CN101671338B - Citric acid alidenafil crystal form D and preparation method and usage thereof - Google Patents
Citric acid alidenafil crystal form D and preparation method and usage thereof Download PDFInfo
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Abstract
The invention relates to 1-[3-(6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazole parallel [4, 3-d] pyridine-5-thyl)-4-ethoxylbenzene sulfonyl]-cis-3, 5-lupetazin citrate or citric acid alidenafil crystal form D and preparation method thereof and also relates to drug combination containing citric acid alidenafil crystal form D and application thereof in preparation of drug for treating erection disturbance. Citric acid alidenafil raw material is dissolved in distilled water/acetone mixed solution in certain proportion, and heat preservation is carried out for 50-72 hours while stirring is carried out at certain temperature, thus obtaining the product. Test by an X-ray powder diffractometer, thermogravimetric analysis and infrared spectrometer proves that an unprecedented citric acid alidenafil crystal form D is obtained, the crystal form D can form a combination with one or multiple pharmaceutically acceptable carrier, excipient or diluent and can be effectively applied to treatment on andropathy.
Description
Technical field
[3-(6 to the present invention relates to 1-; 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4; 3-d] pyrimidine-5-yl)-4-phenetole alkylsulfonyl]-cis-3; 5-lupetazin citrate (Citric Acid edenaphy, Aildenafil citrate) crystal formation D, and preparation method thereof, the pharmaceutical composition and this crystal formation D that contain gained crystal formation D of the present invention be used for making treatment male erectile dysfunction (male erectile dysfunction, the application in medicine ED).
Background technology
Male erectile dysfunction (male erectile dysfunction; ED) be common disease, may be defined as the penis anorthosis, can not ejaculate or the two has concurrently, according to statistics; Its sickness rate accounts for 1.9% in the male sex more than 40 years old, the male sex of over-65s then reaches 65%.The whole world has 1.25 hundred million male sex to suffer from erective dysfunction in various degree at present approximately, expects 2025 and can reach 3.22 hundred million (Moreland RB, et al, J Pharmacol Exp Ther, 2001,296 (2): 225-234.).Therefore, research and development have important clinic value and social benefit to safe and effective newtype drug of ED or new drug delivery system.For this reason, some novel structures, the unique new drug of mechanism of action are pushed to the market or are being carried out clinical, preclinical study.
Citric Acid edenaphy (Aildenafil citrate); Chemical name: 1-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-4-phenetole alkylsulfonyl]-cis-3; 5-lupetazin citrate, molecular formula: C
23H
32N
6O
4SC
6H
8O
7, molecular weight: 680.73, chemical structural formula:
Be a kind of new drug that is in the clinical study, effective to ED.Chinese patent (application number 02100198.7) discloses edenaphy and preparation method thereof etc., but does not relate to Aildenafil citrate crystal form type and preparation method thereof.
The inventor finds that there is polymorphism in the Citric Acid edenaphy, has 4 kinds of crystal formations: A type, Type B, C type, D type in the process of research Citric Acid edenaphy.A type, Type B, C type are the crystal habit of not moisture and other solvent, and the D type is a hydrate.Four kinds of crystal formation purity are high, and good stability has meliority on industrial production, are fit to preparation technical process and standing storage.
Summary of the invention
The pharmaceutical composition and the citric acid alidenafil crystal form D that the invention discloses the preparation method of a kind of citric acid alidenafil crystal form D, citric acid alidenafil crystal form D and contain citric acid alidenafil crystal form D are being made treatment male erectile dysfunction (male erectile dysfunction, ED) application in the medicine.
Combine the object of the invention that content of the present invention is specifically described at present.
The invention provides a kind of citric acid alidenafil crystal form D,, it is characterized by through X-ray crystallography research:
Crystal system and spacer are: triclinic(crystalline)system, spacer are P-1;
Unit cell parameters:
alpha=83.724 (3) deg
Unit cell volume: molecule number in
structure cell=2, contain 2 Citric Acid edenaphy molecules and 2 water moleculess;
Calculate crystalline density 1.382mg/mm
3
The final stoichiometric equation of confirming: C
29H
42N
6O
12S;
Calculate relative molecular mass: 698.75.
