Atorvastatin calcium anhydride crystal, method for manufacturing said anhydride crystal, and medicine containing said anhydride crystal

Abstract

[Problem] To provide an atorvastatin calcium anhydride crystal having higher solubility than that of a conventional hydrate crystal and being more stable than an amorphous form. [Solution] The present invention pertains to an atorvastatin calcium anhydride crystal that exhibits an X-ray diffraction pattern, which has peaks at 2θ = 8.7°, 10.4°, 18.1°, 19.5°, 20.9°, 22.5°, 24.1°, and 25.6°, by X-ray powder diffraction measurement (XRPD) using CuKα radiation.

Description

Atorvastatin calcium anhydrate crystals, method for producing the anhydrate crystals, and pharmaceutical product containing the anhydrate crystals ,

[0007] ,

[0006] , ,

[0005] ,

[0001] The present invention relates to atorvastatin calcium anhydrate crystals, a method for producing (preparing) the anhydrate crystals, and a pharmaceutical product (pharmaceutical composition) containing the anhydrate crystals.

[0002] Statins are widely used as oral drugs for treating hyperlipidemia, and atorvastatin is one of the statins. Atorvastatin calcium is a salt composed of two atorvastatin molecules and one calcium atom (see formula (1) described later).

[0003] Atorvastatin calcium has been reported to exist not only in an amorphous (amorphous, non-crystalline) form but also in many crystal forms. For example, in Patent Document 1, three different crystal forms, Forms I to III, have been reported. Among these, the most stable Form I of atorvastatin calcium is a trihydrate crystal that incorporates three molecules of water as water of hydration, and this crystal form (Form I) has been commercialized as a drug for hyperlipidemia (a statin-based HMG-CoA reductase inhibitor) (Lipitor (registered trademark)).

[0004] In addition, in Patent Document 2, a plurality of crystal forms of atorvastatin calcium different from those in Patent Document 1 have been reported. For example, in paragraph 0111 of Patent Document 2, it is reported that a solution of amorphous atorvastatin calcium in acetone / water (1:1) was stirred overnight to obtain VII crystal form atorvastatin. The VII crystal form atorvastatin is a sesquihydrate that incorporates 1.5 molecules of water as water of hydration.

[0005] Japanese Patent No. 3296564 Japanese Patent No. 3965155

[0006] Generally, after a drug is ingested into the body, its action appears when the drug concentration in the blood reaches a certain range. However, for example, the atorvastatin calcium hydrate crystals disclosed in Patent Documents 1 and 2, etc., have low solubility, making it difficult to formulate them for efficient absorption.

[0007] On the other hand, it is known that removing water molecules from the trihydrate crystal (form (I)) described in Patent Document 1 results in amorphous material, improving solubility. However, amorphous material presents a new challenge: preventing crystallization during storage. Furthermore, removing crystallization solvents and impurities from amorphous materials can be difficult.

[0008] The present invention solves the above problems. Specifically, the present invention provides anhydrous atorvastatin calcium crystals that have higher solubility than conventional hydrate crystals and are more stable than amorphous forms.

[0009] As a result of diligent research to achieve the above objectives, the inventors have found that the above objectives can be achieved with the following configuration.

[0010] [1] Anhydrous atorvastatin calcium crystals exhibiting an X-ray diffraction pattern with peaks at 2θ = 8.7°, 10.4°, 18.1°, 19.5°, 20.9°, 22.5°, 24.1°, and 25.6°, as measured by powder X-ray diffraction (XRPD) using CuKα radiation. [2] Anhydrous atorvastatin calcium crystals according to [1], having an endothermic peak in the range of 185°C to 200°C when measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min. [3] Anhydrous atorvastatin calcium crystals according to [1] or [2], having a melting point below 185°C. [4] A method for producing atorvastatin calcium anhydrous crystals, comprising: suspending raw material atorvastatin calcium in a mixed solvent of acetone and water to prepare a suspension; stirring the suspension; separating solids from the suspension solution; and drying the solids, wherein the volume ratio (A / W) of acetone (A) to water (W) in the mixed solvent is 34 / 66 to 97 / 3. [5] The method for producing atorvastatin calcium anhydrous crystals according to [4], wherein the volume ratio (A / W) is 40 / 60 to 90 / 10. [6] The method for producing atorvastatin calcium anhydrous crystals according to [4] or [5], wherein the raw material atorvastatin calcium is atorvastatin calcium trihydrate crystals. [7] A pharmaceutical product containing atorvastatin calcium anhydrous crystals according to any one of [1] to [3].

