KR20090074712A - Method for preparation of anhydrous crystalline docetaxel - Google Patents

Abstract

A method for manufacturing anhydrous crystalline docetaxel is provided to produce the anhydrous crystalline or hydrated crystalline docetaxel with high yield by the solvent precipitation method and colloid formation method. A method for producing an anhydrous crystalline docetaxel comprises: a step of mixing a solvent which is able to colloidize with docetaxel-containing material or 1-30%(w/v) of decetaxel to colloidize in the suspended state; and a step of evaporating and compression-drying the solvent at 35-40°C and collecting the anhydrous crystalline docetaxel of fine powder. The solvent which is able to colloidize is a acetone.

Description

Method for producing anhydrous crystalline docetaxel {METHOD FOR PREPARATION OF ANHYDROUS CRYSTALLINE DOCETAXEL}

The present invention relates to a method for obtaining high purity amorphous, anhydrous or hydrated crystalline docetaxel with high conversion and high yield by solvent precipitation, colloid formation, etc. using various solvents.

Docetaxel, along with paclitaxel, has been used as an important anticancer agent. Docetaxel is semisynthesized by obtaining precursors such as 10-deacetylbaccatin III and bacaccin III from leaves and stems of yew trees and then converting them to docetaxel by chemical reaction.

Docetaxel, like paclitaxel, has very low solubility in most pharmaceutical solvents, including water, and therefore has very limited formulation and prescription.

The solubility of the material is influenced by the solid-state properties and it is suggested that the solubility of the amorphous structure is 10 to 1600 times higher than the most stable crystalline structure (Bruno C. Hancock and Michael Parks, What is the true solubility advantage for amorphous pharmaceuticals.Pharmaceutical Res. 2000, 17, 397-404). This indicates that the solubility in a particular solvent is mainly dependent on the nature of the material itself, but can be improved by changing the shape of the material. In addition to the change in the shape of the substance, solubility and dissolution rate can be improved by reducing the particle size of the substance to increase the surface area. On the other hand, when the particle shape is generally amorphous, there is a disadvantage in that the stability according to the storage period is lower than the crystalline form. Dovez Zach et al. In Korean Patent Registration No. 10-0391753 describes that docetaxel is more stable in hydrate than anhydride.

Therefore, since the physical properties of docetaxel varies depending on the final properties such as amorphous, crystalline, hydrate, and anhydride, it is necessary to selectively obtain a suitable property according to the intended use. However, until now, little is known about the method of selectively obtaining docetaxel having a certain property.

Recently, due to the stability of the hydrate, there is a growing interest in the production of docetaxel hydrate. Dovez Zach et al. In Korean Patent Registration No. 10-0391753, docetaxel trihydrate crystallizes docetaxel from a mixture of water and aliphatic alcohols having 1 to 3 carbon atoms, and the obtained product is subjected to a relative humidity of about 80% in a humid atmosphere. And obtained by drying under a temperature of about 40 ° C. and reduced pressure of 4-7 kPa. The method presented here consists of a crystallization step and a hydration step. In the crystallization step, docetaxel is preferably dissolved in an aliphatic alcohol having 1 to 3 carbon atoms at a temperature of 40 to 60 ° C., purified water is added at the same temperature, and then cooled to form a crystal. In the examples, it is described that 303 g of docetaxel is heated to 50 ° C. until it is completely dissolved in 0.983 L of ethanol, and 4.39 L of purified water is added over 1 hour while maintaining the temperature at 50 ° C. However, such a crystallization process requires warming at a high temperature for at least one hour or more under solution, in which case docetaxel is unstable and decomposes. Although the titer of the sample used in the Example shows an improvement of 98.7% through crystallization at the initial 92.4%, the impurity contained may include a substance decomposed in the crystallization process. Therefore, since the presented example is the final step in the production process to determine the properties of the final product, it should be combined with the evaluation and comparison of impurities generated during the process using high-purity docetaxel purified to 99.5% or more. However, the use of samples with low titers has neglected the evaluation of degradation products that can be produced during the crystallization process.

