Effect of mannitol crystallization on the stability and aerosol performance of a spray-dried pharmaceutical protein, recombinant humanized anti-IgE monoclonal antibody

We have examined the stability and aerosol performance of the pharmaceutical protein recombinant humanized anti-IgE monoclonal antibody (rhuMAbE25) spray dried with mannitol. The aerosol performance was measured by the fine particle fraction (FPF), and stability was assessed by the formation of soluble aggregates. When mannitol was added to the spray-dried rhuMAbE25 formulation, its ability to stabilize the protein leveled off above about 20% (w/w, dry basis). The FPF of the spray-dried formulations was stable during storage for rhuMAbE25 containing 10% and 20% mannitol, but the 30% formulation exhibited a dramatic decrease upon storage at both 5 degreesC and 30 degreesC, due to mannitol crystallization. We tested the addition of sodium phosphate to a 60:40 rhuMAbE25:mannitol (w:w) mixture, which otherwise crystallized upon spray drying and yielded a nonrespirable powder. The presence of sodium phosphate was successful in inhibiting mannitol crystallization upon spray drying and dramatically lowering the rate of solid-state aggregation. However, over long-term storage some crystallization was observed even for the phosphate-containing samples, concomitantly with increased particle size and decreased suitability for aerosol delivery. Therefore, the physical state of mannitol (i.e., amorphous or crystalline) plays a role both in maintaining protein stability and providing suitable aerosol performance when used as an excipient for spray-dried powders. Agents which retard mannitol crystallization, e.g., sodium phosphate, may be useful in extending the utility of mannitol as an excipient in spray-dried protein formulations.     

Evaluation of amorphous ursodeoxycholic acid by thermal methods

PURPOSE: The purpose of this study was to characterize the amorphous state of ursodeoxycholic acid (UDCA) samples by using isothermal microcalorimetry, X-ray diffraction, infrared (IR) spectroscopy and solid state carbon 13 nuclear magnetic resonance (13C-NMR) spectroscopy, and to demonstrate the application of the thermal methods (microcalorimetry and differential scanning calorimetry (DSC) for studying the amorphous state and clarifying the dissolution mechanism of UDCA. METHODS: Amorphous UDCA was prepared by grinding and rapid cooling of the melts. The heat of solution of UDCA was measured by an isothermal heat-conduction twin microcalorimeter at 25.0 degrees C. Some physicochemical properties of amorphous UDCA were also studied. RESULTS: The intensities of X-ray diffraction peaks of crystalline UDCA decreased with an increase in grinding time. The heat levels of solution of crystalline UDCA and UDCA ground for 1 min were endothermic, and became exothermic with an increase in grinding time. A good correlation was obtained between the heat of solution and the heat of crystallization determined from the peak area in DSC. Although no significant difference was observed in X-ray diffraction patterns of amorphous UDCA prepared by the two methods, significant differences were recognized in DSC, IR and 13C-NMR, and the heat of solution indicated different values among the two samples. The stability of amorphous UDCA samples stored under 74.5% relative humidity at 40 degrees C was found to depend upon the preparation methods. CONCLUSIONS: Different states of amorphous UDCA were obtained depending on the preparation method. The application of thermal methods to evaluate the amorphous state was demonstrated. The mechanism of dissolution of UDCA was discussed from the results of the heat of solution examination.     

部分稳定氧化锆(PSZ)的化学稳定性研究

本文研究喷雾干燥法和无机胶化法制得PSZ粉末和陶瓷片,在不同介质及条件下Y_2O_3的溶解度。结果表明:PSZ粉末或陶瓷体在碱性介质中均稳定,不会发生Y_2O_3溶解。在水溶液中有少部分溶解。但在酸性介质中,PSZ粉末和陶瓷体中Y_2O_3均有明显的溶解。其溶解度是随着盐酸的浓度升高而明显增大,当盐酸浓度述3wt%时,Y_2O_3溶解量达到最高值。随着烧结温度升高,材料中Y_2O_3的溶解度明显下降。证实材料中Y_2O_3固溶ZrO_2较完全,只有微量游离Y_2O_3保留着,不影响材料的性能。喷雾干燥获得的粉末比胶化法的粉末,其Y_2O_3溶解度更低(0.3wt%);证明,喷雾法的PSZ粉比胶化法粉的化学稳定性高。     

纳米氧化锆喷涂材料的制备及表征

采用聚合物网络法制备了具有纳米结构的氧化锆粉体,将粉末进行了喷雾干燥球形化制粒及等离子致密化处理。结果表明采用该方法制备的纳米结构的氧化锆粉末松装密度高、流动性好,表面光亮,有利于提高涂层的综合性能。     

Effect of excipients on the stability and structure of lyophilized recombinant human growth hormone

We have investigated the effect of mannitol, sorbitol, methyl alpha-D-mannopyranoside, lactose, trehalose, and cellobiose on the stability and structure of the pharmaceutical protein recombinant human growth hormone (rhGH) in the lyophilized state. All excipients afforded significant protection of the protein against aggregation, particularly at levels to potentially satisfy water-binding sites on the protein in the dried state (i.e., 131:1 excipient-to-protein molar ratio). At higher excipient-to-protein ratios, X-ray diffraction studies showed that mannitol and sorbitol were prone to crystallization and afforded somewhat less stabilization than at lower ratios where the excipient remained in the amorphous, protein-containing phase. The secondary structure of rhGH was determined using Fourier transform infrared (FTIR) spectroscopy. rhGH exhibited a decrease in alpha-helix and increase in beta-sheet structures upon drying. Addition of excipient stabilized the secondary structure upon lyophilization to a varying extent depending on the formulation. Samples with a significant degree of structural conservation, as indicated by the alpha-helix content, generally exhibited reduced aggregation. In addition, prevention of protein-protein interactions (indicated by reduced beta-sheet formation) also tended to result in lower rates of aggregation. Therefore, in addition to preserving the protein structure, bulk additives that do not crystallize easily and remain amorphous in the solid state can be used to increase protein-protein distance and thus prevent aggregation.     

Spray forming of bulk Al85Y8Ni5Co2 with co-existing amorphous, nano- and micro-crystalline structures

A 12 mm thick Al₈₅Y₈Ni₅Co₂ plate was spray deposited on a 30 mm thick pre-heated copper substrate. The deposit was characterized using optical, high resolution scanning and transmission electron microscopy. Differential scanning calorimetry was performed to assess the crystallization behaviour of the deposit compared to melt spun ribbons of the same composition. The deposit shows an amorphous phase fraction of 83 and 56 vol.% (based on the total crystallization energy), in the bottom and top regions of the deposit. The deposit consists of amorphous and nanoscale structures along with microcrystalline intermetallic phases. The large amorphous phase fraction in the deposit is attributed to the chilling effect upon deposition of highly undercooled/partially crystallized droplets onto the pre-heated substrate and rapid heat extraction thereof due to bonding at the deposit/substrate interface.     

湿磨铜锌合金粉干燥光亮退火方法的研究

根据铜及铜合金可在水蒸气中实现光亮退火和湿磨铜锌合金粉的特点,对湿磨铜锌合金粉干燥光亮退火方法及工艺参数进行了研究。试验结果表明:压实装罐法可一步实现湿磨铜锌合金粉的干燥、光亮退火,同时,原始粉的含水量、压实度、退火温度、保温时间等对其结果有重要影响。提出了湿磨铜锌合金粉干燥光亮退火的最佳工艺,使干燥光亮退火前后铜锌合金粉的光亮程度及颜色用肉眼难以分辨,干燥光亮退火后的铜锌合金粉含氧量比退火前增加了千分之三。该方法具有操作简单,生产效率高的特点,解决了湿磨铜及铜合金粉的光亮干燥和光亮退火问题。     

