JP2002020379A - Citalopram hydrobromide crystal and method for crystallization - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrial method for crystallizing citalopram hydrobromide which enables ready control of the crystal characteristics such as particle size, the distribution and aspect ratio and to provide a citalopram hydrobromide crystal having characteristics useful for a pharmaceutical. SOLUTION: According to the present invention, citalopram hydrobromide dissolved in a solvent containing at least one member selected from the group consisting of a 1-3C alcohol, water and acetone is crystallized or recrystallized while controlling the cooling rate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for crystallizing citalopram hydrobromide useful as an antidepressant, and to citalopram hydrobromide having specific crystal properties.

[0002]

2. Description of the Related Art Citalopram hydrobromide is a compound useful as an antidepressant. When a drug is formulated using citalopram hydrobromide as a drug substance, the particle size, distribution and aspect ratio of crystals are reduced. Are important crystal characteristics. However, what crystal properties of citalopram hydrobromide would be advantageous as a drug substance has not been described so far, nor has there been any method for obtaining advantageous crystal properties. Was not known.

[0003] As a method for crystallizing citalopram hydrobromide, for example, Japanese Patent Publication No. 6-25099 discloses crystallization in acetone alone, first recrystallization in water alone, methanol and isopropyl alcohol. There is a method in which a second recrystallization with a mixed solvent of the following, and a third recrystallization with a mixed solvent of methanol, acetone and hexane are sequentially performed. This method only purifies citalopram crystals and does not intend to adjust the crystal grain size, its distribution or aspect ratio, and of course does not suggest any of these adjusting methods.

[0004] Further, when crystallization of citalopram hydrobromide is carried out by the method described in this publication, many fine crystals having a particle size of less than 5 µm are produced (41.
9%). When the content of fine crystals is large, not only does the filterability after crystallization during pharmaceutical production deteriorate, but also during the formulation, problems such as scattering of fine particles and exposure of workers due to it, It is not preferable as a drug substance.

Further, when crystallization of citalopram hydrobromide is carried out by the method described in the publication, crystals having a small value such as an average aspect ratio of less than 2 are generated,
Such crystals cause problems such as poor filterability after crystallization at the time of manufacturing a drug and poor fluidity at the time of removing the crystals, and are not preferable as a drug substance.

[0006]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide: 1) industrial use of citalopram hydrobromide, which can easily adjust crystal characteristics such as crystal grain size, distribution and aspect ratio; And 2) to provide crystals of citalopram hydrobromide having advantageous crystal properties as a drug substance.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies in order to achieve the above object, and crystallized or recrystallized citalopram hydrobromide dissolved in a specific solvent while adjusting the cooling rate. The present inventors have found that the crystallinity of citalopram hydrobromide can be adjusted by crystallization to control the particle size, distribution and aspect ratio of the crystals, and have completed the present invention. Furthermore, the inventors have found that the content of crystals obtained by this method, which is less than 5 μm, is at most 35%
And the crystal of citalopram hydrobromide having an average aspect ratio of 4.5 or more and 6.0 or less were found to be advantageous as a drug substance.

