Method and system for thermal stabilization of pharmaceutical formulations containing enveloped and nonenveloped virus particles

Abstract

Disclosed are a method and system for thermal stabilization of pharmaceutical formulations containing enveloped and nonenveloped viruses. The disclosed method of Rapid Room Temperature Aerosol Dehydration (RTAD) provides a scalable system for continuous dehydration of liquid pharmaceutical and biopharmaceutical formulations that provides thermal stabilization of biological drugs by converting liquid drugs into powder form, enabling their transportation, storage and handling at room temperature. The disclosed process can generate sprays / aerosols with droplets that are 100x smaller (0.2-20 μm) than existing spray drying technologies and perform dehydration, without applying heat, which mitigates the risk of damage of thermolabile biologicals and provides a significant reduction in energy requirements. The technology has demonstrated superiority of the system over traditional spray drying and freeze drying with respect to energy consumption, biological activity, scalability, powder solubility, particle size and size uniformity, and high-quality of produced inhalable and reconstitutable biologic formulations.

Description

METHOD AND SYSTEM FOR THERMAL STABILIZATION OF PHARMACEUTICAL FORMULATIONS CONTAINING ENVELOPED AND NONENVELOPED VIRUS PARTICLESCROSS-REFERENCED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 632,604, filed on April 11, 2024, the entire contents of which are incorporated herein by reference.STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under Grant No. 2304461 awarded by the National Science Foundation and Grant No. TR004571 awarded by the National Institu tes of Health. The government has certain rights in the invention .BACKGROUND

[0003] This section is intended to introduce the reader io various aspects of art, which may be related to various aspects of the present invention that are described and / or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a beter understanding of the various aspects of the present invention. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art .

[0004] Various techniques exist for drying particles and droplets. However, conventional techniques are typically incompatible with desired compounds - for example, if a DNA or RN A material is desired io be encapsulated, the product cannot be exposed to a very- high shear rate, or extremes of temperature. Therefore, there is a need to develop systems for drying particles at lower temperatures, which can be extremely challenging for some conventional techniques to provide.SUMMARY

[0005] In some aspects, the techniques described herein relate to a method for rapid room-temperature dehydration (RTAD), including: atomizing a dispersion of a material in a liquid, suspension or combination thereof using a nozzle device, thereby forming an aerosol containing a plurality of atomized particles, wherein the material includes a viral particle; mixing and dehydrating the plurality of atomized particles using a drying gas at a temperatureof 0-45 °C so as to sufficiently dry the plurality of atomized particles, thereby forming an aerosol of dry particles; and coating the atomized particles with an excipient or adjuvant such that the aerosol of dry particles includes the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the dry particles as measured relative to a control particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, wherein less than 10% of the material sustains thermal damage, and wherein less than 10% of the dry’ particles in the aerosol of dry particles form aggregates.(0006] In some aspects, the techniques described herein relate to a method, wherein the nozzle device includes at least three channels including an inner channel, at least one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel, the at least one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular channel and having a gap width sufficient so as to atomize a liquid, suspension or combination thereof flowing through the at least one middle annular channel upon flow of one or more gases through at least the inner channel and the at least one outer annular channel(0007] In some aspects, the techniques described herein relate to a method, wherein the material includes a biologic material,(0008] Io some aspects, the techniques described herein relate to a method, wherein the material includes a virus.

[0009] In some aspects, the techniques described herein relate to a method, wherein the material includes a vaccine, an enveloped virus or a non-enveloped virus.

[0010] In some aspects, the techniques described herein relate to a method, wherein a surface tension, of the dispersion is less than, water.

[0011] In some aspects, the techniques described herein relate to a method, wherein a flow rate of the dispersion from the nozzle device is 0.1 mL- 10 L / min,

[0012] In some aspects, the techniques described herein relate to a method, wherein a median size of the plurality Of atomized particles i s less than 50 pm.

[9013] In some aspects, the techniques described herein relate to a method, wherein a median size of toe plurality of atomized particles is less than 20 pin.

[0014] In some aspects, the techniques described herein relate to a method, wherein a median size of the plurality of atomized particles is less than 10 pm.

[0015] In some aspects, the techniques described herein relate to a method, wherein the drying gas includes nitrogen, helium, air, or a combination thereof.

[0016] In some aspects, the techniques described herein relate to a method, wherein the drying gas is provided at a rate of 5-200 standard liters / min.

[0017] In some aspects, the techniques described herein relate to a method, wherein the dehydrating is performed at a negative pressure.

[0018] In some aspects, the techniques described herein relate to a method, wherein the temperature is provided between about 15 °C and about 35 °C,

[0019] In some aspects, the techniques described herein relate to a method, further including recovering particles after mixing and dehydrating.

[0020] hi some aspects, the techniques described herein relate to a method, wherein a membrane filter is utilized to recover panicles.

[0021] hi some aspects, the techniques described herein relate to a method, wherein a cyclone separator is utilized to recover particles.

[0022] In some aspects, the techniques described herein relate to a method, further including analyzing the recovered particles.

[0023] In some aspects, the techniques described herein relate to a method, wherein analyzing the recovered particles includes confirming biological activity of the recovered particles.

[0024] In some aspects, the techniques described herein relate to a method, wherein FT-IR is used to analyze the recovered particles.

[0025] In some aspects, the techniques described herein relate to a method, further including storing the recovered particles at a temperature Ts, where 0°C < Ts < 30’'C for a period of time.

[0026] In some aspects, the techniques described herein relate to a method, wherein the period of time is at least 2 months.

[0027] hi some aspects, the techniques described herein relate to a method, further including reconstituting the recovered particles after storage.

[0028] In some aspects, the techniques described herein relate to a method, wherein the excipient or adjuvant is in an amount sufficient to ex tend a shelf life of the dry particles.

[0029] In some aspects, the techniques described herein relate to a method, wherein the excipient or adjuvant is in an amount sufficient to control a release of the material in a bodily fluid.

[0030] In some aspects, the techniques described herein relate to a method, wherein the excipient or adjuvant is in an amount sufficient to control a release of the material at a desired pH,

[0031] In some aspects, the techniques described herein relate to a method, further including delivering the aerosol of dry particles through a nebulizer, an inhaler, a nasal spray, or a microneedle patch.

[0032] In some aspects, the techniques described herein relate to a method, further including reconstituting the dry particles into a pharmaceutically acceptable solvent.

[0033] In some aspects, the techniques described herein relate to a method, wherein less than 5% of the dry particles in the aerosol of dry particles form aggregates.

[0034] In some aspects, the techniques described herein relate to a spraying system, including: a nozzle device adapted to atomize a dispersion of amaterial in a liquid, suspension, or combination thereof to sufficiently form an aerosol containing a plurality of atomized particles, wherein the material includes a viral particle, wherein the nozzle device includes at least, three channels including an inner channel, at. least one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel, the at least one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular channel and having a gap width sufficient so as to atomize a liquid, suspension, or combination thereof flowing through the at least one middle annular channel upon flow of one or more gases through at least the inner channel and the at least one outer annular channel; and a drying chamber operatively connected to the nozzle device, the drying chamber adapted to apply a drying gas at a temperature of 0-45 °C so as to mix and dehydrate the plurality of atomized particles, thereby forming a dry particle aerosol ; wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosol includes the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the plurality of atomized particles as measured relative to a control particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle io generate an immune response of a host cell upon contact with the host cell, wherein less than 10% of the material sustains thermal damage, and wherein less than 10% of the dry particles in the aerosol of dry partic les form aggregates.(0035] In some aspects, the techniques described herein relate to a. spraying system, further including at least one flow controller, wherein the al least one flow controller isconfigured to control a flow rate Of the one or more gases through at least the inner channel and the at least one outer annular channel of the nozzle device.

[0036] In some aspects, the techniques described herein relate to a spraying system any one, further including at least one flow controller, wherein the at least one flow controller is configured to control a flow rate of one or more of the dispersion and the drying gas.

[0037] In some aspects, the techniques described herein relate to a spraying system, wherein the material includes a biologic material.

[0038] In some aspects, the techniques described herein relate to a spraying system, wherein the material includes a virus.

[0039] In some aspects, the techniques described herein relate to a spraying system, wherein the material includes a vaccine, an enveloped virus or a non-enveloped virus.

[0040] In some aspects, the techniques described herein relate to a spraying system, wherein a surface tension of the dispersion is less than water.

[0041] In some aspects, the techniques described herein relate to a spraying system, wherein a flow rate of the dispersion from the nozzle device is 0,1 mL-10 L / min.

[0042] In some aspects, the techniques described herein relate to a spraying system, wherein a median size of the plurality of atomized particles is less than 50 pm.

[0043] In some aspects, the techniques described herein relate to a spraying system, wherein a median size of the plurality of atomized particles is less than 20 gm.

[0044] In some aspects, the techniques described herein relate to a spraying system, wherein a median size of the pl urality of atomized particles is less than 10 gm,

[0045] In some aspects, the techniques described herein relate to a spraying system, wherein the drying gas includes nitrogen, helium, a ir, or a combination thereof

[0046] In some aspects, the techniques described herein relate to a spraying system, wherein the drying gas is provided at a rate of 5-200 standard liters / min.

[0047] In some aspects, the techniques described herein relate to a spraying system, wherein the temperature is provided between about 15 °C and about 35 ':'C.[0048[ in some aspects, the techniques described herein relate to a spraying system, further including recovering particles after mixing and dehydrating.

[0049] In some aspects, the techniques described herein relate to a spraying system, wherein the dryfog chamber includes a filter assembly, the filter assembly is being configured to recover particles.

[0050] ln some aspects, the techniques described herein relate to a spraying system, further including a cyclone separator downstream of the drying chamber, wherein the cyclone separator is configured to recover particles,

[0051] In some aspects, the techniques described herein relate to a spraying system, wherein one or more of the nozzle device or the drying chamber is adapted to be retrofitted io a second spraying system.

[0052] In some aspects, the techniques described herein relate to an aerosol composition including a plurality of dried atomized particles, wherein the plurality of dried atomized particles is formed from drying a liquid, suspension, or combination thereof including a dispersion of biological material at a temperature of 0-45 °C, wherein the biological material includes a viral particle, wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosol includes the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the plurality of atomized particles as measured relative to a control particle that, is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, wherein less than 10% of the biological material sustains thermal damage, and wherein less than 10% of the dried atomized particles form aggregates,

[0053] In some aspects, the techniques described herein relate to an aerosol composition, wherein the liquid, suspension, or combination thereof includes one or more active agents.

[0054] In some aspects, the techniques described herein relate to an aerosol composition, wherei n the liquid, suspension, or combination thereof includes plurality of solid particles having a size in a range of from 1 ran to I (XX) nm, from 1 nm to 80(1 nm, from 1 nm to 500 nm, from 1 nm to 300 nm, from 1 nm to 100 nm, from 100 nm to 1000 nm, from 100 nm to 800 nm, from 100 nm to 500 nm, from 100 nm to 300 nm, from 300 nm to 1000 nm, from 300 nm to 800 nm, from 300 nm to 500 nm, from 500 nm to 1000 nm, from 500 nm to 800 nm, or from 800 nm to 1000 nm.

[6055] in some aspects, the techniques described herein relate to an aerosol composition, wherein more than 99% of the plurality of dried atomized particles having median diameters less than 20 microns,

[0056] In some aspects, the techniques described herein relate to an aerosol composition, wherein the plurality of dried atomized particles include one or more active agents.

[0057] In some aspects, the techniques described herein relate to an aerosol composition, wherein the plurality of dried atomized particles retain at least 80% biological activity relative to the liquid, suspension, or combination thereof,

[0058] In some aspects, the techniques described herein relate to an aerosol composition, wherein the liquid, suspension, or combination thereof is non-Newtonian.

[0059] In some aspects, the techniques described herein relate to an aerosol composition, wherein the liquid, suspension, or combination thereof is Newtonian.

[0060] In some aspects, the techniques described herein relate to an aerosol composition, wherein the liquid, suspension, or combination thereof has an absolute viscosity greater than 100 cP.

[0061] In some aspects, the techniques described herein relate to an aerosol composition, wherein the liquid, suspension, or combination thereof forms a plurality of atomized particles prior to forming rhe plurality of dried atomized particles, wherein the plurality of atomized particles are in the form of droplets,

[0062] In some aspects, the techniques described herein relate to an aerosol composition, wherein the liquid, suspension, or combination thereof includes a suspension of an organic and / or inorganic material

[0063] In some aspects, the techniques described herein relate to an aerosol composition, wherein the liquid, suspension, or combination thereof includes a viscoelastic liquid.

[0064] In some aspects, the techniques described herein relate to an aerosol composition, wherein the liquid, suspension, or combination thereof includes at least one microorganism selected from at least one of a vaccine, an enveloped virus, a non-enveloped virus, or a combination thereof.

[0065] In some aspects, the techniques described herein relate to an aerosol composition, wherein at least 50% of the at least one microorganism retains biological activity.

[0066] In some aspects, the techniques described herein relate to an aerosolComposition, wherein the liquid, suspension, or Combination thereof includes a plurality of therapeutic agents selected from at least one of a virus, a virus vector, a non-viral vector, viral fragments, virus particles, virus-like particles, imaging agents, small molecules, or a combination thereof(0067] In some aspects, the techniques described herein relate to an aerosol composition, wherein the liquid, suspension, or combination thereof? includes a plurality ofvirus nanoparticles loaded with a plurality of therapeutic agents selected from at least one of: nucleic acids, proteins, peptides, genes, imaging agents, microorganisms, small molecules, or a combination thereof.

[0068] In some aspects, the techniques described herein relate to an aerosol composition, wherein a median size of the plurality of virus nanoparticles does not increase more than 25%,

[0069] In some aspects, the techniques described herein relate to an aerosol composition, wherein at least 50% of the plurality of therapeutic agents retain biological activity.

[0070] In some aspects, the techniques described herein relate to an aerosol composition, wherein less than 5% of tire dried atomized particles form aggregates.[0071 In some aspects, the techniques described herein relate to a composition for use in a spraying system, including: a liquid, suspension, or combination there 30, causes the liquid, suspension, or combination thereof to produce a plurality of dried atomized particles, wherein less titan 10% of the material sustains thermal damage, and whe rein less than 10% of the dried atomized particles form aggregates.

[0072] In some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof includes one or more active agents,

[0073] In some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof includes a plurality of solid particles having a size in a range of from I nm to 1000 nm, from 1 nm to 800 nm, from 1 nm to 500 nm, from I nm to 300 nm, from 1 nm to 100 nm, from 100 nm to 1000 nm, from 100 nm to 800 nm, from 100 nm to 500 nm, from 100 nm to 300 nm, from 300 nm to 1000 nm, from 300 nm to 800 nm, from 300 nm to 500 nm, from 500 nm to 1000 nm, from 500 nm to 800 nm, or from 800 nm to 1000 nm.

[0074] In some aspects, the techniques described herein relate to a composition, wherein more than 80% of the plurality of dried atomized particles having median diameters less than 5 microns.

[0075] In some aspects, the techniques described herein relate to a composition, wherein the plural tty of dried atomized particles includes one or more active agents.

[0076] In some aspects, the techniques described herein relate to a composition, wherein the plurality of dried atomized particles retain at least 80% biological activity relative to the liquid, suspension, or combination thereof.

[0077] fa some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof is .non-Newtonian.

[0078] hi some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof is Newtonian.[0079| In some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof has an absolute viscosity greater than 100 cP.

[0080] fa some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof' forms a plurality of atomized particles prior to forming the plurality of dried atomized particles, wherein the plurality of atomized particles are in the form of droplets,

[0081] In some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof includes a suspension of an organic and / or inorganic material.

[0082] In some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof includes a viscoelastic l iquid.

[0083] fa some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof includes at least one microorganism selected from at least one of: a vaccine, an enveloped virus, a non-envelopcd virus, or a combination thereof.

[0084] hi some aspects, die techniques described herein relate to a composition, wherein at least 50% of the at least one microorganism retains biological activity.

[0085] In some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof includes a plurality of therapeutic agents selected from at least one of: a vims, a virus vector, a non-viral vector, viral fragments, virus particles, virus-like particles, imaging agents, small molecules, or a combination thereof.

[0086] In some aspects, the techniques described herein relate to a composition, wherein the liquid, suspension, or combination thereof includes a plurality of virus nanoparticles loaded with a plurality of therapeutic agents selected from at least one of: nucleic acids, proteins, peptides, genes, imaging agents, microorganisms, small molecules, or a combination thereof

[0087] fa some aspects, the techniques described herein relate to a composition, wherein a median size of the plurality of virus nanoparticles does not increase more than 25%.

[0088] In some aspects, the techniques described herein relate to a composition, wherein at least 50% of the plurality of therapeutic agents retain biological activity.

[0089] hi some aspects, the techniques described herein relate to a composition, wherein less than 5% of the dry particles in the aerosol of dry particles form aggregates.

[0090] In some aspects, the techniques described herein relate to an aerosol composition including: a plurality of dried atomized particles, wherein the plurality of dried atomized particles are formed from a liquid, suspension, or combination thereof including a dispersion of biological material, wherein the biological material includes a viral particle, wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosol includes the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the plurality of atomized particles as measured relative to a control particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, and wherein less than 10% of the biological material sustains thermal damage, and wherein less than 10% of the dried atomized particles form aggregates.

[0991] In some aspects, the techniques described herein relate to a system for formulating an aerosol composition including: a nozzle device adapted to atomize a dispersion of a material in a liquid, suspension, or combination thereof to sufficiently form an aerosol containing a plurality of atomized particles, wherein the nozzle device includes at least three channels including an inner channel, at least one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel, the at least one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular channel and having a gap width sufficient so as to atomize a liquid, suspension, or combination thereof flowing through the at least one middle annular channel upon flow of one or more gases through at least the inner chanuel and the at least one outer annular channel: and a drying chamber operatively connected to the nozzle device, the drying chamber adapted to apply a drying gas at a temperature of 0-45£'C so as to mix and dehydrate the plurality of atomized particles, thereby forming a dry particle aerosol; wherein at least 50% of the plurality of the biological material retains biological activity,

[0992] In some aspects, the techniques described herein relate to a rapid roomtemperature dehydration (RTAD) system, including:: a nozzle device adapted to atomize a dispersion of a material in a liquid, suspension, or combination thereof to sufficiently form an aerosol containing a plurali ty of atomized particles, wherein the nozzle device includes at leastthree channels including an inner channel, at least one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel, the at. least one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular channel and having a gap width sufficient so as to atomize a liquid, suspension, or combination thereof flowing through the at least one middle annular channel upon flow of one or more gases through at least the inner channel and the at least one outer annular channel; a drying chamber operatively connected to the nozzle device, the drying chamber adapted to apply a drying gas at a temperature of 0-45 °C so as to mix and dehydrate the plurality of atomized particles, thereby forming a dry particle aerosol; and at least one liquid pump coupled to the at least one middle annular channel; and a liquid source coupled to each liquid pump, the at least one liquid source including the dispersion; wherein the material includes a viral particle, wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosol includes the excipient or adjuvant in an amount sufficient to retain at. least. 50% of a viral activity of the plurality of atomized particles as measured relative to a control particle that, is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, wherein less than 10% of the material sustains thermal damage; and wherein less than 10% of the dry panicles in the dry particle aerosol form aggregates,

[0093] In some aspects, the techniques described herein relate to a RTAD system, further including at least one flow controller, wherein the at least one flow controller is configured to control a flow rate of the one or more gases through at least the inner channel and the at least one outer annular channel of the nozzle device.

[0094] In some aspects, the techniques described herein relate to a RTAD system, further including at least one mass flow controller, wherein the at least one mass flow controller is configured to control a flow rate of one or more of the dispersion and the drying gas.

[0095] In some aspects, the techniques described herein relate to a RTAD system, wherein the material includes a biologic material.

[0096] in some aspects, the techniques described herein relate to a RTAD system, wherein the biologic material includes a virus.

[0097] In some aspects, the techniques described herein relate to a RI AD system, wherein the biologic material includes a. vaccine, an enveloped virus or a non-enveloped virus.

[0098] In some aspects, the techniques described herein relate to a RTAD system, wherein a surface tension of the dispersion is less than water.

[0105] ln some Aspects, the techniques described herein relate to a RT AD system, wherein a flow rate of the dispersion from the nozzle device is 0,1 ml.-10 L / m.in.

[0105] in some aspects, the teclmiques described herein relate to a RTAD system, wherein a median size of the plurality of atomized particles is less than 50 pm.

[0101] In some aspects, the techniques described herein relate to a RTAD system, wherein a median size of the plurality of atomized particles is less than 20 pm.

[0102] In some aspects, the techniques described herein relate to a RTAD system, wherein a median size of the plurality of atomized particles is less than 10 pm.

[0103] In some aspects, die techniques described herein relate to a RTAD system, wherein the drying gas includes nitrogen, helium, air, or a combination thereof.

[0104] hr some aspects, the techniques described herein relate to a RTAD system, wherein the drying gas is provided at a rate of 5-200 standard liters / min.

[0105] In some aspects, the techniques described herein relate to a RTAD system, wherein the temperature is provided between about 15 °C and about 35 °C.

[0106] In some aspects, the techniques described herein relate to a RT AD system, further Including recovering particles after mixing and dehydrating.

[0107] In some aspects, the techniques described herein relate to a RTAD system, wherein the drying chamber includes a filter assembly, the filter assembling being configured to recover particles.

[0108] In some aspects, the techniques described herein relate to a RTAD system, further including a cyclone separator downstream of the drying chamber, wherein the cyclone separator is configured to recover particles.

[0109] In some aspects, the techniques described herein relate to a RTAD system, wherein the drying chamber includes a temperature control probe, a humidity probe, a pressure, probe, or a combination thereof

[0110] In some aspects, the techniques described herein relate to a RTAD system, wherein the drying chamber is operatively connected to one or more inlet or outlet.

[0111] hr some aspects, the techniques described herein relate to a RTAD system, wherein the drying chamber includes a sensor at an outlet of the drying chamber, wherein the sensor is configured to determine a particle number, a particle size, or a combination thereof at the outlet of the drying chamber.

[0112] In some aspects, the techniques described herein relate to a RTAD system, wherein one or more of the nozzle device or the drying chamber is adapted to be retrofitted to a second spraying system.BRIEF DESCRIPTION OF FIGURES

[0113] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the present invention and. together with a general description of the invention given above, and the detailed description of the embodiments given below, serve to explain the princ iples of the presen t invention.

[0114] FI GS. I A- 1 B illustrate droplet temperature (FI G. 1 A) and droplet evaporation time (FIG. IB) as functions of drying air temperature for exemplary room-temperature aerosol dehydration (RTAD) processes of this disclosure compared to conventional spray drying.

[0115] FIGS. 2A-2D illustrate embodiments of various channel configurations of a nozzle device, including devices configured to provide liquid film shaped as a hollow cylinder sandwiched between two coaxial gas flows (FIG. 2A), liquid film shaped as a hollow converging cone sandwiched between two coaxial gas flows (.FIG. 2B), liquid film shaped as a hollow diverging cone sandwiched between two coaxial gas flows (FIG. 2Cj, and liquid film shaped as a diverging cone cylinder sandwiched between two coaxial gas flows in a converging-diverging (de Laval) nozzle configuration (FIG. 2D).

[0116] FIGS. 3A-3B illustrate embodiments of a nozzle device with respect to a plane of one or more outlets.

[0117] FIG, 4 illustrates a schematic diagram of rapid room-temperature dehydration (RTAD) process, according to exemplary' embodiments of this disclosure.

[0118] FIG. 5 illustrates a schematic diagram of an RTAD system, according to exemplary embodiments of this disclosure.

[0119] FIG. 6 provides a comparison of droplet patterns produces by different liquid atomization methods.

[0120] FIG. 7 is a bar graph showing protein abundance for human cytomegalovirus (HCMV) particles in spray droplets analyzed by Western Blot that arc generated at generated at 2000 mbar (spray 1 ), 1500 mbar (spray 2) and 1000 mbar (spray 3). For controls. Western Blot analysis was performed prior to atomization. The Western Blot was performed for three different proteins associated with the HCMV particles, UL99, UL26 and IEI . FIG. 7 summarizes protein abundance determined by Western Blot for each of the three proteins, fromleft to right, prior to atomization at 2000 mbar (control 1), within droplets generated at 2000 mbar (spray 1), prior to atomization at 1500 mbar (control 2), within droplets generated at 1500 mbar (spray 2), prior to atomization at 1000 mbar (control 3), and within droplets generated at 1000 mbar (spray 3), respectively.

[0121] FIG. 8 is a bar graph demonstrating retention of activity of human cytomegalovints (HC.MV) in spray droplets generated at 2000 mbar (spray 1 ), 1500 mbar (spray 2) and 1000 mbar (spray 3 ). For controls, analysis was performed with the solution prior to atomization. FIG. 9 summarizes particles / PFU observed for HCMV particles prior to atomization (left) and after atomization (right).

[0122] FIGS. 9A-9B provide retention of viral titers of human cytomegalovirus (HCMV) in powder formulations produced with RTAD technology and encapsulated with various excipients at l ; 10 and 1:100 dilutions, respectively. FIG. 9C provides biological activity of HCMV powder produced with RTAD technology and encapsulated with lactose and trehalose, respectively. FIG. 9D provides an SE.M image of the RTAD powder microstructure demonstrating morphology of the particles containing HCMV virus encapsulated by trehaloseleucine excipient mixture.

[0123] FIGS. 10A-10B provides biological activity of HCMV in powder produced with RTAD technology and encapsulated with lactose and trehalose, respectively.

[0124] FIGS. 11 A-11C show results of experiments showing retention of adenovirus AdV5 virus particles by atomized particles, and retention of infectious activity by the AdV5 virus particles following atomization. The atomized particles were generated at 2000 mbar (spray I ), 1500 mbar (spray 2) and 1000 mbar (spray 3). FIG. 11A shows results of a spectroscopic analysis for determining concentrations of virus particles prior to atomization (control), and following atomization (spray). Controls show AdV5 virus particles present in the suspension, prior to atomization. FIG. 11 B and 1 IC show results of a comparati ve analysis of retention of infectious activity by virus particles prior to atomization (control), and following atomization (spray). Controls show infectious activity of AdV5 virus particles prior to atomization. FIG. 110 illustrates an SEM micrograph of powder microstructure demonstrating morphology of the particles containing AdV5 adenovirus encapsulated by trehalose-leucine excipient mixture.

[0125] FIG. 12 shows results of experiments showing retention of infectious activity by adeno-associated AAV2 virus particles following atomization. The atomized particles weregenerated at 2000 mbar (spray 1), 1500 m bar (spray 2) and 1000 mbar (spray 3). Controls show infectious activity of AAV2 virus particles prior to atomization.

[0126] FIGS. 13A-13C are graphs demonstrating retention of infectivity of AdV5 in sprays of virus-containing aerosol droplets by comparing viral titers measured by plaque assays (FIG. 13.4), particle counts measured by quantitative polymerase chain reaction (qPCR) (FIG. 13B), and ratios of particle count and PFU concentrations (FIG. 13C) before and after spraying using RTAD dehydration. FIG. 13D illustrates a long-term study comparing foe particle-to- PFU ratios of sprayed particles when stored for 1 month at different temperatures.

[0127] FIG. 14 illustrates a particles size distribution measured by dynamic light scattering of the initial alum adjuvant (AlhydrogeKi5), and of reconstituted powder formulations made by RTAD and Freeze drying.

[0128] FIGS- 15A-15B illustrate volume- and number-weighted droplet size distributions, respectively, of aerosol droplets produced at water flow rate of 5 ml / min and atomization pressure of 5 bar and liquid flow gap width 25 microns. FIGS. 15C-15D illustrate mass median droplet diameter of water sprays as a function of atomizing gas pressure for various water flow rates and liquid, flow gap width 25 microns. FIG. 15E illustrates mass median droplet diameter of water sprays as a function of liquid flow rate and air pressure 5 bar gauge for various nozzles.

[0129] It should be understood that the appended drawings are not necessarily to scale, presenting a somewhat simplified representation of various features illustrative of the basic principles of foe invention. The specific design features of the sequence of operations as disclosed herein, including, for example, specific dimensions, orientations, locations, and shapes of various illustrated components, will be determined in part by the particular intended application and use environment. Certain features of the illustrated embodiments have been enlarged or distorted relative to others to facilitate visualization and clear understanding. In particular, thin features may be thickened, for example, for clarity or illustration.DETAILED DESCRI PTION

[0130] Disclosed are also methods and systems for thermal stabilization of pharmaceutical formulations containing enveloped and non-enveloped vims partides. The disclosed technology utilizes rapid room temperature dehydration of biopharmaceutical formulations using ultra-fine droplet aerosols and eliminates the need for logistically challenging cold chain infrastructure.Disclosed herein arc methods and systems for thermal stabilization of atomized liquids, suspensions or combinations thereof including bulk dispersions of organic and inorganic materials. As the atomized liquids, suspensions or combinations thereof are mixed and dehydrated, a drying gas at a temperature of 0-45 °C allow for the production of an aerosol of dry particles or droplets such that less than 10% of the organic and inorganic materials therein sustain thermal damage, where such organic and inorganic materials include, for example, active agents such as vaccines, viruses (e.g.„ enveloped or non-enveloped viruses), a virus vector, a nou-viral vector, viral fragments, virus particles, virus-like particles, proteins, monoclonal antibodies, antibody fragments, nucleic acids (DN.A, RNA, mRNA, siRNA), peptides, imaging agents and small molecules. Other suspended materials or droplets arc described in more detail below. The methods and systems herein allow for atomization that does not substantially affect or decrease the biological activity of such agents, and can be suitable for spraying of both solutions and suspensions . The methods and devices herein also allow for high-consistency particle or droplet size distributions of a desired size and amount, and thus are highly scalable for various applications, iucluding pharmaceutical, biomedical and environmental industries.

[0132] Disclosed are also methods and systems for thermal stabilization of atomized dispersions of materials in a liquid, suspension, or combination thereof The methods and systems have a wide range of utility across various industries. For example, in some embodiments, the methods and systems comprise applications including but not limited to spray drying, encapsulation, agricultural spraying, spray painting, spray coating, medical sprays and drug delivery (nasal and throat drug delivery, wound healing), 3D printing, electronics, fragrance and cosmetics, humidification and dust fighting, decontamination, fuel injection, and laser-assisted powder deposition. In some embodiments, methods and systems described herein allow for forming an aerosol containing a plurality of atomized particles. In sonic embodiments, methods and systems described herein allow for mixing and dehydrating the plurality of atomized particles using a drying gas at a temperature of 0-45 °C. In some embodiments, methods and systems described herein sufficiently dry the plurality of atomized particles, thereby forming an aerosol of dry particles. Accordingly, in some embodiments, less than 10% of the ma terials herein sustain thermal damage. In some embodiments, methods and devices atomize high viscosity liquids, suspensions of organic and inorganic materials, and viscoelastic liquids. Additionally, the methods and devices are advantageously gentle and compatible with biological materials and microorganisms. Accordingly, in some embodiments,biological materials and microorganisms retain their biological activity, such as, for example, a viral infectivity, after atomization. Moreover, in some embodiments, methods and devices enable spraying suspensions of vaccines or enveloped and nonenveloped viruses as aerosols without causing aggregation of the nanoparticles in atomized droplets. In some embodiments, methods and devices allow for the creation of aerosols of particles or droplets with core and layer structures, multiple layers, and matrix-type encapsulation.DEFINITIONS

[0133] As used herein, “about” and its grammatical equivalents in relation to a reference numerical value and its grammatical equivalents as used herein can include a range of values plus or minus 10% from that value. For example, the amount “about 10” includes amounts from 9 to 1 I . The term “about” in relation to a reference numerical value can also include a range of values plus or minus 1 (1%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.

[0134] As used herein, a “cell” refers to a biological cell. Some non-limiting examples include' a prokaryotic cell, eukaryotic cell, a bacterial cell, an archaea cell, a cell of a singlecell eukaryotic organism, a protozoa cell, a cell from a plant, an algal cell, a fungal cell, a fungal protoplast cell, an animal cell, and the like. Sometimes a cell is not originating from a natural organism, e.g., a cell can be a synthetically made, sometimes termed an artificial cell.

[0135] As used herein, a “plurality” contains at least 2 members. In certain cases, a plurality may have at least 10, at least 100, at least 100, at least 10,000, at least 100,000, at least 106, at least 107, at least 108or at least 109'tor more members.

[0136] The terms "adenovirus" and "adenoviral particle" as used herein include any and all viruses that may be categorized as an adenovirus, including any adenovirus that infects a human or an animal, including all groups, subgroups, and serotypes. Thus, as used herein, "adenovirus” and "adenovirus particle" refer to the virus itself or derivatives thereof and cover all serotypes and subtypes and both naturally occurring and recombinant forms. In one embodiment, such adenoviruses infect human cells. Such adenoviruses may be wildtype or may be modified in various ways known in the art or as disclosed herein. Such modifications include modifications to the Adenovirus genome that is packaged in the particle in order to make an infectious virus. Such modifications include deletions known in the art.

[0137] Although various features of the disclosure may be described in the context of a single embodiment, the features can also be provided separately or in any suitablecombination. Conversely, although the disclosure may be described herein in the context of separate embodiments for clarity, various aspects and embodiments can be implemented in a single embodiment.Rapid Room-Temperature Aerosol Dehydration (RTAD) methods and systems

[0138] Described herein are rapid room-temperature aerosol dehydration (RTAD) methods and systems for generating aerosols of dry particles. In some embodiments, the methods comprise atomizing a dispersion of a material in a liquid, suspension or combination thereof using a nozzle device, thereby forming an aerosol containing a plurality of atomized particles. In some embodiments, the methods comprise mixing and dehydrating the plurality of atomized particles using a drying gas at a temperature of 0-45 °C so as to sufficiently dry the plurality of atomized particles, thereby forming an aerosol of dry particles. In some embodiments, less than 10% of the material from the methods herein sustains thermal damage.

[0139] In some embodiments, the systems described herein comprise a nozzle device adapted to atomize a dispersion of a material in a liquid to sufficiently form an aerosol containing a plurality of atomized particles. In some embodiments, the systems comprise a drying chamber, the drying chamber adapted to apply a drying gas at a temperature of 0-45 °C so as to mix and dehydrate the plurality of atomized particles, thereby forming a dry particle aerosol. In some embodiments, less than 1.0% of the material in the dry particle aerosol sustai ns thermal damage.

[0140] Disclosed are a method and a system for thermal stabilization of pharmaceutical formulations containing vaccines or enveloped and nonenveloped viruses. The technology utilizes proprietary rapid room temperature dehydration of biopharmaceutical formulations using ultra- line droplet aerosols and eliminates the need for logistically challenging cold chain infrastructure. By way of background, freeze-drying of biological formulations, which is traditional in the production of pharmaceuticals, introduces time-consuming (1-3 days of processing), poorly scalable, energy inefficient, and expensive batch manufacturing. Alternative spray drying methods are thermodynamically inefficient, energy intense, as well as pose risk of biological product thermal damage due to high drying temperatures (1 (Xi-200 °C). Disclosed herein is a method of Rapid Room Temperature Aerosol Dehydration (RTAD), a scalable system for continuous dehydration of liquid pharmaceutical and biopharmaceutical formulations that provides thermal stabilization of biological drugs by converting liquid drugs into powder form, enabling their transportation, storage and handling at room temperature. Thedisclosed process can generate sprays / aerosols with droplets that are 100x smaller (0.2-20 pm) than existing spray drying technologies and perform dehydration without applying heat, which mitigates the risk of damage of thermolabile biologicals and provides a significant reduction in energy requirements. The disclosed technology has demonstrated superiority of the system over traditional spray drying and freeze drying with respect to energy consumption, biological activity, scalability, powder dissolution, protein aggregation, particle size and size uniformity, and high-qual ity of produced inhalable and reconstituiable biologic formulations.

[0141] More particularly, the disclosed approach provides a process of dehydration of en veloped and non-enveloped viruses. The method provides for producing room-temperature steady powders and enables thermal stabilization of pharmaceutical drugs containing viral particles, including enveloped and non-enveloped viruses, eliminating the need for refrigeration and freezing during transportation, storage and handling. In this way, the method enables avoiding the need in sophisticated cold supply chain logistics for those biological drugs and materials.

[0142] Interr alia, the disclosed approach allows for:• Dehydration and thermal stabilization of biologies and vaccines• Dehydration and thermal stabiliza tion of biologies and small molecule drugs• Manufacturing of high-quality- inhalable powdered biologies and vaccines (median particle size less than 5 microns)• Micro-encapsulation of thermal sensitive materials into particulate matter• Improving solubility and bioavailability of drug substances.

[0143] In contrast to spray drying processes and systems, the disclosed rapid roomtemperature dehydration process (RTAD) utilizes room / near room temperature for drying of liquid materials and eon verting them into powders. This is achieved by employing a liquid atomization technique generating spray / aerosol with droplets 10-100 times smaller than generated by conventional nozzles (as disclosed separately hi the U.S. provisional patent application No. 63 / 526,866, filed July 14, 2023 (the ‘866 application), which is also part of the application and is incorporated by reference in its entirety as if fully set forth herein). This system has also been disclosed for use in production of an aerosol of dry particles or droplets containing proteins and monoclonal antibodies (as disclosed separately in the U.S. provisional patent application No. 63 / 540,723, filed September 27, 2023 (the ‘723 application), which is also part of the application and is incorporated by reference in its entirety as if fully set forth herein).

[0144] The process is scalable similar to spray drying, and can reach out capacities of kg / hour per setup. At the same time, the biological materials are expensive, and only a few milligrams of a drug can be considered as a therapeutic drug dose in many cases. Therefore, the current laboratory' scale setup has a production capacity of hundreds of therapeutic doses of biologic powder per batch.[0014S] FIGS. 1A-1B and TABLE 1 illustrate a comparison between the disclosed rapid room-temperature aerosol dehydration (RTAD) process and conventional spray drying and freeze drying (lyophilization) processes. In particular, FIGS. 1A-1B illustrate droplet temperature and droplet evaporation time, respectively, as functions of drying air temperature for the RTAD process and con ventional spray drying process.

[0146] TABLE 1. Comparison between spray drying, lyophilization and rapid room-temperature aerosol drying (RTAD) technologies.

[0147] In some embodiments, the RTAD methods described herein comprise preparing a dispersion of a material. As used herein, the term “dispersion” refers to a plurality of a material in a continuous phase of another material. In some embodiments, a material comprises a biologic material. As used herein, the term “biological material’’ refers to an active agent, anadjuvant, a pharmaceutical composition, or die like or a combination thereof. In some embodiments, a material of a dispersion comprises liquid (e.g., solution, suspension, emulsion, or combinations thereof). In some embodiments, a material of a dispersion comprises an active agent, an adjuvant, a pharmaceutical composition, or die like or a combination thereof. Ln some embodiments, a dispersion comprises biological materials within liquid solutions. In some embodiments, a dispersion comprises a plurality of biological materials within a liquid solution, where the liquid solution is in a continuous phase. I

[0148] In some embodiments, the RTAD methods comprise controlling a flow of the dispersion through at least one channel of a nozzle device described herein so as to create a spray or aerosol of fine or ultra-fine droplets or particles. In some embodiments, methods comprise controlling a flow of a liquid (e.g. , solution, suspension, emulsion, or combinations thereof) flowing through at least one channel of a nozzle device such that Reynolds number is within a range of from 100 to 100000, from 100 to 50000, from 100 to 25000, from 100 to 10000, from 100 to 1000, from 100 to 500, from 300 to 100000, from 300 to 50000, from 300 to 25000, from 300 to 10000, from 300 to 1000, from 300 to 500, from 800 to 100000, from 800 to 50000, from 800 to 25000, from 800 to 10000, from 800 to 1000, from 5000 to 100000, from 5000 to 50000, from 5000 to 25000, from 5000 to 10000, from 15000 to 100000, from 15000 to 50000, from 15000 to 25000, from 35000 to 100000, from 35000 to 50000, or from 75000 to 100000. Jn some embodiments, methods comprise controlling a flow of a liquid i.e.y . . solution, suspension, emulsion, or combinations thereof) flowing through at least one channel of a nozzle device such that Waber number is within a range of from 10 to 5000, from 10 to 2500, from 10 to 1000, from 10 to 500, from 10 to 400, from 10 to 300, from 10 to 200, from 10 to 100, from 10 to 50, from 10 to 25, from 25 to 5000, from 25 to 2500, from 25 to 1000, 25 to 500, from 25 to 400, from 25 to 300, from 25 to 200, from 25 to 100, from 25 to 50, from 50 to 5000, from 50 to 2500, from 50 to 1000, 50 to 500, from 50 to 400, from 50 to 300, from 50 to 200, from 50 to 100, from 100 to 5000, from 100 to 2500, from 100 to 1000, 100 to 500, from 100 to 400, from 100 to 300, from 100 to 200, from 200 to 5000, from 200 to 2500, from 200 to 1000, 200 to 500, from 200 to 400, from 200 to 300, from 300 to 5000, from 300 to 2500, from 300 to 1000, from 300 to 500, from 300 to 400, from 400 to 5000, from 400 to 2500, from 400 to 1000, from 400 to 500, from 500 to 5000, from 500 to 2500, from 500 to 1000, from 1000 to 5000, from 1000 to 2500, or from 2500 to 5000. In some embodiments, methods comprise controlling a flow of a liquidsolution, suspension, emulsion, or combination thereof) flowing through at least one channel of a nozzle device such thatOhnesorge number is within a range of from 0.0001 to 10, from 0.0001 to 5, from 0.0001 to 1, from 0.0001 to 0.1, from 0.0001 to 0.01, from 0.0001 to 0.001, from 0.001 to 10, from 0.001 to 5, from 0,001 to 1 , from 0,001 to 0,1, from 0.001 to 0.01, from 0.01 to 10, from 0.01 to 5, from 0.01 to 1, from 0.01 to 0.1, from 0.1 to 10, from 0.1 to 5, from 0.1 to 1, from 1 to 10, from 1 to 5, or from 5 to 10.

[0149] In some embodiments, the methods and systems provided herein may be capable of atomization of relatively thick liquids (e.g., solutions, suspensions, emulsions, or combinations thereof') that result in droplet form. Such capabilities can be extremely challenging for some conventional techniques to provide. In particular, a thicker liquid would normally require a greater pressure to atomize the particles and / or form droplet) s) from the liquid. The methods and systems provided herein may be adapted to adjust a combination of various operating parameters so as to atomize or produce droplets from relatively thicker liquids, such as those with viscosities described in more detail below.

[0150] In some embodiments, the liquids (e.g, solutions, suspensions, emulsions, or combinations thereof) comprise at least one solvent. In some embodiments, water is used as a solvent, but other solvents may be included. In some embodiments, the solvent is a pharmaceutically acceptable solvent. Non-limiting examples of pharmaceutically acceptable solvents include ketones (e.g., acetone), alcohols (e.g., methanal, ethanol, or propanol, a mixture thereof), water, methylene chloride, and a combination thereof. In some embodiments, a solvent, as described herein, comprises a mixed solvent of water with one or more of the other pharmaceutically acceptable solvents described herein. These pharmaceutically acceptable solvents may be used alone or as an appropriate combination of two or more thereof

[0151] In some embodiments, the .liquids (e.g., solutions, suspensions, emulsions, or combinations thereof) are non-aqueous. In some embodiments, the solvent is an oil lit for human consumption, such as castor oil, soybean oil, sunflower oil, coconut oil, hemp oil or olive oil. in some embodiments, the solvent comprises one or more saturated fatty acids, one or more unsaturated fatty acids, or a combination thereof.

[0152] hi some embodiments, disclosed herein are RTAD systems and methods are capable of processing a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) flown through a nozzle device at a flowrate in a range of from 0.1 ml / min to 50 nil / min, from 0.3 ml / min to 50 ml / min, from 0.5 ml / min to 50 ml / min, from 0.8 ml / min to 50 ml / min, from 1 ml / min to 50 ml / min, from 3 ml / min to 50 ml / min, 5 ml / min to 50 ml / min, 8 ml / min to 50 ml / min, from 0.1 ml / min to 25 ml / min, from 0.3 ml / min to 25 ml / min, from 0.5 ml / min to25 ml / min, from 0.8 ml / min to 25 ml / min, or from 1 ml / min to 25 ml / min, from 0.1 ml / min to 10 ml / min, from 0.3 ml / min to 10 ml / min, from 0.5 ml / min to 10 ml / min, from 0.8 ml / min to 10 ml / min, or from 1 ml / min to 10 ml / min, from 0. 1 ml / min to 10 ml / min, from 0.3 ml / min to 10 ml / min, from 0.5 ml / min to 10 ml / min, from 0.8 ml / min to 10 ml / min, from 1 ml / min to 10 ml / min, from 3 ml / min to 10 ml / min, 5 ml / min to 10 ml / min, 8 ml / min to 10 ml / min, from 0.1 ml / min to 5 ml / min, from 0.3 ml / min to 5 ml / min, from 0.5 ml / min to 5 ml / min, from 0.8 mb'min to 5 ml / min, from 1 mb'min to 5 ml / min, from 0.1 ml / min to 0.01 L / min, from 0.01 L / min to 0.1 L / min, from 0.1 L / min to 1 L / min, from 0.3 L / min to 10 L / min, from 0.5 L / min to 10 L / min, from 0.8 L / min to 10 L / min, from 1 L / min to 10 L / min, from 0.1 L / min to 10 L / min, from 0.3 L / min to 10 L / min, from 0.5 L / min to 10 L / min, from 0.8 L / min to 10 L / min, from 1 L / min to 10 L / min, from 3 L / min to 10 L / min, 5 L / min to 10 L / min, from 8 L / min to 10 L / min, from 0.1 L / min to 1 L / min, from 0.3 L / min to 20 L / min, from 0.5 L / min to 20 L / min, from 0.8 L / min to 20 L / min, from 1 L / min to 20 L / min, from 0.1 L / min to 20 L / min, from 0.3 L / min to 20 L / min, from 0.5 L / min to 20 L / min, from 0.8 L / min to 20 L / min, from 1 L / min to 20 L / min, from 3 L / min to 20 L / min, 5 L / min to 20 L / min, or from 10 L / min to 20 L / min. In some embodiments, a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) is flown through a nozzle device at a pressure in a range of from 0. 1 bar to 2500 bar, from 0.1 bar to 1500 bar, from 0.1 bar to 500 bar, from 0.1 bar to 100 bar, from 0.1 bar to 50 bar, from 0. 1 bar to 20 bar, from 0.1 bar to 10 bar, from 0.1 bar to 5 bar, from 0.1 bar to 2 bar, from 0. 1 bar to 1 bar, from 3 bar to 2500 bar, from 3 bar to 1500 bar, from 3 bar to 500 bar, from 3 bar to 100 bar, from 3 bar to 50 bar, from 3 bar to 20 bar, from 3 bar to 10 bar, from 3 bar to 5 bar, from 8 bar to 2500 bar, from 8 bar to 1500 bar, from 8 bar to 500 bar, from 8 bar to 100 bar, from 8 bar to 50 bar, from 8 bar to 20 bar, from 8 bar to 10 bar, from 30 bar to 2500 bar, from 30 bar to 1500 bar, from 30 bar to 500 bar, from 30 bar to 100 bar, from 30 bar to 50 bar, from 80 bar to 2500 bar, from 80 bar to 1500 bar, from 80 bar to 500 bar, from 80 bar to 100 bar, from 300 bar to 2500 bar, from 300 bar to 1500 bar, from 300 bar to 500 bar, from 500 bar to 2500 bar, from 500 bar to 1500 bar, or from 500 bar to 1000 bar.In some embodiments, the liquid solution is atomized by employing a liquid atomization method, disclosed separately in the ‘866 application. In some embodiments, the disclosed RTAD systems and. methods generate an aerosol comprising atomized droplets with diameters 10-lOOx smaller than competing technologies, described in more detail below with respect to FIG. 5 in Example 2.

[0154] ln some embodiments, a flow of a liquid (e.g., solution, suspension, emulsion, or combinations thereof) flowing through at least one channel is controlled to obtain an aerosol comprising a size distribution of a plurality of atomized particles comprises a median particle diameter <20 pm, <15 pm, <10 pm, <5 pm, <1 pm, <0.5 pm, or <0.1 pm. In some embodiments, a flow of a liquid (e.g., solution, suspension, emulsion, or combinations thereof) flowing through at least one channel is controlled to obtain an aerosol comprising a size distribution of a plurality of atomized particles comprises a median particle diame ter in a range of from 0,05 pm to 20 pm, from 0.05 pm to 15 pm, from 0.05 pm to 10 pm, from 0.05 pm to 5 pm, from 0.05 pm to 1 pm, from 0.05 pm to 0.5 pm, from 0.05 pm to 0.1 pm, from 0.1 pm to 20 pm, from 0.1 pm to 15 pm, from 0.1 pm to 10 pm, from 0. 1 pm to 5 pm, from 0.1 pm to 1 pm, from 0.1 pm to 0.5 pm, from 1 pm to 20 pm, from 1 pm to 15 pm, from 1 pm to 10 pm, from 1 pm to 5 pm, from 10 pm to 20 pm, or from 10 pm to 15 pm.

[0155] In some embodiments, nozzle devices are used for producing aerosols comprising atomized water particles. Atomized water droplets have smaller size that results in higher surface area and lesser evaporation time relative to larger water droplets. In some embodiments, small particles refer to atomized particles having a size in a range of from 0.01 pm to 50 pm, from 0.01 pm to 20 pm, from 0.01 pm to 10 pm, from 0.01 pm to 1 pm, from 0. 1 pm to 50 pm, from 0. 1 pm to 20 pm, from 0, 1 pm to 10 pm, from 0.1 pm to 1 pm, from 1 pm to 50 pm, from I pm to 20 pm, from I pm to 10 pm, from 10 pm to 50 pm, or from 10 pm to 20 pm. In some embodiments, small particles refer to atomized particles having a size of less than 10 pm, less than 5 pm, less than 1 pm, less than 0.1 pm, or less than 0.01 pm. Accordingly, in some embodiments, nozzle devices disclosed herein improve function of humidifying systems relative to other conventional humidifying systems.

[0156] In some embodiments, a nozzle device increases a surface area of dispensed particles (e.g., atomized particles) and, thereby, reduces evaporation, time. In some embodiments, tire surface area of the dispensed particles increase in surface area between about .1% to about 5%, between about 5% to about 10%, between about 10% to about 20%, between about 20% to about 30%, between about 30% to about 40%, between about 40% to about 50%, between about 50% to about 60%, between about 60% to about 70%, between about 70% to about 80%, between about 80% to about 90%, between about 90% to about 100%, or above 100%,

[0157] In some embodiments, RTAD systems disclosed herein may include nozzles attached to an appropriate gas or liquid source via, e.g. , a pump. The nozzles may be configuredto generate aerosols into a vessel, which may be a collection device. In some embodiments, a vessel may include a filter disposed in the path of the aerosol droplets. In some embodiments, a vessel may be under vacuum or negative pressure. In some embodiments, a system is configured to operate using a batch process. In some embodiments, a system is configured to operate using a continuous process.

[0158] In some embodiments, the disclosed RTAD systems comprise an integrated nozzle device. The nozzle device may be adapted to atomize a dispersion of a material in a liquid to sufficiently form an. aerosol containing a plurality of atomized particles. In some embodiments^ the nozzle device .includes at least three channels comprising an inner channel, at least one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel. In some embodiments, the at least, one middle annular channel is coaxially arranged between the inner channel and the at least one outer annular channel. In some embodiments, at least one middle annular channel comprises a gap width sufficient so as to atomize a liquid flowing through the at least one middle annular channel upon flow of one or more gases through at. least, the inner channel and the at least one outer annular channel,

[0159] FIG. 2A illustrates an embodiment of the device 100 configured to provide liquid film shaped as a hollow cylinder sandwiched between two coaxial gas flows. FIG. 28 illustrates an embodiment of the device 100 configured to provide liquid film shaped as a hollow converging cone sandwiched between two coaxial gas flows. FIG. 2C illustrates an embodiment of the device 100 configured to provide liquid film shaped as a hollow diverging cone sandwiched between two coaxial gas flows. FIG. 2D illustrates an embodiment of the device 100 configured io provide a liquid film shaped as a diverging cone cylinder sandwiched between two coaxial gas flows in a converging-diverging (de Laval) nozzle configuration.

[0160] In some embodiments, an. initial liquid film (or annulus film) comprises a thickness in a range, of from 5 microns to 200 microns, from 5 microns to 150 microns, from 5 microns to .125 microns, from 5 microns to 100 microns, from 5 microns to 50 microns, from 5 microns to 30 microns, from 20 microns to 200 microns, from 20 microns to 150 microns, from 20 microns to 125 microns, from 20 microns to 100 microns, from 20 microns to 50 microns, from 20 microns to 30 microns, from 50 microns to 200 microns, from 50 microns to 150 microns, from 50 microns to 125 microns, from 50 microns to 100 microns, from 100 microns to 200 microns, from 100 microns to 150 microns, or from 150 microns to 200 microns. In some embodiments, an initial liquid film comprises a thickness of more than 5microns, more than 10 microns, more than 15 microns, more than 25 microns, more than 50 microns, more than 75 microns, more than 100 microns, more than 125 microns, or more than 150 microns. In some embodiments, the initial liquid film (or annulus film) has a typical thickness of 25 microns or more. In some embodiments, a resulting spray can have > 99% of droplets smaller than one micron in diameter, as can be observed from the measured number- weighted drop size distributions.

[0161] FIGS. 3A-3B illustrate coaxial nozzle devices, according to exemplary embodiments of this disclosure, where outlet edges of all the channels (i.e., inner channel 102, middle annular channel 101, outer annular channel 103) formed by the tabular members making up the nozzle can lay in the same plane perpendicular the nozzle axis, as seen at bottom of the nozzle. In some embodiments, the channels can have different lengths and / or their outlet edges can lay in different planes perpendicular to the nozzle axis. FIG. 3A illustrates an embodiment where gas flows through each of the inner channel 102 and the outer annular channel 103 from different inlets. FIG. 3B illustrates an embodiment where gas flows through each of the inner channel 102 and the outer annular channel 103 from the same inlet.

[0162] In some embodiments, the nozzle(s) herein are configured to discharge a liquid (e.g., a solution, an emulsion, a suspension or a combination thereof} so as to form a spray film. In some embodiments, the nozzle(s) is configured to aerosolize the liquid. In some embodiments, the nozzlel's) is configured to spray the liquid, suspension or combination. In some embodiments, the nozzle(s) is configured to dispense the liquid. In some embodiments, the nozzle(s) is configured to dispense droplets of the liquid. In some embodiments, the nozzle(s) is configured to disperse droplets of the liquid. In some embodiments, the nozzlefs) is configured to discharge droplets the liquid. In some embodiments, the nozzle(s) is configured to release droplets of the liquid. In some embodiments, the nozzle(s) comprises at least one of a spray device, an aerosol sprayer, an aerosol container, an aerosol spray pump, a device comprising a dispenser for spray delivery of the liquid, a device comprising a hose, an aerosol spray gun, an atomizer device, a manual aerosol sprayer, an automatic aerosol sprayer, or any combinati on thereof.

[0163] In some embodiments, the methods provided herein may inc! ude atomization of suspensions of organic and inorganic materials. In some examples, aqueous insulin suspensions and suspensions of HCMV and AAV viruses suspended in biological buffers were successfully sprayed. Accordingly, in some embodiments, methods and devices described, herein are used for producing atomized particles from a suspension of virus (e.g., HCMV, AAV) particlessuspended in biological buffers. In some embodiments, methods and devices described herein are used .for producing atomized particles from a protein suspension (e.g., insulin suspension). In some embodiments, the methods provided herein may include atomization of viscoelastic liquids. In some examples, polyvinyl alcohol and PEO / PEG water solutions were successfully sprayed. Accordingly, in some embodiments, methods and devices described herein are used for producing atomized particles from polyvinyl alcohol and PEO / PEG water solutions.

[0164] In some embodiments, methods described herein are gentle and compatible with biological materials and microorganisms. Accordingly, in some embodiments, methods and devices are used for producing atomized particles comprising biological materials and / or microorganisms. For example, it was found that atomization did not decrease the biological activity, e.g., a viral activity, infectious activity, or infectivity, of HCMV virus particles. In some embodiments, "activity” or "infectivity" in reference to a virus means the characteristic of a virus that embodies capability of entering, surviving in, and multiplying or causing an immunological response in a susceptible host, such as upon contact with the host. In some embodiments, a viral infectivity is the capacity of a virus or viral particle to enter a host cell and exploit its resources to replicate and produce progeny infectious viral particles, leading to potential infection and subsequent disease in a host Any methods known to a skilled artisan for determination of virus infectivity can be used for the purposes described herein, e.g., the assays described in Examples 4-6 can be employed.

[0165] In some embodiments, methods are suitable for spraying of both solutions and suspensions. In some examples, suspensions of biological particles (NOVOLIN insulin suspension, virus particle suspensions - HCMV, AdV, AAV) have been successfully dispensed (see FIG. 7 and FIG. 8, described in more detail below). In some embodiments, suspensions may comprise virus nanoparticles (VNPs).

[0166] The embodiments of method and device can include flaw configurations resulting in thin liquid film flow as a hollow cylinder, as a converging hollow cone, and as a diverging hollow cone. The flow of gas can be organized in either straight cylinder, converging, diverging or converging-diverging (de Laval) shape nozzle configurations. In some embodiments, a triple coaxial nozzle can be used to employ a three-channel process for direct atomization of liquid into droplets by the disclosed methods. In some embodiments, the gas comprises air, O2, CO2, N2, Ar, He, or any other gas or oxidizer mixture.

[0167] In some embodiments, each of the channels (i.e., inner channel 102, middle annular channel 101, outer annular channel 103) of the devices described herein comprisevarying length and diameter dimensions. In some embodiments, the length of the channel is <200 cm, <150 cm, <100 cm, <50 cm, <25 cm, <10 cm, <5 cm, <3 cm, or <1 cm. In some cases, the diameter of one or more of the proximal portion, the intermediate portion, or the distal portion is less than <20 cm, <10 cm, <8 cm, <5 cm, <1 cm, <0.5 cm, or <0.1 cm.

[0168] In some embodiments, converging, diverging or converging-diverging (de Laval) shape nozzle configurations comprise varying length and diameter dimensions. In some embodiments, the length of" one or more of a proximal portion, an intermediate portion, or a distal portion is <200 cm, <150 cm, <100 cm, <50 cm, <25 cm, <10 cm, <5 cm, <3 cm, or <1 cm. In some cases, the diameter of one or more of the proximal portion, the intermediate portion, or the distal portion is less than <20 cm, <10 cm, <8 cm, <5 cm, <1 cm, <0.5 cm, or <0.1 cm.

[0169] In some embodiments, nozzle devices described herein comprise length of a channel (e.g., inner channel,, middle annular channel, or outer annular channel) that is at least 3 times, at least 5 times, at least 10 times, at least 20 times, at least 50 times, or more than width of the channel. In some embodiments, length of a channel (fi.g., inner channel, middle annular channel, or outer annular channel) is at least 3 times width of' the channel. In some embodiments, length of a channel (e.g. , inner channel, middle annular channel, or outer annular channel) is at least 5 times width of the channel, hi some embodiments, length of a channel (e.g , inner channel, middle annular channel, or outer annular channel) is at least 10 times width of the channel. In some embodiments, a ratio of length of a channel (e.g., inner channel, middle annular channel, or outer annular channel) and width of the channel is in a. range of from 2 to 100, from 2 to 80, from 2 to 50, from 2 to 40, from 2 to 20, from 2 to 10, from 2 to 5, from 8 io 100, from 8 to 80, from 8 to 50, from 8 to 40, from. 8 to 20, from 8 to 10, from 15 io 100, from 15 to 80, from 15 to 50, from 15 to 40, from 15 to 20, from 40 to 100, from 40 to 80, from 40 to 50, from .75 to 100, from 75 to 80, or from 90 to 100. In some embodiments, a ratio of length of a channel (e.g., inner channel, middle annular channel, or outer annular channel) and width of the channel is in a range of from 3 to 10.[00l70] In some embodiments, a fluid stream that is flowing through a channel of a nozzle device described. .herein is configured to flow with a swirl or vortex. In some embodiments, a flow with a swirl or vortex, is such that rotation is imparted to one of the at least two fluid, streams selected from, a fluid, stream within an outer annular channel, a fluid stream within a middle annular channel, a fluid stream within an inner channel. In some embodiments, rotation may be imparted to the flow by a swirl chamber that generates atangential flow by the injection of one or more fluids through any number Of tangential slots. In some embodiments, an application of a swirl or vortex to a first fluid stream flowing through a channel of a nozzle device is such that the flow travels with a different angular velocity relative to a second fluid stream flowing through a different channel of the nozzle device. In some embodiments, an overall degree of swirl may be characterized through a non-dimensional swirl number, S, and estimated from laser-Doppler velocimetry measurements obtained at an exit plane of the nozzle device. In some embodiments, a range of swirl levels of a fluid stream is of S<2.5, S<2.0, S<1 .5, S£0.5, S<0.1 , or S<0.05. In some embodiments, a fluid stream leads to a faster decrease of the break- up length, and this influence may increase when such a swirl or vortex is imparted to the fluid stream, as well as for increasing swirl levels. In some embodiments, higher velocities of a fluid stream leads to a break-up length to show smaller variations, hi some embodiments, the use of swirl in a fluid stream increases atomization efficacy and quality.

[0171] For multilayer encapsulation, it will be understood that more than four, multichannel configurations can be utilized. In some embodiments, multiple channels (i.e„ n~ channels) for secondary liquid flows can be added in between the two gas streams. Such n~ channel coaxial nozzle can have 3“ possible variants of channel length organizations for each of straight cylinder, converging, diverging, or converging-diverging (de Laval) shape nozzle configurations. In some embodiments, n>6. In some embodiments, 3<n<6. In some embodiments, 3<n<5. In some embodiments, 3<n<4. In some embodiments, 3< / ?<10.

[0172] In some embodiments, to organize the disclosed atomization process in three or more channel nozzle, the supplied liquid flow rate can be controlled using, e.g., a syringe pump or a peristaltic pump. In some embodiments, the pressure of atomizing gas flow can be controlled using, e.g., a microfluidic gas pump. The regulation of liquid mass flow rate and gas pressure can be used to control the generated spray in terms of droplet size distribution and flow rate.

[0173] In some embodiments, the inner (ID) and outer (OD) diameters of each of the inner channel, the at least One middle annular channel, and the at least One outer annular channel may be defined at a desired ratio relati ve to one another so as to affect droplet size distributions. A gap value or gap width, as used herein, may refer to a thickness of the at least one middle annular channel. In some embodiments, a gap value may range from about 10 gm to about 125 gm. In some embodiments, a gap value may be 25 um, 75 gm and 125 gm.

[0174] ln sane embodiments, a ratio between a diameter, or diameter ratio, of each of the channels (i.e., inner channel 102, middle annular channel 101, outer annular channel 103) of the nozzles may vary. la some embodiments, a diameter ratio comprises a ratio ranging from 0.05 to less than 1, from 0.1 to less than 1, from 0.5 to less than I, from 0.8 to less than 1 , from 0.05 to 0.7, from 0.1 to 0.7, from 0.5 to 0.7, from 0.05 to 0.3, from 0.1 to 0.3, or from 0.05 to 0.1 . In various embodiments, the diameter ratio may have a ratio within a range bounded by any two of the following values: 0,05, 0,1 , 0.2, 0.3, 0.4, 0.5, 0.6. 0,7, 0.8, 0.9, and 1. In some embodiments, the diameter ratio comprises a ratio between a diameter of an inner channel and at least one middle annular channel. In some embodiments, the diameter ratio comprises a ratio between a diameter of the at least one middle annular channel and a diameter of at least one outer annular channel. In some embodiments, the diameter ratio comprises a ratio between a diameter of the inner channel and a diameter of at least one outer annular channel. In some embodiments, the diameter ratio comprises a ratio between a diameter of one of the at least one outer annular channel to a diameter of another of the at least one outer annular channel.

[0175] In some embodiments, a plurality of channels (i.e., inner channel 102, middle annular channel 101, outer annular channel 103) of a nozzle device described herein comprise a bluff body. In some embodiments, a bluff body is placed at a center of any one of plurality of channels of a nozzle device in z-axis direction. In some embodiments, a bluff body is used for achieving targeted gas flow (e.g., reduce / minimize gas flow) at a center of any one of a plurality of channels of a nozzle device in a z-axis direction. In some embodiments, a bluff body is configured to reduce fluid consumption in a center of any one of a plurality of channels of a nozzle device in a z-axis direction. Alternatively, in some embodiments, a bluff body minimizes a fluid flow cross sectional area of inner channel and / or helps achieve more efficient atomization process relative to a device without bluff body. In some embodiments, a gap between a bluff body and an. inner wall of an inner channel is a same dimension as a gap between an outer wall of a middle annular channel and an inner wail of an outer annular channel, ln some embodiments, a bluff body is a cylindrical rod introduced along z-axis of inner channel 102 of a nozzle device. In some embodiments, a bluff body is a cylindrical rod introduced along a direction of fluid flow of inner channel 102 of a nozzle device. In some embodiments, a bluff body is positioned adjacent to a first side of a channel of a nozzle device. In some embodiments, the bluff body is positioned adjacent to a second side of a channel of a nozzle device. In some embodiments, a ratio of a cross section area of a bluff body relative to a cross section area of any one of a plurality of channels of a nozzle device is in a range of fromabout more than 0 to about less than 1. In various embodiments, a ratio of a cross section area of a bluff body relative to a cross section area of any one of a plurality of channels of a nozzle device is within a range bounded by any two of the following values: 0.05, 0,1, 0,2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1. In some embodiments, a cross-section of a bluff body is shaped to be circular, rectangular, square, triangular or star-shaped. In some embodiments, a crosssection of the bluff body has at least one convex side or at least one concave side. In some embodiments, a bluff body is configured for cleaning a channel of a nozzle device described herein. In some embodiments, a nozzle device optionally includes forming a negative pressure hi any number of a pl urality of channels in a nozzle device.

[0176] In some embodiments, a droplet diameter is controlled or determined based on one or more of; densities of gas and liquid, liquid surface tension, pressure of atomizing gas, cross-section areas of nozzle for liquid and gas flows (nozzle dimensions), liquid and gas viscosities, ratio between gas and liquid flow rate, or a combination thereof. As many of the other factors are fixed based on tire design of the nozzle and / or the desired particles, during normal operation, it is typically the pressure of the gas that is used to control droplet diameter. In some embodiments, the flow rate of spray is controlled by, e.g., a pump supplying liquid to the nozzle.

[0175] To generate sprays of core-shell or matrix encapsulated subtnicron and micron- size droplets, in which the droplets consist of a core and one or multiple layers surrounding the core or one / multiple materials are dispersed as matrix, in addition to the liquid atomization theory described above, those immiscible liquid materials need to follow the phase rule and the surface tension relationship described in the article: S. Mao, M. S. Chafanverti-Wuertlnvein, H. Gaudio, and A. Kosmrlj, Designing the Morphology of Separated Phases in Multicomponent Liquid Mixtures, Phys. Rev. Lett. 125, 218003 (2020). More details are provided in PCT / US2023, 024520, filed June 6, 2023.

[0178] hi some embodiments, disclosed methods comprise forming atomized particles, wherein the atomized particles comprise a core, and at least one layer surrounding the core. In some embodiments, a core and at least one layer surrounding the core are immiscible. In some embodiments, a core comprises a liquid (e.g., a solution, an emulsion, a suspension, or a combination there of) ,

[0179] As noted pre viously, the disclosed method of liquid atomization is based on the shear-induced disintegration of a liquid film of a hollow cylindrical or cone shape jammed in between two co-flowmg gas streams. Hence, if the liquid film is not properly produced, the]iquid is not flowing or the liquid flow rate is not sufficient, atidfor the gas streams do notproperly flow and / or do not provide sufficient shear, the method will not provide proper disintegration of the l iquid into spray of droplets,[00180| In some embodiments, no spray or poor spray can be the result of numerous factors, including the liquid is of high viscosity leading to insufficient liquid flow, there is a clogging of fluids in supplying channels, liquid has suspended particles that are too big, or their aggregates are bigger than the liquid channel cross section, the liquid flow is too high, or the gas supply pressure is too low. To overcome those possible problems, the flow regime needs to be reestablished as disclosed above, by altering various process parameters, and geometrical dimensions and material of the channels. The geometry dimensions of the channel cross sections can be increased or decreased, the supply pressure of liquid and / or gas flows can be increased or decreased, the material of the channels can be chosen between glass, plastic or steel to withstand the applied pressures and provide chemical and physical compatibility, in some embodiments, a material of the channels comprise one or more properties selected for an anticorrosive property and a leach resistant, property. Thus, in some embodiments, a camera may be present to capture images of droplet formation, which is then analyzed and used to control the various process parameters if, for example, few or no droplets are seen.

[0181] In some embodiments, nozzle devices disclosed herein are configured to functionally attached to one or more appropriate dispensers. In some embodiments, a dispenser comprises a fluid reservoir fo.g., a gas reservoir, a liquid reservoir, a suspension reservoir, an emulsion reservoir, or a combination thereof)- In some embodiments, a fluid reservoir is in fluid communication with a nozzle device. For example, in some embodiments, nozzle devices are in fluid communication with two or more fluid reservoirs. In some embodiments, nozzle devices are in fluid communication with two or more fluid reservoirs, wherein at least one of the two or more fluid reservoirs is an aerosol can. In some embodiments, nozzle devices are configured to operate in batch processing devices. In some embodiments, nozzle devices are configured to operate using continuous processing devices. In some embodiments, a dispenser Comprises a microchip. Accordingly, in some embodiments, a system comprising a nozzle device is made from polydimethylsiloxane (PDMS) or an equivalent or derivative thereof. In some embodiments, a dispenser optionally includes forming a negative pressure in a dispenser.

[0182] In some embodiments, a nozzle device increases a surface area of dispensed particles (e.g.,, atomized particles) and, thereby, reduces evaporation time. For example, in some embodiments, nozzle devices are configured to dispense, atomized particles comprisingfragrance fluid compositions. A fragrance fluid composition generally comprises a high concentration of alcohol (e,g., ethanol) for reducing evaporation time. Accordingly, in some embodiments, nozzle devices advantageously reduce use of alcohol in fragrance fluid compositions. For example, in some embodiments, a nozzle device forms atomized particles comprising a fragrance fluid composition to increase surface area and, thereby, reduces evaporation time. In some embodiments, evaporation time of atomized particles comprising a fragrance fluid composition is in a range of from 5 milliseconds to 200 milliseconds, from 5 milliseconds to 150 milliseconds, from 5 milliseconds to 100 milliseconds, from 5 milliseconds to 50 milliseconds, from 5 milliseconds to 20 milliseconds, from 25 milliseconds to 200 milliseconds, from 25 milliseconds to 150 milliseconds, from 25 milliseconds to 100 milliseconds, from 25 milliseconds to 50 milliseconds, from 75 milliseconds to 200 milliseconds, from 75 milliseconds to 150 milliseconds, from 75 milliseconds to 100 milliseconds, from 125 milliseconds to 200 milliseconds, from 125 milliseconds to 150 milliseconds, or from 150 milliseconds to 200 milliseconds, hi some embodiments, evaporation time of atomized particles comprising fragrance fluid composition is in a range of from 10 mi lliseconds to 100 mill iseconds. In some embodiments, fragrance fluid compositions for use with nozzle devices comprises alcohol in a concentration ranging from 5% (v / v) to 65% (v / v), from 5% (v / v) to 60% (v / v), from 5% (v / v) to 50% (v / v), from 5% (v / v) io 40% (v / v), from 5% (v / v) to 30% (v / v), from 5% (v / v) to 20% (v / v), from 5% (v / v) to 10% (v / v), from 15% (v / v) to 65% (v / v), from 15% (v / v) to 60% (v / v), from 15% (v / v) to 50% (v / v), from 15% (v / v) to 40% (v / v), from 15% (v / v) to 30% (v / v), from 15% (v / v) to 20% (v / v), from 25% (v / v) to 65% (v / v), from 25% (v / v) to 60% (v / v), from 25% (v / v) to 50% (v / v), from 25% (v / v) to 40% (v / v), from 25% (v / v) to 30% (v / v), from 35% (v / v) to 65% (v / v), from 35% (v / v) to 60% (v / v), from 35% (v / v) to 50% (v / v), from 35% (v / v) to 40% (v / v), from 45% (v / v) to 65% (v / v), from 45% (v / v) to 60% (v / v), from 45% (v / v) to 50% (v / v), from 55% (v / v) to 65% (v / v), or from 55% (v / v) to 60%s (v / v). In some embodiments, fragrance fluid compositions for use with nozzle devices is essentially free of alcohol. In some embodiments, essentially free of alcohol refers to a concentration of alcohol of less than 5% (v / v), less than 4% (v / v), less than 3'% (v / v), less than 2% (v / v), or less than 1% (v / v). Accordingly, in some embodiments, use of nozzle de vices described herein reduces chance of fire hazard for dispensers, wherein dispensers are configured to dispense fragrance fluid composition comprising higher concentration of alcohol relative to fragrance fluid composition for use with the nozzle devices.

[0183] la some embodiments, nozzle devices described herein are configured for use in agriculture. For example, in some embodiments, nozzle devices are used for dispensing atomized particles comprising one or more fertilizers, one or more pesticides, or combinations thereof, hi some embodiments, atomized particles formed by nozzle devices described herein have higher surface area and, therefore, require less time to evaporate fluid content leaving pesticides on surfaces of treated crops. Similarly, atomized particles formed by nozzle devices described herein have higher surface area and, therefore, require less time to evaporate fluid content leaving fertilizers on surfaces of treated crops and allow absorption from the surface of the treated crop. Accordingly, nozzle devices described herein advantageously reduce use of pesticides, fertilizers, or combinations thereof in agriculture relative to conventional droplet dispensers , Moreover, in some embodiments, atomized water particles arc also used in crop irrigation. As described above, atomized water particles require less time for evaporation. Therefore, nozzle devices described herein advantageously increases humidity and reduce waler usage in crop irrigation,

[0184] In some embodiments, nozzle devices disclosed herein are configured for use hi fuel injection systems. For example, in some embodiments, nozzle devices are used for dispensing atomized particles comprising one or more fuels. In some embodiments, atomized particles comprising one or more fuels comprises a more efficient mixture of foci and gas. Accordingly, in some embodiments, nozzle devices disclosed herein improve function of fuel injection systems relative to other conventional fuel injection systems.

[0185] hi some embodiments, nozzle devices disclosed herein are configured forhumidifying systems. For example, in some embodiments, nozzle devices are used for producing atomized water particles. Atomized water droplets have smaller size that results in higher surface area and lesser evaporation time relative to larger water droplets. In some embodiments, small particles refer to atomized particles having a size in a range of from 0.01 pin to 50 pin, from 0.01 pm to 20 pm, from 0,01 pm to 10 pm, from 0.01 gm to I uni. from 0.1 pm to 50 pm, from 0.1 gm io 20 urn, from 0. 1 gm to 10 gm, from 0.1 pm to 1 gm, from 1 pm to 50 pm, from 1 pm to 20 pm, from 1 gm to 1.0 p m, from 10 pm to 50 pm, or from 10 pm io 20 gm. In some embodiments, small particles refer to atomized particles having a size of less titan 10 gm, less than 5 pm, less than I pm, less than 0.1 pm, or less than 0.01 gm. Accordingly, in some embodiments, nozzle devices disclosed herein improve fimction of humidifying systems relative to other conventional humidifying systems.

[0186] ln some embodiments, nozzle systems disclosed herein may include nozzles attached to an appropriate gas or liquid source via, e.g; , a pump. The nozzles may be configured to generate aerosols into a vessel, which may be a collection device. In some embodiments, a vessel may include a filter disposed in the path of the aerosol droplets. In some embodiments, a vessel may be under negative pressure. In some embodiments, a system is configured to operate using a batch process. In some embodiments, a system is configured to operate using a continuous process. In some embodiments, a nozzle device optionally includes forming a negative pressure in a nozzle device.

[0187] In some embodiments, one or more circuits may be present to control some or all of the process. The circuits may include one or more processors operably coupled to one or more non- transitory computer-readable storage devices. The circuits may be configured to control one or more valves. In some embodiments , a valve controls a flow of a fluid (e.g,, gas or liquid) through a channel of nozzle device described herein .

[0188] In some embodiments, the RTAD systems herein comprise a means for conveying the aerosol of fine droplets from the nozzle. In some embodiments, the aerosol of fine droplets is flowed into a drying chamber. In some embodiments, the flowing is via an outlet of a nozzle. In some embodiments, the flowing is via an inlet of a drying chamber. In some embodiments, the aerosol of fine droplets is flowed into a drying chamber using a syringe or peristaltic pump. In some embodiments, the systems comprise a drying chamber, the drying chamber adapted to flow a drying gas at a temperature of 0-45 °C so as to mix and dehydrate the plurality of atomized particles, thereby forming a dry particle aerosol.

[0189] In some embodiments, a drying chamber is adapted for drying under a negative pressure condition, hi some embodiments, a drying chamber comprises a vacuum pump for generating negati ve pressure condition. In some embodiments, a drying chamber is adapted for drying under negative pressure condition at room temperature. The RTAD methods described herein, in particular the drying processes, may be. performed at a negative pressure, and, optionally, may be performed in addition to atmospheric drying. In some embodiments, drying under negative pressure condition may be controlled based on a gas flow rate out of a drying chamber. In some embodiments, gas flow rate is controlled such that an absolute pressure in a drying chamber is lower than I kPa, ranges from 1 to 10 kPa, ranges from 10 to 50 kPa, ranges from 50 to 100 kPa, or ranges from 100 to 250 kPa.

[0190] In some embodiments, the drying chamber includes one or more inlet or one or more outlet. In some embodiments, one or more inlet or one or more outlet can be used tocontrol pressure and / or humidity within the drying chamber, in some embodiments, the drying chamber is connected to a gas source for providing one or .more gases into the drying chamber via one or more inlet of the drying chamber. In some embodiments, the gas source comprises a cylinder In some embodiments, the one or more gases comprise nitrogen, air, helium, or the like. In some embodiments, the gas source is configured to apply the one or more gases into the drying chamber. In some embodiments, flow of the gas source into the drying chamber is performed using a mass flow controller. Its some embodiments, the one or more gases are flowed into the drying chamber with drying gas flow rates in a range of from 0.01 liters / min to 500 liters / min, from 0.01 liters / min to 300 liters / min, from 0.01 liters / min to 100 liters / min, from 0.01 liters / min to 50 liters / min, from 0.01 liters / min to 20 liters / min, from 0.01 liters / min to 10 liters / min, from 0.1 liters / min to 500 liters / min, from 0.1 liters / min to 300 liters / min, from 0.1 liters / min to 100 liters / min, from 0.1 liters / min to 50 liters / min, from 0.1 liters / min to 20 liters / min, from 0.1 liters / min to 10 liters / min, from 2 liters / min to 500 liters / min, from 2 liters / min to 300 liters / min, from 2 liters / min to 100 liters / min, from 2 liters / min to 50 liters / min, from 2 liters / min to 20 liters / min, from 2 liters / min to 10 liters / min, from 5 liters / min to 100 liters / min, from 5 liters / min to 150 liters / min, from 5 liters / min to 500 liters / min, from 30 liters / min to 500 liters / min, from 30 liters / min to 300 liters / min, from 30 liters / min to 100 liters / min, from 30 liters / min to 50 liters / min, from 80 liters / min to 500 liters / min, from 80 liters / min to 300 liters / min, from 80 liters / min to 100 liters / min, from 200 liters / min to 500 liters / min, from 200 liters / min to 300 liters / min, or from 400 liters / min to 500 liters / min.

[0191] In some embodiments, the RTAD systems and methods disclosed herein are scalable for reaching capacities of kg / hour per setup. In some embodiments, the process is scalable for flowing one or more gases into the drying chamber with drying gas flow rates up to 100 kg / h, up to 200 kg / h, up to 360 kg / h, up to 400 kg / h, up to 500 kg / h, up to 630 kg / h, up to 700 kg'h, up to 1000 kg / h, up to 1250 kg / h, up to 2000 kg / h, up to 2500 kg / h, up to 5000 kg / h, up to 7500 kg / h or up to 10000 kg / h. hi some embodiments, a drying gas chamber optionally includes forming a negative pressure in a drying gas chamber.