[0011] The anhydrous atorvastatin calcium crystals of the present invention have higher solubility than conventional hydrate crystals and are also more stable than amorphous forms.

[0012] This is the powder X-ray diffraction (XRPD) data of the sample prepared in Example 1 (volume ratio of acetone (A) to water (W) in the mixed solvent (A / W) = 95 / 5). This is a flowchart of the method for producing atorvastatin calcium anhydrous crystals in the embodiment. These are the powder X-ray diffraction (XRPD) data of the samples prepared in Comparative Example 2 ((A / W) = 98 / 2), Example 1 ((A / W) = 95 / 5), Example 2 ((A / W) = 40 / 60), Comparative Example 1 ((A / W) = 30 / 70), and the raw material atorvastatin calcium (trihydrate crystal). This is the thermogravimetric analysis (TG) data of the sample prepared in Example 1. This is the thermogravimetric analysis (TG) data of the sample prepared in Example 2. This is the thermogravimetric analysis (TG) data of the sample prepared in Comparative Example 1. This is the thermogravimetric analysis (TG) data of the sample prepared in Comparative Example 2. This is the thermogravimetric analysis (TG) data of the raw material (atorvastatin calcium trihydrate crystals). This is the differential scanning calorimetry (DSC) data of the samples prepared in Comparative Example 2, Example 1, Example 2, Comparative Example 1, and the raw material (atorvastatin calcium trihydrate crystals). This is the differential scanning calorimetry (DSC) data of the samples prepared in Comparative Examples 3 to 7, and the raw material (atorvastatin calcium trihydrate crystals).

[0013] The embodiments of the present invention will be described in detail below. The following descriptions of constituent elements may be based on representative embodiments of the present invention, but the present invention is not limited to such embodiments. In this specification, numerical ranges expressed using "~" mean a range that includes the numbers written before and after "~" as the lower and upper limits.

[0014] [Anhydrous Atorvastatin Calcium Crystals] This embodiment relates to anhydrous crystals of atorvastatin calcium (ATC) represented by the following formula (1). The anhydrous ATC crystals of this embodiment exhibit an X-ray diffraction pattern with major peaks at 2θ = 8.7°, 10.4°, 18.1°, 19.5°, 20.9°, 22.5°, 24.1°, and 25.6°, as measured by powder X-ray diffraction (XRPD) using CuKα radiation. In this specification, having a diffraction peak at 2θ = x° means having a diffraction peak (maximum value) within the range of 2θ = x ± 0.2°, that is, within the range of (x - 0.2)° to (x + 0.2)°. As an example, Figure 1 shows the powder X-ray diffraction pattern of the anhydrous ATC crystals prepared in Example 1, which will be described later.

[0015]

[0016] As mentioned above, many crystalline forms of atorvastatin calcium have been reported (for example, in Patent Documents 1 and 2), but all of them were hydrates containing water of crystallization. On the other hand, for example, Patent Document 1 discloses that "Atorvastatin in crystalline forms I, II, and IV can exist in anhydrous and hydrated forms. In general, the hydrated form is equivalent to the unhydrated form and is included within the scope of the present invention" (see page 17, column 33 of Patent Document 1). However, academically, the crystalline structure changes when stoichiometric water of hydration is lost, so the hydrated form and the unhydrated form cannot be equivalent. Furthermore, Patent Document 1 does not disclose any data regarding the unhydrated form (anhydrous crystals), and the manufacturing method disclosed in Patent Document 1 could not produce anhydrous crystals.

[0017] Under these circumstances, the inventors of the present invention conducted diligent research and succeeded in obtaining ATC anhydrous crystals, for example, by the manufacturing method described later. The ATC anhydrous crystals of this embodiment are a novel crystalline form that exhibits a different X-ray diffraction pattern from conventional hydrate crystals. ATC anhydrous crystals have higher solubility than conventional hydrate crystals. Therefore, it is expected that using ATC anhydrous crystals in pharmaceuticals will improve the bioavailability of the drugs. This is expected to reduce the dosage of the drug and the amount of active pharmaceutical ingredient used, thereby reducing the risk of side effects. Furthermore, since ATC anhydrous crystals are more stable than amorphous forms, they are easier to handle in pharmaceutical formulations.

