Effect of Temperature and Moisture on the Physical Stability of Binary and Ternary Amorphous Solid Dispersions of Celecoxib

The effectiveness of different polymers, alone or in combination, in inhibiting the crystallization of celecoxib (CEX) from amorphous solid dispersions (ASDs) exposed to different temperatures and relative humidities was evaluated. It was found that polyvinylpyrrolidone (PVP) and PVP-vinyl acetate formed stronger or more extensive hydrogen bonding with CEX than cellulose-based polymers. This, combined with their better effectiveness in raising the glass transition temperature (T_g) of the dispersions, provided better physical stabilization of amorphous CEX against crystallization in the absence of moisture when compared with dispersions formed with cellulose derivatives. In ternary dispersions containing 2 polymers, the physical stability was minimally impaired by the presence of a cellulose-based polymer when the major polymer present was PVP. On exposure to moisture, stability of the CEX ASDs was strongly affected by both the dispersion hygroscopicity and the strength of the intermolecular interactions. Binary and ternary ASDs containing PVP appeared to undergo partial amorphous–amorphous phase separation when exposed 94% relative humidity, followed by crystallization, whereas other binary ASDs crystallized directly without amorphous–amorphous phase separation.     

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.     

Remote Trice Light,Temperature, and pH-actuation of Switchable Magneto-Plasmonic Nanocarriers for Combinational Photothermal and Controlled/Targeted Chemotherapies

Three magneto-plasmonic nanohybrids were synthesized using Au- and Ag-coated Fe₃O₄ nanoparticles (NPs)-modified dual pH- and temperature-responsive triblock copolymer of poly (butyl methacrylate-co-acrylamide-co-methacrylic acid) to serve as drug carriers with potential of using in both photothermal and controlled/targeted chemotherapies. The internal superparamagnetic core gives the carriers targeted-delivery characteristics, and surface plasmon resonance–based noble metallic Au/Ag shells give them on-demand photothermal and photo-triggering release properties. To investigate the effect of coating method on the targeting property of synthesized carriers, Au NPs were attached to the magnetic core by 2 different direct/indirect procedures and the properties of the synthesized carriers including swelling ratio and thermal and optical sensitivity and switching were comprehensively investigated in 2 different buffer solutions with pH 5.5 and 7.4 at 37°C. Letrozole was used as a model anticancer drug and its loading and release properties were evaluated for the four nanocarriers. The cytotoxicity of drug-free and letrozole-loaded nanocarriers on normal L929 fibroblast and MDAMB 231 breast cancer cell lines was evaluated in absence/presence of laser radiation. The results revealed that the carriers have the potential of serving as switchable trimodal light/temperature/pH-triggered and targeted/controlled drug delivery platforms for chemophotothermal therapy.     

Antibacterial efficacy of silver nanoparticles of different sizes,surface conditions and synthesis methods

Abstract

Silver nanoparticles (Ag-nps) are used as a natural biocide to prevent undesired bacterial growth in clothing and cosmetics. The objective of this study was to assess the antibacterial efficacy of Ag-nps of different sizes, surface conditions, and synthesis methods against Escherichia coli, Ag-resistant E. coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Salmonella sp. Ag-nps samples were synthesized by: Base reduction with unmodified surfaces and used as synthesized (‘unwashed’; 20, 50 and 80 nm) or after 20 phosphate buffer washes (‘washed’; 20, 50 and 80 nm), or synthesized by laser ablation with carbon-stabilized surfaces (‘carbon-coated’; 25 and 35 nm). Unwashed Ag-nps were toxic to all bacterial strains at concentrations between 3.0–8.0 μg/ml. The washed Ag-nps and carbon-coated Ag-nps were toxic to all bacterial strains except Ag-resistant E. coli at concentrations between 64.0–1024.0 μg/ml. Ag-resistant E. coli died only when treated with unwashed Ag-nps or its supernatant, both of which contained formaldehyde.     

