CN103936808A - Isonicotinamide eutectic crystal of 17beta estradiol, and preparation method and application thereof - Google Patents
Isonicotinamide eutectic crystal of 17beta estradiol, and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides an isonicotinamide eutectic crystal of 17beta estradiol, and a preparation method and application thereof. Particularly, the invention provides the isonicotinamide eutectic crystal of 17beta estradiol. X-ray powder diffraction analysis, thermogravimetic analysis, differential scanning thermometric analysis and other analysis indicate that the eutectic crystal provided by the invention has more excellent physicochemical property and pharmaceutical property. The invention provides the preparation method of the eutectic crystal. The method is simple to operate, easy to control and favorable in reproducibility, and can stably obtain the target eutectic crystal.
Description
Technical field
The present invention relates to pharmaceutical chemistry and crystallization processes technical field, particularly, relate to Isonicotinamide cocrystallization of 17 β estradiol and its preparation method and application.
Background technology
The chemistry of 17 β estradiol (17 β E2) is by name: female steroid-1, and 3,5 (10)-triolefin-3,17-isoallopregnane-3β, its chemical structural formula is as follows:
17 β estradiol are steroids of ovarian secretion, are main female hormone.The clinical various symptoms that cause for hypoovarianism or ovarian hormone deficiency, are mainly dysfunctional uterine hemorrhages, primary amenorrhea, climacteric syndrome and prostate cancer etc.
Due to the insoluble of 17 β estradiol in water, cause the interior bioavailability of its body low.In addition,, at pharmacy field, the physicochemical property of 17 β estradiol is sometimes unsatisfactory.
Medicine cocrystallization refers to active constituents of medicine (API, active pharmaceutical ingredient) molecule and other physiologically acceptable acid, alkali, salt, non-ionic compound molecule is with hydrogen bond, pi-pi accumulation effect, Van der Waals force is connected and is combined in same lattice with other non covalent bonds.
With salt, other solid form such as solvate are compared, and eutectic has larger advantage in medicament research and development.
First, for solvate, because acceptable solvent species is limited in pharmaceutics, and solvate frequent desolventizing (water) phenomenon that occurs in preparation process, change the unsettled amorphous or worse crystal formation of solvability into.
Secondly, with respect to salt, because salify requires bulk drug to have an Ionized center at least, and each component in pharmaceutical co-crystals can be neutral molecule, thereby pharmaceutical co-crystals can contain all API, comprises acid, alkali and non-ionic compound.
And potential being used for forms eutectic molecule with API is also a lot, these materials may comprise foodstuff additive, sanitas, and pharmaceutical excipient, mineral substance, VITAMIN, amino acid and other bioactive molecules, can be even other API.
Up to now, in this area, not yet there is the cocrystallization of the gratifying 17 β estradiol of performance.
In sum, in order to improve 17 β estradiol bioavailabilities, this area is in the urgent need to developing a kind of medicament forms with water-soluble, the stability of improvement and/or 17 β estradiol of pharmacology and pharmacy characteristic.
Summary of the invention
Object of the present invention is to provide a kind of medicament forms and method for making and application with water-soluble, the stability of improvement and/or 17 β estradiol of pharmacology and pharmacy characteristic.
In a first aspect of the present invention, provide a kind of Isonicotinamide cocrystallization of 17 β estradiol.
In another preference, in the Isonicotinamide cocrystallization molecule of described 17 β estradiol, the mol ratio of 17 β estradiol and Isonicotinamide is 1:1.
In another preference, the X-ray powder diffraction of described crystal comprises >=5 be selected from the represented charateristic avsorption band of 2 θ value of lower group: 10.86 ° ± 0.1 °, 12.87 ° ± 0.1 °, 13.35 ° ± 0.1 °, 13.53 ° ± 0.1 °, 15.11 ° ± 0.1 °, 16.31 ° ± 0.1 °, 16.78 ° ± 0.1 °, 17.55 ° ± 0.1 °, 18.42 ° ± 0.1 °, 19.89 ° ± 0.1 °, 20.63 ° ± 0.1 °, 21.17 ° ± 0.1 °, 21.53 ° ± 0.1 °, 21.97 ° ± 0.1 °, 22.51 ° ± 0.1 °, 23.68 ° ± 0.1 °, 26.84 ° ± 0.1 ° and 26.99 ° ± 0.1 °.
