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WO2012055163A1 - Cristal de létrozole de type i et son procédé de préparation - Google Patents

Cristal de létrozole de type i et son procédé de préparation Download PDF

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Publication number
WO2012055163A1
WO2012055163A1 PCT/CN2011/001760 CN2011001760W WO2012055163A1 WO 2012055163 A1 WO2012055163 A1 WO 2012055163A1 CN 2011001760 W CN2011001760 W CN 2011001760W WO 2012055163 A1 WO2012055163 A1 WO 2012055163A1
Authority
WO
WIPO (PCT)
Prior art keywords
letrozole
crystal
type
anhydrous
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2011/001760
Other languages
English (en)
Chinese (zh)
Inventor
唐田
王彦青
马春铭
陈佳
陈学明
李勇
叶冠豪
刘碧秀
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Neptunus Pharmaceutical Co Ltd
Original Assignee
Shenzhen Neptunus Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Neptunus Pharmaceutical Co Ltd filed Critical Shenzhen Neptunus Pharmaceutical Co Ltd
Publication of WO2012055163A1 publication Critical patent/WO2012055163A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens

Definitions

  • the present invention relates to letrozole type I crystals, a process for the preparation thereof, and a pharmaceutical composition comprising letrozole type I crystals. Background technique
  • Letrozole English name Letrozole, chemical name 1-[bis(4-aminophenyl)indolyl]-1,2,4-triazole, is a new generation of aromatase inhibitor, synthetic benzyl Triazole derivatives. Letrozole reduces estrogen levels by inhibiting aromatase, thereby eliminating the stimulating effects of androgens on tumor growth. In vitro and in vivo studies have shown that letrozole can effectively inhibit the conversion of androgens to estrogen, while estrogen in postmenopausal women is mainly derived from the aromatization of androgen precursors in peripheral tissues, so it is particularly suitable for the treatment of postmenopausal Breast cancer patients.
  • letrozole has a complicated polymorphic phenomenon, and that the letrozole crystals prepared conventionally in the literature are mostly a mixture of replicating polymorphic crystals and/or amorphous powders, and thus the measured melting point. And the melting range is different.
  • the crystalline form of the drug is known to affect the solubility of the drug, biological absorption, and the biological activity of the drug. Therefore, the drug crystal form may have a significant influence on the drug activity, particularly on the oral solid preparation, including the therapeutic activity of the drug, adverse reactions, and the like. In addition, the crystalline form of the drug may also affect the formulation process of the drug, the shelf life, and the like that are closely related to the drug application.
  • the active substance in general, in pharmaceutical applications, especially when applied to pharmaceuticals in solid form, the active substance should have a defined physical form and definitive physical and chemical properties.
  • the physical form and/or physicochemical properties of the active substance are inconsistent, which may cause difficulty in formulation molding techniques of solid preparations and even liquid preparations, and may cause the final product of the preparation to be difficult to be applied to the clinic due to uneven properties. It can be seen that the stable availability of letrozole with certain physicochemical properties has important application value and theoretical significance for the preparation of its preparations, especially solid preparations. Summary of the invention
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • IR infrared spectroscopy
  • Another object of the present invention is to provide a process for the preparation of a new crystalline form of letrozole.
  • Still another object of the present invention is to provide a use of a new crystal form of letrozole in a pharmaceutical preparation, in particular, a pharmaceutical composition containing such a new crystalline form of letrozole.
  • an anhydrous organic solvent such as anhydrous isopropanol, anhydrous chloroform, a pure solvent of anhydrous acetone or a mixture thereof is used as a crystallization solvent by a method of recrystallization.
  • the crude crystal form of letrozole of the present invention can be obtained by crystallizing the crude letrozole. By measuring and analyzing the melting point of the crystal, X-ray powder diffraction, DSC, IR spectrum, etc., it was confirmed that the obtained crystal is a novel crystal of letrozole, which is called letrozole type I crystal.
  • the letrozole type I crystal of the present invention can be characterized by its X-ray powder diffraction pattern.
  • the crystal When X-ray powder diffraction is performed with a Cu radiation source, the crystal is characterized by a characteristic diffraction peak at 13.8 ⁇ 0.2, 14.06 ⁇ 0.2, 17 ⁇ 04 ⁇ 0 ⁇ 2, 21.44 ⁇ 0.2, 29.24 ⁇ 0.2 ( ⁇ ) at 2 ⁇ . , the relative intensity of these peaks ( ⁇ 0 ) All are greater than or equal to 35%.
  • the crystal may further comprise, in X-ray powder diffraction, at 16.14 ⁇ 0.2, 19.64 ⁇ 0.2, 22.10 ⁇ 0.2, 23.30 ⁇ 0.2, 25.66 ⁇ 0.2, 26.02 ⁇ 0.2, 266.96 ⁇ 0.2, 29.64.
