KR20030024833A - Pharmaceutical composition containing citalopram - Google Patents

Abstract

A solid unit formulation containing citalopram prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, or by filling the mixture into hard gelatin capsules. Large crystals of the pharmaceutically acceptable salt of citalopram and methods of making these large crystals.

Description

Pharmaceutical composition containing citalopram {PHARMACEUTICAL COMPOSITION CONTAINING CITALOPRAM}

Citalopram is a known antidepressant having the structure:

It is an optional, major active serotonin (5-hydroxytrytamine; 5-HT) reuptake inhibitor and therefore has antidepressant activity.

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

The preparation of crystalline citalopram base is disclosed in co-pending DK 2000 00402. This patent publication describes the use of crystalline citalopram base as an intermediate in the preparation of crystalline citalopram base and in the purification of crude citalopram hydrobromide into pure citalopram hydrobromide. The publication also summarizes the preparation of tablets containing citalopram base.

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

It is well recognized that in the manufacture of tablets with renewable compositions all dry ingredients need to have good flowability. If the active ingredient has good fluidity, tablets can be made by direct compression of the ingredients. In many cases, however, the particle size of the active material is small and the active material is cohesive or has poor flowability.

Moreover, active materials with small particle diameters mixed with excipients with larger particle diameters will typically not be separated or mixed during the purification process.

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

One such granulation method is a "wet" granulation method. Using this method, a dry solid (active ingredient, filler, binder, etc.) is combined with water or another wetting agent (eg alcohol) and wetted to produce agglomerates or granules from the wet solid. Wet massing is continued until the desired uniform particle size is obtained, and the granulated product is dried.

As an alternative to the "wet" granulation method there is also "melt" granulation, also known as the "thermoplastic" granulation method, in which low melt solids are used as granulating agents. Initially, the dry solid is blended and heated until the binder is dissolved. As the binder liquefies and spreads over the surface of the particles, the particles will adhere to each other and form granules. The binder solidifies upon cooling to form a dry granular product.

Wet granulation as well as melt granulation is an energy high input unit operation that requires a complex and expensive apparatus as well as technology.

The method used to prepare citalopram hydrobromide produces products with very small particle diameters of approximately 2-20 μm, with very poor flowability, as in many other particulate products with small particle diameters. Thus, in order to achieve proper administration of citalopram during the purification process, it is considered necessary to produce granules of citalopram having a larger particle size and improved flowability.

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

There is a need for a direct compression method of citalopram hydrobromide in view of the fact that direct compression is simpler and cheaper than the granulation involved.

Until now, obstacles that prevented direct compression of citalopram tablets were avoided after extensive laboratory research.

Larger particles, ie particles of a size comparable to the size of the filler, can be produced by novel, advanced crystallization methods, which have been found to be useful for the preparation of direct compressed tablets. Accurate administration in capsules may also be possible using such large particles.

It has also been found that tablets with surprisingly small variations in the content of citalopram can be prepared by direct compression of citalopram hydrobromide having a particle size significantly smaller than the filler. Accurate administration in capsules can also be achieved despite the small particle size of citalopram.

Purpose of the Invention

It is an object of the present invention to provide novel pharmaceutical dosage forms containing citalopram with moderately large particle diameters, which can be prepared by direct compression.

A second object of the present invention is to provide a capsule containing citalopram.

It is a third object of the present invention to provide large crystals of pharmaceutically acceptable salts of citalopram suitable for use in direct compression.

It is a fourth object of the present invention to provide a process for the preparation of large crystals of pharmaceutically acceptable salts of citalopram.

The present invention provides a novel pharmaceutical composition containing citalopram, i.e. 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile It is about.

The invention particularly includes the following alone or in combination:

A solid unit formulation containing citalopram prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, or by filling the mixture into hard gelatin capsules.

Determination of a pharmaceutically acceptable salt of citalopram suitable for use in solid unit preparations with a median particle size of at least 40 μm.

A process for the preparation of a pharmaceutically acceptable salt crystal of citalopram suitable for use in solid unit formulations with a median particle size of at least 40 μm, wherein the pharmaceutically acceptable citalopram in a suitable solvent system at a first temperature The possible salt solution is first cooled to a second temperature and then seeded by the addition of crystals of the citalopram salt followed by a holding time at the second temperature and controlled cooling to a third temperature. The crystals are isolated by conventional solid / liquid separation techniques.

