CN101735205B - Crystalline form V of azimilide dihydrochloride, preparation method and application thereof - Google Patents
Crystalline form V of azimilide dihydrochloride, preparation method and application thereof Download PDFInfo
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- CN101735205B CN101735205B CN 200910244879 CN200910244879A CN101735205B CN 101735205 B CN101735205 B CN 101735205B CN 200910244879 CN200910244879 CN 200910244879 CN 200910244879 A CN200910244879 A CN 200910244879A CN 101735205 B CN101735205 B CN 101735205B
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- azimilide dihydrochloride
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Abstract
The invention relates to crystalline form V of azimilide dihydrochloride and a preparation method thereof, further relates to a pharmaceutical composition prepared by the crystalline form V of azimilide dihydrochloride obtained by the invention and application thereof. The crystalline form V of azimilide dihydrochloride uses powder X-ray diffractogram and infrared spectrogram as token.
Description
Technical field
The invention belongs to the antiarrhythmic drug field, more particularly, relate to 1-{[5-(4-chloro-phenyl-) fural of azimilide dihydrochloride (Azimilide dihydrochloride) or formula (I)] amino }-3-[4-(4-methyl isophthalic acid-piperazinyl) butyl] crystal form V and preparation method thereof of glycolylurea dihydrochloride, the pharmaceutical composition that contains it and the purposes in making antiarrhythmic drug thereof.
Background technology
Irregular pulse is the serious fatal disease of a class, and according to incompletely statistics, the U.S. is approximately 40～600,000 because of the cardiac sudden death number that ventricle fibrillation causes every year.Present internationally recognized Vaughan Williams classification is divided into I～IV class by electrophysiological property with antiarrhythmic Agents.Based on external large-scale clinical experiment result as can be known, I class medicine more easily brings out serious ventricular arrhythmia, simultaneously part not fully up to expectations is being arranged all also aspect curative effect and patient tolerability.Therefore, antiarrhythmic drug treatment in recent years has the tendency that changes to III class medicine from using I class medicine.The acting in conjunction mechanism of III class antiarrhythmic drug is specific inhibition Delayed Rectifier Potassium Channels electric current (I
K), extend myocardial action potential time-histories (APD) and effective refractory period (ERP), thereby extend repolarization.But, the first-generation medicine take amiodarone (Amiodarone), sotalol (Sotalol) as representative and untoward reaction has occured and had reverse heart rate dependency (reverse ratedependence) take ibutilide (Ibutilide), P162a (Dofetilide) as the s-generation medicine of representative wherein, and because life-time service has produced tolerance, clinical application is subject to a lot of restrictions.
Azimilide dihydrochloride (Azimilide dihydrochloride), chemistry 1-{[5-(4-chloro-phenyl-) fural by name] amino }-3-[4-(4-methyl isophthalic acid-piperazinyl) butyl] the glycolylurea dihydrochloride is the compound III class of third generation antiarrhythmic drug.By US P﹠G Company (Procter﹠amp; Gamble) develop, at present among the U.S., Germany, Canada have been in clinical study.It both can block quick delayed rectification Outward (I
Kr), also can block delayed rectification Outward (I at a slow speed
Ks), the mechanism of action of neither one medicine with this novelty still in the market.Its undesirable action shows lower incidence with respect to many other traditional antiarrhythmic drugs, better tolerance, and do not have reverse heart rate dependency.The prevention of dying suddenly after treatment, atrial fibrillation and the myocardial infarction for ventricular tachycardia, supraventricular arrhythmia clinically is also for the ventricular tachycardia that prevents embedded cardioversion defibrillator (ICD) patient.Clinical study shows, this medical instrument has following characteristics: the impact on blood pressure and heart rate is lower; On the PR of human body electrocardio figure or QRS interval without impact; Oral can the absorption fully, the impact of unable to take food thing; But take every day once; Using dosage and age, sex, liver, renal function are irrelevant etc., therefore become the focus of domestic and international antiarrhythmic drug research.
