride salts as well.
• Crystalline escitalopram hydrobromide has now been disclosed in WO2004/056791 Al .
• the escitalopram oxalate product prepared by crystallisation from acetone as outlined in US Patent No 4,943,590 has, as the citalopram hydrobromide product described above, a very small particle size around 2-20 ⁇ m resulting in similarly poor flow properties.
• WO03/000672 discloses a process for the preparation of racemic as well as enantiomerically pure citalopram from the compound R-4-[4-(dimethylamino)- 1 -(4 '-fluorophenyl)- 1 -hydroxybutyl] -3 -(hydroxymethyl)-benzonitrile by ring-closure under acidic conditions.
• WO03/011278 discloses crystalline particles of escitalopram oxalate with a particle size of at least 40 ⁇ m. Method for the manufacture of said crystalline particles and pharmaceutical compositions comprising said crystalline particles are also disclosed.
• the inventors of the present invention have now surprisingly realised that the particle sizes obtained if escitalopram prepared according to the process disclosed in WO03/000672 is precipitated as the oxalate salt according to the method disclosed in WO03/011278, are significantly smaller than those obtained from escitalopram prepared by ring-closure of S-4-[4-(dimethylamino)-l-(4'-fluorophenyl)- l-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile via a labile ester under alkaline conditions and precipitated under otherwise identical precipitation conditions.
• the reduction in particle size of the escitalopram oxalate crystals is related to the presence of a specific impurity, Z-4-(4-dimethyl- amino-l-(4-fluorophenyl)-but-l-enyl)-3-hydroxymethyl-benzonitrile.
• This impurity is unique for the acidic ring-closure process as compared to the ring-closure via a labile ester under alkaline conditions.
• One aspect of the present invention is to provide crystalline particles of escitalopram oxalate with a broad particle size distribution, said particles being suitable for use in direct compression.
• a second aspect of the invention is to provide large crystalline particles of escitalopram oxalate comprising at least 0.01 % (w/w) of Z-4-(4-dimethylamino- l-(4-fluorophenyl)-but-l-enyl)-3-hydroxymethyl-benzonitrile, said particles being suitable for use in direct compression.
• a third aspect of the invention is to provide a novel pharmaceutical unit dosage form containing crystalline particles of escitalopram oxalate, wherein said particles have a broad particle size distribution and said unit dosage form may be a tablet, which preferably may be prepared by direct compression, or a capsule.
• a fourth aspect of the invention is to provide a method for manufacture of large crystalline particles of escitalopram oxalate with a broad particle size distribution.
• a fifth aspect of the invention is to provide a method for manufacture of large crystalline particles of escitalopram oxalate comprising reduction of the amount of hydroxyl containing impurities in a solution of escitalopram and crystallising the resulting escitalopram as the oxalate salt.
• a sixth aspect of the invention is to provide a method for reduction of the amount of hydroxyl containing impurities in a solution of citalopram or escitalopram.
• the invention then, inter alia, comprises the following alone or in combination:
• Crystalline particles of escitalopram oxalate having a ratio between the median particle size and the particle size at the 95% quantile that is less than 0.42, preferably less than 0.40. Such particles are suitable for use in a solid unit dosage form.
• Crystalline particles of escitalopram oxalate having a median particle size of at least 20 ⁇ m and a content of E- or Z-4-(4-dimethylamino-l-(4-fluorophenyl)-but-l-enyl)- 3-hydroxymethyl-benzonitrile of at least 0.01% (w/w), preferably the median particle size of the crystals is at least 40 ⁇ m and more preferred in the range of 50-200 ⁇ m. Such particles are suitable for use in a solid unit dosage form.
• Crystalline particles of escitalopram oxalate having a median particle size of at least 20 ⁇ m and being crystallised from a solution wherein the content of E- or Z-4-(4-dimethylamino- 1 -(4-fluorophenyl)-but- 1 -enyl)-3 -hydroxymethyl-benzonitrile prior to the crystallisation is at least 0.01% (w/w) relative to escitalopram, preferably the median particle size of the crystals is at least 40 ⁇ m and more preferred in the range of 50-200 ⁇ m. Such particles are suitable for use in a solid unit dosage form.
