WO2014056396A1 - 甲磺酸氟马替尼晶型及其制备方法和用途 - Google Patents
甲磺酸氟马替尼晶型及其制备方法和用途 Download PDFInfo
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- WO2014056396A1 WO2014056396A1 PCT/CN2013/083968 CN2013083968W WO2014056396A1 WO 2014056396 A1 WO2014056396 A1 WO 2014056396A1 CN 2013083968 W CN2013083968 W CN 2013083968W WO 2014056396 A1 WO2014056396 A1 WO 2014056396A1
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- crystal form
- flumatinib
- mesylate
- flumatinib mesylate
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- 239000013078 crystal Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- ZSASDYCFROUKTJ-UHFFFAOYSA-N methanesulfonic acid;4-[(4-methylpiperazin-1-yl)methyl]-n-[6-methyl-5-[(4-pyridin-3-ylpyrimidin-2-yl)amino]pyridin-3-yl]-3-(trifluoromethyl)benzamide Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=NC=2)C=C1C(F)(F)F ZSASDYCFROUKTJ-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 10
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims abstract description 9
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims abstract description 9
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 26
- 239000007787 solid Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 238000002441 X-ray diffraction Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- BJCJYEYYYGBROF-UHFFFAOYSA-N 4-[(4-methylpiperazin-1-yl)methyl]-n-[6-methyl-5-[(4-pyridin-3-ylpyrimidin-2-yl)amino]pyridin-3-yl]-3-(trifluoromethyl)benzamide Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=NC=2)C=C1C(F)(F)F BJCJYEYYYGBROF-UHFFFAOYSA-N 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 238000001228 spectrum Methods 0.000 claims 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 13
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 13
- 229940080856 gleevec Drugs 0.000 description 11
- 239000003826 tablet Substances 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 5
- 102000020233 phosphotransferase Human genes 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
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- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010056708 bcr-abl Fusion Proteins Proteins 0.000 description 2
- 102000004441 bcr-abl Fusion Proteins Human genes 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000034951 Genetic Translocation Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102000003425 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910002055 micronized silica Inorganic materials 0.000 description 1
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 description 1
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the present invention relates to a crystalline form of flumatinib mesylate and a process for the preparation thereof, and to a therapeutically effective amount of the crystalline form of the pharmaceutical composition and its use in the treatment of chronic myeloid leukemia. Background technique
- drugs for the treatment of chronic myelogenous leukemia include recombinant interferon a-2a, cytarabine, homoharringtonine and imatinib.
- Gleevec (imatinib) is the main drug for the treatment of chronic myelogenous leukemia. The mechanism of treatment is to inhibit the proliferation of cancer cells by inhibiting the activity of BCR-ABL, and also induce apoptosis of cancer cells; 95% of patients take medication After one to three months, the cancer cells decrease and the number of blood cells returns to normal.
- Gleevec (Imartini) is the first drug based on human genome research to identify target kinases and regulate signaling, and is a major breakthrough in the history of scientific research.
- WO 2006069525 discloses flomatin mesylate, the chemical name of which is 4-((4-methyl-1-piperazinyl)methyl)-N-[6-A 5-[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-3-(trifluoromethyl)-benzamide methanesulfonate, the structure is as follows Show:
- Flumazinib mesylate introduces a suitable group based on the structure of Gleevec to increase the binding of the compound to the kinase, and it is expected to increase the binding capacity to the kinase mutant.
- fammadani mesylate inhibited intracellular BCR-ABL tyrosinase activity by about 30 times stronger than Gleevec.
- flumatinib mesylate is also designed for BCR-ABL.
- the object of the present invention is to provide a crystal form of flumatinib mesylate, which is a crystal form C which has been subjected to X-ray diffraction detection using Cu-Ka radiation and having a characteristic peak of 2 ⁇
- They are 9.60, 11.12, 12.78, 13.34, 14.94, 15.24, 15.48, 17.38, 17.70, 18.74, 19.24, 19.72, 20.10, 20.52, 22.08, 23.30, 24.08, 24.52, 25.76, 27.18, 29.18 ⁇ 0.2.
- Another object of the present invention is to provide a process for the preparation of the above crystal form of flumatinib mesylate, which is produced in two ways:
- the heating temperature is any temperature between room temperature and reflux temperature, preferably 50 ⁇ 5 °C.
- the cooling crystallization temperature is from 0 to 40 ° C, preferably 25 ° C.
- the crystallization time is stirred for 5 to 60 hours, preferably at 24 hours, and the obtained solid is flomatin mesylate crystal form C.
- Another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising flomatin mesylate Form C comprising flumatin mesylate Form C and one or more pharmaceutically acceptable excipients;
- the form is selected from the group consisting of tablets, capsules, dispersing agents and suspending agents, preferably tablets and capsules; the compositions include those suitable for oral and injectable routes of administration, preferably oral routes of administration.
- Another object of the present invention is to provide a pharmaceutical composition of the above-mentioned form of Flumazinib mesylate or a pharmaceutical composition containing the above-mentioned form C of fimatatin mesylate in the preparation of a medicament for treating chronic myeloid leukemia.
- the form F of fimatatin mesylate provided by the invention has good stability and solubility, and the crystal form is easily soluble in water, and the sample of the crystal form can be dissolved in 9 ml of purified water. Research is very beneficial. DRAWINGS
- Figure 1 XRD pattern of flumatin mesylate Form C.
- Figure 2 XRD pattern of flumatin mesylate Form C formulation (tablets).
- Example 1 10 g of flumatanil, 10 ml of water and 53 ml of acetone were placed in a reaction flask, and 1.7 g of methanesulfonic acid was added under stirring, followed by heating to 50 ° C, and the solid was dissolved, and naturally stirred. After cooling to room temperature, stirring for 24 hours, solids were precipitated, filtered, and dried in vacuo to give crystal form C.
- Example 2 10 g of flumatinib mesylate was added to a mixed solvent of 12 ml of water and 120 ml of acetone, and heated to 50 ° C. The solid was completely dissolved, and naturally cooled to room temperature under stirring, stirred for 24 hours, and filtered. The crystal form C was obtained by vacuum drying, and its XRD pattern is shown in Fig. 1.
- the invention has the stability of the formulation process and the dissolution in vitro of the sample of the crystal form c.
- tablets are prepared separately.
- the preparations are as follows:
- Table 3 X-ray diffraction data for flematin mesylate crystal form C, tablets and blank excipients
