Atmospheric spray freeze drying with temperature control

Abstract

Provided herein are methods and systems for forming a dried product by drying frozen particles comprising both a substance and a frozen carrier liquid. The methods involve spraying a composition into a chamber to create liquid droplets, freezing the droplets, and subsequently drying them by increasing the temperature of a gas. Initially, the temperature is raised to just below the melting point of the carrier liquid and then the temperature further increased to remove most of the carrier liquid while preserving the substance. Systems incorporate means for forming droplets, freezing, drying, and temperature control, with mechanisms to prevent particle adherence and enhance drying efficiency. Selective carrier liquids and gases support material integrity.

Description

ATP0002-401-PCATMOSPHERIC SPRAY FREEZE DRYING WITH TEMPERATURE CONTROL

[0001] This application claims the benefit of priority of the United States Provisional Patent Application Serial No. 63 / 758,451 filed on February 14, 2025, and also claims the benefit of priority of the United States Provisional Patent Application Serial No. 63 / 904,223 filed on October 23, 2025, the disclosures of which are each incorporated by reference in their entirety for all purposes.

[0002] The present disclosure relates to compositions, methods, and systems for preparing dried powders, specifically those for preparing dried powders of pharmacologically active compositions.

[0003] Proteins, hormones, antibodies, vaccines, blood plasma components, and similar fragile molecules and cells in solution have limited potency in a solvent and / or shelf lives, requiring refrigeration between 2 and 8 °C (35.6 and 46.4 °F). Despite storage conditions, these solutionbased compositions will degrade, dimerize, and / or aggregate, diminishing in potency and effectiveness within hours and / or over time.

[0004] Drying these materials can extend their storage time, allowing transportation and later reconstitution to their active forms. Since these materials are often heat-sensitive and exposed to challenging conditions during manufacturing, compositions typically include stabilizing additives like buffers, surfactants, and antioxidants alongside other excipients to enhance composition stability for drying and dosing.

[0005] Lyophilization has been a common method for drying these sensitive substances. The lyophilizing equipment first freezes the material and then lowers vapor pressure to enable the sublimation of water from the solid to the gas phase, bypassing the liquid stage. Although lyophilization protects heat-sensitive products because of its low operating temperatures, lyophilization is slow, costly, and energy-intensive. Lyophilized cakes, the final output, are often further milled or sieved to achieve flowing powders. Formulating these products demands cryoprotectants to mitigate damage during freezing, increasing development costs and time. Moreover, the heat and energy of mechanical processing can alter the pharmacologically active compositions, thereby reducing their shelf-life, stability, and / or efficacy.

[0006] Spray drying is an alternate method for manufacturing powders from solutions of therapeutic proteins and similar substances. However, this method also poses risks of degradation and loss of secondary structure for proteins, hormones, antibodies, and cytokinesATP0002-401-PCdue to heat and pressure. This indicates a pressing need for an improved drying method for biologically active compositions. Such a method would affordably preserve biological activity over extended periods, addressing the limitations of current drying techniques.SUMMARY

[0007] Atmospheric Spray Freeze Drying (“ASFD”) is a process in which a liquid solution or suspension of a substance is sprayed, for example, as fine droplets, a flow of liquid droplets, or as individual droplets. The droplets are cooled to a temperature below the freezing point of the solvent of the pre-spray freeze-dry composition, causing the droplets to freeze. The frozen droplets are collected, and then the solvent is removed by passing a gas flow through the frozen particles and forming a dry powder. The process takes place at or near atmospheric pressure. This contrasts with the often-employed approach, i.e., lyophilization, or sublimation in a vacuum.

[0008] The present disclosure provides a method for forming a dried product, which comprises drying frozen particles containing a frozen carrier liquid. The process includes forming the frozen particles from liquid droplets of a composition that comprises a substance and a liquid carrier. The drying method comprises an initial increase in the temperature of a gas to below about the melting point of the frozen carrier liquid, followed by a further increase in the temperature of the gas to a maximum temperature level between about 95 °C and about 170 °C above the initial temperature until the carrier liquid is evaporated, resulting in a dried product.

[0009] The present disclosure provides a method for forming a dried product, which comprises spraying a composition into a chamber to form a flow of liquid droplets, where the composition comprises a substance and a carrier liquid. The method includes freezing the liquid droplets into frozen particles, comprising the substance and a frozen carrier liquid, and then drying the frozen particles. This is achieved by increasing the temperature of a gas from the initial temperature to below about the melting point of the frozen carrier liquid, and then further increasing the temperature to a maximum level between about 95 °C and about 170 °C above the initial temperature until the carrier liquid evaporates, forming a dried product.

[0010] The present disclosure provides a system for forming a dried product, which comprises a chamber where a composition is sprayed to form a flow of liquid droplets. The composition comprises a substance and a carrier liquid. The system includes a freezing mechanism to freeze the liquid droplets into frozen particles, a gas supply system to contact the frozen particles withATP0002-401-PCan initial temperature gas, and a temperature control unit connected to the gas supply. The unit is configured to first increase the temperature from the initial temperature to just below the melting point of the frozen carrier liquid, then further increase the temperature to a maximum level between about 95 °C and about 170 °C above the initial temperature until the carrier liquid evaporates, forming a dried product.

[0011] The present disclosure provides a system for forming a dried product, comprising a means for forming a flow of liquid droplets in a chamber from a composition that includes a substance and a carrier liquid. The system comprises means for freezing the droplets into frozen particles, a means for contacting these particles with a gas with an initial temperature, and a means for temperature control. The system is configured to increase the gas temperature from the initial temperature to below the melting point of the frozen carrier liquid, followed by a further temperature increase to a maximum level between about 95 °C and about 170 °C above the initial temperature, resulting in the evaporation of the carrier liquid and drying of the particles.BRIEF DESCRIPTION OF THE DRAWING

[0012] FIG. 1 shows the effect of temperature on moisture content and total moisture and, thus, the rate of the drying of the frozen particles.DETAILED DESCRIPTION

[0013] When introducing elements of the present disclosure or the preferred embodiment s) thereof, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements. As used herein, “comprising,” “including,” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0014] As used herein, “and / or,” when used in a list of two or more items, means that any one of the listed items can be employed by itself or in combination with any one or more of the listed items. For example, the expression “A and / or B” means either or both of A and B, i.e., A alone, B alone, or A and B in combination. The expression “A, B, and / or C” means A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination, or A, B, and C in combination.

[0015] “About,” as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount.ATP0002-401-PC

[0016] The term “substance” refers to one or more pharmaceutical, nutraceutical, food, or other substances that can be dried from a composition into powder form by ASFD and have utility in powder form.

[0017] As used herein, “carrier liquid” refers to a non-reactive liquid that carries the substance. The combination of the carrier liquid and substance may form a solution, emulsion, or suspension.

[0018] As used herein, “SCFM” refers to the gas flow rate in Standard Cubic Feet per Minute. SCFM is typically defined under conditions of 14.7 psi (pounds per square inch) at 60 °F (15.6 °C), which translates to about 101.3 kPa (since one psi = 6.89476 kPa).

[0019] As used herein, “substance” refers to one or more pharmaceutical, nutraceutical, food, or other materials that have utility in powder form. It may also refer to other materials from a solution in a powder form, such as a cell or cellular component.

[0020] As used herein, “non-reactive” refers to a substantially inert gas, a carrier liquid, substance, and excipients. Suitable gases include, but are not limited to, carbon dioxide, nitrogen, helium, argon, and mixtures of these gases with or without other gases. Other such materials referred to in this way are not chemically active.

[0021] As used herein, “evaporate” refers to the process where a liquid changes into a vapor or gas, typically subjected to a flow of drying gas and / or due to being heated. In certain embodiments, this process removes a carrier liquid from a substance to dry the substance.

[0022] As used herein, the “freezing mechanism” or “means for freezing” encompasses any system or device designed to reduce the temperature of a substance below its freezing point, resulting in the solidification of the substance.

[0023] As used herein, “frozen carrier liquid” denotes a carrier liquid that has undergone the freezing process and has transitioned from a liquid to a solid state taking the solute with it.

[0024] As used herein, a “gas supply system” is a configuration or apparatus engineered to provide, control, and direct gas flow to a specific area or within a device, often used to circulate or apply gas in a controlled manner during various manufacturing or processing operation stages.

[0025] As used herein, “increasing” or “gradually increasing” describes a controlled method of incrementally raising a parameter, such as temperature or pressure, over time on average to achieve a desired result without abrupt changes.ATP0002-401-PC

[0026] As used herein, “initial exposure” refers to the first instance or phase where a substance or mixture is subjected to a specific condition or process. When the increase starts “immediately after initial exposure,” the increase occurs as soon as physically or measurably possible to attain the desired effect, such as removing frozen carrier liquid without causing meltback in the process of drying the product.

[0027] As used herein, “initial temperature” is the temperature of a substance or environment at the beginning of a process or experiment. In some embodiments, “initial” means the lowest temperature attained when cooling the chamber. Therefore, there is a difference in the meaning of initial temperature vs. spray temperature; “initial temperature” and “spray temperature” are two different temperatures.

[0028] As used herein, “composition” or “mixed substance” comprises two or more components, such as a carrier liquid and a pharmacologically active compound, blended to form a homogenous or heterogeneous mixture.

[0029] As used herein, a “temperature controller,” “temperature control unit,” or “mean for controlling temperature” is a device or system designed to monitor and adjust the temperature within an environment or piece of equipment, ensuring that the temperature remains within a predefined range suitable for the specific application or process, such as maintaining the temperature range for the drying or freezing of pharmaceutical compositions.

[0030] As used herein, a “glucan molecule” refers to a polysaccharide of D-glucose monomers linked by glycosidic bonds. a-Glucans (alpha-glucans) are polysaccharides of D-glucose monomers linked with glycosidic bonds of the alpha form; P-Glucans (beta-glucans) are polysaccharides of D-glucose monomers linked by |3-gly cosidic bonds.

[0031] As used herein, “loosely packed” or “loosely structured” refer to particles resting on each other to minimize contact between neighboring particles and maximize interstitial spaces between adjacent particles. “Loosely” is used here in contrast with “tightly.”

[0032] As used herein, “cryoprotectant” includes agents that provide stability to a biologically or chemically active compound in a composition to mitigate against freezing-induced stresses and disruption to structure or function of the compound. The term is used loosely and includes “lyoprotectants.” Conventional cryoprotectants are glycols (alcohols containing at least two hydroxyl groups), such as ethylene glycol, propylene glycol, and glycerol. Dimethyl sulfoxide (DMSO) is also regarded as a conventional cryoprotectant. Glycerol and DMSO have been usedATP0002-401-PCfor decades by cryobiologists to reduce ice formation in cells that are cold preserved in liquid nitrogen. In addition, some sugars, such as sucrose or trehalose as well as others, are cryoprotective.

[0033] Some cryoprotectants function by lowering the glass transition temperature of a composition or a material. In this way, the cryoprotectant prevents actual freezing, and the composition maintains some flexibility in a glassy phase. Many cryoprotectants also function by forming hydrogen bonds with biological molecules as water molecules. Hydrogen bonding in aqueous compositions contributes to proper protein and DNA function. Thus, as the cryoprotectant replaces the water molecules, the biological material retains its native physiological structure and function, although they are no longer immersed in an aqueous environment. This preservation strategy is often used in anhydrobiosis and, specifically, lyophilization.

[0034] The cryoprotectant, if included in the composition, is generally added to a final concentration of between about 0.1% and about 10% (weight / volume), e.g., between about 0.5% and about 10%, between about 0.5% and about 5%, between about 0.5% and about 2%, between about 1% and about 5%, or between about 5% and about 10%.

[0035] Similar to cryoprotectants, some molecules protect freeze-dried material. Known as “lyoprotectants,” these molecules are typically polyhydroxy compounds such as sugars (mono-, di-, and polysaccharides), polyalcohols, and their derivatives. Trehalose and sucrose are natural lyoprotectants. The term “lyoprotectant,” as used herein, includes agents that provide stability to a biologically active compound during the drying process, e.g., by providing an amorphous glassy matrix and by binding with a protein through hydrogen bonding, replacing the water molecules that are removed during the drying process. This helps to maintain protein conformation, reduce protein degradation during the drying cycle, and improve long-term product stability. In the case of drying cells, they preserve cellular viability. Non-limiting examples of lyoprotectants include sugars, such as sucrose or trehalose; an amino acid, such as monosodium glutamate (MSG), non-crystalline glycine or histidine; methylamine, such as betaine; a lyotropic salt, such as magnesium sulfate; a polyol, such as trihydric or higher sugar alcohols, e.g., glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol; propylene glycol; polyethylene glycol; Pluronics™; and combinations thereof.ATP0002-401-PC

[0036] The amount of lyoprotectant added to a composition generally does not lead to an unacceptable amount of degradation / aggregation of the protein or cellular component when the composition is dried. In some embodiments, the composition and / or dried substance do not comprise a cryoprotectant and / or lyoprotectant. That is, the composition and / or dried substance is substantially free of a cryoprotectant and / or lyoprotectant, such as sucrose or trehalose.

