MXPA06009976A - Crystalline composition containing escitalopram oxalate - Google Patents

Abstract

The present invention discloses crystalline particles of escitalopram oxalate which either have a broad particle size distribution or comprise at least 0.01%(w/w) of Z-4-(4- dimethylamino-1 -(4-fluorophenyl)-but -1-enyl)-3 -hydroxymethyl -benzonitrile, said particles being suitable for use in direct compression. Furthermore, the invention discloses a novel pharmaceutical unit dosage form containing such crystalline particles of escitalopram oxalate as well as methods for manufacture of such crystalline particles of escitalopram oxalate. Finally, the invention provides a method for reduction of the amount of hydroxyl containing impurities in a solution of citalopram or escitalopram.

Description

CRYSTALLINE COMPOSITION CONTAINING ESCITALOPRAM OXALATE The present invention relates to crystalline preparations of the oxalate salt of the compound escitalopram (name INN), which is the S-enantiomer of the well-known antidepressant drug citalopram, ie, (S) -1- [3- (dimethylamino) oxalate propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitr BACKGROUND OF THE INVENTION Citalopram is a well-known antidepressant drug that has the following structure: It is a selective reabsorption inhibitor, centrally active serotonin (5-hydroxytryptamine, 5-HT), and therefore has antidepressant activities. Citalopram was previously described in DE 2,657,013, which corresponds to US Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by a method, and indicates an additional method, which can be used to prepare citalopram. The prepared citalopram was isolated in crystalline form in the form of the oxalate salt, hydrobromide and hydrochloride, respectively. In addition, the citalopram base was obtained in the form of an oil (boiling point 175 ° C / 0.03 mm Hg). The publication also points out the manufacture of tablets containing citalopram salts. Citalopram is marketed as the hydrobromide and the hydrochloride, respectively. Escitalopram, the pharmaceutical activity thereof and crystalline escitalopram oxalate have been described in US Pat. No. 4,943,590. Methods for the pharmaceutical preparations of escitalopram have been described. Citalopram is marketed in several countries in the form of a tablet prepared by compression of granulated citalopram hydrobromide, lactose and other excipients. It is well recognized that the preparation of tablets with a reproducible composition requires that all dry ingredients have good flow properties.

In cases in which 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. In addition, active substances with small particle size, mixed with excipients having a larger particle size, are typically segregated or demixed during the tabletting process. The problem that arises with small particle size and low fluidity is conventionally solved by enlarging the particle size of the active substance, usually by granulation of the active ingredient, alone or in combination with a filler and / or other conventional ingredients for tablets. . One such granulation method is the "wet" granulation process. Using this method, the dry solids (active ingredients, filler, binder, etc.), are mixed and moistened with water or with another wetting agent (for example, an alcohol), and accumulate in agglomerates or in wet solid granules. The wetting of the mass is continued until a homogeneous particle size is achieved, after which the granulated product is dried.

An alternative for the "wet" granulation method is the "melt" granulation, which is also known as the "thermal plastic" granulation process, where a low melting point solid is used as the granulating agent. Initially, the solids are mixed and heated until the binder is melted. As the binder liquefies and spreads on the surface of the particles, the particles adhere to one another and form granules. The binder is solidified by cooling to form a dry granulated product. Wet granulation, as well as melt granulation, are energy intensive unit operations, which require complicated and expensive equipment, as well as technical experience. If the active ingredient has, however, proper flow properties, the granulation step can be avoided, and tablets can be prepared by direct compression, which is a more economical production method. The process used for the preparation of citalopram hydrobromide results in a product with a very small particle size of around 2-20 μm, which, as with many other particulate products, with a small particle size, It has poor flow properties. Therefore, in order to achieve an appropriate dosage of citalopram hydrobromide during the tablet formation, it was considered necessary to prepare a granulation of citalopram hydrobromide with a larger particle size and with better flow properties. The citalopram tablets that are marketed are tablets constituted by granulated citalopram hydrobromide with various excipients. We have discovered that escitalopram has salt formation and solubility properties that are significantly different from those of the citalopram racemate. For example, the only pharmaceutically crystalline salt known to date is oxalate, while the citalopram racemate also forms crystalline hydrobromide and hydrochloride salts. Crystalline escitalopram hydrobromide has now been described in patent WO2004 / 056791 Al. The escitallopram oxalate product, prepared by crystallization from acetone as set forth in US Pat. No. 4,943,590, has, as the product of hydrobromide • of citalopram. described above, a very small particle size of 2-20 μm which results in similarly poor flow properties.

Patent WO03 / 000672 describes 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 μm. Also disclosed is a method for the manufacture of said crystalline particles and pharmaceutical compositions comprising said crystalline particles. The inventors of the present invention have now surprisingly realized that the particle size obtained, if the escitalopram prepared according to the process described in the patent O03 / 000672, is precipitated as an oxalate salt according to the method described in patent O03 / 011278, is significantly smaller than that obtained with escitalopram prepared by ring closure of S-4- [4- (dimethylamino) -1- (4 '-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile through a labile ester under alkaline conditions and precipitated under precipitation conditions which are otherwise identical.