Arun Prakash Sharma et al., US Pat. No. 6,838,569, discloses a process for the preparation of trihydrates of paclitaxel and docetaxel. In this method, partially purified docetaxel is purified by chromatography purity of 99.53% under alkane-chloroalk alkanes, acetone-hexane conditions, and then crystallized with acetonitrile and water. The purified docetaxel is dissolved in acetonitrile at 50 to 70 ° C., and then purified water is added slowly and further stirred at 15 to 20 ° C. to obtain a precipitate. The method presented in this document does not mention the dissolution time, but by warming to 50 to 70 ° C., although the change in purity before and after crystallization showed little, the decomposition of docetaxel cannot be ruled out. In addition, the applied process is a final purification process, recovery may be a very important factor. In the above examples, 415 g (moisture 6.8%) of trihydrate was obtained using 460 g of anhydride before crystallization, but the actual yield corresponds to a relatively low level of about 84% in consideration of moisture. This is an example of the shortcomings seen in the general recrystallization method.

Li Jinliang et al. Proposed a method for obtaining trihydrate by crystallizing anhydrous docetaxel under a mixed solution of purified water and acetone in international patent WO2004 / 099167. In Example, 87 g of anhydride was dissolved in acetone and 1.5 times of purified water was added, followed by crystallization at 0 ° C. for 2 days to obtain 85 g of trihydrate (moisture 6.43%). However, the presented method is also a general recrystallization method. If the actual recovery is 91%, there is a disadvantage that shows a low recovery.

Lee et al. Proposed a method for preparing paclitaxel having amorphous, anhydrous and hydrated crystal forms using various solvents (Jeong Hoon Lee, Un-Sook Gi, Jin-Hyun Kim, Yongae Kim, Seon-Ho Kim, Hunseung Oh, and Bumchan Min, Preparation and characterization of solvent induced dihydrated, anhydrous, and amorphous paclitaxel, Bull.Korean Chem. Soc., 2001, 22, 925-928). In the above method, the crystal structure of paclitaxel can be selected by various solvents applied, but there are many problems in the vacuum drying and recrystallization methods as follows.

First, in the case of simple pressure-drying such as Lee, it is dried while gelling as if paclitaxel is coated in a container used for drying, and it is difficult to recover, and since the size of the particles is formed very large, the particles are recovered even after crushing The size is very large, over 100 μm. Such large particle sizes can cause solubility deterioration and make it difficult to dry to maintain a very small amount of residual solvent. Drugs used for medicine should remain below a certain level for each solvent according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines, and if dried by a method such as vacuum evaporation, Particle size and physical properties of the particles are difficult to manufacture, such as takes a long time to sufficiently lower the residual solvent level. In addition, the existing recrystallization method has a problem in that the yield is low and should be carried out for a long time at low temperature for recrystallization and the crystal size is large.

In order to solve such a problem, an object of the present invention is to provide a method for efficiently and selectively preparing docetaxel having an amorphous, anhydrous or hydrated crystal form using various kinds of solvents.

The present invention relates to a method for producing docetaxel, comprising the steps of preparing amorphous, anhydrous or hydrated crystal docetaxel for various kinds of solvents, and obtaining in high conversion and high yield. .

The docetaxel production method of the present invention has the advantage that it can efficiently produce the docetaxel of the fine particles in a high yield. In addition, it has the advantage that it is possible to obtain docetaxel having a desired property with high conversion and high yield in a simpler manner while maintaining its purity from high purity docetaxel.

All the docetaxel production methods of the present invention described below are applicable not only to docetaxel as a single substance but also to docetaxel-containing substances containing a taxane-based substance other than docetaxel. In the present invention, the 'docetaxel-containing substance' contains taxane-based substances such as paclitaxel together with docetaxel, and the docetaxel content (purity) is 50% or more, preferably 70% or more, more preferably 90% or more, Most preferably, it is 98.5% or more.

First, the present invention provides a method for preparing amorphous docetaxel using solvent precipitation with a polar non-polar solvent. As described above, docetaxel is known to have a solubility of 10 to 1600 times higher in the case of poorly soluble but having an amorphous structure compared to the case of having a stable crystalline structure. Conventionally, a complicated and difficult process has to be performed to obtain amorphous docetaxel, but the present invention is simple and simple to prepare amorphous docetaxel with high conversion and high yield by performing solvent precipitation using a specific polar non-polar solvent. Can be.

The amorphous docetaxel production method of the present invention comprises the following steps:

Docetaxel content or docetaxel is dissolved in a polar solvent;

Adding the obtained solution to a nonpolar solvent to produce a precipitate;

Filtering and drying the resulting precipitate to obtain amorphous docetaxel.