The structural analysis of monocrystalline X-ray diffraction is a kind of directly, accurately and the most effectively crystal formation analytical procedure; Be to generally acknowledge conclusive evidence polymorphic structure method the most reliably in the world; It can directly obtain the three-dimensional arrangement information of molecule number, molecule (containing solvent) in the crystalline unit cell parameters, spacer, structure cell, and then calculates arrangement, intramolecularly and intermolecular hydrogen bond, sat linkage and the co-ordination bond etc. of molecule in molecular configuration and conformation, the crystal.
The crystallographic data that this crystal formation D is detailed, like atomic coordinate, the angle between the key (bond angle), characteristic windup-degree etc. is listed in table 1-table 5.
The location parameter of table 1. crystal formation D (xln)
Bond distance and the bond angle of table 2. crystal formation D (xln)
The anisotropy location parameter of table 3. crystal formation D (xln)
The location parameter of the hydrogen of table 4. crystal formation D (xln)
The conformation of table 5. crystal formation D (xln) and characteristic windup-degree
The crystallographic data in the 1-table 5 is especially shown in X-ray crystallography research, has proved the structure of crystal formation D (xln), visible intuitively Fig. 1 and Fig. 2.
The reliable in structure sex factor:
Final?R?indices[I＞2sigma(I)]
R
1＝0.0451，WR
2＝0.1062
R?indices(all?data)
R
1＝0.0778，WR
2＝0.1275
S(Goodness-of-fit?on?F
2)：1.039
The Citric Acid edenaphy of this crystal formation D is pressed the Chinese Pharmacopoeia melting point determination, and the fusing point that uses the oil bath intensification to record is 201.9-203.1 ℃.
The outward appearance of the Citric Acid edenaphy of this crystal formation D is light yellow.
Owing to exist more weak interaction force (like hydrogen bond, complex bonds etc.) between the structure cell interior molecules in the crystalline state medicine, there is some difference to make different crystal forms intramolecularly covalent linkage intensity.Infrared absorption spectrum (IR) is the result to covalent linkage motion energy level transition in the molecule, and the difference of covalent linkage intensity can cause the IR spectrographic to change.The difference that the ir spectra of different crystal forms solid pharmaceutical exists mainly comprises peak shape variation, the strong change of peak position skew and peak etc.With Nicolet 5700 determination of infrared spectroscopy, rectify an instrument with polystyrene film before measuring, make the regulation that meets Chinese Pharmacopoeia, with the Citric Acid edenaphy and Potassium Bromide (top grade the is pure) mixed pressuring plate of this crystal formation (D type), write down 4000-400cm during mensuration
-1Spectrogram.The result shows that its infrared spectrogram is at 2970 ± 5cm
-12758 ± 5cm
-11727 ± 5cm
-11705 ± 5cm
-11169 ± 2cm
-1Have and can itself and other crystal formation be distinguished the charateristic avsorption band that comes, see Fig. 3.Limit of error is confirmed according to Chinese Pharmacopoeia.
Another object of the present invention discloses the preparation method of citric acid alidenafil crystal form D, and its process comprises: through the Citric Acid edenaphy being dissolved in doubly (quality-volume ratio of 28-32; Grams per milliliter) in zero(ppm) water and the absolute ethyl alcohol mixed solution, with regard to mixed solution, absolute ethyl alcohol accounts for the 30%-70% (volume ratio) of mixed solution; Preferred 45%-55% (volume ratio) then, starts stirring; Heat temperature raising is to reflux temperature, filtered while hot after 15-20 minute.Airtight holding filtrated in filter flask, indoor placement, and cooling is cooled to 30 ℃-35 ℃ naturally, and insulation was left standstill 50-72 hour, separated out crystallization, filter, indoor placement 1 hour, drying promptly obtains Citric Acid edenaphy compound crystal formation D.In filtrating insulation put procedure, leaving standstill and hold the filter flask of filtrating airtight is essential condition.
Used Citric Acid edenaphy makes according to following synthetic route:
Compound 2:4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide
Compound 3:2-ethoxy benzoyl chloride
Compound 4:4-(2-Lucamide)-1-methyl-3-n-propyl pyrazoles-5-acid amides
Compound 5:1-methyl-3-propyl group-5-[(2-oxyethyl group) phenyl]-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones
Compound 6:1-methyl-3-propyl group-5-[(2-oxyethyl group-5-alkylsulfonyl) phenyl]-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones
Compound 7: cis-2,6-lupetazin
Compound 8: edenaphy
Final compound 1: Citric Acid edenaphy
Wherein, compound 2,3,7 can buy, if can't buy in market, can be made by the raw material that is easy to get by conventional synthesis method according to the precedent of document, can be by document (Chem.Pharm.Bull.1984,32 (4): 1568-1577 like compound 2; Fine chemistry industry, 2001,18 (7): preparation 396-397 etc.); Compound 3 can be by document (chemical research and application, 2002,14 (5): preparation 605-607 etc.); Compound 7 also can make by existing literature method easily.
Wherein, compound 4,5,6,8, the Citric Acid edenaphy can be according to document (US4666908; Chinese Journal of Pharmaceuticals, 2000,31 (4): 145-147; Chemical research and application, 2002,14 (5): 605-607; Shenyang Pharmaceutical University's journal, 2002,19 (3), 174-175. etc.) method that provides, by compound 6 preparation compounds 8, only need will be wherein N methyl piperazine with cis-2, the 6-lupetazin is replaced, and just can synthesize edenaphy (8) easily.In order to obtain highly purified Citric Acid edenaphy, the available recrystallizing methanol of edenaphy (8) once.Then, edenaphy doubly methyl alcohol or ethanol of 23-28 (quality-volume ratio, g/ml) in, under the reflux temperature, and wait mole Citric Acid reaction 0.5-1 hour, generate Citric Acid edenaphy bullion, after the recrystallizing methanol, be used for crystal formation research.Its chemical structure through proton nmr spectra (
1H-NMR), carbon-13 nmr spectra (
13C-NMR) etc. conclusive evidence proves that chemical structure is correct, sees Fig. 4 and Fig. 5.In addition, when crystal formation was studied, the collection of illustrative plates from the monocrystalline X-diffraction of Type B and D type can prove that also chemical structure is correct.
All above-mentioned reactions all are popular responses, as long as with reference to common textbook and pertinent literature, and suitable reagent and the condition that just can easily confirm to carry out these reactions, this is apparent to those skilled in the art.
Another purpose of the present invention provides the pharmaceutical composition that comprises citric acid alidenafil crystal form D.In pharmaceutical composition, can use any routine known and in this area widely used vehicle, for example carrier, filler, swelling agent, tackiness agent, moistening agent, disintegrating agent, tensio-active agent, lubricant or thinner.Wherein carrier includes but not limited to lactose, white sugar, sodium-chlor, glucose, starch, lime carbonate, crystalline cellulose and silicic acid.Tackiness agent includes but not limited to water, ethanol, propyl alcohol, glucose solution, starch solution, gelatin solution, CMC 99.5, methylcellulose gum, potassiumphosphate and Vinylpyrrolidone polymer.Disintegrating agent includes but not limited to dry starch, sodium-alginate, agar powder, sodium hydrogencarbonate, lime carbonate, sodium lauryl sulphate, glyceryl monostearate, starch or lactose.Moistening agent includes but not limited to glycerine or starch.Lubricant includes but not limited to talcum powder, stearate, boric acid powder and the polyoxyethylene glycol of purifying.
The preferred route of administration of pharmaceutical composition of the present invention is oral.Formulation comprises tablet, granule, capsule, slow releasing tablet, sustained release pellet or the like.Preferred tablet, granule, capsule.
The amount of the Citric Acid edenaphy of this crystal formation that contains in the pharmaceutical composition contains 50-70mg by unit dosage form.
The present invention also provides the application of citric acid alidenafil crystal form D in making treatment male erectile dysfunction medicine.
