FR2812811A1 - PHARMACEUTICAL COMPOSITION CONTAINING CITALOPRAM - Google Patents

Abstract

The invention relates to a solid unit dosage form comprising citalopram prepared by direct compression of a mixture of citalopram base or a citalopram salt for pharmaceutical use and excipients for pharmaceutical use or by filling a capsule with gelatin hard by said mixture. It also relates to large crystals of a citalopram salt for pharmaceutical use and a process for the manufacture of said large crystals.

Description

PHARMACEUTICAL COMPOSITION CONTAINING CITALOPRAM

  The present invention relates to a new composition

  pharmaceutical composition containing citalopram, 1- [3-

  (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile. BACKGROUND ART Citalopram is a well known antidepressant drug that has the following structure:

N C -.... CH3

  CH3 This is a selective, centrally acting serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor

  therefore has an antidepressant action.

  Citalopram has been described for the first time in DE 2,657,013 which corresponds to US Pat. No. 4,136,193. This patent describes a process for the preparation of citalopram and schematically indicates another process which can be used for the preparation of citalopram. The prepared citalopram is isolated in crystallized form respectively as oxalate, hydrobromide and hydrochloride. In addition, citalopram base is obtained as an oil (boiling point 175 ° C / 0.03 mm Hg). The patent also discloses the manufacture of tablets containing citalopram salts. Citalopram is marketed as hydrobromide and hydrochloride, respectively. The manufacture of crystallized citalopram base is described in patent application DK 2000 00402. This patent application describes the preparation of crystallized citalopram base and its use as an intermediate in the purification of crude citalopram hydrobromide into pure citalopram hydrobromide. The application also describes the manufacturing

  of tablets containing citalopram base.

  Citalopram is marketed in a number of countries as tablets prepared by granular citalopram hydrobromide, lactose and other excipients. It is well known that the preparation of tablets having a reproducible composition requires that all dry ingredients have good flowability. When the active ingredient has good flow properties, the tablets can be prepared by direct compression of the ingredients. However, in many cases, the active ingredients have a small particle size, which makes them

  cohesive or gives them poor flowability.

  In addition, an active ingredient having a small particle size mixed with excipients which consist of larger particles will most often exhibit segregation or demixing during the course of the process.

manufacture of tablets.

  The problem of small particle size and poor flowability is traditionally solved by increasing the particle size of the active ingredient, generally by granulation of the active ingredient alone or in combination with a filler and / or other ingredients

  usually included in tablets.

  Such a granulation process is the "wetting" granulation process. In this process, dry solids (active ingredient, filler, binder, etc.) are mixed and moistened with water or other wetting agent (an alcohol for example), and the agglomerates or granules are formed from moistened solids. Moisture agglomeration is continued until the particle size is homogeneous

  desired, the granulated product being then dried.

  Another possible method is "melt" granulation, also referred to as the "thermal plastic" granulation process, wherein a low melting solid is used as the granulating agent. The dry solids are first mixed and then heated until the binder melts. The liquefied binder then spreads on the surface of the particles which adhere to each other and form granules. The binder solidifies on cooling, forming a

dry granular product.

  The wetting granulation process and the melt granulation process are both intensive processes that consume large amounts of energy and require

  expensive and complex and skilled operators.

  The process used for the preparation of citalopram hydrobromide results in a product of very small particles, about 2 to 20 gm, which, like many other small particle products, has very poor flow. In order to obtain a suitable dosage of citalopram during tablet manufacture, it is therefore necessary to manufacture a citalopram granulate having a higher particle size and

  better flowability.

  Commercialized citalopram tablets are made from granulated citalopram hydrobromide in combination with various excipients. Since direct compression is much simpler and less expensive than processes involving granulation, it would be desirable to develop a method of

  direct compression of citalopram hydrobromide.

  The barriers to the production of direct compression citalopram tablets to date have now been circumvented as a result of

  important laboratory research.

  This research has found that larger particles, ie particles of a size comparable to that of the particles of the charge, can be prepared by a new and innovative crystallization process and that the particles obtained can be used to the manufacture of tablets by direct compression. These large particles also make it possible to obtain an accurate dosage

in capsules.

