CN109251162A - Tryptophan derivative and application thereof - Google Patents
Tryptophan derivative and application thereof Download PDFInfo
- Publication number
- CN109251162A CN109251162A CN201711235472.5A CN201711235472A CN109251162A CN 109251162 A CN109251162 A CN 109251162A CN 201711235472 A CN201711235472 A CN 201711235472A CN 109251162 A CN109251162 A CN 109251162A
- Authority
- CN
- China
- Prior art keywords
- tryptophan
- preparation
- compound
- impurity
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Indole Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
This disclosure relates to tryptophan derivative and application thereof.Specifically, this disclosure relates to compound or its salt shown in Formulas I, which can be used for detecting the impurity in tryptophan or preparation containing tryptophan and bisulfites, and then for the control of the quality of tryptophan or the preparation containing tryptophan and bisulfites, ensure the drug effect consistency of drug
Description
Technical field
This disclosure relates to tryptophan derivative and application thereof.
Background technique
Tryptophan (Tryptophan), its chemical name is L-2- amino -3 (β-indoles) propionic acid, molecular formula are as follows:
C11H12N2O2, belong to Branchamin.Tryptophan is white to yellowish crystallization or crystalline powder, odorless, in water slightly soluble,
Soluble,very slightly in ethanol, it is insoluble in chloroform, it is readily soluble in formic acid, it is dissolved in sodium hydroxide test solution or dilute hydrochloric acid.Color ammonia
Acid is the precursor substance that auxin biosynthesis is important in plant, generally existing in higher plant.
The substance of any influence pharmaceutical purity is referred to as impurity.Miscellaneous Quality Research is an important content of drug research and development.
By Control of Impurities within a safety, reasonable limits, the quality and safety of marketed products will be directly related to.
Impurity in drug is generally divided into three classes by its physicochemical property: organic impurities, inorganic impurity and residual solvent.It is organic
Impurity includes the impurity introduced in technique and catabolite etc., it may be possible to known or unknown, volatile or fixedness
, since the chemical structure of this kind of impurity is generally similar with active constituent or tool original relationship, therefore usually again can be referred to as related
Substance.Starting material, intermediate, condensate, the side reaction product mainly brought into process of production in relation to substance, and storage
Catabolite etc. during hiding.Related substance research is one of critical project in drug quality research, and content is anti-
Reflect the direct indicator of drug purity.
For the impurity in tryptophan or tryptophan preparation, 12 organic impurities have been recorded altogether in European Pharmacopoeia (EP),
Name is from impurity A successively to impurity L.
For the impurity in tryptophan or tryptophan preparation, more particularly to substance, it is also necessary to further research.
Summary of the invention
Inventor is during tryptophan quality research, it was found that a new impurity, is tryptophan derivative.It should
Tryptophan derivative can be used for detecting the impurity in tryptophan or tryptophan preparation, and then for tryptophan or tryptophan preparation
Quality control, ensures the drug effect consistency of drug.Based on above-mentioned discovery, the disclosure is completed.
This disclosure relates to compound or its salt shown in Formulas I,
In certain embodiments, the compound of formula I or its salt have structure shown in Formula II:
In certain embodiments, the Formula II compound or its salt is selected from:
Or its salt.
Present disclosure also relates to the preparation methods of compound shown in Formulas I, comprising the following steps:
1) bisulfites is made to react in a solvent with tryptophan；
2) optionally, reaction solution obtained by step 1) is isolated and purified.
In certain embodiments, bisulfites and tryptophan react under illumination condition.Preferably, illumination item
Part is natural light irradiation or black light and/or radiation of visible light.Preferred intensity of illumination is 4500 ± 500Lux.Preferably
Light application time is 5 days or more, preferably 9 days or more, example 20 days or 30 days.
In certain embodiments, both bisulfites and tryptophan reaction solution occur anti-under conditions of heating water bath
It answers.Preferably, the time of heating water bath is 8~12 hours, such as 10 hours.Preferably, water bath heating temperature is 70 DEG C or more,
Such as 80 DEG C, 90 DEG C or 100 DEG C.
