CN101735204B - Crystalline form III of azimilide dihydrochloride, preparation method and application thereof - Google Patents
Crystalline form III of azimilide dihydrochloride, preparation method and application thereof Download PDFInfo
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- CN101735204B CN101735204B CN2009102448774A CN200910244877A CN101735204B CN 101735204 B CN101735204 B CN 101735204B CN 2009102448774 A CN2009102448774 A CN 2009102448774A CN 200910244877 A CN200910244877 A CN 200910244877A CN 101735204 B CN101735204 B CN 101735204B
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- azimilide
- azimilide dihydrochloride
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- MREBEPTUUMTTIA-PCLIKHOPSA-N Azimilide Chemical compound C1CN(C)CCN1CCCCN1C(=O)N(\N=C\C=2OC(=CC=2)C=2C=CC(Cl)=CC=2)CC1=O MREBEPTUUMTTIA-PCLIKHOPSA-N 0.000 title claims abstract description 60
- 229950001786 azimilide Drugs 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000000843 powder Substances 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 239000013078 crystal Substances 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 9
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- ALOBUEHUHMBRLE-UHFFFAOYSA-N Ibutilide Chemical compound CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ALOBUEHUHMBRLE-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
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- IYIKLHRQXLHMJQ-UHFFFAOYSA-N amiodarone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCCN(CC)CC)C(I)=C1 IYIKLHRQXLHMJQ-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
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- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 2
- 229960002370 sotalol Drugs 0.000 description 2
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- 206010047302 ventricular tachycardia Diseases 0.000 description 2
- HHPSICLSNHCSNZ-BYEGLACWSA-N 1-[(e)-[5-(4-chlorophenyl)furan-2-yl]methylideneamino]-3-[4-(4-methylpiperazin-1-yl)butyl]imidazolidine-2,4-dione;dihydrochloride Chemical compound Cl.Cl.C1CN(C)CCN1CCCCN1C(=O)N(\N=C\C=2OC(=CC=2)C=2C=CC(Cl)=CC=2)CC1=O HHPSICLSNHCSNZ-BYEGLACWSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
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- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000013975 Delayed Rectifier Potassium Channels Human genes 0.000 description 1
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- 108010010803 Gelatin Proteins 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 206010049418 Sudden Cardiac Death Diseases 0.000 description 1
- 206010042600 Supraventricular arrhythmias Diseases 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960002994 dofetilide Drugs 0.000 description 1
- IXTMWRCNAAVVAI-UHFFFAOYSA-N dofetilide Chemical compound C=1C=C(NS(C)(=O)=O)C=CC=1CCN(C)CCOC1=CC=C(NS(C)(=O)=O)C=C1 IXTMWRCNAAVVAI-UHFFFAOYSA-N 0.000 description 1
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- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical class CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to crystalline form III of azimilide dihydrochloride and a preparation method thereof, further relates to a pharmaceutical composition prepared by the crystalline form III of azimilide dihydrochloride obtained by the invention and application thereof. The crystalline form III 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] amino of azimilide dihydrochloride (Azimilide dihydrochloride) or formula (I) }-the crystal form II I 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 (IK), prolongs myocardial action potential time-histories (APD) and ERP (ERP), thereby prolongs 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.
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 absolute ethyl alcohol-water (9: 2) is made with extra care.Or use acetone to replace absolute ethyl alcohol, in acetone-water (7～5: 2～4) attempt in the scope, all obtain single crystal X-powder diffraction data, characteristic (is seen accompanying drawing 1) as follows:
The characteristic absorbance that ir spectra shows (is seen accompanying drawing 2) as follows:
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 azimilide dihydrochloride crystal form II I.
Another object of the present invention provides the preparation method of azimilide dihydrochloride crystal form II I.
A further object of the invention provides azimilide dihydrochloride crystal form II I 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:
Azimilide dihydrochloride crystal form II I has following characteristic:
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.
Azimilide dihydrochloride crystal form II I, with Potassium Bromide (KBr) compressing tablet, the infrared spectrogram that records has following charateristic avsorption band:
3459cm
-1、2980cm
-1、2444cm
-1、1769cm
-1、1711cm
-1、1451cm
-1、1253cm
-1、949cm
-1、755cm
-1、698cm
-1。
Be used to prepare the azimilide dihydrochloride of azimilide dihydrochloride crystal form II I, 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 3,4,5).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 crystal form II I of azimilide dihydrochloride obtains through the salifiable method of soda acid.The saturated solution concentration (sodium hydroxide is about 40%, and Pottasium Hydroxide is about 30%) that the sodium hydroxide that neutralization is used or the concentration of potassium hydroxide aqueous solution are 10% (w/w) to the normal temperature.
The propione volume that is used for the salt-forming reaction solvent is 4～8 times (mL/g) of corresponding Azimilide quality.Two-step reaction all carries out under coldcondition, and temperature is that common ice water-bath and cryosel bath can reach-10 ℃～5 ℃.
Specific operation process is:
Get a certain amount of azimilide dihydrochloride and be dissolved in the water, dissolve clear after, the aqueous solution of dropping sodium or Pottasium Hydroxide to pH value of solution is 9～10 under the low temperature.Separate out solid, filter filtration cakes torrefaction.Gained Azimilide solid is dissolved in the propione, dissolve clear after, the propione solution of dripping hydrochloric acid under the low temperature, to pH be 1～2, separate out solid, filter, drying promptly gets azimilide dihydrochloride crystal form II I.
Then through the X-powder diffraction method, infrared absorption spectrometry characteristic.
Do not contain crystal water and recrystallisation solvent among the thermogravimetric analysis demonstration azimilide dihydrochloride crystal form II I.
The crystal form II I 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.In the described process parameters range of this method, repeat a plurality of batches, circulation ratio is fabulous.
Azimilide dihydrochloride crystal form II I 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 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 II I.
Fig. 7 is the infrared spectrogram of azimilide dihydrochloride crystal form II I.
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 60mL zero(ppm) water, stir to make and dissolve clearly.Ice-water bath is cooled to 5 ℃, slowly drip 10% aqueous sodium hydroxide solution to reaction solution pH be 9, separate out solid.Continue to stir 1h, filter, dry about 24 hours of filter cake in vacuum.The Azimilide drying solid is dissolved in the 80mL propione, dissolve clear after, 5 ℃ of following dripping hydrochloric acid-propione solution of ice-water bath, to pH be 1, separate out solid, continue to stir 0.5h, filter, dry about 24 hours of filter cake in vacuum, yellow crystalline powder.
Embodiment 2:
Take by weighing azimilide dihydrochloride 20.0g, add 120mL zero(ppm) water, stir to make and dissolve clearly.Cryosel is bathed and to be cooled to-10 ℃, slowly drip 40% aqueous sodium hydroxide solution to reaction solution pH be 10, separate out solid.Continue to stir 0.5h, filter, dry about 24 hours of filter cake in vacuum.The Azimilide drying solid is dissolved in the 100mL3-pentanone, dissolve clear after, cryosel is bathed-10 ℃ of following dripping hydrochloric acid-propione solution, to pH be 1, separate out solid, continue to stir 1.5h, filter, dry about 24 hours of filter cake in vacuum, yellow crystalline powder.
Embodiment 3:
Take by weighing azimilide dihydrochloride 20.0g, add 240mL zero(ppm) water, stir to make and dissolve clearly.Ice bath is cooled to 0 ℃, slowly drip 10% potassium hydroxide aqueous solution to reaction solution pH be 9, separate out solid.Continue to stir 1.5h, filter, dry about 24 hours of filter cake in vacuum.The Azimilide drying solid is dissolved in the 130mL propione, dissolve clear after, 0 ℃ of following dripping hydrochloric acid-propione solution of ice bath, to pH be 1, separate out solid, continue to stir 1h, filter, dry about 24 hours of filter cake in vacuum, yellow crystalline powder.
Embodiment 4:
Take by weighing azimilide dihydrochloride 20.0g, add 200mL zero(ppm) water, stir to make and dissolve clearly.Ice bath is cooled to 0 ℃, slowly drip 30% potassium hydroxide aqueous solution to reaction solution pH be 10, separate out solid.Continue to stir 0.5h, filter, dry about 24 hours of filter cake in vacuum.The Azimilide drying solid is dissolved in the 160mL propione, dissolve clear after, 5 ℃ of following dripping hydrochloric acid-propione solution of ice-water bath, to pH be 1, separate out solid, continue to stir 0.5h, filter, dry about 24 hours of filter cake in vacuum, yellow crystalline powder.
Embodiment 5:
Every tablet prepn that contains the 100mg activeconstituents:
Consumption/sheet
Azimilide dihydrochloride crystal form II I 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 6:
Every capsule contains the capsule preparation of 80mg activeconstituents:
Consumption/capsule
Azimilide dihydrochloride crystal form II I 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 crystal form II I 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, and said 2 θ angular units are degree, and error is 0.2,
2. the preparation method of an azimilide dihydrochloride as claimed in claim 1 (Azimilide Dihydrochloride) crystal form II I is characterized in that: azimilide dihydrochloride is dissolved in the water, under-10 ℃～5 ℃; The aqueous solution of dropping sodium or Pottasium Hydroxide to pH be 9～10, separate out solid, filter; Drying is dissolved in filter cake in the propione, under-10 ℃～5 ℃; The propione solution of dripping hydrochloric acid, to pH be 1～2, separate out solid; Filter, drying gets yellow powder shape azimilide dihydrochloride crystal form II I.
3. the preparation method of an azimilide dihydrochloride crystal form II I as claimed in claim 2, the concentration of said aqueous sodium hydroxide solution is 10%～40%, w/w, the concentration of potassium hydroxide aqueous solution is 10%～30%, w/w.
4. the preparation method of an azimilide dihydrochloride crystal form II I as claimed in claim 2, the volume of said propione is 4～8 times of corresponding Azimilide quality, mL/g.
5. a pharmaceutical composition is characterized in that: comprise azimilide dihydrochloride crystal form II I as claimed in claim 1 and one or more pharmaceutically useful inert non-toxic carriers as activeconstituents.
6. the purposes of azimilide dihydrochloride crystal form II I as claimed in claim 1 in making antiarrhythmic drug.
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