[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN118561761A - Enzalutamide-saccharin eutectic and preparation method thereof - Google Patents

Enzalutamide-saccharin eutectic and preparation method thereof Download PDF

Info

Publication number
CN118561761A
CN118561761A CN202310202663.0A CN202310202663A CN118561761A CN 118561761 A CN118561761 A CN 118561761A CN 202310202663 A CN202310202663 A CN 202310202663A CN 118561761 A CN118561761 A CN 118561761A
Authority
CN
China
Prior art keywords
enzalutamide
saccharin
crystal
degrees
acetic acid
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.)
Pending
Application number
CN202310202663.0A
Other languages
Chinese (zh)
Inventor
刘忠
翟立海
张明明
李玲
刘玉婷
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.)
Shandong New Time Pharmaceutical Co Ltd
Original Assignee
Shandong New Time 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 Shandong New Time Pharmaceutical Co Ltd filed Critical Shandong New Time Pharmaceutical Co Ltd
Priority to CN202310202663.0A priority Critical patent/CN118561761A/en
Publication of CN118561761A publication Critical patent/CN118561761A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • 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

Landscapes

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

Abstract

The crystal uses Cu-K alpha radiation, and an X-ray diffraction spectrum represented by 2 theta is at least 9.47+/-0.2 degrees, 15.51+/-0.2 degrees, 19.03+/-0.2 degrees, 19.09+/-0.2 degrees, 19.79+/-0.2 degrees, 22.18+/-0.2 degrees, 24.85+/-0.2 degrees and has characteristic peaks, and the crystal has the advantages of good chemical and physical stability, simple preparation method, easy industrialization, and the like, provides a better basis for the application of the enzalutamide in the aspect of drug co-treatment, and further gives play to the medicinal value of the enzalutamide more efficiently.

