CN114478673A - Estriol drug cocrystal and preparation method and application thereof - Google Patents
Estriol drug cocrystal and preparation method and application thereof Download PDFInfo
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- CN114478673A CN114478673A CN202210133273.8A CN202210133273A CN114478673A CN 114478673 A CN114478673 A CN 114478673A CN 202210133273 A CN202210133273 A CN 202210133273A CN 114478673 A CN114478673 A CN 114478673A
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- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 229960001348 estriol Drugs 0.000 title claims abstract description 49
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 title claims abstract description 48
- 239000003814 drug Substances 0.000 title claims abstract description 30
- 229940079593 drug Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000013078 crystal Substances 0.000 claims abstract description 45
- 239000004202 carbamide Substances 0.000 claims abstract description 34
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 32
- 230000005496 eutectics Effects 0.000 claims abstract description 26
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 238000000498 ball milling Methods 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000843 powder Substances 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 206010003693 Atrophic vulvovaginitis Diseases 0.000 claims description 3
- 206010027304 Menopausal symptoms Diseases 0.000 claims description 3
- 208000006374 Uterine Cervicitis Diseases 0.000 claims description 3
- 206010008323 cervicitis Diseases 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 201000010808 postmenopausal atrophic vaginitis Diseases 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 12
- 238000000034 method Methods 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 7
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 229910002483 Cu Ka Inorganic materials 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- -1 isonicotinine Chemical compound 0.000 description 2
- CAWHJQAVHZEVTJ-UHFFFAOYSA-N methylpyrazine Chemical compound CC1=CN=CC=N1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 description 2
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- TWGNOYAGHYUFFR-UHFFFAOYSA-N 5-methylpyrimidine Chemical compound CC1=CN=CN=C1 TWGNOYAGHYUFFR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000005102 attenuated total reflection Methods 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- RDYMFSUJUZBWLH-UHFFFAOYSA-N endosulfan Chemical compound C12COS(=O)OCC2C2(Cl)C(Cl)=C(Cl)C1(Cl)C2(Cl)Cl RDYMFSUJUZBWLH-UHFFFAOYSA-N 0.000 description 1
- 125000000251 estriol group Chemical group 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940110266 farxiga Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 description 1
- 229950000991 ipragliflozin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- VHNQIURBCCNWDN-UHFFFAOYSA-N pyridine-2,6-diamine Chemical compound NC1=CC=CC(N)=N1 VHNQIURBCCNWDN-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Reproductive Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Gynecology & Obstetrics (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a medicine cocrystal of estriol, a preparation method and application thereof. The estriol pharmaceutical co-crystal is formed by an active ingredient estriol and a co-crystal formation urea, wherein the estriol and the urea are connected through hydrogen bonds. The estriol-urea eutectic prepared by the invention has good stability, obviously improved solubility and obviously increased bioavailability, can control the release of estriol, prolongs the delivery of estriol, and has the potential of reducing dosage and related side effects. The price of the eutectic reagent used in the invention is low, and the eutectic preparation adopts methods with lower production cost such as ball milling, so that the eutectic method is adopted to improve the water solubility of the drug, meanwhile, the production cost of the drug is not obviously increased, and the basic stability of the price of the eutectic drug can be ensured.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical co-crystal preparation, and particularly relates to a pharmaceutical co-crystal of estriol and a preparation method and application thereof.
Background
The pharmaceutical co-crystal is a supermolecule which is formed by acting force between molecules such as hydrogen bonds and the like between drug molecules and a co-crystal reagent and has a fixed composition and a single melting point. The existing research results show that the pharmaceutical cocrystal is formed by using a cocrystal reagent with better water solubility and an insoluble drug, so that the water solubility and the bioavailability of the insoluble drug can be obviously improved under the condition of not changing the molecular structure of the drug, and the cocrystal is the latest key technology for improving the physicochemical properties of the drug such as water solubility, permeability, stability and the like. The U.S. FDA has provided a guiding principle in the pharmaceutical co-crystal industry in 2013, and the pharmaceutical co-crystal is listed as a pharmaceutical excipient; the principle is revised in 2016, and the pharmaceutical co-crystal is further classified as a solid pharmaceutical solvate, so that a guiding principle is provided for approval and marketing of the co-crystal drug. In 2014, two co-crystal drugs for treating diabetes, namely, farxiga and Suglat, were approved to be on the market, and in 2015, a heavy-pound co-crystal drug for treating heart failure, namely, LCZ696, by Nowa, was approved to be on the market.