In another preference, the X-ray powder diffraction of described crystal comprises the represented charateristic avsorption band of following 2 θ value: 10.86 °, 12.87 °, 13.35 °, 13.53 °, 15.11 °, 16.31 °, 16.78 °, 17.55 °, 18.42 °, 19.89 °, 20.63 °, 21.17 °, 21.53 °, 21.97 °, 22.51 °, 23.68 °, 26.84 ° and 26.99 °.
In another preference, the relative intensity of the charateristic avsorption band of the X-ray powder diffraction of described cocrystallization is as follows:
Table 1
| 2θ(°±0.2) | Relative intensity (% ± 2%) |
| 10.86 | 29.1 |
| 12.87 | 26.5 |
| 13.35 | 8.0 |
| 13.53 | 27.0 |
| 15.11 | 3.2 |
| 16.31 | 39.4 |
| 16.78 | 6.4 |
| 17.55 | 12.3 |
| 18.42 | 3.1 |
| 19.89 | 100 |
| 20.63 | 41.4 |
| 21.17 | 16.3 |
| 21.53 | 29.8 |
| 21.97 | 9.6 |
| 22.51 | 5.6 |
| 23.68 | 21.1 |
| 26.84 | 17 |
| 26.99 | 11.5 |
In another preference, the dsc collection of illustrative plates of described cocrystallization has feature endotherm(ic)peak at 173 ± 1 DEG C.
In another preference, the dsc of described cocrystallization is analyzed collection of illustrative plates substantially as shown in Figure 2.
In another preference, the water absorbability≤1wt% of the dynamic water absorption test of described crystal.
In another preference, in the time that relative humidity RH is less than 80%, the water absorbability≤0.5wt% of the dynamic water absorption test of described crystal.
In another preference, described dynamic water absorption test is by room temperature, and 40%-95%-0%RH method is measured.
In another preference, the Isonicotinamide cocrystallization of described 17 β estradiol is triclinic(crystalline)system, and spacer is P-1.
In another preference, the unit cell parameters of described cocrystallization is:
α=74.300 (1) °, β=79.907 (1) °, γ=68.455 (1) °, unit cell volume is
In another preference, the Isonicotinamide cocrystallization of 17 described β estradiol is anhydrous cocrystallization.
In a second aspect of the present invention, provide as the preparation method of the Isonicotinamide cocrystallization of 17 β estradiol of first aspect present invention, comprise the steps:
(a). a solution that contains 17 β estradiol and Isonicotinamide is provided, and the solvent of wherein said solution is organic solvent; With
(b). described solution is carried out to crystallization treatment, thereby form the Isonicotinamide cocrystallization of 17 β estradiol; With
(c). optionally from described solution, isolate the Isonicotinamide cocrystallization of 17 β estradiol.
In another preference, described step c comprises:
(c1) by filtering, thus the Isonicotinamide cocrystallization of acquisition 17 β estradiol; And/or
(c2) by centrifugal, thus the Isonicotinamide cocrystallization of acquisition 17 β estradiol; And/or
(c3) solvent described in evaporative removal, thereby the Isonicotinamide cocrystallization of 17 β estradiol described in obtaining.
In another preference, in step (b), described solution is carried out to cocrystallization processing, thereby form the cocrystallization solution system containing the Isonicotinamide cocrystallization of 17 β estradiol.
In another preference, described preparation method is further comprising the steps of before in step (a): by 17 β estradiol and Isonicotinamide in molar ratio 1:1 join in organic solvent, thereby form the solution that contains 17 β estradiol and Isonicotinamide.
