CN104597192B - A kind of butyrate clevidipine and preparation thereof have the detection method of related substance - Google Patents
A kind of butyrate clevidipine and preparation thereof have the detection method of related substance Download PDFInfo
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Abstract
The invention discloses the detection method having related substance in a kind of butyrate clevidipine and preparation thereof.This method uses reversed phase high-performance liquid chromatography, uses C18 chromatographic column, carries out gradient elution with methanol acetonitrile phosphate buffered saline mutually for flowing, uses UV-detector.The method is capable of efficiently separating of butyrate clevidipine and all known impurities, solves its synthesis and the interference to product purity of all kinds of impurity that formulation process produces, it is possible to control butyrate clevidipine raw material or the quality of preparation comprehensively and effectively.The method is simple to operate, specificity is strong, highly sensitive, can detect well has related substance in butyrate clevidipine raw material and preparation, and the quality control for research and development and process of manufacture provides analysis method the most reliably.
Description
Technical field
The invention belongs to pharmaceutical technology field, a kind of butyrate clevidipine and preparation thereof have related substance
Detection method.
Background technology
The nomenclature of drug of heretofore described butyrate clevidipine is:
Common name: butyrate clevidipine
Chemical name: 4-(2,3-Dichlorobenzene base)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl (1-butyryl
Epoxide) methyl ester 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-
Pyridinedicarboxylic acid methyl(1-oxobutoxy)methyl ester
English name: Clevidipine butyrate
Chemical structural formula:
Molecular formula: C21H23Cl2NO6
Molecular weight: 456.32
Butyrate clevidipine is the novel fugitive dihydro of the third generation developed by Britain's AstraZeneca (AstraZeneca) company
Pyridines calcium-channel antagonists.Butyrate clevidipine Emulsion used for intravenous injection listed in the U.S. first in August, 2008, trade name
Cleviprex, is the only one intravenous injection antihypertensive agent ratifying listing in nearly 10 years.This medicine is used for treating unsuitable mouth
Take medicine or the invalid hypertension of oral medication it can also be used to treatment surgical site infections acute blood pressure raises.Owing to butanoic acid chlorine is tieed up
Horizon is unstable, it may happen that degraded in preparation processing and storage, likely introduces in this product building-up process simultaneously
Retained material, intermediate and other by-products etc. have related substance, and these have related substance not only can reduce butyrate clevidipine
Purity and clinical efficacy, also the most known because of it and genotoxic potential can endanger the life security of patient.Related substances separation is medicine
The important component part of quality standard, both can guarantee that the safe and effective of medication, can examine again production technology and the storage of medicine
Condition.In the several years in past, butyrate clevidipine and containing butyrate clevidipine as the compositions of active component in
Identified plurality of impurities.Some impurity derive from the process preparing butyrate clevidipine raw material and preparation thereof, and other are then
It it is the progressively degraded due to active component.
The synthesis of butyrate clevidipine is presently mainly using chlorobenzaldehyde and methyl acetoacetate or derivatives thereof as rising
Beginning raw material, through intermediate 3-(2,3-Dichlorobenzene base)-2-acetyl group acrylic acid or derivatives thereof, then through intermediate 4-(2,3-bis-
Chlorphenyl)-Isosorbide-5-Nitrae-dihydro-2,6-dimethyl-3,5-dipicolinic acid monomethyl ester, then react generation butanoic acid chlorine with butanoic acid chloromethyl ester
Dimension Horizon.The most common byproduct of reaction that may introduce and the residual impurity such as intermediate be mainly 4-(2,3-Dichlorobenzene base)-
1,4-dihydro-2,6-dimethyl-3,5-dipicolinic acid monomethyl ester, 3-(2,3-Dichlorobenzene base)-2-acetyl group acrylic acid or its
Derivant or 3-(2,3-Dichlorobenzene base)-2-acetyl group acrylic acid butyryl oxygen methyl ester etc..
Patent US20100105743A1, CN102170786A (PCT application data PCT/US2009/
0043992009.07.30) and in CN 102186351 A (PCT application data PCT/US2009/0521272009.07.29),
The degradation pathway mentioning butyrate clevidipine includes 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 thing by the way of hydrolysis and condensation further
Matter 23, material 24 and/or material 25.Above-mentioned patent is mentioned isocratic, the normal phase high performance liquid chromatography of employing with heptane: ethanol
(90: 10) carry out separation determination mutually as flowing, and it has related substance.Experiment proves that, found that the balance that the method needs
For up to 4 hours as long as, and each peak separated and retains unsatisfactory, butyrate clevidipine peak and by-product impurities H and G impurity
Peak almost overlap (see accompanying drawing 1), and normal-phase chromatography method is inconvenient to be combined mass spectrometer detector and is carried out each impurity the fastest
The qualitative analysis of speed, therefore in this patent, the method for report is unsatisfactory.