Estriol is a natural estrogen that is mainly present in urine. Is characterized by having selective action on vagina and cervical canal, and having no influence on uterine entity and endometrium. Can be used for treating cervicitis, especially menopausal syndrome and senile vaginitis. Estriol is an odorless, tasteless white crystalline powder that is insoluble in water and has the following structural formula:
a novel idea and attempt are provided for improving the water solubility and stability of the steroid hormone indissoluble oral contraceptive by adopting a pharmaceutical co-crystal method.
Disclosure of Invention
The invention aims to provide a medicine cocrystal of estriol and a preparation method and application thereof.
The drug cocrystal of estriol is formed by estriol as an active ingredient and urea as a eutectic formation, and the estriol and the urea are connected through hydrogen bonds.
The femaleThe pharmaceutical co-crystal of triol has the formula C19H28N2O4Wherein the mole ratio of estriol to urea is 1: 1.
The estriol pharmaceutical cocrystal belongs to a triclinic system, and the space group is P1The unit cell parameters are:
α is 90 °, β is 116.556(14 °), γ is 90 °, Z is 2, and the unit cell volume is
The drug cocrystal of estriol has characteristic peaks at 13.398 °, 15.239 °, 17.980 °, 18.860 °, 19.960 °, 20.981 °, 22.341 °, 29.081 ° in an X-ray powder diffraction pattern expressed by 2 θ degrees, wherein the error range of 2 θ of each characteristic peak is ± 0.2 °.
The melting point of the estriol drug eutectic is 135.1 +/-0.1 ℃.
The preparation method of the estriol medicine eutectic comprises the following steps: and (3) placing the estriol, the urea and the ethyl acetate into a ball mill for ball milling for 20-60 minutes to obtain white solid powder, namely the estriol-urea eutectic.
The preparation method of the estriol drug eutectic single crystal comprises the following steps: mixing estriol, urea and ethyl acetate to obtain a suspension, stirring at room temperature for 20-30 hours, filtering, and volatilizing the solvent from the filtrate at room temperature to obtain colorless blocky crystals, namely the single crystals of the estriol-urea eutectic.
In the above preparation method, the addition amount of estriol and urea is 1:1 by mole.
The estriol pharmaceutical cocrystal is applied to the preparation of medicines for treating cervicitis, menopausal syndrome and senile vaginitis.
A pharmaceutical composition comprising a pharmaceutical co-crystal of estriol as described above and a pharmaceutically acceptable carrier or adjuvant.
The estriol-urea eutectic prepared by the invention has good stability, obviously improved solubility and obviously increased bioavailability, can control the release of estriol, prolongs the delivery of estriol, and has the potential of reducing dosage and related side effects. The price of the eutectic reagent used in the invention is low, and the eutectic preparation adopts methods with lower production cost such as ball milling, so that the eutectic method is adopted to improve the water solubility of the drug, meanwhile, the production cost of the drug is not obviously increased, and the basic stability of the price of the eutectic drug can be ensured.
Drawings
Fig. 1 is a graph showing the results of simultaneous thermal analysis (TG-DSC) of estriol-urea cocrystals prepared in example 2.
Fig. 2 is a fourier transform infrared (FT-IR) spectrum of the estriol-urea co-crystal prepared in example 2.
Fig. 3 is a powder X-ray diffraction (PXRD) pattern of the estriol-urea co-crystal prepared in example 2.