Description

Enzalutamide-saccharin eutectic and preparation method thereof
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to the technical field of enzalutamide, and specifically relates to a preparation method and application of an enzalutamide-saccharin eutectic.
Background
Pharmaceutical co-crystals are based on the principle of supermolecule chemistry, i.e. molecular recognition and supermolecule self-assembly by intermolecular interactions. Pharmaceutical co-crystals are novel co-crystals formed by combining pharmaceutically active ingredients with physiologically acceptable co-crystal formers in the same crystal lattice in the form of non-covalent bonds such as hydrogen bonds. The pharmaceutical co-crystal does not need to form a new covalent bond or destroy the existing covalent bond, can modify the physical properties of the medicine while preserving the pharmacological action of the medicine, such as improving the stability of the medicine, reducing the hygroscopicity, improving the solubility, improving the bioavailability and the like, and provides a wide development prospect for the application of the pharmaceutical co-crystal in the pharmaceutical industry. For imitation pharmacy, the research of the pharmaceutical co-crystal can break the patent protection of the original research pharmaceutical company on the pharmaceutical crystal form, and is beneficial to the market of imitation medicines. Therefore, it is important to obtain more novel, practical and creative pharmaceutical co-crystals, especially some water-insoluble drugs.
Enzalutamide (enzalutamide) trade name: xtandi, chemical name 4- [3- [ 4-cyano-3- (trifluoromethyl) phenyl ] -5, 5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl ] -2-fluoro-N-methylbenzamide, structural formula is shown below:
The medicine belongs to an oral androgen receptor antagonist, is developed by Medivation company and An Si Tay (Astellas) company cooperatively, is approved by the United states Food and Drug Administration (FDA) for treating advanced male castration resistant prostate cancer which has spread or recurred in 8-31 days 2012, and can prolong the life span of patients. Prostate cancer has a high incidence rate in the united states, with nearly 24 tens of thousands of patients (highest among all cancers) newly increasing each year, nearly 3 tens of thousands of deaths each year (next to lung cancer, breast cancer, colorectal cancer), and a low incidence rate in china.
Saccharin is a sweetener that does not contain calories. The structural formula is shown as follows, and the molecular formula is as follows: c 7H5O3 NS, chemical name of phthalylsulfonyl imide, which is white crystalline powder, is insoluble in water. The sweetness of the sweet potato is 300-500 times of that of sucrose, the sweet potato does not contain calories, and slight bitter taste and metallic taste remain on the tongue after eating the sweet potato, and the sweet potato can be used as a pharmaceutical auxiliary material. The structural formula is as follows:
Different crystal forms of enzalutamide can influence the solubility and stability, so as to change the dissolution and release of the pharmaceutical composition in vitro and further influence the bioavailability of the drug in vivo. Therefore, the development of different forms of crystalline enzalutamide has profound significance. The invention provides a simple and easy-to-operate method for preparing the high-purity enzalutamide-saccharin eutectic crystal form, which provides a better basis for the application of the enzalutamide in the aspect of drug co-treatment, thereby more effectively exerting the medicinal value of the enzalutamide.
Disclosure of Invention
The invention aims to provide an enzalutamide-saccharin eutectic crystal which has the advantages of good chemical and physical stability, simple preparation method, easy industrialization, and the like.
The specific technical content is as follows:
An enzalutamide-saccharin eutectic, using Cu-ka radiation, has an X-ray diffraction pattern expressed in 2θ with characteristic peaks at least at 9.47±0.2°,15.51±0.2°,19.03±0.2°,19.09±0.2°,19.79±0.2°,22.18±0.2°,24.85±0.2°.
Preferably, the enzalutamide-saccharin co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed in 2 theta has a characteristic peak at 9.47±0.2°,10.83±0.2°,13.40±0.2°,13.66±0.2°,15.51±0.2°,15.87±0.2°,19.03±0.2°,19.09±0.2°,19.79±0.2°,20.24±0.2°,22.18±0.2°,23.68±0.2°,24.8553±0.2°,28.44±0.2°,28.73±0.2°,28.81±0.2°,29.91±0.2°.
Preferably, the enzalutamide-saccharin co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the enzalutamide-saccharin co-crystal has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve, which is 177.84 ℃.
In a second aspect, the present invention provides a method for preparing the enzalutamide-saccharin co-crystal, comprising the steps of:
dissolving the enzalutamide and saccharin in the solvent A, heating to dissolve, cooling to crystallize after clarifying the solution, filtering and drying to obtain the enzalutamide-saccharin eutectic.
Preferably, the solvent A is selected from one of mixed solvents of isopropanol-acetic acid, methanol-acetic acid, ethanol-acetic acid and n-butanol-acetic acid.
Preferably, the solvent A is selected from one of mixed solvents of isopropanol-acetic acid and methanol-acetic acid.
Preferably, the molar ratio of the enzalutamide to the saccharin is 1:1-1.8; further preferably 1:1 to 1.5.
Preferably, the mass volume ratio of the enzalutamide to the solvent A in the system is 6-8: 1, wherein the mass is in mg and the volume is in mL.
Preferably, the temperature of the dissolution heating is 60-70 ℃.
Preferably, the crystallization temperature is 0 to 25 ℃, and more preferably 10 to 20 ℃.
Preferably, the crystallization time is 48-72 hours.
Preferably, the drying temperature is 50-60 ℃ and the drying time is 8-10 hours.
In a third aspect, the present invention provides a pharmaceutical composition comprising an enzalutamide-saccharin co-crystal prepared as described above, and containing other active ingredients and/or pharmaceutically acceptable adjuvant ingredients for use in combination.
Preferably, the other components include other active ingredients, excipients, fillers, and the like, which may be used in combination.
Preferably, the pharmaceutical composition can be prepared into spray, tablet, capsule, powder injection, liquid injection, etc. using standard and conventional techniques.
