CN108872431B - Method for detecting 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or/and hydrochloride thereof - Google Patents
Method for detecting 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or/and hydrochloride thereof Download PDFInfo
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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Abstract
The invention discloses a method for detecting 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or/and hydrochloride thereof from medetomidine or dexmedetomidine hydrochloride, wherein the method for qualitatively or/and quantitatively detecting the 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or/and the hydrochloride thereof by adopting a high performance liquid chromatography method comprises the following detection conditions: a chromatographic column: c18 chromatographic column, wherein the mobile phase comprises water phase and organic phase, wherein the water phase is phosphate buffer solution; the organic phase is selected from methanol or/and acetonitrile; the mobile phase is eluted by adopting an isocratic elution method. The method can effectively detect the 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or/and hydrochloride thereof in the bulk drugs, and has specificity and stability indication capability.
Description
Technical Field
The invention relates to the field of detection methods, in particular to a method for detecting impurities in a medicament.
Background
Dexmedetomidine hydrochloride is an alpha 2-adrenoceptor agonist with sympatholytic, sedative and analgesic effects for sedation during endotracheal intubation and mechanical ventilation of surgically operated patients under general anesthesia.
Clinical experience of more than 5 years in the United states shows that dexmedetomidine hydrochloride can produce stable calming and wakefulness effects, has unique synergistic effect on the physiological and psychological requirements of severe patients, and can obviously reduce the dosage of anesthetic required for inducing anesthesia; the preoperative administration of the product can reduce the dosage of opioid or non-opioid analgesics before and after the operation, and the characteristic has important significance for anesthesia and intensive care; can also promote the stability of catecholamine hemodynamics, effectively relieve tracheal intubation and surgical stress and anesthesia, and recover early hemodynamic response.
It is well known that the content of process impurities in the drug determines the quality of the drug, and the main impurities contained in the finished dexmedetomidine hydrochloride product are shown in table 1. At present, methods for measuring raw material and reaction related impurities in a dexmedetomidine hydrochloride finished product are being intensively researched, wherein methods for measuring the content of some impurities such as YM-1, YM-Z2, YM-Z3, YM-Z5 and the like are reported, but for the impurity YM-Z6, the content of the impurity is one of important byproducts in the production process of dexmedetomidine hydrochloride, and the method for measuring the content of the impurity in the dexmedetomidine hydrochloride finished product is not reported.
The main difficulty is that the dexmedetomidine hydrochloride structure contains a dimethyl phenyl group, and because benzene ring substitution has a plurality of reaction sites, the dexmedetomidine hydrochloride structure may contain methyl isomer impurity 4- (1- (2, 5-dimethyl phenyl) ethyl) -1H-imidazole (formula I) at different positions, and the hydrochloride of the dexmedetomidine hydrochloride is similar to the structure of the dexmedetomidine hydrochloride, and under the USP dexmedetomidine hydrochloride related substance analysis method, the compound is completely coincided with the dexmedetomidine (formula II) peak.
Therefore, the method for determining the content of the impurity YM-Z6 in the dexmedetomidine hydrochloride finished product has important significance for drug analysis and drug quality control.
Table 1 dexmedetomidine hydrochloride impurity information table
Disclosure of Invention
The inventor adopts chromatographic conditions of a substance-related method of dexmedetomidine hydrochloride USP standard (USP40s1) to separate a YM-Z6 impurity peak from a main peak, and surprisingly adopts the chromatographic conditions of the substance-related method of the invention in reference to the dexmedetomidine hydrochloride USP standard (USP40s1) to optimize the conditions, successfully separate the YM-Z6 impurity peak from the main peak, and ensure that the separation degree meets the specification.
Specifically, the invention provides a method for detecting 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or/and hydrochloride thereof from medetomidine or dexmedetomidine hydrochloride, wherein high performance liquid chromatography is adopted for qualitative or/and quantitative detection, and the detection conditions of the liquid chromatography comprise:
a chromatographic column: an alkyl-bonded silica gel column further selected from C18 chromatography columns;
mobile phase: an aqueous phase, an organic phase;
wherein the water phase is phosphate buffer solution; the organic phase is selected from acetonitrile or/and methanol, and is not methanol alone; the water phase (percent) is organic phase (45-70: 30-55); the mobile phase adopts isocratic elution.
