Static Micromixer Research Articles

Flow-through ultrasonic emulsification combined with static micromixing for aseptic production of microspheres by solvent extraction

Final sterilisation of drug-loaded polymeric microspheres is problematic as dry heat or steam sterilisation are not applicable, and γ-irradiation may result in radiolytic scission of the polymer chains, and potentially damage the bioactive compound. Therefore, aseptic production is the method of choice to obtain a sterile product. A novel process for the production of microspheres is introduced based on the principle of double emulsion–solvent extraction. The process uses a flow-through ultrasonic cell for the preparation of the primary emulsion, in combination with a static micromixer for the production of the double emulsion. Because of its small scale, the equipment is readily accommodated in a laminar air-flow cabinet or an isolator. Thanks to the low technical complexity and easy handling of the process, only minimal manual interventions is required. Finally, the possibility for in-place cleaning and sterilisation makes the equipment and process well suited for aseptic microsphere preparation. Microspheres were prepared from poly(lactic-co-glycolic acid) (PLGA), and bovine serum albumin (BSA) served as model protein for microencapsulation. The BSA-in-PLGA (w/o) emulsions produced by the ultrasonic flow-through cell exhibited mean droplet sizes of <700 nm. Further processing into microspheres of 15–40 μm mean diameter resulted in approx. 70% BSA encapsulation efficiency. Batch-to-batch reproducibility was excellent. Microsphere batches produced under aseptic conditions to assure product sterility exhibited no microbial contamination when examined by a simplified sterility test. The presented technology offers great potential for aseptic microsphere production for batch-sizes suitable, e.g. for clinical investigations. Complete validation of product sterility would, however, demand more extended tests.

Formation of isolated and clustered Au nanoparticles in the presence of polyelectrolyte molecules using a flow-through Si chip reactor

The formation of colloidal gold at room temperature was studied in a micro-reaction system. Ascorbic acid and Fe(II) were used as reducing agents. Besides citric acid, sodium metasilicate and poly(vinyl alcohol) were added as effectors for the formation of nanoparticles. The experimental set-up was based on a 2 + 1 + 1 static micro-mixer in order to test the successive addition of reaction components in a micro-continuous flow process. The residence times for a single mixing step in the chip device were chosen in the range between about 1 second and 1 minute. As a result, single particles of different sizes, simple particle aggregates, core–shell particles as well as complex aggregates and hexagonal nanocrystallites were obtained under different reaction conditions. The reaction mixtures were characterized by UV-Vis spectroscopy as well as by differential centrifugal sedimentation (DCS) and scanning electron microscopy (SEM) reflecting the variety of colloidal gold formed in the microreactor.

Development of a Plate Static Micromixer Utilizing Rotation of Fluid Interface and Its Mixing Performance

三次元屈曲チャネル内での流体層の分割，180°回転，再合流・重ね合せを組み合わせて流体を多層化する静止型マイクロミキサーの単位エレメントの構成則を求め，それに基づいてY字分岐と120°と60°の屈曲チャネルからなるY型平板静止マイクロミキサーを開発した．正方形のチャネル断面をもつY型ミキサーを用いてヨウ素の脱色実験を行い，混合完了に必要な単位エレメント数nを測定した．レイノルズ数Reが低い場合にはnはReの増加とともに増加した．1単位エレメント通過ごとに厚さが1/2となる流体層内の混合過程をモデル化し，nを表す関数関係を導出し，この関係に基づいてReが低い場合のnの実験結果を相関した．Reが高い場合，Reの増加とともにnは減少した．この場合のnについては上記の関数に用いられる変数を用いて実験的に相関した．Reを50まで変化させてCFD解析を行い，Reの影響を調べた結果，Re=50では流体層は三次元屈曲チャネル内で発生する二次流によって大きく変形していることがわかった．この界面の変形が混合速度を加速させ，nを減少させる．さらに，ミキサーを構成するチャネルのアスペクト比a/bの影響をCFD計算によって検討した．a/bが2.0以上では流体界面の湾曲が大きく，a/bが0.2以下では分岐チャネルで流体が均一に分割されない．したがって，本研究で開発した平板静止型ミキサーにおいて理想的な流体層の分割・再合流を進行させるためには，できるだけ正方形に近いアスペクト比をもつ流路断面を採用することが望ましい．

Characterisation of residence time and residence time distribution in chip reactors with modular arrangements by integrated optical detection

An experimental setup was built for the characterisation of residence time distribution (RTD) in microreactors. In order to determine the residence time distribution of those devices, the method of pulse marking with a dye tracer was used. For this method of marking, a specially constructed microstructured injection unit came to use. Detection of the tracer concentration was made by analysing the transmittance with a self-developed transmittance detection unit. The obtained residence time distributions were compared with common RTD models by means of fitting methods. The examined static micromixer showed laminar flow behaviour.

