人工鼻和气体流量设置对气道内吸入气温度和湿度的影响

目的：观察麻醉机呼吸环路气体低、中、高流量设置和呼吸环路加入人工界对气道内吸入气温度和湿度的影响。方法：选择60名ASA I～Ⅱ级病人，随机分为6组，3组呼吸环路内加入人工界，流量设置分别是0，5，1．5，4．5L/min；另3组不使用人工界，流量设置同上。应用温度湿度仪连续监测吸入气温度和相对湿度，公式计算绝对温度。机械通气3min后的测量值设为基础值，然后纪录15，30，45和60min的值。结果：随机械通气时间延长，人工鼻组的不同流量设置均显著增加气道内吸入气温度和湿度，当流量设置为0．5L/min最高，其次是1．5L/min，再其次为4．5L/min；不用人工鼻组，低、中、高流量设置显著影响气道内吸入气温度和湿度，随通气时间延长，流量为0．5L/min时温度和湿度逐渐升高，1．5L/min略有下降，4．5L/min则明显降低。结论：人工界能补偿气体中、高流量时气道内温度和湿度的降低，低流量增加气道内的温度和湿度。临床采用低流量麻醉技术和人工界对保护病人气道粘膜有利。     

Suitability of near-infrared methods for the determination of moisture in a freeze-dried injection product containing different amounts of the active ingredient

A near-infrared reflectance (NIR) method for determination of moisture in an experimental freeze-dried injection product was developed and validated. NIR spectra were collected through the bases of unopened product vials using a horizontal instrument accessory, before generating primary reference data on the same individual vials by Karl-Fischer titration. Data were collected for product containing different concentrations of the active ingredient in the same matrix. NIR calibrations were developed with second derivative spectral data using regression facilities within the NIR software, and validated using independent test sets. An assessment is given of the applicability of moisture calibrations developed on product at one active ingredient level to the prediction of moisture contents in the product containing a different concentration of active ingredient.     

Effect of Spray Drying and Subsequent Processing Conditions on Residual Moisture Content and Physical/Biochemical Stability of Protein Inhalation Powders

Purpose. To understand the effect of spray drying and powder processing environments on the residual moisture content and aerosol performance of inhalation protein powders. Also, the long-term effect of storage conditions on the powder's physical and biochemical stability was presented. Methods. Excipient-free as well as mannitol-formulated powders of a humanized monoclonal antibody (anti-IgE) and recombinant human deoxyribonuclease (rhDNase) were prepared using a Buchi 190 model spray dryer. Residual moisture content and moisture uptake behavior of the powder were measured using thermal gravimetric analysis and gravimetric moisture sorption isotherm, respectively. Protein aggregation, the primary degradation product observed upon storage, was determined by size-exclusion HPLC. Aerosol performance of the dry powders was evaluated after blending with lactose carriers using a multi-stage liquid impinger (MSLI). Results. Spray-dried powders with a moisture level (~ 3%) equivalent to the freeze-dried materials could only be achieved using high-temperature spray-drying conditions, which were not favorable to large-male manufacturing, or subsequent vacuum drying. These dry powders would equilibrate with the subsequent processing and storage environments regardless of the manufacturing condition. As long as the relative humidity of air during processing and storage was lower than 50%, powders maintained their aerosol performance (fine particle fraction). However, powders stored under drier conditions exhibited better long-term protein biochemical stability. Conclusions. Manufacturing, powder processing, and storage environments affected powder's residual moisture level in a reversible fashion. Therefore, the storage condition determined powder's overall stability, but residual moisture had a greater impact on protein chemical stability than on powder physical stability.     

Moisture-Induced Aggregation of Lyophilized DNA and its Prevention

Purpose To investigate the moisture-induced aggregation (i.e., a loss of solubility in water) of DNA in a solid state and to develop rational strategies for its prevention.Methods Lyophilized calf thymus DNA was exposed to relative humidity (RH) levels from 11% to 96% at 55°C. Following a 24-h incubation under these stressed conditions, the solubility of DNA in different aqueous solutions and the water uptake of DNA were determined. The effects of solution pH and NaCl concentration and the presence of excipients (dextran and sucrose) on the subsequent moisture-induced aggregation of DNA were examined. The extent of this aggregation was compared with that of a supercoiled plasmid DNA.Results Upon a 24-h incubation at 55°C, calf thymus DNA underwent a major moisture-induced aggregation reaching a maximum at a 60% RH; in contrast, the single-stranded DNA exhibited the maximal aggregation at a 96% RH. Moisture uptake and aqueous solubility studies revealed that the aggregation was primarily due to formation of inter-strand hydrogen bonds. Aggregation of DNA also proceeded at 37°C, albeit at a slower rate. Solution pH and NaCl concentration affected DNA aggregation only at higher RH levels. This aggregation was markedly reduced by co-lyophilization with dextran or sucrose (but not with PEG). The aggregation pattern of a supercoiled plasmid DNA was similar to that of its linear calf thymus counterpart.Conclusions The moisture-induced aggregation of lyophilized DNA is caused mainly by non-covalent cross-links between disordered, single-stranded regions of DNA. At high RH levels, renaturation and aggregation of DNA compete with each other. The aggregation is minimized at low RH levels, at optimal solution pH and salt concentration prior to lyophilization, and by co-lyophilizing with excipients capable of forming multiple hydrogen bonds, e.g., dextran and sucrose.     

《中国药典》2005年版一部水分测定法比较

目的通过中成药水分测定将《中国药典》2005年版一部附录ⅨH水分测定法前三种方法进行比较。方法药典附录水分测定法烘干法、甲苯法、减压干燥法。结果一般品种烘干法与甲苯法测定结果差异无显著性;烘干法与减压干燥法测定结果差异有显著性。结论取样量不同对烘干法测定结果影响较大判定边缘数据时应慎重。减压干燥法除试验耗时长外方法准确、可靠、操作简单易行。     

更安颗粒成型工艺研究

目的探讨更安颗粒的成型工艺条件。方法以成型性、流动性、吸湿性和制粒情况为指标,筛选各处方加入辅料的种类、配比及最佳成型工艺。结果最佳制粒工艺为浸膏粉与糊精按1∶1混匀,以75%乙醇为润湿剂制软材,湿粒在60℃下干燥,成品的流动性和抗吸湿性好,临界相对湿度为78%。结论筛选出的工艺简便可行,不失为更安颗粒较好的成型工艺。     

眩晕定颗粒的吸湿性研究

目的:研究眩晕定颗粒的吸湿性,确定眩晕定颗粒生产过程中合理的湿度条件及暴露时间。方法:通过测定眩晕定颗粒的吸湿速度及平衡吸湿量,建立其动力学模型,提取吸湿速度参数并比较大小。结果:眩晕定颗粒在不同湿度下的吸湿动力学符合房室模型,吸湿量达到6%对应的相对湿度为56.11%,在此湿度下包装前最久可摆放10.15h。结论:眩晕定颗粒生产中应控制环境湿度在56%以下,分装时暴露时间不可超过10.15h。     

Evaluation of Tableting and Tablet Properties of Kollidon SR: The Influence of Moisture and Mixtures with Theophylline Monohydrate

The aim of the study was firstly to investigate the influence of moisture on the tableting and tablet properties of Kollidon SR and secondly to investigate the influence of theophylline monohydrate on the tableting behavior and tablet properties produced from binary mixtures with Kollidon SR. In comparison to Kollidon SR, microcrystalline cellulose (MCC) was used. The glass transition temperature (T_g) of the powder over the whole range of RH (0–90%), and in addition, the T_g of tablets of Kollidon SR were measured. Densities and flowability of the powders were analyzed. The tablets were produced at five different maximum relative densities (ρ_{rel, max}) on an instrumented eccentric tableting machine. They were produced at three different relative humidities (RH), 30%, 45%, and 60% RH for the pure substances and binary mixtures with different ratios of drug and excipient were tableted at 45% RH. The tableting properties were analyzed by 3D modeling, force-displacement profiles, and compactibility plots. First, the T_g of the powder decreased with increasing RH and the T_g of the tablet was 4–8 K lower than the powder. The predominant deformation of Kollidon SR is plastic deformation and Kollidon SR showed a higher compactibility than MCC. The parameters of the 3D model showed an extreme change between 45 and 60% RH, and at higher RH more and more particles deformed elastically. This was confirmed by analysis of force-displacement profiles. At 60% RH, the radial tensile strength of the Kollidon SR tablets was half of the radial tensile strength at 45% RH. The reason is a higher relative energy of plastic deformation than for MCC. This results in a better utilization of the energy to deform the powder into a tablet and the exceeding of the glass transition temperature at higher RH. In conclusion, at 60% RH at the same ρ_{rel, max}, tableting and tablet properties of Kollidon SR are extremely changed since plasticity is significantly higher. In the second part of the study, the insufficient flowability of theophylline monohydrate can be compensated by using Kollidon SR in a mixture with up to 20% theophylline. Further, pressure plasticity ε of MCC and Kollidon SR was lowered in the mixture with theophylline monohydrate. The same is valid for the compactibility. The influence of theophylline monohydrate on the pressure plasticity e of the mixtures was better compensated in the mixture with MCC than in a mixture with Kollidon SR. This compensation was also visible by analyzing the force-displacement-profiles. However, hardly any influence on the radial tensile strength could be detected. Kollidon SR and Kollidon SR mixtures exhibited a higher compactibility than MCC and MCC mixtures. The differences became smaller with increasing theophylline content.     

