CN108794555A - A kind of ethinyloestradiol pharmaceutical co-crystals and preparation method thereof - Google Patents
A kind of ethinyloestradiol pharmaceutical co-crystals and preparation method thereof Download PDFInfo
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- CN108794555A CN108794555A CN201810384769.6A CN201810384769A CN108794555A CN 108794555 A CN108794555 A CN 108794555A CN 201810384769 A CN201810384769 A CN 201810384769A CN 108794555 A CN108794555 A CN 108794555A
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- ethinyloestradiol
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- niacinamide
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- 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
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- 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
Abstract
The invention discloses a kind of ethinyloestradiol novel crystal forms, the crystal form is a kind of nicotinamide eutectic drug, which is monoclinic system, which stablizes under high temperature, high humidity, illumination condition, and there is preferable solubility in 0.2%SDS and 0.5%SDS solution, help to improve the bioavilability of drug.
Description
Technical field
The invention belongs to field of medicaments, it is related to a kind of ethinyloestradiol pharmaceutical co-crystals and preparation method thereof, is specifically related to one kind
Ethinyloestradiol-nicotinamide eutectic.
Background technology
Ethinyloestradiol is -17 α of 3- hydroxy-19-nors-pregnant steroid -1,3, and 5 (10)-triolefin -20- alkynes -17- alcohol, empirical formula is
C20H24O2.Ethinyloestradiol is the crystalline powder of white or off-white color, odorless, readily soluble in ethyl alcohol, propyl alcohol or ether, in chloroform
Dissolving, it is insoluble in water.Ethinyloestradiol can be used for complementing estrogen deficiency, and treatment female gonad dysfunction, amenorrhoea, climacteric are comprehensive
Simulator sickness etc.；Treatment for advanced breast cancer (postmenopausal women), advanced prostate cancer；It shares, can press down with progestogens medicine
System ovulation, can make contraceptive；It is additionally operable to children cryptorchidism and Hyperandrogenism, pituitary tumor etc.；It hangs down for diagnosing hypothalamus-gland
Body-gonad function obstacle.
Oral contraceptive be the women of child-bearing age, particularly it is unmarried, do not educate the measure that avoids conception and control birth that women most often takes.It is oral
Contraceptive is mostly steroid hormone class drug, and excessive use can cause abnormal ovulation even infertile, be educated to seriously affect China
The healthy reproduction of age women threatens China next generation newborn population quantity and quality.Poorly water-soluble is being total to for steroid compound
Sex chromosome mosaicism, ethinyloestradiol need large dosage oral (0.02-1 mg/days) to can be only achieved necessary blood concentration.Improve steroid hormone
The water solubility and bioavilability of class drug, it is current China's oral contraceptive urgent problem to be solved to reduce oral dose.
In pharmacy procedure, we are often the requirement according to drug self property and to target formulation to select drug
The effect of dosage form, drug, is largely dependent upon its dosage form and kenel.And most of drug is solid-type, difference is solid
Influence of the drug of body crystal form to drug quality is different.In preparation research, the different solid-types of drug have difference
Particle properties and powder property, such as the appearance of particle, size, porosity and powder mobility, these factors all can shadow
The quality rung to drug products even seriously affects clinical efficacy.Therefore, the selection of medical solid form is pharmaceutical preparation research
The most important thing.
Pharmaceutical co-crystals are as a kind of novel medical solid existence form, its fusing point to pharmaceutical preparation, qualitative, solubility
There is considerable effect with many aspects such as bioavilability.By designing and developing out more bulk pharmaceutical chemicals to pharmaceutical co-crystals
The physicochemical property and curative effect of novel form and improvement bulk pharmaceutical chemicals make pharmaceutical co-crystals become an emerging field of medicament research and development.
Invention content
In order to make up for the deficiencies of the prior art, the purpose of the present invention is to provide a kind of novel crystal forms of ethinyloestradiol, to improve
The solubility of ethinyloestradiol bulk pharmaceutical chemicals is small, the low disadvantage of bioavilability.
