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1H NMR quantification of spray dried and spray freeze-dried saccharide carriers in dry powder inhaler formulations

Mai Babenko, Jean-Marie R. Peron, Waseem Kaialy, Gianpiero Calabrese, Raid G. Alany, Amr ElShaer

Abstract

Quantitative analysis using proton NMR (¹H qNMR) has been employed in various areas such as pharmaceutical analysis (e.g., dissolution study), vaccines, natural products analysis, metabolites, and macrolide antibiotics in agriculture industry. However, it is not routinely used in the quantification of saccharides in dry powder inhaler (DPI) formulations. The aim of this study was to develop a ¹H NMR method for the quantification of saccharides employed in DPI formulations. Dry powders as DPI carriers were prepared by spray drying (SD) and spray freeze drying (SFD) using three saccharides: namely D-mannitol, D-sorbitol and D-(+)-sucrose. The calibration curves constructed for all three saccharides demonstrated linearity with R² value of 1. The ¹H qNMR method produced accurate (relative error %: 0.184–3.697) and precise data with high repeatability (RSD %: 0.517–3.126) within the calibration curve concentration range. The ¹H qNMR method also demonstrated significant sensitivity with low values of limit of detection (0.058 mM for D-mannitol, 0.045 mM for D-(+)-sucrose, and 0.056 mM for D-sorbitol) and limit of quantitation (0.175 mM for D-mannitol, 0.135 mM for D-(+)-sucrose, and 0.168 mM for D-sorbitol). Pulmonary deposition via impaction experiments of the three saccharides was quantified using the developed method. It was found that SFD D-mannitol (68.99%) and SFD D-(+)-sucrose (66.62%) exhibited better delivered dose (total saccharide deposition in throat and all impactor stages) than SD D-mannitol (49.03%) and SD D-(+)-sucrose (57.70%) (p < 0.05). The developed ¹H qNMR methodology can be routinely used as an analytical method to assess pulmonary deposition in impaction experiments of saccharides employed as carriers in DPI formulations.

Effect of skimmed milk powder concentrations on the biological characteristics of microencapsulated Saccharomyces cerevisiae by vacuum-spray-freeze-drying

Lin Cao, Qinglian Xu, Yage Xing, Xunlian Guo, Wenxiu Li, Yimin Cai

Abstract

The effects of skimmed milk powder (SMP) concentrations on the biological characteristics of microencapsulated Saccharomyces cerevisiae prepared by employing vacuum-spray-freeze-drying (VSFD) technology are evaluated. Results show that the live bacteria rate of S. cerevisiae embedded with 11% SMP is 76.36%, which is higher than that in other concentrations. Scanning electron microscope (SEM) photographs indicate that the SMP concentration exhibits a significant impact on the surface morphology of microencapsulation. Moreover, microparticles with SMP at the concentration of 11% provide the highest stability levels in both high and low temperature conditions. Cell counts in the microparticles with 11% SMP show a reduction of 3.9 (60 °C, 20 min) log CFU mL⁻¹, 3.13 (50 °C, 20 min) log CFU mL⁻¹, 0.23 (40 °C, 20 min) log CFU mL⁻¹, 2.74 (4 °C, week) and 0.72 (10 °C, week) log CFU mL⁻¹, respectively, which are all lower than that of powders with 3% SMP. Furthermore, the best-quality icewine exhibiting the typical features of a fresh fragrance and a delicate taste is used for the in vivo fermentation process. Fermentation is initialized by the microencapsulated cells with 11% SMP. These results indicate that the complex materials containing an SMP concentration of 11% as a carrier can be considered as a better choice for improving the stability and survival rate of S. cerevisiae.

Spray freeze drying: Emerging applications in drug delivery

D.A. Vishali, J. Monisha, S.K. Sivakamasundari, J.A. Moses, C. Anandharamakrishnan

Abstract

Spray freeze drying is relatively a recent drying technique involving heterogeneous set of steps which includes droplet formation, freezing, and sublimation. It has proven benefits over other drying methods in terms of producing products with improved structural integrity, superior quality, and better shelf stability. With such merits, spray freeze drying has found numerous applications in the field of drug delivery. Spray freeze drying yields particles of sizes and densities that show higher stability in the lungs, nasal mucosa, intestine, and skin, as compared to other drying technologies. These particles also possess the vital trait of sustained release and specificity through various delivery routes as compared to conventional drying techniques. This drives the market for commercialization of spray freeze dried drugs. The focus of this paper is on manufacturing approaches of spray freeze dried powders, with emphasis on its application in drug delivery systems. An overview of other applications of spray freeze drying is also presented.

