冻干过程在线气体质谱的研究

为了探索检测生化药品真空冷冻干燥过程中冻干室内发生微量漏油和判断升华干燥结束点的有效方法,采用质谱仪对冻干机内硅油泄漏和一次升华干燥过程进行在线监测。结果表明,质谱仪能检测到冻干室内本底硅油量为1×10^-12,当硅油泄漏量为1×10^-6时,采用质谱仪可在15min内检测到;当冻干机空载运行时,采用质谱仪检测N₂、O₂、H₂O、Ar占气体体积分数分别为82.31%、15.68%、1.37%、0.64%,药品在一次升华干燥过程后期,4种气体占气体体积分数分别为82.47%、14.9%、1.75%、0.88%,可用空载冻干室内空气各组分所占比重判断药品一次升华干燥过程的结束。本研究为冻干机内硅油泄漏和生化药品冻干进程的判断提供了新方法。     

真空冷冻干燥过程的模拟研究

在升华干燥阶段应用传热传质理论对 URIF模型进行了改进与完善 ,在解吸干燥阶段假设结合水的脱除随物料温升的变化率为常数 ,建立冷冻干燥模型 ,通过解析求解 ,得出了冷冻干燥过程时间的解析表达式 ,在工程应用中预测冻干时间十分方便。还分析了干燥室压力、物料厚度对冷冻干燥时间的影响。     

梅州金柚柚子皮的真空冷冻干燥工艺研究

目的以梅州金柚柚子皮为原料,研究柚皮真空冷冻干燥工艺技术,确定最佳工艺参数和加工工艺,为柚皮综合利用提供参考依据。方法通过单因素实验和正交实验设计,以冻干速率作为考察指标,研究了压力(真空度)、加热温度、物料厚度对真空冷冻干燥速率的影响。结果实验表明,对冻干柚皮干燥速率的影响主次顺序为加热温度、压力(真空度)、物料厚度,最佳工艺条件分别为:加热温度50℃、压力(真空度)40 Pa、物料厚度5 mm,在此干燥工艺条件下,产品在色泽等方面保持较好。结论该正交试验筛选出的工艺稳定可行。     

基于模型的银杏叶提取物冷冻干燥优化的研究

为了对银杏叶提取物冷冻干燥工艺进行优化,文章进行了传热传质模型的建立及简化,测量了银杏叶提取物的干层传质阻力系数等,进行了工艺模拟,给出了温度在-40—-15℃,压力从2—40 Pa的范围,升华时间小于100 h的模拟结果,模拟结果显示:压力越低升华时间越短,温度越高升华时间越短。在温度较低时,压力的变化对升华时间影响较大,温度较高时,压力的变化对升华时间影响较小。据此模拟结果及冻干显微镜实验,确定了优化的工艺操作参数为P_C=8 Pa,制品的最高温度为32℃,并进行了冻干实验,实验获得冻干产品性能好。该方法可以为其他药品的冷冻干燥最优参数的确定及升华时间的预测提供借鉴。     

注射用亚叶酸钙的冻干曲线优化研究

为了提高生产效率,降低生产成本,对注射用亚叶酸钙的冻干曲线进行优化。采用正交实验法L9(34)考察不同冻干参数对注射用亚叶酸钙成品质量的影响。优化之后的冻干工艺参数为:预冻温度-50℃,时间2.5 h;升华干燥温度变化从-50℃升温至-20℃,再由-20℃升温至-10℃,总耗时14 h,真空压力0.15 mbar,解析干燥温度30℃,真空压力为0.02 mbar,终点测试压力无变化时结束。对亚叶酸钙冻干参数筛选优化后,可得到较佳的冻干曲线,经验证该曲线适用于生产。     

香蕉粉真空冷冻干燥实验研究

对香蕉浆的真空冷冻干燥进行了两因素三水平的正交实验研究。利用电阻法测得了香蕉浆的共晶点温度。通过对实验结果的分析，搁板加热温度和干燥室工作压力对缩短干燥时间有影响，其中压力因素起了主要作用。在现有的实验条件下。得到一组最佳工艺参数及相应冻干曲线。     