To achieve the goals above, the present invention adopts the following technical scheme that：
The present invention provides a kind of ethinyloestradiol pharmaceutical co-crystals, the pharmaceutical co-crystals be using ethinyloestradiol as active constituent, with
Niacinamide is eutectic formation, and the two is connected using hydrogen bond, and the empirical formula of pharmaceutical co-crystals is C26H30N2O3。
Further, the pharmaceutical co-crystals are monoclinic system, and P2 (1) space group, cell parameter is α=γ=90o, β=99.603 (6) o, Z=2, unit cell volume
For
Further, radiated using Cu-K α, the X-ray powder diffraction indicated with 2 θ angles about 11.30 °, 14.25 °,
Existing characteristics diffraction maximum at 16.14 °, 18.43 °.
Further, radiated using Cu-K α, the X-ray powder diffraction indicated with 2 θ angles also about 12.51 °, 13.28 °,
There is characteristic diffraction peak at 17.20 °, 18.12 °, 21.90 °, 22.27 °, 24.50 °, 25.07 °, 27.31 °, 28.98 °.
Further, using infrared absorption spectrum analysis, there is feature at 1675,1448,1225,1017,874,639cm-1
Absorption peak.
The present invention provides a kind of preparation method of above-mentioned ethinyloestradiol pharmaceutical co-crystals, the specific steps are：By ethinyloestradiol and cigarette
Amide is added in mortar, with acetonitrile solvent assisted milling 1h to get white powder samples.
Further, the molar ratio of ethinyloestradiol and niacinamide is 1:1.
The present invention provides application of the above-mentioned ethinyloestradiol pharmaceutical co-crystals in preparing contraceptive.
The present invention provides above-mentioned ethinyloestradiol pharmaceutical co-crystals answering in the pharmaceutical composition for preparing treatment gynecological disease
With wherein gynecological disease includes dysfunctional uterine bleeding, Stein-Leventhal syndrome, endometriosis, uterine gland flesh
Disease, primary dysmenorrhea, amenorrhoea etc..
The present invention provides a kind of pharmaceutical composition, the pharmaceutical composition include ethinyloestradiol pharmaceutical co-crystals recited above with
And pharmaceutically acceptable carrier.
Pharmaceutically acceptable carrier includes but is not limited to diluent, adhesive, surfactant, Humectant, absorption
The appropriate form of carrier, lubricant, filler, disintegrant, the composition will be determined according to the mode of medication.
By it is being mixed with and be suitable for taking orally, parenteral or the pharmaceutical composition of local administration its dosage form can be pieces
Agent, oral liquid, pulvis, pastille, pastille, the pulvis that can match again, the solution or suspension of injection and perfusion, suppository and
Transcutaneous assemblies.Orally available composition is preferred, especially has shaped Orally administered composition, makes because they are generally facilitated
With.
Oral tablet and capsule is typically unit dose, and contains common excipients such as binder, filler, dilution
Agent, piece agent, lubricant, colorant, flavoring agent and wetting agent.These tablets can be coated by methods known in the art.
It includes starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate to be suitble to the filler used.It closes
Suitable lubricant is for example including magnesium stearate.The suitable acceptable wetting agent of medication includes lauryl sodium sulfate.
Solid oral composition can use the common methods such as blending, filling, film-making to prepare.Blending behaviour repeatedly may be used
Activating agent is distributed to in those of mass filler composition by work comprehensively.Way is very convenient naturally in the art in this way
's.
The form of oral liquid for example can be aqueous or oiliness suspension, solution, lotion, syrup or elixir,
Or can be the product that can be again assembled with water or other suitable carriers before use of drying.This liquid preparation can contain
Common additive such as suspending agent such as sorbierite, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose
Element, aluminium stearate gel or edible hydrogenated fat；Emulsifier such as lecithin, anhydro sorbitol list olein or Arabic gum；
The ester such as glycerine, propylene glycol or ethyl alcohol of non-aqueous carrier (may include edible oil) such as apricot kernel oil, fraction cupu oil, oily
Ester；Preservative such as methyl p-hydroxybenzoate or ethyl ester or sorbic acid, and may also include common flavoring agent if necessary
Or colorant.