More preferably, described in contain 17 β estradiol and Isonicotinamide solution in, the mol ratio of 17 β estradiol and Isonicotinamide is 1:1, and removes solvent by slow volatilization, thereby forms 17 β estradiol and Isonicotinamide cocrystallization body.
In another preference, comprising in step (a): during Isonicotinamide is dissolved in to organic solvent, make saturated solution (or near saturated solution), then add 17 β estradiol, form the solution that contains 17 β estradiol and Isonicotinamide.
One of the present invention is preferred preparation method comprise the following steps: Isonicotinamide is dissolved in and in organic solvent, makes saturated solution, then add 17 β estradiol, at the lower suspension forming containing the Isonicotinamide cocrystallization of 17 β estradiol that stirs of certain temperature (as room temperature condition or as 0-40 DEG C), but to described suspension filter and vacuum-drying after, thereby obtain the Isonicotinamide cocrystallization body of 17 β estradiol.
In another preference, described agitation condition is not particularly limited, and for example churning time can be 2-200 hour, is preferably 12-72 hour or 24-48 hour.
In another preference, while adding 17 β estradiol to the saturated solution of Isonicotinamide, the mol ratio of 17 β estradiol and Isonicotinamide is about 10:1-1:5.
In another preference, described crystallization treatment comprises in described solution adds crystal seed.
In another preference, described organic solvent is selected from lower group: acetone, tetrahydrofuran (THF), acetonitrile, ethyl acetate, methylene dichloride, methylethylketone or its combination.
In another preference, water content≤10% of described organic solvent, preferably≤5%, more preferably≤1% or be anhydrous organic solvent.
In a third aspect of the present invention, provide a kind of pharmaceutical composition, Isonicotinamide cocrystallization and the pharmaceutically acceptable carrier of the 17 β estradiol that comprise first aspect present invention.
In a fourth aspect of the present invention, provide a kind of purposes of Isonicotinamide cocrystallization of 17 β estradiol, for the preparation of as medicine.
In another preference, described medicine is used for the treatment of the disease that is selected from lower group: the estrogen deficiency symptom producing after Monitoring Ovarian Function complete or deterioration, ovarian hormone deficiency, dysfunctional uterine hemorrhage, prostate cancer, ovarian function decline, estrogen secretion minimizing, menopausal syndrome, osteoporosis, nature or the menopause of performing the operation, as vasomotor symptoms, flush Hong heat, palpitaition, agitation, atrophic vaginitis etc.
In a fifth aspect of the present invention, a kind of mixture of Isonicotinamide cocrystallization of the 17 β estradiol that are used to form first aspect present invention is provided, 17 β estradiol and Isonicotinamide that wherein said mixture is 1:1 by mol ratio form.
In a fifth aspect of the present invention, a kind of purposes of compound combination is provided, described combination comprises 17 β estradiol and Isonicotinamides, wherein, described compound combination is used to the Isonicotinamide cocrystallization of the 17 β estradiol of preparing first aspect present invention.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can combining mutually between specifically described each technical characterictic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tire out and state no longer one by one at this.
Brief description of the drawings
Fig. 1 has shown X-ray powder diffraction (XRPD) figure of the Isonicotinamide cocrystallization of the 17 β estradiol of embodiment 1
Fig. 2 has shown thermogravimetic analysis (TGA) (TG) figure of the Isonicotinamide cocrystallization of the 17 β estradiol of embodiment 1.
Fig. 3 has shown differential scanning calorimetric analysis (DSC) figure of the Isonicotinamide cocrystallization of the 17 β estradiol of embodiment 1.
Fig. 4 has shown infrared spectra (IR) figure of the Isonicotinamide cocrystallization of the 17 β estradiol of embodiment 1.
Fig. 5 has shown Raman spectrum (Raman) figure of the Isonicotinamide cocrystallization of the 17 β estradiol of embodiment 1.
Fig. 6 has shown dynamic water absorption (DVS) figure of the Isonicotinamide cocrystallization of the 17 β estradiol of embodiment 1.
