CN101698668B

CN101698668B - Crystal form V of Aildenafil citrate and preparation method and application thereof

Info

Publication number: CN101698668B
Application number: CN200910193823XA
Authority: CN
Inventors: 刘桂坤
Original assignee: Individual
Current assignee: Individual
Priority date: 2009-11-10
Filing date: 2009-11-10
Publication date: 2012-07-25
Anticipated expiration: 2029-11-10
Also published as: CN101698668A

Abstract

The invention relates to a crystal form V of 1-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H- pyrazolo[4,3-d] 5-pyrimidinyl)-4-ethyoxylbenzenesulfonyl]-cis-3,5-dimethylpiperazine citrate or Aildenafil citrate, and a preparation method thereof. The preparation method comprises the following steps: dissolving raw materials of the Aildenafil citrate in distilled water, stirring, and raising temperature to a reflux temperature; and adding acetone solution, and stirring and raising temperature continuously. The prepared product meets product requirements after being tested by an X-ray powder diffractometer and an infrared spectrometer. The invention also relates to a medicinal composition comprising the crystal form V of the Aildenafil citrate, and application of the crystal form V of the Aildenafil citrate in preparing medicaments for treating erection disturbance (ED).

Description

Crystal form V of Aildenafil citrate

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 form V and preparation method thereof, the pharmaceutical composition that contains gained crystal form V of the present invention and this crystal form V 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 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.

The inventor finds that there is polymorphism in the Citric Acid edenaphy in the process of research preparation Citric Acid edenaphy, crystal form V biological activity of the present invention is high; Purity is high; Good stability has meliority on industrial production, be fit to preparation technical process and standing storage.

Summary of the invention

The pharmaceutical composition and the crystal form V of Aildenafil citrate that the objective of the invention is to disclose the preparation method of a kind of crystal form V of Aildenafil citrate and crystal form V of Aildenafil citrate and contain crystal form V of Aildenafil citrate are being made treatment male erectile dysfunction (male erectiledysfunction, 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 crystal form V of Aildenafil citrate, the X-ray powder diffraction charateristic avsorption band of this crystal formation (2 θ), D value and relative intensity are following, and the error of 2 θ diffraction angle is ± 0.2.

Diffraction angle (2 θ)	The D value	Relative intensity (%)
			6.840	12.9123	23
7.620	11.5922	33
			9.200	9.6046	60
9.940	8.8912	65
			10.900	8.1102	22
12.140	7.2844	21
			12.580	7.0306	23
13.160	6.7220	69
			13.480	6.5632	28
14.840	5.9646	43
			15.200	5.8241	100
16.920	5.2358	34
			17.220	5.1452	55
17.540	5.0521	61
			18.220	4.8650	67
18.560	4.7767	42
			19.380	4.5764	28
19.800	4.4802	29
			20.100	4.4140	33
20.680	4.2915	20
			20.820	4.2630	24
21.160	4.1952	52
			21.960	4.0442	27
22.480	3.9518	83
			22.960	3.8703	25

23.440	3.7921	30
			24.120	3.6867	23
24.580	3.6187	45
			25.400	3.5037	57
27.080	3.2901	29
			30.280	2.9493	26

(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 (2 θ) of this crystal form V is 15.200.

Its infrared spectrogram is at 3403 ± 5cm ^-13354 ± 5cm ^-12969 ± 5cm ^-12936 ± 5cm ^-12510 ± 5cm ^-11701 ± 2cm ^-11664 ± 2cm ^-11172 ± 2cm ^-11018 ± 2cm ^-1786 ± 2cm ^-1Have and can itself and other crystal formation be distinguished the charateristic avsorption band that comes, use the KBr compressing tablet during mensuration, limit of error is confirmed according to Chinese Pharmacopoeia.

The hot analytical results of this crystalline powder shows: sample does not contain recrystallisation solvent.

