CN104597192A - Method for detecting clevidipine butyrate and related substances in preparations of clevidipine butyrate - Google Patents
Method for detecting clevidipine butyrate and related substances in preparations of clevidipine butyrate Download PDFInfo
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Abstract
The invention discloses a method for detecting clevidipine butyrate and related substances in preparations of the clevidipine butyrate. The method is characterized in that gradient elution is carried out by virtue of a C18 chromatographic column by taking methanol-acetonitrile-phosphate buffer salt solution as a mobile phase according to a reversed-phase high-performance liquid chromatography and an ultraviolet detector is used. By means of the method, effective separation of the clevidipine butyrate from all known impurities can be realized; interference of various impurities generated in the synthesis and preparation production processes to the purity of products can be avoided; the quantity of the clevidipine butyrate or preparations can be controlled comprehensively and effectively; the method is simple to operate and high in specificity and sensitivity and is capable of well detecting the clevidipine butyrate and related substances in the preparations; and an effective and reliable analysis method is provided for quality control of research, development and production processes.
Description
Technical field
The invention belongs to medical art, specifically the detection method of related substance in a kind of butyrate clevidipine and preparation thereof.
Background technology
The nomenclature of drug of butyrate clevidipine described in the present invention is:
Common name: butyrate clevidipine
Chemical name: 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl (1-butyryl acyloxy) methyl esters 4-(2,3-dichlorophenyl)-Isosorbide-5-Nitrae-dihydro-2,6-dimethyl-3,5-Pyridinedicarboxylic acid methyl (1-oxobutoxy) methyl ester
English name: Clevidipine butyrate
Chemical structural formula:
Molecular formula: C
21h
23cl
2nO
6
Molecular weight: 456.32
Butyrate clevidipine is the novel fugitive dihydropyridine calcium channel antagonist of the third generation developed by Britain's AstraZeneca (AstraZeneca) company.Butyrate clevidipine emulsion used for intravenous injection is in August, 2008 first in U.S.'s listing, and trade name Cleviprex is the unique intravenous injection antihypertensive agent ratifying in nearly 10 years to go on the market.This medicine is used for the treatment of unsuitable oral medication or the invalid hypertension of oral medication, also can be used for treatment surgical site infections acute blood pressure and raises.Because butyrate clevidipine is unstable, may degrade in preparation processing and storage, in this product building-up process, likely introduce retained material simultaneously, the related substances such as intermediate and other accessory substances, these related substances not only can reduce purity and the clinical efficacy of butyrate clevidipine, simultaneously also because its known and genotoxic potential can endanger the life security of patient.Related substances separation is the important component part of drug standard, can ensure the safe and effective of medication, can examine again production technology and the condition of storage of medicine.In several years in the past, butyrate clevidipine and containing butyrate clevidipine as the composition of active component in identify plurality of impurities.Some impurity derive from the process preparing butyrate clevidipine raw material and preparation thereof, and other are then the progressively degradeds due to active component.
The synthesis of butyrate clevidipine is at present mainly using chlorobenzaldehyde and methyl acetoacetate or derivatives thereof as initiation material; through intermediate 3-(2; 3-dichlorophenyl)-2-acetyl group acrylic acid or derivatives thereof; again through intermediate 4-(2; 3-dichlorophenyl)-Isosorbide-5-Nitrae-dihydro-2,6-dimethyl-3; 5-dipicolinic acid monomethyl ester, then react with butyric acid chloromethyl ester and generate butyrate clevidipine.Wherein the common impurity such as byproduct of reaction and residual intermediate that may introduce is mainly 4-(2; 3-dichlorophenyl)-1; 4-dihydro-2; 6-dimethyl-3; 5-dipicolinic acid monomethyl ester, 3-(2; 3-dichlorophenyl)-2-acetyl group acrylic acid or derivatives thereof or 3-(2,3-dichlorophenyl)-2-acetyl group acrylic acid butyryl oxygen methyl esters etc.
In patent US20100105743A1, CN102170786A (PCT application data PCT/US2009/0043992009.07.30) and CN 102186351 A (PCT application data PCT/US2009/0521272009.07.29), the degradation pathway mentioning butyrate clevidipine comprises many chemical reaction processes and can produce much impurity, such as H324/78, H152/66, H152/81, H168/79, H207/59, and H207/36, be degraded to material 23, material 24 and/or material 25 further by the mode of hydrolysis and condensation.Mention in above-mentioned patent and adopt degree such as grade, normal phase high performance liquid chromatography using heptane: ethanol (90: 10) is as mobile phase to carry out its related substance of separation determination.Through verification experimental verification, found that the equilibration time that the method needs reaches 4 hours, and each peak is separated and retains unsatisfactory, butyrate clevidipine peak is close to overlap (see accompanying drawing 1) with the peak of by-product impurities H and G impurity, and the inconvenient coupling mass spectrometer detector of normal-phase chromatography method carries out directly qualitative analysis fast to each impurity, therefore the method reported in this patent is unsatisfactory.
1998, the people such as Jaremo (Supercritical Fluid Extraction of Clevidipine from a WaterBased Vegetable Oil Emulsion, Volume 21, Issue 3,1998) report the method that is analyzed butyrate clevidipine and Partial digestion product (H324/78 and H152/81) thereof.Method take octadecylsilane chemically bonded silica as filling agent, acetonitrile: methyl alcohol: (phosphoric acid of 15ml 1mol/L mixes with the sodium dihydrogen phosphate of 100ml1mol/L phosphate buffered solution, being diluted to 2000ml, regulating pH3.0)=40:20:40 is mobile phase.Empirical tests, under the process conditions, degraded H207/59 and the impurity G degree of separation of butyrate clevidipine are 1.06, can not separate, another one degradation impurity H168/79 go out peak serious before drag, cause can not reaching with oxidation impurities H324/78 below being fully separated, degree of separation is only 1.31.
