The Preparation of Hollow Silica Spheres with Mesoporous Shell via Polystyrene Emulsion Latex Template and the Investigations of Ascorbic Acid and Potassium Sulfate Release Behaviors

本研究採用AIBA( 2,2-azobisisobutyramidine dihydrochloride)陽離子起始劑無乳化聚合方式製備聚苯乙烯乳液作為模板，在PS達到70%的轉化率時，加入適量的苯二乙烯 (divinyl benzene, DVB) 及甲基丙烯氧基丙基三甲基矽烷 (methacryl oxypropyl trimethoxy silane, MPS) 作為改質劑參與共聚合。再以溶凝膠法使四乙氧基矽烷 (tetraethyl orthosilicate, TEOS) 在PS表面水解縮合生成PS/Silica核殼粒子，因為二氧化矽帶負電荷，因此等電位點由pH 10.4偏移至pH 3.7。經過系列實驗獲得標準配方參數為：styrene 2.0 wt %、AIBA 0.01 M、MPS 0.22 wt %、DVB 0.02 wt % 及TEOS/styrene = 3/1(weight ratio)。SEM顯示合成PS 與PS/silica其直徑分別約 360 nm與 411 nm。PS/Silica經過萃取與煅燒去除聚苯乙烯，得到中空二氧化矽球(PSM0.1D-T3-E-C)，TEM顯示，由於殼層結構不緻密，經過煅燒後，殼層厚度由平均21.4 nm降為 9.3 nm，直徑由433 nm降為 383 nm。直接煅燒製備中空二氧化矽球(PSM0.1D-T3-C)，平均孔徑 8.70 nm，屬於中孔洞多孔材料。BET實驗結果顯示，中空二氧化矽球包覆抗壞血酸後，比表面積由 508.9 m2/ g 降為 47.2 m2/ g，孔洞體積由 0.95 cm3/g 降為 0.18 cm3/g；此外，中空二氧化矽球包覆硫酸鉀後，比表面積降為 171.2 m2/ g，孔洞體積降為 0.44 cm3/g；上述可說明藥物均已成功置入二氧化矽中空球之孔隙。另以SEM和碳元素顯影作為驗證，確認抗壞血酸已置入中空二氧化矽球內，並可應用於釋放研究。分別以Higuchi模式、零級模式及一級模式分析累積釋放百分比，探討釋放動力學行為。結果顯示，一級模式與零級模式皆可以描述抗壞血酸在中空二氧化矽球的釋放動力學，一級模式釋放速率常數在3小時前後分別是0.87與0.03；零級模式的釋放速率常數分別是25.89與2.4。抗壞血酸在釋放初期 0-3 小時，位在殼層孔隙之抗壞血酸其釋放較快。釋放後期 3-10小時，核心的抗壞血酸須穿越殼層孔穴之立體障礙而擴散至溶液，屬於質傳阻力較大之慢速釋放。同樣的分析也應用在硫酸鉀的釋放研究，結果顯示，以Higuchi模式最適合描述硫酸鉀在中空二氧化矽球的釋放行為，釋放速率常數在初期與後期釋放速率分別是217.14與0.9087。The positively charged polystyrene latexes (PS) were prepared via surfactant-free emulsion polymerization of styrene by using the cationic initiator AIBA (2,2-azobisisobutyramidine dihydrochloride). When the styrene conversion of 70 % was reached, appropriate amounts of divinylbenzene (DVB) and methacryl oxypropyl trimethoxy silane (MPS) were added to the emulsion as a functional comonomer. Emulsion particle surfaces bear silanol (Si-OH) functional groups that facilitate the reaction of the silica layer formation on PS particles with silica precursor solution through hydrolysis and condensation of tetraethoxysilane (TEOS) at the acidic aqueous/ethanol medium. PS/silica hybrid colloids with core-shell morphology were obtained. The negatively charged shell showed an isoelectric point (IEP) at pH= 3.7 that was different from the IEP of 10.4 for the original positively charged PS latex based on the Zeta-potential analysis. Typical optimal parameters to prepare PS/silica colloids have been developed from series of experiments. The fomulations for core-shell PS/SiO2 as follows: styrene 2.0 wt %, AIBA 0.01 M, MPS 0.22 wt %, DVB 0.02 wt % and TEOS/styrene = 3/1 (weight ratio). The diameter of PS and PS/silica is roughly 360 nm and 411 nm in SEM image, repectively. The TEM analysis shows that the diameter reduces from 433 nm to 383 nm with a shell thickness of 9.3 nm after extraction and calcination (PSM0.1D-T3-E-C). The hollow silicon dioxide spheres (PSM0.1D-T3-C) prepared by calcination were analyzed using BET analysis. The adsorption and desoption isotherms of these spheres show that the specific surface area of 508.9 m2/g and the pore volume of 0.95 cm3/g. After the encapsulation of ascorbic acid, the specific surface area reduces to 47.2 m2/g and the pore volume reduces to 0.18 cm3/g. After the encapsulation of potassium sulfate, the specific surface area reduces to 171.2 m2/g and the pore volume