CN102351784A - Benidipine hydrochloride crystal form and application thereof - Google Patents
Benidipine hydrochloride crystal form and application thereof Download PDFInfo
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- CN102351784A CN102351784A CN2011103203856A CN201110320385A CN102351784A CN 102351784 A CN102351784 A CN 102351784A CN 2011103203856 A CN2011103203856 A CN 2011103203856A CN 201110320385 A CN201110320385 A CN 201110320385A CN 102351784 A CN102351784 A CN 102351784A
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Abstract
The invention belongs to the technical field of medicine chemistry and particularly relates to a benidipine hydrochloride crystal form and an application thereof, which are characterized in that 2theta of the used Cu-Ka radiated X diffraction powder diffraction optical spectrum has the characteristic peak at 7.08 degrees, 8.34 degrees, 9.58 degrees, 10.14 degrees, 12.02 degrees, 12.98 degrees, 13.58 degrees, 15.06 degrees, 16.82 degrees, 17.18 degrees, 17.62 degrees, 19.02 degrees, 20.5 degrees, 20.64 degrees, 21.8 degrees, 23.28 degrees, 23.64 degrees and 23.74 degrees. Compared with the prior art, the benidipine hydrochloride crystal form has the advantages that the purity is high (higher than 99.3), the stability is good, the absorption is good, the benidipine hydrochloride crystal form can be easily crushed into powder with large specific surface area after being dried, the configuration and the application of medicine composition are easy to realize, a method for preparing the benidipine hydrochloride crystal form (A) is simple, the yield is high, used solvents have an environment-protection effect and low toxicity, and the benidipine hydrochloride crystal form is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, a kind of specifically KW-3049 crystal formation and application thereof.
Background technology
Medicine when crystallization owing to receive the influence of various factors; Its intramolecularly or intermolecular bonding mode are changed; It is different to cause molecule or atom to be arranged at lattice vacancy; Form different crystalline structures; The different crystal forms of same medicine possibly have remarkable difference at aspects such as outward appearance, solubleness, fusing point, dissolution rate, bioequivalences; Influence stability of drug, bioavailability and curative effect; This kind phenomenon is particularly evident what show aspect the oral solid type preparation, and medicine different crystal forms phenomenon is one of important factor that influences drug quality and clinical efficacy.Therefore, the research to the medicine crystal formation is the most important thing in the drug research process.
KW-3049 (Benidipine), chemical being called (R, R)-(+/-)-2,6-dimethyl-4-(3-oil of mirbane)-1,4-dihydro-3,5-pyridine dicarboxyl-methyl-(R)-1-benzyl-3-piperidyl ester.Its chemical structure as shown in the formula
(I):
Molecular formula is C
28H
32ClN
3O
6, molecular weight is 541.20.KW-3049 is the dihydropyridines calcium antagonists.Pharmacodynamics shows that the dihydropyridines calcium antagonists can suppress to stride stream in the film calcium; Reduce endocellular liberation calcium concn and utilization ratio; Thereby can optionally relax blood vessel; Reduce its resistance and produce hypotensive effect; Can also enlarge markedly simultaneously the volume of blood flow of vertebra artery coronarius, can vasodilator with increase coronary flow, its hypotensive effect is better than similar dihydropyridines calcium antagonistss such as nifedipine; Oral post-absorption is rapid, and the transformation period is about two hours.Be usually used in treating hypertension and stenocardia.
The method of KW-3049 preparation is disclosed in EP0106275; Back JP 2007008819 discloses industrial production process; Deliver the physicochemical property and the stability study of KW-3049 on the Japan consonance Kyowa Hakko drug research place Arzneimittelforschung magazine, Japanese Pharmacopoeia 15 editions records this medicine.Above-mentioned document provides its infrared spectra (IR) of KW-3049 at 3170cm
-1, 3066 cm
-1, 2950cm
-1, 2523cm
-1, 1694cm
-1, 1666cm
-1, 1642cm
-1, 1533cm
-1, 1491cm
-1, 1432cm
-1, 1348cm
-1, 1299cm
-1, 1218cm
-1, 1116cm
-1, 1088cm
-1, 1017cm
-1, 982cm
-1, 960cm
-1, 902cm
-1, 827cm
-1, 745cm
-1, 706cm
-1There is absorption peak at the place.Shown in accompanying drawing 1; 2 θ of the X-ray diffracting spectrum of KW-3049 crystal formation have characteristic peak at 8.06 °, 10.4 °, 12.64 °, 17.38 °, 19.48 °, 24.1 °, 32.36 °, as shown in Figure 2; The dsc analysis of KW-3049 crystal formation has endothermic signal in 186-192 ℃ of scope, peak temperature is 188.6 ℃, shown in accompanying drawing 3.