Embodiment
The inventor, through extensive and deep research and experiment, finds that 17 β estradiol can form cocrystallization with Isonicotinamide unexpectedly.The degree of crystallinity of this cocrystallization is high, and water absorbability is little, and forms regular crystal kenel, and water-soluble obvious enhancing is conducive to the art breading of medicine and the improvement of physical and chemical performance and improves patent medicine performance.In addition, preparation method provided by the invention is simple to operate, is applicable to industrialized production.On this basis, contriver has completed the present invention.
17 β estradiol
As used herein, " active pharmaceutical ingredient of the present invention ", " API ", " active pharmaceutical ingredient ", " active pharmaceutical ingredient " is used interchangeably, and refers to 17 β estradiol in content of the present invention.
Isonicotinamide
Isonicotinamide, claims again Isonicotinamide, carbamyl pyridine or pyridine carboxamide, English name: Isonicotinamide (INA).Chemical formula: C6H6N2O.Isonicotinamide is a kind of important medicine intermediate, the anti-microbial activity that tool is certain.
Cocrystallization
As used herein, " cocrystallization " and " eutectic " can exchange use.
As used herein, term " cocrystallization of the present invention ", " eutectic of the present invention " or " the Isonicotinamide cocrystallization of 17 β estradiol " are used interchangeably, and refer to by the 17 β estradiol as API and the cocrystallization that forms as the Isonicotinamide of CCF.
Due to the existence of part (CCF, cocrystal former also make cocrystallization formation), make the corresponding adjusting obtaining in various degree of character of cocrystallization medicine of the present invention.Particularly, eutectic of the present invention is introduced new component Isonicotinamide in not changing medicine covalent structure, thereby greatly improves the physico-chemical property of medicine, especially water-soluble and bioavailability etc.
The Isonicotinamide cocrystallization of 17 β estradiol of the present invention, the solid-state approach such as available X-ray powder diffraction, thermogravimetic analysis (TGA), differential scanning calorimetric analysis, Raman spectrum, infrared spectra, dynamic water absorption characterize.
Preparation method
The invention provides the preparation method of cocrystallization of the present invention.
Typically, the method for the Isonicotinamide cocrystallization of preparation 17 β estradiol of the present invention comprises step:
(a). a solution that contains 17 β estradiol and Isonicotinamide is provided, and the solvent of wherein said solution is organic solvent; With
(b). described solution is carried out to crystallization treatment, thereby form the Isonicotinamide cocrystallization of 17 β estradiol; With
(c). optionally from described solution, isolate the Isonicotinamide cocrystallization of 17 β estradiol.
In the present invention, in described solution, can add the Isonicotinamide cocrystallization of 17 β estradiol as crystal seed, to promote the formation of cocrystallization.
In the present invention, for the Isonicotinamide cocrystallization of 17 β estradiol forming, conventionally can separate by conventional the whole bag of tricks, comprising (but being not limited to): filter, centrifugal, evaporation (volatilization) solvent or its combination.
One of the present invention is preferred preparation method comprise the following steps: by 17 β estradiol and Isonicotinamide in molar ratio 1:1 join in organic solvent, thereby form the solution that contains 17 β estradiol and Isonicotinamide; Then remove solvent by slowly volatilizing, thereby form 17 β estradiol and Isonicotinamide cocrystallization body.For the cocrystallization body forming, can be by continuing to boil off solvent, or obtain the Isonicotinamide cocrystallization of 17 β estradiol by other separation means.
One of the present invention is preferred preparation method comprise the following steps: Isonicotinamide is dissolved in and in organic solvent, makes saturated solution, then add 17 β estradiol (wherein, the mol ratio of 17 β estradiol and Isonicotinamide is about 10:1-1:5), at the lower suspension forming containing the Isonicotinamide cocrystallization of 17 β estradiol that stirs of certain temperature (as room temperature condition or as 0-40 DEG C), but to described suspension filter and vacuum-drying after, thereby obtain the Isonicotinamide cocrystallization body of 17 β estradiol.Described agitation condition is not particularly limited, and for example churning time can be 2-200 hour, is preferably 12-72 hour or 24-48 hour.