Chemical structure:
Molecular formula: C
23H
28ClN
5O
32HCl
Molecular weight: 450.5
CAS#：149888-94-8
The preparation method of this product has been reported both at home and abroad, as document US 5462940 and document WO9955700.Article " synthesizing of azimilide dihydrochloride ", Chinese pharmaceutical chemistry magazine, 2006:16 (4): also put down in writing the preparation method of azimilide dihydrochloride in 226-228, but all do not related to the crystal formation of azimilide dihydrochloride.In view of the pharmacy value of this compound, acquisition purity is high, compound that have very definite crystal formation and favorable reproducibility is important.
The inventor has repeated " synthesizing of azimilide dihydrochloride ", Chinese pharmaceutical chemistry magazine, and 2006:16 (4): the purification process of putting down in writing in 226-228, namely dehydrated alcohol-water (9: 2) is made with extra care.Or use acetone to replace dehydrated alcohol, in acetone-water (7～5: 2～4) attempt in scope, all obtain single crystal X-powder diffraction data, feature following (seeing accompanying drawing 1):
The characteristic absorbance following (seeing accompanying drawing 2) that infrared spectra shows:
3435cm
-1、2940cm
-1、2834cm
-1、1777cm
-1、1731cm
-1、1516cm
-1、1417cm
-1、1235cm
-1、798cm
-1、609cm
-1。
Summary of the invention
An object of the present invention is to provide the azimilide dihydrochloride crystal form V.
Another object of the present invention is to provide the preparation method of azimilide dihydrochloride crystal form V.
A further object of the invention is to provide the azimilide dihydrochloride crystal form V as effective constituent, and the medicinal compositions that contains one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect antiarrhythmic drug.
Now in conjunction with the object of the invention, content of the present invention is specifically described.
Azimilide dihydrochloride of the present invention has following structural formula:
The azimilide dihydrochloride crystal form V has following characteristics:
Measure with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, its collection of illustrative plates have following diffraction angle (2 θ), spacing (d value) and intensity (%), the error of 2 θ is 0.2.
The azimilide dihydrochloride crystal form V, with Potassium Bromide (KBr) compressing tablet, the infrared spectrogram that records has following charateristic avsorption band:
3427cm
-1、2947cm
-1、2480cm
-1、1774cm
-1、1717cm
-1、1452cm
-1、1335cm
-1、1254cm
-1、1024cm
-1、745cm
-1。
For the preparation of the azimilide dihydrochloride of azimilide dihydrochloride crystal form V, can be made by three kinds of synthetic methods.
A kind of is the method for report in patent US 5462940, and reaction scheme is as follows:
Also having a kind of is the synthetic method of report in patent WO 9955700, and reaction scheme is as follows:
The paper " synthesizing of azimilide dihydrochloride " that the azimilide dihydrochloride that the present invention uses has adopted the contriver to deliver, China's pharmaceutical chemistry magazine, 2006:16 (4): the synthesis technique of the azimilide dihydrochloride of introducing in 226-228 is expressed as follows with reaction formula:
Synthetic azimilide dihydrochloride is refining with alcohol-water, and through proton nmr spectra (
1H-NMR), carbon-13 nmr spectra (
13C-NMR), DEPT135 ° of carbon spectrum conclusive evidence its chemical structure (seeing accompanying drawing 3,4,5).Testing tool is Bruker AV 400 type nuclear magnetic resonance analyser, and deuterated reagent is the D of Cambridge IsotopeLaboratories company
2O。The maximum single contaminant that high performance liquid chromatography (HPLC) records is 1.135%.
But above-mentioned product namely uses the mixed solvent alcohol-water to re-refine twice, and maximum single contaminant still is not less than 0.3%.
The crystal form V of azimilide dihydrochloride is that crystallization obtains in the mixed solution of tetrahydrofuran (THF)-water.The usage quantity of mixed solution be 3～12 times of the azimilide dihydrochloride quality (volume-mass ratio, mL/g), wherein preferred 5～9 times.
Water accounts for 10%～20% of mixed solution cumulative volume.
Temperature during dissolving is 30 ℃～65 ℃.Then naturally be cooled to room temperature, placed 1～5 hour, namely obtain the new crystal V-type of azimilide dihydrochloride.
Specific operation process is:
Get a certain amount of azimilide dihydrochloride, add tetrahydrofuran (THF)-water mixed liquid, heated and stirred after dissolving, naturally cools to room temperature, then is incubated for some time.Separate out solid, filter, namely get the azimilide dihydrochloride crystal form V.
Then through the X-powder diffraction method, infrared absorption spectrometry feature.
Do not contain crystal water and recrystallisation solvent in thermogravimetric analysis demonstration azimilide dihydrochloride crystal form V.
The crystal form V purity that the method makes is high, and single contaminant has reached the relevant requirements of U.S. food Drug Administration (FDA) less than 1 ‰, and is very important to making high-quality medicine.In the described process parameters range of the method, repeat a plurality of batches, circulation ratio is fabulous.
The preparation method of azimilide dihydrochloride crystal form V pharmaceutical composition of the present invention is as follows: Application standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis etc.
The amount of the active ingredient that contains in pharmaceutical composition and unit dosage form can specifically be applied according to patient's the state of an illness, the situation of diagnosis, the amount of compound used or concentration are regulated in a wider scope, usually, the weight range of active compound is 0.5%～90% (weight) of composition.Another preferred scope is 0.5%～70%.
Figure of description
Fig. 1 is the X-powder diagram of contrast azimilide dihydrochloride.
Fig. 2 is the infrared spectrogram of contrast azimilide dihydrochloride.
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of azimilide dihydrochloride.
Fig. 4 is the carbon-13 nmr spectra figure of azimilide dihydrochloride.
Fig. 5 is DEPT135 ° of carbon spectrogram of azimilide dihydrochloride.
Fig. 6 is the X-powder diagram of azimilide dihydrochloride crystal form V.
Fig. 7 is the infrared spectrogram of azimilide dihydrochloride crystal form V.
Embodiment
Below in conjunction with embodiment, the present invention is described further, embodiment is only indicative, means that never it limits the scope of the invention by any way.
Embodiment 1:
Take azimilide dihydrochloride 20.0g, add 60mL tetrahydrofuran (THF)-water mixed liquid (volume ratio 4: 1), be heated to 65 ℃, after stirring and dissolving, filtered while hot, filtrate naturally cools to room temperature, places 1 hour.Separate out solid, filter, vacuum-drying approximately 24 hours gets yellow crystalline powder.
Embodiment 2:
Take azimilide dihydrochloride 20.0g, add 150mL tetrahydrofuran (THF)-water mixed liquid (volume ratio 17: 3), be heated to 50 ℃, after stirring and dissolving, filtered while hot, filtrate naturally cools to room temperature, places 3 hours.Separate out solid, filter, vacuum-drying approximately 24 hours gets yellow crystalline powder.
Embodiment 3:
Take azimilide dihydrochloride 20.0g, add 240mL tetrahydrofuran (THF)-water mixed liquid (volume ratio 9: 1), be heated to 30 ℃, after stirring and dissolving, filtered while hot, filtrate naturally cools to room temperature, places 5 hours.Separate out solid, filter, vacuum-drying approximately 24 hours gets yellow crystalline powder.
Embodiment 4:
Every tablet preparation that contains the 100mg activeconstituents:
Consumption/sheet
Azimilide dihydrochloride crystal form V 100mg
Lactose 80mg
Microcrystalline Cellulose 20mg
Starch 50mg
Hypromellose 10mg
Add 5mg in carboxymethylstach sodium, add 5mg
Magnesium Stearate 1mg
Technique: activeconstituents, lactose, starch, Microcrystalline Cellulose are crossed respectively 100 mesh sieves, take and abundant mixing by recipe quantity, the 2% hypromellose aqueous solution is joined in said mixture granulate, cross 20 mesh sieve softwoods processed, make wet granular in 45～55 ℃ of dryings approximately 2-3 hour, residue carboxymethylstach sodium, Magnesium Stearate are joined compressing tablet in above-mentioned dried particles.
Embodiment 5:
Every capsule contains the capsule preparation of 80mg activeconstituents:
Consumption/capsule
Azimilide dihydrochloride crystal form V 80mg
Microcrystalline Cellulose 20mg
Lactose 60mg
Sodium starch glycolate 6mg
Hypromellose 5mg
Micropowder silica gel 5mg
Magnesium Stearate 1mg
Talcum powder 1mg
Technique: activeconstituents, auxiliary material are crossed respectively 100 mesh sieves; the main ingredient and the auxiliary material that take recipe quantity fully mix; add hypromellose solution softwood processed in right amount; cross 24 mesh sieves; make wet granular in 50-60 ℃ of baking oven dry approximately 2-3 hour, Magnesium Stearate and talcum powder and particle are mixed whole grain; measure intermediate content, with No. 2 capsule cans.
Claims (9)
1. the crystal form V of an azimilide dihydrochloride, is characterized in that the powder x-ray diffraction collection of illustrative plates is as shown in Figure of description 6.
2. according to claim 1 the crystal form V of azimilide dihydrochloride, the characteristic absorbance that its infrared spectra shows is as follows:
3427cm
-1、2947cm
-1、2480cm
-1、1774cm
-1、1717cm
-1、1452cm
-1、1335cm
-1、1254cm
-1、1024cm
-1、745cm
-1。
3. the preparation method of an azimilide dihydrochloride crystal form V as claimed in claim 1, is characterized in that: after azimilide dihydrochloride is dissolved in warm tetrahydrofuran (THF)-water mixed liquid, naturally cool to room temperature, then be incubated for some time, crystallize out.
4. the preparation method of an azimilide dihydrochloride crystal form V as claimed in claim 3, described warm tetrahydrofuran (THF)-water mixed liquid, the cumulative volume of mixed solution are 3～12 times of corresponding azimilide dihydrochloride quality, mL/g.
5. the preparation method of an azimilide dihydrochloride crystal form V as claimed in claim 3, described tetrahydrofuran (THF)-water mixed liquid, wherein the volume of water accounts for 10%～20% of mixed solution cumulative volume.
6. the preparation method of an azimilide dihydrochloride crystal form V as claimed in claim 3, described warm tetrahydrofuran (THF)-water mixed liquid, temperature is 30 ℃～65 ℃.
7. the preparation method of an azimilide dihydrochloride crystal form V as claimed in claim 3, described insulation for some time is 2～3 hours.
8. a pharmaceutical composition, is characterized in that: comprise azimilide dihydrochloride crystal form V as described in claim 1～2 any one and one or more pharmaceutically useful inert non-toxic carriers as activeconstituents.
9. the purposes of azimilide dihydrochloride crystal form V as described in claim 1～2 any one in making antiarrhythmic drug.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200910244879 CN101735205B (en) | 2009-12-17 | 2009-12-17 | Crystalline form V of azimilide dihydrochloride, preparation method and application thereof |
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| CN 200910244879 CN101735205B (en) | 2009-12-17 | 2009-12-17 | Crystalline form V of azimilide dihydrochloride, preparation method and application thereof |
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| CN101735205A CN101735205A (en) | 2010-06-16 |
| CN101735205B true CN101735205B (en) | 2013-05-15 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5462940A (en) * | 1991-08-14 | 1995-10-31 | Norwich Eaton Pharmaceuticals, Inc. | 4-oxocyclic ureas useful as antiarrhythmic and antifibrillatory agents |
| CN1298403A (en) * | 1998-04-29 | 2001-06-06 | 宝洁公司 | Process for making 1,3-disubstituted-4-oxocyclic ureas |
-
2009
- 2009-12-17 CN CN 200910244879 patent/CN101735205B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5462940A (en) * | 1991-08-14 | 1995-10-31 | Norwich Eaton Pharmaceuticals, Inc. | 4-oxocyclic ureas useful as antiarrhythmic and antifibrillatory agents |
| CN1298403A (en) * | 1998-04-29 | 2001-06-06 | 宝洁公司 | Process for making 1,3-disubstituted-4-oxocyclic ureas |
Non-Patent Citations (3)
| Title |
|---|
| 张翌."盐酸阿齐利特的合成".《中国优秀博硕士学位论文全文数据库（硕士）工程科技Ⅰ辑》.2007,(第5期),B016-155. |
| 张翌."盐酸阿齐利特的合成".《中国优秀博硕士学位论文全文数据库(硕士)工程科技Ⅰ辑》.2007,(第5期),B016-155. * |
| 郑其萍等."盐酸阿齐利特合成工艺的改进".《华西药学杂志》.2009,第24卷(第1期),第51-53页. |
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