In the amorphous docetaxel production method, it is preferable to use one selected from the group consisting of halogenated alkanes, ketones and mixed solvents thereof as the polar solvent. The halogenated alkanes may be used dichloromethane, chloroform and the like, ketones may be acetone. When docetaxel is dissolved in a polar solvent, dissolution at a concentration of 1 to 30% (w / v), preferably 5 to 20% (w / v) is preferred in view of initial purity maintenance and high yield of high purity amorphous docetaxel. Do.

It is preferable to use at least one solvent selected from the group consisting of alkanes, cycloalkanes and nonpolar solvents having a polarity value of diisopropyl ether or less as the nonpolar solvent, since precipitation can be formed immediately. The alkanes may be hexane or pentane, the cycloalkanes may be cyclohexane or cyclopentane, and the nonpolar solvent having a polarity value less than or equal to the diisopropyl ether may be dialkyl ether.

In the step of adding a docetaxel-containing solution or a solution in which docetaxel is dissolved in a polar solvent to the nonpolar solvent, the volume of the nonpolar solvent is preferably 5 times or more of the volume of the added solution, and more preferably, the solution and the nonpolar solvent The volume ratio is preferably 1: 8 to 1:20. If the amount of the nonpolar solvent is out of the above range, no effective precipitation formation can be achieved. The precipitate thus obtained can be easily filtered off and dried under reduced pressure to obtain amorphous docetaxel.

The present invention also provides a method of preparing anhydrous crystalline docetaxel by colloidating a docetaxel-containing substance or docetaxel in a suspended state in a colloidable solvent, followed by drying under reduced pressure. Anhydrous crystalline docetaxel has excellent storage stability, but has a disadvantage of low solubility. However, by the production method of the present invention, the particles of docetaxel obtained are very fine, so that the solubility can be remarkably improved. Accordingly, the present invention provides a method for preparing anhydrous crystalline docetaxel having excellent storage stability and improved solubility.

The process for preparing anhydrous crystalline docetaxel of the present invention comprises the following steps:

Docetaxel content or docetaxel is colloided in suspension without complete dissolution in a colloidable solvent;

Evaporating the solvent in the colloidal solution obtained to dry under reduced pressure to obtain anhydrous crystalline docetaxel of fine powder.

The colloidal solvent of docetaxel may be present in a suspended state without completely dissolving docetaxel, and acetone may be used.

When docetaxel is dissolved in acetone, docetaxel is added at a concentration of 1 to 30% (w / v), preferably 5 to 10% (w / v). The solvent evaporation can be carried out using a conventional rotary evaporator, the temperature condition is preferably 35 ℃ to 40 ℃. In the present invention, 'colloid' means a state in which docetaxel is not dissolved in a solvent and suspended.

When the anhydrous crystalline docetaxel is prepared by the method described above, the formation of fine particles through the colloid is induced, unlike the larger particles, while being coated in a container, which is a disadvantage in general vacuum drying as described in Lee et al. Therefore, there is an advantage that the drying is easy and the residual solvent level can be kept low. In addition, the particle size of the docetaxel obtained is fine to 5 to 30 ㎛ solubility can be significantly improved.

The present invention also provides a method for preparing a hydrated crystalline docetaxel by dissolving a docetaxel-containing or docetaxel in an organic solvent at room temperature, adding purified water or a buffer solution and then precipitating. The hydrated crystalline form is advantageous in terms of solubility, but the conventional method for preparing a hydrated crystalline docetaxel has a disadvantage in that it is performed at a relatively high temperature, which lowers the stability of the docetaxel and does not maintain initial purity until the final product. However, the method for producing hydrated crystal docetaxel of the present invention has the advantage that it can be carried out at a relatively low temperature, which is advantageous in terms of stability of docetaxel and maintains its initial purity.

The method for preparing the hydrated crystal docetaxel comprises the following steps:

Docetaxel content or docetaxel is dissolved in an organic solvent at room temperature;

Purified water or buffer solution is added dropwise to the obtained solution;

Leaving precipitate at −20 ° C. to 20 ° C., preferably at 0 ° C. to 10 ° C., for 1 hour to 48 hours, preferably 5 hours to 24 hours;

Filtering the resulting precipitate to obtain hydrated crystalline docetaxel.