For parenteral administration, the compounds of this invention and sterilant carriers are configured to fluid unit dosage forms.The compound
Can suspend or can also be dissolving, the preparation of parenteral administration solution is usually to be dissolved in reactive compound
In carrier, filtration sterilization is first carried out before pouring into bottle or ampoule appropriate and being sealed.Preferably by some adjuvants such as office
Anesthetic, preservative and buffer also it is molten in the carrier.In order to improve the stability of pharmaceutical composition, bottle and true is being poured into
Sky can be freezed after removing moisture content.
Parenteral is prepared with suspension with substantially the same mode, and only reactive compound is suspended in carrier
And do not dissolve, and by making its sterilizing with ethylene oxide treatment before being suspended in sterilant carriers.Preferably add in the composition
There are surfactant or wetting agent being uniformly distributed in favor of reactive compound.
Can be the percutaneous ointment or patch of systemic delivery compound for the composition of local administration, preparing can be with
With such as standard textbook ' Dermatological Formulations '-B.W.Barry (Drugs and
Pharmaceutical Sciences-Ddkker) or Harrys Cosmeticology (Leonard Hill Books) in institute
The common method stated.
The advantages of the present invention：
Ethinyloestradiol-niacinamide pharmaceutical co-crystals of the present invention have preferable stability, and dissolubility has larger improvement, has
Help improve bioavilability.
Description of the drawings
Fig. 1 is the mono-crystalline structures figure of ethinyloestradiol-niacinamide, wherein figure A is molecular structure；Figure B is the hydrogen along b axis directions
Key connection figure；
Fig. 2 is X-ray powder diffraction (PXRD) collection of illustrative plates of ethinyloestradiol-niacinamide pharmaceutical co-crystals；
Fig. 3 is the TGA/DSC heat analysis collection of illustrative plates of ethinyloestradiol-niacinamide pharmaceutical co-crystals；
Fig. 4 is infrared (IR) scanning spectra of ethinyloestradiol-niacinamide pharmaceutical co-crystals；
Fig. 5 is ethinyloestradiol-niacinamide pharmaceutical co-crystals1H-NMR nuclear magnetic resonance maps；
Fig. 6 is solubility curve figure of the ethinyloestradiol-niacinamide pharmaceutical co-crystals in different medium；Wherein figure A is 0.2%
Solubility curve figure in SDS；It is the solubility curve figure in 0.5%SDS to scheme B.
Specific embodiment
The present invention is described in further detail with reference to the accompanying drawings and examples.Following embodiment is merely to illustrate this
It invents rather than limits the scope of the invention.Test method without specific conditions in embodiment, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.
The preparation of 1 ethinyloestradiol pharmaceutical co-crystals of embodiment
296.4mg ethinyloestradiols and 122.1mg niacinamide is taken to be added in mortar respectively, with acetonitrile solvent assisted milling 1h, i.e.,
Obtain white powder samples.
Monocrystalline-X-ray diffraction (SXRD) of 2 ethinyloestradiol pharmaceutical co-crystals of embodiment detects
1, it using German Bruker companies APEX II CCD area-detector type X-ray single crystal diffractometers, chooses
The clear crystal of 0.30mm × 0.24mm × 0.22mm sizes, using graphite monochromatised Mo-K alpha rays, radiation wavelengthMeasuring temperature：293(2)K.Structure elucidation and refine are completed using SHELXT-97 (Version 5.1) program.Profit
Atom site is determined with direct method, then finds out whole non-hydrogen atom coordinates with difference function method and least square method, with minimum
Square law is modified structure.