Producing Amorphous Solid Dispersions via Co-Precipitation and Spray Drying: Impact to Physicochemical and Biopharmaceutical Properties

Many small-molecule active pharmaceutical ingredients (APIs) exhibit low aqueous solubility and benefit from generation of amorphous dispersions of the API and polymer to improve their dissolution properties. Spray drying and hot-melt extrusion are 2 common methods to produce these dispersions; however, for some systems, these approaches may not be optimal, and it would be beneficial to have an alternative route. Herein, amorphous solid dispersions of compound A, a low-solubility weak acid, and copovidone were made by conventional spray drying and co-precipitation. The physicochemical properties of the 2 materials were assessed via X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and scanning electron microscopy. The amorphous dispersions were then formulated and tableted, and the performance was assessed in vivo and in vitro. In human dissolution studies, the co-precipitation tablets had slightly slower dissolution than the spray-dried dispersion, but both reached full release of compound A. In canine in vitro dissolution studies, the tablets showed comparable dissolution profiles. Finally, canine pharmacokinetic studies showed that the materials had comparable values for the area under the curve, bioavailability, and C_max. Based on the summarized data, we conclude that for some APIs, co-precipitation is a viable alternative to spray drying to make solid amorphous dispersions while maintaining desirable physicochemical and biopharmaceutical characteristics.     

Alternative Manufacturing Concepts for Solid Oral Dosage Forms From Drug Nanosuspensions Using Fluid Dispensing and Forced Drying Technology

Flexible manufacturing technologies for solid oral dosage forms with a continuous adjustability of the manufactured dose strength are of interest for applications in personalized medicine. This study explored the feasibility of using microvalve technology for the manufacturing of different solid oral dosage form concepts. Hard gelatin capsules filled with excipients, placebo tablets, and polymer films, placed in hard gelatin capsules after drying, were considered as substrates. For each concept, a basic understanding of relevant formulation parameters and their impact on dissolution behavior has been established. Suitable matrix formers, present either on the substrate or directly in the drug nanosuspension, proved to be essential to prevent nanoparticle agglomeration of the drug nanoparticles and to ensure a fast dissolution behavior. Furthermore, convection and radiation drying methods were investigated for the fast drying of drug nanosuspensions dispensed onto polymer films, which were then placed in hard gelatin capsules. Changes in morphology and in drug and matrix former distribution were observed for increasing drying intensity. However, even fast drying times below 1 min could be realized, while maintaining the nanoparticulate drug structure and a good dissolution behavior.     

Spray Drying for Generation of a Ternary Amorphous System of Celecoxib,PVP, and Meglumine

Generation of amorphous forms of a poorly soluble drug by solid dispersion techniques has been a subject of intensive research for decades. Apart from the stability of the dispersions, development of a suitable production technology is a major challenge to the successful commercialization of these products. Coprocessing of celecoxib (CEL), poly(vinyl pyrrolidone), and meglumine by spray drying resulted in an amorphous drug product that provided enhanced solubility and stability to an otherwise poorly soluble crystalline form of CEL. The spray-drying process parameters were optimized to provide an amorphous product with required characteristics. The product was stable for 3 months under the accelerated stability storage conditions. This technique can serve as a suitable means for generating a ready-to-formulate amorphous drug-additive(s) composite that can be directly filled into hard gelatin capsules.     

JS—140型胶塞清洗灭菌干燥联合机组与GMP

JS－140型胶塞清洗、灭菌、干燥联合机组将药用天然胶塞的清洗、灭菌、干燥结为一体。本文从设备及工艺两方面将该机与传统处理方法相比较,证明了该机在无菌条件下进行清洗、灭菌、干燥,减少了环境对胶塞的污染,提高了胶塞的处理质量,符合GMP要求。     

Applications of the Tunable Diode Laser Absorption Spectroscopy: In-Process Estimation of Primary Drying Heterogeneity and Product Temperature During Lyophilization

