CN108872431A - A method of detection 4- (1- (2,5- 3,5-dimethylphenyl) ethyl) -1H- imidazoles or/and its hydrochloride - Google Patents
A method of detection 4- (1- (2,5- 3,5-dimethylphenyl) ethyl) -1H- imidazoles or/and its hydrochloride Download PDFInfo
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Abstract
The invention discloses 4- (1- (2 is detected from Medetomidine or dexmedetomidine hydrochloride, 5- 3,5-dimethylphenyl) ethyl) -1H- imidazoles or/and its hydrochloride method, using the method for high performance liquid chromatography to 4- (1- (2,5- 3,5-dimethylphenyl) ethyl) -1H- imidazoles or/and its hydrochloride carry out qualitative or/and quantitative detection, and the testing conditions of liquid chromatogram include：Chromatographic column：C18 chromatographic column, mobile phase include water phase, organic phase, wherein water phase is phosphate buffer；Organic phase is organic phase, and organic phase is selected from methanol or/and acetonitrile；Mobile phase is eluted using isocratic elution method.4- (1- (2,5- 3,5-dimethylphenyl) ethyl) -1H- imidazoles or/and its hydrochloride in bulk pharmaceutical chemicals can effectively be detected using method of the invention, there is specificity and stability to indicate ability.
Description
Technical field
The present invention relates to detection method fields, more particularly to the method for checked for impurities in drug.
Background technique
Dexmedetomidine hydrochloride is α 2- adrenoceptor agonists, has and resists sympathetic, calm and analgesic effect, is used
Calmness when the patient with operation trachea cannula and mechanical ventilation of row general anesthesia.
Show that dexmedetomidine hydrochloride can produce stable calm and awakening and make using the clinical experience more than 5 years in the U.S.
With the demand of physiology and psychological aspects to critically ill patient has unique synergistic effect, can obviously reduce needed for induced anesthesia
Anesthetic dosage；The preoperative dosage given this product and can reduce preoperative and postoperative opium or non-opium analgesic, this characteristic
There is important meaning for anesthesia and Intensive Care Therapy；It can also promote the stability of catecholamine haemodynamics, effectively mitigate
Trachea cannula, Fundamental Operations and anesthesia and recovery early stage haemodynamics response.
It is well known that the process impurity content in drug decides the quality of drug, contain in dexmedetomidine hydrochloride finished product
Some major impurities are shown in Table 1.Currently, for raw material in dexmedetomidine hydrochloride finished product and reacting the measuring method of relative substance just
It is being studied energetically, wherein the content assaying method of some such as YM-1, YM-Z2, YM-Z3, YM-Z5 impurity has been reported, but
It is one of the important by-products during producing dexmedetomidine hydrochloride, in dexmedetomidine hydrochloride for impurity YM-Z6
The measuring method of content really has not been reported in finished product.
Main difficult point is, " 3,5-dimethylphenyl " group is contained in dexmedetomidine hydrochloride structure, since phenyl ring replaces
There are multiple reaction sites, it is thus possible to the Methyl Isomers body impurity 4- (1- (2,5- 3,5-dimethylphenyl) containing different location
Ethyl) -1H- imidazoles (Formulas I), hydrochloride is due to close with dexmedetomidine hydrochloride structure, in the dexmedetomidine hydrochloride of USP
Under Related substance method, which is completely coincident with Dexmedetomidine (Formula II) peak.
Therefore, the measuring method for developing dexmedetomidine hydrochloride lmpurities YM-Z6 content, for Pharmaceutical Analysis and medicine
Amount of substance control is all of great significance.
1 dexmedetomidine hydrochloride impurity information table of table
Summary of the invention
Inventor uses the chromatographic condition of dexmedetomidine hydrochloride USP standard (USP40s1) in relation to substance method, cannot make
YM-Z6 impurity peaks are separated with main peak, and unexpectedly, being referred in dexmedetomidine hydrochloride USP standard (USP40s1) using the present invention is had
The chromatographic condition for closing substance, has carried out the optimization of condition, has successfully separated YM-Z6 impurity peaks with main peak, separating degree meets rule
It is fixed.
Specifically, the present invention provides one kind detects 4- (1- (2,5- dimethyl from Medetomidine or dexmedetomidine hydrochloride
Phenyl) ethyl) -1H- imidazoles or/and its hydrochloride method, qualitative or/and quantitative detection is carried out using high performance liquid chromatography,
The testing conditions of liquid chromatogram include：
Chromatographic column：Alkyl linked silicagel column is further selected from C18 chromatographic column；
Mobile phase：Water phase, organic phase；
Wherein, water phase is phosphate buffer；Organic phase is organic phase, and organic phase is selected from acetonitrile or/and methanol, not individually
For methanol；Water phase (%):Organic phase (%)=45~70:30~55；Mobile phase uses isocratic elution.
Medetomidine is the key intermediate of dexmedetomidine hydrochloride, and Medetomidine is acidified after splitting to can be obtained hydrochloric acid
Dexmedetomidine generally takes the optical isomer Dexmedetomidine in Medetomidine.The present invention is in dexmedetomidine hydrochloride
The detection method of YM-Z6 impurity can be used for its key intermediate --- YM- in Medetomidine (including Dexmedetomidine)
The detection of Z6.
The impurity is the impurity that synthesis etc. introduces in technical process, including reactant, intermediate, by-product, reagent, is urged
Agent etc..
The detection method can detect 4- (1- (2,5- 3,5-dimethylphenyl) ethyl) -1H- imidazoles or/and its hydrochloric acid in drug
Salt refers to when containing any one in 4- (1- (2,5- 3,5-dimethylphenyl) ethyl) -1H- imidazoles or its hydrochloride in drug, or
4- (1- (2,5- 3,5-dimethylphenyl) ethyl) -1H- imidazoles and its hydrochloride both contain sometimes, can be examined with the method
It surveys.
The organic phase is selected from acetonitrile or/and methanol, is not individually for methanol, refers to that organic phase can be individually for acetonitrile,
It can be the mixed solvent of acetonitrile and methanol, but not select methanol individually.The isocratic elution refers to that liquid chromatogram operates
In, in the analytical cycle of sample component, the constant type of elution of the composition ratio and constant flow rate of mobile phase.With the prior art
The gradient elution method of impurity analysis is compared, and is operated easier.
During the test, the phosphate buffer of different kinds and concentrations is tested, can satisfy YM-Z6
Separation, detection.Different types of phosphate buffer mainly includes using phosphate or/and hydrophosphate or/and di(2-ethylhexyl)phosphate
The phosphate buffer that hydrogen salt or/and acid or/and alkali or/and other salt are formulated.
Further, phosphoric acid hydrogen radical ion, dihydrogen phosphate ions, phosphate anion are contained in the phosphate buffer
And alkali metal ion；Further, the alkali metal ion is selected from one or both of potassium ion, sodium ion.Such as it can be
Solution containing phosphoric acid hydrogen radical ion, dihydrogen phosphate ions, phosphate anion and potassium ion, or containing phosphoric acid hydrogen radical ion,
The solution of dihydrogen phosphate ions, phosphate anion and sodium ion, or contain phosphoric acid hydrogen radical ion, dihydrogen phosphate ions, phosphorus
The solution of acid ion, potassium ion and sodium ion.
In the specific embodiment of the invention, it is water-soluble that phosphate buffer can choose disodium hydrogen phosphate-sodium dihydrogen phosphate
Liquid, or dipotassium hydrogen phosphate-potassium dihydrogen phosphate aqueous solution can also be the mixed solution of aforementioned two kinds of buffers.
Further, the phosphate buffer pH value is 7~9.
In the specific embodiment of the present invention, the organic phase is acetonitrile, water phase (%):Organic phase (%)=
70:30。
Further, water phase (%):Organic phase (%)=60:40, wherein organic phase is acetonitrile (%):Methanol (%)=
20~30:10~20.
In a specific embodiment of the invention, the liquid chromatographic detection condition further includes one in i~iii below
Item is multinomial：
I chromatographic column specification：4.6 × (150~250) mm, 5 μm；
Ii column temperature：25~40 DEG C；
Iii flow velocity：1.2~0.8ml/min.
Further, the liquid chromatographic detection condition further includes one or more in i~iv below：
I chromatographic column specification：4.6 × 150mm, 5 μm；
Ii column temperature：40℃；
Iii flow velocity：1.0ml/min；
Iv Detection wavelength：220nm.
Chromatographic column trade name used in the specific embodiment of the invention has ACE Excel 5 Super C18, ACE
Exel 3 C18-PFP, Agilent InfinityLabPoroshell 120 EC-C18, PhenomenexTitank F5,
Kromasil 100-5C18, Inertsil ODS-3, Phenomenex Gemini C18, still, as long as meeting foregoing description
Chromatographic column can operate with detection method of the invention, be not limited to above-mentioned commodity.
Further, the detection method further includes the following contents：
(1) test solution is prepared；
(2) contrast solution is prepared；
(3) by contrast solution sample detection；
(4) by test solution sample detection.
The analysis of the methods of area normalization method, Self-control method, internal standard method, external standard method, meter can be used in the detection method
Calculate testing result.
In a specific embodiment of the invention, prepare solvent that test solution or/and contrast solution use be selected from water,
The mixed solvent of one or more of phosphate buffer, methanol, acetonitrile.
The solvent is selected from the mixed solvent of one or more of water, phosphate buffer, methanol, acetonitrile, is
When finger prepares test solution or/and contrast solution, solvent can individually be selected in water, phosphate buffer, methanol or acetonitrile
Any one, water and phosphate buffer, water and methanol, water and acetonitrile, phosphate buffer and methanol, phosphoric acid also can be selected
Salt buffer and acetonitrile, methanol and acetonitrile, water and phosphate buffer and methanol, water and phosphate buffer and acetonitrile, water and
Any one in methanol and acetonitrile, phosphate buffer and methanol and acetonitrile, water and phosphate buffer and methanol and acetonitrile is mixed
Bonding solvent.
Further, the mixed solvent is selected from one of following：Water (%):Phosphate buffer (%)=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 (%)=1~69:1~69:30
~60, water (%):Phosphate buffer (%):Acetonitrile (%)=1~69:1~69:30~60, water (%):Methanol (%):Second
Nitrile (%)=40~70:10~30:20~30, phosphate buffer (%):Methanol (%):Acetonitrile (%)=40~70:10~
30:20~30 and water (%):Phosphate buffer (%):Methanol (%):Acetonitrile (%)=1~69:1~69:10~30:20~
30。
The beneficial effects of the invention are as follows：
(1) 4- (1- (2,5- 3,5-dimethylphenyl) second in drug can effectively be detected using detection method of the invention
Base) -1H- imidazoles or/and its hydrochloride, there is specificity and stability to indicate ability, and other known impurities are under this condition
The detection to the compound or/and its hydrochloride is not interfered.
(2) present invention directlys adopt isocratic elution, and compared with the gradient elution method of prior art impurity analysis, operation is more
It is easy.
(3) sensitivity of analytical method of the present invention is high, and the separating degree of Dexmedetomidine peak and other impurity peaks meets measurement and wants
It asks, this method durability is good, can meet the impurity monitoring in technical process and the Control of Impurities requirement in finished product well.
Detailed description of the invention
Fig. 1 is the ultraviolet absorpting spectrum of YM-Z6；
Fig. 2 is the ultraviolet absorpting spectrum of YM-Z6 Dexmedetomidine main peak；
Fig. 3 is the related spectrogram of chromatographic condition of the present invention (1)；
Fig. 4 is the related spectrogram of chromatographic condition of the present invention (2)；
Fig. 5 is the related spectrogram of chromatographic condition of the present invention (3)-(I)；
Fig. 6 is the related spectrogram of chromatographic condition of the present invention (3)-(II)；
Fig. 7 is the related spectrogram of chromatographic condition of the present invention (4)-(I)；
Fig. 8 is the related spectrogram of chromatographic condition of the present invention (4)-(II)；
Fig. 9 is the related spectrogram of chromatographic condition of the present invention (5).
Specific embodiment
Instrument and equipment：
Table 2
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, 4
μm PhenomenexTitank F5,4.6 × 150mm, 3 μm；Kromasil 100-5 C18,4.6 × 150mm；Inertsil
ODS-3,4.6 × 250mm, 5 μm；Phenomenex Gemini C18,4.6 × 250mm, 5 μm.
Reagent and standard items, reference substance：
Table 3
Embodiment 1
Blank solvent (following to make diluent)：Phosphate buffer-methanol (60:40, v/v), water or acetonitrile-water (3 ︰ 7,
v/v)。
Dexmedetomidine pharmaceutical product is taken, corresponding diluent is added to dissolve and is made in every 1ml containing about Dexmedetomidine 0.5mg
Solution, as test solution；Precision measures appropriate test solution, with corresponding dilution dilution agent be made in every 1ml containing about
The solution of 1 μ g of Dexmedetomidine, as contrast solution.Precision weighs dexmedetomidine hydrochloride and YM-Z6 reference substance is each appropriate, uses
Corresponding diluent dissolves and is made in every 1ml the solution respectively containing about 0.5 μ g of Dexmedetomidine about 0.5mg, YM-Z6, as being
System applicability solution.
It is measured according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015), precision measures system suitability
20 μ l of solution injects liquid chromatograph, records chromatogram, and main peak and impurity YM-Z6 peak-to-peak separating degree should meet regulation.It is accurate
It measures 20 μ l of contrast solution and injects liquid chromatograph, adjust detector sensitivity, make the peak height full scale of principal component chromatographic peak
10%~20%；Precision measures test solution and each 20 μ l of contrast solution injects liquid chromatograph, records chromatogram.For examination
In product solution chromatogram deduct solvent peak after, if any with the consistent chromatographic peak of YM-Z6 retention time in system suitability solution, press
Calculated by peak area (multiplied by correction factor) after correction is not greater than 0.5 times (0.1%) of contrast solution main peak area.
The screening of 2 Detection wavelength of embodiment
The ultraviolet absorpting spectrum of impurity YM-Z6 is shown in that Fig. 1, the ultraviolet absorpting spectrum of main peak Dexmedetomidine are shown in Fig. 2.
By scanning spectra it is found that principal component and the UV absorption of impurity YM-Z6 are that end absorbs, with reference to the related object of USP
The Detection wavelength of matter method comprehensively considers, and Detection wavelength is set to 220nm.
The screening of 3 chromatographic condition of embodiment
(1) chromatographic condition of dexmedetomidine hydrochloride USP standard (USP40s1) in relation to substance method is referred to：
Mobile phase：Phosphate buffer (weighs disodium hydrogen phosphate 0.71g and is dissolved in 1L water, with bis- hypophosphite monohydrate dihydro of 16g/L
It is 7.0)-methanol (40 that sodium, which adjusts pH value,:60)；
Chromatographic column：Agilent InfinityLabPoroshell 120EC-C18,4.6 × 150mm, 4 μm；
Flow velocity：1ml/min, Detection wavelength：220nm；
Column temperature：25 DEG C, sample volume：100μl；
Diluent：Phosphate buffer-methanol (60:40).
As seen from Figure 3, YM-Z6 is overlapped with main peak under this method, and illustrating cannot be by YM-Z6 and Dexmedetomidine under this method
It separates.
(2) with reference to the related substance method of dexmedetomidine hydrochloride USP standard (USP40s1), different chromatographic columns is replaced and are investigated
Separating effect：
Mobile phase：Phosphate buffer (weighs disodium hydrogen phosphate 0.71g and is dissolved in 1L water, with bis- hypophosphite monohydrate dihydro of 16g/L
It is 7.0)-methanol (40 that sodium, which adjusts pH value,:60)；
Chromatographic column：(I) ACE Exel3C18-PFP, 4.6 × 150mm, (II) PhenomenexTitank F5,4.6 ×
150mm, 3 μm, (III) Kromasil 100-5C18,4.6 × 150mm, (IV) Inertsil ODS-3,4.6 × 250mm, 5 μm
(phosphate buffer-methanol (45:55)；
Flow velocity：1ml/min, Detection wavelength：220nm；
Column temperature：25 DEG C, sample volume：100μl；
Diluent：Phosphate buffer-methanol (60:40).
The experimental results showed that impurity YM-Z6 different brands specification chromatographic column elute map in principal component YM not
It can separation.From fig. 4, it can be seen that when using Inertsil ODS column, slightly reduction methanol ratio, YM-Z6 has to be initially separated with main peak
Sign.
In addition, inventor also carries out overtesting to the mobile phase for further decreasing methanol ratio, cannot have to YM-Z6
Imitate separation detection.
(3) methanol system of USP method is changed to acetonitrile system：
(I) mobile phase：Phosphate buffer (weighs disodium hydrogen phosphate 0.71g and is dissolved in 1L water, with bis- hypophosphite monohydrate of 16g/L
It is 7.0)-acetonitrile (70 that sodium dihydrogen, which adjusts pH value,:30)；
Chromatographic column：Phenomenex Gemini C18,4.6 × 250mm, 5 μm；
Flow velocity：1ml/min, Detection wavelength：220nm；
Column temperature：40 DEG C, sample volume：20 μ l, diluent：Water；
(II) mobile phase：Phosphate buffer (weighs disodium hydrogen phosphate 0.71g and is dissolved in 1L water, with bis- hypophosphite monohydrate of 16g/L
It is 7.0/9.0 that sodium dihydrogen, which adjusts pH value)-acetonitrile (70:30)
Chromatographic column：Inertsil ODS-3 (18 alkyl filler), 4.6 × 250mm, 5 μm
Flow velocity：1ml/min, Detection wavelength：220nm
Column temperature：40, DEG C sample volume：20 μ l, diluent：Water
As seen from Figure 5, principal component can be separated with impurity YM-Z6 under this method, and separating degree reaches 2.0；As seen from Figure 6, change
Becoming flowing phase pH value influences less its separating degree.
(4) acetonitrile system and methanol acetonitrile mixed system are compared：
Mobile phase：(I) phosphate buffer (weighs disodium hydrogen phosphate 0.71g and is dissolved in 1L water, with bis- hypophosphite monohydrate of 16g/L
It is 7.0)-acetonitrile (70 that sodium dihydrogen, which adjusts pH value,:30)；
(II) phosphate buffer (weighs disodium hydrogen phosphate 0.71g and is dissolved in 1L water, with 16g/L sodium dihydrogen phosphate dihydrate
Adjusting pH value is 7.0)-acetonitrile-methanol (60:25:15)；
Chromatographic column：Phenomenex Gemini C18,4.6 × 250mm, 5 μm；
Flow velocity：1ml/min, Detection wavelength：220nm；
Column temperature：40, DEG C sample volume：20 μ l, diluent：Water.
By Fig. 7-8 as it can be seen that two kinds of mobile phases are to the separating effect of principal component and impurity YM-Z6 without obvious poor under this method
It is different.
(5) separation of principal component and impurity YM-Z6 is investigated using ACE-C18 chromatographic column：
Mobile phase：Phosphate buffer (weighs disodium hydrogen phosphate 0.71g and is dissolved in 1L water, with bis- hypophosphite monohydrate dihydro of 16g/L
It is 7.0)-acetonitrile (70 that sodium, which adjusts pH value,:30)；
Chromatographic column：ACE Excel 5Super C18,4.6mm × 150mm, 5 μm；
Flow velocity：1ml/min, Detection wavelength：220nm；
Column temperature：40, DEG C sample volume：20 μ l, diluent：Acetonitrile-water (30:70).
As seen from Figure 9, principal component and the peak shape of impurity YM-Z6 are preferable under this method, and separating degree reaches 2.0, known to other
Impurity does not interfere the detection of YM-Z6 under this condition.
From the above results, it is screened by chromatographic condition, principal component and impurity YM-Z6 are separated under the conditions of method (5)
Well, the detection method by method (5) as this product impurity YM-Z6.
The verifying of 4 analysis method of embodiment
By the screening of chromatographic condition, the chromatostrip of dexmedetomidine hydrochloride impurity YM-Z6 analysis method is tentatively established
Part such as table 4：
The chromatographic condition that table 4 is drafted
The result shows that the above method can efficiently separate YM-Z6 and main ingredient and other different impurities.
Specific verification result such as table 5：
5 DMD raw material impurity YM-Z6 analysis method verification result table of table
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this hair
Equivalent structure or equivalent flow shift made by bright specification and accompanying drawing content is applied directly or indirectly in other relevant skills
Art field, is included within the scope of the present invention.
Claims (10)
1. one kind detects 4- (1- (2,5- 3,5-dimethylphenyl) ethyl) -1H- imidazoles from Medetomidine or dexmedetomidine hydrochloride
Or/and the method for its hydrochloride, which is characterized in that qualitative or/and quantitative detection, liquid chromatogram are carried out using high performance liquid chromatography
Testing conditions include：
Chromatographic column：Alkyl linked silicagel column is further selected from C18 chromatographic column；
Mobile phase：Water phase, organic phase；
Wherein, water phase is phosphate buffer；Organic phase is selected from acetonitrile or/and methanol, is not individually for methanol；Water phase (%): have
Machine phase (%)=60~70: 30~40；Mobile phase uses isocratic elution.
2. detection method according to claim 1, which is characterized in that in the phosphate buffer containing hydrogen phosphate from
Son, dihydrogen phosphate ions, phosphate anion and alkali metal ion；Further, the alkali metal ion is selected from potassium ion, sodium
One or both of ion.
3. detection method according to claim 2, which is characterized in that the phosphate buffer pH value is 7~9.
4. detection method according to claim 1, which is characterized in that the organic phase is acetonitrile, water phase (%): organic phase
(%)=70: 30.
5. detection method according to claim 1, which is characterized in that water phase (%): organic phase (%)=60: 40, wherein
Organic phase is acetonitrile (%): methanol (%)=20~30: 10~20.
6. detection method according to claim 1, which is characterized in that the liquid chromatographic detection condition further includes below
It is one or more in i~iii：
I chromatographic column specification：4.6 × (150~250) mm, 5 μm；
Ii column temperature：25~40 DEG C；
Iii flow velocity：1.2~0.8ml/min.
7. detection method according to claim 1, which is characterized in that the liquid chromatographic detection condition further includes below
It is one or more in i~iv：
I chromatographic column specification：4.6 × 150mm, 5 μm；
Ii column temperature：40℃；
Iii flow velocity：1.0ml/min；
Iv Detection wavelength：220nm.
8. detection method according to claim 1, which is characterized in that the detection method includes the following contents：
(1) test solution is prepared；
(2) contrast solution is prepared；
(3) by contrast solution sample detection；
(4) by test solution sample detection.
9. detection method according to claim 8, which is characterized in that prepare test solution or/and contrast solution uses
Solvent be selected from one or more of water, phosphate buffer, methanol, acetonitrile mixed solvent.
10. detection method according to claim 9, which is characterized in that the mixed solvent is selected from one of following：Water (%)
: phosphate buffer (%)=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 (%): second
Nitrile (%)=40~70: 30~60, methanol (%): acetonitrile (%)=50~75: 25~50, water (%): phosphate buffer
(%): methanol (%)=1~69: 1~69: 30~60, water (%): phosphate buffer (%): acetonitrile (%)=1~69: 1~
69: 30~60, water (%): methanol (%): acetonitrile (%)=40~70: 10~30: 20~30, phosphate buffer (%): first
Alcohol (%): acetonitrile (%)=40~70: 10~30: 20~30 and water (%)：Phosphate buffer (%): methanol (%): acetonitrile
(%)=1~69: 1~69: 10~30: 20~30.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN109580854A (en) * | 2018-12-03 | 2019-04-05 | 石药银湖制药有限公司 | Detection method in relation to substance in a kind of dexmedetomidine hydrochloride raw material or preparation |
| CN111141849A (en) * | 2020-01-06 | 2020-05-12 | 江苏开元药业有限公司 | Liquid phase detection and separation method for positional isomer of dexmedetomidine starting material |
| 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 |
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