[0037] As used herein, “surfactant” includes agents that reduce the surface tension of a liquid by adsorption at the air-liquid interface. Examples of surfactants include, without limitation, nonionic surfactants, such as polysorbates (e.g., polysorbate 80 or polysorbate 20); poloxamers (e.g., poloxamer 188); Triton™ (e.g., Triton™ X-100); sodium dodecyl sulfate (SDS); sodium octyl glycoside; lauryl-sulfobetaine; myristyl-sulfobetaine; linoleoyl-sulfobetaine; stearyl-sulfobetaine; lauryl-sarcosine; myristyl-sarcosine; linoleoyl-sarcosine; stearyl-sarcosine; linoleoyl-betaine; myristyl- betaine; cetyl-betaine; lauroamidopropyl-betaine; cocamidopropyl-betaine; linoleamidopropyl-betaine; myristamidopropyl-betaine, palmidopropyl-betaine; isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristarnidopropyl-, palmidopropyl-, or isostearamidopropyl- dimethylamine; sodium methyl cocoyl-, or disodium methyl ofeyl-taurate; and the Monaquat™ series (Mona Industries, Inc., Paterson, NJ); polyethylene glycol; polypropylene glycol; and copolymers of ethylene and propylene glycol (e.g., Pluronic™, PF68). The amount of surfactant added is such that it maintains aggregation of a reconstituted protein at an acceptable level as assayed using, e.g., SEC-HPLC to determine the percentage of high molecular weight (HMW) species or low molecular weight (LMW) species and minimizes the formation of particulates after reconstitution of a dried powder described herein. For example, the surfactant can be present in a composition (liquid or before drying) from about 0.001-0.5%, e.g., from about 0.05-0.3%. In some embodiments, the surfactant acts as a cryoprotectant or a lyoprotectant. That is, the composition and / or dried substance is substantially free of a surfactant.

[0038] As used herein, “bulking agent” includes agents that provide the structure of the dried product without interacting directly with the biologically active compound. In addition to providing a pharmaceutically elegant cake, bulking agents may be useful in modifying the collapse temperature, providing freeze-thaw protection, and enhancing protein stability over long-term storage during freeze drying. Non-limiting examples of bulking agents include mannitol, glycine, lactose, and sucrose. Bulking agents may be crystalline (such as glycine, mannitol, or sodium chloride) or amorphous (such as dextran or hydroxyethyl starch) and areATP0002-401-PCgenerally used in powder compositions from 0.5% to 10%. In some embodiments, the bulking agent is formulated with the dried substance after drying is completed and the dried substance no longer needs a cryoprotectant, lyoprotectant, or surfactant to protect it from damage caused by freezing or drying.

[0039] As used herein, “snap freezing,” “rapid freezing,” or “quick freezing” interchangeably refer to freezing a solvent or composition, including compositions containing macromolecules, such as proteins and cellular components, by spraying the composition into a supercooled atmosphere having a temperature well below the freezing point of the solvent or composition. “Snap freezing” and “rapid freezing” generally occur within milliseconds up to 1-2 seconds as compared to “standard freezing” that takes place over hours.Methods

[0040] The present disclosure provides a method for forming a dried product. This method comprises drying frozen particles which are contained in a frozen carrier liquid. The process includes forming the frozen particles from liquid droplets of a composition that comprises a substance and a liquid carrier. The method comprises an initial decrease in the temperature of a surrounding gas to below the melting point of the frozen carrier liquid, followed by an increase in the temperature of the gas to a maximum temperature level between about 5 °C and about 70 °C above the initial temperature until the carrier liquid is evaporated, resulting in a dried product.

[0041] In certain embodiments, the maximum temperature level is between about 5 °C and 70 °C above the melting point of the frozen carrier liquid, or optionally, between about 95 °C and about 170 °C above the initial temperature of the frozen carrier liquid. In certain embodiments, the maximum temperature is between about 70 °C and about 60 °C, between about 60 °C and about 50 °C, between about 50 °C and about 40 °C, between about 40 °C and about 30 °C, between about 30 °C and about 20 °C above, between about 20 °C and about 10 °C, or between about 10 °C and about 5 °C above the melting point of the frozen carrier liquid. In certain embodiments, the maximum temperature level is at least about 5 °C above the melting point of the frozen carrier liquid. In other embodiments, the maximum temperature level is not more than about 70 °C above the melting point of the frozen carrier liquid. In certain embodiments, the maximum temperature level is between about 170 °C and about 160 °C, between about 160 °C and aboutATP0002-401-PC150 °C, between about 150 °C and about 140 °C, between about 140 °C and about 130 °C, between about 130 °C and about 120 °C, between about 120 °C and about 110 °C, between about 110 °C and about 100 °C, between about 100 °C and about 95 °C above the initial temperature of the frozen carrier liquid. In certain embodiments, the maximum temperature level is at least about 95 °C above the initial temperature of the frozen carrier liquid. In other embodiments, the maximum temperature level is not more than about 170 °C above the initial temperature of the frozen carrier liquid.

[0042] The present disclosure provides a method for forming a dried product, which comprises spraying a composition into a chamber to form a flow of liquid droplets, where the composition comprises a substance and a carrier liquid. The method includes freezing the liquid droplets into frozen particles, comprising the substance and a frozen carrier liquid, and then drying the frozen particles. This is achieved by increasing the temperature of a gas from the initial temperature to below about the melting point of the frozen carrier liquid, and then further increasing the temperature to a maximum level between about 95 °C and about 170 °C above the initial temperature until the carrier liquid evaporates, forming a dried product.

[0043] In some embodiments, the increase starts immediately after initial exposure of the frozen particles to the gas; and maintaining the gas flow for a duration sufficient to evaporate the carrier liquid and dry the substance in the frozen particles, thereby forming a dried product.