The domestic bibliographical information that yet there are no butyrate clevidipine analytical approach at present, the pharmaceutical standards that this medicine is ununified yet, therefore, in order to control the quality of butyrate clevidipine product better, a set of simple and reliable and stable effective method need be set up detect to the related substance carrying out this product, solve the interference that all kinds of known or unknown impuritie that synthesis technique is introduced or degraded and formulation process produce measures product purity.
Summary of the invention
Technical matters to be solved by this invention is the detection method providing related substance in a kind of butyrate clevidipine and preparation thereof.The method overcomes current normal phase chromatography and Reversed Phase Isocratic elution process all cannot realize the drawback that butyrate clevidipine is effectively separated with related substance, the reversed phase high performance liquid adopting the mode of gradient elution to realize butyrate clevidipine and related substance is separated, and realizes the quality control to butyrate clevidipine raw material or its preparation.
Consider that normal-phase chromatography condition is not suitable for LC-MS instrument, the separation of butyrate clevidipine related substance and structure-characterized detection cannot be carried out further, therefore our primary study reversed-phase high-performance liquid chromatography method.
Ultraviolet curved scanning is carried out through the accessory substance that obtains butyrate clevidipine, intermediate and being separated and degradation impurity etc., they have maximum absorption wavelength in 220nm-240nm scope substantially, wherein 220nm is the maximum absorption wavelength of butyrate clevidipine and most of impurity, therefore the wavelength that preferred 220nm detects as butyrate clevidipine related substance.
First our reference literature (Supercritical Fluid Extraction of Clevidipine from a WaterBased Vegetable Oil Emulsion, J.LIQ.CHROM. & REL.TECHNOL., Volume 21, Issue 3, 1998) method described in, take octadecylsilane chemically bonded silica as filling agent, acetonitrile: methyl alcohol: (phosphoric acid of 15ml 1mol/L mixes with the sodium dihydrogen phosphate of 100ml 1mol/L phosphate buffered solution, be diluted to 2000ml, regulating pH3.0)=40:20:40 is mobile phase, found that degradation impurity L drags before going out peak, cannot be separated with oxidation impurities K, the degree of separation of degradation impurity M and by-product impurities G is only 1.06, attempt again having changed the C18 chromatographic column of dissimilar filler model, all cannot obtain desired separated effect.
Applicant surprisingly finds when methanol-acetonitrile-phosphate buffered solution (pH=3.8)=33:25:42 carries out gradient elution as mobile phase to given the test agent, each peak is obtained for good separation, just impurity H goes out peak too late, the elution time of impurity H after main peak was have adjusted afterwards by gradient, obtain methanol-acetonitrile-phosphate buffered solution three-phase gradient elution program, just can realize effective separation of butyrate clevidipine and related substance thereof, no matter intermediate, synthesising by-product or catabolite (table 1) all each peak degree of separation can be greater than 1.5 under this gradient elution program, also the interference at solvent peak and auxiliary material peak is avoided, peak shape is good, baseline is steady, the major component peak purity factor also meets the requirements, result is satisfactory.When methyl alcohol: acetonitrile: during phosphate buffered solution=30:30:40, the peak degree of separation near main peak is best, and degree of separation is all greater than 2, but impurity M can not separate with impurity G under this methodology, and degree of separation is less than 1.And methyl alcohol: acetonitrile: during phosphate buffered solution=15:45:40, the peak degree of separation near main peak is less than 1.5.When pH value is greater than 4.0 in addition, can affect impurity J and be separated with impurity K's with impurity C, impurity L, when pH is less than 3.5, impurity L can trail, and affect its being separated with front and back impurity, the pH scope that therefore mobile phase is suitable is 3.5-4.0.Preferred pH=3.8.
Table 1
Technical scheme of the present invention is achieved in that it comprises the following steps:
The detection method of related substance in a kind of butyrate clevidipine and preparation thereof:
(1) butyrate clevidipine bulk drug or butyrate clevidipine formulation samples is got, with organic solvent dissolution, preparation need testing solution;
(2) reversed-phased high performace liquid chromatographic is adopted, chromatographic column is C18 post, column temperature scope 20-40 DEG C, the flow velocity of mobile phase is 0.7-1.1ml/min, with A: methyl alcohol, B: the mixed solution of the phosphate buffer of acetonitrile and C:0.005-0.1mol/L pH 3.5-4.0 is mobile phase, adopts gradient elution mode; In elution process, in mobile phase, the volumn concentration of A, B, C is as follows:
0-55min, A are 33%, B be 25%, C is 42%; 55-65min, A are at the uniform velocity increased to 35%, B by 33% and are at the uniform velocity increased to 30%, C by 25% and are at the uniform velocity reduced to 35% by 42%; 65-85min, A are 35%, B be 30%, C is 35%; 85-93min, A are at the uniform velocity reduced to 33%, B by 35% and are at the uniform velocity reduced to 25%, C by 30% and are at the uniform velocity increased to 42% by 35%; 93-105min, A are 33%, B be 25%, C is 42%;
(3) adopt UV-detector, determined wavelength 220-260nm, record chromatogram, completes the mensuration of related substance in butyrate clevidipine need testing solution.
