HRP20030054A2 - Pharmaceutical composition containing citalopram - Google Patents

Description

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

Previous state of the profession

Citalopram is a well-known antidepressant that has the following structure:

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

Citalopram was first described in DE 2,657,013, corresponding to US 4,136,193. That patent publication describes the preparation of citalopram in one way and suggests a further method that can be used to prepare citalopram. The prepared citalopram was isolated in the form of crystals as an oxalate, that is, a hydrobromide and hydrochloride salt. In addition, citalopram base was obtained as an oil (B.P. 175 C/0.03 mmHg). That announcement also talks about the production of tablets containing citalopram salts. Citalopram comes on the market as hydrobromide or hydrochloride.

Production of citalopram base in crystalline form is described in DK 2000 00402, which is still in process. That patent publication describes the preparation of citalopram base in crystalline form and the use of citalopram base in crystalline form as an intermediate in the purification of crude citalopram hydrobromide into pure citalopram hydrobromide. That patent also describes the production of tablets containing citalopram base.

Citalopram is available on the market in many countries in the form of a tablet prepared by compressing granulated citalopram hydrobromide, lactose and other excipients.

It is well known that the preparation of reproductive mixture tablets requires that all dry ingredients have good flow properties. In cases where the active substances have good flow properties, tablets can be prepared by direct compression of the ingredients. However, in many cases the particle size of the active substance is small, the active substance is cohesive or has weak flow properties.

In addition, the active ingredient with a small particle size mixed with excipients having a larger particle size will typically separate or not mix during the tableting process.

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

One of the methods of granulation is the "wet" granulation process. Using this method, dry solids (active substances, fillers, binders, etc.) are crushed and moistened with water or some other wetting agent (e.g. alcohol), and agglomerates or granules are formed from the moistened solids. Wet concentration continues until the 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 "thermally plastic" granulation process, where a solid with a low melting point is used as the granulating agent. First, the dry solids are pulverized and heated until the binder dissolves. As the binder becomes liquid and spreads over the surface of the particles, the particles adhere to each other and form granules. After cooling, the binder hardens and forms a dry granulate.

Both wet and melt granulation are unit energy intensive operations that require complicated and expensive equipment and technical skill.

The process used to prepare citalopram hydrobromide produces a product with a very small particle size of around 2-20 μm which, like many other small particle size products, has very poor flow properties.

Thus, in order to achieve the correct dosage of citalopram during tableting, it was considered necessary to create a citalopram granulate with larger particles and better flow properties.

The citalopram tablet that comes on the market is a tablet made of granulated citalopram hydrobromide with various excipients.

In view of the fact that direct compression is much simpler and cheaper than a process involving granulation, we desire a process for direct compression of citalopram hydrobromide.

The obstacles that have stood in the way of direct compression of citalopram tablets are now, after extensive laboratory research, gone.

It has been found that larger particles, i.e. particles of a size comparable to the size of the filler particles, can be prepared by a new and inventive crystallization process and that these particles are useful for the production of direct compressed tablets. Such larger particles also enable accurate dosing into capsules.

It has also been found that tablets with surprisingly little variation in citalopram content can be prepared by direct compression of citalopram hydrobromide, which has significantly smaller particles than the filler. Even here, despite the small size of the citalopram particles, accurate dosing in the capsules can be achieved.

Subjects of the invention

The object of this invention is to obtain a new form of pharmaceutical dosage unit containing citalopram with an appropriate particle size, whereby said pharmaceutical dosage unit can be prepared by direct compression.

Another object of this invention is to obtain a capsule containing citalopram.

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

The fourth object of this invention is a method of obtaining large crystals of a pharmaceutically acceptable salt of citalopram.

Brief description of the invention

This invention therefore includes, inter alia, the following, alone or in combination:

A solid dosage form containing citalopram prepared by directly compressing 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.

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

A method of obtaining crystals of a pharmaceutically acceptable salt of citalopram which have a median particle size of at least 40 μm and are suitable for use in a solid dosage form, wherein a solution of a pharmaceutically acceptable salt of citalopram in a suitable solvent at a first temperature is first cooled to a second temperature, and then in crystals of the said citalopram salt are added to it, followed by a period of rest at the said temperature and controlled cooling to a third temperature, after which the crystals are isolated by a conventional solid-liquid separation technique.

The direct compression of citalopram, fillers and other pharmaceutically acceptable excipients into tablets has a great advantage, because granulation and the drying phase are avoided. In addition, as granulation is avoided, there is no longer any need to add a binding agent.

The term "direct compression" used here means that the solid dosage form is prepared by compressing a simple mixture of active substances and excipients, without first subjecting the active substance to the granulation process in order to incorporate it into a larger particle and improve its flow properties.