Direct compression of citalopram, fillers and other pharmaceutically acceptable excipients into tablets has the great advantage of avoiding granulation and drying steps. In addition, when avoiding the granulation step, it is no longer necessary to add a binder.

As used herein, “direct compression” refers to the active ingredient being made into larger particles, without undergoing an intermediate granulation process to improve their flowability, wherein the solid unit preparation is prepared by compression of a simple mixture of the active ingredient and excipients. Means that.

As used herein, "binder" refers to a material used in wet or melt granulation methods and acts as a binder in the granulated product.

As used herein, “particle size distribution” means the distribution of equivalent apertures measured by laser diffraction at 1 bar dispersion pressure in a Sympatec Helos device. Similarly, "medium particle diameter" means the middle of the particle size distribution.

As used herein, "reflux temperature" means the temperature at which the solvent or solvent system refluxs or boils at atmospheric pressure.

Thus, in one embodiment of the invention, the invention relates to tablets prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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 pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In one embodiment, the present invention relates to a solid unit formulation containing citalopram of crystals having a median particle diameter of less than 20 μm.

In another embodiment, the present invention contains citalopram of crystals having a median particle diameter of at least 40 μm, preferably 40-200 μm, more preferably 45-150 μm, most preferably 50-100 μm. It relates to a solid unit formulation.

The suitability of the citalopram crystals for flow, separation and immiscibility, and thus for direct compression, depends on the particle size distribution, in addition to the medium particle size.

Preferably, the solid unit preparation according to the invention does not contain a binder.

The solid unit preparation according to the invention has a 2-60% w / w active ingredient, preferably 10-40% w / w active ingredient, more preferably 15-25% w / w activity, calculated as citalopram base It may contain components. Suitably, the solid unit formulation of the present invention contains 20% w / w active ingredient calculated as citalopram base.

In particular, the present invention relates to solid unit preparations wherein the active ingredient is citalopram hydrobromide or citalopram hydrochloride. Preferably the active ingredient contained in the solid unit preparation of the present invention is citalopram hydrobromide.

Solid unit preparations according to the invention are lactose, other sugars such as sorbitol, mannitol, dextrose and sucrose, calcium phosphate (dibasic, tribasic, hydrate and anhydride), starch, modified starch, microcrystalline cellulose, sulfuric acid It may contain a filler selected from calcium and / or calcium carbonate. In a preferred embodiment, the solid unit preparation of the present invention does not contain lactose.

Suitably the filler is 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, the solid pharmaceutical unit preparations may comprise various other conventional excipients such as disintegrants and optionally small amounts of lubricants, colorants and sweeteners.

Lubricants according to the invention may suitably be one or more of the following metallic stearates (magnesium, calcium, sodium), stearic acid, waxes, hydrogenated vegetable oils, talc and colloidal silica.

Suitably the lubricant is magnesium stearate or calcium stearate.

Disintegrants include sodium starch glycolate, croscarmellose, crospovidone, low substituted hydroxypropylcellulose, modified corn starch, pregelatinized starch and natural starch.

The solid, pharmaceutical unit preparations of the present invention can be prepared by conventional methods using tablet presses with a forcing capability.

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

In one embodiment of the invention, the median particle diameter of the crystal of the pharmaceutically acceptable salt of citalopram is 40-200 μm, preferably 45-150 μm, more preferably 50-120 μm.

In a preferred embodiment of the invention, the crystal is citalopram hydrobromide or citalopram hydrochloride, preferably citalopram hydrobromide.

