CN116514776A - Crystal form of TRC-253 hydrochloride, preparation method and application thereof - Google Patents

Crystal form of TRC-253 hydrochloride, preparation method and application thereof Download PDF

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CN116514776A
CN116514776A CN202310063236.9A CN202310063236A CN116514776A CN 116514776 A CN116514776 A CN 116514776A CN 202310063236 A CN202310063236 A CN 202310063236A CN 116514776 A CN116514776 A CN 116514776A
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trc
hydrochloride
preparation
solvent
crystal form
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盛晓霞
盛晓红
吕康乐
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Hangzhou Lingye Pharmaceutical Technology Co ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P5/28—Antiandrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a crystal form 1 and a crystal form 2 of TRC-253 hydrochloride, and a preparation method and application thereof. The crystal form provided by the invention has better physicochemical properties, such as good crystal form stability, low hygroscopicity, good solubility, good compressibility, good tablet stability and the like, has better drug properties, and has important value for optimizing and further developing medicines.

Description

Crystal form of TRC-253 hydrochloride, preparation method and application thereof
Technical Field
The invention relates to the field of medicine synthesis, in particular to the technical field of crystals, and in particular relates to a crystal form of TRC-253 hydrochloride, a preparation method and application thereof.
Background
AR (androgen receptor) antagonists or antiandrogens are therapeutic agents by inhibiting the androgen receptor and blocking the androgens from exerting their corresponding biological activity. AR antagonists can be classified into both steroids and non-steroids based on the differences in chemical structure.
TRC-253, also known as JNJ-63576253, a non-steroidal AR antagonist, discovered by Janssen, post-authorization TRACON Pharmaceuticals, developed globally under the chemical name 5- [8-oxo-5- (6-pirocin-4-yl) -6-sulfanyl-5, 7-diazaspiro [3.4] octaspiro-7-yl ] -3- (trifluormethyl) pyridine-2-carborile, the structural formula of which is disclosed in CN108473471A, and the hydrochloride salt of which is disclosed as formula (I):
at present, no crystalline form of TRC-253 hydrochloride has been found to be disclosed, and further investigation of solid state forms suitable for preparation in the form of a formulation is still required.
The information in the background section is only for the purpose of illustrating the general background of the invention and is not to be construed as an admission or any form of suggestion that such information forms the prior art that is well known to those of ordinary skill in the art.
Disclosure of Invention
To solve at least some of the technical problems in the prior art, the present invention provides a specific crystalline form of TRC-253 hydrochloride that has more suitable properties for preparing pharmaceutical formulations or other superior properties. The present invention provides a crystalline form having at least one of the following improved properties: stability, crystallinity, hygroscopicity, particle size distribution, fluidity, compressibility, preparation processability, dissolution, solubility and bioavailability, meets the requirements of medicine, can be stably stored, is simple and convenient in preparation method, and has important value for optimizing and further developing medicines. Specifically, the present invention includes the following.
In a first aspect of the present invention, there is provided crystalline form 1 of TRC-253 hydrochloride as shown in the structural formula (I),
the crystal form 1 has at least one characteristic diffraction peak selected from 6.7+/-0.2 degrees, 10.3+/-0.2 degrees, 16.1+/-0.2 degrees, 16.7+/-0.2 degrees and 19.9+/-0.2 degrees in an X-ray powder diffraction pattern expressed by a diffraction angle 2 theta; preferably having at least three and more characteristic peaks.
The crystalline form 1 of TRC-253 hydrochloride according to the first aspect of the present invention preferably further has at least one characteristic diffraction peak selected from 13.3±0.2°, 13.6±0.2°, 14.2±0.2°, and 23.4±0.2° in an X-ray powder diffraction pattern expressed as diffraction angle 2θ.
The crystalline form 1 of TRC-253 hydrochloride according to the first aspect of the present invention preferably further has at least one characteristic diffraction peak selected from 21.4±0.2°, 21.9±0.2°, 23.0±0.2°, 26.2±0.2°, and 27.7±0.2° in an X-ray powder diffraction pattern expressed as diffraction angle 2θ.
Preferably, the X-ray powder diffraction data of form 1 according to the first aspect of the present invention are shown in table 1.
Preferably, form 1 of the first aspect of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 1.
Form 1 of the TRC-253 hydrochloride salt according to the first aspect of the invention, preferably in a Fourier infrared spectrum at a wavelength selected from 1756+ -2, 1467+ -2, 1420+ -2, 1385+ -2, 1276+ -2, 1170+ -2, 1143+ -2, 1109+ -2, 1058+ -2, 963+ -2, 1032+ -2, 826+ -2 cm -1 Having a characteristic peak at least one of them; preferably, the crystalline form has substantially the fourier infrared spectrum as shown in fig. 4.
Form 1 of TRC-253 hydrochloride according to the first aspect of the invention, the form 1 being an anhydrate. Preferably, the TGA profile of form 1 loses weight 0.3% before 100 ℃; preferably, its TGA profile is substantially as shown in figure 2.
Form 1 of TRC-253 hydrochloride according to the first aspect of the invention, which has a hygroscopicity of 1.5% (w/w) at a humidity of 0-80% rh.