[0192] hr some embodiments, the RTAD methods comprise controlling a flow of the dispersion through at least one channel of a nozzle device described herein so as to create a spray or aerosol of fine oz ultra- fine droplets or particles. In some embodiments, the one or more gases are flowed into the drying chamber with a Reynolds number within a range of from 100 to 100000, from 100 to 50000, from 100 to 25000, from 100 to 10000, from 100 to 1000, from 100 to 500, from 300 to 100000, from 300 to 50000, from 300 to 25000, from 300 to10000, from 300 to 1000, from 300 to 500, from 800 to 100000, from 800 to 50000, from 800 to 25000, from 800 to 10000, from 800 to 1000, from 5000 to 100000, from 5000 to 50000, from 5000 to 25000, from 5000 to 10000, from 15000 to 100000, from 15000 to 50000, from 15000 to 25000, from 35000 to 100000, from 35000 to 50000, or from 75000 to 100000.

[0193] In some embodiments, the gas source is configured to apply the one or more gases into the drying chamber at temperatures 0-200 °C for solvent evaporation from the sprayed and aerosolized droplets. In some embodiments, the gas source is configured to apply the one or more gases into the drying chamber at temperatures 25-200 °C, 25-175 *C, 0-45°C, 100-200 °C, 75-.175 °C, 50-125 °C, or 25-100 °C for solvent evaporation from the sprayed and aerosolized droplets. In some embodiments, the gas source is configured to apply the one or more gases into the drying chamber at temperatures 0-45 °C for solvent evaporation from the sprayed and aerosolized droplets. In some embodiments, the gas source is configured to apply the one or more gases into the drying chamber at temperatures 15-35 °C for solvent evaporation from the sprayed and aerosolized droplets. In some embodiments, the technique for solvent evaporation some or all of the aerosol of dry particles or droplets is exposed to a gas having a temperature between O°C and 120°'C. In some embodiments, the solvent evaporation is via lyophilization.

[0194] The use of lower temperatures, e,g., 0-45 °C, for solvent evaporation has several benefits. Not only do such temperatures eliminate the need for logistically challenging cold or hot chain infrastructure, but there is a reduced risk of catching fire to areas of the system. This protects the resulting particles and droplets, as well as the biological agents and species contained or present within. This also allows for a safer processing environment, especially when flammable solvents are used in the liquid, suspension or combination thereof. Thus, the reduced temperature allows for safer removal of solvent-based systems, and a reduced risk to thermal damage. Further, the use of reduced temperatures allows for safely removal of solvents with final concentrations in a range of from 1 ppm to 2,000 ppm, from 1 ppm to 1,000 ppm, from 1 ppm to 500 ppm, from 1 ppm to 200 ppm, from 1 ppm to 100 ppm, from 1 ppm to 50 ppm, from 1 ppm to 20 ppm, from 1 ppm to 10 ppm, from 1 ppm to 5 ppm, from 10 ppm to 2,000 ppm, from 10 ppm to 1,000 ppm, from 10 ppm to 500 ppm, from 10 ppm to 200 ppm, from 10 ppm to 100 ppm, from 10 ppm to 50 ppm, from 10 ppm to 20 ppm, from 40 ppm to 2,000 ppm, from 40 ppm to 1,000 ppm, from 40 ppm to 500 ppm, from 40 ppm to 200 ppm, from 40 ppm to 100 ppm, from 40 ppm to 50 ppm, from 100 ppm to 2,000 ppm, from 100 ppm to 1,000 ppm, from 100 ppm to 500 ppm, or from 100 ppm to 200 ppm.

[0195] In some embodiments, there is a cocurrent flow between the spray, ''aerosol of droplets and flow of drying gas supplied from the gas source. In some embodiments, the cocurrent flow is performed using a mass flow controller or a microfluidic flow controller, In some embodiments, an additional stream of gas from the gas source may be applied for spraying / aerosolization of liquid (as disclosed separately in the ‘866 application). In some embodiments, the addi tional stream of gas may be supplied in controlled way by means of a second mass flow controller or a second microfluidic flow’ controller,

[0196] Generally, mass flow controllers and microfluidi c flow controllers are both used to supply gases, vapors, or liquids to a system, but are selected based on the application. For example, a mass flow controller is generally known io be used in larger-scalc systems such as, for example, manufacturing, industrial, or gas delivery systems, whereas a microfluidic flow controller is generally known to be used in small-scale systems such as, for example, lab-on-a- chip systems or for drug delivery applications. Further, microfluidic flow controllers are generally known to provide greater precision in flow control over flow rates.

[0197] In some embodiments, the RTAD systems herein comprise one or more sensors or a probe thereof The one or more sensors or probes may be positioned at any number of components in RTAD systems for regulating characteristics throughout the RTAD methods disclosed herein, such as, for example, heating, cooling, humidity, pressure, etc. In some embodiments, the one or more sensors are located at a nozzle device, a drying chamber, a filter assembly, the one or more gas source(s), the mass flow controller(s), the microfluidic flow controller(s), or any other components in the RTAD system. In some embodiments, the one or more sensors are configured for measuring a temperature, a humidity, a flow rate, a pressure including partial pressures of each of one or more gases, a viscosity, or any other features relevant to a characteristic of the particl es, droplets, or aerosol of dried particles of droplets. In some embodiments, the one or more sensors comprise a hygrometer, a flow meter, a manometer, etc. In some embodiments, the one or more probes include a temperature control probe, a humidity probe, a pressure probe, or the like or a combination thereof.(00198] hi some embodiments, one or more Of sensor(s), mass flow controllerts) and microfluidic flow controllers) are guided by one or more computer system. In some embodiments, one or more computer may be present to control some or all of foe process. The computer may include one or more processors operably coupled to one or more non-transitory computer-readable storage devices. The computer may be configured to control one or more valves. In some embodiments, a valve controls a flow of a fluid (e.g., gas or liquid) through achannel of nozzle device described herein. The computer may be configured to control flow rates of one or more streams of liquid, gas, or a combination thereof.

[0199] In some embodiments, the disclosed RTAD systems comprise a particle collector for collection of dry particulates from the two-phase gas-particle flow stream. In some embodiments, the drying chamber includes one or more outlet for conveying sprayed or aerosolized droplets or particles to a particle collector. In some embodiments, die particle collector comprises a filter assembly. In some embodiments, die filter assembly is positioned at a bottom of a drying chamber. In sonic embodiments, a filter assembly comprises a membrane filter. In some embodiments, the membrane filter comprises a filter selected from polytetrafluoroethylene (PTFE), polypropylene, polyethersulfone, nylon, polyvinylidene fluoride (PVDF), or the like. In some embodiments, the membrane filter has a charged surface. In some embodiments, the membrane filter is hydrophobic. In some embodiments, a filter assembly comprises a cyclone separator, which may be utilized for particle collection from the gas-particle flow stream (see FIG. 4) and organization of continuous dehydration and powder production processes, hi some embodiments, a particle collector optionally includes forming a negative pressure in a particle collector.

[0200] An exemplary method of an RTAD method for room temperature dehy dration of biologies is schematically depicted in F IG. 4. The process is based on rapid evaporation of solvents from ultra-fine small droplets, sprayed into a closed drying vessel and subjected to a stream of room-temperature / near room temperature drying gas. The special atomization method is used to produce ultra-fine droplets and it has been disclosed separately in the ‘866 application. In some embodiments, the median droplet size in the spray is usually less than 20 microns for solutions with surface tension equal to that of water at room temperature (72 mN / m).

[0201] The size of the generated spray droplets is proportional to surface tension of sprayed liquid and inversely proportional to the utilized atomizing pressure. For typical biologic solution, the surface tension is smaller than that of pure water by the factor 2-3, so spray droplets containing biological material like virus particles of nanoscale size, including enveloped or non-enveloped viruses, have typical median diameters less than 10 microns. Correspondingly, the solvent in such small droplets evaporates rapidly even in roomtemperature gas stream, and a droplet with dissolved biological material converts into a dry particle (containing solute material) within fractions of a second.

[0202] fa some embodiments, the RTAD systems and methods disclosed herein may be adapted for be reversibly retrofited on conventional or existing spray drying equipment. In some embodiments, retrofitting includes changing a nozzle in spray drying equipment with a nozzle device described herein. In some embodiments, retrofiting includes connecting an inlet of a nozzle device herein to an outlet of a chamber or container holding a liquid, suspension or combination thereof, or an inlet of an inner channel and / or outer annular channel of a nozzle device herein to an outlet of a gas source, on a conventional or existing spray drying equipment. In some embodiments, retrofitting includes the use of an adapter with one or more heads, depending on the number of outlets to be connected. In some embodiments, retrofiting includes changing a drying chamber in spray drying equipment with a drying chamber described herein. In sonic embodiments, retrofitting includes connecting an inlet of a drying chamber described herein with an outlet of a nozzle of a conventional or existing spray drying equipment. In some embodiments, retrofiting includes connecting one or more inlet or outlet of one or more of a nozzle device or drying chamber described herein with a flow controller. In some embodiments, retrofitting includes screwing, welding, fitting, or the like between system components to be connected, in some embodiments, the retrofitting with a nozzle device described herein allows for improving a gas-to-spray mixing in a drying chamber and / or particle collector (e.g., using a cyclone separator or filter assembly) so as to capture <10 micrometer size dry particles. In some embodiments, the retrofitting optionally includes forming a negative pressure in a drying chamber.

[0203] hi some embodiments, the RTAD systems and methods disclosed herein allow for conservation of electric energy power and CO2 emissions due to a reduction in energy consumption. In some embodiments, the reduction in energy consumption and / or CO2 emissions is proportional to a decrease in temperature used for drying gas in the disclosed methods and systems, e.g., a reduction in temperature from 100-251PC ' to 20-45°C of drying gas. In some embodiments, the disclosed methods and systems allow for conservation based on a scale of the system, such as for laboratory scale or a manufacturing scale. In some embodiments, the disclosed methods and systems allow for electric power conservation at a laboratory scale of up to about 1 kW, up to about 5 kW, up to about 1.0 kW, up to about 50 kW, or up to about 100 kVV. In some embodiments, the disclosed methods and systems allow for electric power conservation at a manufacturing scale of up to about 1 MW, up to about 5 MW, up to about 10 MW, up to about 50 MW, or up to about 100 MW. In some embodiments, the disclosed methods and systems allow for reduction in CO2 emissions at a laboratory scale ofup to about 1 ton, up to about 2 tons, up to about 5 tons, up to about 10 tons, or up to about 100 tons per year. In some embodiments, the disclosed methods and systems allow for reduction in CO;2 emissions at a manufacturing scale of up to about 1000 tons, up to about 5000 tons, up to about 10000 tons, up to about 50000 tons, or up to abou t 100000 tons per year.

[0204] In some embodiments, the RTAD systems and methods disclosed herein allow for an increase in particle or droplet solubility. Such an increase in solubility allows for reducing aggregating particles or biological materials therein as compared to conventional spray drying methods and systems. In some embodiments, the RTAD systems and methods disclosed herein allow for an increase in ratio of dried non-aggregated particles or active biological materia! to dried aggregated particles or active biological material compared to conventional spray drying systems, ail while keeping particle size and intact biological material after drying. In some embodiments, the RTAD systems and methods disclosed herein allow for producing an amount of aggregated particles and / or inactive biological material to less than 10%, to less than 5%, io less than 1%, to a. range of between 1 to 10%, to a range of between 1 to 9%, to a range of between 1 to 8%, to a range of between I to 7%, to a range of between I to 6%, to a range of between 1 to 5%, to a range of between 1 to 4%, to a range of between 1 to 3%, or to a range of be tween 1 to 2 %.

[0205] In some embodiments, the RTAD systems and methods disclosed herein allow for an increase in concentration of active agent and also inactive agent in the particles. In traditional spray drying systems, increasing a concentration of active agent in the particles is more likely to form aggregates of the resulting particles or droplets and / or active biological material. The RTAD systems and methods disclosed herein result in a reduction in amount of dried aggregated particles and / or active biological material relative to dried non-aggregated particles and / or active biofogical material, thereby allowing for a formulation of the particle to include a greater concentration of the active agent that is non-aggregated, e.g., an active biological agent or other active agents discussed in more detail below, in addition, increasing overall concentration of solute (including both active and inactive agents) in liquid formulation results in increase of size of produced particles, because the size of produced dry particles is proportional to diameter of sprayed droplets multipliedby cubic root of the solids concentration in liquid formulation. hr traditional spray drying using nozzles generating droplets with diameters >40 micron., the solute concentrations are usually limited to 1 -2 wt% for manufacturing of inhalable powder formulations with >80% of dry particles smaller than 5 micron in size. In contrast, generation of sub-20 micron diameter droplets in RTAD systemenables usage of higher solute concentrations than in traditional spray drying for production of inhalable powders. In some embodiments, the RTAD systems and methods disclosed herein allow for a 1-10% increase in concentration, a 1-20% increase in concentration, a 5-25% increase in concentration, a 10-20 increase in concentration, a 10-25% increase in concentration, a 5-30% increase in concentration, a 20-40% increase in concentration, a 25- 50% increase in concentration, a 50-75% increase in concentration, a 75-95% increase in concentration, a 70-100% increase in concentration, a 50-100% increase in concentration, a 40- 90% increase in concentration, a 70-90% increase in concentration, a 90-100% increase in concentration, an 80-100% increase in concentration, an 80-90% increase in concentration, a 50-75% increase in concentration, a 75-100% increase in concentration, a 100-200% increase in concentration, a 200-500% increase in concentration, a 500-1000% increase in concentration, or a greater than 1000% increase in concentration of active agent in the particles and / or of overall solute in initial liquid formulation.

[0206] In some embodiments, the RTAD systems and methods disclosed herein allow for a preservation of a formulation, such as, for example, a formulation for submission to FDA under 505(b)(2) provision. Because the RTAD system does not change an active agent, e.g., an acti ve pharmaceutical ingredient (API), or an excipient of the particles, the dried formulation is substantially similar to the original formulation absent water.

[0207] Extensive verification of the disclosed method and sy stem has been performed, as provided in the Examples below using a laboratory-scale prototype of the RTAD systems described herein.

[0208] The disclosed techniques can be used in a variety of industries and applications, including, e.g., the chemical industry (e.g., spray drying, encapsulation, spray fluidized bed coating), the biopharmaceutical, pharmaceutical and biotechnological industry (e.g., spray drying, encapsulation, to provide services of drag dehydration to such companies and / or to manufacture dehydrated drug products for sale to patients), by equipment manufacturers, healthcare industry and medical devices (e.g., medical diagnostics and drug delivery, decontamination or humidification and dust fighting, or decontamination), fragrances and perfumes, material manufacturers (e.g., 3D printing, laser assisted powder deposition), flavor preservation, cosmetics industry, agriculture industry, food industry, food and nutrients manufacturing, laundry care and detergents, recreation industry, and automobiles, aircrafts, gas turbines, power generation (e.g., fuel injection).

[0209] In addition, governmental entities may employ the disclosed approach to create emergency stocks of drugs, which do not require refrigeration and freezing during emergency events involving electricity outages.

[0210] In some embodiments, described herein are methods of decontaminating a composition. In some embodiments, the decontaminating process can comprise: causing a suspension or solution of one or more active agents to be dispensed as an aerosol of dry particles or droplets from a nozzle. In some embodiments, one or more active agents comprise decontaminating agent. The methods may further include atomizing a dispersion of one or more decontaminating agents in a liquid, suspension or combination thereof using a nozzle device, thereby forming an aerosol containing a plurality of atomized particles. The methods may further include mixing and dehydrating the plurality of atomized panicles using a drying gas at a temperature of 0-45 °C so as to sufficiently dry the plurality of atomized particles, thereby forming an aerosol of dry' particles comprising the one or more decontaminating agents.

[0211] In some embodiments, described herein are methods of humidifying or dehumidifying a surface or composition. In some embodiments, the humidifying or dehumidifying processes can comprise: causing a suspension or solution of the active agents to be dispensed as an aerosol of dry particles or droplets from a nozzle. In some embodiments, one or more active agents comprise one or more humidifying agent, one or more dehumidifying agents, or combinations thereof. The methods may further include atomizing a dispersion of one or more materials (e.g., active agents) in a liquid, suspension or combination thereof using a nozzle device, thereby spraying an aerosol containing the plurality of atomized particles encapsulating one or more active agents (e.g., a humidifying agent, a dehumidifying agent). The methods may further include mixing and dehydrating the plurality of atomized particles using a drying gas at a temperature of 0-45 *C so as to sufficiently dry the plurality of atomized particles, thereby forming an aerosol of dry particles comprising the one or more active agents (e.g., a humidifying agent, a dehumidifying agent). In some embodiments, tire method further includes humidifying or dehumidifying the surface or composition until a desired relative humidity is achieved.

[0212] In some embodiments, described herein are methods of nebulizing of a liquid ty.g., solution, suspension, emulsion or combinations thereof) for delivery of aerosols of submicron-size particles or droplets. Such aerosols may be used for humidification purposes or inhalation of the particles or droplets for therapeutic purposes. In some embodiments, the nebulizing can comprise: causing a suspension or solution of the active agents to be dispensedas all aerosol of dry particles or droplets from a nozzle. In some embodiments, die suspension or solution comprises a humidifying agent In some embodiments, the suspension or solution comprises an active agent.

[0213] In some embodiments, described herein are methods of nebulizing of a liquid (e.g., solution, suspension, emulsion or combinations thereof) tor delivery of submicron-size particles or droplets in various delivery applications. In some embodiments, particles or droplets may be delivered transdermally, such as, for example, using microneedle patches. In some embodiments, particles or droplets may be delivered orally or nasally. In some embodiments, the particles or droplets may be deli vered through a dry powder inhaler (DPI), a nebulizer, or the like.

[0214] The methods may further include atomizing a dispersion of one or mote humidifying agents and / or acti ve agents in a liquid, suspension or combination thereof using a nozzle device, thereby spraying an aerosol containing the plurality of atomized particles encapsulating one or more active agents. The methods may further include mixing and dehydrating the plurality of atomized particles using a drying gas at a temperature of 0-45 °C so as to sufficiently dry the plurality of atomized particles, thereby forming an aerosol of dry particles comprising the humidifying agent and / or active agent.Compositions for use in R I AD methods and systems

[0215] Disclosed herein are compositions comprising one or more active agents. In some embodiments, a composition is a liquid (e.g.. a solution, a suspension, an emulsion, or a combination thereof). In some embodiments, a composition is suitable for atomization. In some embodiments, a composition upon passing through a nozzle device forms atomized particles. In some embodiments, atomized particles upon being mixed and dehydrated forms aerosols of dry particles.

[0216] In some embodiments, compositions described herein comprise a viscosity in a range of from I cP to 2000 cP, from I cP to 1500 cP, from 1 cP io 1200 cP, from 1 cP to WOO cP, from 1 cP to 800 cP, from i cP to 500 cP, from 1 cP to 300 cP, from 1 cP to 100 cP, from 1 cP to 50 cP, from 100 cP to 2000 cP, from 100 cP to 1500 cP, from 100 cP to 1200 cP, from 100 cP to 1000 cP, from 100 cP to 800 cP, from 100 cP to 500 cP, from 100 cP to 300 cP, from 500 cP to 2000 cP, from 500 cP to 1500 cP, from 500 cP to 1200 cP, from 500 cP to 1000 cP, from 500 cP to 800 cP, from 1000 cP to 2000 cP, from 1000 cP to 1500 cP, from 1000 cP to 1200 cP, or from 1500 cP to 2000 cP. In some embodiments, a composition is a highviscosity liquid (e.g. , a solution, a suspension, an emulsion, or a combination thereof / . In some embodiments, a high viscosity refers a viscosity is at least ten times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times or more than a viscosity of water under die same condition. Alternatively, in some embodiments, a high viscosity refers to a viscosity that is greater than 10 cP, greater than 20 cP, greater than 30 cP, greater than 40 cP, greater than 50 cP, greater than 100 cP, greater than 200 cP, greater than 500 cP, or more at 20CC, in some embodiments, a high viscosity refers to a viscosity that is greater than 10 cP, greater than 20 cP, greater than 30 cP, greater than 40 cP, greater than 50 cP, greater than 100 cP, greater than 200 cP, greater than 500 cP, greater than 1000 cP, greater than 1500 cP or more at 25 "C, Accordingly, in some embodiments, a composition comprises a viscosity of more than 100 cP at 20 °C, In some embodiments, a composition comprises a viscosity of more than 100 cP at 25 °C In some embodiments, a composition comprises viscoelastic properties.

[0217] In some embodiments, a viscosity of a liquid (e.g., solution, suspension, emulsion, or combinations thereof) is based on a total weight of the particles in a liquid (e.g., solution, suspension, emulsion, or combination thereof) in an amount ranging from about 1 wt% to about 1 IK) wt% (for example, from about 1 wt% to about I 0 wt%, from about 1 wt% to about 15 wt%, from about 1 wt% to about 20 wt%, from about 1 wt% to about 25 wt%, from about 1 wt% to about 30 wt%, from about 1 wt% to about 35 wt%, from about 1 wt% io about 40 wt %, from about 1 wt% to about 45 wt%, from about 1 wt% to about 50 wt%, from about 1 wt% to about 55 wt%, from about 1 wt% to about 60 wt%, from about 1 wt% to about 65 wt%, from about 1 wt% to about 70 wt%, from about I wt% to about 75 wt%, from about 1 wt% to about 80 wt%, from about I wt% to about 85 wt%, from about I wt% to about 90 wt%, from about 1 wt% to about 95 wt%, or from about 1 wt% to about 100 wt%).

[0218] In some embodiments, suspensions described herein comprise plurali ty of solid particles having a size in a range of from 1 nm to 1000 nm, from 1 nm to 800 nm, from I nm to 500 nm. from 1 nm to 300 nm, from 1 nm to 100 nm, from 100 nm to 1000 nm, from 100 nm to 800 nm, from 100 nm to 500 nm, from 100 nm to 300 nm, from 300 nm to 1000 nm, from 300 nm to 800 nm, from 300 nm to 500 nm, from 500 nm to 1000 nm, from 500 nm to 800 nm, or from 800 nm to 1000 nm. In some embodiments, a suspension comprises a plurality of solid particles having a size of at least 5 times, at least 10 times, at least 20 times, at least 50 times , or at least 100 times smaller than a diameter of a channel through which the suspension is flowing through. In some embodiments, a suspension comprises a plurality' of solid particleshaving a size of at least 10 times smaller than a diameter of a channel through which the suspension is flowing.

[0219] In some embodiments, compositions described herein comprise a pH of about 2, about 2.3, about 2.5, about 2.8, about 3, about 3.3, about 3.5, about 3.8, about 4, about 4.3, about 4.5, about 4.8, about 5, about 5.3, about 5.5, about 5.8, about 6, about 6.3, about 6.5, about 6.8, about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8,4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, or about 9. In some embodiments, compositions comprise pH in a range of from 2 to 9, from 2 to 8, from 2 to 7, from 2 to 6, from 2 to 5, from 2 to 4, from 2 to 3, from 3 to 5, from 3 to 7, from 4 to 6, from 6 to 8, from 7 to 9, from 7 to 7.5, from 7.5 to 8, from 8 to 8,5, from 8.5 to 9, or from 7 to 8.5. In some embodiments, compositions comprise pH in a range of from 2 to 9. In some embodiments, compositions comprise pH of less than 7. In some embodiments, compositions comprise pH of greater than 7.

[0220] In some embodiments, compositions described herein comprise a physiological osmolarity. In some embodiments, a physiological osmolarity refers to an osmolarity between 280 mOsm / L to about 310 mOsm / L. In some embodiments, atomized droplets comprise an osmolarity of greater than about 250 mOsm / L, greater than about 300 mOsm / L, greater than about 350 mOsm / L, greater than about 400 mOsm / L, or greater than about 500 mOsm / 'L. In some embodiments, atomized droplets comprises an osmolarity in a range of from 100 mOsm / L to about 2000 mOsm / L, from 100 mOsm / L to about 1500 mOsm / L, from 100 mOsm / L to about 1000 mOsm / L, from 100 mOsm / L to about 500 mOsm / L, from 500 mOsm / L to about 2000 mOsm / L, from 500 mOsm / L to about 1500 mOsm / L, from 500 mOsm / L to about 1000 mOsm / L, or from 1000 mOsm / L to about 2000 mOsm / L.

[0221] In some embodiments, compositions described herein comprise a particle to non-particle weight ratio ranging from about 0 to about 2, such as from about 0.5 to about i .9, or from about 1 .3 io about. 1 .4. In various embodiments, tire composition may have a particle to non-particle weight ratio within a range bounded by any two of the following values: 0, 0. 1 , 0.2, 03, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, i , Li , L2, 13, 1.4, 1.5, 1.6, 1.7, LS, 1.9, or 2.

[0222] In some embodiments, compositions described herein comprise a particle concentration ranging from 0.1 pg / mL to 2000 mg / mL, In some embodiments, compositions described herein comprise a particle concentration ranging from 0.1 pg / mL -I mg / mL, 1 pg / mL -10 mg / mL, 10 pg / mL -100 mg / mL, 100 pg / mL -500 mg / mL, 500 pg / mL -1000 mg / mL, or 1000 pg / mL -2000 mg / mL.Active Agents

[0223] In some embodiments, active agents comprise a nucleic acid. In some embodiments, a nucleic acid is a double stranded nucleic acid (e.g., DNA). In some embodiments, a nucleic acid is a single stranded nucleic acid (e.g., a RNA, wherein the RNA comprises a mRNA, a rRNA, a tRNA, a non-coding RNA, a long non-coding RNA, a microRNA (miRNA), a small interfering RNA (siRNA), and a single-stranded RNA (ssRN A)).

[0224] In some embodiments, active agents comprise a virus. In some embodiments, a virus comprises one or more of wild-type (natural) viruses, modified viruses, viral vectors, recombinant viruses, retro viruses (e.g., lendviruses and y-rctroviruses), adenoviruses (AdVs), Epstein-Barr viruses (EBVs), Modified Vaccinia virus Ankara (MVAs), bacteriophages, arenaviruses, alphaviruses, adeno-associated viruses (AA Vs), baculoviruses, vaccinia viruses, herpes simplex viruses, and poxviruses. The term “bacteriophage” as used herein refers to a virus that infects bacteria, hi some embodiments, a virus is a live-attenuated virus or a deactivated virus. In some embodiments, an adenovirus is a self-complementary adenovirus.

[0225] In some embodiments, a nucleic acid described herein is a vector. In some embodiments, a vector comprises a therapeutic nucleic acid. In some embodiments, a therapeutic nucleic acid encodes a protein that upon expression prevents or cures a condition. In some embodiments, a therapeutic nucleic acid comprises nucleotides in a range of from 5 to 100, 10 to 100, 20 to 100, 50 to 100, 70 to 100, or more nucleotides. In some embodiments, a therapeutic nucleic acid comprises nucleotides in a range of from 0.1 kb to 5 kb, from 0.5 kb to 5 kb, from 1 kb to 5 kb, from 2 kb to 5 kb, from 3 kb to 5 kb, or from 4 kb to 5 kb. hi some embodiments, a vector is a viral vector. In some embodiments, a viral vector is derived from one or more types of viruses, including but not limited to retroviruses (e.g.,, tend viruses and y- retroviruses), adenoviruses (AdVs), Epstein-Barr viruses (EBVs), Modified Vaccinia virus Ankara (MV As), arenaviruses, alphaviruses, adeno-associaied viruses (AAVs), baculoviruses, vaccinia viruses, herpes simplex viruses and poxviruses. In some embodiments, a viral vector is a live-attenuated viral vector or a deactivated viral vector. In some embodiments, a viral vector is an adenovirus viral vector (AdV). In some embodiments, an adenovirus viral vector is derived from an AdVI serotype, an AdV2 serotype, AdV3 serotype, an AdV4 serotype, AdV5 serotype, an AdV6 serotype, AdV7 serotype, an AdV8 serotype, an AdV9 serotype, an AdV 10 serotype, an AdVll serotype, an AdV 12 serotype, an AdV~rhl0 serotype, and any combination, derivative, or variant thereof. In some embodiments, an adenovirus viral vectoris a self-complementary AdV (sCAdV) vector. In some embodiments, a viral vector is an adeno- associated viral vector. In some embodiments, an adeno-associated viral vector is derived from an AAV1 serotype, an AAV2 serotype, AAV3 serotype, an AAV4 serotype, AAV5 serotype, an AAV6 serotype, AAV7 serotype, an AAV8 serotype, an AAV9 serotype, an AAV10 serotype, an AAV1 1 serotype, an AAV12 serotype, an AAV-rhlO serotype, and any combination, derivative, or variant thereof. In some embodiments, an adeno-associated viral vector is a self-complementary AAV (sc AAV) vector.

[0226] In some embodiments, an active agent comprises one or more microorganisms. In some embodiments, a microorganism comprises a virus, a bacterium, a bacteriophage, or a combination thereof, in some embodiments, a microorganism is alive, dead, or attenuated for generating an immune response in a subject. In some embodiments, a virus comprises an enveloped virus, a non-enveloped virus, an enveloped viral vector, a non~enveloped viral vector, or a combination thereof. In some embodiments, a nozzle device described herein is used for administering a microorganism in a subject in need thereof.

[0227] Any vector systems can be used in active agents provided herein including, but not limited to, plasmid vectors, retroviral vectors, lentivirai vectors, adenovirus vectors, poxvirus vectors; herpesvirus vectors and adeno-associated vims vectors, recombinant herpes simplex virus (HSV) vectors, recombinant poxvirus vectors, recombinant parvovirus vectors, recombinant papillomavirus vectors, recombinant simian virus vectors, recombinant alphavirus vectors, recombinant polyoma virus vectors, recombinant picomavirus vectors, recombinant lentivirus vectors, recombinant retrovirus vectors, recombinant adenovirus vectors, recombinant adenovirus associated virus (AAV) vectors, recombinant flavivirus vectors, recombinant rhabdovirus vectors, recombinant measles virus vectors, recombinant Newcastle disease virus vectors, and recombinant bacteriophage vectors, etc.

[0228] In some embodiments, an active agent comprises a protein. In some embodiments, a protein comprises a polypeptide chain of greater than 10 amino acids, greater than 20 amino acids, greater than 50 amino acids, greater than 100 amino acids, greater than 500 amino acids, greater than 1000 amino acids, greater than 1500 amino acids, greater than 2000 amino acids, or more, hi some embodiments, a protein comprises a polypeptide chain of at least 10 amino acids, at least than 20 amino acids, at least than 50 amino acids, at least than 100 amino acids, at least than 500 amino acids, at least than 1000 amino acids, at least 1500 amino acids, at least 2000 amino acids, or more. In some embodiments, a protein comprises a polypeptide chain has a molecular weight of greater than I kDa, greater than 2 kDa, greaterthan 5 kDa, greater than 10 kDa, greater than 20 kDa, greater than 30 kDa, greater than 40 kDa, greater than 50 kDa, or more. In some embodiments, a protein comprises a polypeptide chain has a molecular weight of at least 1 kDa, at least 2 kDa, a t least 5 kDa, at least 10 kDa, at least. 20 kDa, at least 30 kDa, at least 40 kDa, at least 50 kDa, at least 100 kDa, at least 150 kDa, or more. In some embodiments, a protein comprises an antibody, an antigen, an enzyme, a hormone, or a functional fragment thereof. In some embodiments, an antibody is a monoclonal antibody (mAh) or antibody-drug conjugate. In some embodiments, active ingredients comprise at least one of metal-organic frameworks, stem and functional cells, functional nanoparticles, virus-like particles, viral vectors, DMAs, carbon nanotubes, liposomes, polymcrsotncs, polyplexcs, quantum dots, nanocrystais, hydrogels, and cxosotncs. In some embodiments, a nozzle device described herein is used for administering an antibody, an antigen, an enzyme, a hormone, or a functional fragment thereof in a subject in need thereof.

[0229] In some embodiments, an active agent comprises an imaging agent, in. some embodiments, an imaging agent comprises one or more contrast agents, one or more radiopharmaceutical agents, or combinations thereof. In some embodiments, a nozzle device described herein is used for administering an imaging agent in a subject in need thereof.

[0230] In some embodiments, an active agent comprises a vaccine. In some embodiments, a vaccine comprises a microorganism, a nucleic acid, a virus, a protein, an antigen, or a functional fragment thereof In some embodiments, a vaccine induces an immunological response in subject that is administered with the vaccine.

[0231] In some embodiments, active agents comprise virus particles. In some embodiments, virus particles are selected from AAV2 virus particles, AAV5 virus particles, human cytomegalovirus particles, Epstein Bar virus (EBV), or combinations thereof. In some embodiments, a nozzle device described herein is used for administering a composition comprising virus particles.

[0232] In some embodiments, an active agent comprises a small molecule. In some embodiments, a small molecule comprises a molecular weight of up to 1000 Da. In some embodiments, a small molecule comprises a molecular weight of less than 1000 Da, less than 900 Da, less than 800 Da, less than 700 Da, less than 600 Da, less than 500 Da, less than 400 Da, less than 300 Da, less than 200 Da, or less than 100 Da, In some embodiments, a small molecule comprises a molecular weight in a range of from 10 Da to 1000 Da, from 10 Da to 800 Da, from 10 Da to 500 Da, from 10 Da to 300 Da, from 50 Da to 1000 Da, from 50 Da to 800 Da, from 50 Da to 500 Da, from 50 Da to 300 Da, from 100 Da to 1000 Da, from 100 Dato 800 Da, from 100 Da to 500 Da, from 100 Da to 300 Da, from 300 Da to 1 OCX) Da, from 300 Da to 800 Da, from 300 Da to 500 Da, from 500 Da to 1000 Da, from 500 Da to 800 Da, or from 800 Da to 1000 Da. hi some embodiments, a nozzle device described herein is used for administering a small molecule to a subject in need thereof.

[0233] In some embodiments, active agents described herein comprise a concentration of active agent in particles ranging from 0.1 pg / mL io 3000 mg / mL. In some embodiments, compositions described herein comprise an active agent concentration ranging from 0, 1 pg / mL -1 mg / mL, 1 pg / mL -10 mg / mL, 10 pg / mL -100 mg / mL, 100 pg / mL -500 mg / mL, 500 pg / mL -1000 mg / mL, 1000 pg / mL -2000 mg / mL, 2000 pg / mL -2500 mg / mL, or 2500 pg / mL -3000 mg / mL, adjuvants

[0234] in some embodiments, a composition comprises one or more adjuvants. An adjuvant may be a substance that accelerates, prolongs and / or enhances the quality and / or strength of an immune response to an active agent., in comparison t o the adminis tra tion of the acti ve agent alone, thus, reducing the quantity of active agent necessary' in any given vaccine, and / or the frequency of injection necessary in order to generate an adequate immune response to the active agent of interest In some embodiments, one or more adjuvants includes an aluminum hydroxide (e.g., aihydrogelj, aluminum-salt, aluminum phosphate, and the like. In some embodiments, one or more adjuvants includes polysaccharides; peptides and dipeptides; oligonucleotides; bacterial products from the outer membrane of Gram-negative bacteria, lipopolysaccharides (LPS), muramyl dipeptides and derivatives thereof; liposomes, in particular neutral liposomes, liposomes containing the composition and optionally cytokines; non-ionic block copolymers; synthetic lipopeptide derivatives; peptidoglycan; heat shock proteins; dsRNA and synthetic derivatives thereof; polycationic peptides; taxo1; fibronectin; flagellar; imidazoquinoline; cytokines with adjuvant activity, in particular interleukin-(iL-)2, IL-6, IL-7, IL-18, type I and II interferons, in particular interferon-gamma, TNF-alpha; synthetic oligopeptides; or non-ionic block polymers, in some embodiments, one or more adjuvants includes any water in oil emulsion, any oil in water emulsion that contains one or more of the following constituents: any pharmaceutically acceptable oil, tween-80, sorbitan trioleate, alpha-tocopherol, cholecalcifcrol or any of the analogues and derivatives of the molecules thereof, or calcium phosphate or any combination of the adjuvants.

[0235] ln some embodiments, a composition comprises one or more lipids. In some embodiments, a lipid comprises a cationic lipid, an anionic lipid, a zwitterionic lipid, or an uncharged lipid. In some embodiments, one or more lipids stabilize one or more active agents. In some embodiments, one or more lipids encapsulate one or more active agents.

[0236] In some embodiments, a composition comprises lipid nanoparticles (LNPs). In some embodiments, LNPs comprise one or more lipids, and one or more surfactants. In some embodiments, a lipid comprises a cationic lipid, an anionic lipid, a zwitterionic lipid, or an uncharged lipid. In some embodiments, a surfactant comprises a cationic surfactant, an anionic surfactant, or a zwiterionic surfactant In some embodiments, one or more surfactants stabilize LNPs. In some embodiments, the lipids comprise modified lipids. In some embodiments, modified lipids comprise pegylated lipids, in some embodiments, surfactants comprise modified surfactants. In some embodiments, modified surfactants comprise pegylated surfactants. In some embodiments, LNPs comprise one or more ionizable lipids, phospholipids, cholesterols, and PEG lipids. In some embodiments, LNPs comprise a vector described herein.

[0237] In some embodiments, compositions comprise one or more viscosity modifier. In some embodiments, viscosity modifiers comprise viscosity lowering agents, viscosity enhancing agents, or combinations thereof. Non-limiting examples of viscosity lowering agents include ethanol, isopropyl alcohol, water, arginine, ornithine monohydrochloride, phenylalanine, thiamine phosphoric acid ester chloride dihydrate, benzenesulfonic, acid and pyridoxine hydrochloride. Non-limiting examples of viscosity enhancing agents include sorbitol, maltitol, sucrose, fructose, dextrose, maltodextrin and polydextrose.

[0238] In some embodiments, compositions comprise one or more buffers. Nonlimiting examples of buffer includes phosphate buffered saline (PBS); 4-(2-hydroxyethy!)-l- piperazineethanesulfonic acid (HEPES); 2-(N-Morpho1ino)-ethanesuIfonic acid (MES); piperazine-N,N'-bis(2-ethanesulfbnic acid) (PIPES); N-(2-acetamida)-2-aminoethanesulfonic acid (ACES); 3-(N-inorpholino)propanesulfonic acid (MOPS); 2-{| 1 ,3-Dihydroxy-2- (hydroxyanethy1)propan-2-yl]amino } ethane- 1 -sulfonic acid (TES ); N ,N-Bis(2- hydroxyethyl)glyeine (Bicine)' 3- ]4-(2-hydroxyethyl)piperazin- 1 -yl ]propane~ 1 -sulfonic acid (HEPPS or EPPS); N-[l ,3-dihydroxy-2-(hydroxymethyl)propari-2-yl(glycine (Tricinc); and 2- amino-2-(hydroxymethyl)propane- 1 ,3 -diol (Tris),Dried atomized particles

[0239] In some embodiments, atomized particles described herein are further processed to dry and form dried atomized particles. Accordingly, in some embodiments, compositions comprise dried atomized particles. In some embodiments, dried atomized particles comprise one or more active agents described herein. In some embodiments, dried atomized particles re tain an activity of at least 60 %, at least 70%, at least 80%, at least 90% or at least 95% relative to activity of atomized particles before drying, wherein the activity refers to one or more of an enzymic activity, a binding activity, an immunogenic activity, or a combination thereof. Accordingly, in some embodiments, dried atomized particles comprise at least 90% immunogenic activity relative to immunogenic activity of atomized particles before drying.

[0240] la some embodiments, less than 1 % of the material of the dried atomized particles sustains thermal damage. In some embodiments, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, less than 90%, less than 95%, or less than 100’%, of the material of the dried atomized particles sustains thermal damage.Pharmaceutical Composition

[0241] In some embodiments, compositions described herein comprise pharmaceutical compositions. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt, one or more of a vehicle, adjuvant, excipient, or carrier, such as a filler, disintegrate, a surfactant, a binder, a lubricant, a coating, or combinations thereof.

[0242] The term, '‘pharmaceutically acceptable excipient, carrier or diluent,” as used herein, refers to substances formulated alongside the active agent of a pharmaceutical composition that allows the active agent to retain biological activity or viral infectivity and is non-reactive in other aspects. Such a substance can be included for purposes including, but not limited to: long-term stabilization, bulking up solid formulations that contain active agents in small amounts, or to confer a therapeutic enhancement on the active agent in the final dosage form, such as facilitating absorption, reducing viscosity, or enhancing solubility. The selection of an appropriate substance can depend upon the route of administration, the dosage form, the active agent and other factors.

[0243] Excipients may facilitate drug absorption, reduce viscosity, or enhance solubility. Excipients may also facilitate the handling of the active ingredients, improve to vitrostabil ity, and / or extend pharmaceutical product shelf life. Excipient selection may vary with the route of administration for drug delivery, the unit dose, as well as the active ingredients comprising the composition,

[0244] Non-limiting examples of pharmaceutically acceptable excipients, carriers and diluents suitable for the pharmaceutical compositions disclosed herein include buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose, dextran, mannitol, trehalose, lactose, and the like; polypeptides or amino acids such as glycine, leucine, and the like; antioxidants; chelating agents such as EDTA, glutathione and the like; adjuvants such as aluminum hydroxide (e.g., Alhydrogel®), and the like; surfactants such as Polysorbate 80, Polysorbate 20, Pluronic F68 and the like; glycerol; sorbitol; mannitol; polyethyleneglycol (PEG); and preservatives. In some embodiments, an excipient may comprise; anhydrous calcium phosphate, dihydrate calcium phosphate, hydroxypropyl methylcellulose, croscarmellose sodium, GMO-free croscarmellose sodium, carbomers, magnesium aluminometasilicate, povidone (PVP), poly(laciic-co-glycolic acid) (PLGA), polylactic acid (FLA), crospovidonc, sorbitol, dimethicone, sodium stearyl fimiarate, sodium starch glycollate, hydroxypropylcellulose, native corn starch, modified com starch, carrageenan, alginates, silicon dioxide, microcrystalline cellulose, carboxymethylcellulose sodium, alginates, carboxymefhylcellulose (CMC), sodium carboxymethylcellulose (Na CMC), carbomers, natural gums, maltitol, glucose syrup, silicones, carbomers, fatty alcohols, alcohols, carbohydrates, petrolatum derivatives, butters, waxes, DMSO, esters, fatty acids, oil- in-water (O / W) emulsifiers, water-in-oil ( W / O) emulsifiers, silicas, fumed silicas, isopropyl myristate, cellulosic derivates, xanthan gum, propylenglycol, dimethyl isosorbate, flavors, colors, functional coatings, aesthetic coatings, a pharmaceutically acceptable salt of any of these, or any combination thereof.

[0245] In some embodiments, pharmaceutical compositions comprise one or more active agents described herein. Accordingly, in some embodiments, a pharmaceutical composition comprises a virus vector, a non-viral vector, or a combination thereof. In some embodiments, a pharmacal composition comprises a virus. In some embodiments, a pharmaceutical composition comprises a vaccine, an enveloped or a .noa-envelopcd virus. In some embodimen ts, a pharmaceutical composition comprises a protein. In some embodiments, a pharmaceutical composition comprises a small molecule. In some embodiments, a pharmaceutical composition comprises an imaging agent.Methods of making atomized particles

[0246] .Disclosed herein are methods of drying atomized particles described herein. In some embodiments, methods of drying atomized particles comprise method of making atomized particles, hi some embodiments, methods of making atomized particles comprise flowing a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) from a nozzle along with a gas to form a plurality of atomized particles. In some embodiments, a liquid fo.g., a solution, a suspension, an emulsion, or a combination thereof) is flown through at least one channel of a nozzle device described herein. In some embodiments, a gas is flown through at least one channel of a nozzle device described herein.

[0247] In some embodiments, a liquid (e.g. , a solution, a suspension, an emulsion, or a combination thereof) described herein comprise a concentration of particles and / or active agents ranging from 0. 1 pg / mL to 3000 mg / mL. In some embodiments, compositions described herein comprise a particle and / or active agent concentration ranging from 0.1 gg / mL -1 mg / mL, 1 pg / mL -10 mg / mL, 10 gg / mL -100 mg / mL, 100 g.g / mL -500 mg / mL, 500 pg / mL -1000 mg / mL, 1000 pg / mL -2000 mg / mL, 2000 gg / niL -2500 mg / mL, or 2500 pg / mL -3000 mg / mL.

[0248] In some embodiments, a liquid (e.g. , a solution, a suspension, an emulsion, or a combination thereof) is flown through a nozzle device at a flowrate in a range of from 0. 1 mi / mm to 50 ml / min, from 0.3 ml / min to 50 ml / min, from 0.5 ml / min to 50 ml / min, from 0.8 ml / min to 50 ml / min, from 1 ml / min to 50 ml / min, from 3 ml / min to 50 ml / min, 5 ml / min to 50 ml / min, 8 ml / min to 50 ml / min, from 0.1 ml / min to 25 ml / min, from 0.3 ml / min to 25 ml / min, from 0.5 ml / min to 25 ml / min, from 0.8 ml / min to 25 ml / min, or from 1 ml / min to 25 ml / min, from 0.1 ml / min to 10 ml / min, from 0.3 ml / min to 10 ml / min, from 0.5 ml / min to 10 ml / min, from 0.8 ml / min to 10 ml / min, or from 1 ml / min to 10 ml / min, from 0.1 ml / min to 10 ml / min, from 0.3 ml / min to 10 ml / min, from 0.5 ml / min to 10 ml / min, from 0.8 ml / min to 10 ml / min, from 1 ml / min to 10 ml / min, from 3 ml / min to 10 ml / min, 5 ml / min to 10 ml / min, 8 ml / min to 10 ml / min, from 0.1 ml / min to 5 ml / min, from 0.3 ml / min to 5 ml / min, from 0.5 ml / min to 5 ml / min, from 0.8 ml / min to 5 ml / min, from 1 ml / min to 5 ml / min, from 0. 1 ml / min to 0.01 L / min, from 0.01 L / min to 0.1 L / min, from 0. 1 L / min to 1 L / min, from 0.3 L / min to 10 L / min, from 0.5 L / min to 10 L / min, from 0.8 L / min to 10 L / min, from 1 L / min to 10 L / min, from 0.1 L / min to 10 L / min, from 0.3 L / min to 10 L / min, from 0.5 L / min to 10 L / min, from 0.8 L / min to 10 L / min, from 1 L / min to 10 L / min, from 3 L / min to 10 L / min, 5 L / min to 10 L / min, from 8 L / min to 10 L / min, from 0.1 L / min to 1 L / min, from 0.3 L / min to 20 L / min, from 0.5 L / min to 20 L / min, from 0.8 L / min to 20 L / min, from 1 L / min to 20 L / min, from 0.1L / min to 20 L / min, from 0.3 L / min to 20 L / min, from 0.5 L / min to 20 L / min, from 0.8 L / min to 20 L / min, from .1 L / min to 20 L / min, from 3 L / min to 20 L / min, 5 L / min to 20 L / min, or from 10 L / min to 20 L / min. In some embodiments, a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) is flown through a nozzle device at a pressure in a range of from 0.1 bar to 2500 bar, from 0.1 bar to 1500 bar, from 0.1 bar to 500 bar, from 0.1 bar to 100 bar, from 0.1 bar to 50 bar, from 0.1 bar to 20 bar, from 0.1 bar to 10 bar, from 0.1 bar to 5 bar, from 0.1 bar to 2 bar, from 0.1 bar to 1 bar, from 3 bar to 2500 bar, from 3 bar to 1500 bar, from 3 bar to 500 bar, from 3 bar to 100 bar, from 3 bar to 50 bar, from 3 bar to 20 bar, from 3 bar to 10 bar, from 3 bar to 5 bar, from 8 bar to 2500 bar, from 8 bar to 1500 bar, from 8 bar to 500 bar, from 8 bar to 100 bar, from 8 bar to 50 bar, from 8 bar to 20 bar, from 8 bar to 10 bar, from 30 bar to 2500 bar, from 30 bar to 1500 bar, from 30 bar to 500 bar, from 30 bar to 100 bar, from 30 bar to 50 bar, from 80 bar to 2500 bar, from 80 bar to 1500 bar, from 80 bar to 500 bar, from 80 bar to 100 bar, from 300 bar to 2500 bar, from 300 bar to 1500 bar, from 300 bar to 500 bar, from 500 bar to 2500 bar, from 500 bar to 1500 bar, or from 500 bar to 1000 bar.

[0249] In some embodiments, a gas is flown through a nozzle device at a flowrate of in a range of from 0.1 L / min to 100 L / miu, from 0.5 L / min to 100 L / min, from 1 L / min to 100 L / min, from 5 L / min to 100 L / min, from 10 L / min to 100 L / min, from 20 L / min to 100 L / min, from 50 L / min to 100 L / min, from 70 L / min to 100 L / min, from 0.1 L / min to 80 L / min, from 0.5 L / min to 80 L / min, from 1 L / min to 80 L / min, from 5 L / min to 80 L / min, from 10 L / min to 80 L / min, from 20 L / min to 80 L / min, from 50 L / min to 80 L / min, from 0.1 L / min to 40 L / min, from 0.5 L / min to 40 L / min, from 1 L / min to 40 L / min, from 5 L / min to 40 L / min, from 10 L / min to 40 L / min, from 20 L / min to 40 L / min, from 0.1 L / min to 30 L / min, from 0.5 L / min to 30 L / min, from 1 L / min to 30 L / min, from 5 L / min to 30 L / min, or from 10 L / min to 30 L / min. In some embodiments, a gas is flown through a nozzle device at a pressure in a range of from 0. 1 bar to 2500 bar, from 0. 1 bar to 1500 bar, from 0. 1 bar to 500 bar, from 0.1 bar to 100 bar, from 0.1 bar to 50 bar, from 0.1 bar to 20 bar, from 0. 1 bar to 10 bar, from 0.1 bar to 5 bar, from 0.1 bar to 2 bar, from 0.1 bar to 1 bar, from 3 bar to 2500 bar, from 3 bar to 1500 bar, from 3 bar to 500 bar, from 3 bar to 100 bar, from 3 bar to 50 bar, from 3 bar to 20 bar, from 3 bar to 10 bar, from 3 bar to 5 bar, from 8 bar to 2500 bar, from 8 bar to 1500 bar, from 8 bar to 500 bar, from 8 bar to 100 bar, from 8 bar to 50 bar, from 8 bar to 20 bar, from 8 bar to 10 bar, from 30 bar to 2500 bar, from 30 bar to 1500 bar, from 30 bar to 500 bar, from 30 bar to 100 bar, from 30 bar to 50 bar, from 80 bar to 2500 bar, from 80 bar to 1500 bar, from80 bar to 500 bar, from 80 bar to 100 bar, from 300 bar to 2500 bar, from 300 bar to 1500 bar, from 300 bar to 500 bar, from 500 bar to 2500 bar, from 500 bar to 1500 bar, or from 500 bar to 1000 bar. hi some enibodiments, gas flowing through at least one channel is independently in a range of from 0.1 SLPM to 500 SLPM, from 0.1 SLPM to 300 SLPM, from 0.1 SLPM to 100 SLPM, from 0.1 SLPM to 50 SLPM, from 0.1 SLPM to 10 SLPM, from 5 SLPM to 500 SLPM, from 5 SLPM to 300 SLPM, from 5 SLPM to 100 SLPM, from 5 SLPM to 50 SLPM, from 5 SLPM to 10 SLPM, from 20 SLPM to 500 SLPM, from 20 SLPM to 300 SLPM, from 20 SLPM to 100 SLPM, from 20 SLPM to 50 SLPM, from 80 SLPM to 500 SLPM, from 80 SLPM to 300 SLPM, from 80 SLPM to 100 SLPM, from 200 SLPM io 500 SLPM, from 200 SLPM to 300 SLPM, or from 400 SLPM to 500 SLPM. In some embodiments, a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) flowing through at least one channel is independently in a range of from 0.01 ml / min to 500 ml / min, from 0.01 ml / min to 300 ml / min, from 0.01 ml / min to 100 ml / min, from 0.01 ml / min to 50 ml / min, from 0.01 ml / min to 20 ml / min, from 0.01 ml / min to 10 ml / min, from 0.1 ml / min to 500 ml / min, from 0.1 ml / min to 300 ml / min, from 0.1 ml / min to 100 ml / min, from 0.1 ml / min to 50 ml / min, from 0.1 ml / min to 20 ml / min, from 0.1 ml / min to 10 ml / min, from 2 ml / min to 500 ml / min, from 2 ml / min to 300 ml / min, from 2 ml / min to 100 ml / min, from 2 ml / min to 50 ml / min, from 2 ml / min to 20 ml / min, from 2 ml / min to 10 ml / min, from 30 ml / min to 500 ml / min, from 30 ml / min to 300 ml / min, from 30 ml / min to 100 ml / min, from 30 ml / min to 50 ml / min, from 80 ml / min to 500 ml / min, from 80 ml / min to 300 ml / min, from 80 ml / min to 100 ml / min, from 200 ml / min to 500 ml / min, from 200 ml / min to 300 ml / min, from 400 ml / min to 500 ml / min, from 0.1 ml / min to 10 L / min, from 0.3 ml / min to 10 L / min, from 0.5 ml / min to 10 L / min, from 0.8 ml / min to 10 L / min, or from 1 ml / min to 10 L / min, from 0.1 ml / min to 10 L / min, from 0.3 ml / min to 10 L / min, from 0.5 ml / min to 10 L / min, from 0.8 ml / min to 10 L / min, from 1 ml / min to 10 L / min, from 3 ml / min to 10 L / min, 5 ml / min to 10 L / min, or from 8 ml / min. to 10 L / min.

