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Solid state of inhalable high dose powders

Bishal Raj Adhikari, Keith C. Gordon, Shyamal C. Das

Abstract

High dose inhaled powders have received increased attention for treating lung infections. These powders can be prepared using techniques such as spray drying, spray-freeze drying, crystallization, and milling. The selected preparation technique is known to influence the solid state of the powders, which in turn can potentially modulate aerosolization and aerosolization stability. This review focuses on how and to what extent the change in solid state of high dose powders can influence aerosolization. It also discusses the commonly used solid state characterization techniques and the application of potential strategies to improve the physical and chemical stability of the amorphous powders for high dose delivery.

Keywords

Aerosolization, Amorphous, Antibiotic, Chemical stability, Co-amorphous, Crystalline, Dry powder inhaler, Lung infection, Pulmonary drug delivery

Effect of spray freeze drying on the structural modification and rehydration characteristics of micellar casein powders

Jinbo Ren, Minjie Liao, Lingjun Ma, Fang Chen, Xiaojun Liao, Xiaosong Hu, Song Miao, John Fitzpatrick, Junfu Ji

Abstract

Micellar casein (MC) is usually spray-dried into powder form for transportation and storage. However, the micellar structure maintained by colloidal calcium phosphate (CCP) and hydrophobic forces leads to poor rehydration ability of MC powders, which limits its potential applications. Here, spray freeze drying (SFD) with controlled droplet size was used to produce MC powders. Their effects on the structure of MC and the subsequent rehydration characteristics including wetting, dispersion and dissolution were investigated. The results showed SFD powders obtained from smaller droplet size caused more than 50% of serum Ca²⁺ and PO₄³⁻ to release from the micellar structure. These powder particles exhibited extremely high porosity (92%) and spherical morphology, which thus greatly shortened their wetting time. Furthermore, the smallest droplets during SFD were believed to produce the MC powders with the quickest dispersion and best solubility, as over 80% of the solids could be completely dissolved in just 15 min.

Keywords

Micellar casein (MC), Spray freeze drying (SFD), Droplet size, Rehydration behaviors, Colloidal calcium phosphate (CCP)

Ointment containing spray freeze-dried metronidazole effective against rosacea

Klára Szentmihályi, Krisztina Móricz, Gábor Gigler, Zoltán May, Eszter Bódis, Judit Tóth, Mónika Bakonyi, Szilvia Klébert, Tivadar Feczkó, Zoltán Károly

Abstract

Rosacea is a chronic, inflammatory skin disease that affects about 10% of the population. Metronidazole-containing ointments are typically recommended for the daily treatment of symptoms. For increasing bioavailability and effectiveness, it is needed to reduce the particle size. Therefore, micronized metronidazole was prepared by spray freeze-drying (SFD) method, then its most important features were examined such as morphology, crystallinity and particle size. The anti-inflammatory effect of the as-prepared agent was tested on a mouse model of rosacea for effectiveness against oedema and redness of the ears, and it was compared to a reference cream.

Metronidazole size was reduced successfully by SFD to 2.7 μm from 162.6 μm. The material was non-porous and preserved its crystalline state. The spray freeze-dried metronidazole mixed into ointment was effective against oedema and ear-redness. The ointment reduced oedema in five times lower doses (2 × 0.04 mg metronidazole) and the ear-redness in half dose (2 × 0.2 mg metronidazole) than the cream containing reference metronidazole (2 × 0.2 mg and 2 × 0.4 mg metronidazole, respectively). In conclusion, the SFD technique is an adequate and gentle procedure for reducing the size of metronidazole, which is highly effective in rosacea.

Keywords

Rosacea, Metronidazole, Spray freeze-drying, Particle size, Mouse, Oedema

Microencapsulation of High-Content Actives Using Biodegradable Silk Materials

Muchun Liu, Pierre-Eric Millard, Henning Urch, Ophelie Zeyons, Douglas Findley, Rupert Konradi, Benedetto Marelli

Abstract

There is a compelling need across several industries to substitute non-degradable, intentionally added microplastics with biodegradable alternatives. Nonetheless, stringent performance criteria in actives’ controlled release and manufacturing at scale of emerging materials hinder the replacement of polymers used for microplastics fabrication with circular ones. Here, the authors demonstrate that active microencapsulation in a structural protein such as silk fibroin can be achieved by modulating protein protonation and chain relaxation at the point of material assembly. Silk fibroin micelles’ size is tuned from several to hundreds of nanometers, enabling the manufac-turing—by retrofitting spray drying and spray freeze drying techniques—of micro capsules with tunable morphology and structure, that is, hollow-spongy, hollow-smooth, hollow crumpled matrices, and hollow crumpled multi-domain. Microcapsules degradation kinetics and sustained release of soluble and insoluble payloads typically used in cosmetic and agriculture applications are controlled by modulating fibroin’s beta-sheet content from 20% to near 40%. Ultraviolet-visible studies indicate that burst release of a commonly used herbicide (i.e., saflufenacil) significantly decreases from 25% to 0.8% via silk fibroin microencapsulation. As a proof-of-concept for agrochemicals applications, a 6-day greenhouse trial demonstrates that saflufenacil delivered on corn plants via silk microcapsules reduces crop injury when compared to the non-encapsulated version.