In a second aspect of the present invention, there is provided a process for preparing crystalline form 1 of TRC-253 hydrochloride according to the first aspect:
(1-1) weighing a proper amount of starting material TRC-253 hydrochloride, adding a solvent to form a suspension, stirring at 30-70 ℃ for more than or equal to 1 day, and centrifuging or filtering the solid to obtain the crystal form 1 of the TRC-253 hydrochloride.
Or alternatively
(1-2) weighing a proper amount of starting material TRC-253 hydrochloride, and placing the starting material TRC-253 hydrochloride in a container with RH humidity of more than or equal to 60% for more than or equal to 1 day to obtain the crystal form 1 of TRC-253 hydrochloride.
According to the production method (1-1) of the second aspect of the present invention, the solvent is selected from one or a mixture of two or more of acetone, isopropyl alcohol, toluene, ethyl acetate.
Further, the ratio of the starting materials to the solvent is not less than 5:1 (mg: ml), preferably 10:1 to 50:1.
Preferably, the stirring temperature is 40-60 ℃.
Preferably, the stirring process may be performed with a warm-up operation.
Preferably, the stirring time is not less than 5 days.
According to the preparation method (1-2) of the second aspect of the invention, the temperature control operation can be further performed when the opening is placed, and the temperature is 20-50 ℃, preferably 35-45 ℃. Preferably, the container is a surface dish.
According to the production method (1-2) of the second aspect of the present invention, preferably, the open-ended holding time is not less than 5 days, more preferably not less than 10 days.
According to the production method (1-2) of the second aspect of the present invention, preferably, the humidity is not less than 75% RH, more preferably not less than 97% RH.
According to the preparation method (1-1) or (1-2) of the second aspect of the present invention, a drying step is further included after the solid is obtained. Preferably, the drying temperature is not less than 10 ℃, preferably not less than 30 ℃, more preferably 40 ℃ to 60 ℃.
The crystal form 1 of the TRC-253 hydrochloride has at least the following beneficial effects:
(1) The crystallinity is higher.
(2) The crystal form has good stability. The crystal form 1 is placed for 14 days under the conditions of high humidity (open) and acceleration (open) respectively, and the crystal form is kept unchanged for 5 days or more under the higher temperature, so that the crystal form 1 still has better crystal form stability under the conditions of acceleration (open) and harsher high temperature and high humidity, the raw material medicine is not easy to be converted into other crystal forms in the process of storage and preparation, the consistent and controllable quality of the product is ensured, and the guarantee is provided for preparing the high-quality preparation.
(3) The chemical stability is good. The decomposition temperature of the crystal form 1 is higher, which indicates that the crystal form 1 can still keep the stability of chemical properties at a higher temperature, and the stability of the chemical properties has important significance for ensuring the curative effect and the safety of the medicine and preventing the occurrence of adverse reactions of the medicine.
(4) The tablet has good stability. After the crystal form 1 is mixed with auxiliary materials to prepare a pharmaceutical preparation, the crystal form is kept unchanged for at least 90 days under the conditions of 40 ℃ +/-5 ℃ and 75% RH, and the chemical purity is basically kept unchanged, so that the preparation prepared by the crystal form 1 has good storage stability.
(5) Low hygroscopicity. Only 1.5% or less mass change at 0% RH-80% humidity, with slight hygroscopicity.
(6) The solubility is good. The crystal form 1 of the invention has the solubility of about 1.7mg/mL in water, is beneficial to achieving ideal bioavailability and efficacy of the drug and meets the requirement of the drug. (7) good compressibility. The crystal form 1 has good compressibility, is beneficial to preparation technology, improves the appearance of products and improves the quality of the products.
In a third aspect of the present invention, there is provided crystalline form 2 of TRC-253 hydrochloride as shown in structural formula (I) having at least one characteristic diffraction peak selected from 9.4±0.2°, 12.0±0.2°, 15.0±0.2°, 17.9±0.2° and 19.2±0.2° in an X-ray powder diffraction pattern expressed by diffraction angle 2θ; preferably having at least three and more characteristic peaks.
Form 2 of the TRC-253 hydrochloride according to the third aspect of the present invention preferably further has at least one characteristic diffraction peak selected from the group consisting of 6.0±0.2°, 14.4±0.2°, 16.6±0.2° and 20.3±0.2° in an X-ray powder diffraction pattern expressed as diffraction angle 2θ.
Form 2 of the TRC-253 hydrochloride according to the third aspect of the present invention preferably further has at least one characteristic diffraction peak selected from 21.2±0.2°, 22.9±0.2°, 23.9±0.2° and 25.8±0.2° in an X-ray powder diffraction pattern expressed as diffraction angle 2θ.
Preferably, the X-ray powder diffraction data of form 2 according to the third aspect of the present invention are shown in table 2.
Preferably, form 2 of the third aspect of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 6.