Pharmacodynamics test: to the mensuration of castration mouse sexual function
60 of Kunming mouses, (raising 60 of 18～22g female mices the same period) is divided into 6 groups at random by body weight; Every group 10, wherein under etherization extract bilateral testes for 5 groups, make castration and handle; Remain one group of separation that only undergos surgery, do not extract testis, as Sham-operated control group.Each treated animal steams again raises, and makes an experiment behind the 3d.Sham-operated control group, model control group all give 0.5%CMC, receive reagent to give alidenafil crystal form D 2,6,20mg.kg
-1, positive controls is given Virga 6mg.kg
-1, being the ig administration, the administration volume is 10ml.kg
-160min after the administration only places cage with the male mice list, adds 1 of female mice in every cage, and record is thrown the time (promptly catching latent period) that male mouse catches female mouse for the 1st time in cage from female mice, and the interior male mice of 30min is climbed the number of times of the back of the body.The result shows, 15mg/kg
-1(by anhydride) can make castration mouse catch to shorten 185% latent period, and catching number of times increases by 4.0 times.
The influence factor test:
Influence to outward appearance
| Sample | Project | 0 month | 0.5 month | January |
| Citric Acid edenaphy compound crystal formation D | The high wet test exposure experiments to light of high temperature test | The light yellow crystallization of the light yellow crystallization of light yellow crystallization | The light yellow crystallization of the light yellow crystallization of light yellow crystallization | The light yellow crystallization of the light yellow crystallization of light yellow crystallization |
Influence to content (HPLC area normalization method)
| Sample | Project | 0 month (%) | Month 0.5 (%) | January (%) |
| Citric Acid edenaphy compound crystal formation D | The high wet test exposure experiments to light of high temperature test | 99.92 99.92 99.92 | 99.92 99.91 99.91 | 99.91 99.92 99.91 |
Influence to related substance
| Sample | Project | 0 month (%) | Month 0.5 (%) | January (%) |
| Citric Acid like ground that | High temperature test | 0.08 | 0.09 | 0.08 |
| Non-compound crystal formation D | High wet test exposure experiments to light | 0.08 0.08 | 0.08 0.08 | 0.08 0.09 |
Influence to infrared absorption spectrum
| Sample | Project | 0 month | 0.5 month | January |
| Citric Acid edenaphy compound crystal formation D | The high wet test exposure experiments to light of high temperature test | See that Fig. 3 sees that Fig. 3 sees Fig. 3 | Do not change not change and change | Do not change not change and change |
Influence to X powder diffraction
| Sample | Project | 0 month | 0.5 month | January |
| Citric Acid edenaphy compound crystal formation D | The high wet test exposure experiments to light of high temperature test | See that Fig. 6 sees that Fig. 6 sees Fig. 6 | Do not change not change and change | Do not change not change and change |
The result: citric acid alidenafil crystal form D at high light (under 4500lx ± 500lx), high temperature (60 ± 2 ℃), high humidity (RH92.5%) condition from 0 one 1 months; Outward appearance, X powder diffraction, infrared absorption spectrum all do not change; Stable crystal form is described, is not had the trichite of commentaries on classics and give birth to, still keep original crystal formation; Related substance, content do not change in addition, explain that the citric acid alidenafil crystal form D chemicalstability is good, are fit to the manufacturing and the standing storage of pharmaceutical prepn.
Figure of description:
Fig. 1 is the molecule stereo structure sciagraph of citric acid alidenafil crystal form D;
Fig. 2 is the structure cell sciagraph of citric acid alidenafil crystal form D;
Fig. 3 is the infrared spectrogram of citric acid alidenafil crystal form D;
Fig. 4 be the Citric Acid edenaphy proton nmr spectra (
1H-NMR);
Fig. 5 be the Citric Acid edenaphy carbon-13 nmr spectra (
13C-NMR);
Fig. 6 is the X-ray powder diffraction figure of citric acid alidenafil crystal form D.
Embodiment:
Below in conjunction with embodiment and accompanying drawing the present invention is done further explanation, make this area professional and technical personnel better understand the present invention.It is indicative that embodiment is merely, and means that never it limits scope of the present invention by any way.
Used Citric Acid edenaphy among the present invention, the front is narrated, its chemical structure through ultimate analysis, proton nmr spectra (
1H-NMR), carbon-13 nmr spectra (
13C-NMR DEPT), high resolution mass spectrometry (HRMs) conclusive evidence, proves that chemical structure is correct, wherein proton nmr spectra (
1H-NMR), carbon-13 nmr spectra (
13C-NMR) see Fig. 4 and Fig. 5.