reduces to 0.44 cm3/g. It shows that drugs already enter the cavities of the hollow silica succesfully. Finally, ascorbic acid was encapsulated in the hollow silica spheres, as inspected by SEM and carbon element mapping images, to examine their kinetics of controlled release behavior. The cumulative release percentage was analyzed using the Higuchi model, a zero-model, and a first model for kinetic study of release behaviors. Results show that both zero-order and first-order models describe the release kinetics of ascorbic acid equally well. The release rate constants for the zero-order model before and after 3 hours are 25.89 and 2.4, respectively, and for the first-order model are 0.87 and 0.03, respectively. We speculated that during the first 3 hours, the ascorbic acid is released from the sphere surfaces. After 3 hours, the ascorbic acid diffues from the core through the pores of shell layer into the solution. During the release process, the ascorbic acid may encounter steric barriers in various pore channels, which causes a significant resistance for mass transfer and results in the slow release of ascorbic acid. In addition, cumulative release percentages of potassium sulfate were also analyzed by various models. Comparing the regression fitness of these models, the Higuchi model shows the best fit for potassium sulfate release kinetics. The release rate constant for the initial stage and the later stage is 217.14 and 0.9087, respectively.中文摘要....................................................i 英文摘要...................................................ii 目錄......................................................iv 表目錄....................................................vii 圖目錄.....................................................ix 第一章 緒論.................................................1 前言.......................................................1 1.2 二氧化矽中空結構球體的製備.............................1 1.3 中空奈米粒子藥物釋放..................................3 1.4 中空球載體藥物釋放的動力學模式..........................7 1.5 研究動機與目的.......................................8 第二章 文獻回顧.............................................10 2.1 中空二氧化矽球載體製備................................10 2.1.1 溶凝膠(Sol-Gel)法合成二氧化矽..................10 2.1.2 核殼乳液與中空微球的製備................................12 2.1.2.1 表面帶正電荷之PS乳液作為核心模板...............12 2.1.2.2 表面帶負電荷之PS乳液作為核心模板...............14 2.1.2.3 矽氧烷MPS改質PS乳液作為核心模板...............15 2.1.2.4 DVB交聯劑參與共聚合PS乳液作為核心模板..............16 2.1.2.5 界面活性劑作為軟核心模板..........................17 2.2 多孔隙中空球之藥物釋放................................18 2.3 中空二氧化矽球之製備專利概況...........................27 第三章 實驗................................................30 3.1 實驗項目...........................................30 3.2 實驗材料...........................................31 3.3實驗儀器............................................33 3.4實驗架構與實驗流程....................................36 3.5 實驗步驟...........................................47 第四章 聚苯乙烯無乳化聚合及PS/SiO2核殼乳液與中空二氧化矽球 配方變數探討與界面現象觀察觀察..........................53 4.1 引言..............................................53 4.2 結果與討論.........................................53 4.2.1 不同聚合系統製備核心模板之探討...................53 4.2.1.1 總體聚合(bulk or mass polymerization) .....54 4.2.1.2 溶液聚合(solution polymerization) .........56 4.2.1.2 a 在甲苯中進行自由基聚合製備不同比例的PS-MPS 共聚物.....................................56 4.2.1.2 b 以Alfrey-Price Q-e scheme法計算styrene與MPS 的r1、r2..................................58 4.2.1.3 無乳化聚合(emulsifier-free polymerization).60 4.2.1.3 a 無乳化聚合製備PS乳液實驗參數探討.............60 4.2.1.3 b 無乳化聚合製備PS/SiO2核殼乳液實驗參數探討.....67 4.2.2 SiO2反應時間參數與溶劑去除PS/SiO2核心後之中 空二氧化矽殼層型態.............................82 4.2.3 PS與PS/SiO2之界面電位(Zata-potential)變化.....84 4.2.4 PS/ SiO2與中空二氧化矽球的固-液相界面現象........88 4.3 結論..............................................92 第五章 以聚苯乙烯乳液模板製備具有中孔洞殼層之中空二氧化矽 球研究..............................................93 5.1 引言..............................................93 5.2 結果與討論.........................................93 5.2.1 中空二氧化矽球之製備及其型態與表面特性.............93 5.2.1.1 PS、PS/ SiO2與中空二氧化矽球之型態分析........94 5.2.1.2 中空二氧化矽球的表面特性.....................105 5.2.2 中空二氧化矽材料包覆抗壞血酸與硫酸鉀…............109 5.2.2.1 利用BET與SEM、元素分佈驗證中空二氧化矽 材料包覆抗壞血酸.............................109 5.2.2.2 利用BET驗證中空二氧化矽材料包覆硫酸鉀..........121 5.3 結論.............................................127 第六章 以中空二氧化矽球包覆抗壞血酸(L-ascorbic acid)與硫酸鉀之釋放研究.........128 6.1引言................128 6.2 結果與討論................128 6.2.1 以中空二氧化矽球包覆抗壞血酸之釋放行為研究..128 6.2.1.1 抗壞血酸之檢測.................129 6.2.1.2 抗壞血酸累積釋放率之釋放動力學模式探討…...130 6.2.2 以中空二氧化矽球包覆硫酸鉀之釋放行為研究......138 6.2.2.1 硫酸鉀之檢測................138 6.2.2.2 中性環境下( pH=7.01 )與不同酸鹼環境下( pH=4.01、 pH=10.01 )硫酸鉀累積釋放率之釋放動力學模式.....138 6.3 結論...............................157 第七章 總結...............................................158 參考文獻..................................................161 附錄一 實驗樣品代號說明......................................168 附錄二 中空二氧化矽球包覆抗壞血酸之實驗代號說明及中空二氧化 矽球包覆抗壞血酸理論值計算............................169 附錄三 以TGA及UV計算抗壞血酸釋放量............................170 附錄四 中空二氧化矽球包覆硫酸鉀之實驗代號說明....................171 附錄五 以鉀離子選擇器電極計算硫酸鉀釋放量.......................17

The preparation of hollow silica spheres with mesoporousshell via polystyrene emulsion latex templateand the investigation of ascorbic acid release behavior

In this study, the emulsifier-free polymerizationwas employed to prepare polystyrene (PS) latex particles.When the styrene conversion of 80 % was reached, appropriateamounts of methacryl oxypropyl trimethoxy silane(MPS) and divinylbenzene (DVB) were added to the emulsionsolution. Emulsion particle surfaces bear silanol functionalgroups that facilitate the rapid reaction with silicaprecursor solution, which is formed through the hydrolysisof tetraethyl orthosilicate (TEOS) and silanol groups of MPSon the emulsion surface. Consequently, a core-shell structurewith PS core and silica shell structure was developed. Usingextraction and calcination to remove the central polystyrenecore, a hollow glass sphere with porous shell structure wasobtained. Finally, ascorbic acid was placed and encapsulatedin these hollow glass spheres, as inspected by SEM andcarbon element mapping images, to examine their controlledrelease behavior. The cumulative release percentage wasanalyzed using the Higuchi model, a zero-order model, anda first-order model for kinetic study of release behavior.Results show that the zero order and first order modelsdescribe the release kinetics of ascorbic acid equally wellfor hollow glass spheres