In a fourth aspect, the present application provides an use of an enzalutamide-saccharin co-crystal as an active ingredient in the manufacture of a medicament for the treatment of cancer.
Confirmation of Crystal Structure
X-ray crystal data were collected on a model XtaLAB Synergy of Japanese science, test temperature 293 (2) K, irradiated with CuKa, data were collected in omega scan mode and Lp corrected. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
Testing and analyzing the enzalutamide-saccharin chemistry data (as in table 1) prepared by the invention, the crystallography parameters: orthorhombic system, chiral space group is Pbca; the unit cell parameters are: α=90°, β=90°, γ=90°, unit cell volume The molecular formula: c 28H21F4N5O5S2, molecular weight: 647.62.
Table 1 main crystallographic data of enzalutamide saccharin
The X-ray powder diffraction test instrument and test conditions in the enzalutamide-saccharin eutectic test are as follows: PANALYTICAL EMPYREAN X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction optical path: PIXCEL, voltage 45KV, current 40mA, divergence slit of 1/4 DEG, anti-scattering slit of 1 DEG, cable-stayed slit of 0.04rad, counting time of 0.5s per step and scanning range of 3-50 deg.
According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in the accompanying figure 1 and the table 2.
TABLE 2 main PXRD peaks of enzalutamide-saccharin co-crystals
The structural analysis ORTEP diagram of the enzalutamide-saccharin co-crystal of the present invention shows that one molecule of enzalutamide and one molecule of saccharin are present in the crystal, as shown in fig. 2. The stacking diagram of the enzalutamide-saccharin eutectic of the invention is shown in figure 3. TGA/DSC thermal analysis tester and test conditions in the invention: TGA/DSC thermal analyzer: METTLER TOLEDO TGA/DSC < 3+ >; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/mIVn; program segment gas N 2; gas flow rate: 50mL/mIVn; crucible: 40 μl of aluminum crucible.
The results of TGA/DSC test of the Enzalutamine and saccharin eutectic prepared by the method are shown in figure 4, the DSC spectrum shows an endothermic peak in the range of 164.39-189.78 ℃, the peak value corresponding to the endothermic peak is 177.84 ℃, the melting point of Enzalutamine and saccharin eutectic is obtained, and the results of DSC/TGA test show that the crystal forms prepared by the method are Enzalutamine and saccharin eutectic crystal forms.
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns as described above.
The method for preparing the enzalutamide-saccharin eutectic is simple and convenient to operate, and the prepared crystals are high in purity, and the enzalutamide-saccharin eutectic has good chemical stability in a solid state or a solution state and has good solubility.
Drawings
Fig. 1: x-ray powder diffraction pattern of enzalutamide-saccharin co-crystals.
Fig. 2: ORTEP diagram of enzalutamide-saccharin co-crystals.
Fig. 3: a stacking diagram of enzalutamide-saccharin co-crystals.
Fig. 4: DSC-TGA diagram of Enzalutamine-saccharin eutectic
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
Example 1
46.5Mg of enzalutamide and 18.3mg of saccharin are added into 4mL of isopropyl alcohol and 2mL of acetic acid, heated to 60 ℃ for stirring and dissolution, reflux reaction is carried out for 5 hours, after the temperature is slowly reduced to 10-20 ℃, standing and crystallization are carried out for 48 hours under the controlled temperature, filtration is carried out, a filter cake is washed by isopropanol, vacuum drying is carried out for 8 hours at 55 ℃, and the enzalutamide-saccharin eutectic is obtained, and the yield is 96.88% and the purity is 99.45%.
Example 2
46.5Mg of enzalutamide and 22.0mg of saccharin are added into 4mL of methanol and 2mL of acetic acid, the mixture is heated to 65 ℃ for stirring and dissolution, reflux reaction is carried out for 5 hours, after the temperature is slowly reduced to 10-20 ℃, standing and crystallization are carried out for 60 hours under the control of temperature, filtration is carried out, a filter cake is washed by methanol, and vacuum drying is carried out for 9 hours at 50 ℃ to obtain the enzalutamide-saccharin eutectic, and the yield is 95.61% and the purity is 99.35%.
Example 3
46.5Mg of enzalutamide and 27.5mg of saccharin are added into 4mL of ethanol and 3mL of acetic acid, the mixture is heated to 70 ℃ for stirring and dissolution, reflux reaction is carried out for 6 hours, after the temperature is slowly reduced to 10-20 ℃, standing and crystallization are carried out for 60 hours under the control of temperature, filtration is carried out, filter cakes are washed by ethanol, vacuum drying is carried out for 10 hours at 60 ℃, and the enzalutamide-saccharin eutectic is obtained, the yield is 96.75%, and the purity is 99.37%.
Example 4
46.5Mg of enzalutamide and 19.0mg of saccharin are added into 4mL of n-butanol and 2.5mL of acetic acid, the mixture is heated to 60 ℃ for stirring and dissolution, reflux reaction is carried out for 6 hours, after the temperature is slowly reduced to 10-20 ℃, standing and crystallization are carried out for 72 hours under the controlled temperature, filtration is carried out, a filter cake is washed by isopropanol, vacuum drying is carried out for 8 hours at 55 ℃, and the enzalutamide-saccharin eutectic is obtained, the yield is 95.33%, and the purity is 99.28%.
Example 5
46.5Mg of enzalutamide and 32.94mg of saccharin are added into 4mL of isopropyl alcohol and 2mL of acetic acid, the mixture is heated to 60 ℃ for stirring and dissolution, the reflux reaction is carried out for 5 hours, the temperature is slowly reduced to 10-20 ℃, the crystallization is carried out for 48 hours under the control of temperature, the filtration is carried out, the filter cake is washed by isopropanol, the vacuum drying is carried out for 8 hours at 55 ℃, and the enzalutamide-saccharin eutectic is obtained, the yield is 94.43%, and the purity is 99.19%.
Example 6
46.5Mg of enzalutamide and 18.3mg of saccharin are added into 4mL of isopropanol and 3.5mL of acetic acid, the mixture is heated to 70 ℃ for stirring and dissolution, the reflux reaction is carried out for 5 hours, the temperature is slowly reduced to 10-20 ℃, the crystallization is carried out for 48 hours under the control of temperature, the filtration is carried out, the filter cake is washed by isopropanol, the vacuum drying is carried out for 8 hours at 55 ℃, and the enzalutamide-saccharin eutectic is obtained, the yield is 94.59%, and the purity is 99.39%.