In certain embodiments, solvent described in disclosure step 1) is water or polar organic solvent；It is preferred that water.
In certain preferred embodiments, the bisulfites is sodium hydrogensulfite.
Present disclosure also relates to the method for compound shown in another preparation formula I, this method is to contain tryptophan and sulfurous
The preparation of sour hydrogen salt is raw material, comprising the following steps:
1) by the preparation visible light or natural light irradiation 1 day or more, preferably irradiate 2 days or more, such as 5 days, 8 days, 9
It or 10 days；Or
By the preparation heating water bath；The time of preferred heating water bath is 8~12 hours, such as 10 hours；It is preferred that
Water bath heating temperature be 70 DEG C or more, such as 80 DEG C, 90 DEG C or 100 DEG C；
2) optionally, step 1) acquired solution is isolated and purified.
In certain embodiments, pure using the chromatography progress separation in two kinds of preparation methods described in the disclosure
Change；Preferably, the chromatography is selected from normal-phase chromatography, reverse-phase chromatography and gel chromatography.
In certain embodiments, isolating and purifying preferably using efficient liquid phase in two kinds of preparation methods described in the disclosure
Chromatography carries out.Preferred chromatographic condition be it is following 1)~5) it is one or more in item:
1) chromatographic column is preparative octadecylsilane chemically bonded silica column, and preferred chromatographic column is waters XBridge
C18,150*19mm, 5 μm；
2) mobile phase is the aqueous solution of organic solvent-volatile acid or alkali, and organic solvent can be acetonitrile or methanol, preferably
Methanol；The aqueous solution of volatile acid or alkali can be the aqueous solution of formic acid, acetic acid, trifluoroacetic acid, ammonium acetate etc., preferably formic acid water
Solution, more preferable pH2.7 aqueous formic acid.Methanol and the preferred volume ratio of pH2.7 aqueous formic acid are (80~90): (20~
10) such as 85:15；
3) Detection wavelength 200nm-360nm, preferably 220nm, 275nm or 316nm；
4) 5~15ml/min of flow velocity, preferably 8~12ml/min, such as 10ml/min；
5) the ultraviolet chromatogram of liquid phase and/or mass collection target compound are pressed.
In certain embodiments, it in two kinds of preparation methods described in the disclosure, isolates and purifies preferably using efficient liquid phase
Chromatography carries out.Preferred chromatographic condition be it is following 1)~5) it is one or more in item:
1) chromatographic column is preparative octadecylsilane chemically bonded silica column, and preferred chromatographic column is waters XBridge
C18,150*19mm, 5 μm；
2) mobile phase is acetonitrile-pH2.7 aqueous formic acid, and acetonitrile and the preferred volume ratio of pH2.7 aqueous formic acid are (80
~90): (20~10) such as 85:15；
3) Detection wavelength 200nm-360nm, preferably 220nm, 275nm, 316nm；
4) 5~15ml/min of flow velocity, preferably 8~12ml/min, such as 10ml/min；
5) sample is connect by the ultraviolet chromatogram of liquid phase and/or molecular weight.
In certain preferred embodiments, the bisulfites is sodium sulfite.
Present disclosure also relates to system of the compound or its salt shown in Formulas I as tryptophan or containing tryptophan and bisulfites
The purposes of impurity reference substance in agent.In certain preferred embodiments, the bisulfites is sodium sulfite.
Present disclosure also relates to compound or its salts shown in Formulas I for detecting tryptophan or containing tryptophan and bisulfites
Preparation in impurity content purposes.In certain embodiments, the impurity is related substance.In certain embodiments
In, the impurity is related substance or active constituent.In certain preferred embodiments, the bisulfites is sulfurous acid
Sodium.
Present disclosure also relates to compound or its salts shown in Formulas I in tryptophan or preparation containing tryptophan and bisulfites
Production in for quality control purposes.In certain preferred embodiments, the bisulfites is sodium sulfite.
Present disclosure also relates to compound or its salts shown in Formulas I for detecting tryptophan or containing tryptophan and bisulfites
Preparation purity purposes.In certain preferred embodiments, the bisulfites is sodium sulfite.
