Method for producing epirubicin hydrochloride crystals

Abstract

This invention provides a novel crystallization method for epirubicin hydrochloride. [Solution] A method for producing epirubicin hydrochloride crystals is provided, comprising the steps of (a) obtaining a mixture containing epirubicin hydrochloride, two types of alcohol, and water, and (b) adding ether to the mixture obtained in step (a) to crystallize the epirubicin hydrochloride. A novel crystal of epirubicin hydrochloride is also provided.

Description

Technical Field

[0001] The present invention relates to a method for producing crystals of epirubicin hydrochloride.

Background Art

[0002] Epirubicin hydrochloride is one of the anthracycline anticancer agents and is used for the treatment of acute leukemia, malignant lymphoma, breast cancer, ovarian cancer, gastric cancer, etc. Compared with doxorubicin hydrochloride, another anthracycline anticancer agent, epirubicin hydrochloride has lower side effects such as cardiotoxicity and is an extremely useful anticancer agent.

[0003] A method for obtaining epirubicin hydrochloride as an amorphous form is known (Patent Document 1), but amorphous epirubicin hydrochloride has problems in terms of chemical stability during storage.

[0004] As a method for solving stability, several methods for obtaining crystals have been reported. One of them is a method for obtaining crystals from a gel state using only a parent solvent. This method is a method for obtaining crystals by adding a hydrophilic solvent to a gel solution of epirubicin hydrochloride (Patent Document 2). Although the obtained crystals had improved stability, the methods described in these patent documents have been pointed out to have poor reproducibility (Patent Document 3). In addition, there are a method of adding CO2 under high pressure to a hydrophilic solution (Patent Document 4) and a method of adding a polymer (Patent Document 5).

[0005] On the other hand, methods for obtaining crystals using poor solvents such as ethers and esters have also been reported. This method includes a method of dropping a poor solvent into an epirubicin hydrochloride solution (the solvent is a parent solvent) while performing ultrasonic treatment (Patent Document 6), and a method of suspending epirubicin hydrochloride in a poor solvent to obtain it (Patent Document 7).

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

[0007] The crystallization methods for epirubicin hydrochloride reported to date have not always been preferable from a manufacturing perspective, as they require special conditions and procedures such as gelation, addition of polymer reagents, and sonication, as well as high and low temperature conditions.

[0008] An object of the present invention is to provide a novel method for crystallizing epirubicin hydrochloride. Another object of the present invention is to provide novel crystals of epirubicin hydrochloride. [Means for solving the problem]

[0009] The inventors of this invention conducted diligent research to solve the above problems and, as a result, discovered that by using a predetermined solvent, crystallization of epirubicin hydrochloride can be performed under mild conditions with good operability, thus completing the present invention.

[0010] This invention provides the following: [1] A method for producing crystals of epirubicin hydrochloride, (a) A step to obtain a mixture containing epirubicin hydrochloride, two types of alcohol, and water. and (b) A step in which ether is added to the mixture obtained in step (a) to crystallize epirubicin hydrochloride. A manufacturing method that includes this. [2] The method for producing the alcohol according to [1], wherein the two alcohols are selected from the group consisting of n-propanol, iso-propanol, ethanol, methanol, n-butanol, iso-butanol, and tert-butanol. [3] The method for producing the product according to [1] or [2], wherein in step (a), the volume of water relative to the mass of epirubicin hydrochloride is 8 to 15 mL / g. [4] The manufacturing method according to any one of [1] to [3], wherein in step (a), water is used in an amount of 8.9 to 15.6% by volume, based on two types of alcohol. [5] The method for producing an alcohol according to any one of [1] to [4], wherein the two alcohols are n-propanol and ethanol. [6] The manufacturing method according to [5], wherein the volume ratio of n-propanol to water used in step (a) (volume of n-propanol:volume of water) is 1.9:1 to 4.6:1. [7] The manufacturing method according to [5] or [6], wherein the volume ratio of ethanol to water used in step (a) (volume of ethanol:volume of water) is 3.0:1 to 5.6:1. [8] The manufacturing method according to any one of [5] to [7], wherein in step (a), water is used in amounts of 8.9 to 15.6% by volume, n-propanol in amounts of 28.2 to 46.2% by volume, and ethanol in amounts of 40.3 to 58.7% by volume, based on water, n-propanol, and ethanol. [9] The manufacturing method according to any one of [1] to [8], wherein the pH value of the mixture obtained in step (a) is 3.0 to 5.5.