Comparative example 1
2.0G of enzalutamide solid is taken, 6ml of mixed solvent (DMSO: toluene=1:2) is added to heat and dissolve the mixture to 90 ℃, then the mixture is cooled to 50 ℃, 8ml of isopropyl acetate is used for dilution, the diluted solution is washed twice by 8ml of saturated saline water and then is dried by anhydrous sodium sulfate and filtered, the filtrate is dried by spinning at 50 ℃ and the oily matter is pulped by 20ml of isopropanol for 16 hours and then is filtered, and a filter cake is dried in air at room temperature for 24 hours and then is dried in vacuum at 60 ℃ to obtain 1.91g of enzalutamide type Lu Anjing, and the yield is 95.52% and the purity is 99.04%.
Comparative example 2
Methyl 2- (3-fluoro-4-methylcarbamoyl-phenylamino) -2-methylpropionate (33.0 g) and 4-cyano-3-trifluoromethylphenyl isothiocyanate (56.1 g) obtained in example 1 were dissolved in a mixed solvent of dimethyl sulfoxide (DMSO) (33 mL)/IPAc (66 mL) under nitrogen atmosphere, and the mixture was heated to an internal temperature of 75 to 85℃and stirred at that temperature for 12 hours or more. After the reaction, methanol (4.95 mL) was added dropwise at 55 to 80℃and stirred at that temperature for 60 to 90 minutes. Then, the mixture was cooled to 15 to 25℃and diluted with IPAc (198 mL) and pure water (99 mL), stirred at that temperature for 10 to 30 minutes, and then allowed to stand for 30 to 45 minutes. 2-propanol (IPA) (49.5 mL) was slowly added dropwise at an internal temperature of 15 to 25℃to break the emulsion. The organic layer was separated, and the line was purged with IPAc (15 mL). The separated organic layer was concentrated under reduced pressure to a volume of about 165 mL. The concentrated liquid is heated to 80-85℃and stirred at this temperature for 30-60 min in order to dissolve the suspension completely. IPA (330 mL) was added to the concentrated liquid and maintained at 70℃or higher, and the IPA was clarified and filtered at 60 to 70 ℃. The solution was concentrated at normal pressure to a liquid volume of around 660 mL. IPA (165 mL) was added to the concentrated liquid and maintained at 70℃or higher, and the IPA was clarified and filtered at 60 to 70 ℃. The solution was concentrated at normal pressure to a volume of about 264 mL. The internal temperature was adjusted to 75-85 ℃, and seed crystals were added. Cooling to the internal temperature of 55-65 ℃ at 10-20 ℃/h, and stirring for 30-60 min at the temperature. Then, the mixture is cooled to an internal temperature of 0 to 10 ℃ at 10 to 20 ℃/h. After confirming that the internal temperature reached 0 to 10 ℃, the slurry was transferred to a filter, and filtration was performed. After filtration, a washing operation with IPA (138 mL) was performed twice. Next, the pre-prepared IPAc/n-heptane=3/7 (volume ratio) solution (about 99 mL) was added to the filter and stirred at 5-30 ℃ for 10 minutes. After completion of stirring, liquid removal was performed. Next, the pre-prepared IPAc/n-heptane=3/7 (volume ratio) solution (about 99 mL) was added to the filter and stirred at 5-30 ℃ for 10min. After completion of stirring, liquid removal was performed. In addition, a pre-prepared IPAc/n-heptane=3/7 (volume ratio) solution (about 165 mL) was added and stirred at 20 to 30 ℃ for 1 hour or more. After completion of stirring, the resulting crystals were subjected to liquid removal and dried under reduced pressure at an external temperature of 45 to 55℃for 240 minutes. The obtained enzalutamide form A crystals were 45.79g, and the yield was 90.22% and the purity was 99.25%.
Comparative example 3
10G of 4- [3- [ 4-cyano-3- (trifluoromethyl) phenyl ] -5, 5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl ] -2-fluoro-N-methylbenzamide is taken and added into 200ml of absolute methanol according to the volume ratio, 10ml of dioxane is added, 300ml of water is added at room temperature, and stirring is carried out until crystals are slowly separated out; filtering and collecting the obtained solid, and stirring until crystals slowly precipitate; the resulting solid was collected by filtration to give crystals of enzalutamide form a in a yield of 85.47% and a purity of 99.18%.
Comparative example 4
50G of enzalutamide and 270ml of water, 30ml of acetone are added into a 5L reaction kettle provided with a stirrer, a thermometer and a condenser, stirring is started, heating is carried out until the solution is dissolved, and filtering is carried out while the solution is still hot. Naturally cooling the filtrate to 38-43 ℃, preserving heat and stirring for 0.5h, then cooling to 25-30 ℃, preserving heat and stirring for 2-3 h, precipitating crystals, filtering, and drying the solid indoors to obtain 47.6g of white crystals, wherein the yield is 95.20% and the purity is 99.21%.
Stability test
The specific stability test method is carried out by referring to the guidance method related to stability investigation in the fourth section of Chinese pharmacopoeia, the purity detection is carried out by using an HPLC method, and the specific detection result is shown in Table 3.
TABLE 3 stability test results of different Enzalutamide crystals under light, high temperature and high humidity conditions
Experimental results show that the enzalutamide-saccharin eutectic prepared by the embodiment of the invention has high purity, small sample purity change under high temperature, high humidity and strong light conditions and good stability. Examples 1 to 6 were examined and found to have similar stability test results.
Solubility experiment
The method comprises the following steps: respectively weighing 10ml of medium (water, 0.01mol/LHCl solution) in a penicillin bottle, adding excessive sample to be tested, sealing the penicillin bottle, placing in a constant-temperature water bath at 25 ℃ for stirring for 1 hour, filtering by a filter membrane, and taking filtrate; the absorbance was measured at a wavelength of 270nm, and the solubility was calculated by measuring the absorbance of the standard control.
TABLE 4 solubility (mg/ml) of different enzalutamide crystals in different media
Test results show that the solubility of the enzalutamide-saccharin eutectic in 0.01mol/L HCl and water is obviously improved compared with other crystal forms of the enzalutamide, and the bioavailability of the enzalutamide-saccharin eutectic is improved. Examples 1 to 6 were examined and found to have similar solubility test results.

Claims (10)

1. An enzalutamide-saccharin eutectic, which is characterized in that the molar ratio of the enzalutamide to the saccharin is 1:1, and a eutectic basic unit consists of one molecule of the enzalutamide and one molecule of the saccharin, and the crystallographic parameters are as follows: orthorhombic system, chiral space group is Pbca; the unit cell parameters are: α=90°, β=90°, γ=90°, unit cell volume
2. The enzalutamide-saccharin co-crystal of claim 1, wherein: the enzalutamide-saccharin co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 9.47+/-0.2 degrees, 15.51+/-0.2 degrees, 19.03+/-0.2 degrees, 19.09+/-0.2 degrees, 19.79+/-0.2 degrees and 22.18+/-0.2 degrees, and 24.85+/-0.2 degrees.
3. The enzalutamide-saccharin co-crystal of claim 1, wherein: the enzalutamide-saccharin co-crystal has a characteristic peak at least at 9.47±0.2°,10.83±0.2°,13.40±0.2°,13.66±0.2°,15.51±0.2°,15.87±0.2°,19.03±0.2°,19.09±0.2°,19.79±0.2°,20.24±0.2°,22.1853±0.2°,23.68±0.2°,24.85±0.2°,28.44±0.2°,28.73±0.2°,28.81±0.2°,29.91±0.2° using an X-ray diffraction pattern expressed in 2θ of Cu-ka radiation.
4. The enzalutamide-saccharin co-crystal of claim 1, wherein: the enzalutamide-saccharin co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1.
5. A process for the preparation of an enzalutamide-saccharin co-crystal according to claims 1 to 3, which comprises the steps of:
dissolving the enzalutamide and saccharin in the solvent A, heating to dissolve, cooling to crystallize after clarifying the solution, filtering and drying to obtain the enzalutamide-saccharin eutectic.
6. The method for preparing an enzalutamide-saccharin co-crystal according to claim 4, wherein the solvent a is one or a combination of isopropanol-acetic acid, methanol-acetic acid, ethanol-acetic acid, and n-butanol-acetic acid, and particularly preferably one of isopropanol-acetic acid and methanol-acetic acid.
7. The method for preparing an enzalutamide-saccharin co-crystal according to claim 4, wherein the molar ratio of the enzalutamide to the saccharin is 1:1-1.8; preferably, the molar ratio of enzalutamide to saccharin is 1:1-1.5.
8. The method for preparing the enzalutamide-saccharin co-crystal according to claim 4, wherein the mass-volume ratio of the enzalutamide to the solvent A in the system is 6-8: 1, wherein the mass is in mg and the volume is in mL.
9. The method for preparing an enzalutamide-saccharin eutectic according to claim 4, wherein the dissolution heating temperature is 60-70 ℃ and the crystallization time is 48-72 hours.
10. Use of an enzalutamide-saccharin co-crystal according to any one of claims 1 to 3, for the preparation of a male castration-resistant prostate cancer drug as an active ingredient.
CN202310202663.0A 2023-02-28 2023-02-28 Enzalutamide-saccharin eutectic and preparation method thereof Pending CN118561761A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310202663.0A CN118561761A (en) 2023-02-28 2023-02-28 Enzalutamide-saccharin eutectic and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310202663.0A CN118561761A (en) 2023-02-28 2023-02-28 Enzalutamide-saccharin eutectic and preparation method thereof