In the method for producing hydrated crystal docetaxel, at least one selected from the group consisting of alcohols having 1 to 3 carbon atoms such as methanol, ethanol or propanol, ketones such as acetone and acetonitrile can be used. When docetaxel is dissolved in an organic solvent, docetaxel is dissolved at a concentration of 1 to 30% (w / v), preferably 5 to 20% (w / v).

The hydrated crystalline docetaxel obtained by the above method is not limited in hydration form, and preferably may be in the form of monohydrate, dihydrate or trihydrate.

To the obtained solution, purified water or buffer solution at a volume ratio of 10: 4 to 10:15 (solution volume: purified water or buffer volume), preferably 10:10 to 10:12 (solution volume: purified water or buffer volume) It is preferable to add dropwise. If the volume ratio of purified water is smaller than the ratio, precipitation may not be slow or precipitation may occur. If the volume ratio of purified water is larger than the ratio, the volume of the solution may be excessively large during the reaction. Phosphate buffer, ammonia buffer, etc. may be used as the buffer solution.

The method of dissolving docetaxel-containing or docetaxel in an organic solvent at room temperature and adding purified water and then precipitating to obtain a hydrated crystal docetaxel uses a solvent similar to that described in Korean Patent Registration No. 10-0391753 to Dovez Jacque et al. On the other hand, it has the advantage that it can be applied more easily industrially.

That is, the method of Dovez Zach et al. Is a method of dissolving in an aliphatic alcohol having 1 to 3 carbon atoms at a temperature of 40 to 60 ℃, can cause serious problems in the stability of docetaxel in the process. Dovez Zach et al. Proposed that the purity of docetaxel obtained after dissolving alcohol at 50 ° C. for 1 hour and then adding purified water to form crystals increased from 92.4% to 98.7%. After 99.7% of docetaxel was dissolved in methanol at 50 ° C. and left for 0 to 24 hours, purity analysis was performed for 0 hours, 1 hour, 5 hours, 10 hours, and 24 hours. Unlike Korean patent registration 10-0391753, It was confirmed that the purity was sharply lowered (see Comparative Example 2 below). As suggested by Dovez Zach et al., After dissolving in methanol to maintain a minimum of 1 hour at 50 ℃, the purity of docetaxel was lowered to 95.7%, it was confirmed that the phenomenon of docetaxel decomposition. This is a result that can confirm the general fact that docetaxel decomposes when heated after dissolving in a solvent such as alcohols. Therefore, the method by Dovez Jacque et al., Although it is possible to produce a hydrated crystal form, it is difficult to commercialize in high purity to secure the stability of docetaxel, so the solvent precipitation method at low temperature after dissolution at room temperature proposed in the present invention is It is very useful and distinguishes from industrial methods. That is, while the method of Dobezzak et al. Proposed an attempt to increase the yield by increasing the concentration of docetaxel in the solution, the method for producing a hydrated crystal docetaxel of the present invention, keeping the temperature low in stabilizing docetaxel and maintaining high purity Recognizing that it is a very important factor, it is characterized by determining the temperature range most suitable for maintaining docetaxel stability and high purity.

In addition, the present invention is another method for producing a hydrated crystal docetaxel, the solution obtained after dissolving the docetaxel-containing or docetaxel in a mixed solvent of an organic solvent and purified water or a mixed solvent of an organic solvent and a buffer solution to precipitate by concentration under reduced pressure It provides a method for obtaining a hydrated crystalline docetaxel by forming a.

The method for preparing hydrated crystalline docetaxel using the mixed solvent includes the following steps:

Dissolving docetaxel-containing or docetaxel in a mixed solvent of an organic solvent and purified water or a mixed solvent of an organic solvent and a buffer solution;

The resulting solution is evaporated to remove the organic solvent in the mixed solvent to form a precipitate;

Filtration and drying of the obtained precipitate under reduced pressure to prepare a hydrated docetaxel.

The hydrated crystalline docetaxel obtained by the above method is not limited in hydration form, and preferably may be in the form of monohydrate, dihydrate or trihydrate.

