CN101691372A - Aildenafil citrate crystal form C and preparation method and application thereof - Google Patents
Aildenafil citrate crystal form C and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to 1-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-4-ethoxybenzenesulfonyl]-cis-3,5-dimethyl-piperazine citrate or a aildenafil citrate crystal form C and a preparation method thereof. The invention also relates to a medicinal composition containing the aildenafil citrate crystal form C and application thereof in preparing medicaments for treating male erection disturbance. An unprecedented aildenafil citrate crystal form C is proved to be obtained through the steps of dissolving an aildenafil citrate raw material in a mixed solution of distilled water and acetone at a certain proportion, keeping the temperature for 8 to 10 hours at a certain temperature while stirring, and testing the prepared product by an X-ray powder diffractometer, a thermogravimetric analyzer and an infrared spectrometer; and the crystal form C can form a composition together with one or more pharmaceutically acceptable carriers, an excipient or a diluent, and can be effectively applied to the treatment of andropathy.
Description
Technical field
The present invention relates to 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 (Citric Acid edenaphy; Aildenafil citrate) new crystal C and preparation method thereof, the pharmaceutical composition that contains gained crystal C of the present invention and this new crystal C are 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 now has 1.25 hundred million male sex to suffer from various degree erective dysfunction 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, the new drug of some novel structures, mechanism of action uniqueness is pushed to the market or is 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 is:
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 preparation 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 height, good stability has superiority on industrial production, be fit to preparation technical process and standing storage.
Summary of the invention
The invention discloses Aildenafil citrate crystal form C, the preparation method of Aildenafil citrate crystal form C, the pharmaceutical composition that contains Aildenafil citrate crystal form C and Aildenafil citrate crystal form C are being made treatment male erectile dysfunction (male erectile dysfunction, ED) application in the medicine.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
The invention provides a kind of Aildenafil citrate crystal form C, X-ray powder diffraction charateristic avsorption band of this crystal formation (2 θ) and D value are as follows, and error is ± 0.2.
| Diffraction angle (2 θ) | The D value | ??I/I0 |
| ??7.14 | ??12.3704 | ??17 |
| ??7.58 | ??11.6533 | ??54 |
| ??8.76 | ??10.0860 | ??21 |
| ??10.66 | ??8.2922 | ??22 |
| ??11.10 | ??7.9645 | ??22 |
| ??13.68 | ??6.4677 | ??42 |
| ??14.06 | ??6.2937 | ??19 |
| ??14.98 | ??5.9092 | ??22 |
| ??15.32 | ??5.7713 | ??18 |
| ??16.54 | ??5.3552 | ??43 |
| ??16.84 | ??5.2605 | ??56 |
| ??18.54 | ??4.7818 | ??20 |
| ??20.60 | ??4.3080 | ??18 |
| ??21.64 | ??4.1033 | ??100 |
| ??22.60 | ??3.9140 | ??61 |
| ??24.26 | ??3.6657 | ??34 |
| ??24.58 | ??3.6187 | ??24 |
| Diffraction angle (2 θ) | The D value | ??I/I0 |
| ??27.70 | ??3.2178 | ??20 |
(powder x-ray diffraction PXRD) is usually used in polymorphous structural confirmation, thermodynamic stability and the research of other qualitative, quantitatives to powder X-ray-X-ray analysis X, is one of the most frequently used method of research medicine polymorphic.
The mensuration of 2 θ values is used light source among the present invention, and precision is ± 0.2 °, therefore represents above-mentioned value of getting to allow certain reasonably limit of error, and its limit of error is ± 0.2.The strongest charateristic avsorption band of this crystal C (2 θ) is 21.64.
And its infrared spectrogram is at 3502 ± 5cm
-13317 ± 5cm
-12980 ± 5cm
-12942 ± 5cm
-12491 ± 5cm
-11716 ± 2cm
-11174 ± 2cm
-1606 ± 2cm
-1Have charateristic avsorption band, use the KBr compressing tablet during mensuration, limit of error is determined according to Chinese Pharmacopoeia.