[0018] The ATC anhydrous crystals of this embodiment preferably have an endothermic peak in the range of 185°C to 200°C when measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min, and preferably do not have an endothermic peak below 185°C other than that derived from adsorbed water dehydration. For example, the ATC anhydrous crystals of this embodiment may not have a clear endothermic peak below 185°C (i.e., they may not have a melting point below 185°C), and may also undergo thermal decomposition between 185°C and 200°C.

[0019] The ATC anhydrous crystals of this embodiment may exhibit a mass loss of less than 1.5% at 100°C when measured by thermogravimetric analysis (TG) at a heating rate of 10°C / min. Since a 1.5% mass loss occurs when ATC is hydrated to 1 mole, a mass loss of less than 1.5% is presumed to be due to the desorption of adsorbed water. Furthermore, while ATC hydrates containing crystal water lose crystal water upon heating, resulting in a large mass loss, the mass loss of ATC anhydrous crystals without crystal water upon heating is small. For example, the ATC anhydrous crystals of this embodiment may exhibit a mass loss of 2% or less at 150°C when measured by thermogravimetric analysis (TG) at a heating rate of 10°C / min.

[0020] [Method for producing atorvastatin calcium anhydrous crystals] The method for producing ATC anhydrous crystals in this embodiment is not particularly limited, but for example, they can be produced by a manufacturing method including the following steps S1 to S4 (see Figure 2).

[0021] (Step S1): Suspending the raw material atorvastatin calcium in a mixed solvent of acetone and water to obtain a suspension; (Step S2): Stirring the suspension; (Step S3): Separating the solids from the suspension solution; and (Step S4): Drying the solids.

[0022] As mentioned above, many hydrate crystalline forms of atorvastatin calcium and their manufacturing methods have been reported. Despite this, a method for producing anhydrous ATC crystals had not been discovered until now. Under these circumstances, the inventors of the present invention finally discovered, after trying a vast number of compositions, that a solvent-mediated translocation of the raw material atovastatin (e.g., atovastatin trihydrate) occurs in a mixed solvent of a specific composition, specifically a mixed solvent with a volume ratio (A / W) of acetone (A) to water (W) of 34 / 66 to 97 / 3, thereby obtaining anhydrous crystals, thus completing the present invention. The mechanism by which anhydrous crystals are obtained is presumed to be that, in the above-mentioned specific mixed solvent composition, the activity of water is insufficient to hydrate the crystals, and acetone is an excellent crystallization solvent for ATC anhydrous crystals. As will be shown in detail in the examples described later, the inventors of the present invention have confirmed that ATC anhydrous crystals cannot be obtained when other aqueous solvents such as methanol or ethanol are used instead of acetone. While it is generally known that the crystal form can change depending on the crystallization solvent, the inventors' discovery that anhydrous ATC crystals can only be obtained when a mixed solvent of acetone and water is used was remarkable. The details of each step in the manufacturing method are described below.

[0023] <Step S1> First, the raw material atorvastatin calcium (hereinafter sometimes simply referred to as "raw material") is suspended in a mixed solvent of acetone and water to prepare a suspension. The raw material is not particularly limited as long as it is a compound represented by the above formula (1), and examples include atorvastatin calcium hydrate crystals, amorphous atorvastatin, etc. The raw material may be a commercially available product or may be synthesized by a known method. From the viewpoint of ease of crystallization, atorvastatin calcium trihydrate crystals are preferred as the raw material. The raw material may consist of only one type or a mixture of two or more types. Naturally, the raw material is different from the target product, ATC anhydrous crystals. However, in order to promote the reaction, the suspension may contain ATC anhydrous crystals as seed crystals.

[0024] In the mixed solvent, the volume ratio of acetone (A) to water (W) is (A / W) = 34 / 66 to 97 / 3, preferably (A / W) = 40 / 60 to 95 / 5. If the volume ratio (A / W) is below the lower limit of the above range, the proportion (activity) of water in the mixed solvent becomes too large, which may lead to the formation of hydrate crystals. Conversely, if the volume ratio (A / W) exceeds the upper limit of the above range, crystallization becomes difficult. The volume ratio of acetone (A) to water (W) may also be (A / W) = 60 / 40 to 95 / 5.

[0025] The concentration (mixing ratio) of the starting material in the mixed solvent is not particularly limited, but the amount of starting material should be mixed with the mixed solvent in an amount greater than or equal to the saturation solubility amount so that a suspension is formed. From the viewpoint of promoting the reaction, the concentration of the starting material in the mixed solvent may be, for example, 1 mg / mL to 20 mg / mL.

[0026] The suspension may consist only of a mixed solvent of acetone and water, and the raw material atorvastatin calcium. In particular, since the solvent composition is important in the preparation of anhydrous crystals, it is preferable that no solvents other than acetone and water are included. In addition, other components may be included as long as they do not impair the effects of the present invention. For example, as described above, the suspension may contain ATC anhydrous crystals as seed crystals.

[0027] <Step S2> Next, the prepared suspension is stirred. The stirring method is not particularly limited; it is sufficient to stir so that the raw materials and the mixed solvent are in sufficient contact, and any known stirrer such as a general mixing stirrer or an in-line mixer may be used.

[0028] The stirring time of the suspension is not particularly limited, but from the viewpoint of promoting the reaction, for example, 12 hours or more, 24 hours or more (1 day or more), 72 hours or more (3 days or more), or 144 hours or more (6 days or more) are preferred. The upper limit of the stirring time is not particularly limited, but for example, it may be 10 days or less. The temperature of the suspension during stirring is not particularly limited, and for example, it may be 4°C to 60°C. The stirring speed is also not particularly limited, but for example, it may be 10 rpm to 300 rpm.

[0029] <Steps S3 and S4> Next, the solids are separated from the suspension solution (step S3), and the separated solids are dried (step S4). The method for separating the solids is not particularly limited, and general methods such as filtration, centrifugation, and decantation can be used. The method for drying the solids is also not particularly limited, and may be air-dried, or dried under reduced pressure using a general-purpose dryer, or heated. The drying temperature, drying time, etc., can be adjusted as appropriate.

[0030] [Pharmaceuticals containing atorvastatin calcium anhydrous crystals] The atorvastatin calcium anhydrous crystals of this embodiment, as described above, can be used as an active ingredient in pharmaceuticals (pharmaceutical compositions), similar to conventional hydrate crystals. Examples of pharmaceuticals include therapeutic agents and / or preventive agents for hyperlipidemia, hypercholesterolemia, cardiovascular diseases, osteoporosis, and Alzheimer's disease. Pharmaceuticals may be in dosage forms for oral administration, such as tablets, capsules, lozenges, or powders.

[0031] The present invention will be further described using examples and comparative examples, but the scope of the present invention is not limited in any way by the examples and comparative examples.

[0032] [Example 1] A suspension was prepared by suspending atorvastatin calcium trihydrate crystals (Kyongbo Pharmaceutical, Form I) at a concentration of 5 mg / mL in a mixed solvent of acetone (A) and water (W) with a volume ratio of A / W = 95 / 5. The suspension was stirred at room temperature for 7 days, and the precipitate was collected on filter paper and dried under reduced pressure at room temperature overnight to obtain the target product (sample).

[0033] [Example 2] The target substance (sample) was obtained in the same manner as in Example 1, except that the volume ratio of the mixed solvent of acetone and water was (A / W) = 40 / 60.

[0034] [Comparative Example 1] The target substance (sample) was obtained in the same manner as in Example 1, except that the volume ratio of the mixed solvent of acetone and water was (A / W) = 30 / 70.

[0035] [Comparative Example 2] The target substance (sample) was obtained in the same manner as in Example 1, except that the volume ratio of the mixed solvent of acetone and water was (A / W) = 98 / 2.

[0036] [Evaluation] (1) Powder X-ray diffraction (XRPD) and thermal analysis (TG and DSC) The samples prepared in Examples 1-2 and Comparative Examples 1-2 were evaluated by powder X-ray diffraction (XRPD) and thermal analysis (thermogravimetric analysis (TG) and differential scanning calorimetry (DSC)). For comparison, the raw material (atorvastatin calcium trihydrate) was also evaluated in the same manner. The measuring equipment and measurement conditions used are as follows.

[0037] <XRPD> Rint-Ultima (Rigaku Denki, Tokyo, Japan) Approximately 10 mg of the sample was placed on a glass sample plate, the surface was carefully smoothed, and the measurement was performed under the following conditions: X-ray source: CuKα Output: 40kV, 40mA Measurement range: 2-40° (2θ) Scanning speed: 0.3° / min at 0.02° intervals <TG> SDT-Q600 (TA Instruments, New Castle, DE, USA) Measurement was performed at a heating rate of 10°C / min <DSC> Q2000 (TA Instruments, New Castle, DE, USA) Measurement was performed at a heating rate of 10°C / min

[0038] The XRPD measurement results are shown in Figures 1 and 3, the TG measurement results in Figures 4 to 8, and the DSC measurement results in Figure 9. The discussion results are shown in Table 1. The details of the evaluation results for each sample are explained below.

[0039] According to TG measurements, the sample prepared in Example 1 showed a mass decrease of approximately 1.2% when heated from room temperature to 100°C, as shown in Figure 4. Since a mass decrease of 1.5% occurs when ATC is hydrated to 1 mole, this could be interpreted as a decrease due to the desorption of adsorbed water. Subsequently, the mass decrease when heated up to 150°C was small, less than 2%, and the decrease accelerated from around 200°C. Upon examination of the sample after TG measurement, there was no evidence of melting, and the mass decrease from around 200°C could be interpreted as decomposition. As shown in Figure 9, no clear peaks were observed in DSC measurement up to 180°C, and an endothermic peak was observed at approximately 200.7°C. From the results of the above thermal analysis, it is presumed that the sample in Example 1 is anhydrous ATC crystal and decomposes from around 200°C. From the XRPD measurement results of Example 1 shown in Figures 1 and 3, the following characteristic major peaks were detected. 2θ = 8.7°, 10.4°, 18.1°, 19.5°, 20.9°, 22.5°, 24.1°, 25.6°. The peak pattern of the sample in Example 1 was different from existing crystal forms (for example, the raw material atorvastatin calcium trihydrate), confirming that the sample in Example 1 is a novel crystal.

[0040] According to TG measurements, the sample prepared in Example 2 showed a mass decrease of approximately 1.3% when heated from room temperature to 100°C, as shown in Figure 5. This could be interpreted as being due to the desorption of adsorbed water, similar to Example 1. Subsequently, similar to Example 1, the mass decrease when heated up to 150°C was small, less than 2%, and the decrease accelerated from around 200°C. Upon examination of the sample after TG measurement, there was no evidence of melting, and the mass decrease from around 200°C could be interpreted as being due to decomposition. As shown in Figure 9, no peaks were observed in DSC measurements up to 180°C, and an endothermic peak was observed at approximately 192.2°C. From the results of the above thermal analysis, it is presumed that the sample in Example 2 is anhydrous ATC crystal and decomposes from around 200°C. From the XRPD measurement results of Example 2 shown in Figure 3, characteristic major peaks similar to those in Example 1 were detected. It was confirmed that the sample in Example 2 is the same anhydrous ATC crystal as in Example 1.

[0041] According to TG measurements, the sample prepared in Comparative Example 1 showed a mass loss of approximately 4.5% in three stages when heated from room temperature to 150°C, as shown in Figure 6, and then the loss accelerated from around 200°C. As shown in Figure 9, DSC measurements showed an endothermic peak due to transition (melting) at approximately 165.4°C. The XRPD measurement results for Comparative Example 1 shown in Figure 3 did not show some of the characteristic major peaks observed in Examples 1 and 2. The peak pattern of Comparative Example 1 matched the peak pattern of the raw material (atorvastatin calcium trihydrate). From these results, the sample of Comparative Example 1 was identified as the same atorvastatin calcium trihydrate crystal as the raw material.

[0042] According to the TG measurement, the sample prepared in Comparative Example 2 showed a mass loss of about 9.4% upon heating from room temperature to 175°C as shown in Fig. 7, and then the decrease accelerated from around 200°C. As shown in Fig. 9, a heat absorption peak was observed at about 115.7°C in the DSC measurement. This heat absorption peak is presumed to be due to the desorption of the solvent. In the XRPD measurement results of Comparative Example 2 shown in Fig. 3, some of the characteristic main peaks observed in Examples 1 and 2 were absent. Comparative Example 2 showed a peak pattern different from those of Examples 1 - 2, Comparative Example 1, and the raw material. From the above results, the sample of Comparative Example 2 is presumed to be atorvastatin calcium solvate containing 2 moles of acetone.

[0043]

[0044] (2) Solubility Measurement (I) Powders of the samples (anhydrous crystals) of Examples 1 and 2, and the raw material (atorvastatin calcium trihydrate) were each suspended in a phosphate buffer (PB, 37°C, pH 7.4) to a concentration of 2 mg / mL to prepare suspensions. The suspensions were continuously stirred, sampled and filtered after 5 hours and 24 hours, and the ATC concentration in the filtrate was measured by high performance liquid chromatography (HPLC, manufactured by Shimadzu Corporation, Prominence). Three specimens each were evaluated after 5 hours and 24 hours, and the average value and standard deviation of the ATC concentration were determined. The results are shown in Table 2.