The aim of this research was to evaluate the impact of variability in ice sublimation rate (dm/dt) measurement and vial heat transfer coefficient (K_v) on product temperature prediction during the primary drying phase of lyophilization. The mathematical model used for primary drying uses dm/dt and K_v as inputs to predict product temperature. A second-generation tunable diode laser absorption spectroscopy (TDLAS)–based sensor was used to measure dm/dt. In addition, a new approach to calculate drying heterogeneity in a batch during primary drying is described. The TDLAS dm/dt measurements were found to be within 5%-10% of gravimetric measurement for laboratory- and pilot-scale lyophilizers. Intersupplier variability in K_v was high for the same “type” of vials, which can lead to erroneous product temperature prediction if “one value” of vial heat transfer coefficient is used for “all vial types” from different suppliers. Studies conducted in both a laboratory- and a pilot-scale lyophilizer showed TDLAS product temperature to be within ±1°C of average thermocouple temperature during primary drying. Using TDLAS data and calculations to estimate drying heterogeneity (number of vials undergoing primary drying), good agreement was obtained between theoretical and experimental results, demonstrating usefulness of the new approach.     

苦参提取纯化浓缩液喷雾干燥工艺优化

摘 要 目的： 优选苦参水提纯化浓缩液喷雾干燥最佳工艺参数。方法: 采用L9(34)正交设计试验法,以浸膏粉重量及苦参碱和氧化苦参碱两者含量之和为评价指标,通过考察药液浓缩密度、进风温度、泵药速度等对苦参提取纯化浓缩液喷雾干燥工艺条件的影响。结果: 最佳喷雾干燥工艺条件为：药液密度1.07,进风温度120℃,泵药速度4 r·min^-1。结论: 该优选工艺科学、合理、稳定、可行,可为苦参提取纯化浓缩液的喷雾干燥工业化生产提供试验依据。     

Medical and pharmaceutical nanoengineering conference/International conference on MEMS,nano and smart systems

Researchers representing all the northern hemispheric continents gathered for 3 days in Banff, Canada, to hear a wide range of talks on the application of micro- and nanotechnology to drug delivery. Topics included nanotubes, nanoparticles, liposomes, micelles, novel inhaled aerosols, antibody engineering and vaccines. Also featured were talks on the application of micro- and nanotechnology to diagnostics, including microfluidics, as well as biomolecular computing. The conference showcased the first demonstration of preliminary concepts for ‘smart particle aerosols’, in which nanofabrication methods are used to produce inhaled aerosol particles with ‘intelligent’ features. The conference provided an excellent forum for cross-fertilisation and discussion between disciplines, with attendees covering a broad range of areas in engineering and the physical and life sciences that are not often found together at a single conference. This breadth of attendees and topics provided a highly stimulating environment. An invitation to next year’s conference (24 – 29 July 2005, Banff, Alberta, Canada) was extended, as listed at the conference website [101].     

Physicochemical Parameters Associated with Nanoparticle Formation in the Salting-Out,Emulsification-Diffusion,and Nanoprecipitation Methods

PURPOSE: The aim of this work was to relate the physicochemical properties of the aqueous and organic phases used for nanoparticle (NP) preparation to the formation of NP produced by salting-out, emulsification-diffusion, and nanoprecipitation. METHODS: Methacrylic acid copolymer and poly(vinyl alcohol) (PVAL) were selected as NP polymer and emulsifying agent, respectively. Salting-out and emulsification-diffusion NP batches were prepared modifying the PVAL content in the aqueous phase. For nanoprecipitation, NP were produced with variation of the polymer content and type of solvent in the organic phase. RESULTS: For salting-out and emulsification-diffusion, NP formation was discussed in terms of the emulsification theory. The nanoemulsion obtained during NP preparation was visualized by scanning electron microscopy. Aqueous and organic phases used for NP preparation were characterized by their viscosity and surface tension. NP characteristics such as particle mean size, residual surfactant, suspendability in water after freeze-drying, and morphology were explained in terms of these properties. For nanoprecipitation, NP formation was analyzed considering the diffusion-stranding phenomenon. CONCLUSIONS: NP formation by salting-out and emulsification-diffusion was related to PVAL chain interactions at the droplet interface (e.g., reduction in the interfacial tension, mechanical stabilization, and steric stabilization) and in the bulk solution (hydrodynamic stabilization). For nanoprecipitation, chi(solvent-water) and delta(delta solvent-water) of the organic phase solvents were well related to the NP characteristics.     

