JP2005053782A - New crystal of cyclic lipopeptide compound - Google Patents

New crystal of cyclic lipopeptide compound Download PDF

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Publication number
JP2005053782A
JP2005053782A JP2001263320A JP2001263320A JP2005053782A JP 2005053782 A JP2005053782 A JP 2005053782A JP 2001263320 A JP2001263320 A JP 2001263320A JP 2001263320 A JP2001263320 A JP 2001263320A JP 2005053782 A JP2005053782 A JP 2005053782A
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Prior art keywords
compound
cyclic lipopeptide
lipopeptide compound
crystal
acetone
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Inventor
Kazumi Kawai
一美 河合
Katsuhiko Ito
勝彦 伊藤
Tomoomi Higaki
知臣 檜垣
Mitsuisa Matsuda
充功 松田
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Priority to JP2001263320A priority Critical patent/JP2005053782A/en
Priority to PCT/JP2002/008694 priority patent/WO2003018615A1/en
Priority to ARP020103266A priority patent/AR036317A1/en
Publication of JP2005053782A publication Critical patent/JP2005053782A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new crystal of a cyclic lipopeptide compound. <P>SOLUTION: The crystal of the cyclic lipopeptide compound (I) can be obtained by dissolving the cyclic lipopeptide compound (I) represented by structural formula (I) in a hydrous alcohol or hydrous acetone, and post-adding ethyl acetate, dichloromethane, acetone, acetonitrile, or a mixture thereof to the solution under cooling or heating. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

【０００１】
【発明の属する技術分野】
【０００２】
本発明は、環状リポペプチド化合物の新規結晶に関するものである。この発明の環状リポペプチド化合物（Ｉ）は、下記の構造式：
【化２】

Figure 2005053782
で示される。この化合物は、抗微生物活性、特に抗真菌活性およびβ−１，３−グルカンシンターゼ阻害作用を有し、ニューモシスティス・カリニ（Ｐｈｅｕｍｏｃｙｓｔｉｓ ｃａｒｉｎｉｉ）感染症、例えばカリニ肺炎を含む各種感染症の予防および治療に有用である。
【０００３】
【従来の技術および発明が解決しようとする課題】
環状リポペプチド化合物（Ｉ）は公知の化合物であり、例えばＷＯ９６／１１２１０号公報中に実施例２５の化合物として記載されている。しかしながら、該公報中の実施例２５に記載された方法によって得られる化合物（Ｉ）は、無晶形の化合物であった。その後、鋭意検討の結果、本発明の発明者らは化合物（Ｉ）を特別な結晶型を有するものとして得ることに成功し、本発明を完成した［以下、この特別の結晶型を有する環状リポペプチド化合物（Ｉ）を化合物（Ｉ）のＢ８２型結晶と呼称する］。
以下に、本発明を詳細に説明する。
【０００４】
【課題を解決するための手段】
化合物（Ｉ）のＢ８２型結晶の物理化学的特性
本発明により得られる化合物（Ｉ）のＢ８２型結晶の物理化学的特性を以下に説明する。
【０００５】
１）結晶形態
針状結晶
【０００６】
２）粉末Ｘ線回折パターン
化合物（Ｉ）のＢ８２型結晶は粉末Ｘ線回折パターンにおいて以下の表に示される回折角［２θ（゜）］にその特徴的なピークを示す。
【０００７】
【表２】
Figure 2005053782
【０００８】
第１図として、後記の実施例１で得られた化合物（Ｉ）のＢ８２型結晶の粉末Ｘ線回折パターンを示す。
ただし、この回折パターンはあくまで参考として挙げられたものであり、化合物（Ｉ）の結晶であってその粉末Ｘ線回折パターンが本質的にこの回折パターンと同じであるものはいかなるものも、化合物（Ｉ）のＢ８２型結晶と同定されるものである。
【０００９】
３）赤外吸収スペクトル
第２図として、後記の実施例１で得られた化合物（Ｉ）のＢ８２型結晶の赤外吸収スペクトルを示す。
ただし、このスペクトルはあくまで参考として挙げられたものであり、化合物（Ｉ）の結晶であってその赤外吸収スペクトルがこのスペクトルと本質的に同じものはいかなるものも、化合物（Ｉ）のＢ８２型結晶と同定されるものである。
【００１０】
化合物（Ｉ）のＢ８２型結晶の製造法
以下に、本発明により得られる化合物（Ｉ）のＢ８２型結晶の製造法を詳細に説明する。
化合物（Ｉ）のＢ８２型結晶は、化合物（Ｉ）を含水アルコールまたは含水アセトンに溶解させ、冷却下ないし加温下で、酢酸エチル、ジクロロメタン、アセトンまたはアセトニトリルあるいはそれらの混合溶液を後添加して、冷却下ないし加温下で結晶を析出させることにより得ることができる。
化合物（Ｉ）を含む溶液の好ましい例としては、例えば、化合物（Ｉ）の含水メタノール溶液、含水エタノール溶液、含水イソプロパノール溶液および含水ブタノール溶液が挙げられる。
【００１１】
また、化合物（Ｉ）のＢ８２型結晶は、化合物（Ｉ）を含水アルコールに溶解させ、常温ないし加温下（好ましくは、４０℃〜４５℃）で、酢酸エチル、ジクロロメタン、アセトンまたはアセトニトリルあるいはそれらの混合溶液を後添加して、ゆっくりと撹拌を続け、次いで、これを冷却（好ましくは、１０℃〜５℃）し、結晶を析出させることによっても得ることができる。
【００１２】
化合物（Ｉ）のＢ８２型結晶を析出させる場合には、溶液を飽和状態をわずかに越えた状態に保つのが好ましい。
以上の製法により得られる化合物（Ｉ）のＢ８２型結晶は、常法により濾取、乾燥される。
【００１３】
本発明で使用される無晶型化合物（Ｉ）は、前述のＷＯ９６／１１２１０号公報に記載された方法により製造することができる。
【００１４】
【発明の効果】
化合物（Ｉ）のＢ８２型結晶は、無晶形の化合物（Ｉ）よりも純度が非常に高いため、化合物（Ｉ）のＢ８２型結晶は、医薬として適しており、また製剤上や保存上の取り扱いが容易である。
以上述べたように、化合物（Ｉ）のＢ８２型結晶は、きわめてすぐれた利点を有しており、無晶形の化合物（Ｉ）に比べて非常に優れているものである。
【００１５】
化合物（Ｉ）のＢ８２型結晶のそのような利点を示すために、化合物（Ｉ）のＢ８２型結晶と前述のＷＯ９６／１１２１０号公報中に記載された無晶形の化合物（Ｉ）との安定性に関する比較実験結果を以下に述べる。
試験サンプル
試験サンプル１：ＷＯ９６／１１２１０号公報中の実施例２５で得られる無晶形
化合物（Ｉ）
試験サンプルＡ：本発明の化合物（Ｉ）のＢ８２型結晶
試験方法：高速液体クロマトグラフィー（ＨＰＬＣ）によって、不純物測定した。
【００１６】
Figure 2005053782
【表３】
Figure 2005053782
【００１７】
Figure 2005053782
【表４】
Figure 2005053782
【００１８】
試験結果から明らかなように、試験サンプルＡは、試験サンプル１に比べて、不純物含有の割合が少ないことがわかる。
【００１９】
以上述べたように、化合物（Ｉ）のＢ８２型結晶と、ＷＯ９６／１１２１０号公報中に記載された無晶形の化合物（Ｉ）との間には、その純度に大きな違いが見られた。つまり、本発明の化合物（Ｉ）のＢ８２型結晶は、該特許公報中に記載された無晶形の化合物（Ｉ）に比べてきわめて優れたものであることが明ら
かとなったのである。
【００２０】
【実施例】
実施例１
化合物（Ｉ）（無晶形）０．５ ｇを、７０％ メタノール水を用いて、５０ ｍｇ／ｍＬ 濃度に溶解した。化合物（Ｉ）を溶解したメタノール水溶液に、酢酸エチルを、化合物（Ｉ）の濃度が８ ｍｇ／ｍＬとなるように添加（一次添加後、２０ ｍｇ／ｍＬ 濃度とし、一昼夜攪拌熟成し、その後、酢酸エチルを二次添加し、最終濃度を８ ｍｇ／ｍＬとした。）した。総量添加終了後、分離・濾取により化合物（Ｉ）のＢ８２型結晶を得た（０．５ ｇ）。本実施例は、常温（２５℃）にて実施された。
