CN102351784B - Benidipine hydrochloride crystal form and application thereof - Google Patents
Benidipine hydrochloride crystal form and application thereof Download PDFInfo
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- CN102351784B CN102351784B CN 201110320385 CN201110320385A CN102351784B CN 102351784 B CN102351784 B CN 102351784B CN 201110320385 CN201110320385 CN 201110320385 CN 201110320385 A CN201110320385 A CN 201110320385A CN 102351784 B CN102351784 B CN 102351784B
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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, specifically a kind of benidipine hydrochloride crystal form and application thereof.
Background technology
Medicine when crystallization owing to be subject to the impact of various factors, make in its molecule or intermolecular bonding mode changes, 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 may have remarkable difference at aspects such as outward appearance, solubleness, fusing point, dissolution rate, bioequivalences, affect stability, bioavailability and the curative effect of medicine, 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 affects drug quality and clinical efficacy.Therefore, be the most important thing in the drug research process to the research of drug crystal forms.
KW-3049 (Benidipine), chemistry (R, R) by name-(+/-)-2,6-dimethyl-4-(3-oil of mirbane)-Isosorbide-5-Nitrae-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 Dihydropyridine calcium antagonist.Pharmacodynamics shows that Dihydropyridine calcium antagonist can suppress stream in the cross-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 and increase coronary flow, its hypotensive effect is better than the similar Dihydropyridine calcium antagonists such as nifedipine, oral rear 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, rear JP 2007008819 discloses industrial production process, deliver 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.As shown in Figure 1; 2 θ of the X-ray diffracting spectrum of benidipine hydrochloride crystal form 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 benidipine hydrochloride crystal form has endothermic signal in 186-192 ℃ of scope, peak temperature is 188.6 ℃, as shown in Figure 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 benidipine hydrochloride crystal form method for making pharmaceutical composition and the purposes of drug regimen and configuration and use.
The present invention can reach by following measures:
A kind of benidipine hydrochloride crystal form is characterized in that 2 θ of the alpha-emitting X diffraction of the Cu-K powdery diffractometry spectrum 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 benidipine hydrochloride crystal form of the present invention adopts the infrared spectra of KBr compressing tablet-transmission method mensuration 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 benidipine hydrochloride crystal form 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 benidipine hydrochloride crystal form, it is characterized in that comprising the steps: the KW-3049 organic solvent dissolution, reflux, stopped heating refluxes behind the KW-3049 dissolve complete, slowly leave standstill cooling and cultivate, separate out and obtain benidipine hydrochloride crystal form.
The preparation method of a kind of benidipine hydrochloride crystal form of the present invention, described organic solvent for the dissolving 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 benidipine hydrochloride crystal form of the present invention, the temperature under the described reflux condition is 40-110 ℃.
The preparation method of a kind of benidipine hydrochloride crystal form of the present invention, the temperature of cooling crystallization are 0-5 ℃.
The preparation method of a kind of benidipine hydrochloride crystal form 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 benidipine hydrochloride crystal form in the described 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 benidipine hydrochloride crystal form of the present invention (A) purity), stablize, good absorption is easy to be ground into the large powder of surface-area after the drying, be easy to configuration and the use of pharmaceutical composition; 2. the present invention prepares that the method for benidipine hydrochloride crystal form (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 the infrared spectra of pressing the benidipine hydrochloride crystal form of literature method preparation.
Accompanying drawing 2 is the X-ray diffracting spectrum of pressing the benidipine hydrochloride crystal form of literature method preparation.
Accompanying drawing 3 is the dsc analysis chart of pressing the benidipine hydrochloride crystal form of literature method preparation.
Accompanying drawing 4 is the X-ray diffracting spectrum of benidipine hydrochloride crystal form (A) among the present invention.
Accompanying drawing 5 is benidipine hydrochloride crystal form (A) among the present invention and existing benidipine hydrochloride crystal form X-ray diffraction Comparative map, wherein Fig. 5 a is that the X-of benidipine hydrochloride crystal form (A) is accused of diffractogram, and Fig. 5 b is existing benidipine hydrochloride crystal form x-ray diffraction pattern.
Accompanying drawing 6 is the infrared spectra of benidipine hydrochloride crystal form (A) among the present invention.
Accompanying drawing 7 is benidipine hydrochloride crystal form (A) among the present invention and existing benidipine hydrochloride crystal form infrared spectra difference comparison diagram.
Accompanying drawing 8 is the dsc analysis chart of benidipine hydrochloride crystal form (A) among the present invention.
Accompanying drawing 9 is analyzed comparison diagram for the hot method of benidipine hydrochloride crystal form (A) among the present invention and existing benidipine hydrochloride crystal form differential scanning, wherein accompanying drawing 9a is the hot method analysis chart of benidipine hydrochloride crystal form (A) differential scanning, and accompanying drawing 9b is the existing hot method analysis chart of benidipine hydrochloride crystal form differential scanning.
Embodiment:
The present invention is further illustrated below in conjunction with drawings and Examples:
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 benidipine hydrochloride crystal form of drug regimen and configuration and use, this crystal formation is named the type into A, existing benidipine hydrochloride crystal form is denoted as Type B in presents, Type B is prior art, this does not give unnecessary details, the A type be characterised in that this crystal formation at 2 θ of X diffraction powdery diffractometry spectrum 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, as shown in Figure 4.
The X-ray diffractogram of crystal formation of the present invention is to be 1.54 dusts at wavelength, measures under the K α spectral line with the Cu target; As shown in Figure 5, benidipine hydrochloride crystal form of the present invention (A), its X-ray diffractogram have significant difference with bibliographical information benidipine hydrochloride crystal form X-ray diffractogram on the quantity at peak type and peak.
As shown in Figure 6, benidipine hydrochloride crystal form 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.
As shown in Figure 7, benidipine hydrochloride crystal form of the present invention (A), its infrared spectra (IR) is at 1698 cm
-1It is unimodal that the place has characteristic, compares with the benidipine hydrochloride crystal form 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.
Such as accompanying drawing 8, shown in benidipine hydrochloride crystal form 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 ℃; As shown in Figure 9, the dsc analysis of the benidipine hydrochloride crystal form 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 has that technique is simple, a mild condition, the high significant advantage of yield compared with the prior art.
A kind of preparation method of above-mentioned benidipine hydrochloride crystal form comprises the steps:
(1) KW-3049 raw material (containing existing benidipine hydrochloride crystal form B) is used organic solvent dissolution and reflux;
(2) crystallize out, after above-mentioned KW-3049 material dissolution was complete, stopped heating refluxed, and leaves standstill, cools off under 0～5 ℃ condition 6～12 hours, and 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 benidipine hydrochloride crystal form.
Raw material for the preparation of benidipine hydrochloride crystal form (A) can prepare by the disclosed method of document.
Preparation method's all kinds of SOLVENTS or the condition of above-mentioned benidipine hydrochloride crystal form (A) are as follows: because the specific physical character of benidipine hydrochloride crystal form (A), described organic solvent for the 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 benidipine hydrochloride crystal form described in the present invention (A) is preferably used ethanol, and its concentration is 80～100%.
The present invention is used for the usage quantity of the ethanol of describing of last crystallization, should be the threshold value that KW-3049 forms saturated solution, wherein can have the volumetric usage (V) of the solvent of choosing to be 5～8 times (V/W) of KW-3049 weight (W).
The drying conditions of the filtrate that obtains for suction filtration described in the present invention, for effectively saving the removal of test period and dissolvent residual, shown in for example testing, 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 benidipine hydrochloride crystal form of the present invention in the described pharmaceutical composition.
Described pharmaceutical composition can be and contains benidipine hydrochloride crystal form of the present invention and KW-3049 indefiniteness powdered mixture or contain benidipine hydrochloride crystal form of the present invention and other benidipine hydrochloride crystal form mixtures for the moment.
Described pharmaceutical composition can also be to contain acceptable carrier and/or vehicle on one or more medicines.
That described 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 effectively be used for the treatment of hypertension and angina pectoris treatment.
The present invention is achieved through the following technical solutions, but the working of an invention mode is not limited to this.
Embodiment 1, benidipine hydrochloride crystal form
(A)Preparation:
Get bulk drug 10g and place the 1000ml eggplant type flask, add simultaneously 50ml dehydrated alcohol (raw material: solvent=1:5), 78 ℃ of lower 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 benidipine hydrochloride crystal form
(A)Product 8.5g, purity 99.5%.
Embodiment 2, benidipine hydrochloride crystal form
(A)Preparation:
Get bulk drug 10g and place the 1000ml eggplant type flask, 95% ethanol (the raw material: solvent=1:5) that adds simultaneously 50ml, 78 ℃ of lower 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 benidipine hydrochloride crystal form
(A)Product 8.6g, purity 99.5%.
Above-described embodiment is preferred embodiment of the present invention; but embodiments of the present invention are 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 benidipine hydrochloride crystal form of the present invention (A) purity), stablize, good absorption is easy to be ground into the large powder of surface-area after the drying, be easy to configuration and the use of pharmaceutical composition; 2. the present invention prepares that the method for benidipine hydrochloride crystal form (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 (5)
1. benidipine hydrochloride crystal form, 2 θ that it is characterized in that the alpha-emitting X diffraction of the Cu-K powdery diffractometry spectrum 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 °, in the dsc analysis chart, this new crystal has endothermic signal in 162.5-180.4 ℃ of scope, peak temperature is 174.93 ℃.
2. a kind of benidipine hydrochloride crystal form according to claim 1 is characterized in that, adopts the infrared spectra of KBr compressing tablet-transmission method mensuration 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. preparation method such as claim 1,2 each described benidipine hydrochloride crystal forms, it is characterized in that comprising the steps: the KW-3049 organic solvent dissolution, reflux, stopped heating refluxes behind the KW-3049 dissolve complete, slowly leaving standstill cooling cultivates, separate out and obtain such as benidipine hydrochloride crystal form as described in any one in claim 1 or 2, described organic solvent for the dissolving KW-3049 is ethanol, the temperature of cooling crystallization is 0-5 ℃, wherein the solute quality: the scope of solvent volume is at 1:1-1:10.
4. a pharmaceutical composition is characterized in that: contain claim 1,2 described benidipine hydrochloride crystal forms in the described pharmaceutical composition.
5. purposes for preparing hypertension or angina drug such as claim 1,2 described benidipine hydrochloride crystal forms.
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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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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. |
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