FIG. 4 shows the nuclear magnetic hydrogen spectrum of the estriol-urea cocrystal prepared in example 2: (1H-NMR)。
Fig. 5 is a structural analysis diagram of the estriol-urea cocrystal prepared in example 2.
Fig. 6 is a graph showing the stability evaluation results of the estriol-urea cocrystal prepared in example 2.
Fig. 7 is a graph showing the results of comparing the water solubility of the estriol-urea co-crystal prepared in example 2.
Detailed Description
Example 1
Ball milling method: placing 0.2884g (0.001mol) of estriol, 0.06g (0.001mol) of urea and 1 drop of ethyl acetate into a ball mill (German RetschMM200), and then carrying out ball milling at 25Hz for 30 minutes to obtain white solid powder, namely estriol-urea eutectic.
Example 2
A suspension method comprises the following steps: mixing 0.2884g (0.001mol) of estriol, 0.06g (0.001mol) of urea and 5mL of ethyl acetate, stirring at room temperature for reaction for 24 hours, filtering, and volatilizing the solvent from the filtrate at room temperature to obtain colorless blocky crystals, namely the estriol-urea eutectic single crystal.
The estriol-urea eutectic prepared above was subjected to characterization analysis:
1. simultaneous thermal analysis (TG-DSC): STA 449F3+ ASC, German Steed instruments manufacturing Ltd. The analysis conditions are as follows: an aluminum crucible, a nitrogen atmosphere (20 mL/min of protective gas and 60mL/min of purge gas), a temperature range of room temperature to 400 ℃, and a heating rate of 10 ℃/min. The Differential Scanning Calorimeter (DSC) of fig. 1 shows: the eutectic melting point is 135.1 ℃; thermogravimetric analysis (TGA) shows: decomposition of urea and decomposition of estriol were observed over the temperature range tested.
2. Fourier transform infrared spectroscopy (FT-IR) test: bruker Vertex 70, Bruker Brooks analysis, Inc. Germany. And (3) testing conditions are as follows: scanning range 4000--1Resolution 4.000cm-1The number of scanning times is 128, and the attenuated total reflection technology is used for measurement. FIG. 2 Fourier transform Infrared Spectroscopy (FT-IR) data as follows:
3. powder X-ray diffraction (PXRD) test: bruker D8 PHASER, Bruker, Germany, Bruk, Inc. And (3) testing conditions are as follows: normal temperature, light source Cu Ka
Voltage 30kV, current 10mA, test step size 0.014 degree, scanning speed 0.1s/step and scanning range 3-60 degrees (2 theta). Figure 3 powder diffraction pattern data are:
4. nuclear magnetic hydrogen spectrum (1H-NMR) test: AVANCE III 400MHz, Bruker analysis, Germany. And (3) testing conditions are as follows: solvent d6DMSO, 16 scans. The nuclear magnetic hydrogen spectrum chemical shift data is as follows:
5. single crystal X-ray diffraction (SXRD) test: gemini A Ultra, Agilent, USA. And (3) testing conditions are as follows: the light source is Cu Ka
Data was collected in a ω/2 θ scan. Reduction and absorption correction of data: CrysAlis PRO software. Space group: and determining according to the extinction rule of the system, and verifying by the fine modification result. Crystal structure analysis: the SHELXS-97 program, the direct method, corrects the result by a full matrix least square method, the coordinates of hydrogen atoms on carbon are added according to theoretical calculation, and the coordinates of hydrogen atoms on other atoms are added according to calculation of an electron density map. From the following single crystal structure analysis results, it is found that the estriol-urea eutectic has a molecular ratio of 1:1, and the two are connected by a hydrogen bond.
6. Evaluation of stability: a drug stability test kit (model DAA-1, Shanghai-Hengchun scientific instruments, Inc.) was used. And (3) testing conditions are as follows: the sample is placed in a drug stability experimental box for 10 days under the conditions of high temperature (60 ℃), high humidity (90 +/-5%) and illumination (4500 +/-500 lx), and the sample is sampled for PXRD analysis. From fig. 6 it can be seen that the co-crystal is stable under high temperature, high humidity, light conditions.
7. Evaluation of water solubility: a dissolution apparatus (RC806D, Technology Ltd. Tianjin Tiandada). The experimental conditions are as follows: deionized water (degassed standby), volume: 1000mL, temperature: 37 ℃, rotation speed: grinding estriol with different eutectic crystals at 100rpm, respectively taking 20mg of the fine powder, placing in a dissolution instrument, sampling 10mL for 5min, 15min, 30min, 60min, 120min, 240min, 300min and 360min, supplementing 10mL of liquid, filtering with 0.45 μm membrane, and measuring content by high performance liquid chromatography. As can be seen from fig. 7, the co-crystal is more water soluble than estriol, and thus the water solubility of estriol can be increased by forming the co-crystal.
Comparative example:
the single crystal of the drug cocrystal of estriol could not be synthesized by the method of example 2 using acetamide, piperazine, isonicotinine, tetrabutylammonium bromide, 2-methylpyrazine, imidazole, 5-methylpyrimidine, 4' -bipyridine, tetramethylurea, anthranilamide, 2, 6-diaminopyridine, uracil instead of urea, which is the eutectic former in example 2.
Claims (9)
1. A pharmaceutical co-crystal of estriol, characterized in that it is formed by the active ingredient estriol and the co-crystal former urea, the estriol and urea being linked by hydrogen bonds.
2. The pharmaceutical co-crystal of estriol according to claim 1, characterized in that said co-crystal has the formula C19H28N2O4Wherein the mole ratio of estriol to urea is 1: 1.
3. The pharmaceutical co-crystal of estriol according to claim 1, characterized in that said co-crystal belongs to the triclinic system with the space group P1The unit cell parameters are:
α is 90 °, β is 116.556(14 °), γ is 90 °, Z is 2, and unit cell volume is
4. The pharmaceutical co-crystal of estriol according to claim 1, characterized in that said co-crystal has characteristic peaks in the X-ray powder diffraction pattern expressed in degrees 2 Θ at 13.398 °, 15.239 °, 17.980 °, 18.860 °, 19.960 °, 20.981 °, 22.341 °, 29.081 °, wherein each characteristic peak has an error in 2 Θ in the range ± 0.2 °.
5. The pharmaceutical co-crystal of estriol according to claim 1, characterized in that said co-crystal has a melting point of 135.1 ± 0.1 ℃.
6. A preparation method of estriol drug cocrystal is characterized by comprising the following specific operations: and (3) placing the estriol, the urea and the ethyl acetate into a ball mill for ball milling for 20-60 minutes to obtain white solid powder, namely the estriol-urea eutectic.
7. A preparation method of estriol drug eutectic single crystal is characterized by comprising the following specific operations: mixing estriol, urea and ethyl acetate to obtain a suspension, stirring at room temperature for 20-30 hours, filtering, and volatilizing the solvent from the filtrate at room temperature to obtain colorless blocky crystals, namely the single crystals of the estriol-urea eutectic.
8. Use of a pharmaceutical co-crystal of estriol according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of cervicitis, menopausal syndrome, senile vaginitis.
9. A pharmaceutical composition comprising a pharmaceutical co-crystal of estriol according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier or adjuvant.
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| CN112675180A (en) * | 2019-10-18 | 2021-04-20 | 国家卫生健康委科学技术研究所 | Ethinylestradiol pharmaceutical co-crystal and preparation method and application thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794555A (en) * | 2018-04-26 | 2018-11-13 | 国家卫生计生委科学技术研究所 | A kind of ethinyloestradiol pharmaceutical co-crystals and preparation method thereof |
| CN112675180A (en) * | 2019-10-18 | 2021-04-20 | 国家卫生健康委科学技术研究所 | Ethinylestradiol pharmaceutical co-crystal and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
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| 徐娟: ""雌三醇的共晶研究"", 《医学导报》 * |
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