CN1446089A - Pharmaceutical composition containing citalopram - Google Patents

Abstract

A solid unit dosage form containing citalopram is obtained by directly compressing citalopram base or its pharmaceutically acceptable salt with a pharmaceutically acceptable excipient, or by filling the mixture into a hard capsule. The invention also relates to large crystals of pharmaceutically acceptable citalopram salts and a method for preparing such large crystals.

Description

Pharmaceutical composition containing citalopram

The invention relates to a compound containing citalopram, i.e. 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzo-furan nitrile new pharmaceutical compositions.

Background of the invention

Citalopram is a known antidepressant with the following structure:

It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor and thus has antidepressant activity.

Citalopram was first disclosed in DE2657013, corresponding to US4136193. This patent document describes a generalized process for the preparation of citalopram. The obtained citalopram was isolated in crystalline form of oxalate, hydrobromide and hydrochloride, respectively. Furthermore, citalopram base is available in oil form (boiling point 175C/0.03mmHg). This document also outlines the preparation of tablets containing citalopram salts. Citalopram is commercially available as its hydrobromide and hydrochloride salts, respectively.

The preparation of crystals of citalopram base is disclosed in co-pending DK200000402. This patent application describes the preparation of crystals of citalopram base and the use of citalopram base as an intermediate in the purification of crude citalopram hydrobromide into pure citalopram hydrobromide. This document also outlines the preparation of tablets containing citalopram base.

Citalopram is commercially available in many countries by granulating citalopram hydrobromide, lactose and other excipients into tablets.

It is well known that the preparation of tablets requires good flowability of all dry ingredients. Tablets can be prepared by direct compression if the active ingredient has good flowability. However, in many cases, the particle size of the active material is too small, the active material sticks together, and the fluidity is poor.

Moreover, in the process of preparing tablets, active substances with small particle sizes are mixed with larger excipients, and uneven mixing often occurs.

The problem of too small particles and poor fluidity can be conventionally solved by increasing the particle size of the active substance, usually by granulating the active substance alone or mixed with fillers and/or conventional tablet-making substances.

One method of granulation is known as "wet" granulation. Using this method, dry solid substances (active substances, fillers, binders, etc.) are mixed and wetted with water or another wetting agent (such as alcohol) to obtain wet solid mass or granules. The resulting granules are dried until the desired uniform particle size is obtained.

Another type of "wet" granulation is "melt" granulation, also known as "thermoplastic" granulation, in which a low-melting solid is used as the granulation agent. Initially, the dry solids are mixed and heated until the binder melts. The binder is melted and distributed on the surface of the particles, and these particles are bonded to each other to obtain the desired particles. The binder cools and solidifies to form a dry granular product.

Mixed granulation like melt granulation requires more complex and expensive equipment, and requires higher operating techniques.

The particle size of citalopram hydrobromide obtained by conventional methods is very small, about 2-20 μm, and its fluidity is very poor. Therefore, in order to obtain an appropriate citalopram dosage when preparing tablets, it is necessary to prepare citalopram granules with a larger particle size to improve their fluidity.

The commercially available citalopram tablet is obtained by mixing citalopram hydrobromide with various excipients and granulating.

Considering that the direct compression method is simple and cheap relative to the granulation method, it is desired to invent a direct compression method of citalopram hydrobromide.

The difficulties hindering the preparation of citalopram tablets by the direct compression method have been resolved through extensive laboratory studies.

It has been found that large particles, ie particle sizes comparable to those of fillers, can be obtained by a new, inventive manufacturing process, and these can be used in the manufacture of tablets by direct compression. Capsules for precise dosage can also use the large particles.

Surprisingly, it has also been found that by direct compression of citalopram hydrobromide which has a particle size much smaller than that of the filler, citalopram tablets with very little variation in content can be obtained. Despite the small particle size of citalopram, precise dosage capsules are available.

purpose of invention

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

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

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

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

Summary of the invention

The present invention particularly includes following individual schemes or their combination:

A solid unit dosage form, comprising citalopram obtained by directly compressing citalopram base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, or filling the above mixture into a hard capsule.

Crystals of a pharmaceutically acceptable salt of citalopram having an average particle size of at least 40 [mu]m suitable for use in solid unit dosage forms.

A method for preparing crystals of pharmaceutically acceptable salts of citalopram having an average particle size of at least 40 μm and usable in solid unit dosage forms, the method is to dissolve a solution system of pharmaceutically acceptable salts of citalopram in a suitable solvent first from a first temperature Cool to the second temperature, then add the citalopram salt seed crystals, place at the second temperature for a period of time, control cooling to the third temperature to precipitate crystals, and separate using conventional solid/liquid separation technology.

There is a great advantage in directly compressing citalopram, fillers and other pharmaceutically acceptable excipients into tablets, which can omit the steps of granulation and drying. Moreover, since the granulation step is omitted, the addition of binders is no longer required.

Here, "direct compression" means that the preparation of the solid unit dosage form is obtained by simply mixing the active ingredient with excipients and then compressing, without making the active ingredient into intermediate granules to form large particles and improve its fluidity.

As used herein, "binder" means an agent used in wet or melt granulation to act as a binding agent in the granulated product.

Here, "particle distribution" refers to the distribution of equivalent spherical diameters determined by laser diffraction with a Sympatec Helos apparatus at a dispersion pressure of 1 bar. "Mean particle size" accordingly refers to the mean value of the distribution of said particles.

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

In a specific embodiment of the present invention, it relates to a tablet obtained by directly compressing a mixture of citalopram base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In another specific embodiment, the present invention relates to a hard capsule filled with a mixture of citalopram base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In a particular embodiment, the invention relates to a solid unit dosage form comprising a crystalline form of citalopram having an average particle size of less than 20 μm.

In another particular embodiment, the invention relates to solid unit dosage forms comprising crystalline forms having an average particle size of at least 40 μm, preferably between 40-200 μm, more preferably between 45-150 μm, most preferably between 50-100 μm.

Flowability, separation and layering, and suitability of citalopram crystals for direct compression depend on particle distribution in addition to particle size.

Preferably, the solid unit dosage forms of the present invention contain no binders.

The solid unit dosage form of the present invention may contain 2-60% by weight of the active ingredient calculated as citalopram base, preferably 10-40% w/w, more preferably 15-25% w/w. Suitably, the solid unit dosage form of the invention comprises 20% w/w active ingredient calculated as citalopram base.

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

The solid unit dosage forms of the present invention may contain fillers selected from lactose, or other sugars, such as sorbitol, mannitol, glucose and sucrose, calcium phosphate (binary, ternary, aqueous and anhydrous), Starch, modified starch, microcrystalline cellulose, calcium sulfate, and/or calcium carbonate. In preferred embodiments, the solid unit dosage forms of the invention are lactose-free.

Suitably, the filler is microcrystalline cellulose, such as ProSolv SMCC90 manufactured by Penwest Pharmaceuticals, or Avicel PH200 from FMC Corporation.

In addition to active ingredients and fillers, pharmaceutical solid unit dosage forms may contain various other conventional excipients, such as disintegrants and, optionally, small amounts of lubricants, colorants and sweeteners.

The lubricant used in the present invention may be one or more of the following metal stearates (magnesium, calcium, sodium), stearic acid, waxes, hydrogenated vegetable oils, talc and colloidal silicon dioxide.

Suitable lubricants are magnesium stearate or calcium stearate.

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

The pharmaceutical solid unit dosage form of the present invention can be prepared by conventional methods using a tablet press capable of pressurized feeding.

The capsules of the present invention can be filled by conventional methods using a capsule filling machine suitable for powder filling.

In a specific embodiment of the present invention, the crystals of the pharmaceutically acceptable salt of citalopram have an average particle size of 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 particular embodiment of the present invention, crystals of the pharmaceutically acceptable salt of citalopram having an average particle size of at least 40 μm and suitable for solid unit dosage form are precipitated from a solution of the pharmaceutically acceptable salt of citalopram in a suitable solvent system. The above solvent system may comprise one or more alcohols and optionally water, preferably the solvent system is a mixture of methanol and water, wherein the weight ratio of methanol to water is from 5:1 to 50:1, more preferably 10:1 to 30:1, most preferably 15:1 to 25:1. The above pharmaceutically acceptable salt of citalopram is preferably dissolved in the solvent system at 50°C to the reflux temperature of the solvent system, preferably at 60°C to the reflux temperature, more preferably at 64°C to the reflux temperature. The amount of citalopram pharmaceutically acceptable salt and used solvent is preferably 0.5:1 to 5:1 according to solvent and solute weight ratio, more preferably 0.7:1 to 2:1, most preferably 0.9:1 to 1.5:1 to determine . The solution of the pharmaceutically acceptable salt of citalopram is cooled to the temperature for crystallization, which is in the range of 20-40°C, preferably in the range of 25-35°C, citalopram crystals are precipitated at this temperature, and at this The growth is maintained at temperature for 30 minutes to 7 days, preferably 1 hour to 4 days, more preferably 12-36 hours. After this standing time, control to gradually cool down to the temperature at which the crystallization will be separated from the mother liquor, the above-mentioned controlled gradual cooling process is to gradually cool down in the time frame of 5 minutes to 6 hours, preferably in 15 minutes to 4 hours, more preferably Preferably it is 30 minutes to 2 hours. The temperature at which the pharmaceutically acceptable salt crystals of citalopram are separated from the mother liquor is preferably in the range of 0-20°C, more preferably in the range of 5-15°C, and the separation is carried out according to conventional separation techniques, such as filtration.

In a specific embodiment of the present invention, the small crystals of the pharmaceutically acceptable salt of citalopram are prepared according to the method described in US4136193.

The citalopram base crystals in a specific embodiment of the present invention are prepared according to the method described in NL Patent No. 1016435.

The present invention will be illustrated by way of examples below. However, these examples are only for illustrating the present invention, and do not limit the present invention in any way.

Example 1

Citalopram hydrobromide crystallizes into large crystals

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

Example 2

Citalopram hydrobromide crystallizes into large crystals

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

Example 3

Citalopram hydrobromide crystallizes as small crystals

Citalopram hydrobromide (200 kg) was dissolved in a mixed solvent of methanol (170 L) and acetone (680 L) at 56°C. The solution was cooled to 15°C, and citalopram hydrobromide crystals (50 g) were used as seed crystals, and hexane (1600 L) was gradually added within 60 minutes, and the resulting suspension was maintained under medium-speed stirring and allowed to cool for 8 hours . The crystals were separated by filtration, washed first with a mixture of cold (10°C) acetone (50 L) and hexane, then washed with cold (10°C) hexane (220 L), and dried. The particle size distribution of the obtained crystals is shown in Table 1.

Example 4

Crystallization of citalopram free base

Citalopram hydrobromide (101 g) was suspended in a mixed solvent of water (500 ml) and toluene (500 ml). NaOH (60ml, 5N(aq)) was added, the mixture (pH>10) was stirred for 15 minutes, and the layers were separated. The organic phase was washed with water (2 x 100ml) and filtered through a filter pad. The solvent was evaporated under reduced pressure to obtain an oily compound. n-Heptane (400ml) was added and the mixture was heated to 70°C. Crystallization was obtained on cooling. White crystals of citalopram base were obtained by filtration and dried under vacuum overnight at ambient temperature.

Table 1: Particle size distribution of crystalline citalopram hydrobromide and ProSolv SCMC90 (Sympatec Helos) Quantity distribution (%) 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

Preparation of tablets by direct compression of small crystals of citalopram hydrobromide

Tablet Composition:

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

ProSolv SMCC90 23055g (79.5%w/w)

Magnesium Stearate 145g (0.5% w/w)

Citalopram hydrobromide crystals from Example 3 were mixed with ProSolv SMCC90 in a 100 liter Bohle PTM 200 mixer at 7 rpm for 10 minutes. Magnesium stearate was added and blending continued for 3 minutes.

The resulting 25 kg blend was compressed on a 30 station Fette P 1200/IC tablet press using rectangular, convex 5,5 x 8 mm punches (125,000 tablets/hour). The tablet core weight is set at 125mg. The design output is about 200,000 pieces. The tableting process was carried out until the blend level exceeded the pressurized feeder, that is, the tableting process was as long as possible until it was determined that the blend had reached an amount that would create a tendency to separate.

Tablet performance parameters:

Compressive strength: 70N

Disintegration time: 30 seconds

Brittleness: NA

Weight variance: 0.84% relative standard deviation (20 pieces measured)

Sticking situation: not observed

Composition citalopram content during tablet compression

To measure separation tendency, samples were taken at any time throughout the compression process. Due to the significant difference in particle size between the active ingredient citalopram hydrobromide and the filler ProSolv SMCC90, as shown in Table 1, the During the process, when the material remains in the feeder, the components with different particle sizes may be separated, that is, separated and mixed.

Sampling inspections are carried out regularly 50 times during the tableting process, equivalent to one sampling inspection for every 4000 tablets. Two slices were drawn for each sample test.

The content of the tablets was determined by the UV absorption method of standard aqueous solutions, and a total of 100 tablets were analyzed. The relative standard deviation for citalopram content was 1.6%.

Tablet strength varied very little due to the small particle size of citalopram hydrobromide relative to the filler.

One possible explanation for this surprisingly favorable result is that the tendency of the small size citalopram crystals to separate from the larger bulking agent is balanced by the poorer flowability of the small crystals.

Example 6

Preparation of Tablets by Direct Compression of Large Citalopram Hydrobromide Crystals

Tablet Composition:

Citalopram, HBr (20% w/w)

ProSolv SMCC90 (79.5% w/w)

Magnesium Stearate (0.5% w/w)

The crystalline citalopram hydrobromide from Example 2 was mixed with ProSolv SMCC90. Magnesium stearate was then added and blending continued.

Tablets designed for a tablet weight of 125 mg were prepared.

Tablets have satisfactory process properties.

Example 7

Preparation of Tablets by Direct Compression of Citalopram Crystals

Tablet Composition:

Citalopram base (16% w/w)

ProSolv SMCC90 (83.3% w/w)

Magnesium Stearate (0.7% w/w)

The citalopram base from Example 4 was crystallized through a 0.3 mm sieve and then mixed with ProSolvSMCC90 in a Turbula mixer for 3 minutes. The magnesium stearate is then added and blending is continued for an additional 30 seconds.

Tablets were compressed using a single punch Korsch EK0 tablet press.

Tablet performance parameters:

Tablet strength, mg: 20

Theoretical tablet weight, mg: 125

Diameter, mm: 7

Shape: enveloped, specific

Compressive strength: 61.6N

Disintegration time, min: <1

Brittleness: 0.1%

Average tablet weight: 125.4

Weight variance: 0.22% relative standard deviation

The obtained tablets had satisfactory processing properties.

Claims (33)

1. The solid unit dosage form containing citalopram is characterized in that it is obtained by directly compressing citalopram base or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient, or the above-mentioned mixture is filled into a hard in capsules. 2. The solid unit dosage form according to claim 1, characterized in that it is a tablet formed by directly compressing citalopram base or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients. 3. The solid unit dosage form as claimed in claim 1, characterized in that it is formed by filling a mixture of citalopram base or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient into a hard capsule. 4. The solid unit dosage form according to claims 1-3, characterized in that it does not contain a binder. 5. The solid unit dosage form according to claim 1-4, characterized in that it contains 2-60% by weight of the active ingredient calculated as citalopram base, preferably 10-40% w/w, more preferably 15- 25% w/w. 6. The solid unit dosage form according to claims 1-5, characterized in that it contains a filler selected from lactose, sugar, preferably sorbitol, mannitol, glucose and/or sucrose, calcium phosphate, preferably binary , ternary, aqueous and/or non-aqueous, starch, modified starch, microcrystalline cellulose, calcium sulfate, and/or calcium carbonate. 7. The solid unit dosage form according to claim 6, wherein the filler is microcrystalline cellulose, such as ProSolv SMCC90 or Avicel PH 200. 8. The solid unit dosage form as claimed in claim 1-7, characterized in that it contains a lubricant selected from stearate (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talcum powder and gum silica. 9. The solid unit dosage form of claim 8, wherein the lubricant is magnesium stearate or calcium stearate. 10. The solid unit dosage form according to claims 1-9, which is substantially lactose-free. 11. Solid unit dosage form according to claims 1-10, characterized in that the active ingredient is citalopram base. 12. Solid unit dosage form according to claims 1-10, characterized in that the active ingredient is citalopram hydrobromide or hydrochloride. 13. The solid unit dosage form of claim 12, wherein the active ingredient is the hydrobromide salt of citalopram. 14. Solid unit dosage form according to claims 12-13, characterized in that the active ingredient is in crystalline form with an average particle size of less than 20 [mu]m. 15. Solid unit dosage form according to claims 12-13, characterized in that the active ingredient is in crystalline form with an average particle size of at least 40 μm, preferably 40-200 μm, more preferably 45-150 μm, most preferably 50 μm -100 μm. 16. Crystals of a pharmaceutically acceptable salt of citalopram, characterized in that the average particle size of the crystals is at least 40 [mu]m. 17. The crystal according to claim 16, characterized in that the crystal is the hydrobromide or hydrochloride salt of citalopram. 18. The crystal according to claim 17, characterized in that said crystal is the hydrobromide salt of citalopram. 19. The crystal according to claims 16-18, characterized in that the average particle size of the crystal is 40-200 μm, preferably 45-150 μm, more preferably 50-120 μm. 20. A method for preparing crystals of pharmaceutically acceptable salts of citalopram having an average particle size of at least 40 μm, characterized in that the solution system of pharmaceutically acceptable salts of citalopram dissolved in a suitable solvent is first cooled from a first temperature to a second temperature, Then add the seed crystals of the citalopram salt, maintain at the second temperature for a period of time, control cooling to the third temperature to precipitate crystals, and separate with conventional solid/liquid separation technology. 21. The method according to claim 20, characterized in that the average particle size of the crystals is 40-200 μm, preferably 45-150 μm, more preferably 50-100 μm. 22. The method according to claims 20-21, characterized in that the dissolved substance is citalopram hydrobromide or hydrochloride. 23. The method of claim 22, wherein said dissolved substance is citalopram hydrobromide. 24. Process according to claims 20-23, characterized in that the solvent system comprises one or more alcohols and optionally water. 25. The method according to claim 24, characterized in that the solvent system is a mixed solvent of methanol and water. 26. The method according to claim 25, characterized in that the weight ratio of methanol to water is 5:1 to 50:1, preferably 10:1 to 30:1, more preferably 15:1 to 25:1. 27. The method according to claims 20-26, characterized in that the weight ratio of solvent to solute is 0.5:1 to 5:1, preferably 0.7:1 to 2:1, more preferably 0.9:1 to 1.5:1. 28. The method according to claims 20-27, characterized in that the first temperature is from 50°C to the reflux temperature of the solvent system, preferably from 60°C to the reflux temperature, more preferably from 64°C to the reflux temperature. 29. The method according to claims 20-28, characterized in that the second temperature is in the range of 20-40°C, preferably in the range of 25-35°C. 30. The method according to claims 20-29, characterized in that the standing time is 30 minutes to 7 days, preferably 1 hour to 4 days, more preferably 12-36 hours. 31. The method according to claims 20-30, characterized in that the third temperature is in the range of 0-20°C, preferably in the range of 5-15°C. 32. The method according to claims 20-31, characterized in that the controlled cooling is a gradual cooling within the time range of 5 minutes to 6 hours, preferably 15 minutes to 4 hours, more preferably 30 minutes to 2 hours. 33. The method according to claims 20-32, characterized in that the method for separating the crystals of the pharmaceutically acceptable salt of citalopram from the mother liquor is filtration.