JP5850697B2 - Method for producing candesartan cilexetil - Google Patents

Description

  Following formula (1)

で示されるカンデサルタンシレキセチル（化学名称：（±）−１−（シクロヘキシルオキシカルボニルオキシ）エチル ２―エトキシ−１−［［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル］ベンズイミダゾール−７−カルボキシラート）は、アンジオテンシンＩＩ受容体拮抗薬として優れた効果を示す治療薬として有用である。

Candesartan cilexetil (chemical name: (±) -1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] Methyl] benzimidazole-7-carboxylate) is useful as a therapeutic agent that exhibits excellent effects as an angiotensin II receptor antagonist.

  Candesartan cilexetil useful as such a therapeutic agent is desired to have a very high purity and needs to be stable. Here, it is known that candesartan cilexetil has various crystal forms (see, for example, Patent Documents 1 to 5 and Non-Patent Document 1). Among these documents, Patent Document 1 describes a crystal having a melting point of 158 ° C. or higher and 166 ° C. or lower as a C-type crystal (hereinafter, sometimes referred to as Form I crystal). Crystals having a melting point of about 120 ° C. are described as Form II crystals. Among these crystal forms, candesartan cilexetil of Form I crystal is known to be the most stable and is usually used as a drug substance. Form I crystals can be produced by crystallizing candesartan cilexetil in an alcohol solvent or a mixed solvent of acetone and water, as described in the above-mentioned document.

  Moreover, since candesartan cilexetil is very hardly soluble in water, when it is formulated as a pharmaceutical, it is necessary to make it fine particles in order to improve solubility. However, as described in Non-Patent Document 1, when mechanically pulverizing candesartan cilexetil using a jet mill or the like in order to make fine particles of candesartan cilexetil, even in the most stable Form I crystal, a decrease in stability is avoided. I can't. And it is estimated that the cause of such a problem is due to the following mechanism. That is, when mechanical pulverization is performed, it is estimated that a part (or most) of the crystal is in an amorphous state having low stability (see Patent Document 6). ). Note that the degree of amorphization is very slight and difficult to quantify, and the degree of decrease in stability is also slight, and it is a decomposition product generated during storage when stored for a long time. Following formula (2)

で示されるデスエチル体の増加量によってしか把握できないものであることが原因であると思われるが、アモルファス化と安定性の関係は定量的に確認されてはいない。

It seems that the cause is that it can be grasped only by the increase in the amount of desethyl body shown in (3), but the relationship between amorphization and stability has not been quantitatively confirmed.

  It is considered that the problem of destabilization accompanying amorphization by pulverization as described above can be avoided, for example, by obtaining fine particle crystals in a crystallization process for obtaining I-type crystals. For example, if fine crystals can be precipitated from a solution and can be crushed with a weak force even if agglomeration occurs during filtration or drying, a fine powder can be obtained without causing amorphization. Conceivable.

However, it is difficult to precipitate only fine crystal crystals without forming coarse crystal grains in the crystallization step.
For example, in Patent Document 4, water is added to an acetone solution of candesartan cilexetil, stirred at 55 ± 2 ° C. for about 1 hour, and then cooled to 25 ± 2 ° C. for about 30 minutes to form Form I crystals. A method for precipitating candesartan cilexetil crystals is shown. However, as a result of further trials by the present inventors, it was found that in the above method, hard agglomerated particles having a particle diameter of about 200 μm to 2000 μm exist in a part of the powder. Since these agglomerated particles have a hard shape, as described in Non-Patent Document 2, it is considered that they adversely affect the dissolution properties of the preparation. In addition, when there are coarse particles with a particle size of 100 μm or more in the powder, even if the number is very small, it can be recognized by touch etc., so such coarse particles are accepted for quality control. I can't. It has also been found that it is difficult to selectively remove such coarse agglomerated particles. For example, when the present inventors tried to remove coarse particles by sieving, these coarse aggregated particles could not be completely removed.

  Patent Documents 1, 3 and 5 describe a method of crystallization using an alcohol solvent. However, even in this method, it has been found that hard agglomerated particles having a particle diameter of about 200 μm to 2000 μm exist in a part of the powder. Also in this method, it was necessary to pulverize and use the obtained candesartan cilexetil crystal powder for practical use. Furthermore, Patent Document 5 describes a method in which candesartan cilexetil is dissolved in acetone, and the resulting solution is added dropwise to water. In this method, too, coarse aggregated particles are easily generated. It was necessary to grind.

  As described above, according to the conventional method, the powder obtained by crystallization includes only those containing hard particles having a particle diameter of 100 μm or more. Therefore, pulverization was absolutely necessary when actually used as a preparation. Therefore, as described in Non-Patent Document 1, the desethyl body may increase, and there is room for improvement in that respect.

  On the other hand, a method for suppressing the formation of desethyl body has been studied for finely divided candesartan cilexetil (see Patent Document 6). Specifically, first, candesartan cilexetil is pulverized into fine particles. Next, the fine particles and an alcohol solvent are mixed to form a slurry, and then the fine particles are collected to produce candesartan cilexetil (form I crystal) in which an increase in the desethyl body is suppressed.

  However, in this method, in addition to the step of crystallizing candesartan cilexetil and making it fine by pulverization, a slurry step, a recovery step, and the like are necessary, and the process becomes complicated and the process becomes complicated. There was room for improvement in terms of low yield. Further, when the present inventors produced candesartan cilexetil according to the method described in the above document, the particles aggregated in the recovery step, and the obtained aggregated particles were not easily crushed, It has been found that mechanical pulverization is required to achieve the above-mentioned, and the problem of amorphization cannot be completely avoided. This is because, in the method described in Patent Document 6, since the powder finely divided by pulverization is slurried, an excessively fine fine particle is generated, and the operation of applying pressure such as centrifugation or filtration is performed. This is considered to be because the above-mentioned fine particles increase the agglomeration force and produce agglomerated particles that cannot be easily pulverized.