Summary of the invention
The present invention is directed to the shortcoming and defect that exists in the prior art, it is high to propose a kind of crystal formation purity, and good stability is the crystalline powder shape, is easy to the KW-3049 crystal formation method for making pharmaceutical composition and the purposes of drug regimen and configuration and use.
The present invention can reach through following measure:
A kind of KW-3049 crystal formation is characterized in that the alpha-emitting X diffraction of Cu-K powdery diffractometry spectrographic 2 θ of its use have characteristic peak at 7.08 °, 8.34 °, 9.58 °, 10.14 °, 12.02 °, 12.98 °, 13.58 °, 15.06 °, 16.82 °, 17.18 °, 17.62 °, 19.02 °, 20.5 °, 20.64 °, 21.8 °, 23.28 °, 23.64 °, 23.74 °.
A kind of KW-3049 crystal formation of the present invention, the infrared spectra that adopts KBr compressing tablet-transmission method mensuration is at 3420cm
-1, 3078 cm
-1, 2948 cm
-1, 2484 cm
-1, 1698 cm
-1, 1647 cm
-1, 1524 cm
-1, 1489 cm
-1, 1433 cm
-1, 1382 cm
-1, 1348 cm
-1, 1314 cm
-1, 1273 cm
-1, 1211 cm
-1, 1118 cm
-1, 1095 cm
-1, 1018 cm
-1, 923 cm
-1, 826 cm
-1, 806 cm
-1, 781 cm
-1, 749 cm
-1, 702 cm
-1, 681 cm
-1, 619 cm
-1Charateristic avsorption band is arranged.
A kind of KW-3049 crystal formation of the present invention, in the dsc analysis chart, this new crystal has endothermic signal in 162.5-180.4 ℃ of scope, and peak temperature is 174.93 ℃.
A kind of preparation method of above-mentioned KW-3049 crystal formation; It is characterized in that comprising the steps: the KW-3049 organic solvent dissolution, reflux is treated to stop reflux after the KW-3049 dissolving fully; Slowly leave standstill cooling and cultivate, separate out and obtain the KW-3049 crystal formation.
The preparation method of a kind of KW-3049 crystal formation of the present invention, the said organic solvent that is used to dissolve KW-3049 is ethanol, ethyl acetate, acetone, methyl alcohol, acetonitrile, tetrahydrofuran (THF), methylene dichloride, ether.The mixture of one or more in Virahol, chloroform and the toluene.
The preparation method of a kind of KW-3049 crystal formation of the present invention, the temperature under the said reflux condition is 40-110 ℃.
The preparation method of a kind of KW-3049 crystal formation of the present invention, the temperature of cooling crystallization are 0-5 ℃.
The preparation method of a kind of KW-3049 crystal formation of the present invention, in the process of with an organic solvent dissolving the KW-3049 raw material, the solute quality: the scope of solvent volume is preferably 1:5-1:8 at 1:1-1:10.
A kind of pharmaceutical composition is characterized in that: contain above-mentioned KW-3049 crystal formation in the said drug regimen.
The application of acid hydrochloride salt benidipine crystal formation in treatment hypertension and angina drug that the present invention is above-mentioned compared with prior art, has significant curative effect.
The present invention compared with prior art has following outstanding advantage and beneficial effect: 1. high (> 99.3 of KW-3049 crystal formation of the present invention (A) purity); Stablize; Good absorption is easy to be ground into the big powder of surface-area after the drying, be easy to the configuration and the use of pharmaceutical composition; 2. the present invention prepares that the method for KW-3049 crystal formation (A) is simple, exhausted, preparation condition is gentle, and yield is high, uses the solvent environmental protection, and toxicity is extremely low, is fit to large-scale commercial production.
Description of drawings:
Accompanying drawing 1 is an infrared spectra of pressing the KW-3049 crystal formation of literature method preparation.
Accompanying drawing 2 is an X-ray diffracting spectrum of pressing the KW-3049 crystal formation of literature method preparation.
Accompanying drawing 3 is a dsc analysis chart of pressing the KW-3049 crystal formation of literature method preparation.
Accompanying drawing 4 is the X-ray diffracting spectrum of KW-3049 crystal formation (A) among the present invention.
Accompanying drawing 5 compares collection of illustrative plates for KW-3049 crystal formation (A) among the present invention and existing KW-3049 crystal form X-ray diffraction; Wherein Fig. 5 a is that the X-of KW-3049 crystal formation (A) is accused of diffractogram, and Fig. 5 b is existing KW-3049 crystal form X-x ray diffration pattern x.
Accompanying drawing 6 is the infrared spectra of KW-3049 crystal formation (A) among the present invention.
Accompanying drawing 7 is KW-3049 crystal formation (A) among the present invention and existing KW-3049 crystal formation infrared spectra difference comparison diagram.
Accompanying drawing 8 is the dsc analysis chart of KW-3049 crystal formation (A) among the present invention.
Accompanying drawing 9 is analyzed comparison diagram for KW-3049 crystal formation (A) among the present invention and existing KW-3049 crystal formation differential scanning calorimeter method; Wherein accompanying drawing 9a is the hot method analysis chart of KW-3049 crystal formation (A) differential scanning, and accompanying drawing 9b is existing KW-3049 crystal formation differential scanning calorimeter method analysis chart.
Embodiment:
The present invention is further illustrated below in conjunction with accompanying drawing and embodiment:
The present invention is directed to the shortcoming and defect that exists in the prior art; It is high to propose a kind of crystal formation purity; Good stability; Be the crystalline powder shape; Be easy to the KW-3049 crystal formation of drug regimen and configuration and use; This crystal formation is named the type into A; Existing KW-3049 crystal formation is remembered in presents and is made Type B; Type B is a prior art; This does not give unnecessary details; The A type be characterised in that this crystal formation at X diffraction powdery diffractometry spectrographic 2 θ at 7.08 °; 8.34 °; 9.58 °; 10.14 °; 12.02 °; 12.98 °; 13.58 °; 15.06 °; 16.82 °; 17.18 °; 17.62 °; 19.02 °; 20.5 °; 20.64 °; 21.8 °; 23.28 °; 23.64 °; 23.74 ° characteristic peak is arranged, shown in accompanying drawing 4.
The X-ray diffractogram of crystal formation of the present invention is to be 1.54 dusts at wavelength, measures down with the K α spectral line of Cu target; Shown in accompanying drawing 5, KW-3049 crystal formation of the present invention (A), its X-ray diffractogram have significant difference with bibliographical information KW-3049 crystal form X x ray diffration pattern x on the quantity at peak type and peak.
Shown in accompanying drawing 6, KW-3049 crystal formation of the present invention (A), its infrared spectra (IR) is at 3420cm
-1, 3078 cm
-1, 2948 cm
-1, 2484 cm
-1, 1698 cm
-1, 1647 cm
-1, 1524 cm
-1, 1489 cm
-1, 1433 cm
-1, 1382 cm
-1, 1348 cm
-1, 1314 cm
-1, 1273 cm
-1, 1211 cm
-1, 1118 cm
-1, 1095 cm
-1, 1018 cm
-1, 923 cm
-1, 826 cm
-1, 806 cm
-1, 781 cm
-1, 749 cm
-1, 702 cm
-1, 681 cm
-1, 619 cm
-1There is absorption peak at the place.
Shown in accompanying drawing 7, KW-3049 crystal formation of the present invention (A), its infrared spectra (IR) is at 1698 cm
-1It is unimodal that the place has characteristic, compares with the KW-3049 crystal formation in the bibliographical information, and its infrared spectra (IR) is at 1694 cm
-1, 1666 cm
-1Characteristic is bimodal, has significantly confirmed two kinds of qualitative differences of crystal formation.
Like accompanying drawing 8, shown in KW-3049 crystal formation of the present invention (A), its dsc is analyzed, and in 162.5-180.4 ℃ of scope, endothermic signal is arranged, peak temperature is 174.93 ℃; Shown in accompanying drawing 9, the dsc analysis of the KW-3049 crystal formation of bibliographical information has endothermic signal in 186-192 ℃ of scope, and peak temperature is 188.6 ℃; Thereby two kinds of qualitative differences of crystal formation have been confirmed significantly.
The present invention also provides the preparation method of above-mentioned crystal formation, and this preparation method and prior art ratio have that technology is simple, a mild condition, the high significant advantage of yield.
A kind of preparation method of above-mentioned KW-3049 crystal formation comprises the steps:
(1) KW-3049 raw material (containing existing KW-3049 crystal form B) is used organic solvent dissolution and reflux;
(2) separate out crystal, treat that above-mentioned KW-3049 material dissolution fully after, stop reflux, under 0～5 ℃ condition, left standstill, cool off 6～12 hours, crystal is separated out;
(3) gained mixture in the step (2) is carried out suction filtration, and the gained filtrate is carried out drying treatment, obtain the KW-3049 crystal formation.
The raw material that is used to prepare KW-3049 crystal formation (A) can prepare through the document disclosed method.
The preparing method's all kinds of SOLVENTS or the condition of above-mentioned KW-3049 crystal formation (A) are following: because the specific physical character of KW-3049 crystal formation (A); The said organic solvent that is used for dissolving KW-3049 can be selected one or more mixture of ethanol, ethyl acetate, acetone, methyl alcohol, acetonitrile, tetrahydrofuran (THF), methylene dichloride, ether, Virahol, chloroform and toluene; Preferred alcohol wherein; The acetone blending ratio is volume ratio 1:20; Perhaps ethanol, the ethyl acetate blending ratio is volume ratio 1:20.
The solvent of the KW-3049 crystal formation (A) described in the present invention is preferably used ethanol, and its concentration is 80～100%.
The present invention is used for separating out crystalline at last and describes the alcoholic acid usage quantity, should be the threshold value that KW-3049 forms saturated solution, and 5～8 times (V/Ws) of the volumetric usage (V) of the solvent of choosing for KW-3049 weight (W) wherein can be arranged.
The drying conditions that is used for the filtrate that suction filtration obtains described in the present invention, for practicing thrift the removal of test period and dissolvent residual effectively, for example shown in the experiment, wherein can be preferably with vacuum-drying under 70～90 ℃ of conditions, be 24 ~ 30 hours time of drying.
The invention allows for a kind of pharmaceutical composition, it is characterized in that: contain KW-3049 crystal formation according to the invention in the said pharmaceutical composition.
Said pharmaceutical composition can be and contains KW-3049 crystal formation of the present invention and KW-3049 indefiniteness powdered mixture or contain KW-3049 crystal formation of the present invention and other KW-3049 crystal formation mixtures for the moment.
Said pharmaceutical composition can also be to contain acceptable carrier and/or vehicle on one or more medicines.
That said pharmaceutical composition goes for is oral, use on suction, parenterai administration or surface; Formulation includes but not limited to injection, pharmaceutical solutions, tablet, capsule, granule etc.; On curative effect, can be used to treat hypertension and angina pectoris treatment effectively.
The present invention realizes through following technical scheme, but the working of an invention mode is not limited thereto.
Embodiment 1, the KW-3049 crystal formation
(A)Preparation:
Get bulk drug 10g and place the 1000ml eggplant type flask; Add 50ml dehydrated alcohol (raw material: solvent=1:5) simultaneously; 78 ℃ of following oil baths reflux and make bulk drug all be dissolved in ethanol; After the filtered while hot; Leave standstill 0-5 ℃ of lucifuge; Suction filtration after 12 hours, 70 ℃ of vacuum-drying 24 hours obtains the KW-3049 crystal formation
(A)Product 8.5g, purity 99.5%.
Embodiment 2, the KW-3049 crystal formation
(A)Preparation:
Get bulk drug 10g and place the 1000ml eggplant type flask; 95% ethanol (the raw material: solvent=1:5) that adds 50ml simultaneously; 78 ℃ of following oil baths reflux and make bulk drug all be dissolved in ethanol; After the filtered while hot; Leave standstill 0-5 ℃ of lucifuge; Suction filtration after 12 hours, 70 ℃ of vacuum-drying 24 hours obtains the KW-3049 crystal formation
(A)Product 8.6g, purity 99.5%.
The foregoing description is a preferred embodiment of the present invention; But embodiment of the present invention is not restricted to the described embodiments; Other any do not deviate from change, the modification made under spirit of the present invention and the principle, substitutes, combination, simplify; All should be the substitute mode of equivalence, be included within protection scope of the present invention.
The present invention compared with prior art has following outstanding advantage and beneficial effect: 1. high (> 99.3 of KW-3049 crystal formation of the present invention (A) purity); Stablize; Good absorption is easy to be ground into the big powder of surface-area after the drying, be easy to the configuration and the use of pharmaceutical composition; 2. the present invention prepares that the method for KW-3049 crystal formation (A) is simple, exhausted, preparation condition is gentle, and yield is high, uses the solvent environmental protection, and toxicity is extremely low, is fit to large-scale commercial production.
Claims (10)
1. a KW-3049 crystal formation is characterized in that the alpha-emitting X diffraction of Cu-K powdery diffractometry spectrographic 2 θ of its use have characteristic peak at 7.08 °, 8.34 °, 9.58 °, 10.14 °, 12.02 °, 12.98 °, 13.58 °, 15.06 °, 16.82 °, 17.18 °, 17.62 °, 19.02 °, 20.5 °, 20.64 °, 21.8 °, 23.28 °, 23.64 °, 23.74 °.
2. a kind of KW-3049 crystal formation according to claim 1 is characterized in that, the infrared spectra that adopts KBr compressing tablet-transmission method mensuration is at 3420cm
-1, 3078 cm
-1, 2948 cm
-1, 2484 cm
-1, 1698 cm
-1, 1647 cm
-1, 1524 cm
-1, 1489 cm
-1, 1433 cm
-1, 1382 cm
-1, 1348 cm
-1, 1314 cm
-1, 1273 cm
-1, 1211 cm
-1, 1118 cm
-1, 1095 cm
-1, 1018 cm
-1, 923 cm
-1, 826 cm
-1, 806 cm
-1, 781 cm
-1, 749 cm
-1, 702 cm
-1, 681 cm
-1, 619 cm
-1Charateristic avsorption band is arranged.
3. according to claim 1,2 described a kind of KW-3049 crystal formations, it is characterized in that in the dsc analysis chart this new crystal has endothermic signal in 162.5-180.4 ℃ of scope, peak temperature is 174.93 ℃.
4. preparation method like claim 1,2 each described KW-3049 crystal formations; It is characterized in that comprising the steps: that KW-3049 (B) uses organic solvent dissolution; Reflux; Treat to stop reflux after the KW-3049 dissolving fully; Slowly leave standstill cooling and cultivate, separate out and obtain KW-3049 crystal formation (A).
5. the preparation method of a kind of KW-3049 crystal formation according to claim 4, the mixture of one or more that it is characterized in that the said organic solvent that is used for dissolving KW-3049 (B) is ethanol, ethyl acetate, acetone, methyl alcohol, acetonitrile, tetrahydrofuran (THF), methylene dichloride, ether, Virahol, chloroform and toluene.
6. the preparation method of a kind of KW-3049 crystal formation according to claim 5 is characterized in that the temperature under the said reflux condition is 40-110 ℃.
7. the preparation method of a kind of KW-3049 crystal formation according to claim 5, the temperature that it is characterized in that cooling crystallization is 0-5 ℃.
8. the preparation method of a kind of KW-3049 crystal formation according to claim 5, it is characterized in that wherein solute quality: the scope of solvent volume is at 1:1-1:10.
9. a pharmaceutical composition is characterized in that: contain claim 1,2 said KW-3049 crystal formations in the said pharmaceutical composition.
10. according to claim 1, the application of 2 described acid hydrochloride salt benidipine crystal formations in treatment hypertension and angina drug.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110320385 CN102351784B (en) | 2011-10-20 | 2011-10-20 | Benidipine hydrochloride crystal form and application thereof |
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|---|---|---|---|
| CN 201110320385 CN102351784B (en) | 2011-10-20 | 2011-10-20 | Benidipine hydrochloride crystal form and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679416A (en) * | 2020-12-31 | 2021-04-20 | 济南朗科医药技术有限公司 | Preparation method of benidipine hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0106275A2 (en) * | 1982-10-15 | 1984-04-25 | Kyowa Hakko Kogyo Co., Ltd. | 1,4-Dihydropyridine derivatives |
| JP3763538B1 (en) * | 2005-06-28 | 2006-04-05 | ダイト株式会社 | Industrial production method of high-purity benidipine hydrochloride |
| JP4544895B2 (en) * | 2004-03-31 | 2010-09-15 | 大日本印刷株式会社 | Method for producing dihydropyridine derivatives |
-
2011
- 2011-10-20 CN CN 201110320385 patent/CN102351784B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0106275A2 (en) * | 1982-10-15 | 1984-04-25 | Kyowa Hakko Kogyo Co., Ltd. | 1,4-Dihydropyridine derivatives |
| JP4544895B2 (en) * | 2004-03-31 | 2010-09-15 | 大日本印刷株式会社 | Method for producing dihydropyridine derivatives |
| JP3763538B1 (en) * | 2005-06-28 | 2006-04-05 | ダイト株式会社 | Industrial production method of high-purity benidipine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 白树华: "新型长效钙拮抗剂-盐酸贝尼地平及其类似物的合成", 《沈阳药科大学硕士学位论文》, 24 May 2005 (2005-05-24) * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679416A (en) * | 2020-12-31 | 2021-04-20 | 济南朗科医药技术有限公司 | Preparation method of benidipine hydrochloride |
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Effective date of registration: 20180410 Address after: 264200 private and private economic Industrial Park, Yang Ting Town, Weihai, Shandong Patentee after: Shandong wellso Pharmaceutical Co. Ltd. Address before: 264200 No. 692 Taishan Road, Huancui District, Weihai, Shandong (Huaxia Industrial Park) Patentee before: Huaxia Pharmaceutical Group Co., Ltd. |