In the 100ml reaction flask, add 3 gram Citric Acid edenaphies, 85ml zero(ppm) water/absolute ethyl alcohol (50: 50, volume ratio), start stirring; Heat temperature raising is to reflux temperature, filtered while hot after 15 minutes, and airtight holding filtrated in filter flask, indoor placement; Naturally cooling is reduced to 30 ℃-35 ℃, and insulation was left standstill 58 hours, separated out crystallization; Filter, indoor placement 1 hour, drying promptly obtains citric acid alidenafil crystal form D 1.8g; Its fusing point is m.p 201.9-203.1 ℃, refining rate 60%, and adopting the HPLC area normalization method to record content is 99.92%.See Fig. 1, Fig. 2, Fig. 3 and Fig. 6, be citric acid alidenafil crystal form D molecule stereo structure sciagraph, structure cell sciagraph, infrared spectrogram and X-ray powder diffraction figure, show the characteristic of citric acid alidenafil crystal form D.
In the 200ml reaction flask, add 5 gram Citric Acid edenaphies, 160ml zero(ppm) water/absolute ethyl alcohol (40: 60, volume ratio), start stirring; Heat temperature raising is to reflux temperature, filtered while hot after 15 minutes, the airtight filter flask that holds filtrating, indoor placement; Naturally cooling is reduced to 30 ℃-35 ℃, and insulation was left standstill 65 hours, separated out crystallization; Filter, indoor placement 1 hour, drying promptly obtains citric acid alidenafil crystal form D 2.8g; Its fusing point is m.p 201.9-203.1 ℃, refining rate 56%, and adopting the HPLC area normalization method to record content is 99.92%.Through test, show the characteristic of citric acid alidenafil crystal form D.
Embodiment 3
The granule that contains citric acid alidenafil crystal form D
Prescription: citric acid alidenafil crystal form D 50 grams, lactose 650 grams, cross-linked dimension 100 grams, the PEG-400090 gram, Vltra tears 135 grams, zero(ppm) water is an amount of, processes 1000 bags.
Technology: PEG-4000 and citric acid alidenafil crystal form D are pulverized jointly, cross 80 mesh sieves, with behind other material mixing with being packed as granule after zero(ppm) water system softwood, granulation, the cryodrying.
The capsule that contains citric acid alidenafil crystal form D
Prescription: citric acid alidenafil crystal form D 60 grams, starch 50 grams, lactose 40 grams, sucrose 10 grams, Microcrystalline Cellulose 35 grams, 10% Vinylpyrrolidone polymer ethanolic soln is an amount of, and Magnesium Stearate 1 gram is processed 1000.
Technology: citric acid alidenafil crystal form D and auxiliary material are crossed 80 mesh sieves, takes by weighing by recipe quantity, and be tackiness agent with 10% Vinylpyrrolidone polymer ethanolic soln; Process suitable particle with 16 mesh sieves, 65 ℃ of dryings, the whole grain of 14 mesh sieves; Adding Magnesium Stearate mixes; The survey granule content calculates loading amount, incapsulates to get final product.
The tablet that contains citric acid alidenafil crystal form D
Prescription: citric acid alidenafil crystal form D 70 grams, Microcrystalline Cellulose 5 grams, lactose 140 grams, 10 gram PEG-4000, Magnesium Stearate 1 gram, 14 gram 30 POVIDONE K 30 BP/USPs 30, Sodium Croscarmellose 10 grams, zero(ppm) water is an amount of, processes 1000.
Technology: PEG-4000 and citric acid alidenafil crystal form D are pulverized jointly, cross 80 mesh sieves, with behind other material mixing with zero(ppm) water system softwood; 16 mesh sieve system particles are put in the loft drier in 40-45 ℃ of drying, the whole grain of 16 mesh sieves; Magnesium Stearate adds mixing in the dried particle, compressing tablet.
Above content is merely preferred embodiment of the present invention, and for those of ordinary skill in the art, according to thought of the present invention, the part that on embodiment and range of application, all can change, this description should not be construed as limitation of the present invention.