Japanese Patent No. 2853611 JP 2009-185060 A Japanese Patent No. 2514282 Japanese Patent No. 3003030 JP-A-2005-330277 Special Table 2008-505935

Chemical Permanent Bulletin Vol. 47, no. 2,182-186, 1999 Farm Tech Japan Vol. 27, no. 5,921-934,2011

  Therefore, an object of the present invention is to provide a simple powder of Form I crystal of candesartan cilexetil which has improved stability and solubility without causing the above-described problem of stability reduction due to amorphization accompanying pulverization. Is to provide a simple manufacturing method.

  In order to solve the above problems, the present inventor has conducted earnest research. As a result, in the step of crystallizing candesartan cilexetil from a solution obtained by dissolving a mixture of ketone and water or a solvent made of alcohol, the crystallization aging temperature is controlled to control the particle size to 100 μm. A method for obtaining Form I crystals of candesartan cilexetil that does not contain the above hard-shaped aggregated particles has been found, and the present invention has been completed.

That is, the present invention is a powder of candesartan cilexetil represented by the above formula (1), and in a powder X-ray diffraction spectrum, 2θ = 9.8, 17.2, 20.2, and 25.0 ± becomes 0.2 ° aggregate of crystal grains having characteristic peaks, containing particles having a particle diameter of 100μm or more and having the following volume average particle diameter and the following cumulative volume 99% particle diameter 90 [mu] m 15 [mu] m No increase in the content of the desethyl compound represented by the formula (2) is 0.05% or less when stored for 1 year or longer in an environment of 60% relative humidity and 25 ° C. A method for producing a powder of candesartan cilexetil having
Candesartan cilexetil is dissolved in a solvent consisting of a mixture of a ketone having 1 to 4 carbon atoms and water, or an alcohol without causing the solvent temperature to exceed 60 ° C., and the liquid temperature is 40 ° C. or higher and 60 ° C. or lower. The solution is cooled, and the solution is cooled and kept at a temperature of 32 ° C. to 38 ° C. for 5 hours to 10 hours to precipitate candesartan cilexetil crystals from the solution It is a manufacturing method characterized by including a process.

  The content of the desethyl body is the ratio (%) of the desethyl body in the powder of candesartan cilexetil. Specifically, the high performance liquid chromatography (under the conditions described in the following examples) HPLC) peak area% value, and the increase amount is the content (%) in the initial powder from the value (%) in the powder stored in a predetermined environment for a predetermined period. The value obtained by subtracting the value of.

  According to the present invention, a fine powder of candesartan cilexetil Form I crystals that does not contain hard agglomerated particles having a particle size of 100 μm or more can be obtained efficiently and in a high yield by a simple method. The method according to the present invention does not require pulverization that is usually performed to form fine particles, and can maintain the state of the form I crystal, which is a stable crystal form, thereby improving stability and increasing the desethyl body that is an impurity. Candesartan cilexetil can be obtained. In addition, since the powder obtained by the present invention is highly pure, candesartan cilexetil can be obtained with little desethyl isomer and little increase in desethyl isomer during storage.

This figure is the particle size distribution of candesartan cilexetil obtained in Example 1. This figure is a powder X-ray diffraction pattern of candesartan cilexetil obtained in Example 1. This figure is an SEM image of candesartan cilexetil obtained in Example 1. This figure is the particle size distribution of candesartan cilexetil obtained in Example 2. This figure is a SEM image of candesartan cilexetil obtained in Example 2. This figure is the particle size distribution of candesartan cilexetil obtained in Example 3. This figure is the particle size distribution of candesartan cilexetil obtained in Example 4. This figure is an SEM image of candesartan cilexetil obtained in Example 4. This figure is the particle size distribution of candesartan cilexetil obtained in Example 9. This figure is the particle size distribution of candesartan cilexetil obtained in Example 10. This figure is the particle size distribution of candesartan cilexetil obtained in Example 11. This figure is the particle size distribution of candesartan cilexetil obtained in Example 12.

In the present invention, the temperature of the solution in which candesartan cilexetil is dissolved is set to 40 ° C. or more and 60 ° C. or less, and then the mixed solution is cooled, and the temperature of the solution is maintained at 32 ° C. or more and 38 ° C. or less. Is aged to precipitate crystals of candesartan cilexetil.
First, candesartan cilexetil dissolved in a solvent will be described.

(Dissolving candesartan cilexetil (object))
Candesartan cilexetil (hereinafter sometimes referred to as the target) dissolved in the solvent is not particularly limited, and can be produced by a known method, for example, the method described in Patent Document 1 or 4. Can do. Further, the crystal form of the object is not particularly limited, and may be Form I crystal, other crystal, amorphous, or a mixed form thereof. Furthermore, the object only needs to be dissolved in the solvent, and may be a lump. Therefore, the refined lump, and the pulverized product obtained by pulverizing the lump, for example, the candesartan cilexetil lump obtained in Reference Example 12 of Patent Document 4 and the pulverized product can also be used as objects. . In the present invention, since a mixed solution in which candesartan cilexetil is dissolved in a solvent described in detail below may be used, a wet body containing a solvent may be an object.

  An example of a method for producing candesartan cilexetil is trityl candesartan cilexetil (chemical name: (±) -1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[ 2 '-(1-triphenylmethyl-1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate can be detritylated.This trityl candesartan A method for producing cilexetil is also described in Patent Document 1 or 4.