Form 2 of the TRC-253 hydrochloride salt according to the third aspect of the invention, preferably in a Fourier infrared spectrum at a wavelength selected from 1756+ -2, 1487+ -2, 1460+ -2, 1416+ -2, 1306+ -2, 1279+ -2, 1190+ -2, 1134+ -2, 1058+ -2, 1032+ -2, 959+ -2, and 829+ -2 cm -1 Having a characteristic peak at least one of them; preferably, the crystalline form has substantially the fourier infrared spectrum as shown in fig. 9.
Form 2 of the TRC-253 hydrochloride according to the third aspect of the present invention is an anhydrate. Preferably, the TGA profile of form 2 loses weight 0.3% before 100 ℃; preferably, its TGA profile is substantially as shown in fig. 7.
Form 2 of TRC-253 hydrochloride according to the third aspect of the invention, the form having a hygroscopicity of 0.6% (w/w) at a humidity of 0-80% rh; preferably, the DVS characterization is substantially as shown in fig. 8.
In a fourth aspect of the present invention, there is provided a process for preparing crystalline form 2 of TRC-253 hydrochloride according to the second aspect as follows:
(2-1) weighing a proper amount of the starting material TRC-253 hydrochloride, adding an anti-solvent after adding a good solvent solution, stirring, centrifuging or filtering the solid to obtain the crystal form 2 of the TRC-253 hydrochloride.
Or alternatively
(2-2) weighing a proper amount of the starting material TRC-253 hydrochloride, adding a solvent to form a suspension, stirring at room temperature, centrifuging or filtering the solid to obtain the crystal form 2 of the TRC-253 hydrochloride.
Or alternatively
(2-3) weighing a proper amount of the starting material TRC-253 hydrochloride, adding a solvent for dissolving, filtering and volatilizing to obtain the crystal form 2 of the TRC-253 hydrochloride.
In the production method (2-1) according to the fourth aspect of the present invention, the good solvent is an alcohol, preferably methanol; the antisolvent is an ether, preferably one or a mixture of two or more of diethyl ether, methyl tertiary butyl ether and isopropyl ether.
According to the preparation method (2-1) disclosed by the fourth aspect of the invention, the ratio of the starting materials to the good solvent is more than or equal to 5:1 (mg: ml), preferably 10:1-50:1; the ratio of the anti-solvent to the good solvent is 0.1:1-5:1, preferably 0.5:1-3:1; the stirring time is more than or equal to 0.1 day, preferably 0.5-4 days.
The preparation method (2-2) of the fourth aspect of the present invention, wherein the solvent is an alcohol; the alcohol is preferably selected from methanol; the ratio of the starting materials to the solvent is not less than 5:1 (mg: ml), preferably not less than 10:1, more preferably 10:1 to 50:1. The stirring time is more than or equal to 0.1 day, preferably 0.5-4 days.
The preparation method (2-3) of the fourth aspect of the present invention, wherein the solvent is an alcohol; the alcohol is preferably selected from methanol or ethanol.
The ratio of the starting materials to the solvent in the preparation method (2-3) according to the fourth aspect of the invention is 0.1:1-2.5:1. The volatilization temperature is 10-30 ℃, preferably room temperature.
According to the preparation method (2-1) or (2-2) or (2-3) of the fourth aspect of the present invention, a drying step is further included after the solid is obtained. Preferably, the drying temperature is not less than 10 ℃, preferably not less than 30 ℃, more preferably 40 ℃ to 60 ℃.
The crystalline form 2 of the TRC-253 hydrochloride of the present invention has at least the following beneficial effects:
(1) The crystallinity is higher.
(2) The crystal form has good stability. Form 2 was left under accelerated (open) conditions for 14 days with form remaining unchanged.
(3) The tablet has good stability. After the crystal form 2 is mixed with auxiliary materials to prepare a pharmaceutical preparation, the crystal form is kept unchanged for at least 90 days under the conditions of 40 ℃ +/-5 ℃ and 75% RH, and the chemical purity is basically kept unchanged, so that the preparation prepared by the crystal form 2 has good storage stability.
(4) The hygroscopicity is very low. Only 0.6% or less mass change at 0% RH-80% humidity, with slight hygroscopicity. The crystal form with low hygroscopicity does not need special drying conditions in the preparation process, simplifies the preparation and post-treatment process of the medicine, is easy for industrial production, is very favorable for long-term storage of the medicine, and provides guarantee for stable quality of the medicine.
(5) The solubility is good. The crystal form 2 of the invention has the solubility of about 2.5mg/mL in water, is beneficial to achieving ideal bioavailability and efficacy of the drug and meets the requirement of the drug.
(6) The compressibility is good. The crystal form 2 has good compressibility, is beneficial to preparation technology, improves the appearance of products and improves the quality of the products.
In a fifth aspect of the invention, there is provided a pharmaceutical composition comprising form 1 and/or form 2 of TRC-253 hydrochloride according to the invention and at least one pharmaceutically acceptable carrier.