[10] The method of production according to any one of [1] to [9], wherein in step (b), the ether is at least one selected from the group consisting of methyl-tert-butyl ether, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, and dipropyl ether and dibutyl ether.

[11] The manufacturing method according to any one of [1] to

[10] , wherein the total volume of ether added in step (b): the ratio of the total volume of the two alcohols used in step (a) and water is 1.5:1 to 2.3:1.

[12] The manufacturing method according to any one of [1] to

[11] , wherein the ratio of the total volume of the two alcohols and water used in step (a) to the volume of ether added per minute in step (b) is 31.52:1 to 126.07:1.

[13] A method for producing the product according to any one of [1] to

[12] , comprising crystallizing the mixture at a temperature of 40 to 50°C in step (b).

[14] X-ray powder diffraction measurements using CuKα radiation showed peaks at diffraction angles (2θ) of 4.98°~5.18°, 8.94°~9.33°, 10.10°~10.31°, 13.47°~13.74°, 15.21°~15.47°, 20.43°~20.65°, 21.15°~21.37°, 22.29°~22.50°, 23.83°~24.05°, 25.61~25.83°, 27.51°~27.73°, 28.05°~28.56°, and 29.51°~29.75°, and Epirubicin hydrochloride crystals in which, when the integrated intensity of the peak at diffraction angle (2θ) 4.98°~5.18° is set to 100%, the relative integrated intensities of the peaks at diffraction angle (2θ) 8.94°~9.33°, 10.10°~10.31°, 13.47°~13.74°, 15.21°~15.47°, 20.43°~20.65°, 21.15°~21.37°, 22.29°~22.50°, 23.83°~24.05°, 25.61~25.83°, 27.51°~27.73°, 28.05°~28.56°, and 29.51°~29.75° are 5% or more.

[15] In X-ray powder diffraction measurements using CuKα radiation, a peak is observed at the diffraction angle (2θ) shown in Table 1, and When the integrated intensity of the peak with a diffraction angle (2θ) of 4.98° to 5.18° is taken as 100%, the relative integrated intensities of the peaks at diffraction angles (2θ) of 8.94° to 9.33°, 10.10° to 10.31°, 13.47° to 13.74°, 15.21° to 15.47°, 20.43° to 20.65°, 21.15° to 21.37°, 22.29° to 22.50°, 23.83° to 24.05°, 25.61 to 25.83°, 27.51° to 27.73°, 28.05° to 28.56°, and 29.51° to 29.75° are as shown in Table 1, the crystals of epirubicin hydrochloride. [Table 1] [Brief Description of the Drawings]

[0011] [Figure 1] Figure 1 shows the results of the X-ray powder diffraction analysis of Example 1. [Modes for Carrying Out the Invention]

[0012] The present invention will be described in detail below. Note that the features of the present invention described below can be arbitrarily combined.

[0013] In the present invention, when it is said that "including X", it is intended that other elements other than X may be included. On the other hand, when it is said that "consisting of X", it is intended that no other elements other than X are included (X represents an arbitrary element). In the present invention, "including" and "consisting of" can be arbitrarily replaced.

[0014] In the present invention, volume% represents v / v%. Also, in the present invention, when it is said that YY is used at ZZ volume% based on XX, it means that the ratio of the volume of YY is ZZ% (v / v%) when the volume of XX is 100% (XX and YY each represent an arbitrary element).

[0015] <Method for Producing Crystals of Epirubicin Hydrochloride> One embodiment of the present invention relates to a method for producing crystals of epirubicin hydrochloride.

[0016] (Epirubicin hydrochloride) Epirubicin is a compound represented by the chemical name (2S,4S)-4-(3-Amino-2,3,6-trideoxy-α-L-arabino-hexopyranosyloxy)-2,5,12-trihydroxy-2-hydroxyacetyl-7-methoxy-1,2,3,4-tetrahydrotetracene-6,11-dione.