Keywords

Spray freeze drying, Drug delivery, Sustained release, Improved quality, Shelf stability

Bulk Dynamic Spray Freeze-Drying Part 2: Model-Based Parametric Study for Spray-Freezing Process Characterization

Israel B. Sebastião, Bakul Bhatnagar, Serguei Tchessalov, Satoshi Ohtake, Matthias Plitzko, Bernhard Luy, Alina Alexeenko

Abstract

Spray freeze-drying is an evolving technology that combines the benefits of spray-drying and conventional lyophilization techniques to produce drug substance and drug product as free-flowing powders. The high surface-to-volume ratio associated to the submillimeter spray-frozen particles contributes to shorter drying and reconstitution times. The formation of frozen particles is the most critical part of this dehydration technique because it defines the properties of final product. Based on a previously proposed and validated model, the current goal is to understand the role of various controllable parameters in the spray-freezing process. More specifically, given a set of spraying conditions, the model is used to predict the minimum distance required to cool and freeze the droplets below a temperature that prevents coalescence and product agglomeration. A parametric study is carried out to map the operational limit conditions of the actual spray-freezing column apparatus under consideration. For the spray freeze-drying conditions of interest, model simulations indicate that convection contributes to at least 80% of the total droplet heat transfer and, consequently, that freezing column gas temperature and droplet diameter are the most important process parameters affecting the freezing distance.

Keywords

spray freeze-drying, sucrose, quality by design (QBD), lyophilization, freeze-drying, mathematical model(s)

Bulk Dynamic Spray Freeze-Drying Part 1: Modeling of Droplet Cooling and Phase Change

Israel B. Sebastião, Bakul Bhatnagar, Serguei Tchessalov, Satoshi Ohtake, Matthias Plitzko, Bernhard Luy, Alina Alexeenko

Abstract

In spray freeze-drying (SFD), the solution is typically dispersed into a gaseous cold environment producing frozen microparticles that are subsequently dried via sublimation. This technology can potentially manufacture bulk lyophilized drugs at higher rates compared with conventional freeze-drying in trays and vials because small frozen particles provide larger surface area available for sublimation. Although drying in SFD still has to meet the material collapse temperature requirements, the final characteristics of the respective products are mainly controlled by the spray-freezing dynamics. In this context, the main goal of this work is to present a single droplet spray-freezing model and validate it with previously published simulations and experimental data. For the investigated conditions, the droplet temperature evolutions predicted by the model agree with experiments within an error of ±10%. The proposed engineering-level modeling framework is intended to assist future development of efficient SFD processes and support scale up from laboratory to commercial scale equipment.

Keywords

spray freeze-drying, sucrose, quality by design (QBD), lyophilization, freeze-drying, mathematical model(s)

Micro and nano encapsulation, retention and controlled release of flavor and aroma compounds: A critical review

Md. Saifullah, Mohammad Rezaul Islam Shishir, Rayhana Ferdowsi, Md Ramim Tanver Rahman, Quan Van Vuong

Abstract

Background

Encapsulation of flavor and aroma in an appropriate form is an important concern for a long time. Encapsulation is the most successful way not only to preserve or mask flavor and aroma compounds but also to enhance their thermal and oxidative stability, overcome the limitations of high volatility, to control the fast release and improve the poor bioavailability, as well as to increase their application in food systems.
Scope and approach

This review focuses on the recent advances in micro and nano-encapsulation of flavor and aroma compounds. We comprehensively highlight the suitability of micro and nano-encapsulation approaches for the retention of flavor and aroma including emerging techniques, new formulations and novel encapsulate systems, to illustrate the flavor release mechanisms, and depict the industrial applications of encapsulated flavor and aroma compounds.
Key findings and conclusions

Nano-encapsulation has attracted more attention compared to microencapsulation; showing better encapsulation efficiency, enhanced stability of capsule, and more control on flavor release. Recently, spray chilling and spray freeze drying as an alternative to spray drying, can overcome the thermal loss of flavor, promising for the microencapsulation of heat sensitive compounds. In contrast, electro-spraying and electro-spinning in combination with the emulsion or coaxial approach are novel and promising for the nano-encapsulation of flavor and aroma compounds. The combination of carrier materials, e.g. polysaccharide with protein can improve the encapsulation efficiency and capsule functionality. However, application of micro and nano-encapsulates into different food and gastrointestinal systems needs to be explored in order to expose their release mechanisms and application efficiency.

Keywords

Flavor, Aroma, Microencapsulation, Nano-encapsulation, Stability, Industrial application, Food

Porous and highly dispersible voriconazole dry powders produced by spray freeze drying for pulmonary delivery with efficient lung deposition

Liao Q, Yip L, Chow MYT, Chow SF, Chan HK, Kwok PCL, Lam JKW

Abstract

Systemic administration of antifungal agents for the treatment of pulmonary aspergillosis is limited by the poor lung deposition and severe adverse effects. In contrast, pulmonary delivery allows a higher amount of drug to be delivered directly to the infection site and therefore a lower dose is required. This study aimed to develop porous and inhalable voriconazole dry powder with good lung deposition by spray freeze drying (SFD), using tert-butyl alcohol (TBA) as a co-solvent. A three-factor two-level full factorial design approach was used to investigate the effect of total solute concentration, drug content and co-solvent composition on the aerosol performance of the SFD powder. In general, the SFD voriconazole powder exhibited porous and spherical structure, and displayed crystalline characteristics. The analysis of factorial design indicated that voriconazole content was the most significant variable that could influence the aerosol performance of the SFD powders. The formulations that contained a high voriconazole content (40% w/w) and high TBA concentration in the feed solution (70% v/v) displayed the highest fine particle fraction of over 40% in the Next Generation Impactor study in which the powder was dispersed with a Breezhaler® at 100 L/min. In addition, the fine particle dose of the SFD powder showed a faster dissolution rate when compared to the unformulated voriconazole. Intratracheal administration of SFD voriconazole powder to mice resulted in a substantially higher drug concentration in the lungs when comparing to the group that received an equivalent dose of liquid voriconazole formulation intravenously, while a clinically relevant plasma drug concentration was maintained for at least two hours. Overall, an inhalable voriconazole dry powder formulation exhibiting good aerosol property and lung deposition was developed with clinical translation potential.

Keywords

Antifungal; Factorial design; Next generation impactor; Pulmonary delivery; Spray freeze drying; Voriconazole

Fabrication of homogenous pellets by freeze granulation of optimized TiO₂-Y₂O₃ suspensions

F. La Lumia, L. Ramond, C. Pagnoux, G. Bernard-Granger

Abstract

MOX fuels are used in nuclear reactors. To ensure the manufacture of MOX, wet processes are investigated. Freeze granulation of water-based powder suspension seems a promising way to yield homogenous and easy-to-press UO₂-PuO₂ granules. These granules are expected to form dense and homogenous pellets by uniaxial pressing. Granules and pellet properties are affected by suspension formulation and atomization conditions. Therefore, these conditions must be studied and optimized to produce granules with good processability and thus MOX pellets with compliant density, homogeneity and absence of defects. In this scope, key properties of water-based suspensions of UO₂ and PuO₂ surrogate powders, TiO₂ and Y₂O₃ respectively, were firstly studied to assess their suitability for the freeze granulation process. These properties were compared to those of UO₂ and PuO₂ suspensions to verify and confirm the correctness in the choice of surrogate powders. Then, the freeze granulation process itself was investigated focusing on TiO₂-Y₂O₃ suspensions.

Keywords

Suspension, Granulation, Freeze drying, UO₂, PuO₂

Supporting data and methods for the multi-scale modelling of freeze-drying of microparticles in packed-beds

Luigi C. Capozzi, Antonello A. Barresi, Roberto Pisano

Abstract

A multi-scale approach can be used to simulate the drying behavior of microparticles in packed-bed. Data outcomes from discrete element method (DEM) and computational fluid dynamics (CFD) simulations can be used to estimate some relevant product characteristics, such as the porosity, tortuosity, voids in the bed and permeability which are required by the multi scale model. Data from DEM simulations are presented, with a particular focus on the influence of the model parameters, packing characteristics and inhomogeneities (wall effect and particles segregation); computational costs and scala bility are also considered. Data on the properties of packings as modeled at the macroscale are presented with regard to the thermal conductivity of gases in the Knudsen regime and effective properties of packed-beds modeled as a pseudo-homogeneous medium. A mathematical model of the freeze-drying of single microparticles and its outcomes are first presented. Data outcomes from the mathematical model at the macroscale concerning the drying behavior of microparticles in a tray and in a vial are then presented and can be used for process design. Some further data, with detailed interpretation and discussion of the presented data, can be found in the related research data article, “A multi-scale computational framework for modelling the freeze-drying of microparticles in packed-beds” (Capozzi et al., 2019).

Keywords

Freeze-drying, Packed-bed, Lyophilization, DEM, CFD, Spray-freeze drying