CN101735206B - Crystalline form IV of azimilide dihydrochloride, preparation method and application thereof - Google Patents
Crystalline form IV of azimilide dihydrochloride, preparation method and application thereof Download PDFInfo
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- CN101735206B CN101735206B CN2009102448806A CN200910244880A CN101735206B CN 101735206 B CN101735206 B CN 101735206B CN 2009102448806 A CN2009102448806 A CN 2009102448806A CN 200910244880 A CN200910244880 A CN 200910244880A CN 101735206 B CN101735206 B CN 101735206B
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- azimilide dihydrochloride
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- azimilide
- dihydrochloride
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- MREBEPTUUMTTIA-PCLIKHOPSA-N CN1CCN(CCCCN(C(CN2/N=C/c3ccc(-c(cc4)ccc4Cl)[o]3)=O)C2=O)CC1 Chemical compound CN1CCN(CCCCN(C(CN2/N=C/c3ccc(-c(cc4)ccc4Cl)[o]3)=O)C2=O)CC1 MREBEPTUUMTTIA-PCLIKHOPSA-N 0.000 description 1
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Abstract
The invention relates to crystalline form IV of azimilide dihydrochloride and a preparation method thereof, further relates to a pharmaceutical composition prepared by the crystalline form IV of azimilide dihydrochloride obtained by the invention and application thereof. The crystalline form IV of azimilide dihydrochloride uses monocrystal X-ray diffractogram as token.
Description
Technical field
The invention belongs to the antiarrhythmic drug field; More particularly, relate to 1-{ [5-(4-chloro-phenyl-) fural] amino of azimilide dihydrochloride (Azimilide dihydrochloride) or formula (I) }-form IV of 3-[4-(4-methyl isophthalic acid-piperazinyl) butyl] glycolylurea dihydrochloride and preparation method thereof, contain its pharmaceutical composition and the purposes in making antiarrhythmic drug thereof.
Background technology
Irregular pulse is one type of serious fatal disease, and according to incompletely statistics, the U.S. is approximately 40～600,000 because of the cardiac sudden death number that the fibrillation of ventricle property causes every year.Present internationally recognized Vaughan Williams classification is divided into I～IV class by electrophysiological property with antiarrhythmic Agents.Can know that based on external large-scale clinical experiment result I class medicine is prone to bring out serious ventricular arrhythmia, simultaneously part not fully up to expectations arranged all also aspect curative effect and the patient tolerability.Therefore, antiarrhythmic drug treatment in recent years has the tendency that changes to III class medicine from Application of I 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 ERP (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 receives a lot of restrictions.
Azimilide dihydrochloride (Azimilide dihydrochloride), chemistry 1-{ [5-(4-chloro-phenyl-) fural] amino by name }-3-[4-(4-methyl isophthalic acid-piperazinyl) butyl] glycolylurea dihydrochloride, be the compound III class of third generation antiarrhythmic drug.Develop by US P&G Company (Procter&Gamble), 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 like 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, it is important obtaining purity compound high, that have very definite crystal formation and favorable reproducibility.
Summary of the invention
An object of the present invention is to provide the azimilide dihydrochloride form IV.
Another object of the present invention provides the preparation method of azimilide dihydrochloride form IV.
A further object of the invention provides the azimilide dihydrochloride form IV as effective constituent, and the medicinal compsns that contains one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect antiarrhythmic drug.
Combine the object of the invention that content of the present invention is specifically described at present.
Azimilide dihydrochloride of the present invention has following structural formula:
The azimilide dihydrochloride form IV has following characteristic:
Determining instrument: Bruker Smart 1000 type diffractometers, graphite monochromator, Mo target.Measure wavelength: 0.71073
.Measure temperature: 294 (2) K.Crystalline size: 0.20 * 0.14 * 0.08mm.
Its characteristic is represented with following parameters: crystallographic system, spacer, lattice parameter, unit cell volume (V
Unit is brilliant Lattice), molecule number (Z), density (d) in the unit cell.
Be used to prepare the azimilide dihydrochloride of azimilide dihydrochloride form IV, can make by three kinds of compound methods.A kind of is reported method among the patent US 5462940, and reaction scheme is following:
Also having a kind of is the compound method of report among the patent WO 9955700, and reaction scheme is following:
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, represent 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 1,2,3).Testing tool is Bruker AV 400 type NMRs, and deuterated reagent is the D of Cambridge IsotopeLaboratories company
2O.The maximum single impurity that 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 form IV of azimilide dihydrochloride is that crystallization obtains in the mixed solution of acetonitrile-water.The usage quantity of mixed solution be 3～10 times of the azimilide dihydrochloride quality (volume-mass ratio, mL/g), wherein preferred 5～8 times.
Water accounts for 10%～30% of mixed solution TV.
Temperature during dissolving is 40 ℃～78 ℃.Naturally be cooled to room temperature then, placed 4～6 days, promptly obtain the new crystal IV type of azimilide dihydrochloride.
Specific operation process is:
Get a certain amount of azimilide dihydrochloride, add the acetonitrile-water mixed solution, 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 form IV.
Measure characteristic through X-single crystal diffraction method then, be shown as semihydrate (seeing accompanying drawing 4,5).
The form IV purity that this method makes is high, and single impurity has reached the relevant requirements of U.S. food Drug Administration (FDA) less than 1 ‰, and is very important to making high-quality medicine.
Azimilide dihydrochloride form IV preparation of drug combination method of the present invention is following: use standard and conventional technology; Acceptable solid or liquid vehicle are combined, and make it at random with technology of pharmaceutics on acceptable auxiliary and vehicle combine to be prepared into particulate or microballoon.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, Ucar 35, 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-s 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 compsn.Another preferred range is 0.5%～70%.
Figure of description
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of azimilide dihydrochloride.
Fig. 2 is the carbon-13 nmr spectra figure of azimilide dihydrochloride.。
Fig. 3 is a DEPT135 ° of carbon spectrogram of azimilide dihydrochloride.
Fig. 4 is the space conformation figure of azimilide dihydrochloride form IV.
Fig. 5 is the packing of molecules figure of azimilide dihydrochloride form IV.
Embodiment
Below in conjunction with embodiment the present invention is done further explanation, it is indicative that embodiment is merely, and means that never it limits scope of the present invention by any way.
Embodiment 1:
Take by weighing azimilide dihydrochloride 20.0g, add 130mL acetonitrile-water mixed solution (volume ratio 4: 1), be heated to 60 ℃, after the stirring and dissolving, filtered while hot, filtrating naturally cools to room temperature, places 5 days, separates out solid, filters, and gets yellow crystal.
Embodiment 2:
Every tablet prepn that contains the 100mg activeconstituents:
Consumption/sheet
Azimilide dihydrochloride form IV 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 3:
Every capsule contains the capsule preparation of 80mg activeconstituents:
Consumption/capsule
Azimilide dihydrochloride form IV 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 midbody content, with No. 2 capsule cans.
Claims (6)
1. the form IV of an azimilide dihydrochloride, its characteristic is represented with following parameters: crystallographic system, spacer, lattice parameter, unit cell volume (V
Unit cell), molecule number (Z), density (d) in the unit cell,
2. the preparation method of an azimilide dihydrochloride form IV as claimed in claim 1 is characterized in that: after azimilide dihydrochloride is dissolved, naturally cool to room temperature in warm acetonitrile one aqueous solution, be incubated for some time again, separate out crystal.
3. the preparation method of an azimilide dihydrochloride form IV as claimed in claim 2, the volume of said warm acetonitrile one aqueous solution is 3～10 times of corresponding azimilide dihydrochloride quality, mL/g.
4. the preparation method of an azimilide dihydrochloride form IV as claimed in claim 2, said acetonitrile one aqueous solution, wherein the volume of water accounts for 10%～30% of overall solution volume.
5. the preparation method of an azimilide dihydrochloride form IV as claimed in claim 2, said warm acetonitrile one aqueous solution, temperature is 40 ℃～78 ℃.
6. the preparation method of an azimilide dihydrochloride form IV as claimed in claim 2, said insulation for some time is 4～6 days.
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| CN2009102448806A CN101735206B (en) | 2009-12-17 | 2009-12-17 | Crystalline form IV of azimilide dihydrochloride, preparation method and application thereof |
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| CN101735206B true CN101735206B (en) | 2012-07-25 |
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| CN105153133B (en) * | 2015-09-01 | 2018-01-26 | 安徽省逸欣铭医药科技有限公司 | A kind of atrial fibrillation conversion compound and preparation method, medical composition and purposes |
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