[0017] The production of epirubicin hydrochloride crystals can be confirmed by appropriate methods known to those skilled in the art. For example, if a pattern characteristic of epirubicin hydrochloride crystals is observed when measured by powder X-ray diffraction, it can be determined that epirubicin hydrochloride crystals have been produced. The characteristic powder X-ray diffraction pattern of epirubicin hydrochloride crystals is typically shown in Figure 1, and is characterized by peaks at diffraction angles (2θ) of 4.98°~5.18°, 8.94°~9.33°, 10.10°~10.31°, 13.47°~13.74°, 15.21°~15.47°, 20.43°~20.65°, 21.15°~21.37°, 22.29°~22.50°, 23.83°~24.05°, 25.61~25.83°, 27.51°~27.73°, 28.05°~28.56°, and 29.51°~29.75°. The magnitude of the peak intensity of each peak is not considered in this case.

[0018] The crystals of epirubicin hydrochloride may be in any solvate form, such as monohydrate, dihydrate, or trihydrate.

[0019] ((a) A step to obtain a mixture containing epirubicin hydrochloride, two types of alcohol, and water.) The present invention provides a method for producing epirubicin hydrochloride crystals, comprising the step of (a) obtaining a mixture containing epirubicin hydrochloride, two types of alcohol, and water. The mixture can be obtained by conventional methods, and typically by mixing epirubicin hydrochloride, two types of alcohol, and water simultaneously or in any order. In this mixture, it is preferable that at least a portion of the epirubicin hydrochloride is dissolved, and more preferably that the epirubicin hydrochloride is completely dissolved. That is, step (a) can also be described as a step of dissolving epirubicin hydrochloride in a mixture of two types of alcohol and water.

[0020] The epirubicin hydrochloride used in step (a) may be amorphous or crystalline in any form, and is preferably amorphous. The amorphous epirubicin hydrochloride may be obtained by any method known to those skilled in the art. For such a method, see, for example, the method described in Patent Document 1. The amorphous epirubicin hydrochloride may also be a commercially available product, for example, it can be obtained from Japan Microbiopharma Co., Ltd. The amorphous epirubicin hydrochloride refers to a material in which, when measured by powder X-ray diffraction, the characteristic peaks of epirubicin hydrochloride crystals are substantially not observed.

[0021] The two alcohols used in step (a) are not particularly limited as long as they can dissolve epirubicin hydrochloride in a mixture with water, and may be any two alcohols arbitrarily selected from the group consisting of n-propanol (1-propanol), iso-propanol (2-propanol), ethanol, methanol, n-butanol (1-butanol), iso-butanol (2-butanol), and tert-butanol. Preferably, the two alcohols used in step (a) are n-propanol and ethanol.

[0022] The type of water is not particularly limited as long as the objective of the present invention is achieved, and may be purified water, distilled water, RO water, ion-exchanged water, pure water, tap water, industrial water, etc.

[0023] In step (a), the volume of water relative to the mass of epirubicin hydrochloride is preferably less than 18 mL / g, more preferably 17 mL / g or less, even more preferably 16 mL / g or less, and even more preferably 15 mL / g or less. On the other hand, in step (a), the volume of water relative to the mass of epirubicin hydrochloride may be 0.5 mL / g or more, 1 mL / g or more, 2 mL / g or more, 3 mL / g or more, 4 mL / g or more, 5 mL / g or more, 6 mL / g or more, or 7 mL / g or more, preferably 8 mL / g or more. The above upper and lower limits may be arbitrarily combined to represent a certain range of the volume of water relative to the mass of epirubicin hydrochloride.

[0024] In step (a), water can be used at a rate of 18% by volume or less, preferably 17% by volume or less, more preferably 16% by volume or less, and even more preferably 15.6% by volume or less, based on the two types of alcohol and water. On the other hand, in step (a), water can be used at a rate of 0.5% by volume or more, 1% by volume or more, 2% by volume or more, 3% by volume or more, 4% by volume or more, 5% by volume or more, 6% by volume or more, 7% by volume or more, or 8% by volume or more, based on the two types of alcohol and water, and preferably 8.9% by volume or more. The above upper and lower limits may be arbitrarily combined to express a certain range of volume % of water.

[0025] When n-propanol is used in step (a), the volume ratio of n-propanol to water (volume of n-propanol:volume of water) is not particularly limited as long as the objective of the present invention can be achieved, and may be, for example, 1.9:1 to 4.6:1.

[0026] When n-propanol is used in step (a), it can be used in amounts of, for example, 100% by volume or less, 90% by volume or less, 80% by volume or less, 70% by volume or less, 60% by volume or less, or 50% by volume or less, based on water and two types of alcohol. On the other hand, when n-propanol is used in step (a), it can be used in amounts of, for example, 1% by volume or more, 5% by volume or more, 10% by volume or more, 20% by volume or more, or 30% by volume or more, based on water and two types of alcohol. The above upper and lower limits may be arbitrarily combined to express a certain range of n-propanol by volume %.

[0027] When ethanol is used in step (a), the volume ratio of ethanol to water (volume of ethanol:volume of water) may be, for example, 2.6:1 to 100:1, more preferably 2.7:1 to 50:1, even more preferably 2.8:1 to 30:1, still more preferably 2.9:1 to 10:1, and particularly preferably 3.0:1 to 5.6:1.

[0028] Furthermore, when ethanol is used in step (a), the ethanol can be used in amounts of, for example, 100% by volume or less, 90% by volume or less, 80% by volume or less, 70% by volume or less, or 60% by volume or less, based on water and two types of alcohol. On the other hand, when ethanol is used in step (a), the ethanol can be used in amounts of, for example, 1% by volume or more, 5% by volume or more, 10% by volume or more, 20% by volume or more, 30% by volume or more, or 40% by volume or more, based on water and two types of alcohol. The above upper and lower limits may be arbitrarily combined to express a certain range of ethanol by volume percentage.

[0029] When n-propanol and ethanol are used in step (a), water, n-propanol, and ethanol can be used in amounts of, for example, 18% by volume or less, 17% by volume or less, 16% by volume or less, or 15.6% by volume or less, while other amounts can be used in amounts of, for example, 0.5% by volume or more, 1% by volume or more, 2% by volume or more, 3% by volume or more, 4% by volume or more, 5% by volume or more, 6% by volume or more, 7% by volume or more, 8% by volume or more, or 8.9% by volume or more, n-propanol can be used in amounts of, for example, 28.2% by volume or more, or 46.2% by volume or less, and ethanol can be used in amounts of, for example, 40.3% by volume or more, or 58.7% by volume or less. The volume percentages of water, n-propanol, and ethanol can be expressed as a certain range by arbitrarily combining the above-mentioned upper and lower limits.

[0030] The pH value of the mixture obtained in step (a) may be, for example, 3.0 to 5.5, preferably 4.0 to 5.5, and more preferably 4.5 to 5.5.

[0031] ((b) A step in which ether is added to the mixture obtained in step (a) to crystallize epirubicin hydrochloride.) This embodiment includes a step of adding ether to the mixture obtained in step (a) to crystallize epirubicin hydrochloride. The addition of ether may be carried out by any suitable method using a dropping funnel, pipette, syringe, pump, etc.

[0032] In step (b), the ether may be at least one selected from the group consisting of, for example, methyl-tert-butyl ether, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, and dipropyl ether, and preferably includes methyl-tert-butyl ether.

[0033] The volume of ether added in step (b) is not particularly limited, as long as epirubicin hydrochloride crystals can be obtained. For example, the ratio of the total volume of ether added in step (b) to the total volume of the two alcohols and water used in step (a) (volume of the two alcohols used in step (a) + volume of water) can be 1.5:1 to 2.3:1.

[0034] In step (b), the rate of ether addition is not particularly limited, as long as epirubicin hydrochloride crystals are obtained. In step (b), for example, ether can be added such that the ratio of the total volume of the two alcohols and water used in step (a) to the volume of ether added per minute in step (b) is 31.52:1 to 126.07:1.

[0035] The present invention's method for producing epirubicin hydrochloride crystals may include, in step (b), crystallizing the mixture at a temperature of, for example, 30°C or higher, 35°C or higher, 40°C or higher, or 45°C or higher. Alternatively, in step (b), the mixture may be crystallized at a temperature of, for example, 60°C or lower, 55°C or lower, or 50°C or lower. The above upper and lower limits may be arbitrarily combined to represent a temperature range.

