CN112326843A - Quantitative method of related substances of vinpocetine - Google Patents
Quantitative method of related substances of vinpocetine Download PDFInfo
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Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
- G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The invention relates to a quantitative method of related substances of vinpocetine, belonging to the field of pharmaceutical analysis, and having characteristic absorption peaks at positions with 2 theta values of 11.32, 12.60, 17.68, 19.20, 23.01, 23.88, 24.94, 29.64, 36.74 and the like in a Cu/K-alpha source X-ray powder diffraction pattern.
Description
Technical Field
The invention relates to the field of drug analysis, in particular to a quantitative method of related substances of vinpocetine.
Background
Vinpocetine (vinpocetin) is an indole alkaloid, which was first isolated from plants in 1975 by the hungarian chemist CsabaSz a. Mass production was started in 1978 by Richter germane, hungarian pharmaceutical company. Vinpocetine is a cerebral vasodilator, can inhibit phosphodiesterase activity, increase the action of messenger C-GMP of vascular smooth muscle relaxation, selectively increase cerebral blood flow, inhibit platelet aggregation, reduce blood viscosity of a human body, enhance erythrocyte deformability, improve blood fluidity and microcirculation, and promote glucose uptake by brain tissues. Increase oxygen consumption of brain, and improve brain metabolism. The indications are various symptoms induced by cerebral infarction sequelae, cerebral hemorrhage sequelae, cerebral arteriosclerosis and the like.
The qualitative and quantitative determination of the good related substances is a necessary way to obtain the good vinpocetine, but the quantitative determination method of the related substances of the vinpocetine has less reports so far, so the problem to be solved by the invention is as follows: the problem of a quantitative method of related substances of vinpocetine is solved, and the company innovates a control method of related substances, so that the vinpocetine with higher yield, lower toxicity of residual solvent and better preparation performance is obtained on the basis.
Disclosure of Invention
The invention relates to a quantitative method of related substances of vinpocetine, which comprises the following steps:
the structure of the related substances of the vinpocetine related to the invention is as follows:
the related substances relate to vinpocetine or a new crystal form thereof.
The invention relates to a quantitative method of related substances of vinpocetine, which comprises the following chromatographic conditions and system applicability:
a chromatographic column: octadecylsilane chemically bonded silica gel as filler (YMC-Pack Pro C185 μm 4.6 x 250mm or equivalent performance column)
Mobile phase: phosphate buffer (taking 0.5g phosphoric acid and 0.8g sodium dihydrogen phosphate, adding 1000ml water, shaking to dissolve, adjusting pH to 2.5 with phosphoric acid) -methanol (30:70) as mobile phase
Detection wavelength: 248nm
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
Sample introduction amount: 20 μ l
System applicability solution: weighing appropriate amount of related substance control respectively, adding appropriate amount of anhydrous ethanol, shaking for dissolving, and quantitatively diluting with anhydrous ethanol to obtain mixed solution containing about 10 μ g of related substance per 1ml as related substance stock solution;
accurately weighing 10mg of vinpocetine reference substance, placing the vinpocetine reference substance into a 10ml measuring flask, accurately adding 1ml of the related substance stock solution, shaking to dissolve the vinpocetine reference substance, quantitatively diluting the vinpocetine reference substance to a scale by using n-hexane, and shaking uniformly to obtain a system applicability solution.
Injecting 10 μ l of the system applicability solution into high performance liquid chromatograph, wherein the separation degree of vinpocetine peak and related substance control is greater than or equal to 2.0.
The related substance control is compound B.
Preparing a solution:
test solution: taking 10mg of the recrystallized sample, precisely weighing, placing in a 10ml measuring flask, adding 1ml of anhydrous methanol, shaking to dissolve, diluting with n-hexane to scale, and shaking up to obtain a sample solution.
Control solution: precisely weighing the reference substance about 10mg, placing in a 100ml measuring flask, adding appropriate amount of methanol, ultrasonically dissolving and diluting to scale, shaking, precisely weighing 1ml, placing in a 20ml measuring flask, diluting with methanol to scale, and shaking to obtain reference substance solution.
