CN1733727A - Crystalline carvedilol, processes for the manufacture thereof, pharmaceutical compositions and uses thereof - Google Patents
Crystalline carvedilol, processes for the manufacture thereof, pharmaceutical compositions and uses thereof Download PDFInfo
- Publication number
- CN1733727A CN1733727A CN 200510086095 CN200510086095A CN1733727A CN 1733727 A CN1733727 A CN 1733727A CN 200510086095 CN200510086095 CN 200510086095 CN 200510086095 A CN200510086095 A CN 200510086095A CN 1733727 A CN1733727 A CN 1733727A
- Authority
- CN
- China
- Prior art keywords
- carvedilol
- solvent
- solution
- type
- crystallized
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000000034 method Methods 0.000 title claims abstract description 93
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 29
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Images
Abstract
This invention relates to an improved process of preparing carvedilol, as well as a new crystalline hydrate and solvate and forms of carvedilol, processes for the manufacture thereof, pharmaceutical compositions and the pharmacy usage thereof.
Description
The application is that international application no is the dividing an application of China national phase application CN01814616.3 of PCT/US01/20760.
Cross-reference with related application
The application requires to incorporate into by reference the rights and interests of No. 60/246,358, the U.S. Provisional Patent Application of No. 60/214,356, U.S. Provisional Patent Application proposing in 28 days June in 2000 of this paper and proposition on November 7th, 2000.
Technical field
The present invention relates to the new crystalline hydrate of a kind of modification method for preparing carvedilol and a kind of carvedilol and solvate and form, their preparation method and medicinal compositions thereof.
Background technology
Carvedilol is a kind of tool α
1Block active non-selective beta-adrenergic blocking agent.Carvedilol is also referred to as (±) 1-(9H-carbazole-4-base oxygen base)-3-[[2-(2-methoxyl group phenoxy group) ethyl] amino]-2-propyl alcohol (CAS registration number 72956-09-3), have the structure of formula I:
Carvedilol has a chirality center, can be so that independently steric isomer or racemic form exist.The racemize carvedilol is to be used for the treatment of congestive heart failure and hypertensive COREG
Activeconstituents.The non-selective beta-adrenergic activity of carvedilol is present in S (-) enantiomorph, α
1Blocking-up is active to be present in R (+) and S (-) enantiomorph with equal efficient.Racemic modification and steric isomer can obtain according to the method (EP B 0127099) that this area people are familiar with.
Synthesizing of carvedilol
The United States Patent (USP) of incorporating this paper by reference into discloses for 4,503, No. 067 a kind of by showing the method for prepared in reaction carvedilol down:
Wherein 4-(oxyethane-2-ylmethoxy)-9H-carbazole (formula II) is with (reaction of 2-(2-methoxyl group phenoxy group) ethamine (formula III) forms carvedilol (I).Aforesaid method produces the carvedilol of low yield, at least in part because except carvedilol this method also produce the impurity that contains two formula II compound molecules (bis impurity) (formula IV) of following structure:
(referring to EP918055).
For formation that reduces formula IV and the yield that improves carvedilol, EP918055 proposes to use the benzyl protection form of 2-(2-methoxyl group phenoxy group) ethamine (formula III).
The carvedilol polymorphic form
The International Patent Application WO of incorporating this paper by reference into discloses carvedilol for No. 99/05105 and can be separated into two kinds of polymorphic forms according to the preparation method.It is reported that two kinds of polymorphic forms that are called type I and type II are monotropic, can be infrared, Raman and X-ray powder diffraction spectrum distinguished by it.Find to exist the evidence of the hydration solvate form of carvedilol in the literature.
Polymorphism is that some molecules and molecular complex present the character that surpasses a kind of crystal formation under solid-state.Single molecule of planting can produce multiple crystal formation (being also referred to as " polymorphic form ", " hydrate " or " solvate ") with different physical properties.Summary for the pharmaceutical use of polymorphic form and polymorphic form can be referring to G.M.Wall, Pharm Manuf.3,33 (1986); J.K.Haleblian and W.McCrone, R Pharm.Sci., 58,911 (1969); And J.K.Haleblian, J.Pharm.Sci., 64,1269 (1975), these documents are all incorporated this paper by reference into.
The existence of different crystal forms and physical properties can be measured by various technology such as X-ray diffraction spectrography, dsc and infrared spectroscopy.Difference on the different crystal forms physical properties comes from the orientation and the molecular interaction of adjacent molecule in the bulk solid thing (complex compound).Therefore, polymorphic form, hydrate and solvate are to have the same molecular formula but compare the different solidss with different favourable and/or unfavorable physicalies with other form in the polymorphic form family.The existence of polymorphic form, hydrate and solvate and physical properties are uncertain.
One of the most important physical properties that can form the medicinal compound of polymorphic form, hydrate or solvate is its solvability in the aqueous solution, the particularly solvability in patient's gastric juice.Other critical nature relates to the difficulty or ease that described form are processed into medicament, such as the crystal of the easy mobility of powder or particle form and this form of decision mutual adherent surface property during at tablet forming whether.
The present invention's summary
The invention provides a kind of method for preparing carvedilol, comprise making formula II compound 4-(oxyethane-2-ylmethoxy)-9H-carbazole
With the step of formula III compound 2-(2-methoxyl group phenoxy group) ethamine reaction,
Wherein the formula III compound is with respect to formula II compound molar excess.
The present invention also provides the crystallized carvedilol hydrate.
The present invention also provides crystallized carvedilol.
The present invention also provides crystallized carvedilol (methylethylketone) solvate.
The present invention also provides crystallized carvedilol type III, it is characterized in that its X-powder diffraction pattern has the peak at about 8.4 ± 0.2,17.4 ± 0.2 and 22.0 ± 0.2 degree 2 θ.
The present invention also provides crystallized carvedilol type IV, it is characterized in that its X-powder diffraction pattern has the peak at about 11.9 ± 0.2,14.2 ± 0.2,18.3 ± 0.2,19.2 ± 0.2,21.7 ± 0.2 and 24.2 ± 0.2 degree, 2 θ.
The present invention also provides crystallized carvedilol (methylethylketone) solvate type V, it is characterized in that its X-powder diffraction pattern has the peak at about 4.1 ± 0.2,10.3 ± 0.2 and 10.7 ± 0.2 degree 2 θ.
The present invention also provides the carvedilol HCI hydrate, it is characterized in that its X-powder diffraction pattern has the peak at about 6.5 ± 0.2,10.2 ± 0.2,10.4 ± 0.2,15.8 ± 0.2,16.4 ± 0.2 and 22.2 ± 0.2 degree, 2 θ.
