CN110105419A - The synthetic method of fluticasone propionate impurity - Google Patents
The synthetic method of fluticasone propionate impurity Download PDFInfo
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Abstract
The present invention provides the synthetic method of fluticasone propionate impurity, the method for preparing fluticasone propionate impurity E P-ZB and impurity E P-ZG is specifically included: first using flumethasone as raw material, synthesizing compound I；Compound I is reacted with sulphur reagent, is post-processed and silicagel column purification process reaction product obtains impurity E P-ZB；It again using compound I as raw material, is reacted with acylting agent and generates compound ii, compound ii is condensed with impurity E P-ZB, generates compound IV；Compound IV reacts in organic solvent with sulphur reagent, through catalyst, generates compound V；Compound V reacts under the conditions of acid binding agent is added generates compound VI；Final compound VI is reacted with fluorine bromomethane generates impurity E P-ZG, and the synthetic method craft route is simple and convenient to operate, the good, high income of selectivity.
Description
Technical field
The invention belongs to impurity of the drug to synthesize field, in particular to fluticasone propionate impurity E P-ZB and impurity E P-ZG's
Synthetic method.
Background technique
Fluticasone propionate is the product that Ge Lansu history company gram, Britain releases market, is main living with fluticasone propionate
The drug of sexual element mainly has: Flixonase, fluticasone propionate, Cutivate, is respectively used to treat quick property rhinitis, asthma and dermatitis
Deng.Fluticasone propionate has the characteristics that high-affinity, high specific and high intrinsic activity, rapid-action, adverse reaction is few, alive
It is widely used within the scope of boundary.Currently, all import kinds of high-end preparation of domestic fluticasone propionate, the kind of domestic production
For emulsifiable paste to be, and all relied in terms of aerosol, powder spray, nasal spray and Neulized inhalation are with the high-end preparation such as suspension into
Mouthful.
Requirement of the respiratory system preparation to bulk pharmaceutical chemicals is high, so high-quality feedstocks medicine in order to obtain, first has to propionic acid
The impurity of fluticasone is studied in detail and formulates detailed control strategy.Europe is incorporated into the bulk pharmaceutical chemicals of fluticasone propionate
The impurity of pharmacopeia and United States Pharmacopeia shares 11, and wherein most is not easy to buy corresponding reference substance in China, both makes part
Pharmacopeia impurity is on sale at home, and cost is also higher, this is very big to deepening to bring the research of fluticasone propionate bulk pharmaceutical chemicals
Obstacle.Therefore, reinforce the research to fluticasone propionate bulk pharmaceutical chemicals for breaking the monopolization of import drug, reducing production cost tool
It plays an important role；And impurity E P-ZB and impurity E P-ZG uses reference substance as the detection and research of fluticasone propionate, in propionic acid
The quality of fluticasone bulk pharmaceutical chemicals and its preparation control aspect has irreplaceable role.Currently, in the prior art without one
Kind is directed to the synthetic method of fluticasone propionate impurity E P-ZB and impurity E P-ZG.
Summary of the invention
To solve deficiency in the prior art, the invention proposes a kind of easy to operate, high income fluticasone propionates
The synthetic method of impurity E P-ZB and impurity E P-ZG.
A kind of synthetic method of fluticasone propionate impurity E P-ZB, includes the following steps:
(1) compound I is synthesized
By flumethasone and tetrahydrofuran stirring and dissolving, it is then slowly added into the mixed liquor of periodic acid and water, keeps solution temperature
Degree is reacted for 0~20 DEG C, and water is added after the reaction was completed, and simultaneously temperature control is to 0~20 DEG C, successively stirring and crystallizing, suction filtration, elution filter
Cake, suction filtration, dry cake obtain compound I；
(2) impurity E P-ZB is synthesized
Using compound I as raw material, compound I, sulphur reagent, triethylamine and catalyst are added in reaction dissolvent and mixed
It is even, it is heated to 0~50 DEG C and is reacted, dimethyl acetamide and water are added after the reaction was completed and is cooled to 0~5 DEG C of crystallization, mistake
Filter, washing filter cake, filtering, dry cake, to obtain solid, then silica gel column purification is carried out to obtained solid, elution, decompression are steamed
It is dry to obtain impurity E P-ZB；
Synthetic route are as follows:
Further, the sulphur reagent is N, N- dimethyl thio formyl chloride, N, in N- carbonyl dimidazoles or hydrogen sulfide
It is one or more.