Another object of the present invention discloses the preparation method of crystal form V of Aildenafil citrate, it is characterized in that: give in the reaction flask that fills the Citric Acid edenaphy to add 25～30 times of (weight-volume ratio, ebullient zero(ppm) water of gram/milli; Can add the gac that accounts for Citric Acid edenaphy weight 1%, start stirring, be warming up to reflux temperature, filtered while hot after 15-20 minute; Filtrating is reduced to 45 ℃-50 ℃, adds the acetone of used zero(ppm) water 2 times (volumes), continues to stir 1 hour; Separate out crystallization, filter indoor placement 1 hour; Move to then in the vacuum drying oven, vacuum-drying 2-3 hour, obtain above-mentioned crystal form V of Aildenafil citrate.

Used Citric Acid edenaphy makes according to following synthetic route:

Wherein:

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

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 (ChVm.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. 3 and Fig. 4.

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 crystal form V of Aildenafil citrate.

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, 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 crystal form V of Aildenafil citrate 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 edenaphy crystal formation V 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 195% latent period, catching number of times increases by 4.2 times.The influence factor test:

Influence to outward appearance

Sample	Project	0 month	0.5 month	January
					Crystal form V of Aildenafil citrate	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 (%)
					Crystal form V of Aildenafil citrate	The high wet test exposure experiments to light of high temperature test	99.95 99.95 99.95	99.95 99.94 99.96	99.96 99.95 99.95

Influence to related substance

Sample	Project	0 month (%)	Month 0.5 (%)	January (%)
					Citric Acid edenaphy compound crystal form V	The high wet test exposure experiments to light of high temperature test	0.05 0.05 0.05	0.05 0.06 0.05	0.04 0.05 0.05

Influence to infrared absorption spectrum

Sample	Project	0 month	0.5 month	January
					The Citric Acid edenaphy	High temperature test	See Fig. 2	Do not change	Do not change

The compound crystal form V

High wet test exposure experiments to light

See that Fig. 2 sees Fig. 2

Do not change and change

Influence to X powder diffraction

Sample	Project	0 month	0.5 month	January
					Citric Acid edenaphy compound crystal form V	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

Beneficial effect of the present invention: crystal form V of Aildenafil citrate 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, explain that the new crystal chemicalstability is good, are fit to the manufacturing and the standing storage of pharmaceutical prepn.

Description of drawings:

Fig. 1 is the X-ray diffractogram of crystal form V of Aildenafil citrate;

Fig. 2 is the infrared spectrogram of crystal form V of Aildenafil citrate;

Fig. 3 be the Citric Acid edenaphy proton nmr spectra ( ¹H-NMR) figure;

Fig. 4 be the Citric Acid edenaphy carbon-13 nmr spectra ( ¹³C-NMR) figure.

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 DVPT), 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. 3 and Fig. 4.

Embodiment 1

In the 3000ml reaction flask, add 30 gram Citric Acid edenaphies, 870ml zero(ppm) water, start stirring, heat temperature raising is to refluxing; Filtered while hot after 15 minutes, filtrating is reduced to 45 ℃-50 ℃, adds 1740ml acetone, continues to stir 1 hour; Separate out crystallization, filter, indoor placement 1 hour moves in the vacuum drying oven then; Vacuum-drying 2 hours promptly obtains above-mentioned crystal form V of Aildenafil citrate 27.3g, and refining rate 91% adopts the HPLC area normalization method to record content 99.95%.(see Fig. 1, Fig. 2), show the characteristic of crystal form V of Aildenafil citrate through X-ray diffractometer, IR detection.

Embodiment 2

In the 1000ml reaction flask, add 10 gram Citric Acid edenaphies, 250ml zero(ppm) water, start stirring, heat temperature raising is to refluxing; Filtered while hot after 15 minutes, filtrating is reduced to 45 ℃-50 ℃, adds 500ml acetone, continues to stir 1 hour; Separate out crystallization, filter, indoor placement 1 hour moves in the vacuum drying oven then; Vacuum-drying 3 hours promptly obtains above-mentioned crystal form V of Aildenafil citrate 9.2g, and refining rate 92% adopts the HPLC area normalization method to record content 99.95%.Detect through X-ray diffractometer, IR, (seeing Fig. 1, Fig. 2) shows the characteristic of crystal form V of Aildenafil citrate.