2, result
As a result as shown in table 1 and Fig. 1, the female novel crystal forms of alkynes are ethinyloestradiol-niacinamide pharmaceutical co-crystals, to specific mono-crystalline structures
It is found that not containing solvent molecule on ethinyloestradiol-niacinamide crystal structure, ethinyloestradiol is connected with niacinamide by hydrogen bond for parsing,
Ratio between the two is 1:1.
The crystallographic parameters of 1 ethinyloestradiol of table-nicotinamide eutectic
The PXRD of 3 ethinyloestradiol pharmaceutical co-crystals of embodiment is detected
1, sample
Ethinyloestradiol-nicotinamide eutectic sample (EE-NTA)
2, the setting of X-ray powder diffraction detector
It is detected using German Bruker companies D8 ADVANCE type x-ray powder instrument, specific acquisition information is as follows：Copper
Target, 40KV/40mA, 5 ° of initial angle, 40 ° of end angle, step width 0.02, sweep speed 17.7s/ steps, wavelengthGraphite list
Color device, continuous scanning.
Theoretical spectra：Theoretical spectra is simulated to obtain using Mercury softwares.Software can be downloaded in website：
https://www.ccdc.cam.ac.uk/solutions/csd-system/components/mercury/
3, result
As a result as shown in table 2 and Fig. 2, the X-ray powder diffraction collection of ethinyloestradiol pharmaceutical co-crystals is in the corresponding position of 2 θ values
It is corresponding with characteristic diffraction peak, the theoretical value that abrasive flour is parsed with monocrystalline is consistent in the intensity at peak and position, and explanation is ground
The powder sample of mill and EE-NTA monocrystalline space structure having the same, crystal form are consistent.
The characterize data of the X-ray powder diffraction figure of 2 ethinyloestradiol pharmaceutical co-crystals of table
The TG-DSC heat analysis of 4 ethinyloestradiol pharmaceutical co-crystals of embodiment detects
1, using NETZSCH STA 449C thermogravimetrics-differential scanning calorimetry instrument and Perkin Elmer TGA-7 amount analyzers
(TG) TG-DSC heat analysis, heating rate are carried out to ethinyloestradiol pharmaceutical co-crystals：10 DEG C/min, temperature range：25--500℃
2, result
TG-DSC testing results are as shown in figure 3, differential scanning calorimetry instrument (DSC) is shown：In Range of measuring temp
(25---500 DEG C), sample ethinyloestradiol-niacinamide do not observe fusing point at 25-500 DEG C；Thermogravimetric analysis (TG) is shown：Sample alkynes
Female alcohol-niacinamide decomposes weightlessness at 174.9 DEG C, and before 174.9 DEG C, TG curves prompt the drug without crystallization without weightlessness
Water.
Infrared (IR) of 5 ethinyloestradiol pharmaceutical co-crystals of embodiment is analyzed
1, infrared spectrum analysis is carried out to novel crystal forms using platinum Elmer Co., Ltd Spectrum Two types infrared spectrometers,
2, result
As a result as shown in Fig. 4 and table 3, ethinyloestradiol-niacinamide 1675,1448,1225,1017,874,639cm-1Etc.
Existing characteristics absorption peak.
The infrared absorption spectrum of 3 ethinyloestradiols of table-niacinamide
6 ethinyloestradiol pharmaceutical co-crystals of embodiment1H-NMR nmr analysis
1, it is detected using Bruker AVANCE III 400MHz type nuclear magnetic resonance chemical analysers, solvent CD3OD.
