P1-修飾微乳液相色譜高通量測(cè)定藥物親脂性的研究
發(fā)布時(shí)間：2018-10-15 14:18
【摘要】：目的 在本研究中，將P1和微乳結(jié)合作為流動(dòng)相，使在流動(dòng)相和固定相上引入P1分子，建立新的生物分配高效液相色譜，用于高通量篩選藥物親脂性和模擬藥物與生物膜的相互作用。本研究建立的P1修飾微乳液相色譜利用logk建立模型預(yù)測(cè)logP（正辛醇/水分配系數(shù)的對(duì)數(shù)，用于描述化合物親脂性），并且應(yīng)用于電離和不電離藥物親脂性研究中。除了藥物親脂性，本研究還將利用P1修飾微乳液相色譜模擬藥物通過(guò)血腦屏障的過(guò)程，利用logk建立模型預(yù)測(cè)logBB。 研究方法 1. P1用量和表面活性劑類型的確定 通過(guò)測(cè)定不同P1含量的P1修飾微乳溶液的相對(duì)粘度（25℃）和紫外吸收，選擇相對(duì)粘度小的且P1含量多的體系，并且紫外吸收要弱，這樣才符合液相色譜流動(dòng)相的要求。 2.引入P1的微乳組成的篩選 在引入P1前，要得到最佳的微乳組成。配制多種不同組成的微乳液相色譜流動(dòng)相，通過(guò)logk-logP的相關(guān)性分析，選擇相關(guān)性大的微乳組成作為用于引入P1的條件。 3. P1修飾微乳液相色譜的建立 將P1引入最佳微乳條件，初步建立P1修飾微乳液相色譜�？疾齑松V體系的穩(wěn)定性和重現(xiàn)性。通過(guò)線性溶劑化方程描述分析物分子與色譜體系間的相互作用，用歐氏距離和主成分分析評(píng)價(jià)此色譜體系，并與文獻(xiàn)報(bào)道的體系比較預(yù)測(cè)logP的能力。 4. P1修飾微乳液相色譜預(yù)測(cè)logP模型的建立 在P1修飾微乳液相色譜體系條件下，建立logk-logP模型，并引入分子結(jié)構(gòu)參數(shù)，，提高模型預(yù)測(cè)logP的能力。 5. P1修飾微乳液相色譜的優(yōu)化在初步獲得的P1修飾微乳液相色譜條件下，對(duì)其進(jìn)行優(yōu)化，并制備P1修飾微乳柱系統(tǒng)。通過(guò)logk-logP相關(guān)性分析評(píng)價(jià)優(yōu)化的結(jié)果。 6.電離和不電離分析物在P1修飾微乳液相色譜的應(yīng)用 將優(yōu)化后得到的P1修飾微乳液相色譜體系應(yīng)用于電離和不電離分析物，建立預(yù)測(cè)藥物親脂性模型。比較logk-logP與logk-logD的相關(guān)性結(jié)果，并通過(guò)logk值的主成分分析將本研究所得體系與文獻(xiàn)報(bào)道體系進(jìn)行比較。 7. P1修飾微乳液相色譜預(yù)測(cè)logBB模型的建立 在最佳P1修飾微乳液相色譜體系下，建立logk-logBB模型，并引入分子結(jié)構(gòu)參數(shù)，提高模型預(yù)測(cè)logBB的能力。 成果和結(jié)論 通過(guò)確定P1用量、表面活性劑類型和篩選微乳組成實(shí)驗(yàn)和數(shù)據(jù)分析，初步建立P1修飾微乳液相色譜系統(tǒng)（流動(dòng)相組成為0.08%P1-3.0%SDS-6.0%正丁醇-0.8%乙酸乙酯-90.2%水），并獲得好的穩(wěn)定性和重現(xiàn)性。線性溶劑化方程指出溶質(zhì)體積和氫鍵堿度對(duì)分析物保留影響最大。通過(guò)歐氏距離和主成分分析證明此體系與正辛醇/水體系性質(zhì)相似，可用于預(yù)測(cè)logP。建立logk-logP模型（R2=0.797），但通過(guò)逐步回歸引入了摩爾體積（MV）參數(shù)至模型后，使得模型的預(yù)測(cè)能力有明顯的提高(logP=2.168logkMP12+0.003MV+1.551, R2=0.856)。將初步獲得的P1修飾微乳液相色譜流動(dòng)相優(yōu)化后，獲得最佳流動(dòng)相組成為0.2%P1-3.0%SDS-6.0%正丁醇-0.8%乙酸乙酯-90.0%水。P1修飾微乳柱色譜的logk-logP線性關(guān)系較差，預(yù)測(cè)logP能力弱。將優(yōu)化后得到的P1修飾微乳液相色譜體系應(yīng)用于電離和不電離分析物，比較發(fā)現(xiàn)logk-logD的相關(guān)性（logD7.0=2.030logkMP9+1.796, R2=0.673）比logk-logP好。通過(guò)與其他文獻(xiàn)體系比較，P1修飾微乳液相色譜體系有好的預(yù)測(cè)logD能力。在最佳P1修飾微乳液相色譜體系下，建立logk-logBB模型，發(fā)現(xiàn)logk與logBB沒(méi)有明顯的線性關(guān)系，但將摩爾分子量（MW）大于250的藥物剔除后，logk-logBB線性關(guān)系有明顯的提高（R2=0.612），且在此基礎(chǔ)上引入?yún)?shù)（MW），能獲得好的預(yù)測(cè)logBB模型（logBB=0.347logk-0.002MW+0.352, R2=0.793）。
[Abstract]:Purpose In this study, P1 and microemulsion are combined as mobile phases, P1 molecules are introduced into the mobile phase and the stationary phase, and new biodistribution high performance liquid chromatography is established for high-throughput screening of drug lipophilic and simulated drugs and biofilm The P1 modified microemulsion chromatography established in this study uses the logk set up model to predict logP (the log of n-octanol/ water distribution coefficients for describing the lipophilic nature of the compound) and is applied to both ionization and non-ionization drug lipophilic research. in addition to that lipophilic nature of the drug, the study will use P1 to modify the microemulsion chromatography to simulate the process of the drug through the blood-brain barrier, and use the logk to establish the model prediction log. BB. Study Method 1. P1 Usage and Table Determination of surfactant type by measuring the relative viscosity (25.degree. C.) and ultraviolet absorption of P1-modified microemulsion solution with different P1 contents, with a relatively low viscosity and a higher P1 content. the system, and the ultraviolet absorption is weak, Requirements for liquid chromatography mobile phase. 2. Screening of Microemulsion Composition with P1 Before the introduction of P1, the optimal microemulsion composition was obtained. A variety of different compositions of microemulsion chromatography mobile phase were prepared. The correlation analysis of logk-logP was used to select the correlation. Large micro-emulsion composition as used for the introduction of P1 Conditions. 