CN101735205A - Crystalline form V of azimilide dihydrochloride, preparation method and application thereof - Google Patents

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

Crystalline form V of azimilide dihydrochloride and its production and use

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 the patient tolerability.Therefore, antiarrhythmic drug treatment in recent years has from using the tendency that I class medicine changes to III class medicine.The acting in conjunction mechanism of III class antiarrhythmic drug is specific inhibition Delayed Rectifier Potassium Channels electric current (I _K), prolong myocardial action potential time-histories (APD) and effective refractory period (ERP), thereby prolong myocardium multipole.But, be the first-generation medicine of representative wherein and be that the s-generation medicine of representative untoward reaction has taken place and had reverse heart rate dependency (reverse ratedependence) with ibutilide (Ibutilide), P162a (Dofetilide) with amiodarone (Amiodarone), sotalol (Sotalol), and because of life-time service has produced tolerance, clinical application is subjected 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 a 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 the export-oriented potassium channel (I of quick delayed rectification _Kr), also can block the export-oriented potassium channel (I of delayed rectification at a slow speed _Ks), the mechanism of action of none medicine still in the market with this novelty.Its undesirable action shows lower incidence with respect to many other traditional antiarrhythmic drugs, better tolerance, and do not have reverse heart rate dependency.Be used for the prevention of dying suddenly after treatment, atrial fibrillation and the myocardial infarction of ventricular tachycardia, supraventricular arrhythmia clinically, also be used to prevent embedded heart to change multiple defibrillator (ICD) patient's ventricular tachycardia.Clinical study shows that this medical instrument has following characteristics: the influence to blood pressure and heart rate is lower; The PR of human body electrocardio figure or QRS interval there is not influence; Oral can the absorption fully, the influence 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 existing both at home and abroad report of the preparation method of this product is as document US 5462940 and document WO 9955700.Article " synthesizing of azimilide dihydrochloride ", Chinese pharmaceutical chemistry magazine, 2006:16 (4): also put down in writing the preparation method of azimilide dihydrochloride among the 226-228, but all do not related to the crystal formation of azimilide dihydrochloride.In view of the pharmacy value of this compound, the compound that obtain the purity height, has very definite crystal formation and a 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 among the 226-228, promptly 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 the 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 provides the preparation method of azimilide dihydrochloride crystal form V.

A further object of the invention provides 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 content of the present invention is specifically described in conjunction with the object of the invention.

Azimilide dihydrochloride of the present invention has following structural formula:

The azimilide dihydrochloride crystal form V has following feature:

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。

Be used to prepare the azimilide dihydrochloride of azimilide dihydrochloride crystal form V, can make by three kinds of synthetic methods.

A kind of is reported method among the patent US 5462940, and reaction scheme is as follows:

Also having a kind of is the synthetic method of report among the 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, Chinese pharmaceutical chemistry magazine, 2006:16 (4): the synthesis technique of the azimilide dihydrochloride of introducing among the 226-228 is expressed as follows with reaction formula:

The 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 impurity that high performance liquid chromatography (HPLC) records is 1.135%.

But above-mentioned product promptly uses the mixed solvent alcohol-water to re-refine twice, and maximum single impurity 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 ℃.Naturally be cooled to room temperature then, placed 1～5 hour, promptly 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 the dissolving, naturally cools to room temperature, is incubated for some time again.Separate out solid, filter, promptly 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 the thermogravimetric analysis demonstration azimilide dihydrochloride crystal form V.

The crystal form V purity height that this method makes, single impurity have reached the relevant requirements of U.S. food Drug Administration (FDA) less than 1 ‰, and be very important to making high-quality medicine.In the described process parameters range of this method, repeat a plurality of batches, circulation ratio is fabulous.

Azimilide dihydrochloride crystal form V preparation of drug combination method of the present invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.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 for example 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 or the like.

The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form can specifically be applied according to patient's the state of an illness, the situation of diagnosis, the amount of used compound or concentration are regulated in the scope of a broad, usually, the weight range of active compound is 0.5%～90% (weight) of composition.Another preferred range 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 a 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 only is indicative, means that never it limits the scope of the invention by any way.

Embodiment 1:

Take by weighing azimilide dihydrochloride 20.0g, add 60mL tetrahydrofuran (THF)-water mixed liquid (volume ratio 4: 1), be heated to 65 ℃, after the stirring and dissolving, filtered while hot, filtrate naturally cools to room temperature, places 1 hour.Separate out solid, filter, about 24 hours of vacuum-drying gets yellow crystalline powder.

Embodiment 2:

Take by weighing azimilide dihydrochloride 20.0g, add 150mL tetrahydrofuran (THF)-water mixed liquid (volume ratio 17: 3), be heated to 50 ℃, after the stirring and dissolving, filtered while hot, filtrate naturally cools to room temperature, places 3 hours.Separate out solid, filter, about 24 hours of vacuum-drying gets yellow crystalline powder.

Embodiment 3:

Take by weighing azimilide dihydrochloride 20.0g, add 240mL tetrahydrofuran (THF)-water mixed liquid (volume ratio 9: 1), be heated to 30 ℃, after the stirring and dissolving, filtered while hot, filtrate naturally cools to room temperature, places 5 hours.Separate out solid, filter, about 24 hours of vacuum-drying 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 the carboxymethylstach sodium, add 5mg

Magnesium Stearate 1mg

Technology: activeconstituents, lactose, starch, Microcrystalline Cellulose are crossed 100 mesh sieves respectively, take by weighing and abundant mixing by recipe quantity, the 2% hypromellose aqueous solution joined in the said mixture granulate, cross 20 mesh sieve system softwoods, make wet granular in 45～55 ℃ dry about 2-3 hour, with remain carboxymethylstach sodium, Magnesium Stearate joins compressing tablet in the 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

Technology: activeconstituents, auxiliary material are crossed 100 mesh sieves respectively; take by weighing the main ingredient and the auxiliary material thorough mixing of recipe quantity; add hypromellose solution and make softwood in right amount; cross 24 mesh sieves; make wet granular in 50-60 ℃ of baking oven dry about 2-3 hour, Magnesium Stearate and talcum powder and particle are mixed whole; measure intermediate content, with No. 2 capsule cans.

Claims (9)

1. the crystal form V of an azimilide dihydrochloride (Azimilide Dihydrochloride), its powder x-ray diffraction collection of illustrative plates has following diffraction angle (2 θ angle), spacing (d value) and relative intensity.Described 2 θ angular units are degree, and error is 0.2.

2. according to the crystal form V of the azimilide dihydrochloride of claim 1, 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 (Azimilide Dihydrochloride) crystal form V, it is characterized in that: after azimilide dihydrochloride is dissolved in warm tetrahydrofuran (THF)-water mixed liquid, naturally cool to room temperature, be incubated for some time again, separate out crystal.

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 (mL/g) of corresponding azimilide dihydrochloride quality.

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 1～5 hour, wherein preferred 2～3 hours.

8. pharmaceutical composition is characterized in that: comprise as activeconstituents as the described azimilide dihydrochloride crystal form V of claim 1～2 and one or more pharmaceutically useful inert non-toxic carriers.

9. as the purposes of the described azimilide dihydrochloride crystal form V of claim 1～2 in making antiarrhythmic drug.

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