In addition they have realized that the reduction of the particle size of the oxalate crystals of escitalopram is related to the presence of a specific impurity, Z-4- (4-dimethylamino-l- (4-fluorophenyl) -but-1-enyl -3-hydroxymethyl-benzonitrile. This impurity is unique to the process of ring closure acid compared to ring closure through a labile ester under alkaline conditions. In view of the fact that direct compression is much simpler and more economical than processes involving granulation, there is a constant objective of obtaining large crystals of escitalopram or pharmaceutically acceptable salts thereof by addition thereof. Large-scale laboratory investigations have now resulted in a novel and inventive process that produces large crystalline particles of escitalopram oxalate, ie particles of a size comparable to the size of the filler, by a novel and inventive method for reduction of the amount of Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile in escitalopram solution before the crystallization of the oxalate. Said particles are useful for the manufacture of directly compressed tablets. Appropriate dosage in capsules can also be achieved with such large particles.

OBJECTS OF THE INVENTION One aspect of the present invention is to provide crystalline particles of escitalopram oxalate with a broad particle size distribution, where said particles are suitable for use by 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-1- (4-fluorophenyl) -but-1 -enyl) -3-hydroxymethyl-benzonitrile, where said particles are suitable for use in direct compression. A third aspect of the invention is to provide a new pharmaceutical unit dosage form, which contains crystalline particles of escitalopram oxalate, wherein said particles have a broad particle size distribution, and wherein said unit dosage form can be a tablet, which preferably can be prepared by direct compression, or a capsule.

A fourth aspect of the invention is to provide a method for the manufacture of large particles - crystallites of escitalopram oxalate with a wide particle size distribution. A fifth aspect of the invention is to provide a method for the manufacture of large crystalline particles of escitalopram oxalate comprising reducing the amount of hydroxyl containing impurities in a solution of escitalopram and crystallizing the resulting escitalopram as the oxalate salt. A sixth aspect of the invention is to provide a method for reducing the amount of hydroxyl containing impurities in a solution of citalopram or escitalopram.

DETAILED DESCRIPTION OF THE INVENTION The invention then comprises, inter alia, what follows alone or in combination: crystalline particles of escitalopram oxalate having a ratio between the particle size of the median and the particle size of the 95% quantile is less than 0.42, preferably less than 0.40. Said particles are suitable for use in a solid unit dosage form.

The crystalline particles of escitalopram oxalate have a particle size of a mean of at least 20 μm and a content of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl ) -3-hydroxymethyl-benzonitrile of at least 0.01% (w / w), preferably the average particle size of the crystals is at least 40 μm, and more preferably it is in the range of 50-200 μm. Said particles are suitable for use in a solid unit dosage form. The crystalline particles of escitalopram oxalate which have a mean-particle size of and which crystallize from a solution in which the content of E- or Z-4- (4-dimethylamino-1- (4- fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile before crystallization is at least 0.01% (w / w) in relation to escitalopram, preferably the particle size of the average of the crystals is at least 40 μm and more preferably is in the range of 50-200 μm. Said particles are suitable for use in a solid unit dosage form. A solid unit dosage form comprises crystalline particles of escitalopram oxalate, wherein said crystalline particles of escitalopram oxalate are in accordance with the invention that has been previously described.

A solid unit dosage form comprising crystalline particles of escitalopram oxalate manufactured from crystalline particles of escitalopram oxalate according to the invention has been described above as described above. A method for the manufacture of crystalline particles of escitalopram oxalate wherein said 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 hydroxyls contain impurities with a scrubber of the hydroxyl group, b) separate the escitalopram from the products resulting from the reaction of said hydroxyl containing impurities with said scrubber of the hydroxyl group, c) optionally transfer escitalopram to its oxalate salt if the escitalopram is not already in the form of its oxalate salt, d) optionally transfer the escitalopram to a suitable solvent system for the crystallization process that the escitalopram is no longer in a solvent system, and e) gradually cool the escitalopram oxalate solution in said solvent system appropriate from a first temperature to a second tempe at the same time maintaining a controlled cooling profile, and sowing said escitalopram oxalate solution by the addition of escitalopram oxalate crystals during said cooling followed by a holding time at the second temperature. A method for the manufacture of crystalline particles of escitalopram oxalate wherein said crystalline particles of escitalopram oxalate are as described above, and said method comprises a gradual cooling of a solution of escitalopram oxalate in an appropriate solvent system from a first temperature to a second temperature while maintaining a controlled cooling profile, and said escitalopram oxalate solution is seeded by the addition of escitalopram oxalate crystals during said cooling followed by a holding time at said second temperature, wherein said The escitalopram solution 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-1- (4-fluorophenyl) -but- 1-enyl) -3-hydroxymethyl-benzonitrile in relation to the total weight of the crystallization 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 of said impurities with a hydroxyl group scavenger and b) separating said citalopram or escitalopram of the products resulting from the reaction of said hydroxyl containing impurities with said hydroxyl group scavenger. The direct compression of escitalopram, a filler and other pharmaceutically acceptable excipients in tablets has the great advantage that a granulation and drying step is avoided. In addition, because the granulation step is avoided, it is no longer necessary to add a binding agent. As used herein, "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, ie the salt consisting of one molecule of escitalopram per oxalic acid molecule, as well as the oxitallate salt of escitalopram, ie the salt consisting of two molecules of escitalopram per molecule of oxalic acid.