• a solid unit dosage form comprising crystalline particles of escitalopram oxalate wherein said crystalline particles of escitalopram oxalate are according to the invention as described above.
• a solid unit dosage form comprising crystalline particles of escitalopram oxalate manufactured from crystalline particles of escitalopram oxalate according to the invention as described above.
• a method for manufacture of crystalline particles of escitalopram oxalate which crystalline particles of escitalopram oxalate are as described above and said method comprises the steps of: a) Treating a solution comprising escitalopram together with one or more hydroxyl containing impurities with a hydroxyl group scavenger, b) separating the escitalopram from the products resulting from reaction of said hydroxyl containing impurities with said hydroxyl group scavenger, c) optionally transferring the escitalopram into its oxalate salt if the escitalopram is not already in the form of its oxalate salt, d) optionally transferring the escitalopram to a solvent system suitable for the crystallisation process if the escitalopram is not already in such a solvent system, and e) gradual cooling of the solution of escitalopram oxalate in said suitable solvent system from a first temperature to
• a method for manufacture of crystalline particles of escitalopram oxalate which crystalline particles of escitalopram oxalate are as described above and said method comprises gradual cooling of a solution of escitalopram oxalate in a suitable solvent system from a first temperature to a second temperature while maintaining a controlled cooling profile and seeding said solution of escitalopram oxalate by addition of crystals of escitalopram oxalate during said cooling followed by a holding time at said second temperature wherein said solution of escitalopram comprises at least 1 ppm, particularly at least 10 ppm, and more particularly at least 0.01 % by weight of E- or Z-4-(4-dimethylamino-l-(4-fluorophenyl)-but-l-enyl)-3-hydroxy- methyl-benzonitrile relative to the total weight of the crystallisation batch.
• a method for reducing the amount of hydroxyl containing impurities in citalopram or escitalopram comprising the steps of: a) Treating a solution comprising citalopram or escitalopram together with one or more such impurities with a hydroxyl group scavenger and b) separating said citalopram or escitalopram from the products resulting from reaction of said hydroxyl containing impurities with said hydroxyl group scavenger.
• the direct compression of escitalopram, a filler and other pharmaceutically acceptable excipients into tablets has the great advantage, that the granulation and a drying step are avoided. Further, as the granulation step is avoided, it is no longer necessary to add a binding agent.
• escitalopram oxalate means any addition salt consisting of escitalopram, oxalic acid and optionally water.
• examples of such salts are the hydrogen oxalate salt of escitalopram, i.e. the salt consisting of one molecule of escitalopram per molecule of oxalic acid, as well as the oxalate salt of escitalopram, i.e. the salt consisting of two molecules of escitalopram per molecule of oxalic acid.
• crystalline particles means any combination of single crystals, aggregates and agglomerates.
• 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 cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction at 1 bar dispersive pressure in a Sympatec Helos equipment.
• Median particle size “MPS” and “X50” refer, correspondingly, each to the median or 50% quantile of said particle size distribution.
• XI 0 and “X95” refer, correspondingly, to the 10% respectively the 95% quantile.
• X10/X50” and “X50/X95” refer to the ratio between X10 and X50 respectively X50 and X95.
• Particle size distributions may be unimodal, i.e. the density volume size distribution contains only one peak, bimodal, i.e. the density volume size distribution contains two peaks, or polymodal, i.e. the density volume size distribution contains more than two peaks.
• Particle size distributions may be bimodal or multimodal inter alia if the crystalline particles is a mixture of single crystals and aggregates or agglomerates.
• refluxing temperature means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
• cooling profile means the temperature of the crystallisation batch as a function of time.
• cooling rate means the decrease in temperature per time unit.
• hydroxyl group scavenger means a molecule or reactant, which is able to react with a hydroxyl group and transform it into another substituent.
• the hydroxyl group scavenger is preferably selected such that the substituent, which the hydroxyl group is transformed into, facilitates separation of the transformed molecule or impurity from the escitalopram or citalopram.
