CN109721557A - Letrozole crystalline substance II type solid matter and preparation method and its pharmaceutical composition and purposes - Google Patents
Letrozole crystalline substance II type solid matter and preparation method and its pharmaceutical composition and purposes Download PDFInfo
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- CN109721557A CN109721557A CN201811265036.7A CN201811265036A CN109721557A CN 109721557 A CN109721557 A CN 109721557A CN 201811265036 A CN201811265036 A CN 201811265036A CN 109721557 A CN109721557 A CN 109721557A
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Abstract
The invention discloses the brilliant II type substance of Letrozole compound (chemical name: 1- [bis- (4- cyano-phenyl) methyl] -1,2,4- triazoles, English name: Letrozole) and preparation methods and its pharmaceutical composition and purposes.Specifically, the invention discloses a kind of crystalline substance II type solid matter states of Letrozole compound；A kind of preparation method of crystalline substance II type solid matter sample；The application in antihormones series antineoplastic medicament is being prepared using Letrozole crystal-form substances as active constituent.
Description
Technical field
The present invention relates to have found a kind of Letrozole compound existing crystalline substance II type substance existence form in the solid state；
It is related to having invented a kind of preparation method of Letrozole crystalline substance II type；It is related to having invented containing Letrozole crystalline substance II type and containing arbitrary proportion crystalline substance
The pharmaceutical composition of the mixing crystal form of II type；The invention further relates to Letrozole crystal-form substances as effective ingredient, is preparing
Application in antihormones series antineoplastic medicament.
Background technique
Letrozole compound (chemical name: 1- [bis- (4- cyano-phenyl) methyl] -1,2,4- triazole；English name:
Letrozole)
A kind of " high purity letrozole of Liu Kun et al. invention is described in Chinese patent CN 1754876A (publication number)
Preparation method "[1].Wherein, a kind of method for preparing high purity letrozole is related to, i.e., by compound (1), compound (2)
Mixture, at separating after salt, obtains substantially pure compound (1) or its salt in solvent, then uses substantially pure compound (1)
Or its salt is reacted with compound (3), prepares the Letrozole of high-purity.Letrozole sample is obtained using ethyl alcohol recrystallization in the patent
Product.
Bright " the preparation method of Letrozole of old scholar's flare is described in Chinese patent CN 101033214A (publication number)
”[2].Wherein, it is mild to relate to a kind of reaction, preparation side easily operated, economic, suitable for high purity letrozole is mass produced
Method.It is that sodium ethoxide alkalinity is relatively weak as catalytic benefits that the invention, which prepares Letrozole using sodium ethoxide, reacts milder,
Either in laboratory or producing upper reaction condition readily satisfies and controls.It is obtained in the patent using re-crystallizing in ethyl acetate
Letrozole sample.
" preparing next bent for P.L. Mai Tangna et al. invention is described in Chinese patent CN 101253160A (publication number)
The improved method of azoles "[3].Wherein, a kind of high yield method for preparing high purity letrozole is related to, during method therefor no longer needs to
Between the stage remove 4- [1- (1,3,4- triazolyl) methyl] benzonitrile impurity.The method of synthesis Letrozole is additionally provided, wherein the
The formation of one stage impurity 4- [1- (1,3,4- triazolyl) methyl] benzonitrile is minimized, in this inventive method, by 4- (halogen
For methyl) benzonitrile and 1H-1, the reactant salt of 2,4- triazoles reduce the formation of impurity.
Described in Chinese patent CN 102070541A (publication number) Tang field et al. invention " Letrozole I-type crystal and
Preparation method "[4].Wherein, a kind of Letrozole anhydrous crystal is related to, structure and features passes through X-ray powder diffraction, difference
Show that scanning thermometric analysis, infrared spectroscopy etc. are characterized.Additionally provide by anhydrous pure organic solvent as recrystallisation solvent prepare Lai
The drug system of the method for bent azoles anhydrous crystal and the crystallization in the advanced breast cancer postmenopausal patients for the treatment of anti-estrogen therapy
Application in agent.Anhydrous organic solvent (anhydrous isopropyl acetone, anhydrous chloroform, nothing are dissolved in using by Letrozole crude product in the patent
Water acetone or their any combination) in, filtering, filtrate decompression concentration is dry, obtains the crystallization of Letrozole crystalline substance I type.
Chinese medical practice describe that Gu Bei et al. delivers in magazine " arimedex is late in breast cancer
Clinical application "[5].Wherein, it is related to observing the curative effect and adverse reaction of Letrozole (Fu Rui) treatment postmenopausal women with advanced breast cancer,
Prove that Letrozole can effectively treat advanced breast cancer, adverse reaction is light, and patient tolerability is good.