  • Characteristic diffraction peaks of ⁇ 0.2 30.96 ⁇ 0.2, 40.20 ⁇ 0.2, 47.30 ⁇ 0,2 (A) the relative intensities of these peaks are all greater than or equal to 15% (see Figure 1).
  • the present invention also uses a differential scanning calorimetry (DSC) technique to characterize letrozole type I crystals (see figure
  • the melting point range of the letrozole type I crystal of the present invention is: 183.6 to 187.8 °C.
  • the infrared spectrum of the letrozole type I crystal of the present invention is shown in Figure 3, wherein at 2122, 1608, 1504, 1435, 1409, 1271, 1200, 1139, 1004, 955, 868, 858, 791, 678, 658, 569, 555, 548 and 494cm have strong absorption peaks.
  • the letrozole type I crystal of the present invention is an anhydrous crystal having a low hygroscopicity, and after 10 days at 25 ° C and a relative humidity of 92.5%, the Karl Fischer method has a water content of not more than 0.1%.
  • the oxazole type I anhydrous crystalline material was sealed in an aluminum foil bag and placed at a temperature of 40 ° C and a relative humidity of 75% for 6 months, and its appearance, melting point, water content and content did not change significantly.
  • the triazole type I anhydrous crystalline drug substance was sealed in an aluminum foil bag, and it was left at a temperature of 25 ° C and a relative humidity of 60% for 12 months, and its appearance, melting point, water content and content did not change significantly.
  • a process for preparing a sample of letrozole type I crystal there is provided a process for preparing a sample of letrozole type I crystal.
  • the aqueous crystallization solvent can affect the purity of the letrozole crystalline product to varying degrees, and a mixture of polymorphic crystals and/or amorphous powders appears.
  • the present invention uses recrystallized anhydrous pure organic solvent as a crystallization solvent. The method was prepared to obtain the letrozole type I crystal. Specifically, in the future, crude trazodone is dissolved in an anhydrous organic solvent, filtered, and the filtrate is concentrated under reduced pressure and dried to give a letrozole type I crystal.
  • the anhydrous organic solvent may be anhydrous isopropyl alcohol, anhydrous chloroform, a pure solvent of anhydrous acetone or a mixed solution thereof.
  • letrozole type I crystals Due to the stable crystalline morphology and clear physical and chemical properties of letrozole type I crystals, it is suitable for the preparation of tablets or other solid preparations or even liquid preparations.
  • the application range of letrozole type I crystals in the field of pharmaceutical preparations The presence of the letrozole compound in the art is consistent, and the application value expected of letrozole is ensured. Therefore, the present invention simultaneously provides the use of letrozole type I crystal in a pharmaceutical preparation, specifically Is a pharmaceutical composition comprising letrozole type I crystals, the pharmaceutical composition comprising an effective amount of letrozole type I crystals and optionally a pharmaceutically acceptable carrier and/or excipient, which can be used for therapeutic treatment Postmenopausal patients with advanced breast cancer treated with estrogen.
  • the "therapeutically effective amount” means that at this dose, the letrozole type I anhydrous crystal of the present invention can ameliorate or alleviate the symptoms of the disease, or can inhibit or block the progression of the disease.
  • the above pharmaceutical composition may be further formulated into a form for administration according to a conventional preparation method, and includes an oral or parenteral administration form, for example, a tablet, a gelatin, a powder, a granule, a lozenge, a suppository, a patch. , gelling agent.
  • Preferred formulations are in the form of tablets and capsules.
  • These compositions for administration can also be prepared as a sustained release preparation or a targeted preparation as needed.
  • the dosage forms for oral administration may be tablets and capsules, which may contain conventional excipients such as binders, including syrup, dextrin, starch syrup, gum arabic, gelatin, sorbitol, tragacanth, hydroxypropyl group a cellulose or polyvinylpyrrolidone or the like; a filler such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, mannitol, microcrystalline cellulose, sulfuric acid, or glycine; a tableting lubricant such as magnesium stearate; Disintegrating agents such as croscarmellose sodium, starch, polyvinylpyrrolidone, crospovidone, sodium hydroxyethyl starch, low-substituted sodium hydroxypropylcellulose or microcrystalline cellulose and/or pharmaceutically acceptable Wetting agents such as sodium lauryl sulfate, water, ethanol, and the like.
  • any pharmaceutically acceptable colorant can be used to color to improve
  • the letrozole type I crystal prepared by the invention has stable morphology and determined melting point and good chemical stability.
  • the form of letrozole has the properties required for preparing a solid preparation, and has good compressibility during preparation. Easy to form, the raw material cost is greatly reduced when the medicine is prepared in the industry, and the storage is convenient, the production operation is simpler, and the quality is easier to control.