1998, Jaremo et al. (Supercritical Fluid Extraction of Clevidipine from
A Water Based Vegetable Oil Emulsion, Volume 21, Issue 3,1998) report an analysis fourth
Acid clevidipine and the method for Partial digestion product (H324/78 and H152/81) thereof.Method is with octadecylsilane chemically bonded silica
For filler, acetonitrile: methanol: phosphate buffered solution (phosphoric acid of 15ml 1mol/L and the sodium dihydrogen phosphate of 100ml1mol/L
Mixing, is diluted to 2000ml, regulates pH3.0)=40:20:40 is flowing phase.Empirical tests, under the process conditions, butanoic acid chlorine is tieed up
Degraded H207/59 and the impurity G separating degree of Horizon are 1.06, it is impossible to separately, it is serious that another one degradation impurity H168/79 goes out peak
Before drag, cause can not reaching to be sufficiently separated with oxidation impurities H324/78 below, separating degree is only 1.31.
The most domestic butyrate clevidipine that yet there are no analyzes the document report of method, the medicine that this medicine is the most unified
Standard, therefore, in order to better control over the quality of butyrate clevidipine product, need to set up a set of simple and reliable and stable effective
Method carries out the related substance that has of this product and detects, and solution synthesis technique introduces or degraded and formulation process produce
The interference that product purity is measured by all kinds of known or unknown impuritie.
Summary of the invention
The technical problem to be solved is to provide in a kind of butyrate clevidipine and preparation thereof related substance
Detection method.The method overcome current normal phase chromatography and Reversed Phase Isocratic elution process all cannot realize butyrate clevidipine with
There is the drawback that related substance efficiently separates, use the mode of gradient elution to realize butyrate clevidipine and the reversed phase high efficiency having related substance
Liquid phase separation, it is achieved to butyrate clevidipine raw material or the quality control of its preparation.
It is not suitable for LC-MS instrument, it is impossible to carry out the relevant thing of butyrate clevidipine further in view of normal-phase chromatography condition
The separation of matter and structure-characterized detection, therefore our primary study reversed-phase high-performance liquid chromatography method.
Sweep through the by-product of butyrate clevidipine, intermediate and isolated and degradation impurity etc. are carried out ultraviolet curve
Retouching, they have maximum absorption wavelength in 220nm-240nm scope substantially, wherein 220nm be butyrate clevidipine and major part miscellaneous
The maximum absorption wavelength of matter, therefore the wavelength that preferred 220nm has related substance to detect as butyrate clevidipine.
First our reference literature (Supercritical Fluid Extraction of Clevidipine from a
Water Based Vegetable Oil Emulsion, J.LIQ.CHROM.&REL.TECHNOL., Volume 21, Issue
3,1998) method described in, with octadecylsilane chemically bonded silica as filler, acetonitrile: methanol: phosphate buffered solution
(phosphoric acid of 15ml 1mol/L mixes with the sodium dihydrogen phosphate of 100ml 1mol/L, is diluted to 2000ml, regulates pH3.0)=40:
20:40 is flowing phase, found that degradation impurity L is dragged before going out peak, cannot separate with oxidation impurities K, degradation impurity M and by-product
The separating degree of impurity G is only 1.06, attempts again having changed the C18 chromatographic column of dissimilar filler model, all cannot obtain ideal
Separating effect.
Applicant has been surprisingly found that at methanol-acetonitrile-phosphate buffered solution (pH=3.8)=33:25:42 as flowing phase
When given the test agent is carried out gradient elution, each peak is obtained for well separation, and simply impurity H goes out peak too late, later by ladder
Degree have adjusted the elution time of impurity H after main peak, obtains methanol-acetonitrile-phosphate buffered solution three-phase gradient elution program,
Just can realize butyrate clevidipine and have efficiently separating of related substance, no matter intermediate, synthesising by-product or degrade product
Thing (table 1) all each peak separating degree more than 1.5, can also avoid the dry of solvent peak and adjuvant peak under this gradient elution program
Disturbing, peak shape is good, and baseline is steady, and the main constituent peak purity factor also complies with requirement, and result is satisfactory.Work as methanol: acetonitrile: phosphoric acid
During salt buffer solution=30:30:40, the peak separating degree near main peak is best, and separating degree is all higher than 2, but the most miscellaneous
Matter M can not be separated with impurity G, and separating degree is less than 1.And methanol: acetonitrile: during phosphate buffered solution=15:45:40, main peak
Neighbouring peak separating degree is less than 1.5.When additionally pH value is more than 4.0, can affect impurity J and impurity C, impurity L and impurity K point
From, when pH is less than 3.5, impurity L can trail, and affects it and separates with front and back impurity, and the suitably pH scope mutually that therefore flows is
3.5-4.0.Preferably pH=3.8.