Keywords

Agrochemicals, controlled release, microcapsules, microplastics, vitamin c, silk

Spray freeze drying of dairy products: Effect of formulation on dispersibility

Alberto Baldelli, Hale Oguzlu, Diana Yumeng Liang, Alison Subiantoro, Meng Wai Woo, Anubhav Pratap-Singh

Abstract

Milk powders are commonly produced by using the technique of spray drying. In this work, we propose the use of spray freeze drying technology to improve the re-dispersibility of milk powders in aqueous systems. We explore how formulation can influence the re-dispersibility of dairy products. Due to higher porosity and lower tapped density, milk powder produced by spray freeze drying showed an average 15% percentage higher re-dispersibility than spray-dried powders after only 20 s of agitation. Higher fat percentages and the presence of an additive, maltodextrin, worsened the re-dispersibility of spray freeze-dried dairy powders. An increase in 6% of fat percentage decreased the percentage of redissolved powder by 30%. Similarly, an increase in 5% maltodextrin weight resulted in a 5% lower re-dispersibility. The results of this study shall be fundamental in providing future guidelines for the use of spray freeze drying technique for producing milk and other dairy powders with high quality and nutrient retention.

Keywords

Spray freeze drying, Particle formation, Milk powder, Redispersibility

Spray Freezing Coating on the Carrier Particles for Powder Preparation

Qing Xu, Ruixin Wang, Fan Zhang, Ruifang Wang, Long Wu, Bo Lin

Abstract

Carrier particle spray freeze-drying is a new technology with high added value for thermosensitive powder spray freeze-drying. The technology includes the following steps: atomization, coating, freezing, and drying. Due to the action of carrier particles, the condensation of frozen droplets in the conventional spray freeze-drying process is overcome. However, there are many influencing factors involved in the process of freezing coating. The mechanism of the complex droplet collision freezing process still needs to be studied. In this paper, from the perspective of spray freezing coating after atomized droplets collide with low-temperature carrier particles, the coating process and freezing process of single droplets impacting the sphere are analyzed microscopically. The freezing coating processes of static and dynamic carrier particles are reviewed. Moreover, the surface evaluation of powder and equipment development for creating powder products is discussed.

Keywords

spray freezing coating, carrier particles, drying, powder characteristics, integrated equipment

Debate: Nanoparticles – a blessing or a curse?

Hans Leuenberger

Abstract

This chapter was inspired by Ilya Prigogine (Nobel laureate 1977) and by six axioms derived1 earlier, such as A1, Far from equilibrium conditions, favoring transformations from disorder into order leading to the creation of life, and A5 and 6, The evolutionary process uses all existing physical laws of the present standard cosmological model and beyond to find a niche for a successful survival of the biological system being complemented by A7, Nature’s principle of self-similarity, A8, Bionic inspired philosophical solutions, and most important by A9, The human society is a living biological system. Thus, life of a society is governed by the same laws as for a human being. From a global point of view, society’s life depends on system relevant organs such as brain (pool of scientists), heart (system of banks) pumping blood (money) to the muscles (industry), to the lungs (combustion engines), and to the digestive system (recycling industry). As in case of a human being, the society’s health, life, and death depend on framework conditions such as technologies improving quality of life. For this reason, an innovative spray-freeze drying process is presented, allowing manufacturing nanocomposite pellets for nanomedicine. The chapter shows that this technological solution based on scientific integrity is not sufficient for securing the public acceptance. It is necessary to respect religion and ethics, business ethics, legal framework, and to complement the nine axioms by A10, Common denominator of all Religions = Ethical Codex, by A11, Common denominator of Marketing and Politics = Trustworthy Communication and by A12, Common denominator of all Trustworthy Sciences = Scientific Integrity. In conclusion, the chapter defines rigorous prerequisites for public acceptance of nanotechnology and beyond, such as science diplomacy for the survival of mankind.

Spray freeze drying for protein encapsulation: Impact of the formulation to morphology and stability

Alberto Baldelli, Yigong Guo, Hui Xin Ong, Aylin Cidem, Anika Singh, Daniela Traini, Anubhav Pratap-Singh

Abstract

Proteins, the building blocks of life, are increasingly being used as therapeutics for treating several diseases. Yet, there are challenges in the delivery of highly labile materials like proteins, which is often circumvented with the help of encapsulation for targeted delivery and enhanced stability. Spray drying technology has recently been employed for encapsulation due to its’ low cost and scale-up capabilities, yet the high temperatures of drying air makes the technology unsuitable for proteins. More recently, spray freeze drying has evolved as an emerging technology that combines spray drying with freeze drying by using low temperatures, and is thus suitable for maintaining the stability of proteins. This study investigates the correlation between formulation parameters and the properties of protein encapsulated microparticles prepared by spray freeze drying. Morphology was investigated using microscopic methods, and protein stability was examined using infrared and mass spectrometry. By using bovine serum albumin, we verify that increasing the total weight to 15 mg/ml results in microencapsulates with a projected area equivalent diameter of 100 µm larger. We demonstrate that some types of amino acids are essential for shell formation; however, glutamine generates an increase in dimer areas in mass spectra of 5.5. D-Mannitol is the suggested carrier for high encapsulation efficiency (above 90 %). The formulation containing polyvinylpyrrolidone, mannitol, and leucine (at 6, 9, and 2 mg/ml, respectively) produced the lowest reduction in the stability of a few types of proteins; deconvoluted infrared peaks show a difference of less than 2% compared to the free protein. Understanding the spray freeze drying phenomenon for protein encapsulation would allow the control over morphological and chemical properties of microparticles containing active proteins.

Keywords

Spray freeze drying, encapsulation, proteins, particle formation

Modulating the Pore Architecture of Ice-Templated Dextran Microparticles Using Molecular Weight and Concentration

Tero Kämäräinen, Kazunori Kadota, Jun Yee Tse, Hiromasa Uchiyama, Shinya Yamanaka, Yuichi Tozuka

Abstract

Spray freeze drying (SFD) is an ice templating method used to produce highly porous particles with complex pore architectures governed by ice nucleation and growth. SFD particles have been advanced as drug carrier systems, but the quantitative description of the morphology formation in the SFD process is still challenging. Here, the pore space dimensions of SFD particles prepared from aqueous dextran solutions of varying molecular weights (40-200 kDa) and concentrations (5-20%) are analyzed using scanning electron microscopy. Coexisting morphologies composed of cellular and dendritic motifs are obtained, which are attributed to variations in the ice growth mechanism determined by the SFD system and modulation of these mechanisms by given precursor solution properties leading to changes in their pore dimensions. Particles with low-aspect ratio cellular pores showing variation of around 0.5-1 μm in diameter with precursor composition but roughly constant with particle diameter are ascribed to a rapid growth regime with high nucleation site density. Image analysis suggests that the pore volume decreases with dextran solid content. Dendritic pores (≈2-20 μm in diameter) with often a central cellular region are identified with surface nucleation and growth followed by a slower growth regime, leading to the overall dendrite surface area scaling approximately linearly with the particle diameter. The dendrite lamellar spacing depends on the concentration according to an inverse power law but is not significantly influenced by molecular weight. Particles with highly elongated cellular pores without lamellar formation show intermediate pore dimensions between the above two limiting morphological types. Analysis of variance and post hoc tests indicate that dextran concentration is the most significant factor in affecting the pore dimensions. The SFD dextran particles herein described could find use in pulmonary drug delivery due to their high porosity and biocompatibility of the matrix material.

Spray freeze-drying for inhalation application: process and formulation variables

Mostafa Rostamnezhad, Hossein Jafari, Farzad Moradikhah, Sara Bahrainian, Homa Faghihi, Reza Khalvati, Reza Bafkary, Alireza Vatanara

Abstract

High porous particles with specific aerodynamic properties were processed by the spray freeze-drying (SFD) method. Comprehensive knowledge about all aspects of the SFD method is required for particle engineering of various pharmaceutical products with good flow properties. In this review, different types of the SFD method, the most frequently employed excipients, properties of particles prepared by this method, and most recent approaches concerning SFD are summarized. Generally, this technique can prepare spherical-shaped particles with a highly porous interior structure, responsible for the very low density of powders. Increasing the solubility of spray freeze-dried formulations achieves the desired efficacy. Also, due to the high efficiency of SFD, by determining the different features of this method and optimizing the process by model-based studies, desirable results for various inhaled products can be achieved and significant progress can be made in the field of pulmonary drug delivery.

Keywords

Spray freeze-drying, Aerodynamic properties, Particle engineering, Pulmonary drug delivery, Inhaled products