[0045] As shown in Table 2, the solubility of the anhydrous crystals (Examples 1 and 2) was higher than that of the raw material (trihydrate crystals) at both 5 hours and 24 hours. The solubility of the anhydrous crystals (24 hours after Example 2: 841 μg / mL) was about 1.2 times the solubility of the trihydrate crystals (24 hours after the raw material: 719 μg / mL).

[0046]

[0047] (3) Solubility Measurement (II) The sample (anhydrous crystals) and the raw material (atorvastatin calcium trihydrate) from Example 1 were suspended in appropriate amounts in HEPES buffer (25°C, pH 7) to prepare suspensions. The suspensions were continuously stirred, and samples were taken and filtered after 30 minutes and 60 minutes. The ATC concentration in the filtrate was measured by high-performance liquid chromatography (HPLC, Shimadzu Corporation, Prominence). Three samples were evaluated at 30 minutes and 60 minutes, and the mean and standard deviation of the ATC concentration were calculated. The results are shown in Table 3.

[0048] As shown in Table 3, at both 30 minutes and 60 minutes, the anhydrous crystals (Example 1) had higher solubility than the raw material (trihydrate crystals). The solubility of the anhydrous crystals (Example 1 after 60 minutes: 846 μg / mL) was approximately 2.1 times that of the trihydrate crystals (raw material after 60 minutes: 395 μg / mL).

[0049]

[0050] [Comparative Examples 3-7] The target product (sample) was obtained in the same manner as in Example 1, except that instead of a mixed solvent of acetone and water, a mixed solvent of one of the solvents shown in Table 4 below (methanol, ethanol, dioxane, and tetrahydrofuran) and water was used. The stirring time of the suspension was 7 days or 1 day, as shown in Table 4.

[0051]

[0052] The samples prepared in Comparative Examples 3 to 7 were evaluated by powder X-ray diffraction (XRPD) and thermal analysis (differential scanning calorimetry (DSC)). The measuring equipment and conditions used were as described above. For comparison, the raw material (atorvastatin calcium trihydrate) was also evaluated in the same manner. The DSC measurement results are shown in Figure 10.

[0053] The XRPD measurement results (not shown) for Comparative Examples 3 to 7 did not show some of the characteristic major peaks observed in Examples 1 and 2. The peak patterns of Comparative Examples 3 to 7 all matched those of the raw material (atorvastatin calcium trihydrate). Furthermore, as shown in Figure 10, the DSC measurements of Comparative Examples 3 to 7 showed an endothermic peak due to transition (melting) around 160°C, similar to the raw material (atorvastatin calcium trihydrate). From these results, it was estimated that the sample of Comparative Example 1 was the same atorvastatin calcium trihydrate crystal as the raw material.

[0054] The atorvastatin calcium anhydrous crystals of this embodiment, as described above, can be used as an active ingredient in pharmaceuticals (pharmaceutical compositions), similar to conventional hydrate crystals. Examples of pharmaceuticals include therapeutic agents and / or preventive agents for hyperlipidemia, hypercholesterolemia, cardiovascular diseases, osteoporosis, and Alzheimer's disease.

Claims

1. Anhydrous atorvastatin calcium crystals exhibiting an X-ray diffraction pattern with peaks at 2θ = 8.7°, 10.4°, 18.1°, 19.5°, 20.9°, 22.5°, 24.1°, and 25.6°, as measured by powder X-ray diffraction (XRPD) using CuKα radiation.

2. The atorvastatin calcium anhydrous crystal according to claim 1, wherein when measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min, it has an endothermic peak in the range of 185°C to 200°C.

3. Anhydrous atorvastatin calcium crystals according to claim 1 or 2, which do not have a melting point below 185°C.

4. A method for producing anhydrous atorvastatin calcium crystals, comprising: suspending raw material atorvastatin calcium in a mixed solvent of acetone and water to prepare a suspension; stirring the suspension; separating solids from the suspension solution; and drying the solids, wherein the volume ratio (A / W) of acetone (A) to water (W) in the mixed solvent is 34 / 66 to 97 / 3.

5. The method for producing atorvastatin calcium anhydrous crystals according to claim 4, wherein the volume ratio (A / W) is 40 / 60 to 90 / 10.

6. The method for producing anhydrous atorvastatin calcium crystals according to claim 4 or 5, wherein the raw material atorvastatin calcium is atorvastatin calcium trihydrate crystals.

7. A pharmaceutical product containing atorvastatin calcium anhydrous crystals as described in any one of claims 1 to 3.

Images