CN102336701A - Carvedilol sulphate crystals, preparation method and application thereof in medicine - Google Patents
Carvedilol sulphate crystals, preparation method and application thereof in medicine Download PDFInfo
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Abstract
The invention relates to carvedilol sulphate crystals, a preparation method and application thereof in medicine, in particular to medicaments carvedilol sulphate type A, B, C and D crystals for treating hypertension, congestive heart failure and angina pectoris, a preparation method and application thereof. The preparation method comprises the following step: crystallizing a carvedilol sulphate solid in any crystal form or an amorphous carvedilol sulphate solid with conventional polar organic solvents and aqueous solutions thereof to obtain the type A, B, C or D crystal. The carvedilol sulphate crystals disclosed by the invention have favorable crystal form, and the used crystallizing solvents have the advantages of low toxicity and low residue. The carvedilol sulphate crystals prepared by the method can be better used for clinical treatment.
Description
Technical field
The present invention relates to sulfuric acid carvedilol A type, Type B, C type and the crystallization of D type, its preparation method and the purposes in preparation treatment hypertension, congestive heart failure and anginal medicine thereof.
Background technology
Carvedilol (Carvedilol) chemistry (±)-1-(9H-carbazyl-4-oxygen base) by name-3-[[2-(2-methoxyl group phenoxy) ethyl] amino]-2-propyl alcohol; Developed by the graceful Boehringer Mannhei of German width of cloth spirit company, FDA ratifies to go on the market in the U.S. September 14 nineteen ninety-five first.Commodity are called DilatrendTM (Dilatrend).Carvedilol is a kind of racemic mixture of two steric isomers; It is a kind of non-selective beta-blockers; It also has the characteristic of α receptor-blocking agent simultaneously; Two kinds of effects can be worked in coordination with patients with heart failure is benefited, and are used to treat hypertension, congestive heart failure and stenocardia, and curative effect is superior to the conventional beta receptor-blocking agent.
Carvedilol contains the Alpha-hydroxy secondary amine functional groups, and the Pka value is 7.8, and carvedilol is dissolved in neutrality or the alkaline medium; Be that the pH value was greater than 9 o'clock; The solubleness of carvedilol relatively low (less than 1ug/mL), about 23ug/mL when pH=7, about 100ug/mL when pH=5.Therefore the salt of the synthetic carvedilol of people, hope can improve that it is water-soluble, increase chemicalstability, for use in the composition of medicine.
Reported the hydrochloride of carvedilol among the International Patent Application WO 0200216A1.But this salt is under the sour condition of SGF, and its solvability is relatively poor, and the composition that therefore is used for medicine does not possess advantage.Then reported phosphoric acid salt, dihydrogen phosphate and the solvate thereof of carvedilol among the one Chinese patent application CN1678305A, it is well water-soluble to find that its hydrochloride than corresponding carvedilol and carvedilol has.International Patent Application WO 200808310 has mainly been introduced the preparation and the medicine thereof of unformed carvedilol phosphate salts and has been formed.Reported preparation in the International Patent Application WO 2005051325, but do not related to relevant medicine composition, crystal formation and crystal formation preparing method's thereof research about the sulfuric acid carvedilol.In view of medicine crystal formation itself all might produce special influence to solubleness, stability and the preparation characteristic etc. of medicine, therefore the crystal formation research to sulfuric acid carvedilol salt has crucial meaning.
Summary of the invention
The technical problem that the present invention will solve provides a kind of stable sulfuric acid carvedilol crystal formation and preparation method thereof.
We are surprisingly found out that in the salify research process; Though the vitriol of carvedilol is suitable in the drug evaluation index with dihydrogen phosphate; The composition that can be used for medicine; But carvedilol vitriol is more stable than hydrochloride, dihydrogen phosphate, hydrosulfate, so carvedilol vitriol is used for medicine and forms the advantage that is equipped with oneself that has more.Although International Patent Application WO 2005051325 has been reported the preparation about the sulfuric acid carvedilol; But do not relate to relevant crystal formation and crystal formation preparing method's thereof research; The inventor by its reported method salify, can't obtain purer crystallized product through experimental verification.In view of the medicine crystal formation might exert an influence to solubleness, stability and the preparation characteristic of medicine, the inventor has carried out extensive and deep research to the crystallization crystal formation and the preparation method of sulfuric acid carvedilol.
