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Impact of excipient choice on the aerodynamic performance of inhalable spray-freeze-dried powders

Stefan Wanning, Richard Süverkrüp, Alf Lamprecht

Abstract

Spray-freeze-drying (SFD) is a process in which a solution is dispersed into a freezing medium and dried by sublimation, resulting in lyophilized powders with spherical particles. This study aims at screening and evaluating the impact of the excipient choice and spray solution characteristics in SFD on the physico-chemical characteristics of lyospheres and rate their suitability for producing pulmonary applicable powders using a novel SFD method. A monodisperse droplet-stream was injected into a vortex of cold gas for the production of inhalable, uniform spherical lyophilisates with a narrow particle size distribution. Model solutions containing graded contents (0.3%, 1.0%, and 3.0% w/v) of common bulk-forming excipients like mannitol, lactose, poylvinylpyrrolidone (PVP), maltodextrin or hydroyxpropyl methylcellulose (HPMC) and their blends were dispersed using a single 20 μm pinhole diaphragm. Powders were analyzed regarding their geometric particle size, apparent density, mechanical stability and aerodynamic performance. The diameter of the frozen droplets partially correlated with the Ohnesorge number of the spray solutions. The lyosphere powders had median geometric particle diameters ranging from 20 µm to 81 µm. Some powders showed signs of particle shrinkage during the drying step and diameters were reduced down to 30% of their initial size. The apparent particle densities ranged from 0.009 g/cm³ to 0.087 g/cm³. The mechanical stability of the lyospheres depended on the constituents and concentration of the initial spray solution. Mannitol/maltodextrin formulations yielded large porous particles with promising performance in the Next-Generation-Impactor, emitted fractions between 92 and 98% (w/w) and fine-particle-fractions of over 55% (w/w). According to our first steps towards formulations for free-flowing inhalable spray freeze-dried powders the impact of excipient choice on the SFD process is significant and based on the current findings we consider mannitol or mannitol/maltodextrin as best performing formulations.

Keywords

Spray freeze drying, Droplet-stream generator, Protein formulations, Lyophilization, Porous particles, Pulmonary drug delivery, Droplet collision, Lyosphere

A nanoindentation based study to evaluate the effect of carbon nanofibers on the mechanical properties of SiC composites

Shaik Mubina, P Sudharshan Phani, Asit Kumar Khanra, Bhaskar Prasad Saha

Abstract

An advanced high-speed nanoindentation technique is employed to analyze the combined benefit of the particulate and continuous fiber’s reinforcing effect of carbon fibers in the SiC matrix. Spray freeze granulated well-dispersed carbon nanofibers (CNF) containing precursor SiC-CNF (1 wt%) composite powder was used as a base matrix in which continuous carbon fibers were introduced in a systematic laying pattern to produce hybrid composite tubes with 10–12 mm wall thickness. Thin tubes with a wall thickness of 1–2 mm were produced with SiC, SiC-CNF composite powder. The two types of tubes with various lengths were cold isostatically pressed and pressureless sintered at 2150°C/1hour under Argon (Ar). The surface properties of the sintered tubes were further enhanced by coating with a dense SiC layer by adopting a CVD technique. The properties of the fiber-matrix interface and coating-matrix interfaces of the tube samples were evaluated using conventional processes as well as the nanoindentation techniques and compared at different length scales. Attempts have been made to correlate the structure-property relations of complex multi-phase of SiC composites employing high-speed nanoindentation mapping as well as XRD, Digital optical, SEM, and TEM analysis.

Recent progress in structural development and band engineering of perovskites materials for photocatalytic solar hydrogen production: A review

Sehar Tasleem, Muhammad Tahir

Abstract

Photocatalytic water splitting for hydrogen production is a promising technology for the conversion of solar light to clean energy. In this perspective, several semiconductors have been under investigation, but they show less efficiency, selectivity and stability for hydrogen production. Recently, perovskites are most demanding due to their exceptional characteristics such as controlled structure and morphology, adjustable band structure, controlled valence state, adjustable oxidation state and visible light response. This review highlights structural classification of perovskites and band engineering for solar energy assisted photocatalytic hydrogen production. In the main stream, overview and fundamentals of perovskite materials for selective solar to hydrogen conversion are presented. The structural modification and band alteration to stimulate quantum efficiency and stability are specifically demonstrated. Photoactivity enhancement through metals, noble metals, non-metals doping, oxygen vacancies and fermi level adjustments are also deliberated. The role of perovskites with binary semiconductors towards hydrogen production has also been discussed. Up conversion effect of doping luminescent agents (Er, Ho, Eu, Nd) for improved photocatalytic activity by band gap narrowing is also deliberated. Various conventional and non-conventional synthesis methods for perovskites including solid-state, hydrothermal, sol-gel, co-precipitation, spray-freeze drying, microwave assisted, spray pyrolysis, low temperature combustion, pulse laser deposition and wet chemical method for enhanced photocatalytic activity are also demonstrated in this work. Finally, the key challenges and future directions for sustainable energy systems are also included.

Keywords

Photo-catalysis, Hydrogen production, Perovskites, Structural classification, Synthesis methods, Binary semiconductors

Microstructure of spray freezing dried powders affected by the presence of inert particles

Fan Zhang, Linsong Wang, Xiaoyu Ma, Qing Xu, Wei Tian, Zhanyong li

Abstract

Spray freeze-drying is a process to directly produce high quality powders with short drying time. The difference of microstructures has a great influence on the physical properties of powders. However, during the spray freeze-drying process, the freezing degree of droplets in the drying chamber will change the product structure and affect the powder quality. In this study, the surface structure and morphology of dry powders were observed using scanning electron microscopy. The formation mechanism of droplet morphology during spray freeze-drying was analyzed. The results show that the rapid freezing process can produce finer microstructures.

Nacre-like alumina composites based on heteroaggregation

Mariana Muňoz, Manuella Cerbelaud, Arnaud Videcoq, Hassan Saad, Alexandre Boulle, Sylvain Meille, Sylvain Deville, Fabrice Rossignol

Abstract

High strength and high toughness are usually mutually exclusive in materials. Among all material classes, ceramics exhibit a high stiffness and strength, but they present a limited plastic deformation, which results in a moderate toughness. However, tough ceramics have been obtained using anisotropic particles organized in a ‘brick and mortar’ microstructure, inspired by the structure of the natural nacre. Here, we propose to build nacre-like ceramic composites from colloidal suspensions using heteroaggregation of particles. Two different shaping processes are used: direct settling of suspensions or freeze-granulation. After sintering, in both cases, the platelets alignment is very good, close to that of platelets in natural nacre, with a slightly better one noted for direct settling. Despite a better platelet alignment, the toughness is lower than in previous studies showing that further improvement of the interfacial phases present in the material must now be considered to reinforce its mechanical behavior.

Keywords

Nacre-like composite, Heteroaggregation, Platelet alignment, Settling, Freeze-granulation

Dynamical in-situ observation of the lyophilization and vacuum-drying processes of a model biopharmaceutical system by an environmental scanning electron microscope

Abstract

The paper discusses the real-time monitoring of the changing sample morphology during the entire lyophilization (freeze-drying) and vacuum-drying processes of model biopharmaceutical solutions by using an environmental scanning electron microscope (ESEM); the device’s micromanipulators were used to study the interior of the samples in-situ without exposing the samples to atmospheric water vapor. The individual collapse temperatures (Tc) of the formulations, pure bovine serum albumin (BSA) and BSA/sucrose mixtures, ranged from −5 to −29 °C. We evaluated the impact of the freezing method (spontaneous freezing, controlled ice nucleation, and spray freezing) on the morphologies of the lyophiles at the constant drying temperature of −20 °C. The formulations with Tc above −20 °C resulted in the lyophiles’ morphologies significantly dependent on the freezing method. We interpret the observations as an interplay of the freezing rates and directionalities, both of which markedly influence the morphologies of the frozen formulations, and, subsequently, the drying process and the mechanical stability of the freeze-dried cake. The formulation with Tc below −20 °C yielded a collapsed cake with features independent of the freezing method. The vacuum-drying produced a material with a smooth and pore-free surface, where deep cracks developed at the end of the process.

Keywords

Bovine serum albumin, Freeze-drying, Vacuum-drying, Environmental scanning electron microscopy

Sintering investigations of a UO₂-PuO₂ powder synthesized using the freeze-granulation route

Marion Le Guellec, Florent Lebreton, Laure Ramond, Abibatou Ndiaye, Thierry Gervais, Guillaume Bernard-Granger

Abstract

Sintering investigations of a UO₂-PuO₂ powder, integrating 11 wt% of PuO₂ and synthesized by freeze-granulation, were completed at temperatures up to 1700°C, in an atmosphere of Ar/4 vol% H₂ and 1200 vpm H₂O. Analyzing the “grain size versus relative density” trajectory enabled to propose that densification was controlled by volume diffusion and grain growth by the grain boundaries. An activation energy around 630 kJ/mol was obtained for densification, which was close to the value reported for volume diffusion of plutonium cations in U_1-xPu_xO₂ polycrystals. The sintered microstructure appeared homogeneous regarding the plutonium and uranium cations distribution.

Keywords

Sintering, Ceramics, Oxides, Microstructure, MOX

Physicochemical changes of MTGase cross-linked surimi gels subjected to liquid nitrogen spray freezing

Xiaoying Luo, Jinling Li, Wenli Yan, Ru Liu, Tao Yin, Juan You, Hongying Du, Shanbai Xiong, Yang Hu

Abstract

Physicochemical properties of microbial transglutaminase (MTGase) cross-linked surimi gels subjected to liquid nitrogen (LN) spray freezing with different temperatures and cross-linking degrees were investigated. Gels with lower LN spray temperature (−90 °C) were found taking less time in cooling down themselves to maximum-ice-crystal generating temperature. Microstructure images showed the pores of gels became smaller and the structure gradually became denser, as freezing temperature decreased and cross-linking degree increased. It also revealed T₂₂ relaxation time of gels decreased significantly with surimi gels cross-linking degree increasing, indicating the binding ability of gels to moisture was enhanced accordingly. Meanwhile, the proton density weighted image brightness declined along with the LN spray temperature decreasing, and the image brightness showed a decreasing trend from outside to inside, indicating that water migrated and permeated easier from the inside of the gel network to the outside undergone higher LN temperature and lower cross-linking degree. Besides, the L^⁎ and W values of LN groups decreased along with LN spray temperature and cross-linking degree increasing. Moreover, −90 °C LN group with 46.70% cross-linking degree presented the highest breaking force which ascribed to their synergistic efforts in maintaining a stable and dense structure of gels via controlling ice crystals and cross-linkages’ generation.

Keywords

Surimi gel, Cross-linking degree, Liquid nitrogen spray freezing

Effect of formulation and inhaler parameters on the dispersion of spray freeze dried voriconazole particles

Qiuying Liao, Ivan C.H. Lam, Hinson H.S. Lin, Leon T.L. Wan, Jason C.K. Lo, Waiting Tai, Philip C.L. Kwok, Jenny K.W. Lam

Abstract

Spray freeze drying is a particle engineering technique that allows the production of porous particles of low density with excellent aerosol performance for inhalation. There are a number of operating parameters that can be manipulated in order to optimise the powder properties. In this study, a two-fluid nozzle was used to prepare spray freeze dried formulation of voriconazole, a triazole antifungal agent for the treatment of pulmonary aspergillosis. A full factorial design approach was adopted to explore the effects of drug concentration, atomisation gas flow rate and primary drying temperature. The aerosol performance of the spray freeze dried powder was evaluated using the next generation impactor (NGI) operated with different inhaler devices and flow rates. The results showed that the primary drying temperature played an important role in determining the aerosol properties of the powder. In general, the higher the primary drying temperature, the lower the emitted fraction (EF) and the higher the fine particle fraction (FPF). Formulations that contained the highest voriconazole concentration (80% w/w) and prepared at a high primary drying temperature (−10 °C) exhibited the best aerosol performance under different experimental conditions. The high concentration of the hydrophobic voriconazole reduced surface energy and cohesion, hence better powder dispersibility. The powders produced with higher primary drying temperature had a smaller particle size after dispersion and improved aerosol property, possibly due to the faster sublimation rate in the freeze-drying step that led to the formation of less aggregating or more fragile particles. Moreover, Breezhaler®, which has a low intrinsic resistance, was able to generate the best aerosol performance of the spray freeze dried voriconazole powders in terms of FPF.

Keywords

Aerosol performance, Antifungal agent, Factorial design, Freeze drying, Inhalation, Pulmonary delivery, Spray freeze drying

Evaluation of Process Conditions for Ultrasonic Spray-Freeze Drying of Transglutaminase

Hilal İşleroğlu, Izzet Turker

Abstract

In this study, a commercial transglutaminase enzyme was dried using an ultrasonic spray freeze drying method and the effects of the process conditions were optimized to maximize the final transglutaminase activity. Accordingly, process parameters affecting enzyme activity were selected, such as nozzle frequency (48 and 120 kHz), flow rate (2, 5 and 8 mL/min) and plate temperature for secondary drying (25, 35 and 45 °C). Moreover, the effects of different pH values (pH=2.0 and 9.0) and high temperature (80 °C) on enzyme activity, physical properties and particle morphology of transglutaminase were discussed. According to the results, transglutaminase preserved its activity despite ultrasonic spray freeze drying. Sonication enhanced the enzyme activity. Using the desirability function method, the optimum process conditions were determined to be flow rate 3.10 mL/min, plate temperature 45 °C and nozzle frequency 120 kHz. The predicted activity ratio was 1.17, and experimentally obtained ratio was 1.14±0.02. Furthermore, enzyme produced by ultrasonic spray freeze drying had low moisture values (2.92-4.36 %) at 8 h of drying. When the morphological structure of the transglutaminase particles produced by ultrasonic spray freeze drying under the optimum conditions was examined, spherical particles with pores on their surfaces were observed. In addition, flow properties of the transglutaminase powders were considered as fair under most conditions according to the Carr index.