The term "filler" used here means an agent used in wet or melt granulation processes and which acts as a binder in the granulate.

As used herein, the term "particle size distribution" means the distribution of equivalent spherical diameters determined by laser refraction at a dispersive pressure of 1 bar on a Sympatec Helos device. "Median particle size", therefore, means the median of said particle size distribution.

As used herein, the term ``reflux temperature'' means the temperature at which a solvent or solvent system refluxes or boils at atmospheric pressure.

Thus, in one version, this invention relates to a tablet prepared by direct compression of a mixture of citalopram base or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients.

In another version, this invention relates to a capsule prepared by filling a mixture of citalopram base or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients into a hard gelatin capsule.

In one version, the present invention relates to a solid dosage form containing citalopram in crystals with a median particle size below 20 μm.

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

The properties of flow, separation and immiscibility, and hence the suitability of citalopram crystals for direct compression, depend, in addition to the median particle size, on the lateral distribution of the particles.

Preferably, the solid dosage forms of the present invention do not contain a binder.

The solid dosage form according to the present invention may contain 2-60% w/w active substance calculated as citalopram base, preferably 10-40% w/w active substance calculated as citalopram base, and even more preferably 15-25% w/w active substance calculated as citalopram base. Suitably, the solid dosage form of the present invention contains 20% w/w of the active substance calculated as citalopram base.

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

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

Suitably, the filler is microcrystalline cellulose such as ProSolv SMCC90 manufactured by Penwest Pharmaceuticals or Avicel PH 200 manufactured by FMC Corporation.

In addition to the active ingredient and fillers, the solid dosage form may contain various other conventional excipients such as disintegrants and optionally smaller amounts of lubricants, colors and sweeteners.

Lubricants used in accordance with the present invention may conveniently be one or more of the following metal stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc or colloidal silicon.

A suitable lubricant is magnesium stearate or calcium stearate.

Disintegrants are sodium starch glycolate, croscarmellose, crospovidone, low substituted hydroxypropyl cellulose, modified starch flour, pregelatinized starch and natural starch.

The solid pharmaceutical dosage form of the present invention can be prepared in conventional ways using an automatic filling tablet press.

A solid hard gelatin capsule according to the present invention can be prepared in conventional ways using a powder capsule filling machine.

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

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

In another embodiment of the present invention, crystals of a pharmaceutically acceptable salt of citalopram having a median particle size of at least 40 μm and suitable for use in a solid dosage form are crystallized from a solution of a pharmaceutically acceptable salt of citalopram in a suitable dissolution system. Said solvent system may contain one or more alcohols and optionally water, the preferred solvent system is a mixture of methanol and water, wherein the preferred weight ratio of methanol:water is in the range of 5:1 to 50:1, more preferably 10:1 to 30: 1, and most preferred 15:1 to 25:1. Said pharmaceutically acceptable salt of citalopram preferably dissolves in the dissolution system at a temperature between 50°C and reflux of the dissolution system, preferably between 60°C and reflux, and even more preferably between 64°C and reflux.

The amounts of pharmaceutically acceptable salts 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 5 :1. A solution of a pharmaceutically acceptable salt of citalopram is cooled to the addition temperature, in the range of 20-40°C, preferably 25-35°C, after which citalopram crystals are added to it, and then it is maintained for crystal growth to stand still at that temperature for 30 minutes up to 7 days, preferably 1 hour to 4 days, and even more preferably 12 to 36 hours. After said resting time, the crystallization batch is gradually and controlled cooled from the addition temperature to the temperature at which the crystals will be isolated from the mother liquid, whereby this gradual cooling is performed in the time range of 5 minutes to 6 hours, preferably 15 minutes to 4 hours and more preferably 30 minutes 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 0-20°C, more preferably 5-15°C, using a conventional separation technique, eg filtration.

The small crystals of a pharmaceutically acceptable salt of citalopram used in one version of the present invention can be obtained by methods described in US 4,136,193.

The citalopram base crystals used in one version of the present invention can be obtained by the methods described in Dutch patent no. 1016435.

In the following, this invention is illustrated by examples. However, these examples are for illustration purposes only and should not be considered limiting.

Example 1

Crystallization of citalopram hydrobromide into large crystals

Citalopram hydrobromide (200 g) was dissolved in a mixture of methanol (200 g) and water (20 g) at 69°C. The solution is cooled to 30°C, citalopram hydrobromide crystals are added to it and kept at 30°C for 24 hours, after which it is cooled to 10°C for 1 hour. The crystals are isolated by filtration, washed with cold methanol and dried. The particle size distribution for the obtained 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) under reflux. The solution is cooled to 30°C, crystals of citalopram hydrobromide (27 g) are added to it and kept at 30°C for 16 hours, after which it is cooled to 10°C for 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 obtained crystals is shown in Table 1.

Example 3

Crystallization of citalopram hydrobromide into small crystals

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

Example 4

Crystallization of citalopram as a free base

A suspension of citalopram hydrobromide (101 g) in water (500 mL) and toluene (500 mL) was made. NaOH (60 mL, 5 N (aq.)) was added and the mixture (pH>10) was stirred for 15 minutes before phase separation. The organic phase is washed with water (2 x 100 mL) and filtered through a filter insert. Volatile compounds are 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. On cooling, crystals form. The white crystals of citalopram base are filtered off and dried overnight at room temperature in vacuo.

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

Quantiles Example 1 Example 2 Example 3 ProSolv SCMC90

(%) (μm) (μm) (μm) (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

A tablet prepared by direct compression of small crystals of citalopram hydrobromide

Tablet ingredients:

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

ProSolv SMCC90 23055 g (79.5% w/w)

Magnesium stearate 145 g (0.5% w/w)

Citalopram hydrobormide crystals from Example 3 and ProSolv SMCC90 were ground for 10 min at 7 rpm in a 100 liter Bohle PTM 200 mixer. Magnesium stearate was added and grinding was continued for another 3 min.

25 kg of the resulting mixture was tableted (125,000 tablets/hour) on a Fette P 1200/IC 30-place tableting press with elongated, bulging punches spaced 5.5 x 8. The tablet core weight was adjusted to 125 mg. The nominal utilization was 200,000 tablets. The tableting press was operated until the level of the mixture was just above the automatic belt, i.e. tableting was continued as long as possible, in order to observe any separation tendencies in the last volumes of the mixture.

Properties of the tablet:

Diametral crushing strength: 70 N

Disintegration time: 30 sec

Lightness: NA

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

Stamp Adhesion: Not observed

Content of citalopram in the mixture during compression

During compression, tablet samples were taken to measure the tendency towards separation. Since there is a significant difference in size between the active ingredient, citalopram hydrobromide, and the inert filler, ProSol SMCC90, as seen in Table 1, one would expect segregation of the ingredients of unequal size, i.e. separation of the mixture during transfer from the mixer to the tank or lag on the tank tableting presses.

Sampling was done 50 times at equal time intervals, which corresponds to sampling every 4000 tablets produced. Two tablets were taken for each sample.

The tablets were tested using a reliable method using UV absorption in an aqueous solution, and a total of 100 tablets were tested. The relative standard deviation in citalopram content was 1.6%.

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

One explanation for this surprising and useful result could be that the tendency towards segregation between small citalopram crystals and larger filler particles was uniquely equalized due to the poor flow properties of small crystals.

Example 6

Tablet prepared by direct compression of large citalopram hydrobromide crystals

Tablet ingredients:

Citalopram, HBR (20% w/w)

ProSolv SMCC90 (79.5% w/w)

Magnesium stearate (0.5% w/w)

Citalopram hydrobromide crystals from Example 2 and ProSol SMCC90 were ground. Magnesium stearate was added and comminution continued.

Tablets (125 mg nominal weight) were produced.

The tablets had satisfactory technical properties.

Example 7

Tablet prepared by direct compression of citalopram crystals

Tablet ingredients:

Citalopram base (16% w/w)

ProSolv SMCC90 (83.3% w/w)

Magnesium stearate (0.7% w/w)

Citalopram base crystals from Example 4 were sieved through a 0.3 mm sieve and mixed with ProSolv SMCC90 in a Turbula mixer for 3 min. Magnesium stearate was added and grinding was continued for 30 seconds.

Tablets are produced on a Korsch EKO tabletting machine with individual formation.

Properties of the tablet:

Tablet strength, mg: 20

Nominal tablet weight, mg: 125

Tablet diameter, mm: 7

Tablet form: Coated with a special protective film

Diametral crushing strength: 61.6 N

Disintegration time, min: < 1

Looseness: 0.1%

Average tablet weight: 125.4

Weight change: 0.22% relative standard deviation

The tablets produced had satisfactory technical properties.

Claims (33)

1. A solid dosage form containing citalopram, characterized in that it is prepared by directly compressing a mixture of citalopram base or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients or by filling said mixture into hard gelatin capsules. 2. Solid dosage form according to patent claim 1, characterized in that the tablet is prepared by direct compression of a mixture of citalopram base or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients. 3. Solid dosage form according to patent claim 1, characterized in that it is prepared by filling a mixture of citalopram base or its pharmaceutically acceptable salt into a hard gelatin capsule. 4. Solid dosage form according to claims 1-3, characterized in that it does not contain a binder. 5. Solid dosage form according to patent claims 1-4, characterized in that it contains 2-60% w/w of active substance calculated as citalopram base, preferably 10-40% w/w of active substance calculated as citalopram base and even more preferably 15- 25% w/w active substance calculated as citalopram base. 6. Solid dosage form according to patent claims 1-5, characterized in that it contains a filler selected from lactose, sugar, preferably sorbitol, mannitol, dextrose and/or sucrose, calcium phosphates, preferably dibasic, tribasic, aqueous or anhydrous, starch flour, modified starch flour, microcrystalline cellulose, calcium sulfate and/or calcium carbonate. 7. Solid dosage form according to claim 6, characterized in that the filler is microcrystalline cellulose, such as ProSolv SMCC90 or Avicel PH 200. 8. Solid dosage form according to claims 1-7, characterized in that it contains a lubricant selected from metal stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil and colloidal silicon. 9. Solid dosage form according to claim 8, characterized in that the lubricant is magnesium stearate or calcium stearate. 10. Solid dosage form according to claims 1-9, characterized in that it basically does not contain lactose. 11. Solid dosage form according to patent claims 1-10, characterized in that the active substance is citalopram base. 12. Solid dosage form according to patent claims 1-10, characterized in that the active substance is citalopram hydrobromide or citalopram hydrochloride. 13. Solid dosage form according to claim 12, characterized in that the active substance is citalopram hydrobromide. 14. Solid dosage form according to patent claims 12-13, characterized in that the active substance is in the form of crystals with a median particle size below 20 μm. 15. Solid dosage form according to claims 12-13, characterized in that the active substance is in the form of crystals with a median 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 μm. 16. Crystals of a pharmaceutically acceptable salt of citalopram, characterized in that the median crystal particle size is at least 40 μm. 17. Crystals according to claim 16, characterized in that they are crystals of citalopram hydrobromide or citalopram hydrochloride. 18. Crystals according to patent claim 17, characterized in that they are crystals of citalopram hydrobromide. 19. Crystals according to claims 16-18, characterized in that the median crystal particle size is in the range of 40-200 μm, preferably 45-150 μm and even more preferably 50-120 μm. 20. The method of preparing crystals of a pharmaceutically acceptable salt of citalopram that have a median particle size of at least 40 μm, characterized by the fact that the solution of a pharmaceutically acceptable salt of citalopram in a suitable dissolution system at the first temperature is first cooled to the second temperature, and then crystals of said citalopram salt are added to it, followed by a period of rest at said second temperature and controlled cooling to the third temperature, after which the crystals are isolated by the usual solid-liquid separation technique. 21. The method according to claim 20, characterized in that the median crystal particle size is in the range of 40-200 μm, preferably 45-150 μm and even more preferably 50-120 μm. 22. Method according to claims 20-21, characterized in that the dissolved substance is citalopram hydrobromide or citalopram hydrochloride. 23. Method according to claim 22, characterized in that the dissolved substance is citalopram hydrobromide. 24. The method according to claims 20-23, characterized in that the dissolution system contains one or more alcohols and optionally water. 25. The method according to claim 24, characterized in that the solvent system is a mixture of methanol and water. 26. The method according to claim 25, characterized in that the methanol:water weight ratio is in the range of 5:1 to 50:1, preferably 10:1 to 30:1, and even more preferably 15:1 to 25:1. 27. The method according to claims 20-26, 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 even more preferably 0.9 :1 to 1.5:1. 28. The method according to claims 20-27, characterized in that said first temperature is in the range of 50°C and the reflux temperature of the dissolution system, preferably between 60°C and the reflux temperature, and most preferably between 64°C and the reflux temperature. 29. Method according to patent claims 20-28, characterized in that said second temperature is in the range of 20-40°C, preferably 25-35°C. 30. Method according to patent claims 20-29, characterized in that the resting time is in the range of 30 minutes to 7 days, preferably 1 hour to 4 days, and most preferably 12 to 36 hours. 31. Method according to patent claims 20-30, characterized in that said third temperature is in the range of 0-20°C, preferably 5-15°C. 32. The method according to claims 20-31, characterized in that the controlled cooling is gradual cooling over a time period ranging from 5 minutes to 6 hours, preferably 15 minutes to 4 hours and even more preferably 30 minutes to 2 hours. 33. The method according to patent claims 20-32, characterized in that said isolation of crystals of a pharmaceutically acceptable salt of citalopram from the mother liquid is performed by filtration.