The sulfuric acid carvedilol is white or off-white color crystalline powder, and slightly soluble in water or methyl alcohol is almost insoluble in ethanol, chloroform or acetone; The aqueous solution of water or alcohols is ideal refining solvent comparatively, under different crystallization conditions, whether has polymorphic in order to investigate the sulfuric acid carvedilol, and we select methyl alcohol for use; Ethanol, Virahol, acetone; The acetonitrile and their aqueous solution are as recrystallisation solvent; To resulting sulfuric acid carvedilol crystallized product, behind vacuum-drying and heat drying, carried out the X-diffraction and measured.
The recrystallisation solvent of being selected for use comprises: methyl alcohol, methanol, water, 95% ethanol, ethanol/water, isopropanol, acetone, acetonitrile/water etc.The resulting crystallized sample of above solvent has been carried out X-diffraction and DSC respectively to be detected.Experimental result shows, the crystallization in the aqueous solution of the polar organic solvent that routine is used of sulfuric acid carvedilol mainly obtains containing the crystal formation of the sub-crystal water of half point, i.e. A type crystallization; Crystallization in the methanol aqueous solution that routine is used obtains containing the make a concerted effort B crystal formation of crystal water of weak bond; Crystallization in the low water content methyl alcohol that routine is used, the sulfuric acid carvedilol C crystal formation of the sub-crystal water of half point that is that obtains; Crystallization in the acetonitrile solution that routine is used, the sulfuric acid carvedilol D crystal formation that does not contain crystal water that is that obtains.The x-ray diffraction pattern of these crystal formations shows that they have diffractive features separately.
The stability of sulfuric acid carvedilol A crystal formation is stronger; What crystallization obtained the most easily in different solvents is the A crystal formation; Such as at recrystallisation solvent: in acetone, 95% ethanol, ethanol/water, isopropanol, the water equal solvent; Shown identical crystal formation (X-ray) collection of illustrative plates, the characteristic peak among its X-ray powder diffraction figure ° is located (Fig. 1) in 2 θ=5.86,6.3,13.9,17.7,24.1,25.3 ± 0.2.
With methanol as recrystallisation solvent, then shown other a kind of crystal formation (X-ray) collection of illustrative plates.We are defined as the B crystal formation with it.Characteristic peak among its X-ray powder diffraction figure ° is located (Fig. 3) in 2 θ=6.8,13.2,13.6,18.0,19.9,24.0,25.1,30.0 ± 0.2.
With the methyl alcohol of low water content as recrystallisation solvent, then obtained other a kind of crystal formation (X-ray) collection of illustrative plates.We are defined as the C crystal formation with it.Characteristic peak among its X-ray powder diffraction figure ° is located (Fig. 5) in 2 θ=6.5,7.4,10.0,11.8,13.1,14.8,16.3,18.3,19.6,20.8,24.3,25.9 ± 0.2.
As recrystallisation solvent, then obtained other a kind of anhydrous crystal forms with acetonitrile/water.We are defined as the D crystal formation with it.Characteristic peak among its X-ray powder diffraction figure ° is located (Fig. 7) in 2 θ=6.4 ± 0.2.
Discover that under the homogeneous solvent condition, alr mode does not exert an influence to A crystal formation selectivity, mechanical stirring, magnetic agitation or leave standstill under the crystallization condition are example with the solvent system of ethanol/water, have all obtained stable A type crystallization.
In the crystal formation research process, we find that crystal formation and moisture content have confidential relation.Crystallization in water-containing solvent, such as in acetone, the A crystal formation (Fig. 1) that crystallization goes out; Under 60 ℃ of vacuum drying conditions, the sample drying that crystallization is obtained is surveyed its moisture content to constant weight; Discovery in DSC collection of illustrative plates (Fig. 2), shows the existence of crystal water between 2.0-2.8%.According to the moisture content calculation formula: moisture content %=[n * 18/ (2 [M]+H
2SO
4+ n * 18)] * 100% (wherein M is the molecular weight of carvedilol), the product that can calculate us should be semihydrate: two molecules carvedilol+a part sulfuric acid+a part water.Because moisture content has influence to crystal formation, therefore, we crystallization control product suitable time of drying under 20～80 ℃ of temperature condition, promptly be dried to dehydration and slowly be tending towards constant weight, can stably obtain the A crystal form samples of moisture content between 2.0-3.0%.
