SK2842003A3 - A solid unit dosage form comprising citalopram, crystals of a pharmaceutical acceptable salt of citalopram and method for the manufacture of said crystals - Google Patents

Abstract

A solid unit dosage form comprising citalopram, which is prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, or by filling of said mixture in a hard gelatine capsule. Large crystals of a pharmaceutical acceptable salt of citalopram and method for the manufacture of said large crystals.

Description

Technical field

The present invention relates to a pharmaceutical composition comprising citalopram, 1- [3 (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile, a pharmaceutical salt of citalopram in the form of crystals and their use

BACKGROUND OF THE INVENTION

Citalopram is a well known antidepressant drug having the following formula

NC

It is a selective, centrally acting serotonin reuptake inhibitor (5-hydroxytryptamine; 5-HT) with antidepressant effects.

Citalopram was first described in DE 2,657,271, which corresponds to U.S. Pat. No. 4,136,193. This patent application describes one method of preparing citalopram and indicates another method that can be used to prepare citalopram. The obtained citalopram was isolated in crystalline form as the oxalate, hydrobromide and hydrochloride salts. In addition, citalopram base was obtained as an oil (B.P. 175 C / 4 Pa (0.03 mmHg)). The patent application also suggests the manufacture of tablets containing citalopram salt. Citalopram is marketed as hydrobromide and hydrochloride.

The production of crystalline citalopram base is described in DK 2000 00402, which is also pending. This patent application describes preparation

And the use of crystalline citalopram base as an intermediate for the purification of crude citalopram hydrobromide to pure citalopram hydrobromide. The application also indicates the manufacture of tablets containing citalopram base.

Citalopram is marketed in many countries as a tablet made by compressing granulated citalopram hydrobromide, lactose and other excipients.

It is well known that the preparation of tablets with a reproducible mixture requires that all dry ingredients have good flow properties. If the active ingredient has good flow properties, tablets can be made by direct compression of the ingredients. However, in many cases, the particle size of the active agent is small, the active agent is cohesive or has poor flow properties.

In addition, small particle size active ingredients mixed with excipients having a larger particle size will usually be segregated or mixed during the tabletting process.

The problem of small particle size and poor flowability is usually solved by increasing the particle size of the active ingredient, usually by granulating the active ingredient either alone or in combination with a filler and / or other conventional tableting ingredients.

One such granulation method is the "wet" granulation process. Using this method, dry substances (active ingredients, filler, binder, etc.) are mixed and moistened with water or other wetting agents (e.g. alcohol) and agglomerates or granules are formed from wetted solids. The wetting is continued until the desired homogeneous particle size is attained and then the granular product is dried.

An alternative to the "wet" granulation method is a "melting" granulation, also known as a "thermoformable" granulation process, where a low melting solid is used as the granulating agent. First, the dry substances are mixed and heated until the binder melts. Once the binder has liquefied and covered the surface of the particles, the particles bond together to form a granule. Upon cooling, the binder solidifies to form a dry granulation product.

Wet granulation as well as melting granulation are energy-intensive operations requiring complex and costly equipment as well as technical skill.

The process used to prepare citalopram hydrobromide provides a product with a very small particle size of about 2 to 20 µm, which, like many other particle products with a small particle size, has very poor flow properties. Thus, in order to achieve a suitable dosage of citalopram during tabletting, it is considered necessary to produce citalopram granules with larger particle sizes and improved flow properties.

The citalopram tablet that is sold is a tablet made of granulated citalopram hydrobromide with various excipients.

Given the fact that direct compression is much simpler and cheaper than the method involving granulation, there is a requirement for a direct compression method of citalopram hydrobromide.

Difficulties that have hitherto prevented direct compression of citalopram tablets have been avoided after extensive laboratory research.

It has been found that larger particles can be produced by the novel and inventive crystallization process, i. particles of a size comparable to that of the filler and that these particles are suitable for the manufacture of directly compressed tablets. Such larger particles can also be used for accurate dosing into capsules.

It has also been found that direct compression of citalopram hydrobromide having substantially smaller particle sizes than the filler can produce tablets with a surprisingly small variation in the citalopram content. Despite the small particle sizes of citalopram, accurate dosing into and into capsules can be achieved.

It is an object of the invention to provide novel pharmaceutical unit dosage forms comprising citalopram with a suitably large particle size, wherein said unit dosage form can be made by direct compression.