Publications (1)

Publication Number Publication Date
CN118561761A true CN118561761A (en) 2024-08-30

Family

ID=92469200

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310202663.0A Pending CN118561761A (en) 2023-02-28 2023-02-28 Enzalutamide-saccharin eutectic and preparation method thereof

Country Status (1)

Country Link
CN (1) CN118561761A (en)

Similar Documents

Publication Publication Date Title
TWI597277B (en) Form i crystal of dimaleate salt of tyrosine kinase inhibitor and preparation method thereof
CN112047892B (en) Gefitinib and 3-hydroxybenzoic acid eutectic
CN112142679B (en) Gefitinib and vanilloid eutectic methanol solvate and preparation method thereof
CN112047893B (en) Gefitinib and salicylic acid co-crystal
EP2651952A2 (en) Polymorphic forms of asenapine maleate and processes for their preparation
TWI819502B (en) Triethylenetetramine tetrahydrochloride and its preparation method and composition
CN109438370B (en) Methylpyrazine derivative anhydrous crystal form
CN118561761A (en) Enzalutamide-saccharin eutectic and preparation method thereof
CN108570045B (en) Crystal form of anisodamine hydrobromide, preparation method and pharmaceutical composition thereof
CN109438372B (en) Methyl pyrazine derivative methanol compound
CN113754596A (en) Gefitinib co-crystal
TW201739750A (en) An amine solvent complex of sodium-dependent glucose co-transporter protein, a preparation method for same and applications thereof
CN114685455A (en) AZD9291 crystalline solid
CN113968822B (en) Gefitinib-resveratrol eutectic crystal
CN113121456B (en) Acipimox urea eutectic
CN114656448A (en) Topiroxostat-sulfamic acid eutectic crystal
CN113121419A (en) Acipimox-1, 2-di (4-pyridyl) ethylene eutectic crystal
CN114685435B (en) Alitinib maleate crystal form and preparation thereof
CN113929630B (en) Gefitinib drug co-crystal
CN114181211B (en) Ketorolac and benzamide eutectic and preparation method thereof
CN114560822B (en) Mosapride dicarboxylic acid crystal
KR102150825B1 (en) Novel sglt-2 inhibitors cocrystal
CN114315750B (en) Mosapride-succinic acid eutectic crystal
CN111518098B (en) Methylpyrazine derivative theophylline dihydrate
CN114591260A (en) Mosapride organic acid salt

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication