CN106995381A - A kind of Crystal form of metoprolol succinate and preparation method thereof - Google Patents
A kind of Crystal form of metoprolol succinate and preparation method thereof Download PDFInfo
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- CN106995381A CN106995381A CN201710181419.5A CN201710181419A CN106995381A CN 106995381 A CN106995381 A CN 106995381A CN 201710181419 A CN201710181419 A CN 201710181419A CN 106995381 A CN106995381 A CN 106995381A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a kind of crystal formation of metroprolol succinate and preparation method thereof, Crystal form of metoprolol succinate X x ray diffractions of the invention are in the θ of angle of reflection 2：There is peak at 7.4 ± 0.2,14.4 ± 0.2,20.4 ± 0.2,21.5 ± 0.2,24.4 ± 0.2.The Crystal form of metoprolol succinate content (or purity) of the present invention is high, impurity content is low, steady quality, and the clinical practice for metroprolol succinate medicine provides safety guarantee.
Description
The application be Application No. CN201210208496.2, the applying date be on 06 25th, 2012, entitled " one
The divisional application of the application for a patent for invention of kind Crystal form of metoprolol succinate and preparation method thereof ".
Technical field
The invention belongs to drug for hypertension field, and in particular to Crystal form of metoprolol succinate and preparation method thereof.
Background technology
Metoprolol is β 1- selectivity (heart selectivity) adrenocepter blocking agent, i.e. heart selectivity medicine.Its
Clinically it is widely used in a variety of cardiovascular diseases such as hypertension and ischemic heart disease, chronic stable DHF, arrhythmia cordis
The treatment of patient, is the drug of first choice of world's hypertension therapeutic in recent years, is also the essential drugs of China.
1975, Astrazeneca AB was listed with its tartrate salt, trade name " Betaloc ".Because tartaric acid is beautiful
Tuo Luoer solubility it is very big (>700mg/ml), in order to obtain purpose that is more slow and persistently discharging metoprolol, A Sili
Kanggong department develops trade name " Toprol-XL " metroprolol succinate again, its solubility (270mg/ in 37 DEG C of water
Ml metoprolol tartrate) is substantially less than, and U.S. FDA was obtained in 1992 and ratifies to be used to treat hypertension and angina pectoris.At present
The country widely uses metoprolol tartrate, and the country there is no metroprolol succinate raw material to list.
Metroprolol succinate (Metroprolol Succinate, structural formula is as shown in Equation 1), chemical entitled 1- isopropyls
Amino -3- [p- (2- methoxyethyls) phenoxy group] -2- propyl alcohol succinates, the medical instrument has relatively low solubility, is adapted to prepare and delays
Controlled release preparation, Small side effects, drug safety is high, can as hyperpietic long-term prescription.
On metroprolol succinate, it is disclosed directly below in the prior art：
Chinese patent CN102295569 discloses a kind of preparation method of (S)-metroprolol succinate, using ethanol, third
Ketone, isopropanol crystallization, but crystal formation is not studied.
WO2007141593 discloses a kind of crystal formation of metroprolol succinate, and the X-ray powder diffraction of its crystal formation is in 2 θ
For 7.1,11.5,12.2,13.1,14.1,14.4,14.9,17.2,20.1,22.8,23.1,24.3,24.6,25.8,26.2,
27.2nd, there is peak at 30.1,31.9,33.4, recrystallisation solvent is isopropanol.
In view of the medical value of metroprolol succinate, still need to study its crystal formation that there is provided (or pure with content
Degree) height, low impurity content, steady quality, the crystal formation of metroprolol succinate suitable for pharmaceutical preparation is made.
The content of the invention
It is unexpected, the inventors discovered that a kind of new Crystal form of metoprolol succinate, content (or purity) is high, miscellaneous
Matter content is low, steady quality, and the clinical practice for metroprolol succinate medicine provides safety guarantee.
A kind of Crystal form of metoprolol succinate, it is characterised in that radiated using Cu-K α, is penetrated with the X- that 2 θ angles (°) are represented
Line diffraction has peak in following position：7.4±0.2、14.4±0.2、20.4±0.2、21.5±0.2、24.4±0.2.
A kind of crystal formation of new metroprolol succinate, it is characterised in that radiated using Cu-K α, is represented with 2 θ angles (°)
X-ray diffraction have peak in 7.4 ± 0.2,14.4 ± 0.2,20.4 ± 0.2,21.5 ± 0.2,24.4 ± 0.2 positions, also with
Bottom is equipped with peak：
(1)14.7±0.2、23.4±0.2、26.5±0.2；Or
(2)11.8±0.2、14.7±0.2、15.2±0.2、17.5±0.2、23.4±0.2、26.5±0.2、27.4±
0.2、32.2±0.2；Or
(3)11.2±0.2、11.8±0.2、12.5±0.2、13.4±0.2、14.7±0.2、15.2±0.2、17.5±
0.2、19.2±0.2、23.4±0.2、25.5±0.2、26.5±0.2、27.4±0.2、30.4±0.2、32.2±0.2、
33.1±0.2、34.9±0.2、35.6±0.2、36.5±0.2、37.6±0.2、37.9±0.2、38.5±0.2、39.8±
0.2、40.6±0.2、47.1±0.2、48.5±0.2、50.4±0.2；
A kind of crystal formation of new metroprolol succinate, it is characterised in that radiated using Cu-K α, is represented with 2 θ angles (°)
X-ray diffraction have peak in 7.4 ± 0.2,14.4 ± 0.2,20.4 ± 0.2,21.5 ± 0.2,24.4 ± 0.2 positions, also with
Bottom is equipped with peak：
(1)14.1±0.2；Or
(3)14.1±0.2、14.7±0.2；Or
(4)14.1±0.2、14.7±0.2、21.2±0.2、23.0±0.2、23.4±0.2、26.5±0.2、27.4±
0.2、40.0±0.2；
The crystal formation of above-mentioned metroprolol succinate, fusing point is 136.0~138.0 DEG C.
The crystal formation of above-mentioned metroprolol succinate, using means of differential scanning calorimetry (DSC) technology, with 10 DEG C/min of heatings
Speed is measured, and Endotherm Maximum is at 136.0~138.0 DEG C, and the endothermic process shows sharp for one on DSC spectrograms
Endothermic peak；The endothermic peak is not have obvious exothermic peak in unique significant endothermic peak, spectrogram on DSC spectrograms.
Another aspect of the present invention additionally provides a kind of original for including Crystal form of metoprolol succinate solid matter of the present invention
Expect medicine, the bulk drug is used to prepare antihypertensive medicine.
Another aspect of the present invention additionally provides a kind of medicine for including Crystal form of metoprolol succinate solid matter of the present invention
Compositions.The pharmaceutical composition can also specifically not limited pharmaceutically comprising one or more of pharmaceutically acceptable carriers
The species of acceptable carriers, as long as they can't significantly affect the drug effect of Crystal form of metoprolol succinate of the present invention suitable for medicinal
.
Another aspect of the present invention additionally provides a kind of agent for including Crystal form of metoprolol succinate solid matter of the present invention
The species of type, not concrete restriction formulation, can be the different pharmaceutical preparation shapes such as tablet, capsule, sustained release preparation, controlled release preparation
Formula, preferably metroprolol succinate sustained-release preparation.
Another aspect of the present invention also provides the preparation side of Crystal form of metoprolol succinate solid matter of the present invention
Method：Metroprolol succinate crude product is added in absolute ethyl alcohol, is heated to reflux to dissolving, -10~10 DEG C are cooled to, crystal is separated out
For Crystal form of metoprolol succinate sample.
A kind of preparation method of Crystal form of metoprolol succinate：Metroprolol succinate crude product is added in absolute ethyl alcohol,
It is heated to reflux to dissolving, is cooled to 40~60 DEG C, insulated and stirred 0.5~3.0 hour is cooled to -10~10 DEG C, insulation stands 2
~10 hours, precipitation crystal was Crystal form of metoprolol succinate sample.
Wherein,
The weigh-volume ratio of metroprolol succinate crude product and absolute ethyl alcohol can be 1:2~10, preferably 1:3~8.
Described is cooled to 40~60 DEG C, is to be cooled to 40~60 DEG C in 0.5~2 hour.
Described insulated and stirred, speed of agitator is 100~300 revs/min.
Described is cooled to -10~10 DEG C, is to be cooled to -10~10 DEG C in 1.0~3.0 hours.
A kind of preparation method of Crystal form of metoprolol succinate：Metroprolol succinate crude product is added in absolute ethyl alcohol,
It is heated to reflux to dissolving, is cooled to -10~10 DEG C, insulated and stirred 5~15 hours, precipitation crystal is Crystal form of metoprolol succinate
Sample.
Wherein,
The weigh-volume ratio of metroprolol succinate crude product and absolute ethyl alcohol can be 1:2~10, preferably 1:3~8.
Described is cooled to -10~0 DEG C, is to be cooled to -10~0 DEG C in 3.0~5.0 hours.
Described insulated and stirred, speed of agitator is 20~80 revs/min.
The method that described metroprolol succinate crude product can refer to disclosed in CN1128786C and CN102295569 is carried out
Prepare, above-mentioned literature content is hereby incorporated by reference.
Described metoprolol crude product can be prepared in accordance with the following methods：
Crystal form of metoprolol succinate obtained by the present invention, quality stability is good, and content is high, and impurity content is low, is more suitable for
Store and developed as bulk drug.
Brief description of the drawings
The testing conditions of powder x-ray diffraction spectrum accompanying drawing are as follows：
Instrument：XRD D8ADVANCE, are manufactured by German Bruker
Remove from office bar：Cu-K α are radiated
Step angle：0.02°
Pipe pressure：40KV
Guan Liu：50mA
The calculating time：0.3 second.
Fig. 1 a：The powder x-ray diffraction figure of the gained Crystal form of metoprolol succinate sample of embodiment 1.Axis of ordinates is represented
Diffracted intensity (cps), axis of abscissas represents the angle of diffraction (2 θ), 2 θ=5-60 °.
Fig. 1 b：Fig. 1 a spectrum datas.
Fig. 2：The DSC collection of illustrative plates of the gained Crystal form of metoprolol succinate sample of embodiment 1.
Fig. 3 a：The powder x-ray diffraction figure of the gained Crystal form of metoprolol succinate sample of embodiment 8.Axis of ordinates is represented
Diffracted intensity (cps), axis of abscissas represents the angle of diffraction (2 θ), 2 θ=5-60 °.
Fig. 3 b：Fig. 3 a spectrum datas.
Fig. 4：The DSC collection of illustrative plates of the gained Crystal form of metoprolol succinate sample of embodiment 8.
Embodiment
Embodiment 1：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 565ml, it is heated to reflux to product dissolving, in 1.5 hours
45 DEG C are cooled to, speed of agitator is 150 revs/min, insulated and stirred is cooled to 0 DEG C in 1.0 hours, 2.0 hours, insulation stands 5.0
Hour, crystal is separated out, suction filtration after vacuum drying, obtains white solid 131.05g, weight yield is 93.6%, and fusing point is 136.6
~137.4 DEG C.
Embodiment 2：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 280ml, it is heated to reflux to product dissolving, in 0.5 hour
55 DEG C are cooled to, speed of agitator is 100 revs/min, insulated and stirred is cooled to 5 DEG C in 0.5 hour, 1.5 hours, insulation stands 5.0
Hour, crystal being separated out, suction filtration after vacuum drying, obtains white solid 70.14g, weight yield is 50.1%, fusing point is 136.1~
136.7℃。
Embodiment 3：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 420ml, it is heated to reflux to product dissolving, in 1.5 hours
47 DEG C are cooled to, speed of agitator is 150 revs/min, insulated and stirred is cooled to -5 DEG C in 1.0 hours, 2.0 hours, insulation stands 2.0
Hour, crystal is separated out, suction filtration after vacuum drying, obtains white solid 133.42g, weight yield is 95.3%, and fusing point is 136.2
~136.8 DEG C.
Embodiment 4：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 700ml, it is heated to reflux to product dissolving, in 2.0 hours
40 DEG C are cooled to, speed of agitator is 250 revs/min, insulated and stirred is cooled to -5 DEG C in 2.5 hours, 2.5 hours, insulation stands 7.0
Hour, crystal is separated out, suction filtration after vacuum drying, obtains white solid 132.58g, weight yield is 94.7%, and fusing point is 136.9
~137.7 DEG C.
Embodiment 5：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 840ml, it is heated to reflux to product dissolving, in 0.5 hour
60 DEG C are cooled to, speed of agitator is 300 revs/min, insulated and stirred is cooled to -10 DEG C in 2.0 hours, 3.0 hours, insulation is stood
6.0 hours, crystal is separated out, suction filtration after vacuum drying, obtains white solid 133.42g, weight yield is 95.3%, and fusing point is
137.2~137.8 DEG C.
Embodiment 6：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 980ml, it is heated to reflux to product dissolving, in 1.0 hours
50 DEG C are cooled to, speed of agitator is 200 revs/min, insulated and stirred is cooled to 10 DEG C in 1.5 hours, 1.0 hours, insulation is stood
10.0 hours, crystal is separated out, suction filtration after vacuum drying, obtains white solid 126.14g, weight yield is 90.1%, and fusing point is
136.5~137.2 DEG C.
Embodiment 7：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 1400ml, it is heated to reflux to product dissolving, 1.0 hours
52 DEG C are inside cooled to, speed of agitator is 200 revs/min, insulated and stirred is cooled to 0 DEG C in 3.0 hours, 2.0 hours, insulation stands 4
Hour, crystal is separated out, suction filtration after vacuum drying, obtains white solid 119.28g, weight yield is 85.2%, and fusing point is 136.8
~137.4 DEG C.
Embodiment 8：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 560ml, it is heated to reflux to product dissolving, in 4.0 hours
0 DEG C is cooled to, speed of agitator is 70 revs/min, insulated and stirred 9.0 hours separates out crystal, and suction filtration after vacuum drying, obtains white solid
Body 129.92g, weight yield is 92.8%, and fusing point is 137.1~137.8 DEG C.
Embodiment 9：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 280ml, it is heated to reflux to product dissolving, in 3.0 hours
10 DEG C are cooled to, speed of agitator is 60 revs/min, insulated and stirred 10.0 hours separates out crystal, and suction filtration after vacuum drying, obtains white
Solid 77.28g, weight yield is 55.2%, and fusing point is 136.6~137.4 DEG C.
Embodiment 10：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 420ml, it is heated to reflux to product dissolving, in 4.5 hours
- 5 DEG C are cooled to, speed of agitator is 50 revs/min, insulated and stirred 12.0 hours separates out crystal, and suction filtration after vacuum drying, obtains white
Solid 131.32g, weight yield is 93.8%, and fusing point is 136.5~137.1 DEG C
Embodiment 11：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 700ml, it is heated to reflux to product dissolving, in 3.5 hours
5 DEG C are cooled to, speed of agitator is 40 revs/min, insulated and stirred 5.0 hours separates out crystal, and suction filtration after vacuum drying, obtains white solid
Body 130.06g, weight yield is 92.9%, and fusing point is 137.2~137.8 DEG C
Embodiment 12：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 840ml, it is heated to reflux to product dissolving, in 5.0 hours
- 10 DEG C are cooled to, speed of agitator is 30 revs/min, insulated and stirred 8.0 hours separates out crystal, and suction filtration after vacuum drying, obtains white
Solid 131.74g, weight yield is 94.1%, and fusing point is 136.4~137.1 DEG C
Embodiment 13：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 980ml, it is heated to reflux to product dissolving, in 3.5 hours
3 DEG C are cooled to, speed of agitator is 20 revs/min, insulated and stirred 15.0 hours separates out crystal, and suction filtration after vacuum drying, obtains white
Solid 127.68g, weight yield is 91.2%, and fusing point is 136.3~137.0 DEG C
Embodiment 14：The preparation of Crystal form of metoprolol succinate
By metroprolol succinate crude product 140g, plus absolute ethyl alcohol 1400ml, it is heated to reflux to product dissolving, 4.5 hours
- 8 DEG C are inside cooled to, speed of agitator is 80 revs/min, insulated and stirred 13.0 hours separates out crystal, and suction filtration after vacuum drying, obtains white
Color solid 114.1g, weight yield is 81.5%, and fusing point is 136.9~137.7 DEG C.
