A Direct Characterization Method of the Ice Morphology. Relationship Between Mean Crystals Size and Primary Drying Times of Freeze-Drying Processes

In the freeze-drying process, the freezing step is one of the most important steps which determines the texture of the frozen material and, consequently, the final morphological characteristics of the freeze-dried material and its biological activity and its stability. As a matter of fact, the parameters of the freezing protocol have a direct effect on the pore size distribution and on the pore connectivity of the porous network of the freeze-dried matrix. Thus, the ice crystal morphology determines indirectly the mass and the heat transfer rates through the dry layer and, consequently, the freezing parameters have a strong influence on the total duration of the primary and secondary sublimation steps. The main objective of this study was to adapt and to develop a new optical direct microscopy method, based on the reflected flux differences, with episcopic axial lighting to characterize the structure of the different phases of a standard pharmaceutical matrix used for pharmaceutical proteins freeze-drying. First, the results obtained have been validated by another independent method, the scanning electron microscopy, carried out with freeze-dried samples. Finally, this technique has been principally used to investigate the effects of the freezing conditions on the ice crystal structure characterized by the distribution of the ice crystals mean sizes. Moreover, the influence of annealing treatment on ice crystal mean diameter and primary drying times has been also investigated.     

Experimental Study and Modeling of Freeze-Drying in Syringe Configuration. Part I: Freezing Step

This article concerns the experimental study and the modeling of the freezing step during freeze-drying of a model lyoprotectant formulation in syringe configuration. First, ice crystal morphology observations were carried out in a cold chamber equipped with stereomicroscopy to determine the ice crystal size distribution. We observed that the ice crystal morphology was homogeneous as a function of the radial position and that, contrary to our previous observations in glass vial configuration, no significant ice morphology differences existed between the bottom and the top of syringes. Thus, it seems that the gas cooling by free convection at the walls of the syringe during the freezing step led to higher homogeneity in the ice crystal morphology. These data allowed calculation of the mean ice crystal diameter (which was supposed to represent the mean porous diameter) and then the permeability of the freeze-dried cake. Moreover, a two-dimensional axisymmetric (2D) mathematical model in cylindrical geometry of the freezing step for aqueous sucrose solution was elaborated. It has been proved that this model was able to simulate quite precisely the whole temperature profiles during the freezing step, except the exothermic peak of nucleation. In the last part of this work on syringe geometry, the impact of annealing treatments on the freeze-dried matrix morphology was investigated. Some heterogeneity of sublimation rates was observed, with significant variation of residual humidity. Additionally, the water vapor mass transfer resistance values decreased if a convenient annealing treatment (shelf temperature at ?10°C) was applied.     

冷冻干燥过程强化中冷冻阶段优化的研究进展

冷冻干燥产品质量高,但时间长、能耗高。本文综述了冷冻干燥过程强化中冷冻阶段的优化方法,控制冷冻速率、调节冰晶成核和退火处理可以获得大而均匀的冰晶从而提高升华干燥阶段速率,但物料内部比表面积的减小会降低解吸干燥阶段速率,这类常规的冷冻阶段优化方法对弱吸湿性的物料有一定的强化效果。有机溶剂具有较高的蒸气压,作为共溶剂时可以增加传质推动力,但较低的有机溶剂残留量要求阻碍了其进一步应用。“初始非饱和多孔介质冷冻干燥”的技术思想是将液体物料首先制备成具有一定初始孔隙的冷冻物料,然后再进行冷冻干燥。物料具有的初始孔隙为水蒸气的迁移提供了便捷的通道,而且纤薄的固体基质也有利于结合水的解吸,可以同时强化升华干燥阶段和解吸干燥阶段。该技术思想是过程低消耗和产品高质量的完美结合,为解决冷冻干燥过程速率低的问题提供了新的方案。     

Theoretical Study on Microwave Freeze-Drying of an Aqueous Pharmaceutical Excipient with the Aid of Dielectric Material