  It has also been observed that it is possible to prepare tablets in which the variations in the citalopram content are surprisingly low, by direct compression of citalopram hydrobromide particles of a size much smaller than that of the filler. A precise dosage can also be obtained in capsules despite

  small size of citalopram particles.

  OBJECTS OF THE INVENTION The present invention relates to a novel pharmaceutical unit dosage form containing citalopram particles of sufficiently large size, the dosage form

  in question that can be prepared by direct compression.

  A second subject of the invention is a capsule containing citalopram. A third object of the invention is large crystals of a citalopram salt for pharmaceutical use which can be

  used for direct compression.

  A fourth object of the invention is to propose a process for manufacturing large crystals of a citalopram salt with

pharmaceutical use.

Presentation of the invention

  The invention thus includes, inter alia, the following elements:

  separately, or in combination: A solid unit dosage form comprising citalopram prepared by direct compression of a mixture of citalopram base or a citalopram salt for pharmaceutical use and excipients for pharmaceutical use, or by filling a hard gelatin capsule with said mixture, crystals of a citalopram salt for pharmaceutical use that can be used in a solid unit dosage form and having a median particle size of at least 40 gm, a method for producing a citalopram salt for pharmaceutical use having a median particle size of at least 40 μm and which may be used in a solid unit dosage form, wherein a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system at a first temperature is first cooled to a second temperature and then seeded by the supply of crystals of said s and citalopram, this operation being followed by a waiting time at said second temperature and then controlled cooling at a third temperature, whereby said crystals are isolated by usual solid / liquid separation techniques. Direct compression of citalopram, a filler and other pharmaceutical excipients to make tablets has the great advantage of avoiding the granulation and drying steps. In addition, since granulation is avoided, it is no longer necessary to add a binder. As used herein, the term "direct compression" means that the solid unit dosage form is prepared by compression of a simple mixture of active ingredient and excipients without the active ingredient having been subjected to a intermediate granulation intended to include it in a particle of larger size and

  thus improve its flowability.

  As used herein, the term "binder" refers to an agent used in the wetting or melt granulation processes and which acts as a binder in the granulated product. As used herein, the term "particle size distribution" means the distribution of equivalent spherical diameters determined by laser diffraction at a dispersive pressure of 1 bar using a Sympatec Helos device. Similarly, the term "median particle size" refers to the median of

  particle size distribution.

  As used herein, the term "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure. Thus, in one of its embodiments, the present invention relates to a tablet prepared by compression

  directly from a mixture of citalopram base or a salt of

  f ci for pharmaceutical use and excipients for pharmaceutical use. In another embodiment, the present invention relates to a capsule prepared by filling a hard gelatin capsule with a mixture of citalopram base or a salt thereof for pharmaceutical use and excipients for pharmaceutical use. In one embodiment, the present invention relates to a solid unit dosage form comprising crystallized citalopram having a median particle size

is less than 20 jm.

  In another embodiment, the present invention relates to a solid unit dosage form comprising crystallized citalopram having a median particle size greater than or equal to 40 mm, preferably 40 to 40 μm, or more preferably 45 to 150 μm. gm, sizes

  preferred being 50 to 100 nm.

  The flowability and segregation and demixing characteristics, and thus the ability of the citalopram crystals to direct compression, depend not only on the median particle size but also on the

  particle size distribution.

  Preferably, solid unit dosage forms

  according to the invention do not contain binder.

  The solid unit dosage form according to the invention may contain from 2 to 60% by weight of active ingredient calculated as citalopram base, preferably from 10 to 40% by weight of active ingredient calculated as citalopram base and preferably still 15 to 25% by weight of active ingredient calculated as citalopram base. Suitably, the solid unit dosage form of the invention contains 20% by weight of active ingredient calculated as

base citalopram.

  In particular, the present invention relates to a solid unit dosage form in which the active ingredient is citalopram hydrobromide or citalopram hydrochloride. Preferably, the active ingredient contained in the solid unit dosage form of the invention is the

citalopram hydrobromide.