As the organic solvent, one or more selected from the group consisting of alcohols having 1 to 3 carbon atoms such as methanol, acetone, acetonitrile, and the like may be used as a solvent mixed with purified water. The organic solvent is mixed with purified water or buffer solution and used as a mixed solvent, wherein the mixing ratio of organic solvent and purified water or buffer solution is 7: 0.5 to 7: 5, preferably 7: 1 to 7: 4. It is better to use the volume ratio. If the ratio of the purified water is lower than the above, there is a fear that the precipitate is not formed well, if the ratio is higher than the ratio there is a problem that the volume of the reaction solution is excessive. Phosphate buffer, ammonia buffer, or the like can be used as the buffer solution. Docetaxel is dissolved in the mixed solvent at a concentration of 0.1 to 5% (w / v), preferably 1 to 2% (w / v).

The evaporation may be performed at 35 ° C. to 40 ° C. using a conventional rotary evaporator.

After dissolving docetaxel-containing or docetaxel in a mixed solution of the organic solvent and purified water or buffer solution, the precipitate formed by evaporating the solvent using a conventional rotary evaporator is filtered and dried to obtain a hydrated crystal docetaxel in a short time. This is an effective way to achieve high yields. That is, when docetaxel is dissolved in a mixed solvent of organic solvent and purified water and concentrated under reduced pressure, the ratio of the remaining purified water or buffer solution is increased while the organic solvent is evaporated first. This lowers the solubility of docetaxel and begins to form precipitates. When all organic solvents are evaporated, solubility of the docetaxel in purified water is very low, and most of the docetaxel forms a precipitate. When the precipitate formed is filtered under reduced pressure, a hydrated crystal form can be obtained relatively easily, and the precipitate obtained is characterized by very small particles, and has a much higher recovery rate than the crystallization method. In addition, there is an advantage that the hydrated crystal form can be obtained in a stable method in a very short time compared to the crystallization method.

In addition, the present invention provides a method for producing a hydrated crystalline docetaxel by dissolving the docetaxel-containing or docetaxel in an organic solvent and then adding an excess of purified water to form a precipitate.

The method for preparing hydrated crystalline docetaxel by dissolving docetaxel in the organic solvent and then adding it to an excess of purified water to form a precipitate includes the following steps:

Docetaxel content or docetaxel is dissolved in an organic solvent or a mixed solvent of organic solvent and purified water at room temperature;

The obtained solution is suspended and precipitated with slow addition to excess purified water or buffer solution;

Filtration and drying of the obtained precipitate under reduced pressure to obtain a hydrated crystal docetaxel.

The hydrated crystalline docetaxel obtained by the above method is not limited in hydration form, and preferably may be in the form of monohydrate, dihydrate or trihydrate.

As the organic solvent, one or more organic solvents selected from the group consisting of alcohols having 1 to 3 carbon atoms, such as methanol, which is a solvent mixed with purified water, acetone, acetonitrile, tetrahydrofuran, and the like may be used. The organic solvent may be used alone or as a mixed solvent by mixing with purified water. When the organic solvent is mixed with purified water and used as a mixed solvent, the concentration of the mixed solvent is preferably 0.5% to 50% (v / v), preferably 10% to 30% (v / v).

The solution is slowly added to 1-20 times, preferably 5-10 times, purified water or buffer by volume to obtain a precipitate.

Dissolving docetaxel in the organic solvent and then adding an excess of purified water to form a precipitate to obtain a hydrated crystalline docetaxel is able to obtain a hydrated crystalline form in a very short time compared to the crystallization method and the like. That is, when docetaxel is dissolved in an organic solvent or a mixed solvent of organic solvent and purified water, and slowly added to excess purified water, the solubility of docetaxel in purified water is lowered to form a precipitate. Since dissolution of docetaxel proceeds at room temperature and the precipitate formed can be simply obtained by a vacuum filtration method, it is possible not only to secure the stability of docetaxel with high recovery rate but also to obtain a short and very easy process time.

As described above, the present invention provides a method for selectively preparing amorphous, anhydrous or hydrated crystalline docetaxel using various solvents. According to the present invention, docetaxel of amorphous, anhydrous, and hydrated crystals can be selectively produced in high yield while maintaining initial high purity according to the desired use.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are merely illustrative of the present invention, and the present invention is not limited by these examples.