3. P1 Modified Microemulsion Gas Chromatography Establishment of P1 The optimal microemulsion condition was introduced, and P1 repair was initially established. The stability and reproducibility of the chromatographic system were investigated by gas chromatography. The interaction between the analyte molecules and the chromatographic system was described by the linear solvation equation. The chromatogram was evaluated by Euclidean distance and principal component analysis. The ability of logP to be compared with the system reported by the literature. 4.P1 Modified microemulsion chromatography to predict logP model was established under the condition of P1 modified microemulsion chromatography system, and logk-l was established. ogp model and the introduction of molecular structure parameters to improve the ability of the model to predict logp. 1, optimizing the micro-emulsion chromatographic conditions and preparing P 1. Modified micro-emulsion column system. Through logk-logP correlation analysis The results of evaluation optimization. 6. The application of ionization and non-ionization analytes in P1-modified microemulsion chromatography will be optimized. The P1 modified microemulsion chromatography system was applied to ionization and non-ionization analytes to establish a predicted drug lipophilic model. The phase of logk-logP and logk-logD was compared. Pass the results and analyze the study by the principal component analysis of the logk value A comparison was made between the system and the literature reporting system. 7. P1 modified microemulsion chromatography to predict the logBB model was established in the best P1 modified microemulsion phase color. under the spectrum system, The logk-logBB model was established and the molecular structure parameters were introduced to improve the ability of the model to predict logBB. Results and conclusions were established by determining P1 dosage, surfactant type and screening micro-emulsion composition experiment and data analysis, and initially establishing P1-modified microemulsion chromatography system (mobile phase composition was 0. 0 8% P1-3.0% SDS-6.0% n-butanol-0.8% ethyl acetate-90. 2% water) and good stability and reproducibility. Linear solvation equation indicates solute volume and hydrogen bond alkalinity It is proved that this system is similar to that of n-octanol/ water system by Euclidean distance and principal component analysis. It can be used to predict logP. The log-log P model (R2 = 0. 044) is established, but Moore volume (MV) parameter is introduced into the model by stepwise regression, so that the model can be predicted. There was a significant increase in the force (logP = 2.168logkMP12 + 0.003MV + 1.551, R2 = 0.9856). The optimum flow phase was 0.2% P1-3.0% SDS-6.0% n-butanol-0. 8% ethyl acetate-90. 0% water. The log-log P linear relation of P1 modified microemulsion column chromatography was poor, and the prediction log P was weak. The P1 modified microemulsion chromatography system obtained after optimization was applied to ionization and non-ionization analysis to find the phase of logk-logD. Off (logD7. 0 = 2. 030logkMP9 + 1. 796, R2 = 0. 6 73) It is better than logk-logP. By comparison with other literature systems, P1-modified microemulsion chromatography system has good predictive logD ability. Under the optimum P1 modified microemulsion chromatography system, the logk-logBB model is established. It is found that logk does not have a significant linear relationship with logBB, but the molar molecular weight (MW) is greater than 250. The linear relationship between logk-logBB and logk-logBB is obviously improved (R2 = 0.9612), and the parameters (MW) are introduced on this basis, which can be obtained.