In the present invention, applicable organic solvent comprises all raw material is had certain solubility and raw material do not caused to rotten organic solvent, representational example comprises (but being not limited to): the combination of one or several of the organic solvents such as ketone, nitrile, ethers, ester class, alkane, aromatic hydrocarbon or halogenated alkane, preferably, described organic solvent is one or more the mixture in acetone, tetrahydrofuran (THF), acetonitrile, ethyl acetate, methylene dichloride, methylethylketone.
Pharmaceutical composition
The present invention also provides a kind of Isonicotinamide cocrystallization of 17 β estradiol that has as the composition of pharmaceutical cpd, comprises pharmaceutical composition.
Typically, pharmaceutical composition of the present invention has the Isonicotinamide cocrystallization of 17 β estradiol of the present invention, and pharmacy acceptable salt.Conventionally, this pharmaceutical composition preferably contains the cocrystallization of the present invention that weight ratio is 0.01%-99%, and more preferably containing weight ratio is the cocrystallization of the present invention of 0.1%-90%.
" pharmaceutically acceptable carrier " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for people's use, and must have enough purity and enough low toxicity." consistency " referred to herein as each component energy and cocrystallization of the present invention and blending mutually between them in composition, and the drug effect of not obvious reduction by 17 β estradiol and/or Isonicotinamide.Pharmaceutically acceptable carrier part example has Mierocrystalline cellulose and derivative thereof (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant is (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil is (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol is (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as tween 80), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
Can be by cocrystallization of the present invention or its pharmacy acceptable salt and pharmaceutically acceptable vehicle, the mixture of thinner etc. is with tablet, capsule, granule, the form oral administration of powder or syrup, the parenteral administrations of form such as injection, patch, paster agent or suppository.
In the present invention, particularly preferred formulation comprises oral preparations or passes through " Transcutaneous Therapeutic System " (TTS) formulation of administration.Typically, the pharmaceutical dosage forms of these and skin contact comprises for example ointment, emulsifiable paste, washing lotion and the ointment that contains medicine, these preparations, for discharging 17 β estradiol and/or Isonicotinamide Transcutaneous Therapeutic System by skin to human organ, are treated some diseases.Described disease includes but not limited to: the dysfunctional uterine hemorrhage that the complete or ovarian hormone of Monitoring Ovarian Function is not enough etc. causes, prostate cancer etc.
Above-mentioned preparation can be prepared by conventional pharmaceutical methods.The example of available medicinal adjuvant comprises vehicle, and (for example carbohydrate derivative is as lactose, sucrose, glucose, mannitol and Sorbitol Powder, starch derivative is as W-Gum, potato starch, dextrin and carboxymethyl starch, derivatived cellulose is as crystalline cellulose, hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, Xylo-Mucine, gum arabic, dextran, silicate derivative is as Neusilin US2, phosphate derivative is as calcium phosphate, carbonate derivative is as calcium carbonate, sulfate-derivatives is as calcium sulfate etc.), tackiness agent (for example gelatin, polyvinylpyrrolidone and polyoxyethylene glycol), (for example derivatived cellulose is as Xylo-Mucine for disintegrating agent, polyvinylpyrrolidone), lubricant (for example talcum, calcium stearate, Magnesium Stearate, spermaceti, boric acid, Sodium Benzoate, leucine), stablizer (methyl p-hydroxybenzoate, propylparaben etc.), correctives (for example conventional sweeting agent, acidic flavoring agent and spices etc.), thinner and solvent (for example water for injection liquid, ethanol and glycerine etc.).
For pharmaceutical dosage forms described and skin contact, can comprise that the toughener of optional concentration or skin permeate promotor are as pharmaceutically acceptable carrier.Conventionally, these are the fluid additives that can improve human skin absorptive character.Described toughener includes but not limited to: glyceryl monooleate, azone, glyceryl ester, eucalyptol etc.
The dosage of cocrystallization of the present invention or its pharmaceutical composition is with patient's age, sex, race, the difference of the state of an illness etc. and difference.
The compounds of this invention can be individually dosed, also can be together with other medicine or activeconstituents or Combined Preparation.
In the present invention, the method for application of cocrystallization of the present invention or pharmaceutical composition is not particularly limited.Can select the administering mode identical or close with conventional 17 β estradiol, comprising (but being not limited to): oral, through skin, intravenously, flesh Inner, topical etc.
Major advantage of the present invention comprises:
1) the Isonicotinamide cocrystallization stability of the present invention's 17 β estradiol is better, water-soluble better, can improve bioavailability;
2) preparation method who the present invention relates to is simple to operate, easily controls, and favorable reproducibility, can stablize and obtain target cocrystallization body, and applicable industrialized production.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.Wherein, " room temperature " of the present invention is 22-28 DEG C.
Universal method and instrument
X-ray powder diffraction instrument:
Bruker D8advance X-Ray diffractometer, target: Cu K α (40KV, 40mA), sample is to detector distance: 30cm, sweep limit: 3 °-40 ° (2theta value), scanning speed: 0.1sec/step, scanning step footpath: 0.02.
Dsc (DSC) instrument:
Perkin Elmer8500DSC, temperature range: 50-200 DEG C, scanning speed: 10 DEG C/min, nitrogen flow rate: 50ml/min.Thermogravimetic analysis (TGA) testing tool:
Netzsch TG209F3, temperature range: 30-400 DEG C, scanning speed: 10 DEG C/min, sweep gas: 25mL/min, protection gas: 15mL/min.
Infrared spectroscopy testing tool:
Perkin Elmer341, KBr compressing tablet.
Raman spectroscopy testing tool:
Thermo Scientific DXR Raman Microscope, laser detection wavelength: 532nm, exposure intensity: 2 seconds 5 times.
Dynamic water absorption (DVS) test/water-absorbent testing tool:
SMS DVS Intrinsic, 40～95～0%RH, temperature: 25 DEG C.
Embodiment 1
The Isonicotinamide cocrystallization (No.1) of 17 β estradiol
Isonicotinamide (0.5mol) is dissolved in the mixing solutions (200 milliliters) of ethyl acetate and normal heptane (3:2) and makes saturated solution, then add 17 β estradiol (5mol), the mol ratio of 17 β estradiol and Isonicotinamide is 10:1, room temperature condition (22-28 DEG C) is lower stirs balance 24 hours, rotating speed is 100rpm, suspension is filtered after also vacuum-drying, obtain the Isonicotinamide cocrystallization (0.44mol) of 17 β estradiol.
Embodiment 2
The Isonicotinamide cocrystallization (No.2) of 17 β estradiol
Isonicotinamide (0.5mol) is dissolved in the mixing solutions (200 milliliters) of ethyl acetate and normal heptane (3:2) and makes saturated solution, then add 17 β estradiol (2.5mol), the mol ratio of 17 β estradiol and Isonicotinamide is 5:1, room temperature condition (22-28 DEG C) is lower stirs balance 48 hours, rotating speed is 200rpm, suspension is filtered after also vacuum-drying, obtain the Isonicotinamide cocrystallization (0.42mol) of 17 β estradiol.
Embodiment 3
The Isonicotinamide cocrystallization (No.3) of 17 β estradiol
Isonicotinamide (0.5mol) is dissolved in the mixing solutions (200 milliliters) of ethyl acetate and normal heptane (3:2) and makes saturated solution, then add 17 β estradiol (1.5mol), the mol ratio of 17 β estradiol and Isonicotinamide is 3:1, room temperature condition (22-28 DEG C) is lower stirs balance 36 hours, rotating speed is 200rpm, suspension is filtered after also vacuum-drying, obtain the Isonicotinamide cocrystallization (0.45mol) of 17 β estradiol.
Embodiment 4
The Isonicotinamide cocrystallization (No.4) of 17 β estradiol
Isonicotinamide (0.5mol) is dissolved in the mixing solutions (100 milliliters) of tetrahydrofuran (THF) and normal heptane (3:2) and makes saturated solution, then add 17 β estradiol (0.5mol), the mol ratio of 17 β estradiol and Isonicotinamide is 1:1, room temperature condition (22-28 DEG C) is lower stirs balance 48 hours, rotating speed is 600rpm, suspension is filtered after also vacuum-drying, obtain the Isonicotinamide cocrystallization (0.46mol) of 17 β estradiol.
Embodiment 5
The Isonicotinamide cocrystallization (No.5) of 17 β estradiol
Isonicotinamide (1mol) is dissolved in the mixing solutions (100 milliliters) of acetone and normal heptane (3:2) and makes saturated solution, then add 17 β estradiol (0.5mol), the mol ratio of 17 β estradiol and Isonicotinamide is 1:2, room temperature condition (22-28 DEG C) is lower stirs balance 48 hours, rotating speed is 300rpm, suspension is filtered after also vacuum-drying, obtain the Isonicotinamide cocrystallization (0.48mol) of 17 β estradiol.
Embodiment 6
The Isonicotinamide cocrystallization (No.6) of 17 β estradiol
17 β estradiol and Isonicotinamide are joined in ethyl acetate by stoichiometric ratio 1:1, after dissolving completely, slowly volatilize, obtain the Isonicotinamide cocrystallization of 17 β estradiol.
Experimental example 7
The Isonicotinamide cocrystallization (No.7) of 17 β estradiol
17 β estradiol and Isonicotinamide are joined in tetrahydrofuran (THF) by stoichiometric ratio 1:1, after dissolving completely, slowly volatilize, obtain the Isonicotinamide cocrystallization of 17 β estradiol.
Experimental example 8
The Isonicotinamide cocrystallization (No.8) of 17 β estradiol
17 β estradiol and Isonicotinamide are joined in acetone by stoichiometric ratio 1:1, after dissolving completely, slowly volatilize, obtain the Isonicotinamide cocrystallization of 17 β estradiol.
Test implementation example 1
Isonicotinamide cocrystallization to the 17 β estradiol that make in embodiment 1-8 carries out performance test
Result shows, has all formed the Isonicotinamide cocrystallization of 17 β estradiol in embodiment 1-8, and wherein in cocrystallization, the mol ratio of 17 β estradiol and Isonicotinamide is all 1:1.The result of X-ray powder diffraction, thermogravimetic analysis (TGA), differential scanning calorimetric analysis, Raman spectrum, infrared spectra, dynamic water absorption is almost identical.
Wherein, cocrystallization No.1 X-ray powder diffraction (XRPD) result as shown in Figure 1, thermogravimetic analysis (TGA) test result is as shown in Figure 2; Differential scanning calorimetric analysis (DSC) result as shown in Figure 3; Infrared spectroscopy and Raman spectroscopy test result are as shown in Figures 4 and 5; Dynamic water absorption (DVS) test/water-absorbent test result as shown in Figure 6.
These the performance test results show, cocrystallization of the present invention is water-absorbent low (Fig. 6) not only, and good stability, and water-soluble significantly improving, therefore contributes to improve bioavailability
Comparative example 1
Repeat embodiment 2, difference is, Isonicotinamide (0.5mol) is dissolved in completely in the mixing solutions (2 liters) of ethyl acetate and normal heptane (3:2) and makes unsaturated solution, then add 17 β estradiol (2.5mol), the mol ratio of 17 β estradiol and Isonicotinamide is 5:1, room temperature condition (22-28 DEG C) is lower stirs balance 48 hours, rotating speed is 200rpm, suspension is filtered and vacuum-drying, as a result, cannot obtain the Isonicotinamide cocrystallization of 17 β estradiol.
All documents of mentioning in the present invention are all quoted as a reference in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. the Isonicotinamide cocrystallization of a β estradiol.
2. the Isonicotinamide cocrystallization of 17 β estradiol according to claim 1, is characterized in that, in the Isonicotinamide cocrystallization molecule of described 17 β estradiol, the mol ratio of 17 β estradiol and Isonicotinamide is 1:1.
3. the Isonicotinamide cocrystallization of 17 β estradiol according to claim 1, it is characterized in that: the X-ray powder diffraction of described crystal comprises >=5 be selected from the represented charateristic avsorption band of 2 θ value of lower group: 10.86 ° ± 0.1 °, 12.87 ° ± 0.1 °, 13.35 ° ± 0.1 °, 13.53 ° ± 0.1 °, 15.11 ° ± 0.1 °, 16.31 ° ± 0.1 °, 16.78 ° ± 0.1 °, 17.55 ° ± 0.1 °, 18.42 ° ± 0.1 °, 19.89 ° ± 0.1 °, 20.63 ° ± 0.1 °, 21.17 ° ± 0.1 °, 21.53 ° ± 0.1 °, 21.97 ° ± 0.1 °, 22.51 ° ± 0.1 °, 23.68 ° ± 0.1 °, 26.84 ° ± 0.1 ° and 26.99 ° ± 0.1 °.
4. the Isonicotinamide cocrystallization of 17 β estradiol according to claim 1, is characterized in that, described cocrystallization has the one or more features that are selected from lower group:
(i) the dsc collection of illustrative plates of described cocrystallization has feature endotherm(ic)peak at 173 ± 1 DEG C;
(ii) water absorbability≤1wt% of the dynamic water of described crystal absorption test;
(iii) the Isonicotinamide cocrystallization of described 17 β estradiol is triclinic(crystalline)system, and spacer is P-1.
5. the preparation method of the Isonicotinamide cocrystallization of 17 β estradiol described in any one in claim 1-4, is characterized in that, comprises the steps:
(a). a solution that contains 17 β estradiol and Isonicotinamide is provided, and the solvent of wherein said solution is organic solvent; With
(b). described solution is carried out to crystallization treatment, thereby form the Isonicotinamide cocrystallization of 17 β estradiol; With
(c). optionally from described solution, isolate the Isonicotinamide cocrystallization of 17 β estradiol.
6. according to the preparation method described in claim 5, it is characterized in that, described organic solvent is selected from lower group: acetone, tetrahydrofuran (THF), acetonitrile, ethyl acetate, methylene dichloride, methylethylketone or its combination.
7. a pharmaceutical composition, is characterized in that, the Isonicotinamide cocrystallization and the pharmaceutically acceptable carrier that comprise arbitrary 17 described β estradiol in claim 1-4.
8. a purposes for the Isonicotinamide cocrystallization of 17 β estradiol, is characterized in that, for the preparation of as medicine.
9. a mixture that is used to form the Isonicotinamide cocrystallization of 17 β estradiol claimed in claim 1, is characterized in that, 17 β estradiol and Isonicotinamide that described mixture is 1:1 by mol ratio form.
10. a purposes for compound combination, described combination comprises 17 β estradiol and Isonicotinamides, it is characterized in that, described compound combination is used to prepare the Isonicotinamide cocrystallization of 17 β estradiol described in claim 1-4.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108047294A (en) * | 2017-12-25 | 2018-05-18 | 国家卫生计生委科学技术研究所 | A kind of estradiol novel crystal forms and preparation method thereof |
| 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 |
| CN108929265A (en) * | 2018-07-03 | 2018-12-04 | 东华理工大学 | A kind of the eutectic product and method for crystallising of Pyrazinamide and 1,3,5- benzenetricarboxylic acid |
| 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 |
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| ALAA ABDUL RASOOL ET AL.，: "Solubility Enhancement of Some Water-Insoluble Drugs in the Presence of Nicotinamide and Related Compounds", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047294A (en) * | 2017-12-25 | 2018-05-18 | 国家卫生计生委科学技术研究所 | A kind of estradiol novel crystal forms and preparation method thereof |
| 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 |
| CN108929265A (en) * | 2018-07-03 | 2018-12-04 | 东华理工大学 | A kind of the eutectic product and method for crystallising of Pyrazinamide and 1,3,5- benzenetricarboxylic acid |
| 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 |
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