As used herein, "crystalline particles" means any combination of simple crystals, aggregates and agglomerates. As used herein, "direct compression" means that according to the solid unit claim is prepared by compression of a simple mixture of the active ingredient and the excipients, without the active ingredient must be subjected to an intermediate granulation process to embed in a larger particle and improve its flow properties. As used herein, "binder" means an agent, which is used in wet or melt granulation processes and which acts as a binder in the granulated product. As used herein, "particle size distribution" means the distribution of a cumulative volumetric size of equivalent spherical diameters, determined by laser diffraction at a dispersive pressure of 1 bar, in a Sympatec Helos equipment. The "mean particle size" "MPS" and "X50" refer, correspondingly, to each of the mean or 50% of the quantile of said particle size distribution. "X10" and "X95" refer correspondingly to 10% respectively and 95% of the quantile. "X10 / X50" and "X50 / X95" refer to the relationship between XlO and X50 respectively X50 and X95. The particle size distributions can be unimodal, that is, the density volumetric density distribution contains only one peak, bimodal, that is, the volumetric density distribution contains two peaks, or polymodal, that is, the distribution of the volume size. Volumetric density size contains more than two peaks. The particle size distributions can be bimodal or multimodal, among other things, if the crystalline particles consist of a mixture of single crystals and aggregates or agglomerates. As used herein, "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure. As used herein, "cooling profile" means the temperature of the crystallization batch as a function of time. As used herein, "cooling rate" means the decrease in temperature per unit time. As used herein, "hydroxyl group scavenger" means a molecule or reagent, which is capable of reacting with a hydroxyl group and transforming it into another substituent. The hydroxyl group scrubber is preferably selected so that the substituent, to which the hydroxyl group is transformed, facilitates the separation of the transformed molecule or impurity from escitalopram or citalopram. The hydroxyl group scrubber is preferably selected from those that react rapidly with hydroxyl groups, under light conditions without affecting the citalopram or escitalopram. Examples of hydroxyl group cleaners are the cyclic anhydrides, P0C13, PC15, POBr3, PBr5, POI3, PI5, BCI3, BBr3 and Bl3, which all introduce an acidic group into the molecule of impurities, due to which they can be separated from citalopram and / or escitalopram by extraction in an aqueous alkaline solution from an organic solvent. Therefore, in one embodiment of the present invention, the crystalline particles of escitalopram oxalate have an average particle size of at least 20 μm, in particular, of at least 40 μm, and preferably they are in the range of 50 μm. -200 μm. Therefore, in a particular embodiment of the present invention, the particle size distribution of the crystalline particles of escitalopram oxalate is bimodal or polymodal, and the peak in the smallest particle size is located at a particle size of at least 20 μm, in particular at least 40 μm and preferably in the range 50-200 μm. In one embodiment, the escitalopram oxalate crystals comprise at least 0.01% (w / w) relative to the escitalopram of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1- enyl) -3-hydroxymethyl-benzonitrile. In particular embodiments, the amount of E- or Z-4- (4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile in the crystals is in the range of 0.01. to 0.3%, more particularly from 0.02 to 0.2% and more particularly from 0.03 to 0.1%. In a particular embodiment, the hydroxyl containing impurities is Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile. In another particular embodiment, the hydroxyl containing impurities is E-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile. The properties of flowability, segregation and demixing and, therefore, the suitability of escitalopram oxalate crystals for direct compression depend, in addition to the particle size of the average, on the particle size distribution. In some purposes such as wet granulation, a broad particle size distribution is advantageous. The small particles can be dissolved during wet granulation, and then solidified into larger crystals by drying, and therefore, will impart strength to the granulate. In addition, in certain tabletting processes such as wet granulation (compaction), a broader particle size distribution may be desirable, to increase the loading efficiency of the particles, and therefore the inherent adhesion capacity . Another aspect of the invention is to provide a method for reducing 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 an impurity such as E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1 -enyl) -3-hydroxymethyl-benzonitrile are dissolved in an appropriate solvent such as anhydrous toluene. A scrubber of the hydroxyl group, such as a cyclic anhydride, for example succinic anhydride, in an amount sufficient to purify the hydroxyl group containing impurities, is added to the solution and the mixture is stirred at an appropriate temperature, for example 45 ° C. , for an appropriate period, for example 120 minutes. The impurity is then separated from citalopram, escitalopram or non-racemic mixture of R- and S- in an appropriate form. Those forms are known to those skilled in the art. If the impurity is converted to an acidic compound, for example, by reaction with an anhydride - cyclic, preferably a cyclic anhydride C_3, more preferably succinic anhydride, the separation can be carried out by dividing between the organic solvent and an aqueous phase, in particular by dividing between the organic solvent and an alkaline aqueous phase. Water and a base, such as aqueous ammonia, are added at an appropriate pH, for example pH = 10.5-11.0. The phases are separated and the organic phase is washed with water. The organic phase is evaporated to provide citalopram, escitalopram or non-racemic mixture of R- and S-citalopram. In a particular embodiment, the invention provides a method for reducing the amount of hydroxyl containing impurities in citalopram. In another, equally particular, embodiment, the invention provides a method for reducing the amount of hydroxyl containing impurities in escitalopram. In a further, equally particular, embodiment, the invention provides a method for reducing the amount of hydroxyl containing impurities in a non-racemic mixture of R- and S-citalopram. In another aspect of the present invention, the crystalline particles of escitalopram oxalate, described above and suitable for use in a solid unit dosage form, are crystallized from a solution of escitalopram oxalate in an appropriate solvent system. Such crystalline particles may have, inter alia, a ratio between the particle size of the average and the particle size comprised in 95% of the quantile, ie, less than 0.42, preferably less than 0.40; and / or having a particle size between the average of at least 20 μm, preferably at least 20 μm, and even more preferably in the range of 50-200 μm. In a particular embodiment, said crystalline particles have a particle size between the average of at least 20 μm, and a content of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1 -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. The escitalopram oxalate is preferably dissolved in the solvent system at a temperature in the range of between 50 ° C and the reflux temperature of the solvent system, preferably between 60 ° C and the reflux temperature and still more preferably between 70 ° C and the reflux temperature, conveniently escitalopram oxalate dissolves at the reflux temperature. The amounts of pharmaceutically acceptable salt of escitalopram and solvent, which are used, preferably correspond to a weight ratio of solute: solvent in the range of 0.05: 1 to 0.6: 1, more preferably 0.1: 1 to 0.5: 1 and further preferably from 0.2: 1 to 0.4: 1. The escitalopram oxalate solution will gradually cool to the temperature, under which, the crystals will be isolated from the mother liquor, within a range of 0-20 ° C, preferably 0-15 ° C, and even more preferably 7-15. ° C maintaining a controlled cooling profile so that the cooling rate in an initial cooling period does not exceed 0.6 ° C / minute and preferably keeping the cooling rate within the range of 0.2-0.4 ° C / minute, and Initial cooling period is extended until the temperature of the crystallization batch is below 60 ° C, preferably below 50 ° C and even more preferably below 40 ° C, conveniently the cooling rate can be maintained within this interval during the entire cooling period. The crystallization batch is seeded by addition of escitalopram oxalate crystals, at least once during the cooling time to avoid excessive supersaturation with respect to escitalopram oxalate, and to result in spontaneous crystallization in particle sizes. little. Seeding is preferably repeated to ensure the constant presence of crystalline escitalopram oxalate during cooling; Conveniently, the crystallization batch is seeded semi-continuously until crystallization begins. The crystallization batch is optionally maintained at the second temperature during a maintenance period during which the growth of the crystals can take place. In a particular embodiment, said holding time is at least 1 hour, preferably it is in the range of 4 to 24 hours, and more preferably from 6 to 12 hours. Finally, the crystalline oxalate particles of escitalopram are isolated from the mother liquor using conventional separation techniques, for example, filtration. In a particular embodiment, the solution from which escitalopram oxalate crystallizes comprises at least 0.01% E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile. In particular embodiments, 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 0.5. %, more particularly from 0.01 to 0.3%, even more particularly from 0.02 to 0.2%, and more particularly from 0.03 to 0.1%.