[0250] In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 60%, more than 70%), more than 80%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, or more than 99% of the plurality of atomized particles of a desired size. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 99% of the plurality of atomized particles of a desired size. In some embodiments, a desired size refers to a size in a range of from 0.1 micron to 10 micron, from 0.1 micron to 5 micron, from 0.1 micron to 1 micron, from 0.1 micron to 0.8 micron, from 0.1 micron to 0.5 micron, from 0.1 micron to 20 micron, from0.1 micron to 50 micron, from 0.4 micron to 10 micron, from 0.4 micron to 5 micron, from 0.4 micron to 1 micron, from 0.4 micron to 20 micron, from 0. 1 micron to 50 micron, from 0.4 micron to 0.8 micron, from 0.7 micron to 10 micron, from 0.7 micron to 5 micron, from 0.7 micron to 20 micron, from 0.7 micron to 50 micron, or from 0.7 micron to 1 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 99% of the plurality atomized of particles of smaller than 1 micron. In some embodiments, a number-weigh ted size distribution of the pl urality of particles comprises more than 99% of the plurality atomized of particles of smaller than 1 micron . In some embodiments, a number- weighted size distribution of the plurality of particles comprises more than 99% of the plurality atomized of particles of smaller than 1 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 99% of the plurality atomized of particles of smaller than 5 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 80% of the plurality atomized of particles of smaller than 5 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 90% of the plurality atomized of particles of smaller than 5 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 99% of the plurality atomized of particles of smaller than 10 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 80% of the plurality atomized of particles of smaller than IQ micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 90% of the plurality atomized of particles of smaller than 10 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 99% of the plurality atomized of particles of smaller than 20 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 80% of the plurality atomized of particles of smaller than 20 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 90% of the plurality atomized of particles of smaller than 20 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 99% of the plurality atomized of particles of smaller than 30 micron, in some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 80% of the plurality atomized of particles of smaller than 30 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 90% of the plurality atomized of particles of smaller than 30 micron. In someembodiments, a number -weighted size distribution of the plurality of particles comprises more than 99% of the plurality atomized of particles of smaller than 40 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 80% of the plurality atomized of particles of smaller than 40 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 90% of the plurality atomized of particles of smaller than 40 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 99% of the plurality atomized of panicles of smaller than 50 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 80% of the plurality atomized of particles of smaller than 50 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 90% of the plurality atomized of particles of smaller than 50 micron.

[0251] In some embodiments, a flowrate of a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) thereof flowing through a nozzle device is adjusted based on a viscosity of a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) for making a plurality of atomized particles of a desired size. For example, in some embodiments, a viscosity and a flowrate of a liquid (e.g... a solution, a suspension, an emulsion, or a combination thereof) flowing through a nozzle device are inversely proportional to each other. Tn some embodiments, a flowrate of a gas thereof flowing through a nozzle device is adjusted based on a viscosity of a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) for making a plurality of atomized particles of a desired size. For example, in some embodiments, a viscosity of a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof), and a flowrate of a gas flowing through a nozzle device are directly proportional to each other.

[0252] In some embodiments, a pressure of a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) flowing through a nozzle device is adjusted based on a viscosity of a liquid (e,g., a solution, a suspension, an emulsion, or a combination thereof) for making a plurality of atomized particles of a desired size. For example, in some embodiments, a viscosity and a pressure of a liquid (g.g., a solution, a suspension, an emulsion, or a combination thereof) flowing through a nozzle device are inversely proportional to each other. In some embodiments, a pressure of a gas thereof flowing through a nozzle device is adjusted based on a viscosity of a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) for making a plurality of atomized particles of a desired size. For example, in someembodiments, a viscosity of a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof!, and a pressure of a gas flowing through a nozzle device are directly proportional to each other.

[0253] In some embodiments, methods described, herein form a plurality of atomized particles, wherein a number-weighted size distribution of the plurality of particles comprises more titan 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, or more than 99% of the plurality atomized of particles of a desired size. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 99% of the plurality atomized of particles of a desired size. In some embodiments, a desired size refers to a size of smaller than 10 micron, smaller titan 5 micron, smaller than I micron, smaller than 0.8 micron, smaller titan 0.5 micron, or smaller than 0.2 micron. In some embodiments, a number-weighted size distribution of the plurality of particles comprises more than 99% of the plurality atomized of particles of smaller than 1 micron,

[0254] In some embodiments, a gas flown through a nozzle device comprises a relative humidity in a range of from 5% to 100%, from 5% to 70%, from 5% to 50%, from 5% to 30%, from 5% to 20%, from 5% to 10%, from 15% to 100%, from 15% to 70%, from 15% to 50%, from 15% to 30%, from 15% to 20%, from 25% to 100%, from 25% to 70%!, from 25% to 50%, from 25% to 30%, from 55% to 100%, from 55% io 70%, or from 75% to 100%. In some embodiments, a gas flown through a nozzle device comprises a relative humidity of less than 5%. Relative humidity refers to a percent of saturation humidity at a particular temperature .Methods of making dried atomized partides

[0255] Disclosed herein are methods of making dried atomized particles described herein . In some embodiments, methods of making dried atomized particles comprise: flowing a liquid (e.g., a solution, a suspension, an emulsion, or a combination thereof) from a nozzle along with a gas to form a plurality of atomized particles; and exposing the plurality of atomized particles to a desired temperature for drying or dehydrating and, thereby, forming a plurality of dried atomized particles. In some embodiments, methods of drying atomized particles comprise mixing and dehydrating the atomized particles using a drying gas at a temperature of 0-45 'C so as to sufficiently dry the plurality of atomized particles, thereby forming an aerosol of dry particles. In some embodiments, a plurality of atomized particles is formed by any one of the methods described herein.

[0256] In some embodiments, a liquid (e.g. , a solution, a suspension, an emulsion, or a combination thereof) described herein comprise a concentration of particles and / or active agents ranging from 0.1 p.g / mL to 3000 mg / mL. In some embodiments, compositions described herein comprise a particle and / or active agent concentration ranging from 0.1 pg / mL - 1 mg / mL, 1 pg / niL -10 mg / mL, 10 pg / mL -100 mg / mL, 100 pg / mL -500 mg / mL, 500 pg / niL -1000 mg / mL, 1000 pg / mL -2000 mg / mL, 2000 pg / tnL -2500 mg / mL, or 2500 pg / mL -3000 mg / mL.

[0257] In some embodiments, a desired temperature for drying is in a range of from 0 °C to 300 °C, from 0 °C to 250 °C, from 0 °C to 200 °C, from 0 °C to 150 °C, from 0 °C to 100 °C, from 0 °C to 90 °C, from 0 °C to 80 °C, from 0 °C to 70 °C, from 0 °C to 60 °C, from 0 °C to 50 °C, from 0 °C to 40 °C, from 0 °C to 30 °C, from 0 °C to 20 °C, from 0 °C to 10 °C, from 10 °C to 70 °C, from 10 °C to 60 °C, from 10 °C to 50 °C, from 10 °C to 40 °C, from 10 °C to 30 °C, from 10 °C to 20 °C, from 20 °C to 70 °C, from 20 °C to 60 °C, from 20 °C to 50 °C, from 20 °C to 40 T, from 20 °C to 30 °C, from 30 °C to 70 °C, from 30 T to 60 °C, from 30 ‘X? to 50 °C, or from 30 °C to 40 °C In some embodiments, a plurality of atomized particles is dried by exposing the plurality of atomized particles to a temperature in a range of from 0 °C to 40 °C

[0258] In some embodiments, a gas is flown through a nozzle device at in a temperature in a range of from 3 °C to 95 °C, from 3 X to 90 "C, from 3 °C to 80 °C, from 3 °C to 70 °C, from .3yC to 60 “C, from .3 “C to 50 “C, from 3 °C to 40 °C, from 3 °C to 30 °C, from 3 °C to 20 °C, from 3 °C to 10 °C, from 10 °C to 70 °C, from 10 °C to 60 °C, from 10 °C to 50 °C, from 10 °C to 40 °C, from 10 °C to 30 °C, from 10 °C to 20 T. from 20 ‘X to 70 'V. from 20 °C to 60 °C, from 20 °C to 50 °C, from 20 °C to 40 °C, from 20 T to 30 °C, from 30 °C to 70 °C, from 30 °C to 60 °C, from 30 °C to 50 °C, or from 30 to 40 °C. In some embodiments, a gas is flown, through a nozzle device at a temperature in a range of from 3 °C to 40

[0259] In some embodiments, methods described herein, form a plurality of dried atomized particles, wherein the plurality of dried atomized particles retain at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% activity relative to activity of atomized particles before drying, wherein the activity refers to one or more of an infectivity or a virus or viral particle, an enzymic activity, a binding activity, an immunogenic activity, or a combination thereof.

[0260] In some embodiments, less than 1% of the material of the dried atomized particles sustains thermal damage. In some embodiments, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than45%, less than 50%, less than 55%, less than 60%. less than 65%, less than 70'%, less than 75’%, less than 80%, less than 85%, fess than 90% , less than 95%, or less than 100%, of the material of the dried atomized particles sustains thermal damage.Methods of coaling

[0261] Described herein are methods of coating. In some embodiments, methods of coating comprise: flowing a liquid (e.g. , a solution, a suspension, an emulsion, or a combination thereof) from a nozzle to form a plurality of atomized particles; exposing a surface of a substrate to the plurality of atomized particles; and exposing the substrate to a desired temperature for coating the substrate with a plurality of dried atomized particles. In some embodiments, a desired temperature for drying is in a range of from 3 °C to 70 '’’C, from 3 °C to 60 °C, from 3 °C to 50 °C, from 3 °C to 40 °C, from 3 °C to 30 °C, from 3 °C to 20 °C, from 3 °C to 10 °C, from 10 °C to 70 °C, from 10 °C to 60 °C, from 10 °C to 50 °C, from 10 °C to 40 °C, from 10 °C to 30 °C, from 10 °C to 20 °C, from 20 °C to 70 °C, from 20 °C to 60 °C, from 20 °C to 50 °C, from 20 °C to 40 °C, from 20 °C to 30 °C, from 30 °C to 70 °C, from 30 °C to 60 ”C, from 30 ®C to 50 “C, or from 30 °C to 40 "C. In some embodiments, a plurality of atomized particles is dried by exposing the plurality of atomized particles to a temperature in a range of from 0 °C to 45 °C.

[0262] In some embodiments, a substrate comprises a composition, wherein the composition comprises a tablet, a capsule, a plurality of beads, or a combination thereof. In some embodiments, a coating of a composition extends shelf life of the composition. In some embodiments, a composition comprises one or more ingredients. Accordingly, in some embodiments, a coating extends shelf life one or more ingredients of a composition. In some embodiments, a coating extends a shelf life of one or more ingredients of a composition, by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%o, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 300%, about 400%, or at least 400% relative to a composition that is not coated with the coating. In some embodiments, coating of a composition with a plurality of dried atomized particles allows slow release of one or more ingredients of a composition in bodily fluids. In some embodiments, a coating of a composition with a plurality of dried atomized particles allow release of one or more ingredient of the composition at a desired pH. For example, in some embodiments, enteric coating of a composition with a plurality of dried atomized particles allows release ofingredients of the composition in basic pH. Accordingly, in some embodiments, enteric coating of a composition with a plurality of dried atomized particles prevents degradation of one or more ingredients of the composition in gastric acid. In some embodiments, coating of a first composition with a plurality of dried atomized particles prevents chemical and / or physical interaction of one or more ingredients of the first composition with one or more ingredients of a second composition, wherein the first composition and the second composition are mixed together. For example, in some embodiments, a composition comprises at least two sets of plurality of beads, wherein coating of at least one set of beads with dried atomized particles prevents chemical and / or physical interaction between coated beads and uncoated beads. In some embodiments, coating serves as a physical barrier between two layers of ingredients of a composition. For example, in some embodiments, coating serves as a physical barrier between two distinct layers of a tablet, wherein a first layer of the two distinct layers comprise at least ingredient that is different than a second layer of the two distinct layers.

[0263] In some embodiments, a substrate comprises a metallic, wood, plastic, fabric, paper, leather, fabric, stone, cardboard, or a combination thereof. In some embodiments, coating of a surface of a substrate extends shelf life of the substrate. In some embodiments, coating is performed for enhancing aesthetics of a substrate. In some embodiments, coating is performed for affecting a color of a substrate. In some embodiments, coating is performed for enhancing an electromagnetic property of a substrate. In some embodiments, coating is performed for enhancing a conductivity of a substrate. In some embodiments, coating is performed for enhancing an insulating property of a substrate. In some embodiments, coating is performed for enhancing an optical property of a substrate. In some embodiments, coating is performed for enhancing a mechanical property of a substrate. In some embodiments, coating is performed for enhancing a fluorescence of a substrate. In some embodiments, coating is performed for enhancing a reactivity of a substrate. In some embodiments, a surface coated with a plurality of dried atomized particles is further subjected to a downstream processing. In some embodiments, a downstream processing comprises exposing a substrate or a portion thereof to a chemical reaction, a photo reaction, a lithography reaction, an electromagnetic radiation, or combinations thereofIllustrative Embodiments

[0264] Embodiment LA spraying system for thermal stabilization of pharmaceutical formulations, comprising:

[0265] a nozzle device comprising:

[0266] a set of at least three coaxial tubular .members that define at least three coaxial channels,

[0267] each tubular member having an inlet and an outlet, the at least three coaxial tubular members including:

[0268] an inner coaxial tubular member having an inner surface and an outer surface, the inner surface defining an inner coaxial channel;

[0269] at least one intermediate coaxial tubular member comprising a first intermediate coaxial tubular member, each intermediate coaxial tubular member having an inner surface and an outer surface, a first intermediate coaxial channel being defined by a distance between the inner surface of the first intermediate coaxial tubular member and the outer surface of the inner coaxial tubular member;

[0270] an outer coaxial tubular member having an inner surface and an outer surface, an outer coaxial channel being defined by a distance between an inner surface of the outer coaxial tubular member and an outer surface of the at least one intermediate coaxial tubular member;

[0271] wherein the inlet of the inner tubular member and the inlet of the outer coaxial tubular member are configured to be operably coupled to a gas source, and the inlet of the intermediate coaxial tubular member is configured to be operably coupled to a liquid source;

[0272] a drying chamber, where an inlet of the drying chamber is operably coupled to the outlets of each tubular member;

[0273] a filter assembly or separator, where an inlet of the filter assembly or separator is operably coupled to an outlet of the drying chamber;

[0274] a source for a gas operably coupled to at least the inner coaxial tubular member and the outer coaxial tubular member;

[0275] at least one gas pump operably coupled to at least one two or more of the at least three coaxial tubular members;

[0276] at least one liquid pump coupled to each intermediate coaxial tubular member;

[0277] a liquid source coupled to each liquid pump, at least one liquid source comprising a liquid dispersion of a biological material and / or a small molecule drug.

[0278] Embodiment 2.The spraying system of Embodiment 1 , further comprising at least one flow controller disposed between the gas source and the nozzle device.

[0279] Embodiment 3. T he spraying system of Embodiment 2, wherein a flow of fluid or gas to each inlet of the nozzle device is controlled by a flow controller.

[0280] Embodiment 4. The spraying system of Embodiment 1, further comprising a separate inlet into the drying chamber to allow a drying gas at a target temperature to enter the drying chamber.

[0281] Embodiment 5. The spraying system of Embodiment 1, further comprising a flow sensor operably coupled to the filter assembly, a moisture sensor operably coupled to the filter assembly, a pressure sensor operably coupled to the drying chamber, or a combination thereof

[0282] Embodiment 6. The spraying system of Embodiment 1, wherein the inner coaxial tubular member and the outer coaxial tubular member are operably coupled to different gas sources.

[0283] Embodiment 7. The spraying system of Embodiment 1, wherein the inner coaxial tubular member and the outer coaxial tubular member are operably coupled to a same gas source.

[0284] Embodiment 8.The spraying system of Embodiment 1, wherein each intermediate coaxial tubular member is operably coupled to a different liquid, source.

[0285] Embodiment. 9,The spraying system of Embodiment 1 , wherein at least two intermediate coaxial tubular members are operably coupled to a same liquid source.

[0286] Embodiment I O.The spraying system of Embodiment 1 , wherein the at least one intermediate coaxial tubular member further comprises a second intermediate coaxial tabular member having an inner surface and an outer surface, a second intermediate coaxial channel being defined by a distance from the inner surface of the second intermediate coaxial tubular member and an outer surface of the first intermediate coaxial tubular member.

[0287] Embodiment 11. The spraying system of Embodiment I , wherein the set of at least three coaxial channels are configured as a hollow straight cylinder, a hollow converging cone, or a diverging hollow cone.

[0288] Embodiment 12.The spraying system of Embodiment 1, wherein the set of at least three coaxial channels are configured as a converging-diverging nozzle.

[0289] Embodiment 13. The spraying system of Embodiment 1, wherein a distance separating the inner surface of the intermediate tubular member from an outer surface of the inner tubular member is between 10 to 125 micrometers.

[0290] Embodiment 14. The spraying system of Embodiment I, wherein the outlets of each tubular member of the set of at least three coaxial tubular members are coplanar.

[0291] Embodiment 15. The spraying system of Embodiment 14, wherein the outlet of each tubular member is positioned within a first plane, the first plane being perpendicular to an axis of the inner coaxial tubular member.

[0292] Embodiment 16.The spraying system of Embodiment 1 , wherein the outlet of at least one tubular member of the set of at least three coaxial tubular members is non-coplanar with at least one other tubular member of the set of at least three coaxial tubular members.

[0293] Embodiment !7.The spraying system of Embodiment 1 , wherein the biological material is a vaccine, an enveloped or non-cnvelopcd virus.

[0294] Embodiment 18. A method of thermal stabilization of pharmaceutical formal ations, comprising:

[0295] causing at least one liquid to be dispensed in an annulus film from a nozzle: and controlling a flow of at least one gas stream through a central portion of the annulus film and around an outside of the annulus film, to form a thin cylindrical liquid surface outside of the nozzle by stretching the annulus film, to further make the cylindrical liquid. surface thinner by tangential flow of gas streams inside and around the outside of the surface, and causing hydrodynamic instabilities to this cylindrical thin liquid film leading to breakup into a plurality of fine droplets, where a diameter of each droplet of the plurality of fine droplets scales with a thickness of the stretched thin cylindrical liquid surflice formed out of the annulus liquid film by the gas flows through a central portion of the annulus film, and around the outside of the annulus film,

[0296] wherein each gas stream is at a target temperature of I (EC - 4Q°C, and(00297] wherein the at least one liquid includes a liquid dispersion of a biological ma terial and / or a small molecule drug.

[0298] Embodiment 19. The method of Embodiment 18, wherein the target temperature is 15%- 35CC.

[0299] Embodiment 20.The method of Embodiment 19, wherein the target temperature is 20*C •••- 25% / .

[0300] Embodiment 21. The method of Embodiment 18, wherein the at least one liquid includes a first liquid, and a flow rate of the first liquid into the nozzle is 0. 1 - 10 mL / min.

[0301] Embodiment 22,The method of Embodiment 18, wherein a total flow rate of the at least one gas stream is 5-150 standard liters / min.

[0302] Embodiment 23. The method of Embodiment 18, wherein the biological material includes a vaccine, an enveloped or nou-enveloped virus.

[0303] Embodiment 24. The method of Embodiment 18, wherein tire biological material comprises therapeutic agents, including but not limited to proteins, monoclonal antibodies, antibody fragments, nucleic acids (DNA, R.NA, mR.NA, siRNA), peptides, or a combination thereof.

[0304] Embodiment 25.Thc method of Embodiment 18, wherein at least 50% of biological material retains biological activity after being sprayed.

[0305] Embodiment 26. The method of Embodiment .18, wherein a median size of virusnanoparticles in Suspension does not increase more than 25% after spraying into droplets.

[0306] Embodiment 27. The method of Embodiment 18, further comprising controlling parameters of flow to obtain droplet size distributions with median diameter 20 gm or smaller.

[0307] Embodiment 28.The method of Embodiment 18, further comprising controlling parameters of flow to obtain droplet size distributions with median diameter 15 gm or smaller. (00308] Embodimen t 29,The method of Embodiment 18, further comprising controlling parameters of flow to obtain droplet size distributions with median diameter 10 um or smaller.

[0309] Embodiment 30.The method of Embodimen t 18, furth er comprising controlling parameters of flow to obtain droplet size distributions with median diameter 5 pm or smaller.

[0310] Embodiment 31. A method for rapid room-temperature dehydration (RTAD), comprising:

[0311] atomizing a dispersion of a material in a liquid, suspension or combination thereof using a nozzle device, thereby forming an aerosol containing a plurality of atomized particles, wherein the material comprises a viral particle; and

[0312] mixing and dehydrating the plurality of atomized particles using a drying gas at a temperature of 0-45 °C so as io sufficiently dry the plurality of atomized particles, thereby forming an aerosol of dry particles; and

[0313] coating the atomized particles with an excipient or adjuvant such that the aerosol of dry particles comprises the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the dry particles as measured relative to a control particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host ceil,

[0314] wherein less than 10% of the material sustains thermal damage, and

[0315] wherein less than 10% of the dry particles in die aerosol of dry particles form aggregates.(00316] Embodiment 32.The method of Embodiment 31, wherein the nozzle device includes at least three channels comprising an inner channel, at least one middle annular channel, outsid e of the inner channel, and al least one outer annular channel outside of the at least one middle annular channel, the at least one middle annular channel being coaxially arranged between the inner channel and the at least, one outer annular channel and having a gap width sufficient so as to atomize a liquid, suspension or combination thereof flowing through the at least one middle annular channel upon flow of one or more gases through at least the inner channel and the at least one outer annular channel.

[0317] Embodiment. 33. The method of any one of Embodiments 31-32, wherein the material comprises a biologic material.

[0318] Embodiment 34. The method of any one of Embodiments 31 -33, wherein the material comprises a virus,

[0319] Embodiment 35. The method of any one of Embodiments 31 -34, wherein the material comprises a vaccine, an enveloped virus or a nomenveloped virus.

[0320] Embodiment 36.The method of any one of Embodiments 31-35, wherein a surface tension of the dispersion is less than water.(00321 ] Embodiment 37.The method of any one of Embodiments 31 -36, wherein a flow rate of the dispersion from the nozzle device is 0. 1 mL-10 L / miu.

[0322] Embodiment 38.The method of any one of Embodiments 31 -37, wherein a median size of the plurality of atomized particles is less than 50 gm.

[0323] Embodiment 39.The method of any one of Embodiments 31-38, wherein a median size of the plurality of atomized particles is less than 20 pm.

[0324] Embodiment 4O.The method of any one of Embodiments 31-39, wherein a median size of the plurality of atomized particles is less than 10 pm.

[0325] Embodiment 41. The method of any one of Embodiments 31 -40, wherein the drying gas comprises nitrogen, helium, air, or a combination thereof.

[0326] Embodiment 42. The method of any one of Embodiments 31-41 , wherein the drying gas is provided at a rate of 5-200 standard liters? min.

[0327] Embodiment 43.The method of any one of Embodiments 31-42, wherein the dehydrating is performed at a negative pressure.

[0328] Embodiment 44. The method of any one Of Embodiments 31-43, wherein the temperature is provided between about 15&C and about 35

[0329] Embodiment 45.The method of any one of Embodiments 31-44, further comprising recovering particles after mixing and dehydrating.

[0330] Embodiment 46. The method of any one of Embodiments 31-45, wherein a membrane filter is utilized to recover particles.

[0331] Embodiment 47. The method of any one of Embodiments 31 -46, wherein a cyclone separator is utilized to recover particles.

[0332] Embodiment 48. The method of any one of Embodiments 45-47, further comprising analyzing the recovered particles.

[0333] Embodiment 49. The method of any one of Embodiments 45-48, wherein analyzing the recovered particles includes confirming biological activity of the recovered particles.

[0334] Embodimen t 50. The method of any one of Embodiments 45-49, wherein FT-IR is used to analyze the recovered particles.

[0335] .Embodiment 51 .The method of any one of Embodiments 45-50, further comprising storing the recovered particles at a temperature Ts, where 0°C < Ts < 3l)°C for a period of time.

[0336] Embodiment 52. The method of Embodiment 5.1 , wherein the period of time is at least 2 months.

[0337] Embodiment 53.The method of any one of Embodiments 45-52, further comprising reconstituting the recovered particles after storage.

[0338] Embodiment 54. The method of any one of Embodiments 31-53, wherein the excipient or adjuvant is in an amount sufficient to extend a shelflife of the dry particles.

[0339] Embodiment 55.The method of any one of Embodiments 31-54, wherein the excipient or adjuvant is in an amount sufficient to control a release of the material in a bodily fluid.

[0340] Embodiment 56.The method of any one of Embodiments 31-55 , wherein the excipient or adjuvant is in an amount sufficient to control a .release of the material at a desired pH.

[0341] Embodiment 57.The method of any one of Embodiments 31-56, further comprising delivering the aerosol of dry' particles through a nebulizer, an inhaler, a nasal spray, or a microneedle patch.

[0342] Embodiment 58.The method of any one of Embodiments 31 -56, further comprising reconstituting the dry particles into a pharmaceuticafly acceptable solvent.

[0343] 'Embodiment 59.The method of any one of Embodiments 31-56, wherein less than 5% of the dry particles in die aerosol of dry particles form aggregates.

[0344] Embodiment 60. A spraying system, comprising'

[0345] a nozzle device adapted to atomize a dispersion of a material in a liquid, suspension, or combination thereof to sufficiently form an aerosol containing a plurality of atomized particles, wherein the material comprises a viral particle, wherein the nozzle device includes at least three channels comprising an inner channel, at least one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel, the al least one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular channel and having a gap width sufficient so as to atomize a liquid, suspension, or combination thereof flowing through the at least one middle annular channel upon flow of one or more gases through at least the inner channel and the at least one outer annular channel; and

[0346] a drying chamber operatively connected to the nozzle device, the drying chamber adapted to apply a drying gas at a temperature of 0-45 °C so as to mix and dehydrate the plurality of atomized particles, thereby forming a dry particle aerosol;

[0347] wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosol comprises the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the plurality of atomized particles as measured relative to a control particle that is not atomized, wherein die viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell,

[0348] wherein less than 10% of the material sustains thermal damage, and

[0349] wherein less than 10*% of the dry particles in. the aerosol of dry particles form aggregates.

[0350] Embodiment 61 .The spraying system of Embodiment 60, farther comprising at. least one flow controller, wherein the at least one flow controller is configured to control a flow rate of the one or more gases through at least the inner channel and the at least one outer annular channel of the nozzle device.

[0351] Embodiment 62,The spraying system of Embodiment any one of Embodiments 60-61, farther comprising at least one flow controller, wherein the at least one flow controller is configured to control a flow rate of one or more of the dispersion and the drying gas.

[0352] Embodiment 63. The spraying system of any one of Embodiments 60-62, wherein the material comprises a biologic material.

[0353] Embodiment 64. The spraying system of any one of Embodiments 60-63, wherein the material comprises a virus.

[0354] Embodiment 65. The spraying system of any one of Embodiments 60-64, wherein the material comprises a vaccine, an enveloped virus or a non-enveloped virus.

[0355] Embodiment 66. The spraying system of any one of Embodiments 60-65, wherein a surface tension of the dispersion is less than water.

[0356] Embodiment 67,The spraying system of any one of Embodiments 60-66, wherein a flow rate of the dispersion from the nozzle device is 0.1 mL-10 L / min,

[0357] Embodiment 68.The spraying system of any one of Embodiments 60-67, wherein a median size of the plurality of atomized particles is less than 50 pm.

[0358] Embodiment 69. The spraying system of any one of Embodiments 60-68, wherein a median size of the plurality of at omized particles is less than 20 pm.

[0359] Embodiment 70. The spraying system of any one of Embodiments 60-69, wherein a median size of the plurality of atomized particles is less than 10 pm.

[0360] Embodiment 71. The spraying system of any one of Embodiments 60-70, wherein the drying gas comprises nitrogen, helium, air, or a combination thereof.

[0361] Embodiment 72. The spraying system of any one of Embodiments 60-71, wherein the drying gas is provided at a rate of 5-200 standard liters / min.

[0362] Embodiment 73.The spraying system of any one of Embodiments 60-72, wherein the temperature is provided between about 15 °C and about 35 °C.

[0363] Embodiment 74.The spraying system of any one of Embodiments 60-73, further comprising recovering particles after mixing and dehydrating.

[0364] Embodiment 75.The spraying system of any one of Embodiments 60-74, wherein the drying chamber comprises a filter assembly, the filter assembly is being configured to recover particles.

[0365] Embodiment 76. The spraying system of any one of Embodiments 60-75, further comprising a cyclone separator downstream of the drying chamber, wherein the cyclone separator is configured to recover particles.

[0366] Embodiment 77.The spraying system of any one of Embodiments 60-75, wherein one or more of the nozzle device or the drying chamber is adapted to be retrofitted to a second spraying system.

[0367] Embodiment 78 An aerosol composition comprising a plurality of dried atomized particles, wherein the plurality of dried atomized particles is formed from drying a liquid, suspension, or combination thereof comprising a dispersion of biol ogical material at a temperature of 0-45 °C, wherein the biological material comprises a vi ral particle, wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosol comprises the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the plurality of atomized particles as measured relative to a control particle that is not atomized, wherei n the viral acti vity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, wherein less than 10% of the biological material sustains thermal damage, and wherein less than 10% of the dried atomized particles form aggregates,

[0368] Embodiment 79.The aerosol composition of Embodiment 78, wherein the liquid, suspension, or combination thereof comprises one or more active agents.

[0369] Embodiment 80. The aerosol composition of Embodiment 78 or 79, wherein the liquid, suspension, or combination thereof comprises plurality of solid particles having a size in a range of from 1 nm to 1000 nm, from 1 nm to 800 nm, from 1 nm to 500 nni, from 1 nm to 300 nm, from 1 nm to 100 nm, from 100 nm to 1000 nm, from 100 nm to 800 nm, from 100 nm to 500 nm, from 100 nm to 300 nm, from 300 nm to 1000 nm, from 300 nm to 800 nm, from 300 nm to 500 nm, from 500 nm to 1000 nm, from 500 nm to 800 nm, or from 800 nm to 1000 nm.

[0370]

[0371] Embodiment 81 .The aerosol composition of any one of Embodiments 78-80, wherein more than 99% of the plurality of dried atomized particles having median diameters less than 20 microns.

[0372] Embodiment 82. The aerosol composition of any one of Embodiments 78-81 , wherein the plurality of dried atomized particles comprise one or more active agents.

[0373] Embodiment 83.The aerosol composition of any one of Embodiments 78-82, wherein the plurality of dried atomized particles retain at least 80% biological activity relative io the liquid, suspension, or combination thereof

[0374] Embodiment 84. The aerosol composition of any one of Embodiments 78-83, wherein the liquid, suspension, or combination thereof is non-Ncwtonian.

[0375] Embodiment 85.The aerosol composition of any one of Embodiments 78-84, wherein the liquid, suspension, or combination thereof is Newtonian.

[0376] Embodiment 86. The aerosol composition of any one of Embodiments 78~85, wherein the liquid, suspension, or combination thereof has an absolute viscosity greater than 100 cP.

[0377] Embodiment 87.The aerosol composition of any one of Embodiments 78-86, wherein the liquid, suspension, or combination thereof forms a plurality of atomized particles prior to forming die plurality of dried atomized particles, wherein the plurality of atomized particles are in the form of droplets .

[0378] Embodiment 88.The aerosol composition of any one of Embodiments 78-87, wherein die liquid. Suspension, or combination thereof comprises a suspension of an organic and / or inorganic material.

[0379] Embodiment 89. The aerosol composition of any one of Embodiments 78-88, wherein the liquid, suspension, or combination thereof comprises a viscoelastic liquid,

[0380] Embodiment 90.The aerosol composition of any one of Embodiments 78-89, wherein the liquid, suspension, or combination thereof comprises at least one microorganism selected from at least one of: a vaccine, an enveloped virus, a non-enveloped virus, or a combination thereof

[0381] Embodiment 91. The aerosol composition of Embodiment 90, wherein al least50% of the at least one microorganism retains biological activity.

[0382] Embodiment 92.The aerosol composition of any one of Embodiments 78-91, wherein the liquid, suspension, or combination thereof comprises a plurality of therapeutic agents selected from at least one of: a virus, a virus vector, a non-viral vector, viral fragments, virus particles, virusdike particles, imaging agents, small molecules, or a combination thereof. (00383] Embodiment 93.The aerosol composition of any one of Embodiments 78-92, wherein the liquid, suspension, of combination thereof comprises a plurality of virus nanoparticles loaded with a plurality of therapeutic agents selected from at least one of: nucleic acids, proteins, peptides, genes, imaging agents, microorganisms, small molecules, or a combination thereof.

[0384] Embodiment 94. The aerosol composition of Embodiment 93, wherein a median size of the plurality of virus nanoparticles does not increase more than 25%.

[0385] Embodiment 95. The aerosol composition of any one of Embodiments 93-94, wherein at least 50% of the plurality of therapeutic agents retain biological activity.

[0386] Embodiment 96.The aerosol composition of any one of Embodiments 49-95, wherein less than 5% of the dried atomized particles form aggregates.

[0387] Embodiment 97. A composition for use in a spraying system, comprising:

[0388] a liquid, suspension, or combination thereof comprising a dispersion of a material;

[0389] wherein:

[0390] the liquid, suspension, or combination thereof upon passing through the spraying system of Embodiment 60, causes the liquid, suspension, or combination thereof to produce a plurality of dried atomized particles, wherein less than 10% of the material sustains thermal damage, and wherein less than 10% of the dried atomized particles form aggregates.

[0391] Embodiment 98.The composition of Embodiment 97, wherein the liquid, suspension, or combination thereof comprises one or more active agents,

[0392] Embodiment 99. The composition of Embodiment 97 or 98, wherein the liquid, suspension, or combination thereof comprises a plurality of solid particles having a size in a range of from 1 nm to 1000 nm, from 1 nm to 800 nm, from i nm to 500 nm, from 1 nm to 300 nm, from i nm to 100 tint, from 100 nm to 1000 nm, from 100 nm to 800 nm, from 100 nm to 500 nm, from 100 nm to 300 nm, from 300 nm to 1000 nm, from 300 nm to 800 nm, from 300 nm to 500 nm, from 500 nm to 1000 nm, from 500 nm to 800 nm, or from 800 nm to 1000 nm.

[0393]

[0394] Embodiment 100.The composition of any one of Embodiments 97-99, wherein more than 80% of the plurality of dried atomized particles having median diameters less than 5 microns.

[0395] Embodiment 101.The composition of any one of Embodiments 97- 100, w herein the plurality of dried atomized particles comprises one or more active agents.

[0396] Embodiment 102.The composition of any one of Embodiments 97-101, wherein the plurality of dried atomized particles retain at least 80% biological activity relative to the liquid, suspension, or combination thereof.

[0397] Embodiment lO3,The composition of any one of Embodiments 97- 102, wherein the hquid, suspension, or combination thereof is non-Newtonian.

[0398] Embodiment 104.The composition of any one of Embodiments 97- 103 , wherein the liquid, suspension, or combination thereof is Newtonian.

[0399] Embodiment 105.The composition of any one of Embodiments 97* 104, wherein the liquid, suspension, or combination thereof has an absolu te viscosity greater than 100 cP.

[0400] Embodiment 106. The composition of any one of Embodiments 97- 105, wherein the liquid, suspension, or combination thereof forms a plurality of atomized particles prior toforming the plurality of dried atomized particles, wherein the plurality of atomized particles are in the form of droplets.

[0401] Embodiment 107 The composition of any one of Embodiments 97-106, wherein the liquid, stispension, or combination thereof comprises a suspension of an organic and / or inorganic material,[ 004021 Embodiment 108, The composition of any one of Embodiments 97- 107, wherein the liquid, suspension, or combination thereof comprises a viscoelastic liquid,

[0403] Embodiment lOO.The composition of any one of Embodiments 97-108, wherein the liquid, suspension, or combination thereof comprises at least one microorganism selected from at least one of: a vaccine, an enveloped virus, a non-enveloped virus, or a combination thereof

[0404] Embodiment 1 10. The composition of Embodiment 109, wherein at least 50% of the at least one microorganism retains biological activity.

[0405] Embodiment 11 1 .The composition of any one of Embodiments 97-1 10, wherein the liquid, suspension, or combination thereof comprises a plurality of therapeutic agents selected from at least one of: a virus, a virus vector, a non~viral vector, viral fragments, virus particles, virus-like particles, imaging agents, small molecules, or a combination thereof.

[0406] Embodiment 112 The composition of any one of Embodiments 97-1 10, wherein the liquid, suspension, or combination thereof comprises a plurality of virus nanoparticles loaded with a plurality of therapeutic agents selected from at least one of: nucleic acids, proteins, peptides, genes, imaging agents, microorganisms, small molecules, or a combination thereof.

[0407] Embodiment 1 '13.The composition of Embodiment 1 12, wherein a median size of the plurality of virus nanoparticles does not increa se more than 25%.

[0408] Embodiment 114.The composition of any one of Embodiments 1 12-113, wherein at least 50% of the plurality of therapeutic agents retain biological activity.(00409] Embodiment 1 15.The composition of any one of Embodiments 97- I 14, wherein less than 5% of the dry particles in the aerosol of dry particles form aggregates.

[0410] Embodiment 1 16. An aerosol composition comprising:

[0411] a plurality of dried atomized particles, wherein the plurality of dried atomized particles are formed from a liquid, suspension, or combination thereof comprising a dispersion of biological material, wherein the biological material comprises a viral particle, wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosolcomprises the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the plurality of atomized particles as measured relative to a control particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, and wherein less than 10% of the biological material sustains thermal damage, and wherein less than 10% of the dried atomized particles form aggregates.

[0412] Embodiment 117. A system for formulating an aerosol composition of any one of Embodiments 78-95 or 116 comprising;

[0413] a nozzle device adapted to atomize a dispersion of a material in a liquid, suspension, or combination thereof to sufficiently form an aerosol containing a plurality of atomized particles, wherein the nozzle device includes at least three channels comprising an inner channel, at least one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel, the at least one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular channel and having a gap width sufficient so as io atomize a liquid, suspension, or combination thereof flowing through the at least one middle annular channel upon flow of one or more gases through at least the inner channel and the at least one outer annular channel; and

[0414] a drying chamber operatively connected to the nozzle device, the drying chamber adapted to apply a drying gas at a temperature of 0-45 °C so as to mix and dehydrate the plurality of atomized particles, thereby forming a dry particle aerosol:

[0415] wherein at least 50% of Che plurality’ of the biological material retains biological activity’.

[0416] Embodiment 118. A. rapid room-temperature dehydration (RTAD) system, comprising:

[0417] a nozzle device adapted to atomize a dispersion of a material in a liquid, suspension, or combination thereof to sufficiently form an aerosol containing a plurality of atomized particles, wherein the nozzle device includes at least three channels comprising an inner channel, at least one .middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the al least one middle annular channel, the at least one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular channel and having a gap width sufficient so as to atomize a liquid, suspension, or combination thereof flowing through the at least one middle annular channel upon flow ofone or more gases through at least the inner channel and the at least one outer annular channel; and

[0418] a drying chamber operatively connected to the nozzle device, the drying chamber adapted to apply a drying gas at a temperature of 0-45 *C so as to mix and dehydrate the plurality of atomized particles, thereby forming a dry particle aerosol;

[0419] at least one liquid pump coupled to the at least one middle annular channel; and

[0420] a liquid source coupled to each liquid pump, the at least one liquid source comprising the dispersion;

[0421] wherein die material comprises a viral particle,

[0422] wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosol comprises the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the plurali ty of atomized particles as measured relative to a control particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell,

[0423] wherein less than 10% of the material sustains thermal damage; and

[0424] wherein less than 10% of the dry particles in the dry particle aerosol form aggregates.

[0425] Embodiment 119,The RTAD system of Embodiment 118, further comprising at least one flow controller, wherein the at least one flow controller is configured to control a flow rate of the one or more gases through at least the inner channel and the at least one outer annular channel of the nozzle device.

[0426] Embodiment 120,The RTAD system of any one of Embodiments 1 18-1 19, further comprising at least one mass flow controller, wherein the at least one mass flow controller is configured to control a flow rate of one or more of the dispersion and the drying gas.

[0427] Embodiment 121. The RTAD system of any one of Embodiments 1 18-120, wherein the material comprises a biologic material.

[0428] Embodiment 122. The RTAD system of Embodiment 121, wherein the biologic material comprises a virus.

[0429] Embodiment 123, The RTAD system of any one of Embodiments 121-122, wherein the biologic material comprises a vaccine, an enveloped virus or a non-enveloped virus.

[0430] Embodiment 124.'rhe RTAD system of any one of Embodiments 1 18-123, wherein a surface tension of the dispersion is less than water.

[0431] Embodiment 125. The RTAD system of any one of Embodiments 1 18-124, wherein a flow rate of the dispersion from the nozzle device is 0.1 mL~10 L / min.(00432] Embodiment 126. The RTAD system of any one of Embodiments 1 18-125, wherein a median size of die plurality of atomized particles is less than 50 pm.

[0433] Embodiment 127.The RTAD system of any one of Embodiments 1 18-126, wherein a median size of the plurality of atomized particles is less than. 20 pm.

[0434] Embodiment 128.T1ie RTAD system of any one of Embodiments 1 18-127, wherein a median size of the plurality of atomized particles is less than 10 pm.(00435'1 Embodiment 129. The RTAD system of any one of Embodiments 1 18-128, wherein the drying gas comprises nitrogen, helium, air, or a combination thereof.

[0436] Embodiment 130. The RTAD system of any one of Embodiments 1 18-129, wherein the drying gas is provided at a rate of 5-200 standard liters / min.

[0437] Embodiment 131. The RTAD system of any one of Embodiments 1 18-130, wherein the temperature is provided between about 15 *C and about 35 °C.(00438] Embodiment 132,The RTAD system of any one of Embodiments 1 18-131 , further comprising recovering particles after mixing and dehydrating.

[0439] Embodiment 133. The RTAD system of any one of Embodiments 1 18-132, wherein the drying chamber comprises a filter assembly, the filter assembling being configured to recover particles.

[0440] Embodiment 134.The RTAD system of any one of Embodiments 1 18-133, further comprising a cyclone separator downstream of t he drying chamber, wherein the cyclone separator is configured to recover particles.

[0441] Embodiment 135. The RTAD system of any one of Embodiments 1 18-134, wherein the drying chamber comprises a temperature control probe, a humidity probe, a pressure probe, or a combinat ion thereof

[0442] Embodiment 136.The RTAD system of any one of Embodiments 1 18-135, wherein the drying chamber is operatively connected to one or more inlet or outlet.

[0443] Embodiment 137.The RTAD system of any one of Embodiments 1 18-136, wherein the drying chamber comprises a sensor at an outlet of the drying chamber, wherein the sensor is configured to determine a particle number, a particle size, or a combination thereof at the ou tlet of the drying chamber.

[0444] Embodiment 138. The RTAD system of any one of Embodiments 1 18-137, wherein one or more of the nozzle device or the drying chamber is adapted to be retrofited to a second spraying system.EXAMPLES

[0445] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.Example I: Schematic diagram of exemplary rapid room-temperature aerosol dehydration (R TAD) system

[0446] The purpose of this example is to provide exemplary system of a rapid roomtemperature aerosol dehydration (RTAD) system described herein.

[0447] FIG. 5 illustrates a schematic diagram of the exemplary' RTAD system. The RTAD system comprises a nozzle device (1 ), indicated as “aerosol generator assembly”, which was integrated into a laboratory scale prototype of the RTAD system for realizing liquid atomization (as disclosed separately in the ‘866 application). The nozzle device (1 ) was capable of processing liquid solutions of enveloped and non-enveloped virus particles supplied as spray / aerosol of ultra-fine droplets with flow rates of 0.1-10 mL / min and even up to 100 mL / min using syringe or peristaltic pump (8) into the drying chamber (2), and utilizing nitrogen / air / helium / other drying gas (supplied from cylinder 4) with flow rates 5-150 standard liters / min at temperatures 15-35 °C for solvent evaporation from the sprayed and aerosolized droplets. There was a co-current flow between the spray / aerosol of droplets and flow of drying gas supplied from nitrogen cylinder (4) using a mass flow controller (6). Another stream of gas from the nitrogen cylinder (4) was utilized for spraying / aerosolization of liquid (as disclosed separately hi the *866 application), and it was supplied in controlled way by means of microfluidie flow controller (7) guided by computer (5). At the botom of the drying chamber (2), the filter assembly (3 ) with a membrane filter was utilized for collection of dry particulates from the two-phase gas-particle flow stream.

[0448] In the experiments, the volume of batches of liquid solution containing enveloped and non-cnveloped virus particles which were dehydrated was between 2-50 mL, and the collected powder mass on the membrane filter was up to 5 g for the laboratory-scale RTAD setup.Example 2: Comparison of droplet patterns produces by different liquid atomization methods

[0449] The purpose of this example is to provide exemplary testing results of the methods and systems described herein.

[0450] FIG. 6 provides a comparison of droplet patterns produces by different liquid atomization methods. The liquid atomization method using the R'I'AD system of Example 1 was applied for the generation of ultra-fine spray / aerosol droplets (right), and is compared to a con ventional spray (left) and an aerosol generator (middle). The sprayed liquid contained water with a small amount of blue dye and the spraying was directed on a paper sheet. The RTAD system of Example 1 provides more homogeneous droplet pattern, with more uniform and smaller droplet sizes, compared to conventional spray bottle and aerosol generator can. In general, the liquid atomization method generates atomized droplets with diameters HMOOx smaller than competing technologies.Example 3: Retention of activity of human cytomegalovirus after spraying with respect to initial suspension

[0451] The purpose of this example is to illustrate the retention of human cytomegalovirus (HCMV) activity after being sprayed as atomized particles.

[0452] FIG. 7 is a graph showing protein abundance for HCMV in spray droplets analyzed by Western Blot, indicating the retention of activity of HCMV after spraying? with respect to initial suspension. The initial concentration of HCMV before spraying was around 1 plaque forming units (PFU) / mL in buffer suspension, and the suspension was supplied at 0.5 nil. / min to the triple coaxial nozzle. .Nitrogen was used as atomizing gas and supplied at various pressures: spray 1 was generated by using 2000 mbar, spray 2 was generated by using 1500 mbar and spray 3 was generated by using 1000 mbar of nitrogen pressure.

[0453] FIG. 8 is a graph demonstrating retention of activity of human cytomegalovirus (HCMV) in sprays of virus-containing aerosol droplets by comparing particIe-to-PFU ratios before and after spraying. The sprays were generated by using nitrogen as atomizing gas and supplied at pressures of 2000, 1500 and 1000 mbar. The initial concentration ofHCMV before spraying was around 10*’ PFU / mL in buffer suspension, and the suspension was supplied at 0,5 mL / min. to the triple coaxial nozzle.Example 4: Viral Infectivity of the powder of viruses produced by the RTAD system

[0454] The purpose of this example is to illustrate the retention of human cytomegalovirus (HCMV) vital infectivity in powder formulation with different excipients after being sprayed as atomized particles by the RTAD setup of Example 1 .

[0455] T 'he initial concentration of HCMV before spraying was around IO6PFIJ / mL in buffer suspension, and the feedstock suspension was supplied at 0.5 mL / min to the RTAD nozzle described above. Nitrogen was used as atomizing gas and supplied at 2000 mbar of manometric pressure.

[0456] An example of virus infectivity confirmation of produced powder of commercial enveloped virus solution HCMV (Department of Molecular Biology, Princeton University), freshly dried, is given in FIGS. 9A-9B. For this purpose, commercial HCMV, as is without any changes in formulation, was processed ia the RTAD setup and encapsulated in various excipients, and the vims infectivity of the powder reconstituted with water was confirmed using the plaque assay technique. Controls included initial non-processed HCMV virus suspensions. The excipients used were mannitol, lactose, and trehalose (7.5 wt.% concentration in feedstock in each case), and FIGS. 9A-9B illustrate results comparing a 1 :10 and. 1:100 dilution, respectively, of the powder In water. It can be observed that there is no reduction of virus infectivity in all the studied powders upon reconstitution in water and comparison with initial feedstock virus suspension (control).

[0457] An example of particle-to-PFU parameter confirmation of the HCMV in powder formulations with different excipients is given in FIG, 9C. For this purpose, commercial HCMV, as is without any changes in formulation, was processed in the RTAD setup and encapsulated in mannitol, lactose or trehalose, and the biological activity of the powder reconstituted with water was confirmed using the virus genome counting and plaque assay to determine particle-ro-PFU values. It Can be observed that HCMV fonnulation in trehalose demonstrated the best performance in terms of particle-to-PFU value, whereas HCMV formulation in mannitol was the worst with zero HCMV genome counting ( iiot shown on the figure to conserve space).

[0458] The corresponding SEM image of the powder morphology is given in FIG.9D.Specifically, FIG. 9D illustrates an SEM micrograph of powder microstructure demonstrating morphology of the particles containing HCMV virus encapsulated by a trehalose-leucine excipient mixture (obtained by RTAD dehydration of the feedstock with 5.63 wt% trehalose, 1.87 wt% leucine). Furthermore, the samples of the produced HCMV powder were stored at room temperature *22 °C and 25% humidity and in a fridge at +4&C and 25% humidity duringseveral weeks, and their biological activity was confirmed to be similar to the original HCMV solution after reconstitution with water.

[0459] An example of biological activity confirmation of the HCMV in powders produced by the RTAD system is given in FIGS. 10A-10B. For this purpose, commercial HCMV, as is without any changes in formulation, was processed in the RTAD setup and encapsulated in lactose and trehalose (7.5 wt.% concentration in feedstock in each case) in FIGS. 10A and 108, respectively, and the biological activity of the powder reconstituted with water was confirmed using Western Blot. The Western Blot was performed for three different proteins associated with the HCMV particles, UL99, UL26 and IE I , It can be observed that powdered HCMV formulation in trehalose demonstrated the best performance in terms of protein expression study.Example 5: Retention of activity7of AdV5 and AAV2 after spraying with respect to initial suspension

[0460] The purpose of this example is to illustrate the retention of active adenovirus (Ad V5) and adeno-associated virus (AAV2) activity after being sprayed in atomized droplets. Here, active adenovirus and adeno-associated virus (non-env eloped viruses) particles in buffer solution were sprayed using the nozzle of the RTAD setup, and the biological activity of the produced droplets collected after spraying step was confirmed. The example of biological activity confirmation of powders containing adenovirus (AdV5) are given in FIGS. 11A-11C, and the example of biological activity confirmation of powders containing adeno-associated virus (AAV2) is given in FIG, 12.

[0461] Briefly, a suspension comprising AdV5 particles was purified using successive cesium chloride gradients and diluted in 10 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0. 1% BSA. A spectroscopic analysis was performed on a suspension, comprising purified AdV5 particles, and atomized particles formed from the suspension using a nozzle device described herein. The atomized particles were formed by flowing the suspension at 0.5 mL / min through a middle annular channel of the nozzle device, and ni trogen gas through an inner channel and an outer annular channel of the nozzle device at 2000, 1500 or 1000 mbar. FIG. 1.1 A shows results of spectroscopic analysis for determining concentrations of purified AdV5 particles in the suspension (control) and atomized particles (spray), i.e., the virus particle counting was performed by spectrophotometry of collected droplets and compared to that of the controls (initial nonprocessed AdV5 virus suspensions).

[0462] Next, retention of activity of purified AdV5 particles in atomized particles was determined by plaque assay technique via comparing plaque forming units per milliliter (PFU / mL) observed for the initial feedstock suspension and the atomized droplets. The results of the experiment are shown in FIG. 11 B. The virus infectivity was determined by plaque assay of collected droplets and compared to that of the controls (initial non-processed AdV5 virus suspensions).

[0463] Additionally, retention of activity of purified AdV5 particles in atomized particles was determined by comparing a ratio of adenovirus particle to plaque formation unit (parricIe-to-PFU) observed for the suspension and the atomized particles. Results of the experiment arc shown FIG. 11C. The particle-to-PFU was determined by counting virus particles (spectrophotometry) and virus titer (plaque assay) in collected droplets, and compared to that of the controls (initial non-processed AdV5 virus suspensions). The corresponding SEM image of the adenovirus powder is given in FIG. 1 II). Specifically, FIG. I ll) illustrates an SEM micrograph of powder microstructure demonstrating morphology of the particles containing AdV5 adenovirus encapsulated by trehalose-leucine excipient mixture,

[0464] Regarding FIG. 12, AAV2 particles were produced from an AAV plasmid containing a green fluorescence protein (GFP) transgene sequence under the control of CAG promoter (CAG-GFP). AAV2 droplets were then purified using an iodixanol gradient and diluted in PBS. Atomized particles were formed by flowing the suspension comprising purified AAV2 particles at 0.5 mL / min through a middle annular channel of the nozzle device, and nitrogen gas through an inner channel and an outer annular channel of the nozzle device at 2000, 1500 or WOO mbar. Next, retention of activity of purified AAV2 particles in atomized droplets was determined by comparing infectious particles / mL observed for the initial feedstock suspension and the atomized droplets. FIG. 12 shows results of the experiment. The virus infectivity in collected droplets was determined by using the GFP and microscopy, and the results compared to those of the controls (initial non-processed AAV 2 virus suspensions).Example 6: Retention of infectivity of AdV5 after RTAD dehydration with respect to initial feedstock virus suspension

[0465] The purpose of this example is to illustrate the retention of active adenovirus (AdV5) infectivity after being sprayed as atomized droplets and dehydrated using RTAD process. The results indicate that the RTAD process can transform AdV5 into a solid-statepowder for pulmonary delivery, potentially improving stability compared to liquid formulations.