Further, the reaction dissolvent is one of acetone, ethyl acetate, tetrahydrofuran or dioxane or more
Kind.
Further, the catalyst is sodium iodide or tetrabutylammonium iodide.
A kind of synthetic method of fluticasone propionate impurity E P-ZG, includes the following steps:
(1) compound IV is synthesized
The compound I obtained using synthetic method described in any one of claim 1-4 is molten by the compound I as raw material
Solution is added n,N-Dimethylformamide and is stirred evenly in methylene chloride, after being cooled to 0~10 DEG C, then temperature control is to 0~10 DEG C
Acylting agent is added dropwise, 10~20 DEG C of temperature control are reacted, after the reaction was completed temperature control to 20~30 DEG C of evaporated under reduced pressure solvents, to residual
Addition toluene in object is stayed to be dissolved, solvent evaporated, obtains compound ii again, then is added into the compound ii and wants with right
Impurity E P-ZB, 4-dimethylaminopyridine and the methylene chloride for asking synthetic method described in any one of 1-4 to obtain, are cooled to 0~5
Triethylamine is added dropwise after DEG C, then temperature control is reacted to 20~30 DEG C, after the reaction was completed solvent evaporated, carry out silica gel post separation,
Target components and evaporated under reduced pressure solvent are collected in elution, obtain compound IV；
(2) compound V is synthesized
Using the compound IV as raw material, compound IV and sulphur reagent are added in organic solvent A and are uniformly mixed, is cooled to
Catalyst and water are added after 0~10 DEG C, temperature control is reacted to 25~35 DEG C after the completion of sample-adding, after the reaction was completed to reaction solution
Middle addition n,N-Dimethylformamide and water, sample-adding are cooled to 0~10 DEG C of progress crystallization after the completion, are filtered, washed filter cake, are dry
It is dry, obtain compound V；
(3) compound VI is synthesized
Using the compound V as raw material, compound V is dissolved in protonic solvent, acid binding agent is added, then is led into reaction solution
Enter nitrogen, 0~50 DEG C of heating is reacted, after the reaction was completed concentration of reaction solution, added into the reaction solution after concentration methanol,
Water, toluene simultaneously carry out liquid separation, and water phase is collected after liquid separation, and 0~10 DEG C of addition acid of temperature control adjusts pH to 1~2, and crystallization is filtered, washed
Filter cake is washed, compound VI is obtained；
(4) impurity E P-ZG is synthesized
Using the compound VI as raw material, it is cooled to -10~0 DEG C, compound VI is added in organic solvent B, addition is tied up
Fluorine bromomethane is added in sour agent after being cooled to -20~-10 DEG C, temperature control is reacted after the completion of sample-adding for -30~20 DEG C, has been reacted
Bi Houjia water carries out extracting reaction of going out, and 0~10 DEG C of crystallization of temperature control is filtered, washed filter cake, dry cake, obtains impurity E P-ZG；
Synthetic route are as follows:
Further, in the synthesis compound ii the step of, the acylting agent includes: oxalyl chloride, dimethyl
One of sulfoxide or phosphorus oxychloride are a variety of.
Further, in the synthesis compound V the step of, the sulphur reagent is N, N- dimethyl thio formyl chloride,
One of N, N- carbonyl dimidazoles or hydrogen sulfide are a variety of；The organic solvent A is acetone, methylene chloride, chloroform or acetic acid
One of ethyl ester is a variety of；The catalyst is sodium iodide or tetrabutylammonium iodide.
Further, in the synthesis compound VI the step of, the protonic solvent be methanol, ethyl alcohol, isopropanol,
One of n-butanol or water are a variety of；The alkali is in saleratus, potassium carbonate, sodium bicarbonate, sodium carbonate or triethylamine
It is one or more.
Further, in the synthesis impurity E P-ZG the step of, the organic solvent B is N, N- dimethylformamide,
One of N, N- dimethylacetamide ammonia, tetrahydrofuran, dioxane or acetone are a variety of.
The present invention synthesizes compound I first using flumethasone as raw material；Compound I is reacted with sulphur reagent, is post-processed and silicon
Rubber column gel column purification process reaction product obtains impurity E P-ZB, i.e. impurity B in fluticasone propionate European Pharmacopoeia；It is again original with compound I
Material reacts with acylting agent and generates compound ii, and compound ii is condensed with impurity E P-ZB, generates compound IV；Chemical combination
Object IV reacts in organic solvent with sulphur reagent, through catalyst, generates compound V；Acid binding agent condition is being added in compound V
Lower reaction generates compound VI；Final compound VI is reacted with fluorine bromomethane generates impurity E P-ZG, i.e. fluticasone propionate Europe
Impurity G in pharmacopeia.The results show: the synthetic method can be obtained with higher yield purity is high impurity E P-ZB and
Impurity E P-ZG, and organic solvent used in the synthetic method, sulphur reagent, catalyst, acylting agent, eluant, eluent, acid,
The substances such as alkali are commercially available in the market, easy to operate.The synthetic method craft route is simple and convenient to operate, is selective
Well, yield is higher；The fluticasone propionate impurity E P-ZB and impurity E P-ZG of synthesis can be used as fluticasone propionate detection and
Research reference substance, controls applied to the quality of fluticasone propionate and its related preparations, controls fluticasone propionate bulk pharmaceutical chemicals
Or the purity of its preparation.Other features and advantages of the present invention will be illustrated in the following description, also, partly from froming the perspective of
It is become apparent in bright book, or understand through the implementation of the invention.The objectives and other advantages of the invention can be by saying
Pointed structure is achieved and obtained in bright book, claims and attached drawing.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is this hair
Bright some embodiments for those of ordinary skill in the art without creative efforts, can be with root
Other attached drawings are obtained according to these attached drawings.
Fig. 1 shows the synthesis route figure of fluticasone propionate impurity E P-ZB according to an embodiment of the present invention；
Fig. 2 shows the synthesis route figures of fluticasone propionate impurity E P-ZG according to an embodiment of the present invention.
Specific embodiment
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention
In attached drawing, technical solution in the embodiment of the present invention clearly and completely illustrated, it is clear that described embodiment is
A part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art
Every other embodiment obtained without making creative work, shall fall within the protection scope of the present invention.
Embodiment 1
(1) compound I is synthesized
Three mouthfuls of reaction flasks of 1.0L are taken, 30.0g flumethasone and 165mL tetrahydrofuran is added, stirring and dissolving claims 25.0g high
The dissolution of 225mL water is added in acid iodide, and periodic acid solution is slowly added into reaction flask, after the completion of sample-adding, 0~20 DEG C of temperature control reaction
2h；After the reaction was completed, into reaction solution be added 225mL purified water, temperature control to 0~20 DEG C, be stirred crystallization 40min, suction filtration,
Filter cake is eluted with 90mL water, is filtered, 40 DEG C of dryings of filter cake, obtains 28.72g off-white powder, i.e. compound I, yield
99.12%, purity 98%.Wherein, the periodic acid concentration (mass fraction) is 10%.
(2) impurity E P-ZB is synthesized
Tri- mouthfuls of reaction flasks of 250mL are taken, 2.01g compound I and 25mL acetone is added, 10~20 DEG C of temperature control, 1.24g is added
N, N- dimethyl thio formyl chloride, 1.55mL triethylamine and sodium iodide aqueous solution after the completion of sample-adding, are warming up to 20~30 DEG C of progress
React 3.5h；After completion of the reaction, 2mL dimethyl acetamide and 50mL purified water is added, is cooled to 0~5 DEG C of crystallization 0.5h, mistake
Filter, filter cake 15mL water washing, filtering, 30 DEG C of filter cake vacuum drying, obtain 1.85g yellow solid；To the yellow solid into
Row silica gel column purification, collects target components at elution, and evaporated under reduced pressure obtains 1.22g yellow solid, i.e. impurity E P-ZB, yield
50%, purity 96.561%.Wherein, the sodium iodide aqueous solution is that 75mg sodium iodide adds 0.20mL purified water to dissolve to obtain, institute
It states sodium iodide aqueous solution and is used as catalyst in the present embodiment；The elution uses methylene chloride and methanol volume ratio for 50:1's
Mixed liquor is as eluant, eluent.
Embodiment 2
(1) compound I is synthesized
Three mouthfuls of reaction flasks of 1.0L are taken, 30.0g flumethasone and 165mL tetrahydrofuran is added, stirring and dissolving claims 25.0g high
The dissolution of 225mL water is added in acid iodide, and periodic acid solution is slowly added into reaction flask, after the completion of sample-adding, 0~20 DEG C of temperature control reaction
2h；After the reaction was completed, into reaction solution be added 225mL purified water, temperature control to 0~20 DEG C, be stirred crystallization 40min, suction filtration,
Filter cake is eluted with 90mL water, is filtered, 40 DEG C of dryings of filter cake, obtains 28.72g off-white powder, i.e. compound I, yield
99.12%, purity 98%.
(2) compound IV is synthesized
Tri- mouthfuls of reaction flasks of 250mL are taken, 8.02g compound I and 50mL methylene chloride is added, are cooled to 0~10 DEG C, are added
0.3mL n,N-Dimethylformamide simultaneously stirs 20min, later temperature control to 0~10 DEG C of dropwise addition 6.42g oxalyl chloride, and sample-adding is completed
Afterwards, temperature control to 10~20 DEG C of reactions are stayed overnight；After completion of the reaction, controlled at 20~30 DEG C of evaporated under reduced pressure solvents, to residue
Middle addition 40mL toluene is with dissolution residual substance, and solvent evaporated, obtains faint yellow solid, i.e. compound ii again；Add 3.0g
Impurity E P-ZB, 3.0g 4-dimethylaminopyridine and 80mL methylene chloride, then it is cooled to 0~5 DEG C of dropwise addition 2.56g triethylamine, add
After the completion of sample, it is warming up to 20~30 DEG C of reactions overnight；After completion of the reaction, the solvent being evaporated in reaction flask, then carry out 200~300
Mesh silica gel post separation, collects target components, evaporated under reduced pressure solvent at elution, obtains 1.02g yellow solid, i.e. compound IV, yield
21.16%, purity 93%.Wherein, the elution uses methylene chloride to be used as with methanol volume ratio for the mixed liquor of 40~5:1 and washes
De- agent carries out gradient elution, and contains 0.5% acetic acid in the eluant, eluent；The collection target components are detected using LC-MS
Reaction solution, collection component after elution.
(3) compound V is synthesized
Two mouthfuls of reaction flasks of 50mL are taken, 410mg compound IV, 196mg N, N- dimethyl thio formyl chloride and 10mL is added
Acetone is cooled to 0~10 DEG C, adds 78mg sodium iodide and 40mg purified water, after the completion of sample-adding, is warming up to 25~35 DEG C of reactions
4h；After completion of the reaction, 5mL n,N-Dimethylformamide and 25mL purified water are added into reaction solution, is then cooled to 0~10
DEG C, crystallization is overnight, filtering, filter cake 10mL purify water washing, 30 DEG C of forced air drying filter cakes, obtains faint yellow solid 396mg, i.e.,
Compound V, yield 86.8%, purity 90%.
(4) compound VI is synthesized
Two mouthfuls of reaction flasks of 50mL are taken, 0.36g compound V, 0.2g Anhydrous potassium carbonate and 20mL anhydrous methanol, Xiang Fanying is added
It is passed through nitrogen in bottle and replaces three times, then heats to 25~35 DEG C of reaction 4h；After completion of the reaction, reaction solution volume is concentrated into
18mL methanol, 20mL purified water and 20mL toluene are added into the solution after concentration by 5mL or so, then carry out liquid separation, collect lower layer
Water phase, then 0~10 DEG C of the temperature control hydrochloric acid with 1mol/L adjusts gained water phase pH to 1~2,0.5~1h of crystallization, filtering, filter cake
With 10mL water washing, 0.29g pink solid, i.e. compound VI, yield 88%, purity 90% are obtained.
(5) impurity E P-ZG is synthesized
Tri- mouthfuls of reaction flasks of 100mL are taken, 10mL n,N-Dimethylformamide is added and is cooled to -10~0 DEG C, by 1.10g chemical combination
Object VI is added in n,N-Dimethylformamide, adds 195mg saleratus, is cooled to -20~-10 DEG C, and 0.18g fluorine is added
Bromomethane, sample-adding are warming up to -10~0 DEG C of reaction 2h after the completion；After completion of the reaction, then 0~10 DEG C of the temperature control salt with 1mol/L
The pH of reaction system is adjusted to 1~2 by acid, and 20mL ethyl acetate and 15mL purified water are then added into reaction system, is extracted
It takes, liquid separation, collect upper organic phase, evaporated under reduced pressure ethyl acetate, obtain faint yellow solid 1.41g；Again with methanol and dichloromethane
The mixed dissolution solid of alkane, is then added dropwise purified water into reaction system, and temperature control 0~10 DEG C of crystallization, filtering, drying obtain
0.70g off-white powder, i.e. impurity E P-ZG, yield 61%, purity 97.9%.
Although the present invention is described in detail referring to the foregoing embodiments, those skilled in the art should manage
Solution: it is still possible to modify the technical solutions described in the foregoing embodiments, or to part of technical characteristic into
Row equivalent replacement；And these are modified or replaceed, various embodiments of the present invention technology that it does not separate the essence of the corresponding technical solution
The spirit and scope of scheme.
Claims (9)
1. a kind of synthetic method of fluticasone propionate impurity E P-ZB, which is characterized in that synthesizing the impurity E P-ZB includes such as
Lower step:
(1) compound I is synthesized
By flumethasone and tetrahydrofuran stirring and dissolving, it is then slowly added into the mixed liquor of periodic acid and water, keeping solution temperature is 0
~20 DEG C are reacted, and water and temperature control are added after the reaction was completed to 0~20 DEG C, successively stirring and crystallizing, suction filtration, elution filter cake, take out
Filter, dry cake, obtain compound I；
(2) impurity E P-ZB is synthesized
Using compound I as raw material, compound I, sulphur reagent, triethylamine and catalyst are added in reaction dissolvent and are uniformly mixed,
0~50 DEG C is heated to be reacted, dimethyl acetamide and water are added after the reaction was completed and be cooled to 0~5 DEG C of crystallization, filtering,
Washing filter cake, filtering, dry cake, to obtain solid, then silica gel column purification, elution, evaporated under reduced pressure are carried out to obtained solid
Obtain impurity E P-ZB；
Synthetic route are as follows:
2. the synthetic method of impurity E P-ZB according to claim 1, which is characterized in that the sulphur reagent is N, N- diformazan
The thio formyl chloride of base, N, one of N- carbonyl dimidazoles or hydrogen sulfide or a variety of.
3. the synthetic method of impurity E P-ZB according to claim 1, which is characterized in that the reaction dissolvent is acetone, second
One of acetoacetic ester, tetrahydrofuran or dioxane are a variety of.
4. the synthetic method of impurity E P-ZB according to claim 1, which is characterized in that the catalyst be sodium iodide or
Tetrabutylammonium iodide.
5. a kind of synthetic method of fluticasone propionate impurity E P-ZG, which is characterized in that synthesizing the impurity E P-ZG includes such as
Lower step:
(1) compound IV is synthesized
The compound I is dissolved in by the compound I obtained using synthetic method described in any one of claim 1-4 as raw material
It in methylene chloride, is added and n,N-Dimethylformamide and stirs evenly after being cooled to 0~10 DEG C, then temperature control is added dropwise to 0~10 DEG C
Acylting agent, 10~20 DEG C of temperature control are reacted, and temperature control is to 20~30 DEG C of evaporated under reduced pressure solvents after the reaction was completed, to residue
Middle addition toluene is dissolved, again solvent evaporated, obtains compound ii, then is added into the compound ii with claim 1-
Impurity E P-ZB, 4-dimethylaminopyridine and the methylene chloride that synthetic method described in any one of 4 obtains, after being cooled to 0~5 DEG C
Triethylamine is added dropwise, then temperature control is reacted to 20~30 DEG C, after the reaction was completed solvent evaporated, carry out silica gel post separation, elution,
Target components and evaporated under reduced pressure solvent are collected, compound IV is obtained；
(2) compound V is synthesized