The Nonsteady State Modeling of Freeze Drying: In-Process Product Temperature and Moisture Content Mapping and Pharmaceutical Product Quality Applications

Introduction. Theoretical models of the freeze-drying process are potentially useful to guide the design of a freeze-drying process as well as to obtain information not readily accessible by direct experimentation, such as moisture distribution and glass transition temperature, T_g, within a vial during processing. Previous models were either restricted to the steady state and/or to one-dimensional problems. While such models are useful, the restrictions seriously limit applications of the theory. An earlier work from these laboratories presented a nonsteady state, two-dimensional model (which becomes a three-dimensional model with an axis of symmetry) of sublimation and desorption that is quite versatile and allows the user to investigate a wide variety of heat and mass transfer problems in both primary and secondary drying. The earlier treatment focused on the mathematical details of the finite element formulation of the problem and on validation of the calculations. The objective of the current study is to provide the physical rational for the choice of boundary conditions, to validate the model by comparison of calculated results with experimental data, and to discuss several representative pharmaceutical applications. To validate the model and evaluate its utility in studying distribution of moisture and glass transition temperature in a representative product, calculations for a sucrose-based formulation were performed, and selected results were compared with experimental data. Theoretical Model. The model is based on a set of coupled differential equations resulting from constraints imposed by conservation of energy and mass, where numerical results are obtained using finite element analysis. Use of the model proceeds via a “modular software package” supported by Technalysis Inc. (Passage?/Freeze Drying). This package allows the user to define the problem by inputing shelf temperature, chamber pressure, container properties, product properties, and numerical analysis parameters required for the finite element analysis. Most input data are either available in the literature or may be easily estimated. Product resistance to water vapor flow, mass transfer coefficients describing secondary drying, and container heat transfer coefficients must normally be measured. Each element (i.e., each small subsystem of the product) may be assigned different values of product resistance to accurately describe the nonlinear resistance behavior often shown by real products. During primary drying, the chamber pressure and shelf temperature may be varied in steps. During secondary drying, the change in gas composition from pure water to mostly inert gas is calculated by the model from the instantaneous water vapor flux and the input pumping capacity of the freeze dryer. Results. Comparison of the theoretical results with the experiment data for a 3% sucrose formulation is generally satisfactory. Primary drying times agree within two hours, and the product temperature vs. time curves in primary drying agree within about ± 1°C. The residual moisture vs. time curve is predicted by the theory within the likely experimental error, and the lack of large variation in moisture within the vial (i.e., top vs. side vs. bottom) is also correctly predicted by theory. The theoretical calculations also provide the time variation of “T_g–T” during both primary and secondary drying, where T is product temperature and T_g is the glass transition temperature of the product phase. The calculations demonstrate that with a secondary drying protocol using a rapid ramp of shelf temperature, the product temperature does rise above Tg during early secondary drying, perhaps being a factor in the phenomenon known as “cake shrinkage”. Conclusion. The theoretical results of in-process product temperature, primary drying time, and moisture content mapping and history are consistent with the experimental results, suggesting the theoretical model should be useful in process development and “trouble-shooting” applications.