Equally, the sulfuric acid carvedilol B crystal formation (Fig. 3) that crystallization obtains in methanol aqueous solution is controlled at the dry suitable time under 20～60 ℃ of temperature condition, can stably obtain the B crystal form samples of moisture content between 2.0-3.0%.DSC collection of illustrative plates (Fig. 4) shows that the B crystal formation has the make a concerted effort existence of crystal water of weak bond, compares with the A crystal form samples, if the crystal water of B crystal form samples in the temperature drying overlong time more than 60 ℃, will cause crystal water that the possibility of further sloughing is arranged.Experimental result is illustrated under 80 ℃ of vacuum drying conditions, and the sample moisture content that obtains detects possibly be lower than 2.0%.
Further, under with low water content methanol crystallization condition, the sulfuric acid carvedilol C crystal formation (Fig. 5) that crystallization goes out; Under 40～80 ℃ of vacuum drying conditions; The sample drying that obtains to constant weight, is surveyed its moisture content, find between 2.0-2.8%; In DSC collection of illustrative plates (Fig. 6), show that sulfuric acid carvedilol C crystal formation has than the make a concerted effort existence of crystal water of strong bond.The C crystal formation product that moisture content calculation result shows should be semihydrate.The crystallization control product is the dry suitable time under 20～80 ℃ of temperature condition, is dried to dehydration and slowly is tending towards constant weight, can stably obtain the C crystal form samples of moisture content between 2.0-3.0%.
As alternative recrystallisation solvent; The inventor with acetonitrile solution as recrystallisation solvent; Crystallization obtains sulfuric acid carvedilol D crystal formation crystallized product (Fig. 7), and sample is under 40～80 ℃ of vacuum drying conditions, with the sample drying that obtains 3 hours; DSC collection of illustrative plates (Fig. 8) shows that sulfuric acid carvedilol D crystal formation does not have the existence of crystal water.The crystallization control product is the dry suitable time under 20～80 ℃ of temperature condition, removes planar water, can obtain moisture content in the D crystal form samples below 1.0%.
Can be used as not special qualification of form kind of the sulfuric acid carvedilol of raw material use in the inventive method, can be the crystallization or the unformed solid of any crystal formation.
The inventive method is characterised in that uses rudimentary organic solvent, and preferred carbon atom quantity is less than alcohols, nitrile, ketone isopolarity organic solvent 3, that can volatilize and can be used as simultaneously recrystallisation solvent, or their mixture and the aqueous solution thereof; More preferably ethanol or methyl alcohol or their mixture, or the mixture of they and water is as sulfuric acid carvedilol crystalline recrystallization solvent.Can also can use the mixed solvent of alcohols and other polar organic solvent, perhaps the aqueous solution of polar organic solvent with pure water or pure organic solvent during crystallization.The not special restriction of the ratio of polar organic solvent and water can be arbitrarily, but this ratio often possibly exert an influence to the kind and the purity of crystal formation.
The invention provides a kind of preparation sulfuric acid carvedilol A type crystalline method.This method may further comprise the steps:
(1) with any crystal formation or unformed sulfuric acid carvedilol heating for dissolving in an amount of polar organic solvent or its aqueous solution, stir or place cooling crystallization, said polar organic solvent is selected from one or more in the following solvents: ethanol, Virahol or acetone;
(2) filter washing; In 40～80 ℃ of vacuum-dryings.
The present invention also provides a kind of preparation sulfuric acid carvedilol Type B crystalline method.This method may further comprise the steps:
(1) with any crystal formation or unformed sulfuric acid carvedilol heating for dissolving in methanol aqueous solution, place cooling crystallization;
(2) filter washing; In 20～60 ℃ of vacuum-dryings.
The present invention also provides a kind of preparation sulfuric acid carvedilol C type crystalline method.This method may further comprise the steps:
(1) with any crystal formation or unformed sulfuric acid carvedilol heating for dissolving in methyl alcohol, place cooling crystallization;
(2) filter washing; In 20～80 ℃ of vacuum-dryings.
The present invention prepares B crystal formation method and is characterised in that with methanol aqueous solution as recrystallisation solvent.For crystallisation process itself, the not special restriction of the ratio of methanol solvate and water can be arbitrarily; But result of study also shows, when the methyl alcohol ratio is lower than 40% when following, then might obtain impure mixing crystal formation; And the ratio of working as methyl alcohol further reduces; The ratio of water trends towards at 100 o'clock, and what in fact refer to is exactly pure water as solvent, and the crystallization that obtain this moment is the crystallization of A type.Therefore; Alcohol generally was limited to 40: 60 to 90: 10 with the ratio of water; Can obtain sulfuric acid carvedilol B crystal formation,, then possibly obtain impure mixing crystal formation if the ratio of methanol solvate further raises more than 10%; When methanol content trends towards 100% and contain can supply crystalline moisture the time, then can obtain containing the sulfuric acid carvedilol C crystal formation of the sub-crystal water of half point.The content of general may command moisture is 2% to 0.2%.
The present invention also provides a kind of preparation sulfuric acid carvedilol D type crystalline method.This method may further comprise the steps:
(1) with any crystal formation or unformed sulfuric acid carvedilol heating for dissolving in acetonitrile solution, place cooling crystallization;
(2) filter washing; In 20～80 ℃ of vacuum-dryings.
The present invention prepares D crystal formation method and is characterised in that with acetonitrile solution as recrystallisation solvent.For crystallisation process itself, the not special restriction of the ratio of acetonitrile solvent and water can be arbitrarily; But result of study shows; Cross when low when the acetonitrile ratio, obtain impure mixing crystal formation, and when the ratio of acetonitrile is too high; The solubleness of recrystallisation solvent is too low, and can not get satisfied productive rate.Usually, the ratio of acetonitrile and water can be limited to 30: 70 to 90: 10, and more preferably at 40: 60 to 80: 20, operation can obtain sulfuric acid carvedilol D crystal formation as stated above.
The method of recrystallization is not special to be limited, and is undertaken by common recrystallization working method.For example, earlier with sulfuric acid carvedilol heating for dissolving in the mixed solvent of organic solvent or organic solvent and water, the postcooling crystallization, filtration, gained crystallization are under 40～80 ℃ heating condition, and vacuum-drying just can reach the effect of removing recrystallization solvent.
The dissolvent residual that does not contain or only contain lower aq according to the sulfuric acid carvedilol crystallization of method preparation of the present invention.Ethanol, methyl alcohol, Virahol and acetone etc. all are the 3rd type of low poison solvents in the pharmaceutical prod residual solvent of NF regulation, thereby crystallization of the present invention can be used as medical effective constituent preferably.
Description of drawings
In conjunction with following accompanying drawing, above purpose and characteristic with other of the present invention will become obviously, and said accompanying drawing is represented respectively:
Fig. 1 is the X-ray powder diffraction of sulfuric acid carvedilol A type crystallization (20081121)
Fig. 2 is the DSC collection of illustrative plates of sulfuric acid carvedilol A type crystallization (20081121)
Fig. 3 is the X-ray powder diffraction of sulfuric acid carvedilol Type B crystallization (20081125)
Fig. 4 is the DSC collection of illustrative plates of sulfuric acid carvedilol Type B crystallization (20081125)
Fig. 5 is the X-ray powder diffraction of sulfuric acid carvedilol C type crystallization (20081129)
Fig. 6 is the DSC collection of illustrative plates of sulfuric acid carvedilol C type crystallization (20081129)
Fig. 7 is the X-ray powder diffraction of sulfuric acid carvedilol D type crystallization (20090503)
Fig. 8 is the DSC collection of illustrative plates of sulfuric acid carvedilol D type crystallization (20090503)
Fig. 9 is the X-ray powder diffraction of sulfuric acid carvedilol imperfect crystal formation (20090421)
Figure 10 is the DSC collection of illustrative plates of sulfuric acid carvedilol imperfect crystal formation (20090421)
Figure 11 is the X-ray powder diffraction (synthetic according to patent WO2005051325) of sulfuric acid carvedilol (20090422)
Figure 12 is the DSC collection of illustrative plates (synthetic according to patent WO2005051325) of sulfuric acid carvedilol (20090422)
Embodiment
Below will combine embodiment to explain the present invention in more detail, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Test used testing tool
X-ray diffraction pattern
Instrument model: D/Max-RA Japan RigakuX-ray powder diffraction appearance
Ray: monochromatic Cu-K alpha-ray
Scan mode: θ/2 θ, sweep limit: 3-40 °
Voltage: 30KV electric current: 50mA
Comparative Examples: synthetic (synthetic) of sulfuric acid carvedilol according to patent WO2005051325:
The acetone that in 250 milliliters there-necked flask, adds 38 milliliters adds the carvedilol of 10.25 grams and 6 milliliters water, heating for dissolving; In this reaction system, 25.2 milliliters of the sulphuric acid solns of adding 1N, reaction mixture temperature maintains 25 ℃; Have solid to separate out and stirred 20 hours, filter, filter cake is with the mixture washing of 20.5 milliliters of acetone and water; Then solid is added in 44 milliliters the mixing solutions of acetone and water (10: 1),, soup compound is filtered 20-35 ℃ of pulping 30 hours; Filter cake is dried to constant weight under vacuum condition, get white solid 4.95 grams.Productive rate: 43.1%, moisture: 2.83%.The x-ray diffraction pattern characteristic absorbance and the DSC collection of illustrative plates of this solid sample are seen Figure 11 and Figure 12.Be judged as mixed crystal.
25g (0.062mol) is dissolved in the 250ml ethanol with carvedilol (synthetic according to patent US4503067 (1983)), and heating makes its dissolving, and sulfuric acid (0.031mol, 3.04g, the vitriol oil of 1.68ml98%) is diluted in the water of 30ml.Slowly be added drop-wise in the carvedilol ethanolic soln, the adularescent solid is separated out, and continues stirred overnight.Next day suction filtration, 60 ℃ of drying under reduced pressure 3 hours, sulfuric acid carvedilol white solid 25.8g, moisture content 2.29%.Molar yield 92.1%.
The sulfuric acid carvedilol 2.0g (2.2mmol) that the last step was made joins in 65ml 95% ethanolic soln, and reflux kept 30 minutes to clarification; Stirring is cooled to the room temperature crystallization; Filter, resulting crystallization obtains crystallization 1.86g 60 ℃ of vacuum-dryings 3 hours; Mass yield 93%, moisture content 2.63%.The X-ray diffraction spectrogram of this crystallized sample is seen accompanying drawing 1, is the crystallization of A type, and DSC collection of illustrative plates (seeing accompanying drawing 2) shows that the crystallization of A type begins to have the dehydration endotherm(ic)peak at 107.2 ℃, and 113.4 ℃ of peak values begin to occur the fusion endotherm(ic)peak at 147.4 ℃, 149.4 ℃ of peak values.
The sulfuric acid carvedilol 2.0g (2.2mmol) that embodiment 1 is made joins in the water of 250ml, and reflux slowly cools to the room temperature crystallization to clarification; Filter; Resulting crystallization obtains crystallization 1.87g 60 ℃ of vacuum-dryings 3 hours, moisture content 2.73%; Mass yield 93.5%, the x-ray diffraction pattern characteristic absorbance of this crystallized sample is with the crystallization of A type.
The sulfuric acid carvedilol 2.0g (2.2mmol) that embodiment 1 is made joins in 50% aqueous acetone solution of 25ml, and reflux kept 30 minutes to clarification; Slowly cool to the room temperature crystallization; Filter, resulting crystallization obtains crystallization 1.72g 60 ℃ of vacuum-dryings; Mass yield 85.9%, moisture content: 2.59%.The x-ray diffraction pattern characteristic absorbance of this crystallized sample is with the crystallization of A type.
The sulfuric acid carvedilol 10.0g (11.0mmol) that embodiment 1 is made joins in the aqueous solution of 50% Virahol of 30ml, and reflux kept 30 minutes to clarification; Slowly cool to the room temperature crystallization; Filter, resulting crystallization obtains crystallization 9.5g 60 ℃ of vacuum-dryings; Mass yield 95%, moisture content: 2.42%.The x-ray diffraction pattern characteristic absorbance of this crystallized sample is with the crystallization of A type.
Embodiment 5
The sulfuric acid carvedilol 10.0g (11.0mmol) that embodiment 1 is made joins in the 50% alcoholic acid aqueous solution of 50ml, and reflux kept 30 minutes to clarification; Cooling, magneton stirs the room temperature crystallization, filters; Resulting crystallization is 60 ℃ of vacuum-dryings; Obtain crystallization 9.5g, mass yield 95%, moisture content: 2.18%.The X-ray diffraction spectrogram characteristic absorbance of this crystallized sample is with the crystallization of A type.
Embodiment 6
The sulfuric acid carvedilol 2.0g (2.2mmol) that embodiment 1 is made joins in 80ml 50% methanol aqueous solution, and reflux kept 30 minutes to clarification; Stirring is cooled to the room temperature crystallization; Filter, resulting crystallization to constant weight, obtains crystallization 1.8g 40 ℃ of vacuum-dryings; Mass yield 90.0%, moisture content: 2.56%.The X-ray diffraction spectrogram of this crystallized sample is the Type B crystallization with accompanying drawing 3, and DSC collection of illustrative plates (seeing accompanying drawing 4) shows that the Type B crystallization begins to have flat dehydration endotherm(ic)peak at 60 ℃, and about 87 ℃ of peak value shows that the crystal water or the planar water that have weak bond to make a concerted effort exist; Begin to occur sharp-pointed fusion endotherm(ic)peak at 147.8 ℃, 150.2 ℃ of peak values.
The sulfuric acid carvedilol 2.0g (2.2mmol) that embodiment 1 is made joins in the methyl alcohol of 160ml, and reflux kept 30 minutes to clarification; Slowly cool to the room temperature crystallization; Filter, resulting crystallization to constant weight, obtains crystallization 1.54g 60 ℃ of vacuum-dryings; Mass yield 76.9%, moisture content 2.24%; The X-ray diffraction spectrogram of this crystallized sample is seen accompanying drawing 5, is the crystallization of C type, and DSC collection of illustrative plates (seeing accompanying drawing 6) shows that the crystallization of C type begins to have flat dehydration endotherm(ic)peak at 103 ℃, about 112.1 ℃ of peak value, and showing has the crystal water of making a concerted effort than strong bond to exist; The fusion endotherm(ic)peak was not seen in the crystallization of C type before 270 ℃, begin to decompose gradually after 270 ℃.
The sulfuric acid carvedilol 10.0g (11.0mmol) that embodiment 1 is made joins in the aqueous solution of 50% acetonitrile of 50ml, and reflux kept 30 minutes to clarification; Be cooled to room temperature, leave standstill crystallization, filter; Resulting crystallization is 60 ℃ of vacuum-dryings; Obtain crystallization 7.9g, mass yield 79.0%, moisture content: 1.73%.The X-ray diffraction spectrogram of this crystallized sample is seen accompanying drawing 7, is the crystallization of D type.DSC collection of illustrative plates (seeing accompanying drawing 8) shows that the crystallization of D type all do not have the dehydration endotherm(ic)peak and occur 100 ℃ of front and back, begins to occur sharp-pointed fusion endotherm(ic)peak at 146.9 ℃, 149.3 ℃ of peak values.
Embodiment 9
The sulfuric acid carvedilol 2.0g (2.2mmol) that embodiment 1 is made joins in the 80ml Virahol, and reflux kept 30 minutes to clarification; Be cooled to room temperature, stirring and crystallizing is filtered; Resulting crystallization was 60 ℃ of vacuum-dryings 3 hours; Obtain crystallization 1.73g, moisture content 2.55%, mass yield 86.5%.The X-ray diffraction spectrogram of this crystallized sample does not have obvious characteristic absorption peak (accompanying drawing 9), is judged as imperfect crystal formation.DSC collection of illustrative plates (seeing accompanying drawing 10) shows that this imperfect crystal formation begins to occur sharp-pointed fusion endotherm(ic)peak at 179.5 ℃, 182.5 ℃ of peak values.
Reference examples 1:
Prepare carvedilol alkali (20080903) by patent US4503067 (1983) disclosed method; Prepare the hydrochloride (lot number 20080824) of carvedilol by patent WO0200216A1 disclosed method; Prepare the dihydrogen phosphate (lot number 20080904) of carvedilol by patent CN1678305A disclosed method; Method by embodiment 1 prepares sulfuric acid carvedilol (lot number 20080904), and the method for pressing embodiment 1 obtains carvedilol hydrosulfate (lot number 20080903) with sulfuric acid and carvedilol reaction with same mole; Above sample is carried out study on the stability and solubility test, and the result sees the following form.
The stability of table 1. carvedilol alkali and several kinds of salt (HPLC related substance)
Stability test is the result show, no matter carvedilol vitriol is under the condition of high temperature, high humidity or illumination, all shows good chemical stability, and the related substance of other salt all has increase in various degree, and carvedilol hydrosulfate stability is the poorest.
The solvability of table 2. carvedilol alkali and several kinds of salt
Solubility experiment is the result show, carvedilol vitriol is under the condition of simulation hydrochloric acid in gastric juice, and its solvability and dihydrogen phosphate are suitable, all are superior to carvedilol alkali and hydrochloride.
Claims (19)
1. the A type crystallization of a sulfuric acid carvedilol is characterized in that having powder x-ray diffraction figure as shown in Figure 1, uses the Cu-Ka radiation, and is the strongest at 13.90 (6.36) characteristic peaks located with the X-ray powder diffraction of 2 θ angles and spacing d value representation.
2. one kind prepares sulfuric acid carvedilol A type crystalline method as claimed in claim 1, it is characterized in that comprising the steps:
1) with any crystal formation or unformed sulfuric acid carvedilol heating for dissolving in an amount of polar organic solvent aqueous solution, place cooling crystallization, described polar organic solvent is selected from one or more in the following solvents: ethanol, Virahol or acetone;
2) filter washing; In 20～80 ℃ of vacuum-dryings.
3. preparation sulfuric acid carvedilol A type crystalline method as claimed in claim 2, wherein said heating for dissolving temperature are meant the temperature that solution refluxes.
4. preparation sulfuric acid carvedilol A type crystalline method as claimed in claim 2, wherein said cooling is meant and naturally cools to room temperature.
5. the Type B crystallization of a sulfuric acid carvedilol is characterized in that having powder x-ray diffraction figure as shown in Figure 3, uses the Cu-Ka radiation, and is the strongest at 18.00 (4.92) characteristic peaks located with the X-ray powder diffraction of 2 θ angles and spacing d value representation.
6. a preparation method who prepares sulfuric acid carvedilol Type B as claimed in claim 5 is characterized in that comprising the steps:
(1) with any crystal formation or unformed sulfuric acid carvedilol heating for dissolving in the amount of methanol aqueous solution, place cooling crystallization;
(2) filter washing; In 20～60 ℃ of vacuum-dryings.
7. preparation sulfuric acid carvedilol Type B crystalline method as claimed in claim 6, wherein said heating for dissolving temperature are meant the temperature that solution refluxes.
8. preparation sulfuric acid carvedilol Type B crystalline method as claimed in claim 6, wherein said cooling is meant and naturally cools to room temperature.
9. the C type crystallization of a sulfuric acid carvedilol; It is characterized in that having powder x-ray diffraction figure as shown in Figure 5; Use the Cu-Ka radiation, the strongest with the X-ray powder diffraction of 2 θ angles and spacing d value representation at 6.52 (13.54), 7.38 (11.97) characteristic peaks located.
10. one kind prepares sulfuric acid carvedilol C type crystalline method as claimed in claim 9, it is characterized in that comprising the steps:
1) with any crystal formation or unformed sulfuric acid carvedilol heating for dissolving in amount of methanol, place cooling crystallization;
2) filter washing; In 20～80 ℃ of vacuum-dryings.
11. preparation sulfuric acid carvedilol C type crystalline method as claimed in claim 10, wherein said heating for dissolving temperature is meant the temperature of methanol eddy.
12. preparation sulfuric acid carvedilol C type crystalline method as claimed in claim 10, wherein said cooling is meant and naturally cools to room temperature.
13. the D type crystallization of a sulfuric acid carvedilol is characterized in that having powder x-ray diffraction figure as shown in Figure 7, uses the Cu-Ka radiation, and is the strongest at 6.40 (13.80) characteristic peaks located with the X-ray powder diffraction of 2 θ angles and spacing d value representation.
14. one kind prepares sulfuric acid carvedilol D type crystalline method as claimed in claim 13, it is characterized in that comprising the steps:
1) with any crystal formation or unformed sulfuric acid carvedilol heating for dissolving in an amount of acetonitrile solution, place cooling crystallization;
2) filter washing; In 20～80 ℃ of vacuum-dryings.
15. preparation sulfuric acid carvedilol D type crystalline method as claimed in claim 14, wherein said heating for dissolving temperature are meant the temperature that solution refluxes.
16. preparation sulfuric acid carvedilol C type crystalline method as claimed in claim 14, wherein said cooling is meant and naturally cools to room temperature.
17. sulfuric acid carvedilol A type as claimed in claim 1 crystallization, sulfuric acid carvedilol Type B as claimed in claim 5 crystallization, sulfuric acid carvedilol C type as claimed in claim 9 crystallization, the purposes of sulfuric acid carvedilol D type as claimed in claim 13 crystallization in preparation treatment hypertension, congestive heart failure and anginal medicine.
18. a pharmaceutical composition, it contains one or more sulfuric acid carvedilol A type as claimed in claim 1 crystallizations, sulfuric acid carvedilol Type B as claimed in claim 5 crystallization, sulfuric acid carvedilol C type as claimed in claim 9 crystallization, sulfuric acid carvedilol D as claimed in claim 13 type crystallization and pharmacy acceptable salt.
19. the purposes of pharmaceutical composition as claimed in claim 18 in preparation treatment hypertension, congestive heart failure and anginal medicine.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102378844A CN102336701B (en) | 2010-07-26 | 2010-07-26 | Carvedilol sulphate crystals, preparation method and application thereof in medicine |
| PCT/CN2011/077150 WO2012013118A1 (en) | 2010-07-26 | 2011-07-14 | Carvedilol sulfate crystals, preparation method thereof, and pharmaceutical use thereof |
| HK12105807.8A HK1164883A1 (en) | 2010-07-26 | 2012-06-14 | Carvedilol sulfate crystals, preparation methods and pharmaceutical use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102378844A CN102336701B (en) | 2010-07-26 | 2010-07-26 | Carvedilol sulphate crystals, preparation method and application thereof in medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102336701A true CN102336701A (en) | 2012-02-01 |
| CN102336701B CN102336701B (en) | 2013-09-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102378844A Active CN102336701B (en) | 2010-07-26 | 2010-07-26 | Carvedilol sulphate crystals, preparation method and application thereof in medicine |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN102336701B (en) |
| HK (1) | HK1164883A1 (en) |
| WO (1) | WO2012013118A1 (en) |
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 |
| CN103467363A (en) * | 2013-09-27 | 2013-12-25 | 中国药科大学 | Carvedilol-asccharin amorphous compound |
| CN110668994A (en) * | 2019-11-12 | 2020-01-10 | 山东创新药物研发有限公司 | Levaldecolonite crystal form, preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005051322A2 (en) * | 2003-11-25 | 2005-06-09 | Sb Pharmco Puerto Rico Inc. | Controlled release pharmaceutical formulations comprising carvedilol, free based and its salts |
| WO2005051325A2 (en) * | 2003-11-25 | 2005-06-09 | Sb Pharmco Puerto Rico Inc. | Carvedilol compositions methods of treatment and delivery |
| WO2005051383A1 (en) * | 2003-11-25 | 2005-06-09 | Sb Pharmco Puerto Rico Inc. | Carvedilol salts, corresponding compositions, methods of delivery and/or treatment |
-
2010
- 2010-07-26 CN CN2010102378844A patent/CN102336701B/en active Active
-
2011
- 2011-07-14 WO PCT/CN2011/077150 patent/WO2012013118A1/en active Application Filing
-
2012
- 2012-06-14 HK HK12105807.8A patent/HK1164883A1/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005051322A2 (en) * | 2003-11-25 | 2005-06-09 | Sb Pharmco Puerto Rico Inc. | Controlled release pharmaceutical formulations comprising carvedilol, free based and its salts |
| WO2005051325A2 (en) * | 2003-11-25 | 2005-06-09 | Sb Pharmco Puerto Rico Inc. | Carvedilol compositions methods of treatment and delivery |
| WO2005051383A1 (en) * | 2003-11-25 | 2005-06-09 | Sb Pharmco Puerto Rico Inc. | Carvedilol salts, corresponding compositions, methods of delivery and/or treatment |
Cited By (4)
| 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 |
| CN103467363A (en) * | 2013-09-27 | 2013-12-25 | 中国药科大学 | Carvedilol-asccharin amorphous compound |
| CN110668994A (en) * | 2019-11-12 | 2020-01-10 | 山东创新药物研发有限公司 | Levaldecolonite crystal form, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012013118A1 (en) | 2012-02-02 |
| CN102336701B (en) | 2013-09-18 |
| HK1164883A1 (en) | 2012-09-28 |
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