In the disclosure, the tryptophan or preparation containing tryptophan and bisulfites be injection, eye-drops preparations,
Nasal formulations, sucking preparation, aerosol, gelling agent, syrup, liniment, tincture, oral solution, oral suspensions, oral emulsion
Agent, aural preparations, lotion, irrigation, enema, mixture, soft extract, vina, distillate medicinal water, medicinal tea, liquid extract, extract, piece
Preparation in the Chinese Pharmacopoeias general rule such as agent, capsule or granule.In certain preferred embodiments, the bisulfites is
Sodium sulfite.
The method of impurity in a kind of preparation present disclosure also relates to detection tryptophan or containing tryptophan and bisulfites,
This method is using compound or its salt described in claim 1 as impurity reference substance.
In certain embodiments, detection tryptophan or the preparation containing tryptophan and bisulfites described in the disclosure
The method of middle impurity, comprising the following steps:
1) compound or its salt described in claim 1 is provided, as impurity reference substance；
2) impurity content in tryptophan or preparation containing tryptophan and bisulfites is detected.
In certain preferred embodiments, the bisulfites is sodium sulfite.
As needed, tryptophan described in the disclosure can be L-Trp, D-trp or its racemic modification.
Detailed description of the invention
Fig. 1 is the chromatogram of the related substance in the preparation photo damage sample containing tryptophan and sodium hydrogensulfite.
Fig. 2 is extraction ion flow graph, ultraviolet chromatogram and the extraction ion flow graph with tryptophan of target impurity.
Fig. 3 is to contain 2- bisulfite in the preparation photo damage sample of tryptophan and sodium hydrogensulfite using external standard method
The chromatogram of tryptophan.
Specific embodiment
It is described in detail below in conjunction with embodiment of the embodiment to the disclosure, but those skilled in the art will
Understand, the following example is merely to illustrate the disclosure, and should not be regarded as limiting the scope of the present disclosure.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
It can be with conventional products that are commercially available.
The tryptophan used in following example is L-Trp；And the tryptophan and contain tryptophan and bisulfite
The preparation of sodium is that Chinese Pharmacopoeia records and commercially available.
In following example in addition to embodiment 8, the tryptophan being all made of in following high performance liquid chromatography test samples has
Close substance or 2- bisulfite tryptophane.It is described that the specific method is as follows:
1) sample to be tested are as follows: the preparation containing tryptophan and sodium hydrogensulfite or self-control tryptophan aqueous solution, contrast solution
For 1% tryptophan solution.
2) stationary phase is octadecylsilane chemically bonded silica (phenomenex Gemini 5U C18110A), column temperature 40
DEG C, Detection wavelength 220nm, flow velocity 0.7ml/min.With 2.3 buffer of acetonitrile-pH (10:990V/V) for mobile phase A, with second
2.3 buffer of nitrile-pH (350:650V/V) is Mobile phase B, is eluted by following procedure.Sample volume: 20 μ l.
PH2.3 buffer: taking about 700ml concentration is the phosphoric acid solution of 2.9g/L, and 3.90g potassium dihydrogen phosphate is added,
Make to dissolve, adjusts pH value to 2.3 with concentrated phosphoric acid.
Embodiment 1 contains tryptophan and the related substance-measuring of tryptophan in the preparation of sodium hydrogensulfite
The preparation containing tryptophan and sodium hydrogensulfite is taken to detect the related substance of tryptophan therein, using high-efficient liquid phase color
Spectrometry measurement finds there is a unknown tryptophan impurity in chromatogram, and appearance 32min (referring to attached drawing 1), area normalization calculates
Its content is 0.2%.
Embodiment 2 contains tryptophan and the related substance-measuring of tryptophan in the preparation photo damage sample of sodium hydrogensulfite
Preparation containing tryptophan and sodium hydrogensulfite is set into lighting box (purchased from MMM company of Germany, CLC-E/CL 707)
Irradiation 2 days, obtain sample 1, then detect the related substance of tryptophan therein, it has been found that have in chromatogram one it is identical unknown
Tryptophan impurity, content have increased, and are 3.7%.