Table 1
The technical scheme is that and be achieved in that, it comprises the following steps:
A kind of butyrate clevidipine and preparation thereof have the detection method of related substance:
(1) taking butyrate clevidipine crude drug or butyrate clevidipine formulation samples, dissolve with organic solvent, preparation is for examination
Product solution；
(2) using reversed phase high-performance liquid chromatography, chromatographic column is C18 post, column temperature scope 20-40 DEG C, the flow velocity of flowing phase
For 0.7-1.1ml/min, with A: methanol, the phosphate buffer of B: acetonitrile and C:0.005-0.1mol/L pH 3.5-4.0
Mixed solution is flowing phase, uses gradient elution mode；In elution process, A in flowing mutually, the volumn concentration of B, C is as follows:
0-55min, A are 33%, and B is 25%, and C is 42%；55-65min, A are at the uniform velocity improved by 33% to 35%, B by
25% at the uniform velocity improves to 30%, and C is at the uniform velocity reduced to 35% by 42%；65-85min, A are 35%, and B is 30%, and C is 35%；85-
93min, A are at the uniform velocity reduced to 33% by 35%, and B is at the uniform velocity reduced to 25% by 30%, and C is at the uniform velocity improved to 42% by 35%；93-
105min, A are 33%, and B is 25%, and C is 42%；
(3) use UV-detector, detect wavelength 220-260nm, record chromatogram, complete butyrate clevidipine test sample
Solution has the mensuration of related substance.
In described method step (1), take butyrate clevidipine raw material medicinal organic solvent and dissolve and dilute, make every 1ml
Containing the need testing solution of butyrate clevidipine 0.1-10mg, or take the dissolving of butyrate clevidipine formulation samples organic solvent also
It is diluted to every 1ml solution containing butyrate clevidipine 0.01-0.1mg, after taking supernatant after being centrifuged or filtering, takes filtrate as confession
Test sample solution；
In described method step (1), the organic solvent used in preparation need testing solution is methanol, acetonitrile, ethanol, different
One or more in propanol or oxolane.
In described method step (2), chromatographic column is with C18 as filler, and particle diameter is 3.0～5.0 μm, column length be 150～
250mm, column internal diameter is 4.6mm.The most 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 speed control is at 0.8ml/min.
In described method step (2), the pH value of flowing phase phosphate buffered solution is 3.8.
In described method step (3), detection wavelength is set as 220nm.
In described method step (3), there is the content of related substance to be not added with the main constituent Self-control method of correction factor with peak
Areal calculation.
The present invention uses gradient elution to achieve in butyrate clevidipine and preparation being kept completely separate of related substance, it is achieved that
To product synthesis impurity, intermediate and the control of degradation impurity, various needs are had the butanoic acid chlorine dimension ground that related substance detects
The quality control aspect of the related preparations put down and contain butyrate clevidipine is significant.
Accompanying drawing explanation
Fig. 1, heptane: ethanol (90: 10) is as the chromatogram of flowing phase.
Fig. 2, acetonitrile: methanol: phosphate buffered solution (40:20:40) can not be totally separated known impurities mutually and mix for flowing
Close the chromatogram (Waters chromatographic column) of solution.
Fig. 3, acetonitrile: methanol: phosphate buffered solution (40:20:40) can not be totally separated known impurities mutually and mix for flowing
Close the chromatogram (Yi Lite chromatographic column) of solution.
Fig. 4～5, gradient elution can not in varing proportions mutually for flowing for acetonitrile-0.01mol/L ammonium dihydrogen phosphate buffer solution
It is totally separated the chromatogram of known impurities mixed solution.
Fig. 6, gradient elution can not be complete in varing proportions mutually for flowing for methanol-0.01mol/L ammonium dihydrogen phosphate buffer solution
Part is from the chromatogram of known impurities mixed solution.
Fig. 7, more than 10 kind of intermediate, synthesising by-product and the known impurities mixed solution of catabolite composition, by we
Method tests the chromatogram obtained.Result shows, all impurity all can be analyzed out in a collection of illustrative plates, can be complete between each impurity
Fully separating, there is no the mensuration of impurity interference main peak.
Fig. 8, in order to verify reliability and the specificity of the inventive method further, by the crude product solution to be refined of synthesis
Sample, tests the chromatogram obtained by this method.Result shows that each impurity separates well with main constituent peak, shows the present invention's
Method can be applicable under synthesis condition its various known or unknown relevant magazins' layout produced detection.
Fig. 9～13, in order to verify reliability and the specificity of the inventive method further, be respectively adopted through peracid destroy,
The chromatograph collection of illustrative plates obtained tested by alkali destruction, illumination, high temperature, the butyrate clevidipine raw material of Oxidative demage by this method, each miscellaneous
Mass peak shape and separating degree are good, show the method for the present invention can be applicable to various acutely and extremely complicated under the conditions of it produces
Various known or unknown relevant magazins' layout detects.
Figure 14, in order to verify reliability and the specificity of the inventive method further, is carried out butyrate clevidipine Emulsion
Relevant substance-measuring, tests the chromatogram obtained by this method.Result shows that each impurity separates well with main constituent peak, shows
The various known or unknown relevant magazins' layout detection that the method for the present invention can produce be applicable to preparation produces.
Detailed description of the invention
By below embodiment, the technical method of the present invention is further described, but not as the restriction of the present invention.
Embodiment 1 acetonitrile: methanol: phosphate buffered solution (pH=3.0)=40:20:40 (volume ratio) is for flowing the most not
The test of known impurities mixed solution can be totally separated
1. instrument: Agilent 1260 high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: precision weigh butyrate clevidipine, impurity G, the reference substance of impurity F and H324/78, H168/79,
The reference substance of H207/59, H152/81 and H152/66 is appropriate, adds methanol and dissolves and be diluted in every 1ml containing butanoic acid chlorine dimension ground
The known impurities mixed solution of flat 1mg and each impurity about 1 μ g is as need testing solution.Chromatographic column Waters sunfire
C18150 × 4.6mm, 3.5 μm；Flowing is acetonitrile mutually: methanol: phosphate buffered solution=40:20:40, phosphate buffered solution
Mixed with the sodium dihydrogen phosphate of 100ml1mol/L by the phosphoric acid of 15ml 1mol/L, be diluted with water to 2000ml, regulate with phosphoric acid
PH is formulated to 3.0.Detection wavelength is 220nm, and column temperature is 35 DEG C, flow velocity 1.0ml/min.Precision measures need testing solution 10
μ l injects chromatograph of liquid, records chromatogram.The high-efficient liquid phase chromatogram obtained as stated above such as accompanying drawing 2.Result shows this
Chromatographic system can not be totally separated each known impurities in mixed solution.
Embodiment 2 acetonitrile: methanol: phosphate buffered solution (pH=3.0)=40:20:40 (volume ratio) is for flowing the most not
The test of known impurities mixed solution can be totally separated
1. instrument: Agilent 1260 high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method (1): precision weighs impurity A～the reference substance of I and H324/78, H168/79, H207/59, H152/
The reference substance of 81 and H152/66 is appropriate, adds methanol and dissolves and be diluted in every 1ml the known impurities mixing containing each impurity about 20 μ g
Solution is as need testing solution.Chromatographic column Yi Lite Hypersil BDS C18150 × 4.6mm, 3 μm；Flowing is acetonitrile mutually: first
Alcohol: phosphate buffered solution=40:20:40, phosphate buffered solution is by the phosphoric acid of 15ml 1mol/L and 100ml 1mol/L
Sodium dihydrogen phosphate mixes, and is diluted with water to 2000ml, formulated to 3.0 with phosphorus acid for adjusting pH.Detection wavelength is 220nm, post
Temperature is 35 DEG C, flow velocity 1.0ml/min.Precision measures need testing solution 10 μ l and injects chromatograph of liquid, records chromatogram.By above-mentioned
The high-efficient liquid phase chromatogram that method obtains such as accompanying drawing 3.This chromatographic system can not be totally separated each known impurities in mixed solution.
Gradient elution can not in varing proportions mutually for flowing for embodiment 3 acetonitrile-0.01mol/L ammonium dihydrogen phosphate buffer solution
It is totally 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 weighs butyrate clevidipine, impurity G, the reference substance of impurity F and H324/78, H168/
79, the reference substance of H207/59, H152/81 and H152/66 is appropriate, adds methanol and dissolves and be diluted in every 1ml the butanoic acid chlorine Han 1mg
Tie up the known impurities mixed solution of gentle each impurity about 1 μ g as need testing solution.Chromatographic column Waters sunfire
C18150 × 4.6mm, 3.5 μm；Flow visualizing, A is acetonitrile, and B is 0.01mol/L ammonium dihydrogen phosphate buffer salt buffer solution,
0.01mol/L ammonium dihydrogen phosphate buffer solution is mixed by 1.15g ammonium dihydrogen phosphate, is diluted with water to 1000ml, regulates with phosphoric acid
PH is formulated to 3.5, and 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.Detection wavelength is 220nm, and column temperature is 35 DEG C, flow velocity 0.8ml/
min.Precision measures need testing solution 10 μ l and injects chromatograph of liquid, records chromatogram.The efficient liquid phase obtained as stated above
Chromatogram such as accompanying drawing 4.Result shows each known impurities that this chromatographic system can not be totally separated in mixed solution.
3. assay method (2): chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm, flow visualizing, A is
Acetonitrile, B is 0.01mol/L ammonium dihydrogen phosphate buffer salt buffer solution, and 0.01mol/L ammonium dihydrogen phosphate buffer solution is by 1.15g
Ammonium dihydrogen phosphate mixes, and is diluted with water to 1000ml, and formulated to 3.5 with phosphorus acid for adjusting pH, 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.Detection wavelength is 220nm, and column temperature is 35 DEG C, flow velocity 0.8ml/min.Precision measures need testing solution 10 μ l note in 2
Enter chromatograph of liquid, record chromatogram.The high-efficient liquid phase chromatogram obtained as stated above such as accompanying drawing 5.Result shows this chromatograph
System can not be totally separated each known impurities in mixed solution.
Embodiment 4 methanol-0.01mol/L ammonium dihydrogen phosphate buffer solution can not be totally separated with gradient elution for flowing
The test of known impurities mixed solution
1. instrument: Agilent 1260 high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: precision weighs reference substance and H324/78, H168/ of butyrate clevidipine reference substance, impurity A～I
79, the reference substance of H207/59, H152/81 and H152/66 is appropriate, adds methanol and dissolves and be diluted in every 1ml the butanoic acid chlorine Han 1mg
Tie up the known impurities mixed solution of gentle each impurity about 1 μ g as need testing solution.Chromatographic column Waters sunfire
C18150 × 4.6mm, 3.5 μm；Flow visualizing, A phase is methanol, and B phase is that 0.01mol/L ammonium dihydrogen phosphate buffer salt buffering is molten
Liquid, 0.01mol/L ammonium dihydrogen phosphate buffer solution is mixed by 1.15g ammonium dihydrogen phosphate, is diluted with water to 1000ml, adjusts with phosphoric acid
PH is formulated to 3.5 for joint, and 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.Detection wavelength is 220nm, and column temperature is 35 DEG C, flow velocity
0.8ml/min.Precision measures need testing solution 10 μ l and injects chromatograph of liquid, records chromatogram.The height obtained as stated above
Effect liquid phase chromatogram figure such as accompanying drawing 6.Result shows each known impurities that this chromatographic system can not be totally separated in mixed solution.