Dexmedetomidine hydrochloride is a key intermediate of dexmedetomidine hydrochloride, and dexmedetomidine hydrochloride can be obtained after the medetomidine is split and is hydrochlorinated, and an optical isomer of dexmedetomidine in the medetomidine is generally taken. The invention aims at the detection method of YM-Z6 impurity in dexmedetomidine hydrochloride, and can also be used for detecting YM-Z6 in dexmedetomidine (including dexmedetomidine) which is a key intermediate of the dexmedetomidine hydrochloride.
The impurities are introduced in the technological processes of synthesis and the like, and comprise reactants, intermediates, byproducts, reagents, catalysts and the like.
The detection method for detecting 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or/and a hydrochloride thereof in a drug means that the detection can be performed by the method when the drug contains any one of 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or a hydrochloride thereof, or both of 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole and a hydrochloride thereof.
The organic phase is selected from acetonitrile or/and methanol, and is not independently methanol, which means that the organic phase can be independently acetonitrile or a mixed solvent of acetonitrile and methanol, but is not independently methanol. The isocratic elution refers to an elution mode in which the composition ratio and the flow rate of a mobile phase are constant in an analysis period of a sample component in the liquid chromatography operation. Compared with the gradient elution method for impurity analysis in the prior art, the method is simpler and more convenient to operate.
In the test process, the phosphate buffer solutions with different types and concentrations can meet the requirements of separation and detection of YM-Z6. The different kinds of phosphate buffers mainly include phosphate buffers formulated with phosphate or/and hydrogen phosphate or/and dihydrogen phosphate or/and acid or/and alkali or/and other salts.
Further, the phosphate buffer solution contains hydrogen phosphate ions, dihydrogen phosphate ions, phosphate ions and alkali metal ions; further, the alkali metal ions are selected from one or two of potassium ions and sodium ions. For example, a solution containing hydrogen phosphate ions, dihydrogen phosphate ions, and potassium ions, a solution containing hydrogen phosphate ions, dihydrogen phosphate ions, and sodium ions, or a solution containing hydrogen phosphate ions, dihydrogen phosphate ions, potassium ions, and sodium ions may be mentioned.
In the embodiment of the present invention, the phosphate buffer may be an aqueous solution of disodium hydrogenphosphate-sodium dihydrogenphosphate, an aqueous solution of dipotassium hydrogenphosphate-potassium dihydrogenphosphate, or a mixed solution of the two buffers.
Further, the pH value of the phosphate buffer solution is 7-9.
In one embodiment of the invention, the organic phase is acetonitrile and the aqueous phase (%): organic phase (%): 70: 30.
Furthermore, the water phase (%) is an organic phase (%) of 60:40, wherein the organic phase (%) is acetonitrile and the methanol (%) -20-30: 10-20.
In a specific embodiment of the invention, the liquid chromatography detection conditions further comprise one or more of the following i to iii:
i specification of chromatographic column: 4.6X (150 to 250) mm, 5 μm;
ii column temperature: 25-40 ℃;
iii flow rate: 1.2-0.8 ml/min.
Further, the liquid chromatography detection conditions further comprise one or more of the following i to iv:
i specification of chromatographic column: 4.6X 150mm, 5 μm;
ii column temperature: 40 ℃;
iii flow rate: 1.0 ml/min;
iv detection wavelength: 220 nm.
The chromatography columns used in the embodiment of the present invention have tradenames of ACE Excel 5Super C18, ACE Exel3C18-PFP, Agilent Infinity LabPoroshell 120EC-C18, PhenomenexTitank F5, Kromasil 100-5C18, Inertsil ODS-3, and Phenomenex Gemini C18, but the chromatography columns satisfying the above description can be applied to the detection method of the present invention, and are not limited to the above commercial products.
Further, the detection method further comprises the following steps:
(1) preparing a test solution;
(2) preparing a control solution;
(3) injecting a control solution for detection;
(4) and (5) injecting a sample solution for detection.
The detection method can analyze and calculate the detection result by using methods such as an area normalization method, a self-comparison method, an internal standard method, an external standard method and the like.
In a specific embodiment of the present invention, the solvent used for preparing the test solution or/and the control solution is one or a mixture of two or more selected from water, phosphate buffer, methanol, and acetonitrile.
The solvent is selected from one or more than two mixed solvents of water, phosphate buffer solution, methanol and acetonitrile, and refers to that when the sample solution or/and the control solution is prepared, the solvent can be selected from any one of water, phosphate buffer solution, methanol or acetonitrile alone, or can be selected from any one of water, phosphate buffer solution, methanol, water and acetonitrile, phosphate buffer solution and methanol, phosphate buffer solution and acetonitrile, methanol and acetonitrile, water, phosphate buffer solution and methanol, water, phosphate buffer solution and acetonitrile, water, methanol and acetonitrile, phosphate buffer solution and methanol and acetonitrile, water, phosphate buffer solution and methanol and acetonitrile.
Further, the mixed solvent is selected from one of the following: water (%) (phosphate buffer solution) 1-99: 1-99, water (%) (methanol (%) (40-70: 30-60), water (%) (acetonitrile (%) 40-70: 30-60), phosphate buffer solution (%) (methanol (%) (40-70: 30-60), phosphate buffer solution (%) (acetonitrile) (40-70: 30-60), methanol (%) (acetonitrile (%) (50-75: 25-50), water (%) (phosphate buffer solution (%) (methanol (%) (1-69: 30-60), water (%) (phosphate buffer solution (%) (acetonitrile) (1-69: 30-60), water (%) (methanol (%) (acetonitrile) (30-30: 10-30: 20-30), phosphate buffer solution (%) (methanol (%) (acetonitrile) (40-70: 30-30), phosphate buffer solution (%) (acetonitrile) (30-30) (30): 1-69: 10-30: 20-30.
The invention has the beneficial effects that:
(1) the detection method can effectively detect the 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or/and hydrochloride thereof in the medicament, has specificity and stability indicating capability, and other known impurities do not interfere with the detection of the compound or/and hydrochloride thereof under the condition.
(2) The method directly adopts isocratic elution, and compared with the gradient elution method for impurity analysis in the prior art, the method is simpler and more convenient to operate.
(3) The analysis method has high sensitivity, the separation degree of the dexmedetomidine peak and other impurity peaks meets the measurement requirement, the method has good durability, and the impurity monitoring in the process and the impurity control requirement in the finished product can be well met.
Drawings
FIG. 1 is a UV absorption spectrum of YM-Z6;
FIG. 2 is a UV absorption spectrum of the major peak of YM-Z6 dexmedetomidine;
FIG. 3 is a graph correlating chromatographic conditions (1) of the present invention;
FIG. 4 is a graph correlating chromatographic conditions (2) of the present invention;
FIG. 5 is a graph correlating chromatographic conditions (3) to (I) according to the invention;
FIG. 6 is a graph correlating chromatographic conditions (3) to (II) according to the invention;
FIG. 7 is a graph correlating chromatographic conditions (4) to (I) according to the invention;
FIG. 8 is a graph correlating chromatographic conditions (4) to (II) of the present invention;
FIG. 9 is a graph correlating chromatographic conditions (5) of the present invention.
Detailed Description
Instruments and devices:
TABLE 2
A chromatographic column: ACE Excel 5Super C18, 4.6mm × 150mm, 5 μm (L-C18-293)#、302#、294#)；ACE Exel3 C18-PFP，4.6×150mm；Agilent InfinityLabPoroshell 120 EC-C18，4.6×150mm，4μm PhenomenexTitank F5，4.6×150mm，3μm；Kromasil 100-5 C18，4.6×150mm；Inertsil ODS-3，4.6×250mm，5μm；Phenomenex Gemini C18，4.6×250mm，5μm。
Reagents and standards, controls:
TABLE 3
Example 1
Blank solvent (as diluent below): phosphate buffer-methanol (60:40, v/v), water or acetonitrile-water (3: 7, v/v).
Taking a dexmedetomidine finished product, adding a corresponding diluent for dissolving, and preparing a solution containing about 0.5mg of dexmedetomidine in every 1ml as a test solution; a proper amount of test solution is precisely measured and diluted by a corresponding diluent to prepare a solution containing about 1 mu g of dexmedetomidine in each 1ml, which is used as a control solution. Proper amounts of dexmedetomidine hydrochloride and YM-Z6 reference substances are precisely weighed, dissolved by corresponding diluents and prepared into solutions containing about 0.5mg of dexmedetomidine and about 0.5 mu g of YM-Z6 per 1ml as system applicability solutions.
Measuring by high performance liquid chromatography (China pharmacopoeia 2015 edition four-part general rules 0512), precisely measuring 20 μ l of system applicability solution, injecting into a liquid chromatograph, recording chromatogram, and determining the separation degree between main peak and impurity YM-Z6 peak. Precisely measuring 20 mul of the control solution, injecting into a liquid chromatograph, and adjusting the sensitivity of the detector to make the peak height of the main component chromatographic peak be 10-20% of the full range; precisely measuring 20 μ l of each of the test solution and the control solution, injecting into a liquid chromatograph, and recording chromatogram. After the solvent peak is deducted from the chromatogram of the test solution, if a chromatogram peak consistent with the retention time of YM-Z6 in the system applicability solution exists, the chromatogram peak is calculated according to the corrected peak area (multiplied by a correction factor), and the chromatogram peak is not more than 0.5 times (0.1%) of the main peak area of the control solution.
EXAMPLE 2 screening of detection wavelengths
The ultraviolet absorption spectrum of the impurity YM-Z6 is shown in figure 1, and the ultraviolet absorption spectrum of the dexmedetomidine as the main peak is shown in figure 2.
According to a scanning map, ultraviolet absorption of the main component and ultraviolet absorption of the impurity YM-Z6 are both terminal absorption, and the detection wavelength is determined to be 220nm by comprehensively considering the detection wavelength of a USP related substance method.
Example 3 screening of chromatographic conditions
(1) Reference is made to the chromatography conditions of the substance method related to dexmedetomidine hydrochloride USP standard (USP40s 1):
mobile phase: phosphate buffer (0.71 g disodium hydrogen phosphate was weighed, dissolved in 1L water, adjusted to pH 7.0 with 16g/L sodium dihydrogen phosphate dihydrate) -methanol (40: 60);
a chromatographic column: agilent InfinityLabPoroshell 120EC-C18, 4.6X 150mm, 4 μm;
flow rate: 1ml/min, detection wavelength: 220 nm;
column temperature: 25 ℃, sample introduction: 100 mul;
diluent agent: phosphate buffer-methanol (60: 40).
As can be seen in FIG. 3, YM-Z6 coincides with the main peak under this method, indicating that YM-Z6 cannot be separated from dexmedetomidine under this method.
(2) The separation effect was examined by changing different chromatographic columns with reference to the substance method of dexmedetomidine hydrochloride USP standard (USP40s 1):
mobile phase: phosphate buffer (0.71 g disodium hydrogen phosphate was weighed, dissolved in 1L water, adjusted to pH 7.0 with 16g/L sodium dihydrogen phosphate dihydrate) -methanol (40: 60);
a chromatographic column: (I) ACE Exel3C18-PFP, 4.6X 150mm, (II) phenomenex Titank F5, 4.6X 150mm, 3 μm, (III) Kromasil 100-5C18, 4.6X 150mm, (IV) Inertsil ODS-3, 4.6X 250mm, 5 μm (phosphate buffer-methanol (45: 55);
flow rate: 1ml/min, detection wavelength: 220 nm;
column temperature: 25 ℃, sample introduction: 100 mul;
diluent agent: phosphate buffer-methanol (60: 40).
The experimental result shows that the impurity YM-Z6 can not be separated from the main component YM in the elution patterns of chromatographic columns with different brand specifications. As can be seen from FIG. 4, when using the Inertsil ODS column, the methanol ratio was slightly decreased, and YM-Z6 showed signs of separation from the main peak.
In addition, the inventors have also tried a mobile phase with a further reduced methanol ratio and failed to perform an effective separation test for YM-Z6.
(3) The methanol system of the USP method is changed into an acetonitrile system:
(I) mobile phase: phosphate buffer (0.71 g disodium hydrogen phosphate was weighed, dissolved in 1L water, adjusted to pH 7.0 with 16g/L sodium dihydrogen phosphate dihydrate) -acetonitrile (70: 30);
a chromatographic column: phenomenex Gemini C18, 4.6X 250mm, 5 μm;
flow rate: 1ml/min, detection wavelength: 220 nm;
column temperature: 40 ℃, sample introduction: 20 μ l, diluent: water;
(II) mobile phase: phosphate buffer (disodium hydrogen phosphate 0.71g was weighed, dissolved in 1L water, adjusted to pH 7.0/9.0 with 16g/L sodium dihydrogen phosphate dihydrate) -acetonitrile (70:30)
A chromatographic column: inertsil ODS-3(18 alkyl packing), 4.6X 250mm, 5 μm
Flow rate: 1ml/min, detection wavelength: 220nm
Column temperature: 40, sample size at ° c: 20 μ l, diluent: water (W)
As can be seen from FIG. 5, the main component can be separated from the impurity YM-Z6 with a separation degree of 2.0; as can be seen from fig. 6, changing the pH of the mobile phase does not greatly affect its separation.
(4) And (3) comparing an acetonitrile system with a methanol acetonitrile mixed system:
mobile phase: (I) phosphate buffer (0.71 g disodium hydrogen phosphate was weighed, dissolved in 1L water, adjusted to pH 7.0 with 16g/L sodium dihydrogen phosphate dihydrate) -acetonitrile (70: 30);
(II) phosphate buffer (0.71 g disodium hydrogen phosphate was weighed, dissolved in 1L water, adjusted to pH 7.0 with 16g/L sodium dihydrogen phosphate dihydrate) -acetonitrile-methanol (60:25: 15);
a chromatographic column: phenomenex Gemini C18, 4.6X 250mm, 5 μm;
flow rate: 1ml/min, detection wavelength: 220 nm;
column temperature: 40, sample size at ° c: 20 μ l, diluent: and (3) water.
As can be seen from FIGS. 7 to 8, there was no significant difference in the separation effect of the two flows with respect to the main component and the impurity YM-Z6 in this method.
(5) And (3) observing the separation of the main component and an impurity YM-Z6 by using an ACE-C18 chromatographic column:
mobile phase: phosphate buffer (0.71 g disodium hydrogen phosphate was weighed, dissolved in 1L water, adjusted to pH 7.0 with 16g/L sodium dihydrogen phosphate dihydrate) -acetonitrile (70: 30);
a chromatographic column: ACE Excel 5Super C18, 4.6mm × 150mm, 5 μm;
flow rate: 1ml/min, detection wavelength: 220 nm;
column temperature: 40, sample size at ° c: 20 μ l, diluent: acetonitrile-water (30: 70).
As can be seen from FIG. 9, the peak shape of the main component and the impurity YM-Z6 is better under the method, the separation degree reaches 2.0, and other known impurities do not interfere with the detection of YM-Z6 under the condition.
From the above results, it was found that the main component and the impurity YM-Z6 were separated well under the conditions of the method (5) by screening under chromatographic conditions, and the method (5) was used as a method for detecting the impurity YM-Z6.
Example 4 analytical methods validation
After the screening of chromatographic conditions, the chromatographic conditions of the analysis method of the dexmedetomidine hydrochloride impurity YM-Z6 are preliminarily established as shown in Table 4:
TABLE 4 chromatographic conditions as set forth
The result shows that the method can effectively separate YM-Z6 from the main drug and other different impurities.
The specific validation results are shown in table 5:
TABLE 5 DMD raw material impurity YM-Z6 analysis method verification result table
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present specification and drawings, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (11)
1. A method for detecting 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or/and hydrochloride thereof from medetomidine or dexmedetomidine hydrochloride, characterized in that qualitative or/and quantitative detection is carried out by high performance liquid chromatography, wherein the detection conditions of the liquid chromatography comprise:
a chromatographic column: a C18 chromatography column;
mobile phase: an aqueous phase, an organic phase;
wherein the water phase is phosphate buffer solution; the organic phase is selected from acetonitrile or/and methanol, and is not methanol alone; aqueous phase (%) = 60-70: 30-40; the mobile phase adopts isocratic elution.
2. The method according to claim 1, wherein the phosphate buffer solution contains hydrogen phosphate ions, dihydrogen phosphate ions, and alkali metal ions.
3. The detection method according to claim 2, wherein the alkali metal ion is one or two selected from potassium ion and sodium ion.
4. The detection method according to claim 2, wherein the phosphate buffer has a pH of 7 to 9.
5. The detection method according to claim 1, wherein the organic phase is acetonitrile, and the aqueous phase (%) =70: 30.
6. The detection method according to claim 1, wherein the aqueous phase (%) =60:40 organic phase (%) = acetonitrile (%) = methanol (%) = 20-30: 10-20.
7. The detection method according to claim 1, wherein the liquid chromatography detection conditions further comprise one or more of the following i to iii:
i specification of chromatographic column: 4.6X (150 to 250) mm, 5 μm;
ii column temperature: 25-40 ℃;
iii flow rate: 1.2-0.8 ml/min.
8. The detection method according to claim 1, wherein the liquid chromatography detection conditions further comprise one or more of the following i to iv:
i specification of chromatographic column: 4.6X 150mm, 5 μm;
ii column temperature: 40 ℃;
iii flow rate: 1.0 ml/min;
iv detection wavelength: 220 nm.
9. The detection method according to claim 1, characterized in that it comprises the following:
(1) preparing a test solution;
(2) preparing a control solution;
(3) injecting a control solution for detection;
(4) and (5) injecting a sample solution for detection.
10. The detection method according to claim 9, wherein the solvent used for preparing the sample solution or/and the control solution is one or a mixture of two or more selected from water, phosphate buffer, methanol, and acetonitrile.
11. The detection method according to claim 10, wherein the mixed solvent is selected from one of: water (%) = 1-99: 1-99, water (%) = methanol (%) = 40-70: 30-60, water (%) = acetonitrile (%) = 40-70: 30-60, phosphate buffer (%) = methanol (%) = 40-70: 30-60, phosphate buffer (%) = acetonitrile (%) = 40-70: 30-60, methanol (%) = acetonitrile (%) = 50-75: 25-50, water (%) (phosphate buffer (%) = methanol (%) = 1-69: 30-60, water (%) (phosphate buffer (%) = acetonitrile (%) = 1-69: 30-60, water (%) = methanol (%) = acetonitrile (%) = 40-70: 10-30: 20-30, phosphate buffer (%) = methanol (%) = acetonitrile (%) = 40-69: 1-69: 30: 10-30, water (%) = methanol (%) = 30-30, phosphate buffer (%) = methanol (%) = 30 (%): 1-69: 10-30: 20-30.
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| CN111141849B (en) * | 2020-01-06 | 2023-11-03 | 江苏开元药业有限公司 | Liquid phase detection separation method for positional isomer of dexmedetomidine initial raw material |
| CN112730702A (en) * | 2020-12-30 | 2021-04-30 | 南京百泽医药科技有限公司 | Method for determining related substances of 6-acetoxyl-7-methoxy-3H-quinazoline-4-one |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4826864A (en) * | 1981-07-10 | 1989-05-02 | Farmos Group Ltd. | Substituted imidazole derivatives useful as antihypertensive or antithromtic agent or divretic |
| JP2006112835A (en) * | 2004-10-12 | 2006-04-27 | Maruishi Pharmaceutical Co Ltd | Quantification method of dexmedetomidine |
| WO2011070069A1 (en) * | 2009-12-09 | 2011-06-16 | I-Tech Ab | Process for preparation of medetomidine |
| US8242158B1 (en) * | 2012-01-04 | 2012-08-14 | Hospira, Inc. | Dexmedetomidine premix formulation |
| CN106442763A (en) * | 2016-08-31 | 2017-02-22 | 辰欣药业股份有限公司 | Method for detecting related substances of dexmedetomidine hydrochloride raw material or preparation |
| WO2017194835A1 (en) * | 2016-05-09 | 2017-11-16 | Vetcare Oy | Compositions comprising substituted benzofuroquinolizine and psychoactive drug |
| CN107402262A (en) * | 2016-05-20 | 2017-11-28 | 湖北生物医药产业技术研究院有限公司 | Determine the method about content of material in dexmedetomidine hydrochloride bulk drug |
| EP3053576B1 (en) * | 2010-09-16 | 2018-05-16 | Allergan, Inc. | Ester pro-drugs of [3-(1-(1h-imidazol-4-yl)ethyl)-2-methylphenyl] methanol for lowering intraocular pressure |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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-
2018
- 2018-07-09 CN CN201810743104.XA patent/CN108872431B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4826864A (en) * | 1981-07-10 | 1989-05-02 | Farmos Group Ltd. | Substituted imidazole derivatives useful as antihypertensive or antithromtic agent or divretic |
| JP2006112835A (en) * | 2004-10-12 | 2006-04-27 | Maruishi Pharmaceutical Co Ltd | Quantification method of dexmedetomidine |
| WO2011070069A1 (en) * | 2009-12-09 | 2011-06-16 | I-Tech Ab | Process for preparation of medetomidine |
| EP3053576B1 (en) * | 2010-09-16 | 2018-05-16 | Allergan, Inc. | Ester pro-drugs of [3-(1-(1h-imidazol-4-yl)ethyl)-2-methylphenyl] methanol for lowering intraocular pressure |
| US8242158B1 (en) * | 2012-01-04 | 2012-08-14 | Hospira, Inc. | Dexmedetomidine premix formulation |
| WO2017194835A1 (en) * | 2016-05-09 | 2017-11-16 | Vetcare Oy | Compositions comprising substituted benzofuroquinolizine and psychoactive drug |
| CN107402262A (en) * | 2016-05-20 | 2017-11-28 | 湖北生物医药产业技术研究院有限公司 | Determine the method about content of material in dexmedetomidine hydrochloride bulk drug |
| CN106442763A (en) * | 2016-08-31 | 2017-02-22 | 辰欣药业股份有限公司 | Method for detecting related substances of dexmedetomidine hydrochloride raw material or preparation |
Non-Patent Citations (5)
| Title |
|---|
| Analytical method development for the simultaneous quantitation of dexmedetomidine and three potential metabolites in plasma;Y.-H. Hui et al;《Journal of Chromatography A》;19971231;第762卷;第281-291页 * |
| HPLC法测定盐酸右美托咪定有关物质;李鸿雁 等;《药物分析杂志》;20151231;第35卷(第12期);第2193页摘要；第2194页第2.1节；第2196页第2.8节；图1，表1 * |
| Simultaneous quantitation of dexmedetomidine and glucuronide metabolites (G-Dex-1 and G-Dex-2) in human plasma utilizing liquid chromatography with tandem mass spectrometric detection;Qin C. Ji et al;《Rapid Communication in Mass Spectrometry》;20041231;第18卷;第1753-1760页 * |
| Stability indicating HPLC Method Validation for the Assay of Dexmedetomidine in Dexmedetomidine Hydrochloride Injection;Muralee Krishna et al;《International Journal of TechnoChem Research》;20161231;第2卷(第1期);第54-61页 * |
| 盐酸右美托咪定的质量研究;姜瑞玲;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20130215(第02期);第E079-20页 * |
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