  • the obtained letrozole type I anhydrous crystalline drug substance can be used to prepare the letrozole particles by a conventional formulation technique, and is further used for preparing solid preparations such as tablets and capsules.
  • a diluent such as lactose, pregelatinized starch or starch
  • a disintegrant such as corn starch, low-substituted hydroxypropyl cellulose or crospovidone
  • the auxiliary materials are uniformly mixed, and a soft material made of a binder (such as microcrystalline cellulose, gum tragacanth or gelatin or hydroxypropylmethylcellulose) is added, and the wet particles are filtered, dried, and sieved to obtain an I crystal form.
  • Anhydrous letrozole bulk drug granule The above granules are uniformly mixed with a lubricant (e.g., magnesium stearate) to compress the letrozole tablet; and the granules are filled into an empty capsule to prepare a tropazole capsule.
  • a lubricant e.g., magnesium stearate
  • the solid preparation of the modified azole was placed at 25 ° C and the relative humidity of 92.5% for 10 days, the appearance, related substances, dissolution and content did not change significantly.
  • the solid preparation of the azole was sealed in an aluminum foil bag at a temperature of 40 ° C. After being placed at a relative humidity of 75% for 6 months, there was no significant change in appearance, dissolution and content.
  • the solid preparation of the letrozole was sealed in an aluminum foil bag and left at a temperature of 25 ° C and a relative humidity of 60% for 12 months, and the appearance, related substances, dissolution and content did not change significantly.
  • Figure 1 is a powder X-ray diffraction spectrum of letrozole type I anhydrous crystals.
  • Figure 2 is a differential scanning calorimetry (DSC) spectrum of letrozole type I anhydrous crystals.
  • Figure 3 is an infrared spectrum of the letrozole type I anhydrous crystal.
  • Fig. 4 is a powder X-ray diffraction spectrum of a conventional letrozole crystal form.
  • Figure 5 is a DSC spectrum of a conventional letrozole crystal form. Detailed ways
  • Nai divergence (1.), acceptance gap (0.3 mm), color chromaticity (1.), tube pressure 40 kV, tube flow 60 mA.
  • Example 1 1-[Bis(4-cyanophenyl)methyl]-1,2,4-triazole (letrozole) control crystal form
  • Preparation of control crystal form 1- [double (4 The crude cyanophenyl)methyl]-1,2,4-triazole compound can be prepared by the method described in U.S. Patent No. 20,070,100,149: In the future, 20 g of crude trazole is added to 140 ml of dichloro Oxane was then added to 500 ml of sterol.
  • the XRD spectrum is shown in Figure 1.
  • the DSC is shown in Figure 2.
  • the infrared language is shown in Figure 3.
  • the main diffraction peaks of the XRD spectra are shown in Table 1.
  • Letrozole type I crystal is mixed with starch, lactose and dextrin by equal amount multiplication method.
  • Pre-formed HPMC solution is added to make soft material, 20 mesh sieve granules, dried at 60 ° C for 30 minutes, 18 Mesh the whole grain, add the micro-silica gel, mix well, and put it into 2# glue Yuan.
  • the purpose of developing the crystal form is mainly to solve the problem of dissolution and increase the dissolution.
  • the out-patient test showed that the prescription 1 ⁇ 2 had a dissolution rate of more than 80% in 15 minutes.
  • the prescription 3 has a dissolution rate of less than 70% in 15 minutes.
  • the indicators of prescription 1 are better than prescription 3, so the products of I crystal and control crystal form are not only different in melting point, solubility, crystal solubility, etc., the stability of the latter, dissolution of the preparation
  • the indicators of degree, compressibility, disintegration and the like were not as good as the letrozole I crystal form of the present invention.
  • a new type of letrozole type I crystal which has high purity and good stability, and is particularly suitable for preparation of a preparation; and the process for preparing the crystal is simple and practical, the amount of solvent used is small, the crystallization is complete and the yield is high.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un cristal de létrozole anhydre. La structure et les caractéristiques du cristal de létrozole anhydre sont caractérisées par diffraction des rayons X sur poudre, calorimétrie différentielle à balayage, spectre infrarouge et similaire. Le cristal a des pics de diffraction caractéristiques à un 2θ de 13,08 ± 0,2, 14,06 ± 0,2, 17,04 ± 0,2, 21,44 ± 0,2 et 29,24 ± 0,2 degrés dans un diagramme de diffraction des rayons X sur poudre. L'invention porte également sur un procédé pour la préparation du cristal de létrozole anhydre à l'aide d'un solvant organique anhydre et pur servant de solvant de cristallisation et sur l'utilisation du cristal dans une formulation pharmaceutique pour la thérapie anti-œstrogène pour le traitement de patientes ménopausées atteintes d'un cancer du sein avancé.
PCT/CN2011/001760 2010-10-25 2011-10-24 Cristal de létrozole de type i et son procédé de préparation Ceased WO2012055163A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201010521069.0 2010-10-25
CN2010105210690A CN102070541B (zh) 2010-10-25 2010-10-25 来曲唑i型结晶及其制备方法

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Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102070541B (zh) * 2010-10-25 2013-07-10 深圳海王药业有限公司 来曲唑i型结晶及其制备方法
CN103450099B (zh) * 2013-09-06 2015-03-25 杭州华东医药集团新药研究院有限公司 阿那曲唑及其一水合物的新晶型、制备和用途
CN109721557B (zh) * 2017-10-27 2025-11-18 中国医学科学院药物研究所 来曲唑晶ii型固体物质及制备方法和其药物组合物与用途
CN109721558B (zh) * 2017-10-27 2025-11-18 中国医学科学院药物研究所 来曲唑晶iii型固体物质及制备方法和其药物组合物与用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007128561A1 (fr) * 2006-05-04 2007-11-15 Synthon B.V. Formes cristallines du létrozole et leurs procédés de fabrication
WO2007144896A1 (fr) * 2006-06-13 2007-12-21 Natco Pharma Limited Procédé de préparation de létrozole
WO2008090565A1 (fr) * 2007-01-22 2008-07-31 Natco Pharma Limited Nouvelle forme polymorphe l de létrozole thermodynamiquement stable
CN102070541A (zh) * 2010-10-25 2011-05-25 深圳海王药业有限公司 来曲唑i型结晶及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007128561A1 (fr) * 2006-05-04 2007-11-15 Synthon B.V. Formes cristallines du létrozole et leurs procédés de fabrication
WO2007144896A1 (fr) * 2006-06-13 2007-12-21 Natco Pharma Limited Procédé de préparation de létrozole
WO2008090565A1 (fr) * 2007-01-22 2008-07-31 Natco Pharma Limited Nouvelle forme polymorphe l de létrozole thermodynamiquement stable
CN102070541A (zh) * 2010-10-25 2011-05-25 深圳海王药业有限公司 来曲唑i型结晶及其制备方法

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CN102070541A (zh) 2011-05-25

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