Embodiment 5 methanol-acetonitrile-phosphate buffered solution can efficiently separate impurity mixing for flowing with gradient elution
The test of solution
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: precision weighs reference substance and H324/78, H168/ of butyrate clevidipine reference substance, impurity A～I
79, the reference substance of H207/59, H152/81 and H152/66 is appropriate, adds methanol and dissolves and be diluted in every 1ml the butanoic acid chlorine Han 1mg
Tie up the known impurities mixed solution of gentle each impurity about 1 μ g as need testing solution.Chromatographic column Waters sunfire
C18150 × 4.6mm, 3.5 μm；Flowing phase: methanol is mobile phase A, and acetonitrile is Mobile phase B, and 0.01mol/L phosphate buffer is molten
(0.01mol/L sodium dihydrogen phosphate buffer is mixed liquid by 1.20g sodium dihydrogen phosphate, is diluted with water to 1000ml, adjusts with phosphoric acid
PH is formulated to 3.8 for joint) it is flowing phase C, use 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.Detection ripple
A length of 220nm, column temperature is 35 DEG C, flow velocity 0.8ml/min.Precision measures need testing solution 10 μ l and injects chromatograph of liquid, record
Chromatogram.The high-efficient liquid phase chromatogram obtained as stated above such as accompanying drawing 7.Result shows that this chromatographic system can be totally separated mixing
Each known impurities in solution, can be kept completely separate between each impurity, does not has the mensuration of impurity interference main peak.
It is former that embodiment 6 methanol-acetonitrile-phosphate buffered solution condition of gradient elution can efficiently separate butyrate clevidipine
The test of material crude product 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 is (according to patent
CN201310003732.1 synthesis obtains), add methanol and dissolve and be diluted in every 1ml the butanoic acid chlorine dimension containing each impurity about 1mg
Horizon is as need testing solution.Chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm；Flowing phase: methanol is flowing
Phase A, acetonitrile is Mobile phase B, and (0.01mol/L ammonium dihydrogen phosphate buffer solution is by 1.15g for 0.01mol/L phosphate buffered solutions
Ammonium dihydrogen phosphate mixes, and is diluted with water to 1000ml, formulated to 3.5 with phosphorus acid for adjusting pH) it is flowing phase C, use gradient
Type of elution: 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.Detection wavelength is 220nm, and column temperature is 35 DEG C.Precision measures need testing solution 10
μ l injects chromatograph of liquid, records chromatogram.The high-efficient liquid phase chromatogram obtained as stated above such as accompanying drawing 8.Result display pair
Product, intermediate separate well with main constituent peak.
It is former that embodiment 7 methanol-acetonitrile-phosphate buffered solution condition of gradient elution can efficiently separate butyrate clevidipine
Material acid, alkali, light, heat, the test of Oxidative demage solution
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. take butyrate clevidipine raw material (synthesize, according to patent CN201310003732.1, the butyrate clevidipine that obtains,
Afterwards together) about 10mg is respectively placed in 10ml volumetric flask, prepares test sample according to following each condition.
Acid destroys: adds 2ml methanol by butyrate clevidipine material dissolution, adds the hydrochloric acid of 0.5ml 0.1mol/L, after mixing
Lucifuge places 4h, neutralizes with sodium hydroxide, add methanol dilution to scale after 4h；
Alkali destroys: adds 2ml methanol by butyrate clevidipine material dissolution, adds the sodium hydroxide of 0.5ml 0.01mol/L, mixed
Even rear lucifuge places 0.5h, neutralizes with hydrochloric acid solution, add methanol dilution to scale after 0.5h；
Illumination destroys: add methanol dissolved dilution to scale, and mixing puts (4500Lx) under high light standby after irradiating 24h；
High temperature: add 2ml methanol by butyrate clevidipine material dissolution, is placed on boiling water bath heating 4h, adds methanol dilute
Release to scale；
Oxidative demage: add 2ml methanol by butyrate clevidipine material dissolution, add 30% hydrogen peroxide 0.5ml, lucifuge after mixing
Place 4h, add methanol dilution after 4h to scale；
3. assay method: chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm；Flowing phase: methanol is flowing
Phase A, acetonitrile is Mobile phase B, and (0.01mol/L sodium dihydrogen phosphate buffer is by 1.2g phosphorus for 0.01mol/L phosphate buffered solutions
Acid dihydride sodium mixes, and is diluted with water to 1000ml, formulated to 4.0 with phosphorus acid for adjusting pH) it is flowing phase C, use gradient to wash
Off-square formula: 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.Detection wavelength is 220nm, and column temperature is 35 DEG C.Precision measures acid destruction respectively, and alkali breaks
Bad, illumination, high temperature, each 10 μ l of need testing solution of Oxidative demage inject chromatograph of liquid, record chromatogram.As stated above
The high-efficient liquid phase chromatogram arrived such as accompanying drawing 9～13.Result shows, butyrate clevidipine raw material is through acid, alkali, oxidation, high temperature and light
After destroying degraded under the conditions of grade, the impurity in need testing solution all can detect.Wherein test sample is through acid, alkali, oxidation and light
All there is new degradation impurity peak according to after destroying, separate between degradation impurity with main peak and degradation impurity and can be kept completely separate, and newly
The retention time of the impurity that degradation impurity peak and raw material carry has significantly difference.Specificity result of the test shows, this method
Be applicable to butyrate clevidipine raw material various acutely and extremely complicated under the conditions of its produce various known or unknown relevant miscellaneous
The separation detection of matter.