[0466] Briefly, a suspension comprising AdV5 particles was purified using successive cesium chloride gradients and diluted in 10 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA. The feedstock formulation also contained excipients 3.75 wt% trehalose and 1 .25 wt% leucine, A spectroscopic analysis was performed on a suspension comprising purified AdV5 particles, and atomized droplets formed from the suspension using a nozzle device described herein. The atomized droplets were formed by flowing the suspension at 0.5 mL / niin through a middle annular channel of the nozzle device, and nitrogen gas through an inner channel and an outer annular channel of the nozzle device at 2000 mbar. The formed droplets were dehydrated in the RTAD drying chamber using 90 SLPM flow of nitrogen supplied at room temperature 22 °C, while the manometric pressure inside the drying chamber was kept at slight vacuum -3 psig. The powder was collected in RTAD chamber using PVDF filter with pore size of 0.45 gm,

[0467] FIGS. 13A-I3C are graphs demonstrating retention of infectivity of Ad V 5 in powders of virus-containing dry particles by comparing viral titers measured by plaque assays (FIG. 13A), particle counts measured by quantitative polymerase chain reaction (qPCR) (FIG. 13B), and ratios of particle count and PFU concentrations (FIG. 13C) before and after using RTAD dehydration.

[0468] The droplet sprays were generated by using nitrogen as atomizing gas and supplied at a pressure of 2000 mbar. The initial concentration of AdV5 before spraying was around 4.9- 109PFU / mL in feedstock suspension, and the virus suspension was supplied at 0.5 rnL / miu to the RTAD triple coaxial nozzle described herein. The virus iiifcctivity showed no significant variation before and after dehydration with RTAD, i.e,, near 100% of viral infectivity was preserved following the RTAD process, paving the way for further development of inhalable and stable adenovirus powders,

[0469] FIG. 13D illustrates a long-term study comparing the particle-to-PFU ratios of RTAD-dehydrated powder particles containing AdV5 when stored for I month at different temperatures, specifically at 4 *C and 40 °C. A first .formulation of a feedstock for forming the particles included. 3.75 wt% trehalose, 1 ,25 wt% leucine, lOOmM NaCl, 0.1 wt% human Albumin, 10 mM Tris-HCl, pH8, and AdV5 at a concentration. of 4.9-.109PFU / mL. The RTAD operating conditions for forming the powder included: collection using a 450 nm PVDF filter;drying gas flow rate Of 90 standard litcrs / min (SLPM) nitrogen; a drying chamber pressure of -3 PSIG; an atomization pressure of 2 bar: and a feedstock flow rate of 0.5 mL / min.

[0470] The results of testing with additional feedstock formulations are described herein. A second formulation for a feedstock for forming particles included Dextran 140k Da 2 wt%, D-Mannitol 4 wt%, 1 XPBS, and AdV5 4.9- 10sPFU / mL. The RTAD operating conditions were the same as those used for producing foe powder in FIG. 13D. No viral plaques were detected w ithin foe tested dilution range of the plaque assay. The PFU concentration of the feedstock decreased by over 100-fold compared to the PFU concentration of foe first formulation of feedstock described above.

[0471] A second formulation for a feedstock for forming particles included Dextran 140k Da 2 wt%, D-Mannitol 4 wt%, 1 XPBS, and AdV54.9 - 10° PFU / mL. The RTAD operating conditions were the same as those used for producing foe powder in FIG. 13D, No viral plaques were detected w'ithin the tested dilution range of the plaque assay.Example 7: Prevention of adjuvant particles aggregation after RTAD process with respect to lyophilization

[0472] The purpose of this example is to illustrate the use of the RTAD setup for eliminating aggregation of adjuvant particles as compared to lyophilization,

[0473] Alum adjuvants are widely used in virus-based vaccines io enhance the immune response by stimulating foe body’s defense mechanisms. However, they suffer from aggregation upon freezing which will alter their functions as adjuvant. Thus, alum adjuvants- based vaccines cannot by lyophilized (freeze dried) and require stringent logistical temperature control io avoid freezing while keeping the temperature slightly above the feezing temperature. By leveraging the room temperature dehydration capability of RTAD, the particles size distribution of reconstituted alum adjuvants did not show any aggregation while the reconstituted powder formulations made by traditional freeze drying showed significant aggregation .

[0474] FIG. 14 illustrates a particles size distribution measured by dynamic light scattering of the initial alum adjuvant (Alhydrogel®), and of reconstituted powder formulations made by RTAD and. freeze drying. Here, trehalose excipient was mixed with alum adjuvant particles to form a. feedstock which was processed in the RTAD setup, and the particle size distribution of the produced powder subsequently reconstituted rvith DI water was characterized by dynamic light scattering.

[0475] A formulation for a feedstock for forming the particles included 1 mL Alhydrogel&!adjuvant (2% aluminum hydroxide) 500 mg trehalose ■+• 9 ml DI water. The final formulation is 0.2 wt% aluminum hydroxide suspension, 5 wt.% trehalose. The RTAD operating conditions were the same as those used for producing the powder in FIG. 13D. The results in FIG. 14 illustrate the abili ty of RTAD process to prevent aggregation of adjuvant particles with respect to traditional lyophilization (freeze drying).Example 8: Droplet size distribution measurements for three-channel nozzle assemblies with straight channels

[0476] The purpose of this example is to provide graphs showing examples of profiles of the droplet size distribution measured by laser diffraction from a Malvern Spraytec instrument of water and deionizing water sprays. All data were measured for atomizing deionized water. T his example further illustrates the scalability of the RTAD nozzles of the instant application, specifically from 0. 1-10 niL / min feedstock flow rate on the lab scale to up to 100 mL / min feedstock flow rate in a pilot scale atomization capacity, illustrating a scale-tip capacity by 10x. The average droplet size remains the same, in contrast to traditional nozzles with exponentially growing droplet average diameter upon feedstock flow rate increase. This example further illustrates an ability of t he RTAD nozzles of the instant application to retrofit or upgrade nozzles in traditional spray drying process by switching to RTAD nozzle producing 10x smaller droplet sizes than traditional two-fluid nozzles, allowing for use of the RTAD process on existing spray drying chambers and equipment both on the lab and industrial scale. The RTAD system allows for decreasing dehydration temperatures of spray drying processes from 100-200 °C down to 20-40°C (such as, for example, at about 22°C), and allow all the benefits of RTAD.

[0477] FIGS. 15A-15B illustrate the volume- and number- weighted droplet size distributions, respectively, of aerosol droplets produced at water flow rate of 5 ml / min and atomization pressure of 5 bar and liquid flow gap width 25 microns. FIGS, 15C-15D illustrate mass median droplet diameter of water sprays as a function of air pressure for various water flow rates and liquid flow gap width 25 microns, specifically Dv50 (volume-weighted median ) (FIG. 15C) and D32 (Sauter mean) diameters ( FIG. 15D) of the produced droplets as a function of atomizing gas pressure and liquid feed flow rate. FIG, 15E illustrates mass median droplet diameter of water sprays as a function of liquid flow rate and air pressure 5 bar gaugefor various nozzles, specifically a commercial lab-scale Spray Dryer (Buchi B-290) as compared to two nozzles of the instant application having nozzle diameters of 25 pm.

Claims

CLAIMSWhat is claimed:

1. A method for rapid room-temperatnre dehydration (RTAD), comprising: atomizing a dispersion of a material in a liquid, suspension or combination thereof using a nozzle device, thereby forming an aerosol containing a plurality of atomized particles* wherein the material comprises a viral particle: mixing and dehydrating the plurality of atomized particles using a drying gas at a temperature of 0-45 °C so as to sufficiently dry the plurality of atomized particles, thereby forming an aerosol of dry particles; and coating the atomized particles with an excipient or adjuvant such that the aerosol of dry particles comprises the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the dry particles as measured relative to a control particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, wherein less than 10% of the material sustains thermal damage, and wherein less than 10% of the dry particles in the aerosol of dry particles form aggregates.

2. The method of claim 1, wherein the nozzle device includes at least three channels comprising art inner channel, at least one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel, the at least, one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular channel and having a gap width sufficient so as to atomize a liquid, suspension or combination thereof flowing through the at least one middle annular channel upon, flow of one or more gases through at least the inner channel and the at least one outer annular channel.

3. The method of any one of claims 1-2, wherein the material comprises a biologic material.

4. The method of any one of claims 1 -3, wherein th© material comprises a virus.

5. The method of any one of claims 1 -4, wherein the material comprises a vaccine, an enveloped virus or a non-envdoped virus.

6. The method of any one of claims 1 -5, wherein a surface tension of the dispersion is less than water.

7. The method of any one of claims 1 -6, wherein a flow rate of the dispersion from the nozzle device is 0.1 mL-10 L / min.

8. The method of any one of claims 1 -7, wherein a median size of the plurality of atomized particles is less than 50 pm.

9. The method of any one of claims .1 -8, wherein a median size of the plurality of atomized particles is less than 20 pm.

10. The method of' any one of claims 1-9, wherein a median size of the plurality of atomized particles is less than 10 pm.

11. The method of any one of claims 1-10, wherein the drying gas comprises nitrogen, helium, air, or a combination thereof.

12. The method of any one of claims 1-1 1, wherein the drying gas is provided at a rate of 5-200 standard liters / min.

13. The method of any one of claims 1 -12, wherein the dehydrating is performed at a negative pressure.

14. The method of any one of claims 1 -13, wherein the temperature is provided between about 15 °C and about 35 °C.

15. The method of any one of claims 1 -14, further comprising recovering particles after mixing and dehydrating.

16. The method of any one of claims 1 -15 , wherein a membrane fil ter is utilized to recover particles.

17. The method of any one of claims .1-16, wherein a cyclone separator is utilized to recover particles.

18. The method of any one of claims 15-17, further comprising analyzing the recovered particles.

19. The method of any one of claims 15-18, wherein analyzing the recovered particles includes confirming biological activity of the recovered particles.

20. The method of any one of claims 15- 19, wherein FT-IR is used to analyze the recovered particles.

21. The method of any one of claims 15-20, further comprising storing the recovered particles at a temperature Zl, where 0°C < T:< < 30°C for a period of time.

22. The method of claim 21 , wherein the period of time is at least 2 months.

23. The method of any one of claims 15-22, further comprising reconstituting the recovered particles after storage.

24. The method of any one of claims I -23, wherein the excipient or adjuvant is in an amount sufficient to extend a shelf life of the dry particles.

25. The method of any one of claims 1 -24, wherein the excipient or adjuvant is in an amount sufficient to control a release of the material in a bodily fluid26. The method of any one of claims 1 -25, wherein the excipient or adjuvant is in an amount sufficient to control a release of the material at a desired pH.

27. The method of any one of claims 1 -26, further comprising delivering the aerosol of dry particles through a nebulizer, an inhaler, a nasal spray, or a microneedle patch.

28. The method of any one of claims 1-26, further comprising reconstituting the dry particles into a pharmaceutically acceptable solvent.

29. The method of any one of claims 1 -26, wherein less than 5% of the dry particles in the aerosol of dry particles form aggregates.

30. A spraying system, comprising: a nozzle device adapted to atomize a dispersion of a material in a liquid, suspension, or combination thereof' to sufficiently form an aerosol containing a plurality of atomized particles, wherein the material comprises a viral particle, wherein the nozzle de vice includes at least three channels comprising an inner channel, at least one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel, the at least one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular channel and having a gap width sufficient so as to atomize a liquid, suspension, or combination thereof flowing through the at least one middle annular channel upon flow of one or more gases through at least the inner channel and the at least one outer annular channel; and a drying chamber operatively connected to the nozzle device, the drying chamber adapted to apply a drying gas at a temperature of 0»45 °C so as to mix and dehydrate the plurality' of atomized particles, thereby forming a dry particle aerosol; wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosol comprises the excipient or adjuvant in an amount sufficient to retain at least 50% of a. viral activity of the plurality of atomized particles as measured relative io a control particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, wherein less than 10% of the mater ial sustains thermal damage, and wherein less than 10% of the dry particles in the aerosol of dry particles form aggregates.

31. The spraying system of claim 30, further comprising at least one flow controller, wherein the at. least one flow controller is configured to control a flow rate of the one or more gases through at least the inner channel and the at least one outer annular channel of the nozzle device.

32. The spraying system of claim any one of claims 30-31 , further comprising at least one flow controller, wherein the at least one flow controller is configured to control a flow rate of one or more of the dispersion and the drying gas."33. The spraying system of any one of claims 30-32, wherein the material comprises a biologic material.

34. The spraying system of any one of claims 30-33. wherein the material comprises a vims.

35. The spraying system of any one of claims 30-34, wherein the material comprises a vaccine, an enveloped virus or a non-enveloped virus.

36. The spraying system of any one of claims 30-35, wherein a surface tension of the dispersion is less than water.

37. The spraying system of any one of claims 30-36, wherein a flow rate of the dispersion from the nozzle device is 0. 1 mL-10 L / min.

38. The spraying system of any one of claims 30-37, wherein a median size of the plurality of atomized particles is less than 50 pm.

39. The spraying system of any one of claims 30-38, wherein a median size of the plurality of atomized particles is less than 20 gm.

40. The spraying system of any one of claims 30-39, wherein a median size of the plurality of atomized partic les is less than 10 pm.

41. The spraying system of any one of claims 30-40, wherein the drying gas comprises nitrogen, helium, air, or a combination thereof.

42. The spraying system of any one of claims 30-41 , wherein the drying gas is provided at a rate of 5-200 standard liters.' min.

43. The spraying system of any one of claims 30-42, wherein the temperature is provided between about 15 °C and about 35 °C.

44. The spraying system of any one of claims 30-43, further comprising recovering particles after mixing and dehydrating.

45. The spraying system of any one of claims 30-44, wherein the drying chamber comprises a filter assembly, the filter assembly is being configured to recover particles.

46. The spraying system of any one of claims 30-45, further comprising a cyclone separator downstream of the drying chamber, wherein the cyclone separator is configured to recover particles.

47. The spraying system of any one of claims 30-45, wherein one or more of the nozzle device or the drying chamber is adapted to be retrofited to a second spraying system.

48. An aerosol composition comprising a plurality of dried atomized partides, wherein the plurality of dried atomized particles is formed from drying a liquid, suspension, or combination thereof comprising a dispersion of biological material at a temperature of 0-459C, wherein the biological material comprises a viral particle, wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosol comprises the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the plurality of atomized particles as measured relative to a control particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, wherein less than 10% of the biological material sustains thermal damage, and wherein less than 10% of the dried atomized particles form aggregates,49. The aerosol composition of claim 48, wherein the liquid, suspension, or combination thereof comprises one or more active agents.

50. The aerosol composition of claim 48 or 49, wherein the liquid, suspension, or combination thereof comprises plurality of solid particles having a size in a range of from 1 nm to 1000 nm, from 1 nm to 800 nm, from I nm io 500 nm, from 1 om to 300 nm, from I nm to 100 nm, from 100 nm to 1000 nm, from 100 nm to 800 lira, from 100 nm to 500 nm, from 100 nm to 300 nm, from 300 nm to 1000 nm, from 300 nm to 800 nm, from 300 nm to 500 nm, from 500 nm to 1000 nm, from 500 nm to 800 nm, or from 800 nm to 1000 nm.

51. The aerosol composition of any one of claims 48-50, wherein more than 99% of the plurality of dried, atomized particles having median diameters less than 20 microns.

52. The aerosol composition of any one of claims 48-51 , wherein the plurality of dried atomized particles comprise one or more active agents.

53. The aerosol composition of any one of claims 48-52, wherein the plurality of dried atomized partides retain at least 80% biological activity relative to the liquid, suspension, or combination thereof.

54. The aerosol composition of any one of claims 48-53, wherein the liquid, suspension, or combination thereof is non-Newtonian.

55. The aerosol composition of any one of claims 48-54, wherein the liquid, suspension, or combination thereof is Newtonian.

56. The aerosol composition of any one of claims 48-55, wherein the liquid, suspension, or combination thereof has an absolute viscosity greater than 100 cP.

57. The aerosol composition of any one of claims 48-56, wherein the liquid, suspension, or combination thereof forms a plurality of atomized particles prior to forming the plurality of dried atomized particles, wherein the plurality of atomized particles arc in the form of droplets.

58. The aerosol composition of any one of claims 48-57, wherein the liquid, suspension, or combination thereof comprises a suspension of an organic and / or inorganic material.

59. The aerosol composition of any one of claims 48-58, wherein the liquid, suspension, or combination thereof comprises a viscoelastic liquid.

60. The aerosol composition of any one of claims 48-59, wherein the liquid, suspension, or combination thereof comprises at least one microorganism selected from at least one of: a vaccine, an enveloped virus, a non-enveloped virus, or a combination thereof61. The aerosol composition of claim 60, wherein at least 50% of the at least one microorganism retains biological activity.

62. The aerosol composition of any one of claims 48-61, wherein the liquid, suspension, or combination thereof comprises a plurality of therapeutic agents selected from at least one of: avirus, a virus vector, a non-viral vector, viral fragments, virus particles, virus-like particles, imaging agents, small molecules, or a combination thereof.

63. The aerosol composition of any one of claims 48-62, wherein the liquid, suspension, or combination thereof comprises a plurality of virus nanoparticles loaded with a plurality of therapeutic agents selected from at least one of: nucleic acids, proteins, peptides, genes, imaging agents, microorganisms, small molecules, or a combination thereof.

64. The aerosol composition of claim 63, wherein a median size of the plurality' of virus nanoparticles does not increase more than 25%.

65. The aerosol composition of any one of claims 63-64, wherein at least 50% of the plurality of therapeutic agents retain biological activity.

66. The aerosol composition of any one of claims 49-65, wherein less than 5% of the dried atomized particles form aggregates.

67. A composition for use in a spraying system, comprising: a liquid, suspension, or combination thereof comprising a dispersion of a ma terial; wherein: the Liquid, suspension, or combination thereof upon passing through the spraying system of claim 30, causes the liquid, suspension, or combination thereof to produce a plurality of dried atomized particles, wherein Jess than 10% of the material sustains thermal damage, and wherein less than 10% of the dried atomized particles form aggregates.

68. The composition of claim 67, wherein the liquid, suspension, or combination thereof comprises one or more active agents.

69. The composition of claim 67 or 68, wherein the liquid, suspension, or combination thereof comprises a plurality' of solid particles having a size in a range of from 1 am to 1000 ntn, from 1 nm to 800 nm, from 1 nm to 500 nm. from I nm to 300 nm, from I nm to 100 nm, from 100 nm to 1000 nm, from 100 nm to 800 nm, from 100 nm to 500 nm, from 100 nm to 300 nm, from 300 nm to 1000 nm, from 300 nm to 800 nm, from 300 nm to 500 nm, from 500 nm to 1000 nm, from 500 nm to 800 nm, or from 800 nm to 1000 nm.

70. The composition of any one of claims 67-69, wherein more than 80% of the plurality of dried atomized particles having median diameters less than 5 microns.71, The composition of any one of claims 67-70, wherein the plurality of dried atomi zed particles comprises one or more active agents.

72. The composition of any one of claims 67-71 , wherein the plurality of dried atomized particles retain at least 80% biological activity relative to the liquid, suspension, or combination thereof.

73. The composition of any one of claims 67-72, wherein the liquid, suspension, or combination thereof is non-Newtonian.

74. The composition of any one of claims 67-73, wherein the liquid, suspension, or combination thereof is Newtonian.

75. The composition of any one of claims 67-74, wherein the liquid, suspension, or combination thereof has an absolute viscosity greater than 100 cP.

76. The composition of any one of claims 67-75, wherein the liquid, suspension, or combination thereof forms a plurality of atomized particles prior to forming the plurality of dried atomized particles, wherein the plurali ty of atomized particles are in the form of droplets.

77. The composition of any one of claims 67-76, wherein the liquid, suspension, or combination thereof comprises a suspension of an organic and / or inorganic material.

78. The composition of any one of claims 67-77, wherein the liquid, suspension, or combination thereof comprises a viscoelastic liquid.

79. The composition of any one of claims 67-78, wherein the liquid, suspension, or combination thereof comprises at least one microorganism selected from at least one of: a vaccine, an enveloped virus, a non-envelopcd virus, or a combination thereof.

80. The composition of claim 79, wherein at least 50% of tire at least one microorganism retains biological activity.

81. The composition of any one of claims 67-80, wherein the liquid, suspension, or combination thereof comprises a plurality of therapeutic agents selected from at least one of: a virus, a virus vector, a non-viral vector, viral fragments, virus particles, virus-like particles, imaging agents, small molecules, or a combination thereof.

82. The composition of any one of claims 67-80, wherein the liquid, suspension, or combination thereof comprises a plurality of virus nanoparticles loaded with a plurality of therapeutic agents selected from at least one of: nucleic acids, proteins, peptides, genes, imaging agents, microorganisms, small molecules, or a combination thereof.

83. The composition of claim 82, wherein a median size of the plurality of virus nanoparticles does not increase more than 25%.

84. The composition of any one of claims 82-83, wherein at least 50% of the plurality of therapeutic agents retain biological activity.

85. The composition of any one of claims 67-84, wherein less than 5% of the dry particles in. the aerosol of dry particles form aggregates.

86. An aerosol composition comprising: a plurality of dried atomized particles, wherein the plurality of dried atomized particles are formed from a liquid, suspension, or combination thereof comprising a dispersion of biological material, wherein the biological material comprises a viral particle, wherein the atomized particles arc coated with an excipient or adjuvant such that the dry particle aerosol comprises the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the plurality of atomized particles as measured relative to a con trol particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, and wherein less than 10% of the biological material sustains thermal damage, and wherein less than 10% of the dried atomized particles form aggregates.

87. A system for formulating an aerosol composition of any one of claims 48-65 or 86 comprising;a nozzle device adap ted to atomize a dispersion of a material in a liquid, suspension, or combination thereof to sufficiently form an aerosol containing a plurality of atomized particles, wherein the nozzle device includes at least three channels comprising an inner channel, at least, one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel, the at least one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular channel and having a gap width sufficient so as to atomize a liquid, suspension, or combination thereof flowing through the at least one middle annular channel upon flow of one or more gases through at least the inner channel and the at least one outer annular channel; and a drying chamber operatively connected to the nozzle device, the drying chamber adapted to apply a drying gas at a temperature of 0-45 °C so as to mix and dehydrate the plurality of atomized particles, thereby forming a dry particle aerosol; wherein at least 50% of the plurality of the biological material retains biological activity.88, A rapid room-temperature dehydration (RTAD) system, comprising: a nozzle device adapted to atomize a dispersion of a material in a liquid, suspension, or combination thereof to sufficiently form an aerosol containing a plurality of atomized particles, wherein the nozzle device includes at least three channels comprising an inner channel, at least one middle annular channel, outside of the inner channel, and at least one outer annular channel outside of the at least one middle annular channel, the at least one middle annular channel being coaxially arranged between the inner channel and the at least one outer annular' channel and having a gap width sufficient so as to atomize a liquid, suspension, or combination thereof flowing through the at least one middle annular channel upon flow of one or more gases through at least the inner channel and the at least one outer annular channel; a drying chamber operatively connected to the nozzle device, the drying chamber adapted to apply a drying gas at a temperature of 0-45 °C so as to mix and dehydrate the plurality of atomized particles, thereby forming a dry particle aerosol; and at least one liquid pump coupled to the at least one middle annular channel; and a liquid source coupled to each liquid pump, the at least one liquid source comprising the dispersion; wherein the material comprises s viral particle,wherein the atomized particles are coated with an excipient or adjuvant such that the dry particle aerosol comprises the excipient or adjuvant in an amount sufficient to retain at least 50% of a viral activity of the plurality of atomized particles as measured relative to a control particle that is not atomized, wherein the viral activity is measured by an ability of the viral particle to generate an immune response of a host cell upon contact with the host cell, wherein less than 10% of the material sustains thermal damage; and wherein less than 10% of the dry particles in the dry particle aerosol form aggregates.

89. The RTAD system of claim 88, further comprising at least one flow controller, wherein the at least one flow controller is configured to control a flow rate of the one or more gases through at least the inner channel and the at. least one outer annular channel of the nozzle device.

90. The RTAD system of any one of claims 88-89, further comprising at least one mass flow controller, wherein the at least one mass flow controller is configured to control a flow rate of one or more of the dispersion and the drying gas.

91. The RTAD system of any one of claims 88-90, wherein the material comprises a biologic material.

92. The RTAD system of claim 91 , wherein the biologic material comprises a virus.

93. The RTAD system of any one of claims 91-92, wherein the biologic material comprises a vaccine, an enveloped virus or a non-enveloped virus.

94. The RTAD system of any one of claims 88-93, wherein a surface tension of the dispersion is less than water,95. The RTAD system of any one of claims 88-94, wherein a flow rate of the dispersion from the nozzle device is 0.1 mL-10 L / min.

96. The RTAD system of any one of claims 88-95, wherein a median size of the plurality of atomized particles is less than 50 urn.

97. The RTAD system of any one of claims 88-96, wherein a median size of the plurality of atomized particles is less than 20 pm.

98. The RTAD system of any one of claims 88-97, wherein a median size of the plurality of atomized particles is less than 10 um.

99. The RTAD system of any one of claims 88-98, wherein the drying gas comprises nitrogen, helium, air, or a combination thereof.

100. The RTAD system of any one of claims 88-99, wherein the drying gas is provided at a rate of 5-200 standard liters / min.

101. The RTAD system of any one of claims 88-100, wherein the temperature is provided between about 15 °C and about 35 *C.

102. The RTAD system of any one of claims 88-101 , further comprising recovering particles after mixing and dehydrating.

103. The .RTAD system of any one of claims 88-102, wherein, the drying chamber comprises a filter assembly, the filter assembling being configured to recover particles,104. The RTAD system of any one of claims 88-103, further comprising a cyclone separator downstream of the drying chamber, wherein the cyclone separator is configured to recover particles.

105. The RTAD system of any one of claims 88-104, wherein the drying chamber comprises a temperature control probe, a humidity probe, a pressure probe, or a combination thereof.

106. The RTAD system of any one of claims 88-105, wherein the drying chamber is operati vely connected to one or more inlet or outlet.

107. The RTAD system of any one of claims 88-106, wherein the drying chamber comprises a sensor at an outlet of the drying chamber, wherein the sensor is configured to determine a particle number, a particle size, or a combination thereof at the outlet of the drying chamber.

108. The RTAD system of any one of claims 88-107, wherein one or more of the nozzle device or the drying chamber is adapted to be retrofitted to a second spraying system.

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