JP2023510684A - Lenvatinib Mesylate Crystalline Form XI and Process for its Preparation - Google Patents
Lenvatinib Mesylate Crystalline Form XI and Process for its PreparationDownload PDFInfo
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Abstract
Translated fromJapaneseDescription
Translated fromJapanese 〔技術分野〕
本出願は医薬結晶形の分野に関し、特にレンバチニブメシル酸塩結晶形及びその調製方法に関する。〔Technical field〕
The present application relates to the field of pharmaceutical crystalline forms, in particular to lenvatinib mesylate crystalline form and methods for its preparation.
〔背景技術〕
レンバチニブ（Ｌｅｎｖａｔｉｎｉｂ）、化学名：４－［３－クロロ－４－（シクロプロピルアミノカルボニル）アミノフェノキシ］－７－メトキシ－６－キノリンカルボキサミド、その構造式は式Ｉで表される通りである。[Background technology]
Lenvatinib, chemical name: 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, its structural formula is as represented by Formula I;
レンバチニブは、日本のエーザイ株式会社が開発した甲状腺癌及び肝臓癌の治療薬である。レンバチニブは経口マルチ受容体チロシンキナーゼ（ＲＴＫ）阻害剤であり、その受容体と新型結合モードを有し、腫瘍増殖に関与する他の血管新生促進及び発癌性シグナル伝達経路関連ＲＴＫを阻害する他、更に血管内皮の成長因子（ＶＥＧＦ）受容体のキナーゼ活性を選択的に阻害することを可能とする。２０１５年２月１３日、放射性ヨード不応性局所再発又は転移性進行性分化型甲状腺癌の患者の為の治療薬としてＦＤＡに承認され、その後、欧州連合及び日本での販売が承認され、２０１８年９月５日には、中国食品医薬品管理局により、過去に全身療法を受けたことがない切除不能な肝癌患者の為の治療薬として承認された。 Lenvatinib is a treatment for thyroid and liver cancer developed by Eisai Co., Ltd. of Japan. Lenvatinib is an oral multi-receptor tyrosine kinase (RTK) inhibitor that has novel binding modes with its receptors and inhibits RTKs associated with other pro-angiogenic and oncogenic signaling pathways involved in tumor growth, Furthermore, it makes it possible to selectively inhibit the kinase activity of vascular endothelial growth factor (VEGF) receptors. Approved by the FDA on February 13, 2015 for the treatment of patients with radioiodine-refractory locally recurrent or metastatic advanced differentiated thyroid cancer, and subsequently approved for marketing in the European Union and Japan, 2018 On September 5, it was approved by the Chinese Food and Drug Administration for the treatment of unresectable liver cancer patients who have not received prior systemic therapy.
特許ＣＮ１００５６９７５３Ｃ、ＣＮ１０１３３７９３１Ｂ、ＣＮ１０１３３７９３２Ｂ、及びＣＮ１０１３３７９３３Ｂは、レンバチニブメシル酸塩の結晶形Ａ、Ｂ、Ｃ、Ｆ及びＩを開示している。そのうち、無水結晶形Ｂは、異なる湿度条件下で結晶形Ｃ又は結晶形Ｃとの混合結晶に変化し、結晶形Ｉも、異なる湿度条件下で結晶形Ｃ又は結晶形Ｃとの混合結晶に変化する。従って、結晶形Ｂ及び結晶形Ｉは安定性が低くなる。 Patents CN100569753C, CN101337931B, CN101337932B, and CN101337933B disclose crystalline forms A, B, C, F and I of lenvatinib mesylate. Among them, the anhydrous crystalline form B will change to crystalline form C or mixed crystals with crystalline form C under different humidity conditions, and the crystalline form I will also change to crystalline form C or mixed crystals with crystalline form C under different humidity conditions. Change. Therefore, crystalline form B and crystalline form I are less stable.
上記から分かるように、当技術分野では、安定性が良好であり、製品品質がより優れて、調製プロセスが簡単で、且つ産業化生産に適したレンバチニブメシル酸塩の結晶形及びその調製方法を提供することを依然として必要とする。 As can be seen from the above, in the art, crystalline forms of lenvatinib mesylate with good stability, better product quality, simple preparation process, and suitable for industrial production and its preparation There is still a need to provide a method.
〔発明の概要〕
本発明の目的は、レンバチニブメシル酸塩の結晶形が安定しておらず、製品の品質が不安定で、調製プロセスが煩雑で、大規模生産ができないという従来技術の問題を解決する為の、レンバチニブメシル酸塩の結晶形を提供することである。[Outline of the Invention]
The purpose of the present invention is to solve the problems of the prior art that the crystal form of lenvatinib mesylate is not stable, the product quality is unstable, the preparation process is complicated, and large-scale production is not possible. is to provide a crystalline form of lenvatinib mesylate.
上記の技術的問題を解決する為に、本発明の技術的解決手段は以下の通りである。 In order to solve the above technical problems, the technical solutions of the present invention are as follows.
レンバチニブメシル酸塩結晶形ＸＩであり、そのＸ線粉末回折パターンは約５．７３°±０．２°、８．０３°±０．２°、１１．４５°±０．２°、１２．７５°±０．２°、１６．１５°±０．２°、１７．２４°±０．２°、１８．１６°±０．２°、１９．６９°±０．２°、２０．６８°±０．２°、２２．１５±０．２°、２２．９６±０．２°、２３．７６±０．２°、２４．３２±０．２°、２５．１３±０．２°、２６．３２±０．２°、２７．００±０．２°、２８．８７±０．２°、２９．５１±０．２°、３４．９０±０．２°の回折角（２θ）におけるピークを含む。 Lenvatinib mesylate crystalline Form XI, which has an X-ray powder diffraction pattern of about 5.73° ± 0.2°, 8.03° ± 0.2°, 11.45° ± 0.2°, 12.75°±0.2°, 16.15°±0.2°, 17.24°±0.2°, 18.16°±0.2°, 19.69°±0.2°, 20.68°±0.2°, 22.15±0.2°, 22.96±0.2°, 23.76±0.2°, 24.32±0.2°, 25.13± 0.2°, 26.32±0.2°, 27.00±0.2°, 28.87±0.2°, 29.51±0.2°, 34.90±0.2° Includes peaks at diffraction angles (2θ).
好ましくは、前記結晶形ＸＩのＸ線粉末回折パターンは基本的に図１に示される通りである。 Preferably, the X-ray powder diffraction pattern of said crystalline Form XI is essentially as shown in FIG.
好ましくは、前記結晶形ＸＩの示差走査熱量測定（ＤＳＣ）の吸熱ピークの温度はそれぞれ１１４．０５±５℃及び１５８．５６±５℃である。 Preferably, the differential scanning calorimetry (DSC) endothermic peak temperatures of said crystalline Form XI are 114.05±5° C. and 158.56±5° C., respectively.
好ましくは、前記結晶形ＸＩの熱重量分析（ＴＧＡ）は、３０～１４０℃の範囲で約６．９４％の重量損失を示している。 Preferably, a thermogravimetric analysis (TGA) of said crystalline form XI shows a weight loss of about 6.94% in the range of 30-140°C.
好ましくは、前記結晶形ＸＩの水分含有量は６．５％である。 Preferably, the water content of said crystalline Form XI is 6.5%.
好ましくは、前記結晶形ＸＩは、２つの結晶水を含むレンバチニブメシル酸塩二水和物である。 Preferably, said crystalline form XI is lenvatinib mesylate dihydrate containing two waters of crystallization.
本発明は更に前記レンバチニブメシル酸塩結晶形ＸＩの調製方法を提供し、以下の工程を含む：
１、酢酸エチル及び精製水を、室温で一定の体積比で攪拌して均一に混合し、
２、レンバチニブメシル酸塩を工程１の混合溶媒に加え、
３、工程２の懸濁液を均一に分散させた後、結晶形ＸＩの種結晶を一定量加え、１５～４０℃の温度で４～２４時間撹拌し、吸引濾過により乾燥させて、固体粉末、即ち、前記レンバチニブメシル酸塩結晶形ＸＩを得る。The present invention further provides a process for preparing said lenvatinib mesylate Form XI, comprising the steps of:
1. Ethyl acetate and purified water are uniformly mixed at room temperature by stirring at a constant volume ratio,
2. Add lenvatinib mesylate to the mixed solvent of
3. After uniformly dispersing the suspension in
好ましくは、工程１において、酢酸エチルと精製水との一定の体積比は１００ｍＬ：（２～１０）ｍＬであり、より好ましくは、酢酸エチルと精製水との一定の体積比は１００ｍＬ：（２～５）ｍＬであり、最も好ましくは、１００ｍＬ：３ｍＬである。 Preferably, in
好ましくは、工程２において、レンバチニブメシル酸塩と工程１における混合溶媒中の酢酸エチルとの質量対体積比は１ｇ：（１０～３０）ｍＬであり、より好ましくは、レンバチニブメシル酸塩と工程１における混合溶媒中の酢酸エチルとの質量対体積比は１ｇ：（１５～２５）ｍＬであり、最も好ましくは、１ｇ：２０ｍＬである。 Preferably, in
好ましくは、工程３において、一定量の結晶形ＸＩの種結晶は、レンバチニブメシル酸塩供給量の０～１０％質量分率であり、より好ましくは、一定量の結晶形ＸＩの種結晶は、レンバチニブメシル酸塩供給量の２～６％質量分率であり、最も好ましくは、５％質量分率である。 Preferably, in
好ましくは、反応温度は２０～３０℃であり、より好ましくは、２０～２５℃であり、最も好ましくは、２５℃である。 Preferably, the reaction temperature is 20-30°C, more preferably 20-25°C, most preferably 25°C.
好ましくは、攪拌時間は６～１２時間であり、より好ましくは、６～１０時間であり、最も好ましくは、８時間である。 Preferably, the stirring time is 6-12 hours, more preferably 6-10 hours, most preferably 8 hours.
更に好ましくは、前記レンバチニブメシル酸塩結晶形ＸＩの調製方法は、以下の工程を含む：
１、酢酸エチル及び精製水を、室温で攪拌して均一に混合し、ここで、酢酸エチルと精製水との体積比は１００ｍＬ：３ｍＬであり、
２、レンバチニブメシル酸塩を工程１の混合溶媒に加え、ここで、レンバチニブメシル酸塩と酢酸エチルとの質量対体積比は１ｇ：２０ｍＬであり、
３、工程２の懸濁液を均一に分散させた後、結晶形ＸＩの種結晶をレンバチニブメシル酸塩供給量の５％質量分率で加え、２５℃の温度で８時間撹拌し、吸引濾過により乾燥させて、固体粉末、即ち、前記レンバチニブメシル酸塩結晶形ＸＩを得る。More preferably, said process for preparing lenvatinib mesylate Form XI comprises the following steps:
1. Ethyl acetate and purified water are stirred at room temperature to mix uniformly, wherein the volume ratio of ethyl acetate and purified water is 100 mL:3 mL;
2. Add lenvatinib mesylate to the mixed solvent of
3. After uniformly dispersing the suspension of
本発明によって調製されるレンバチニブメシル酸塩結晶形ＸＩは、以下の利点を有する：
１、本発明によるレンバチニブメシル酸塩結晶形ＸＩは、良好な溶解性、良好な薬物動態特性及び良好な安定性を有し、医薬製剤の調製に適している。Lenvatinib mesylate Form XI prepared according to the present invention has the following advantages:
1, Lenvatinib mesylate crystalline Form XI according to the present invention has good solubility, good pharmacokinetic properties and good stability, and is suitable for the preparation of pharmaceutical formulations.
２、本発明によるレンバチニブメシル酸塩結晶形ＸＩは、高温、高湿度及びビームの条件下で結晶形を安定に保つことができる。 2. Lenvatinib mesylate crystalline form XI according to the present invention can keep the crystalline form stable under the conditions of high temperature, high humidity and beam.
３、本発明によるレンバチニブメシル酸塩結晶形ＸＩは、良好な流動性、良好な圧縮性、高いかさ密度、低い吸湿性、及び均一な粒子径分布を有する。 3. Lenvatinib mesylate Form XI according to the present invention has good flowability, good compressibility, high bulk density, low hygroscopicity, and uniform particle size distribution.
４、本発明によるレンバチニブメシル酸塩結晶形ＸＩは、高純度であり、有機溶媒和物ではなく、有機溶媒残留リスクがなく、そして高い安全性を有する。 4. The lenvatinib mesylate crystalline Form XI according to the present invention is of high purity, is not an organic solvate, has no organic solvent residual risk, and has high safety.
５、本発明によるレンバチニブメシル酸塩結晶形ＸＩの調製方法は、酢酸の使用を回避することができ、得られた生成物は、高純度、低不純物、高収率であり、穏やかなプロセス条件、単純且つ回収容易な溶媒系、単純な操作、良好な安定性を有し、キログラムレベルの製品を安定して調製できる為、大規模産業化生産に有利である。 5. The process for preparing lenvatinib mesylate Crystalline Form XI according to the present invention can avoid the use of acetic acid, and the resulting product is of high purity, low impurity, high yield and mild It has process conditions, simple and easily recoverable solvent system, simple operation, good stability, and can stably prepare kilogram-level products, which is advantageous for large-scale industrial production.
〔図面の説明〕
〔図１〕実施例１によるレンバチニブメシル酸塩結晶形ＸＩのＸＲＤパターン。[Description of the drawing]
1: XRD pattern of lenvatinib mesylate Form XI according to Example 1. FIG.
〔図２〕実施例１によるレンバチニブメシル酸塩結晶形ＸＩのＤＳＣパターン。 2. DSC pattern of lenvatinib mesylate Form XI according to Example 1. FIG.
〔図３〕実施例１によるレンバチニブメシル酸塩結晶形ＸＩのＴＧＡパターン。 3. TGA pattern of lenvatinib mesylate Form XI according to Example 1. FIG.
〔図４〕実施例１によるレンバチニブメシル酸塩結晶形ＸＩのＤＶＳパターン。 4. DVS pattern of lenvatinib mesylate Form XI according to Example 1. FIG.
〔図５〕実施例１１による異なる配置条件下でのレンバチニブメシル酸塩結晶形ＸＩのＸＲＤ比較パターン。 FIG. 5. XRD comparative patterns of lenvatinib mesylate Form XI under different configuration conditions according to Example 11.
〔発明を実施するための形態〕
以下、実施例を参照して本出願について更に詳細に説明する。本出願の実施例は、本出願の技術的解決手段を説明する為に使用されるものであり、本出願の本質及び範囲を限定するものではない。[Mode for carrying out the invention]
The present application will now be described in more detail with reference to examples. The examples of this application are used to describe the technical solutions of this application, and do not limit the essence and scope of this application.
本出願で使用される略語の意味は以下の通りである。 Abbreviations used in this application have the following meanings.
ＸＲＤ：Ｘ線粉末回折
本出願に記載のＸ線粉末回折（ＸＲＤ）の測定は、中国遼寧丹東浩元社ＤＸ－２７００Ｂ粉末回折計を使用して収集し、具体的なパラメーターは次の通りである。XRD: X-Ray Powder Diffraction X-ray powder diffraction (XRD) measurements described in this application were collected using a China Liaoning Dandong Haoyuan DX-2700B powder diffractometer, with specific parameters as follows: be.
ＤＳＣ：示差走査熱量計
本出願に記載の示差走査熱量測定（ＤＳＣ）の測定値は、ＭＥＴＴＬＥＲ ＴＯＬＥＤＯのモデルＤＳＣ－１を使用して収集し、加熱速度は１０℃／分、温度範囲は２５～２５０℃であり、テスト中に窒素パージ速度は６０ｍＬ／分である。DSC: Differential Scanning Calorimeter Differential scanning calorimetry (DSC) measurements described in this application were collected using a METTLER TOLEDO model DSC-1 with a heating rate of 10°C/min and a temperature range of 25-25°C. 250° C. and a nitrogen purge rate of 60 mL/min during the test.
ＴＧＡ：熱重量分析装置
本出願に記載の熱重量分析（ＴＧＡ）測定は、ＭＥＴＴＬＥＲ ＴＯＬＥＤＯのモデルＴＧＡ－２を使用して収集し、加熱速度は１０℃／分、温度範囲は３０～２５０℃であり、テスト中に窒素パージ速度は２０ｍＬ／分である。TGA: Thermogravimetric Analyzer Thermogravimetric analysis (TGA) measurements described in this application were collected using a METTLER TOLEDO model TGA-2 with a heating rate of 10°C/min and a temperature range of 30-250°C. Yes, and the nitrogen purge rate is 20 mL/min during testing.
ＤＶＳ：動的蒸気吸着分析装置
本出願に記載の動的蒸気吸着分析（ＤＶＳ）は、ＴＡモデルＱ５０００ＳＡを使用して収集し、平衡温度は２５℃であり、具体的なテストパラメータは次の表に示す通りである。DVS: Dynamic Vapor Sorption Analyzer The Dynamic Vapor Sorption Analysis (DVS) described in this application was collected using a TA model Q5000SA with an equilibrium temperature of 25°C and specific test parameters in the following table. as shown in
ＫＦ：カールフィッシャー水分計
本出願に記載の水分はＭｅｔｒｏｈｍ（メトローム）のモデル８７０ＫＦ Ｔｉｔｒｉｎｏ ｐｌｕｓのカールフィッシャー水分計を使用して測定している。KF: Karl Fischer Moisture Meter Moisture content in this application is measured using a Metrohm Model 870 KF Titrino plus Karl Fischer Moisture Meter.
ＧＣ：ガスクロマトグラフ
本出願に記載の溶媒残留物は、Ａｇｉｌｅｎｔのモデル７８９０Ｂのガスクロマトグラフを使用して測定し、具体的なパラメータは次の表に示す通りである。GC: Gas Chromatograph Solvent residues described in this application were measured using an Agilent model 7890B gas chromatograph, the specific parameters of which are given in the following table.
ＨＰＬＣ：高速液体クロマトグラフィー
ＨＰＬＣスペクトルの測定は、アジレントのＡｇｉｌｅｎｔ１２６０ＤＡＤ型液体クロマトグラフを使用して実施した。本出願において、レンバチニブメシル酸塩のＨＰＬＣ純度は次の方法によって実行した。HPLC: High Performance Liquid Chromatography HPLC spectra were measured using an Agilent 1260 DAD liquid chromatograph from Agilent. In this application, HPLC purity of lenvatinib mesylate was performed by the following method.
（１）オクタデシルシラン結合シリカゲルを充填剤として使用したカラム
（２）検出器：ＵＶ検出器（波長２５２ｎｍ及び２０５ｎｍ）
（３）流速：１ｍＬ／分
（４）運行時間：溶媒ピークからタイムを計り、レンバチニブピークの保持時間の約２．７倍である。(1) Column using octadecylsilane-bonded silica gel as packing material (2) Detector: UV detector (wavelength 252 nm and 205 nm)
(3) Flow rate: 1 mL/min (4) Run time: approximately 2.7 times the retention time of the lenvatinib peak, timed from the solvent peak.
（５）試験液：本製品を１２．５ｍｇ取り、正確に秤量し、溶媒に溶解し、希釈して、１ｍＬあたり約０．５ｍｇを含む溶液を作成して試験溶液とする。 (5) Test solution: Take 12.5 mg of this product, weigh it accurately, dissolve it in a solvent, and dilute it to prepare a solution containing about 0.5 mg per 1 mL as the test solution.
（６）注入量：１０μｌ、自動積分法により試験液を測定し、ピーク面積に応じて試験サンプル中のレンバチニブの純度を算出する。 (6) Injection volume: 10 μl, the test solution is measured by an automatic integration method, and the purity of lenvatinib in the test sample is calculated according to the peak area.
溶媒スクリーニング実験
レンバチニブメシル酸塩の新たな結晶形を発見する為に、本発明者らは、一定量のレンバチニブメシル酸塩を反応溶媒に懸濁させ、２５℃で６～８時間撹拌し、吸引濾過により乾燥させる方法により、新たな結晶形をスクリーニングした。Solvent Screening Experiments To discover new crystalline forms of lenvatinib mesylate, we suspended a certain amount of lenvatinib mesylate in a reaction solvent and incubated at 25° C. for 6-8 hours. New crystal forms were screened by the method of stirring and drying by suction filtration.
反応溶媒をスクリーニングしたところ、反応溶媒が酢酸エチルと水との混合溶媒である場合、新たなレンバチニブメシル酸塩結晶形ＸＩが得られることが明らかになり、その結果を以下の表１に示す。 Screening of the reaction solvent revealed that a new lenvatinib mesylate Form XI was obtained when the reaction solvent was a mixture of ethyl acetate and water, the results of which are shown in Table 1 below. show.
上記の表１に示すように、メタノール、エタノール、アセトン等の純粋な有機溶媒を反応溶媒として使用した場合、得られる生成物は結晶形Ａ又は結晶形Ｃであり、エタノールと水との混合溶媒等の他の混合溶媒を反応溶媒として使用した場合、得られる生成物は結晶形Ａである。表１に示すように、酢酸エチルと水との体積比が１００ｍＬ：（２～１０）ｍＬの場合のみ、生成物として結晶形ＸＩを得ることが可能であり、その効果が最高であり、最も安定した方法である。 As shown in Table 1 above, when pure organic solvents such as methanol, ethanol, and acetone are used as the reaction solvent, the resulting product is crystalline form A or crystalline form C, and a mixed solvent of ethanol and water. When other mixed solvents such as are used as the reaction solvent, the product obtained is crystalline form A. As shown in Table 1, it is possible to obtain crystalline form XI as a product only when the volume ratio of ethyl acetate to water is 100 mL:(2-10) mL, the effect of which is the highest and the highest. It is a stable method.
〈実施例１：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル２００ｍＬ及び精製水１０ｍＬを室温で攪拌して均一に混合した後、レンバチニブメシル酸塩１０．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後、２５℃で２４時間攪拌し、吸引濾過により乾燥させて、収率９１．０％、純度９９．７３％、９．１ｇの固体粉末を得た。<Example 1: Preparation of lenvatinib mesylate crystal form XI>
After 200 mL of ethyl acetate and 10 mL of purified water are stirred at room temperature and mixed uniformly, 10.0 g of lenvatinib mesylate is added to the mixed solvent of ethyl acetate and purified water to uniformly disperse the suspension. After that, it was stirred at 25° C. for 24 hours and dried by suction filtration to obtain 9.1 g of solid powder with a yield of 91.0% and a purity of 99.73%.
１Ｈ－ＮＭＲデータは次の通りである。1 H-NMR data are as follows.
１Ｈ ＮＭＲ（４００ＭＨｚ、ｄ６－ＤＭＳＯ）δ９．００（ｄ、Ｊ＝６．５Ｈｚ、１Ｈ）、８．７２（ｓ、１Ｈ）、８．３６（ｄ、Ｊ＝９．１Ｈｚ、１Ｈ）、８．０９（ｓ、１Ｈ）、７．９５（ｄ、Ｊ＝２４．３Ｈｚ、２Ｈ）、７．６８（ｓ、１Ｈ）、７．６６（ｄ、Ｊ＝２．８Ｈｚ、１Ｈ）、７．３７（ｄｄ、Ｊ＝９．１、２．８Ｈｚ、１Ｈ）、７．２８（ｄ、Ｊ＝２．４Ｈｚ、１Ｈ）、６．９７（ｄ、Ｊ＝６．６Ｈｚ、１Ｈ）、４．１０（ｓ、３Ｈ）、２．５８（ｍ、１Ｈ）、２．４０（ｓ、３Ｈ）、０．６４－０．７０（ｍ、２Ｈ）、０．５６－０．３０（ｍ、２Ｈ）。1 H NMR (400 MHz, d -DMSO) δ 9.00 (d, J = 6.5 Hz, 1 H) , 8.72 (s, 1 H), 8.36 (d, J = 9.1 Hz, 1 H), 8.09 (s, 1H), 7.95 (d, J=24.3Hz, 2H), 7.68 (s, 1H), 7.66 (d, J=2.8Hz, 1H), 7. 37 (dd, J=9.1, 2.8 Hz, 1 H), 7.28 (d, J=2.4 Hz, 1 H), 6.97 (d, J=6.6 Hz, 1 H), 4.10 (s, 3H), 2.58 (m, 1H), 2.40 (s, 3H), 0.64-0.70 (m, 2H), 0.56-0.30 (m, 2H).
得られたレンバチニブメシル酸塩結晶形ＸＩに対して、Ｃｕ－ｋａ光線を用いて、Ｘ線粉末測定を行って得られたＸＲＤスペクトルを図１に、関連データを表２に示す。 The XRD spectrum obtained by X-ray powder measurement using Cu-ka light for the obtained lenvatinib mesylate crystalline Form XI is shown in FIG. 1 and the relevant data are shown in Table 2.
そのうち、２θ回折角の誤差は±０．２°である。 Among them, the error of the 2θ diffraction angle is ±0.2°.
得られたレンバチニブメシル酸塩結晶形ＸＩに対して、ＤＳＣ分析を行うと、図２に示すように、その吸熱ピークは１１４．０５±５℃及び１５８．５６±５℃である。 DSC analysis is performed on the obtained lenvatinib mesylate crystalline Form XI, and its endothermic peaks are at 114.05±5° C. and 158.56±5° C., as shown in FIG.
得られたレンバチニブメシル酸塩結晶形ＸＩに対して、ＴＧＡ分析を行うと、図３に示すように、３０～１４０℃の範囲でその重量損失は約６．９４％である。 TGA analysis of the resulting lenvatinib mesylate Form XI shows a weight loss of about 6.94% in the range of 30-140° C., as shown in FIG.
得られたレンバチニブメシル酸塩結晶形ＸＩに対して、水分測定を行うと、その水分含有量は６．５％である。 Moisture determination is performed on the obtained lenvatinib mesylate Form XI and the water content is 6.5%.
得られたレンバチニブメシル酸塩結晶形ＸＩに対して、酢酸エチル溶媒残留物測定を行うと、その酢酸エチル溶媒残留物は０．０６８％である。 Ethyl acetate solvent residue determination is performed on the resulting lenvatinib mesylate Form XI and the ethyl acetate solvent residue is 0.068%.
ＴＧＡ重量損失、水分及び溶存残留物のデータを参照すると、結晶形ＸＩは２つの結晶水を含むレンバチニブメシル酸塩二水和物であることが分かる（理論上の含水量は６．４４％である）。 Referring to the TGA weight loss, water and dissolved residue data, it can be seen that Form XI is lenvatinib mesylate dihydrate containing two waters of crystallization (theoretical water content is 6.44 %).
〈実施例２：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル２００ｍＬ及び精製水４ｍＬを室温で攪拌して均一に混合した後、レンバチニブメシル酸塩１０．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後、０．３ｇの結晶形ＸＩの種結晶を加え、次いで２５℃で８時間撹拌し、吸引濾過により乾燥させて、９．２ｇの固体粉末を得た。収率は９２．０％、純度は９９．７７％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。<Example 2: Preparation of lenvatinib mesylate crystal form XI>
After 200 mL of ethyl acetate and 4 mL of purified water are stirred at room temperature and uniformly mixed, 10.0 g of lenvatinib mesylate is added to the mixed solvent of ethyl acetate and purified water to uniformly disperse the suspension. After that, 0.3 g of seed crystals of Form XI was added, then stirred at 25° C. for 8 hours and dried by suction filtration to obtain 9.2 g of solid powder. The yield is 92.0%, the purity is 99.77%, and the XRD data are basically consistent with those of Example 1.
〈実施例３：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル２０００ｍＬ及び精製水６０ｍＬを室温で攪拌して均一に混合した後、レンバチニブメシル酸塩１００．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後、５．０ｇの結晶形ＸＩの種結晶を加え、次いで２５℃で８時間撹拌し、吸引濾過により乾燥させて、９３．０ｇの固体粉末を得た。収率は９３．０％、純度は９９．７６％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。<Example 3: Preparation of lenvatinib mesylate crystal form XI>
After 2000 mL of ethyl acetate and 60 mL of purified water are stirred at room temperature and mixed uniformly, 100.0 g of lenvatinib mesylate is added to the mixed solvent of ethyl acetate and purified water to uniformly disperse the suspension. After that, 5.0 g of seed crystals of Form XI were added, then stirred at 25° C. for 8 hours and dried by suction filtration to obtain 93.0 g of solid powder. The yield is 93.0%, the purity is 99.76%, and the XRD data are basically consistent with those of Example 1.
〈実施例４：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル２００ｍＬ及び精製水２０ｍＬを室温で攪拌して均一に混合した後、レンバチニブメシル酸塩１０．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後、１．０ｇの結晶形ＸＩの種結晶を加え、次に２０℃で８時間撹拌し、吸引濾過により乾燥させて、９．２ｇの固体粉末を得た。収率は９２．０％、純度は９９．７５％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。<Example 4: Preparation of lenvatinib mesylate crystal Form XI>
After 200 mL of ethyl acetate and 20 mL of purified water are stirred at room temperature and uniformly mixed, 10.0 g of lenvatinib mesylate is added to the mixed solvent of ethyl acetate and purified water to uniformly disperse the suspension. After that, 1.0 g of seed crystals of Form XI was added, then stirred at 20° C. for 8 hours and dried by suction filtration to obtain 9.2 g of solid powder. The yield is 92.0%, the purity is 99.75%, and the XRD data are basically consistent with those of Example 1.
〈実施例５：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル１００ｍＬ及び精製水２ｍＬを室温で攪拌して均一に混合した後、レンバチニブメシル酸塩１０．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後、０．５ｇの結晶形ＸＩの種結晶を加え、次いで１５℃で８時間撹拌し、吸引濾過により乾燥させて、９．３ｇの固体粉末を得た。収率は９３．０％、純度は９９．７３％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。<Example 5: Preparation of lenvatinib mesylate crystal form XI>
After 100 mL of ethyl acetate and 2 mL of purified water are stirred at room temperature and mixed uniformly, 10.0 g of lenvatinib mesylate is added to the mixed solvent of ethyl acetate and purified water to uniformly disperse the suspension. After that, 0.5 g of seed crystals of Form XI was added, then stirred at 15° C. for 8 hours and dried by suction filtration to obtain 9.3 g of solid powder. The yield is 93.0%, the purity is 99.73%, and the XRD data are basically consistent with those of Example 1.
〈実施例６：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル１００ｍＬ及び精製水１０ｍＬを室温で攪拌して均一に混合した後、レンバチニブメシル酸塩１０．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後、０．５ｇの結晶形ＸＩの種結晶を加え、次いで３０℃で８時間撹拌し、吸引濾過により乾燥させて、９．１ｇの固体粉末を得た。収率は９１．０％、純度は９９．７１％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。<Example 6: Preparation of lenvatinib mesylate crystal form XI>
After 100 mL of ethyl acetate and 10 mL of purified water are stirred at room temperature and mixed uniformly, 10.0 g of lenvatinib mesylate is added to the mixed solvent of ethyl acetate and purified water to uniformly disperse the suspension. After that, 0.5 g of seed crystals of Form XI was added, then stirred at 30° C. for 8 hours and dried by suction filtration to obtain 9.1 g of solid powder. The yield is 91.0%, the purity is 99.71%, and the XRD data are basically consistent with those of Example 1.
〈実施例７：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル３００ｍＬ及び精製水６ｍＬを室温で攪拌して均一混合した後、レンバチニブメシル酸塩１０．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後、０．２ｇの結晶形ＸＩの種結晶を加え、次いで４０℃で４時間撹拌し、吸引濾過により乾燥させて、９．０ｇの固体粉末を得た。収率は９０．０％、純度は９９．６９％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。<Example 7: Preparation of lenvatinib mesylate crystal form XI>
After stirring and uniformly mixing 300 mL of ethyl acetate and 6 mL of purified water at room temperature, 10.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and the suspension was uniformly dispersed. Afterwards, 0.2 g of seed crystals of Form XI were added, then stirred at 40° C. for 4 hours and dried by suction filtration to obtain 9.0 g of solid powder. The yield is 90.0%, the purity is 99.69%, and the XRD data are basically consistent with those of Example 1.
〈実施例８：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル３００ｍＬ及び精製水３０ｍＬを室温で攪拌して均一に混合した後、レンバチニブメシル酸塩１０．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後、０．６ｇの結晶形ＸＩの種結晶を加え、次いで２５℃で８時間撹拌し、吸引濾過により乾燥させて、９．１ｇの固体粉末を得た。収率は９１．０％、純度は９９．７６％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。<Example 8: Preparation of lenvatinib mesylate crystal form XI>
After 300 mL of ethyl acetate and 30 mL of purified water are stirred at room temperature and uniformly mixed, 10.0 g of lenvatinib mesylate is added to the mixed solvent of ethyl acetate and purified water to uniformly disperse the suspension. After that, 0.6 g of seed crystals of Form XI was added, then stirred at 25° C. for 8 hours and dried by suction filtration to obtain 9.1 g of solid powder. The yield is 91.0%, the purity is 99.76%, and the XRD data are basically consistent with those of Example 1.
〈実施例９：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル１５０ｍＬ及び精製水３ｍＬを室温で攪拌して均一に混合した後、レンバチニブメシル酸塩１０．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後、０．５ｇの結晶形ＸＩの種結晶を加え、次いで２５℃で６時間撹拌し、吸引濾過により乾燥させて、９．２ｇの固体粉末を得た。収率は９２．０％、純度は９９．７２％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。<Example 9: Preparation of lenvatinib mesylate crystal form XI>
After 150 mL of ethyl acetate and 3 mL of purified water are stirred at room temperature and uniformly mixed, 10.0 g of lenvatinib mesylate is added to the mixed solvent of ethyl acetate and purified water to uniformly disperse the suspension. After that, 0.5 g of seed crystals of Form XI was added, then stirred at 25° C. for 6 hours and dried by suction filtration to obtain 9.2 g of solid powder. The yield is 92.0%, the purity is 99.72%, and the XRD data are basically consistent with those of Example 1.
〈実施例１０：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル２５０ｍＬ及び精製水５ｍＬを室温で攪拌して均一に混合した後、レンバチニブメシル酸塩１０．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後、０．５ｇの結晶形ＸＩの種結晶を加え、次いで２５℃で１２時間撹拌し、吸引濾過により乾燥させて、９．１ｇの固体粉末を得た。収率は９１．０％、純度は９９．７３％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。Example 10 Preparation of Lenvatinib Mesylate Crystalline Form XI
After 250 mL of ethyl acetate and 5 mL of purified water are stirred at room temperature and uniformly mixed, 10.0 g of lenvatinib mesylate is added to the mixed solvent of ethyl acetate and purified water to uniformly disperse the suspension. After that, 0.5 g of seed crystals of Form XI was added, then stirred at 25° C. for 12 hours and dried by suction filtration to obtain 9.1 g of solid powder. The yield is 91.0%, the purity is 99.73%, and the XRD data are basically consistent with those of Example 1.
〈実施例１１：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル５０００ｍＬ及び精製水１５０ｍＬ室温で攪拌して均一に混合した後、レンバチニブメシル酸塩２５０．０ｇを、酢酸エチルと精製水との混合溶媒に加え、懸濁液を均一に分散させた後。１２．５０ｇの結晶形ＸＩの種結晶を加え、次いで２５℃で８時間撹拌し、吸引濾過により乾燥させて、２３２．８ｇの固体粉末を得た。収率は９３．１％、純度は９９．７８％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。Example 11 Preparation of Lenvatinib Mesylate Crystalline Form XI
After 5000 mL of ethyl acetate and 150 mL of purified water were stirred at room temperature and uniformly mixed, 250.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water to uniformly disperse the suspension. rear. 12.50 g of seed crystals of Form XI were added, then stirred at 25° C. for 8 hours and dried by suction filtration to obtain 232.8 g of solid powder. The yield is 93.1%, the purity is 99.78%, and the XRD data are basically consistent with those of Example 1.
〈実施例１２：レンバチニブメシル酸塩結晶形ＸＩの調製〉
酢酸エチル３０Ｌ及び精製水７５０ｍＬを室温で攪拌して均一に混合した後、レンバチニブメシル酸塩１．５ｋｇを、酢酸エチルと精製水との混合溶媒に加え、２５℃で１０時間攪拌し、吸引乾燥させて、１．４ｋｇの固形粉末を得た。収率は９３．３％、純度は９９．９５％であり、そのＸＲＤデータは基本的に実施例１のデータと一致している。Example 12 Preparation of Lenvatinib Mesylate Crystalline Form XI
After 30 L of ethyl acetate and 750 mL of purified water are stirred at room temperature and uniformly mixed, 1.5 kg of lenvatinib mesylate is added to the mixed solvent of ethyl acetate and purified water, and stirred at 25° C. for 10 hours, It was sucked dry to obtain 1.4 kg of solid powder. The yield is 93.3%, the purity is 99.95%, and the XRD data are basically consistent with those of Example 1.
［試験例１：レンバチニブメシル酸塩結晶形ＸＩの吸湿性試験］
実施例１で調製されたレンバチニブメシル酸塩結晶形ＸＩに対して、ＤＶＳ分析を行い、図４に示す。図４に示すように、その相対湿度０～４０％の範囲で重量損失は約０．３３％であり、これは、該結晶形が比較的安定し、相対湿度が０％に低下しても結晶水が失われないことを示している。該結晶形は、相対湿度４０～８０％の範囲での吸湿性の重量増加は約０．２５％であり、これは、該結晶形の吸湿性が非常に小さく、相対湿度が８０％に達したとしても吸湿性の重量増加は非常に小さいということを示している。[Test Example 1: Hygroscopicity Test of Lenvatinib Mesylate Crystalline Form XI]
DVS analysis was performed on lenvatinib mesylate Form XI prepared in Example 1 and is shown in FIG. As shown in FIG. 4, the weight loss is about 0.33% in the 0-40% relative humidity range, which indicates that the crystalline form is relatively stable and even when the relative humidity drops to 0%. This indicates that water of crystallization is not lost. The crystalline form has a hygroscopic weight gain of about 0.25% in the range of 40-80% relative humidity, which means that the crystalline form is very low hygroscopic and reaches 80% relative humidity. This indicates that the hygroscopic weight gain, if any, is very small.