In the present invention, pharmaceutically acceptable carriers include diluents or excipients or other additives, examples of which include, but are not limited to, for example, wetting agents, disintegrants, lubricants, binders, surfactants, and the like. Examples of other additives include, but are not limited to, for example, shellac, gum arabic, talc, titanium oxide, sugar (e.g., sucrose), gelatin, water, polysaccharides such as lactose or glucose, paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), and pharmaceutically acceptable organic solvents such as alcohols (e.g., ethanol or glycerol), natural mineral powders (e.g., kaolin, clay, talc, and chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), emulsifiers (e.g., lignin, sulfite solutions, methyl cellulose, starch, and polyvinylpyrrolidone), magnesium stearate, stearic acid, sodium lauryl sulfate, and the like.
The pharmaceutical composition of the present invention may be prepared into various dosage forms including, but not limited to, semi-solid pharmaceutical preparations such as ointments, gels, etc. suitable for topical skin administration, or pharmaceutical preparations suitable for oral administration such as solid oral preparations including tablets, coatings, capsules, granules, powders, pills, powders, etc., or liquid oral preparations including solutions, syrups, suspensions, emulsions, etc.; pharmaceutical preparations suitable for parenteral administration, for example intravenous drip preparations, intramuscular or subcutaneous preparations, suppositories for rectal administration, inhalant preparations for intranasal administration, or further transdermal patch forms for topical administration. In the preparation production, additional auxiliary materials can be further included, and preferably, the addition of the auxiliary materials does not cause the transformation of the crystal forms.
In a sixth aspect of the invention, the invention provides the use of form 1 of TRC-253 hydrochloride and/or form 2 of TRC-253 hydrochloride and compositions thereof for the manufacture of a medicament for prostate cancer and other diseases, syndromes, disorders or conditions associated with androgen-resistant AR or castration-resistant prostate cancer-associated AR mutants.
In a seventh aspect of the invention, there is provided a method of the invention for the prophylaxis or treatment of prostate cancer and other diseases, syndromes, disorders or conditions associated with androgen-resistant AR or castration-resistant prostate cancer-associated AR mutants of form 1 of TRC-253 hydrochloride and/or form 2 of TRC-253 hydrochloride.
In an eighth aspect of the invention, there is provided a method for preventing or treating a disease, the method comprising the step of administering to a subject form 1 of TRC-253 hydrochloride and/or form 2 of TRC-253 hydrochloride according to the invention and compositions thereof, wherein the disease is prostate cancer and other diseases, syndromes, disorders, or conditions associated with androgen-resistant AR or castration-resistant prostate cancer-associated AR mutants. Preferably, the pharmaceutical composition comprises a prophylactically and/or therapeutically effective amount of form 1 of the TRC-253 hydrochloride and/or form 2 of the TRC-253 hydrochloride. Preferably, the prophylactically and/or therapeutically effective amount ranges from about 1 to 1000mg, preferably from 10 to 500mg, per day.
In a ninth aspect of the invention, there is provided the use of form 1 of TRC-253 hydrochloride and/or form 2 of TRC-253 hydrochloride according to the invention and a composition thereof in combination with other medicaments. Preferably, the other drug is other anticancer agent or cancer symptomatic treatment drug.
The "other anticancer agent" is selected from other AR antagonists, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFRTK inhibitors, aurora kinase inhibitors, PIK-1 modulators, bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, cdk inhibitors, EGFRTK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK/STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, map kinase (mek) inhibitors, VEGF capture antibodies.
Preferably, the other drug is selected from the group consisting of flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, proxalutamide, ONC1-13B, APC-100, SHR-3680, TAS-3681, HC-1119, pemetrexed (pemetrexed), erlotinib, dasatanib (dasatanib), nilotinib, decatanib (decatanib), panitumumab (panitumumab), amrubicin (amyubicin), ago Fu Shan anti (orego vomab), 5-fluorouracil, vorinostat (vorinostat), etoposide (etoposide), gemcitabine (gemcitabine), doxorubicin (doxuboricin).
Drawings
FIG. 1 is an XRPD pattern for form 1 of TRC-253 hydrochloride prepared according to example 1-1;
FIG. 2 is a TGA spectrum of crystalline form 1 of TRC-253 hydrochloride prepared according to example 1-1;
FIG. 3 is a DVS plot of form 1 of TRC-253 hydrochloride prepared according to example 1-1;
FIG. 4 is a Fourier IR spectrum of form 1 of TRC-253 hydrochloride prepared according to example 1-1;
FIG. 5 is an XRPD pattern for form 1 of TRC-253 hydrochloride when placed under high humidity and acceleration conditions for 14 days;
FIG. 6 is an XRPD pattern for form 2 of TRC-253 hydrochloride prepared according to example 2-1;
FIG. 7 is a TGA spectrum of form 2 of TRC-253 hydrochloride prepared according to example 2-1;
FIG. 8 is a DVS plot of form 2 of TRC-253 hydrochloride prepared according to example 2-1;
FIG. 9 is a Fourier infrared spectrum of form 2 of TRC-253 hydrochloride prepared according to example 2-1;
FIG. 10 is an XRPD pattern for form 2 of TRC-253 hydrochloride when placed under accelerated conditions for 14 days;
FIG. 11 is a graphical representation of XRPD patterns of form 1 of TRC-253 hydrochloride before and after tableting;
FIG. 12 is a graphical XRPD comparison of form 2 of TRC-253 hydrochloride before and after tabletting;
FIG. 13 is an XRPD pattern for form 1 of TRC-253 hydrochloride prepared according to examples 1-5.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in the present invention, it is understood that the upper and lower limits of the ranges and each intermediate value therebetween are specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control. Unless otherwise indicated, "%" is percent by weight.