分程变温对不同商品等级党参干燥特性及动力学模型的影响

目的 比较不同干燥方式对党参的干燥特性、水分有效扩散系数以及偏倚活化能的影响,明确3种分程变温（45-55-60,60-55-45,60-45-60℃）和3种恒温（45,55,60℃）对不同商品等级党参干燥特性曲线的影响。方法 以R²、χ²和RMSE为评价指标,选用10种典型干燥动力学模型对党参的干燥曲线进行拟合,并计算不同干燥方式下有效水分扩散系数和偏倚活化能。结果 Midilli模型能较好地描述不同商品等级的党参药材的干燥过程,党参的水分比呈现指数下降的趋势。若初始干燥温度>55℃,能在2 h内达到最大干燥速率。商品等级和温度对党参有效水分扩散系数有一定影响,同一温度条件下,党参干燥过程中水分迁移的平均速度：一等品＞二等品＞三等品,其D_eff依次为10.433 9×10^–8,5.545 2×10^–8,2.249 6×10^–8·m²·s。计算党参的偏倚活化能在2.943×10⁴~4.378×10⁴J·mol^–1,不同干燥方式的偏倚活化能排序为60-55-45℃变温<60-45-60℃变温<45-55-60℃变温<55℃恒温<60℃恒温<45℃恒温,说明分程变温干燥与恒温干燥相比,药材中水分更容易溢出,耗能更少,尤其60-55-45℃分程变温的偏倚活化能仅为其他2种变温干燥的77.54%和81.86%,是3种恒温干燥的67.22%,75.13%和74.26%。结论 干燥过程中运用分程变温中的降温模式更省时节能,可为党参干燥技术的提升和干燥工艺优化提供实验依据。     

Chitosan Nanoparticles as New Ocular Drug Delivery Systems: in Vitro Stability,in Vivo Fate,and Cellular Toxicity

PURPOSE: To assess the potential of chitosan (CS) nanoparticles for ocular drug delivery by investigating their interaction with the ocular mucosa in vivo and also their toxicity in conjunctival cell cultures. METHODS: Fluorescent (CS-fl) nanoparticles were prepared by ionotropic gelation. The stability of the particles in the presence of lysozyme was investigated by determining the size and their interaction with mucin, by measuring the viscosity of the mucin dispersion. The in vivo interaction of CS-fl nanoparticles with the rabbit cornea and conjunctiva was analyzed by spectrofluorimetry and confocal microscopy. Their potential toxicity was assessed in a human conjunctival cell line by determining cell survival and viability. RESULTS: CS-fl nanoparticles were stable upon incubation with lysozyme and did not affect the viscosity of a mucin dispersion. In vivo studies showed that the amounts of CS-fl in cornea and conjunctiva were significantly higher for CS-fl nanoparticles than for a control CS-fl solution, these amounts being fairly constant for up to 24 h. Confocal studies suggest that nanoparticles penetrate into the corneal and conjunctival epithelia. Cell survival at 24 h after incubation with CS nanoparticles was high and the viability of the recovered cells was near 100%. CONCLUSIONS: CS nanoparticles are promising vehicles for ocular drug delivery.     

Comparative Rates of Freeze-Drying for Lactose and Sucrose Solutions as Measured by Photographic Recording,Product Temperature,and Heat Flux Transducer

Sublimation from lactose and sucrose solutions has been monitored by temperature measurement, visual observation, heat flux sensing and manometric measurements. Estimates of energy transfer rates to the subliming mass made from visual observations and heat flux measurements are in broad agreement, demonstrating for the first time that heat flux sensors can be used to monitor the progress of lyophilization in individual vials with low sample volumes. Furthermore, it is shown that under identical lyophilization conditions the initial rate of drying for lactose solutions is low with little water sublimation for up to 150 minutes, which contrasts markedly with the much faster initial rate of drying for sucrose solutions. Measurement of the initial heat flux between shelf and vial indicated a lower flux to a 10% lactose solution than to a 10% sucrose solution.     

Effects of pH-sensitive nanoparticles prepared with different polymers on the distribution,adhesion and transition of Rhodamine 6G in the gut of rats

To investigate the effect of different enteric polymers on the characteristics of pH-sensitive nanoparticles, Rhodamine 6G (Rho) was incorporated in various pH-sensitive nanoparticles. The different patterns of pH-dependent release profiles were observed, although some polymers have the same dissolving pH. The distribution, adhesion and transition of different nanoparticles in rat gut showed significant difference, closely related to the release characteristics of nanoparticles, and their release behaviour are dependent on the dissolving pH and the structure of the polymers, as well as the drug property. Most nanoparticle formulations decreased the distribution and adhesion of Rho in the stomach but increased these values in the intestine. The nanocarriers also control the drug release sites and release rate in the GI tract. In conclusion, pH-sensitive nanoparticles seem favourable for drug absorption and it is important to choose the proper materials to obtain the suitable characteristics for the oral pH-sensitive nanoparticles.     

Effect of Temperature during Drying and Storage of Dried Figs on Growth,Gene Expression and Aflatoxin Production

Dried fig is susceptible to infection by Aspergillus flavus, the major producer of the carcinogenic mycotoxins. This fruit may be contaminated by the fungus throughout the entire chain production, especially during natural sun-drying, post-harvest, industrial processing, storage, and fruit retailing. Correct management of such critical stages is necessary to prevent mould growth and mycotoxin accumulation, with temperature being one of the main factors associated with these problems. The effect of different temperatures (5, 16, 25, 30, and 37 °C) related to dried-fig processing on growth, one of the regulatory genes of aflatoxin pathway (aflR) and mycotoxin production by A. flavus, was assessed. Firstly, growth and aflatoxin production of 11 A. flavus strains were checked before selecting two strains (M30 and M144) for in-depth studies. Findings showed that there were enormous differences in aflatoxin amounts and related-gene expression between the two selected strains. Based on the results, mild temperatures, and changes in temperature during drying and storage of dried figs should be avoided. Drying should be conducted at temperatures >30 °C and close to 37 °C, while industry processing, storage, and retailing of dried figs are advisable to perform at refrigeration temperatures (<10 °C) to avoid mycotoxin production.     

Assessment of Patient Exposure to Leachables From Lyophilized Drug Formulations Following Reconstitution,Storage, and Administration via Polymeric Packaging/Delivery Systems

It has been demonstrated that lyophilized drug formulations have an increased propensity to leach substances from the rubber stoppers comprising their primary packaging system when compared to aqueous liquid formulations stored in the same manner. Unfortunately, patient exposure to leachables originating in lyophilized drug products is not known. To that end, the goal of this study was to assess patient exposure to these leachables after reconstitution, storage, and administration of the lyophilized drug. To achieve this goal, several leachables present in 2 commercial lyophilized drug products were quantified after contact with polyvinyl chloride and non–polyvinyl chloride medication bags as well as an infusion set for durations of 15 min to 7 days at refrigerated and ambient temperature. The results obtained from this study showed that the bag’s material of construction and the drugs formulation did not impact the mass of the leachables administered. Conversely, the mass of each leachable administered to the patient was reduced or eliminated as the contact duration with the intravenous bag and the temperature increased. However, for shorter contact durations, refrigerated storage, and higher molecular weight compounds, the patient would be exposed to a majority of the leachables originating from the vial.