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Numerical analysis of in-flight freezing droplets: Application to novel particle engineering technology

Andrew Tait, Jonathan G.M. Lee, Bruce R.Williams, Gary A. Montague

Abstract

The freezing of a stream of free-falling monodispersed droplets was simulated through the development of numerical models in this work. Prediction of the freezing time and temperature transition of a single droplet is beneficial for optimisation of novel continuous spray freeze drying (cSFD) processes. Estimations of the vertical free-falling distance of the droplets in a slip stream and predictions of the chances of droplet coalescence greatly enhance process understanding and can be leveraged to direct equipment design and process development. A design space of droplet diameters in the range from 100 μm to 400 μm and ambient temperatures from −120 °C to −40 °C was explored. The rate of supercooling within the design space was predicted to range from 48 to 830 °C s⁻¹ depending on the ambient temperature and droplet size. A comparison of the vertical free-falling distances of solitary droplets and streams of droplets at different temperatures showed that the terminal velocity of a vertically falling stream of droplets is always in excess of the terminal velocity of a solitary droplet of the same size. A difference of 1.35 m was predicted for the free-falling distance of a 400 μm droplet compared to a stream of droplets at −42 °C. A comparison between flow rates for consecutively generated 100 μm droplets showed that droplet coalescence was predicted at 0.05 Lh⁻¹, whilst at 0.02 Lh⁻¹ a separation distance of 23 μm was maintained thus preventing coalescence.

Keywords

Continuous spray freeze drying, Freeze drying, Lyophilisation, Freezing transitions, Freezing, Numerical modelling, Spray freezing

Fabrication of three-dimensional TKX-50 network-like nanostructures by liquid nitrogen-assisted spray freeze-drying method

Xiong Cao, Yiping Shang, Kejuan Meng, Guodong Yue, Liyuan Yang, Yang Liu, Peng Deng, Lishuang Hu

Abstract

Design and fabrication of micro- and nanostructures for energetic materials have attracted more attention recently to improve safety properties and enhance detonation performance. Exploring and developing dihydroxylammonium 5,5′-bistetrazole-1,1′-diolate (TKX-50) with unique microstructures, an emerging high-energy-density material with superior comprehensive properties, is of great significance for the potential applications. In this work, we reported that three-dimensional (3D) TKX-50 network-like nanostructures were designed and fabricated successfully via the liquid nitrogen-assisted spray freeze-drying method. Characterization results suggested 3D TKX-50 network-like nanostructures were constructed by self-assembly of small nanoparticles. Furthermore, a nucleation-and-growth self-assembly formation mechanism of the network-like nanostructures depended on the different concentrations of the aqueous solution of TKX-50 was proposed in detail based on the experimental results. More interestingly, thermal analysis results demonstrated these novel 3D TKX-50 network-like nanostructures are much easier to be activated and have a lower decomposition temperature than the raw material, due to decrease in particle sizes, and the impact sensitivity of 3D TKX-50 network-like nanostructures become more sensitive than that of raw TKX-50. Their friction sensitivity of as-prepared samples is similar to the raw materials. Therefore, this work could provide a new prospect for fabrication and application of TKX-50 nanostructures.

Can spray freeze-drying improve the re-dispersion of crystalline nanoparticles of pure naproxen?

Veronika Braig, Christoph Konnerth, Wolfgang Peukert, Geoffrey Lee

Abstract

Spray freeze drying (SFD) was used to prepare re-dispersible powders of crystalline, pure-drug nanodispersions of naproxen in lactose and stabilized with hydroxypropyl cellulose. The particle size of the rehydrated powders was determined using static light scattering/Mie analysis. The nanoparticles present in the SFD powders were aggregated but could be dispersed on re-dispersion with water and stirring either with or without additional ultrasonic treatment. The disaggregation of the SFD nanoparticles was superior to that reported in the literature for spray dried nanoparticles of the same composition. It appears that the moderately-rapid freezing of the large spray droplets in LN2 during SFD produces less aggregation than does evaporative drying of the much smaller droplets during spray drying. Re-dispersion was also found to depend strongly on the pH of the original nanodispersion. The solubility of this weak acid is greater at higher pH which resulted in formation of a dissolved fraction of drug in the nanodispersions during media milling. After SFD, the dissolved naproxen fraction formed an amorphous solid which re-dissolves on re-hydration whereas the crystalline nanoparticles disaggregate.

Keywords

Nanoparticles, Poorly soluble drug, Spray freeze drying, Re-dispersion, Particle size

Oral immunization with bacteriophage MS2-L2 VLPs protects against oral and genital infection with multiple HPV types associated with head & neck cancers and cervical cancer

Lukai Zhai, Rashi Yadav, Nitesh K. Kunda, Dana Anderson, Elizabeth Bruckner, Elliott K. Miller, Rupsa Basu, Pavan Muttil, Ebenezer Tumban

Abstract

Human papillomaviruses (HPVs) are the most common sexually transmitted infections. HPVs are transmitted through anogenital sex or oral sex. Anogenital transmission/infection is associated with anogenital cancers and genital warts while oral transmission/infection is associated with head and neck cancers (HNCs) including recurrent respiratory papillomatosis. Current HPV vaccines protect against HPV types associated with ∼90% of cervical cancers and are expected to protect against a percentage of HNCs. However, only a few studies have assessed the efficacy of current vaccines against oral HPV infections. We had previously developed a mixed MS2-L2 candidate HPV vaccine based on bacteriophage MS2 virus-like particles (VLPs). The mixed MS2-L2 VLPs consisted of a mixture of two MS2-L2 VLPs displaying: i) a concatemer of L2 peptide (epitope 20–31) from HPV31 & L2 peptide (epitope 17–31) from HPV16 and ii) a consensus L2 peptide representing epitope 69–86. The mixed MS2-L2 VLPs neutralized/protected mice against six HPV types associated with ∼87% of cervical cancer. Here, we show that the mixed MS2-L2 VLPs can protect mice against additional HPV types; at the genital region, the VLPs protect against HPV53, 56, 11 and at the oral region, the VLPs protect against HPV16, 35, 39, 52, and 58. Thus, mixed MS2-L2 VLPs protect against eleven oncogenic HPV types associated with ∼95% of cervical cancer. The VLPs also have the potential to protect, orally, against the same oncogenic HPVs, associated with ∼99% of HNCs, including HPV11, which is associated with up to 32% of recurrent respiratory papillomatosis. Moreover, mixed MS2-L2 VLPs are thermostable at room temperature for up to 60 days after spray-freeze drying and they are protective against oral HPV infection.

Keywords

HPV vaccine, Bacteriophage MS2-L2 VLPs, Buccal immunization, Gardasil-9, Mucosal adjuvants, Thermostable vaccine

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)