The term "subject" as used herein includes mammals. The mammal may be, for example, any mammal, e.g., human, primate, bird, mouse, rat, poultry, dog, cat, cow, horse, goat, camel, sheep, or pig. Preferably the mammal is a human.
The term "room temperature" as used herein generally refers to 10-30℃and preferably 20.+ -. 5 ℃.
In the present invention, the term "crystalline form" refers to a certain lattice configuration of a crystalline substance. It is known in the art that crystalline forms are related to stability, dissolution and mechanical properties in the manufacture of a medicament. Different crystal forms of the same substance typically have different lattices (e.g., unit cells) with different physical properties that are characteristic thereof. The different crystal forms may be characterized by methods known in the art. For example, it can be identified by solid state characterization methods, such as by X-ray powder diffraction (XRPD). Other characterization methods include Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor adsorption (DVS), solid state NMR, and the like. The crystalline form may be characterized using any of the methods described above, or by using two or more methods in combination.
In the present invention, the terms "property" or "crystalline form property" or "pharmaceutical property" include physical and chemical properties thereof, and evaluation indexes include, but are not limited to, for example, melting point, water solubility, dissolution rate, mechanical properties, stability, pharmacokinetics or pharmacodynamics, hygroscopicity, flowability, compressibility, competitiveness, and the like.
The term "effective" may mean, but is not limited to, the amount/dose of an active pharmaceutical ingredient, which, when used in the context of its intended use, achieves or is sufficient to prevent a condition, disorder or disease state, inhibit its occurrence, ameliorate, delay or treat its symptoms (to some extent, preferably completely alleviate the symptoms) in a subject in need of such treatment or receiving such treatment. The term effective encompasses all other effective amounts or effective concentration terms, such as "effective amount/dose", "pharmaceutically effective amount/dose" or "therapeutically effective amount/dose", which are otherwise described or used in this application.
The terms "pharmacological composition," "therapeutic formulation," or "pharmaceutically acceptable formulation" may refer to, but are in no way limited to, a composition or formulation that allows for the effective distribution of the agents provided by the present disclosure in a form suitable for administration to a body site most suitable for its desired activity, such as systemic administration.
The term "pharmaceutically acceptable" or "pharmacologically acceptable" may mean, but is in no way limited to, entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal or human, as appropriate.
In the process of the present invention, the crystalline form of the present invention is generally prepared with TRC-253 hydrochloride as starting material, which can be prepared by the method of CN108473471A or by purchase.
The various reagents used in the examples were commercially available unless otherwise specified. Unless otherwise indicated, the examples were all run at room temperature.
Other experimental methods are known in the art, except for the specific description of the present invention, and reference is made to, for example, the pharmacopoeia of the people's republic of China. Wherein, the parameters for detection are set as follows:
x-ray powder diffraction (XRPD) data were taken from Bruker D8 Advance diffractometer. The parameters are as follows: a Cu target; wavelength ofCurrent voltage: 40KV and 40mA; angular range: 3-40 degrees 2 theta.
Fourier infrared spectroscopy (FT-IR) data was obtained from Bruker Tensor 27. The parameters are as follows: the detection method comprises the following steps: ATR process; the acquisition range is as follows: 600cm-1 to 4000cm-1; resolution ratio: 4.0cm-1.
Differential thermal analysis (DSC) data were taken from TA Instruments Q200 DSC. The parameters are as follows: rate of temperature rise: 10 ℃/min; protective gas: n2; sample tray: a capped aluminum crucible.
Thermogravimetric analysis (TGA) data were taken from TA Instruments Q500 TGA. The parameters are as follows: mode: a high resolution mode; rate of temperature rise: 10 ℃/min; protective gas: n2; sample tray: platinum crucible.
Dynamic moisture sorption analysis (DVS) data and isothermal sorption analysis data were taken from the ta instruments q5000TGA. The parameters are as follows: temperature: 25 ℃; relative humidity range: 0% RH-80% RH; dm/dt=0.001%/min; equilibration time: for 90min; protective gas: n2; sample tray: platinum crucible.
High Performance Liquid Chromatography (HPLC):
chromatographic column: titank-C18 μm (150 x 4.6 mm)
Mobile phase: a:0.1% TFA in water; b: pure acetonitrile
The operating gradient is as follows:
time (min) A(％) B(％)
0 80 20
3 80 20
15 5 95
20 5 95
20.1 80 20
25 80 20
Flow rate: l.0mL/min
Detection wavelength: 280nm of
Column temperature: 25 ℃.
Preparation example 1
The TRC-253 hydrochloride prepared and obtained by the method described in the paragraph [0972] of CN108473471A has extremely high hygroscopicity.
Example 1-1
About 20mg of TRC-253 hydrochloride of preparation example 1 was taken, 1.0mL of acetone was added to form a suspension, the mixture was stirred at 50℃for 5 days, and the solid was filtered to obtain crystalline form 1 of TRC-253 hydrochloride.
The sample of example 1-1 was taken for characterization, as follows.
1. XRPD pattern analysis
FIG. 1 is an XRPD pattern for form 1 of TRC-253 hydrochloride, and Table 1 shows X-ray powder diffraction data for form 1 of TRC-253 hydrochloride.
Table 1: x-ray powder diffraction data for form 1 of TRC-253 hydrochloride
2θ±0.2° I％ 2θ±0.2° I％
6.7 19.9 21.4 26.0
7.2 13.3 21.9 19.2
10.3 23.3 23 12.1
13.3 12.4 23.4 26.1
13.6 11.3 24.7 5.4
14.2 14.2 25.5 7.7
14.9 6.7 26.2 21.8
15.6 12.7 26.6 21.6
16.1 100.0 27 19.7
16.7 34.2 27.7 16.3
17.6 7.2 28.5 7.2
19.9 30.3 29.4 6.7
20.3 17.1 29.8 8.9
20.5 14.5 30.7 7.3
2. TGA profile analysis
The TGA (thermogravimetric analysis) results are shown in fig. 2, showing a weight loss of 0.3% before 100 ℃ and a decomposition temperature of 257 ℃.
3. DVS graph analysis
The DVS diagram measurement results are shown in fig. 3. Form 1 absorbs about 1.5% (w/w) at 0% RH to 80% RH humidity.
4. Fourier infrared spectroscopy
The fourier infrared spectrum results are shown in fig. 4. Form 1 of TRC-253 hydrochloride has the following characteristic peaks: 1756+ -2, 1467+ -2, 1420 cm-1+ -2, 1385+ -2, 1276+ -2, 1170+ -2, 1143+ -2, 1109+ -2, 1058+ -2, 963+ -2, 1032+ -2, 826+ -2 cm -1 。
Examples 1 to 2
The TRC-253 hydrochloride of preparation example 1 was weighed to be about 50mg, 1.0mL of acetone was added to form a suspension, stirring was continued at 50℃for 9 days, stirring was continued at 60℃for 2 days, and the solid was filtered to obtain crystalline form 1 of TRC-253 hydrochloride.
Examples 1 to 3
The TRC-253 hydrochloride of preparation example 1 was weighed in a petri dish at about 13mg, and left open at room temperature in a 97% RH humidifier for 7 days to obtain crystalline form 1 of TRC-253 hydrochloride.
Examples 1 to 4
The TRC-253 hydrochloride of preparation example 1 was weighed in a petri dish at about 13mg, and placed in a 40 ℃ C./75% RH humidifier with an opening, and after 7 days, the crystalline form 1 of the TRC-253 hydrochloride was obtained.
Examples 1 to 5
The TRC-253 hydrochloride of preparation example 1 was weighed to be about 20mg, 1.0mL of isopropyl alcohol was added to form a suspension, and the suspension was stirred overnight at 50 ℃, centrifuged, and dried in vacuo at room temperature overnight to obtain crystalline form 1 of TRC-253 hydrochloride. Which has an XRPD pattern as shown in figure 13.
Example 2-1
Taking 50mg of TRC-253 hydrochloride of preparation example 1, adding 1.0mL of methanol, dissolving, adding 1.8mL of isopropyl ether, stirring overnight at room temperature, and drying in vacuum at 50 ℃ to obtain a crystal form 2 of TRC-253 hydrochloride.
The sample of example 2-1 was taken for characterization, as follows.
1. XRPD pattern analysis
FIG. 6 is an XRPD pattern for form 2 of TRC-253 hydrochloride, and Table 2 shows the X-ray powder diffraction data for form 2 of TRC-253 hydrochloride.
Table 2: x-ray powder diffraction data for form 2 of TRC-253 hydrochloride
2. TGA profile analysis
The TGA (thermogravimetric analysis) results are shown in fig. 7, showing a weight loss of 0.3% before 100 ℃ and a decomposition temperature of 256 ℃.
3. DVS profile analysis
The DVS profile measurement results are shown in fig. 8. Form 2 absorbs about 0.6% (w/w) at 0% RH to 80% RH humidity.
4. Fourier infrared spectroscopy
The fourier infrared spectrum results are shown in fig. 9. Form 2 has the following characteristic peaks: 1756+ -2, 1487+ -2, 1460+ -2, 1416+ -2, 1306+ -2, 1279+ -2, 1190+ -2, 1134+ -2, 1058+ -2, 1032+ -2, 959+ -2, and 829+ -2 cm -1 。
Example 2-2
About 30mg of TRC-253 hydrochloride of preparation example 1 was weighed, 0.5mL of methanol was added to form a suspension, stirred overnight at room temperature, and dried under vacuum at 50℃to obtain crystalline form 2 of TRC-253 hydrochloride.
Examples 2 to 3
About 5mg of TRC-253 hydrochloride of preparation example 1 was weighed, 2mL of methanol was added for dissolution, then filtration, evaporation to dryness at room temperature, and vacuum drying at 50℃for 3 hours, to obtain crystalline form 2 of TRC-253 hydrochloride.