Abstract
提供一种甲磺酸氟马替尼晶型C、其制备方法、药物组合物以及其在制备治疗慢性髓性白血病的药物中的用途。该晶型C具有良好的稳定性和溶解性。
Description
甲磺酸氟马替尼晶型及其制备方法和用途 技术领域
本发明涉及一种甲磺酸氟马替尼晶型及其制备方法， 以及含有治 疗有效量的该晶型药物组合物及其在治疗慢性髓性白血病中的应用。 背景技术
患有慢性髓性白血病的病人中， 有 95%以上是由于染色体易位， 产生 BCR-ABL融合蛋白， 导致高表达 ABL酪氨酸激活酶活性， 产生 大量异常白细胞。
现有技术中， 用于治疗慢性髓性白血病药物有重组干扰素 a-2a， 阿糖胞苷， 高三尖杉酯碱和伊马替尼。 格列卫 （伊马替尼） 是治疗慢 性髓性白血病的主要药物，治疗机理是通过抑制 BCR-ABL的活性从而 抑制癌细胞的增殖， 同时还诱导癌细胞凋亡； 95%的病人在服药一到三 月之后起效， 癌细胞减少， 血细胞数目回到正常值。 格列卫 （伊马替 尼） 是第一个基于人类基因组研究来确定靶点激酶和调控信号传导的 药物，是科学研究史上一个重大突破。 2002年其销售额为 6.15亿美元， 2003年销售额突破 10亿美元， 跻身于 "畅销药"行列。 但是， 近年来 发现服用格列卫的许多慢性髓性白血病患者产生了耐药性。 在多数情 况下，耐药性的产生是因为 BCR-ABL发生了变异，导致酶的结构改变， 使得格列卫不能与其结合。 许多服用该药的患者出现了耐药性， 原因 是由于 BCR-ABL融合蛋白变异， 导致了 ABL酶结构改变。 通过研究 格列卫与 ABL激酶的相互作用的晶体结构， 发现该激酶有一个格列卫 没有利用到的重要的结合亚位点。
WO 2006069525 (其中国同族专利为 CN 200580020883.1 ) 公开了 甲磺酸氟马替尼， 其化学名为 4- ( (4-甲基 -1-哌嗪基） 甲基） -N-[6-甲 基—5-[[4- (3-吡啶基) -2-嘧啶基]氨基]吡啶基 -3-]-3- (三氟甲基) -苯甲 酰胺甲磺酸盐， 结构如下式所示：
甲磺酸氟马替尼在格列卫的结构基础上引入了合适的基团来提高 化合物与激酶的结合力， 同时期望提高与激酶突变型的结合力。 通过 甲磺酸氟马替尼抗肿瘤作用机制研究发现， 甲磺酸氟马替尼抑制细胞 内 BCR-ABL酪氨酸酶活性比格列卫强约 30倍。作为格列卫的 "me too" 药物， 甲磺酸氟马替尼也是针对 BCR-ABL设计。相比较于格列卫， 甲 磺酸氟马替尼在结构上引入了合适的基团可以改善与激酶的结合力， 而且有望提高对激酶突变型的结合力。 同时在治疗慢性髓性白血病方 面， 甲磺酸氟马替尼的药效要明显高于格列卫， 因此具有更为广阔的 市场潜力。 发明内容
本发明的目的在于提供甲磺酸氟马替尼的晶型， 所述晶型为晶型 C, 该晶型经过了 X射线衍射检测， 使用的 Cu-Ka辐射， 其特征峰的 2 Θ角为 9.60， 11.12, 12.78, 13.34， 14.94， 15.24, 15.48, 17.38, 17.70, 18.74, 19.24, 19.72, 20.10, 20.52, 22.08, 23.30, 24.08, 24.52, 25.76, 27.18， 29.18 ±0.2。
本发明的另一目的在于提供上述甲磺酸氟马替尼晶型的制备方 法， 该晶型的制备方法有两种：
( 1 )将任意固态形式的氟马替尼置于水、 有机溶剂和甲磺酸组成 的混合溶剂中， 加热至固体溶清， 补加一定量有机溶剂， 之后在搅拌条 件下自然冷却， 析出固体， 过滤干燥得到晶型 c。 加热的温度为室温 至回流温度之间的任意温度， 优选于 50 ± 5 °C。 冷却析晶温度是从 0-40 °C , 优选 25 °C。 搅拌析晶时间 5-60小时， 优选于 24小时， 所得 到的固体即为甲磺酸氟马替尼晶型 C。
(2 ) 将任意固态形式的甲磺酸氟马替尼在水溶剂中加热溶解， 保
持温度加入丙酮， 然后在搅拌条件下自然冷却， 析出固体， 过滤干燥 得到晶型 c。 加热的温度为室温至回流温度之间的任意温度， 优选于 50±5°C。 冷却析晶温度是从 0-40 °C， 优选 25°C。 搅拌析晶时间 5-60 小时， 优选于 24小时， 所得到的固体即为甲磺酸氟马替尼晶型 C。
本发明的另一目的在于提供含有甲磺酸氟马替尼晶型 C的药物组 合物， 其包括甲磺酸氟马替尼晶型 C和一种或多种药用赋形剂； 其存 在形式选自片剂， 胶囊， 分散剂和混悬剂， 优选片剂和胶囊； 该组合 物包括适于口服和注射等给药途径， 优选口服给药途径。
本发明另一目的在于提供上述甲磺酸氟马替尼晶型 C或者含有上 述甲磺酸氟马替尼晶型 C的药物组合在制备治疗慢性髓性白血病药物 中的应用。
本发明所提供的甲磺酸氟马替尼晶型 C具有较好的稳定性和溶解 性， 该晶型易溶于水， lg该晶型样品可以溶解于 9ml纯化水， 这个优 点对制剂处方研究非常有利。 附图说明
图 1 : 甲磺酸氟马替尼晶型 C的 XRD图谱。
图 2: 甲磺酸氟马替尼晶型 C制剂 （片剂） 的 XRD图谱。
图 3 : 甲磺酸氟马替尼晶型 C制剂空白辅料的 XRD图谱。 具体实施方式
实施例一： 将氟马替尼 10g， 水 10ml和丙酮 53ml置于反应瓶中， 在搅拌的条件下加入甲磺酸 1.7g， 之后加热至 50°C， 固体溶解， 在搅 拌的条件下自然冷却至室温， 搅拌 24小时， 析出固体， 过滤， 真空干 燥得到晶型 C, 其 XRD图谱如图 1所示。
实施例二：将甲磺酸氟马替尼 10g加入到水 12ml和丙酮 120ml混 合溶剂中， 加热至 50°C， 固体全部溶解， 在搅拌的条件下自然冷却至 室温， 搅拌 24小时， 过滤， 真空干燥得到晶型 C, 其 XRD图谱如图 1 所示。
试验例一 稳定性试验
制备三批该晶型样品， 在温度 40°C、 湿度 75%条件下进行了 6个
月稳定考察， 结果表明该晶型非常稳定， 稳定性数据如表 1:
表 1 温度 40°C、 湿度 75%条件下的稳定性数据
将样品在温度 25 V、湿度 60%条件下进行 12个月稳定性考察， 果表明该晶型非常稳定， 稳定性数据如表 2:
表 2温度 25。C、 湿度 60%条件下的稳定性数据
试验例二 制剂工艺稳定性和制剂体外溶出度
本发明对晶型 c样品进行了制剂工艺稳定性和制剂体外溶出度测
按照制剂工艺分别制备成片剂， 制剂处方如下:
甲磺酸氟马替尼 2g
低取代羟丙纤维素 3g
磷酸氢钙 0.4g
微粉硅胶 0.3g
50%乙醇水溶液 0.8g
羧甲基淀粉钠 0.6g
硬脂酸镁 o.ig
(一） 制剂工艺稳定性试验
通过 X射线粉末衍射仪检测所制备片剂 （图谱如图 2所示） 和制 剂所用辅料混合物 （图谱如图 3所示）， 将相应的数据进行对比， 发现 在制剂过程中， 晶型没有发生变化。 具体数据如表 3所示。
表 3: 甲磺酸氟马替尼晶型 C、 片剂和空白辅料的 X射线衍射数据
(二） 片剂体外溶出度的测试
用本发明同一批次制得的晶型 C为原料制备 3批制剂样品， 分别 为制剂样品一、 制剂样品二和制剂样品三。 从每批制剂样品中随机抽
取 6片样品， 在模拟胃液环境中测定 45分钟内甲磺酸氟马替尼溶出数 据， 结果表明甲磺酸氟马替尼晶型 C样品溶出数据非常好， 达到了药 用的要求。 具体数据如表 4所示：
表 4该晶型制剂 （片剂） 体外溶出数据
样品
名称 平均值
1 2 3 4 5 6
制剂样品一 98.1% 98.3% 99.1% 97.4% 95.5% 97.9% 制剂样品二 96.6% 96.2% 95.7% 95.2% 101.5% 100.6% 97.6% 制剂样品三 92.9% 90.8% 102.6% 95.5% 95.4% 97.1% 95.7%
Claims
1、 甲磺酸氟马替尼晶型， 其特征在于， 所述晶型为晶型 c， 其
XRD图谱特征峰具有 2 Θ角 ( ± 0.2。 )： 9.60， 11.12， 13.34, 15.48， 17.70， 18.74， 19.24， 19.72， 22.08, 24.08， 24.52, 25.76， 27.18， 29.18。
2、 根据权利要求 1所述的甲磺酸氟马替尼晶型， 其 XRD图谱如 附图 1所示。
3、 一种制备根据权利要求 2所述的甲磺酸氟马替尼晶型的方法， 包括如下步骤：
①将氟马替尼与水、 有机溶剂和甲磺酸混合， 加热至一定温度使 其溶解， 形成溶液；
②加入有机溶剂， 降温至固体析出；
③过滤晶体得到甲磺酸氟马替尼晶型 C。
4、 一种制备根据权利要求 2所述的甲磺酸氟马替尼晶型的方法， 包括如下步骤：
①将甲磺酸氟马替尼的任意固体形式与水和有机溶剂混合液混 合， 加热一定温度使其溶解， 形成溶液；
②降温至固体析出；
③过滤晶体得到甲磺酸氟马替尼晶型 C。
5、 根据权利要求 3或 4任意一项所述的制备甲磺酸氟马替尼晶型 的方法， 其中所述的有机溶剂为丙酮。
6、 根据权利要求 3或 4任意一项所述的制备甲磺酸氟马替尼晶型 的方法， 其中所述的一定温度选自室温至回流温度之间的任意温度。
7、 根据权利要求 6所述的制备甲磺酸氟马替尼晶型的方法， 其中 所述的一定温度选自 50 ±5°C。
8、 一种药物组合物， 其包括根据权利要求 1或 2所述的甲酸酸氟 马替尼晶型和一种或多种药用赋形剂。
9、 根据权利要求 8所述的药物组合物， 其中所述药物组合物的存 在形式选自片剂或胶囊。
10、 根据权利要求 1或 2所述的甲磺酸氟马替尼晶型或者根据权 利要求 8或 9所述的药物组合物在制备治疗慢性髓性白血病药物中的 应用。
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| CN105777714B (zh) * | 2016-03-11 | 2018-09-07 | 江苏豪森药业集团有限公司 | 氟马替尼的精制方法 |
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