A second object of the invention is to provide capsules containing citalopram.

A third object of the invention is to provide large crystals of a pharmaceutically acceptable salt of citalopram for use in direct compression.

A fourth object of the invention is to provide a process for producing large crystals of a pharmaceutically acceptable salt of citalopram.

SUMMARY OF THE INVENTION

The present invention provides a solid unit dosage form containing citalopram, which is made by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, or by filling said mixture into a hard gelatin capsule.

Further, the invention provides crystals of a pharmaceutically acceptable salt of citalopram suitable for use in solid unit dosage form with a mean particle size of at least 40 µm.

Further, the invention provides a process for producing crystals of a pharmaceutically acceptable salt of citalopram having a mean particle size of at least 40 µm suitable for use in a solid unit dosage form, wherein the solution of the pharmaceutically acceptable salt of citalopram is cooled first to a second temperature in a suitable solvent system. inoculate by adding crystals of said citalopram salt, followed by holding at said second temperature and controlled cooling to a third temperature, and immediately thereafter isolating said crystals by conventional solid / liquid separation procedures.

Direct compression of citalopram, filler and other pharmaceutically acceptable excipients into tablets has the great advantage of avoiding the granulation and drying step and, since the granulation step is avoided, there is no need to further add a binder.

As used herein, the term "direct compression" means that solid unit dosage forms are made by compressing a simple mixture of the active ingredient and the excipients without subjecting the active ingredient to a transient granulation process to incorporate it into larger particles and improve their flow properties.

As used herein, the term "binder" means an agent that is used in a wet or melting granulation process and behaves as a binder in a granular product.

As used herein, the term "particle size distribution" means the distribution of equivalent spherical diameters determined by laser diffraction at a dispersion pressure of 1 MPa in a Sympatec Helos. 'Mean particle size' means correspondingly the mean value of the said granulometric composition.

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

Thus, in one embodiment of the invention, the present invention relates to a tablet made by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

In another embodiment, the invention relates to a capsule made by filling a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients into a hard gelatin capsule.

In one embodiment, the invention relates to a solid unit dosage form comprising citalopram crystals having a mean particle size of less than 20 µm.

In another embodiment, the invention relates to a solid unit dosage form comprising citalopram crystals having a mean particle size of at least 40 µm, preferably in the range of 40 to 200 µm, more preferably 45 to 150 µm, and most preferably 50 to 100 µm.

The flow, segregation and agitation properties and hence the suitability of the cytalopram crystals for direct compression depend, in addition to the mean particle size, on the granulometric composition.

Preferably, the solid unit dosage form of the invention does not contain a binder.

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

Preferably, the present invention relates to a solid unit dosage form wherein the active ingredient is citalopram hydrobromide or citalopram hydrochloride. Preferably, the active ingredient comprising the solid unit dosage form of the invention is citalopram hydrobromide.

The solid unit dosage form of the invention may comprise a filler selected from the group consisting of lactose or other sugars, e.g. sorbitol, mannitol, dextrose and sucrose, calcium phosphate (dibasic, tribasic, aqueous and anhydrous), starch, modified starches, microcrystalline cellulose, calcium sulfate

-6a / or calcium carbonate. In a preferred embodiment, the solid unit dosage form of the invention does not contain lactose.

Preferably, 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 the filler, the solid pharmaceutical unit dosage forms contain various other conventional excipients such as disintegrants and optionally insignificant amounts of lubricants, colorants or sweeteners.

The lubricants used according to the invention may preferably be one or more of the following metal stearates (magnesium, calcium, sodium), stearic acid, paraffin, hardened vegetable oil, talc and colloidal silicon dioxide.

A preferred 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 dosage forms of the invention can be made by conventional methods using a tabletting press with a pressure capability.

The filled, hard gelatin capsule can be made by conventional methods using a capsule filler suitable for powder filling.

In one embodiment of the invention, the pharmaceutically acceptable salt of citalopram crystals have a mean particle size in the range of 40 to 200 µm, preferably 45 to 150 µm, and more preferably 50 to 120 µm.

In a preferred embodiment of the present invention, the crystals are citalopram hydrobromide or citalopram hydrochloride, preferably citalopram hydrobromide.