Embodiment 3 contains tryptophan and the related substance-measuring of tryptophan in the preparation photo damage sample of sodium hydrogensulfite
Preparation containing tryptophan and sodium hydrogensulfite is placed in lighting box to irradiate 9 days, sample 2 is obtained, then detects it
In the related substance of tryptophan, obtained chromatogram is as shown in Figure 1, it is again seen that have an identical unknown color ammonia in chromatogram
Sour impurity, content have obviously increased, and are 10%.
The preparation of 4 target impurity crude product of embodiment
It weighs sodium hydrogensulfite 4g to set in conical flask, adds purified water, be stirred to dissolve, add tryptophan 1g, ultrasound is simultaneously
Being sufficiently stirred makes to dissolve, this conical flask is set and is irradiated 30 days under daylight, sample 3 is obtained, wherein above-mentioned identical unknown impuritie content
Up to 10% or more, it is heated overnight alternatively, conical flask is placed in water-bath, obtains sample 4, above-mentioned identical unknown impuritie content can
Up to 10% or more.
The preparation of 5 target impurity crude product of embodiment
It weighs sodium hydrogensulfite 4g to set in conical flask, adds purified water, be stirred to dissolve, add tryptophan 1g, ultrasound is simultaneously
Being sufficiently stirred makes to dissolve, this conical flask is set lighting box and is distinguished illumination 9 days and 30 days, is taken out, is obtained sample 5 and sample 6, survey respectively
The content of the fixed unknown impuritie, content is respectively 10% and 23%.
The separation and purifying of 6 target impurity of embodiment:
Separation method: device therefor waters preparative high performance liquid chromatography-mass spectrometer (waters e2545-
2767-2489-QDa, Mass (m/z) 50-1250；ESI positive ion mode), chromatographic column is the bonding of preparative octadecylsilane
Silicagel column (waters XBridge C18,150*19mm, 5 μm), mobile phase are methanol-pH2.7 aqueous formic acid (85:15v/
V), Detection wavelength 220nm, flow velocity 10ml/min draw sample 1,2,3,4,5 or 6 prepared by above-described embodiment 2 to embodiment 5
Deng, 10-1000 microlitres, injection preparative high performance liquid chromatography instrument, by the ultraviolet chromatogram of liquid phase and/or extraction ion stream chromatogram
Molecular weight ([M+H] 285) connects sample, repeated multiple times preparation.Quadrat method is connect as shown in Fig. 2, wherein grey and white stylolitic part are
Connect sample part, the upper part of Fig. 2 show be the unknown impuritie extraction ion flow graph (EIC figure), what middle part was shown
It is ultraviolet chromatogram, lower part is divided into the EIC figure of tryptophan.Sample solution will be connect to be placed in 500ml eggplant-shape bottle, drying is concentrated under reduced pressure,
At 40 DEG C hereinafter, analyzing content in drying process, the concentrate to content lower than 90% carries out secondary separation for temperature control.Finally
After decompressed concentrate is dry, white powder is obtained.Through purity assay up to 95%.
The Structural Identification of 7 target impurity of embodiment
6 gained sterling compound of embodiment is subjected to ultraviolet, mass spectrum, nuclear magnetic resonance measuring.UV characteristic absorption is 275nm.
It is identified through high resolution mass spectrum Q-TOF-MS (Agilent 6230TOF LC/MS), the molecular weight of the unknown tryptophan impurity are as follows:
(m/z, [M+H]+) 285.0536, the molecular formula provided is C11H12N2O5S.Through mass spectrum (QSTAR Elite LC/MS/MS
System (CADM-YQ-014)), nuclear magnetic resonance (BRUKER AVANCEIII-400 type) measurement1HNMR(400MHz,CD3OD)
With13CNMR(400MHz,CD3OD), data are referring to table 1, and structural formula is as shown in Formula II -1, and its chemical name is 2- sulfurous acid
Hydrogen tryptophan (2-Bisulfite tryptophan).