［試験例２：レンバチニブメシル酸塩結晶形ＸＩの安定性試験］
実施例１１で調製されたレンバチニブメシル酸塩結晶形ＸＩサンプルを、それぞれ異なる貯蔵条件に置き、サンプルの結晶形及び不純物の安定性を調査した。３０日間のサンプリングを行い、提供されたＨＰＬＣ検出方法によって純度を検出し、結果を表３に示し、ＸＲＤパターンは図５に示す通りである。[Test Example 2: Stability test of lenvatinib mesylate crystal form XI]
The lenvatinib mesylate Form XI samples prepared in Example 11 were each subjected to different storage conditions to investigate the stability of the crystalline forms and impurities of the samples. A 30-day sampling was performed and the purity was detected by the provided HPLC detection method, the results are shown in Table 3 and the XRD pattern is as shown in FIG.
上記の条件下で、図５に示すように、実施例１１で調製されたレンバチニブメシル酸塩結晶形ＸＩは、０日間及び３０日間のＸＲＤパターンは基本的に同様であり、結晶形は変化していない。 Under the above conditions, as shown in FIG. 5, lenvatinib mesylate Form XI prepared in Example 11 has essentially similar XRD patterns at 0 and 30 days, and the crystalline form is not changed.
上記の条件下で、表３のデータから分かるように、実施例１１で調製されたレンバチニブメシル酸塩結晶形ＸＩは、高温６０℃、高湿度９２．５％、高湿度７５％及びビーム条件下で、純度に明らかな変化が起こってない。 Under the above conditions, as can be seen from the data in Table 3, the lenvatinib mesylate Form XI prepared in Example 11 showed high temperature of 60°C, high humidity of 92.5%, high humidity of 75% and beam Under these conditions, no appreciable change in purity occurs.
以上の説明から分かるように、実施例１１で調製されたレンバチニブメシル酸塩結晶形ＸＩは、高温、高湿度及びビーム条件下で安定性を維持することが可能であり、良好な耐高温性、高耐湿性及び耐光性を有する。 As can be seen from the above description, lenvatinib mesylate Form XI prepared in Example 11 is able to maintain stability under high temperature, high humidity and beam conditions, and has good high temperature resistance. high resistance to humidity and light.
［試験例３：レンバチニブメシル酸塩結晶形ＸＩ粉末の流動性試験］
実施例１２で調製されたレンバチニブメシル酸塩結晶形ＸＩ及び参照特許ＣＮ１００５６９７５３Ｃによって調製された結晶形Ｃに対して、粉末流動性試験を行い、試験結果は以下の表４に示す通りである。[Test Example 3: Fluidity test of lenvatinib mesylate crystal form XI powder]
A powder flowability test was performed on lenvatinib mesylate Form XI prepared in Example 12 and Form C prepared by reference patent CN100569753C and the test results are shown in Table 4 below. .
『製剤配合技術百科事典』第２版第１巻の「固体材料の流動性」の記載によると、タップ密度試験において材料がより強く圧縮されるほど、流動性は悪化し、圧縮率を用いて粉末の流動性を評価することができる。圧縮率（％）＝１００％（タップ密度－かさ密度）／タップ密度、圧縮率が大きいほど、粉末の流動性が悪くなり、粉末の均一な混合が難しくなり、従って、ダイプレス又はカプセル充填に不利であり、最終的には、調製製品の品質、含有量の均一性、硬度、崩壊及び溶出に影響を及ぼす。表４に示すように、結晶形Ｃの圧縮率は結晶形ＸＩの圧縮率よりも大幅に高い。従って、結晶形ＸＩの流動性は明らかに結晶形Ｃの流動性より優れて、後続の製剤生産プロセスを行うのに有利である。 According to the description of "Fluidity of solid materials" in "Encyclopedia of Pharmaceutical Formulation Technology", 2nd edition,
［試験例４：ラットにおけるレンバチニブメシル酸塩結晶形ＸＩの薬物動態試験］
１、試験目的
同一投与量の条件下で、ラットにレンバチニブメシル酸塩結晶形ＸＩを単回経口投与した後の血漿におけるレンバチニブ濃度レベル及びその薬物動態特性を調べる。[Test Example 4: Pharmacokinetic study of lenvatinib mesylate Crystal Form XI in rats]
1. Study purpose To investigate the lenvatinib concentration level in plasma and its pharmacokinetic properties after single oral administration of lenvatinib mesylate crystal form XI to rats under the same dosage conditions.
２、材料及び方法
２．１．試験薬：実施例１２で調製されたレンバチニブメシル酸塩結晶形ＸＩ。2. Materials and methods 2.1. Study Drug: Lenvatinib Mesylate Crystalline Form XI prepared in Example 12.
２．２．実験動物
ＳＤラット３匹、雄、体重２２０～２４０ｇ、中国成都Ｅｎｓｉｗｅｉｅｒ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ．に依頼して、中国湖南ＳＪＡ Ｌａｂｏｒａｔｏｒｙ Ａｎｉｍａｌ Ｃｏ．、Ｌｔｄ．から購入（ライセンス番号：ＳＣＸＫ（湘）２０１９－０００４）。2.2.
２．３．試験方法
コーン油を用いて試験薬を１．２５ｍｇ／ｋｇの均一懸濁液に調製した後、４ｍＬ／ｋｇの量で直ちにラットに経口投与し、且つ、投与前及び投与後１５分、３０分、１時間、２時間、３時間、４時間、５時間、６時間、７時間、８時間、及び２４時間後に、頸静脈から０．１ｍＬの血液を採取し、ＥＤＴＡ－Ｋ２チューブに入れ、３０００ｒ／ｍｉｎで１０分間遠心分離し、血漿を分離させ、－８０℃の冷凍庫に凍結保存した。2.3. Test method After preparing a uniform suspension of 1.25 mg/kg of the test drug using corn oil, it was immediately orally administered to rats in an amount of 4 mL/kg, and 15 minutes and 30 minutes before and after administration. , 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, and 24 hours later, 0.1 mL of blood was collected from the jugular vein, placed in an EDTA-K2 tube, and placed at 3000 r. /min for 10 minutes to separate the plasma and cryopreserved in a -80°C freezer.
２．４．ＬＣ／ＭＳ／ＭＳ生物学的サンプル分析：
５０μＬの血漿を５μＬの作業溶液又はブランク希釈液と混合し、内部標準を含む１５０μＬのアセトニトリル沈殿剤を加え、２分間ボルテックスし、１２０００ｒ／ｍｉｎで１０分間遠心分離し、２μＬの上清を取って２００μＬの純水：アセトニトリル（１：１）と均一に混合し、３μＬの容量でサンプルに注入し分析した。2.4. LC/MS/MS Biological Sample Analysis:
50 μL of plasma is mixed with 5 μL of working solution or blank diluent, 150 μL of acetonitrile precipitant containing internal standard is added, vortexed for 2 minutes, centrifuged at 12000 r/min for 10 minutes, and 2 μL of supernatant is removed. It was uniformly mixed with 200 μL of pure water:acetonitrile (1:1) and injected into the sample in a volume of 3 μL for analysis.
３、試験結果：
すべての採血が完了した後、各血液サンプル中の薬物濃度を個別に分析及び測定し、試験物質のパラメーター（最大血漿濃度に達するまでの時間Ｔｍａｘ、最大血漿濃度Ｃｍａｘ、ＡＵＣｌａｓｔ）を計算した。得られたパラメータに基づいて、平均値及び標準偏差を計算し、具体的な結果は表５に示す通りである。3, test results:
After all blood collection was completed, the drug concentration in each blood sample was analyzed and determined individually, and the test substance parameters (time to reach maximum plasma concentration Tmax, maximum plasma concentration Cmax, AUClast) were calculated. Based on the obtained parameters, the average value and standard deviation were calculated, and the specific results are shown in Table 5.
表５に示すように、本発明の結晶形ＸＩが最大血漿濃度に達するまでの時間は４．００±１．７３時間であり、最大血漿濃度は２２９０±２１６ｎｇ／ｍＬであり、ＡＵＣｌａｓｔは２２８５２±２８４０ｈ＊ｎｇ／ｍＬである。これは、結晶形ＸＩの動物体内でのより良い吸収を示し、薬物の生物学的利用能を向上させ、それによって薬物の治療効果を向上させるのに有利であることを示している。As shown in Table 5, the time to reach the maximum plasma concentration of crystalline Form XI of the present invention was 4.00±1.73 hours, the maximum plasma concentration was 2290±216 ng/mL, and the AUClast was 22852. ±2840 h* ng/mL. This indicates that crystalline Form XI exhibits better absorption in the animal body, which is advantageous for improving the bioavailability of the drug and thereby improving the therapeutic effect of the drug.
［試験例５：レンバチニブメシル酸塩結晶形ＸＩの溶出試験］
実施例１２で調製されたレンバチニブメシル酸塩結晶形ＸＩをカプセルにした後、９００ｍｌのｐＨ４．０媒介物を加え、３７℃（回転速度７５ｒ／分）で撹拌し、パドル法によって、１０分、１５分、２０分、３０分、４５分、６０分、９０分、１２０分に溶液を取り、ＵＶ分光光度法を用いて、２５０ｎｍの波長での吸光度を測定し、各粒子の溶出性を計算した。実験結果は以下の表６に示す通りである。[Test Example 5: Dissolution test of lenvatinib mesylate crystal form XI]
After encapsulating lenvatinib mesylate Form XI prepared in Example 12, add 900 ml of pH 4.0 vehicle, stir at 37° C. (rotation speed 75 r/min), and 10% by paddle method. Take the solution at minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes and measure the absorbance at a wavelength of 250 nm using UV spectrophotometry to determine the dissolution rate of each particle. was calculated. The experimental results are shown in Table 6 below.
上記の表のデータから分かるように、ｐＨ４．０の媒介物（該媒介物の識別度が最も高い）への結晶形ＸＩの溶出は基本的に１２０分で完了し、結晶形ＸＩの溶出性が優れ、良好な生物学的利用能を有する。 As can be seen from the data in the table above, the elution of Form XI into the medium at pH 4.0 (the medium with the highest discrimination) was essentially complete in 120 minutes, and the dissolution rate of Form XI are excellent and have good bioavailability.
当業者にとって明らかであることは、本出願の精神又は範囲から逸脱することなく、本出願の化合物及びそれらの調製方法について様々な修正及び変更を加えることができる。従って、特許請求の範囲及びその同等の実施形態の範囲内にある限り、本願の保護範囲は、本願に対する様々な修正及び変更を含む。 It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds of the present application and their methods of preparation without departing from the spirit or scope of this application. Therefore, the scope of protection of the present application includes various modifications and changes to the present application insofar as they come within the scope of the claims and their equivalent embodiments.
Claims (20)
Translated fromJapanese（２）レンバチニブメシル酸塩を工程（１）の混合溶媒に加え、
（３）工程（２）の懸濁液を均一に分散させた後、結晶形ＸＩの種結晶を一定量加え、１５～４０℃の温度で４～２４時間撹拌し、吸引濾過により乾燥させて、固体粉末、即ち、前記レンバチニブメシル酸塩結晶形ＸＩを得る、
上記の工程を含む、請求項１～３のいずれか一項に記載のレンバチニブメシル酸塩結晶形ＸＩの調製方法。(1) Ethyl acetate and purified water are uniformly mixed at room temperature by stirring at a constant volume ratio,
(2) adding lenvatinib mesylate to the mixed solvent of step (1);
(3) After uniformly dispersing the suspension of step (2), a certain amount of seed crystals of crystal form XI is added, stirred at a temperature of 15 to 40°C for 4 to 24 hours, and dried by suction filtration. to obtain a solid powder, namely said lenvatinib mesylate Form XI,
A process for preparing lenvatinib mesylate Form XI according to any one of claims 1 to 3, comprising the above steps.
（２）レンバチニブメシル酸塩を工程（１）の混合溶媒に加え、ここで、レンバチニブメシル酸塩と酢酸エチルとの質量対体積比は１ｇ：２０ｍＬであり、
（３）工程（２）の懸濁液を均一に分散させた後、結晶形ＸＩの種結晶をレンバチニブメシル酸塩供給量の５％質量分率で加え、２５℃の温度で８時間撹拌し、吸引濾過により乾燥させて、固体粉末、即ち、前記レンバチニブメシル酸塩結晶形ＸＩを得る、上記の工程を含む、請求項４に記載のレンバチニブメシル酸塩結晶形ＸＩの調製方法。(1) Ethyl acetate and purified water are stirred and mixed uniformly at room temperature, wherein the volume ratio of ethyl acetate and purified water is 100 mL:3 mL;
(2) adding lenvatinib mesylate to the mixed solvent of step (1), wherein the mass to volume ratio of lenvatinib mesylate and ethyl acetate is 1 g:20 mL;
(3) After uniformly dispersing the suspension of step (2), seed crystals of Form XI were added at a mass fraction of 5% of the amount of lenvatinib mesylate supplied, at a temperature of 25°C for 8 hours. 5. Lenvatinib mesylate Form XI according to claim 4, comprising the above steps of stirring and drying by suction filtration to obtain a solid powder, i.e., said lenvatinib mesylate Form XI. Method of preparation.
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| KR20230003036A (en) | 2023-01-05 |
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