In described method step (1), get butyrate clevidipine bulk drug organic solvent dissolution and dilute, make the need testing solution of every 1ml containing butyrate clevidipine 0.1-10mg, or get butyrate clevidipine formulation samples organic solvent dissolution and be diluted to the solution of every 1ml containing butyrate clevidipine 0.01-0.1mg, getting supernatant after centrifugal or get filtrate as need testing solution after filtering;
In described method step (1), in preparation need testing solution the organic solvent that uses be methyl alcohol, one or more in acetonitrile, ethanol, isopropyl alcohol or tetrahydrofuran.
In described method step (2), chromatographic column take C18 as filler, and particle diameter is 3.0 ~ 5.0 μm, and column length is 150 ~ 250mm, and column internal diameter is 4.6mm.Further preferably, particle diameter is 3.5 μm, and column length is 150mm.
In described method step (2), column temperature is set as 35 DEG C.
In described method step (2), flow control is at 0.8ml/min.
In described method step (2), the pH value of mobile phase phosphate buffered solution is 3.8.
In described method step (3), determined wavelength is set as 220nm.
In described method step (3), the content of related substance with the major component Self-control method of the not correction up factor with calculated by peak area.
The present invention adopts gradient elution to achieve the separation completely of related substance in butyrate clevidipine and preparation, achieve the control to product synthesis impurity, intermediate and degradation impurity, the quality control aspect of the various butyrate clevidipine needing to carry out related substance detection and the related preparations containing butyrate clevidipine is significant.
Accompanying drawing explanation
Fig. 1, heptane: ethanol (90: 10) is as the chromatogram of mobile phase.
Fig. 2, acetonitrile: methyl alcohol: phosphate buffered solution (40:20:40) all can not be separated the chromatogram (Waters chromatographic column) of known impurities mixed solution for mobile phase.
Fig. 3, acetonitrile: methyl alcohol: phosphate buffered solution (40:20:40) all can not be separated the chromatogram (Yi Lite chromatographic column) of known impurities mixed solution for mobile phase.
Fig. 4 ~ 5, acetonitrile-0.01mol/L ammonium dihydrogen phosphate (ADP) buffer solution be mobile phase in varing proportions gradient elution all can not be separated the chromatogram of known impurities mixed solution.
Fig. 6, methyl alcohol-0.01mol/L ammonium dihydrogen phosphate (ADP) buffer solution be mobile phase in varing proportions gradient elution all can not be separated the chromatogram of known impurities mixed solution.
Fig. 7, the known impurities mixed solution of more than 10 kind of intermediate, synthesising by-product and catabolite composition, tests the chromatogram obtained by this method.Result shows, and all impurity all can be analyzed out in a collection of illustrative plates, can be separated completely between each impurity, does not have impurity to disturb the mensuration of main peak.
Fig. 8, in order to verify reliability and the specificity of the inventive method further, by the crude product solution sample to be refined of synthesis, tests the chromatogram obtained by this method.Result shows each impurity and is separated well with major component peak, shows that method of the present invention can be applicable to various known or unknown relevant magazins' layout that it produces under synthesis condition and detect.
Fig. 9 ~ 13, in order to verify reliability and the specificity of the inventive method further, the butyrate clevidipine raw material through peracid destruction, alkali destruction, illumination, high temperature, Oxidative demage is adopted to be tested the chromatogram collection of illustrative plates obtained by this method respectively, each impurity peak shape and degree of separation well, show that method of the present invention can be applicable to various violent and its various known or unknown relevant magazins' layout detection produced of extreme complex condition.
Figure 14, in order to verify reliability and the specificity of the inventive method further, carries out determination of related substances to butyrate clevidipine emulsion, is tested the chromatogram obtained by this method.Result shows each impurity and is separated well with major component peak, shows that the various known or unknown relevant magazins' layout that method of the present invention can be applicable to produce during preparation is produced detects.
Embodiment
By following embodiment, technical method of the present invention is further described, but not as restriction of the present invention.
Embodiment 1 acetonitrile: methyl alcohol: phosphate buffered solution (pH=3.0)=40:20:40 (volume ratio) all can not be separated the test of known impurities mixed solution for mobile phase
1. instrument: Agilent 1260 high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: precision take butyrate clevidipine, impurity G, the reference substance of impurity F and H324/78, H168/79, H207/59, H152/81 and H152/66 reference substance appropriate, add methyl alcohol dissolves and be diluted to contain butyrate clevidipine 1mg and each impurity about 1 μ g in every 1ml known impurities mixed solution as need testing solution.Chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Mobile phase is acetonitrile: methyl alcohol: phosphate buffered solution=40:20:40, and phosphate buffered solution is mixed with the sodium dihydrogen phosphate of 100ml1mol/L by the phosphoric acid of 15ml 1mol/L, is diluted with water to 2000ml, formulated with phosphorus acid for adjusting pH to 3.0.Determined wavelength is 220nm, and column temperature is 35 DEG C, flow velocity 1.0ml/min.Precision measures need testing solution 10 μ l injection liquid chromatography, record chromatogram.The high-efficient liquid phase chromatogram obtained as stated above is as accompanying drawing 2.Result shows that this chromatographic system all can not be separated each known impurities in mixed solution.
