NL1018741C1 - Citalopram-containing pharmaceutical preparation. - Google Patents

Description

Title: Citalopram-containing pharmaceutical preparation

FIELD OF THE INVENTION

The present invention relates to a new pharmaceutical preparation containing citalopram, 1- [3- (dimethylamino) -propyl] -1- (4-fluorophenyl) -1,2-5 dihydro-5-isobenzofurancarbonitrile.

BACKGROUND OF THE INVENTION

Citalopram is a known antidepressant drug with the following structure: T [o? H3 - (X / Sss / N -)

F

It is a selective, centrally acting inhibitor of reuptake of serotonin (5-hydroxytryptamine; 5-HT), which therefore has anti-depressant activities.

Citalopram was first described in DE 2,657,013, corresponding to US 4,136,193. This patent publication describes the preparation of citalopram according to one method and describes a further method that can be used for the preparation of citalopram. The prepared citalopram was resp. as the oxalate, hydrobromide and hydrochloride salts isolated in crystalline form. Furthermore, the citalopram base was obtained in the form of an oil (b.p. 175 ° C / 0.03 mmHg). This publication also describes the manufacture of tablets containing citalopram salts. Citalopram is used as the hydrobromide resp. the hydrochloride.

1018741 2

The preparation of crystalline citalopram base is described in the attached Danish patent application DK 2000 00402. This patent publication describes the preparation of crystalline citalopram base and the use of crystalline citalopram base as intermediate in the purification of crude citalopram hydrobromide to pure citalopram hydrobromide. The publication also describes the manufacture of tablets containing citaloprambase.

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

It is known that the manufacture of tablets with reproducible composition requires that all dry ingredients have good flow properties. In the case that the active ingredient has good flow properties, tablets can be made by direct compression of the ingredients. In many cases, however, the particle size of the active substance is small, the active substance is cohesive or has poor flow properties.

20

Furthermore, typically segregation or demixing will occur during the tableting process in the case that small particle size active substances are mixed with larger particle size excipients.

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

One of those granulation methods is the "wet" granulation process. According to this method, the dry solids (active ingredients, filler, binder, etc.) are mixed and moistened with water or another wetting agent (e.g., an alcohol) and agglomerates or granules are built up from the wetted solids. This wet process is continued 'r <| Q <? g T z · 3 until a desired homogeneous particle size is reached, after which the granulated product is dried.

An alternative to the "wet" granulation method is the "melt" granulation, which is also known as the "thermal plastic" granulation process, wherein a low melting point solid is used as the granulating agent. The dry solids were initially mixed and heated until the binder melts. When the binder becomes liquid and spreads over the surface of the particles, the particles will stick to each other and form granules. The binder solidifies after cooling to form a dry granular product.

Both wet granulation and melt granulation are energy-intensive unit operations that require complicated and expensive equipment as well as technical expertise.

The method used for the preparation of citalopram hydrobromide leads to a product with a very small particle size around 2-20 µm, which product, like many other particulate products with a small particle size, has very poor flow properties. To achieve suitable dosing of the citalopram during tableting, it was therefore considered necessary to make a granulate of citalopram with larger particle size and better flow properties.

The citalopram tablet that is commercially available is a tablet made from granulated citalopram hydrobromide with various excipients.

Since direct compression is much simpler and cheaper than the granulation processes, a method of direct compression of citalopram hydrobromide is desirable.

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

35 1018741 4

It has been found that larger particles, i.e. particles with a size comparable to the size of the filler, can be prepared by a new and inventive crystallization process and that these particles are useful for the manufacture of directly compressed tablets. Accurate dosing in capsules can also be carried out with such large particles.

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

Objects of the invention

The object of the present invention is to provide a new pharmaceutical unit dosage form containing citalopram with a suitable large particle size, whereby this unit dosage form can be produced by direct compression.

20

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 that are suitable for use in direct compression.

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

Summary of the invention

The invention includes, inter alia, the following, alone or in combination: 10

A solid unit dosage form comprising citalopram, prepared by direct compression of a mixture of citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, or by filling this mixture into a hard gelatin capsule.

5

Crystals of a pharmaceutically acceptable salt of citalopram, suitable for use in a solid unit dosage form with a medium particle size of at least 40 µm.

A method for preparing crystals of a pharmaceutically acceptable salt of citalopram with a middle particle size of at least 40 µm and suitable for use 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 15 is first cooled to a second temperature, then inoculated by the addition of crystals of said citalopram salt, followed by a standing time at this second temperature and a controlled cooling to a third temperature, after which the crystals are isolated by conventional solid / liquid separation techniques .

20

The direct compression of citalopram, a filler and other pharmaceutically acceptable excipients into tablets has the great advantage that the granulation and a drying step are avoided. Because the granulation step is avoided, it is furthermore no longer necessary to add a binder.

As used herein, "direct compression" means that the solid unit dosage form is prepared by compression of a simple mixture of the active ingredient and excipients, without the active ingredient being subjected to an intermediate granulation process to embed it in a larger particle and improve its flow properties.

As used herein, "binder" means an agent that is used in wet or melt-granulation processes and acts as a binder in the granulated product.

'1018741 6

As used herein, "particle size distribution" means the distribution of equivalent bulb diameters as determined by laser diffraction at 1 bar dispersion pressure in Sympatec Helos equipment. Accordingly, "middle particle size" indicates the median of this particle size distribution.

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

10

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.

15

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

20

In one embodiment, the present invention relates to a solid unit dosage form comprising citalopram in crystals with a medium particle size below 20 µm.

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

Flow, segregation and demixing properties and hence the suitability of the citalopram crystals for direct compression depend, in addition to the medium particle size, on the particle size distribution.

The solid unit dosage forms according to the invention preferably contain no binder.

10187 41 7

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

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

The solid unit dosage form according to the invention may contain a filler selected from lactose, or other sugars, e.g. sorbitol, mannitol, dextrose and sucrose, calcium phosphates (dibasic, tribasic, anhydrous and anhydrous), starch, modified starches, microcrystalline cellulose, calcium sulfate and / or calcium carbonate. In a preferred embodiment, the solid unit dosage form of the invention contains no lactose.

20

The filler is suitably a microcrystalline cellulose, such as ProSolv SMCC90, produced by Penwest Pharmaceuticals, or Avicel PH200, from FMC Corporation.

In addition to the active ingredient and filler, the solid pharmaceutical unit dosage forms may contain various other conventional excipients, such as disintegrants, as well as, if desired, minor amounts of lubricants, colorants, and sweeteners.

Lubricants used according to the invention may suitably be one or more of the following metal stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica. 1 .1018741

Preferably the lubricant is magnesium stearate or calcium stearate.

8

Disintegrants include sodium starch glycolate, croscaramellose, crospovidone, low-substituted hydroxypropyl cellulose, modified corn starch, pre-gelatinized starch and natural starch.

The solid pharmaceutical unit dosage form of the invention can be prepared by conventional methods using a tablet press with the option of forced feeding.

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

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

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

In yet another embodiment of the present invention, crystals of a pharmaceutically acceptable salt of citalopram with a middle particle size of at least 40 µm and suitable for use in a solid unit dosage form are crystallized from a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system. This solvent system may comprise one or more alcohols and optionally water, and preferably the solvent system is a mixture of methanol and water, wherein the methanol: water weight ratio is preferably in the range of 5: 1 to 50: 1, more preferably 10: 1 to 30: 1 and most preferably 15: 1 to 25: 1. The pharmaceutically acceptable salt of citalopram is preferably dissolved in the solvent system at a temperature in the range 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 the reflux temperature . The amounts used of pharmaceutically acceptable salt of citalopram and solvent preferably correspond to a solvent-discharged substance 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: 1. The solution of a pharmaceutically acceptable salt of citalopram is cooled to a temperature, the grafting temperature, in the range of 20-40 ° C, preferably 25-35 ° C, after which it is inoculated with citalopram crystals and kept at the grafting temperature during a crystal growth stand time in the range of 30 minutes to 7 days, preferably 1 hour to 4 days, and most preferably 12 to 36 hours. After this standing time, the crystallization batch is gradually cooled in a controlled manner from the seeding temperature to the temperature at which the crystals will be isolated from the mother liquor, this gradual cooling being carried out over a period of time in the range of 5 minutes to 6 hours, preferably 15 minutes to 4 hours and preferably 30 minutes to 2 hours. The crystals of the 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, using conventional separation techniques, e.g. filtration.

The small crystals of a pharmaceutically acceptable salt of citalopram, which are used in an embodiment of the invention, can be produced according to methods described in US 4,136,193.

The crystals of citaloprambase that are used in an embodiment of the invention can be produced according to methods described in Dutch patent NL 1016435.

The invention is explained in more detail below with reference to examples. However, the examples are for the purpose of illustrating the invention only and are not to be construed as limiting.

Example 1: crystallization of citalopram hydrobromide into large crystals

Citalopram hydrobromide (200 g) is dissolved at 69 ° C in a mixture of methanol (200 g) and water (20 g). The solution is cooled to 30 ° C, inoculated with 1018741 citalopram hydrobromide crystals and held at 30 ° C for 24 hours, after which it is cooled to 10 ° C within 1 hour. The crystals are isolated by filtration, washed with cold methanol and dried. The particle size distribution for the resulting crystals is shown in Table 1.

5

Example 2: crystallization of citalopram hydrobromide into large crystals

Citalopram hydrobromide (12.0 kg) is dissolved at reflux temperature in a mixture of methanol (12.5 kg) and water (1.2 kg). The solution is cooled to 10 to 30 ° C, inoculated with citalopram hydrobromide crystals (27 g) and held at 30 ° C for 16 hours, after which it is cooled to 10 ° C within 1 hour. The crystals are isolated by filtration, washed with cold (10 ° C) methanol (3.5 kg) and dried. The particle size distribution for the resulting crystals is shown in Table 1.

15

Example 3: crystallization of citalopram hydrobromide to small crystals

Citalopram hydrobromide (200 kg) is dissolved at 56 ° C in a mixture of methanol (170 L) and acetone (680 L). The solution is cooled to 15 ° C, inoculated with citalopram hydrobromide crystals (50 g), hexane (1600 L) is gradually added within 60 minutes and the suspension is allowed to stand for 8 hours with moderate stirring and cooling. The crystals are isolated by filtration, first washed with a cold (10 ° C) mixture of acetone (50 L) and hexane and then with cold (10 ° C) hexane (220 L) and dried. The particle size distribution for the resulting crystals is shown in Table 1.

Example 4: crystallization of citalopram as the free base. Citalopram hydrobromide (101 g) is suspended in water (500 mL) and toluene (500 mL). NaOH (60 mL, 5 N (aq)) is added and the mixture (pH> 10) is stirred for 15 minutes before the phases are separated. The organic phase is washed with water (2 x 100 mL) and filtered through a pad of filter aid. The volatiles are removed under reduced pressure and the title compound is obtained in the form of an oil. N-heptane (400 mL) is added and the mixture is heated to 70 ° C. Crystals form on cooling. The white crystals of citaloprambase are filtered off and dried overnight at room temperature under reduced pressure.

Table 1: particle size distribution (Sympatec Helos) for citalopram hydrobromide crystals and ProSolv SCMC90 amount Example 1 Example 2 Example 3 ProSolv (%) __ (um) __ (um) __ (um) __ SCMC90 (um) _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 __16.54_11.97__1.19 32.10 5 8.23 6.67 0.82 20.56 10

Example 5: Tablet produced by direct compression of small citalopram hydrobromide crystals

Tabletin ingredients: 15 Citalopram, HBr 5800 g (20% w / w)

ProSolv SMCC90 23055 g (79.5% w / w)

Magnesium stearate 145 g (0.5% w / w)

Citalopram hydrobromide crystals of Example 3 and ProSolv SMCC90 were mixed for 10 minutes at 7 rpm in a 100 liter Bohle PTM200 mixer. Magnesium stearate was added and the mixing was continued for 3 minutes.

25 kg of the resulting mixture was tableted (125,000 tablets per hour) on a 30-station Fette P1200 / IC tablet press, embossed with ovals and 5.5 x 8 mm embossed stamps. The tablet core weight was set to 125 mg. The nominal yield was 200,000 tablets. The tablet press was operated if 1187 41 12 until the level of the mixture was just above the forced feed member, i.e., tableting was continued for as long as possible to identify any tendencies towards segregation in the final amounts of the mixture.

5

Tablet forks: diametral crushing strength: 70 N

disintegration time: 30 seconds brittleness: n / a 10 weight variation: 0.84% relative standard deviation (measured on 20 tablets) adhesion to stamp: not observed

Citalonram content in the preparation during compression 15

Tablet samples were taken during compression to measure the tendency to segregate. Since there is a significant difference in size between the active ingredient, citalopram hydrobromide, and the inert filler, ProSolv SMCC90, as shown in Table 1, it would be expected that the components of unequal dimensions would segregate, i.e.

during transfer from the mixing vessel to the tablet press hopper or during the stay in the tablet press hopper during tableting.

Samples were taken 50 times, at regular intervals during tableting, which is equivalent to taking samples after every 4000 tablets produced. Two tablets were taken for each sample.

The tablets were tested by a validated method using UV absorption in an aqueous solution, thus analyzing a total of 100 tablets. The relative standard deviation in the citalopram content was 1.6%.

§0H7 4 ^ t

The variability in tablet strength is surprisingly low, considering the small particle size of citalopram hydrobromide compared to that of the inert filler.

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

Example 6: tablet produced 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)

Citalopram hydrobromide crystals of Example 2 and ProSolv SMCC90 were mixed. Magnesium stearate was added and the mixing was continued.

Tablets (125 mg nominal weight) were prepared.

The tablets had satisfactory technical properties.

25

Example 7: tablet produced by direct compression of citalopram crystals

Tablet ingredients: 30 Citaloprambase (16% w / w)

ProSolv SMCC90 (83.3% w / w)

Magnesium stearate (0.7% w / w)

Citalopram base crystals of Example 4 were sieved through a 35 mm mesh screen and mixed with ProSolv SMCC90 10187 47 14 for 3 minutes in a Turbula mixer. Magnesium stearate was added and the mixing was continued for 30 seconds.

Tablets were made on a Korsch EKO tableting machine with a single stamp.

Tablet eggcans: tablet strength: 20 mg nominal tablet weight: 125 mg 10 tablet diameter: 7 mm tablet form: film coating, with special doom

diametrical crushing strength: 61.6 N

disintegration time: <1 minute brittleness: 0.1% average tablet weight: 125.4 mg weight variation: 0.22% relative standard deviation

The tablets produced had satisfactory technical properties.

20 1018741

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 pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients, or by filling this mixture into a hard gelatin capsule. A solid unit dosage form according to claim 1, characterized in that it is a tablet made by direct compression of a mixture of citaloprambase or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients. A solid unit dosage 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. A solid unit dosage form according to any one of claims 1-3, characterized in that it contains no binder. A solid unit dosage form according to any one of claims 1-4, characterized in that it contains 2-60% w / w active ingredient calculated as citalopram base, preferably 10-40% w / w active ingredient calculated as citalopram base, and preferably 15-25% w / w active ingredient, calculated as citalopram base. Solid unit dosage form according to any one of 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, 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 a microcrystalline cellulose, such as ProSolv SMCC90 or Avicel PH200. Solid unit dosage form according to any of claims 1-7, characterized in that it contains a lubricant selected from metal stearates 1018741 (magnesium, calcium, sodium), stearic acid, hydrogenated vegetable oil, talc and colloidal silica. A solid unit dosage form according to claim 8, characterized in that the lubricant is magnesium stearate or calcium stearate. The solid unit dosage form according to any of claims 1-9, characterized in that it is highly lactose-free. Solid unit dosage form according to any of claims 1-10, characterized in that the active ingredient is citalopram base. A solid unit dosage form according to any one of claims 1-10, characterized in that the active ingredient is citalopram hydrobromide or citalopram hydrochloride. A solid unit dosage form according to claim 12, characterized in that the active ingredient is citalopram hydrobromide. A solid unit dosage form according to claim 12 or 13, characterized in that the active ingredient is in the form of crystals with a medium particle size below 20 µm. A solid unit dosage form according to claim 12 or 13, characterized in that the active ingredient is in the form of crystals with a medium particle size of at least 40 µm, preferably in the range of 40-200 µm, more preferably 45-150 µm and preferably 50-100 µm. Crystals of a pharmaceutically acceptable salt of citalopram, suitable for use in a solid unit dosage form according to claim 15, characterized in that the middle particle size of the crystals is at least 40 µm. Crystals according to claim 16, characterized in that the crystals are citalopram hydrobromide or citalopram hydrochloride. Crystals according to claim 17, characterized in that the crystals are citalopram hydrobromide. 19. Crystals according to any of claims 16-18, characterized in that the middle particle size of the crystals is in the range of 40-200 µm, preferably 45-150 µm and most preferably 50-120 µm. 20. A method for producing crystals of a pharmaceutically acceptable salt of citalopram with a middle particle size of at least 40 µm and suitable for use in a solid unit dosage form according to claim 15, characterized in that a 1018741 solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent system at a first temperature is first cooled to a second temperature, is then inoculated by adding crystals of the citalopram salt, followed by a standing time at this second temperature, and a controlled cooling to a third temperature, after which the crystals are isolated by conventional solid / liquid separation techniques. A method according to claim 20, characterized in that the middle particle size of the crystals is in the range of 40-200 µm, preferably 45-150 µm and most preferably 50-120 µm. Method according to claim 20 or 21, characterized in that the solute is citalopram hydrobromide or citalopram hydrochloride. A method according to claim 22, characterized in that the solute is citalopram hydrobromide. The method according to any of claims 20 to 23, characterized in that the solvent system comprises one or more alcohols and optionally water. The method according to claim 24, characterized in that the solvent system is a mixture of methanol and water. A method according to claim 25, characterized in that the weight ratio of methanol to water is in the range of 5: 1 to 50: 1, preferably 10: 1 to 30: 1 and most preferably 15: 1 to 25: 1. 27. A method according to any one of claims 20-26, characterized in that the weight ratio of solvent-discharged substance is in the range of 0.5: 1 to 5: 1, preferably 0.7: 1 to 2: 1 and most preferably 0.9: 1 to 1.5: 1. A method according to any of claims 20-27, characterized in that said first temperature is in the range 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. A method according to any one of claims 20-28, characterized in that said second temperature is in the range of 20-40 ° C, preferably 25-35 ° C. A method according to any of claims 20-29, characterized in that said standing time is in the range of 30 minutes to 7 days, preferably 1 hour to 4 days and most preferably 12-36 hours. 1018741 A method according to any of claims 20-30, characterized in that said third temperature is in the range of 0-20 ° C, preferably 5-15 ° C. A method according to any one of claims 20 to 31, characterized in that the 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 most preferably 30 minutes to 2 o'clock. A method according to any of claims 20-32, characterized in that the isolation of the crystals of a pharmaceutically acceptable salt of citalopram from the mother liquor is carried out by filtration.