Using the compound IV as raw material, compound IV and sulphur reagent are added in organic solvent A and are uniformly mixed, it is cooled to 0~
Catalyst and water are added after 10 DEG C, temperature control is reacted to 25~35 DEG C after the completion of sample-adding, after the reaction was completed into reaction solution
N,N-Dimethylformamide and water is added, is cooled to 0~10 DEG C of progress crystallization after the completion of sample-adding, is filtered, washed filter cake, drying,
Obtain compound V；
(3) compound VI is synthesized
Using the compound V as raw material, compound V is dissolved in protonic solvent, acid binding agent is added, then be passed through nitrogen into reaction solution
Gas, 0~50 DEG C of heating are reacted, concentration of reaction solution after the reaction was completed, added into the reaction solution after concentration methanol, water,
Toluene simultaneously carries out liquid separation, and water phase is collected after liquid separation, and 0~10 DEG C of addition acid of temperature control adjusts pH to 1~2, and crystallization is filtered, washed filter
Cake obtains compound VI；
(4) impurity E P-ZG is synthesized
Using the compound VI as raw material, it is cooled to -10~0 DEG C, compound VI is added in organic solvent B, acid binding agent is added,
Fluorine bromomethane is added after being cooled to -20~-10 DEG C, temperature control is -30~20 DEG C and is reacted after the completion of sample-adding, after completion of the reaction plus
Water carries out extracting reaction of going out, and 0~10 DEG C of crystallization of temperature control is filtered, washed filter cake, dry cake, obtains impurity E P-ZG；
Synthetic route are as follows:
6. the synthetic method of impurity E P-ZG according to claim 5, which is characterized in that in the synthesis compound ii
In step, the acylting agent includes: one of oxalyl chloride, dimethyl sulfoxide or phosphorus oxychloride or a variety of.
7. the synthetic method of impurity E P-ZG according to claim 5, which is characterized in that in the step of the synthesis compound V
In rapid,
The sulphur reagent is N, N- dimethyl thio formyl chloride, N, one of N- carbonyl dimidazoles or hydrogen sulfide or a variety of；
The organic solvent A is one of acetone, methylene chloride, chloroform or ethyl acetate or a variety of；
The catalyst is sodium iodide or tetrabutylammonium iodide.
8. the synthetic method of impurity E P-ZG according to claim 5, which is characterized in that the synthesis compound VI's
In step,
The protonic solvent is one of methanol, ethyl alcohol, isopropanol, n-butanol or water or a variety of；
The alkali is one of saleratus, potassium carbonate, sodium bicarbonate, sodium carbonate or triethylamine or a variety of.
9. the synthetic method of impurity E P-ZG according to claim 5, which is characterized in that the synthesis impurity E P-ZG's
In step, the organic solvent B is N, N- dimethylformamide, N, N- dimethylacetamide ammonia, tetrahydrofuran, dioxane or third
One of ketone is a variety of.
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| WO2004052912A1 (en) * | 2002-12-09 | 2004-06-24 | Farmabios S.P.A. | 17.beta- (alpha-hydroxy) -esters of androstanes as intermediates for the preparation for the preparation of 17.beta.-fluorinated-androstane esters |
| CN101659688A (en) * | 2008-08-25 | 2010-03-03 | 天津金耀集团有限公司 | Method for recrystallizing and refining fluticasone propionate |
| CN107108690A (en) * | 2014-10-03 | 2017-08-29 | 美药星制药有限公司 | The preparation method of fluticasone propionate thio-acid intermediate |
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2019
- 2019-05-28 CN CN201910452912.5A patent/CN110105419B/en active Active
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| WO2004052912A1 (en) * | 2002-12-09 | 2004-06-24 | Farmabios S.P.A. | 17.beta- (alpha-hydroxy) -esters of androstanes as intermediates for the preparation for the preparation of 17.beta.-fluorinated-androstane esters |
| CN101659688A (en) * | 2008-08-25 | 2010-03-03 | 天津金耀集团有限公司 | Method for recrystallizing and refining fluticasone propionate |
| CN107108690A (en) * | 2014-10-03 | 2017-08-29 | 美药星制药有限公司 | The preparation method of fluticasone propionate thio-acid intermediate |
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| Title |
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| MISTRY, N: "Impurity profiling in bulk pharmaceutical batches using F-19 NMR spectroscopy and distinction between monomeric and dimeric impurities by NMR-based diffusion measurements", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
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