Embodiment 2 acetonitrile: methyl alcohol: phosphate buffered solution (pH=3.0)=40:20:40 (volume ratio) all can not be separated the test of known impurities mixed solution for mobile phase
1. instrument: Agilent 1260 high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method (1): the reference substance that precision takes the reference substance of impurity A ~ I and H324/78, H168/79, H207/59, H152/81 and H152/66 is appropriate, add methyl alcohol dissolves and be diluted to contain each impurity about 20 μ g in every 1ml known impurities mixed solution as need testing solution.Chromatographic column Yi Lite Hypersil BDS C18150 × 4.6mm, 3 μm; Mobile phase is acetonitrile: methyl alcohol: phosphate buffered solution=40:20:40, and phosphate buffered solution is mixed with the sodium dihydrogen phosphate of 100ml 1mol/L by the phosphoric acid of 15ml 1mol/L, is diluted with water to 2000ml, formulated with phosphorus acid for adjusting pH to 3.0.Determined wavelength is 220nm, and column temperature is 35 DEG C, flow velocity 1.0ml/min.Precision measures need testing solution 10 μ l injection liquid chromatography, record chromatogram.The high-efficient liquid phase chromatogram obtained as stated above is as accompanying drawing 3.This chromatographic system all can not be separated each known impurities in mixed solution.
Embodiment 3 acetonitrile-0.01mol/L ammonium dihydrogen phosphate (ADP) buffer solution be mobile phase in varing proportions gradient elution all can not be separated the test of known impurities mixed solution
1. instrument: Agilent 1260 high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method (1): precision take butyrate clevidipine, impurity G, the reference substance of impurity F and H324/78, H168/79, H207/59, H152/81 and H152/66 reference substance appropriate, add methyl alcohol dissolves and be diluted to contain 1mg butyrate clevidipine and each impurity about 1 μ g in every 1ml known impurities mixed solution as need testing solution.Chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Flow visualizing, A is acetonitrile, B is 0.01mol/L ammonium dihydrogen phosphate (ADP) buffer salt buffer solution, 0.01mol/L ammonium dihydrogen phosphate (ADP) buffer solution is mixed by 1.15g ammonium dihydrogen phosphate (ADP), be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 3.5, gradient elution mode is 0-50min, 55%A-70%A, 45%B-30%B; 50-60min, 70%A-55%A, 30%B-45%B; 60-70min, 55%A, 45%B.Determined wavelength is 220nm, and column temperature is 35 DEG C, flow velocity 0.8ml/min.Precision measures need testing solution 10 μ l injection liquid chromatography, record chromatogram.The high-efficient liquid phase chromatogram obtained as stated above is as accompanying drawing 4.Result shows that this chromatographic system all can not be separated each known impurities in mixed solution.
3. assay method (2): chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm, flow visualizing, A is acetonitrile, and B is 0.01mol/L ammonium dihydrogen phosphate (ADP) buffer salt buffer solution, 0.01mol/L ammonium dihydrogen phosphate (ADP) buffer solution is mixed by 1.15g ammonium dihydrogen phosphate (ADP), be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 3.5, gradient elution mode is 0-50min, 35%A-70%A, 65%B-30%B; 50-60min, 70%A-35%A, 30%B-65%B; 60-70min, 35%A, 65%B.Determined wavelength is 220nm, and column temperature is 35 DEG C, flow velocity 0.8ml/min.Precision measures need testing solution 10 μ l injection liquid chromatography in 2, record chromatogram.The high-efficient liquid phase chromatogram obtained as stated above is as accompanying drawing 5.Result shows that this chromatographic system all can not be separated each known impurities in mixed solution.
Embodiment 4 methyl alcohol-0.01mol/L ammonium dihydrogen phosphate (ADP) buffer solution is that mobile phase all can not be separated the test of known impurities mixed solution with gradient elution
1. instrument: Agilent 1260 high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: precision take butyrate clevidipine reference substance, the reference substance of impurity A ~ I and H324/78, H168/79, H207/59, H152/81 and H152/66 reference substance appropriate, add methyl alcohol dissolves and be diluted to contain 1mg butyrate clevidipine and each impurity about 1 μ g in every 1ml known impurities mixed solution as need testing solution.Chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Flow visualizing, A phase is methyl alcohol, B phase is 0.01mol/L ammonium dihydrogen phosphate (ADP) buffer salt buffer solution, 0.01mol/L ammonium dihydrogen phosphate (ADP) buffer solution is mixed by 1.15g ammonium dihydrogen phosphate (ADP), be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 3.5, gradient elution mode is 0-50min, 55%A-75%A, 45%B-25%B; 50-60min, 75%A-55%A, 25%B-45%B; 60-70min, 55%A, 45%B.Determined wavelength is 220nm, and column temperature is 35 DEG C, flow velocity 0.8ml/min.Precision measures need testing solution 10 μ l injection liquid chromatography, record chromatogram.The high-efficient liquid phase chromatogram obtained as stated above is as accompanying drawing 6.Result shows that this chromatographic system all can not be separated each known impurities in mixed solution.
Embodiment 5 methanol-acetonitrile-phosphate buffered solution is mobile phase can the test of effective removing impurities mixed solution with gradient elution
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: precision take butyrate clevidipine reference substance, the reference substance of impurity A ~ I and H324/78, H168/79, H207/59, H152/81 and H152/66 reference substance appropriate, add methyl alcohol dissolves and be diluted to contain 1mg butyrate clevidipine and each impurity about 1 μ g in every 1ml known impurities mixed solution as need testing solution.Chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Mobile phase: methyl alcohol is mobile phase A, acetonitrile is Mobile phase B, (0.01mol/L sodium dihydrogen phosphate buffer is mixed by 1.20g sodium dihydrogen phosphate 0.01mol/L phosphate buffered solutions, be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 3.8) be mobile phase C, adopt gradient elution mode: 0-55min, 33%A, 25%B, 42%C; 55-65min, 33%A-35%A, 25%B-30%B, 42%C-35%C; 65-85min, 35%A, 30%B, 35%C; 85-93min, 35%A-33%A, 30%B-25%B, 35%C-42%C; 93-105min, 33%A, 25%B, 42%C.Determined wavelength is 220nm, and column temperature is 35 DEG C, flow velocity 0.8ml/min.Precision measures need testing solution 10 μ l injection liquid chromatography, record chromatogram.The high-efficient liquid phase chromatogram obtained as stated above is as accompanying drawing 7.Result shows that this chromatographic system all can be separated each known impurities in mixed solution, can be separated completely between each impurity, does not have impurity to disturb the mensuration of main peak.