  The solid unit dosage form according to the invention may contain a filler which may be lactose or other sugars such as sorbitol, mannitol, dextrose or sucrose, a calcium phosphate (dicalcium or tricalcium phosphate, hydrated or anhydrous), starch, modified starches, microcrystalline cellulose, calcium sulphate and / or calcium carbonate. According to a preferred embodiment, the solid unit dosage form of

  the invention does 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 ingredient and the charge, solid unit pharmaceutical dosage forms may include various other conventional excipients such as disintegrants and possibly minor amounts of lubricants,

dyes and sweeteners.

  The lubricants used according to the invention can be one or more of the following compounds: metal stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc or colloidal silica. The lubricant may be magnesium stearate or

calcium stearate.

  Disintegrators include sodium starch glycolate, croscarmellose, crospovidone, hydroxypropylcellulose

  low substitution, modified corn starch, starch pre-

gelatinized and natural starch.

  The solid unit pharmaceutical dosage form of the invention may be prepared by methods common to

  using a pressurized tablet press.

  The filled hard gelatin capsule according to the invention can be prepared by standard methods using a capsule filling machine suitable for the filling of capsules.

powdered products.

  In one embodiment of the present invention, crystals of a citalopram salt for pharmaceutical use have particles having a median particle size of from 200 to 200, preferably from 45 to 150, and preferably

still 50 to 120 Mm.

  In a preferred embodiment of the present invention, the crystals are citalopram hydrobromide or citalopram hydrochloride, preferably citalopram hydrobromide. According to yet another embodiment of the present invention, crystals of a citalopram salt for pharmaceutical use having a median particle size of at least 40 μm and which can be used in a solid unit dosage form are crystallized from a solution of a citalopram salt for pharmaceutical use in a suitable solvent system. Said solvent system may comprise one or more alcohols and optionally water, preferably the solvent system is a mixture of methanol and water in which the methanol / water ratio by weight is preferably from 5/1 to 1, more preferably from 10/1 to 30/1, more preferably from 15/1 to 25/1. Said citalopram salt for pharmaceutical use is preferably dissolved in the solvent system at a temperature in the range of 50 ° C. to the reflux temperature of the solvent system, preferably 60 ° C. at the reflux temperature, and more preferably 64 C at the reflux temperature. The amounts of citalopram salt used for pharmaceutical purposes and solvents preferably correspond to a solvent / solute ratio by weight of 0.5 / 1 to 5/1, more preferably of 0.7 / 1 to 2/1, more preferably from 0.9 / 1 to 1.5 / 1. The solution of citalopram salt for pharmaceutical use is cooled to a temperature, called the seeding temperature, of 20 to 40 ° C., and preferably of 25 to 35 ° C. The solution is then seeded with citalopram crystals and stored. at said sowing temperature for the waiting time required for crystal growth, in the range of 30 minutes to 7 days, preferably 1 hour to 4 days, and more preferably 12 to 36 hours. After the end of said standby time, the batch of crystallization is gradually cooled in a controlled manner from the seeding temperature to the temperature at which the crystals can be isolated from the mother liquor, this gradual cooling period being in the range from 5 minutes to 6 hours, preferably from 15 minutes to 4 hours, and more preferably from 30 minutes to 2 hours. The crystals of said citalopram salt for pharmaceutical use are preferably separated from the mother liquor at a temperature of 0 to 20 C, preferably 5 to 15 C, using

  usual separation such as filtering.

  The small crystals of a citalopram salt for pharmaceutical use used in one of the embodiments of the invention may be produced according to the described methods.

in US Patent 4,136,193.

  In one embodiment, the crystals of the citalopram base can be produced according to the methods

  described in NL Patent No. 1016435.

  In the following section, the invention is described by several examples. However, these examples are for illustrative purposes only and should not be

  understood as a limitation of said invention.