In another embodiment of the invention, the determination of the pharmaceutically acceptable salt of citalopram suitable for use in solid unit formulations with a median particle size of at least 40 μm is such that the pharmaceutically acceptable salt of citalopram in a suitable solvent system is determined. Crystallize from salt solution. The solvent system may contain one or more alcohols and optionally water, preferably the solvent system is a mixture of methanol and water, wherein the methanol: water weight ratio is preferably 5: 1 to 50: 1, more preferably Is from 10: 1 to 30: 1, most preferably from 15: 1 to 25: 1. The pharmaceutically acceptable salt of citalopram is preferably dissolved in the solvent system at 50 ° C. to the reflux temperature of the solvent system, preferably 60 ° C. to the reflux temperature, more preferably 64 ° C. to the reflux temperature. The amount of pharmaceutically acceptable salts and solvents of citalopram used preferably has a solvent: solute weight ratio of 0.5: 1 to 5: 1, more preferably 0.7: 1 to 2: 1, most preferably 0.9: It corresponds to 1 to 1.5: 1. A pharmaceutically acceptable salt solution of citalopram is cooled to a seeding temperature in the range of 20-40 ° C., preferably 25-35 ° C., seeded with citalopram crystals, and at this seeding temperature It is maintained for a holding time for crystal growth in the range of 30 minutes to 7 days, preferably 1 hour to 4 days, more preferably 12 to 36 hours. After the holding time, the crystallization batch is cooled in a controlled manner gradually at the seeding temperature to the temperature at which the crystals are isolated from the mother liquor, the gradually cooling being 5 minutes to 6 hours, preferably 15 minutes to 4 hours, more preferably. Preferably over a time interval in the range of 30 minutes to 2 hours. Determination of said pharmaceutically acceptable salts of citalopram is preferably isolated from the mother liquor using conventional separation techniques such as filtration at temperatures in the range of 0-20 ° C, more preferably 5-15 ° C.

Small crystals of the pharmaceutically acceptable salt of citalopram used in one embodiment of the present invention can be prepared according to the methods described in US Pat. No. 4,136,193.

The crystals of citalopram base used in one embodiment of the present invention can be prepared according to the method described in NL Patent No. 1016435.

In the following, the invention is illustrated by way of examples. However, the examples are only intended to illustrate the present invention and should not be construed as limiting.

Example 1

Crystallization of Citalopram Hydrobromide to Large Crystals

Citalopram hydrobromide (200 g) was dissolved in a mixture of methanol (200 g) and water (20 g) at 69 ° C. The solution was cooled to 30 ° C., seeded using citalopram hydrobromide crystals, left at 30 ° C. for 24 hours and then cooled to 10 ° C. in 1 hour. The crystals were isolated by filtration, washed with cold methanol and dried. The particle size distribution of the resulting crystals is listed in Table 1.

Example 2

Crystallization of Citalopram Hydrobromide to Large Crystals

Citalopram hydrobromide (12.0 kg) was dissolved in a mixture of methanol (12.5 kg) and water (1.2 kg) at reflux temperature. The solution was cooled to 30 ° C., seeded using citalopram hydrobromide crystals (27 g), left at 30 ° C. for 16 hours and then cooled to 10 ° C. in 1 hour. The crystals were isolated by filtration, washed with cold (10 ° C.) methanol (3.5 kg) and dried. The particle size distribution of the resulting crystals is listed in Table 1.

Example 3

Crystallization of Citalopram Hydrobromide into Small Crystals

Citalopram hydrobromide (200 kg) was dissolved in a mixture of methanol (170 L) and acetone (680 L) at 56 ° C. The solution is cooled to 15 ° C., seeded with citalopram hydrobromide crystals (50 g), and hexane (1600 L) is gradually added within 60 minutes, then the suspension is left to stir and cool for 8 hours with moderate stirring. It was. The crystals were isolated by filtration and washed with a mixture of cold (10 ° C.) acetone (50 L) and hexane followed by cold (10 ° C.) hexane (220 L) and dried. The particle size distribution of the resulting crystals is listed in Table 1.

Example 4

Crystallization of Citalopram as Free Base

Citalopram Hydrobromide (101 g) was suspended in water (500 mL) and toluene (500 mL). NaOH (60 mL, 5 N (aq)) was added and the mixture (pH> 10) was stirred for 15 minutes before the phases were separated. The organic phase was washed with water (2 x 100 mL) and filtered through a pad of filter paper. The volatiles were removed in vacuo and the title compound was obtained as an oil. n-heptane (400 mL) was added and the mixture was heated to 70 ° C. Upon cooling, crystals formed. The white crystals of citalopram base were filtered and dried overnight at ambient temperature under vacuum.