Claims (9)
1. citric acid alidenafil crystal form D, it is characterized in that: crystal system and spacer: triclinic(crystalline)system, spacer are P-1;
Unit cell parameters: a=8.8415 (14), alpha=83.724 (3) deg
b=9.6926(15)?,beta=?86.899（3）deg
c=19.740(3)?，gamma=89.374（3）deg；
Unit cell volume: 1679.0 (5)
3, 2 Citric Acid edenaphy molecules and 2 water moleculess are contained in molecule number in the structure cell=2;
Calculate crystalline density 1.382mg/mm
3
The final stoichiometric equation of confirming: C
29H
42N
6O
12S;
Calculate relative molecular mass: 698.75.
2. citric acid alidenafil crystal form D according to claim 1 is characterized in that: the infrared spectrogram of said crystal formation D is at 3581 ± 5cm
-1, 3459 ± 5cm
-1, 3420 ± 5cm
-1, 3266 ± 5cm
-1, 2970 ± 5cm
-1, 2757 ± 5cm
-1, 1727 ± 5cm
-1, 1705 ± 2cm
-1, 1169 ± 2cm
-1There is characteristic peak at the place.
3. citric acid alidenafil crystal form D according to claim 1 is characterized in that: its fusing point is 201.9-203.1 ℃.
4. the preparation method of the described citric acid alidenafil crystal form D of claim 1 is characterized in that: through the Citric Acid edenaphy being dissolved in the 28-32 times of zero(ppm) water and absolute ethyl alcohol mixed solution of its quality-volume ratio in grams per milliliter, be cooled to 30 ℃-35 ℃; Airtight, insulation was left standstill 50-72 hour; Separate out crystallization, filter indoor placement 1 hour; Drying promptly obtains citric acid alidenafil crystal form D.
5. the preparation method of citric acid alidenafil crystal form D according to claim 4, it is characterized in that: described zero(ppm) water and absolute ethyl alcohol mixed solution, absolute ethyl alcohol accounts for the 30-70% of mixeding liquid volume.
6. the preparation method of citric acid alidenafil crystal form D according to claim 5, it is characterized in that: described zero(ppm) water and absolute ethyl alcohol mixed solution, absolute ethyl alcohol accounts for the 45-55% of mixeding liquid volume.
7. the compsn of any described citric acid alidenafil crystal form D of claim 1 to 3 is characterized in that: become compsn by the pharmaceutically acceptable carrier of citric acid alidenafil crystal form D and one or more, vehicle group.
8. the purposes of the described citric acid alidenafil crystal form D compsn of claim 7, it is characterized in that: described compsn is used to prepare oral prepns.
9. the application of the compsn of the described citric acid alidenafil crystal form D of claim 8 is characterized in that: the application of citric acid alidenafil crystal form D in making treatment male erectile dysfunction medicine.
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| CN101830903B (en) * | 2010-05-10 | 2012-07-04 | 刘桂坤 | Aildenafil citrate crystal form O, preparation method and application thereof |
| CN102952138B (en) * | 2011-08-17 | 2016-07-06 | 上海特化医药科技有限公司 | The salt of a kind of pyrazolopyrimidinone compound, polymorph and pharmaceutical composition, preparation method and application |
| CN107602571A (en) * | 2017-11-07 | 2018-01-19 | 中国医药集团总公司四川抗菌素工业研究所 | That noncrystal and preparation method thereof and pharmaceutical composition of citric acid Chinese mugwort ground |
| CN112745323B (en) * | 2020-12-30 | 2021-10-29 | 北京悦康科创医药科技股份有限公司 | Citric acid alidenafil crystal form H and preparation method and application thereof |
| EP4450072A1 (en) * | 2021-12-14 | 2024-10-23 | Zhenao Jinyinhua Pharmaceutical | Use of aildenafil or salt thereof in preparation of medicine for preventing or treating ischemic brain damage |
| CN115054585B (en) * | 2022-07-11 | 2022-11-18 | 北京悦康科创医药科技股份有限公司 | Tablets containing Aidenafil citrate and preparation method and application thereof |
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