That is, the present invention relates to (1) a crystal of citalopram hydrobromide, wherein the content of the crystal having a crystal particle diameter of less than 5 μm is at most 35%; (1) The crystal of citalopram hydrobromide according to the above (1), wherein the content of the crystal having a crystal particle diameter of 20 μm or more is 10% or more. (3) The average aspect ratio is 2.0 or more and 9 or more. (1) the crystal of citalopram hydrobromide according to (1) above, wherein (4) the average aspect ratio is 2.5 or more and less than 4.5. (1) a crystal of citalopram hydrobromide, (5) a crystal of citalopram hydrobromide of (1), wherein the crystal has an average aspect ratio of 4.5 or more and 6.0 or less. 6) The average aspect ratio is 2.0 or more and 9.0 or less. (7) a crystal of citalopram hydrobromide, wherein the average aspect ratio is 2.5 or more and less than 4.5, (8) a crystal of citalopram hydrobromide, A crystal of citalopram hydrobromide, characterized in that the average aspect ratio is 4.5 or more and 6.0 or less, (9) citalopram hydrobromide,
A step of heating and dissolving in a solvent containing at least one selected from the group consisting of alcohol, water and acetone, and a step of cooling and adjusting the cooling rate to crystallize the citalopram smell. (10) The crystallization method of (9), wherein the cooling rate is adjusted within a temperature range of 0 to 80 ° C. (11) The temperature of 20 to 40 ° C The crystallization method of (9), wherein the average cooling rate in the range is adjusted to 30 ° C./hour or more and 60 ° C./hour or less, (12) the average cooling rate in the temperature range of 20 to 40 ° C. Is adjusted to 0.5 ° C./hour or more and less than 30 ° C./hour. (13) Citalopram after cooling to a temperature range of 30 ° C. or more and less than 48 ° C. Hydrogen bromide And performing crystallization by adding seed crystals of the salt, crystallization method (9), (14) citalopram hydrobromide, 1 carbon atoms
(3) heating and dissolving in a solvent containing at least one selected from the group consisting of alcohol, water and acetone, cooling the obtained solution and performing crystallization, and heating and dissolving a part of the obtained crystal again A method of crystallizing citalopram hydrobromide, comprising a step of recrystallizing while adjusting the cooling rate, wherein the temperature of 30 ° C. or more and less than 48 ° C. in the step of (15). The above (1), characterized in that cooling is performed within the range.
(4) The crystallization method according to (16), wherein after cooling to a temperature range of 30 ° C. or more and less than 48 ° C., crystallization is performed by adding a seed crystal of citalopram hydrobromide. The crystallization method of (14), wherein in the step of (17), a part of the crystal is dissolved by heating to a temperature range of 48 ° C. or more and 60 ° C. or less. In the crystallization method, in the step (18), the average cooling rate in the temperature range of (the heating temperature in the step) to (the heating temperature-30 ° C.) is adjusted to 30 ° C./hour or more and 90 ° C./hour or less. In the crystallization method of (14) and the step of (19), the average cooling rate in the temperature range of (the heating temperature in the step) to (the heating temperature−30 ° C.) is 1 ° C. / More than hour and less than 30 ° C / hour Characterized in that it relates to the crystallization method of the above (14).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. The average particle diameter in the present invention is an average value of the diameter when the volume of a crystal particle is converted into a sphere. The average aspect ratio in the present invention refers to the major axis of the crystal particle /
This is the average of the minor axis values.

In the present invention, the following two methods for industrial crystallization of citalopram hydrobromide, which can easily adjust crystal characteristics such as crystal grain size, distribution and aspect ratio, are provided. Is mentioned.

Method 1 The first method for crystallizing citalopram hydrobromide according to the present invention comprises: dissolving citalopram hydrobromide in a specific solvent; (Hereinafter referred to as method 1).
Generally, the particle size distribution of the crystals obtained by Method 1 shows a gentle mountain shape. Hereinafter, and steps will be described. In each step, stirring was performed so that the temperature of the entire system became uniform, and that the aspect ratio of the generated crystal was not reduced by destruction.
It is preferable to stir at 10 to 250 rpm, particularly 50 to 220 rpm.

In method 1, adjustment of the cooling rate within a specific temperature range is particularly important for adjusting the crystal characteristics. That is, the present inventors, in the step of,
It has been found that the cooling rate in a temperature range of preferably 0 to 80 ° C, particularly 20 to 40 ° C, affects the crystal grain size of citalopram hydrobromide. For example, the average cooling rate in the temperature range of 20 to 40 ° C. is 0.5 ° C./hour or more.
The crystals obtained when adjusted to less than 0 ° C./hour
The content of the crystals less than 35% is at most 35%, the average particle size thereof is about 10 to 20 μm, and 30 ° C. /
The crystal obtained when the temperature is adjusted to 60 ° C./hour or less has a crystal content of less than 5 μm at most 35% and an average particle diameter of about 7 to 15 μm. Cooling within the above temperature range is preferably performed such that the cooling rates are substantially uniform.

The next important operation in adjusting the crystal characteristics is to add a seed crystal within a specific temperature range in the step. The addition of a seed crystal when crystallizing a certain compound is known as a preferable method for growing a crystal, and even in the case of citalopram hydrobromide, it is performed in Japanese Patent Publication No. 6-25099. I have. In this publication, the addition of a seed crystal was carried out at a cooling temperature of 2
The test was carried out at 0 ° C., and as a result of additional tests by the inventors of the present invention, the deposited crystals were not accompanied by appropriate growth, and there were considerably many fine crystals of less than 5 μm.
When the content of fine crystals is large, not only does the filterability after crystallization during pharmaceutical production deteriorate, but also problems such as scattering of fine particles and exposure of workers due to the scattering of fine particles occur during formulation.

In the step (2), after cooling to a temperature range of preferably 30 ° C. or more and less than 48 ° C., more preferably 40 ° C. or more and less than 48 ° C., crystallization is performed by adding a seed crystal. As a result, the crystals are precipitated with an appropriate growth, so that the grain size of the crystals can be better adjusted.
It has been found that the generation of fine crystals of less than μm can be further suppressed.

