KR20060126587A - 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 {CRYSTALLINE COMPOSITION CONTAINING ESCITALOPRAM OXALATE}

The present invention relates to the oxalate salt of the escitalopram (INN-name) compound, the S-enantiomer of the well-known antidepressant citalopram, namely (S) -1- [3- (dimethylamino) propyl] A crystalline preparation of -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile oxalate.

Citalopram is a well known antidepressant drug having the structure:

It is thus a selective and centrally active serotonin (5-hydroxytrytamine; 5-HT) reuptake inhibitor with antidepressant activity.

Citalopram was first disclosed in DE 2,657,013, corresponding to US 4,136,193. The patent publication describes the production of citalopram by one method and outlines additional methods that can be used to prepare citalopram. The prepared citalopram was isolated in crystalline form as oxalate, hydrobromide and hydrochloride salt, respectively. The citalopram base was also obtained as an oil (B.P. 175 ° C./0.03 mmHg). The publication also outlines a process for the preparation of tablets containing salts of citalopram. Citalopram is sold as hydrobromide and hydrochloride, respectively.

Escitalopram, its pharmaceutically active and crystalline escitalopram oxalate, are disclosed in US Pat. No. 4,943,590. A method for preparing a pharmaceutical formulation of escitalopram is outlined.

Citalopram is sold in many countries as tablets made by compression of granulated citalopram hydrobromide, lactose and other excipients.

In the manufacture of tablets with regenerating compositions, it is well recognized that all dry ingredients are required to have good flowability. If the active ingredient has good fluidity, tablets can be prepared by direct compression of the ingredients. However, in many cases where the particle size of the active material is small, the active material is tacky or has poor flowability.

In addition, active materials with small particle sizes mixed with excipients with larger particle sizes will typically be separated or de-mixed during the tableting process.

The problem of small particle size and poor fluidity is usually solved by enlarging the particle size of the active ingredient, usually by granulation of the active ingredient alone or in combination with fillers and / or other conventional tablet ingredients.

One such granulation method is a "wet" granulation process. Using this method, dry solids (active ingredients, fillers, binders, etc.) are blended, wetted with water or another wetting agent (eg alcohol), and aggregates or granules are formed with the wet solids. Wet coagulation is continued until the desired uniform particle size is achieved, and then the granulation product is dried if the goal is achieved.

An alternative to the “wet” granulation method is “melt” granulation, also known as a “thermoplastic” granulation process, where low melt solids are used as granulating agents. First, the dry solids are blended and heated until the binder melts. Once the binder has liquefied to cover the surface of the particles, the particles will adhere to each other to form granules. The binder solidifies upon cooling to form a dry granular product.

Not only wet granulation, but also melt granulation is an energy intensive unit operation that requires expertise as well as complex and expensive devices.

However, if the active ingredient has adequate fluidity, the granulation step can be omitted and tablets can be produced by direct compression, which is a low cost manufacturing method.

The method used to prepare citalopram hydrobromide produces products with very small particle sizes of about 2 to 20 μm, which have very poor flowability, like many other particulate products with small particle sizes. In other words, it was considered necessary to produce granules of citalopram hydrobromide with larger particle size and improved flowability in order to achieve a suitable dosage of citalopram hydrobromide during tableting.

Citalopram tablets sold are tablets made from granulated citalopram hydrobromide with various excipients.

The inventors have found that escitalopram has significantly different solubility and salt forming properties than citalopram racemate. For example, while the only pharmaceutical crystalline salt known to date is oxalate, citalopram racemate also forms crystalline hydrobromide and hydrochloride salts. Crystalline escitalopram hydrobromide is currently disclosed in WO 2004/056791 A1.

The escitalopram oxalate product prepared by crystallization from acetone as outlined in US Pat. No. 4,943,590, has a very small particle size of about 2-20 μm, like the citalopram hydrobromide product described above. Which similarly results in poor fluidity.

WO 03/000672 discloses R-4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl by ring-closing under acidic conditions Disclosed is a process for preparing racemates as well as enantiomerically pure citalopram from) -benzonitrile compounds.

WO 03/011278 discloses crystalline particles of escitalopram oxalate having a particle size of at least 40 μm. Also disclosed are methods of preparing the crystalline particles and pharmaceutical compositions comprising the crystalline particles.

The inventors of the present invention now surprisingly find that the particle size obtained when the escitalopram prepared according to the method disclosed in WO 03/000672 is precipitated as an oxalate salt according to the method disclosed in WO 03/011278 is characterized by alkaline conditions. Ring-closure of S-4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile under labile ester Was found to be significantly smaller than that obtained from escitalopram, which was prepared and precipitated under the same precipitation conditions.

They are also Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxy, in which the particle size reduction of escitalopram oxalate crystals is a specific impurity. It was found that it is related to the presence of methyl-benzonitrile. This impurity is unique to the acidic ring-closure process as compared to the ring-close through the labile esters under alkaline conditions.

In view of the fact that direct compression is much simpler and cheaper than the method involving granulation, there is a continuing need for large determinations of escitalopram or its pharmaceutically acceptable addition salts.

Laboratory scale and full-scale studies are now conducted on Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl)-in a solution of escitalopram before crystallization of oxalate. By a novel process of the invention which reduces the amount of 3-hydroxymethyl-benzonitrile, a novel pattern for producing large crystalline particles of escitalopram oxalate, ie particles of a size comparable to the size of the filler The method of the invention has been reached. Such particles are useful for the manufacture of direct compressed tablets. Precise capsule preparations can also be made with these large particles.

Purpose of the Invention

It is a first aspect of the present invention to provide crystalline particles of escitalopram oxalate having a wide particle size distribution suitable for use in direct compression.

A second aspect of the present invention provides at least 0.01% (w / w) of Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl), suitable for use in direct compression. To provide large crystalline particles of escitalopram oxalate, including 3-hydroxymethyl-benzonitrile.

A third aspect of the present invention is to provide a novel pharmaceutical unit dosage form containing crystalline particles of escitalopram oxalate, wherein the particles have a broad particle size distribution, wherein the unit dosage form is preferred. Preferably a tablet, or capsule, which can be prepared by direct compression.

A fourth aspect of the present invention is to provide a process for producing large crystalline particles of escitalopram oxalate having a wide particle size distribution.

A fifth aspect of the present invention is directed to a large amount of escitalopram oxalate, which includes reducing the amount of hydroxyl containing impurities in solution of escitalopram and crystallizing the resulting escitalopram as an oxalate salt. It is to provide a method for producing crystalline particles.

A sixth aspect of the present invention is to provide a method for reducing the amount of hydroxyl containing impurities in a solution of citalopram or escitalopram.

The present invention then includes in particular the following, alone or in combination:

Crystalline particles of escitalopram oxalate having a ratio between the median particle size and the particle size at 95% displacement, less than 0.42, preferably less than 0.40. Such particles are suitable for use in solid unit dosage forms.

Median particle size of at least 20 μm and at least 0.01% (w / w) of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl As crystalline particles of escitalopram oxalate having a -benzonitrile content, preferably the median particle size of the crystals is at least 40 μm, more preferably in the range from 50 to 200 μm. Such particles are suitable for use in solid unit dosage forms.

Have a median particle size of at least 20 μm, and before crystallization of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile Crystalline particles of escitalopram oxalate crystallized from a solution having a content of at least 0.01% (w / w) relative to escitalopram, preferably the median particle size of the crystals is at least 40 μm, more preferably Is in the range from 50 to 200 μm. Such particles are suitable for use in solid unit dosage forms.

A solid unit dosage form comprising crystalline particles of escitalopram oxalate, wherein the crystalline particles of escitalopram oxalate are in accordance with the invention as described above.

A solid unit dosage form comprising crystalline particles of escitalopram oxalate prepared from crystalline particles of escitalopram oxalate according to the invention as described above.

A process for preparing crystalline particles of escitalopram oxalate, wherein the crystalline particles of escitalopram oxalate are as previously described, comprising the following steps:

a) treating a solution comprising escitalopram with a hydroxyl group scavenger together with one or more hydroxyl containing impurities,

b) separating escitalopram from the product obtained from the reaction of the hydroxyl group scavenger with the hydroxyl containing impurity,

c) optionally converting escitalopram to its oxalate salt if escitalopram is not yet in the form of its oxalate salt,

d) optionally, escitalopram if it is not already in a solvent system suitable for the crystallization process, and transferring escitalopram to this solvent system, and

e) a solution of escitalopram oxalate in the appropriate solvent system is gradually cooled from the first temperature to the second temperature while maintaining a controlled cooling profile and crystallization of escitalopram oxalate is carried out during the cooling. Nucleating the solution of escitalopram oxalate by adding and maintaining at the second temperature.

Crystalline particles of escitalopram oxalate are as described above, and the solution of escitalopram oxalate in an appropriate solvent system is gradually cooled from the first temperature to the second temperature while maintaining a controlled cooling profile And nucleating the solution of escitalopram oxalate by adding crystals of escitalopram oxalate during the cooling, and then maintaining at the second temperature, wherein the escitalop The solution of ram is at least 1 ppm, specifically at least 10 ppm, more specifically at least 0.01% by weight relative to the total weight of the crystallization batch, E- or Z-4- (4-dimethylamino-1- (4-fluoro). A method for producing crystalline particles of escitalopram oxalate, comprising phenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile.

A method of reducing the amount of hydroxyl containing impurities in citalopram or escitalopram, comprising the following steps:

a) treating a solution comprising citalopram or escitalopram with at least one such impurity with a hydroxyl group scavenger, and

b) separating the citalopram or escitalopram from the product obtained from the reaction of the hydroxyl group scavenger with the hydroxyl containing impurity.

Direct compression of escitalopram, fillers and other pharmaceutically acceptable excipients into tablets has the great advantage that the granulation and drying steps are omitted. In addition, the granulation step is omitted, so that it is no longer necessary to add the binder.

As used herein, "escitalopram oxalate" means any addition salt consisting of escitalopram, oxalic acid and optional water. Examples of such salts include hydrogen oxalate salts of escitalopram, ie, salts consisting of one molecule of escitalopram per molecule of oxalic acid, as well as oxalate salts of escitalopram, ie two molecules of oxalic acid molecule. There is a salt consisting of citalopram.

As used herein, “crystalline particles” means any combination of single crystals, aggregates and aggregates.

As used herein, "direct compression" refers to a solid by compacting a simple mixture of the active ingredient and excipients without embedding the active ingredient in larger particles and applying it to an intermediate granulation process to improve its fluidity. By means of preparing a unit dosage form.

As used herein, “binder” means an agent that is used in a wet or melt granulation process to act as a binder in the granulation product.

As used herein, “particle size distribution” means cumulative volume size distribution of equivalent sphere diameter as measured by laser diffraction at 1 bar dispersion pressure in a Sympatec Helos device. "MPS" and "X50", which are "medium particle size", correspond correspondingly to the median or 50% displacement of the particle size distribution, respectively. "X10" and "X95" correspond correspondingly to 10% and 95% displacement values, respectively. "X10 / X50" and "X50 / X95" indicate the ratio between X10 and X50 and the ratio between X50 and X95, respectively.

The particle size distribution can be monomodal (i.e. the density volume size distribution contains only one peak), bimodal (i.e. the density volume size distribution contains two peaks), or multimodal (i.e. the density volume size Distribution contains more than two peaks). The particle size distribution can be bimodal or multimodal, especially when the crystalline particles are a mixture of single crystals and aggregates or aggregates.

As used herein, "reflux temperature" means the temperature at which the solvent or solvent system refluxs 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 amount of temperature decrease per unit time.

As used herein, “hydroxyl group scavenger” means a molecule or reactant that can react with a hydroxyl group and transform it into another substituent. The hydroxyl group scavenger is preferably selected such that the modified substituents from the hydroxyl groups facilitate the separation of the modified molecules or impurities from escitalopram or citalopram. The hydroxyl group scavenger is preferably selected from those which react rapidly with hydroxyl groups under moderate conditions without affecting citalopram or escitalopram. Examples of hydroxyl group scavengers are cyclic anhydrides, POCl ₃ , PCl ₅ , POBr ₃ , PBr ₅ , POI ₃ , PI ₅ , BCl ₃ , BBr ₃ and BI ₃ , all of which will introduce acidic groups into the impurity molecule In this case, it can be separated from citalopram and / or escitalopram by extraction with an alkaline aqueous solution from an organic solvent.

That is, in one embodiment of the present invention, the crystalline particles of escitalopram oxalate have a median particle size of at least 20 μm, in particular at least 40 μm, preferably in the range from 50 to 200 μm.

That is, in certain embodiments of the invention, the particle size distribution of the crystalline particles of escitalopram oxalate is bimodal or multimodal, and the peak at the minimum particle size is at least 20 μm, in particular at least 40 μm, preferably Is located at a particle size in the range from 50 to 200 μm.

In one embodiment, the escitalopram oxalate crystals have at least 0.01% (w / w) E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) relative to escitalopram. ) -But-1-enyl) -3-hydroxymethyl-benzonitrile. In certain embodiments, the amount of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile in the crystal is from 0.01 to 0.3 %, More specifically 0.02 to 0.2%, most specifically 0.03 to 0.1%.

In certain embodiments, the hydroxyl containing impurity is Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile.

In another specific embodiment, the hydroxyl containing impurity is E-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile.

Therefore, the flowability, separability and de-mixability, and suitability for direct compaction of escitalopram oxalate crystals depend on the particle size distribution, in addition to the median particle size. For certain purposes, such as wet granulation, it may be advantageous to have a broad particle size distribution. Small particles can be dissolved during wet granulation and then solidified between the larger crystals upon drying, thereby imparting rigidity to the granules. In addition, in certain tableting processes such as dry granulation (densification), it may be desirable to have a wide particle size distribution in order to increase the inherent binding capacity by increasing the packing efficiency of the particles.

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. Citalop containing hydroxyl group containing impurities such as E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile The non-racemic mixture of ram, escitalopram or R- and S-citalopram is dissolved in a suitable solvent such as dry toluene. A hydroxyl group scavenger such as cyclic anhydride, such as succinic anhydride, is added to the solution in an amount sufficient to remove the hydroxyl group containing impurities, and the mixture is added at a suitable temperature, for example 45 ° C., for a suitable period of time, eg For example, it is stirred for 120 minutes. The impurities are then separated in a suitable manner from citalopram, escitalopram or non-racemic mixtures of R- and S-citalopram. Those skilled in the art will be aware of this approach. For example, a cyclic anhydride, preferably a cyclic C _{4 -8} - anhydride, more preferably in the case of modifying the impurities with acid compounds by reaction with succinic anhydride, the organic solvent and the aqueous phase between, in particular, an organic solvent and Separation can be carried out by dividing between alkaline aqueous phases. Water and a base such as aqueous ammonia are added to an appropriate pH, for example pH = 10.5 to 11.0. The phases are separated and the organic phase is washed with water. The organic phase is evaporated to give citalopram, escitalopram or a non-racemic mixture of R- and S-citalopram.

In certain embodiments, the present invention provides a method of reducing the amount of hydroxyl containing impurities in citalopram.

In another equally specific embodiment, the present invention provides a method of reducing the amount of hydroxyl containing impurities in escitalopram.

In yet another equivalent particular embodiment, the present invention provides a method of reducing the amount of hydroxyl containing impurities in a non-racemic mixture of R- and S-citalopram.

In another aspect of the invention, the crystalline particles of escitalopram oxalate as described above and suitable for use in a solid unit dosage form are crystallized from a solution of escitalopram oxalate in a suitable solvent system. Such crystalline particles have a ratio between the median particle size and the particle size at 95% displacement, in particular less than 0.42, preferably less than 0.40; It has a median particle size of at least 20 μm, preferably at least 20 μm, more preferably in the range from 50 to 200 μm. In certain embodiments, such crystalline particles have a median particle size of at least 20 μm and at least 0.01% (w / w) of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1 -Enyl) -3-hydroxymethyl-benzonitrile content. The solvent system may comprise one or more alcohols and optional water, preferably the solvent system is ethanol. The escitalopram oxalate is preferably dissolved in the solvent system at a temperature in the range from 50 ° C. to the reflux temperature of the solvent system, preferably from 60 ° C. to the reflux temperature, more preferably from 70 ° C. to the reflux temperature, and suitably. Preferably, escitalopram oxalate is dissolved at reflux temperature. The amount of pharmaceutically acceptable salt and solvent of escitalopram is preferably 0.05: 1 to 0.6: 1, more preferably 0.1: 1 to 0.5: 1, most preferably 0.2: 1 to 0.4: 1 Corresponds to the solute: solvent weight ratio in the range. The solution of escitalopram oxalate has a cooling rate in the initial cooling period not exceeding 0.6 deg. C / min, preferably a cooling rate in the range of 0.2 to 0.4 deg. Silver extends until the temperature of the crystallization batch is below 60 ° C., preferably below 50 ° C., more preferably below 40 ° C., and suitably adjusted so that the cooling rate can be maintained within this range for the entire cooling. While maintaining the cooling profile, gradual cooling to a temperature in the range of 0 to 20 ° C., preferably 0 to 15 ° C., more preferably 7 to 15 ° C., will crystallize from the mother liquor. Crystallization batches add nuclei by adding one or more crystals of escitalopram oxalate during the cooling time to prevent excessive supersaturation of the escitalopram oxalate and thereby spontaneous crystallization into small crystalline particles. do. Nucleation is preferably repeated to ensure the constant presence of crystalline escitalopram oxalate during cooling; Appropriately, nucleation is formed semi-continuously in the crystallization batch until crystallization begins. Crystallization batches are optionally maintained at the second temperature for a holding time at which crystal growth can occur. In certain embodiments, the holding time is at least 1 hour, preferably in the range of 4 to 24 hours, more preferably in the range of 6 to 12 hours. Finally, crystalline particles of escitalopram oxalate are isolated from the mother liquor using conventional separation techniques such as filtration.

In certain embodiments, the solution from which escitalopram oxalate is crystallized is at least 0.01% E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl)- 3-hydroxymethyl-benzonitrile. In certain embodiments, the amount of E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile in the crystal is from 0.01 to 0.5 %, More specifically 0.01 to 0.3%, even more specifically 0.02 to 0.2%, most specifically 0.03 to 0.1%.

In certain embodiments, the hydroxyl containing impurity is Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile.

In another specific embodiment, the hydroxyl containing impurity is E-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile.

Escitalopram crystallized as escitalopram oxalate, in another specific embodiment, comprises the method described above for the reduction of the hydroxyl group containing impurity content by reaction with a hydroxyl group scavenger Product of the production process.

The methods described above for the reduction and crystallization of hydroxyl group containing impurity amounts are combined with one another and / or R- and S in which one of the enantiomers is greater than 50% as disclosed in WO 03/000672, which is incorporated herein by reference. Racemic citalop by separation of the mixture of citalopram into fractions of racemic citalopram and / or fractions of S-citalopram or R-citalopram containing small amounts of other enantiomers. It may be combined with a process for preparing ram and / or S- or R-citalopram.

Suitable combinations include, but are not limited to, the following: hydroxyl removal followed by crystallization of escitalopram oxalate; Crystallization of hydroxyl removal followed by racemic citalopram and escitalopram followed by escitalopram oxalate; Separation of racemic citalopram and escitalopram followed by removal of hydroxyl followed by crystallization of escitalopram oxalate; And crystallization of racemic citalopram and escitalopram followed by escitalopram oxalate.

In one embodiment of the invention, escitalopram is selected from R-4- [4- (dimethylamino) -1- (4'- under acidic conditions, as disclosed in WO 03/000672, which is incorporated herein by reference. Fluorophenyl) -1-hydroxy-butyl] -3- (hydroxymethyl) -benzonitrile.

In one embodiment of the invention, the invention relates to a tablet prepared from a mixture of crystalline particles of escitalopram oxalate and a pharmaceutically acceptable excipient, wherein the crystalline particles of escitalopram oxalate According to the invention as described above. Such tablets may be prepared by one of the following tableting methods: direct compression, dry granulation (densification), wet granulation or melt granulation. In certain embodiments, tablets are made by direct compression. In another specific embodiment, the tablet is prepared by dry granulation (densification). In yet another specific embodiment, the tablet is made by wet granulation. In another specific embodiment, the tablet is prepared by melt granulation.

In certain embodiments, the tablet is coated.

In another embodiment, the invention relates to a solid unit dosage form prepared by filling a capsule of a mixture of crystalline particles of escitalopram oxalate and a pharmaceutically acceptable excipient, wherein said escitalopram oxal The crystalline particles of rate are in accordance with the invention as described above, preferably the capsule is a hard gelatin capsule.

Preferably, the solid unit dosage form according to the present invention does not contain a binder.

Solid unit dosage forms according to the invention have an activity of 1 to 60% w / w calculated as the escitalopram base, specifically 4 to 40% w / w as the escitalopram base Ingredient, equivalently 1-30% w / w of the active ingredient, specifically calculated as the escitalopram base, more specifically 4-20% w / w of the active ingredient, calculated as the escitalopram base Most specifically, it may contain 6 to 10% w / w of the active ingredient calculated as the escitalopram base. Suitably, the solid unit dosage form of the present invention contains 8% w / w of active ingredient calculated as the escitalopram base.

Solid unit dosage forms according to the invention are lactose, or other sugars such as sorbitol, mannitol, dextrose and sucrose, calcium phosphate (bibasic, tribasic, hydrous and anhydrous), starch, modified starch, microcrystalline It may contain a filler selected from cellulose, calcium sulfate and / or calcium carbonate. In a preferred embodiment, the solid unit dosage forms of the invention do not contain lactose.

Suitably the filler is a microcrystalline cellulose such as ProSolv SMCC90 manufactured by Penwest Pharmaceuticals or Avicel PH 200 manufactured by FMC Corporation.

In addition to the active ingredients and fillers, solid pharmaceutical unit dosage forms can include various other conventional excipients such as disintegrants and optionally small amounts of lubricants, colorants, and sweeteners.

The lubricant used according to the invention may suitably be one or more selected from the group comprising metallic stearate (magnesium, calcium, sodium), stearic acid, waxes, hydrogenated vegetable oils, talc and colloidal silica.

Preferably, the lubricant is at least one selected from the group comprising talc, magnesium stearate or calcium stearate. Suitably, 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%, more preferably in the range of 0.7% to 1.4%.

In certain embodiments, the solid unit dosage form is substantially free of lactose.

Disintegrants include sodium starch glycolate, croscarmellose, crospovidone, low substituted hydroxypropylcellulose, modified corn starch, pregelatinized starch and natural starch. Suitably the disintegrant is croscarmellose, such as Ac-Di-Sol, produced by FMC.

Optionally, the solid pharmaceutical unit dosage form of the invention may be coated. Suitably, the coating is a film coating based on conventional coating compounds such as Opadry OY-S-28849, white manufactured by Colorcon.

Solid pharmaceutical unit dosage forms of the invention can be prepared by conventional methods using tablet presses with a forced feeding capacity.

The filled hard gelatin capsules of the present invention can be prepared by conventional methods using capsule filling machines suitable for powder filling.

Hereinafter, the present invention will be described by way of examples. However, the examples are only intended to illustrate the present invention and should not be construed as limiting.

Example  1 Removal of hydroxyl-containing impurities by succinic anhydride

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

Example  2 Escitalopram Oxalate  Production scale crystallization

A number of crude escitalopram oxalate batches were recrystallized to the production scale following the procedure described below. Batch included:

a) acidic ring-closure of the R-type diol precursor as described in WO 03/000672, followed by removal of hydroxyl containing impurities by the production scale version of the process described in Example 1, followed by WO 03/000672 Escitalopram prepared by separation of racemic citalopram and escitalopram as described. These batches contain Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile, typically with respect to escitalopram It contains in 0.05% (w / w). These batches are referred to as R-diol batches.

b) escitalopram prepared by S-type ring-closure of a diol precursor via an activated ester under alkaline conditions, as described in US Pat. No. 4,943,590. These batches do not contain Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile. These batches are referred to as S-diol batches.

Manufacturing procedure:

100 kg to 300 kg of crude escitalopram oxalate was placed in the first reactor, R1. 4.1-4.3 L of ethanol per kg of crude escitalopram oxalate was loaded into R1. The solution was mixed and heated to the boiling point (˜80 ° C.). Once dissolved, the solution was transferred through a filter to a second reactor, R2.

The stirrer on R2 was turned on (40-60 rpm) and the solution was once again heated to the boiling point. Once all dissolved in R2, automatic cooling was started to cool the solution gradually according to the cooling rates in Table 1.

Cooling Rate Setpoint for Automatic Cooling During Recrystallization of Escitalopram Oxalate Thickness [℃] Speed [℃ / min] Greater than 70.0 0.151 70.0 to 66.0 0.250 66.0 to 60.0 0.300 60.0 to 56.4 0.327 56.4 to 52.0 0.400 52.0 to 47.6 0.550 47.6 to 35.0 0.700 35.0 to 10.0 0.830

Nucleates were formed in the solution with 0.02 to 0.04 kg of escitalopram oxalate every 3 ° C. and the temperature was reduced until crystallization was observed. The solution was automatically cooled to 15 ° C.

The suspension was pumped into a filter drier, where it was washed and dried. If the suspension is not moved immediately, the temperature should be maintained at 0-15 ° C. The filter cake was dried in vacuo. Once the cake was dried, it was washed with 1.1 to 1.2 L of ethanol per kg of crude escitalopram oxalate contained. The cake was once again dried and heated for final drying for approximately 12 hours. Temperature = 50-60 ° C., pressure <0.13 Bar (abs.).

The filter drier was emptied and escitalopram oxalate was passed to the deagglomeration for deagglomeration of aggregates formed during the drying of the crystals. The dried escitalopram oxalate was triturated to separate the crystals from each other. During grinding, the size and shape of the individual crystals did not change.

The resulting escitalopram oxalate batch had particle characteristics as shown in Table 2.

Comparative example  One

Approximately 35 kg of esci, obtained by precipitation of crude escitalopram oxalate by mixing oxalic acid with an ethanol solution of escitalopram prepared by ring-closure through an labile ester under alkaline conditions The wet filter cake containing tallowram oxalate was suspended in 322 L of ethanol. The material was dissolved by heating to reflux, and 150 L of ethanol was removed by distillation. Cooling was applied to cool the mixture to 15 ° C. at reflux at a cooling rate of 0.2-0.5 ° C./min during a temperature interval of 80 to 40 ° C. During cooling, the mixture was nucleated with escitalopram oxalate (10 g each time) at 75, 65 and 60 ° C. After the crystallization mixture was kept at 15 ° C. for 10 hours, crystalline escitalopram oxalate was isolated. The crystalline mixture was filtered, and the filter cake was washed with ethanol and dried to give purified escitalopram oxalate (27.7 kg, 79%). The particle size distribution of the resulting escitalopram oxalate is reported in Table 3.

Escitalopram Oxalate  Decision and Prosolv SMCC90  Particle size distribution for Sympatec Helos ) Displacement value (%) Comparative Example 1 (μm) ProSolv SMCC90 (㎛) 90 455 291 50 163 130 10 13 37

Comparative example  2

Escitalopram Oxalate  Tablets produced by direct compression of large crystalline particles

Tablet Ingredients:

Tablet core

2554 g (10.2% w / w) escitalopram oxalate

Talc 1400 g (5.6% w / w)

ProSolv SMCC90 19896 g (79.6% w / w)

Ac-Di-Sol 900 g (3.6%)

250 g magnesium stearate (1.0% w / w)

Film coating

Opadry OY-S-28849, white 625 g (2.5% w / w of core weight)

Crystalline particles and talc of escitalopram oxalate from Example 1 were sieved through a 710 μm screen and blended at 6 rpm for 15 minutes in a 100 liter Bohle PTM 200 mixer. ProSolv SMCC90 and Ac-Di-Sol were added and blending continued for 15 minutes. Magnesium stearate was added by sieving through a 710 μm screen and blending continued for 3 minutes.

25 kg of the resulting mixture were tableted (125,000 tablets / hour) on a Korsch PH 230 tablet press fitted with an oval embossed 5.5 × 8 mm punch. Tablet core weight was set to 125 mg. Nominal yield was 200,000 tablets. The tablet press was run until the mixture level reached just above the forced feeder, ie to keep the tableting as long as possible in order to identify the likelihood of separation tendency in the final portion of the mixture. The tablets produced showed satisfactory technical properties.

Those skilled in the art will readily appreciate that the crystals according to the invention can be used in tablet preparation in a similar manner.

Claims (46)

Crystalline particles of escitalopram oxalate, characterized in that the ratio between the median particle size and the particle size at 95% displacement is less than 0.42. 2. The crystalline particle of escitalopram oxalate according to claim 1, wherein the ratio between the median particle size and the particle size at 95% displacement is less than 0.40. The crystalline particle of escitalopram oxalate according to claim 1 or 2, wherein the median particle size is 20 µm or more. 4. Crystalline particles according to claim 3, characterized in that the median particle size of the crystals is at least 40 μm, preferably in the range from 50 to 200 μm. The particle size distribution of the crystalline particles of escitalopram oxalate is according to claim 3 or 4, wherein the peak at the minimum particle size is at least 20 μm, in particular at least 40 μm, preferably Is crystalline particles, characterized in that located at a particle size in the range from 50 to 200 μm. The median particle size 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 Crystalline particles of escitalopram oxalate, which is at least 0.01% (w / w). 7. Crystalline particles according to claim 6, characterized in that the median particle size of the crystals is at least 40 μm, preferably in the range from 50 to 200 μm. 8. Crystalline particles of escitalopram oxalate according to claim 6 or 7, wherein the ratio between the median particle size and the particle size at 95% displacement is less than 0.42, preferably less than 0.40. The median particle size is at least 20 μm and E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1 in the solution in which escitalopram oxalate is crystallized before crystallization Crystalline particles of escitalopram oxalate characterized in that the content of -enyl) -3-hydroxymethyl-benzonitrile is at least 0.01% (W / W) relative to the total weight of the crystallization batch. 10. Crystalline particles according to claim 9, characterized in that the median particle size of the crystals is at least 40 μm, preferably in the range from 50 to 200 μm. The crystalline particles of escitalopram oxalate according to claim 9 or 10, characterized in that the ratio between the median particle size and the particle size at 95% displacement is less than 0.42, preferably less than 0.40. A solid unit dosage form comprising crystalline particles of escitalopram oxalate according to any one of claims 1 to 11. A solid unit dosage form prepared from crystalline particles of escitalopram oxalate according to any one of claims 1 to 11. The tablet according to claim 12 or 13, which is a tablet prepared by direct compression, dry granulation (densification), wet granulation or melt granulation of a mixture of escitalopram oxalate and a pharmaceutically acceptable excipient. Solid unit dosage forms. The solid unit dosage form of claim 14, wherein the tablet is coated. 14. A solid unit dosage form according to claim 12 or 13, which is prepared by filling a hard gelatin capsule with a mixture of escitalopram oxalate and a pharmaceutically acceptable excipient. 17. The solid unit dosage form according to any one of claims 12 to 16, which contains no binder. 18. The active ingredient according to claim 12, wherein 1 to 60% w / w of the active ingredient calculated as escitalopram base, specifically 1 to 30% as calculated as escitalopram base. 4-20% w / w of active ingredient, more specifically 6-10% w / w calculated as escitalopram base, more specifically calculated as escitalopram base A solid unit dosage form containing the active ingredient of w. 19. The process according to any one of claims 12 to 18, wherein lactose, sugars, preferably sorbitol, mannitol, dextrose, and / or sucrose, calcium phosphate, preferably dibasic, tribasic, hydrous and / or A solid unit dosage form comprising a filler selected from anhydrous calcium phosphate, starch, modified starch, microcrystalline cellulose, calcium sulfate and / or calcium carbonate. 20. The solid unit dosage form of claim 19, wherein the filler is microcrystalline cellulose such as ProSolv SMCC90 or Avicel PH 200. The solid according to any one of claims 12 to 20, which contains a lubricant selected from metallic stearate (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica. Unit dosage forms. The solid unit dosage form of claim 21, wherein the lubricant is one or more selected from the group of talc, magnesium stearate and calcium stearate. The solid unit dosage form of claim 22, wherein the lubricant is a combination of talc and magnesium stearate. The solid unit dosage of claim 23, wherein the weight percent of magnesium stearate calculated relative to the weight of the solid dosage form is preferably in the range of 0.4% to 2%, more preferably in the range of 0.7% to 1.4%. brother. The solid unit dosage form of any one of claims 12 to 24, wherein the lactose is substantially free. 12. A process for the preparation of crystalline particles of escitalopram oxalate according to any one of claims 1 to 11, comprising the following steps: a) treating a solution comprising escitalopram with a hydroxyl group scavenger together with one or more hydroxyl containing impurities, b) separating escitalopram from the product obtained from the reaction of the hydroxyl group scavenger with the hydroxyl containing impurity, c) optionally converting escitalopram to its oxalate salt if escitalopram is not yet in the form of its oxalate salt, d) optionally, escitalopram if it is not already in a solvent system suitable for the crystallization process, and transferring escitalopram to this solvent system, and e) a solution of escitalopram oxalate in the appropriate solvent system is gradually cooled from the first temperature to the second temperature while maintaining a controlled cooling profile and crystallization of escitalopram oxalate is carried out during the cooling. Nucleating the solution of escitalopram oxalate by addition. The solution of escitalopram oxalate in a suitable solvent system is gradually cooled from the first temperature to the second temperature while maintaining the controlled cooling profile, and by adding crystals of escitalopram oxalate during the cooling. Nucleating the solution of escitalopram oxalate, wherein the solution of escitalopram is at least 1 ppm, specifically at least 10 ppm, more specifically, relative to the total weight of the crystallization batch Claim 1, comprising E- or Z-4- (4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl) -3-hydroxymethyl-benzonitrile at least 0.01% by weight. A process for the preparation of crystalline particles of escitalopram oxalate according to any one of claims 11 to 11. 28. The method of claim 26 or 27, wherein said solvent system comprises one or more alcohols and optional water. 29. The method of claim 28, wherein the solvent system is ethanol. 30. The solute: solvent weight ratio according to claim 26, wherein the solute: solvent weight ratio ranges from 0.05: 1 to 0.6: 1, preferably from 0.1: 1 to 0.5: 1, more preferably from 0.2: 1 to 0.4: 1. Method characterized in that. 31. The process of claim 26, wherein the first temperature is in the range of 50 ° C. to reflux temperature of the solvent system, preferably 60 ° C. to reflux temperature, more preferably 70 ° C. to reflux temperature. How to. 32. The method according to any one of claims 26 to 31, wherein said second temperature is in the range of 0 to 20 ° C, preferably 0 to 15 ° C, more preferably 7 to 15 ° C. 33. The method of any of claims 26 to 32, wherein the adjusted cooling profile comprises an initial cooling period wherein the cooling rate is maintained within a fixed range. 34. The method of claim 33, wherein the initial cooling period comprises a period until the temperature is below 60 ° C, preferably below 50 ° C, more preferably below 40 ° C. 35. The method of claim 33 or 34, wherein the cooling rate is maintained in the range of 0 to 0.9 deg. C / min, preferably in the range of 0 to 0.6 deg. C / min, more preferably in the range of 0.2 to 0.4 deg. How to. 36. The method of any one of claims 26 to 35, wherein said nucleation is performed two or more times during initial cooling. 37. The process according to any one of claims 26 to 36, wherein after said holding time, the crystalline particles are isolated from the mother liquor by conventional solid / liquid separation techniques, preferably by filtration. 38. The process of any of claims 26 to 37, wherein escitalopram is subjected to R-4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxy under acidic conditions. Butyl] -3- (hydroxymethyl) -benzonitrile. A method of reducing the amount of hydroxyl containing impurities in citalopram, escitalopram or a non-racemic mixture of R- and S-citalopram, comprising the following steps: c) treating a solution comprising citalopram, escitalopram or a non-racemic mixture of R- and S-citalopram with at least one such impurity with a hydroxyl group scavenger, and d) separating the citalopram, escitalopram or non-racemic mixture of R- and S-citalopram from the product obtained from the reaction of the hydroxyl group scavenger with the hydroxyl containing impurity step. 40. A method of reducing the amount of hydroxyl containing impurities in escitalopram according to claim 39. 40. A method of reducing the amount of hydroxyl containing impurities in citalopram according to claim 39. A method of reducing the amount of hydroxyl containing impurities in a non-racemic mixture of R- and S-citalopram. 43. The method of any of claims 26, 39-41 or 42, wherein the hydroxyl group scavenger is selected from the group consisting of cyclic anhydrides. 44. The method of claim 43, wherein the hydroxyl group scavengers cyclic C _{4 -8} - anhydride, preferably succinic anhydride method. 45. The method according to any one of claims 39 to 44, wherein the separation of citalopram or escitalopram from the product resulting from the reaction of the hydroxyl group scavenger with the hydroxyl containing impurity comprises A process, which is carried out by extracting the product resulting from the reaction of a practical scavenger with the hydroxyl containing impurity from an aqueous solution of citalopram or escitalopram into an aqueous solution, in particular an alkaline aqueous solution. The process according to any one of claims 39 to 45, wherein escitalopram and / or citalopram are subjected to R-4- [4- (dimethylamino) -1- (4'-fluoro) under acidic conditions. And phenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile.