WO2016165618A1 - 一种艾德力布的无定型物及其制备方法 - Google Patents

一种艾德力布的无定型物及其制备方法 Download PDF

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WO2016165618A1
WO2016165618A1 PCT/CN2016/079152 CN2016079152W WO2016165618A1 WO 2016165618 A1 WO2016165618 A1 WO 2016165618A1 CN 2016079152 W CN2016079152 W CN 2016079152W WO 2016165618 A1 WO2016165618 A1 WO 2016165618A1
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acid
solution
alkali
solvent
amorphous material
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French (fr)
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熊志刚
资春鹏
胡涛
张席妮
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上海方楠生物科技有限公司
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Priority to EP16779593.9A priority Critical patent/EP3284747A4/en
Publication of WO2016165618A1 publication Critical patent/WO2016165618A1/zh
Priority to US15/783,207 priority patent/US10370376B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

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  • the invention relates to an amorphous material of Aidelibu and a preparation method thereof.
  • Idelalisib chemical name 5-fluoro-3-phenyl-2-[(1S)-1-(9H- ⁇ -6-ylamino)propyl]-4(3H)-quinazoline Linoleone, the structure of which is shown in formula (I):
  • Ade Libu (trade name Zydelig) is a selective phosphoinositide 3-kinase ⁇ (PI3K- ⁇ , P110- ⁇ ) inhibitor developed by Gilead Science.
  • FDA US Food and Drug Administration
  • rituximab (Rituxan) in combination with relapsed chronic lymphocytic leukemia (CLL), as a single
  • CLL chronic lymphocytic leukemia
  • the drug treats recurrent follicular B-cell non-Hodgkin's lymphoma (FL) and recurrent small lymphocytic lymphoma (SLL).
  • FL recurrent follicular B-cell non-Hodgkin's lymphoma
  • SLL small lymphocytic lymphoma
  • the FDA has accelerated approval for the latter two indications, and the patient has received at least two systemic treatments before.
  • Adlibu is the first commercially available, selective phosphoinositide 3-kinase ⁇ (PI3K- ⁇ , P110- ⁇ ) inhibitor.
  • P110- ⁇ is involved in changing the immune environment of B lymphocytes and plays a key role in the activation, proliferation, survival and migration of such tumor cells.
  • the approval of Adrienbu for the treatment of chronic lymphocytic leukemia has brought a new choice after ibrutinib. In the United States, chronic lymphocytic leukemia ranks second in adult leukemia patients, with more than 15,000 new patients expected in 2014.
  • U.S. Patent No. 8,865,730 discloses various crystal forms and solvates of Adelibu, including Form I, Form II, Form III (solvates of water and isopropanol), Form IV (N, N-dimethyl Formamide solvate), Form V (solvate of dimethyl sulfoxide), Form VII (solvate of water and ethanol), and the like.
  • the crystal form of Aidelibu tablets is a mixed crystal form of Form I and Form II.
  • the dosage of the drug is 100 mg and 150 mg. As an antitumor drug, the dosage of the drug is relatively large.
  • the other four crystal forms are solvates and are not suitable for medicinal use.
  • the solid form of the drug directly affects the solubility of the drug substance, the dissolution rate of the drug, and the bioavailability.
  • the crystalline state In addition to the crystalline state, there is an amorphous state.
  • the amorphous state of the drug as a special form of solid matter, has important applications in the preparation of drugs.
  • the existing research results show that the amorphous form of many drugs has good stability and can be used for the development of general solid pharmaceutical preparations.
  • the object of the present invention is to provide an amorphous material of Aidelibu and a preparation method thereof, which is a new solid form of Aidelibu, which increases the solubility of Aidelibu and is more beneficial to improve. Bioavailability of pharmaceutical preparations.
  • An amorphous material of Aidelibu which irradiates the amorphous substance with Cu-K ⁇ , and has no sharp diffraction peak in the X-ray powder diffraction spectrum expressed by degree 2 ⁇ .
  • the X-ray powder diffraction spectrum has two broad peaks between 2.0 and 50.0, as shown in FIG.
  • the invention provides a preparation method of an amorphous material of Aideli cloth, comprising the following steps:
  • step 2) The solution of the step 1) is added to the solvent II at a temperature of -80 to 100 ° C to form a suspension in which the solvent I and the solvent II are different, and the volume ratio of the solution to the solvent II is 1:1 to 200. ;
  • the solvent I is selected from at least one of an ether having 8 or less carbon atoms, a halogenated hydrocarbon, an amide, a sulfone or a sulfoxide, and the solvent II is selected from the group consisting of hydrocarbons having 8 or less carbon atoms and aromatic hydrocarbons. At least one of the classes or water.
  • the invention provides a preparation method of another amorphous substance of Aideli cloth, comprising:
  • step 2) adding the acidic solution of step 1) to an aqueous alkali solution, adjusting the pH to not less than 10, and the temperature is -50 to 100 ° C to form a suspension, and the volume ratio of the acidic solution to the aqueous solution of the alkali is 1:1 to 100.
  • the molar ratio of the alkali to the acid in the aqueous solution of the alkali is 0.3 to 10:1;
  • the aqueous solution of the acid or the aqueous solution of the alkali contains an organic solvent selected from at least one of water-miscible alcohols, ethers, ketones or nitriles containing 8 or less carbon atoms.
  • an organic solvent selected from at least one of water-miscible alcohols, ethers, ketones or nitriles containing 8 or less carbon atoms.
  • the acid in the aqueous solution of the acid is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, alkylsulfonic acid, arylsulfonic acid, nitric acid, phosphoric acid or trifluoroacetic acid, and the alkali in the aqueous solution of the alkali is selected from the base.
  • the alkali in the aqueous solution of the alkali is selected from the base.
  • the amorphous substance of Aidelibu provided by the invention is a new solid form of Aidelibu, and the energy of the intermolecular interaction is reduced due to the orderly and periodic arrangement of the crystalline substance molecules, and the energy is low.
  • the molecules in the solid matter in the stereotyped state have higher energy than the molecules in the crystalline solid matter, and are easily dispersed, which is favorable for increasing the solubility.
  • the Aideli cloth substance in the amorphous state of the invention has high dispersibility, and the amorphous state can be disintegrated after being made into a solid preparation, so that the dispersion degree of the drug particles is better, the dispersion speed is faster, and the dispersion is faster. Absorption of the drug.
  • the molecules of the amorphous drug are at a higher level than the crystalline material. In the disordered state, the surface free energy of the substance is larger. Therefore, the solubility of the drug of the Adeili cloth is significantly increased, which is more conducive to the absorption of the drug by the body, so that the drug can better exert the therapeutic effect of the clinical disease.
  • the amorphous substance of the Aideli cloth prepared by the invention has a significantly increased solubility, and is more favorable for improving the bioavailability of the drug, so that the drug can better exert the therapeutic effect of the clinical disease, and the amorphous substance is under the accelerated test condition. (Temperature 40 ° C ⁇ 2 ° C, humidity 75% ⁇ 5%), can maintain good physical stability and chemical stability, therefore, the present invention will have broad application prospects.
  • the preparation method of the Aideli cloth amorphous substance of the invention is simple in operation and easy to realize.
  • Fig. 1 is an X-ray powder diffraction pattern of an amorphous material of Aideli cloth according to Example 1 of the present invention.
  • Fig. 2 is an X-ray powder diffraction pattern of an amorphous material of Aideli cloth according to Example 2 of the present invention.
  • Fig. 3 is an X-ray powder diffraction pattern of an amorphous material of Aideli cloth according to Example 4 of the present invention.
  • the X-ray powder diffraction pattern of the present invention was collected on a Ultima IV X-ray diffractometer.
  • the method parameters of the X-ray powder diffraction according to the present invention are as follows:
  • Scan range: from 2.0 to 60.0 degrees
  • Adeli cloth (30 mg) was suspended in a 1 mol/L aqueous hydrochloric acid solution (300 ⁇ l), and the solution was dissolved by stirring at room temperature. The above solution was added to a 1 mol/L aqueous sodium hydroxide solution (600 ⁇ l) heated to 80 ° C, and a white solid was precipitated under stirring, filtered and dried to give a solid 22 mg, which was an amorphous material of Adelphi. There is no sharp diffraction peak in the X-ray powder diffraction spectrum expressed by degree 2 ⁇ in the X-ray powder diffraction pattern, and there are two broad peaks at a degree 2 ⁇ of 2.0 to 50.0.