  Detritylation of the trityl candesartan cilexetil represented by the formula (3) can be carried out by using methanol, water, acid, or alkali. For example, detritylation of trityl candesartan cilexetil can be performed at room temperature in the presence of methanol and 1N hydrochloric acid. Trityl candesartan cilexetil can also be detritylated in a halogenated hydrocarbon solvent such as methylene chloride in the presence of methanol and hydrogen chloride at room temperature. Thus, when an acid is used, it is preferable to perform a neutralization process. Examples of the method that does not use an acid include a method in which trityl candesartan cilexetil is detritylated in a halogenated hydrocarbon solvent such as methylene chloride or chloroform in the presence of methanol at the reflux temperature of the solvent. . By adopting a method that does not use an acid, neutralization treatment and the like can be omitted.

  As described above, the method of the present invention is intended to use candesartan cilexetil (hereinafter, sometimes referred to as a first crude product) obtained by performing a detritylation reaction of trityl candesartan cilexetil. it can. The first crude product has a candesartan cilexetil purity of about 94.0% or more and 98.0% or less, and a desethyl body of 0.5% or more and 3.0%, depending on the detritylation reaction conditions. The following may be included.

  The purity of the above-mentioned candesartan cilexetil and the content of the desethyl compound are values of peak area% of high performance liquid chromatography (HPLC) determined under the conditions described in the following examples. Hereinafter, in the present invention, the purity of candesartan cilexetil and the content of desethyl body are values of peak area% obtained by the same measurement.

  According to the method of the present invention, even when a desethyl body is contained in an object, the desethyl body can be efficiently reduced. Therefore, the first coarse body can be used as an object. However, in order to further increase the purity of candesartan cilexetil finally obtained, it is preferable to further reduce the amount of impurities such as desethyl compound and trityl candesartan cilexetil contained in the object. Therefore, it is preferable to use what refine | purified the 1st rough body as a target object. Specifically, it is preferable to use a product obtained by recrystallizing and purifying the first crude body with a solvent such as methanol, ethanol, or acetone, or a mixed solvent of acetone and water. Among these, by recrystallizing with methanol, ethanol, or acetone, trityl candesartan cilexetil remaining in the first crude body can be further reduced. Moreover, a desethyl body can be reduced by recrystallizing with the mixed solvent of acetone and water. Especially, in order to make what the impurities, such as a desethyl body and a trityl candesartan cilexetil, reduce more, it is preferable to refine | purify a 1st rough body with the following method.

  That is, first, it is preferable to recrystallize the first crude body with acetone. The amount of acetone used is preferably from 1 ml to 5 ml, more preferably from 1.5 ml to 4 ml, per 1 g of candesartan cilexetil contained in the first crude body. Moreover, it is preferable that the temperature at the time of dissolving a 1st rough body shall be 40 degreeC or more and a reflux temperature or less. The acetone solution in which the first crude body is dissolved is preferably cooled to a temperature of 0 ° C. or higher and 10 ° C. or lower at a cooling rate of 5 ° C./hour or more and 60 ° C./hour or less to precipitate crystals. At this time, a seed crystal can also be used. What is necessary is just to fractionate the obtained crystal | crystallization by a well-known method. The crystal obtained by such a method (hereinafter referred to as second crude product) can have a purity of candesartan cilexetil of about 98.5% or more and 99.9% or less, and the content of desethyl body Can be about 0.05% or more and 0.15% or less. In the method of the present invention, such a second crude product can be used as an object. In particular, in order to reduce the amount of desethyl compound, the second crude product is further purified by the following method. Is preferably the target.

  That is, it is preferable to recrystallize the second crude product with a mixed solvent of acetone and the next. In particular, recrystallization is preferably performed according to the following procedure. Specifically, the solution in which the second crude product is dissolved in acetone is set to 50 ° C. or higher and the reflux temperature or lower, and is cooled to 20 ° C. or higher and 30 ° C. or lower at a cooling rate of 5 ° C./hour or higher and 60 ° C./hour or lower. In this method, crystals are precipitated by adding water, and further cooled to 0 ° C. to 10 ° C. at a cooling rate of 5 ° C./hour or more and 60 ° C./hour or less. At this time, a seed crystal can also be used. What is necessary is just to fractionate the obtained crystal | crystallization by a well-known method. In the above method, the amount of acetone used is preferably 5 ml or more and 15 ml or less, and more preferably 6 ml or more and 13 ml or less, with respect to 1 g of candesartan cilexetil contained in the second crude product. The amount of water used is preferably 1 ml to 6 ml, more preferably 1.5 ml to 4 ml, with respect to 1 g of candesartan cilexetil contained in the second crude product. The crystal obtained by such a method (hereinafter referred to as a third crude product) can have a purity of candesartan cilexetil of about 99.0% to 99.9%, and the content of desethyl body Can be 0.01% or more and 0.1% or less. In addition, the third crude product obtained by the above method often becomes Form II crystals having a melting point of about 120 ° C. Further, the third crude body may contain acetone and water.

  In the present invention, it is preferable to use the third crude product purified by the above method as an object. In particular, when candesartan cilexetil is produced from trityl candesartan cilexetil, the first crude product or the second crude product can be used as a target, but the amount of solvent used, operability, and production efficiency are reduced. Considering this, it is preferable to use the third rough body as an object. By using the third crude product as an object, impurities such as desethyl compound and trityl candesartan cilexetil can be efficiently removed. In addition, when producing the third crude body from the first crude body, it was explained in the order of recrystallization with acetone and recrystallization with a mixed solvent of acetone and water. Purification can also be performed in the order of recrystallization with crystals and acetone.