具有预制孔隙多孔介质冷冻干燥的多相传递模型

基于局部质量非平衡假设,建立了多相多孔介质热、质耦合传递数学模型,理论验证具有预制孔隙的初始非饱和多孔物料对冷冻干燥过程的强化作用。模型考虑了多孔介质的吸湿效应,构建了3种吸附-解吸平衡关系。模型使用基于有限元法的COMSOL Multiphysics软件平台数值求解,并与实验数据进行了比较。结果表明,初始非饱和冷冻物料能够有效地强化冷冻干燥过程。采用不同函数形式的吸附-解吸平衡关系模拟的干燥曲线均与实验数据非常吻合。通过分析物料内部的饱和度、温度和质量源分布,探讨了初始非饱和物料冷冻干燥过程的传热传质机理。初始非饱和物料的干燥速率控制因素主要是传热。模拟考察环境辐射温度对冷冻干燥过程影响的结果表明,所建模型具有良好的预测能力。     

具有预制孔隙多孔介质冷冻干燥的多相传递模型

基于局部质量非平衡假设,建立了多相多孔介质热、质耦合传递数学模型,理论验证具有预制孔隙的初始非饱和多孔物料对冷冻干燥过程的强化作用。模型考虑了多孔介质的吸湿效应,构建了3种吸附-解吸平衡关系。模型使用基于有限元法的COMSOL Multiphysics软件平台数值求解,并与实验数据进行了比较。结果表明,初始非饱和冷冻物料能够有效地强化冷冻干燥过程。采用不同函数形式的吸附-解吸平衡关系模拟的干燥曲线均与实验数据非常吻合。通过分析物料内部的饱和度、温度和质量源分布,探讨了初始非饱和物料冷冻干燥过程的传热传质机理。初始非饱和物料的干燥速率控制因素主要是传热。模拟考察环境辐射温度对冷冻干燥过程影响的结果表明,所建模型具有良好的预测能力。     

结合水对冷冻干燥过程影响的研究

本文通过分析三种结合水去除机理下的数学模拟结果，并辅以一定的实验验证进行了结合水对冷冻干燥过程影响的研究。以脱脂牛奶的瓶装冻干为对象，对残余水含量、物料温度、干燥时间、湿含量分布等参数，进行了比较和分析。结果表明，结合水对冷冻干燥过程有重大影响；结合水在升华阶段的解吸过程不能忽略，这一冻干机理对冻干时间与物料干燥层的湿含量分布的预测，以及对冷冻干燥过程的现象描述与规律阐述都极为重要。     

草菇,菠萝的冷冻干燥过程及影响因素分析

从草菇、菠萝做冷冻干燥试验所得的冻干曲线和冻干时间,用分子运动论的观点分析了温度、压力等因素对冷干燥过程的影响。     

混合型烷醇酰胺组成对油/水动态界面张力的影响

为了探究混合型烷醇酰胺复杂组成对油/水界面张力的作用机制,采用GC-MS联用分析了混合型烷醇酰胺(GYD)的组成,并用自制的不同烷基链长醇酰胺(简记为C_nDEA,n=8,10,12,14,16)在大庆原油条件下研究了GYD组成对油/水界面张力的影响规律。结果表明,降低油/水界面张力能力强弱为C₁₄DEA> C₁₂DEA≈GYD> C₁₆DEA> C₁₀DEA> C₈DEA,C₁₄DEA、C₁₂DEA和GYD在一定浓度范围内能降低油/水界面张力至10^-3mN/m数量级;C_nDEA之间复配体系的界面活性取决于体系中各单分子结构烷醇酰胺相对含量,其中C₁₄DEA/C₁₂DEA相对含量是影响体系油/水界面活性的关键因素,当C₁₄DEA/C₁₂DEA复配比大于1时,体系达到超低界面张力浓度窗口更宽,界面动态特性更好;适量助剂(月桂酸和二乙醇胺)的加入对体系降低界面张力有一定的协同效应;GYD/C₁₄DEA复配体系随C₁₄DEA浓度增加,体系界面活性明显改善。     

A Binary Gas Transport Model Improves the Prediction of Mass Transfer in Freeze Drying

Monitoring partial vapor pressure in the freeze-drying chamber is a cheap, global, and non-intrusive way to assess the end of the primary drying stage. Most existing dynamic freeze-drying models which predict this partial pressure describe mass transfer between the product and the condenser via a mass transfer resistance or a mass transfer coefficient. Experimental evidence suggests that such models can be significantly in error for some values of the sublimation flux, leading to physically inconsistent predictions and possibly incorrect assessment of primary drying termination, with potential risk of product damage if moving to secondary drying and increasing shelf temperature while some ice is still present. Assuming a binary gas transport model for vapor and inert gas leads to improved and consistent predictions and explains the apparent variation of the mass transfer resistance with total pressure, shelf temperature, and product sublimation area.     

On the robustness of the soft sensors used to monitor a vial freeze-drying process

Process monitoring is a key issue in pharmaceutical freeze-drying to evaluate if the limit product temperature is approached, to identify the ending point of the main drying stage, and to estimate the value of some parameters of a mathematical model of the process so that it can be used for cycle optimization. Soft sensors can be used for this purpose: three algorithms, based on the extended Kalman filter and on product temperature measurement, have been compared in this study; they differ on the number of estimated parameters and on the way used to set their initial estimates. Results evidence that the accuracy of estimates is strongly dependent on the initial values of model parameters, and soft sensors #1 and #2 require a preliminary investigation to get accurate initial estimates of the heat and mass transfer coefficients. Soft sensor #2 should be preferred as it just requires an initial estimate of the heat transfer coefficient. Significant advantages are obtained with soft sensor #3: accurate estimates are obtained whichever values of the parameters are used to start the calculations (provided that reasonable values are used) and, thus, it can be effectively used to monitor the freeze-drying cycle without any preliminary investigation. Soft sensor #3 should thus be preferred to the other tools for freeze-drying monitoring.     

Optimization of the Freeze-Drying Cycle: A New Model for Pressure Rise Analysis

The principal aim of this study was to evaluate the Pressure Rise Analysis (PRA) method as a nonintrusive method for monitoring the product temperature during primary drying of the freeze-drying process of model pharmaceutical formulations. The principle of this method, based on the MTM method initially published by Milton et al.1 consisted in interrupting rapidly the water vapor flow from the sublimation chamber to the condenser chamber and by analyzing the resulting dynamics of the chamber total pressure increase. A new physical model, named PRA model, based on elementary heat and mass balance equations and on constitutive equations expressing the elementary fluxes, was proposed and validated in this study for interpreting the experimental pressure rise data. It was possible to identify very precisely the values of some key parameters of the freeze-drying process such as the ice sublimation interface temperature, the mass transfer resistance of the dried layer and the overall heat transfer coefficient of the vial. The identified ice front temperatures were compared with experimental data obtained from vial bottom temperatures measured by thin thermocouples during freeze-drying runs of 5% w/v mannitol solutions. These two sets of data were found consistent with a maximum difference of no more than 2°C. The dried layer mass transfer resistance increased linearly as a function of its thickness, and the values were coherent with the few literature data published for this system. The method also led to reliable values of the vial overall heat transfer coefficient of approximately 20 Wm^-2 K^-1 in accordance with the published data for this type of vials and these experimental freeze-drying conditions.     

On the use of model-based tools to optimize in-line a pharmaceuticals freeze-drying process

This article is focused on the use of model-based tools to design and optimize in-line a pharmaceutical freeze-drying process. Two control systems have been compared, a predictive one that uses the pressure rise test to monitor the state of the system and to estimate in-line the values of model parameters, named LyoDriver in the previous literature, and a controller where a soft sensor uses the temperature measurement obtained by a thermocouple to get the same information and to calculate on-line the design space of the process. In both cases, the goal of the controller is to maintain product temperature as close as possible to a limit value, without trespassing it, throughout the primary drying stage. An extended experimental campaign has been performed, where various products, with different characteristics, have been processed, namely, aqueous solutions containing sucrose, mannitol, or polyvinylpyrrolidone. Results evidence that both systems are effective in optimizing in-line the freeze-drying process, but shorter cycles can be obtained using the soft sensor. This is due to the fact that the soft sensor is not responsible for any product overheating and, thus, product temperature can be maintained very close to the limit value, while when using the pressure rise test as monitoring tool, a safety margin has to be used, because of the temperature increase during the pressure rise test. Besides, when using the soft sensor no least-square optimization problem is solved to estimate model parameters, and this can improve the robustness of the system. The main drawback is represented by the fact that this system requires thermocouples to measure product temperature, and this can be difficult in industrial-scale freeze-dryers, used to process large batches of vials in sterile conditions, but it can be performed quite easily in lab-scale units used for process design.     

An Interactive Tool for the Optimization of Freeze-Drying Cycles Based on Quality Criteria

Among existing dehydration methods, freeze-drying has unique benefits for the stabilization and preservation of biological activity of pharmaceutical products but remains an expensive and time-consuming process. A user-friendly software tool was developed, allowing for interactive selection of process operating condition profiles in order to maximize process productivity while insuring product quality preservation. The software is based on a dynamic, one-dimensional heat and mass transfer model, which can accurately represent both the primary and secondary drying stages and the gradual transition between them. The model was validated in a wide range of operating conditions: ? 25 to + 25°C shelf temperature and 10 to 34 Pa total pressure. By comparing a reference sucrose solution with a formulated pharmaceutical product containing polyvinylpyrrolidone (PVP), it is shown that controlling product properties such as glass transition temperature and sorption isotherm can reduce the minimum achievable cycle duration by 12 h (33%).     

An Interactive Tool for the Optimization of Freeze-Drying Cycles Based on Quality Criteria

Among existing dehydration methods, freeze-drying has unique benefits for the stabilization and preservation of biological activity of pharmaceutical products but remains an expensive and time-consuming process. A user-friendly software tool was developed, allowing for interactive selection of process operating condition profiles in order to maximize process productivity while insuring product quality preservation. The software is based on a dynamic, one-dimensional heat and mass transfer model, which can accurately represent both the primary and secondary drying stages and the gradual transition between them. The model was validated in a wide range of operating conditions: - 25 to + 25°C shelf temperature and 10 to 34 Pa total pressure. By comparing a reference sucrose solution with a formulated pharmaceutical product containing polyvinylpyrrolidone (PVP), it is shown that controlling product properties such as glass transition temperature and sorption isotherm can reduce the minimum achievable cycle duration by 12 h (33%).     

Role of Freeze Drying in Nanotechnology

Governments worldwide have spent more money on nanotechnology between 1997 and 2005 than on the Apollo project. The spending trend is still going upwards. Drying is an indispensable operation in the fabrication of nanosized materials. Hence, it is no surprise to find a large number of papers published in the past decade on drying and nano-related materials. This article reviews the literature and highlights the opportunities and challenges of freeze drying in nanotechnology. Freeze drying has found application in the production of nanoparticles for electrochemical, environmental, engineered materials, and pharmaceutical industries. The retention of the homogenous properties typically found in a solution, the small size of particles produced, and the long shelf life obtained for pharmaceutical applications are the primary reasons for choosing freeze drying. The relatively cheap operation cost compared to supercritical fluid extraction is another reason. Freezing was found to be a very important step in obtaining desired particle size and properties. Primary drying of solvent sublimation should be carried out at a temperature below the collapse temperature. Cryoprotectants are frequently necessary in preserving the original properties of active pharmaceutical ingredients. Spray freezing into liquid was found to be an optimal operation in order to minimize the air–liquid interfacial loss of bioactivity. A continuous freeze-drying process for production of granules of nanoparticles would be in demand, a dream that freeze-drying researchers have had for over a decade. This freeze drying may be carried out under vacuum or at atmospheric pressure using proper gases.     

Role of Freeze Drying in Nanotechnology

Governments worldwide have spent more money on nanotechnology between 1997 and 2005 than on the Apollo project. The spending trend is still going upwards. Drying is an indispensable operation in the fabrication of nanosized materials. Hence, it is no surprise to find a large number of papers published in the past decade on drying and nano-related materials. This article reviews the literature and highlights the opportunities and challenges of freeze drying in nanotechnology. Freeze drying has found application in the production of nanoparticles for electrochemical, environmental, engineered materials, and pharmaceutical industries. The retention of the homogenous properties typically found in a solution, the small size of particles produced, and the long shelf life obtained for pharmaceutical applications are the primary reasons for choosing freeze drying. The relatively cheap operation cost compared to supercritical fluid extraction is another reason. Freezing was found to be a very important step in obtaining desired particle size and properties. Primary drying of solvent sublimation should be carried out at a temperature below the collapse temperature. Cryoprotectants are frequently necessary in preserving the original properties of active pharmaceutical ingredients. Spray freezing into liquid was found to be an optimal operation in order to minimize the air-liquid interfacial loss of bioactivity. A continuous freeze-drying process for production of granules of nanoparticles would be in demand, a dream that freeze-drying researchers have had for over a decade. This freeze drying may be carried out under vacuum or at atmospheric pressure using proper gases.