[0036] The present invention's method for producing epirubicin hydrochloride crystals may include, in step (b), adding ether and stirring the resulting mixture. The stirring time is not particularly limited as long as epirubicin hydrochloride crystals are obtained, and can be, for example, 1 to 72 hours, 2 to 48 hours, or 3 to 24 hours.

[0037] In one preferred embodiment, in terms of yield of epirubicin hydrochloride crystals, the method for producing epirubicin hydrochloride crystals of the present invention includes the following: The two alcohols used in step (a) are n-propanol and ethanol; In step (a), the volume of water relative to the mass of epirubicin hydrochloride is less than 18 mL / g, and based on the ratio of two alcohols to water, water is used in a ratio of 8.9-15.3% by volume, n-propanol in a ratio of 28.2-43.7% by volume, and ethanol in a ratio of 42.1-56.5% by volume; The total volume of ether added in step (b): The ratio of the total volumes of water, n-propanol, and ethanol used in step (a) is 1.9:1 to 2.3:1; and In step (b), the mixture obtained in step (a) is crystallized at a temperature of 41 to 49°C, preferably 42 to 48°C, more preferably 43 to 47°C, even more preferably 44 to 46°C, and particularly preferably 45°C.

[0038] (others) The present invention's method for producing epirubicin hydrochloride crystals may further include isolating or purifying the crystals obtained in step (b). Isolation or purification may be carried out by conventional methods such as filtration, distillation, or recrystallization.

[0039] This embodiment may further include washing the crystals obtained in step (b). The washing may be carried out according to a conventional method, for example, using methyl tert-butyl ether, n-propanol, etc.

[0040] The present invention's method for producing epirubicin hydrochloride crystals may further include drying the crystals obtained in step (b). Drying can be carried out by conventional methods. For example, epirubicin hydrochloride crystals can be dried at 20°C to 60°C for 1 to 50 hours, preferably 10 to 35 hours. Drying may be carried out under reduced pressure.

[0041] In each step of the method for producing epirubicin hydrochloride crystals according to the present invention, any solvent, pH adjuster, crystallization accelerator, or other components not listed above may be used, as long as the objective of the present invention is achieved. Furthermore, each step of the method for producing epirubicin hydrochloride crystals according to the present invention may include operations other than those listed above, such as temperature adjustment of the solution or pH adjustment, as long as the objective of the present invention is achieved.

[0042] In one embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not use supercritical carbon dioxide (carbon dioxide in a fluid state at a temperature of approximately 30°C or higher and a pressure of approximately 6 MPa or higher). In another embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not use supercritical carbon dioxide as an antisolvent. In other words, depending on the circumstances, the method for producing epirubicin hydrochloride crystals of the present invention may include steps (a) and (b), and may not use supercritical carbon dioxide or may not use it as an antisolvent.

[0043] In one embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not use polymers such as ethylene / vinyl acetate copolymer, polyvinyl chloride, polybutylene terephthalate, polyphenylene, or nylon 11. In one embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not involve mixing a mixture containing epirubicin hydrochloride with a polymer.

[0044] In one embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not involve ultrasonic treatment (e.g., ultrasonic treatment at 20 Hz to 40 kHz). In another embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not involve ultrasonic treatment of a mixture containing epirubicin hydrochloride.

[0045] In one embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not involve gelling a mixture containing epirubicin hydrochloride. In one embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not use esters such as ethyl acetate. In one embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not involve suspending epirubicin hydrochloride in a solution containing an ester such as ethyl acetate. In one embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not involve cooling a mixture containing epirubicin hydrochloride to 10°C or below, 5°C or below, or 0°C or below. In one embodiment, the method for producing epirubicin hydrochloride crystals of the present invention does not involve heating a mixture containing epirubicin hydrochloride to 50°C or above, 55°C or above, 60°C or above, 65°C or above, or 70°C or above.

[0046] <Epirubicin hydrochloride crystals> One embodiment of the present invention relates to crystals of epirubicin hydrochloride obtained by the manufacturing method of the present invention.