  In the present invention, the object as described above is mixed with a mixed solvent of a ketone having 1 to 4 carbon atoms and water or a solvent comprising an alcohol having 1 to 4 carbon atoms, and the temperature of the mixed solution is 40 ° C. or more and 60 After being dissolved at a temperature not higher than ° C., the solution is cooled until the temperature becomes 32 ° C. or higher and 38 ° C. or lower, and ripened at 32 ° C. or higher and 38 ° C. or lower for 30 minutes or longer and 10 hours or shorter to precipitate candesartan cilexetil crystals. It is characterized by that. Next, a method for precipitating candesartan cilexetil crystals will be described.

(Method of precipitating candesartan cilexetil crystals)
In the present invention, it is a form I candesartan cilexetil fine particle powder without performing mechanical pulverization to reduce stability, that is, a powder of candesartan cilexetil represented by the above formula (1), The powder X-ray diffraction spectrum has characteristic peaks at 2θ = 9.8, 17.2, 20.2, and 25.0 ± 0.2 °, and preferably has a melting point of 158 ° C. or higher and 166 ° C. or lower. In order to obtain a powder comprising an aggregate of certain crystal particles, having a volume average particle size of 15 μm or less and a cumulative volume 99% particle size of 90 μm or less and containing substantially no particles having a particle size of 100 μm or more First, candesartan cilexetil which is an object is once dissolved in a solvent, and then crystal particles are precipitated.

  At this time, in order to precipitate the crystal particles constituting the powder, (i) a mixture of a ketone having 1 to 4 carbon atoms and water, or a solvent comprising an alcohol having 1 to 4 carbon atoms, After dissolving candesartan cilexetil (target object) without setting the temperature above 60 ° C. to prepare a solution having a liquid temperature of 40 ° C. or higher and 60 ° C. or lower, (ii) It is necessary to cool to below ℃ and precipitate candesartan cilexetil crystals while maintaining this temperature.

  When a mixed solvent of a ketone having 1 to 4 carbon atoms and water, or a solvent other than an alcohol having 1 to 4 carbon atoms is used as a solvent, it is difficult to precipitate Form I crystals, Even if crystal precipitation is performed, crystal particles having an intended particle size distribution cannot be precipitated.

  In the present invention, the method for dissolving the object in the solvent is not particularly limited. Specifically, a method of mixing the solvent and the target object in advance and dissolving the target object can be mentioned.

  Among these, when the solvent to be used is a mixed solvent of a ketone having 1 to 4 carbon atoms and water, in order to reduce the amount of the solvent used, first, the object and the ketone are mixed and dissolved, and then water is added. It is preferable to employ a method of mixing these. The ketone is preferably acetone. Further, although not particularly limited, the volume ratio of ketone to water (ketone / water) is preferably 4/1 to 1/1. Candesartan cilexetil having a small average particle diameter can be produced even outside the above range, but the resulting candesartan cilexetil crystals tend to be Form II crystals having a melting point of around 120 ° C. Therefore, in order to obtain the most useful Form I crystal, it is preferable to use a mixed solvent having a volume ratio of ketone to water (ketone / water) of 4/1 to 1/1. This volume ratio is the ratio of the volume of ketone and water at 23 ° C.

  In the present invention, the amount of the mixed solvent of ketone and water may be appropriately determined according to the volume ratio, the cooling temperature, etc., but is 2 ml or more and 30 ml or less with respect to 1 g of candesartan cilexetil contained in the object. In particular, in order to obtain Form I crystals, the amount is preferably 3 ml or more and 12 ml or less. If it is this range, candesartan cilexetil with high purity can be manufactured efficiently.

  Moreover, when the solvent to be used is a C1-C4 alcohol, it is preferable that it is methanol or ethanol. The amount used may be appropriately determined according to the cooling temperature or the like, but is preferably 2 ml or more and 30 ml or less with respect to 1 g of candesartan cilexetil contained in the object, and in particular, obtains Form I crystals. In order to achieve this, it is preferable that the amount be 3 ml or more and 20 ml or less. If it is this range, candesartan cilexetil with high purity can be manufactured efficiently.

  In the present invention, the temperature of the solution in which the object is dissolved must be 40 ° C. or more and 60 ° C. or less. When the temperature of the mixed solution is lower than 40 ° C., the amount of the solvent used is increased, and the yield of candesartan cilexetil is decreased, which is not preferable. Furthermore, it is not preferable because it is difficult to obtain Form I crystals. On the other hand, when it exceeds 60 ° C., the desethyl body tends to increase, such being undesirable. In consideration of operability, yield of candesartan cilexetil, reduction of desethyl body, ease of acquisition of Form I crystals, the temperature of the mixed solution is preferably 45 ° C. or more and 57 ° C. or less, and further 47 ° C. It is preferable to set it to 55 degreeC or more.

  The method for setting the temperature of the mixed solution in the above range is not particularly limited. For example, after mixing a target object and a solvent, the method of heating this liquid mixture to 40 to 60 degreeC is employable. Moreover, after making the temperature of a solvent into 40 to 60 degreeC previously, the method of mixing a target object is also employable. In the case of a mixed solvent of ketone and water, considering operability and productivity, first, the object and the ketone are mixed, and the reflux temperature of the ketone is 40 ° C. or more, preferably 50 ° C. or more and the ketone reflux temperature or less. It is preferable to employ a method in which a predetermined amount of water (hot water if necessary) is mixed so that the temperature does not become less than 40 ° C. or exceeds 60 ° C. During this time, the mixed solution is preferably mixed with stirring.