[0044] In certain embodiments, freezing occurs at an initial temperature between about -50 °C and about -100 °C, such as between about -50 °C and about -60 °C, between about -60 °C and about -70 °C, between about -70 °C and about -80 °C, between about -80 °C and about -90 °C, and between about -90 °C and about -100 °C. In some embodiments, the initial temperature is about -75 °C. In some embodiments, the initial temperature is less than -50 °C. In some embodiments, the initial temperature is greater than -100 °C. For example, when the initial temperature is -100 °C, the temperature is increased on average to a maximum level of between about -5 °C and 70 °C (that is, between about 95 °C and about 170 °C above the initial temperature).

[0045] In certain embodiments, the gas reaches a temperature of not more than about 80 °C above the melting point of the frozen carrier liquid, such as not more than about 65 °C.

[0046] In certain embodiments, the method further comprises collecting the frozen particles.ATP0002-401-PC

[0047] In certain embodiments, the frozen particles are dried by passing the gas flow downward through the collected frozen particles to remove the carrier liquid.

[0048] In certain embodiments, the gas flow is adjusted to enhance drying efficiency without causing material degradation.

[0049] In certain embodiments, the carrier liquid is chosen from water, alcohols, organic solvents, and mixtures thereof.

[0050] In certain embodiments, the gas is chosen from carbon dioxide, nitrogen, helium, argon, and mixtures thereof.

[0051] In certain embodiments, the composition further comprises an excipient.

[0052] This technique benefits delicate and heat-sensitive materials, including proteins, nucleic acids, and pharmaceutical compounds. While advantageous for large molecules, this method efficiently produces powdered forms of various materials dissolved or suspended in a solvent, regardless of their molecular size. The resulting powders serve diverse purposes, ranging from pharmaceuticals, such as anti-infectives and immunomodulators, to non-pharmaceutical applications. Optional additives like cryoprotectants or excipients may be introduced to the carrier liquid to enhance substance stability through processing, accommodating multiple biologically active substances and excipients.

[0053] Powders are obtained through the described methods.

[0054] In some embodiments, gas flow may be under 10 SCFM (16.93 kPa), 8 SCFM (13.55 kPa), or 6 SCFM (10.16 kPa). Similarly, in some embodiments, the drying gas flow may exceed 15 SCFM (25.4 kPa), 25 SCFM (42.3 kPa), 35 SCFM (59.3 kPa), or even 45 SCFM (76.2 kPa).

[0055] The carrier liquid is chosen for its compatibility with the substance, allowing solutions, emulsions, or suspensions. Examples include water, alcohols, organic solvents, or their mixtures, selected for their neutral interaction with various bioactive substances.

[0056] Generally, an “organic solvent” is a carbon-containing chemical that dissolves a solid, liquid, or gas. Examples of organic solvents include, but are not limited to, alcohols, ketones, alkyl esters, polyols, ethers, aromatic hydrocarbons, and mixtures thereof. In some embodiments, the organic solvent is chosen from ethanol, propanol, isopropanol, acetone, 2-butanone, methyl acetate, ethyl acetate, ethylene glycol monobutyl ether, ethylene glycol monopropyl ether, diethylene monoethyl ether, toluene, xylene, and mixtures thereof.ATP0002-401-PC

[0057] In some embodiments, the substance is dissolved or suspended in the carrier liquid before dispersion, thereby forming a composition.

[0058] In some embodiments, gas dispersion is achieved through various means, such as ring nozzles, porous chamber walls, top chamber injection, or no chamber walls.

[0059] In some embodiments, optionally, droplets undergo snap freezing.

[0060] In some embodiments, the employed gas is initially colder than the carrier liquid’s freezing point, warming only during the drying phase to exceed this threshold.

[0061] In certain embodiments, the gas, chosen for its non-reactive properties, includes nitrogen, argon, helium, carbon dioxide, or their combinations.

[0062] In some embodiments, the method optionally incorporates or excludes physical agitation, and activities like spraying, freezing, and drying may occur within or outside the chamber, depending on the embodiment.

[0063] In some embodiments, processed droplets have a median diameter of 100 pm or less, potentially as small as 1 pm.

[0064] In some embodiments, concentration of the substance in the composition relative to the carrier liquid exceeds 2 wt.%, possibly reaching over 40 wt.%, such as between about 2.5 wt.% and about 40 wt.%, between about 2 wt.% and about 5 wt.%, between about 5 wt.% and about 10 wt.%, between about 10 wt.% and about 15 wt.%, between about 15 wt.% and about 20 wt.%, between about 20 wt.% and about 25 wt.%, between about 25 wt.% and about 30 wt.%, between about 30 wt.% and about 35 wt.%, or between about 35 wt.% and about 40 wt.%. In certain embodiments, the concentration is at least about 2.5 wt.%. In certain embodiments, the concentration is not more than about 40 wt.%.

[0065] In some embodiments, bioactive agents within the powder may be encapsulated in liposomes, structured as multi-layered liquid crystals surrounded by water or aqueous solutions.

[0066] In some embodiments, a low gas flow during freezing formed a loosely structured bed of frozen droplets, optimizing the spaces around each particle for drying. Without wishing to be bound by theory, the drying gas, through convection, removes the carrier from the frozen droplets, leaving a dry, low-density lattice of particles. In some embodiments, this setup improved the flow of drying gas around the particles, facilitating the transition of carrier molecules from solid to liquid and finally to gas phases.ATP0002-401-PC

[0067] Unlike former techniques that used higher gas flows during freezing, resulting in densely packed particles that hindered gas flow and slowed drying, this method avoids dense packing. It also diverges from methods that fluidized particles with an upward drying gas flow, which could disrupt the particle bed.

[0068] In some embodiments, the method features freezing liquid droplets in a gas flow under 13 SCFM (22.06 kPa), with variations including gas flows under 10 SCFM (16.93 kPa), 8 SCFM (13.55 kPa), or 6 SCFM (10.16 kPa). Initially, carrier solvent vapor disperses from the frozen particles’ surface, further diffusing from the particle interior to the surface to enter the gas phase.

[0069] After initiating spray-freezing, the gas flow’s temperature gradually increased while also elevating the net gas flow, ensuring the drying process initially occurred below the carrier’s freezing point. Temperatures above the freezing point were later applied to speed up drying, carefully timed to maintain the particles’ frozen core and prevent premature melting within the particles. “Meltback” should be avoided; otherwise, particles would form a dense, distorted bed, impeding the drying gas’s flow and resultant drying rate.