• the hydroxyl group scavenger is preferably selected among those reacting fast with hydroxyl groups under mild conditions without affecting citalopram or escitalopram.
• hydroxyl group scavengers are cyclic anhydrides, POCl 3 , PC1 5 , POBr 3 , PBr 5 , POI 3 , PI S , BC1 3 , BBr 3 and BI 3 , which all will introduce an acidic group into the impurity molecule whereupon it may be separated from citalopram and/or escitalopram by extraction into an alkaline aqueous solution from an organic solvent.
• the crystalline particles of escitalopram oxalate have a median particle size of at least 20 ⁇ m, in particular of at least 40 ⁇ m, and preferably in the range of 50 - 200 ⁇ m.
• the particle size distribution of the crystalline particles of escitalopram oxalate is bimodal or polymodal and the peak at the lowest particle size is located at a particle size of at least 20 ⁇ m, in particular of at least 40 ⁇ m, and preferably in the range of 50 - 200 ⁇ m.
• the escitalopram oxalate crystals comprise at least 0.01% (w/w) relative to escitalopram of E- or Z-4-(4-dimethylamino-l-(4-fluorophenyl)-but- l-enyl)-3-hydroxymethyl-benzonitrile.
• the amount of E- or Z-4-(4-dimethylamino- 1 -(4-fluorophenyl)-but- 1 -enyl)-3 -hydroxymethyl-benzonitrile in the crystals is in the range of 0.01 to 0.3%), more particularly 0.02 to 0.2%, and most particularly 0.03 to 0.1%.
• the hydroxyl containing impurity is Z-4-(4-dimethylamino-l-(4-fluorophenyl)-but-l-enyl)-3-hydroxymethyl-benzonitrile.
• the hydroxyl containing impurity is E-4-(4-dimethylamino-l-(4-fluorophenyl)-but-l-enyl)-3-hydroxymethyl-benzonitrile.
• Flow, segregation and demixing properties and, hence, the suitability of the escitalopram oxalate crystals for direct compression depends, besides the median particle size, on the particle side distribution. It may for certain purposes such as wet granulation be advantageously to have a broad particle size distribution. Small particles may dissolve during wet granulation and then solidify between the larger crystals upon drying and hence impart strength to the granulate. Further, in certain tabletting processes such as dry granulation (compaction) it may be desirable to have a broader particle size distribution so as to increase the packing efficiency of the particles, and thus the inherent binding capability.
• Another aspect of the invention is to provide a method for reduction of the amount of hydroxyl containing impurities in citalopram, escitalopram or a non-racemic mixture of R- and S-citalopram.
• Citalopram, escitalopram or a non-racemic mixture of R- and S-citalopram containing a hydroxyl group containing impurity such as E- or Z-4-(4-dimethylamino- 1 -(4-fluorophenyl)-but- 1 -enyl)-3 -hydroxymethyl-benzonitrile is dissolved in a suitable solvent such as dry toluene.
• a hydroxyl group scavenger such as a cyclic anhydride e.g.
• succinic anhydride in amount sufficient to scavenge the hydroxyl group containing impurity is added to the solution and the mixture is stirred at a suitable temperature, e.g. 45 °C, for a suitable period, e.g. 120 minutes.
• the impurity is then separated from the citalopram, escitalopram or non-racemic mixture of R- and S-citalopram in a suitable way.
• a suitable temperature e.g. 45 °C
• a suitable period e.g. 120 minutes.
• the impurity is then separated from the citalopram, escitalopram or non-racemic mixture of R- and S-citalopram in a suitable way.
• the impurity is transformed into an acidic compound, e.g. by reaction with a cyclic anhydride, preferably a cyclic C .
• the separation may be done by partitioning between the organic solvent and an aqueous phase, in particular by partitioning between the organic solvent and an alkaline aqueous phase.
• the phases are separated and the organic phase is washed with water.
• the organic phase is evaporated to yield the citalopram, escitalopram or non-racemic mixture of R- and S-citalopram.
• the invention provides a method for reduction of the amount of hydroxyl containing impurities in citalopram.
• the invention provides a method for reduction of the amount of hydroxyl containing impurities in escitalopram. In yet another equally particular embodiment the invention provides a method for reduction of the amount of hydroxyl containing impurities in a non-racemic mixture of R- and S-citalopram.
• crystalline particles of escitalopram oxalate as described above and suitable for use in a solid unit dosage form are crystallised from a solution of escitalopram oxalate in a suitable solvent system.
• Such crystalline particles may wter alia have a ratio between the median particle size and the particle size at the 95%) quantile that is less than 0.42, preferably less than 0.40; and/or have a median particle size of at least 20 ⁇ m, preferably at least 20 ⁇ m and more preferred in the range of 50 - 200 ⁇ m.
• such crystalline particles have a median particle size of at least 20 ⁇ m and a content of E- or Z-4-(4-dimethylamino- l-(4-fluorophenyl)-but-l-enyl)-3-hydroxymethyl-benzonitrile of at least 0.01% (w/w)
• Said solvent system may comprise one or more alcohols and optionally water, preferably the solvent system is ethanol.
• Escitalopram oxalate 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 70 °C and the refluxing temperature, suitably the escitalopram oxalate is dissolved at the refluxing temperature.
• the amounts of pharmaceutically acceptable salt of escitalopram and solvent used are preferably corresponding to a solute: solvent weight ratio in the range of 0.05:1 to 0.6:1, more preferred 0.1:1 to 0.5:1 and most preferred 0.2:1 to 0.4:1.
• the solution of escitalopram oxalate is gradually cooled down to the temperature, at which the crystals will be isolated from the mother liquor, in the range of 0-20 °C, preferably 0-15 °C, and more preferred 7-15 °C maintaining a controlled cooling profile so that the cooling rate in an initial cooling period does not exceed 0.6 °C/min, and preferably the cooling rate is kept within the range of 0.2 - 0.4 °C/min, and said initial cooling period extends until the temperature of the crystallisation batch is below 60 °C, preferably below 50 °C and more preferred below 40 °C, suitably the cooling rate may be kept in this range for the entire cooling.
• the crystallisation batch is seeded by addition of crystals of escitalopram oxalate at least once during the cooling time in order to avoid excessive supersaturation with respect to escitalopram oxalate and resulting spontaneous crystallisation into small crystalline particles.
• the seeding is preferably repeated in order to ensure constant presence of crystalline escitalopram oxalate during the cooling; suitably the crystallisation batch is seeded semicontinuosly until crystallisation has started.
• the crystallisation batch is optionally kept at said second temperature for a holding time during which there may occur crystal growth. In a particular embodiment said holding time is at least 1 hour, preferably in the range of 4 to 24 hours and more preferred 6 to 12 hours.
• the crystalline particles of escitalopram oxalate are isolated from the mother liquor using conventional separation techniques, e.g. filtration.
• the solution from which the escitalopram oxalate is crystallised comprises at least 0.01 %> of E- or Z-4-(4-dimethylamino-l-(4-fluoro- phenyl)-but-l-enyl)-3-hydroxymethyl-benzonitrile.
• the amount of E- or Z-4-(4-dimethylamino-l-(4-fluorophenyl)-but-l-enyl)-3-hydroxy- methylbenzonitrile in the crystals is in the range of 0.01 to 0.5%, more particularly 0.01 to 0.3%), even more particularly 0.02 to 0.2%, and most particularly 0.03 to 0.1%.
• the hydroxyl containing impurity is Z-4-(4-dimethyl- amino-1 -(4-fluorophenyl)-but- 1 -enyl)-3-hydroxymethyl-benzonitrile.
• the hydroxyl containing impurity is E-4-(4-dimethylamino- 1 ⁇ (4-fluorophenyl)-but- 1 -enyl)-3 -hydroxymethyl-benzonitrile.
• the escitalopram which is to be crystallised as escitalopram oxalate, is in another particular embodiment the product of a method of manufacture comprising the method described above for reduction of the content hydroxyl group containing impurities by reaction with a hydroxyl group scavenger.
• the methods described above for reduction of the amount of hydroxyl group containing impurities and crystallisation may be combined with each other and/or with the process for the preparation of racemic citalopram and/or S- or R-citalopram by separation of a mixture of R- and S-citalopram with more than 50 % of one of the enantiomers into a fraction of racemic citalopram and/or a fraction of S-citalopram or R-citalopram containing low amounts of the other enantiomer as disclosed in WO03/000672 which is hereby included by reference.
• Such combinations include but are not limited to: hydroxyl scavenging followed by crystallisation of escitalopram oxalate; hydroxyl scavenging followed by separation of racemic citalopram and escitalopram followed by crystallisation of escitalopram oxalate; separation of racemic citalopram and escitalopram followed by hydroxyl scavenging followed by crystallisation of escitalopram oxalate; and separation of racemic citalopram and escitalopram followed by crystallisation of escitalopram oxalate.
• the escitalopram is manufactured by a process comprising ring-closure of R-4-[4-(dimethylamino)-l-(4'-fluorophenyl)-l-hydroxy- butyl]-3-(hydroxymethyl)-benzonitrile under acidic conditions as disclosed in WO03/000672 which is hereby included by reference.
• the present invention relates to a tablet prepared from a mixture of crystalline particles of escitalopram oxalate and pharmaceutically acceptable excipients wherein said crystalline particles of escitalopram oxalate are according to the invention as described above.
• Such tablets may be made by one of the following tabletting methods: Direct compression, dry granulation (compaction), wet granulation or melt granulation.
• the tablet is prepared by direct compression.
• the tablet is prepared by dry granulation (compaction).
• the tablet is prepared by wet granulation.
• the tablet is prepared by melt granulation.
• the tablet is coated.
• the present invention relates to a solid unit dosage form prepared by filling a mixture of crystalline particles of escitalopram oxalate and pharmaceutically acceptable excipients into a capsule wherein said crystalline particles of escitalopram oxalate are according to the invention as described above, preferably the capsule is a hard gelatine capsule.
• 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 1 -60% w/w active ingredient calculated as escitalopram base, particularly 4-40% w/w active ingredient calculated as escitalopram base, evenly particularly 1-30% w/w active ingredient calculated as escitalopram base, more particularly 4-20% w/w active ingredient calculated as escitalopram base and most particularly 6-10% w/w active ingredient calculated as escitalopram base.
• the solid unit dosage form of the invention contains 8% w/w active ingredient calculated as escitalopram base.
• 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 selected from the group comprising metallic stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica.
• the lubricant is one or more selected from the group comprising talc, magnesium stearate or calcium stearate.
• the lubricant is a combination of talc and magnesium stearate.
• the weight percent of magnesium stearate in the solid unit dosage form is preferably in the range of 0.4% to 2%, and more preferred in the range of 0.7% to 1.4%.
• the solid unit dosage form is substantially free of lactose.
• Disintegrants include sodium starch glycolate, croscarmellose, crospovidone, low substituted hydroxypropylcellulose, modified cornstarch, pregelatizined starch and natural starch.
• the disintegrant is crosscarmellose such Ac-Di-Sol manufactured by FMC.
• the solid, pharmaceutical unit dosage form of the invention may be coated.
• the coating is a film coating based on conventional coating mixtures such as Opadry OY-S-28849, white manufactured by Colorcon.
• 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 toluene phase is evaporated and the yield is 53,0 g (95%).
• the product contains 0,06% of Z-4-(4-dimethylamino- l-(4-fluorophenyl)-but-l-enyl)-3-hydroxymethyl-benzonitrile.
• a large number of batches of crude escitalopram oxalate have been recrystallised in production scale according to the procedure described below.
• the batches comprises: a) Escitalopram prepared by acidic ring-closure of the R-form of the diol precursor as described in WO03/000672 followed by scavenging of hydroxyl containing impurity by a production scale version of the process described in example 1 followed by separation of racemic citalopram and escitalopram as described in WO03/000672.