Citalopram Hydrobromide Crystals and Particle Size Distribution for ProSolv SCMC90 (Sympatec Helos) Percentile (%) Example 1 (μm) Example 2 (μm) Example 3 (μm) ProSolv SCMC90 (μm) 95 465.43 549.42 96.96 279.94 90 342.89 352.23 72.27 231.66 50 96.87 52.70 14.04 114.17 10 16.54 11.97 1.19 32.10 5 8.23 6.67 0.82 20.56

Example 5

Tablets prepared by direct compression of small citalopram hydrobromide crystals

Tablet Ingredients:

Citalopram, HBr 5800 g (20% w / w)

ProSolv SMCC90 23055 g (79.5% w / w)

145 g (0.5% w / w) magnesium stearate

The citalopram hydrobromide crystals of Example 3 and ProSolv SMCC90 were combined for 10 minutes at 7 rpm in a 100 liter Bohle PTM 200 mixer. Magnesium stearate was added and blending continued for 3 minutes.

25 kg of the resulting mixture were purified on a 30 station Fette P 1200 / IC tablet press equipped with a rectangular protruding 5,5 × 8 mm punch (125.000 tablets / hour). The tablet nucleus weight was set to 125 mg. Nominal yield was 200.000 tablets. The tablet press was run until the mixture level was directly above the energized feeder, ie the tableting continued as long as possible to identify possible separation trends in the final mixture amount.

Tablet characteristics:

Diameter compressive strength: 70 N

Disintegration time: 30 seconds

Breakability: NA

Weight variation: 0.84% relative standard deviation (measured on 20 tablets)

Punch Attachment: Unobserved

Citalopram content in the composition during compression

Tablets were taken by compression to determine the separation trend. Since there is a significant size difference between the active ingredient, citalopram hydrobromide and the inert filler ProSolv SMCC90 shown in Table 1, sheeting in the tablet press hopper during transfer from the mixing vessel to the tablet press hopper or during the tableting process ( It is expected that components with unequal sizes during sitting will not be separated, ie mixed.

Sampling was performed 50 times at regular intervals during tableting, corresponding to the resulting 4000 tablets sampling. Two tablets were recovered for each sample.

A total of 100 tablets were analyzed by analyzing the tablets by a proven method using UV absorption in aqueous solution. The relative standard deviation of citalopram content was 1.6%.

Variability in tablet strength was surprisingly low in terms of small particle size of citalopram hydrobromide compared to inert fillers.

One possible explanation for the surprising and advantageous results above may be that the tendency of separation between small citalopram crystals and large filler particles is specifically balanced by the poor flowability of the small crystals.

Example 6

Tablets prepared by direct compression of large citalopram hydrobromide crystals

Tablet Ingredients:

Citalopram, HBr (20% w / w)

ProSolv SMCC90 (79.5% w / w)

Magnesium Stearate (0.5% w / w)

The citalopram hydrobromide crystals of Example 2 and ProSolv SMCC90 were combined. Magnesium stearate was added and blending continued.

A tablet (125 mg nominal weight) was produced.

Tablets had satisfactory technical characteristics.

Example 7

Tablets made by direct compression of citalopram crystals

Tablet Ingredients:

Citalopram base (16% w / w)

ProSolv SMCC90 (83.3% w / w)

Magnesium Stearate (0.7% w / w)

The citalopram base crystals of Example 4 were filtered through a 0.3 mm sieve hole and then mixed with ProSolv SMCC90 for 3 minutes in a Turbula mixer. Magnesium stearate was added and the formulation continued for 30 seconds.

Tablets were produced on a single punch tableting machine Korsch EK0.

Tablet characteristics:

Tablet strength, mg: 20

Nominal tablet weight, mg: 125

Tablet diameter, mm: 7

Tablet Shape: Specially Defined Film Coating

Diameter compressive strength: 61.6 N

Disintegration time, min: <1

Breakability: 0.1%

Average Tablet Weight: 125.4

Weight variation: 0.22% relative standard deviation

The resulting tablets had satisfactory technical characteristics.

Claims (33)

A solid unit containing citalopram, characterized in that it is prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, or by filling the mixture into hard gelatin capsules. Formulation. The solid unit preparation of claim 1, wherein the tablet is prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The solid unit preparation of claim 1, prepared by filling a hard gelatin capsule with a mixture of citalopram base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The solid unit preparation according to any one of claims 1 to 3, which contains no binder. 5-60% w / w active ingredient, preferably 10-40% w / w active ingredient, more preferably 15-, calculated as citalopram base. A solid unit formulation, containing 25% w / w active ingredient. The lactose, sugars, preferably sorbitol, mannitol, dextrose and / or sucrose, calcium phosphate, preferably dibasic, tribasic, hydrate and / or anhydride according to any of the preceding claims. And a filler selected from starch, modified starch, microcrystalline cellulose, calcium sulfate and / or calcium carbonate. 7. The solid unit preparation of claim 6, wherein the filler is microcrystalline cellulose, such as ProSolv SMCC90 or Avicel PH 200. The solid according to any one of claims 1 to 7, characterized in that it contains a lubricant selected from metallic stearates (magnesium, calcium, sodium), stearic acid, waxes, hydrogenated vegetable oils, talc and colloidal silica. Unit formulation. 9. The solid unit preparation of claim 8, wherein the lubricant is magnesium stearate or calcium stearate. 10. The solid unit preparation according to any one of claims 1 to 9, characterized in that it is substantially lactose free. The solid unit preparation according to any one of claims 1 to 10, wherein the active ingredient is citalopram base. The solid unit preparation according to any one of claims 1 to 10, wherein the active ingredient is citalopram hydrobromide or citalopram hydrochloride. 13. The solid unit preparation of claim 12, wherein the active ingredient is citalopram hydrobromide. The solid unit preparation according to claim 12 or 13, wherein the active ingredient is in crystalline form with a median particle size of less than 20 μm. 14. A crystalline form according to claim 12 or 13, wherein the active ingredient is in a crystalline form having a median particle size of at least 40 μm, preferably 40-200 μm, more preferably 45-150 μm, most preferably 50-100 μm. Solid unit preparation, characterized in that. Crystalline pharmaceutically acceptable salt of citalopram, characterized in that the median particle diameter of the crystal is at least 40 μm. 18. The crystal of claim 16, which is citalopram hydrobromide or citalopram hydrochloride. 18. The crystal of claim 17, which is citalopram hydrobromide. The crystal according to any one of claims 16 to 18, characterized in that the median particle diameter of the crystal is 40-200 μm, preferably 45-150 μm, more preferably 50-120 μm. A pharmaceutically acceptable salt solution of citalopram in a suitable solvent system at a first temperature is first cooled to a second temperature, followed by the addition of crystals of the citalopram salt, followed by a holding time at the second temperature. Pharmaceutically acceptable citalopram with a median particle size of 40 μm or more, characterized in that the crystals are seeded by controlled cooling to a third temperature and the crystals are isolated by conventional solid / liquid separation techniques. Method for preparing crystals of possible salts. 21. The method according to claim 20, wherein the median particle diameter of the crystal is 40-200 mu m, preferably 45-150 mu m, more preferably 50-120 mu m. 22. The process of claim 20 or 21, wherein the dissolved material is citalopram hydrobromide or citalopram hydrochloride. 23. The method of claim 22 wherein the dissolved material is citalopram hydrobromide. 24. The method of any of claims 20 to 23, wherein the solvent system contains one or more alcohols and optionally water. The method of claim 24, wherein the solvent system is a mixture of methanol and water. 26. The process of claim 25, wherein the methanol: water weight ratio is 5: 1 to 50: 1, preferably 10: 1 to 30: 1, more preferably 15: 1 to 25: 1. 27. The solvent according to any one of claims 20 to 26 wherein the solvent: solute weight ratio is from 0.5: 1 to 5: 1, preferably from 0.7: 1 to 2: 1, more preferably from 0.9: 1 to 1.5: 1. Characterized in that the method. 28. The method of any of claims 20 to 27, wherein the first temperature is from 50 ° C to reflux temperature of the solvent system, preferably from 60 ° C to reflux temperature, more preferably from 64 ° C to reflux temperature. How to. 29. The method according to any one of claims 20 to 28, wherein the second temperature is 20-40 ° C, preferably 25-35 ° C. 30. The method according to any one of claims 20 to 29, wherein the holding time is 30 minutes to 7 days, preferably 1 hour to 4 days, more preferably 12 to 36 hours. 31. The method according to any one of claims 20 to 30, wherein the third temperature is 0-20 ° C, preferably 5-15 ° C. 32. The method of any of claims 20 to 31, wherein the controlled cooling is gradually over a time interval in the range of 5 minutes to 6 hours, preferably 15 minutes to 4 hours, more preferably 30 minutes to 2 hours. Phosphorus cooling. 33. The method of any one of claims 20-32, wherein said isolation of the crystals of pharmaceutically acceptable salts of citalopram from the mother liquor is carried out by filtration.