Present invention finds a kind of Letrozole crystalline substance II type solids different from above-mentioned patent or literature research Reporting
Matter state and preparation method.
Research purpose of the invention is started with from the research of the crystal form solid matter existence of Letrozole, is screened by crystal form
Technology, crystal form biological evaluation technology are found in the active ingredient raw materials level of drug, find that crystal form solid matter exists
Type and state feature, crystal-form substances are combined with pharmacodynamic study, have optimal clinical curative effect for searching, discovery, exploitation
Letrozole advantage medicinal crystal-form solid matter provide basic science data；Meanwhile also for from Letrozole solid drugs raw material
Apply for that country or international intellectual property invention patent protection provide scientific basis on material base.
Summary of the invention
One of the object of the invention: it is to provide a kind of crystal form solid matter state and describing mode of Letrozole crystalline substance II type.
The two of the object of the invention: there is provided a kind of preparation methods of crystal form solid matter of Letrozole crystalline substance II type.
The three of the object of the invention: it is to provide containing Letrozole crystalline substance II type sterling or containing any non-zero proportions crystalline substance II type
Mix the solid drugs and combinations thereof of crystal form.
The four of the object of the invention: there is provided use Letrozole crystal form solid matter as active pharmaceutical ingredient per daily
Pharmaceutical quantities are within the scope of 0.1~100mg.
The five of the object of the invention: there is provided use Letrozole crystal form solid matter to prepare out as active pharmaceutical ingredient
What is issued is various for the tablet of clinical use, capsule, pill, powder-injection, injection preparation, sustained release or controlled release preparation drug.
The six of the object of the invention: it is to provide Letrozole crystal-form substances and is improved in treatment lysis due to crystal-form substances
Blood concentration in organism and play the effective therapeutic effect of drug.
The seven of the object of the invention: there is provided use the mixing crystal form solid matter of Letrozole crystalline substance II type and crystalline substance II type as
The raw material of effective ingredient is preparing the application in antihormones series antineoplastic medicament.
A kind of invention crystalline substance II type solid matter existence of Letrozole compound, and invented the crystal form sample
The preparation method of product；In addition, present invention finds Letrozole crystalline substance II type solid matters in preparing antihormones series antineoplastic medicament
Application.
Technical characteristic
1. the brilliant II pattern product morphological feature of Letrozole:
1.1 Letrozole crystalline substance II type solid matters of the invention, it is characterised in that used when using powder x-ray diffraction analysis
CuKαWhen radiation experiments condition, diffraction maximum position: 2-Theta value is shown asOr d valueWith diffraction maximum relative intensity: peak height
It is worth the solid matter (table 1, Fig. 1) of (Height%) or peak area value (Area%) with following characteristic peaks when:
The powder x-ray diffraction peak value of 1 Letrozole crystalline substance II pattern product of table
1.2 Letrozole crystalline substance II type solid samples of the invention, which is characterized in that when being analyzed using infrared spectroscopy
3119、3054、2993、2916、2851、2231、2087、1941、1912、1811、1743、1704、1607、1503、1434、
1408、1371、1334、1315、1270、1222、1199、1184、1138、1016、1003、976、954、880、867、858、
821、806、789、764、753、717、697、677、656cm-1±2cm-1Absorption peak be Letrozole crystal form crystalline substance II type solids
The infrared spectroscopy characteristic peak positions (Fig. 2) that matter is presented.
1.3 Letrozole crystalline substance II type solid matters of the invention, it is characterized in that when being analyzed using differential canning calorimetry,
It shows as working as in the DSC map that heating rate is 10 DEG C per minute and contains 1 endothermic peak (Fig. 3) at 184 DEG C ± 3 DEG C.
1.4 Letrozole crystalline substance II type solid matters carry out sample analysis using melting point apparatus, when heating rate is 1 DEG C per minute
When melting point values be 186 DEG C ± 2 DEG C.
2. the preparation method characteristic of Letrozole crystalline substance II pattern product:
The preparation method of Letrozole crystalline substance II type as described in claim 1 of the present invention, it is characterised in that using methanol,
Ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane solvent it is single
Solvent system mixes after Letrozole sample is completely dissolved by solvent system, be added n-hexane, hexamethylene, ether, petroleum ether,
Benzene, toluene solvant precipitating obtain Letrozole crystalline substance II type solid sample.