Embodiment 6 methanol-acetonitrile-phosphate buffered solution condition of gradient elution effectively can be separated the test of butyrate clevidipine crude material solution
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: the crude product of accurately weighed synthetic butyric acid clevidipine raw material (obtaining according to patent CN201310003732.1 synthesis), adds methyl alcohol and dissolves and be diluted in every 1ml and contain each impurity and be about the butyrate clevidipine of 1mg as need testing solution.Chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Mobile phase: methyl alcohol is mobile phase A, acetonitrile is Mobile phase B, (0.01mol/L ammonium dihydrogen phosphate (ADP) buffer solution is mixed by 1.15g ammonium dihydrogen phosphate (ADP) 0.01mol/L phosphate buffered solutions, be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 3.5) be mobile phase C, adopt gradient elution mode: 0-55min, 33%A, 25%B, 42%C; 55-65min, 33%A-35%A, 25%B-30%B, 42%C-35%C; 65-85min, 35%A, 30%B, 35%C; 85-93min, 35%A-33%A, 30%B-25%B, 35%C-42%C; 93-105min, 33%A, 25%B, 42%C.Determined wavelength is 220nm, and column temperature is 35 DEG C.Precision measures need testing solution 10 μ l injection liquid chromatography, record chromatogram.The high-efficient liquid phase chromatogram obtained as stated above is as accompanying drawing 8.Result display accessory substance, intermediate are separated well with major component peak.
Embodiment 7 methanol-acetonitrile-phosphate buffered solution condition of gradient elution effectively can be separated the test of butyrate clevidipine raw material acid, alkali, light, heat, Oxidative demage solution
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. get butyrate clevidipine raw material (synthesizing the butyrate clevidipine obtained according to patent CN201310003732.1, rear same) about 10mg and be placed in 10ml volumetric flask respectively, according to following each condition preparation test sample.
Acid destruction: add 2ml methyl alcohol and dissolved by butyrate clevidipine raw material, add the hydrochloric acid of 0.5ml 0.1mol/L, neutralizes with NaOH after lucifuge places 4h, 4h after mixing, adds methanol dilution to scale;
Alkali destroys: add 2ml methyl alcohol and dissolved by butyrate clevidipine raw material, add the NaOH of 0.5ml 0.01mol/L, with hydrochloric acid solution neutralization after mixing rear lucifuge placement 0.5h, 0.5h, adds methanol dilution to scale;
Illumination destroys: add methyl alcohol dissolved dilution to scale, mixing, and under putting high light, (4500Lx) is for subsequent use after irradiating 24h;
High temperature: add 2ml methyl alcohol and butyrate clevidipine raw material is dissolved, be placed on boiling water bath and heat 4h, add methanol dilution to scale;
Oxidative demage: add 2ml methyl alcohol and dissolved by butyrate clevidipine raw material, add 30% hydrogen peroxide 0.5ml, after mixing, lucifuge adds methanol dilution to scale after placing 4h, 4h;
3. assay method: chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Mobile phase: methyl alcohol is mobile phase A, acetonitrile is Mobile phase B, (0.01mol/L sodium dihydrogen phosphate buffer is mixed by 1.2g sodium dihydrogen phosphate 0.01mol/L phosphate buffered solutions, be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 4.0) be mobile phase C, adopt gradient elution mode: 0-55min, 33%A, 25%B, 42%C; 55-65min, 33%A-35%A, 25%B-30%B, 42%C-35%C; 65-85min, 35%A, 30%B, 35%C; 85-93min, 35%A-33%A, 30%B-25%B, 35%C-42%C; 93-105min, 33%A, 25%B, 42%C.Determined wavelength is 220nm, and column temperature is 35 DEG C.Precision measures acid destruction respectively, and alkali destroys, each 10 μ l injection liquid chromatographies of need testing solution of illumination, high temperature, Oxidative demage, record chromatogram.The high-efficient liquid phase chromatogram obtained as stated above is as accompanying drawing 9 ~ 13.Result shows, butyrate clevidipine raw material is after destroying degraded under the conditions such as acid, alkali, oxidation, high temperature and illumination, and the impurity in need testing solution all can detect.Wherein test sample all has new degradation impurity peak through acid, alkali, oxidation and illumination after destroying, and degradation impurity is separated can both be separated completely with between main peak and degradation impurity, and the retention time of impurity that new degradation impurity peak and raw material carry has obvious difference.Specificity test findings shows, this method is applicable to butyrate clevidipine raw material and is separated detection at its various known or unknown related impurities produced of various violent and extreme complex condition.
Embodiment 8 methanol-acetonitrile-phosphate buffered solution condition of gradient elution effectively can be separated the test of butyrate clevidipine emulsion sample through acid, alkali, light, high temperature, Oxidative demage solution
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. get butyrate clevidipine emulsion (from antigalactic: butyrate clevidipine 0.5mg/mL, soybean oil 200mg/mL, glycerine 22.5mg/mL, lecithin 12mg/mL, oleic acid 0.3mg/mL; Butyrate clevidipine adopts patent CN201310003732.1 synthesis to obtain) about 1ml is placed in 10ml volumetric flask, respectively according to following each condition preparation test sample.
Acid destroys: the hydrochloric acid adding 1ml 0.1mol/L, after lucifuge places 2h after mixing, with NaOH neutralization after 1h, adds isopropyl alcohol/tetrahydrofuran mixed solvent and is diluted to scale, mixing, centrifugal, gets supernatant for subsequent use;
Alkali destroys: the NaOH adding 1ml 0.2mol/L, neutralizes, add isopropyl alcohol/tetrahydrofuran mixed solvent and be diluted to scale, mixing after lucifuge places 1h, 1h after mixing with hydrochloric acid solution, centrifugal, gets supernatant for subsequent use;
Illumination destroys: add isopropyl alcohol/tetrahydrofuran mixed solvent dissolved dilution to scale, mixing, after under putting high light, (4500Lx) irradiates 24h, centrifugal, gets supernatant for subsequent use;
High temperature: sample is destroyed 4h at 100 DEG C, gets 1.0ml, adds isopropyl alcohol/tetrahydrofuran mixed solvent and is diluted to scale, centrifugal, gets supernatant for subsequent use;
Oxidative demage: add 30% hydrogen peroxide 0.5ml, adds isopropyl alcohol/tetrahydrofuran mixed solvent after lucifuge placement 4h, 4h after mixing and is diluted to scale, centrifugal, gets supernatant for subsequent use;
3. assay method: chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Mobile phase: methyl alcohol is mobile phase A, acetonitrile is Mobile phase B, (0.01mol/L sodium dihydrogen phosphate buffer is mixed by 1.20g sodium dihydrogen phosphate 0.01mol/L phosphate buffered solutions, be diluted with water to 100ml, formulated with phosphorus acid for adjusting pH to 3.8) be mobile phase C, adopt gradient elution mode: 0-55min, 33%A, 25%B, 42%C; 55-65min, 33%A-35%A, 25%B-30%B, 42%C-35%C; 65-85min, 35%A, 30%B, 35%C; 85-93min, 35%A-33%A, 30%B-25%B, 35%C-42%C; 93-105min, 33%A, 25%B, 42%C.Determined wavelength is 220nm, and column temperature is 35 DEG C.Precision measures acid and destroys respectively, and alkali destroys, each 10 μ l injection liquid chromatographies of need testing solution of illumination, oxidation and heat damage, record chromatogram.Test findings shows, butyrate clevidipine emulsion is after degraded under the conditions such as acid, alkali, oxidation, illumination and heat, and the impurity in need testing solution all can detect.Butyrate clevidipine emulsion all has new degradation impurity peak after acid, alkali, oxidation and illumination destroy, and degradation impurity is separated can both be separated completely with between main peak and degradation impurity, and not by the interference at auxiliary material peak in emulsion.Specificity test findings shows, this method is applicable to be separated detection containing butyrate clevidipine emulsion at its various known or unknown related impurities produced of various violent and extreme complex condition.
Embodiment 9 phosphate kind, the screening of concentration and pH scope
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: precision take butyrate clevidipine reference substance, the reference substance of impurity A ~ I and H324/78, H168/79, H207/59, H152/81 and H152/66 reference substance appropriate, add methyl alcohol dissolves and be diluted to contain 1mg butyrate clevidipine and each impurity about 1 μ g in every 1ml known impurities mixed solution as need testing solution.Chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Mobile phase: methyl alcohol is mobile phase A, acetonitrile is Mobile phase B, and phosphate buffered solutions is mobile phase C, adopts gradient elution mode: 0-55min, 33%A, 25%B, 42%C; 55-65min, 33%A-35%A, 25%B-30%B, 42%C-35%C; 65-85min, 35%A, 30%B, 35%C; 85-93min, 35%A-33%A, 30%B-25%B, 35%C-42%C; 93-105min, 33%A, 25%B, 42%C.According to the form below 2 carries out phosphate kind, concentration and pH scope.Determined wavelength is 220nm, column temperature: 35 DEG C.Precision measures need testing solution 10 μ l injection liquid chromatography, record chromatogram.Result shows that this chromatographic system all can be separated each known impurities in mixed solution, can be separated completely between each impurity, does not have impurity to disturb the mensuration of main peak.
Phosphate kind, the selection result of concentration and pH scope is as following table 2
Table 2
Phosphate | Concentration (mol/L) | PH value | Degree of separation | Peak shape | Baseline |
Ammonium dihydrogen phosphate (ADP) | 0.005 | 3.5 | >1.5 | Symmetrical | Steadily |
Ammonium dihydrogen phosphate (ADP) | 0.1 | 4.0 | >1.5 | Symmetrical | Steadily |
Sodium dihydrogen phosphate | 0.005 | 4.0 | >1.5 | Symmetrical | Steadily |
Sodium dihydrogen phosphate | 0.1 | 3.8 | >1.5 | Symmetrical | Steadily |
Sodium dihydrogen phosphate | 0.05 | 3.5 | >1.5 | Symmetrical | Steadily |
Potassium dihydrogen phosphate | 0.1 | 3.8 | >1.5 | Symmetrical | Steadily |
Potassium dihydrogen phosphate | 0.01 | 4.0 | >1.5 | Symmetrical | Steadily |
Potassium dihydrogen phosphate | 0.005 | 3.8 | >1.5 | Symmetrical | Steadily |
From table, the damping fluid of sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate (ADP), in 0.005-0.1mol/L concentration range, pH all can be separated butyrate clevidipine degradation impurity and intermediate at 3.5-4.0, and can be separated completely, and peak shape is symmetrical.
Embodiment 10 detectability and quantitative limit test
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Mobile phase: methyl alcohol is mobile phase A, acetonitrile is Mobile phase B, (0.01mol/L sodium dihydrogen phosphate buffer is mixed by 1.20g sodium dihydrogen phosphate 0.01mol/L phosphate buffered solutions, be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 3.8) be mobile phase C, adopt gradient elution mode: 0-55min, 33%A, 25%B, 42%C; 55-65min, 33%A-35%A, 25%B-30%B, 42%C-35%C; 65-85min, 35%A, 30%B, 35%C; 85-93min, 35%A-33%A, 30%B-25%B, 35%C-42%C; 93-105min, 33%A, 25%B, 42%C.Determined wavelength is 220nm, column temperature: 35 DEG C.It is appropriate that precision takes butyrate clevidipine reference substance, with getting need testing solution 10 μ l injection liquid chromatography after methyl alcohol stepwise dilution, and record chromatogram.According to 10:1 signal to noise ratio (S/N ratio) as quantitative limit, result is 0.3 μ g/ml; Be detectability according to 3:1 signal to noise ratio (S/N ratio), result is 0.1 μ g/ml.
Embodiment 11 solution stability testing, linear test
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Mobile phase: methyl alcohol is mobile phase A, acetonitrile is Mobile phase B, (0.01mol/L sodium dihydrogen phosphate buffer is mixed by 1.20g sodium dihydrogen phosphate 0.01mol/L phosphate buffered solutions, be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 3.8) be mobile phase C, adopt gradient elution mode: 0-55min, 33%A, 25%B, 42%C; 55-65min, 33%A-35%A, 25%B-30%B, 42%C-35%C; 65-85min, 35%A, 30%B, 35%C; 85-93min, 35%A-33%A, 30%B-25%B, 35%C-42%C; 93-105min, 33%A, 25%B, 42%C.Determined wavelength is 220nm, and column temperature is 35 DEG C.Precision measures need testing solution 10 μ l injection liquid chromatography, record chromatogram.
3. solution stability testing
Get butyrate clevidipine raw material to be about 10mg and to be placed in 10ml volumetric flask respectively, add methyl alcohol dissolved dilution to scale, mix as need testing solution, respectively at 0,2,4, within 6 hours, get respectively 10 μ l sample introductions measure, record chromatogram, its main peak peak area and impurity determination result basicly stable in 6 hours.
4.0.1% reference substance solution linear test
It is appropriate that precision gets reference substance, dissolves stepwise dilution and become concentration to be about 0.3 μ g/ml, 0.8 μ g/ml, 1 μ g/ml, 1.2 μ g/ml, 1.5 μ g/ml, the contrast solution of 2 μ g/ml with methyl alcohol.Get each 10 μ l of contrast solution of above-mentioned variable concentrations, injection liquid chromatography, record chromatogram.When measurement result shows that contrast solution is in concentration range 0.3 μ g-2 μ g, peak area and concentration are good linear relationship, and its linearly dependent coefficient is 0.9995.The serviceability test of the different column temperature of embodiment 12 and flow velocity and determined wavelength, sample size
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: precision take butyrate clevidipine reference substance, the reference substance of impurity A ~ I and H324/78, H168/79, H207/59, H152/81 and H152/66 reference substance appropriate, add methyl alcohol dissolves and be diluted to contain 1mg butyrate clevidipine and each impurity about 1 μ g in every 1ml known impurities mixed solution as need testing solution.Chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm; Mobile phase: methyl alcohol is mobile phase A, acetonitrile is Mobile phase B, (0.01mol/L sodium dihydrogen phosphate buffer is mixed by 1.20g sodium dihydrogen phosphate 0.01mol/L phosphate buffered solutions, be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 3.8) be mobile phase C, adopt gradient elution mode: 0-55min, 33%A, 25%B, 42%C; 55-65min, 33%A-35%A, 25%B-30%B, 42%C-35%C; 65-85min, 35%A, 30%B, 35%C; 85-93min, 35%A-33%A, 30%B-25%B, 35%C-42%C; 93-105min, 33%A, 25%B, 42%C.Determined wavelength, column temperature and volume according to the form below 3 carries out.Precision measures certain volume need testing solution injection liquid chromatography, record chromatogram.Result shows that this chromatographic system all can be separated each known impurities in mixed solution, can be separated completely between each impurity, does not have impurity to disturb the mensuration of main peak.
The selection result of column temperature, flow velocity, sample size and determined wavelength scope is as following table 3
Table 3
From measurement result, the flow velocity of mobile phase is 0.7-1.1ml/min, and determined wavelength, at 220-260nm, all can be separated butyrate clevidipine degradation impurity and intermediate within the scope of column temperature 20-40 DEG C, sample size 2-20 μ l, and can be separated completely, and peak shape is symmetrical.
The determination of related substances of embodiment 13 butyrate clevidipine raw material
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: it is appropriate that precision takes butyrate clevidipine raw material, add methyl alcohol dissolves and be diluted to contain 1mg butyrate clevidipine in every 1ml solution as need testing solution.It is appropriate that precision measures need testing solution, adds methanol dilution and become the solution containing butyrate clevidipine 1 μ g in every 1ml, product in contrast.Chromatographic column AgilentZORBAX Extend-C18250 × 4.6mm, 5 μm; Mobile phase: methyl alcohol is mobile phase A, acetonitrile is Mobile phase B, (0.01mol/L sodium dihydrogen phosphate buffer is mixed by 1.20g sodium dihydrogen phosphate 0.01mol/L phosphate buffered solutions, be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 3.8) be mobile phase C, adopt gradient elution mode: 0-55min, 33%A, 25%B, 42%C; 55-65min, 33%A-35%A, 25%B-30%B, 42%C-35%C; 65-85min, 35%A, 30%B, 35%C; 85-93min, 35%A-33%A, 30%B-25%B, 35%C-42%C; 93-105min, 33%A, 25%B, 42%C.Precision measures 10 μ l reference substance solution, injection liquid chromatography, and condition detection sensitivity makes major component peak height be about 20% of full scale, then precision gets reference substance solution and each 10 μ l of need testing solution, injection liquid chromatography, record chromatogram.With the major component Self-control method of the not correction up factor with calculated by peak area, the total impurities in need testing solution is 0.07%.
The determination of related substances of embodiment 14 butyrate clevidipine emulsion
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: it is appropriate that precision measures butyrate clevidipine emulsion (from antigalactic), add acetonitrile and dissolve and be diluted to the solution containing 50 μ g butyrate clevidipines in every 1ml, ultrasonic, centrifuging and taking supernatant is as need testing solution.It is appropriate that precision measures need testing solution, adds dilution in acetonitrile and become the solution containing butyrate clevidipine 0.5 μ g in every 1ml, product solution in contrast.Chromatographic column Shimadzu GL intersil ODS-3150 × 4.6mm, 3 μm; Mobile phase: methyl alcohol is mobile phase A, acetonitrile is Mobile phase B, (0.01mol/L sodium dihydrogen phosphate buffer is mixed by 1.20g sodium dihydrogen phosphate 0.01mol/L phosphate buffered solutions, be diluted with water to 1000ml, formulated with phosphorus acid for adjusting pH to 3.8) be mobile phase C, adopt gradient elution mode: 0-55min, 33%A, 25%B, 42%C; 55-65min, 33%A-35%A, 25%B-30%B, 42%C-35%C; 65-85min, 35%A, 30%B, 35%C; 85-93min, 35%A-33%A, 30%B-25%B, 35%C-42%C; 93-105min, 33%A, 25%B, 42%C.Precision measures 20 μ l reference substance solution, injection liquid chromatography, and condition detection sensitivity makes major component peak height be about 20% of full scale, then precision gets reference substance solution and each 20 μ l of need testing solution, injection liquid chromatography, record chromatogram.With the major component Self-control method of the not correction up factor with calculated by peak area, the total impurities in test sample is 0.45%, sees accompanying drawing 14.
Claims (10)
1. the detection method of related substance in butyrate clevidipine and preparation thereof, is characterized in that:
(1) butyrate clevidipine bulk drug or butyrate clevidipine formulation samples is got, with organic solvent dissolution, preparation need testing solution;
(2) reversed-phased high performace liquid chromatographic is adopted, chromatographic column is C18 post, column temperature scope 20-40 DEG C, the flow velocity of mobile phase is 0.7-1.1ml/min, with A: methyl alcohol, B: the mixed solution of the phosphate buffer of acetonitrile and C:0.005-0.1mol/L pH 3.5-4.0 is mobile phase, adopts gradient elution mode; In elution process, in mobile phase, the volumn concentration of A, B, C is as follows:
0-55min, A are 33%, B be 25%, C is 42%; 55-65min, A are at the uniform velocity increased to 35%, B by 33% and are at the uniform velocity increased to 30%, C by 25% and are at the uniform velocity reduced to 35% by 42%; 65-85min, A are 35%, B be 30%, C is 35%; 85-93min, A are at the uniform velocity reduced to 33%, B by 35% and are at the uniform velocity reduced to 25%, C by 30% and are at the uniform velocity increased to 42% by 35%; 93-105min, A are 33%, B be 25%, C is 42%;
(3) adopt UV-detector, determined wavelength 220-260nm, record chromatogram, completes the mensuration of related substance in butyrate clevidipine need testing solution.
2. detection method according to claim 1, it is characterized in that, in described step (1), get butyrate clevidipine bulk drug organic solvent dissolution and dilute, make the need testing solution of every 1ml containing butyrate clevidipine 0.1-10mg, or get butyrate clevidipine formulation samples organic solvent dissolution and be diluted to the solution of every 1ml containing butyrate clevidipine 0.01-0.1mg, getting supernatant after centrifugal or get filtrate as need testing solution after filtering.
3. detection method according to claim 1 and 2, is characterized in that, in described step (1), in preparation need testing solution the organic solvent that uses be methyl alcohol, one or more in acetonitrile, ethanol, isopropyl alcohol or tetrahydrofuran.
4. detection method according to claim 1 and 2, is characterized in that, in described step (2), chromatographic column take C18 as filler, and particle diameter is 3.0 ~ 5.0 μm, and column length is 150 ~ 250mm, and column internal diameter is 4.6mm.
5. detection method according to claim 4, is characterized in that, packing material size is 3.5 μm, and column length is 150mm.
6. detection method according to claim 1 and 2, is characterized in that, in described step (2), column temperature is set as 35 DEG C.
7. detection method according to claim 1 and 2, is characterized in that, in described step (2), flow control is at 0.8 ml/min.
8. detection method according to claim 1 and 2, is characterized in that, in described step (2), the pH value of mobile phase phosphate buffered solution is 3.8.
9. detection method according to claim 1 and 2, is characterized in that, in described step (3), determined wavelength is set as 220nm.
10. detection method according to claim 1 and 2, is characterized in that, in described step (3), the content of related substance with the major component Self-control method of the not correction up factor with calculated by peak area.
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