Solvent extraction employing a static micromixer: a simple, robust and versatile technology for the microencapsulation of proteins

The potential of a static micromixer for the production of protein-loaded biodegradable polymeric microspheres by a modified solvent extraction process was examined. The mixer consists of an array of microchannels and features a simple set-up, consumes only very small space, lacks moving parts and offers simple control of the microsphere size. Scale-up from lab bench to industrial production is easily feasible through parallel installation of a sufficient number of micromixers ('number-up'). Poly(lactic-co-glycolic acid) microspheres loaded with a model protein, bovine serum albumin (BSA), were prepared. The influence of various process and formulation parameters on the characteristics of the microspheres was examined with special focus on particle size distribution. Microspheres with monomodal size distributions having mean diameters of 5-30 micro m were produced with excellent reproducibility. Particle size distributions were largely unaffected by polymer solution concentration, polymer type and nominal BSA load, but depended on the polymer solvent. Moreover, particle mean diameters could be varied in a considerable range by modulating the flow rates of the mixed fluids. BSA encapsulation efficiencies were mostly in the region of 75-85% and product yields ranged from 90-100%. Because of its simple set-up and its suitability for continuous production, static micromixing is suggested for the automated and aseptic production of protein-loaded microspheres.

Solvent extraction employing a static micromixer: A simple, robust and versatile technology for the microencapsulation of proteins

The potential of a static micromixer for the production of protein-loaded biodegradable polymeric microspheres by a modified solvent extraction process was examined. The mixer consists of an array of microchannels and features a simple set-up, consumes only very small space, lacks moving parts and offers simple control of the microsphere size. Scale-up from lab bench to industrial production is easily feasible through parallel installation of a sufficient number of micromixers (‘number-up’). Poly(lactic-co-glycolic acid) microspheres loaded with a model protein, bovine serum albumin (BSA), were prepared. The influence of various process and formulation parameters on the characteristics of the microspheres was examined with special focus on particle size distribution. Microspheres with monomodal size distributions having mean diameters of 5–30 μm were produced with excellent reproducibility. Particle size distributions were largely unaffected by polymer solution concentration, polymer type and nominal BSA load, but depended on the polymer solvent. Moreover, particle mean diameters could be varied in a considerable range by modulating the flow rates of the mixed fluids. BSA encapsulation efficiencies were mostly in the region of 75–85% and product yields ranged from 90–100%. Because of its simple set-up and its suitability for continuous production, static micromixing is suggested for the automated and aseptic production of proteinloaded microspheres.

The potential of micromixers for contacting of disperse liquid phases

The dispersion of two immiscible fluids in a static micromixer comprising interdigital channels with corrugated walls was investigated using silicon oil dispersed in dyed as well as pure water as test systems. Silicon oil and water flow rates between 20 mL/h to 500 mL/h and 150 mL/h to 700 mL/h were used, respectively. The experiments revealed the dependence of the average droplet size and size distribution on geometrical parameters of the micromixer and operating conditions. Dispersions with average droplet sizes as small as 5.6 μm and monomodal size distributions having small standard deviations of the droplet size down to 3.6 μm could be generated using the micromixer. The droplet size decreased with increasing total flow and ratio of the flow rates of the two liquids. In addition, a decrease of the droplet size was found when decreasing the channel width of the mixing device. Generally, the silicon oil – dyed water dispersion showed smaller average droplet sizes and were more stable compared to the dispersions based on silicon oil and pure water.

A modular microfluid system with an integrated micromixer

Microsystems are gaining more and more interest in several technological areas. The complete integration of different basic elements like pumps, valves and reaction chambers is possible by the use of microtechnologies. In the field of micro analysis systems a mixing procedure of different solutions is often required. A static micromixer built up in silicon has been developed. The design and fabrication procedures of the micromixer allow the integration of other microcomponents like pumps, valves or sensors. The micromixer consists of two structures silicon wafers. The structured surfaces are bonded together by using a low temperature silicon direct bonding process. The structure of the mixer consists of several identical mixing elements. The size of one element is about . Each element consists of two or more microchannels for different liquids to be mixed. The arrangements of the microchannels in the elements lead to a mixing of the liquids. We found a homogeneous mixing after about 5 mixing elements for mixable liquids. Not mixable liquids will be emulsified after about 16 - 20 mixing elements.