  • Adeli cloth (30 mg) was suspended in a mixture of 1 mol/liter aqueous hydrochloric acid (200 ⁇ L) and methanol (100 ⁇ L), and the mixture was stirred at room temperature.
  • the above solution was added to a mixture of 2 mol/liter sodium hydroxide aqueous solution (300 ⁇ L) and methanol (300 ⁇ l) cooled to -50 ° C, and a white solid was precipitated with stirring, filtered, and dried to give a solid 22 mg.
  • the amorphous substance of Aidelibu which has no sharp diffraction peak in the X-ray powder diffraction spectrum expressed by degree 2 ⁇ in the X-ray powder diffraction pattern, and has two widths at a degree of 2 ⁇ of 2.0 to 50.0. peak.
  • Test article amorphous material of Aidelibu, prepared according to the method of Example 1; Form I, prepared according to the method of Example 1 of US Pat. No. 8,858,730.
  • the configuration of the reference solution accurately weigh about 25 mg of Form I on a 25 ml volumetric flask, add the diluent (acetonitrile: water 1:1) to dissolve and volume, the concentration of the reference is about 1 mg/ml.
  • Determination of apparent solubility Weigh a certain amount of the test sample into a 1.8 ml cryotube and add Specify 1 ml of the pH dilution and seal tightly. The amount of the test sample to be added must be much larger than the amount of the test sample to form a saturated solution at the pH value, and the amount of the test sample to be added is shown in Table 1. Three parts of the above-mentioned sustained release liquid containing the test sample were prepared in parallel at each pH value.
  • the above-mentioned cryotube containing the test solution was shaken in a water bath at 37 ° C ⁇ 0.5 ° C for 12 hours, then allowed to stand in an oven at 37 ° C for 2 hours, and the supernatant was filtered through a 0.45 ⁇ m microporous membrane.
  • the concentration of the test solution is calculated by an external standard method, and the concentration is multiplied by the dilution factor 2 to obtain the test solution at the pH value.
  • Saturated solubility is the average of the results of three parallel test samples. See Table 2 for the experimental results.
  • Liquid A Take 16.6 ml of phosphoric acid, and add water to 100 ml to shake.
  • Liquid B Take 71.63 g of disodium hydrogen phosphate, and add water to dissolve into 1000 ml. 72.5 ml of the above-mentioned liquid A and 27.5 ml of the liquid B were mixed and shaken to obtain.
  • Phthalate buffer (pH 5.6) Take 10 g of potassium hydrogen phthalate, add 900 ml of water, stir to dissolve, use sodium hydroxide test solution (use necessary if necessary) Hydrochloric acid) adjust the pH to 5.6, dilute with water to 1000ml, mix well, that is.
  • Example 9 Influencing factors test of Adeili cloth amorphous substance
  • Detection method The relevant substances were detected by HPLC method, and the crystal form was detected by X-powder diffraction pattern, and the test results are shown in Table 3.
  • Detection method The relevant substances were detected by HPLC method, and the crystal form was detected by X-powder diffraction pattern, and the test results are shown in Table 4.
  • the solubility of the amorphous substance prepared by the present invention is significantly increased, which is more conducive to improving the bioavailability of the drug, so that the drug can better exert the therapeutic effect of the clinical disease, and the amorphous substance is accelerating. Under the test conditions (40 ⁇ 2 ° C, humidity 75% ⁇ 5%), good physical and chemical stability can be maintained.

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Abstract

本发明公开了一种艾德力布的无定型物及其制备方法，使用Cu-Kα辐射，以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰。本发明还提供了该艾德力布无定型物的制备方法，该方法操作简单，易于实现。本发明所述艾德力布的无定型物大大增加了艾德力布的溶解性，更有利于提高药物制剂的生物利用度，与现有晶型艾德力布相比，其溶解度明显增加，更有利于机体对药物的吸收，使药物能够更好地发挥临床疾病治疗作用，且该无定型物在加速试验条件下，能保持良好的物理稳定性和化学稳定性。

Description

一种艾德力布的无定型物及其制备方法 技术领域
本发明涉及一种艾德力布的无定型物及其制备方法。
背景技术
艾德力布(Idelalisib)，化学名为5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮，其结构如式(I)所示：
Figure PCTCN2016079152-appb-000001
艾德力布(商品名为Zydelig)由美国吉利德公司(Gilead Science)研制开发的选择性的磷酸肌醇3-激酶δ(PI3K-δ，P110-δ)抑制剂。2014年7月23日，美国食品药品监管局(FDA)批准了艾德力布的三个适应症：和利妥昔单抗(Rituxan)联合治疗复发的慢性淋巴细胞白血病(CLL)、作为单药治疗复发性滤泡B细胞非霍奇金淋巴瘤(FL)和复发性小淋巴细胞淋巴瘤(SLL)。FDA对后两个适应症是加速批准，且患者之前都至少接受过两次全身治疗。
艾德力布是首个上市的口服的、选择性的磷酸肌醇3-激酶δ(PI3K-δ，P110-δ)抑制剂。P110-δ参与改变B淋巴细胞的免疫环境，对这类肿瘤细胞的活化、增殖、生存和迁移起着关键作用。艾德力布的获批上市，为慢性淋巴细胞白血病的治疗在依鲁替尼之后又带来一个新的选择。在美国，慢性淋巴细胞白血病在成人白血病患者中人数排第二，预计2014年会增添超过15000名新患者。包括艾德力布和依鲁替尼在内的慢性淋巴细胞白血病新药研发，有望把慢性淋巴细胞白血病从死刑判决演变成一种可控制 的慢性疾病。当然，相应地慢性淋巴细胞白血病市场也逐渐扩大，彭博社分析师认为慢性淋巴细胞白血病市场不久将攀升到90亿美元。
美国专利US8865730报道了艾德力布的多种晶型和溶剂合物，包括Form I、Form II、Form III(水和异丙醇的溶剂合物)、Form IV(N,N-二甲基甲酰胺溶剂合物)、Form V(二甲基亚砜的溶剂合物)和Form VII(水和乙醇的溶剂合物)等。艾德力布片剂上市的晶型为Form I和Form II的混和晶型，该药物的剂量为100毫克和150毫克，作为抗肿瘤药物来说，该药物的剂量是比较大的，该专利中其他四种晶型为溶剂合物，不适合药用。
药物的固体形态直接影响原料药的溶解度、制剂的溶出度和生物利用度，为了提高药物的生物利用度，降低用量、降低毒副作用，有必要开发药物的新的固体形态，药物的固体形态除晶态外，还有无定型状态。
药物的无定型状态作为固体物质的一种特殊形态，在药物制备中有着重要的用途。已有的研究结果证明，许多药物的无定型态具有良好的稳定性，可以用于一般固体药物制剂的开发。
此外，由于药物存在无定型多态现象，而每种无定型态固体物质间的稳定性各不相同，所以，寻找－种稳定性好的无定型态物质，亦是开发固体药物优势晶型的途径之一。
发明内容
本发明的目的在于提供一种艾德力布的无定型物及其制备方法，该无定型物为艾德力布的新的固体形式，增加了艾德力布的溶解性，更有利于提高药物制剂的生物利用度。
为了达到上述目的，本发明提供的技术方案如下：
一种艾德力布的无定型物，使用Cu-Kα辐射该无定型物，以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰。
优选地，所述X-射线粉末衍射光谱在2.0～50.0之间有两个宽峰，如图1所示。
本发明提供一种艾德力布的无定型物的制备方法，包括如下步骤：
1)将5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮溶于溶剂I中，形成浓度为0.01～1克/毫升的溶液；
2)将步骤1)的溶液加入溶剂II中，温度为-80～100℃，形成悬浊液，其中，溶剂I和溶剂II不同，所述溶液和溶剂II的体积比为1:1～200；
3)将步骤2)中形成的悬浊液过滤，干燥滤饼，得到5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮的无定型物。
优选地，所述溶剂I选自含8个以下碳原子的醚类、卤代烃、酰胺、砜或亚砜中的至少一种，溶剂II选自含8个以下碳原子的烃类、芳烃类或水中的至少一种。
本发明提供另一种艾德力布的无定型物的制备方法，包括：
1)将5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮溶于酸的水溶液中，形成浓度为0.01～1克/毫升的酸性溶液，其中，所述酸的水溶液中酸与5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮的摩尔比为1～20:1；
2)将步骤1)的酸性溶液加入碱的水溶液，调节pH值不低于10，温度为-50～100℃，形成悬浊液，酸性溶液与碱的水溶液的体积比为1:1～100；其中，所述碱的水溶液中碱与酸的水溶液中酸的摩尔比为0.3～10:1；
3)过滤步骤2)中形成的悬浊液，干燥滤饼，得到5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮的无定型物。
进一步，所述酸的水溶液或碱的水溶液中含有有机溶剂，所述有机溶剂选自与水混溶的含8个及以下碳原子的醇类、醚类、酮类或腈类溶剂中的至少一种。
优选地，所述酸的水溶液中酸选自盐酸、硫酸、烷基磺酸、芳基磺酸、硝酸、磷酸或三氟乙酸中的至少一种，所述的碱的水溶液中碱选自碱金属氢氧化物、碱金属碳酸盐、碱金属磷酸氢盐或碱金属磷酸盐中的至少一种。
本发明所提供艾德力布的无定型物为艾德力布的新固体形式，由于晶态物质分子的有序和周期性排列，降低了分子间相互作用的能量，能量较低，而无定型态下的固体物质中的分子较晶态固体物质中的分子有更高的能量，容易分散，利于增加溶解度。
本发明的无定型状态的艾德力布物质具有高度分散性，这种无定型态在制成固体制剂后，经过崩解可使药物粒子的分散程度更好，分散速度更快，有利于药物的吸收。同时，与晶态物质相比，无定型态药物的分子处于高度 无序状态，物质的表面自由能更大，因此，艾德力布无定型态药物的溶解度明显增加，更有利于机体对药物的吸收，使药物能够更好地发挥临床疾病治疗作用。
本发明的有益效果：
本发明制备得到的艾德力布的无定型物，其溶解度明显增加，更有利于提高药物的生物利用度，使药物能够更好地发挥临床疾病治疗作用，该无定型物在加速试验条件下(温度40℃±2℃，湿度75％±5％)，能保持良好的物理稳定性和化学稳定性，因此，本发明将会有广阔的应用前景。
本发明艾德力布无定型物的制备方法操作简单，容易实现。
附图说明
图1为本发明实施例1的艾德力布的无定型物的X-射线粉末衍射图。
图2为本发明实施例2的艾德力布的无定型物的X-射线粉末衍射图。
图3为本发明实施例4的艾德力布的无定型物的X-射线粉末衍射图。
具体实施方式
以下以具体实施例是为了更详尽地说明本发明的效果，但本发明的保护范围不受以下实施例的限制。
本发明所述的X-射线粉末衍射图在Ultima IV X-射线衍射仪上采集。本发明所述的X-射线粉末衍射的方法参数如下：
X-射线粉末参数：Cu-Kα
Kα
Figure PCTCN2016079152-appb-000002
：1.5418
电压：40千伏
电流：40毫安
发散狭缝：自动
扫描模式：连续
扫描范围：自2.0至60.0度
取样步长：0.0200度
扫描速率：60度/分钟
实施例1：
将艾德力布(50毫克)悬浮于四氢呋喃(750微升)，室温下搅拌溶清。将上述溶液加入到冷却到-25℃的正庚烷(10毫升)中，搅拌下析出白色固体，过滤，干燥，得到固体45毫克，其X-射线粉末衍射图如图1所示。由图1可知，以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰，在度2θ为2.0～50.0之间有两个宽峰。
实施例2：
将艾德力布(50毫克)悬浮于二氯甲烷(750微升)，室温下搅拌溶清。将上述溶液加入到冷却到-80℃的正庚烷(10毫升)中，搅拌下析出白色固体，过滤，干燥，得到固体47毫克，即艾德力布的无定型物，其X-射线粉末衍射图如图2所示。由图2可知，以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰，在度2θ为2.0～50.0之间有两个宽峰。
实施例3：
将艾德力布(30毫克)悬浮于N,N-二甲基甲酰胺(90微升)，室温下搅拌溶清。将上述溶液加入到加热至80℃的水(450微升)中，搅拌下析出白色固体，过滤，干燥，得到固体27毫克，即艾德力布的无定型物，其X-射线粉末衍射图中以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰，在度2θ为2.0～50.0之间有两个宽峰。
实施例4：
将艾德力布(30毫克)悬浮于甲醇(300微升)，室温下搅拌溶清。将上述溶液加入到水(1500微升)中，搅拌下析出白色固体，过滤，干燥，得到固体23毫克，即艾德力布的无定型物，其X-射线粉末衍射图如图3所示。由图3可知，以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰，在度2θ为2.0～50.0之间有两个宽峰。
实施例5：
将艾德力布(30毫克)悬浮于1摩尔/升的盐酸水溶液(300微升)， 室温下搅拌溶清。将上述溶液加入到1摩尔/升的氢氧化钠水溶液(600微升)中，搅拌下析出白色固体，过滤，干燥，得到固体24毫克，即艾德力布的无定型物，其X-射线粉末衍射图中以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰，在度2θ为2.0～50.0之间有两个宽峰。
实施例6：
将艾德力布(30毫克)悬浮于1摩尔/升的盐酸水溶液(300微升)，室温下搅拌溶清。将上述溶液加入到加热至80℃的1摩尔/升的氢氧化钠水溶液(600微升)中，搅拌下析出白色固体，过滤，干燥，得到固体22毫克，即艾德力布的无定型物，其X-射线粉末衍射图中以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰，在度2θ为2.0～50.0之间有两个宽峰。
实施例7：
将艾德力布(30毫克)悬浮于1摩尔/升的盐酸水溶液(200微升)和甲醇(100微升)的混合物中，室温下搅拌溶清。将上述溶液加入到冷却至-50℃的2摩尔/升的氢氧化钠水溶液(300微升)和甲醇(300微升)的混合物中，搅拌下析出白色固体，过滤，干燥，得到固体22毫克，即艾德力布的无定型物，其X-射线粉末衍射图中以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰，在度2θ为2.0～50.0之间有两个宽峰。
实施例8：艾德力布无定型物和艾德力布晶型物(Form I)的表观溶解性的比较
供试品：艾德力布的无定型物，根据实施例1的方法制备得到；艾德力布晶型物(Form I)，根据美国专利US 8865730的实施例1的方法制备得到。
对照品溶液的配置：精密称取艾德力布晶型物(Form I)约25毫克于25毫升容量瓶中，加入稀释液(乙腈：水1:1)溶解并定容，对照品浓度约1mg/ml。
表观溶解度的测定：称取一定量供试品于1.8毫升的冷冻管中，加入 指定pH值稀释液1毫升，密封盖紧。加入的供试样品量一定要远大于使该供试品在该pH值下形成饱和溶液的量，供试品的加入量见表1。每个pH值下平行制备三份上述含供试品的缓释液。将上述含有供试品溶液的冷冻管放在37℃±0.5℃的水浴中震荡12小时，然后在37℃烘箱中静置2小时，取上清液用0.45微米的微孔滤膜过滤。精密量取200微升续滤液加到已经装有200微升乙腈的液相进样瓶中，摇匀，即得供试品溶液。精密吸取2微升供试品溶液HPLC进样分析，记录供试品溶液主峰峰面积。同法进对照品溶液，记录对照品溶液主峰峰面积。根据供试品溶液主峰面积、对照品溶液主峰面积、对照品溶液浓度，通过外标法计算出供试品溶液浓度，将该浓度乘以稀释倍数2即得该pH值下供试品溶液的饱和溶解度。饱和溶解度最终结果取三个平行供试品测定结果的平均值，实验结果参见表2。
由表2可知，在各个pH值下，本发明制备的艾德力布无定型物的表观溶解度明显高于晶型物(Form I)的表观溶解度。
各种pH值稀释液的配置：
(1)pH＝1.0的稀释液：9ml浓盐酸加水稀释至1000ml。
(2)pH＝2.0的稀释液：甲液：取磷酸16.6ml，加水至100ml摇匀。乙液：取磷酸氢二钠71.63g，加水使溶解成1000ml。取上述甲液72.5ml与乙液27.5ml混合，摇匀，即得。
(3)pH＝3.0的稀释液：取冰醋酸50ml，加水800ml混合后，用氢氧化锂调节pH值至3.0，再加水稀释至1000ml，即得。
(4)pH＝4.5的稀释液：取醋酸铵7.7g，加水50ml溶解后，加冰醋酸6ml与适量的水使成100ml，即得。
(5)pH＝5.6的稀释液：邻苯二甲酸盐缓冲液(pH5.6)取邻苯二甲酸氢钾10g，加水900ml，搅拌使溶解，用氢氧化钠试液(必要时用稀盐酸)调节pH值至5.6，加水稀释至1000ml，混匀，即得。
(6)pH＝6.8的稀释液：取0.2mol/L磷酸二氢钾溶液250ml，加0.2mol/L氢氧化钠溶液118ml，用水稀释至1000ml，摇匀，即得。
(7)pH＝7.4的稀释液：取磷酸二氢钾1.36g，加0.lmol/L氢氧化钠溶液79ml，用水稀释至200ml，即得。
表1
Figure PCTCN2016079152-appb-000003
表2
Figure PCTCN2016079152-appb-000004
实施例9：艾德力布无定型物的影响因素试验
材料：实施例1制备的艾德力布无定型物。
实验条件：分别在温度40℃±2℃、温度60℃±2℃、湿度75％±5％、湿度90％±5％条件下，放置0～10天。
检测方法：有关物质用HPLC法检测，晶型用X-粉末衍射图检测，检测结果参见表3。
由表3可知，艾德力布无定型物在高温、高湿条件下，放置10天，有关物质无显著改变，无艾德力布结晶析出。
表3
Figure PCTCN2016079152-appb-000005
实施例10：艾德力布无定型物的加速稳定性试验
材料：实施例1制备的艾德力布无定型物。
实验条件：温度40℃±2℃，湿度75％±5％。
检测方法：有关物质用HPLC法检测，晶型用X-粉末衍射图检测，检测结果参见表4。
由表4可知：艾德力布无定型物在加速试验条件下，放置6个月，有关物质无显著改变，无艾德力布结晶析出。
表4
Figure PCTCN2016079152-appb-000006
综上所知，本发明制备的艾德力布的无定型物的溶解度明显增加，更有利于提高药物的生物利用度，使药物能够更好地发挥临床疾病治疗作用，该无定型物在加速试验条件下(40±2℃，湿度75％±5％)，能保持良好的物理稳定性和化学稳定性。

Claims (7)

  1. 一种艾德力布的无定型物，其特征在于，使用Cu-Kα辐射，以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰。
  2. 根据权利要求1所述的艾德力布的无定型物，其特征在于：所述X-射线粉末衍射光谱，在度2θ为2.0～50.0之间有两个宽峰。
  3. 一种如权利要求1或2所述艾德力布的无定型物的制备方法，其特征在于，包括如下步骤：
    1)将5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮溶于溶剂I中，形成浓度为0.01～1克/毫升的溶液；
    2)将步骤1)得到的溶液加入溶剂II中，温度为-80～100℃，形成悬浊液，其中，溶剂I和溶剂II不同，所述步骤1)得到的溶液和溶剂II的体积比为1:1～200；
    3)将步骤2)形成的悬浊液过滤，干燥滤饼，得到5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮的无定型物；其中，所述溶剂I选自含8个以下碳原子的醚类、卤代烃、酰胺、砜或亚砜中的至少一种；溶剂II选自含8个以下碳原子的烃类、芳烃类或水中的至少一种。
  4. 一种艾德力布的无定型物的制备方法，其特征在于，包括：
    1)将5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮溶于酸的水溶液中，形成浓度为0.01～1克/毫升的酸性溶液；其中，所述酸的水溶液中酸与5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮的摩尔比为1～20:1；
    2)将步骤1)得到的酸性溶液加入碱的水溶液，调节pH值不低于10，温度为-50～100℃，形成悬浊液，所述酸性溶液与碱的水溶液的体积比为1:1～100；其中，所述碱的水溶液中碱与酸的水溶液中酸的摩尔比为0.3～10:1；
    3)过滤步骤2)形成的悬浊液，干燥滤饼，得到5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮的无定型物。
  5. 根据权利要求4所述艾德力布的无定型物的制备方法，其特征在于，所述酸的水溶液或碱的水溶液中含有有机溶剂，所述有机溶剂选自与 水混溶的含8个及以下碳原子的醇类、醚类、酮类或腈类溶剂中的至少一种。
  6. 根据权利要求4或5所述艾德力布的无定型物的制备方法，其特征在于，所述酸的水溶液中的酸选自盐酸、硫酸、烷基磺酸、芳基磺酸、硝酸、磷酸或三氟乙酸中的至少一种。
  7. 根据权利要求4或5所述艾德力布的无定型物的制备方法，其特征在于，所述碱的水溶液中的碱选自碱金属氢氧化物、碱金属碳酸盐、碱金属磷酸氢盐或碱金属磷酸盐中的至少一种。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110526872A (zh) * 2019-07-24 2019-12-03 瑞普（天津）生物药业有限公司 一种磺胺嘧啶钠晶型及其制备方法

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180064714A1 (en) * 2015-03-13 2018-03-08 Mylan Laboratories Ltd Process for the Preparation of Amorphous Idelalisib and its Premix
CN108033961A (zh) 2015-04-15 2018-05-15 上海方楠生物科技有限公司 一种艾德力布的无定型物及其制备方法
CN106565716B (zh) * 2015-10-10 2021-06-15 上海创诺制药有限公司 一种Idelalisib晶型A及其制备方法
WO2017191608A1 (en) * 2016-05-05 2017-11-09 Laurus Labs Limited Novel process for preparation of idelalisib
WO2019178596A1 (en) 2018-03-16 2019-09-19 Johnson Matthey Public Limited Company Pyridine or n,n-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101031569A (zh) * 2004-05-13 2007-09-05 艾科斯有限公司 作为人磷脂酰肌醇3－激酶δ抑制剂的喹唑啉酮
CN104130261A (zh) * 2014-08-04 2014-11-05 山东康美乐医药科技有限公司 艾德利布的合成方法
CN104262344A (zh) * 2014-08-22 2015-01-07 苏州明锐医药科技有限公司 艾德拉尼的制备方法
CN104334560A (zh) * 2012-03-05 2015-02-04 吉利德卡利斯托加有限责任公司 (s)-2-(1-(9h-嘌呤-6-基氨基)丙基)-5-氟-3-苯基喹唑啉-4(3h)-酮的多晶型物
WO2015092810A2 (en) * 2013-11-20 2015-06-25 Cadila Healthcare Limited Amorphous form of idelalisib
CN104892612A (zh) * 2015-04-15 2015-09-09 上海方楠生物科技有限公司 一种艾德力布的无定型物及其制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2612826A1 (de) 2012-01-04 2013-07-10 RUDOLF WILD GmbH & CO. KG Folienbeutel
WO2015018522A1 (en) * 2013-08-06 2015-02-12 Oncoethix Sa Bet-bromodomain inhibitor shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (dlbcl)
WO2016097314A1 (en) * 2014-12-19 2016-06-23 Sandoz Ag Amorphous and crystalline forms of idelalisib and process for forming the same
US20170260186A1 (en) * 2016-03-09 2017-09-14 Scinopharm Taiwan, Ltd. Process of preparing amorphous form of idelalisib
WO2017175184A1 (en) * 2016-04-07 2017-10-12 Laurus Labs Limited Process for preparation of amorphous form of idelalisib

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101031569A (zh) * 2004-05-13 2007-09-05 艾科斯有限公司 作为人磷脂酰肌醇3－激酶δ抑制剂的喹唑啉酮
CN104334560A (zh) * 2012-03-05 2015-02-04 吉利德卡利斯托加有限责任公司 (s)-2-(1-(9h-嘌呤-6-基氨基)丙基)-5-氟-3-苯基喹唑啉-4(3h)-酮的多晶型物
WO2015092810A2 (en) * 2013-11-20 2015-06-25 Cadila Healthcare Limited Amorphous form of idelalisib
CN104130261A (zh) * 2014-08-04 2014-11-05 山东康美乐医药科技有限公司 艾德利布的合成方法
CN104262344A (zh) * 2014-08-22 2015-01-07 苏州明锐医药科技有限公司 艾德拉尼的制备方法
CN104892612A (zh) * 2015-04-15 2015-09-09 上海方楠生物科技有限公司 一种艾德力布的无定型物及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3284747A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110526872A (zh) * 2019-07-24 2019-12-03 瑞普（天津）生物药业有限公司 一种磺胺嘧啶钠晶型及其制备方法
CN110526872B (zh) * 2019-07-24 2023-04-07 瑞普（天津）生物药业有限公司 一种磺胺嘧啶钠晶型及其制备方法

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