The hot analytical results of this crystalline powder shows: room temperature all is a straight line to about 220 ℃, no absorption peak, and there is a significant absorption peak while at 228 ℃ (TP), shows sample: do not contain crystal water, planar water or adsorption solvent.
Another object of the present invention, the preparation method of Aildenafil citrate crystal form C is disclosed, its process comprises: the Citric Acid edenaphy is dissolved in 18-22 times of distilled water and the acetone mixed solution, and with regard to mixed solution, acetone accounts for the 30%-70% (volume ratio) of mixed solution, preferred 45%-55% (volume ratio), fully stir, be warming up to reflux temperature, filtered while hot after 15-20 minute, filtrate is reduced to 30 ± 2 ℃, insulated and stirred 30-45 minute; Naturally be cooled to 23 ± 3 ℃ then, continue to stir 8-10 hour.Separate out crystallization, filter, indoor placement 1-3 hour, move to then in the vacuum drying oven, under vacuum (0.08-0.10Mpa) condition dry 3-5 hour, promptly obtain above-mentioned Aildenafil citrate crystal form C.
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 according to the precedent of document routinely synthesis method make by the raw material that is easy to get, can be as compound 2 by document (Chem.Pharm.Bull.1984,32 (4): 1568-1577; 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 easily by existing literature method.
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 23-28 doubly methyl alcohol or ethanol (quality-volume ratio, g/ml) in, under the reflux temperature, and wait mole Citric Acid reaction 0.5-1 hour, generate Citric Acid edenaphy crude product, 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 determine 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 Aildenafil citrate crystal form C.
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.For example 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, carboxymethyl cellulose, methylcellulose gum, potassiumphosphate and polyvinylpyrrolidone.Disintegrating agent includes but not limited to dry starch, sodium alginate, agar powder, sodium bicarbonate, 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 Aildenafil citrate crystal form C 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 tests behind the 3d.Sham-operated control group, model control group all give 0.5%CMC, are subjected to reagent to give edenaphy crystal formation C 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
-1Castration mouse is caught shorten 165% latent period, catching number of times increases by 3.6 times.
The influence factor test:
Influence to outward appearance
| Sample | Project | 0 month | 0.5 month | January |
| Citric Acid edenaphy compound crystal C | The high wet test exposure experiments to light of high temperature test | White crystalline powder white crystalline powder white crystalline powder | White crystalline powder white crystalline powder white crystalline powder | White crystalline powder white crystalline powder white crystalline powder |
Influence to content (HPLC area normalization method)
| Sample | Project | 0 month (%) | Month 0.5 (%) | January (%) |
| Citric Acid edenaphy compound crystal C | The high wet test exposure experiments to light of high temperature test | ??99.90??99.90??99.90 | ??99.90??99.89??99.89 | ??99.89??99.90??99.90 |
Influence to related substance
| Sample | Project | 0 month (%) | Month 0.5 (%) | January (%) |
| Citric Acid edenaphy compound crystal C | The high wet test of high temperature test | ??0.10??0.10 | ??0.10??0.09 | ??0.09??0.10 |
| Exposure experiments to light | ??0.10 | ??0.11 | ??0.10 |
Influence to infrared absorption spectrum
| Sample | Project | 0 month | 0.5 month | January |
| Citric Acid edenaphy compound crystal C | The high wet test exposure experiments to light of high temperature test | See that Fig. 2 sees that Fig. 2 sees Fig. 2 | 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 C | The high wet test exposure experiments to light of high temperature test | See that Fig. 1 sees that Fig. 1 sees Fig. 1 | Do not change not change and change | Do not change not change and change |
The result: Aildenafil citrate crystal form C at high light (under 4500lx ± 500lx), high temperature (60 ± 2 ℃), high humidity (RH92.5%) condition from 0-1 month, outward appearance, X powder diffraction, infrared absorption spectrum all do not change, stable crystal form is described, do not have the trichite of commentaries on classics and give birth to, still keep original crystal formation; Related substance, content do not change in addition, illustrate that the new crystal chemical stability is good, are fit to the manufacturing and the standing storage of pharmaceutical preparation.
Figure of description:
Fig. 1 is the X-ray diffractogram of Aildenafil citrate crystal form C;
Fig. 2 is the infrared spectrogram of Aildenafil citrate crystal form C;
Fig. 3 is the thermogram of Aildenafil citrate crystal form C;
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).
Embodiment:
The present invention is described further below in conjunction with embodiment and accompanying drawing, makes this area professional and technical personnel better understand the present invention.Embodiment only is indicative, means that never it limits the scope of the 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.
Embodiment 1
In the 1000ml reaction flask, add 20 gram Citric Acid edenaphies, 440ml distilled water/acetone mixed solution (4.5: 5.5, volume ratio), start stirring, heat temperature raising is to reflux temperature, filtered while hot after 15 minutes.Filtrate is reduced to 28 ℃-32 ℃, insulated and stirred 45 minutes; Naturally be cooled to 23 ± 3 ℃ then, continue to stir 10 hours, separate out crystallization, filter, indoor placement 2 hours moves in the vacuum drying oven then, vacuum-drying (0.08-0.10Mpa) 4 hours promptly obtains above-mentioned Aildenafil citrate crystal form C 17.6g, refining rate 88%.Adopt the HPLC area normalization method to record content 99.90%, see Fig. 1-Fig. 3, detect, show the feature of Aildenafil citrate crystal form C through X-ray diffractometer, infrared spectrometer, thermal analyzer.
In the 2000ml reaction flask, add 35 gram Citric Acid edenaphies, 630ml distilled water/acetone (6: 4, volume ratio), start stirring, heat temperature raising is to refluxing filtered while hot after 18 minutes.Filtrate is reduced to 30 ℃-32 ℃, insulated and stirred 30 minutes; Naturally be cooled to 23 ± 3 ℃ then, continue to stir 8 hours, separate out crystallization, filter, indoor placement 3 hours moves in the vacuum drying oven then, vacuum-drying (0.08-0.10Mpa) 5 hours promptly obtains above-mentioned Aildenafil citrate crystal form C 31.9g, refining rate 91.1%.Adopt the HPLC area normalization method to record content 99.90%, after tested, show the feature of Aildenafil citrate crystal form C.
Embodiment 3
The granule that contains Aildenafil citrate crystal form C
Prescription: Aildenafil citrate crystal form C 50 grams, lactose 650 grams, crosslinked poly-dimension 100 grams, the PEG-400090 gram, Vltra tears 135 grams, distilled water is an amount of, makes 1000 bags.
Technology: PEG-4000 and Aildenafil citrate crystal form C are pulverized jointly, cross 80 mesh sieves, with behind other material mixing with being packed as granule after distilled water system softwood, granulation, the cryodrying.
Embodiment 4
The capsule that contains Aildenafil citrate crystal form C
Prescription: Aildenafil citrate crystal form C 60 grams, starch 50 grams, lactose 40 grams, sucrose 10 grams, Microcrystalline Cellulose 35 grams, 10% polyvinylpyrrolidone ethanolic soln is an amount of, and Magnesium Stearate 1 gram is made 1000.
Technology: Aildenafil citrate crystal form C and auxiliary material are crossed 80 mesh sieves, take by weighing by recipe quantity, with 10% polyvinylpyrrolidone ethanolic soln is tackiness agent, make 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.
Embodiment 5
The tablet that contains Aildenafil citrate crystal form C
Prescription: Aildenafil citrate crystal form C 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, croscarmellose sodium 10 grams, distilled water is an amount of, makes 1000.
Technology: PEG-4000 and Aildenafil citrate crystal form C are pulverized jointly, cross 80 mesh sieves, with behind other material mixing with distilled 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 preferred embodiment of the present invention only, and for those of ordinary skill in the art, according to thought of the present invention, the part that all can change in specific embodiments and applications, this description should not be construed as limitation of the present invention.
Claims (8)
1. Aildenafil citrate crystal form C is characterized in that: in measuring as the characteristic X-ray powdery diffractometry with the CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle and D value, and the error of 2 θ diffraction angle is 0.2;
2. Aildenafil citrate crystal form C according to claim 1 is characterized in that: in thermogram spectrum, room temperature to 220 ℃ is a straight line, simultaneously, at 228 ℃ (Tp) a significant absorption peak is arranged.
3. the preparation method of the described Aildenafil citrate crystal form C of claim 1, it is characterized in that: by the Citric Acid edenaphy being dissolved in doubly (quality-volume ratio of 18-22, grams per milliliter) in distilled water/acetone mixed solution, fully stir, be warming up to reflux temperature, filtered while hot after 15-20 minute, filtrate is reduced to 30 ± 2 ℃, insulated and stirred 30-45 minute, be cooled to 23 ± 3 ℃ then naturally, continue to stir 8-10 hour.Separate out crystallization, filter, indoor placement 1-3 hour, move to then in the vacuum drying oven, under vacuum (0.08-0.10Mpa) condition dry 3-5 hour, promptly obtain Aildenafil citrate crystal form C.
4. the preparation method of Aildenafil citrate crystal form C according to claim 3, it is characterized in that: described distilled water/acetone mixed solution, wherein acetone accounts for the 30%-70% of mixeding liquid volume ratio.
5. the preparation method of Aildenafil citrate crystal form C according to claim 3, it is characterized in that: described distilled water/acetone mixed solution, wherein acetone accounts for the 45%-55% of mixeding liquid volume ratio.
6. a purposes that contains the described Aildenafil citrate crystal form C of claim 1-2 is characterized in that: Aildenafil citrate crystal form C and one or more pharmaceutically acceptable carriers, vehicle or thinner composition composition.
7. the purposes of Aildenafil citrate crystal form C according to claim 6, it is characterized in that: described composition is used to prepare oral preparations.
8. the purposes of Aildenafil citrate crystal form C according to claim 6 is characterized in that: the application of Aildenafil citrate crystal form C in making treatment male erectile dysfunction medicine.
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Cited By (7)
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| WO2011140858A1 (en) * | 2010-05-10 | 2011-11-17 | Liu Guikun | Aildenafil citrate crystal form o, preparation method and use thereof |
| JP2014521729A (en) * | 2011-08-17 | 2014-08-28 | 上海特化医薬科技有限公司 | Pyrazolopyrimidinone compound salts, polymorphs and drug compositions, preparation methods and applications thereof |
| 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 |
| CN112745323A (en) * | 2020-12-30 | 2021-05-04 | 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 |
| CN114478542A (en) * | 2021-12-10 | 2022-05-13 | 厦门恩成制药有限公司 | Compound crystal form and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011140858A1 (en) * | 2010-05-10 | 2011-11-17 | Liu Guikun | Aildenafil citrate crystal form o, preparation method and use thereof |
| JP2014521729A (en) * | 2011-08-17 | 2014-08-28 | 上海特化医薬科技有限公司 | Pyrazolopyrimidinone compound salts, polymorphs and drug compositions, preparation methods and applications thereof |
| 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 |
| CN112745323A (en) * | 2020-12-30 | 2021-05-04 | 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 |
| CN114478542A (en) * | 2021-12-10 | 2022-05-13 | 厦门恩成制药有限公司 | Compound crystal form and preparation method and application thereof |
| CN114478542B (en) * | 2021-12-10 | 2024-02-06 | 厦门恩成制药有限公司 | Compound crystal form and preparation method and application thereof |
| CN115054585A (en) * | 2022-07-11 | 2022-09-16 | 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 |
| CN115919867A (en) * | 2022-12-13 | 2023-04-07 | 北京悦康科创医药科技股份有限公司 | Oral citric acid alidenafil sustained-release preparation and preparation method and application thereof |
| CN115919867B (en) * | 2022-12-13 | 2024-05-24 | 北京悦康科创医药科技股份有限公司 | Aidenafil citrate oral sustained-release preparation and preparation method and application thereof |
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