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Controlling Mannitol Polymorphism for Enhanced Dispersibility in Spray Freeze-Dried Inhalable Microparticles

Lorena Pasero, Andrea Silenzi, Adamo Sulpizi, Tomaso Guidi and Roberto Pisano

Abstract

Spray freeze-drying (SFD) is a novel technique for formulating dry powders, particularly for pulmonary drug delivery via dry powder inhalers (DPIs). Despite their low density and excellent aerodynamic properties, such powders are affected by high cohesiveness due to their surface properties. Sugars such as mannitol (MAN), trehalose, raffinose, and sucrose are commonly used in SFD. MAN is widely employed due to its high MAN—ice eutectic temperature—at which MAN and water (ice) form a stable eutectic mixture—and its crystallinity. However, crystallinity can impact the microparticles’ (MPs) cohesiveness, since MAN exhibits distinct polymorphs (α, β, δ) with peculiar properties. This study provides valuable insights for the development of DPI formulations by ensuring precise control over MAN polymorphism, ultimately enhancing formulation stability and performance. We introduced, for the first time, an intermediate freezing (IF) step within the SFD process to modulate MAN polymorphism, demonstrating its synergy with optimised storage temperature conditions. Furthermore, polyvinylpyrrolidone, 2-hydroxypropyl beta cyclodextrin, dextran, and polysorbate 80 were employed as polymorphism-controlling agents for MAN, contributing to the development of stable formulations with reduced particle cohesion and improved storage stability at room temperature. For the first time, this study shows that MAN polymorphism in SFD can be controlled to drive dry powder inhaler performance.

Keywords:

spray freeze-drying; stability; polymorphism; freezing; storage; crystallinity; dry powder inhalers

Systematic investigation of thermal process parameters on the morphology of spray-freeze-dried powders

Annika Rautenberg, José Ignacio Vázquez-Olvera, Paul Bühlbecker, Alf Lamprecht

Abstract

Hypothesis: During spray freeze drying (SFD), vitrification, recrystallization, and polymorphic transitions govern particle morphology and mechanical integrity. We hypothesize that with control over freezing temperature, annealing relative to the glass transition of the maximally freeze-concentrated matrix (Tg’), and drying temperature it is possible to modulate ice growth, molecular mobility, and solid-state transformations, thereby enabling the production of advanced materials via freeze-casting droplets with designable properties.

Experiments: A full-factorial design was conducted using lactose, mannitol, and trehalose. Formulations were frozen at temperatures above or below water’s glass transition, annealed under four conditions (no annealing, annealing above or below Tg’, and extended times), and dried either near or above Tg’. Resulting powders were analysed regarding ice formation mechanism, solid state composition and morphological behaviour.

Findings: Mannitol displayed pronounced process-dependent polymorphism, which is driven by annealing and temperature during sublimation. Lactose and trehalose remained amorphous throughout. Annealing above Tg’ promoted viscous flow within the vitrified matrices, producing partial particle fusion and reduced mechanical stability. Variations in recrystallization and Ostwald ripening during annealing systematically altered surface area and pore architecture. This connects annealing to sintering mechanisms, electrical conductivity and mechanical stability of micrometre sized spheres. Across all conditions, SFD consistently yielded spherical, low-density particles, yet the interplay of vitrification and phase transitions generated distinct microstructural outcomes.

Keywords:

Freeze-casting; Polymorphs, annealing; Powder design; Spray-freeze-drying.

Correlation analysis of granulation condition, granule properties and green density of alumina ceramics fabricated by spray freeze granulation drying

Ying Chung, Naoki Kondo, Ken’ichiro Kita, Mikinori Hotta, Junichi Tatami, Shinya Kawaguchi

Abstract

A scalable nitrogen‑free granulator that enables freezing temperature to be tuned as a process variable for powder granulation was used to fabricate alumina granules, and the obtained granules were further fabricated into green bodies this study. We quantified links between process conditions, granule properties, and green density using Pearson correlations and principal component analysis (PCA). It is found that higher freezing temperature is likely to produce dried granules with smaller angle of repose and thus results in higher green density. It is suggested that higher freezing temperatures allow surface-level rearrangement to take place easier than lower ones, therefore creating smoother external surfaces of the obtained granules. This is considered as the reason for smaller angle of repose measured in this study. Finally, predictive models of green density were built from granulation conditions and granule properties using multiple regression and artificial neural networks (ANNs). After mitigating multicollinearity among inputs, the ANN achieved an average R2 of 0.84, demonstrating robust predictive capability for process–structure–property relationships in this spray freeze granulation process.

Highlights:

Scalable spray freeze granulation drying with flexible freezing temperature.
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Higher freezing temperature produces granules with smaller angle of repose.
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R2 > 0.8 was obtained when predicting the density of green and bodies.
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Chian of causality successfully established between process-granule-green body.