Abstract

A mathematic model of simultaneous heat and mass transfer for the dielectric material assisted microwave freeze-drying was derived and solved numerically using the finite-deference technique with two moving boundaries. Lactose, a typical pharmaceutical excipient, was used as the representative solid material in the aqueous solution to be freeze-dried. Silicon carbide (SiC) was selected as the dielectric material. Numerical results show that the dielectric material can significantly enhance the microwave freeze-drying process. Under typical operating conditions, the drying time is 43% shorter than that of ordinary microwave freeze-drying. Temperature variations at sublimation fronts were examined in order to determine the appropriate microwave power input. Profiles of temperature, ice saturation, vapor concentration, and pressure during freeze-drying are presented, and rate-controlling mechanisms are discussed.     

A Review on Freeze Drying of Drugs with tert-Butanol (TBA) + Water Systems: Characteristics,Advantages, Drawbacks

Organic cosolvent systems have been evaluated for their potential and increasing use for freeze drying of solutions to produce stabilized powders of marketed pharmaceutical products. The formulations most often investigated include tert-butanol (TBA) + water mixtures. These organic cosolvent systems present many interesting advantages: high freezing temperatures, very short sublimation time, low sublimation enthalpies, high equilibrium vapor/solid pressure values, and low toxicity.

Thus, some main characteristics of water + TBA systems have been reviewed, especially regarding its interesting thermodynamic properties (sublimation enthalpy, equilibrium vapor pressure), impact of freezing conditions on morphological properties of frozen formulations (nucleation, crystal size and shape), influence of operating parameters (total pressure, temperature) on sublimation times, and organic cosolvent and water residual contents.

The crystal morphology of frozen formulations prepared with TBA revealed unexpected results compared with the results reported in the literature for water-based formulations in terms of the complex relationships between freezing rates, supercooling, nucleation temperatures, and solvent crystal morphology (size and shape).

It has been proved that optimum freeze-drying cycles are established by simultaneously taking into account the impact of formulation variables, especially the tert-butanol content, and classical freeze-drying variables during the freezing step (nucleation temperatures, freezing rates) and the sublimation step (shelf temperature, total pressure) to maximize the drying rates and to minimize the residual solvent levels while preserving the main quality attributes of the freeze-dried powder.     

具有预制孔隙的维生素C水溶液微波冷冻干燥

设计和组装了一套实验室规模的多功能微波冷冻干燥装置，探究了具有初始孔隙的非饱和物料微波冷冻干燥过程。以维生素C为溶质，采用“软冰”冷冻技术制备了初始饱和与非饱和的冷冻样品。结果表明，软冰冷冻制备的样品能够避免崩塌。在35℃和20 Pa条件下，初始非饱和物料的干燥时间比饱和物料缩短了30.4%。SEM表征显示，非饱和物料具有疏松的球状孔隙结构、连通性好，有利于水蒸气的迁移。采用吸波材料碳化硅辅助的微波加热能够进一步强化冷冻干燥过程。在相同条件下，非饱和物料的微波冷冻干燥(5 W功率)时间比常规冷冻干燥(0 W功率)缩短了28.1%，比饱和物料的常规冷冻干燥缩短了50.0%。吸波材料辅助的初始非饱和物料微波冷冻干燥实现了传热传质的同时强化。     

Freezing of aqueous solutions in a porous medium Part I. Freezing of air-entraining agent solutions

In this investigation, a pre-formed, autoclaved porous material, of stable pore characteristic, was used to study the freezing characteristics of wet porous materials. Prior to freezing, prisms made from this material were filled with solutions of air-entraining agents. The results show that (i) a major part of a solution could be frozen without any dilation of the matrix, (ii) the dilation, when it occurs, is connected with the later stages of the freezing process when only a limited amount of ice forms, (iii) initially, ice forms on the surfaces of large air-filled pores, (iv) ice formation strengthens the matrix.It is proposed that the initially formed ice-layers on the pore surfaces seal in the remainder of the solutions. Continued ice formation generates a bursting pressure within the unfrozen solution. When this bursting pressure exceeds the tensile strength of the ice-strengthened matrix, it fails.Attention has been drawn to the relevance of the above observations and the hypothesis to freezing of cement paste.     

Ice crystal formation in the carbon nanotube suspension: A modelling approach

Freeze-dried porous solid foams were prepared from carbon nanotube (CNT) suspensions via either contact freezing with a heat exchanger or immersion freezing into a cryo-bath. Microstructures in the freeze-dried foam cast by ice crystals formed during the freezing step. It was found that domains of the carbon nanotubes in the freeze-dried solid foams were fairly well interconnected, and the microstructures were largely influenced by the freezing condition and freezing method. A mathematical model was proposed to simulate the observed thermal history during the freezing step; then theoretical predictions of the microstructural features were attempted. The simulated thermal history was in good agreement with experimental result. The resulting mean ice crystal sizes L* could be estimated from the calculated freezing front velocity (R) and the temperature gradient in the frozen zone (G). Interestingly, it was found that a correlation based on the power law (L*∝R^?0.2G^?0.2) was applicable to the present system for both the contact and immersion freezing methods. Though the fundamental ice crystallization phenomena were essentially the same for both freezing methods, actual temperature distribution and movement of the freezing front through the whole freezing bulk could control the morphology of ice crystal in the frozen matrix. In other words, good control of thermal flow in the freezing system would greatly contribute to rational design of microstructures of the CNT foam.     

Freezing step controls the mannitol phase composition heterogeneity

Freeze-dried samples were prepared from D-mannitol solution by selected freezing conditions. Crystalline structures of prepared samples were determined by XRD analysis, and distributions of the various crystal structures of mannitol were obtained for each sample. It was found that the amount of each polymorph was quite well correlated to the freezing conditions, namely the ice crystal nucleation temperature and the cooling rate. In case of samples prepared at fast cooling rates, the samples where the ice crystals nucleated at higher temperature contained much more stable form than the samples nucleated at lower temperature. Besides, the samples prepared at slow cooling rates predominantly contained stable crystalline forms despite of the variation of nucleation temperatures. Moreover, the experimental results also indicated that the various polymorphs were also distributed vertically through the sample along the direction of the heat flux during freezing. The tendency of the polymorph distribution through the freeze-dried cake was also elucidated by using the simulated temperature profiles during freezing. Thus, the profiles of mannitol polymorphs after the freezing derived from the temperature distributions could predict the global tendency of polymorphism behaviour, and, consequently, would be useful to achieve quality control of freeze-dried formulations.     

Porous SiCnw/SiC ceramics with unidirectionally aligned channels produced by freeze-drying and chemical vapor infiltration

The current study introduces a methodology for the fabrication of porous silicon carbide nanowire/silicon carbide (SiC_nw/SiC) ceramics with macroscopic unidirectionally aligned channels and reports on their microstructural and mechanical properties. The material was produced by freezing of a water-based slurry of β-SiC nanowires (SiC_nw) with control of the ice growth direction. Pores were subsequently generated by sublimation of the columnar ice during freeze-drying. Chemical vapor infiltration (CVI) of SiC into the open pore network of the SiC_nw aerogel with unidirectionally aligned channels, resulted in the formation of highly porous SiC_nw/SiC ceramics which exhibited a unique microstructure as identified by scanning electron microscopy. The pore size distribution and the mechanical properties of the as-fabricated porous ceramics were examined by mercury intrusion porosimetry and three-point bending and compression tests, respectively, while phase composition was investigated through X-ray diffraction.     

Characteristic Evaluation for Volatile Components of Soluble Coffee Depending on Freeze-Drying Conditions

Abstract

Volatile aroma compounds of freeze-dried soluble coffee were investigated to evaluate the effects of freeze-drying temperature conditions on their intensities and aroma characteristics by employing both GC/MS and charm-analysis, which is a GC/Olfactometry (GC/O) method. The coffee solutions with 40% solid content were freeze-dried changing freezing and drying temperatures. According to the results, it was demonstrated that the compounds identified based on human olfactory sense were different from those detected by GC/MS, and that the GC/O analysis method enabled evaluation of the characteristics and intensity of each compound as well as aroma profiles under various freezing and drying temperatures. Subsequently, GC/O method was found to be effective to detect and identify the volatile compounds giving the aroma peculiar to freeze-dried coffee, and useful to obtain the fundamental information for designing the optimal aroma characteristics of final product to conform the consumer preference based on the characteristic changes in aroma affected by freeze-drying conditions.     

Influence of Chemical Composition and Structure on Sorption Properties of Freeze-Dried Pumpkin

The aim of this study was to investigate the influence of chemical composition and material structure on sorption properties of freeze-dried pumpkin. The chemical composition and material structure were changed by osmotic dehydration, blanching, freezing, and temperature of the freeze-drying process. Freeze-dried pumpkin obtained from nonpretreated pumpkin had the best sorption properties, whereas osmotic dehydration significantly decreased the water vapor adsorption ability of the investigated samples. Studies on the influence of different freezing methods on water vapor sorption showed that a combination method of freezing resulted in the best sorption properties. When the temperature of freeze drying was increased, the water vapor adsorption ability of the freeze-dried pumpkin also increased.     

FREEZE DRYING CHARACTERISTICS OF MEDICINAL HERBS

The demand on traditional herb medicine shows a tremendous increase. Conventionally, medicinal herbs are dried at high temperatures, causing quality deterioration. The freeze-drying characteristics of medicinal herbs were studied, and the quality of the freeze-dried products assessed. The herbs studied were medicinal ginger and Javanese pepper.

It was found that drying time, was more influenced by chamber pressure and freezing rate than by the surface temperature of the product. Higher chamber pressures and faster freezing rates tended to shorten the initial (primary) drying time but lengthen the secondary drying time. Quality of the freeze-dried product was assessed as slightly lower than the quality of the raw material, but higher than when oven dried at 35-40°C, and met the MMI standard.     

Carbon aerogels, cryogels and xerogels: Influence of the drying method on the textural properties of porous carbon materials

Carbon materials with tailored texture can be obtained from drying and pyrolysis of resorcinol-formaldehyde gels. The pore texture of both dried and pyrolyzed material depends on the drying process. Several more or less expensive methods (supercritical drying, freeze-drying, evaporative drying) were tested in order to determine which process is the most suitable for the synthesis of a porous carbon with a definite texture. Supercritical drying leads to the highest pore volume and the widest texture range, but residual surface tensions and shrinkage are not avoided when the pore size is small or when the material density is low; this hampers to fix both the pore volume and the pore size easily. Monoliths are very difficult to obtain by freeze-drying, and the appearance of huge channels due to ice crystal growth at high dilution ratio hinders the fabrication of low density materials. Moreover, gels with small pores do not remain frozen throughout drying, which leads to surface tensions and shrinkage. Although generally replaced by more complicated techniques, evaporative drying is suitable when dense carbons are needed or when the only selection criterion is the pore size: all pore sizes are reachable, but this parameter is in this case strongly correlated to the pore volume.     

Heat and mass transfer model of dielectric-material-assisted microwave freeze-drying of skim milk with hygroscopic effect

A new porous media mathematical model for freeze-drying was developed based on the adsorption-desorption relationship proposed in this paper. A finite difference solution was obtained from a moving boundary problem for the dielectric-material-assisted microwave freeze-drying process. Silicon carbide (SiC) was selected as the dielectric material; and frozen skim milk was used as the aqueous solution to be dried. Simulation results showed that the dielectric material can significantly enhance the microwave freeze-drying process. The drying time was 33.1% shorter than that of ordinary microwave freeze-drying under typical operating conditions. When the solid content of the solution to be freeze-dried was very low, or the solid product had a very small loss factor, microwave heating was less effective without the assistance of dielectric material. The mechanisms of heat and mass transfer during drying were analyzed based on profiles of ice saturation, temperature and vapor concentration. Drying rate-controlling factors were discussed. A comparison was made between the model predictions and the reported experimental data.     

溶液冻干法制备纳米粉体之特点分析

总结了溶液冻千法制备纳米粉体的工艺过程和特点。与其他制粉方法相比,溶液冻干法的特点是：所制备的粉体毛硬团聚,粉体粒径小且均匀,粒度大小在一定程度上受冻结速率影响,化学组成准确,多为非晶体颗粒;与其他物料的冻干过程相比,制备纳米粉体的含水量比例大,已经干燥的物质对干燥传质的阻力小,产品的热敏性小。     

Effect of Ultrasonically Induced Nucleation on the Drying Kinetics and Physical Properties of Freeze-Dried Strawberry

Power ultrasound has proved to be very useful in controlling crystallization processes since sonication can enhance both the nucleation rate and crystal growth rate by producing fresh and/or more nucleation sites. Therefore, in this study, power ultrasound was applied to control the freezing step of freeze-dried strawberry. The results showed that when power ultrasound was applied at different temperatures, it increased the nucleation temperature and shortened the characteristic freezing time. The application of power ultrasound in the freezing step increased the drying time in subsequently freeze-dried strawberry samples. This longer drying time was found to be due to increased resistance to moisture diffusion due to the formation of a network of small pores caused by sublimation of small ice crystals induced by the power ultrasound. Scanning electron microscopic images revealed that the freeze-dried sample frozen by ultrasound-assisted freezing (UAFD) had finer cellular structure compared to those frozen in other freezing conditions. UAFD samples had better textural hardness, while the rehydration capacity was lower compared to those of NRFD and NIFD samples.     

药品冷冻干燥过程的退火机理分析

运用热力学和动力学理论分析了药品冷冻干燥过程中的退火操作改变冻结药品结构的机理。通过对化学势随晶粒曲率半径变化、重结晶过程中冰晶半径随时间变化、非晶态基质的粘度随温度变化几个关系式的分析,得出退火温度必须要高于冻结药品的玻璃化转变温度;最佳退火持续时间与重结晶的速率紧密相关,且是退火温度的函数;退火后再冷却过程的冷却速率不影响升华干燥速率等结论。     

Freeze-Drying of Liposomes with Cryoprotectants and Its Effect on Retention Rate of Encapsulated Ftorafur and Vitamin A

Abstract

In this article, the glass transition temperature (T _g ) of liposomal suspensions, in which glucose, sucrose, mannitol, and trehalose are used as cryoprotectants, are measured by differential scanning calorimetry (DSC). The protective effect of the cryoprotectants added for liposomes during freeze-drying is investigated. Results show that the T _g of liposomal suspension with trehalose is the highest, while that with glucose is the lowest. Depending on the concentration, the vesicle size of liposomes with trehalose as cryoprotectant varies less, while the vesicle size of liposomes, with glucose as cryoprotectant varies over a wider range during the process of freeze-drying. Water-soluble ftorafur and lipid-soluble vitamin A encapsulated in liposomes were freeze-dried. The retention rates of the encapsulated pharmaceuticals inside the liposomes are measured with high performance liquid chromatography. The results indicate that the retention rate for liposomes with trehalose is the highest, and the leakage of the pharmaceutical material is less than that with glucose used as a cryoprotectant. Through a series of experimental studies, trehalose is identified as a better cryoprotectant. An optimized freeze-drying procedure for liposomes is presented.