Compound shown in 1 Formula II -1 of table1HNMR and13The chemical displacement value of CNMR
(δ, solvent CD3OD)
Embodiment 8 measures the preparation light containing tryptophan and sodium hydrogensulfite using external standard method high performance liquid chromatograph and breaks
The content of 2- bisulfite tryptophan in bad sample
1. sample to be tested:
Test solution: the preparation containing tryptophan and sodium hydrogensulfite is placed in after lighting box irradiates 9 days and obtains test sample
Solution.
Reference substance solution: 2- bisulfite tryptophan prepared by Example 6 is appropriate, accurately weighed, is dissolved in water, and fixed
Hold to scale, obtains the solution of every 12 μ g of ml bisulfite containing 2- tryptophan.
2. chromatographic condition:
High performance liquid chromatograph: Waters 2998-2489；
Chromatographic column: stationary phase be octadecylsilane chemically bonded silica (Waters Atlantics T3C18,250mm ×
4.6mm, 5 μm)；
Mobile phase:
A: acetonitrile-phosphate buffer (takes the sodium dihydrogen phosphate dihydrate solution 1000ml that concentration is 3.9g/L to be with concentration
The phosphoric acid solution 700ml of 2.9g/L mixes, obtains phosphate buffer) (1:99v/v)；
B: acetonitrile-phosphate buffer (35:65)；
It is accurate respectively to draw test solution and each 20ul of reference substance solution, inject liquid chromatograph, according to the form below method ladder
Degree elution, records liquid chromatogram.
Detection wavelength: 220nm；Column temperature: 50 DEG C；Flow velocity: 1.0ml/min；Sample volume: 20 μ l.
Chromatogram is as shown in Figure 3.2- bisulfite tryptophan appearance time is 28.6min.
The content that external standard method calculates 2- bisulfite tryptophan in test solution is 10%.
Claims (10)
1. compound or its salt shown in Formulas I,
2. compound or its salt described in claim 1, with structure shown in Formula II:
3. compound or its salt of any of claims 1 or 2, is selected from:
Or its salt.
4. the described in any item compound or its salts of claims 1 to 3 are as tryptophan or contain tryptophan and bisulfites
Preparation impurity reference substance purposes.
5. the described in any item compound or its salts of claims 1 to 3 are for detecting tryptophan or containing tryptophan and sulfurous acid
The purposes of impurity content in the preparation of hydrogen salt.
6. purposes described in claim 5, wherein the impurity is related substance or active constituent.
7. the described in any item compound or its salts of claims 1 to 3 are in tryptophan or containing tryptophan and bisulfites
Purposes in the production of preparation for quality control.
8. the described in any item compound or its salts of claims 1 to 3 are for detecting tryptophan or containing tryptophan and sulfurous acid
The purposes of the product purity of the preparation of hydrogen salt.
9. the described in any item purposes of claim 4 to 8, wherein the tryptophan or containing tryptophan and bisulfites
Preparation be injection, eye-drops preparations, nasal formulations, sucking preparation, aerosol, gelling agent, syrup, liniment, tincture, take orally it is molten
Liquor, oral suspensions, Orally taken emulsion, aural preparations, lotion, irrigation, enema, mixture, soft extract, vina, distillate medicinal water, tea
Preparation in the Chinese Pharmacopoeias general rule such as agent, liquid extract, extract, tablet, capsule or granule.
10. a kind of method of impurity in detection tryptophan or preparation containing tryptophan and bisulfites, this method is using power
Benefit require 1 described in compound or its salt as impurity reference substance,
Preferably, method includes the following steps:
1) compound or its salt described in claim 1 is provided, as impurity reference substance；
2) impurity content in tryptophan or preparation containing tryptophan and bisulfites is detected.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2017105644615 | 2017-07-12 | ||
| CN201710564461 | 2017-07-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109251162A true CN109251162A (en) | 2019-01-22 |
| CN109251162B CN109251162B (en) | 2021-09-21 |
Family
ID=65051392
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711235472.5A Active CN109251162B (en) | 2017-07-12 | 2017-11-30 | Tryptophan derivative and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109251162B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112697930A (en) * | 2021-01-25 | 2021-04-23 | 北京市药品检验所 | Method for detecting related substance 2-sulfotryptophan in compound amino acid injection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622481A (en) * | 2014-10-28 | 2016-06-01 | 赵建英 | Process for efficient synthesis of 5-bromoindole |
-
2017
- 2017-11-30 CN CN201711235472.5A patent/CN109251162B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622481A (en) * | 2014-10-28 | 2016-06-01 | 赵建英 | Process for efficient synthesis of 5-bromoindole |
Non-Patent Citations (2)
| Title |
|---|
| MARY W.TRUCKSESS: "Separation and isolation of trace impurities in Ltryptophan by high-performance liquid chromatography", 《JOURNAL OF CHROMATOGRAPHY》 * |
| 仲肇明等: "结晶氨基酸输液研制概述", 《氨基酸通讯》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112697930A (en) * | 2021-01-25 | 2021-04-23 | 北京市药品检验所 | Method for detecting related substance 2-sulfotryptophan in compound amino acid injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109251162B (en) | 2021-09-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109633041B (en) | Method for measuring dihydrotestosterone in medicine by derivatization HPLC method | |
| Lopes et al. | Quantification of carbamazepine and its active metabolite by direct injection of human milk serum using liquid chromatography tandem ion trap mass spectrometry | |
| CN103698424B (en) | Detecting method of detecting organic solvent in slightly-soluble aluminum salt drug | |
| CN105699554A (en) | High-purity daptomycin lactone hydrolysate and application thereof | |
| CN109251161A (en) | The preparation method of 2- bisulfite tryptophan | |
| Ulu | Spectrophotometric and spectrofluorimetric determination of atomoxetine in pharmaceutical preparations | |
| CN109251162A (en) | Tryptophan derivative and application thereof | |
| CN110579559B (en) | Derivatization combined LC-MS method for determining allantoin concentration in cell matrix | |
| CN100402048C (en) | Quality control method of composite prepn. of dry mango tree leaves extract | |
| Othman et al. | Spectrophotometric determination of amoxicillin in pharmaceutical preparations | |
| Dutcher et al. | Determination of plasma procainamide and N-acetylprocainamide concentration by high-pressure liquid chromatography. | |
| Schladitz-Keil et al. | Fluorimetric determination of the quaternary compound trospium and its metabolite in biological material after derivatization with benoxaprofen chloride | |
| Zimmerer Jr et al. | Assay of hyoscyamine, atropine, scopolamine, and phenobarbital in unit doses of tablets and elixirs | |
| Matin et al. | Simultaneous determination of tolbutamide and its metabolites in biological fluids | |
| Rivai et al. | Development and validation of bisacodyl analysis method in tablet with absorbance method and area under curves method in ultraviolet spectrophotometry | |
| CN106589007B (en) | Cis- Quzhazhigan and preparation method thereof and detection method | |
| CN101377475A (en) | Quality control method suitable for solancarpine, solamargine and preparation thereof | |
| CN110850003B (en) | Method for separating impurity succinic acid from ferrous succinate | |
| CN115166091B (en) | Method for simultaneously detecting 5 chemical blood pressure lowering drugs in food by ultra-high performance liquid chromatography-tandem mass spectrometry | |
| TWI706934B (en) | A derivative of sodium phenylaminopropionate, a process for its preparation and use of the same | |
| CN114839288B (en) | Pretreatment method of ranitidine hydrochloride Ding Yangpin | |
| CN115219613B (en) | Method for detecting azelaic acid and potassium azelate in cosmetics | |
| CN114689758B (en) | Method for concentrating, extracting and measuring sorbic acid and benzoic acid in gelatin hollow capsules | |
| US20240133850A1 (en) | Fingerprint spectrum construction method for new compound aloe capsule and fingerprint spectrum | |
| Danhof et al. | Assay of 3-Carboxy-Antipyrine in Urine by Capillary Gas Chromatography with Nitrogen Selective Detection: Some Preliminary Results in Man |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |