CN104892553A - Dronedarone hydrochloride crystal and preparation method thereof and pharmaceutical composition containing dronedarone hydrochloride crystal - Google Patents
Dronedarone hydrochloride crystal and preparation method thereof and pharmaceutical composition containing dronedarone hydrochloride crystal Download PDFInfo
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Abstract
The present invention provides a dronedarone hydrochloride crystal in the crystal form I, the crystal purity is higher than 99.9%, the dronedarone hydrochloride crystal does not contain butyl-removed degradation products. The crystal is prepared as follows: dronedarone hydrochloride in a dronedarone hydrochloride crude product can be extracted at room temperature by a refining method in the manner of solvent-out crystallization, a first solvent used in the solvent-out crystallization process is an organic solvent, and a second solvent used in the solvent-out crystallization process is methyl tert-butyl ether. The refining method is simple in process, and mild in preparation conditions, the yield is 90-98%, compared with the existing technology, the product yield is greatly improved, cost is reduced, the content of impurities is reduced by a greater degree, and the butyl-removed degradation impurities are removed. The present invention provides a high quality pharmaceutical composition of the dronedarone hydrochloride crystal, and the pharmaceutical composition not only has excellent purity, and is excellent in quality stability in the process of preservation, so that the quality of the prepared pharmaceutical composition is greatly improved.
Description
Technical field
The invention belongs to chemicals technical field, relate to crystal of a kind of dronedarone hydrochloride and preparation method thereof and the pharmaceutical composition containing this crystal.
Background technology
Dronedarone hydrochloride (formula I); English name: Dronedarone hydrochloride; its No. CAS is 141625-93-6; chemistry N-[2-normal-butyl-3-[4-[3-(Di-n-Butyl Amine base) propoxy-] benzoyl]-5-benzofuryl] methanesulfonamide hydrochloride by name; it is the antiarrhythmic drug of French Sanofi-Aventis company exploitation; this medicine and amiodarone have similar structure and electro physiology effect; but it is not containing iodine; therefore the untoward reaction relevant to iodine can not be caused, be the alternative more novel drugs of the latter.In July, 2009 goes on the market in the U.S. first through FDA approval.The rhythm of the heart that this product is applicable to atrial fibrillation and atrial flutter patients controls, maintains sinus rhythm and the ventricular rhythm that slows down, and clinical being mainly used in treats irregular pulse.
Patent US5223510 and WO03040120 discloses dronedarone hydrochloride and preparation method thereof, is obtained by acetone refining, and fusing point is mp 143 °, and follow-up being referred to as formerly grinds raw material crystal formation I.
The patent reported about the synthesis of dronedarone hydrochloride and document more, mostly adopt acetone to prepare dronedarone hydrochloride as refining solvent.CN103044369A discloses the preparation method adopting the mode of solvent crystal at room temperature to extract the dronedarone hydrochloride in dronedarone hydrochloride crude product, wherein, one or more in the group of described solvent crystal process the first solvent selected from methanol used, ethanol, acetonitrile, methylene dichloride, trichloromethane, DMF, dimethyl sulfoxide (DMSO) composition; Described solvent crystal process the second solvent used be selected from the group of acetonitrile, purified water, acetone, ethyl acetate, methyl ethyl ketone, propyl alcohol, toluene, tetrahydrofuran (THF), dioxan, butylacetate composition one or more.
Separately there are other crystal formations and the physical aspect preparation method of bibliographical information dronedarone hydrochloride, as:
Marom Ehud etc., report the amorphous of dronedarone hydrochloride, and after being dissolved with single solvent by dronedarone hydrochloride, then steam and desolventize and obtain, its IR characteristic peak is 774,806,843,905,972,1053,1150,1249,1331,1372,1422,1461,1502,1572,1598,1637,2513,2620,2871,2958,3064cm
-1.Also provide a comparison simultaneously and formerly grind raw material crystal formation I and unbodied XRPD collection of illustrative plates.
Stohandl Jiri etc., report the polymorphic of dronedarone hydrochloride, by Dronedarone salify in 2-butanone, are obtained subsequently by 2-butanone crystallization, fusing point 113-115 DEG C, its XRPD characteristic peak is 7.7,13.0,13.8,15.7,21.4,21.7,26.2 ± 0.2 °.
The method that CN103694206A discloses and adopts acetonitrile, the trimethyl carbinol, tetrahydrofuran (THF), dioxane and ether, Novel dronedarone hydrochloride crystal form II prepared by isopropyl ether.