Embodiment 8 methanol-acetonitrile-phosphate buffered solution condition of gradient elution can efficiently separate butyrate clevidipine breast
Agent sample is through acid, alkali, light, high temperature, the test of Oxidative demage solution
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. take butyrate clevidipine Emulsion (from antigalactic: butyrate clevidipine 0.5mg/mL, soybean oil 200mg/mL, sweet
Oil 22.5mg/mL, lecithin 12mg/mL, oleic acid 0.3mg/mL；Butyrate clevidipine uses patent CN201310003732.1 to close
Becoming to obtain) about 1ml is respectively placed in 10ml volumetric flask, prepares test sample according to following each condition.
Acid destroys: add the hydrochloric acid of 1ml 0.1mol/L, after lucifuge places 2h after mixing, neutralizes with sodium hydroxide, add after 1h
Isopropanol/oxolane mixed solvent is diluted to scale, mixing, centrifugal, takes supernatant standby；
Alkali destroys: add the sodium hydroxide of 1ml 0.2mol/L, and after mixing, lucifuge places 1h, neutralizes with hydrochloric acid solution after 1h,
Add isopropanol/oxolane mixed solvent and be diluted to scale, mixing, centrifugal, take supernatant standby；
Illumination destroys: add isopropanol/oxolane mixed solvent dissolved dilution to scale, mixing, puts under high light
(4500Lx) after irradiating 24h, centrifugal, take supernatant standby；
High temperature: sample destroys at 100 DEG C 4h, takes 1.0ml, adds isopropanol/oxolane mixed solvent dilution
To scale, centrifugal, take supernatant standby；
Oxidative demage: add 30% hydrogen peroxide 0.5ml, after mixing, lucifuge places 4h, adds isopropanol/oxolane mixing after 4h
Solvent dilution is to scale, centrifugal, takes supernatant standby；
3. assay method: chromatographic column Waters sunfire C18150 × 4.6mm, 3.5 μm；Flowing phase: methanol is flowing
Phase A, acetonitrile is Mobile phase B, and (0.01mol/L sodium dihydrogen phosphate buffer is by 1.20g for 0.01mol/L phosphate buffered solutions
Sodium dihydrogen phosphate mixes, and is diluted with water to 100ml, formulated to 3.8 with phosphorus acid for adjusting pH) it is flowing phase C, use gradient to wash
Off-square formula: 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.Detection wavelength is 220nm, and column temperature is 35 DEG C.Precision measures acid destruction respectively, and alkali breaks
Bad, each 10 μ l of need testing solution of illumination, oxidation and heat damage inject chromatograph of liquid, record chromatogram.Result of the test shows,
Butyrate clevidipine Emulsion is after degraded under the conditions of acid, alkali, oxidation, illumination and heat etc., and the impurity in need testing solution all can
Detection.Butyrate clevidipine Emulsion all has new degradation impurity peak, degradation impurity and main peak after acid, alkali, oxidation and illumination destroy
And separate between degradation impurity and can be kept completely separate, and do not disturbed by adjuvant peak in Emulsion.Specificity result of the test shows,
This method be applicable to containing butyrate clevidipine Emulsion various acutely and extremely complicated under the conditions of its produce various known or
The separation detection of unknown related impurities.
Embodiment 9 phosphate kind, concentration and the screening of pH scope
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: precision weighs reference substance and H324/78, H168/ of butyrate clevidipine reference substance, impurity A～I
79, the reference substance of H207/59, H152/81 and H152/66 is appropriate, adds methanol and dissolves and be diluted in every 1ml the butanoic acid chlorine Han 1mg
Tie up the known impurities mixed solution of gentle each impurity about 1 μ g as need testing solution.Chromatographic column Waters sunfire
C18150 × 4.6mm, 3.5 μm；Flowing phase: methanol is mobile phase A, and acetonitrile is Mobile phase B, phosphate buffered solutions is flowing phase
C, employing 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.Inspection
Survey wavelength is 220nm, column temperature: 35 DEG C.Precision measures need testing solution 10 μ l and injects chromatograph of liquid, records chromatogram.Result
Show each known impurities that this chromatographic system can be totally separated in mixed solution, can be kept completely separate between each impurity, the most miscellaneous
The mensuration of matter interference main peak.