In yet another embodiment of the present invention, the pharmaceutically acceptable salt of citalopram crystals having an average particle size of at least 40 µm and suitable for use in a solid unit dosage form are crystallized from a solution of the pharmaceutically acceptable salt of citalopram 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 methanocodal weight ratio is preferably in the range of 5: 1 to 50: 1, even more preferably 10: 1 to 30: 1, and most preferably 15: 1 to 25: 1. Said pharmaceutically acceptable salt of citalopram is preferably dissolved in a solvent system at a temperature comprised between 50 ° C and the reflux temperature of the solvent system, preferably between 60 ° C and the reflux temperature, and most preferably between 64 ° C and the reflux temperature. The amounts of the pharmaceutically acceptable salt of citalopram and the solvent used preferably correspond to a solvent: solute weight ratio in the range of 0.5: 1 to 5: 1, more preferably 0.7: 1 to 2: 1 and most preferably 0.9: 1 to 1.5: first The solution of the pharmaceutically acceptable salt of citalopram is cooled down to a seeding temperature in the range of 20 to 40 ° C, preferably 25 to 35 ° C, and then inoculated with the citalopram crystals and left at said seeding temperature for the holding time required for crystal growth. in the range of 30 minutes to 7 days, preferably 1 hour to 4 days, and most preferably 12 to 36 hours. After said holding time, the crystallization batch is gradually cooled in a controlled manner from the inoculation temperature to a temperature at which the crystals will be isolated from the mother liquor, wherein said progressive cooling passes over a time range of 5 minutes to 6 hours, preferably 15 minutes to 4 hours and most preferably 30 minutes. up to 2 hours. Crystals of said pharmaceutically acceptable salt of citalopram are preferably isolated from the mother liquor at a temperature in the range of 0 to 20 ° C, more preferably 5 to 15 ° C, using conventional separation techniques, e.g. filtration.

Small crystals of the pharmaceutically acceptable salt of citalopram used in one embodiment of the invention can be made by the methods described in US 4,136,193.

The citalopram base crystals used in one embodiment of the invention can be made by the methods described in NL patent no. 1,016,435th

The invention is further illustrated by the following examples. However, the examples are intended only to illustrate the invention and should not be construed as limiting the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Crystallization of citalopram hydrobromide into large crystals

-8 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 with citalopram hydrobromide crystals and left at 30 ° C for 24 hours, then cooled to 10 ° C over 1 hour. The crystals were isolated by filtration, washed with cold methanol and dried. The granulometric composition for the resulting crystals is shown in Table 1.

Example 2

Crystallization of citalopram hydrobromide into 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 was cooled to 30 ° C, seeded with citalopram hydrobromide crystals (27 g) and left at 30 ° C for 16 hours, and then cooled to 10 ° C over 1 hour. The crystals were isolated by filtration, washed with cold (10 ° C) methanol (3.5 kg) and dried. The granulometric composition for the resulting crystals is shown 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 was cooled to 15 ° C, seeded with citalopram hydrobromide crystals (50 g), hexane (1600 L) was gradually added over 60 minutes, then the suspension was allowed to stand with gentle stirring and then cooled over 8 hours. The crystals were isolated by filtration, washed first with a cold (10 ° C) mixture of acetone (50 L) and hexane, then with cold (10 ° C) hexane (220 L) and finally dried. The granulometric composition for the resulting crystals is shown in Table 1.

Example 4

Crystallization of citalopram as the free base

-9 Citalopram hydrobromide (101 g) was suspended in water (500 mL) and toluene (500 mL). NaOH (60 mL, 5N (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 aid. The volatiles were removed in vacuo to give the title compound as an oil. N-Heptane (400 mL) was added and the mixture was heated to 70 ° C. Upon cooling, crystals are formed. The white crystals of citalopram base were filtered and dried at room temperature overnight under vacuum.

Table 1

Granulometric composition (Sympatec Helos) for citalopram hydrobromide crystals and ProSolv SCMC90

number Example 1 Example 2 Example 3 ProSolv SCM90 (%) (Am) (Am) (Am) (Am) 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 made by direct compression of small crystals of citalopram hydrobromide

Tablet ingredients: Citalopram, HBr 5800 g (20 wt.%) ProSolv SMCG90 23055 g (79.5 wt.%) Magnesium stearate 145 g (0.5 wt.%)

The citalopram hydrobromide crystals of Example 3 and ProSolv SMCC90 are agitated for 10 minutes at 7 rpm in a 100 L Bohle PTM 200 mixer. Magnesium stearate is then added and stirring is continued for 3 minutes.

kg of the resulting mixture was tabletted (125,000 tablets / hour) on a 30 digit Fette P 1200 / IC tablet press equipped with elongated exit

-10-thundering, grooves forming 5.5 x 8 mm butchers. The tablet core weight was set to 125 mg. The nominal yield was 200,000 tablets. The tablet press worked until the level of the mixture was exactly above the filling head, i. tableting was continued as far as possible to determine the possible mixing tendencies in the last amounts of the mixture.

Tablet Features:

Average compressive strength: 70 N

Disintegration time: 30 seconds

Friability: NA

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

Punch adhesion: none noticed

Content of citalopram in the mixture during compression

Tablets for testing are taken throughout the entire compression period to measure the agitation tendency. Because there is a significant size difference between the active ingredient, citalopram hydrobromide and the inert filler, ProSolv SMCC90, as shown in Table 1, it is believed that unequal sized components could segregate, i. agitate during transfer from the mixing vessel to the tablet press hopper or by placing it in the tablet press hopper during tabletting.

Sampling for testing during tabletting was performed 50 times at regular intervals, corresponding to sampling for testing for each 4000 tablet produced. Two tablets were taken for each sample.

The tablets were tested in a legalized manner using UV-absorption in aqueous solution, thus analyzing a total of 100 tablets. The relative standard deviation for the citalopram content was 1.6%.

The variability in the amount of active ingredient in the individual tablets tested is surprisingly low considering that the particle size of citalopram hydrobromide is small compared to the inert filler.

One possible explanation for this surprising and beneficial outcome is that the tendency of segregation between small citalopram crystals and larger filler particles is specifically compensated by the poor flow properties of the small crystals.

Example 6

Tablet made by direct compression of large crystals of citalopram hydrobromide

Tablet ingredients:

Citalopram, HBr ProSolv SMCC90 (20 wt.%) (79.5 wt.%) Magnesium stearate (0.5 wt.%)

The citalopram hydrobromide crystals of Example 2 and ProSolv SMCC90 were mixed. Magnesium stearate is added and stirring is continued.

Tablets (125 mg nominal weight) were made.

The tablets had satisfactory technical properties.

Example 7

Tablets made by direct compression of citalopram crystals

Tablet ingredients:

Citalopram base ProSolv SMCC90 (16 wt.%) (83.3 wt.%) Magnesium stearate (0.7 wt.%)

The citalopram base crystals of Example 4 are sieved through a 0.3 mm sieve and mixed with ProSolv SMCC90 for 3 minutes in a Turbula mixer. Magnesium stearate is added and stirring is continued for 30 seconds.

The tablets are made on a simple Korsch punch tableting machine

EKO.

-12Properties of tablet:

Active ingredient content, mg:

Tablet nominal weight, mg: 125

Tablet diameter, mm: 7

Tablet shape: coated, special disintegration

Average compressive strength: 61.6 N

Disintegration time, min: <1

Friability: 0.1%

Mean tablet weight: 125.4

Weight deviation: 0.22% relative standard deviation

The tablets produced had satisfactory technical properties.

Claims (33)

PATENT CLAIMS A solid unit dosage form containing citalopram, characterized in that it is produced by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, or by filling the mixture into a hard gelatin capsule. A solid unit dosage form according to claim 1, wherein the tablet is made by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients. A solid unit dosage form according to claim 1, characterized in that it is produced by filling a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients in a hard gelatin capsule. A solid unit dosage form according to claims 1 to 3, characterized in that it does not contain a binder. A solid unit dosage form according to claims 1 to 4, characterized in that it comprises 2 to 60 wt. % of active ingredient based on citalopram base, preferably 10 to 40 wt. % of active ingredient based on citalopram base and more preferably 15 to 25 wt. of the active ingredient based on citalopram base. A solid unit dosage form according to claims 1 to 5, characterized in that it contains a filler selected from the group comprising lactose, sugars, preferably sorbitol, mannitol, dextrose and / or sucrose, calcium phosphate, preferably dibasic, tribasic, aqueous and. / or anhydrous, starch, modified starches, microcrystalline cellulose, calcium sulfate and / or calcium carbonate. A solid unit dosage form according to claim 6, characterized in that the filler is microcrystalline cellulose, for example ProSolv SMCC90 or Avicel PH 200. A solid unit dosage form according to claims 1 to 7 comprising a lubricant selected from the group consisting of metal stearates (magnesium, calcium, sodium), stearic acid, paraffin, hardened vegetable oil, talc and colloidal silicon dioxide. 9. A solid unit dosage form according to claim 8, wherein the lubricant is magnesium stearate or calcium stearate. A solid unit dosage form according to claims 1 to 9, characterized in that it is substantially lactose-free. The solid unit dosage form of claims 1 to 10, wherein the active ingredient is citalopram base. A solid unit dosage form according to claims 1 to 10, wherein the active ingredient is citalopram hydrobromide or citalopram hydrochloride. 13. A solid unit dosage form according to claim 12, wherein the active ingredient is citalopram hydrobromide. A solid unit dosage form according to claims 12 to 13, characterized in that the active ingredient is in the form of crystals with a mean particle size of less than 20 µm. A solid unit dosage form according to claims 12 to 13, characterized in that the active ingredient is in the form of crystals with a mean particle size of at least 40 µm, preferably in the range of 40 to 200 µm, more preferably in the range of 45 to 40 µm. 150 µm and most preferably in the range 50 to 100 µm. 16. The pharmaceutically acceptable salt of citalopram crystals, wherein the mean particle size of the crystals is at least 40 µm. 17. The crystals of claim 16 which are crystals of citalopram hydrobromide or citalopram hydrochloride. 18. Crystals according to claim 17, characterized in that they are crystals of citalopram hydrobromide. Crystals according to claims 16 to 18, characterized in that the mean particle size of the crystals is in the range of 40 to 200 µm, preferably 45 to 150 µm, and more preferably 50 to 120 µm. 20. A process for producing crystals of a pharmaceutically acceptable salt of citalopram having an average particle size of at least 40 µm, characterized in that the solution of the pharmaceutically acceptable salt of citalopram in a suitable solvent system with an initial temperature is first cooled down to a second temperature, then inoculate by adding crystals of said citalopram salt, followed by holding at a second temperature and controlled cooling to a third temperature, and immediately thereafter isolating said crystals by conventional solid / liquid separation procedures. Method according to claim 20, characterized in that the mean particle size of the crystals is in the range of 40 to 200 µm, preferably 45 to 150 µm, and more preferably 50 to 120 µm. 22. A process according to claims 20 to 21, wherein the solute is citalopram hydrobromide or citalopram hydrochloride. 23. The method of claim 22, wherein the solute is citalopram hydrobromide. 24. The process of claims 20 to 23, wherein the solvent system comprises one or more alcohols and optionally water. 25. The process of claim 24, wherein the solvent system is a mixture of methanol and water. The method according to claim 25, characterized in that the weight ratio of methanocodium is in the range from 5: 1 to 50: 1, preferably from 10: 1 to 30: 1 and more preferably from 15: 1 to 25: 1. The method according to claims 20 to 26, characterized in that the solvent: solute weight ratio is in the range of 0.5: 1 to 5: 1, preferably 0.7: 1 to 2: 1 and more preferably 0.9: 1 to 1.5: 1. The method according to claims 20 to 27, characterized in that the initial temperature is between 50 ° C and the reflux temperature of the solvent system, preferably between 60 ° C and the reflux temperature, and more preferably between 64 ° C and reflux temperature. A method according to claims 20 to 28, characterized in that the second temperature is in the range of 20 to 40 ° C, preferably 25 to 35 ° C. The method according to claims 20 to 29, characterized in that the hold time is in the range of 30 minutes to 7 days, preferably 1 hour to 4 days, and more preferably 12 to 36 hours. Method according to claims 20 to 30, characterized in that the third temperature is in the range of 0 to 20 ° C, preferably 5 to 15 ° C. Process according to claims 20 to 31, characterized in that the controlled cooling is a gradual cooling up to a time range of 5 minutes to 6 hours, preferably 15 minutes to 4 hours and more preferably 30 minutes to 2 hours . 33. The process of claims 20 to 32, wherein isolating the crystals of the pharmaceutically acceptable salt of citalopram from the mother liquor is by filtration.