In a particular embodiment, the hydroxyl containing the impurity is Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile. In another particular embodiment, the hydroxyl containing the impurity is E-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile. Escitalopram, which must be crystallized as escitalopram oxalate, is in another particular embodiment, the product of a manufacturing method comprising the method described above for reducing the content of the hydroxyl group containing impurities by reaction with a hydroxyl group scavenger. The methods described above for the reduction of the amount of hydroxyl group containing impurities and for crystallization, can 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 in a fraction of racemic citalopram and / or a fraction of S-citalopram or R-citalopram containing low amounts of the other enantiomer as described in WO03 / 000672 which is included here as a reference. Such combinations include but are not limited to: depuration of the hydroxyl followed by crystallization of escitalopram oxalate; hydroxyl clearance followed by separation of escitalopram and racemic citalopram, followed by crystallization of escitalopram oxalate; separation of escitalopram and racemic citalopram followed by hydroxyl clearance followed by crystallization of escitalopram oxalate; and separation of escitalopram and racemic citalopram followed by crystallization of escitalopram oxalate. In one embodiment of the invention, escitalopram is manufactured by a process comprising the ring closure of R-4- [4- (dimethylamino) -1- (4 '-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) ) -benzonitrile under acidic conditions as described in the patent O03 / 000672 which is included here as reference. In one embodiment of the invention, 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 in accordance with the invention as described earlier. Said tablets can be prepared by one of the following methods for tabletting: direct compression, dry granulation (compaction), wet granulation or melt granulation. In a particular embodiment, the tablet is prepared by direct compression. In another particular embodiment, the tablet is prepared by dry granulation (compaction). In another particular embodiment, the tablet is prepared by wet granulation. In a further particular embodiment, the tablet is prepared by melt granulation. In a particular embodiment, the tablet is coated. In another embodiment, the present invention relates to a solid unit dosage form, prepared by filling a capsule with a mixture of crystalline particles of escitalopram oxalate and pharmaceutically acceptable excipients, wherein said crystalline particles of escitalopram oxalate are in accordance with the invention, as described above, and preferably the capsule is a hard gelatin capsule. Preferably, the solid unit dosage forms according to the invention do not contain a binder. The solid unit dosage forms according to the invention may contain 1-60% w / w of active ingredient calculated as escitalopram base, particularly 4-40% w / w of the active ingredient calculated as escitalopram base, even more particularly 1 -30% w / w of active ingredient calculated as escitalopram base, and more particularly 4-20% w / w of active ingredient calculated as escitalopram base and even more particularly 6-10% w / w of active ingredient calculated as base of escitalopram. Conveniently. , according to the solid unit claim of the invention contains 8% w / w of active ingredient calculated as escitalopram base. The solid unit dosage forms according to the invention may contain a filler selected from lactose, or other sugars, for example, sorbitol, mannitol, dextrose and sucrose, calcium phosphates (dibasic, tribasic, hydrated and anhydrous), starch, starches modified, microcrystalline cellulose, calcium sulfate and / or calcium carbonate. In a preferred embodiment, according to the solid unit claim of the invention, it does not contain lactose. Conveniently, the filler is a microcrystalline cellulose such as ProSolv SMCC90 manufactured by Pen est Pharmaceuticals or Avicel PH 200 manufactured by FMC Corporation. In addition to the active ingredient and the filler, the solid dosage unit dosage forms can include various other conventional excipients such as disintegrators and optionally minor amounts of lubricants, colorants and sweeteners.

One or more of the lubricants used according to the invention may be conveniently selected from the group comprising metal stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica. Preferably, the lubricant is one or more, selected from the group comprising talc, magnesium stearate or calcium stearate. Conveniently the lubricant is a combination of talc and magnesium stearate. The weight percentage of magnesium stearate in accordance with the solid unit claim is preferably in the range of 0.4% to 2% and more preferably in the range of 0.7% to 1.4%. In a particular embodiment, according to the solid unit claim is substantially free of lactose. Disintegrators include sodium starch glycolate, croscarmellose, crospovidone, low substitution hydroxypropylcellulose, modified corn starch, pregelatinized starch and natural starch. Conveniently, the disintegrator is croscarmellose, such as Ac-Di-Sol manufactured by FMC. Optionally, according to the solid pharmaceutical unit claim of the invention it can be coated. Conveniently the coating is a coating film based on conventional coating mixtures such as Opadry OY-S-28849, white manufactured by Colorcon. According to the solid pharmaceutical unit claim of the invention, it can be prepared by conventional methods using a press for tablets with forced feeding capacity. The filled, hard gelatin capsule of the invention can be prepared by conventional methods using a capsule filler, suitable for powder filling.

Examples In the following, the invention is illustrated by examples. However, the examples will be merely to illustrate the invention and should not be considered restrictive.

EXAMPLE 1 Depuration of hydroxyl containing impurities by succinic anhydride.

A mixture of R- and S-Citalopram (55.5 g) containing 0.6% of Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile was dissolved in anhydrous toluene (145.0 g). Succinic anhydride (0.5 g) was added to the solution and the mixture was stirred at 45 ° C (120 minutes). Water (230 ml) and aqueous ammonia (25% by weight) (3 ml) were added (pH = 10.5-11.0). The phases were separated and the toluene phase was washed with water (3 x 120 ml). The toluene phase was evaporated and the yield was 53.0 g (95%). The product contains 0.06% of Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3- (hydroxymethyl) -benzonitrile.