Phosphate kind, the selection result of concentration and pH scope such as table 2 below
Table 2
| Phosphate | Concentration (mol/L) | PH value | Separating degree | Peak shape | Baseline |
| Ammonium dihydrogen phosphate | 0.005 | 3.5 | >1.5 | Symmetrical | Steadily |
| Ammonium dihydrogen phosphate | 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, sodium dihydrogen phosphate, potassium dihydrogen phosphate, the buffer of ammonium dihydrogen phosphate are dense at 0.005-0.1mol/L
In the range of degree, pH all can separate butyrate clevidipine degradation impurity and intermediate at 3.5-4.0, and can be kept completely separate, peak shape pair
Claim.
Embodiment 10 detection limit and quantitative limit are tested
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；Flowing phase: methanol is flowing
Phase A, acetonitrile is Mobile phase B, and (0.01mol/L sodium dihydrogen phosphate buffer is by 1.20g for 0.01mol/L phosphate buffered solutions
Sodium dihydrogen phosphate mixes, and is diluted with water to 1000ml, formulated to 3.8 with phosphorus acid for adjusting pH) it is flowing phase C, use gradient
Type of elution: 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.Detection wavelength is 220nm, column temperature: 35 DEG C.Precision weighs butyrate clevidipine
Reference substance is appropriate, injects chromatograph of liquid with taking need testing solution 10 μ l after methanol stepwise dilution, records chromatogram.According to 10:1
Signal to noise ratio is as quantitative limit, and result is 0.3 μ g/ml；Being detection limit according to 3:1 signal to noise 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；Flowing phase: methanol is flowing
Phase A, acetonitrile is Mobile phase B, and (0.01mol/L sodium dihydrogen phosphate buffer is by 1.20g for 0.01mol/L phosphate buffered solutions
Sodium dihydrogen phosphate mixes, and is diluted with water to 1000ml, formulated to 3.8 with phosphorus acid for adjusting pH) it is flowing phase C, use gradient
Type of elution: 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.Detection wavelength is 220nm, and column temperature is 35 DEG C.Precision measures need testing solution 10
μ l injects chromatograph of liquid, records chromatogram.
3. solution stability testing
Take butyrate clevidipine raw material about 10mg to be respectively placed in 10ml volumetric flask, add methanol dissolved dilution to scale, mixed
Even as need testing solution, respectively at 0, within 2,4,6 hours, take 10 μ l sample introductions respectively and measure, record chromatogram, its main peak peak area
And impurity determination result is basicly stable in 6 hours.
4.0.1% reference substance solution linear test
It is appropriate that precision takes reference substance, dissolves stepwise dilution with methanol and becomes 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.Take each 10 μ l of contrast solution of above-mentioned variable concentrations, inject liquid phase
Chromatograph, records chromatogram.Measurement result shows when contrast solution is in concentration range 0.3 μ g-2 μ g, peak area and concentration in
Good linear relationship, its linearly dependent coefficient is 0.9995.The different column temperature of embodiment 12 and flow velocity and detection wavelength, sample size
Serviceability test
1. instrument: Shimadzu LC-20A high performance liquid chromatograph, electronic analytical balance, pH meter.
2. assay method: precision weighs reference substance and H324/78, H168/ of butyrate clevidipine reference substance, impurity A～I
79, the reference substance of H207/59, H152/81 and H152/66 is appropriate, adds methanol and dissolves and be diluted in every 1ml the butanoic acid chlorine Han 1mg
Tie up the known impurities mixed solution of gentle each impurity about 1 μ g as need testing solution.Chromatographic column Waters sunfire
C18150 × 4.6mm, 3.5 μm；Flowing phase: methanol is mobile phase A, and acetonitrile is Mobile phase B, and 0.01mol/L phosphate buffer is molten
(0.01mol/L sodium dihydrogen phosphate buffer is mixed liquid by 1.20g sodium dihydrogen phosphate, is diluted with water to 1000ml, adjusts with phosphoric acid
PH is formulated to 3.8 for joint) it is flowing phase C, use 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.Detection ripple
Length, column temperature and volume according to the form below 3 are carried out.Precision measures certain volume need testing solution and injects chromatograph of liquid, records chromatogram.
Result shows each known impurities that this chromatographic system can be totally separated in mixed solution, can be kept completely separate, do not have between each impurity
There is the mensuration of impurity interference main peak.
Column temperature, flow velocity, sample size and the selection result such as table 3 below of detection wave-length coverage
Table 3
From measurement result, the flow velocity of flowing phase is 0.7-1.1ml/min, and detection wavelength is at 220-260nm, column temperature
20-40 DEG C, all can separate butyrate clevidipine degradation impurity and intermediate in the range of sample size 2-20 μ l, and can be kept completely separate,
Peak shape is symmetrical.
The relevant substance-measuring 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 weighs butyrate clevidipine raw material, adds methanol and dissolves and be diluted in every 1ml contain
The solution of 1mg butyrate clevidipine is as need testing solution.It is appropriate that precision measures need testing solution, adds methanol dilution and becomes every 1ml
In containing the solution of butyrate clevidipine 1 μ g, as reference substance.Chromatographic column Agilent ZORBAX Extend-C18250 ×
4.6mm, 5 μm；Flowing phase: methanol is mobile phase A, and acetonitrile is Mobile phase B, 0.01mol/L phosphate buffered solutions (0.01mol/
L sodium dihydrogen phosphate buffer is mixed by 1.20g sodium dihydrogen phosphate, is diluted with water to 1000ml, joins to 3.8 with phosphorus acid for adjusting pH
System forms) it is flowing phase C, use 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,
Inject chromatograph of liquid, condition detection sensitivity, make main constituent peak height be about the 20% of full scale, then precision takes reference substance solution
10 μ ls each with need testing solution, inject chromatograph of liquid, record chromatogram.To be not added with the main constituent Self-control method of correction factor
With calculated by peak area, the total impurities in need testing solution is 0.07%.
The relevant substance-measuring 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), adds acetonitrile and dissolves and be diluted to
Containing the solution of 50 μ g butyrate clevidipines in every 1ml, ultrasonic, centrifuging and taking supernatant is as need testing solution.Precision measures for examination
Product solution is appropriate, adds dilution in acetonitrile and becomes the solution containing butyrate clevidipine 0.5 μ g in every 1ml, as reference substance solution.Chromatograph
Post Shimadzu GL intersil ODS-3150 × 4.6mm, 3 μm；Flowing phase: methanol is mobile phase A, and acetonitrile is Mobile phase B,
(0.01mol/L sodium dihydrogen phosphate buffer is mixed 0.01mol/L phosphate buffered solutions by 1.20g sodium dihydrogen phosphate, adds water
It is diluted to 1000ml, formulated to 3.8 with phosphorus acid for adjusting pH) it is flowing phase C, use 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, injects chromatograph of liquid, condition detection sensitivity, makes main constituent peak height
It is about the 20% of full scale, then precision takes reference substance solution and each 20 μ l of need testing solution, injects chromatograph of liquid, records chromatograph
Figure.It is 0.45% to be not added with the main constituent Self-control method of correction factor with calculated by peak area, the total impurities in test sample, sees
Accompanying drawing 14.
Claims (7)
1. a butyrate clevidipine and preparation thereof have the detection method of related substance, it is characterised in that:
Step (1), takes butyrate clevidipine crude drug or butyrate clevidipine formulation samples, dissolves with organic solvent, and preparation supplies
Test sample solution, the organic solvent of use is one or more in methanol, acetonitrile, ethanol, isopropanol or oxolane；
Step (2), uses reversed phase high-performance liquid chromatography, and chromatographic column is C18 post, and packing material size is 3.0 ~ 5.0 μm, and column length is
150 ~ 250mm, column internal diameter is 4.6mm, column temperature scope 20-40 DEG C, and the flow velocity of flowing phase is 0.7-1.1ml/min, with A: methanol,
The mixed solution of the phosphate buffer of B: acetonitrile and C:0.005-0.1mol/L pH 3.5-4.0 is flowing phase, uses gradient
Type of elution；In elution process, A in flowing mutually, the volumn concentration of B, C is as follows: 0-55min, A are 33%, and B is 25%, C
It is 42%；55-65min, A are at the uniform velocity improved by 33% to 35%, and B is at the uniform velocity improved by 25% to 30%, and C is at the uniform velocity reduced to 35% by 42%；
65-85min, A are 35%, and B is 30%, and C is 35%；85-93min, A are at the uniform velocity reduced to 33% by 35%, and B is at the uniform velocity reduced by 30%
To 25%, C is at the uniform velocity improved to 42% by 35%；93-105min, A are 33%, and B is 25%, and C is 42%；
Step (3), uses UV-detector, detects wavelength 220-260nm, records chromatogram, completes butyrate clevidipine for examination
Product solution has the mensuration of related substance, has the content of related substance to calculate with the main constituent Self-control method being not added with correction factor.
Detection method the most according to claim 1, it is characterised in that in described step (1), take butyrate clevidipine raw material
Medicinal organic solvent dissolves and dilutes, and makes every 1ml need testing solution containing butyrate clevidipine 0.1-10mg, or takes butanoic acid
Clevidipine formulation samples organic solvent dissolves and is diluted to every 1ml solution containing butyrate clevidipine 0.01-0.1mg, from
Filtrate is taken as need testing solution after taking supernatant after the heart or filtering.
Detection method the most according to claim 1, it is characterised in that packing material size is 3.5 μm, column length is 150mm.
Detection method the most according to claim 1 and 2, it is characterised in that in described step (2), column temperature is set as 35 DEG C.
Detection method the most according to claim 1 and 2, it is characterised in that in described step (2), flow speed control is 0.8
ml/min。
Detection method the most according to claim 1 and 2, it is characterised in that flowing phase phosphate-buffered in described step (2)
The pH value of solution is 3.8.
Detection method the most according to claim 1 and 2, it is characterised in that in described step (3), detection wavelength is set as
220nm。
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