Example 1

  Crystallization of citalopram hydrobromide in the form of large crystals The citalopram hydrobromide (200 g) is dissolved in a mixture of methanol (200 g) and water (20 g) at 69 ° C. The solution is cooled to 30 ° C., seeded with crystals of citalopram hydrobromide and stored at 30 ° C. for 24 hours, after which it is cooled to 10 ° C. in 1 hour. The crystals are isolated by filtration, washed in cold methanol and dried. The particle size distribution

  crystals obtained is given in Table 1.

Example 2

  Crystallization of Citalopram Hydrobromide as Large Crystals Citalopram hydrobromide (12.0 kg) was dissolved in a mixture of methanol (12.5 kg) and water (1.2 kg) at reflux. The solution is cooled to 30 ° C, seeded with crystals of citalopram hydrobromide (27 g) and stored at 30 ° C. for 16 hours, after which it is cooled to 10 ° C. in 1 hour. The crystals are isolated by filtration, washed in cold (10 C) methanol (3.5 kg) and dried. The particle size distribution of the crystals obtained is given in

table 1.

Example 3

  Crystallization of citalopram hydrobromide in the form of small crystals Citalopram hydrobromide (200 kg) is dissolved in a mixture of methanol (170 l) and acetone (680 l) at 56 ° C. The solution is cooled to 15 ° C. and seeded with crystals of citalopram hydrobromide (50 g). Hexane (1600 L) is added gradually over a period of 60 minutes, then the solution is kept for 8 hours with stirring and moderately cooled. The crystals are isolated by filtration, washed first in a cold mixture (10 C) of acetone (50 L) and hexane, then in hexane (220 L) cold (10 C), and finally dried. . The size distribution

  particulate crystals obtained is given in Table 1.

Example 4

  Crystallization of Citalopram as a Base Citalopram hydrobromide (101 g) was suspended in water (500 ml) and toluene (500 ml). NaOH (60 ml, 5 N (aq)) is added and the mixture is stirred (pH> 10) for 15 minutes before phase separation. The organic phase is washed with water (2 x 100 ml) and filtered through a "filter aid" buffer. Volatiles are removed under vacuum and the title compound is obtained as an oil. N-heptane (400 ml) is added and the mixture is heated to 70 ° C. The crystals are formed during cooling. The white crystals of citalopram base are filtered and dried under vacuum at room temperature overnight.

Table 1

  Particle size distribution (Sympatec Helos) of crystals of citalopram hydrobromide and ProSolv SMCC90 Quantile Example 1 Example 2 Example 3 ProSolv (%) (gm) (gm) (4m) SMCC90 (m)

465.43 549.42 96.96 279.94

342.89 352.23 72.27 231.66

96.87 52.70 14.04 114.17

16.54 11.97 1.19 32.10

8.23 6.67 0.82 20.56

Example 5

  Tablets prepared by direct compression of small crystals of citalopram hydrobromide Tablet Ingredients: citalopram hydrobromide 5800 g (20 wt.%) ProSolv SMCC90 23055 g (79.5 wt.%) Magnesium stearate 145 g (0.5% by weight) weight) The crystals of citalopram hydrobromide of Example 3 were mixed with ProSolv SMCC90 at 7 rpm for 10 minutes in a 100 liter Bohle PTM 200 mixer. Magnesium stearate is added and mixing is continued for 3 minutes. The resulting mixture (25 kg) is tabletted (125,000 tablets per hour) in a 30-station Fette P 1200 / IC tablet press with oblong punched and pre-cut punches of 5.5 x 8 mm. The core weight of the tablets is set at 125 mg. The nominal production is 000 tablets. The operation of the tablet press

  continue until the level of the mixture just

  pressure, which means that the manufacture of tablets is continued for as long as possible in order to identify possible patterns of segregation that could

  appear in the last doses of mixture.

  Properties of the tablets: Diametric compressive strength: 70 N Disintegration time: 30 seconds Friability: not applicable Weight variation: relative standard deviation of 0.84% (measured on tablets) Adhesion to the punch: none was observed Citalopram content of the composition during compression The tablets were sampled throughout the compression to measure the tendency to segregate. Since there is a significant difference in size between the active ingredient (citalopram hydrobromide) and the inert load (ProSolv SMCC90), as shown in Table 1, segregation or demixing could be expected between these components of unequal size during their transfer between the mixing container and the tablet press or during their stay in the press during

the manufacture of tablets.