Embodiment 3

The granule that contains crystal form V of Aildenafil citrate

Prescription: crystal form V of Aildenafil citrate 50 grams, lactose 650 grams, cross-linked dimension 100 grams, the PVG-400090 gram, Vltra tears 135 grams, zero(ppm) water is an amount of, processes 1000 bags.

Technology: PVG-4000 and crystal form V of Aildenafil citrate 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.

Embodiment 4

The capsule that contains crystal form V of Aildenafil citrate

Prescription: crystal form V of Aildenafil citrate 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: crystal form V of Aildenafil citrate 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.

Embodiment 5

The tablet that contains crystal form V of Aildenafil citrate

Prescription: crystal form V of Aildenafil citrate 70 grams, Microcrystalline Cellulose 5 grams, lactose 140 grams, 10 gram PVG-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: PVG-4000 and crystal form V of Aildenafil citrate 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

1. crystal form V of Aildenafil citrate; It is characterized in that: during the crystal form V of Aildenafil citrate compound is measured as the characteristic X-ray powder with the CuKa ray; Its collection of illustrative plates has following 2 θ diffraction angle, D value and relative intensity, and wherein the error of 2 θ diffraction angle is 0.2;

Diffraction angle (2 θ) The D value Relative intensity (%) 6.840 12.9123 23 7.620 11.5922 33 9.200 9.6046 60 9.940 8.8912 65 10.900 8.1102 22 12.140 7.2844 21 12.580 7.0306 23 13.160 6.7220 69 13.480 6.5632 28 14.840 5.9646 43 15.200 5.8241 100 16.920 5.2358 34 17.220 5.1452 55 17.540 5.0521 61 18.220 4.8650 67 18.560 4.7767 42 19.380 4.5764 28 19.800 4.4802 29 20.100 4.4140 33 20.680 4.2915 20 20.820 4.2630 24 21.160 4.1952 52 21.960 4.0442 27 22.480 3.9518 83 22.960 3.8703 25 23.440 3.7921 30 24.120 3.6867 23 24.580 3.6187 45 25.400 3.5037 57 27.080 3.2901 29 30.280 2.9493 26

。

2. crystal form V of Aildenafil citrate according to claim 1 is characterized in that: in the infrared spectrogram, at 3403 ± 5cm ^-13354 ± 5cm ^-12969 ± 5cm ^-12936 ± 5cm ^-12510 ± 5cm ^-11701 ± 2cm ^-11664 ± 2cm ^-11172 ± 2cm ^-11018 ± 2cm ^-1786 ± 2cm ^-1There is characteristic peak at the place.

3. the preparation method of claim 1 or 2 described crystal form V of Aildenafil citrate; It is characterized in that: through Citric Acid edenaphy raw material being dissolved in 25 ~ 30 times of quality-volume ratios in the grams per milliliter ebullient zero(ppm) water; Reduce to 45 ℃-50 ℃, add the acetone of 2 times of volumes of used zero(ppm) water, continue to stir 1 hour; Separate out crystallization, obtain above-mentioned crystal form V of Aildenafil citrate.

4. the compsn of claim 1 or 2 any described crystal form V of Aildenafil citrate is characterized in that: the compsn of being made up of crystal form V of Aildenafil citrate compound and one or more pharmaceutically acceptable carriers, vehicle.

5. the compsn of crystal form V of Aildenafil citrate according to claim 4, it is characterized in that: this above-mentioned compsn is used to prepare oral prepns.

6. the purposes of the compsn of the described crystal form V of Aildenafil citrate of claim 5 is characterized in that: the application in making treatment male erectile dysfunction medicine.