【學(xué)位授予單位】：廣東藥學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R927
本文編號(hào)：2272809
[Abstract]:Purpose In this study, P1 and microemulsion are combined as mobile phases, P1 molecules are introduced into the mobile phase and the stationary phase, and new biodistribution high performance liquid chromatography is established for high-throughput screening of drug lipophilic and simulated drugs and biofilm The P1 modified microemulsion chromatography established in this study uses the logk set up model to predict logP (the log of n-octanol/ water distribution coefficients for describing the lipophilic nature of the compound) and is applied to both ionization and non-ionization drug lipophilic research. in addition to that lipophilic nature of the drug, the study will use P1 to modify the microemulsion chromatography to simulate the process of the drug through the blood-brain barrier, and use the logk to establish the model prediction log. BB. Study Method 1. P1 Usage and Table Determination of surfactant type by measuring the relative viscosity (25.degree. C.) and ultraviolet absorption of P1-modified microemulsion solution with different P1 contents, with a relatively low viscosity and a higher P1 content. the system, and the ultraviolet absorption is weak, Requirements for liquid chromatography mobile phase. 2. Screening of Microemulsion Composition with P1 Before the introduction of P1, the optimal microemulsion composition was obtained. A variety of different compositions of microemulsion chromatography mobile phase were prepared. The correlation analysis of logk-logP was used to select the correlation. Large micro-emulsion composition as used for the introduction of P1 Conditions. 3. P1 Modified Microemulsion Gas Chromatography Establishment of P1 The optimal microemulsion condition was introduced, and P1 repair was initially established. The stability and reproducibility of the chromatographic system were investigated by gas chromatography. The interaction between the analyte molecules and the chromatographic system was described by the linear solvation equation. The chromatogram was evaluated by Euclidean distance and principal component analysis. The ability of logP to be compared with the system reported by the literature. 4.P1 Modified microemulsion chromatography to predict logP model was established under the condition of P1 modified microemulsion chromatography system, and logk-l was established. ogp model and the introduction of molecular structure parameters to improve the ability of the model to predict logp. 1, optimizing the micro-emulsion chromatographic conditions and preparing P 1. Modified micro-emulsion column system. Through logk-logP correlation analysis The results of evaluation optimization. 6. The application of ionization and non-ionization analytes in P1-modified microemulsion chromatography will be optimized. The P1 modified microemulsion chromatography system was applied to ionization and non-ionization analytes to establish a predicted drug lipophilic model. The phase of logk-logP and logk-logD was compared. Pass the results and analyze the study by the principal component analysis of the logk value A comparison was made between the system and the literature reporting system. 7. P1 modified microemulsion chromatography to predict the logBB model was established in the best P1 modified microemulsion phase color. under the spectrum system, The logk-logBB model was established and the molecular structure parameters were introduced to improve the ability of the model to predict logBB. Results and conclusions were established by determining P1 dosage, surfactant type and screening micro-emulsion composition experiment and data analysis, and initially establishing P1-modified microemulsion chromatography system (mobile phase composition was 0. 0 8% P1-3.0% SDS-6.0% n-butanol-0.8% ethyl acetate-90. 2% water) and good stability and reproducibility. Linear solvation equation indicates solute volume and hydrogen bond alkalinity It is proved that this system is similar to that of n-octanol/ water system by Euclidean distance and principal component analysis. It can be used to predict logP. The log-log P model (R2 = 0. 044) is established, but Moore volume (MV) parameter is introduced into the model by stepwise regression, so that the model can be predicted. There was a significant increase in the force (logP = 2.168logkMP12 + 0.003MV + 1.551, R2 = 0.9856). The optimum flow phase was 0.2% P1-3.0% SDS-6.0% n-butanol-0. 8% ethyl acetate-90. 0% water. The log-log P linear relation of P1 modified microemulsion column chromatography was poor, and the prediction log P was weak. The P1 modified microemulsion chromatography system obtained after optimization was applied to ionization and non-ionization analysis to find the phase of logk-logD. Off (logD7. 0 = 2. 030logkMP9 + 1. 796, R2 = 0. 6 73) It is better than logk-logP. By comparison with other literature systems, P1-modified microemulsion chromatography system has good predictive logD ability. Under the optimum P1 modified microemulsion chromatography system, the logk-logBB model is established. It is found that logk does not have a significant linear relationship with logBB, but the molar molecular weight (MW) is greater than 250. The linear relationship between logk-logBB and logk-logBB is obviously improved (R2 = 0.9612), and the parameters (MW) are introduced on this basis, which can be obtained.
【學(xué)位授予單位】：廣東藥學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R927
【參考文獻(xiàn)】
相關(guān)期刊論文 前4條
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