  Sampling was done 50 times at regular intervals during tablet manufacture, which corresponds to sampling every 4000 tablets

  about. Each sample consists of two tablets.

  The 100 tablets thus taken were determined according to a validated method based on the absorption of UV in an aqueous solution. The relative standard deviation of the content of

citalopram is 1.6%.

  The variability of the dosage of the tablets is surprisingly low compared to the small size of the particles of citalopram hydrobromide compared to that of the particles of the inert filler. One possible explanation for this surprising and beneficial result might be that the tendency for segregation between small crystals of citalopram and larger filler particles is balanced by the poor ability to

the flow of small crystals.

Example 6

  Tablets prepared by direct compression of large crystals of citalopram hydrobromide Ingredients tablets: Citalopram hydrobromide (20% by weight) ProSolv SMCC90 (79.5% by weight) Magnesium stearate (0.5% by weight) Hydrobromide crystals citalopram of Example 2 and ProSolv SMCC90 are mixed. Stearate is added

  magnesium and mixing is continued.

  Tablets are manufactured (nominal weight 125 mg).

  The technical properties of the tablets are satisfactory.

Example 7

  Tablets prepared by direct compression of citalopram crystals Ingredients tablets: Citalopram base (16% by weight) ProSolv SMCC90 (83.3% by weight) Magnesium stearate (0.7% by weight) The crystals of citalopram base of the Example 4 are screened on a sieve of 0.3 mm aperture and mixed with ProSolv

  SMCC90 for 3 minutes in a Turbula mixer-mixer.

  Magnesium stearate is added and continued

mixing for 30 seconds.

  The tablets are made in a tablet press

Korsch EK0 with single punch.

  Properties of the tablets: Dosage of the tablets: 20 mg Nominal weight of the tablets: 125 mg Diameter of the tablets: 7 mm Form of the tablets: film coating, special bulge Diameter compression resistance: 61.6 N Duration of disintegration: <1 min Friability : 0.1% Average weight of the tablets: 125.4 Weight variation: relative standard deviation of 0.22% The technical properties of the tablets produced are:

satisfactory.

Claims (33)

  A solid unit dosage form comprising citalopram characterized in that it is prepared by direct compression of a mixture of citalopram base or a salt thereof for pharmaceutical use and excipients for pharmaceutical use or by filling a capsule in gelatin hard by said mixture.   2. The unit dosage form solid according to claim 1 characterized in that it is a tablet prepared by direct compression of a mixture of citalopram base or a salt of celuici to use   pharmaceutical and excipients for pharmaceutical use.   3. The unit dosage form solid according to claim 1 characterized in that it is prepared by filling a hard gelatin capsule of a mixture of citalopram base or a salt thereof for use   pharmaceutical and excipients for pharmaceutical use.   4. The solid unit dosage form according to one   any of claims 1 to 3 characterized by the fact that it does not contain a binder.   5. The solid unit dosage form according to one   any of claims 1 to 4 characterized by the fact   it contains from 2 to 60% by weight of active ingredient calculated in the form of citalopram base, preferably from 10 to   % by weight, more preferably from 15 to 25% by weight.   6. The solid unit dosage form according to one of   any of claims 1 to 5 characterized by the fact   it contains a filler selected from lactose, sugars, preferably sorbitol, mannitol, dextrose and / or sucrose, calcium phosphates, preferably dicalcium, tricalcium, hydrated and / or anhydrous phosphate, starch, modified starches, microcrystalline cellulose, calcium sulphate and / or calcium carbonate. 7. The solid unit dosage form according to claim 6 characterized in that the filler is a microcrystalline cellulose such as ProSolv SMCC90 or the Avicel PH 200.   8. The solid unit dosage form according to one of   any of claims 1 to 7 characterized by the fact   it contains a lubricant selected from metal stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc or colloidal silica.   9. The solid unit dosage form according to claim 8 characterized in that the lubricant   is magnesium stearate or calcium stearate.   10. The solid unit dosage form according to one of   any of claims 1 to 9 characterized by the fact   that it is substantially free of lactose.   11. The solid unit dosage form according to one   any of claims 1 to 10 characterized by the fact   that the active ingredient is citalopram base.   12. The solid unit dosage form according to one of   any of claims 1 to 10 characterized by the fact   that the active ingredient is citalopram hydrobromide or citalopram hydrochloride.   13. The solid unit dosage form according to claim 12 characterized in that the principle   active ingredient is citalopram hydrobromide.   14. The solid unit dosage form according to the   claims 12 and 13, characterized in that the   active ingredient is in the form of crystals having a size   median particle size less than 20 gm.   15. The solid unit dosage form according to one or   the other of claims 12 and 13 characterized by the fact   that the active ingredient is in the form of crystals having a median particle size of at least 40 gm, preferably 40 to 200 gm, more preferably 45 to 150 gm, more   preferably 50 to 100 gm.   16. Crystals of a citalopram salt for pharmaceutical use, characterized by the fact that the size   median particulate crystals is at least 40 Mm.   17. Crystals according to claim 16, characterized in that they are hydrobromide crystals   citalopram or citalopram hydrochloride.   18. Crystals according to claim 17, characterized in that they are crystals of citalopram hydrobromide. 19. Crystals according to any one of   claims 16 to 18 characterized by the fact that the size   The median particle size of the crystals is 40 to 200 μm, preferably 45 to 150 μm and more preferably 50 to 120 μm. 20. A process for manufacturing crystals of a citalopram salt for pharmaceutical use having a median particle size of at least 40 gm, characterized in that a solution of a citalopram salt for pharmaceutical use in a pharmaceutical system. solvents suitable for a first temperature is cooled to a second temperature and then seeded with crystals of said citalopram salt, this operation being followed by a waiting period at said second temperature and then controlled cooling to a third temperature, after which said crystals are isolated by standard techniques of solid / liquid separation.   21. The process as claimed in claim 20, characterized in that the median particle size of the crystals is 40 to 200 μm, preferably 45 to 150 μm, and   more preferably from 50 to 120 gm.   22. The process according to any one of the   claims 20 and 21, characterized in that the   dissolved substance is citalopram hydrobromide or citalopram hydrochloride.   23. The method of claim 22 characterized in that the dissolved substance is citalopram hydrobromide. 24. The process according to any of   claims 20 to 23 characterized in that the system   of solvents comprises one or more alcohols and possibly water.   25. The process according to claim 24, characterized in that the solvent system is a mixture of methanol and water.   26. The method according to claim 25, characterized in that the methanol / water ratio by weight is from 5/1 to 50/1, preferably from 10/1 to 30/1, and more preferably from 15/1 to 25/1.   27. The process according to any of   claims 20 to 26 characterized in that the report   solvent / solute by weight is 0.5 / 1 to 5/1, preferably   0.7 / 1 to 2/1 and more preferably 0.9 / 1 to 1.5 / 1.   28. The process according to any one of   claims 20 to 27 characterized in that said   first temperature is in the range of 50 C at the reflux temperature of the solvent system, preferably 60 C at the reflux temperature, and more preferably   64 C at the reflux temperature.   29. The process according to any of   claims 20 to 28 characterized in that said   second temperature is 20 to 40 C, preferably 25 to C.   30. The process according to any of   claims 20 to 29 characterized in that said   waiting time is 30 minutes to 7 days, preferably 1 hour to 4 days, and more preferably 12 hours to 36 hours. 31. The process according to any of   Claims 20 to 30, characterized in that   third temperature is from 0 to 20 C, preferably from 5 to C. 32. The process according to any one of   claims 20 to 31 characterized in that said   controlled cooling is a gradual cooling which extends over a period of 5 minutes to 6 hours, preferably from 15 minutes to 4 hours, and more preferably from 30 minutes to 2 hours.   33. The process according to any one of   claims 20 to 32 characterized in that said   Crystal isolation of a citalopram salt for pharmaceutical use from the mother liquor is performed by filtration.