Example

The docetaxel recovered by the respective production method shown in the following examples is the form of docetaxel through vacuum drying, purity, yield, X-ray analysis (XRPD) and scanning electron microscope (SEM, JSM-6635F, Jeol) , Particle size and the like were confirmed. X-ray analysis (XRPD) and purity analysis conditions are shown in Table 1 and Table 2.

Measuring equipment Rigaku, D / MAX 3B, XRPD How to measure About 20 mg of sample was fixed in XRPD sampler and measured by scanning from 5 ℃ to 25 ℃ in minutes at room temperature. X-ray source CuKα 40kV, 40mA

Purity and recovery of docetaxel herein was calculated by quantitative analysis using HPLC under the conditions of Table 2.

device Hewlett Packard 1100 HPLC column Curosil PFP 4.6X50, 5micron Column temperature 35 ℃ Mobile phase Acetonitrile: water (35-65% concentration gradient) Flow rate 1ml / min Injection volume 10ul Detector UV (227 nm)

Example  1: amorphous Docetaxel  Manufacture 1

All of the samples used were docetaxel (FIG. 1A) with a purity of 99.7% or more, and there was no degradation after the manufacturing process (FIG. 2B). After dissolving 2 g of docetaxel having a purity of 99.7% at room temperature in 20 ml of acetone, the resulting solution was added to 200 ml of n-pentane with stirring to form a precipitate. The precipitate obtained was filtered and then dried under vacuum at a temperature of 40 ° C. and a vacuum degree of 650 mmHg for 15 hours to obtain 1.94 g of amorphous docetaxel having a purity of 99.7%.

Example  2: amorphous Docetaxel  Manufacture 2

2 g of docetaxel with a purity of 99.7% in 20 ml of dichloromethane was added to 200 ml of n-pentane under stirring to form a precipitate immediately, and the obtained precipitate was filtered and vacuum dried at a temperature of 40 ° C. and a vacuum of 650 mmHg for 15 hours. Then, 1.95 g of amorphous docetaxel having a purity of 99.7% was obtained.

Example  3: amorphous Docetaxel  Manufacture 3

2 g of docetaxel having a purity of 99.7% was dissolved in 20 ml of dichloromethane, and then added to 200 ml of n-hexane under stirring to form a precipitate immediately. The precipitate thus obtained was filtered, vacuum-dried at a temperature of 40 DEG C and a vacuum of 650 mmHg for 15 hours. And 1.92 g of amorphous docetaxel having a purity of 99.7% were obtained.

Example  4: anhydrous crystalline Docetaxel  Produce

2 g of docetaxel having a purity of 99.7% was added to 10 ml of acetone, dissolved, and concentrated under reduced pressure. 2 ml of acetone was added to the obtained solution again to form a colloid in which docetaxel was not completely dissolved but suspended. The solvent was evaporated from the colloid obtained at 35 ° C. to 40 ° C. using a rotary evaporator, and vacuum-dried at a temperature of 40 ° C. and a vacuum of 650 mmHg for 15 hours to obtain 1.96 g of anhydrous crystalline docetaxel having a purity of 99.7%.

Example  5: hydrated crystal type Docetaxel  Manufacture 1

250 mg of docetaxel having a purity of 99.7% was dissolved in 3 ml of methanol at room temperature, 3 ml of distilled water was slowly added, and left to crystallize at 4 ° C. for 24 hours. The obtained crystals were filtered and dried at 650 mmHg at 35 ° C. for 15 hours to obtain 254 mg (moisture: 4.5%) of purity 99.7% hydrated crystalline docetaxel.

Example 6: Hydration Crystal Form Docetaxel  Manufacture 2

300 mg of docetaxel having a purity of 99.7% was dissolved in 60 ml of a mixed solvent having a mixture ratio of acetone and distilled water at a room temperature of 7: 3. The solvent in the obtained solution was evaporated at 35 ° C. to 40 ° C. using a rotary evaporator. A precipitate formed as the solvent evaporated. The resulting precipitate was filtered and vacuum dried for 15 hours at a temperature of 35 ° C. and 650 mmHg to obtain 303 mg (moisture: 4.3%) of purity 99.7% hydrated crystalline docetaxel.

Example 7 Preparation of Hydrated Crystalline Docetaxel by Dissolving in Mixed Solvent of Organic Solvent and Purified Water and Adding Precipitation to Purified Water

300 mg of docetaxel having a purity of 99.7% was dissolved in 60 ml of a mixed solvent having a mixing ratio of methanol and distilled water of 8: 2 at room temperature. The precipitate was formed while slowly adding the obtained solution to 300 ml of purified water. The obtained precipitate was filtered and vacuum-dried at a temperature of 35 ° C. at 650 mmHg for 15 hours to obtain 311 mg (moisture: 4.6%) of purity 99.7% hydrated crystal docetaxel.

Comparative example  One

After dissolving 203 mg of docetaxel with a purity of 99.5% in 6.11 ml of acetonitrile at 68 ° C. by the method shown in US Pat. No. 6,838,569 by Arun Prakash Sharma et al. Stirring was carried out at 20 ° C. for 3 hours to obtain a precipitate. The resulting precipitate was filtered and vacuum dried for 36 hours at a temperature of 36 ° C. and a vacuum of 650 mmHg to obtain 162 mg of purity 78.8% hydrated crystalline docetaxel.

Although the conditions presented through this comparative example may vary in degree depending on the application temperature and time, it can be confirmed that the conditions are very unstable to decompose docetaxel.

Comparative example  2

In order to test the stability of docetaxel in the case of dissolving in alcohol at high temperature to produce a hydrated docetaxel, methanol and ethanol were used as organic solvents, respectively, and the dissolution temperature and the leaving temperature were 50 ° C., 0, 1, 5 Docetaxel purity change and degree of degradation after standing for 10 and 24 hours were measured and shown in Table 3 below. The above measurement was performed under HPLC conditions as described in Table 2.

MeOH EtOH Docetaxel Purity Change (%) 7-epi-docetaxel production (area%) Docetaxel Purity Change (%) 7-epi-docetaxel production (area%) 0hr 99.7469 0 99.7480 0 1hr 95.7399 4.0163 99.2959 0.4494 5hr 81.8743 17.2282 97.8546 1.8948 10hr 69.3707 28.4728 96.8045 2.9451 24hr 50.7338 41.5352 95.1952 4.5544

As can be seen in Table 3, when dissolved and left at 50 ° C., most of the docetaxel was converted to its metabolite, 7-epi-docetaxel, and over time It was confirmed that the purity was significantly reduced. The test results also show that temperature conditions are very important in maintaining docetaxel stability and purity.

Figure 1a and 1b is a result of analysis using HPLC to confirm the purity change of docetaxel before and after the manufacturing process of Example 1, Figure 1a is a result of HPLC analysis of the sample before the manufacturing process, Figure 1b after performing the manufacturing process HPLC analysis of the sample.

Figure 2a is a scanning electron microscopy (SEM) analysis of the amorphous docetaxel prepared by the solvent precipitation method of Example 1, 2b is an X-ray powder diffractometer (XRPD) analysis of the amorphous docetaxel.

Figure 3a is an SEM analysis of the anhydrous crystalline docetaxel prepared by the colloid formation method of Example 4, 3b is an XRPD analysis of the anhydrous crystalline docetaxel.

4 is an XRPD analysis result of hydrated crystalline docetaxel prepared by solvent precipitation at low temperature of Example 5. FIG.

5 is an XRPD analysis result of a hydrated crystalline docetaxel prepared by evaporation under reduced pressure after dissolving in a mixed solvent of an organic solvent and purified water of Example 6.

6 is an XRPD analysis result of a hydrated crystalline docetaxel prepared by dissolving in a mixed solvent of an organic solvent and purified water of Example 7 and then adding precipitated water to purified water.

7a to 7c is a result of HPLC and XRPD analysis to confirm the purity change before and after the manufacturing process for the docetaxel prepared by stirring at room temperature after solvent precipitation at high temperature of Comparative Example 1, 7a is a sample before the manufacturing process HPLC analysis of, 7b is the result of HPLC analysis of the sample after the manufacturing process, 7c is XRPD analysis.

Claims (2)

Colloidal in suspension by mixing docetaxel content or 1-30% (w / v) of docetaxel with a colloidal solvent; Evaporating the solvent in the colloid obtained at 35 ℃ to 40 ℃ and dried under reduced pressure, to obtain anhydrous crystalline docetaxel of fine powder Method for producing anhydrous crystalline docetaxel.  The method for producing anhydrous crystalline docetaxel according to claim 1, wherein the colloidable solvent is acetone.

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