(44.192.112.123) 您好!臺灣時間:2021/03/07 17:19
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

我願授權國圖
: 
twitterline
研究生:王靜亞
研究生(外文):Ching Ya Wang
論文名稱:藥物在高分子薄膜中輸送行為之探討-分子動態模擬及自由體積理論分析
論文名稱(外文):Diffusion of Drug Molecules in Polymeric Membranes- Molecular Dynamics Simulations and Free Volume Theory Analysis
指導教授:王大銘
指導教授(外文):Da Ming Wang
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:化學工程學研究所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:236
中文關鍵詞:藥物控制釋放高分子薄膜分子模擬自由體積
外文關鍵詞:Drug controlled releasepolymer membranemolecular dynamics simulationfree volume
相關次數:
  • 被引用被引用:0
  • 點閱點閱:3232
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
本研究使用三種大小相近、但分子形狀及親疏水性各不相同的藥物,來探討藥物本身性質對其在高分子薄膜中擴散的影響。藉由分子動態模擬方法可以獲得有關分子間引力及高分子鏈運動等微觀資訊,再結合自由體積擴散理論即可分析藥物分子在薄膜中的擴散機制。此外,本文也將探討膨潤劑對藥物擴散的影響,藉以提供合理而有效的方法來控制藥物在高分子薄膜中的釋放速率。
經由分子動態模擬,藥物分子在不同膨潤系統中的擴散速率可以由模擬結果求出,和實驗數據比較可以得到相當吻合的結果。隨著膨潤劑(即水分子)的增加,高分子鏈運動的速度會隨之加快,且系統中的自由體積也會明顯的增加。在純高分子薄膜的系統中,經由比較三種藥物的擴散係數,我們發現如果忽略藥物分子與高分子鏈間引力的效應,將會使得利用自由體積理論所預測出的擴散速率產生一定程度的偏差。而在擴散機制方面, theophylline與benzocaine會以「跳躍機制」的方式來進行,然而,受制於分子引力的影響,aspirin則會以一種緩慢爬行的方式來完成擴散。隨著水分子的增加,藥物與高分子之間的引力作用便會變得較不明顯。在純水系統中,藥物的擴散機制則是以「random walk」的方式來進行,故此時的擴散速率主要取決於藥物本身幾何因素的影響,因此,線性分子的擴散速率將會大於盤狀分子。同時,我們發現水分子在高分子薄膜中並不是全然均勻的分散,當水分子逐漸增加時,水分子團簇(cluster)也會變得愈來愈大。因此,在膨潤程度較為明顯的薄膜中,便會形成兩種擴散路徑,故藥物分子的擴散行為會呈現了兩種不同的機制,在高分子區域中會以所謂的「跳躍機制」進行擴散,而在水分子團簇中則以「random walk」的方式進行。
In the first part of the present study, the effect of swelling on the diffusion of drug molecules is examined by diffusion theories. On the basis of the Flory-Huggins and Yasuda theories, an equation which expresses the diffusion coefficient of drug molecules in powers of the activity of swelling agent is deduced.
In the second part of the present study, molecular dynamics (MD) simulations were performed to investigate the diffusion of drugs in polymer membranes. The microscopic information concerning the intermolecular forces and the dynamics of polymers, which is not readily available by experiments, can be obtained by MD. In addition, the free volume theory, which is commonly used to explain the penetrant diffusion within polymer systems, would be invoked to analyze the simulation results. Initially, the validations of the simulated packing models are examined by comparing the simulated and experimental x-ray diffraction spectra. Afterwards, the diffusion coefficients of drug molecules are calculated and compared with available experimental data.
In order to clarify the effect of swelling agents, the diffusion mechanisms of drugs under various swelling conditions are demonstrated such that the complex interplay among drugs, swelling agents and polymer membranes can be revealed. In pure polymer system, it seems that the ignorance of the energy term may lead to unexpected deviations from what the free volume theory estimates. The importance of the intermolecular forces between drugs and polymers are also manifested: the aspirin molecule is dragged by the stronger attraction forces from the host PVA matrices so that it performs reptile diffusive motions instead of the “hopping mechanism”; on the other hand, the hydrophobic benzocaine molecule would confine the local polymer chain dynamics and lead to a lower accessible free volume, which results in lower diffusion rates in compared with hydrophilic theophyllin molecules. As the swelling agents (water molecule) increases, the interaction between the drugs and polymers becomes modified. In pure water systems, the drug molecule shows a fluid-like diffusion mechanism, which differs from that in pure polymer membranes. Under such circumstances, the steric effect becomes more decisive than others on the diffusion of drugs. Consequently, a bulky penetrant, like theophylline, would diffuse slower than linear ones. However, in swollen membranes, a dual mode diffusion mechanism of the drug molecule is observed. Besides, it is found that some of the water molecules disperse individually into the polymer matrices, while others may get clustered. The higher the swelling condition is, the more and larger the water clusters become. From this point of view, the whole system is no longer microscopically homogeneous and two distinct domains, the water-decorated polymer domain and the water cluster domain, can be seen within swollen membranes. Therefore, it is clearly that the swollen membrane provides two paths for drugs to diffuse, which clearly explains why both the hopping and fluid-like diffusion mechanisms are performed alternatively.
ABSTRACT I
ABSTRACT (in Chinese) III
ACKNOWLEDGEMENT (in Chinese) IV
CONTENT V
SUMMARY (in Chinese) VIII
FUGURE LIST XI
TABLE LIST XVI
Chapter I Introduction 1
Chapter II Literature Survey 7
2.1 Physical models of diffusion in polymers 7
2.1.1 Diffusion theories based on obstruction effects 9
2.1.2 Diffusion theories based on hydrodynamic interactions 14
2.1.3 Diffusion theories based on the free volume theory 18
2.2 Molecular dynamics simulations of diffusion in polymer membranes 28
2.2.1 Molecular dynamics simulations of gas diffusion in amorphous polymer membranes 29
2.2.2 Molecular dynamics simulations of polymer-solvent systems 35
2.2.3 Molecular dynamics simulations of the diffusion of drug molecules in membranes 38
Chapter III Experimental 41
3.1 Diffusion of benzocaine in EVAc and PU membranes 41
3.2. Diffusion of theophylline, benzocaine, and aspirin in PVA membrane 46
Chapter IV Analysis of the Swelling Effect on the Diffusion of Drug Molecules 49
4.1 Background 49
4.2 Theoretical analysis 51
4.2.1 Determining drug diffusion coefficient in polymeric membranes 51
4.2.2 Modeling permeant diffusion coefficient dependence on swelling agent activity 52
4.2.3 Approximate solution of the dependence of the permeant diffusion coefficient on the activity of swelling agent 54
4.3 Experimental results vs. theoretical analysis 56
4.3.1 Swelling of EVAc membranes 56
4.3.2 Dependence of the diffusion coefficient of benzocaine on membrane swelling in EVAc membranes 57
4.3.3 Dependence of the diffusion coefficient of benzocaine on the activity of ethanol in EVAc membranes 61
4.3.4 Dependence of diffusion coefficients of benzocaine and ethanol on ethanol activity in polyurethane membranes 62
4.3.5 Dependence of permeant diffusion coefficient on membrane swelling in PU membranes 64
4.4 Discussion 67
4.5 Summary 70
Chapter V Simulation Methods 71
5.1 Molecular modeling of polymeric systems 71
5.2 Periodic boundary conditions 75
5.3 Force fields 77
5.3.1 General functional forms of empirical force fields 78
5.3.2 Force field parameterization 83
5.3.3 COMPASS force field 85
5.4 Energy minimization 89
5.5 Molecular dynamics 93
5.5.1 Integrating the Equations of motion 94
5.5.2 Molecular dynamics in various ensembles 99
5.6 Simulation details in the present study 108
5.6.1 Bulk PVA model 108
5.6.2 Swollen PVA membrane models 109
5.6.3 Penetrant models 110
5.6.4 The PVA-penetrant models 114
5.6.5 Interface model of drug solution and PVA membrane 114
5.6.6 Calculation of the desired properties 118
Chapter VI Simulation Results 121
6.1 Validation of the simulation models 123
6.1.1 Bulk PVA models 123
6.1.2 Effect of swelling agents on polymer structure 125
6.1.3 Effect of drug molecules on polymer structure 128
6.2 Diffusion coefficient of drug and the effects of swelling agents 131
6.2.1 Evaluation of drug diffusion coefficients from simulation results 131
6.2.2 Effects of swelling agent on local polymer chain dynamics 135
6.2.3 Effects of swelling agent on local polymer free volume 141
6.2.4 Diffusion coefficient of drug versus free volume 155
6.3 Effect of interaction between drugs, polymers and swelling agents on diffusion 159
6.3.1 Comparison of the simulated and experimental drug diffusion coefficients in dry PVA membranes 159
6.3.2 Diffusion versus free volume effect 168
6.3.3. Intermolecular forces on partition and diffusion 179
6.4 Diffusion mechanisms of drugs- the complex interplay between drug, swelling agents, and polymers 191
Chapter VI Conclusion 201
REFERENCE 203
APPENDIX 217
Allen, M. P. and D. J. Tildesley, Computer Simulation of Liquids, Clarendon Press: Oxford (1987).
Alper, H. E. and T. R. Stouch, “Orientation and diffusion of a drug analogue in biomembranes: Molecular Dynamics Simulation,” J. Phys. Chem., 99, 5724-5731 (1995)
Altenberger, A. R., M. Tirrell, and J. S. Dahler , “Hydrodynamic screening and particle dynamics in porous media, semidilute polymer solutions and polymer gels,” J. Chem. Phys., 84, 5122-5130 (1986).
Andersen, H. C., “Molecular dynamics at constant pressure and /or temperature,” J. Chem. Phys., 72, 2384-2393 (1980).
Askadskii, A. A., Physical Properties of Polymers: Prediction and Control, Gordon and Breach Publishers, Amsterdam (1996).
B. R. Gelin, Molecular Modeling of Polymer Structures and Properties, Hanser Publishers: Munich (1994).
Baker, R. W., Controlled Release of Biologically Active Agents, Wiley, New York (1987).
Barrer, R. M., Trans. Faraday Soc., 38, 322 (1942).
Berendsen, H. J. C., F. P. M. Postma, W. F. van Gunsteren, A. DiNola and J. R.Haak, “Molecular dynamics with coupling to an external bath,” J. Chem. Phys., 81, 3684-3690 (1984).
Bharadwaj, R. K., and R. H. Boyd, “Small molecule penetrant diffusion in aromatic polyesters: a molecular dynamics simulation study,” Polymer, 40, 4229-4236 (1999).
Bondi, A., “Free volumes and free rotation in simple liquids and liquid saturated hydrocarbons,” J. Phys. Chem., 58, 929-939 (1954).
Boyd, R. H. and P. V. K. Pant, “Molecular packing and diffusion in polyisobutylene,” Macromolecules, 24, 6325-6331 (1991).
Brook III, C. L., M. Karplus and B. M. Pettitt, Protein: A theoretical perspective of dynamics, structure, and Thermodynamics, Adv. In Chem. Physics, Vol. LXXI, John Wiley & Sons: New York (1988).
Bueche, F., “Segmental mobility of polymer near their glass temperature,” J. Chem. Phys., 21, 1850 (1953).
Chen, S. A., G. W. Hwang, “Structure and properties of the water-soluble self-acid-doped conducting polymer blends: sulfonic acid ring-substituted polyaniline/ poly(vinyl alcohol) and poly( aniline- co-N-propanesulfonic acid aniline)/ poly( vinyl alcohol),” Polymer, 38, 3333-3346 (1997).
Chen, S. X. and R. T. Lostritto, “Diffusion of benzocaine in polyethylene-vinyl acetate membranes: effects of vehicle ethanol concentration and membrane vinyl Acetate,” J. Controlled Release, 38, 185 (1996).
Chung, H. S., “On the macedo-litovitz hybrid equation for liquid viscosity,” J. Chem. Phys., 44, 1362-1364 (1966).
Cohen, M. H. and D. Turnbull, “Molecular transport in liquid and glasses,” J. Chem. Phys., 31, 1164-1169 (1959).
Cukier, R. I., “Diffusion of Brownian spheres in semidilute polymer solutions,” Macromolecules, 17, 252-255 (1984).
Cullity, B. D., R. S. Stock, Elements of X-ray diffraction,3rd ed., Prentice Hall (2001).
Cussler, E. L., Diffusion, Mass Transfer in Fluids Systems, 2nd ed., Cambridge University Press: Cambridge (1997).
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
系統版面圖檔 系統版面圖檔