And the preparation method of Dronedarone alkali crystal formation, as US20110230553 discloses a kind of solvent legal system that adopts for the method for Dronedarone alkali crystal form B, employing is selected from water solvent, water/methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, 2-butanols, isopropylcarbinol, the trimethyl carbinol, 1-amylalcohol, acetone, methyl ethyl ketone, isobutyl methyl ketone, ethyl formate, methyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl-, tetrahydrofuran (THF), Di Iso Propyl Ether, methyl tertiary butyl ether, toluene, acetonitrile, methylene dichloride, 1, 4-dioxan and chloroform etc. prepare the saturated solution of Dronedarone alkali crystal form A, adding the solvent resistant such as Di Iso Propyl Ether and methyl tertiary butyl ether makes it have crystal form A to be converted into crystal form B.
Because the quality stability of dronedarone hydrochloride crystal formation I and bioavailability etc. have excellent effect, the main raw material form still as this medicine uses.But at present, impurity effect is removed better by the side of preparing dronedarone hydrochloride crystal formation I disclosed in prior art, but yield is lower, still needs research and development to be further more conducive to the preparation method of commercial application, improves product yield, reduce costs.
Summary of the invention
The present invention is directed to the defect existed in above prior art, one of its object is to provide a kind of crystal of Dronedarone and the pharmaceutical composition containing this crystal
The present invention compared with prior art has following outstanding advantage and beneficial effect:
A crystal for dronedarone hydrochloride, described crystal is crystal formation I, and described crystal purity is greater than 99.9%, and not containing removing butyl degraded product.
Described crystal is dronedarone hydrochloride crystal formation I, and as shown in Figure 1, detected result as shown in Figure 2 for its XRD figure spectrum.
X-ray diffraction testing conditions is:
Adopt Shimadzu PXRD-600 type X-ray diffractometer, at Cu target K α 1 ray, pipe stream voltage: 40.0kV, electric current: 30.0mA, measures 2 θ scopes under step-length 0.02 ° of condition: 5 °-40 °.
Still a further object of the present invention is in particular to a kind of process for purification of aforementioned dronedarone hydrochloride crystal and the Dronedarone crystal raw material obtained by it with containing the pharmaceutical composition of this crystal.
Concrete is as follows:
A kind of process for purification of dronedarone hydrochloride crystal, the mode of process for purification employing solvent crystal at room temperature extracts the dronedarone hydrochloride in dronedarone hydrochloride crude product, wherein, solvent crystal process the first solvent used is organic solvent, be selected from methyl alcohol, ethanol, acetonitrile, methylene dichloride, trichloromethane, DMF, dimethyl sulfoxide (DMSO) composition group in one or more; Methyl tertiary butyl ether selected by solvent crystal process the second solvent used.
In another preferred embodiment of the present invention, the first solvent is methyl alcohol or ethanol, and the second solvent is methyl tertiary butyl ether.
The step of the solvent crystal in above-mentioned process for purification comprises: step S1, dronedarone hydrochloride dissolving crude product is formed solution in the first solvent; Step S2, add in solution second solvent separate out white mass, carry out solid-liquid separation and obtain white solid and mixed solution; And step S3, drying under reduced pressure white solid obtain the dronedarone hydrochloride refined.
Preferably the first solvent load is: dronedarone hydrochloride weight g: the first solvent volume mL=1:1 ~ 8 (preferred 1:1 can save solvent consumption).And the second solvent load is: the first solvent volume mL: the second solvent volume mL=1:5 ~ 15 (preferred 1:7, can save solvent consumption, and yield is optimum).
Extraction temperature is under room temperature condition, refers to 25 DEG C ± 5 DEG C.Drying conditions can select laboratory conventional drying condition, vacuum-drying at being preferably 25 DEG C-40 DEG C.
The dronedarone hydrochloride crystal prepared by aforesaid method, be crystal formation I, described crystal purity is greater than 99.9%, and not containing removing butyl degraded product.
Described crystal is dronedarone hydrochloride crystal formation I, and as shown in Figure 1, detected result as shown in Figure 2 for its XRD figure spectrum.
In addition, a kind of pharmaceutical composition obtaining high-quality dronedarone hydrochloride crystal containing aforementioned a kind of preceding method is provided further, wherein containing more than one pharmaceutically acceptable vehicle.
Gained pharmaceutical composition comprises solid preparation, as tablet, and granule, capsule, suspensoid etc.; Also pharmaceutical solutions is comprised, as oral liquid etc.Due to high purity and the high quality of dronedarone hydrochloride crystal, be conducive to obtaining more excellent pharmaceutical composition.
The present invention compared with prior art has following outstanding advantage and beneficial effect:
(1). the invention provides a kind of dronedarone hydrochloride crystal, be crystal formation I, described crystal purity is greater than 99.9%, and not containing removing butyl degraded product;
(2). the invention provides a kind of preparation method of dronedarone hydrochloride crystal, technique is simple, and preparation condition is gentle, yield is 95 ~ 98%, significantly improves product yield relative to prior art, reduces costs, reduce Light absorbing impurty to a greater extent, remove butyl degraded product impurity.
(3). the invention provides a kind of pharmaceutical composition of high-quality dronedarone hydrochloride crystal, not only there is excellent purity, it has excellent quality stability in preservation process, thus improve the quality of prepared pharmaceutical composition, good guarantee is provided for the clinical application validity of product and security.
Accompanying drawing explanation
The XRD figure spectrum of Fig. 1, dronedarone hydrochloride crystal formation I.
Fig. 2, the XRD detected result of dronedarone hydrochloride crystal formation I.
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but working of an invention mode is not limited thereto.
Embodiment 1 one kinds of dronedarone hydrochloride crystal and preparation method thereof
A process for purification for dronedarone hydrochloride crystal, process for purification adopts the mode of solvent crystal at room temperature to extract dronedarone hydrochloride in dronedarone hydrochloride crude product, and wherein, solvent crystal process the first solvent used is methyl alcohol; Methyl tertiary butyl ether selected by solvent crystal process the second solvent used.
Preferably the first solvent load is: dronedarone hydrochloride weight g: the first solvent volume mL=1:1 or 1:5, and the second solvent load is: the first solvent volume mL: the second solvent volume mL=1:5 or 1:15.More preferably scheme dronedarone hydrochloride weight g: the first solvent volume mL=1:1, and the first solvent volume mL: the second solvent volume mL=1:7.
The step of the solvent crystal in above-mentioned process for purification comprises: step S1, dronedarone hydrochloride dissolving crude product is formed solution in the first solvent; Step S2, add in solution second solvent separate out white mass, carry out solid-liquid separation and obtain white solid and mixed solution; And step S3, drying under reduced pressure white solid obtain the dronedarone hydrochloride refined.
Adopt Shimadzu PXRD-600 type X-ray diffractometer, at Cu target K α 1 ray, pipe stream voltage: 40.0kV, electric current: 30.0mA, measures 2 θ scopes under step-length 0.02 ° of condition: 5 °-40 °.
Gained crystal example hydrochloric acid Dronedarone crystal formation I XRD figure spectrum as Fig. 1 and detected result as shown in Figure 2.
Embodiment 2 one kinds of dronedarone hydrochloride crystal and preparation method thereof
A process for purification for dronedarone hydrochloride crystal, process for purification adopts the mode of solvent crystal at room temperature to extract dronedarone hydrochloride in dronedarone hydrochloride crude product, and wherein, solvent crystal process the first solvent used is ethanol; Methyl tertiary butyl ether selected by solvent crystal process the second solvent used.
Preferably the first solvent load is: dronedarone hydrochloride weight g: the first solvent volume mL=1:2 or 1:5.And the second solvent load is: the first solvent volume mL: the second solvent volume mL=1:5 or 1:15.
The step of the solvent crystal in above-mentioned process for purification comprises: step S1, dronedarone hydrochloride dissolving crude product is formed solution in the first solvent; Step S2, add in solution second solvent separate out white mass, carry out solid-liquid separation and obtain white solid and mixed solution; And step S3, drying under reduced pressure white solid obtain the dronedarone hydrochloride refined.
Embodiment 3 one kinds of dronedarone hydrochloride crystal and preparation method thereof
A process for purification for dronedarone hydrochloride crystal, process for purification adopts the mode of solvent crystal at room temperature to extract dronedarone hydrochloride in dronedarone hydrochloride crude product, and wherein, solvent crystal process the first solvent used is methylene dichloride; Methyl tertiary butyl ether selected by solvent crystal process the second solvent used.
Preferably the first solvent load is: dronedarone hydrochloride weight g: the first solvent volume mL=1:1 or 1:5.And the second solvent load is: the first solvent volume mL: the second solvent volume mL=1:5 or 1:15.
The step of the solvent crystal in above-mentioned process for purification comprises: step S1, dronedarone hydrochloride dissolving crude product is formed solution in the first solvent; Step S2, add in solution second solvent separate out white mass, carry out solid-liquid separation and obtain white solid and mixed solution; And step S3, drying under reduced pressure white solid obtain the dronedarone hydrochloride refined.
Embodiment 4 one kinds of dronedarone hydrochloride crystal and preparation method thereof
A process for purification for dronedarone hydrochloride crystal, process for purification adopts the mode of solvent crystal at room temperature to extract dronedarone hydrochloride in dronedarone hydrochloride crude product, and wherein, solvent crystal process the first solvent used is acetonitrile; Methyl tertiary butyl ether selected by solvent crystal process the second solvent used.
Preferably the first solvent load is: dronedarone hydrochloride weight g: the first solvent volume mL=1:2 or 1:5.And the second solvent load is: the first solvent volume mL: the second solvent volume mL=1:5 or 1:15.
The step of the solvent crystal in above-mentioned process for purification comprises: step S1, dronedarone hydrochloride dissolving crude product is formed solution in the first solvent; Step S2, add in solution second solvent separate out white mass, carry out solid-liquid separation and obtain white solid and mixed solution; And step S3, drying under reduced pressure white solid obtain the dronedarone hydrochloride refined.
Embodiment 5 one kinds of dronedarone hydrochloride crystal and preparation method thereof
A process for purification for dronedarone hydrochloride crystal, process for purification adopts the mode of solvent crystal at room temperature to extract dronedarone hydrochloride in dronedarone hydrochloride crude product, and wherein, solvent crystal process the first solvent used is DMF; Methyl tertiary butyl ether selected by solvent crystal process the second solvent used.
Preferably the first solvent load is: dronedarone hydrochloride weight g: the first solvent volume mL=1:1 or 1:5.And the second solvent load is: the first solvent volume mL: the second solvent volume mL=1:5 or 1:15.
The step of the solvent crystal in above-mentioned process for purification comprises: step S1, dronedarone hydrochloride dissolving crude product is formed solution in the first solvent; Step S2, add in solution second solvent separate out white mass, carry out solid-liquid separation and obtain white solid and mixed solution; And step S3, drying under reduced pressure white solid obtain the dronedarone hydrochloride refined.
Embodiment 6 one kinds of dronedarone hydrochloride crystal and preparation method thereof
A kind of process for purification of dronedarone hydrochloride crystal, the mode of process for purification employing solvent crystal at room temperature extracts the dronedarone hydrochloride in dronedarone hydrochloride crude product, wherein, the first solvent that solvent crystal process is used is arbitrary solvent (as methyl alcohol): the mixed solvent of another solvent (as ethanol) 1:10-10:1 by volume; Methyl tertiary butyl ether selected by solvent crystal process the second solvent used.
Preferably the first solvent load is: dronedarone hydrochloride weight g: the first solvent volume mL=1:1 or 1:5.And the second solvent load is: the first solvent volume mL: the second solvent volume mL=1:5 or 1:15.
The step of the solvent crystal in above-mentioned process for purification comprises: step S1, dronedarone hydrochloride dissolving crude product is formed solution in the first solvent; Step S2, add in solution second solvent separate out white mass, carry out solid-liquid separation and obtain white solid and mixed solution; And step S3, drying under reduced pressure white solid obtain the dronedarone hydrochloride refined.
Previous embodiment 2-6 prepares the identical crystal formation I of embodiment 1.
Comparative example 1
Get the pending sample of 3.00g, 9ml the formation of methanol solution is added to this pending sample, this solution is stirred under the speed of 70r/min, slowly drip 3ml purified water adularescent solid with same rate of addition after dripping 25ml ethyl acetate with the speed of 2.5ml/min in this solution to separate out simultaneously, 8ml ethyl acetate is dripped with the speed of 3.5/min, a large amount of white solid powder is had to separate out, filtering separation white solid and mixed solution after continuation stirring 2h, the filter cake ethyl acetate obtained is washed, filter cake drying under reduced pressure 12h at 50 DEG C after washing is obtained white solid powder 2.54g, the yield of dronedarone hydrochloride and purity in comparative example 1, go butyl content of degradation products in table 1.
Comparative example 2
Get the pending sample of 3.00g, add 15ml dimethyl sulfoxide (DMSO) to this pending sample and form solution, this solution is stirred under the speed of 70r/min, in this solution, drip tetrahydrofuran (THF) with the speed of 3ml/min to separate out to adularescent solid during 25ml simultaneously, continue to drip tetrahydrofuran (THF) with the speed of 5ml/min to separate out to there being a large amount of white solid during 45ml, filtering separation white solid and mixed solution after continuation stirring 2h, the filter cake tetrahydrofuran (THF) obtained washs, filter cake drying under reduced pressure 8h at 50 DEG C after washing is obtained white solid powder 2.33g, the yield of dronedarone hydrochloride and purity in comparative example 2, go butyl content of degradation products in table 1.
Embodiment 7 effect comparison example
The dronedarone hydrochloride of embodiment 1-6, contrast experiment 1-2 gained measures detection method by the following method and detects
Purity and the high performance liquid chromatography of going butyl degraded product detection method with reference to " Chinese Pharmacopoeia " 2010 editions second annex VD.Instrument: Agilent high performance liquid chromatograph, use C18 chromatographic column, mobile phase A is acetonitrile-0.03mol/L potassium dihydrogen phosphate (being adjusted to pH 3.0 with phosphoric acid) (58: 42), and Mobile phase B is acetonitrile, gradient elution; Determined wavelength 220nm, reference literature (Ding Yimei, the HPLC method of dronedarone hydrochloride related substance measures, " Chinese Journal of Pharmaceuticals " 10 phases in 2013).Result is as following table 1:
Table 1
Wherein, A=dronedarone hydrochloride weight g: the first solvent volume mL; B=the second solvent load is: the first solvent volume mL: the second solvent volume mL.
To sum up, preparation method provided by the invention, obtains the dronedarone hydrochloride crystal that quality is more excellent, and wherein go butyl degraded product to remove completely, purity is higher, and quality product is more excellent, and the conversion yields of crystal formation I significantly improves, and reduces production cost.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. a crystal for dronedarone hydrochloride, described crystal is crystal formation I, and described crystal purity is greater than 99.9%, and not containing removing butyl degraded product, described crystal XRD figure spectrum as shown in Figure 1.
2. a process for purification for dronedarone hydrochloride crystal, process for purification adopts the mode of solvent crystal at room temperature to extract dronedarone hydrochloride in dronedarone hydrochloride crude product, and wherein, solvent crystal process the first solvent used is organic solvent; Methyl tertiary butyl ether selected by solvent crystal process the second solvent used.
3. the process for purification of a kind of dronedarone hydrochloride crystal according to claim 2, it is characterized in that, preferably the first solvent selected from methanol, ethanol, acetonitrile, methylene dichloride, trichloromethane, DMF, dimethyl sulfoxide (DMSO) composition group in one or more.
4. the process for purification of a kind of dronedarone hydrochloride crystal according to Claims 2 or 3, it is characterized in that, the step of the solvent crystal in above-mentioned process for purification comprises: step S1, dronedarone hydrochloride dissolving crude product is formed solution in the first solvent; Step S2, add in solution second solvent separate out white mass, carry out solid-liquid separation and obtain white solid and mixed solution; And step S3, drying under reduced pressure white solid obtain the dronedarone hydrochloride refined.
5. the process for purification of a kind of dronedarone hydrochloride crystal according to the arbitrary claim of claim 2-4, it is characterized in that, preferably the first solvent load is: dronedarone hydrochloride weight g: the first solvent volume mL=1:1 ~ 8.
6. the process for purification of a kind of dronedarone hydrochloride crystal according to the arbitrary claim of claim 2-4, is characterized in that, preferred the second solvent load is: the first solvent volume mL: the second solvent volume mL=1:5 ~ 15.
7. the process for purification of a kind of dronedarone hydrochloride crystal according to claim 5, is characterized in that, preferred the second solvent load is: the first solvent volume mL: the second solvent volume mL=1:5 ~ 15.
8. the process for purification of a kind of dronedarone hydrochloride crystal according to the arbitrary claim of claim 2-7, is characterized in that, prepares dronedarone hydrochloride crystal according to claim 1 by described method.
9. a pharmaceutical composition, is characterized in that, dronedarone hydrochloride crystal according to claim 1, and more than one pharmaceutically acceptable vehicle, and gained pharmaceutical composition comprises solid preparation, as tablet, and granule, capsule, suspensoid etc.; Also pharmaceutical solutions is comprised, as oral liquid etc.
10. pharmaceutical composition according to claim 9, is characterized in that, described dronedarone hydrochloride crystal is prepared by the process for purification described in the arbitrary claim of claim 2-7.
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| 何学军 等: "盐酸决奈达隆的合成", 《生物加工过程》 * |
| 李峰 等: "盐酸决奈达隆合成新工艺", 《高等学校化学学报》 * |
| 汪玉梅 等: "盐酸决奈达隆的合成", 《河北化工》 * |
| 胡永亮 等: "决奈达隆成盐工艺研究", 《煤炭与化工》 * |
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| CN104892553B (en) | 2017-06-20 |
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