EXAMPLE 2 Scale crystallization production of escitalopram oxalate A large number of batches of crude escitalopram oxalate have been recrystallized on a production scale according to the procedure described below. The batches comprise: a) Escitalopram prepared by closing the acid ring of the R form of the diol precursor as described in WO 03/000672, followed by depuration of hydroxyl containing impurities, by means of a production version of the described process in Example 1, followed by separation of racemic citalopram and escitalopram as described in the patent O03 / 000672. These batches contain Z-4- (4-dimethylamino-l- (-fluorophenyl) -but-1-enyl) -3- (hydroxymethyl) -benzonitrile, typically in the range of 0.05% (w / w) relative to escitalopram . These batches are called batches of R-diol. b) Escitalopram prepared by ring closure of the S-form of the diol precursor through an activated ester under alkaline conditions as described in US Patent No. 4,943,590. These batches do not contain Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3- (hydroxymethyl) -benzonitrile. These lots are called batches of S-diol Production procedure: 100 kg to 300 kg of crude escitalopram oxalate were loaded, to a first reactor, Rl. 4.1 - 4.3 liters of ethanol per kilogram of crude escitalopram oxalate were charged to Rl. The solution was mixed and heated to the boiling point (approximately 80 ° C). When all was dissolved, the solution was transferred through a filter to a second reactor, R2. The agitator R2 was started (40-60 rpm) and the solution was heated again to the boiling point. Once it was all dissolved in R2, the automatic cooling was started and the solution gradually cooled according to the cooling rates of Table 1.

Table 1: Cooling regime points for automatic cooling during recrystallization of escitalopram oxalate The solution was seeded with 0.02 - 0.04 kg of escitalopram oxalate, decreasing each time 3 ° C until crystallization was observed. The solution was automatically cooled to 15 ° C. The suspension was pumped into a filter dryer, in which it was washed and dried. If the suspension is not transferred immediately, the temperature should be maintained at 0-15 ° C. The filter cake was dried under vacuum. Once the filter cake was dry, it was washed with 1.1-1.2 liters of ethanol per kg of crude escitalopram oxalate loaded. The cake was dried again and then said cake was heated for a final drying for about 12 hours. Temperature = 50-60 ° C, pressure < 0.13 Bar (abs). The filter drier was emptied and the escitalopram oxalate was sent to deagglomeration, to deagglomerate the agglomerates formed during the drying of the crystals. Dry escitalopram oxalate was ground to separate one crystal from the other. During grinding, the size and shape of the individual crystals did not vary. The resulting batches of escitalopram oxalate had particle characteristics such as those shown in Table 2.

Table 2: Characteristics of the particles for escitalopram oxalate crystals Comparative Example 1 A wet filter cake obtained by precipitation of crude escitalopram oxalate, by mixing ethanol solutions of escitalopram, prepared by ring closure through a labile ester under alkaline conditions and oxalic acid, respectively, and containing approximately 35 kg of oxalate of escitalopram, was suspended in 322 liters of ethanol. The material was dissolved by heating under reflux, and 150 liters of ethanol were removed by distillation. Cooling was applied, and the mixture was cooled from reflux to 15 ° C, with a cooling regime comprised between 0.2 and 0.5 ° C / minute at a temperature range of 80 to 40 ° C. During cooling, the mixture was seeded with escitalopram oxalate at 75, 65 and 60 ° C (10 g each time). The crystallization mixture was maintained at 15 ° C for 10 hours before isolating crystalline escitalopram oxalate. The purified escitalopram oxalate (27.7 kg, 79%) was obtained by filtration of the crystallization mixture, by washing with ethanol and drying the filter cake. The particle size distribution for the resulting escitalopram oxalate is listed in Table 3.

Table 3. Particle size distribution (Sympatec Helos) for the oxalate crystals of escitalopram and ProSolv SMCC90 Comparative Example 2 Tablet prepared by direct compression of large crystalline particles of escitalopram oxalate Tablet Ingredients: Tablet core Escitalopram oxalate 2554 g (10.2% w / w) Talcum 1400 g (5.6% w / w) ProSolv SMNN90 19896 g (79.6% w / w) Ac-Di-Sol 900 g (3.6% Magnesium Stearate 250 g (1.0% w / w) Opadry coating film OY-S-28849, white 625 g (2.5% w / w core weight) Crystalline particles of escitalopram oxalate from example 1 and talc were sieved through a 710 μm sieve and mixed at 6 rpm for 15 minutes in a 100 liter Bohle PTM 200 mixer. ProSolv SMCC90 and Ac-Di-Sol were added. and mixing was continued for 15 minutes. Magnesium stearate was sieved through a 710 μm sieve and the addition and mixing was continued for 3 minutes. Tablets were formed with 25 kg of the resulting mixture (125,000 tablets / hour), in a Korsch PH 230 tablet press, provided with oblong punches, with ridges, with 5.5 x 8 mm slots. The core weight of the tablets was set at 125 mg. The nominal yield was 200,000 tablets. The tablet press was left in operation until the level of the mixture was just above the forced feeder, that is, the tabletting was continued as long as possible to identify the possible segregation tendencies in the last mixing quantities. The tablets produced had satisfactory technical properties. Those skilled in the art readily realized that the crystals according to the invention can be used for the manufacture of tablets in similar forms.

Claims (46)

1. Crystalline particles of escitalopram oxalate, characterized in that the ratio between the mean particle size and the particle size in 95% of the quantile is less than 0.42.

2. Crystalline particles of escitalopram oxalate according to claim 1, characterized in that the ratio between the particle size of the mean and the particle size in 95% of the quantile is less than 0.40.

3. Crystalline particles of escitalopram oxalate according to claims 1 or 2, characterized in that the particle size of the average is at least 20 μm.

4. Crystalline particles according to claim 3, characterized in that the particle size of the crystal measure is at least 40 μm, preferably it is in the range of 50-200 μm.

5. Crystalline particles according to claim 3 or 4, characterized in that the particle size distribution of the crystalline particles of escitalopram oxalate is bimodal or polymodal and the peak in the smallest particle size is located at a particle size of at least 20 μm, in particular of at least 40 μm and preferably in the range of 50-200 μm.

6. Crystalline particles of escitalopram oxalate, characterized in that the particle size of the average is at least 20 μm and the content of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1 -enyl) -3- (hydroxymethyl) -benzonitrile is at least 0.01% (w / w).

7. Crystalline particles according to claim 6, characterized in that the particle size of the average of the crystals is at least 40 μm, and preferably it is in the range of 50-200 μm.

8. Crystalline particles of escitalopram oxalate according to claim 6 or 7, characterized in that the ratio between the particle size of the mean and the particle size to 95% of the quantile is less than 0.42, preferably less than

9. Crystalline particles of escitalopram oxalate, characterized in that the particle size of the average is at least 20 μm and the content of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1 -enyl) -3- (hydroxymethyl) -benzonitrile in the solution, from which crystallizes escitalopram oxalate, before crystallization, is at least 0.01% (w / w) in relation to the total weight of the crystallization batch .

10. Crystalline particles according to claim 9, characterized in that the particle size of the average of the crystals is at least 40 μm, and preferably it is in the range of 50-200 μm.

11. Crystalline particles of escitalopram oxalate according to claims 9 or 10, characterized in that the ratio between the particle size of the mean and the particle size to 95% of the quantile is less than 0.42, preferably less than 0.40.

12. Solid unit dosage form comprising crystalline particles of escitalopram oxalate according to any of claims 1-11.

13. Solid unit dosage form manufactured from crystalline particles of escitalopram oxalate according to any of claims 1-11.

14. Solid dosage unit form according to claim 12 or 13, characterized in that it is a tablet prepared by direct compression, by dry granulation (compaction), wet granulation or melt granulation of a mixture of escitalopram oxalate and pharmaceutically excipients acceptable

15. Solid unit dosage form according to claim 14, characterized in that the tablet is coated.

16. Solid unit dosage form according to claims 12 or 13, characterized in that it is prepared by filling a mixture of escitalopram oxalate and pharmaceutically acceptable excipients in a hard gelatin capsule.

17. Solid unit dosage form according to any of claims 12-16, characterized in that it does not contain a binder.

18. Solid unit dosage form according to any of claims 12-17, characterized in that it contains 1-60% w / w of active ingredient calculated as escitalopram base, particularly 1-30% w / w of active ingredient calculated as the base of escitalopram, more particularly 4-20% w / w of active ingredient calculated as escitalopram base and even more particularly 6-10% w / w of active ingredient calculated as escitalopram base.

19. Solid unit dosage form according to any of claims 12-18, characterized in that it contains a filler selected from lactose, other sugars, preferably sorbitol, mannitol, dextrose, and / or sucrose, calcium phosphates, preferably dibasic, tribasic, hydrated and / or anhydrous, starch, modified starches, microcrystalline cellulose, calcium sulfate and / or calcium carbonate.

20. Solid unit dosage form according to claim 19, characterized in that the filler is a microcrystalline cellulose, such as ProSolv SMCC90 or Avicel PH 200.

21. Solid unit dosage form according to any of claims 12-20, characterized in that it contains a lubricant selected from metal stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica.

22 Solid unit dosage form according to claim 21, characterized in that the lubricant is one or more selected from the group of talc, magnesium stearate and calcium stearate.

23. Solid unit dosage form according to claim 22, characterized in that the lubricant is a combination of talc and magnesium stearate.

24. Solid unit dosage form according to claim 23, characterized in that the weight percentage of magnesium stearate calculated based on the weight of the solid dosage form is preferably in the range of 0.4% to 2% and more preferably in the range from 0.7% to 1.4%.

25. Solid unit dosage form according to any of claims 12-24, characterized in that it is substantially free of lactose.

26. Method for the manufacture of crystalline particles of escitalopram oxalate according to any of claims 1-11, comprising the steps of: a) Treating a solution comprising escitalopram together with one or more hydroxyl containing impurities with a group scrubber hydroxyl; b) separating the escitalopram from the products resulting from the reaction of the hydroxyl containing impurities with the hydroxyl group scavenger; c) optionally transfer escitalopram into its oxalate salt if escitalopram is no longer in the form of its oxalate salt; d) optionally transfer escitalopram to a solvent system, appropriate for the crystallization process if escitalopram is not already in such a solvent system; and e) gradually cooling the escitalopram oxalate solution in the appropriate solvent system from a first temperature to a second temperature while maintaining a controlled cooling profile, and sowing the escitalopram oxalate solution by addition of crystals of escitalopram oxalate during cooling.

27. Method of manufacturing crystalline particles of escitalopram oxalate according to any of claims 1-11, comprising gradual cooling of a solution of escitalopram oxalate in an appropriate solvent system from a first temperature to a second temperature while maintaining a controlled cooling profile, and the escitalopram oxalate solution is seeded by adding escitalopram oxalate crystals during cooling, where the escitalopram solution comprises at least 1 ppm, particularly at least 10 ppm, and more particularly by at least 0.01% by weight of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile in relation to the total weight of the crystallization batch.

28. Method according to any of claims 26-27, characterized in that the solvent system comprises one or more alcohols and optionally water.

29. Method according to claim 28, characterized in that the solvent system is ethanol.

30. Method according to any of claims 26-29, characterized in that the weight ratio of solute: solvent is in the range of 0.05: 1 to 0.6: 1, more preferably 0.1: 1 to 0.5: 1 and even more preferably of 0.2: 1 to 0.4: 1.

31. Method according to any of claims 26-30, characterized in that the first temperature is in the range of between 50 ° C and the reflux temperature of the solvent system is preferably between 60 ° C and the reflux temperature and more preferably between 70 ° C and the reflux temperature.

32. Method according to any of claims 26-31, characterized in that the second temperature is in the range of 0-20 ° C, preferably O-15 ° C, and even more preferably 7-15 ° C.

33. Method according to any of claims 26-32, characterized in that the controlled cooling profile comprises an initial cooling period in which the cooling rate is maintained within a fixed interval.

34. Method according to claim 33, characterized in that the initial cooling period covers the period comprised until the temperature is below 60 ° C, preferably below 50 ° C and even more preferably below 40 ° C.

35. Method according to any of claims 33-34, characterized in that the cooling rate is maintained within the range of 0-0.9 ° C / min, preferably in the range of 0-0.6 ° C / min. , and more preferably in the range of 0.2-0. ° C / min.

36. Method according to any of claims 26-35, characterized in that the seeding is carried out two or more times during the initial cooling.

37. Method according to any of claims 26-36, characterized in that the crystalline particles after the holding time are isolated from the mother liquor by conventional solid / liquid separation techniques, preferably by filtration.

38. Method according to any of claims 26-37, characterized in that escitalopram is manufactured by a process comprising the ring closure of R-4- [4-dimethylamino) -1- (4 '-fluorophenyl) -1-hydroxybutyl ] -3- (hydroxymethyl) -benzonitrile under acidic conditions.

39. Method for reducing the amount of hydroxyl containing impurities in citalopram, escitalopram or in a non-racemic mixture of R- and S-citalopram, comprising the steps of: c) treating a solution comprising citalopram, escitalopram or a non-racemic mixture of R- and S-citalopram in conjunction with one or more of the impurities with a hydroxyl group scavenger; and d) separating the citalopram, escitalopram, or non-racemic mixture of R- or S-citalopram from the products resulting from the reaction of the hydroxyl containing impurities with the hydroxyl group scavenger.

40. Method for reducing the amount of hydroxyl containing impurities in escitalopram according to claim 39.

41. Method for reducing the amount of hydroxyl containing impurities in citalopram according to claim 39.

42. Method for reducing the amount of hydroxyl containing impurities in a non-racemic mixture of R- and S-citalopram.

43. Method according to any of claims 26 and 39-42, wherein the hydroxyl group scrubber is selected from the group consisting of cyclic anhydrides.

44. Method according to claim 43, wherein the hydroxyl group depuration is a cyclic C-3 anhydride, preferably succinic anhydride.

45. Method according to any of claims 39-44, wherein the separation of citalopram or escitalopram from the products resulting from the reaction of the hydroxyl containing impurities with the hydroxyl group scavenger is carried out by extraction of the products resulting from the reaction of the hydroxyl containing impurities with the hydroxyl group scavenger in an aqueous solution, particularly an alkaline aqueous solution, from a solution of citalopram or escitalopram in an organic solvent.

46. Method according to any of claims 39-45, characterized in that escitalopram and / or citalopram is manufactured by a process comprising the ring closure of R-4- [4- (dimethylamino) -1- (4'-fluorophenyl) ) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile under acidic conditions.