The present invention also provides a kind of method for preparing crystallized carvedilol type I, comprises following step: by heating carvedilol is dissolved in the solution; Heated solution dissolves fully up to crystallized carvedilol; Reduce the temperature of solution; With solution stirring for some time; Further reduce solution temperature; Further with solution stirring for some time; Collect crystallized carvedilol type I.
The present invention also provides a kind of method for preparing crystallized carvedilol type II, comprises following step: form solution in the solvent by carvedilol is dissolved in; By cooling solution precipitation carvedilol type II; Fractional crystallization carvedilol type II.
The present invention also provides a kind of method for preparing crystallized carvedilol type II, comprises following step: form carvedilol solution in the solvent mixture by carvedilol is dissolved in; Precipitate carvedilol type II by cooling solution to about-20 ℃; Fractional crystallization carvedilol type II.
The present invention also provides a kind of method for preparing crystallized carvedilol type III, comprises following step: carvedilol is dissolved in forms solvent solution in the solvent; Water is as anti-solvent precipitated crystal carvedilol type III from described solvent solution.
The present invention also provides a kind of method for preparing crystallized carvedilol type III, comprises following step: with carvedilol by heating for dissolving in solution; Cool off this solution mixture; With collection crystallized carvedilol type III.
The present invention also provides a kind of method for preparing crystallized carvedilol type IV, comprises following step: carvedilol is dissolved in forms solvent solution in the solvent; A kind of anti-solvent is joined in this solvent solution; With precipitated crystal carvedilol type IV from this solvent solution.
The present invention also provides a kind of method for preparing crystallized carvedilol type V, comprises carvedilol is dissolved in a kind of solvent forming solvent solution and the step of precipitation and fractional crystallization carvedilol type V from this solvent solution.
The present invention also provides a kind of method for preparing crystallized carvedilol type V, comprise with carvedilol be dissolved in a kind of solvent form solvent solution and from this solvent solution the step of precipitation and fractional crystallization carvedilol type V, wherein settling step is undertaken by adding anti-solvent.
The accompanying drawing summary
Fig. 1 has shown the X-ray diffraction pattern of carvedilol type III.
Fig. 2 has shown the DTG heating curve of carvedilol type III.
Fig. 3 has shown the X-ray diffraction pattern of carvedilol type IV.
Fig. 4 has shown the DTG heating curve of carvedilol type IV.
Fig. 5 has shown the X-ray diffraction pattern of carvedilol type V.
Fig. 6 has shown the DTG heating curve of carvedilol type V.
Fig. 7 has shown the X-ray diffraction pattern of carvedilol HCI.
The present invention describes in detail
Used term " Carvedilol " comprises hydrate and the solvate of Carvedilol in this. Term " water content " refer to based on as at the dry weight-loss method (" LOD " method) described in Pharmacopeial Forum (Pharmacopeia Forum) 1 phase of 24 volumes 5438 pages (1-2 month in 1998), the Ka Er Fischer determination method of measuring water content or the water content of TGA (TGA). Term " water equivalent " refers to the molar equivalent of water. Unless otherwise noted, otherwise herein all percentages all are weight percentage. Those skilled in the art understand term " anhydrous " and refer to when being used in reference to Carvedilol that Carvedilol is basically anhydrous. Those skilled in the art understand term " semihydrate " refers to have about 2.2% (weight) water content when being used in reference to Carvedilol crystalline solid. Those skilled in the art understand term " hydrate " and refer to that water content is about or is higher than the hydrochloric acid Carvedilol crystalline solid of 2% (weight). Those skilled in the art understand term " solvate of MEK " and refer to that contained quantity of solvent is higher than 1% Carvedilol in the lattice. Those skilled in the art also understand " solvate of MEK " that term contains 1 mole and refer to that content of methyl ethyl ketone is the Carvedilol of about 14% (weight).
The hydrate of Carvedilol and solvate form thereof are new model and mutually different on its characteristic powder X-ray diffraction pattern and its heating curve.
For this specification, environment temperature refers to about 20 ℃-Yue 25 ℃.
The method that all powder x-ray diffraction pattern all is familiar with by this area people uses Philips X-ray powder diffraction instrument to obtain. Use the copper radiation line of λ=1.5418 .
In order to estimate contingent physical and chemical changes in heated sample, carry out thermoanalytical measurement. Thermal response can be the endothermic reaction (such as melting, boiling, distillation, vaporization, desolvation, solid-solid phase-change, chemical degradation etc.) or exothermic reaction (such as crystallization, oxidation Decomposition etc.) in essence. This method has obtained being widely used in the pharmacy industry take polymorph as feature. Proved that thermal measurement can be used for characterizing the polymorphic system. The most frequently used technology is TGA (TGA), differential thermal analysis (DTA) and differential scanning calorimetry (DSC).
The method that DTA shown in this and TGA curve negotiating this area people are familiar with uses DTG Shimadzu model DTG-50 type (in conjunction with TGA and DTA) to obtain. Example weight is about 9-13mg. With sample with the rate scanning of 10 ℃/min to about 300 ℃ or more than. With the nitrogen purge of sample with the 20ml/min flow velocity. The lid that a hole is arranged on the standard alumina crucible cover.
Thermogravimetry (TGA) is as the tolerance that applies the material thermic weightlessness of temperature funtion. TGA is limited to and relates to the transformation that increases the mistake quality, and is most commonly used to study desolvation process and compound decomposition.
The Ka Er Fischer analysis that this area people are familiar with also is used for the water yield of working sample.
Used solvent is any liquid substance that can dissolve Carvedilol in this. Term " anti-solvent " used in this refers to that compound is insoluble in liquid wherein. In solvent, add the solubility that anti-solvent has reduced compound. Used solvent mixture refers to comprise the composition that surpasses a kind of solvent in this.
Used term " only " condition refers to that the solvent that wherein reacts is the reaction condition of one of reactant in this.
Synthesizing of Carvedilol
According to an embodiment, the present invention is a kind of method for preparing Carvedilol, and it comprises formula II compound 4-(oxirane-2-ylmethoxy)-9H-carbazole:
With formula III compound 2-(2-methoxyphenoxy) ethamine
Reactions steps. New method obtains the higher Carvedilol yield reported than prior art. In addition, the product of new method does not almost contain the impurity of two formula II compound molecules and reacts quicker.
Preferred formula III Compound Phase is for formula II compound molar excess. The molar ratio of formula III compound and formula II compound is preferably about 1.5: 1 to about 100: 1. More preferably the molar ratio of formula III compound and formula II compound is about 2.8: 1 to about 10: 1. Most preferably the molar ratio of formula III compound and formula II compound is about 2.8: 1 to about 6: 1.
In one embodiment of the invention, described reactions steps is carried out in solvent. Described solvent is preferably selected from toluene, dimethylbenzene and heptane. In another optional embodiment, described reactions steps is carried out in comprising the solvent mixture of multi-solvents. A kind of solvent in the preferred described solvent mixture is selected from toluene, dimethylbenzene and heptane.
Described reactions steps is preferably carried out under about 25 ℃-Yue 150 ℃ temperature. Most preferably described reactions steps is carried out under about 60 ℃-Yue 120 ℃ temperature.
In another optional embodiment, reactions steps is carried out under net terms. Described net terms can be melt into by the formula III compound with solid-state form liquid form and formula II compound is dissolved in and form reactant mixture in this liquid and obtain.
The reaction of carrying out under net terms also can be included in the step that reduces the temperature of reaction mixture behind the dissolution type II compound.Described temperature preferably is reduced to about 70 ℃.
The reaction of carrying out under net terms also can comprise to reaction mixture adding organic solvent: the step of water mixture.Described organic solvent is preferably selected from ethyl acetate, mibk, methylethylketone and butylacetate.
The reaction of carrying out under net terms also can be included in organic solvent: the step of regulating its pH after water mixture joins reaction mixture.Described pH preferably is adjusted to below about pH5.Most preferably pH regulator is arrived about 3-about 5.
Optional described method also is included in regulates the step of separating hydrochloric acid carvedilol and purifying carvedilol behind the pH.
The optional isolated in form of hydrochloric acid carvedilol with hydrate.As the isolating hydrochloric acid carvedilol of hydrate have about 6.5 ± 0.2,10.2 ± 0.2,10.4 ± 0.2,14.2 ± 0.2,14.7 ± 0.2,16.4 ± 0.2,17.7 ± 0.2,20.0 ± 0.2,21.9 ± 0.2,25.2 ± 0.2 the degree 2 θ the XRD peak.
The reaction of carrying out under net terms also can be included in regulates the step of separating carvedilol and purifying carvedilol behind the pH from reaction mixture.Carvedilol can be chosen the method purifying of being familiar with by this area people (referring to EP B 0127099) wantonly.
The novel method of preparation type I and type II crystallized carvedilol
One aspect of the present invention provides a kind of method for preparing type I crystallized carvedilol, this method is undertaken by following step: carvedilol is dissolved in a kind of solvent dissolves fully up to crystallized carvedilol, reduce the temperature of solution and with solution stirring for some time, further reduce the temperature of solution and with solution stirring for some time, the crystallized carvedilol of collection type I.
Described dissolving step is optional to be undertaken by heated solvent.
Optional crystallized carvedilol is heated about 50 ℃-Yue 60 ℃ temperature carried out described dissolving step in about 6 hours.
Described dissolving step is optional to be undertaken by crystallized carvedilol is suspended in the ethyl acetate.
Described dissolving step is optional to be undertaken by solution being heated to about 77 ℃.
The step of reduction solution temperature is optional is undertaken by in 15 minutes time solution being cooled to about 50 ℃.
The step of stirred solution is chosen wantonly at about 50 ℃ and is carried out carrying out in about 48 hours.
Further the step of reduction solution temperature is optional is undertaken by under agitation with about 0.75 hour solution being cooled to about 10 ℃.
Further the step of stirred solution optional by suspension is stirred 5 hours with on carry out.Further the step that stirs can be chosen wantonly by the suspension stir about was carried out in 24 hours.
Drying step can be by heating crystallized carvedilol and carried out in about 6 hours at about 50 ℃-Yue 60 ℃.
The suspension step can be undertaken by crystallized carvedilol is suspended in the ethyl acetate.
Described heating steps can be undertaken by solution being heated to about 77 ℃.
Another aspect of the present invention provides a kind of method for preparing type II crystallized carvedilol, comprises the steps: to form carvedilol solution in a kind of solvent by carvedilol is dissolved in, pass through cooling solution sedimentation type II carvedilol and divergence type II crystallized carvedilol.
The step of optional described dissolving carvedilol is being carried out under the temperature of about solvent boiling temperature from about 40 ℃.
The step of optional cooling solution is carried out to about envrionment temperature for-20 ℃ by temperature being reduced to pact.
Optional described solvent is selected from methyl alcohol, dehydrated alcohol, 1-propyl alcohol, Virahol, propyl carbinol, ethylene glycol, butylacetate, isobutyl methyl ketone, methylene dichloride, ethylene dichloride, acetonitrile, acetone, primary isoamyl alcohol, dimethylbenzene and toluene.
Optional by the sedimentary type II carvedilol of filtering separation.
Another aspect of the present invention provides a kind of method for preparing type II crystallized carvedilol, comprises following step: form carvedilol solution by carvedilol being dissolved in a kind of solvent mixture, by solution being cooled to approximately-20 ℃ of sedimentation type II carvedilols and divergence type II crystallized carvedilol.
Choose wantonly at about 40 ℃ and under the temperature of about solvent boiling point temperature, carvedilol is dissolved in solution.
Optional type II carvedilol passes through filtering separation.
The step of optional cooling reactant is carried out to the temperature of envrionment temperature for-20 ℃ by solution being cooled to pact.
Optional described solvent mixture is selected from: acetone: hexanaphthene, chloroform: hexanaphthene, ethylene dichloride: hexanaphthene, methylene dichloride: hexanaphthene, pyridine: hexanaphthene, tetrahydrofuran (THF): hexanaphthene, diox: hexanaphthene, acetone: hexane, chloroform: hexane, ethylene dichloride: hexane, methylene dichloride: hexane, tetrahydrofuran (THF): hexane and ethanol: hexane.
New carvedilol polymorphic form
In another aspect of this invention, provide new carvedilol crystallized form of being called type III, IV, V and preparation method thereof.In addition, the invention provides the carvedilol and preparation method thereof of the new hydrated form of a kind of tool about 2% (weight) water-content.In another embodiment, the invention provides the carvedilol and preparation method thereof of the novel solvent compound form of tool the highest about 14% (weight) solvent, wherein said solvent is a methyl ethyl ketone.Hydrate/the solvate of these carvedilols can be used as the intermediate of synthetic carvedilol medicine.
The method of crystallization new form carvedilol
New hydrate/the solvate form thereof that provides in this is optional to be formed by the carvedilol that is settled out the crystalline solid form from a kind of solvent or solvent mixture.Those skilled in the art understand other method and also can be used for forming disclosed hydrate/solvate form thereof in this.Perhaps described polymorphic form can be revised by the routine of disclosed method in this and form.
The formation of type III crystallized carvedilol
One embodiment of the invention provide a kind of method for preparing type III crystallized carvedilol, and this method comprises the steps: to form the solvent solution that contains carvedilol; With use water as anti-solvent sedimentation type III crystallized carvedilol from described solvent solution.The invention provides a kind of dissolving step, wherein water is present in the solvent solution in dissolving step.The present invention also provides a kind of settling step, wherein after carvedilol is dissolved in the solvent fully water is joined in the solution.
In order to form the solvent solution that contains carvedilol, can to choose wantonly carvedilol is dissolved in the solvent at elevated temperatures.Preferred elevated temperature is about 40 ℃-Yue 90 ℃.Most preferably the temperature of described rising is about 55 ℃.Perhaps, carvedilol can be dissolved in a kind of solvent at ambient temperature.
Another embodiment of the invention is by being dissolved in carvedilol in a kind of solvent, and by adding a kind of precipitation of anti-solvent-induced generation crystal type III carvedilol, formed the solvent solution that contains carvedilol.Solvent is selected from pyridine, diox, Virahol and chloroform.Anti-solvent is selected from water and hexane.
Another embodiment of the present invention forms the solvent solution that contains carvedilol by carvedilol is dissolved in a kind of organic solvent and the water, and sedimentation type III crystallized carvedilol.In this embodiment, described organic solvent is optional for pure.Described alcohol is preferably selected from methyl alcohol and ethanol.Perhaps, described organic solvent can be selected from pyridine, diox, ethyl acetate and tetrahydrofuran (THF).
Another optional embodiment of the present invention provides a kind of method for preparing type III crystallized carvedilol, and this method comprises following step: at elevated temperatures the drying crystalline carvedilol, with crystallized carvedilol be suspended in a kind of solution mixture, the heated solution mixture up to crystallized carvedilol dissolve fully, cooling solution mixture and collection type III crystallized carvedilol.
Optional described drying step carried out by heating crystallized carvedilol under about 50 ℃-Yue 60 ℃ temperature in about 6 hours.
Optional described suspension step can be by being suspended in ethyl acetate with crystallized carvedilol: carry out in the solution mixture of water (150: 40).
Optional described heating steps can dissolve fully up to crystallized carvedilol and to carry out by under agitation solution mixture being heated to about 70 ℃ from about 60 ℃.
Optional described cooling step can be undertaken by under agitation solution mixture being cooled to about 10 ℃ of about times of 3 hours.
The formation of type IV crystallized carvedilol
The present invention also provides a kind of method for preparing type IV crystallized carvedilol, and it comprises that forming the solvent solution that contains carvedilol also induces the sedimentary step of generation type IV crystallized carvedilol by adding " anti-solvent ".In this embodiment, solvent is selected from methylethylketone and mibk.Anti-solvent is selected from hexanaphthene and heptane.
In order to form type IV crystallized carvedilol, choose wantonly being lower than envrionment temperature and under the temperature that raises, carvedilol is dissolved in the solvent.Preferred temperature is about 10 ℃-Yue 50 ℃.Most preferably temperature is an envrionment temperature.
The formation of formula V crystallized carvedilol
The present invention also provides a kind of method for preparing type V crystallized carvedilol, and it comprises that forming the solvent solution that contains carvedilol also induces the sedimentary step of generation type V crystallized carvedilol by cooling or adding " anti-solvent ".In this embodiment, solvent is selected from the one group of solvent that comprises methylethylketone.Anti-solvent is selected from hexanaphthene and hexane.
In order to form type V crystallized carvedilol, optionally at elevated temperatures carvedilol is dissolved in the solvent solution.The preferred temperature that raises is about 10 ℃-Yue 80 ℃.The temperature of most preferred rising is about 55 ℃.Perhaps, carvedilol can be dissolved in the solvent solution at ambient temperature.
The new hydrate of carvedilol and solvate crystallized form
The invention provides the new carvedilol crystallized form that is called type III, IV and V and hydrochloric acid carvedilol.These forms can be distinguished mutually with the prior art form of carvedilol with heating curve and distinguish mutually by characteristic powder X-ray diffraction figure.
Different crystallized forms also can close state representation by its solvent separately.Modal solvate is 1: 1 stoichiometric those solvate in medicine.Also run into blended solvate type once in a while.When water or solvent were attached in the lattice of compound with stoichiometric ratio, the molecular addition compound of formation was called hydrate or solvate.
The crystallized carvedilol of type III
Type III carvedilol (" type III ") characterizes by its x-ray diffraction pattern, and its peak is about 8.4 ± 0.2,9.3 ± 0.2,11.6 ± 0.2,13.2 ± 0.2,13.5 ± 0.2,14.2 ± 0.2,15.3 ± 0.2,15.8 ± 0.2,17.4 ± 0.2,18.4 ± 0.2,19.4 ± 0.2,20.6 ± 0.2,21.4 ± 0.2,22.0 ± 0.2,26.5 ± 0.2 and 27.6 ± 0.2 degree 2 θ.The peak of the tool feature of type III is at about 8.4 ± 0.2,17.4 ± 0.2 and 22.0 ± 0.2 degree 2 θ.Fig. 1 has duplicated its diffractogram.
Fig. 2 has shown the ripe curve of the DTG of type IV.The dsc of type III (DSC) heating curve demonstrates near the melting peak of (96 ℃-110 ℃) 100 ℃ that depends on sample and particle diameter.This melting peak is accompanied by about 2% drying loss as recording by thermogravimetric analysis (TGA).Water-content in the sample that records by the analysis of Ka Er Fischer is consistent with the value height that is obtained by TGA, thereby confirms that drying loss is because dehydration and show that this material is a.
Type IV crystallized carvedilol
Carvedilol type IV (" type IV ") is characterized by x-ray diffraction pattern, and its peak is about 11.9 ± 0.2,14.2 ± 0.2,15.7 ± 0.2,16.5 ± 0.2,17.7 ± 0.2,18.3 ± 0.2,19.2 ± 0.2,19.6 ± 0.2,21.7 ± 0.2,22.2 ± 0.2,23.9 ± 0.2,24.2 ± 0.2,24.9 ± 0.2,27.4 ± 0.2 and 28.2 ± 0.2 degree 2 θ.The peak of the tool feature of type IV is about 11.9 ± 0.2,14.2 ± 0.2,18.3 ± 0.2,19.2 ± 0.2,21.7 ± 0.2 and 24.2+0.2 degree 2 θ.Fig. 3 has duplicated this diffractogram.
Fig. 4 has shown the DTG heating curve of type IV.The DSC heating curve of type IV has shown at about 104 a ℃ melting peak.
Type V crystallized carvedilol
Type V carvedilol (" type V ") characterizes by x-ray diffraction pattern, and its peak is about 4.1 ± 0.2,10.3 ± 0.2,10.7 ± 0.2,11.5 ± 0.2,12.6 ± 0.2,14.0 ± 0.2,14.8 ± 0.2,15.4 ± 0.2,16.4 ± 0.2,16.8 ± 0.2,18.8 ± 0.2,20.8 ± 0.2,21.1 ± 0.2,21.6 ± 0.2 and 25.4 ± 0.2 degree 2 θ.The peak of the tool feature of type V is at about 4.1 ± 0.2,10.3 ± 0.2,10.7 ± 0.2 and 11.5 ± 0.2 degree 2 θ.Fig. 5 has duplicated its diffractogram.
The DTG heating curve of type V is shown in Fig. 6.The DSC heating curve of type V is presented at the heat absorption of about 67 ℃ solvent desorption, then is recrystallization and at 115 ℃ melting peak.Desorb heat absorption is accompanied by about 14% the drying loss that is recorded by TGA.This feature conform to the loss of per molecule carvedilol a part MEK (stoichiometric number of single MEK of calculating is 15%).
Hydrochloric acid carvedilol hydrate
Crystalline hydrochloric acid carvedilol is by about 6.5 ± 0.2,10.2 ± 0.2,10.4 ± 0.2,14.2 ± 0.2,14.7 ± 0.2,15.8 ± 0.2,16.4 ± 0.2,17.7 ± 0.2,20.0 ± 0.2,21.5 ± 0.2,21.9 ± 0.2,22.2 ± 0.2,22.9 ± 0.2,25.2 ± 0.2,25.3 ± 0.2,27.2 ± 0.2,27.4 ± 0.2,28.2 having the x-ray diffraction pattern at peak, ± 0.2,28.6 ± 0.2,29.6 ± 0.2 degree 2 θ characterize.The peak of the tool feature of crystallization hydrochloric acid carvedilol is at about 6.5 ± 0.2,10.2 ± 0.2,10.4 ± 0.2,15.8 ± 0.2,16.4 ± 0.2 and 22.2 ± 0.2 degree 2 θ.Its diffractogram is seen Fig. 7.
The DTG heating curve of hydrochloric acid carvedilol has shown two endotherm(ic)peaks.At 118 ℃ peak is the dehydration peak.Second endotherm(ic)peak of 135 ℃ is because the sample fusing.The LOD of this sample is 3.5%.The water-content of this sample that the analysis of Ka Er Fischer records is 3.7%.Therefore the analysis of Ka Er Fischer is consistent with the LOD value, has confirmed the existence of hydrate in this sample.The desired value of hydrochloric acid carvedilol monohydrate is 3.9%.
The medicinal compositions that contains carvedilol
According to a further aspect, the present invention relates to contain one or more this in the medicinal compositions of disclosed new crystalline form carvedilol and at least a pharmaceutically acceptable vehicle.This medicinal compositions can a kind of coating for inflamed.
Described formulation can comprise one or more new carvedilol forms, perhaps can comprise one or more carvedilols as the new form of a composition part.No matter be with pure form or with the composition forms administration, carvedilol can be powder, particle, aggregate or any other solid form.Composition of the present invention comprises tablet composition.Tablet composition can have several perhaps polycomponents according to used flaking method, required rate of release and other factors.For example, composition of the present invention can comprise thinner such as cellulose source material such as cellulose powder, Microcrystalline Cellulose, microfine cellulose, methylcellulose gum, ethyl cellulose, Natvosol, hydroxypropylcellulose, Vltra tears, carboxymethyl cellulose salt and other replacement and substituted cellulose not; Starch; Starch,pregelatinized; Inorganic diluents such as lime carbonate and DI-CALCIUM PHOSPHATE and other thinner well known to those skilled in the art.Other thinner that is suitable for comprises that wax, sugar (as lactose) and sugar alcohol resemble mannitol and Sorbitol Powder, acrylic ester polymer and multipolymer, and pectin, dextrin and gelatin.
Other vehicle that the present invention intends adopting comprises that tackiness agent such as gum arabic, starch,pregelatinized, sodiun alginate, glucose and other are used for doing wet the granulation and the tackiness agent of direct compression method; Disintegrating agent such as sodium starch glycolate, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose etc.; Lubricant such as Magnesium Stearate and calcium stearate and stearyl-sodium fumarate; Seasonings; Sweeting agent, sanitas; Pharmaceutically acceptable dyestuff and glidant are such as silicon-dioxide.
Formulation can be suitable for per os, cheek, non-enteron aisle, eye, rectum and through the skin approach to patient's administration.Oral dosage form comprises tablet, pill, capsule, lozenge, pouch, suspension, pulvis, lozenge, elixir etc.Disclosed novel forms of carvedilol also can be used as suppository, eye ointment and suspension agent and the suspension agent administration of non-enteron aisle by other administration in this.The most preferred route of administration of carvedilol form of the present invention is an oral administration.
But capsule comprises the solids composition in the capsule of gelatin coating.The also available enteric coating of tablet and powder coats.Enteric-coated powder forms can have dressing, described dressing comprises the multipolymer and the analogous material of multipolymer, methacrylic acid and the methyl methacrylate of phthalic acid cellulose ethanoate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalic ester, carboxymethylethylcellulose, vinylbenzene and toxilic acid, if desired, they can use together with the softening agent and/or the supplement that are fit to.Coated tablet can have one deck dressing or can be by the powder of tool enteric coating or the tablet of granulometric composition on the surface of tablet.
Present carvedilol commercial form is 3.125mg, 6.25mg, 12.5mg and 25mg tablet, and it comprises following non-active ingredient: colloid silica, polyvinylpolypyrrolidone, Vltra tears, lactose, Magnesium Stearate, polyoxyethylene glycol, polysorbate 80, polyvidone, sucrose and titanium dioxide.
The function of various embodiments of the present invention and advantage can more fully be understood from the following examples.The following examples will be used to illustrate benefit of the present invention, but illustration entire area of the present invention not.
Embodiment
The preparation of carvedilol under net terms
2-(2-methoxyl group phenoxy group) ethamine (III) (4.89g) is heated to about 100 ℃, and (oxyethane-2-ylmethoxy)-9H-carbazole (II) (3.31g) for the 4-of portions adding after this.After about 20 minutes, reaction mixture is cooled to about 70 ℃, adds entry (25ml) and ethyl acetate (15ml) then.PH with this two-phase mixture is adjusted to 5 with 2N hydrochloric acid then.With formed hydrochloric acid carvedilol hydrate solids thing filter, water (20ml) washing and then with ethyl acetate (15ml) washing.
With the material that obtains in ethyl acetate (50ml) with contain that reslurry reaches 7.5 up to pH in the water (20ml) of 5% yellow soda ash.Separate organic phase and through dried over sodium sulfate.The exsiccant solution concentration is become turbid solution and is cooled to about 4 ℃ all night.By the sedimentary carvedilol of filtering separation and from the Virahol recrystallization.
Embodiment 2
The preparation of carvedilol under net terms
2-(2-methoxyl group phenoxy group) ethamine (III) (4.89g) is heated to about 100 ℃, and (oxyethane-2-ylmethoxy)-9H-carbazole (II) (3.31g) for the 4-of portions adding after this.After about 20 minutes, reaction mixture is cooled to about 70 ℃, adds entry (25ml) and ethyl acetate (15ml) then.PH with this two-phase mixture is adjusted to 5 with 2N hydrochloric acid then.With formed hydrochloric acid carvedilol hydrate solids thing filter, water (20ml) washing and then with ethyl acetate (15ml) washing.
With the material that obtains in ethyl acetate (50ml) with contain that reslurry reaches 7.5 up to pH in the water (20ml) of 5% yellow soda ash.Separate organic phase and through dried over sodium sulfate.The exsiccant solution concentration is become turbid solution and is cooled to about 4 ℃ all night.By the sedimentary carvedilol of filtering separation and from recrystallizing methanol.
Embodiment 3
The method for preparing type I carvedilol
Step according to embodiment 3 prepares crystallized carvedilol.Then with crystalline material 50-60 ℃ of drying 6 hours.Dried crystallized carvedilol (220g carvedilol) is dissolved in the 2200ml ethyl acetate.Under agitation ethyl acetate solution being heated to 77 ℃ dissolves fully up to solids.Under agitation ethyl acetate solution is cooled to about 50 ℃ with time of 15 minutes then.Cooled solution was stirred 48 hours.Under agitation solution is cooled to 10 ℃ then with 0.75 hour.After again suspension being stirred 24 hours, filtration product.The pure crystallized carvedilol (170g) of acquisition type I.
Embodiment 4
The preparation of type II crystallized carvedilol
By making carvedilol crystallization from the listed solvent of Table I form type II crystallized carvedilol.Reach clear solution (approaching the solvent boiling point temperature usually) by formation solution and heating and make the carvedilol crystallization.Solution is cooled to envrionment temperature and filtering precipitate and the carvedilol of formation type II then.
Table I
| Solvent | Solvent (ml): the ratio of carvedilol (g) |
| Methyl alcohol | 11 |
| Dehydrated alcohol | 12 |
| The 1- | 14 |
| Virahol | 13 |
| Propyl carbinol | 11 |
| Ethylene glycol | 13 |
| | 10 |
| Butylacetate | 12 |
| Isobutyl methyl ketone | 12 |
| Methylene dichloride | 12 |
| Ethylene dichloride | 25 |
| | 50 |
| | 25 |
Embodiment 5
By filtering preparation type II crystallized carvedilol at-20 ℃
By making the crystallized carvedilol of carvedilol crystallization from the listed solvent of Table II formation type II.The carvedilol solution that is heated to about solvent boiling point temperature by formation makes the carvedilol crystallization.Then solution is cooled to-20 ℃, filtering precipitate is also dry and obtain carvedilol type II.
Table 2
| Solvent | Solvent (ml): the ratio of carvedilol (g) [please the unit of checking] |
| | 50 |
| Toluene | 53 |
| Dimethylbenzene | 51 |
Embodiment 6
Preparation crystallized carvedilol type II in solvent mixture
By making carvedilol crystallization from the listed solvent mixture of Table III prepare crystallized carvedilol type II.Be heated to the carvedilol solution that becomes clear solution (approaching the boiling temperature of solvent mixture usually) by formation and make the carvedilol crystallization.Then solution is cooled to envrionment temperature and filtration.Collect crystallization and the dry carvedilol type II that obtains by filtering.
Table III
| Solvent | The solvent ratio | Solvent (ml): the ratio of carvedilol (g) [please the unit of confirmation] |
| Acetone: | 1∶4.8 | 230 |
| Chloroform: | 1∶3 | 130 |
| Ethylene dichloride: | 1∶2.5 | 142 |
| Methylene dichloride: | 1∶1.7 | 90 |
| Pyridine: hexanaphthene | 1∶3.5 | 45 |
| Tetrahydrofuran (THF): | 1∶2.5 | 53 |
| Diox: hexanaphthene | 1∶2.3 | 70 |
| Acetone: | 1∶2 | 235 |
| Chloroform: | 1∶1.5 | 87 |
| Ethylene dichloride: | 1∶1.2 | 89 |
| Methylene dichloride: | 1∶1.6 | 90 |
| Tetrahydrofuran (THF): | 1∶3 | 49 |
| Ethanol: | 1∶3.8 | 145 |
Embodiment 7
The preparation of crystallized carvedilol type III:
By in 55 ℃ of water-baths, under agitation the heating and carvedilol (4g) is dissolved in the mixture of 45mL 96% ethanol and 4% water.Placed with solution cooling and under not stirring under the room temperature about 14 hours, with crystallization by B filter, with twice of 96% washing with alcohol of about 10ml cold (4 ℃) and under the room temperature in moisture eliminator drying (being connected to pneumatic pump) obtain carvedilol type III up to constant weight.
Embodiment 8
The preparation of crystallized carvedilol type III
By in 55 ℃ of water-baths, under agitation the heating and carvedilol (4g) is dissolved in the mixture of 195mL water/methyl alcohol (being respectively 1: 3 ratio).Placed with the solution cool to room temperature and under not stirring under the room temperature about 15 hours, with crystallization by B filter, and at room temperature in moisture eliminator dry (being connected to pneumatic pump) obtain carvedilol type III up to constant weight.
Embodiment 9
The preparation of crystallized carvedilol type III
By at room temperature stirring carvedilol (4g) is dissolved in the 39mL pyridine.Dropwise add 70mL water then up to the beginning crystallization.Under not stirring, at room temperature solution was not placed about 80 hours, then crystallization is filtered by B, and at room temperature in moisture eliminator dry (being connected to pneumatic pump) obtain carvedilol type III up to constant weight.
The preparation of crystallized carvedilol type III
At room temperature carvedilol (4g) is dissolved in the 76mL diox, the part of 110mL moisture into about 10mL joined in the solution of stirring.Gained solution was at room temperature placed about 15 hours under not stirring, then the crystalline deposit that forms is filtered by B, and at room temperature in moisture eliminator dry (being connected to pneumatic pump) obtain blended carvedilol type III mutually with carvedilol type II up to constant weight.
Embodiment 11
The preparation of crystallized carvedilol type III
Heating is dissolved in 267mL with carvedilol (4g) and is respectively in 1: 1.4 ratio De diox/water by under agitation, in 55 ℃ of water-baths.Gained solution was at room temperature placed about 15 hours under not stirring, then crystallization is filtered by B, and dry (being connected to pneumatic pump) obtains and carvedilol type II blended carvedilol type III up to constant weight in moisture eliminator.
Embodiment 12
The preparation of crystallized carvedilol type III
Heating is dissolved in 180mL1 with carvedilol (4g) by under agitation, in 55 ℃ of water-baths: among the hexane/IPA of 1 ratio.Solution was not at room temperature placed about 15 hours under not stirring, then the crystallization that obtains is filtered by B, and at room temperature in moisture eliminator dry (being connected to pneumatic pump) obtain carvedilol type III up to constant weight.
Embodiment 13
The method for preparing carvedilol type III
Carvedilol (40g) is dissolved in 150ml ethanol and the 40ml water.Under stirring solution being heated to 60-70 ℃ dissolves fully up to solids.Under agitation solution was cooled to 10 ℃ with 3 hours then.After again suspension being stirred 2.75 hours, product is filtered.Obtain pure carvedilol type III (35g).
The preparation of crystallized carvedilol type IV
By at room temperature stirring carvedilol (1g) is dissolved in the 35ml methylethylketone, and dropwise adds the 202mL hexanaphthene.Solution was placed under not stirring under the room temperature about 15 hours, then the crystallization that obtains is filtered by B, and at room temperature in moisture eliminator dry (being connected to pneumatic pump) obtain carvedilol type IV up to constant weight.
Embodiment 15
The preparation of crystallized carvedilol type V
By at room temperature stirring carvedilol (1g) is dissolved in the 70ml methylethylketone, and dropwise adds the 138mL hexane.Under not stirring, solution placed under the room temperature about 15 hours, and then the crystallization that obtains filtered by B, and at room temperature in moisture eliminator dry (being connected to pneumatic pump) obtain carvedilol type V up to constant weight.
Embodiment 16
The preparation of crystallized carvedilol type V
Heat by under agitation, in 55 ℃ of water-baths carvedilol (2g) is dissolved in the 45mL methylethylketone, then solution is cooled off, and under not stirring, at room temperature placed about 14 hours, crystallization is filtered by B, and at room temperature in moisture eliminator dry (being connected to pneumatic pump) obtain carvedilol type V up to constant weight.
Claims (56)
1. crystallized carvedilol type III is characterised in that its X-ray powder diffraction pattern 8.4 ± 0.2, and 17.4 ± 0.2 and 22.0 ± 0.2 degree, 2 θ have the peak.
2. the carvedilol of claim 1, it is further characterized in that its X-ray powder diffraction pattern 9.3 ± 0.2,11.6 ± 0.2,13.2 ± 0.2,13.5 ± 0.2,14.2 ± 0.2,15.3 ± 0.2,15.8 ± 0.2,18.4 ± 0.2,19.4 ± 0.2,20.6 ± 0.2,21.4 ± 0.2,26.5 ± 0.2 and 27.6 ± 0.2 degree 2 θ have the peak.
3. the purposes of crystallized carvedilol type III in the medicine of preparation treatment patients with congestive heart failure.
4. the purposes of crystallized carvedilol type III in preparation treatment hyperpietic's medicine.
5. crystallized carvedilol type IV is characterised in that its X-ray powder diffraction pattern 11.9 ± 0.2, and 14.2 ± 0.2,18.3 ± 0.2,19.2 ± 0.2,21.7 ± 0.2 and 24.2 ± 0.2 degree, 2 θ have the peak.
6. the crystallized carvedilol of claim 5 is further characterized in that its X-ray powder diffraction pattern 15.7 ± 0.2,16.5 ± 0.2,17.7 ± 0.2,19.6 ± 0.2,22.2 ± 0.2,23.9 ± 0.2,24.9 ± 0.2,27.4 ± 0.2 and 28.2 ± 0.2 degree 2 θ have the peak.
7. the crystallized carvedilol hydrate is characterised in that to have as claim 1, the X-ray powder diffraction pattern described in each claim in 2,5 and 6.
8. crystallized carvedilol (methylethylketone) solvate type V is characterised in that its X-ray powder diffraction pattern 4.1 ± 0.2, and 10.3 ± 0.2 and 10.7 ± 0.2 degree, 2 θ have the peak.
9. the crystallized carvedilol of claim 8, it is further characterized in that its X-ray powder diffraction pattern 11.5 ± 0.2,12.6 ± 0.2,14.0 ± 0.2,14.8 ± 0.2,15.4 ± 0.2,16.4 ± 0.2,16.8 ± 0.2,18.8 ± 0.2,20.8 ± 0.2,21.1 ± 0.2,21.6 ± 0.2 and 25.4 ± 0.2 degree 2 θ have the peak.
10. the crystallized carvedilol of claim 8 is characterized in that its content of methyl ethyl ketone is 14% weight.
11. crystallized carvedilol (methylethylketone) solvate is characterised in that the X-ray powder diffraction pattern that has described in claim 8 or 9.
12. the crystallized carvedilol of claim 11 is characterised in that its water-content is 2.0% weight.
13. a medicinal compositions, said composition comprise the crystallized carvedilol and the pharmaceutically acceptable carrier of the claim 11 for the treatment of significant quantity.
14. crystallization hydrochloric acid carvedilol hydrate is characterized in that its X-ray powder diffraction pattern 6.5 ± 0.2,10.2 ± 0.2,10.4 ± 0.2,15.8 ± 0.2,16.4 ± 0.2 and 22.2 ± 0.2 degree, 2 θ have the peak.
15. the crystallized carvedilol of claim 14, it is further characterized in that its X-ray powder diffraction pattern 14.2 ± 0.2,14.7 ± 0.2,16.4 ± 0.2,17.7 ± 0.2,20.0 ± 0.2,21.5 ± 0.2,21.9 ± 0.2,22.9 ± 0.2,25.2 ± 0.2,25.3 ± 0.2,27.2 ± 0.2,27.4 ± 0.2,28.2 ± 0.2,28.6 ± 0.2,29.6 ± 0.2 degree 2 θ have the peak.
16. the crystallized carvedilol of claim 14 is characterised in that its water-content is 3.5% weight.
17. a method for preparing crystallized carvedilol type I, this method comprises following step:
A) by heating carvedilol is dissolved in a kind of solution;
B) the described solution of heating dissolves fully up to crystallized carvedilol;
C) temperature of reduction solution;
D) with solution stirring for some time;
E) further reduce the temperature of solution;
F) further with solution stirring for some time; With
G) collect crystallized carvedilol type I.
18. the method for claim 17, wherein said dissolving step are to be undertaken by solution being heated to 77 ℃.
19. the method for claim 17, the step of wherein said reduction solution temperature are to be undertaken by in 15 minutes time solution being cooled to 50 ℃.
20. the method for claim 17, the step of wherein said stirred solution was carried out 48 hours at 50 ℃.
21. the method for claim 17, the step of wherein said further reduction solution temperature are solution to be cooled to 10 ℃ in 0.75 hour by stirred solution carry out.
22. the method for claim 17, the step of wherein said further stirred solution be by suspension is stirred 5 hours with on carry out.
23. a method for preparing crystallized carvedilol type II, this method comprises following step:
A) by being dissolved in, carvedilol forms carvedilol solution in a kind of solvent;
B) precipitate carvedilol type II by cooling solution; With
C) fractional crystallization carvedilol type II.
24. the method for claim 23, wherein said temperature are 40 ℃ of boiling temperatures to solvent.
25. the method for claim 23, wherein sedimentary carvedilol type II is isolating by filtering.
26. the method for claim 23, wherein said solution are cooled to-20 ℃ of temperature to room temperature.
27. the method for claim 23, wherein said solvent are selected from methyl alcohol, ethanol, 1-propyl alcohol, Virahol, propyl carbinol, ethylene glycol, butylacetate, isobutyl methyl ketone, methylene dichloride, ethylene dichloride, acetonitrile, acetone, primary isoamyl alcohol, dimethylbenzene and toluene.
28. a method for preparing crystallized carvedilol type II, this method comprises following step:
A) by carvedilol being dissolved in the solvent mixture to form carvedilol solution;
B) make carvedilol type II precipitation by solution being cooled to-20 ℃; With
C) fractional crystallization carvedilol type II.
29. the method for claim 28, wherein said solution temperature are 40 ℃ of boiling temperatures to solvent.
30. the method for claim 28, wherein sedimentary carvedilol type II is isolating by filtering.
31. the method for claim 28, wherein said solution are cooled to-20 ℃ of temperature to room temperature.
32. the method for claim 28, wherein said solvent mixture is selected from acetone: hexanaphthene, chloroform: hexanaphthene, ethylene dichloride: hexanaphthene, methylene dichloride: hexanaphthene, pyridine: hexanaphthene, tetrahydrofuran (THF): hexanaphthene, diox: hexanaphthene, acetone: hexane, chloroform: hexane, ethylene dichloride: hexane, methylene dichloride: hexane, tetrahydrofuran (THF): hexane and ethanol: hexane.
33. a method for preparing crystallized carvedilol type III, this method comprises following step:
A) carvedilol is dissolved in a kind of solvent to form solvent solution; With
B) use water as anti-solvent precipitated crystal carvedilol type III from this solvent solution.
34. the method for claim 33, water wherein is present in the solvent solution in dissolving step.
35. the method for claim 33, wherein said settling step be by after being dissolved in the solvent fully at carvedilol, water joined in this solution carry out.
36. the method for claim 33, wherein said dissolving step carries out at elevated temperatures.
37. the method for claim 33, the temperature of wherein said rising are 40 ℃-90 ℃.
38. the method for claim 33, the temperature of wherein said rising are 55 ℃.
39. the method for claim 33, wherein said dissolving step at room temperature carries out.
40. the method for claim 33, wherein said solvent are selected from pyridine, diox, methyl alcohol, ethanol, Virahol and chloroform.
41. the method for claim 33, wherein said solvent is made up of solvent mixture.
42. a method for preparing crystallized carvedilol type IV, this method comprises following step:
A) carvedilol is dissolved in a kind of solvent to form solvent solution;
B) in this solvent solution, add anti-solvent; With
C) precipitated crystal carvedilol type IV from this solvent solution.
43. the method for claim 42, wherein said solvent are methylethylketone.
44. the method for claim 42, wherein said anti-solvent is a hexanaphthene.
45. the method for claim 42, wherein said dissolving step carries out at 10 ℃-50 ℃.
46. the method for claim 42, wherein said dissolving step carries out at 55 ℃.
47. the method for claim 42, wherein said dissolving step at room temperature carries out.
48. a method for preparing crystallized carvedilol type V, this method comprises following step:
A) carvedilol is dissolved in a kind of solvent to form solvent solution; With
B) precipitation and fractional crystallization carvedilol type V from this solvent solution.
49. the method for claim 48, wherein said solvent are methylethylketone.
50. the method for claim 48, wherein said dissolving step is undertaken by dissolving carvedilol at normal temperatures.
51. the method for claim 48, wherein said solvent temperature are 10 ℃-80 ℃.
52. the method for claim 48, wherein carvedilol type V precipitates by cooling.
53. a method for preparing crystallized carvedilol type V, this method comprises following step:
A) carvedilol is dissolved in a kind of solvent to form solvent solution; With
B) precipitation and fractional crystallization carvedilol type V from this solvent solution,
Wherein said settling step is undertaken by adding a kind of anti-solvent.
54. the method for claim 53, wherein said solvent are methylethylketone.
55. the method for claim 53, wherein said dissolving step is undertaken by dissolving carvedilol at normal temperatures.
56. the method for claim 53, wherein said anti-solvent is a hexane.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21435600P | 2000-06-28 | 2000-06-28 | |
| US60/214356 | 2000-06-28 | ||
| US60/246358 | 2000-11-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB018146163A Division CN1245974C (en) | 2000-06-28 | 2001-06-28 | Carvedilol |
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| CN1733727A true CN1733727A (en) | 2006-02-15 |
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| CN 200510086095 Pending CN1733727A (en) | 2000-06-28 | 2001-06-28 | Crystalline carvedilol, processes for the manufacture thereof, pharmaceutical compositions and uses thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373952A (en) * | 2012-04-11 | 2013-10-30 | 江苏恒瑞医药股份有限公司 | New crystal forms of carvedilol sulfate |
| CN110997697A (en) * | 2017-08-11 | 2020-04-10 | 辉凌公司 | Process for preparing pharmaceutical composition |
-
2001
- 2001-06-28 CN CN 200510086095 patent/CN1733727A/en active Pending
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2002
- 2002-12-19 ZA ZA200210282A patent/ZA200210282B/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373952A (en) * | 2012-04-11 | 2013-10-30 | 江苏恒瑞医药股份有限公司 | New crystal forms of carvedilol sulfate |
| CN103373952B (en) * | 2012-04-11 | 2017-02-08 | 江苏恒瑞医药股份有限公司 | New crystal forms of carvedilol sulfate |
| CN110997697A (en) * | 2017-08-11 | 2020-04-10 | 辉凌公司 | Process for preparing pharmaceutical composition |
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|---|---|
| ZA200210282B (en) | 2003-12-19 |
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