Preparation and characterization of alumina granules via tumbling and agitation granulation

Naoki Kondo, Akihiro Shimamura, Mikinori Hotta

Abstract

Granulation of alumina powder was performed, and the characteristics of the resulting granules and the sintered bodies produced from them were evaluated. The granulation processes were conducted under the following conditions: hand sieving (HS), sieving using a rotating and tapping shaker (Ro-Tap sieving, RTS) which involves a tumbling motion; dry agitation granulation using a high-shear mixer (AD); and semi-wet agitation granulation with binder addition (AB). The granulation effect increased progressively in the order of HS, RTS, AD, and AB. As the granulation effect increased, the granules became larger and more spherical, and their size distribution became narrower with a sharper peak. The loose bulk density increased and the angle of repose decreased, whereas the tapped bulk density showed no significant change due to the collapse of the granules. Although the strength of the granules increased with the progression of granulation, the strength of the sintered bodies decreased. This phenomenon is considered to result from the stronger granules being less prone to collapse during compaction, which led to the formation of residual pores between granules in the green bodies. These pores subsequently became defects in the sintered bodies, which reduced their strength.

Keywords:

Alumina, Sieving, Tumbling granulation, Agitation granulation, Sintering, Strength

Performance evaluation of new polymer additives for technical ceramic shaping processes

Ismail M’Barki, Fabrice Rossignol, Anne Aimable, Graham Abramo, Burcu Çelikkol

Abstract

This work evaluates acrylic additives as functional agents in alumina-based ceramic formulations to identify the conditions under which they can act as dispersants, binders and/or plasticizers. The methodology links formulation, shaping, drying, debinding, sintering, and final characterization to establish robust formulation–process–property relationships. Three shaping routes are investigated: freeze granulation followed by pressing, tape casting, and robocasting. Performance is assessed through suspension/paste stability and rheology, green strength and drying sensitivity, as well as debinding/sintering behaviour and the resulting microstructure. The outcomes provide formulation guidelines to improve processability and the quality of advanced ceramic parts.

Keywords:

Tape casting, Robocasting, Rheology, Freeze granulation, Plasticizer, Binder, Dispersant, Acrylic additives, Alumina

Innovations in Orally Disintegrating Tablets Technology: FormulationPrinciples, Taste Masking Mechanisms, and BiopharmaceuticalConsiderations

R Nepolean, K Chandramohan, S Sangeeth Kumar, D Anbarasu and
S Sivasankari

Abstract

Orally disintegrating tablets (ODTs) have become a key patient centric oral dosage form that is
designed to dissolve quickly in the mouth without the need of water, which aids in improving oral
adherence (in pediatric, geriatric, dysphagic and other special care patients). This review looks
at a broad review of how ODT technology has evolved over the decades, from early lyophilized
and moulded systems to modern robust systems that make use of direct compression, particle
engineering and additive manufacturing techniques. The discussion focuses on key formulation
principles such as critical quality attributes, excipient functionality and process considerations
including a special emphasis on achieving the best balance between fast rate of disintegration,
mechanical strength and palatability. Advanced taste masking approaches, including microencapsulation, hot melt coating, cyclodextrin inclusion complexes, nanotechnology based systems
and 3D printing based designs are critically reviewed to explain the efficacy and limitations of
the taste masking methods. Furthermore, biopharmaceutical aspects of saliva mediated drug release, kinetics of absorption, solubility permeability issues, lack of dependence on food and water intake, and biopharmaceutical regulatory are highlighted to offer a holistic view. Emerging
innovations of personalized and precision oral drug delivery such as 3D printing, smart ODTs delivery, with new developments and possibilities for customized therapeutic regimens.

Keywords:

Orally disintegrating tablets; Formulation of taste masking; Patient centered drug delivery; Biopharmaceutical considerations of taste masking; 3D printing

Characterization of dispersion behavior of granular particles using laser diffraction and principal component analysis

Daisuke Sasakura & Sho Kimura

Abstract

The dispersion of granulated particles in a liquid is an important process that significantly affects the quality, stability, and functionality of industrial products. It is also a phenomenon of interest in fundamental science. Changes in the particle size distribution (PSD) in a suspension of granules are widely used as indicators of the progression of various dispersion behaviors. In this study, we used the time-domain laser diffraction method to observe dispersion in a granular suspension. We then applied principal component analysis (PCA) to analyze the measurement data, which were obtained as a time series, and extract the characteristic changes in particle size during the dispersion. By extracting the principal components from multidimensional data using PCA, we could characterize the dispersion-phase behavior and separate the peak components, which could not be captured by conventional analyses using representative values such as percentiles. In particular, by applying the PCA method—commonly used in spectroscopy—to PSD data, we obtained new insights suggesting the presence of complex dispersion pathways and intermediates. The findings of this study advance our understanding of granule dispersion dynamics and help establish a new framework for analyzing particle dispersion processes, which can assist in particle design, formulation optimization, and extending scientific knowledge in this area.

Keywords:

Particle size analysis, Granules, Dispersion, Principal component analysis, Laser diffraction

Encapsulation of food bioactive compounds using electrohydrodynamic techniques: from fundamentals to industrial applications

Soubhagya Tripathy, Prem Prakash Srivastav

Abstract

The encapsulation of food bioactive compounds has gained significant attention as a strategy to improve their stability, bioavailability, and controlled release for functional food applications. Among emerging technologies, electrohydrodynamic (EHD) techniques—primarily electrospinning and electrospraying, offer unique advantages over conventional encapsulation approaches due to their ability to generate nanostructured carriers with high surface area, tunable porosity, and protective matrices under mild processing conditions. This manuscript provides a comprehensive overview of the fundamentals and industrial relevance of EHD-based encapsulation systems, highlighting the influence of processing parameters, solvent selection, and polymer–bioactive interactions on nanostructure morphology and performance. The review discusses the encapsulation of diverse bioactive compounds, including polyphenols, vitamins, peptides, probiotics, and essential oils, emphasizing improvements in stability against environmental stresses and enhanced gastrointestinal release behavior. Advances in multi-fluid electrospinning (coaxial and triaxial) and needleless electrospinning are examined for their scalability and potential in industrial adoption. Additionally, real-world case studies are presented to illustrate the integration of EHD nanostructures into functional foods, while challenges such as low throughput, solvent toxicity, and regulatory hurdles are critically assessed. Future perspectives stress the importance of food-grade polymer development, green solvent use, and process optimization for commercial feasibility. Overall, EHD-based encapsulation represents a transformative technology that bridges nanotechnology and food engineering, offering promising solutions for designing next-generation functional foods with improved health benefits, longer shelf-life, and enhanced consumer appeal.

Keywords:

biosensor, electrohydrodynamic encapsulation, electrospinning, electrosprying, food bioactive compounds, food packaging, functional foods, nanostructured delivery systems

Microencapsulation of anthocyanins extracted from grape skin by emulsification/internal gelation followed by spray/freeze-drying techniques: Characterization, stability and bioaccessibility

Rui Zhang, Lan Zhou, Jia Li, Hélder Oliveira, Ning Yang, Weiping Jin, Zhenzhou Zhu, Shuyi Li, Jingren He

Abstract

Emulsification/internal gelation is an emerging encapsulation technique with a great potential to protect anthocyanins’ stability against the effect of negative environmental conditions. This study aims to microencapsulate anthocyanins extract of grape skin (AEGS) using emulsification/internal gelation associated with spray/freeze-drying techniques. The encapsulation efficiency (EE), particle size and morphology of generated powder microcapsules were further determined. The light (50 W, 5 h) and thermal stabilities (50–90 °C, 2.5 h), as well as in vitro bioaccessibility of microcapsules were evaluated. The results indicated that spray-dried powder microcapsules have smaller median diameter (d50 ≈ 0.56 μm) and better EE of anthocyanins (EE ≈ 75%). Moreover, a series of stability assays revealed that degradation of anthocyanins followed first-order kinetics. However, microencapsulation greatly enhanced light and thermal stabilities of anthocyanins, notably spray-dried microcapsules were the most stable in all assays of this study. The spray-dried microcapsules also showed the lowest degradation constant (0.0207 h−1) and longest half-life (33.47 h) during treatment in the dark. Furthermore, spray-drying favored anthocyanins retention in the microcapsules and improved the prolonged release of anthocyanins in simulated gastrointestinal digestion. These results demonstrated microencapsulation using combined emulsification/internal gelation with drying was feasible for enhancing the stabilization of anthocyanins.

Keywords:

Spray freeze-drying

Batch preparation of Fe2O3/Al2O3 oxygen carriers for chemical looping combustion of lignite

L. Guo, Haibo Zhao, Jinchen Ma, Daofeng Mei

Abstract

Freeze granulation, spray drying, impregnation and mechanical mixing methods were adopted to prepare Fe2O3/Al2O3 oxygen carriers. To identify the appropriate technologies for batch preparation of the oxygen carriers, the four preparation methods were compared in terms of yield rate, preparation period, physical and chemical characteristics and performance in chemical looping combustion (CLC) of lignite. The experimental results show that freeze granulation has the highest yield rate of carrier with the best mechanical strength. CLC tests of lignite demonstrate that the oxygen carriers prepared by freeze granulation and spray drying bring the highest carbon conversion rate, followed by impregnation and mechanical mixing; and the oxygen carriers prepared by the first two methods have higher chemical reactivity and more stable performance. In the four reduction processes with oxygen carriers prepared by all the four preparation methods, CO2 capture efficiencies exceed 88%; the yield rate of CO2 increases with the rate of carbon conversion, finally approaching 100%; and the combustion efficiencies are above 90%. These indicate that the oxygen carriers prepared by the four methods all have good performances for CO2 capture and high utilization degree of the combustible components. Freeze granulation and spray drying methods can be considered preferentially for batch preparation of oxygen carriers for the CLC of lignite.

Keywords:

Freeze granulation, spray drying