BG107578A - Pharmaceutical composition containing citalopram - Google Patents

Abstract

A solid unit dosage for 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 pharmaceutically acceptable salt of citalopram and method for the manufacture of said large crystals. 33 claims

Description

PHARMACEUTICAL COMPOSITION Containing Citalopram

Technical field

The present invention relates to a novel pharmaceutical composition comprising citalopram-1- [3- (dimethylethylamino) propyl] -1- (4fluorophenyl) -1,3-dihydro-5-isobenzo-furancarbonitrile.

BACKGROUND OF THE INVENTION

Citalopram is a well-known antidepressant drug with the following structure:

It is a selective, centrally acting serotonin reuptake inhibitor (5-hydroxytryptamine; 5-HT) and therefore has an antidepressant effect.

Citalopram was first described in DE 2,657,013 corresponding to US 4,136,193. This patent application describes the preparation of citalopram by one method and indicates another method that can be used to prepare citalopram. The resulting citalopram is isolated in crystalline form as the oxalate, hydrobromide and hydrochloride salts, respectively. In addition, the citalopram base was obtained as an oil (BP 175 C / 0.03 mmHg). The publication also discusses the manufacture of tablets containing citalopram salts. Citalopram is marketed as hydrobromide and hydrochloride, respectively.

The production of crystalline citalopram base is discussed in DK 2000 00402. This patent publication describes the preparation of crystalline citalopram base and the application of ^w crystalline citalopram base as an intermediate in the purification of crude citalopram hydrobromide to pure citalopram hydrobromide. The publication also discusses the manufacture of tablets containing citalopram base.

It is well known that the preparation of tablets with a reproducible composition requires that all dry ingredients have good flow properties. In cases where the active ingredient has good flowable properties, the tablets can be prepared by directly compressing the ingredients. However, in many cases the particle size w of the active substance is small, the active ingredient adheres or has poor flow properties.

In addition, small particle size active ingredients mixed with large particle size excipients are usually separated or the mixture disintegrates during the tabletting process.

The problem of small particle size and poor flowability is usually solved by increasing the particle size of the active substance, most often by granulating the active substance. ·· ·· ·· ingredient, alone or in combination with a filler and / or other common tablet ingredients.

One such granulation method is the "wet" granulation process. Using this method, dry solids (active ingredients, fillers, binders, etc.) are mixed and moistened with water or other wetting agent (eg alcohol) to form agglomerates or granules of wet solids. The wet mixing is continued until the desired homogeneous particle size is obtained, after which the granular product w is dried.

An alternative to the wet granulation method is the "melting" granulation, which is also known as the "thermal plastic" granulation process, using a low melting point solid as the granulating agent. Initially, the dry solids are mixed and heated to melt the binder. As the binder liquefies and spreads over the surface of the particles, they adhere to each other to form granules. The binder hardens after cooling to form a dry granular product.

Wet granulation, as well as melting, are energy-intensive operations that require sophisticated and expensive equipment as well as technical skills.

The method used to prepare citalopram-hydrobromide results in a product with a very small particle size of about 2-20 pm, which, like many other small-sized products, The particles have many poor flow properties. Therefore, in order to achieve a proper dosage of citalopram during tableting, it is considered necessary to prepare a larger particle size citalopram granule and improved flow properties.

The marketed citalopram tablet is a tablet made from granulated citalopram hydrobromide with various excipients.

*** In view of the fact that direct compression is much simpler and cheaper than methods involving granulation, it is desirable to develop a method of direct compression of citalopramhydrobromide.

The obstacles that have hitherto prevented the direct compression of citalopram tablets have now been overcome after extensive laboratory testing.

Larger particles, i.e. particles of a size comparable to the size of the filler can be obtained by a novel and inventive method of crystallization, and that these particles are applicable in the production of direct compressed tablets. Neat dosage in capsules can also be done with such large particles.

It has also been found that tablets with surprisingly small variations in citalopram content can be obtained by directly compressing citalopram hydrobromide having a significantly smaller size than that of the filler. Neat dosing in capsules • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ······· can also be achieved, despite the small particle size of citalopram.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a novel pharmaceutical unit dosage form comprising citalopram of a suitable particle size, this unit dosage form being obtainable by direct compression.

Whose *

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

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

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

The invention furthermore provides the following, alone or in combination:

A solid dosage form containing citalopram obtained by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt and pharmaceutically acceptable excipient thereof, or by filling said mixture in a hard gelatin capsule.

• · · · · · · · · · · · · · · · · · · · · · · ·

Crystals of pharmaceutically acceptable salt of citalopram suitable for use in solid, single unit dosage form with an average particle size of at least 40 μπι.

A method of producing crystals of a pharmaceutically acceptable salt of citalopram with an average particle size of at least 40 µg, suitable for use in solid dosage form in which a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system is cooled at an initial temperature to further temperature, followed by the addition of seed crystals of said citalopram salt, followed by standing at said second temperature and controlled cooling to a third temperature, followed by crystals Crystals are isolated by conventional techniques of solid / liquid separation.

The direct compression of citalopram, excipient and other pharmaceutically acceptable excipients into tablets has the great advantage of avoiding granulation and the drying step. Furthermore, since the granulation step is avoided, it is no longer necessary to add a binder.

As used herein, "direct compression" means that the solid unit dosage form is obtained by compressing a simple mixture of the active ingredient and excipients without subjecting the active ingredient to a granulation process to incorporate it into a larger particle and improving its flowability.

As used herein, " binder " means an agent used in wet granulation or granulation processes. * * · · · · · · O '·

7 .........

I · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

As used herein, "particle size distribution" means the distribution of equivalent spherical diameters as determined by laser diffraction at 1 bar dispersion pressure in a Sympatec Helos device. "Average particle size" means, respectively, the average size of said particle distribution.

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

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

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

In one embodiment, the present invention relates to a solid unit dosage form containing citalopram crystals with an average particle size of less than 20 µm.

and * «· ♦ · ·«> ·· ···· · · · ····· · · ··

In another embodiment, the present invention relates to a solid unit dosage form containing citalopram crystals with an average particle size of at least 40 μίτι, preferably in the range of 40 - 200 μπι, more preferably 45 - 150 gm and most preferably 50-100 μηη.

The qualities of flowability, separation and non-mixing, as well as the suitability of citalopram crystals for direct compression depend, in addition to the average particle size, on the particle size distribution.

Preferably, the solid unit dosage forms of the invention do not contain binders.

The solid unit dosage form of the invention may contain 2-60% w / w (w / w) of the active ingredient calculated as citalopram base, preferably 10-40% w / w active ingredient calculated as citalopram base, and more preferably 15-25% w / w active ingredient calculated as citalopram base. It is advantageous that the solid unit dosage form of the invention contains 20% w / w of the active ingredient calculated as citalopram base.

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

• ·

The solid dosage form according to the invention may contain a filler selected from lactose or other sugars, for example sorbitol, mannitol, dextrose and sucrose, calcium phosphates (dibasic, tri-basic, aqueous or anhydrous), starch, modified starches, microcrystalline cellulose, microcrystalline cellulose and / or calcium carbonate. In a preferred embodiment, the solid unit dosage form of the invention does not contain lactose.

Suitable fillers are microcrystalline cellulose such as ProSolv SMC90, manufactured by Penwest Pharmaceuticals, or Avicel PH 200, *** manufactured by FMC Corporation.

In addition to the active ingredient and excipient, solid dosage unit dosage forms may include various other conventional excipients such as disintegrants and optionally smaller amounts of lubricants, colorants and sweeteners.

The lubricants used according to the invention may be one or more of the following metal stearates w (magnesium, calcium, sodium), stearic acid, resin, hydrogenated vegetable oil, talc and colloidal silica.

Suitable lubricants are magnesium stearate or calcium stearate.

Disintegrators include sodium starch glycolate, croscarmellose, crospovidone, low-substituted hydroxypropyl cellulose, modified corn starch, pregelatinized starch and natural starch.

• · · · · · · · ·

The solid unit dosage form of the invention can be prepared by conventional methods using a high power tablet tablet press.

The filled hard gelatin capsule of the invention can be prepared by conventional methods using a capsule filler for powder filling.

In one embodiment of the present invention, the crystals of the pharmaceutically acceptable salt of citalopram have an average particle size in the range of 40 - 200 pm, more preferably 45 - 150 pm and most preferably 50-120 μπι.

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

In yet another embodiment of the present invention, crystals of the pharmaceutically acceptable salt of citalopram with a particle size of at least 40 μηη suitable for administration in solid dosage form are crystallized from a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system. Said solvent system may contain one or more alcohols and optionally water, preferably the solvent system is a mixture of methanol and water, the methanol: water weight ratio being in the range of 5: 1 to 50: 1, 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 in the range between 50 ° C and a reflux temperature of the solvent system, preferably between 60 ° C and a reflux temperature, more preferably between 64 ° C and boiling point. The amounts of the pharmaceutically acceptable salt of citalopram and the solvent system used preferably correspond to the weight ratio of solvent: soluble 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 : 1. The solution of the pharmaceutically acceptable salt of citalopram is extracted to a temperature which is the temperature of formation of the seed crystals, in the range of 20-40 ° C, preferably 25-35 ° C, after which the seed citalopram crystals and the indicated crystallization temperature are placed is maintained for the time required for crystal growth in the range of 30 minutes to 7 days, preferably 1 hour to 4 days and more preferably 12-36 hours. After this retention time, the crystallization batch is gradually cooled in a controlled manner from the nucleation temperature of the crystals to a temperature at which the crystals are isolated from the mother liquor, said gradual cooling being performed over a period of time from 5 minutes to 6 hours. , preferably 15 minutes to 4 hours and more preferably 30 minutes to 2 hours. The crystals of said pharmaceutically acceptable salt of citalopram are preferably isolated from the mother liquor at a temperature in the range of 0-20 ° C, more preferably 5-15 ° C, by conventional separation techniques, for example filtration.

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

• · · ·

The citalopram base crystals used in one embodiment of the invention can be obtained according to the methods described in Dutch patent NL No. 1016435.

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

Examples of carrying out the invention

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, seed crystals of citalopram hydrobromide were placed and kept at 30 ° C for 24 hours, then cooled to 10 ° C for 1 hour. The crystals were isolated by filtration, washed with cold w methanol and dried. The particle size distribution for the crystals obtained is shown 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) under reflux. The solution is cooled down to · 4 4 4 4 * * * * *

30 ° C, seed crystals of citalopram hydrobromide (27 g) were placed and kept at 30 ° C for 16 hours, then cooled to 10 ° C for 1 hour. The crystals were isolated by filtration, washed with cold (10 ° C) methanol (3.5 kg) and dried. The particle size distribution for the crystals obtained is shown in Table 1.

Example 3

Crystallization of citalopram hydrobromide to 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, seed crystals of citalopram hydrobromide (50 g) were placed, hexane (1600 l) was gradually added over 60 minutes, then the suspension was allowed to cool under moderate stirring for 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 dried. The particle size distribution for the crystals obtained is shown 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 phase separation. The organic phase was washed with water (2 x 100 mL) and filtered through a suction filter medium. Volatile fractions have been removed • · • · · · · · f «* * • · · st h« • · · · · · · »• · · · * ·» ** »· · · · · The vacuum and the title compound is obtained as an oil. N-heptane (400 ml) was added and the mixture was heated to 70 ° C. Crystals are formed upon cooling. The white crystals of the citalopram base were filtered and dried at ambient temperature overnight in vacuo.

Table 1: Particle size distribution (Sympatec Helos) for citalopram hydrobromide crystals and ProSolv SCMC90

Quantity (%) Example 1 (lim) Example 2 (mm) Example 3 (mm) ProSolv SCMC90 (μΠΊ) 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 obtained by direct compression of small crystals of citalopram hydrobromide

Tablet Ingredients:

Citalopram, HBr

ProSolv SMCC90

Magnesium stearate

5800 gr

23055 gr

145 g (20% w / w) (79.5% w / w) (0.5% w / w)

Citalopram-hydrobromide crystals from

Example 3 and ProSolv

SMCC90 are mixed at 7 rpm for 10 minutes in a 100 liter mixer

9 · · · 9 * • · ·· · «♦ *» • · * * »

4C · »· · * ··«

I and · · «· *« * - v &

99 · · · · · · ·

Bohle PTM 200. Magnesium stearate was added and stirring continued for another 3 minutes.

kg of the resulting mixture was tableted (125,000 tablets / hour) in a 30-station Fette P 100 / IC tablet press equipped with oblong, embossed, incised 5.5 x 8 mm punchers. The tablet core was set at 125 mg. The nominal yield was 200,000 tablets. The tablet press acted as long as the mixture level was just above the power supply, i.e. tableting continued for as long as possible to identify possible w trends in separation in the latter portions of the mixture.

Qualities of the tablet:

Diameter crushing resistance: 70 N

Breakup time: 30 seconds

Fragility: NA

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

Grip on the perforators: not observed.

w Citalopram content in the composition during compression

The tablets were sampled during compression to measure the separation trend. As there was a significant difference in the size of the active ingredient - citalopramhydrobromide, and the excipient - ProSolv SMCC90, as seen in Table 1, it would be expected that the irregularly sized components would separate, i.e. that the mixture will disintegrate during transfer from the mixing vessel to the tablet press funnel, or be stuck in the tablet press funnel during tableting.

Sampling was performed 50 times at regular intervals during tableting, corresponding to samples from every 4000 tablets obtained. Two tablets were taken for each sample.

The tablets were evaluated by an established method using UV absorption in aqueous solution, thus analyzing 100 tablets. The relative standard deviation in the citalopram content was 1.6%.

The variability in tablet strength is surprisingly low in view of the small particle size of citalopramhydrobromide compared to the excipient.

One possible explanation for this surprising and favorable result may be that the tendency for separation between the small citalopram crystals and the larger filler particles is uniquely balanced by the poor flow properties of the small w crystals.

Example 6

Tablet obtained by direct compression of large crystals of citalopram hydrobromide

Tablet Ingredients:

Citalopram, HBr (20% w / w)

(79.5% w / w) (0.5% w / w)

ProSolv SMCC90

Magnesium stearate

The citalopram hydrobromide crystals of Example 2 and ProSolv SMCC90 are mixed. Magnesium stearate was added and mixing continued.

Tablets of 125 mg nominal weight were obtained.

The tablets had satisfactory technical properties.

W

Example 6

Tablet obtained by direct compression of citalopram crystals

Tablet Ingredients:

Citalopram, HBr

ProSolv SMCC90

Magnesium stearate (16% w / w) (83.3% w / w) (0.7% w / w)

The citalopram hydrobromide crystals of Example 4 were sieved through a 0.3 mm mesh screen and mixed with ProSolv SMCC90 for 3 minutes in a Turbula mixer. Magnesium stearate was added and the mixing continued for another 30 seconds.

The tablets were obtained on a single perforating tablet machine Korsh ECO.

Qualities of the tablet:

Tablet strength, mg: 20

Nominal tablet weight, mg: 125

Tablet diameter, mm: 7

Tablet form: film-coated, special

Diameter crushing resistance: 61.6 N

Disintegration time, min: <1

Roughness: 0.1%

Average tablet weight: 125.4

Weight variations: 0.22% relative standard deviation

Shi »The tablets obtained had satisfactory technical properties.

Claims (33)

Patent Claims CLAIMS 1. A solid dosage form comprising citalopram, which is obtained by directly compressing a mixture of citalopram base or a pharmaceutically acceptable salt and pharmaceutically acceptable excipient thereof, or by filling said mixture in a hard gelatin capsule. Solid dosage unit form according to claim 1, characterized in that it is a tablet prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients. Solid dosage unit form according to claim 1, characterized in that it is prepared by filling a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients in a hard gelatin capsule. Solid dosage unit form according to claims 1-3, characterized in that it does not contain a binder. 5. Solid dosage form according to claims 1-4, characterized in that it contains 2-60% w / w of the active ingredient calculated as citalopram base, preferably 10-40% w / w active ingredient calculated as citalopram base, and preferably 15-25% w / w of the active ingredient calculated as citalopram base. A solid unit dosage form according to claims 1-5, characterized in that it contains a filler selected from lactose, sugars, preferably sorbitol, mannitol, dextrose and / or sucrose, calcium phosphates, preferably dibasic, tri-basic, aqueous and / or anhydrous, starch, modified starches, microcrystalline cellulose, calcium sulfate and / or calcium carbonate. Solid dosage form according to claim 6, characterized in that the filler is microcrystalline cellulose such as ProSolv SMCC90 or Avicel PH 200. Shea- Solid dosage form according to claims 1-7, characterized in that it contains a lubricant selected from metal stearates (magnesium, calcium, sodium), stearic acid, resin, hydrogenated vegetable oil, talc and colloidal silica. Solid dosage form according to claim 8, characterized in that the lubricant is magnesium stearate or calcium stearate. Solid dosage form according to claims 1-9, characterized in that it is substantially lactose free. Solid dosage form according to claims 1-10, characterized in that the active ingredient is citalopram base. • · · - f · ♦ · · • · · · 7τ ···· · • · · · · ♦ · · · · · · · · · · · · · · · · · · · Solid dosage form according to claim 1-10, characterized in that the active ingredient is citalopramhydrobromide or citalopram hydrochloride. Solid dosage form according to claim 12, characterized in that the active ingredient is citalopramhydrobromide. Solid dosage form according to claims 12-13, characterized in that the active ingredient is in the form of crystals with an average particle size of less than 20 µm. Solid dosage form according to claims 12-13, characterized in that the active ingredient is in the form of crystals with an average particle size of at least 40 μπι, preferably in the range of 40-200 gm, more preferably 45-150 gm most preferably 50 -100 μΓΠ. 16. Crystals of a pharmaceutically acceptable salt of citalopram, characterized in that the average crystal size is at least 40 μίτι. Crystals according to claim 16, characterized in that the crystals are of citalopram-hydrobromide or citalopramhydrochloride. Crystals according to claim 17, characterized in that the crystals are of citalopram hydrobromide. Crystals according to claims 16-18, characterized in that the average size of the crystals is in the range 40-200 gm, more preferably 45-150 gm and most preferably 50-120 gm. 20. A method of producing crystals of a pharmaceutically acceptable salt of citalopram with an average particle size of at least 40 gm, characterized in that a solution of the pharmaceutically acceptable salt of citalopram in a suitable solvent system at a first temperature is initially cooled to a second temperature, germinal crystals of said citalopram salt are then placed, followed by a retention time at said second temperature and controlled cooling to a third temperature, after which the crystals are isolated by with the usual liquid / solid separation techniques. 21. The method according to claim 20, wherein the average size of the crystals is in the range 40-200 gm, preferably 45-150 gm and more preferably 50-120 gm. A method according to claims 20-21, characterized in that the solute is citalopram hydrobromide or citalopramhydrochloride. 23. The method of claim 22, wherein the solute is citalopram hydrobromide. 24. The method of claims 20-23, wherein the solvent system comprises one or more alcohols and optionally water. • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 25. The method of claim 24, wherein the solvent system is a mixture of methanol and water. 26. The method of claim 25, wherein the methanol: water weight ratio is in the range of 5: 1 to 50: 1, preferably 10: 1 to 30: 1, and more preferably 15: 1 to 25: 1. 27. The method of claims 20-26, wherein the weight ratio of solvent: soluble 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. <*** A method according to claims 20-27, characterized in that said first temperature is in the range between 50 ° C and the boiling point of the solvent system, preferably between 60 ° C and the boiling point, and more preferably between 64 ° C and boiling point. A method according to claims 20-28, characterized in that said second temperature is in the range of 20-40 ° C, preferably 2535 ° C. W 30. The method of claims 20-29, wherein the retention time is in the range of 30 minutes to 7 days, preferably 1 hour to 4 days, and more preferably 12 to 36 hours. A method according to claims 20-30, characterized in that said third temperature is in the range 0-20 ° C, preferably 515 ° C. • * · · 9 A · · · ·· • 9 9 · 9 9 9 99 9999 999 99 99 9999 99 The method of claims 20-30, wherein said controlled cooling is a gradual cooling over a period of time in the range of 5 minutes to 6 hours, preferably 15 minutes to 4 hours and more preferably 30 minutes to 2 hours. 33. A method according to claims 30-32, characterized in that said isolation of the crystals of the pharmaceutically acceptable salt of citalopram from the mother liquor is carried out by filtration.