第１図として、このＢ８２型結晶の粉末Ｘ線回折パターンを示す。また、第２図として、このＢ８２型結晶の赤外吸収スペクトル（ＫＢｒ法）を示す。
以下に、このＢ８２型結晶の粉末Ｘ線回折パターンにおけるピークを示す。測定条件は次の通りである。
対陰極：Ｃｕ、管電圧：４０ｋｖ、管電流：３０ｍＡ、検出器：比例計数管
【表５】
Figure 2005053782
【００２１】
実施例２
化合物（Ｉ）（無晶形）０．２ ｇを、８０％ エタノール水を用いて、５０ ｍｇ／ｍＬ 濃度に溶解した。化合物（Ｉ）を溶解したエタノール水溶液に、酢酸エチルを、化合物（Ｉ）の濃度が１７ ｍｇ／ｍＬとなるように添加し、一昼夜攪拌熟成し、分離・濾取により化合物（Ｉ）のＢ８２型結晶を得た（０．１８ｇ）。本実施例は常温（２５℃）にて実施された。
【００２２】
実施例３
化合物（Ｉ）（無晶形）３．２ ｇを、７５％ メタノール水を用いて、約４０ ｍｇ／ｍＬ 濃度に溶解した。化合物（Ｉ）を溶解したメタノール水溶液に、化合物（Ｉ）の濃度が約８５％ となるようにメタノールを添加した。その後、５℃まで冷却し、５℃に保持した状態で、更に酢酸エチルを、化合物（Ｉ）の濃度が約２５ｍｇ／ｍＬ となるように添加（一次添加）し、その後、別途用意していた酢酸エチル／アセトン１：１混合溶液を、化合物（Ｉ）の濃度が約３ｍｇ／ｍＬ となるように時間をかけて二次添加した。総量添加終了後、分離・濾取により化合物（Ｉ）のＢ８２型結晶を得た。（２．２ ｇ）
【００２３】
実施例４
化合物（Ｉ）（無晶形）を９０％ アセトン水を用いて、６ ｍｇ／ｍＬ 濃度に溶解した。この化合物（Ｉ）を溶解したアセトン水溶液に、この溶解液の４．４倍量の酢酸エチルを添加した。常温（２５℃）にて３−４時間攪拌後、４０℃まで加温し、その後、５℃まで攪拌しつつ冷却した。１８−２０時間攪拌を続けた後、分離・濾取により化合物（Ｉ）のＢ８２型結晶を得た。
【００２４】
実施例５
化合物（Ｉ）（無晶形）を７０％イソプロピルアルコール水を用いて、６ ｍｇ／ｍＬ 濃度に溶解した。この化合物（Ｉ）を溶解したイソプロピル水溶解液に、この溶解液の１．６倍量の酢酸エチルを添加した。常温（２５℃）にて３−４時間攪拌後、４０℃まで加温し、その後、５℃まで攪拌しつつ、約２０時間かけて冷却した。晶析溶液を顕微鏡下で観察したところ、 Ｂ８２型結晶を認めた。
【００２５】
実施例６
化合物（Ｉ）（無晶形）を９０％メタノール水を用いて、１２．５ ｍｇ／ｍＬ 濃度に溶解した。この化合物（Ｉ）を溶解したメタノール水溶液に、この溶解液の１．５倍量のジクロロメタンを添加した。常温（２５℃）にて３−４時間攪拌後、４０℃まで加温し、その後、５℃まで攪拌しつつ約２０時間かけて冷却した。晶析溶液を顕微鏡下で観察したところ、 Ｂ８２型結晶を認めた。
【００２６】
実施例７
化合物（Ｉ）（無晶形）を８０％メタノール水を用いて、６ ｍｇ／ｍＬ 濃度に溶解した。この化合物（Ｉ）を溶解したメタノール水溶液に、この溶解液の３．２倍量のアセトニトリルを添加した。常温（２５℃）にて３−４時間攪拌後、４０℃まで加温し、その後、５℃まで攪拌しつつ、約２０時間かけて冷却した。晶析溶液を顕微鏡下で観察したところ、 Ｂ８２型結晶を認めた。
【００２７】
実施例８
化合物（Ｉ）（無晶形）を９０％メタノール水を用いて、１００ ｍｇ／ｍＬ 濃度に溶解した。この化合物（Ｉ）を溶解したメタノール水溶液を、常温（２５℃）下で３−４時間攪拌後、４０℃まで加温し、その後、５℃まで攪拌しつつ、約２０時間かけて冷却した。晶析溶液を顕微鏡下で観察したところ、Ｂ８２型結晶を認めた。
【図面の簡単な説明】
【図１】粉末Ｘ線回折パターンを示す。
【図２】赤外吸収スペクトルを示す。[0001]
BACKGROUND OF THE INVENTION
[0002]
The present invention relates to a novel crystal of a cyclic lipopeptide compound. The cyclic lipopeptide compound (I) of the present invention has the following structural formula:
[Chemical 2]
Figure 2005053782
Indicated by This compound has antimicrobial activity, in particular antifungal activity and β-1,3-glucan synthase inhibitory action, and prevents various infections including Pneumocystis carinii infection such as Carini pneumonia Useful for treatment.
[0003]
[Background Art and Problems to be Solved by the Invention]
The cyclic lipopeptide compound (I) is a known compound, and is described, for example, as the compound of Example 25 in WO96 / 11210. However, Compound (I) obtained by the method described in Example 25 in the publication was an amorphous compound. Thereafter, as a result of intensive studies, the inventors of the present invention succeeded in obtaining the compound (I) as having a special crystal form and completed the present invention [hereinafter, cyclic lipos having this special crystal form. Peptide compound (I) is referred to as B82 type crystal of compound (I)].
The present invention is described in detail below.
[0004]
[Means for Solving the Problems]
Physicochemical characteristics of B82 type crystal of compound (I) The physicochemical characteristics of B82 type crystal of compound (I) obtained by the present invention will be described below.
[0005]
1) Crystal form needle crystal
2) Powder X-ray diffraction pattern The B82 type crystal of compound (I) shows a characteristic peak at the diffraction angle [2θ (°)] shown in the following table in the powder X-ray diffraction pattern.
[0007]
[Table 2]
Figure 2005053782
[0008]
FIG. 1 shows a powder X-ray diffraction pattern of a B82 type crystal of compound (I) obtained in Example 1 described later.
However, this diffraction pattern is only given as a reference, and any compound (I) crystal whose powder X-ray diffraction pattern is essentially the same as this diffraction pattern can be used as a compound ( It is identified as B82 type crystal of I).
[0009]
3) Infrared absorption spectrum FIG. 2 shows an infrared absorption spectrum of the B82 type crystal of the compound (I) obtained in Example 1 described later.
However, this spectrum is only given as a reference, and any compound (I) crystal whose infrared absorption spectrum is essentially the same as this spectrum is the type B82 of compound (I). It is identified as a crystal.
[0010]
Method for Producing B82 Type Crystal of Compound (I) Hereinafter, a method for producing the B82 type crystal of Compound (I) obtained by the present invention will be described in detail.
In the B82 type crystal of Compound (I), Compound (I) is dissolved in hydrous alcohol or hydrous acetone, and after cooling or warming, ethyl acetate, dichloromethane, acetone or acetonitrile or a mixed solution thereof is added afterwards. It can be obtained by precipitating crystals under cooling or warming.
Preferable examples of the solution containing compound (I) include a water-containing methanol solution, a water-containing ethanol solution, a water-containing isopropanol solution, and a water-containing butanol solution of compound (I).
[0011]
In addition, the B82 type crystal of compound (I) is prepared by dissolving compound (I) in hydrous alcohol and at normal temperature to warming (preferably 40 ° C. to 45 ° C.), ethyl acetate, dichloromethane, acetone, acetonitrile or the like. It can also be obtained by post-adding a mixed solution of (2) and continuing stirring slowly, then cooling (preferably 10 ° C. to 5 ° C.) and precipitating crystals.
[0012]
In the case of precipitating the B82 type crystal of compound (I), it is preferable to keep the solution slightly beyond the saturation state.
The B82 type crystal of compound (I) obtained by the above production method is filtered and dried by a conventional method.
[0013]
The amorphous compound (I) used in the present invention can be produced by the method described in the aforementioned WO96 / 11210.
[0014]
【The invention's effect】
Since the B82 type crystal of compound (I) is much higher in purity than the amorphous compound (I), the B82 type crystal of compound (I) is suitable as a pharmaceutical, and is handled in preparation and storage. Is easy.
As described above, the B82 type crystal of the compound (I) has very excellent advantages and is very superior to the amorphous compound (I).
[0015]
In order to show such advantages of the B82 type crystal of the compound (I), the stability of the B82 type crystal of the compound (I) and the amorphous compound (I) described in the aforementioned WO96 / 11210 publication The results of comparative experiments on are described below.
Test sample
Test sample 1 : Amorphous compound (I) obtained in Example 25 in WO96 / 11210
Test sample A : B82 type crystal test method of compound (I) of the present invention Test method: Impurities were measured by high performance liquid chromatography (HPLC).
[0016]
Figure 2005053782
[Table 3]
Figure 2005053782
[0017]
Figure 2005053782
[Table 4]
Figure 2005053782
[0018]
As is clear from the test results, it can be seen that test sample A has a lower impurity content ratio than test sample 1.
[0019]
As described above, there was a large difference in purity between the B82 crystal of compound (I) and the amorphous compound (I) described in WO96 / 11210. That is, it became clear that the B82 type crystal of the compound (I) of the present invention is extremely superior to the amorphous compound (I) described in the patent publication.
[0020]
【Example】
Example 1
Compound (I) (amorphous form) 0.5 g was dissolved in a concentration of 50 mg / mL using 70% aqueous methanol. Ethyl acetate was added to an aqueous methanol solution in which the compound (I) was dissolved so that the concentration of the compound (I) was 8 mg / mL (after the primary addition, the concentration was adjusted to 20 mg / mL, and the mixture was aged and stirred overnight, and then (Secondary addition of ethyl acetate gave a final concentration of 8 mg / mL). After completion of the addition of the total amount, B82 type crystals of compound (I) were obtained by separation and filtration (0.5 g). This example was performed at room temperature (25 ° C.).
FIG. 1 shows a powder X-ray diffraction pattern of this B82 type crystal. FIG. 2 shows an infrared absorption spectrum (KBr method) of this B82 type crystal.
The peak in the powder X-ray diffraction pattern of this B82 type crystal is shown below. The measurement conditions are as follows.
Counter cathode: Cu, tube voltage: 40 kv, tube current: 30 mA, detector: proportional counter [Table 5]
Figure 2005053782
[0021]
Example 2
Compound (I) (amorphous) 0.2 g was dissolved in 80 mg ethanol water to a concentration of 50 mg / mL. Ethyl acetate is added to an aqueous ethanol solution in which the compound (I) is dissolved so that the concentration of the compound (I) is 17 mg / mL, and the mixture is stirred and aged for a whole day and then separated and collected by filtration. Crystals were obtained (0.18 g). This example was carried out at room temperature (25 ° C.).
[0022]
Example 3
Compound (I) (amorphous form) 3.2 g was dissolved in a concentration of about 40 mg / mL using 75% aqueous methanol. Methanol was added to a methanol aqueous solution in which compound (I) was dissolved so that the concentration of compound (I) was about 85%. Thereafter, while cooling to 5 ° C. and maintaining at 5 ° C., ethyl acetate was further added (primary addition) so that the concentration of compound (I) was about 25 mg / mL, and then separately prepared. A 1: 1 mixed solution of ethyl acetate / acetone was added over time so that the concentration of compound (I) was about 3 mg / mL. After the addition of the total amount, the B82 type crystal of compound (I) was obtained by separation and filtration. (2.2 g)
[0023]
Example 4
Compound (I) (amorphous form) was dissolved in a concentration of 6 mg / mL using 90% aqueous acetone. To the acetone aqueous solution in which the compound (I) was dissolved, 4.4 times as much ethyl acetate as this solution was added. After stirring at room temperature (25 ° C.) for 3-4 hours, the mixture was heated to 40 ° C. and then cooled to 5 ° C. with stirring. Stirring was continued for 18 to 20 hours, followed by separation and filtration to obtain a B82 type crystal of Compound (I).
[0024]
Example 5
Compound (I) (amorphous form) was dissolved in 70 mg isopropyl alcohol water to a concentration of 6 mg / mL. 1.6 times as much ethyl acetate as this solution was added to an isopropyl water solution in which this compound (I) was dissolved. After stirring at room temperature (25 ° C.) for 3-4 hours, the mixture was heated to 40 ° C. and then cooled to 5 ° C. over about 20 hours. When the crystallization solution was observed under a microscope, B82 type crystals were observed.
[0025]
Example 6
Compound (I) (amorphous form) was dissolved in 12.5 mg / mL concentration using 90% aqueous methanol. To the aqueous methanol solution in which the compound (I) was dissolved, 1.5 times the amount of dichloromethane was added. After stirring at room temperature (25 ° C.) for 3-4 hours, the mixture was heated to 40 ° C. and then cooled to 5 ° C. over about 20 hours. When the crystallization solution was observed under a microscope, B82 type crystals were observed.
[0026]
Example 7
Compound (I) (amorphous) was dissolved in 6 mg / mL concentration using 80% aqueous methanol. To the aqueous methanol solution in which the compound (I) was dissolved, 3.2 times as much acetonitrile as this solution was added. After stirring at room temperature (25 ° C.) for 3-4 hours, the mixture was heated to 40 ° C. and then cooled to 5 ° C. over about 20 hours. When the crystallization solution was observed under a microscope, B82 type crystals were observed.
[0027]
Example 8
Compound (I) (amorphous) was dissolved in a concentration of 100 mg / mL using 90% aqueous methanol. The methanol aqueous solution in which this compound (I) was dissolved was stirred for 3-4 hours at room temperature (25 ° C.), then heated to 40 ° C., and then cooled over about 20 hours while stirring to 5 ° C. When the crystallization solution was observed under a microscope, B82 type crystals were observed.
[Brief description of the drawings]
FIG. 1 shows a powder X-ray diffraction pattern.
FIG. 2 shows an infrared absorption spectrum.

Claims (5)

粉末Ｘ線回折パターンにおいて下記の表に示される回折角にピークを示すことを特徴とする下記の化学構造式で示される環状リポペプチド化合物（Ｉ）の結晶：
Figure 2005053782
Figure 2005053782
 Crystal of the cyclic lipopeptide compound (I) represented by the following chemical structural formula, wherein the powder X-ray diffraction pattern shows a peak at the diffraction angle shown in the following table:
Figure 2005053782
Figure 2005053782
 請求項１記載の環状リポペプチド化合物（Ｉ）を含水アルコールまたは含水アセトンに溶解させ、冷却下ないし加温下で酢酸エチル、ジクロロメタン、アセトンまたはアセトニトリルあるいはそれらの混合溶液を後添加することにより得ることができる環状リポペプチド化合物（Ｉ）の結晶。The cyclic lipopeptide compound (I) according to claim 1 is obtained by dissolving in water-containing alcohol or water-containing acetone and then adding ethyl acetate, dichloromethane, acetone or acetonitrile or a mixed solution thereof under cooling or warming. Crystal of cyclic lipopeptide compound (I) capable of 請求項１記載の環状リポペプチド化合物（Ｉ）を含水アルコールまたは含水アセトンに溶解させ、５℃〜４５℃でゆっくりと撹拌を続け、次いで、これに酢酸エチル、ジクロロメタン、アセトンまたはアセトニトリルあるいはそれらの混合溶液を後添加した後、５℃〜４５℃で撹拌、放置することにより得ることができる請求項２記載の結晶。The cyclic lipopeptide compound (I) according to claim 1 is dissolved in water-containing alcohol or water-containing acetone, and slowly stirred at 5 ° C to 45 ° C. The crystal according to claim 2, which can be obtained by post-adding the solution and stirring and leaving at 5 ° C to 45 ° C. 請求項１記載の環状リポペプチド化合物（Ｉ）を含水アルコールまたは含水アセトンに溶解させ、冷却下ないし加温下で酢酸エチル、ジクロロメタン、アセトンまたはアセトニトリルあるいはそれらの混合物を後添加することにより結晶を得ることを特徴とする環状リポペプチド化合物（Ｉ）の結晶の製造法。Crystals are obtained by dissolving the cyclic lipopeptide compound (I) according to claim 1 in hydrous alcohol or hydrous acetone and then adding ethyl acetate, dichloromethane, acetone or acetonitrile or a mixture thereof under cooling or warming. A method for producing a crystal of cyclic lipopeptide compound (I), wherein 請求項１記載の環状リポペプチド化合物（Ｉ）を含水アルコールまたは含水アセトンに溶解させ、５℃〜４５℃でゆっくりと撹拌を続け、次いで、これに酢酸エチル、ジクロロメタン、アセトンまたはアセトニトリルあるいはそれらの混合物を後添加した後、５℃〜４５℃で撹拌、放置することにより結晶を得ることを特徴とする請求項４記載の製造法。The cyclic lipopeptide compound (I) according to claim 1 is dissolved in water-containing alcohol or water-containing acetone, and the stirring is continued slowly at 5 ° C to 45 ° C. 5. The method according to claim 4, wherein after the addition of is added, the crystals are obtained by stirring and leaving at 5 to 45 ° C.
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