[0070] The gas temperature varied, initially below the freezing point during particle formation, then rising to expedite drying while avoiding melting the frozen carrier inside the particles. This was finely controlled, considering temperature ranges from 0 °F (-17.78 °C) to 3 °F (-16.11 °C) and up to over 20 °F (-6.67 °C) during drying.

[0071] Certain embodiments omitted vibration, internals, or mechanical stirring, focusing on a tranquil environment conducive to controlled drying.

[0072] In some embodiments, the method accommodates both in-chamber and external drying and deposition of particles, adapting to varying operational needs.

[0073] Ultimately, the methods disclosed herein yield dry, porous particles similar in size and shape to their original, frozen counterparts, with median diameters potentially as small as 1 pm and up to 100 pm, influenced by the spraying mechanism’s specifications.Systems

[0074] The present disclosure provides a system for forming a dried product, which comprises a chamber where a composition is sprayed to form a flow of liquid droplets. The composition comprises a substance and a carrier liquid. The system includes a freezing mechanism to freeze the liquid droplets into frozen particles, a gas supply system to contact the frozen particles with an initial temperature gas, and a temperature control unit connected to the gas supply. The unit isATP0002-401-PCconfigured to first decrease, for freezing the particles, and then increase the temperature from the initial temperature to just below the melting point of the frozen carrier liquid, then further increasing it to a maximum level between about 95 °C and about 170 °C above the initial temperature until the carrier liquid evaporates, forming a dried product.

[0075] In certain embodiments, the freezing mechanism can cool between about -50 °C and about -120 °C.

[0076] In certain embodiments, vapor meter readings guide the increase of the temperature of the gas.

[0077] In certain embodiments, the temperature is increased on average at an increment of between about 1 °C and about 20 °C for a duration of between about 5 min and about 30 min, optionally at an increment between about 2 °C and about 5 °C for a duration between about 3 min and about 15 min.

[0078] In certain embodiments, the temperature is further increased on average at an increment of between about 1 °C and about 8 °C for a duration of between about 5 min and about 30 min, optionally at an increment between about 2 °C and about 5 °C for a duration between about 3 min and about 15 min.

[0079] In certain embodiments, the maximum level is between about 30 °C and about 70 °C above the initial temperature.

[0080] In certain embodiments, the system further comprises a collection unit configured to collect the frozen particles.

[0081] In certain embodiments, the system further comprises a drying system configured to pass the gas flow downward through the collected, frozen particles at a flow rate to remove the carrier liquid.

[0082] In certain embodiments, the flow control mechanism and temperature control unit are configured to adjust the gas flow to enhance drying efficiency without causing material degradation.

[0083] In certain embodiments, the carrier liquid is chosen from water, alcohols, organic solvents, and mixtures thereof

[0084] In certain embodiments, the gas supply system is compatible with carbon dioxide, nitrogen, helium, argon, and mixtures thereof.

[0085] In certain embodiments, the composition further comprises an excipient.ATP0002-401-PC

[0086] In certain embodiments, a system is designed to produce a product according to the method.The present disclosure provides a system for forming a dried product, comprising a means for forming a flow of liquid droplets in a chamber from a composition that includes a substance and a carrier liquid. The system comprises means for freezing the droplets into frozen particles, a means for contacting these particles with a gas with an initial temperature, and a means for temperature control. The system is configured to increase the gas temperature from the initial temperature to below the melting point of the frozen carrier liquid, followed by a further temperature increase to a maximum level between about 95 °C and about 170 °C above the initial temperature, resulting in the evaporation of the carrier liquid and drying of the particles.

[0087] In certain embodiments, the system comprises means for collecting the frozen particles.

[0088] In certain embodiments, the system comprises means for drying configured to pass the gas flow downward through the collected frozen particles at a flow rate to remove the carrier liquid.

[0089] In certain embodiments, the system comprises flow control means and temperature control means configured to adjust the gas flow to enhance drying efficiency without causing material degradation, meltback, or both.Compositions

[0090] In certain embodiments, a product is produced by a method disclosed herein.

[0091] The powder includes porous particles with varying degrees of porosity, each exceeding designated volume percentages. Specified porosities highlight the adaptability of the powder, showing porosity levels successively above 50-volume% and progressing to thresholds above 40-volume%, 30-volume%, 20-volume%, 10-volume%, 5-volume%, and even just above 1-volume%. Furthermore, the powder’s composition may encompass glucans, extending to alpha glucans, beta-glucans, dextran, and explicitly dextran 500. This diversity in biochemical constituents showcases the variability of the powder.

[0092] The technique for fabricating a loosely structured bed of frozen liquid particles featuring the substance underscores the method’s efficacy in facilitating drying more efficiently. This involves dispersing a substance-laden carrier liquid into a chamber, forming droplets, turning these droplets into frozen particles with a net gas flow between about 10 SCFM and about 20ATP0002-401-PCSCFM during spraying, and managing these particles with a net gas flow of between about 20 SCFM and about 40 SCFM during drying. In some embodiments, the net gas flow is about 13 SCFM during spraying, and managing these particles with a net gas flow of about 30 SCFM during drying.

[0093] Regarding the bed’s structural density, densities fall below particular markers, showcasing this approach’s effectiveness in forming low-density structures. These markers point to densities dipping below 0.50 g / cm3, further dropping below 0.30 g / cm3, 0.20 g / cm3, and reaching subtleties less than 0.10 g / cm3. Such findings confirm the method’s prowess in yielding powdered products with considerable porosity and reduced weight.

[0094] Other pharmaceutically acceptable carriers, excipients, or stabilizers, such as those described in Remington: The Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2000), may also be included in a composition described herein if they do not adversely affect the desired characteristics of the composition. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients (e.g., patients) at the dosages and concentrations employed and include: additional buffering agents; preservatives; co-solvents; antioxidants, including ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (e.g., Zn-protein complexes); biodegradable polymers, such as polyesters; saltforming counter-ions, such as sodium, polyhydric sugar alcohols; amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, and threonine; organic sugars or sugar alcohols, such as lactitol, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinisitol, galactose, galactitol, glycerol, cyclitols (e.g., inositol), polyethylene glycol; sulfur containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, a-monothioglycerol, and sodium thiosulfate; low molecular weight proteins, such as human serum albumin, bovine serum albumin, gelatin, or other immunoglobulins; and hydrophilic polymers, such as polyvinylpyrrolidone.

[0095] In summary, cryoprotectants, lyoprotectants, surfactants, bulking agents, carriers, excipients, stabilizers, or other excipients may or may not be added to any given composition to aid in preventing the degradation of substances during or after processing. The ingredientcarrying liquid may contain one or several different biologically active, or inactive, compounds and this excipient material in various proportions. For example, a composition with lactose canATP0002-401-PCbe made up of mainly lactose with a little active compound, or there may be proportionately a large amount of active compound in the ingredient-carrying liquid, plus a small amount of lactose or another filler / matrix / excipient compound. In addition, the composition may have more than one active compound. Or the composition may have more than one inactive compound.

[0096] Examples are extended to offer clearer insight, substantiating the practicality and potential applications of the disclosed methods and the attribute-laden resultant product compositions.EXAMPLEExample 1 - Effect of Temperature on Moisture Content (MC) and Total Moisture (TM)

[0097] Referring to FIG. 1, the drying chamber’s exit gas was measured for moisture content (MC) in parts per million (ppm) and total moisture (TM) in ppm per minute. The gas flow was maintained constant while the chamber temperature was varied, causing corresponding changes in the moisture levels of the exit gas that reflect the powder drying process in the chamber.

[0098] Initially, the chamber temperature was raised from -75°C to -30°C between about 13:41 and 14:15 (about 23 minutes). Under these conditions, the MC increased from about 400 ppm to about 900 ppm, and the TM increased from about 8,000 ppm / min to about 18,000 ppm / min. With the temperature and flow settings held substantially constant from about 14: 15 to about 14:44 (about 29 minutes), both the MC and TM stabilized. Next, beginning at about 14:44, the temperature was further increased to -5°C. By about 15:17 (about 33 minutes later), this change resulted in the MC rising from about 900 ppm to about 1,400 ppm, with the TM increasing from about 18,000 ppm / min to around 28,000 ppm / min. Finally, when the temperature was reduced from -5°C to -30°C at about 15:17, the MC decreased from about 1,400 ppm to about 1,100 ppm, and the TM decreased from about 28,000 ppm / min to about 22,000 ppm / min.Example 2 - General procedure

[0099] The substance is dissolved in water as the carrier liquid at a concentration of 15 wt.%, ensuring a homogeneous composition. The composition is then sprayed into a chamber containing nitrogen gas and frozen between -90 °C and 70 °C. The gas temperature is then set below the melting point of the carrier liquid to ensure slow warming without meltback.

[0100] The nitrogen temperature gradually increased on average to a maximum temperature level between about 95 °C and about 170 °C above the initial temperature of the carrier liquidATP0002-401-PCafter ensuring that the composition droplets are adequately cooled frozen and stabilized. This controlled temperature increase efficiently dries the frozen droplets without degrading the substance. The dried substance is then collected at the bottom of the chamber, now in powdered form, ensuring minimal loss and maximum yield.

[0101] Controlled temperature and flow of nitrogen gas, both below and above the melting point of the carrier liquid during the process, results in a uniformly dried powder. The powder exhibits lightness and flowability, as well as possibly purity, stability, and bioavailability, compared to substances dried using conventional and prior art methods. Furthermore, control over drying conditions and temperature minimizes the thermal and chemical stress on the substance, preserving its biological activity.

[0102] Moreover, because of the controls specified by, and under, these methods, systems, and compositions, the present example avoids meltback, which occurs when the temperature of the frozen material rises above the melting point of the carrier liquid, such that the material becomes a composition again from its frozen state.

[0103] After spraying, the material is most protected from meltback because of the low temperature around -90 °C. In some embodiments, after spraying, the temperature of the drying gas flowing downward in the chamber is elevated up to a maximum temperature level between 95 °C and about 170 °C above the initial temperature at which the carrier liquid was frozen. This adjustment is guided by vapor meter readings, which measure the water content in the gas flow, thus indicating the impact of the drying gas temperature on drying. Such monitoring will make for drying without meltback, taking into consideration the cooling effect of the “heat of evaporation,” caused by the evaporation of water or other solvents from the frozen particles. Without wishing to be bound by theory, gas at a higher temperature can absorb more water or other solvents. This absorption cools the surface of the frozen material from where the solvent is coming. Thus, the drying process is accelerated without meltback by pushing up the temperature of the drying gas immediately after spraying.Example 3 - Drying of Serum

[0104] A 50 mb sample of serum (serving as the composition, wherein the liquid carrier is water, and the substance comprises the naturally occurring serum components) was processed using an ASFD apparatus configured as follows. The serum was introduced into the system via anATP0002-401-PCultrasonic spray nozzle. The nozzle was operated at an effective power (about 5 W) and delivered the serum at a flow rate of about 2 mL / min, forming fine liquid droplets in the drying chamber.

[0105] The chamber was initially cooled to a temperature sufficient to freeze the liquid carrier (with the apparatus set to achieve an initial temperature in the range of -50 °C to -120 °C, here nominally -75 °C).

[0106] Once the serum droplets were frozen into particles, a controlled drying process was initiated. In a first drying phase, the gas temperature was raised gradually — from the initial temperature up to a temperature below the melting point of the frozen liquid carrier — to begin controlled sublimation. In the second phase, the temperature of the gas was further increased by an increment falling between about 95 °C and about 170 °C above the initial temperature until the liquid carrier was substantially evaporated. The entire process was completed in about 4 hours.

[0107] The final dried serum product was recovered as a free-flowing yellow powder. Analysis showed a product yield of 5.8 grams (collected on a 5", 5-micron single-use filter) and a moisture content of about 8.5%. Reconstitution with deionized water confirmed that the dried serum was readily rehydrated while maintaining its physical integrity.Example 4 - Drying of Plasma

[0108] In this experiment, a 50 mL sample of plasma was processed using the same ASFD setup and operational parameters as in Example 2.

[0109] The plasma was sprayed via the ultrasonic nozzle (operating at about 5 W, 2 mL / min) into a pre-cooled chamber (initial temperature nominally -75 °C), forming frozen plasma droplets. The frozen droplets were then dried in two gas-heating stages: first, the temperature was increased from the initial value to a level below the melting point of the plasma carrier and subsequently raised by an increment between about 95 and 170 °C above the initial temperature until the carrier was removed. The drying process took about 4.25 hours.

[0110] The dried plasma product was obtained as a yellow powder. Measurements indicated a filter collection yield of 3.8 g and a moisture content of about 10%, confirming that plasma can be processed with the herein-described ASFD protocol.ATP0002-401-PCExample 5 - Drying of Platelets[OHl] A 50 mL suspension enriched in platelets was prepared from platelet-rich plasma. The composition, comprising the platelets (the substance) and its carrier fluid, was fed to the ASFD system under the following conditions.

[0112] Using the ultrasonic nozzle (~5 W, 2 mL / min), the platelet suspension was sprayed into a pre-cooled chamber (initial temperature nominally -75 °C) to form fine droplets that were instantaneously frozen. The frozen particles were then dried by first raising the gas temperature to a level below the melting point of the aqueous carrier and then further increasing the gas temperature by an increment between about 95 °C and about 170 °C above the initial temperature until complete evaporation was achieved. Overall, drying took about 4 hours.

[0113] A dried platelet product was obtained as a uniform yellow powder. The product collected 3.6 g on a 5-micron filter, exhibited a moisture content of 6.7%. The percent solids of the original sample was about 7.8%. For reconstitution, 5 mL of DI water was added to 0.39 g of the dried powder, yielding a rehydrated product that retained physical characteristics expected of platelets.Example 6 - Drying of White Blood Cells

[0114] A 40 mL sample enriched in white blood cells (WBC) was processed using the ASFD apparatus. The process parameters were maintained as follows.

[0115] The WBC suspension was sprayed into the chamber via the ultrasonic nozzle (effective power ~5 W, flow rate ~2 mL / min) into a chamber pre-cooled to an initial temperature nominally within -50 °C to -120 °C (here, -75 °C was used). Upon formation and freezing of the droplets, a two-stage gas-heating process was implemented: first, the gas temperature was increased to a point below the melting point of the frozen carrier, then further increased by an increment within the range of about 95 °C to 170 °C above the initial temperature until the liquid carrier was fully evaporated. Drying took about 4 hours.

[0116] The dried WBC product was collected as a pink powder, weighing about 7 g with a low moisture content of roughly 3%. The percent solids of the original sample was about 26%.Reconstitution was performed by adding 5 mL of DI water to 1.35 g of the dried powder, demonstrating that functional cellular structures were substantially preserved.ATP0002-401-PCExample 7 - Drying of Whole Blood

[0117] A 50 mL sample of whole blood was processed under analogous conditions. The blood, comprising its various cellular elements and plasma as the liquid carrier, was processed as follows.

[0118] The whole blood was sprayed into the ASFD system using an ultrasonic spray nozzle (operated at about 5 W and 2 mL / min) to create a uniform spray of liquid droplets in a pre-cooled chamber (initial temperature nominally -75 °C). The resultant droplets were frozen to form whole blood particles, which were then dried using the two-phase gas heating method: an initial temperature increase to below the liquid carrier’s melting point followed by a further temperature increment (between about 95 °C and about 170 °C above the initial temperature) to effect complete evaporation of the carrier. The drying process was completed in about 4 hours.

[0119] The final dried whole blood was recovered as a pink powder, with an overall yield of about 6.2 g on the filter, a moisture content of about 7%, and a solids content of about 14%. Reconstitution was achieved by adding 5 mL of DI water to 0.7 g of the dried product, indicating that the ASFD process effectively preserved a composition that is readily rehydratable.

[0120] The detailed description above is provided to aid those skilled in the art in practicing the present disclosure. However, the disclosure described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended to illustrate several aspects of the disclosure. Any equivalent embodiments are intended to be within the scope of this disclosure. Indeed, various modifications of the disclosure, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description based on the specific attributes of the material to be dried and the solvent utilized, which does not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.

Claims

AMENDED CLAIMSreceived by the International Bureau on 19 August 2026 (19.08.2026)1. A method for forming a dried product by atmospheric spray freeze drying, comprising:drying frozen particles comprising a frozen carrier liquid, the frozen particles being formed from liquid droplets of a composition comprising a substance and a liquid carrier, in a chamber, by: first increasing temperature of a gas from an initial temperature to below about the melting point of the frozen carrier liquid, wherein vapor meter readings from the chamber indicate when to further increase the temperature, and wherein the temperature is increased on average at an increment of between about 1 °C and about 20 °C for a duration of between about 5 min and about 30 min; and then further increasing the temperature of the gas to a maximum temperature level between about 95 °C and about 170 °C above the initial temperature until the carrier liquid is evaporated and the substance in the frozen particles is dried, thereby forming a dried product, wherein the temperature is further increased on average at an increment of between about 1 °C and about 8 °C for a duration of between about 5 min and about 30 min, wherein flow of the gas is adjusted to enhance drying efficiency without causing material degradation, meltback, or both.

2. A method for forming a dried product by atmospheric spray freeze drying, comprising:spraying a composition into a chamber to form a flow of liquid droplets, wherein the composition comprises a substance and a carrier liquid; freezing the liquid droplets into frozen particles, comprising the substance and a frozen carrier liquid, by contacting the liquid droplets with a gas having an initial temperature; drying the frozen particles by: increasing the temperature of the gas from the initial temperature to below about the melting point of the frozen carrier liquid, wherein vapor meter readings from the chamber indicate when to further increase the temperature, and wherein the temperature is increased on average at an increment of between about 1 °C and about 20 °C for a duration of between about 5 min and about 30 min; and then further increasing the temperature of the gas to a maximum temperature level between about 95 °C and about 170 °C above the initial temperature until the carrier liquid is evaporated and the substance in the frozen particles is dried, thereby forming a dried product, wherein the temperature is further increased on average at an increment of between about 1 °C and about 8 °C for a duration of between about 5 min and about 30 min, wherein flow of the gas is adjusted to enhance drying efficiency without causing material degradation, meltback, or both.

3. The method of either claim 1 or 2, wherein concentration of the substance in the composition relative to the carrier liquid is between about 2.5 wt.% and about 40 wt.%.

4. The method of any one of claims 1 to 3, wherein the initial temperature is between about -50 °C and about -120 °C, optionally at about -75 °C.

285. The method of any one of claims 1 to 4, wherein vapor meter readings from the chamber indicate when to further increase the temperature on average.

