Application Of Novel Chiral Selectors Based On Vicinal Cis-dihydroxy And Boric Acid Complexation In NACE

The activity of chiral drugs is closely related to its configuration,so it is necessary to systematically study the physiological effects of optical pure monomers with different configurations in the process of production and application of chiral drugs.Therefore,the establishment of a method for the separation and analysis of chiral drugs can not only prepare optical pure monomers,but also be of great significance to the study of pharmacology,toxicology,pharmacokinetics and pharmacodynamics of drugs.High performance capillary electrophoresis(HPCE)has been widely used in the separation of chiral drugs.Non-aqueous capillary electrophoresis(NACE)is an important branch of HPCE,which has the advantages of a wide range of analytical objects and good separation selectivity.The use of NACE for the separation and analysis of chiral drugs has been proved to be a promising development direction.On the basis of previous studies,based on the complex reaction of vicinal cis-dihydroxy and boric acid in polyhydroxyl compounds,diacetone-D-mannitol–boric acid and L(+)-tartaric acid–boric acid were in situ synthesized in methanol solution,and they were used as chiral selectors to establish chiral NACE separation methods.The method has been applied to the analysis of ractopamine hydrochloride isomers in pig feed and the determination of salmeterol enantiomers in salmeterol fluticasone powder inhaler.In addition,based on the complex reaction principle of vicinal cis-dihydroxy and boric acid,two new chiral selectors of erythromycin–boric acid and clindamycin hydrochloride–boric acid were synthesized in situ in methanol solution,and 18 kinds of amino alcohol chiral drugs were successfully separated in NACE.The full text is divided into six chapters:Chapter 1,the significance of the separation of chiral drugs and the common separation and analysis methods of chiral drugs are reviewed,and the non-aqueous capillary electrophoresis is introduced.Chapter 2,diacetone-D-mannitol–boric acid complex acid was in situ synthesized in methanol solution and used as chiral selector to enantioseparate ractopamine hydrochloride isomers.In order to obtain the best chiral separation,the effects of diacetone-D-mannitol concentration,boric acid concentration and triethylamine concentration were investigated.The results showed that under the optimized experimental conditions,the baseline separation of four ractopamine hydrochloride isomers could be achieved,and the chiral separation method was applied to the analysis of ractopamine hydrochloride isomers in pig feed.The methodological verification results showed that the four isomers had a good linear relationship in the concentration range of 6.2～200.0μg/m L,the correlation coefficient(r)≥0.9992,the detection limit(LOD)0.6μg/m L,quantitative limit(LOQ)2.0μg/m L;the recovery was 97.5%～102.5%,the extraction recovery was 66.4%～72.5%,and the precision RSD was less than 4.8%(n=9).Chapter 3,L(+)-tartaric acid–boric acid complex acid was in situ synthesized in methanol solution and used as a chiral selector to separate the enantiomers of salmeterol xinaphthalate.In order to obtain the best chiral separation,the effects of L(+)-tartaric acid concentration,boric acid concentration and apparent p H value(p H*)were investigated.The results showed that under the optimized experimental conditions,the resolution of two enantiomers of salmeterol was more than 2.0 in 18 min,and the chiral separation method was applied to the determination of salmeterol enantiomers in salmeterol and fluticasone powder inhalation.The methodological verification results show that the two enantiomers have a good linear relationship in the range of 27.5～800.0μg/m L,the correlation coefficient(r)≥0.9992,the detection limit(LOD)is 7.5μg/m L,the quantitative limit(LOQ)is 25.0μg/m L;the recovery is 98.1%～101.9%,and the precision RSD is less than 4.9%(n=9).The labeled percentage content of enantiomer 1 is 97.1%～103.6%,and that of enantiomer 2 is 97.1%～103.7%.Chapter 4,erythromycin–boric acid complex acid was in situ synthesized in methanol solution and used as chiral selector to enantioseparate 18 amino alcohols and 3 quinolones.In order to obtain the best chiral separation,the effects of erythromycin concentration,boric acid concentration,citric acid concentration,triethylamine concentration and water content were investigated.The results showed that under the optimized experimental conditions,15 amino alcohol chiral drugs were enantioseparated at baseline,and the resolution(R_s)of carteolol reached 4.50;three amino alcohols were partially separated;three quinolones were not separated.The effect of molecular structure of chiral drugs on the enantioseparation was discussed.Chapter 5,clindamycin hydrochloride–boric acid complex acid was in situ synthesized in methanol solution and used as chiral selector to eantioseparate 18 amino alcohols and 3quinolones.In order to obtain the best chiral separation,the effects of clindamycin hydrochloride concentration,boric acid concentration,citric acid concentration,triethylamine concentration and water content were investigated.The results showed that under the optimized experimental conditions,18 kinds of amino alcohol chiral drugs had different separation effects,while 3 kinds of quinolone chiral drugs were not separated.The experimental results in this chapter were compared with those in which erythromycin-boric acid complex acid was used as chiral selector,and the chiral separation mechanism was discussed.Chapter 6,conclusions and prospect.