2, result
The results are shown in Figure 5, and the displacement of nuclear magnetic resonance spectroscopy is as follows：1H NMR(400MHz,Methanol-d4)δ9.02
(d, J=2.4Hz, 1H), 8.68 (dd, J=4.9,1.4Hz, 1H), 8.28 (dt, J=10.04,2.0Hz, 1H), 7.58-
7.51 (dd, 1H), 7.08 (d, J=8.4Hz, 1H), 6.54 (dd, J=8.4,2.6Hz, 1H), 6.47 (d, J=2.5Hz, 1H),
2.89 (s, 1H), 2.81-2.72 (m, 2H), 2.34 (d, J=13.1Hz, 1H), 2.28-2.22 (m, 1H), 2.13 (t, J=
11.0Hz, 1H), 2.02-1.84 (m, 3H), 1.74 (d, J=11.1Hz, 3H), 1.48-1.23 (m, 4H), 0.86 (s, 3H)
The physical and chemical stability of 7 ethinyloestradiol pharmaceutical co-crystals of embodiment is studied
Following experiment is carried out to obtained ethinyloestradiol-nicotinamide eutectic, sampling carries out XRPD experiments.
1, hot test：Crystal form samples are set in clean beaker, are placed 10 days at a temperature of 60 DEG C, and in the 0th day, the 5th
It was sampled with the 10th day.
2, high humidity test：Crystal form samples are set in clean beaker, are placed under the conditions of 25 DEG C in relative humidity 90% ± 5%
10 days, and sampled in the 0th day, the 5th day and the 10th day.
3, exposure experiments to light：Crystal form samples are set in clean beaker, and the lighting box equipped with fluorescent lamp is placed on, in illumination be 4500lx
The condition of ± 500lx is placed 10 days, and is sampled in the 0th day, the 5th day and the 10th day.
4, result
Formula is surveyed through X-ray powder diffraction, the angles main 2 θ do not occur significant changes, illustrate ethinyloestradiol pharmaceutical co-crystals in height
Stablize under temperature, high humidity, illumination.
The dissolved corrosion of 8 ethinyloestradiols of embodiment-nicotinamide eutectic is studied
In order to grasp the relationship of crystal form state and crystal form dissolution properties, dissolution properties are carried out to ethinyloestradiol-nicotinamide eutectic
Evaluation.
1, the selection and preparation of vehicle system
The selection of vehicle system：Provided with water, 0.2%SDS solution, 0.5%SDS solution, the 0.1M hydrochloric acid that pH value is 1.2
This 6 vehicle systems of acetate buffer that solution, pH value are 4.5, pH value are 6.8 phosphate buffer, it is female to investigate alkynes
The dissolution properties of alcohol-nicotinamide eutectic.
2, solubility curve measures
Experimental method：Ethinyloestradiol (EE), ethinyloestradiol-nicotinamide eutectic (CO) sample are weighed in round-bottomed flask, is added molten
Liquid stirs under 25 ± 2 DEG C, 250rmp, is sampled respectively at 5,15,30,60,120,240,300min, and filtering is continuous to take filtrate,
It is detected with high performance liquid chromatography, testing conditions：Mobile phase is water-acetonitrile (1:1), overall flow rate 1mL/min, Detection wavelength are
220nm。
3, result
By experiment, find water, pH value be 4.5 acetate buffer, pH value be 6.8 phosphate buffer this 3
In a vehicle system, ethinyloestradiol, ethinyloestradiol-nicotinamide eutectic can not be detected；In the 0.1M hydrochloric acid solutions that pH value is 1.2,
Ethinyloestradiol, the dissolution properties of ethinyloestradiol-nicotinamide eutectic are consistent, and in 0.2%SDS and 0.5%SDS solution, ethinyloestradiol-cigarette
Amide eutectic dissolubility is better than ethinyloestradiol (shown in Fig. 6).
The explanation of above-described embodiment is only intended to understand the method and its core concept of the present invention.It should be pointed out that for this
For the those of ordinary skill in field, without departing from the principle of the present invention, several improvement can also be carried out to the present invention
And modification, these improvement and modification will also be fallen into the protection domain of the claims in the present invention.
Claims (10)
1. a kind of ethinyloestradiol pharmaceutical co-crystals, which is characterized in that the pharmaceutical co-crystals are using ethinyloestradiol as active constituent, with nicotinoyl
Amine is eutectic formation, and the two is connected using hydrogen bond, and the empirical formula of pharmaceutical co-crystals is C26H30N2O3。
2. ethinyloestradiol pharmaceutical co-crystals according to claim 1, which is characterized in that the pharmaceutical co-crystals are monoclinic system, P2
(1) space group, cell parameter are α=γ=90 °, β=
99.603 (6) °, Z=2, unit cell volume are
3. ethinyloestradiol pharmaceutical co-crystals according to claim 1, which is characterized in that radiated using Cu-K α, indicated with 2 θ angles
X-ray powder diffraction at about 11.30 °, 14.25 °, 16.14 °, 18.43 ° existing characteristics diffraction maximum.
4. ethinyloestradiol pharmaceutical co-crystals according to claim 3, which is characterized in that radiated using Cu-K α, indicated with 2 θ angles
X-ray powder diffraction also about 12.51 °, 13.28 °, 17.20 °, 18.12 °, 21.90 °, 22.27 °, 24.50 °,
There is characteristic diffraction peak at 25.07 °, 27.31 °, 28.98 °.
5. ethinyloestradiol pharmaceutical co-crystals according to claim 1, which is characterized in that infrared absorption spectrum analysis is used,
1675、1448、1225、1017、874、639cm-1There is characteristic absorption peak at place.
6. the preparation method of claim 1-5 any one of them ethinyloestradiol pharmaceutical co-crystals, which is characterized in that by ethinyloestradiol and cigarette
Amide is added in mortar, with acetonitrile solvent assisted milling 1h to get white powder samples.
7. preparation method according to claim 6, which is characterized in that the molar ratio of ethinyloestradiol and niacinamide is 1:1.
8. application of the claim 1-5 any one of them ethinyloestradiol pharmaceutical co-crystals in preparing contraceptive.
9. claim 1-5 any one of them ethinyloestradiol pharmaceutical co-crystals are in the pharmaceutical composition for preparing treatment gynecological disease
Using.
10. a kind of pharmaceutical composition, which is characterized in that including claim 1-5 any one of them ethinyloestradiol pharmaceutical co-crystals with
And pharmaceutically acceptable carrier.
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| CN110105417A (en) * | 2019-05-08 | 2019-08-09 | 国家卫生健康委科学技术研究所 | A kind of pharmaceutical co-crystals body and preparation method and application |
| CN110183310A (en) * | 2019-06-05 | 2019-08-30 | 西北师范大学 | Utilize the method for ultrasonic wave added cocrystallization method preparation resveratrol medicament eutectic |
| CN112159448A (en) * | 2020-09-04 | 2021-01-01 | 国家卫生健康委科学技术研究所 | Ethinylestradiol pharmaceutical co-crystal and preparation method and application 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 |
| CN113292621A (en) * | 2021-05-19 | 2021-08-24 | 国家卫生健康委科学技术研究所 | Pharmaceutical crystal form of progesterone and application thereof |
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| CN110105417A (en) * | 2019-05-08 | 2019-08-09 | 国家卫生健康委科学技术研究所 | A kind of pharmaceutical co-crystals body and preparation method and application |
| CN110003122B (en) * | 2019-05-08 | 2021-01-05 | 国家卫生健康委科学技术研究所 | Pharmaceutical cocrystal of ethinylestradiol and ligustrazine and application thereof |
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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 |
| CN112159448A (en) * | 2020-09-04 | 2021-01-01 | 国家卫生健康委科学技术研究所 | Ethinylestradiol pharmaceutical co-crystal and preparation method and application thereof |
| CN113292621A (en) * | 2021-05-19 | 2021-08-24 | 国家卫生健康委科学技术研究所 | Pharmaceutical crystal form of progesterone and application thereof |
| CN114478673A (en) * | 2022-02-10 | 2022-05-13 | 华润紫竹药业有限公司 | Estriol drug cocrystal and preparation method and application thereof |
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