[0047] In one embodiment, the epirubicin hydrochloride crystals of the present invention, as measured by X-ray powder diffraction using CuKα radiation, have peaks at diffraction angles (2θ) of 4.98°~5.18°, 8.94°~9.33°, 10.10°~10.31°, 13.47°~13.74°, 15.21°~15.47°, 20.43°~20.65°, 21.15°~21.37°, 22.29°~22.50°, 23.83°~24.05°, 25.61~25.83°, 27.51°~27.73°, 28.05°~28.56°, and 29.51°~29.75°, as shown in Table 2, and When the integrated intensity of the peak at diffraction angle (2θ) 4.98°~5.18° is taken as 100%, the relative integrated intensities of the peaks at diffraction angles (2θ) 8.94°~9.33°, 10.10°~10.31°, 13.47°~13.74°, 15.21°~15.47°, 20.43°~20.65°, 21.15°~21.37°, 22.29°~22.50°, 23.83°~24.05°, 25.61~25.83°, 27.51°~27.73°, 28.05°~28.56°, and 29.51°~29.75° are as shown in Table 2. X-ray powder diffraction measurements using CuKα radiation can be performed, for example, using SmartLab (manufactured by Rigaku).

[0048] [Table 2]

[0049] The integrated intensity of each peak is defined as the area in the X-ray diffraction spectrum between the line connecting the lowest points on both sides of each diffraction peak and the curve of that peak. The integrated intensity can be measured using any X-ray diffraction analysis software (for example, DIFFRAC.EVA from Bruker).

[0050] In one embodiment, the epirubicin hydrochloride crystals of the present invention, in X-ray powder diffraction measurements using CuKα radiation, have peaks at the diffraction angles (2θ) shown in Table 2 above, and when the integrated intensity of the peak at diffraction angle (2θ) 4.98°~5.18° is taken as 100%, the peaks at diffraction angles (2θ) 8.94°~9.33°, 10.10°~10.31°, 13.47°~13.74°, 15.21°~15.47°, 20.43°~20.65°, and 21 The relative integrated intensity of each peak in the ranges 0.15°~21.37°, 22.29°~22.50°, 23.83°~24.05°, 25.61~25.83°, 27.51°~27.73°, 28.05°~28.56°, and 29.51°~29.75° is characterized by being 5% or more, preferably 6% or more, more preferably 7% or more, even more preferably 8% or more, still more preferably 9% or more, and particularly preferably 10% or more.

[0051] In one embodiment, the crystals of epirubicin hydrochloride of the present invention, as measured by X-ray powder diffraction using CuKα radiation, have peaks at diffraction angles (2θ) of 5.08±0.2°, 9.14±0.2°, 10.21±0.2°, 13.61±0.2°, 15.34±0.2°, 20.54±0.2°, 21.26±0.2°, 22.39±0.2°, 23.94±0.2°, ±0.2°, 25.72±0.2°, 27.62±0.2°, 28.31±0.2°, and 29.63±0.2°, as shown in Table 3, and When the integrated intensity of the peak at diffraction angle (2θ) 5.08±0.2° is taken as 100%, the relative integrated intensities of the peaks at diffraction angles (2θ) 9.14±0.2°, 10.21±0.2°, 13.61±0.2°, 15.34±0.2°, 20.54±0.2°, 21.26±0.2°, 22.39±0.2°, 23.94±0.2°, ±0.2°, 25.72±0.2°, 27.62±0.2°, 28.31±0.2°, and 29.63±0.2° are as shown in Table 3.

[0052] [Table 3]

[0053] In one embodiment, the epirubicin hydrochloride crystals of the present invention, when measured by X-ray powder diffraction using CuKα radiation, have peaks at the diffraction angles (2θ) shown in Table 3 above, and when the integrated intensity of the peak at diffraction angle (2θ) 5.08±0.2° is taken as 100%, the diffraction angles (2θ) at 9.14±0.2°, 10.21±0.2°, 13.61±0.2°, 15.34±0.2°, 20.54±0.2°, and 21. The relative integrated intensity of each peak at 26±0.2°, 22.39±0.2°, 23.94±0.2°, ±0.2°, 25.72±0.2°, 27.62±0.2°, 28.31±0.2°, and 29.63±0.2° is characterized by being 5% or more, preferably 6% or more, more preferably 7% or more, even more preferably 8% or more, still more preferably 9% or more, and particularly preferably 10% or more. [Examples]

[0054] [Example 1] 5.0 g of epirubicin hydrochloride (Nippon Microbiopharma Co., Ltd.) was dissolved in a mixture of 60 mL of water, 185 mL of 1-propanol, and 267 mL of ethanol, and this solution was heated to 45°C. Next, 889 mL of methyl-tert-butyl ether was added dropwise to this solution at a rate of 7.4 mL / min, and after the addition was complete, the mixture was stirred at this temperature for 16 hours. After removing the solvent contained in this suspension by filtration, the crystals were washed with approximately 112 mL of methyl-tert-butyl ether / 1-propanol and dried in vacuum for 24 hours. 4.6 g of crystals were obtained (yield 91.2%). The obtained crystals were analyzed by X-ray powder diffraction (XRD): characteristic peaks were observed at diffraction angles (2θ) 5.2, 10.3, 13.7, 15.4, 20.6, 22.5, 22.6, 24.0, 25.8, 27.7, 28.2, and 29.7 (Figure 1, Table 4).

[0055] [Table 4]

[0056] [Example 2] Investigation of crystallization conditions The same tests as in Example 1 were performed by varying each parameter of the crystallization conditions. Tables 5 and 6 show the parameters of the crystallization conditions, the recovery rate of the obtained epirubicin hydrochloride crystals, and the XRD results. The amount of epirubicin hydrochloride used as the starting material in each lot was 5.0 g, the same as in the example.

[0057] [Table 5]

[0058] [Table 6]

[0059] [XRD analysis conditions] Equipment used: Rigaku SmartLab X-ray output: 40kV, 30 mA Wavelength:CuKα / λ=1.541862 Å Monochromatic method: Kβ filter Scan Mode: CONTINUOUS Scan axis: 2θ / θ Scan range: 3-40 degrees (step size: 0.01 degrees) Scan speed: 4.0 deg. / min Entrance slit: 2 / 3 degree Light-receiving slit: 8,000 mm / 13,000 mm Detector: High-speed detector D / teX

[0060] From the XRD results of Lots 1-14, the obtained epirubicin hydrochloride crystals had diffraction angles (2θ) of 4.98°~5.18°, 8.94°~9.33°, 10.10°~10.31°, 13.47°~13.74°, 15.21°~15.47°, 20.43°~20.65°, 21.15°~21.37°, 22.29°~22.50°, 23.83°~24.05°, 25.61°~25.83°, and 27.51°~27.7°. Peaks were observed at 3°, 28.05°~28.56°, and 29.51°~29.75° (5.08±0.2°, 9.14±0.2°, 10.21±0.2°, 13.61±0.2°, 15.34±0.2°, 20.54±0.2°, 21.26±0.2°, 22.39±0.2°, 23.94±0.2°, ±0.2°, 25.72±0.2°, 27.62±0.2°, 28.31±0.2°, and 29.63±0.2°).

[0061] Furthermore, if the integrated intensity of the peak at 4.98°~5.18° is taken as 100%, the diffraction angles (2θ) are 8.94°~9.33°, 10.10°~10.31°, 13.47°~13.74°, 15.21°~15.47°, 20.43°~20.65°, 21.15°~21.37°, 22.29°~22.50°, 23.83°~24.05°, 25.61°~25.83°, 27.51°~27.73°, and 28.05°~2. The relative integrated intensities of the peaks at 8.56° and 29.51°~29.75° were in the following ranges: 0.1~27.24%, 11.27~27.57%, 2.23~36.32%, 29.09~87%, 3.46~17.08%, 1.73~18.41%, 6.05~64.32%, 6.32~75.58%, 8.65~53.29%, 3.39~41.54%, 2.63~20.55%, and 2.79~27.21%, respectively. Furthermore, assuming the integrated intensity of the peak at 4.98°~5.18° is set to 100%, the diffraction angles (2θ) are 8.94°~9.33°, 10.10°~10.31°, 13.47°~13.74°, 15.21°~15.47°, 20.43°~20.65°, 21.15°~21.37°, 22.29°~22.50°, 23.83°~24.05°, and 25.61°. The average relative integrated intensities for the peaks at ~25.83°, 27.51°~27.73°, 28.05°~28.56°, and 29.51°~29.75° were 9.0%, 17.8%, 15.0%, 53.3%, 10.1%, 8.2%, 27.1%, 32.8%, 26.2%, 18.9%, 10.7%, and 12.7%, respectively, all of which were above 5%.

Claims

1. A method for producing epirubicin hydrochloride crystals, (a) A step of obtaining a mixture containing epirubicin hydrochloride, two types of alcohol, and water. and (b) A step to add ether to the mixture obtained in step (a) and crystallize epirubicin hydrochloride. A manufacturing method that includes this.

2. The manufacturing method according to claim 1, wherein the two alcohols are selected from the group consisting of n-propanol, iso-propanol, ethanol, methanol, n-butanol, iso-butanol, and tert-butanol.

3. The manufacturing method according to claim 1 or 2, wherein in step (a), the volume of water relative to the mass of epirubicin hydrochloride is 8 to 15 mL / g.

4. The manufacturing method according to claim 1 or 2, wherein in step (a), water is used in an amount of 8.9 to 15.6% by volume, based on two types of alcohol and water.

5. The manufacturing method according to claim 2, wherein the two alcohols are n-propanol and ethanol.

6. The manufacturing method according to claim 5, wherein the volume ratio of n-propanol to water used in step (a) (volume of n-propanol:volume of water) is 1.9:1 to 4.6:

1.

7. The manufacturing method according to claim 5, wherein the volume ratio of ethanol to water used in step (a) (volume of ethanol:volume of water) is 3.0:1 to 5.6:

1.

8. The manufacturing method according to claim 5, wherein in step (a), water is used in amounts of 8.9 to 15.6% by volume, n-propanol in amounts of 28.2 to 46.2% by volume, and ethanol in amounts of 40.3 to 58.7% by volume, based on water, n-propanol, and ethanol.

9. The manufacturing method according to claim 1, wherein the pH value of the mixture obtained in step (a) is 3.0 to 5.

5.

10. The manufacturing method according to claim 1, wherein in step (b), the ether is at least one selected from the group consisting of methyl-tert-butyl ether, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, and dipropyl ether and dibutyl ether.

11. The manufacturing method according to claim 1, wherein the ratio of the total volume of ether added in step (b) to the total volume of the two alcohols and water used in step (a) is 1.5:1 to 2.3:

1.

12. The manufacturing method according to claim 1, wherein the ratio of the total volume of the two types of alcohols and water used in step (a) to the volume of ether added per minute in step (b) is 31.52:1 to 126.07:

1.

13. The manufacturing method according to claim 1, further comprising crystallizing the mixture at a temperature of 40 to 50°C in step (b).

14. In X-ray powder diffraction measurements using CuKα radiation, peaks are observed at diffraction angles (2θ) of 4.98°–5.18°, 8.94°–9.33°, 10.10°–10.31°, 13.47°–13.74°, 15.21°–15.47°, 20.43°–20.65°, 21.15°–21.37°, 22.29°–22.50°, 23.83°–24.05°, 25.61°–25.83°, 27.51°–27.73°, 28.05°–28.56°, and 29.51°–29.75°, and Epirubicin hydrochloride crystals in which, when the integrated intensity of the peak at diffraction angle (2θ) 4.98° to 5.18° is set to 100%, the relative integrated intensities of the peaks at diffraction angle (2θ) 8.94° to 9.33°, 10.10° to 10.31°, 13.47° to 13.74°, 15.21° to 15.47°, 20.43° to 20.65°, 21.15° to 21.37°, 22.29° to 22.50°, 23.83° to 24.05°, 25.61° to 25.83°, 27.51° to 27.73°, 28.05° to 28.56°, and 29.51° to 29.75° are 5% or more.

15. In X-ray powder diffraction measurements using CuKα radiation, a peak is observed at the diffraction angle (2θ) shown in Table 1, and Epirubicin hydrochloride crystals, where the integrated intensity of the peak at diffraction angle (2θ) 4.98° to 5.18° is set to 100%, and the relative integrated intensities of the peaks at diffraction angle (2θ) 8.94° to 9.33°, 10.10° to 10.31°, 13.47° to 13.74°, 15.21° to 15.47°, 20.43° to 20.65°, 21.15° to 21.37°, 22.29° to 22.50°, 23.83° to 24.05°, 25.61° to 25.83°, 27.51° to 27.73°, 28.05° to 28.56°, and 29.51° to 29.75° are as shown in Table 1. Table 1

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