3. the crystal form ingredient of Letrozole, dosage and pharmaceutical preparations composition feature:
A kind of 3.1 mixed crystal solid matters of Letrozole compound, the Letrozole crystalline substance II type ingredient containing any non-zero proportions.
3.2 pharmaceutical compositions of the present invention, which is characterized in that the Letrozole crystalline substance II type containing effective dose, or contain
There are Letrozole mixed crystal solid matter and pharmaceutically acceptable carrier.
3.3 pharmaceutical compositions of the present invention, using Letrozole crystal form solid matter as active pharmaceutical ingredient, per daily
Pharmaceutical quantities are within the scope of 0.1~100mg.
3.4 pharmaceutical compositions of the present invention, which is characterized in that the pharmaceutical composition is tablet, capsule, ball
Agent, powder-injection, injection preparation, sustained release preparation, controlled release preparation.
The 3.5 Letrozole crystalline substance II type mixed crystal ingredient the present invention relates to Letrozole crystalline substance II type or containing any non-zero proportions is being made
Application in standby antihormones series antineoplastic medicament.
The present invention relates to using Letrozole crystalline substance II type ingredient of the present invention, Letrozole mixing crystal form solid matter of the present invention as live
The pharmaceutical composition of sexual element.The pharmaceutical composition can be prepared according to method well known in the art.Can by by the present invention come bent
Azoles crystalline substance II type ingredient, Letrozole mixing crystal form solid matter of the present invention and one or more pharmaceutically acceptable solids or liquid
Excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.Letrozole crystalline substance II type ingredient of the present invention, this
Content of the invention Letrozole mixing crystal form solid matter in its pharmaceutical composition is usually 0.1-95 weight %.
Letrozole crystalline substance II type ingredient, Letrozole mixing crystal form solid matter of the present invention or the pharmaceutical composition containing it of the present invention
Object can be administered in a unit, and administration route can be enteron aisle or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneously
Injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc..
Form of administration of the invention is preferably solid dosage forms.Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets,
Lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), particle
Agent, powder, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc..
Letrozole crystalline substance II type ingredient of the present invention, Letrozole mixing crystal form solid matter of the present invention can be made ordinary preparation,
Also be made is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery systems.
It, can in order to which tablet is made in Letrozole crystalline substance II type ingredient of the present invention, Letrozole mixing crystal form solid matter of the present invention
To be widely used various excipient well known in the art, including diluent, binder, wetting agent, disintegrating agent, lubricant, help stream
Agent.Diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, sulphur
Sour calcium, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, ethyl alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin,
Syrup, honey, glucose solution, microcrystalline cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, methylcellulose,
Hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegration
It is fine that agent can be dried starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, cross-linked carboxymethyl
Tie up plain sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate
Deng；Lubricant and glidant can be talcum powder, silica, stearate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double
Synusia and multilayer tablet.
It, can be by effective component Letrozole crystalline substance II type ingredient of the present invention, the present invention in order to which capsule is made in administration unit
Letrozole mixing crystal form solid matter is mixed with diluent, glidant, and mixture is placed directly in hard capsule or soft capsule.?
Can by effective component Letrozole crystalline substance II type ingredient of the present invention, Letrozole mixing crystal form solid matter of the present invention first with diluent, glutinous
Particle or pellet is made in mixture, disintegrating agent, then is placed in hard capsule or soft capsule.Be used to prepare Letrozole crystalline substance II type of the present invention at
Divide, various diluents, binder, wetting agent, disintegrating agent, the glidant product of Letrozole mixing crystal form solid matter tablet of the present invention
It kind can also be used for preparing the capsule of Letrozole crystalline substance II type ingredient of the present invention, Letrozole mixing crystal form solid matter of the present invention.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any
The administration of prescription method.
Letrozole crystalline substance II type ingredient of the present invention, Letrozole mixing crystal form solid matter pharmaceutical composition of the present invention give medicament
Measure the individual instances according to the property and severity to be prevented or be treated disease, patient or animal, administration route and dosage form
Etc. can have large-scale variation.Above-mentioned dosage with a dosage unit or can be divided into several dosage unit administrations, this is depended on
The clinical experience of doctor and include dosage regimen with other treatment means.
Letrozole crystalline substance II type ingredient, Letrozole mixing crystal form solid matter of the present invention or composition of the present invention can individually take
With, or with other treatment drug or symptomatic drugs merge use.When Letrozole crystalline substance II type ingredient of the present invention, Letrozole of the present invention are mixed
When synthetic type solid matter and other therapeutic agents have synergistic effect, its dosage should be adjusted according to the actual situation.
4. advantageous effects of the invention: the advantage of Letrozole crystalline substance II type ingredient oral administration absorbs and blood concentration is special
Sign:
The present invention relates to the drug for having used Letrozole crystalline substance II type substance to develop as active constituent and its pharmaceutical compositions
Biological absorption effect after by oral administration, it is characterised in that used and contained Letrozole crystalline substance II type as described in claim 1
The advantage that substance is played in disease preventing and treating as active constituent by being rapidly reached maximum concentration value in gastrointestinal tract or blood
It acts on and applies (Fig. 4).Letrozole crystalline substance II type solid matter of the invention improves blood concentration in organism, to play drug
More efficient therapeutic effect.
Detailed description of the invention
The x-ray diffractogram of powder of Fig. 1 Letrozole crystalline substance II type solid matter is composed
The infrared absorpting light spectra of Fig. 2 Letrozole crystalline substance II type solid matter
The DSC map of Fig. 3 Letrozole crystalline substance II type solid matter
In the intracorporal blood concentration-time curve of rat after Fig. 4 Letrozole crystalline substance I type, crystalline substance II pattern product oral absorption
Specific embodiment
More preferably to illustrate technical solution of the present invention, spy provides following embodiment, but the present invention is not limited to this.
Embodiment 1
The preparation method 1 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 150ml conical flask
100ml n-hexane is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 5ml methanol under agitation,
It after being stored at room temperature 1 day, filters, sample is dried under reduced pressure 4h through room temperature, 160mg Letrozole solid matter is obtained, to the sample of acquisition
Powder x-ray diffraction analysis is carried out, diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole crystalline substance II type solid matter.
The preparation method 2 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 150ml conical flask
120ml toluene, room is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 5ml methanol under agitation
After temperature stands 2 days, filter, sample is dried under reduced pressure 4h through room temperature, obtain 150mg Letrozole solid matter, to the sample of acquisition into
Row powder x-ray diffraction analysis, diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole crystalline substance II type solid matter.
The preparation method 3 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 150ml conical flask
120ml benzene, room is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 10ml ethyl alcohol under agitation
After temperature stands 2 days, filter, sample is dried under reduced pressure 4h through room temperature, obtain 170mg Letrozole solid matter, to the sample of acquisition into
Row powder x-ray diffraction analysis, diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole crystalline substance II type solid matter.
The preparation method 4 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 150ml conical flask
120ml second is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 10ml normal propyl alcohol under agitation
Ether after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, 168mg Letrozole solid matter is obtained, to the sample of acquisition
Product carry out powder x-ray diffraction analysis, and diffracting spectrum is consistent with Fig. 1, show that gained sample is Letrozole crystalline substance II type solids
Matter.
The preparation method 5 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 150ml conical flask
120ml hexamethylene is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 12ml n-butanol under agitation
Alkane after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, 164mg Letrozole solid matter is obtained, to the sample of acquisition
Product carry out powder x-ray diffraction analysis, and diffracting spectrum is consistent with Fig. 1, show that gained sample is Letrozole crystalline substance II type solids
Matter.
The preparation method 6 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 150ml conical flask
120ml hexamethylene is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 12ml acetone under agitation
Alkane after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, 146mg Letrozole solid matter is obtained, to the sample of acquisition
Product carry out powder x-ray diffraction analysis, and diffracting spectrum is consistent with Fig. 1, show that gained sample is Letrozole crystalline substance II type solids
Matter.
The preparation method 7 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
250ml benzene, room is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 12ml acetone under agitation
After temperature stands 2 days, filter, sample is dried under reduced pressure 4h through room temperature, obtain 159mg Letrozole solid matter, to the sample of acquisition into
Row powder x-ray diffraction analysis, diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole crystalline substance II type solid matter.
The preparation method 8 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
150ml petroleum ether is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 5ml acetonitrile under agitation,
It after being stored at room temperature 2 days, filters, sample is dried under reduced pressure 4h through room temperature, 138mg Letrozole solid matter is obtained, to the sample of acquisition
Powder x-ray diffraction analysis is carried out, diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole crystalline substance II type solid matter.
The preparation method 9 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
150ml toluene, room is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 5ml acetonitrile under agitation
After temperature stands 2 days, filter, sample is dried under reduced pressure 4h through room temperature, obtain 140mg Letrozole solid matter, to the sample of acquisition into
Row powder x-ray diffraction analysis, diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole crystalline substance II type solid matter.
The preparation method 10 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
250ml petroleum is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 15ml chloroform under agitation
Ether after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, 145mg Letrozole solid matter is obtained, to the sample of acquisition
Product carry out powder x-ray diffraction analysis, and diffracting spectrum is consistent with Fig. 1, show that gained sample is Letrozole crystalline substance II type solids
Matter.
The preparation method 11 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
250ml hexamethylene is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 15ml chloroform under agitation
Alkane after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, 159mg Letrozole solid matter is obtained, to the sample of acquisition
Product carry out powder x-ray diffraction analysis, and diffracting spectrum is consistent with Fig. 1, show that gained sample is Letrozole crystalline substance II type solids
Matter.
The preparation method 12 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
250ml is added through being completely dissolved sample under the conditions of 60 DEG C of heating water bath in middle addition 15ml methylene chloride under agitation
Benzene after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, 150mg Letrozole solid matter is obtained, to the sample of acquisition
Product carry out powder x-ray diffraction analysis, and diffracting spectrum is consistent with Fig. 1, show that gained sample is Letrozole crystalline substance II type solids
Matter.
The preparation method 13 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml methanol and 5ml normal propyl alcohol are added under agitation through being completely dissolved sample under the conditions of 60 DEG C of heating water bath
200ml n-hexane after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solid matter,
Powder x-ray diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is consistent with Fig. 1, shows that gained sample is that Letrozole is brilliant
II type solid matter.
The preparation method 14 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml ethyl alcohol and 5ml isopropanol are added under agitation through being completely dissolved sample under the conditions of 60 DEG C of heating water bath
200ml petroleum ether after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solid matter,
Powder x-ray diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is consistent with Fig. 1, shows that gained sample is that Letrozole is brilliant
II type solid matter.
The preparation method 15 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml normal propyl alcohol and 5ml n-butanol, through sample is completely dissolved under the conditions of 60 DEG C of heating water bath, under agitation plus
Enter 200ml benzene, after being stored at room temperature 2 days, filter, sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solid matter, right
The sample of acquisition carries out powder x-ray diffraction analysis, and diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole crystalline substance II
Type solid matter.
The preparation method 16 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml methanol and 5ml acetone are added under agitation through being completely dissolved sample under the conditions of 60 DEG C of heating water bath
200ml petroleum ether after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solid matter,
Powder x-ray diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is consistent with Fig. 1, shows that gained sample is that Letrozole is brilliant
II type solid matter.
The preparation method 17 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml acetone and 5ml isopropanol are added under agitation through being completely dissolved sample under the conditions of 60 DEG C of heating water bath
200ml ether after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solid matter, right
The sample of acquisition carries out powder x-ray diffraction analysis, and diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole crystalline substance II
Type solid matter.
The preparation method 18 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml acetone and 5ml n-butanol are added under agitation through being completely dissolved sample under the conditions of 60 DEG C of heating water bath
200ml hexamethylene after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solid matter,
Powder x-ray diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is consistent with Fig. 1, shows that gained sample is that Letrozole is brilliant
II type solid matter.
The preparation method 19 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml ethyl alcohol and 5ml acetonitrile are added under agitation through being completely dissolved sample under the conditions of 60 DEG C of heating water bath
200ml petroleum ether after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solid matter,
Powder x-ray diffraction analysis is carried out to the sample of acquisition, diffracting spectrum is consistent with Fig. 1, shows that gained sample is that Letrozole is brilliant
II type solid matter.
The preparation method 20 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml normal propyl alcohol and 5ml ethyl acetate, through being completely dissolved sample under the conditions of 60 DEG C of heating water bath, under agitation
200ml hexamethylene is added, after being stored at room temperature 2 days, filters, sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solids
Matter carries out powder x-ray diffraction analysis to the sample of acquisition, and diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole
Brilliant II type solid matter.
The preparation method 21 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml tetrahydrofuran and 5ml isopropanol, through being completely dissolved sample under the conditions of 60 DEG C of heating water bath, under agitation
200ml ether is added, after being stored at room temperature 2 days, filters, sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solids
Matter carries out powder x-ray diffraction analysis to the sample of acquisition, and diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole
Brilliant II type solid matter.
The preparation method 22 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml methanol and 5ml chloroform are added under agitation through being completely dissolved sample under the conditions of 60 DEG C of heating water bath
200ml benzene after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solid matter, to obtaining
The sample obtained carries out powder x-ray diffraction analysis, and diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole crystalline substance II type
Solid matter.
The preparation method 23 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml normal propyl alcohol and 5ml methylene chloride, through being completely dissolved sample under the conditions of 60 DEG C of heating water bath, under agitation
200ml toluene is added, after being stored at room temperature 2 days, filters, sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solids
Matter carries out powder x-ray diffraction analysis to the sample of acquisition, and diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole
Brilliant II type solid matter.
The preparation method 24 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml n-butanol and 5ml ethyl acetate, through being completely dissolved sample under the conditions of 60 DEG C of heating water bath, under agitation
200ml petroleum ether is added, after being stored at room temperature 2 days, filters, sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solids
Matter carries out powder x-ray diffraction analysis to the sample of acquisition, and diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole
Brilliant II type solid matter.
The preparation method 25 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml normal propyl alcohol and 5ml acetonitrile are added under agitation through being completely dissolved sample under the conditions of 60 DEG C of heating water bath
200ml toluene after being stored at room temperature 2 days, filters, and sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solid matter, right
The sample of acquisition carries out powder x-ray diffraction analysis, and diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole crystalline substance II
Type solid matter.
The preparation method 26 of Letrozole crystalline substance II pattern product:
The brilliant II type sample preparation methods of Letrozole, it is characterized in that 200mg Letrozole sample is placed in 500ml conical flask
Middle addition 5ml n-butanol and 5ml methylene chloride, through being completely dissolved sample under the conditions of 60 DEG C of heating water bath, under agitation
200ml hexamethylene is added, after being stored at room temperature 2 days, filters, sample is dried under reduced pressure 4h through room temperature, obtains 150mg Letrozole solids
Matter carries out powder x-ray diffraction analysis to the sample of acquisition, and diffracting spectrum is consistent with Fig. 1, shows that gained sample is Letrozole
Brilliant II type solid matter.
Embodiment 2
The preparation method 1 (tablet) of combined pharmaceutical formulation:
A kind of preparation method of composition of medicine tablet, it is characterized in that using Letrozole crystalline substance II type sterling or containing any ratio
The mixed crystal solid matter of example crystalline substance II type as composition of medicine bulk pharmaceutical chemicals, use several excipient as preparing composition of medicine tablet
Adjunct ingredient, according to a certain percentage proportion every content of dispersion is made in the tablet samples of 0.5~20mg, table 2 provides tablet and matches
Square ratio:
The preparation formula of 2 Letrozole composite medicine tablet of table
Letrozole crystalline substance II type sterling or the mixed crystal bulk pharmaceutical chemicals containing arbitrary proportion crystalline substance II type are prepared into the side of tablet formulation
Method is: several excipient being uniformly mixed with bulk pharmaceutical chemicals, 1% sodium cellulose glycolate solution of addition is appropriate, and soft material is made, and is sieved
Granulation, the drying of wet grain, whole grain of being sieved, is added magnesium stearate and talcum powder is uniformly mixed, tabletting to get.
The preparation method 2 (capsule) of combined pharmaceutical formulation:
A kind of preparation method of composition of medicine capsule, it is characterized in that using Letrozole crystalline substance II type sterling or containing any ratio
The mixed crystal solid matter of example crystalline substance II type as composition of medicine bulk pharmaceutical chemicals, use several excipient as preparing composition of medicine capsule
Adjunct ingredient, according to a certain percentage proportion every content of dispersion is made in the capsule sample of 0.5~20mg, table 3 provides capsule and matches
Square ratio:
The bulk pharmaceutical chemicals and accessory formula of 3 Letrozole crystalline substance II type composition of medicine capsule preparations of table
Letrozole crystalline substance II type sterling or the mixed crystal bulk pharmaceutical chemicals containing arbitrary proportion crystalline substance II type are prepared into the side of tablet formulation
Method is: several excipient being uniformly mixed with bulk pharmaceutical chemicals, 1% sodium cellulose glycolate solution of addition is appropriate, and wet grain drying is made
Sieving whole grain is added magnesium stearate and is uniformly mixed, and insertion capsule is made；Or granulation step is not used, and directly by Letrozole original
Material medicine is uniformly mixed with several excipients, after sieving, is directly loadable into capsule and is made.
Embodiment 3
The dosage 1 (tablet) of Letrozole crystal form composition of medicine:
The pharmaceutical composition for using crystal form Letrozole sample to manufacture as active pharmaceutical ingredient, it is characterized in that using brilliant
Active constituent of the II type Letrozole as drug, be administered daily dosage be 2.5mg, can be prepared into respectively one time a day/5 tablets once
0.5mg conventional tablet, or one time a day/1 tablet once 2.5mg tablet class.
The dosage 2 (capsule) of Letrozole crystal form composition of medicine:
The pharmaceutical composition for using crystal form Letrozole sample to manufacture as active pharmaceutical ingredient, it is characterized in that using brilliant
Active constituent of the II type Letrozole as drug, be administered daily dosage be 10mg, can be prepared into respectively 2 times a day/2 tablets each time
5.0mg capsule, one time a day/10mg capsule 1 tablet each time.
Need the problem of illustrating: Letrozole crystal form pharmaceutical composition of the present invention is on the dosage of effective component
There are many factors influences, such as: the purposes for prevention and treatment is different and causes the difference of daily dosage；Illness
Property is different from illness severity and causes the difference of daily dosage；Gender, the age, body surface area difference,
Administration route, administration number of times, therapeutic purposes are different and cause the difference of daily dosage；In addition, existing between crystal form samples
It absorbs different with blood concentration etc., also results in and of the invention be in the daily Suitable dosage ranges using Letrozole crystal form ingredient
0.002-2mg/kg weight, preferably 0.01-0.5mg/kg weight.It should be according to actual prevention and treatment different situations when use
Demand formulates different brilliant II type Letrozole effective component accumulated dose schemes, and can be divided into the completion of multiple or single administration mode.
Embodiment 4
Letrozole crystalline substance II type is in rat body absorption feature and blood concentration feature:
12 SD rats are randomly divided into 2 groups, and every group 6,12h is deprived of food but not water before being administered.Rat body weight is weighed, is pressed
100mg·kg-1Letrozole dosage calculate, the Letrozole samples of different crystal forms is packed into solid form delivery device, mouth is passed through
Medicinal powder is directly placed in rat stomach by chamber.Respectively after administration 30min, 1h, 2h, 3h, 5h, 6h, 7h, 9h, 12h, 14h, for 24 hours,
30h, 37h, 48h take blood to set in test tube of hepari pipe in the intraocular corner of the eyes, centrifuging and taking supernatant 100ul.Precision measures blood plasma 100ul, sets 1.5ml
In EP pipe, 800ul ethyl acetate is added, be vortexed concussion 3min, is centrifuged (13400rpm) 10min, takes supernatant organic phase in room temperature
Under be dried with nitrogen, with 100ul acetonitrile-water (40:60) redissolve, be vortexed concussion 3min, be centrifuged (13400rpm) 5min, take supernatant
Sample introduction measurement.
Testing conditions: detection system: Aligent 1200, chromatographic column: Agilent Eclipse XDB-C18 (4.6 ×
250mm,5μm)；Mobile phase: acetonitrile-water (40:60, v/v)；Flow velocity: 1mlmin-1；Column temperature: 25；DEG C Detection wavelength: 239nm；
Sample volume: 20 μ l.
Table 4 provides the blood concentration that rat oral takes Letrozole crystalline substance I type with each time point in blood after crystalline substance II pattern product；
Table 5 provides rat oral and takes Letrozole crystalline substance I type and crystalline substance II pattern product (100mgkg-1) after pharmacokinetics ginseng
Number shows that Letrozole crystalline substance II type has infiltration rate fast, and blood concentration is high, acts on the dominant feature of its length of platform.
Each time point of table 4 blood concentration (n=6,±SD)
Pharmacokinetic parameter after table 5SD Oral Administration in Rats Letrozole polymorphic (100mgkg-1)
Bibliography
1. Chinese patent, publication number CN 1754876A.
2. Chinese patent, publication number CN 101033214A.
3. Chinese patent, publication number CN 101253160A.
4. Chinese patent, publication number CN 102070541A.
5. Chinese medical practices magazine, Gu Bei, the arimedex late clinical application in breast cancer.
Claims (12)
1. a kind of brilliant II type solid matter of Letrozole, which is characterized in that when use powder x-ray diffraction analysis uses CuKαSpoke
When penetrating experiment condition, diffraction maximum position: 2-Theta value (°) or d valueWith diffraction maximum relative intensity: peak value
(Height%) or peak area value (Area%) has the feature that
2. the Letrozole crystalline substance II type solid matter according to claim 1, which is characterized in that when being analyzed using infrared spectroscopy
3119,3054,2993,2916,2851,2231,2087,1941,1912,1811,1743,1704,1607,1503,1434,
1408、1371、1334、1315、1270、1222、1199、1184、1138、1016、1003、976、954、880、867、858、
821、806、789、764、753、717、697、677、656cm-1±2cm-1Absorption peak be Letrozole crystalline substance II type solid matter institute
The infrared spectroscopy characteristic peak positions of presentation.
3. according to Letrozole crystalline substance II type solid matter as claimed in claim 1, which is characterized in that use differential canning calorimetry
When analysis, shows as working as in the DSC map that heating rate is 10 DEG C per minute and contain 1 endothermic peak at 184 DEG C ± 3 DEG C.
4. the Letrozole crystalline substance II type solid matter according to claim 1, which is characterized in that carry out sample point using melting point apparatus
Analysis, the melting point values when heating rate is 1 DEG C per minute are 186 DEG C ± 2 DEG C.
5. a kind of mixed crystal solid matter of Letrozole compound, which is characterized in that in the claim 1 containing any non-zero proportions
The Letrozole crystalline substance II type solid matter.
6. a kind of preparation method of Letrozole crystalline substance II type solid matter as described in claim 1, it is characterised in that use methanol, second
Alcohol, normal propyl alcohol, isopropanol, n-butanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane solvent it is single molten
Agent system mixes after Letrozole sample is completely dissolved by solvent system, be added n-hexane, hexamethylene, ether, petroleum ether, benzene,
Toluene solvant precipitating obtains Letrozole crystalline substance II type solid matter.
7. a kind of pharmaceutical composition, which is characterized in that the Letrozole crystalline substance II type solid described in claim 1 containing effective dose
Substance and pharmaceutically acceptable carrier.
8. a kind of pharmaceutical composition, which is characterized in that Letrozole mixed crystal solids described in the claim 5 containing effective dose
Matter and pharmaceutically acceptable carrier.
9. according to claim 7 or the pharmaceutical composition of claim 8, which is characterized in that Letrozole crystal-form substances per daily
Pharmaceutical quantities are within the scope of 0.1~100mg.
10. according to the pharmaceutical composition of claim 7 or claim 8, which is characterized in that the pharmaceutical composition is selected from piece
Agent, capsule, pill or powder-injection.
11. according to the pharmaceutical composition of claim 7 or claim 8, which is characterized in that the pharmaceutical composition is selected from sustained release
Preparation or controlled release preparation.
12. mixed crystal solid matter described in Letrozole crystalline substance II type solid matter described in claim 1 and/or claim 5 exists
Prepare the application in antihormones series antineoplastic medicament.
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| CN111012752A (en) * | 2019-12-31 | 2020-04-17 | 瀚晖制药有限公司 | Letrozole tablet and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1754876A (en) * | 2004-09-28 | 2006-04-05 | 北京德众万全医药科技有限公司 | Process for preparing high purity letrozole |
| US20070100149A1 (en) * | 2005-11-02 | 2007-05-03 | Palle Venkata Raghavendra A | Process for preparing letrozole |
| CN101033214A (en) * | 2006-07-06 | 2007-09-12 | 上海复旦复华药业有限公司 | Method of preparing letrozole |
| WO2008090565A1 (en) * | 2007-01-22 | 2008-07-31 | Natco Pharma Limited | Novel thermodynamically stable polymorphic form-l of letrozole |
| CN101253160A (en) * | 2005-07-06 | 2008-08-27 | 西科尔公司 | Improved process for the preparation of letrozole |
| CN102070541A (en) * | 2010-10-25 | 2011-05-25 | 深圳海王药业有限公司 | Letrozole I-type crystal and preparation method thereof |
-
2018
- 2018-10-29 CN CN201811265036.7A patent/CN109721557A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1754876A (en) * | 2004-09-28 | 2006-04-05 | 北京德众万全医药科技有限公司 | Process for preparing high purity letrozole |
| CN101253160A (en) * | 2005-07-06 | 2008-08-27 | 西科尔公司 | Improved process for the preparation of letrozole |
| US20070100149A1 (en) * | 2005-11-02 | 2007-05-03 | Palle Venkata Raghavendra A | Process for preparing letrozole |
| CN101033214A (en) * | 2006-07-06 | 2007-09-12 | 上海复旦复华药业有限公司 | Method of preparing letrozole |
| WO2008090565A1 (en) * | 2007-01-22 | 2008-07-31 | Natco Pharma Limited | Novel thermodynamically stable polymorphic form-l of letrozole |
| CN102070541A (en) * | 2010-10-25 | 2011-05-25 | 深圳海王药业有限公司 | Letrozole I-type crystal and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 唐田等: "来曲唑多晶型的研究", 《中国医药指南》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111012752A (en) * | 2019-12-31 | 2020-04-17 | 瀚晖制药有限公司 | Letrozole tablet and preparation method thereof |
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