When the temperature at which the seed crystal is added is lower than 30 ° C., crystallization tends to occur at once, and fine crystals tend to increase. When the temperature is higher than 48 ° C., the seed crystal is easily dissolved. The effect of adding a seed crystal is small. The amount of the seed crystal to be added is not particularly limited, and is preferably 0.0001 to 1% by weight, more preferably 0.001 to 1% by weight based on citalopram hydrobromide used for crystallization.
0.01% by weight.

In the step of the method 1, the dissolution of citalopram hydrobromide in a specific solvent by heating is preferably carried out at 50 to 80 ° C, more preferably at 55 to 75 ° C.

The specific solvent used in the method 1 is at least one selected from the group consisting of alcohols having 1 to 3 carbon atoms (eg, methanol, ethanol, isopropyl alcohol, 1-propanol), water and acetone. Preferably, the solvent contains 70% by weight or more, more preferably 80% by weight or more. An alcohol having 1 to 3 carbon atoms,
Solvents that may be contained in addition to water and acetone are not particularly limited as long as they can be mixed with these solvents and do not react with citalopram hydrobromide, for example, toluene, xylene, tetrahydrofuran,
Diisopropyl ether, 1,2-dimethoxyethane,
And diethylene glycol dimethyl ether. These may be used alone or as a mixture of two or more, but are preferably selected so that their boiling points are higher than the above-mentioned heating temperature. The above-mentioned specific solvent is more preferably a solvent containing at least one selected from the group consisting of methanol, ethanol, isopropyl alcohol and 1-propanol at 80% by weight or more, and particularly preferably 90% by weight of methanol and isopropyl alcohol. It is a solvent containing the above.

The amount of the above-mentioned specific solvent varies depending on the kind of each solvent used alone or mixed, and the heating and dissolving temperature of citalopram hydrobromide. Usually, the amount used is 1 kg of citalopram hydrobromide. And preferably 2 to 30
L, more preferably 4 to 16 L. When a mixed solvent consisting of methanol and isopropyl alcohol is used, the amount of the mixed solvent is citalopram hydrobromide 1
It is particularly preferable that the amount of methanol is 2 to 5 L and the amount of isopropyl alcohol is 4 to 8 L per kg.

In the method 1, after the step (c), crystallization of citalopram hydrobromide is further carried out at a temperature lower than the final cooling temperature (preferably -10 to 30 ° C, more preferably 0 to 20 ° C). The aging is preferably performed for 30 minutes to 48 hours, more preferably 2 to 24 hours, from the viewpoint of improving the yield.

By performing the above operations, the crystal characteristics of citalopram hydrobromide can be adjusted.
For example, in order to shift the crystal particle size distribution to a larger particle size, the cooling rate is reduced in the step of
Seed crystals may be added. In order to increase the aspect ratio, the cooling rate in the step may be reduced, or the stirring rate in the step may be reduced.

Method 2 The second method of crystallizing citalopram hydrobromide according to the present invention comprises the steps of heating and dissolving citalopram hydrobromide in a specific solvent, and cooling the obtained solution to crystallize it. , A step of heating and dissolving a part of the obtained crystals again, and a step of performing recrystallization while adjusting a cooling rate (hereinafter, referred to as method 2). The crystals obtained by the method 2 generally have a smaller fine crystal abundance ratio than the crystals obtained by the method 1. In the method 2, the steps (1) to (4) can be performed in one pot. still,
In each step, so that the temperature of the whole system becomes uniform,
In addition, the stirring is performed so that the aspect ratio of the generated crystal is not reduced due to destruction.
It is preferable to stir at 50 rpm, especially at 50 to 220 rpm.

In method 2, adjustment of the cooling rate within a specific temperature range in the step is particularly important in adjusting the crystal characteristics. That is, the present inventors have proposed Method 2
In the step (1), it was found that the cooling rate particularly in the temperature range of (the heating temperature in the step) to (the heating temperature −30 ° C.) affects the grain size of the finally obtained crystal. For example, a crystal obtained when the average cooling rate in the temperature range is adjusted to 30 ° C./hour or more and 90 ° C./hour or less has a crystal content of less than 5 μm at most 35%, particularly 25% or less. And the average particle size is about 10 to 25 μm, and is not less than 1 ° C./hour.
The crystals obtained when adjusted to less than 0 ° C./hour
At most 35%, in particular 15%, of crystals having a content of less than
The average particle diameter is about 15 to 30 μm. Cooling within the above temperature range is preferably performed such that the cooling rates are substantially uniform.

The next important operations in adjusting the crystal characteristics include the addition of a seed crystal within a specific temperature range in the step and the heating and melting in the step.

In the step, the solution obtained in the step is cooled to a temperature preferably from 30 ° C. to less than 48 ° C., particularly preferably from 40 ° C. to less than 48 ° C. The present inventors, in the step, after cooling to a temperature range of 30 ° C or more and less than 48 ° C, preferably 40 ° C or more and less than 48 ° C, by adding a seed crystal and performing crystallization,
It has been found that, since the crystals are precipitated with proper growth, the grain size of the crystals can be adjusted better, and the generation of fine crystals of less than 5 μm can be further suppressed.

When the temperature at which the seed crystal is added is lower than 30 ° C., crystallization occurs at once and fine crystals tend to increase, and when the temperature is higher than 48 ° C., the seed crystal is easily dissolved. The effect of adding a seed crystal is small. The amount of the seed crystal to be added is not particularly limited, and is preferably 0.0001 to 1% by weight, more preferably 0.001 to 1% by weight based on citalopram hydrobromide used for crystallization.
0.01% by weight.

In the step (3), it is necessary to heat and dissolve a part of the crystals obtained in the step (3) again, that is, to prevent the obtained crystals from being completely dissolved. The average grain size of the crystals can be increased. This is presumably because some of the crystals obtained in the step (3) were heated and dissolved again, and the remaining crystals became seed crystals in the step (3). For this reason, if the addition of the seed crystal in the step is used together, a crystal having a larger average particle size can be finally obtained as compared with the case where the seed crystal is not used together. The "part of the crystals obtained in the step" herein is not particularly limited, and is preferably 10 to 90% by weight, more preferably 20 to 90% by weight of the crystals obtained in the step.
About 80% by weight.

The temperature in the step is not particularly limited as long as it is a temperature at which a part of the crystals obtained in the step is heated and dissolved again, that is, the obtained crystals are not completely dissolved. It is preferable to heat to a temperature range of 60 ° C. or lower, particularly 48 ° C. or higher and 55 ° C. or lower to partially dissolve crystals. If the temperature is lower than 48 ° C., the crystals cannot be dissolved to the extent intended in this step, and if it is higher than 60 ° C., the crystals will be dissolved to the extent intended in this step or more. In other words, the content of the crystal having a crystal particle diameter of less than 5 μm is increased as compared with the case where both steps are performed within the above temperature range.

In the method 2, the adjustment of the cooling rate in the step is also related to the grain size of the finally obtained crystal, similarly to the adjustment of the cooling rate in the step described above.
Its influence is smaller than that in the process. However, in the step of 0-80 ° C., especially 20-4 ° C.
The present inventors have found that the cooling rate in the temperature range of 0 ° C. affects the crystal grain size. Cooling within the above temperature range is preferably performed such that the cooling rates are substantially uniform.

In the step of the method 2, the dissolution of citalopram hydrobromide in a specific solvent by heating is preferably carried out while heating at 50 to 80 ° C, more preferably 55 to 75 ° C.

The specific solvent used in the method 2 includes at least one selected from the group consisting of alcohols having 1 to 3 carbon atoms (eg, methanol, ethanol, isopropyl alcohol, 1-propanol), water and acetone. Preferably, the solvent contains 70% by weight or more, more preferably 80% by weight or more. An alcohol having 1 to 3 carbon atoms,
Solvents that may be contained in addition to water and acetone are not particularly limited as long as they are miscible with these solvents and do not react with citalopram hydrobromide, for example, toluene, xylene , Tetrahydrofuran, diisopropyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and the like. These may be used alone or as a mixture of two or more, but are preferably selected so that their boiling points are higher than the above-mentioned heating temperature. As the specific solvent, more preferably methanol, ethanol,
A solvent containing at least one selected from the group consisting of isopropyl alcohol and 1-propanol at 80% by weight or more, and particularly preferably a solvent containing at least 90% by weight of methanol and isopropyl alcohol.

The amount of the above-mentioned specific solvent varies depending on the kind of each solvent used alone or as a mixture, the heat dissolution temperature of citalopram hydrobromide, and the like. , Preferably 2-30 L,
More preferably, it is 4 to 16 L. When a mixed solvent of methanol and isopropyl alcohol is used, it is particularly preferable that the amount of methanol is 2 to 5 L and the amount of isopropyl alcohol is 4 to 8 L per 1 kg of citalopram hydrobromide.

In the method 2, after the step (1), the steps (2) and (3) may be repeated. Further, the crystallization of citalopram hydrobromide is carried out at a temperature lower than the final cooling temperature (preferably -10 to 30C, more preferably 0 to 25C), preferably 30 minutes to 48 hours, more preferably 2 minutes. Finishing after aging for 熟 24 hours is preferable from the viewpoint of improving the yield.

By performing the above operation, the characteristics of the crystals of citalopram hydrobromide can be adjusted. For example, in order to shift the particle size distribution of the crystals to the larger particle size, the following steps are required. In the step, the cooling rate may be reduced, or in the step, a seed crystal may be added, and in the step, heating and melting may be performed at a specific temperature. In order to increase the aspect ratio, the cooling rate or the stirring rate may be reduced in the step or the like.

The isolation and purification of the crystals obtained in the methods 1 and 2 can be carried out by a conventional method, for example, by filtration and washing with a suitable solvent.

Crystals of citalopram hydrobromide having a crystal content of at most 35%, preferably at most 30%, more preferably at most 20%, more preferably at most 35%, The content of crystals having a particle diameter of 20 μm or more is 10% or more, and more preferably 20% or more.
The above crystals of citalopram hydrobromide can improve the filterability after crystallization during the manufacture of pharmaceuticals, and furthermore, scattering of fine particles generated during formulation and exposure of workers And other problems can be improved. These crystals can be obtained by performing each method as follows.

In the method 1, in the step of
By adjusting the average cooling rate in the temperature range of 0.5 ° C. to 0.5 ° C./hour or more and 60 ° C./hour or less, it is preferable to further add seed crystals in the temperature range of 30 ° C. or more and less than 48 ° C. Can be obtained.
In the method 2, the cooling rate in the temperature range of (the heating temperature in the step) to (the heating temperature −30 ° C.) in the step is preferably adjusted to 1 ° C./hour or more and 90 ° C./hour or less, so that 30 ° C or higher in the process 4
It can be obtained by adding a seed crystal within a temperature range of less than 8 ° C. or by heating and dissolving a part of the crystal obtained in the step of the step.

The average aspect ratio has a lower limit of usually 2.0 or more, preferably 3 or more, more preferably 4.5.
The crystal of citalopram hydrobromide having an upper limit of usually 9.0 or less, preferably 7 or less, more preferably 6.0 or less removes the filterability and the crystal after crystallization at the time of drug production. In this case, problems such as poor fluidity can be improved, and it can be advantageously used in the production of citalopram hydrobromide and its formulation. From this viewpoint, a crystal having an average aspect ratio of 4.5 or more and 6.0 or less is particularly preferable. These crystals can be obtained by performing each method as follows.

In the method 1, in the step of
By adjusting the average cooling rate in the temperature range of 0.5 ° C. to 0.5 ° C./hour or more and 60 ° C./hour or less, the stirring speed in the step is preferably set to 10 to 250 rpm, or the tip of the stirring blade in the step Speed usually 0.1
m / s to 2.5 m / s, preferably 0.5 m / s to 2.
It can be obtained by setting it to 0 m / s.

In the method 2, by adjusting the cooling rate in the temperature range of (the heating temperature in the step) to (the heating temperature −30 ° C.) in the step (1) to 1 ° C./hour or more and 90 ° C./hour or less, Preferably, the stirring speed in the haze process is 10 to 250 rpm, and the speed of the tip of the stirring blade in the haze process is usually 0.1 m / s to
2.5 m / s, preferably 0.5 m / s to 2.0 m / s
Can be obtained.

In the step of the method 1 of the present invention and the step of the method 2 of the present invention, the speed of the tip of the stirring blade is usually 2.5 m / s or more and less than 5.0 m / s, preferably 3.0 m / s. By stirring the mixture at a rate of not less than / s and not more than 4.0 m / s, a crystal having an average aspect ratio of not less than 2.5 and less than 4.5 can be obtained. Crystals having an average aspect ratio of 2.5 or more and less than 4.5 are preferable in that they can be used as they are as pharmaceuticals.

The citalopram hydrobromide to be used may be obtained by any method, and it is preferable to purify it with activated carbon or the like before subjecting it to the crystallization of the present invention. Citalopram hydrobromide can be synthesized, for example, according to the method described in JP-B-6-25099.

[0042]

EXAMPLES The present invention will now be described specifically with reference to examples, but the present invention is not limited to these examples. Powder X in Reference Examples, Examples and Comparative Examples below
The line crystal diffraction and the measurement of the average particle diameter were performed under the following conditions, respectively. Powder X-ray crystal diffraction: Rigaku Corporation Miniflex Irradiated X-ray CuKα Average particle size: SALD1100 manufactured by Shimadzu Corporation (medium:
Diisopropyl ether)

Reference Example 1 Hydrogen bromide gas was added to a solution obtained by dissolving 167 g of citalopram base in 837 ml of acetone at 15 to 40 ° C.
I blew until H was 3. Around half of the hydrogen bromide gas was blown in, crystals began to precipitate. After the reaction solution was stirred at 25 to 35 ° C for 1 hour, it was further stirred at 0 to 5 ° C for 1 hour.
Stirred for hours. The crystals formed are filtered off and cold acetone 16
After washing with 7 ml and vacuum drying at 50 to 70 ° C. (5 to 30 Torr) for 3 hours, 162 g of citalopram hydrobromide crystals were obtained. The HPLC of this crystal
Purity was 97.3% (254 nm). Melting point: 180.3 ° C. ¹ H-NMR (DMSO-d ₆ , 400 MHz) FIG. X-ray powder diffraction pattern is shown in FIG.

Example 1 5.0 g of citalopram hydrobromide synthesized according to Reference Example 1 was dissolved in 15 ml of methanol at 60 ° C., and 0.5 g of activated carbon was added to the solution, followed by stirring for 15 minutes. After filtering off the activated carbon, 25 ml of isopropyl alcohol was added and heated to 58 ° C. to dissolve the crystals. 200 rp
m (diameter of stirring blade: 0.05 m, speed of tip of stirring blade:
0.05 × (200/60) × 3.14 = about 0.5 m /
When cooled to 43 ° C. with stirring in s), about 0.1 mg of citalopram hydrobromide seed crystals was added. 4
After cooling to 0 ° C over 15 minutes, the mixture was cooled from 40 ° C to 200 ° C while stirring at 200 rpm so that the cooling rate became almost uniform.
Cooled to 0 ° C over 5 hours (average cooling rate: 4 ° C /
Time). After the cooled suspension was stirred at 20 ° C. for 18 hours (retention time at 20 ° C.) and 200 rpm, the crystals were filtered off.
While rotating the crystal at 30 rpm, 50 ° C. (0.67
After vacuum drying at 1.33 kPa) for 3 hours, 70 ° C.
(0.4 to 0.8 kPa) for 15 hours.
4.2 g of the obtained crystals of citalopram hydrobromide
The melting point of the crystals was 184.4 ° C. and the HPLC purity was 9
9.9% (254 nm). X-ray powder diffraction pattern is shown in FIG. Grain size distribution Less than 5 μm 17.1%, 5 μm or more 1
Less than 0 μm 22.2%, 10 μm or more and less than 20 μm
29.1%, 20 μm or more and less than 40 μm 27.0%,
40% or more 4.6% (shown in FIG. 6) Average particle size 12.9 μm Micrograph (× 400) FIG. Average aspect ratio 4.8

Examples 2 and 3 Examples 2 and 3 were the same as Example 1 except that the cooling time from 40 ° C. to 20 ° C. and the holding time at 20 ° C. were changed as shown in Table 1 below. I went to.

[0046]

[Table 1]

Example 4 5.0 g of citalopram hydrobromide synthesized according to Reference Example 1 was dissolved in 15 ml of methanol at 50 ° C., 0.5 g of activated carbon was added, and the mixture was stirred for 15 minutes. After filtering off the activated carbon, 25 ml of isopropyl alcohol was added and heated to 58 ° C. to dissolve the crystals. When cooled to 43 ° C. while stirring at 200 rpm (diameter of stirring blade: 0.05 m), 0.1 mg of citalopram hydrobromide seed crystal was added. After cooling to 41 ° C. over 15 minutes, heating to 50 ° C. over 5 minutes, stirring at the same temperature for 80 minutes to dissolve a part (about half amount) of the crystal, and the cooling rate becomes almost uniform For 2 hours from 50 ° C to 20 ° C (average cooling rate: 12 ° C / hour). The cooled suspension was stirred at 20 rpm at 200 rpm for 17.5 hours, and the precipitated crystals were separated by filtration. After rotating the crystal at 50 rpm (0.67 to 1.33 kPa) for 3 hours while rotating the crystal at 30 rpm, the crystal was dried at 70 ° C. (0.4 to 0.8 kPa) for 15 hours.
It was left to dry for hours. The crystals of the obtained citalopram hydrobromide were 4.1 g, the HPLC purity of the crystals was 99.9% (254 nm), and the melting point was 184.7 ° C. Powder X-ray crystal diffraction pattern is shown in FIG. Crystal grain size distribution Less than 5 μm 9.6%, 5 μm or more 10
Less than μm 12.3%, 10 μm or more and less than 20 μm 2
0.9%, 20 μm or more and less than 40 μm 31.7%, 4
0 μm or more 25.5% (shown in FIG. 9) Average particle size 23.8 μm Micrograph (× 400) FIG. Average aspect ratio 5.4

Example 5 Example 5 was carried out in the same manner as in Example 4 except that the cooling time from 50 ° C. to 20 ° C. and the holding time at 20 ° C. were changed as shown in Table 2 below.

[0049]

[Table 2]

Example 6 Citalopram hydrobromide 1 synthesized according to Reference example 1
8.2 kg was dissolved in 37.4 kg of methanol at 45 to 50 ° C., and 1.8 kg of activated carbon was added to this solution, followed by stirring for 55 minutes. After filtering off activated carbon, 7.2 kg of warm methanol
The activated carbon was washed with, and the combined washing solution and solution were heated to about 60 ° C. After adding 71.9 kg of isopropyl alcohol heated to 40 to 50 ° C. and confirming dissolution at 62 ° C., 1
69 rpm (diameter of stirring blade (Faudler type): 0.4)
Cooling was started while stirring at a speed of 5 m at a tip of the stirring blade: about 4.0 m / s). Upon cooling to 44 ° C., about 400 mg of citalopram hydrobromide seed crystals were added. 4
After stirring at 0 to 43 ° C for 30 minutes, it was confirmed that crystals were precipitated at 41.5 ° C. Cool from 40 ° C. to 20 ° C. over 4 hours (average cooling rate: 5 ° C./hour).
Cooled to 10 ° C. over time. The suspension is 5-10 ° C
After stirring at 80 rpm for 13 hours, the crystals were separated by filtration. A mixture of 9.6 kg of isopropyl alcohol and 4.8 kg of methanol was cooled to 0-10 ° C. The crystals were washed with this mixture. The wet crystals (19.8 kg) were reduced under reduced pressure (10 to 1.33 kPa) at 30 to 50 ° C. for 10 hours, 45 to 55 ° C. for 5 hours, 70 to 75 ° C. for 8 hours, and 3
It was dried while stirring at 0 rpm. The resulting crystals of citalopram hydrobromide weigh 15.0 kg (recrystallization yield:
82%) and the HPLC purity of the crystals is 99.75.
% (220 nm), melting point 185.0 ° C. Grain size distribution Less than 5 μm 12.6%, 5 μm or more 1
Less than 0 μm 20.2%, 10 μm or more and less than 20 μm
35.5%, 20 μm or more and less than 40 μm 29.3%,
40% or more 2.4% (shown in FIG. 11) Average particle size 14.6 μm Micrograph (× 400) FIG. Average aspect ratio 3.0 Bulk density 0.2 g / ml Tap density 0.42 g / ml

Comparative Example 1 5.0 g of citalopram hydrobromide synthesized according to Reference Example 1 was dissolved in 15 ml of methanol at 50 ° C., 0.5 g of activated carbon was added, and the mixture was stirred for 15 minutes. After filtering off the activated carbon, 25 ml of isopropyl alcohol was added and heated to 58 ° C. to dissolve the crystals. After cooling to 40 ° C. in 5 minutes, the mixture was further cooled from 40 ° C. to 200 ° C. while stirring at 200 rpm.
Cooled to 0 ° C in 5 minutes. At the time of cooling to 20 ° C., 0.1 mg of seed crystals of citalopram hydrobromide was added, and the mixture was further stirred at the same temperature for 20 hours, and the crystals were separated by filtration. The crystals are kept at 50 ° C. (0.67 to 1.33 kPa) for 3 hours 30
After vacuum drying while rotating at rpm, 70 ° C
(0.4 to 0.8 kPa) for 15 hours.
The crystals of citalopram hydrobromide obtained were 4.3 g, and the HPLC purity of the crystals was 99.9% (254 n).
m), melting point 184.2 ° C. Powder X-ray crystal diffraction pattern is shown in FIG. Grain size distribution Less than 5 μm 41.9%, 5 μm or more 1
Less than 0 μm 30.2%, 10 μm or more and less than 20 μm
23.9%, 20 μm or more and less than 40 μm 4.0%, 4
0 μm or more 0% (shown in FIG. 12) Average particle diameter 6.3 μm Micrograph (× 400) FIG.

[0052]

According to the method of the present invention, the crystal properties of citalopram hydrobromide (for example, crystal grain size, distribution and aspect ratio) can be easily and industrially adjusted. Further, it is possible to provide a crystal of citalopram hydrobromide having advantageous crystal properties as a drug substance.

[Brief description of the drawings]

FIG. 1 shows ¹ H—N of the compound obtained in Reference Example 1.
It is a figure showing MR.

FIG. 2 is a view showing a powder X-ray crystal diffraction pattern of the compound obtained in Reference Example 1.

FIG. 3 is a view showing a powder X-ray crystal diffraction pattern of the compound obtained in Example 1.

FIG. 4 is a view showing a powder X-ray crystal diffraction pattern of the compound obtained in Example 4.

FIG. 5 is a view showing a powder X-ray crystal diffraction pattern of the compound obtained in Comparative Example 1.

FIG. 6 is a graph showing a crystal particle size distribution of the compound obtained in Example 1.

FIG. 7 is a view showing a crystal particle size distribution of the compound obtained in Example 2.

FIG. 8 is a view showing a crystal particle size distribution of the compound obtained in Example 3.

FIG. 9 is a graph showing the crystal particle size distribution of the compound obtained in Example 4.

FIG. 10 is a graph showing a crystal particle size distribution of the compound obtained in Example 5.

FIG. 11 is a view showing a crystal particle size distribution of the compound obtained in Example 6.

FIG. 12 is a view showing a crystal particle size distribution of the compound obtained in Comparative Example 1.

FIG. 13 is a diagram showing a micrograph (× 400) of the compound obtained in Example 1.

FIG. 14 is a photomicrograph (× 400) of the compound obtained in Example 4.

FIG. 15 is a view showing a micrograph (× 400) of the compound obtained in Example 6.

FIG. 16 is a photomicrograph (× 400) of the compound obtained in Comparative Example 1.

FIG. 17 is a diagram showing a micrograph (× 400) of a ruler with a scale of 10 μm.

 ────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Masami Igi 3-1-1, Utashima, Nishiyodogawa-ku, Osaka Sumitomo Finechem Co., Ltd. F-term (reference) 4C086 AA03 AA04 BA05 GA13 GA15 MA01 MA04 ZA12

Claims (19)

[Claims] 1. Crystals of citalopram hydrobromide, characterized in that the content of crystals having a crystal particle size of less than 5 μm is at most 35%. 2. The method according to claim 1, wherein the content of crystals having a crystal particle diameter of 20 μm or more is 10% or more.
A crystal of the described citalopram hydrobromide. 3. The crystal of citalopram hydrobromide according to claim 1, wherein the average aspect ratio is 2.0 or more and 9.0 or less. 4. The crystal of citalopram hydrobromide according to claim 1, wherein the average aspect ratio is 2.5 or more and less than 4.5. 5. The crystal of citalopram hydrobromide according to claim 1, wherein the average aspect ratio is 4.5 or more and 6.0 or less. 6. Citalopram hydrobromide crystals having an average aspect ratio of 2.0 or more and 9.0 or less. 7. A crystal of citalopram hydrobromide, wherein the average aspect ratio is 2.5 or more and less than 4.5. 8. A crystal of citalopram hydrobromide, wherein the average aspect ratio is 4.5 or more and 6.0 or less. 9. A step of heating and dissolving citalopram hydrobromide in a solvent containing at least one selected from the group consisting of alcohols having 1 to 3 carbon atoms, water and acetone, and adjusting the cooling rate of the solvent. A method of crystallizing citalopram hydrobromide, comprising a step of crystallization by cooling while cooling. 10. The crystallization method according to claim 9, wherein a cooling rate in a temperature range of 0 to 80 ° C. is adjusted. 11. The crystallization method according to claim 9, wherein an average cooling rate in a temperature range of 20 to 40 ° C. is adjusted to 30 ° C./hour or more and 60 ° C./hour or less. 12. The crystallization method according to claim 9, wherein an average cooling rate in a temperature range of 20 to 40 ° C. is adjusted to 0.5 ° C./hour or more and less than 30 ° C./hour. 13. The crystallization according to claim 9, wherein after cooling to a temperature range of 30 ° C. or more and less than 48 ° C., crystallization is performed by adding a seed crystal of citalopram hydrobromide. Method. 14. A step of heating and dissolving citalopram hydrobromide in a solvent containing at least one selected from the group consisting of alcohols having 1 to 3 carbon atoms, water and acetone, and cooling the obtained solution. Crystallization of citalopram hydrobromide, comprising a step of performing crystallization, a step of heating and dissolving a part of the obtained crystal again, and a step of performing recrystallization while adjusting a cooling rate. Method. 15. The process according to claim 1, wherein the temperature is from 30 ° C. to 48 ° C.
The crystallization method according to claim 14, wherein cooling is performed within a temperature range of less than. 16. The process of 30 to 48 ° C.
The crystallization method according to claim 14, characterized in that after cooling to a temperature within the range below, seed crystals of citalopram hydrobromide are added for crystallization. 17. The method of claim 17, wherein the temperature is at least 48 ° C. and at least 60 ° C.
The crystallization method according to claim 14, wherein a part of the crystal is dissolved by heating to within the following temperature range. 18. The method according to claim 18, wherein the average cooling rate in the temperature range of (the heating temperature in the step) to (the heating temperature−30 ° C.) is adjusted to 30 ° C./hour or more and 90 ° C./hour or less. The crystallization method according to claim 14, wherein 19. In the step, the average cooling rate in the temperature range of (the heating temperature in the step) to (the heating temperature-30 ° C.) is adjusted to 1 ° C./hour or more and less than 30 ° C./hour. The crystallization method according to claim 14, wherein