The Crystal form of metoprolol succinate sample that embodiment 1~14 is obtained enters to be about to X-ray diffraction analysis (referred to as：
XRD), the X-ray diffraction data of gained are as shown in table 1-1, table 1-2.
The crystal form samples X-ray diffraction data of table 1-1 embodiments 1~7
The crystal form samples X-ray diffraction data of table 1-2 embodiments 8~14
It can be seen that by table 1-1, table 1-2：The crystal form samples X-ray diffraction of the gained of embodiment 1~14 is in the θ of angle of reflection 2
There is peak at 7.4 ± 0.2,14.4 ± 0.2,20.4 ± 0.2,21.5 ± 0.2,24.4 ± 0.2, be same crystal formation.
It can be seen that by table 1-1：The peak position of the crystal form samples characteristic peak of the gained of embodiment 1~7, peak type almost complete one
Cause, be same crystal formation.
It can be seen that by table 1-2：Peak position, the peak type of the gained crystal form samples characteristic peak of embodiment 8~14 are almost completely the same,
It is same crystal formation.
Researcher of the present invention is devoted for years in the research of metroprolol succinate bulk drug, in order to obtain steady quality
The novel crystal forms of metroprolol succinate, inventor has carried out stability test to the crystal formation of the present invention.
Embodiment 15：Crystal form of metoprolol succinate stability test
1st, accelerated test
The accelerated test of this product is carried out according to (two annex XIX C of Chinese Pharmacopoeia version in 2010) relevant regulations.
Take each embodiment sample appropriate, simulation listing packaging is 75% ± 5% in 40 DEG C ± 2 DEG C of temperature, relative humidity
Placed 6 months under part, respectively at the 1st, 2,3,6 the end of month samplings, compare and other inspection targets are tested after outward appearance, as a result with 0 month
Data compare.Sample after accelerating 6 months is subjected to X-ray diffraction analysis (referred to as：XRD), observation and 0 month crystal formation whether one
Cause, accelerated test the results are shown in Table 2-1, table 2-2.
The crystal form samples accelerated test stability result table of table 2-1 embodiments 1~7
The crystal form samples accelerated test stability result table of table 2-2 embodiments 8~14
Accelerated test result shows：Under simulation listing terms of packing, each embodiment sample is in 40 DEG C ± 2 DEG C of temperature, phase
To humidity be 75% ± 5% under the conditions of place 6 months, every Testing index there are no significant change, meet regulation.
X-ray diffraction analysis result shows：The crystal formation of metroprolol succinate of the present invention accelerate 6 months after X-ray
Diffracting spectrum and 0 month collection of illustrative plates are completely the same, show that the crystal formation of the present invention is placed 6 months in acceleration environment, have good stability.
2nd, long-term experiment
The long term test of this product is carried out according to (the X C of two annex of Chinese Pharmacopoeia version in 2010 Ⅺ) relevant regulations.
Take each embodiment sample appropriate, simulation listing packaging is 60% ± 10% in 25 DEG C ± 2 DEG C of temperature, relative humidity
Under the conditions of place, in the 3rd, 6,9, respectively sampling once, was compared and other inspection targets was tested after outward appearance, as a result with 0 month data December
Compare.Sample after long-term 12 months is subjected to X-ray diffraction analysis (referred to as：XRD), observe whether consistent with 0 month crystal formation,
Long-term test results are shown in Table 3-1, table 3-2.
The crystal form samples long term test stability result table of table 3-1 embodiments 1~7
The crystal form samples long term test stability result table of table 3-2 embodiments 8~14
Long-term test results show：Each embodiment sample simulation listing terms of packing under, 25 DEG C ± 2 DEG C, it is relatively wet
Spend in the environment for 60% ± 10% and placed 12 months, the detection data of each moon were compared with 0 month data, indices are without aobvious
The change of work property.Result of the test shows：This product is more stable under the conditions of long term test.
X-ray diffraction analysis result shows：The crystal formation of metroprolol succinate of the present invention, the X- after long-term 12 months is penetrated
Ray diffraction diagram spectrum is completely the same with 0 month collection of illustrative plates, shows that the crystal formation of the present invention is placed 12 months in long-term conditions, has good stability.
Result above shows：The crystal formation of metroprolol succinate of the present invention, content height, low impurity content, steady quality, crystalline substance
Type is stable, can be used as bulk drug.
Claims (14)
1. a kind of Crystal form of metoprolol succinate, it is characterised in that radiated using Cu-K α, the X-ray represented with 2 θ angles (°)
Diffraction has peak in following position：7.4±0.2、14.4±0.2、20.4±0.2、21.5±0.2、24.4±0.2.
2. Crystal form of metoprolol succinate as claimed in claim 1, it is characterised in that radiated using Cu-K α, with 2 θ angles
The X-ray diffraction that (°) is represented has peak in following position：
(1)14.7±0.2、23.4±0.2、26.5±0.2；Or
(2)11.8±0.2、14.7±0.2、15.2±0.2、17.5±0.2、23.4±0.2、26.5±0.2、27.4±0.2、
32.2±0.2；Or
(3)11.2±0.2、11.8±0.2、12.5±0.2、13.4±0.2、14.7±0.2、15.2±0.2、17.5±0.2、
19.2±0.2、23.4±0.2、25.5±0.2、26.5±0.2、27.4±0.2、30.4±0.2、32.2±0.2、33.1±
0.2、34.9±0.2、35.6±0.2、36.5±0.2、37.6±0.2、37.9±0.2、38.5±0.2、39.8±0.2、
40.6±0.2、47.1±0.2、48.5±0.2、50.4±0.2。
3. Crystal form of metoprolol succinate as claimed in claim 1, it is characterised in that radiated using Cu-K α, with 2 θ angles
The X-ray diffraction that (°) is represented has peak in following position：
(1)14.1±0.2；Or
(2)14.1±0.2、14.7±0.2；Or
(3)14.1±0.2、14.7±0.2、21.2±0.2、23.0±0.2、23.4±0.2、26.5±0.2、27.4±0.2、
40.0±0.2。
4. any Crystal form of metoprolol succinate as described in claims 1 to 3, it is characterised in that means of differential scanning calorimetry absorbs heat
Maximum is at 136.0~138.0 DEG C.
5. a kind of bulk drug, includes any Crystal form of metoprolol succinate solid matter described in claims 1 to 3.
6. the preparation method of Crystal form of metoprolol succinate as claimed in claim 1, it is characterised in that by butanedioic acid Mei Tuoluo
You are added in absolute ethyl alcohol crude product, are heated to reflux to dissolving, are cooled to -10~10 DEG C, precipitation crystal is metroprolol succinate
Crystal form samples.
7. the preparation method of Crystal form of metoprolol succinate as claimed in claim 6, it is characterised in that by butanedioic acid Mei Tuoluo
Your crude product is added in absolute ethyl alcohol, is heated to reflux to dissolving, is cooled to 40~60 DEG C, insulated and stirred 0.5~3 hour, be cooled to-
10~10 DEG C, insulation stands 2~10 hours, and precipitation crystal is Crystal form of metoprolol succinate sample.
8. the preparation method of Crystal form of metoprolol succinate as claimed in claim 7, it is characterised in that described is cooled to 40
~60 DEG C, be to be cooled to 40~60 DEG C in 0.5~2 hour.
9. the preparation method of Crystal form of metoprolol succinate as claimed in claim 7, it is characterised in that described insulation is stirred
Mix, speed of agitator is 100~300 revs/min.
10. the preparation method of Crystal form of metoprolol succinate as claimed in claim 7, it is characterised in that it is described be cooled to-
10~10 DEG C, be to be cooled to -10~10 DEG C in 1.0~3.0 hours.
11. the preparation method of Crystal form of metoprolol succinate as claimed in claim 6, it is characterised in that hold in the palm butanedioic acid U.S.
Luo Er crude products are added in absolute ethyl alcohol, are heated to reflux to dissolving, are cooled to -10~10 DEG C, insulated and stirred 5~15 hours is separated out
Crystal is Crystal form of metoprolol succinate sample.
12. the preparation method of Crystal form of metoprolol succinate as claimed in claim 11, it is characterised in that described cooling
It is to be cooled to -10~10 DEG C in 3.0~5.0 hours to -10~10 DEG C.
13. the preparation method of Crystal form of metoprolol succinate as claimed in claim 11, it is characterised in that described insulation is stirred
Mix, speed of agitator is 20~80 revs/min.
14. the preparation method of any Crystal form of metoprolol succinate as described in claim 6 to 13, it is characterised in that amber
The weigh-volume ratio of sour metoprolol crude product and absolute ethyl alcohol can be 1:2~10, preferably 1:3~8.
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| CN201210208496.2A CN103508909A (en) | 2012-06-25 | 2012-06-25 | Crystal form of metoprolol succinate and preparation method thereof |
| CN201710181419.5A CN106995381A (en) | 2012-06-25 | 2012-06-25 | A kind of Crystal form of metoprolol succinate and preparation method thereof |
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| CN104326926B (en) * | 2014-09-15 | 2017-06-20 | 浙江理工大学 | A kind of novel crystal forms of metroprolol succinate and preparation method thereof |
| CN104761458A (en) * | 2015-04-22 | 2015-07-08 | 河南中帅医药科技股份有限公司 | S-metoprolol succinate crystal form and preparation method thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050107635A1 (en) * | 2003-11-14 | 2005-05-19 | Mehra Janakraj K. | Metoprolol manufacturing process |
| WO2007141593A2 (en) * | 2005-12-23 | 2007-12-13 | Medichem, S.A. | Process for the preparation of metoprolol and its salts |
| CN101607918A (en) * | 2008-06-16 | 2009-12-23 | 北京德众万全药物技术开发有限公司 | A kind of preparation method of metoprolol |
| WO2010058407A2 (en) * | 2007-04-25 | 2010-05-27 | Polydrug Laboratories Private Limited | Process of making salts of metoprolol |
| CN102295569A (en) * | 2011-07-04 | 2011-12-28 | 南京工业大学 | Method for preparing (S) -metoprolol succinate |
| CN102432476A (en) * | 2010-09-29 | 2012-05-02 | 湖南康普医药研究院 | Method for preparing metoprolol succinate on scale |
| CN102503843A (en) * | 2011-10-28 | 2012-06-20 | 山东阿如拉药物研究开发有限公司 | Preparation method for metoprolol salt |
-
2012
- 2012-06-25 CN CN201210208496.2A patent/CN103508909A/en active Pending
- 2012-06-25 CN CN201710181419.5A patent/CN106995381A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050107635A1 (en) * | 2003-11-14 | 2005-05-19 | Mehra Janakraj K. | Metoprolol manufacturing process |
| WO2007141593A2 (en) * | 2005-12-23 | 2007-12-13 | Medichem, S.A. | Process for the preparation of metoprolol and its salts |
| WO2010058407A2 (en) * | 2007-04-25 | 2010-05-27 | Polydrug Laboratories Private Limited | Process of making salts of metoprolol |
| CN101607918A (en) * | 2008-06-16 | 2009-12-23 | 北京德众万全药物技术开发有限公司 | A kind of preparation method of metoprolol |
| CN102432476A (en) * | 2010-09-29 | 2012-05-02 | 湖南康普医药研究院 | Method for preparing metoprolol succinate on scale |
| CN102295569A (en) * | 2011-07-04 | 2011-12-28 | 南京工业大学 | Method for preparing (S) -metoprolol succinate |
| CN102503843A (en) * | 2011-10-28 | 2012-06-20 | 山东阿如拉药物研究开发有限公司 | Preparation method for metoprolol salt |
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