用喷雾干燥法制备PSZ-3Y粉末颗粒的形貌研究

用激光衍射法和SEM（Scanning Electron Microscope)法研究了喷雾干燥法制备PSZ-3Y粉末的粒度分布和形貌特征，表明用传统法制备的PSZ-3Y虽然可以获得细颗粒粉末，但是团聚非常严重，分散性能和流动性都很差，而用喷雾干燥法制备的PSZ-3Y粉末和造粒可以获得粒度分布均匀，流动性和分散性好的不团聚的球状颗粒。粉末的形貌与其采用的制粉原料的组成形态和工艺关系不大，但从原粉中喷雾制粒获得粉末的颗粒表面较粗糙和有小裂纹，其分布性能比直接喷雾粉末颗粒性能好。     

纳米Al_2O_3陶瓷粉料喷雾干燥制粒

利用喷雾干燥技术对纳米Al_2O_3粉体进行造粒,研究了浆料固含量、粘结剂含量及分散剂含量对喷雾干燥粉体颗粒形貌、结构、松装密度和流动性的影响。结果表明:当料浆固相含量为50%,分散剂和粘结剂分别为固相质量的0.04%和1.0%时,浆料具有合适的粘度和最佳的分散稳定性,喷雾造粒得到的粉体为球形,表面光滑致密,具有较高的松装密度和流动性,能满足各种压制成型的需要。     

Structural transformations in thermal spray coatings of Ni60Nb40 alloy in vacuum annealings

Conclusions Thermal spray coatings of Ni₆₀Nb₄₀ alloy have primarily an amorphous structure with inclusions of Nb0₂, Ni₃Nb, Ni, and NiO crystalline phases. In the original powder the oxide phases and pure nickel are absent. Under conditions of vacuum anneals the amorphous structure is preserved up to 800°K. Heating of the coatings within the limits of their temperature stability does not change the morphology of the surfaces of the fractures, which is characteristic of amorphous alloys. Heating to the crystallization temperature of the amorphous matrix and above leads to loss of the elasticity and plasticity characteristic of the coatings in the original condition.Oxidation of the niobium during spraying and subsequent precipitation of its oxides in heating changes the sequence of crystallization from the amorphous matrix of stable phases and causes initial precipitation of a phase rich in nickel. Crystallization of the amorphous structure occurs in two basic stages, precipitation of Ni₃Nb and of -NiNb.Translated from Poroshkovaya Metallurgiya, No. 10(286), pp. 39–45, October, 1986.     

Ball-milling-induced crystallization and ball-milling effect on thermal crystallization kinetics in an amorphous FeMoSiB alloy

Microstructure evolution in a melt-spun amorphous Fe_77.2Mo_0.8Si₉B₁₃ alloy subjected to high-energy ball milling was investigated by means of X-ray diffraction (XRD), a transmission electron microscope (TEM), and a differential scanning calorimeter (DSC). It was found that during ball milling, crystallization occurs in the amorphous ribbon sample with precipitation of an α-Fe solid solution, and the amorphous sample crystallizes completely into a single α-Fe nanostructure (rather than α-Fe and borides as in the usual thermal crystallization products) when the milling time exceeds 135 hours. The volume fraction of material crystallized was found to be approximately proportional to the milling time. The fully crystallized sample with a single α-Fe nanophase exhibits an intrinsic thermal stability against phase separation upon annealing at high temperatures. The ball-milling effect on the subsequent thermal crystallization of the amorphous phase in an as-milled sample was studied by comparison of the crystallization products and kinetic parameters between the as-quenched amorphous sample and the as-milled partially crystallized samples. The crystallization temperatures and activation energies for the crystallization processes of the residual amorphous phase were considerably decreased due to ball milling, indicating that ball milling has a significant effect on the depression of thermal stability of the residual amorphous phase.     

Dissolution behavior and bioavailability of phenytoin from a ground mixture with microcrystalline cellulose

The ground mixture of phenytoin and microcrystalline cellulose was prepared by grinding in a vibrational ball mill. The X-ray diffraction patterns indicated the amorphous nature of the ground mixture. Comparative studies were made concerning the in vitro dissolution and in vivo absorption of fine phenytoin powder, phenytoin sodium powder, and the ground mixture. The ground mixture showed a greater dissolution rate than the fine powder and attained supersaturation in the pharmacopeial disintegration media at pH 1.2 and 7.4. In vivo absorption studies of each preparation were carried out in five subjects, using a crossover design, by measuring the urinary excretion rate of a main metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin. The blood levels of phenytoin and the corresponding urinary excretion patterns of the metabolite were determined in two subjects. The ground mixtures significantly improved the bioavailability of phenytoin. The drug was completely and rapidly absorbed after oral administration of the ground mixture. The vibrational ball milling technique for a poorly water-soluble drug with microcrystalline cellulose provides a promising way of improving the in vivo drug absorption.     

The effect of hydrogen on the crystallization behavior of amorphous PdSi alloys

Differential scanning calorimetry, X-ray diffractometry and Optical metallography were used to study the effect of hydrogen atmosphere and surface treatment on the crystallization process in PdSi metallic glasses. In Pd₈₀Si₂₀ metallic glasses, the surface treatment by mechanical polishing with 1200 SiC induces surface crystallization in which preferred nucleation at the surface occurs, while homogenous crystallization occurs in as-quenched samples without surface grinding. In amorphous Pd₈₅Si₁₅, the crystallization occurs simultaneously from the sample surface and in the bulk. Surface treatment by mechanical polishing does not change the crystallization morphology. These results were not affected by the atmosphere of argon or hydrogen. It is shown that the surface crystallization, which is dominant in the initial stages of the transformation, is revealed by the low temperature shoulder of the main peak of crystallization in a DSC trace. The process of crystallization of amorphous Pd₈₀Si₂₀ and Pd₈₅Si₁₅ is found to be impeded by absorbed hydrogen, this having been measured by the increase of both crystallization temperature and activation energy for crystallization process in a hydrogen environment. Such crystallization behavior can be explained by assuming that hydrogen reduces the free volume available for rearrangements of host atoms of the metallic glasses.     

工艺参数对超音速火焰喷涂Fe基非晶涂层性能的影响

Fe基非晶涂层具有优异的耐磨、耐蚀性能,以及较高的性价比,适合在表面防护涂层领域广泛应用。本文通过正交试验研究了煤油流量、氧气流量、送粉速率、喷涂距离对超音速火焰喷涂制备的Fe基非晶涂层的孔隙率、硬度、耐磨性能的影响。采用图像法、显微硬度计和摩擦磨损试验机分别对Fe基非晶涂层的孔隙率、硬度、耐磨性能进行了表征。采用X射线衍射仪和扫描电镜分别对涂层的相组成和显微结构进行了表征。通过极差分析法分析得出以涂层孔隙率最低为目标的优化制备工艺,最佳喷涂工艺参数为:煤油流量0.41 L/min,氧气流量830 L/min,喷涂距离430 mm,送粉速率40 g/min。结果表明:送粉速率和氧气流量对涂层孔隙率影响较大,进而影响涂层的硬度及耐磨性能。孔隙率随着氧气流量和送粉速率的增加而增加,随着煤油流量和喷涂距离的增加而降低。制备的Fe基非晶涂层硬度达到1158.9HV0.2,孔隙率为1.22%,磨损实验的质量损失量只有316L不锈钢的一半。     

用自熔性合金粉末火焰喷焊工艺与现场研磨修复磨损轴实践

主要介绍自熔性合金粉末火焰喷焊与现场研磨的原理、工艺流程及其在首钢长钢连轧车间的应用。用自熔性合金粉末火焰喷焊与现场研磨的方法成功实现在规定时间内不离线现场修复进口剪臂轴。     

含水量对喷雾干燥钼粉性能的影响

将钼粉末和聚乙烯醇（PVA）水溶液按一定比例配置悬浮浆料,经喷雾造粒后进行连续自动压制成型,研究了不同含水量对喷雾干燥钼粉松装密度、流动性和成型性的影响。结果表明：随着含水量的增加,喷雾干燥钼粉松装密度减小,流动性变差;在自动压制成型过程中,随着含水量的增加,填充密度、成型压力降低,压制回弹减小,水含量为0．08％～0．16％（质量分数）时压制效果较为理想。     

合金Co-Zr-B纳米粉末的相组成及磁性能研究

将硼氢化钠(NaBH4)的水溶液加入到氯化钴(CoCl2·6H2O)和硫酸锆(Zr(SO4)2·4H2O)的混合水溶液中,利用BH-4把混合溶液中的CO2 和Zr4 同时还原出来,首次成功制备出非晶态Co-Zr-B三元纳米合金粉末.用电感耦合等离子体发射光谱(ICP)、X射线衍射(XRD)、选区电子衍射(SAED)、透射电子显微镜(TEM)、差示扫描量热法(DSC)以及振动样品磁强计(VSM)分析了样品的成分、结构和磁性能.发现所制备的不同成分的粉末颗粒呈球形,粒径在20～60nm之间.纳米粉末由非晶相基体和少量晶体相杂质组成,而非晶相基体又由Zr基非晶颗粒和含有Zr的Co基非晶颗粒构成.还原产物中的Co原子和Zr原子的分数之比与金属盐混合溶液中的Co2 与Zr4 离子的分数之比几乎相等.提高NaBH4溶液的加入速度,可增加产物中B元素的含量.样品的晶化温度在765.1～771.3K之间,样品的热稳定性随Zr含量的增加而增加,样品的磁性能也与样品中Co、Zr原子的含量之比有关.当原子数x(Co)/x(Zr)比值从1.94增加到5.14时,饱和磁化强度从4.76emu/g增加到8.87emu/g,矫顽力在1271.66A/m(15.98Oe)到2133.49A/m(26.81Oe)之间不规则变化.     

Synthesis and Characterization of Y0.9-x GdxEu0.1 BO3 Phosphors by Spray Drying Process

Y0.9-xGdxEu0. 1 BO3 phosphors were synthesized by spray drying (SD) method, and the results were compared with those by conventional solid state (SS) and citrate gel (CG) methods. The PL intensity of phosphors increases with the increase of x value in Y0.9-xGdxEu0.1BO3(prepared by SD) due to an energy migration process like Gd^3 - (Gd^3 )nEu^3 occurred in the material. Conlpared with the latter two methods, the phosphor particles prepared by spray drying method have a better morphology, such as homogeneous size (about 1 - 3μm) with spherical shape and smooth surface.Furthermore, the spray drying-derived phosphors have higher photoluminescence (PL) intensity than those by citrate gel method, but still a little lower than those by the solid state method.     

纳米晶高密度钨合金的研究进展

介绍了近几年来纳米晶钨基高密度合金的研究状况,讨论了粉末制备的机械合金化法、喷雾干燥法和反应喷射工艺法,同时详细讨论了粉末的注射成形以及包括固相烧结、二步烧结在内的烧结工艺.最后,从这些方面分析了影响纳米晶钨合金性能的具体因素,以及对高密度钨合金今后的发展方向提出了建议.     

A study on the microstructural evolution of Al-25 at. pct V-12.5 at. pct M (M = Cu,Ni, Mn) powders by planetary ball milling

The alloying behavior of Al-25 at. pct V-12.5 at. pct M (M = Cu, Ni, Mn) by planetary ball milling of elemental powders hours as been investigated in this study. In Al₃V binary system, an amorphous phase was produced after 6 hours and the amorphous phase was mechanically crystallized after 20 hours. The large difference in the diffusivities between Al and V atoms in Al matrix results in the formation of the amorphous phase when the homogeneous distribution of all the elements in a powder was achieved at 6 hours. According to thermal analyses, the amorphous phase in the binary Al₃V was crystallized at 350 °C. The addition of ternary elements (Cu, Ni, Mn) increased the activation energy for the crystallization to D0₂₂ phase by interfering with the diffusion process. Therefore, ternary element addition improved the thermal stability of the amorphous structures. The amorphous phase in the 12.5 at. pct Ni added Al₃V was crystallized to D0₂₂ phase at 540 °C. The mechanical crystallization of the amorphous phase in the ternary element-added Al-V system either occurred later or was not observed during ball milling up to 100 hours. It is thought that the amorphous intermetallic compacts could be produced more easily in ternary element-added alloys by using an advanced consolidation method.