Experimental example 1 stability investigation
Taking the crystal form 1 of the TRC-253 hydrochloride prepared by the invention, respectively placing under the conditions of acceleration (40 ℃,75% RH, open) and high humidity (97% RH, open), and the results show that: form 1 of TRC-253 hydrochloride was able to be stably stored under accelerated and high humidity conditions for 14 days without modification of the form as shown in fig. 5.
Taking the crystal form 2 of the TRC-253 hydrochloride prepared by the invention, placing under the condition of acceleration (40 ℃,75% RH, open), and the result shows that: form 2 of TRC-253 hydrochloride can be stably maintained for 14 days under accelerated conditions as shown in fig. 10.
Experimental example 2 investigation of compressibility
About 20g of the crystal form 1 of the TRC-253 hydrochloride prepared by the method is pressed and formed by an infrared tablet press under the pressure of 10MPa, and XRPD tests are carried out before and after tabletting, so that the crystal form 1 is unchanged after tabletting, and the XRPD comparison chart is shown in figure 11.
About 20g of the crystal form 2 of the TRC-253 hydrochloride prepared by the method is pressed and formed by an infrared tablet press under the pressure of 10MPa, and XRPD tests are carried out before and after tabletting, so that the crystal form 2 is unchanged after tabletting, and the XRPD comparison chart is shown in figure 12.
EXAMPLE 3 solubility study
5mL of pure water was taken, an excess of the crystalline form of the present application was added, and it was stirred at room temperature to form a solution, which was sampled at fixed time points and its solubility was checked by HPLC. The experimental results are shown in table 3:
table 3: solubility data for crystalline forms
Crystal form Solubility (mg/mL)
Crystal form 1 1.7
Crystal form 2 2.5
The results show that: in water, form 1 of TRC-253 hydrochloride and form 2 of TRC-253 hydrochloride have good solubility, producing unexpected effects.
Example 4 preparation of tablets
Tablets were prepared according to the conventional method after mixing API, mannitol, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate according to the recipe of table 4.
Table 4: tablet prescription
Example 5 stability of tablet
Form 1 of the prepared TRC-253 hydrochloride and form 2 of the TRC-253 hydrochloride were placed under accelerated conditions (40 ℃ + -5 ℃,75% RH, open) respectively, and HPLC and XRPD were periodically checked, and the results are shown in Table 5.
Table 5: tablet stability results
Initial sample Initial purity Conditions of placement Time of placement Sample after placement Purity after standing
Crystal form 1 99.18％ 40 ℃ +/-5 ℃,75% RH, open 90 days Crystal form 1 99.14％
Crystal form 2 99.73％ 40 ℃ +/-5 ℃,75% RH, open 90 days Crystal form 2 99.04％
The results show that: the tablets of form 1 of TRC-253 hydrochloride and form 2 of TRC-253 hydrochloride can be kept stable for at least 90 days under accelerated conditions (40 ℃ + -5 ℃,75% RH, open).
While the invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. Various modifications or changes may be made to the exemplary embodiments of the present disclosure without departing from the scope or spirit of the invention. The scope of the claims is to be accorded the broadest interpretation so as to encompass all modifications and equivalent structures and functions.

Claims (10)

1. A crystal form 1 of TRC-253 hydrochloride having a structural formula shown in the following formula (I),
wherein the X-ray powder diffraction pattern expressed by diffraction angle 2 theta has at least one characteristic diffraction peak selected from the group consisting of 6.7 + -0.2 DEG, 10.3 + -0.2 DEG, 16.1 + -0.2 DEG, 16.7 + -0.2 DEG and 19.9 + -0.2 DEG; preferably having at least three and more characteristic peaks.
2. The crystalline form 1 of TRC-253 hydrochloride according to claim 1, further comprising at least one characteristic diffraction peak selected from the group consisting of 13.3±0.2°, 13.6±0.2°, 14.2±0.2°, and 23.4±0.2° in an X-ray powder diffraction pattern expressed as diffraction angle 2Θ; preferably, there is at least one characteristic diffraction peak selected from 21.4±0.2°, 21.9±0.2°, 23.0±0.2°, 26.2±0.2°, 27.7±0.2°.
3. A process for the preparation of crystalline form 1 of TRC-253 hydrochloride according to claim 1 or 2 as follows:
(1-1) weighing a proper amount of starting material TRC-253 hydrochloride, adding a solvent to form a suspension, stirring at 30-60 ℃ for more than or equal to 1 day, centrifuging or filtering the solid to obtain a crystal form 1 of TRC-253 hydrochloride; or alternatively
(1-2) weighing a proper amount of starting material TRC-253 hydrochloride, and placing the starting material TRC-253 hydrochloride in a container with RH humidity of more than or equal to 60% for more than or equal to 1 day to obtain a crystal form 1 of TRC-253 hydrochloride;
preferably, in the preparation method (1-1), the solvent is selected from one or a mixture of two or more of acetone, isopropanol, toluene and ethyl acetate; preferably, the ratio of the starting materials to the solvent is not less than 5:1 (mg: ml), preferably 10:1 to 50:1; preferably, the stirring temperature is 40-60 ℃; preferably, the stirring process can be performed by a temperature raising and lowering operation; preferably, the stirring time is more than or equal to 5 days;
preferably, in the preparation method (1-2), the temperature control operation can be further performed when the preparation method is placed in an open state, and the temperature is 20-50 ℃, preferably 35-45 ℃; preferably, the open standing time is not less than 5 days, more preferably not less than 10 days; preferably, the humidity is equal to or higher than 75% RH;
preferably, the preparation method (1-1) or (1-2) further comprises a drying step; preferably, the drying temperature is not less than 10 ℃, preferably not less than 30 ℃, more preferably 40 ℃ to 60 ℃.
4. A crystalline form 2 of TRC-253 hydrochloride represented by structural formula (I), characterized by having at least one characteristic diffraction peak selected from the group consisting of 9.4±0.2°, 12.0±0.2°, 15.0±0.2°, 17.9±0.2° and 19.2±0.2° in an X-ray powder diffraction pattern expressed by a diffraction angle 2θ; preferably having at least three and more characteristic peaks.
5. The crystalline form 2 of TRC-253 hydrochloride according to claim 4, further comprising at least one characteristic diffraction peak selected from the group consisting of 6.0±0.2°, 14.4±0.2°, 16.6±0.2° and 20.3±0.2° in an X-ray powder diffraction pattern expressed as diffraction angle 2Θ; preferably, there is at least one characteristic diffraction peak selected from 21.2±0.2°, 22.9±0.2°, 23.9±0.2° and 25.8±0.2°.
6. A process for the preparation of form 2 of TRC-253 hydrochloride according to claim 4 or 5, as follows:
(2-1) weighing a proper amount of starting material TRC-253 hydrochloride, adding an anti-solvent after a good solvent is added for dissolving, stirring, centrifuging or filtering the solid to obtain a crystal form 2 of TRC-253 hydrochloride;
or alternatively
(2-2) weighing a proper amount of starting material TRC-253 hydrochloride, adding a solvent to form a suspension, stirring at room temperature, centrifuging or filtering the solid to obtain a crystal form 2 of TRC-253 hydrochloride;
or alternatively
(2-3) weighing a proper amount of starting material TRC-253 hydrochloride, adding solvent for dissolving, filtering and volatilizing to obtain a crystal form 2 of TRC-253 hydrochloride;
preferably, in the preparation method (2-1), the good solvent is an alcohol, preferably methanol; the antisolvent is an ether, preferably one or a mixture of two or more of diethyl ether, methyl tertiary butyl ether and isopropyl ether; preferably, the ratio of the starting materials to the good solvent is more than or equal to 5:1 (mg: ml), preferably 10:1-50:1; the ratio of the anti-solvent to the good solvent is 0.1:1-5:1, preferably 0.5:1-3:1; the stirring time is more than or equal to 0.1 day, preferably 0.5-4 days;
preferably, in the preparation method (2-2), the solvent is a small molecular alcohol; preferably from methanol; the ratio of the starting materials to the solvent is more than or equal to 5:1 (mg: ml), preferably more than or equal to 10:1, more preferably 10:1-50:1; preferably, the stirring time is more than or equal to 0.1 day, preferably 0.5 to 4 days;
preferably, in the preparation method (2-3), the ratio of the starting materials to the solvent is 0.1:1-2.5:1; preferably, the volatilization temperature is 10-30 ℃, preferably room temperature.
7. A pharmaceutical composition comprising form 1 of TRC-253 hydrochloride according to claim 1 or 2 and/or form 2 of TRC-253 hydrochloride according to claim 4 or 5 and at least one pharmaceutically acceptable carrier.
8. Use of a crystalline form 1 of TRC-253 hydrochloride according to claim 1 or 2 and/or a crystalline form 2 of TRC-253 hydrochloride according to claim 4 or 5 and a pharmaceutical composition according to claim 7 for the preparation of a medicament for prostate cancer and other diseases, syndromes, disorders or conditions associated with androgen-resistant AR or castration-resistant prostate cancer-associated AR mutants.
9. A method of preventing or treating prostate cancer and other diseases, syndromes, disorders, or conditions associated with androgen-resistant AR or castration-resistant prostate cancer-associated AR mutants in crystalline form 1 of TRC-253 hydrochloride according to claim 1 or 2 and/or crystalline form 2 of TRC-253 hydrochloride according to claim 4 or 5 and the pharmaceutical composition according to claim 7.
10. Use of a crystalline form 1 of TRC-253 hydrochloride according to claim 1 or 2 and/or a crystalline form 2 of TRC-253 hydrochloride according to claim 4 or 5 and a pharmaceutical composition according to claim 7 in combination with other pharmaceutically active ingredients; preferably, the other pharmaceutically active ingredient is other anticancer agent or cancer symptomatic treatment drug.
CN202310063236.9A 2022-01-29 2023-01-16 Crystal form of TRC-253 hydrochloride, preparation method and application thereof Pending CN116514776A (en)

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