  Next, in the present invention, the solution obtained by the above method and having a temperature of 40 ° C. or higher and 60 ° C. or lower is cooled to a temperature of 32 ° C. or higher and 38 ° C. or lower. Thereafter, by aging at 32 ° C. or higher and 38 ° C. or lower for 30 minutes or longer and 10 hours or shorter, stable candesartan cilexetil which has high purity, does not contain hard particles having a particle size of 100 μm or more, and has a small average particle size. Powder can be manufactured. When this temperature range is exceeded, desethyl bodies are likely to increase and the crystal growth rate is slow, which is not preferable. When the temperature range is below this range, hard particles with a particle size of 100 μm or more may be generated. It is not preferable. There is a possibility that hard particles having a particle diameter of 100 μm or more may be generated. When the temperature is below this temperature range, the crystals are very likely to precipitate, and it is considered that the precipitated crystals are likely to be aggregated as nuclei. . In consideration of appropriate purity and generation of hard particles having a particle diameter of 100 μm or more, aging is more preferably performed at a temperature of 33 ° C. or more and 37 ° C. or less.

  Further, seed crystals of Form I crystal can be mixed in the solution. When using a seed crystal, the target object and alcohol can be mixed, the temperature can be set to 40 ° C. or higher and 60 ° C. or lower, and the seed crystal can be mixed after being dissolved. When a mixed solvent of ketone and water is used as the solvent, the target and the ketone are mixed, the temperature is set to 40 ° C. or higher and the ketone reflux temperature or lower, and the solution and water (hot water as necessary) are mixed. In this case, seed crystals can be mixed. When the seed crystal is used, the amount used is not particularly limited, but is 0.1 parts by mass or more and 10.0 parts by mass or less with respect to 100 parts by mass of candesartan cilexetil contained in the object. It is preferable that the amount is 0.2 to 5.0 parts by mass. The seed crystal is preferably 20 μm or less because the crystallization efficiency is not good when the volume average particle diameter d50 is too large.

  In the present invention, when a seed crystal is used, the seed crystal can be prepared from candesartan cilexetil produced by a known method and candesartan cilexetil produced by the method of the present invention. Specifically, it can also be obtained by pulverizing or sieving the candesartan cilexetil of Form I crystals obtained by the above method or the like. The method for pulverizing Form I crystal candesartan cilexetil into seed crystals is not particularly limited, and a known pulverizer may be used. Among these, it is preferable to use a jet mill. A jet mill is a device that accelerates particles with a high-speed air stream and crushes them by collision between particles. It can be continuously processed and processed in large quantities. The generated frictional heat can be removed immediately, and the device can be downsized. There are advantages such as easy maintenance. However, it is preferable to use a seed crystal obtained by pulverization by the above method, which has not been stored for a long time after pulverization. Since the amount of seed crystals used is small, the influence thereof is small, but as described above, the content of desethyl compound tends to increase in the candesartan cilexetil of ground Form I crystals. Therefore, the seed crystal obtained by pulverization is preferably used directly after pulverization or after pulverization and stored in a temperature range of 0 ° C. or higher and 10 ° C. or lower for about one month. The fine particles used as seed crystals are preferably 2% or less in desethyl body. In particular, when considering the productivity of the seed crystal and the purity of candesartan cilexetil finally obtained, the desethyl compound contained in the seed crystal is more preferably 0.01% or more and 1% or less.

  In the present invention, the subsequent treatment is not particularly limited as long as it is aged for 30 minutes to 10 hours at a temperature of 32 ° C. or more and 38 ° C. or less. This ripening operation is considered to determine whether or not the final candesartan cilexetil powder contains hard particles having a particle size of 100 μm or less. Therefore, the conditions thereafter are not particularly limited, but in consideration of the yield of candesartan cilexetil, it is preferable to treat as follows. For example, after aging, the temperature may be cooled to a lower temperature as it is, maintained at 20 ° C. or higher and 30 ° C. or lower, and then further cooled to a lower temperature.

  In particular, in consideration of the yield of candesartan cilexetil, it is preferable to further cool the liquid mixture of 20 ° C. or higher and 30 ° C. or lower to a temperature of 0 ° C. or higher and 15 ° C. or lower (cooling arrival temperature). At this time, it is better not to newly add a solvent such as methanol, ethanol, acetone, water or the like. The cooling rate when the temperature of the mixed solution is cooled from 20 ° C. to 30 ° C. to 0 ° C. to 15 ° C. is not particularly limited, and may be 1 ° C./hour or more and 60 ° C./hour or less. In addition, the time for holding the mixed liquid at the cooling attainment temperature is not particularly limited, but it may be usually 1 hour or more and 48 hours or less. In addition, it is preferable to stir and mix the solution during the period from the time when the temperature reaches the cooling reached until it is cooled to 0 ° C. or higher and 15 ° C. or lower.

  By the method as described above, stable candesartan cilexetil crystals that do not contain hard aggregated particles having a particle diameter of 100 μm or more can be precipitated. The obtained crystals may be separated and recovered by solid-liquid separation by filtration, centrifugation, etc., and drying by natural drying, air drying, vacuum drying or the like. The separated powder is agglomerated in a wet state with a solvent attached, but when it is sufficiently dried, there is no need to perform a crushing operation or when a crushing operation is required. Even if it exists (without performing strong mechanical pulverization such as mill pulverization), it can be loosened only by applying a very weak force, and a fine particle powder having an intended particle size distribution can be obtained. Therefore, since the powder obtained by the method of the present invention has not undergone mechanical pulverization that causes amorphization, it is one year in an environment of high stability, specifically 60% relative humidity and 25 ° C. When stored above, a powder of candesartan cilexetil having the stability that the increase in the content of the desethyl compound represented by the formula (2) is 0.05% or less can be obtained.

  Further, the obtained candesartan cilexetil powder has a volume average particle diameter d50 of 15 μm or less, preferably 3 μm or more and 12 μm or less, more preferably 5 μm or more and 10 μm or less, under the measurement conditions of the following Examples. It is possible to obtain a fine powder of candesartan cilexetil which has a cumulative volume 99% particle diameter d99 of 90 μm or less, more preferably 60 μm or less and substantially does not contain hard-shaped aggregated particles having a particle diameter of 100 μm or more. it can. Therefore, it can be actually used as a medicine as it is without being pulverized.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited by these Examples.
In addition, measurement of the particle size of candesartan cilexetil obtained in Examples and Comparative Examples, purity measurement, measurement of content of desethyl body, measurement of powder X-ray diffraction, measurement of scanning electron microscope, measurement of melting point The following was performed.
In addition, since the production scale is different between the example and the comparative example, each stirring speed was performed by combining the stirring power.

<Measurement of purity of candesartan cilexetil, content of desethyl body>
Apparatus: High performance liquid chromatography Model: 2695-2489-996 (manufactured by Waters)
Detector: UV absorptiometer (measurement wavelength: 254 nm)
Column: Inertsil ODS-3, inner diameter 4.6 mm, length 15 cm (particle diameter 5 μm, pore diameter 12 nm) (manufactured by GL Sciences Inc.)
Column temperature: constant 40 ° C. Sample temperature: constant 25 ° C. Mobile phase: acetonitrile / 1% acetic acid aqueous solution = 80/20
Flow rate: 1.5 ml / min Under the above conditions, a peak of candesartan cilexetil is confirmed at about 4.9 minutes, and a peak of desethyl body is confirmed at about 3.0 minutes. In the following Examples and Comparative Examples, the purity of candesartan cilexetil and the content of desethyl body are both values of peak area% measured under the above conditions.

<Method for measuring particle size>
Apparatus: Laser diffraction type particle size distribution analyzer Model: Helos & Rodos system (manufactured by Sympatec)
Calculation method: Windows 5.2
Dispersion pressure: 1.5 bar
Attraction: 0
Rotation: No volume particle size distribution was determined under the above conditions.
<Measurement of powder X-ray diffraction of candesartan cilexetil>
Equipment: X-ray diffractometer Model: RINT (manufactured by Rigaku Corporation)
X-ray output: 30 mA, 40 kV
Wavelength: CuKa / 1.541858Å
Scanning speed: 10 ° C./min <Measurement of scanning electron microscope for candesartan cilexetil>
Apparatus: Scanning electron microscope (SEM)
Model: S-3400N (manufactured by Hitachi)
The sample was measured with the above apparatus after Pt coating.
<Melting point of candesartan cilexetil>
Apparatus: Melting point measuring apparatus Model: B-540 (manufactured by Shibata Science Co., Ltd.)
Heating rate: 1 ° C / min from 150 ° C to 180 ° C

Production Example 1 (Production of candesartan cilexetil)
Trityl candesartan cilexetil (10.86 kg), chloroform (13 L), and methanol (44 L) were added to a 100 L four-necked flask and reacted at 60 ° C. for 4 hours (at the end of the reaction, the purity of candesartan cilexetil was 96.4%, The content of the desethyl compound was 1.08%.) After the reaction, the solvent was concentrated under reduced pressure at 45 ° C., 33 L of acetone was added, and the mixture was stirred overnight at 10 ° C. or higher and 30 ° C. or lower. Subsequently, after stirring for 2 hours at 0 ° C., the precipitated crystals were separated by centrifugation to obtain a second crude wet body (candesartan cilexetil purity 99.7%, desethyl body 0.11% ). This second crude product was dissolved in 52.5 L of acetone at 50 ° C., dissolved, and then cooled to 27 ° C. 17.5 L of water was added to this solution and stirred overnight at 20 ° C. or higher and 30 ° C. or lower. Next, after stirring at 0 ° C. for 2 hours, the precipitated crystals were separated by centrifugation, dried, and dried to give a candesartan cilexetil having a purity of 99.9% and a desethyl content of 0.04%. 3.96 kg of the three crude bodies were obtained.

Example 1
2. A third crude product (candesartan cilexetil purity 99.9%, desethyl content 0.04%) obtained in Production Example 1 in a 50 L reactor equipped with three receding blades having a diameter of 37 cm. 75 kg and 17.8 kg of acetone were charged, stirred at a stirring speed of 188 rpm, and heated to the reflux temperature (about 56 ° C.) to dissolve candesartan cilexetil. After dissolution, 7.5 kg of water was added, and the temperature of the solution was adjusted to 55 ° C. while stirring. Thereafter, the temperature of the solution was cooled to 35 ° C. while stirring the solution.
Further, the solution was then aged and stirred for 5 hours and cooled to 5 ° C. Crystals were precipitated in the obtained solution, and the crystals were collected with a centrifuge and dried. The obtained crystals were candesartan cilexetil having a purity of 99.9% (desethyl content 0.01%) (yield 27.1 g (yield 90%)). This candesartan cilexetil crystal did not feel rough when touched, and hard particles having a particle size of 100 μm or more were not confirmed in particle size distribution measurement and electron microscope measurement. The volume average particle diameter d50 was 7.9 μm, and the 99% cumulative volume particle diameter d99 was 41.0 μm. Moreover, melting | fusing point was 163.2 degreeC and it was confirmed by the powder X-ray-diffraction measurement that it is a form I crystal | crystallization.

The particle size distribution of this candesartan cilexetil is shown in FIG.
The powder X-ray diffraction pattern of this candesartan cilexetil is shown in FIG.
An SEM image of this candesartan cilexetil is shown in FIG.

  With respect to this candesartan cilexetil, a storage stability test was performed at 25 ° C., 60% RH (relative humidity 60%), 40 ° C., 75% RH (relative humidity 75%), 60 ° C., 90%. Each was conducted for up to 12 months in an environment of RH (90% relative humidity). The results are shown in Table 1.

Example 2
Into a 10 L four-necked flask equipped with two stirring blades having a diameter of 12 cm, the third crude product obtained in Production Example 1 (candesartan cilexetil purity 99.9%, desethyl content 0.04%) ) 300 g and 2.0 L of methanol were charged, stirred at a stirring speed of 400 rpm, and heated and dissolved at a temperature of 55 ° C. It was then cooled and stirred at 34 ° C. for about 6 hours. Thereafter, the mixture was cooled to 5 ° C., and the crystals were collected with a centrifuge. After drying, candesartan cilexetil having a purity of 99.9% (desethyl content 0.02%) was obtained (yield 240.2 g (yield 80%)). This candesartan cilexetil crystal did not feel rough when touched, and hard particles having a particle size of 100 μm or more were not confirmed in particle size distribution measurement and electron microscope measurement. The volume average particle diameter d50 was 7.4 μm, and the 99% cumulative volume particle diameter d99 was 43.9 μm. Moreover, melting | fusing point was 163.8 degreeC and it was confirmed that it is a form I crystal | crystallization.

The particle size distribution of this candesartan cilexetil is shown in FIG.
An SEM image of this candesartan cilexetil is shown in FIG.

  With respect to this candesartan cilexetil, a storage stability test was performed at 25 ° C., 60% RH (relative humidity 60%), 40 ° C., 75% RH (relative humidity 75%), 60 ° C., 90%. Each was conducted for up to 12 months in an environment of RH (90% relative humidity). The results are shown in Table 1.

Example 3
Into a 10 L four-necked flask equipped with two stirring blades having a diameter of 12 cm, the third crude product obtained in Production Example 1 (candesartan cilexetil purity 99.9%, desethyl content 0.04%) ) 300 g and 3.6 L of ethanol were charged, stirred at a stirring speed of 400 rpm, and dissolved by heating at a temperature of 55 ° C. It was then cooled and stirred at 34 ° C. for about 6 hours. Thereafter, the mixture was cooled to 5 ° C., and the crystals were collected with a centrifuge. After drying, candesartan cilexetil having a purity of 99.9% (desethyl content 0.02%) was obtained (yield 246.1 g (yield 82%)). This candesartan cilexetil crystal did not feel rough when touched, and hard particles having a particle size of 100 μm or more were not confirmed in particle size distribution measurement and electron microscope measurement. The volume average particle diameter d50 was 6.8 μm, and the 99% cumulative volume particle diameter d99 was 46.6 μm. Moreover, melting | fusing point was 163.8 degreeC and it was confirmed that it is a form I crystal | crystallization.

  The particle size distribution of this candesartan cilexetil is shown in FIG.

Comparative Example 1
Into a 5 L four-necked flask equipped with two stirring blades having a diameter of 12 cm, the third crude product obtained in Production Example 1 (candesartan cilexetil purity 99.9%, desethyl content 0.04%) ) 300 g and 4.5 L of acetone were charged, stirred at a stirring speed of 400 rpm, and heated at a temperature of 40 ° C. or higher and 50 ° C. or lower to dissolve candesartan cilexetil. Subsequently, the solution was concentrated under reduced pressure to adjust the concentration of candesartan cilexetil to about 30% w / w (acetone amount: 1.25 L). 100 ml of pure water previously heated to 60 ° C. was added and stirred for about 10 minutes. 200 ml of pure water was added dropwise over about 5 minutes, and the mixture was stirred at 53 ° C. for about 1 hour. Cool to 30 ° C. for about 30 minutes (cooling rate 46 ° C./hour), add 300 ml of a mixture of acetone / water = 3/1, cool to 1 ° C., stir at 1 ° C. for 1 hour, and then centrifuge The crystals were collected by a machine. After drying, candesartan cilexetil having a purity of 99.9% (desethyl content 0.05%) was obtained (yield 274.8 g (yield 92%)). The candesartan cilexetil crystals had a rough feel, and when the particle size distribution was measured, a distribution of 100 μm or more was observed. The volume average particle diameter d50 was 4.2 μm, and the cumulative volume 99% particle diameter d99 was 137.6 μm. Furthermore, screening with 1000 μm was performed and SEM images of the obtained crystals were confirmed. As a result, it was found that there were about 200 μm hard particles as shown in FIG.

The particle size distribution of this candesartan cilexetil is shown in FIG.
An SEM image of this candesartan cilexetil is shown in FIG.

2 kg of this candesartan cilexetil powder was pulverized using a jet mill (model PJM-100) manufactured by Nippon Pneumatic Industry Co., Ltd. at a supply rate of 2.5 kg / hour and a pulverization pressure of 0.6 MPa. 1.12 kg (56% recovery rate) of pulverized powder was obtained. This pulverized powder of candesartan cilexetil did not feel rough when touched, and hard particles having a particle size of 100 μm or more were not confirmed in particle size distribution measurement and electron microscope measurement. The volume average particle diameter d50 was 1.1 μm, and the 99% cumulative volume particle diameter d99 was 3.1 μm.
The pulverized powder of candesartan cilexetil was subjected to a storage stability test in an environment of 25 ° C., 60% RH (relative humidity 60%), 40 ° C., 75% RH (relative humidity 75%), 60 Each was conducted for up to 12 months in an environment of 0 ° C. and 90% RH (90% relative humidity). The results are shown in Table 1.

Comparative Example 2
In a 500 ml four-necked flask equipped with two stirring blades having a diameter of 5 cm, the third crude product obtained in Production Example 1 (candesartan cilexetil purity 99.9%, desethyl content 0.04%) ) 30 g and 163 ml of methanol were charged, stirred at a stirring speed of 700 rpm, and heated to reflux temperature for dissolution. The solution was cooled to 23 ° C., stirred for 4 hours, and then the crystals were collected with a centrifuge. After drying, candesartan cilexetil having a purity of 99.8% (desethyl content: 0.10%) was obtained (yield 25.5 g (yield 85%)). The feel of this candesartan cilexetil crystal had a rough feeling, and when the particle size distribution was measured, a distribution was observed even over 100 μm. The volume average particle diameter d50 was 3.3 μm, and the 99% cumulative volume particle diameter d99 was 138.7 μm.

  The particle size distribution of this candesartan cilexetil is shown in FIG.

Comparative Example 3
A 500 ml four-necked flask was charged with 30 g of the third crude product (candesartan cilexetil purity 99.9%, desethyl content 0.04%) obtained in Production Example 1, and 330 ml of acetone at a reflux temperature. To dissolve candesartan cilexetil (an acetone solution was prepared). To a 700 ml four-necked flask equipped with two stirring blades with a diameter of 5 cm, add 150 ml of water, stir at a stirring speed of 500 rpm, add an adjusted acetone solution of candesartan cilexetil at 20-25 ° C., and stir for 30 minutes Thereafter, the mixture was stirred at 0 ° C. for 30 minutes, and then crystals were collected with a centrifuge. After drying, purity 99.8% (desethyl content 0.10%)
Of candesartan cilexetil was obtained (yield 24.9 g (83% yield)). The feel of this candesartan cilexetil crystal had a rough feeling, and when the particle size distribution was measured, a distribution was observed even over 100 μm. The volume average particle diameter d50 was 4.7 μm, and the cumulative volume 99% particle diameter d99 was 283.6 μm.

  The particle size distribution of this candesartan cilexetil is shown in FIG.

Comparative Example 4
30 g of the third crude product obtained in Production Example 1 (candesartan cilexetil purity 99.9%, desethyl content 0.04%) was dissolved in 5 L of methanol at 30 ° C., and the solvent was distilled off. Amorphous candesartan cilexetil was obtained. 180 ml of ethanol was added to the powder and stirred at room temperature for 3 hours. (Stirring speed: 700 rpm) Thereafter, the mixture was stirred at 7 ° C. for 1 hour, the crystals were centrifuged, the obtained crystals were dried, and candesartan cilexetil having a purity of 99.9% (desethyl content 0.02%) (27.2 g (91% yield)) was obtained. The feel of this candesartan cilexetil crystal had a rough feeling, and when the particle size distribution was measured, a distribution was observed even over 100 μm.

  The particle size distribution of this candesartan cilexetil is shown in FIG.

Comparative Example 5
100 g of candesartan cilexetil obtained in Example 1 was pulverized with a jet mill, and 90 g of finely pulverized candesartan cilexetil (candesartan cilexetil purity 99.9%, desethyl content 0.09%). 30 g of that was charged in a 500 ml four-necked flask with 330 ml of methanol and stirred at a stirring speed of 700 rpm at 25 ° C. for 24 hours. Thereafter, it was centrifuged and dried. The feel of this candesartan cilexetil crystal had a slightly rough feeling, and when the particle size distribution was measured, the particles tended to be small overall, but a distribution was also observed at 100 μm or more.

  The particle size distribution of this candesartan cilexetil is shown in FIG.

Claims (3)

A powder of candesartan cilexetil represented by the following formula (1), wherein 2θ = 9.8, 17.2, 20.2, and 25.0 ± 0.2 ° in the powder X-ray diffraction spectrum It consists of an aggregate of crystal particles having a characteristic peak, does not contain particles having a volume average particle diameter of 15 μm or less, a cumulative volume 99% particle diameter of 90 μm or less, and a particle diameter of 100 μm or more, and Candesartan cilexetil which has the stability that the increase in the content of the desethyl compound represented by the following formula (2) is 0.05% or less when stored in an environment of 60% humidity and 25 ° C. for one year or more. A method for producing a powder of
Candesartan cilexetil is dissolved in a solvent comprising a mixture of a ketone having 1 to 4 carbon atoms and water or an alcohol having 1 to 4 carbon atoms without setting the temperature of the solvent to a temperature exceeding 60 ° C. Preparing a solution having a temperature of 40 ° C. or more and 60 ° C. or less, and cooling the solution to 32 ° C. or more and 38 ° C. or less, and maintaining the liquid temperature of the solution at 32 ° C. or more and 38 ° C. or less for 5 hours or more and 10 hours or less. The manufacturing method characterized by including the process of precipitating the crystal | crystallization of candesartan cilexetil from the said solution.

After maintaining the solution at a temperature of 32 ° C. or more and 38 ° C. or less for 5 hours or more and 10 hours or less, the solution is further cooled, and the liquid temperature of the solution is maintained at 0 ° C. or more and 15 ° C. or less. The method according to claim 1, wherein crystals of cilexetil are precipitated.   The method according to claim 1 or 2, wherein a mixture of ketone and water having a ketone / water volume ratio of 4/1 to 1/1 is used as the solvent.

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