And (3) synthesizing related substances in a vinpocetine crude product:
and taking a vinpocetine crude product, adding tetrahydrofuran and water with the volume 5 times and 1 time of the weight of the vinpocetine crude product into the vinpocetine crude product, adding lithium hydroxide with the weight 1 time of the vinpocetine crude product, heating the mixture to 50 ℃, stirring the system, keeping the temperature for 30 minutes, stopping stirring, adding ethyl acetate into the system for extraction, separating liquid, washing an organic phase twice with water, and performing spin drying to obtain a compound B.
The invention relates to a quantitative method of related substances of vinpocetine, which is used for analyzing a new vinpocetine crystal form and is characterized in that the new vinpocetine crystal form has characteristic absorption peaks at positions with 2 theta values of 11.32, 12.60, 17.68, 19.20, 23.01, 23.88, 24.94, 29.64, 36.74 and the like in a Cu/K-alpha source X-ray powder diffraction pattern.
The invention relates to a quantitative method of related substances of vinpocetine, which is characterized by comprising the following steps: used for analyzing a novel vinpocetine crystal form, which is characterized in that the melting point of the novel vinpocetine crystal form is 149.1-152.5 DEG C
The invention relates to a quantitative method of related substances of vinpocetine, which is characterized by comprising the following steps: a composition for assaying vinpocetine comprises vinpocetine or its new crystal form, and GABA.
The invention relates to a quantitative method of related substances of vinpocetine, which is characterized by comprising the following steps: composition for assaying vinpocetine: contains 50-200 parts of vinpocetine or new crystal form thereof and 100-100 parts of GABA 5.
The present invention provides a process for the preparation of a crystalline form which is advantageous for vinpocetine, in particular a crystalline form which can be obtained in high purity, allowing a stable process for the preparation of the crystalline form in commercial scale with low technical expenditure and high yield.
Novel vinpocetine crystal form and preparation method thereof
Heating and dissolving ethanol, standing and crystallizing, wherein an XRD (X-ray diffraction) spectrum is shown in figure 1, and XRD characteristic peaks 2 theta degrees are as follows:
11.32，12.60，17.68，19.20，23.01，23.88，24.94，29.64，36.74。
a method for preparing a novel vinpocetine crystal form comprises the following steps: and adding ethyl acetate, acetone or ethanol with the volume being 12-15 times of the weight of the crude vinpocetine into the crude vinpocetine, stirring and heating the system until the mixture flows back, cooling to 10-20 ℃ after the system is clarified, standing for crystallization for 10-12 hours, filtering, collecting a filter cake, and performing forced air drying at 40-50 ℃ to obtain the product.
After the vinpocetine is recrystallized by using ethanol, the purity of the vinpocetine is obviously improved, and the content of impurities (related substances) is obviously reduced, so that the quality of the vinpocetine product is improved.
The invention relates to a vinpocetine composition, which contains vinpocetine or a new crystal form thereof and GABA.
The invention relates to a vinpocetine composition, which comprises 50-200 parts by weight of vinpocetine or a new crystal form thereof and 100-100 parts by weight of GABA 5.
The vinpocetine crystal form is applied to the preparation of the medicines for resisting coronary heart disease and myocardial infarction.
The vinpocetine composition disclosed by the invention is applied to preparation of medicines for resisting coronary heart disease and myocardial infarction.
The invention relates to a vinpocetine composition, which contains common auxiliary materials in the field of pharmaceutical preparations.
Drawings
FIG. 1: the recrystallization solvent is ethanol
FIG. 2: HPLC (high Performance liquid chromatography) spectrum of crude vinpocetine
FIG. 3: HPLC (high Performance liquid chromatography) spectrum of sample after refining vinpocetine crude product
FIG. 4: synthesis of impurities (related substances) in crude vinpocetine (compound B):
detailed description of the preferred embodiment
The first embodiment is as follows:
and (3) adding ethanol with the volume 12 times of the weight of the crude product of the vinpocetine into the crude product of the vinpocetine, heating to 85 ℃, stirring the system, keeping the temperature for 30 minutes, stopping stirring, naturally cooling to 25 ℃ for crystallization, filtering after 10 hours, collecting a filter cake, and performing forced air drying at 50 ℃ to obtain the product.
Example two:
and (3) adding ethanol with the volume 15 times of the weight of the crude vinpocetine into the crude vinpocetine, heating to 85 ℃, stirring the system, keeping the temperature for 30 minutes, stopping stirring, cooling the system to 10 ℃ by ice water, filtering after 15 hours, collecting a filter cake, and drying by air blowing at 40 ℃ to obtain the product.
Taking about 10mg of the product, precisely weighing, placing in a 10ml measuring flask, adding a proper amount of methanol for ultrasonic dissolution, diluting to scale, and shaking uniformly to obtain a test solution.
Taking vinpocetine reference substance of about 10mg, precisely weighing, placing in a 100ml measuring flask, adding a proper amount of methanol for ultrasonic dissolution and diluting to scale, shaking up, precisely weighing 1ml, placing in a 20ml measuring flask, diluting to scale with methanol, shaking up, and using as reference substance solution.
Performing high performance liquid chromatography test with octadecylsilane chemically bonded silica as filler (YMC-Pack Pro C)185 μm 4.6 x 250mm or equivalent performance columns); phosphate buffer (0.5 g of phosphoric acid and 0.8g of sodium dihydrogen phosphate, 1000ml of water are added, the mixture is shaken to be dissolved, the pH value is adjusted to 2.5 by phosphoric acid) -methanol (30:70) is used as a mobile phase, the flow rate is 1.0ml per minute, the detection wavelength is 248nm, and the column temperature is 30 ℃. Precisely measuring 20 μ l of each of the sample solution and the reference solution, and injecting into liquid chromatographyAnd recording the chromatogram.
HPLC (high Performance liquid chromatography) spectrum of crude vinpocetine:
HPLC (high Performance liquid chromatography) spectrum of a refined vinpocetine crude product:
the removal effect is obvious when the retention time is 21.245min, and the impurities are researched.
Example three:
synthesis of impurities (related to substance B) in crude vinpocetine:
and taking a vinpocetine crude product, adding tetrahydrofuran and water with the volume 5 times and 1 time of the weight of the vinpocetine crude product into the vinpocetine crude product, adding lithium hydroxide with the weight 1 time of the vinpocetine crude product, heating the mixture to 50 ℃, stirring the system, keeping the temperature for 30 minutes, stopping stirring, adding ethyl acetate into the system for extraction, separating liquid, washing an organic phase twice with water, and performing spin drying to obtain a compound B.
H-NMR detection:
1H-NMR(DMSO,500MHz),δ1.342～1.409(t H,H-4),δ4.333～4.452(d,1H,J＝7.5Hz,H-3),δ6.100(d,1H,J＝7.5Hz,H-1),δ0.931～1.012(m,3H,H-2,6,8),δ1.448～1.496(m 1H,H-7),δ1.341～1.377(m 2H,J＝7.5Hz,H-5,9),δ1.631～1.719(m 1H,J＝7.5Hz,H-1),δ2.551～2.579(m,3H,H-2,6,8),δ2.932～2.987(m,1H,H-7),δ7.068～7.145(d,2H,J＝7.5Hz,H-5,9),δ7.228～7.248(m,3H,H-2,6,8)。
example four: product stability test
During long-term three-month stability study, the new sample was stable well without newly added impurities. 5g of each product of example 1 and example 2 is taken out, placed in a watch glass, placed in a constant temperature and humidity box in an open manner, stored for 90 days at the temperature of 30 ℃ and the RH of 60 percent, taken out, observed in appearance, and respectively measured for impurities (related substances), and the data are recorded as follows:
after 90 days, the products of example 1 and example 2 were tested, and the main particle size was about 180 μm, the particle size distribution was concentrated, the angle of repose was about 28 °, the density was high, the fluidity was good, and the product was suitable for a preparation.
Example five: compatibility test of the product
Preparation of vinpocetine tablets: taking 100g of vinpocetine, adding an appropriate amount of beta-cyclodextrin, granulating by a wet method, and drying in vacuum to obtain vinpocetine granules. 2g of vinpocetine granules, 17.9g of crospovidone and 0.1g of magnesium stearate are uniformly mixed and dried for 8 hours; sieving the dried granules with a 200-mesh sieve; and (4) finishing granules and tabletting. Disintegration time limit: compliance with the regulations.
Preparation of vinpocetine composition 1 product: taking 50g of the vinpocetine in the example 1, taking GABA50g, adding a proper amount of beta-cyclodextrin, performing inclusion, performing wet granulation, and performing vacuum drying to obtain the vinpocetine composition 1 granules. 2g of vinpocetine composition 1 granules, 17.9g of crospovidone and 0.1g of magnesium stearate are uniformly mixed and dried for 8 hours; sieving the dried granules with a 200-mesh sieve; and (4) finishing granules and tabletting. Disintegration time limit: compliance with the regulations.
Preparation of vinpocetine composition 2 product: taking 50g of the vinpocetine in the example 2, taking 5g of GABA, adding an appropriate amount of beta-cyclodextrin, performing inclusion, performing wet granulation, and performing vacuum drying to obtain the vinpocetine composition 1 granules. 2g of vinpocetine composition 1 granules, 17.9g of crospovidone and 0.1g of magnesium stearate are uniformly mixed and dried for 8 hours; sieving the dried granules with a 200-mesh sieve; and (4) finishing granules and tabletting. Disintegration time limit: compliance with the regulations.
GABA of the invention is short for 4-aminobutyric acid (gamma-aminobutyric acid).
Example six: content analysis of product
200mg of each of the vinpocetine tablets, the vinpocetine composition 1 product and the vinpocetine composition 2 product in the fifth embodiment are precisely weighed, placed in a 10ml measuring flask, dissolved and diluted to a scale by adding a proper amount of methanol and ultrasonic waves, and shaken up to be used as a test solution.
Taking vinpocetine reference substance of about 10mg, precisely weighing, placing in a 100ml measuring flask, adding a proper amount of methanol for ultrasonic dissolution and diluting to scale, shaking up, precisely weighing 1ml, placing in a 20ml measuring flask, diluting to scale with methanol, shaking up, and using as reference substance solution.
Performing high performance liquid chromatography test with octadecylsilane chemically bonded silica as filler (YMC-Pack Pro-C)18: 5 μm 4.6 x 250mm or equivalent performance columns); phosphate buffer (0.5 g of phosphoric acid and 0.8g of sodium dihydrogen phosphate, 1000ml of water are added, the mixture is shaken to be dissolved, the pH value is adjusted to 2.5 by phosphoric acid) -methanol (30:70) is used as a mobile phase, the flow rate is 1.0ml per minute, the detection wavelength is 248nm, and the column temperature is 30 ℃. Precisely measuring 20 μ l of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram.
Example seven: anti-myocardial infarction drug effect experiment of composition product
(1) Drug dose setting and grouping:
SD rats were divided into 6 groups of 10 rats each (n ═ 10):
a first group: the blank administration group, ligature coronary artery left anterior descending branch, ischemia 45 minutes, reperfusion 2h, before modeling intragastric administration of 0.5% CMC-Na for three days, once in the morning and evening.
Second group: positive control group (valsartan): the left anterior descending branch of the coronary artery was ligated, ischemic for 45min, and reperfusion for 2 h. Before the model is made, the valsartan of 10mg/kg is administrated by stomach irrigation for three days, 0.5 percent of CMC-Na for three days, and the valsartan is taken once in the morning and at night.
Third group: group A, thoracotomy, ligation of left anterior descending coronary artery, ischemia for 45min, and reperfusion for 2 h. Before the model is made, a 10mg/kg (vinpocetine tablet) 0.5% CMC-Na solution is administrated by stomach irrigation for three days, and the solution is taken once in the morning and at night.
And a fourth group: group B, thoracotomy, ligation of left anterior descending coronary artery, ischemia for 45min, and reperfusion for 2 h. The 10mg/kg (product of vinpocetine composition 1) 0.5% CMC-Na solution is administrated by stomach irrigation for three days before molding, and is taken once in the morning and at night.
And a fifth group: group C, thoracotomy, ligation of left anterior descending coronary artery, ischemia for 45min, and reperfusion for 2 h. The 10mg/kg (the product of the vinpocetine composition 2) 0.5 percent CMC-Na solution is administrated by stomach irrigation for three days before the model building, and is taken once in the morning and at night.
A sixth group: group D, thoracotomy, ligation of left anterior descending coronary artery, ischemia for 45min, and reperfusion for 2 h. 40mg/kg (GABA) 0.5% CMC-Na solution is administrated by stomach irrigation before model building for three days, once in the morning and at night.
The survival of the rats was observed 12 hours after reperfusion.
After 12h of reperfusion, rats were anesthetized and femoral artery blood was taken. Taking out the heart, removing blood vessels and residual tissues around the blood vessels, washing with normal saline, sucking water by double-layer filter paper, accurately weighing the whole heart wet weight by an electronic balance, and determining the heart index. The percentage of the ratio of the wet mass of the heart to the mass of the last rat body is the heart index.
The cells were placed at-80 ℃ for 5min and then removed, starting from the apex of the heart, and the heart was transected in the ligation direction with 10 slices of 1-2mm thickness. Putting 10 slices into a 1% tetrazolium red solution, heating in a water bath at 37 ℃ for 12min, fixing with neutral formalin, standing at room temperature for 24 hours, taking a photo, measuring the myocardial infarction area of a single slice, and calculating the myocardial infarction proportion, namely area of an infarct zone/area of a left heart by using Image-Pro plus7.0 Image analysis software.
Determination of serum VEGF content: centrifuging 5ml of the blood at 3000r/min for 10min, separating serum, storing in a refrigerator at-80 deg.C, and determining VEGF content by enzyme-linked immunosorbent assay (ELISA).
Compared with the blank group, the VEGF absorbance of the serum of the third, fourth and fifth groups is obviously increased (P is less than 0.01).
Claims (5)
1. A method for quantifying substances related to vinpocetine comprises the following steps:
the structure of related substances of vinpocetine is as follows:
the method for quantifying the substances related to the vinpocetine comprises the following chromatographic conditions and system applicability:
a chromatographic column: octadecylsilane chemically bonded silica gel as filler
Mobile phase: phosphate buffer (taking 0.5g phosphoric acid and 0.8g sodium dihydrogen phosphate, adding 1000ml water, shaking to dissolve, adjusting pH to 2.5 with phosphoric acid) -methanol (30:70) as mobile phase
Detection wavelength: 248nm
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
Sample introduction amount: 20 μ l
System applicability solution: weighing appropriate amount of related substance control respectively, adding appropriate amount of anhydrous ethanol, shaking for dissolving, and quantitatively diluting with anhydrous ethanol to obtain mixed solution containing about 10 μ g of related substance per 1ml as related substance stock solution;
accurately weighing 10mg of vinpocetine reference substance, placing the vinpocetine reference substance into a 10ml measuring flask, accurately adding 1ml of the related substance stock solution, shaking to dissolve the vinpocetine reference substance, quantitatively diluting the vinpocetine reference substance to a scale by using n-hexane, and shaking uniformly to obtain a system applicability solution.
Injecting 10 μ l of the system applicability solution into high performance liquid chromatograph, wherein the separation degree of vinpocetine peak and related substance control is greater than or equal to 2.0.
2. A method according to claim 1 for the quantification of a substance related to vinpocetine, for the analysis of a new form of vinpocetine characterized by characteristic absorption peaks at 2 θ values of 11.32, 12.60, 17.68, 19.20, 23.01, 23.88, 24.94, 29.64, 36.74, etc. in the X-ray powder diffraction pattern from the Cu/K- α source.
3. A method according to claim 1 for the quantification of substances related to vinpocetine, characterized in that: used for analyzing a novel vinpocetine crystal form, which is characterized in that the melting point of the novel vinpocetine crystal form is 149.1-152.5 DEG C
4. A method according to claim 1 for the quantification of substances related to vinpocetine, characterized in that: a composition for assaying vinpocetine comprises vinpocetine or its new crystal form, and GABA.
5. A method according to claim 1 for the quantification of substances related to vinpocetine, characterized in that: composition for assaying vinpocetine: contains 50-200 parts of vinpocetine or new crystal form thereof and 100-100 parts of GABA 5.
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