• These batches contain Z-4-(4-dimethylamino-l-(4-fluorophenyl)- but-l-enyl)-3-hydroxymethyl-benzonitrile, typically in the range of 0.05% (w/w) relative to escitalopram. These batches are referred to as R-diol batches.
• Escitalopram prepared by ring-closure of the S-form of the diol precursor via an activated ester under alkaline conditions as described in US Patent No. 4,943,590. These batches do not contain Z-4-(4-dimethylamino-l-(4-fluorophenyl)-but- l-enyl)-3-hydroxymethyl-benzonitrile. These batches are referred to as S-diol batches.
• the solution is seeded with 0.02 - 0.04 kg, escitalopram oxalate for every 3 °C the temperature is decreased until crystallization is noticed.
• the solution is automatically cooled until 15 °C.
• the suspension is pumped to a filter dryer, where it is washed and dried. If the suspension is not transferred immediately the temperature must be kept at 0 - 15 °C.
• the filter dryer is emptied and the escitalopram oxalate is sent to deagglomeration, for deagglomeration of agglomerates formed during drying of the crystals.
• the dried escitalopram oxalate is milled to separate the crystals from each other. During the milling the size and shape of the individual crystals is not changed.
• the resulting escitalopram oxalate batches had particle characteristics as shown in table 2.
• a wet filter cake obtained by precipitation of crude escitalopram oxalate by mixing of ethanolic solutions of escitalopram prepared by ring-closure via a labile ester under alkaline conditions and oxalic acid, respectively, and containing approximately 35 kg escitalopram oxalate was suspended in 322 L ethanol.
• the material was dissolved by heating to reflux, and 150 L ethanol was removed by distillation. Cooling was applied, and the mixture was cooled from reflux to 15 °C with a cooling rate between 0.2 and 0.5 °C/min in the temperature interval 80 to 40 °C.
• escitalopram oxalate During cooling, the mixture was seeded with escitalopram oxalate at 75, 65 and 60 °C (10 g each time). The crystallisation mixture was kept at 15 °C for 10 hours before the crystalline escitalopram oxalate was isolated. Purified escitalopram oxalate (27.7 kg, 79%) was obtained by filtration of the crystallisation mixture, washing with ethanol and drying of the filter cake. Particle size distribution for the resulting escitalopram oxalate is listed in table 3.
• Tablet prepared by direct compression of large crystalline particles of escitalopram oxalate Tablet prepared by direct compression of large crystalline particles of escitalopram oxalate.
• Crystalline particles of escitalopram oxalate from example 1 and talc were sieved through 710 ⁇ m screen and blended at 6 rpm for 15 min in a 100 litre Bohle PTM 200 mixer. ProSolv SMCC90 and Ac-Di-Sol were added and blending continued for 15 min. Magnesium stearate was sieved through 710 ⁇ m screen and added and blending continued for 3 min.
• 25 kg of the resulting mixture was tabletted (125.000 tablets/hour) on a Korsch PH 230 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. The tablets produced had satisfactory technical properties.

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• 2005
  • 2005-02-21 WO PCT/DK2005/000115 patent/WO2005084643A1/en active Application Filing
  • 2005-02-21 EA EA200601641A patent/EA200601641A1/ru unknown
  • 2005-02-21 CA CA002558198A patent/CA2558198A1/en not_active Abandoned
  • 2005-02-21 NZ NZ549100A patent/NZ549100A/en not_active Application Discontinuation
  • 2005-02-21 BR BRPI0508266-8A patent/BRPI0508266A/pt not_active IP Right Cessation
  • 2005-02-21 AU AU2005218713A patent/AU2005218713B2/en not_active Withdrawn - After Issue
  • 2005-02-21 JP JP2007501117A patent/JP2007526262A/ja active Pending
  • 2005-02-21 EP EP05706777A patent/EP1732514A1/en not_active Withdrawn
• 2006
  • 2006-10-04 NO NO20064499A patent/NO20064499L/no not_active Application Discontinuation

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