6. The method of any one of claims 1 to 5, wherein the temperature is increased on average at an increment of between about 1 °C and about 20 °C for a duration of between about 5 min and about 30 min, optionally at an increment between about 2 °C and about 5 °C for a duration between about 3 min and about 15 min.

7. The method of any one of claims 1 to 6, wherein the temperature is further increased on average at an increment of between about 1 °C and about 8 °C for a duration of between about 5 min and about 30 min, optionally at an increment between about 2 °C and about 5 °C for a duration between about 3 min and about 15 min.

8. The method of any one of claims 1 to 7, wherein the carrier liquid is chosen from water, alcohols, organic solvents, and mixtures thereof.

9. The method of any one of claims 1 to 8, wherein the gas is chosen from carbon dioxide, nitrogen, helium, argon, and mixtures thereof.

10. The method of any one of claims 1 to 9, wherein the composition further comprises an excipient.

11. The method of any one of claims 2 to 10, further comprising collecting the frozen particles.

12. The method of claim 11, drying the frozen particles by passing the gas flow downward through the collected frozen particles to remove the carrier liquid.

13. The method of any one of claims 1 to 12, wherein flow of the gas is adjusted to enhance drying efficiency without causing material degradation, meltback, or both.

14. A product produced by the method of any one of claims 1 to 13.

15. A system for forming a dried product by atmospheric spray freeze drying, comprising: a chamber into which a composition is sprayed to form a flow of liquid droplets, wherein the composition comprises a substance and a carrier liquid; a freezing mechanism configured to freeze the liquid droplets into frozen particles, comprising the substance and a frozen carrier liquid; a gas supply system configured to contact the frozen particles with a gas having an initial temperature; and a temperature control emit operatively connected to the gas supply system, further comprising a vapor meter in the chamber to indicate when to further increase the temperature of the gas, the temperature control unit being configured to first increase the temperature of the gas from the initial temperature to below about the melting point of the frozen carrier liquid at an increment of between about 1 °C and about 20 °C for a duration of between about 5 min and about30 min, and then to further increase the temperature of the gas to a maximum temperature level between about 95 °C and 170 °C above the initial temperature at an increment of between about 1 °C and about 8 °C for a duration of between about 5 min and about 30 min until the carrier liquid is evaporated and the substance in the frozen particles is dried, thereby forming a dried product, wherein the gas supply system and the temperature control unit are configured to adjust the gas flow to enhance drying efficiency without causing material degradation, meltback, or both.

16. The system of claim 15, wherein concentration of the substance in the composition relative to the carrier liquid is between about 2.5 wt.% and about 40 wt.%.

17. The system of either claim 15 or 16, wherein the freezing mechanism can cool to the initial temperature between about -50 °C and about -120 °C, optionally at about -80 °C.

18. The system of any one of claims 15 to 17, wherein the temperature control unit further comprises a vapor meter in the chamber to indicate when to further increase the temperature of the gas.

19. The system of any one of claims 15 to 18, wherein the temperature is increased on average at an increment of between about 1 °C and about 8 °C for a duration of between about 5 min and about 30 min, optionally at an increment between about 2 °C and about 5 °C for a duration between about 3 min and 15 min.

20. The system of any one of claims 15 to 19, wherein the temperature is further increased on average at an increment of between about 1 °C and about 8 °C for a duration of between about 5 min and about 30 min, optionally at an increment between about 2 °C and about 5 °C for a duration between about 3 min and about 15 min.

21. The system of any one of claims 15 to 20, further comprising a collection unit configured to collect the frozen particles.

22. The system of claim 21, further comprising a drying system configured to pass the gas flow downward through the collected frozen particles at a flow rate to remove the carrier liquid.

23. The system of claim 22, wherein the flow control mechanism and the temperature control unit are configured to adjust the gas flow to enhance drying efficiency without causing material degradation, meltback, or both.

24. The system of any one of claims 15 to 23, wherein the carrier liquid is chosen from water, alcohols, organic solvents, and mixtures thereof.

25. The system of any one of claims 15 to 24, wherein the gas supply system is compatible with carbon dioxide, nitrogen, helium, argon, and mixtures thereof.

26. The system of any one of claims 15 to 25, wherein the composition further comprises an excipient.

27. A system for forming a dried product by atmospheric spray freeze drying, comprising:means for forming a flow of liquid droplets in a chamber, the liquid droplets being from a composition comprising a substance and a carrier liquid; means for freezing the liquid droplets into frozen particles, comprising the substance and a frozen carrier liquid; means for contacting the frozen particles with a gas having an initial temperature; and means for controlling the temperature configured to increase the temperature of the gas from the initial temperature to about below the melting point of the frozen carrier liquid, and then further increasing the temperature of the gas to a maximum temperature level between about 95 °C and about 170 °C above the initial temperature until the carrier liquid is evaporated and the substance in the frozen particles is dried, thereby forming a dried product, wherein the means for controlling the temperature is further configured to adjust flow of the gas to enhance drying efficiency without causing material degradation, meltback, or both.

28. The system of claim 27, wherein concentration of the substance in the composition relative to the carrier liquid is between about 2.5 wt.% and about 40 wt.%.

29. The system of either claim 27 or 28, further comprising means for collecting the frozen particles.

30. The system of any one of claims 27 to 29, further comprising means for drying configured to pass the gas flow downward through the collected frozen particles at a flow rate to remove the carrier liquid.

31. The system of any one of claims 27 to 30, wherein the flow control means and temperature control means are configured to adjust the gas flow to enhance drying efficiency without causing material degradation, meltback, or both.

32. A product produced by the system according to any one of claims 15 to 31.STATEMENT UNDER ARTICLE 19 (1)The Applicant submits this Statement under Article 19(1) of the PCT and Rule 46.4 to accompany the amendments to the claims filed concurrently herewith.

1. Claims AmendedIndependent claims 1, 2, 15, and 27 have been amended. Dependent claims 3 through 14, 16 through 26, and 28 through 32 remain unchanged. No claims have been added or cancelled. Claim numbering is preserved.

2. Nature of the AmendmentsEach of independent claims 1, 2, 15, and 27 has been amended to add a preamble specifying that the recited method or system forms a dried product by atmospheric spray freeze drying.Independent claims 1 and 2 have each been further amended to specify that vapor meter readings indicate when to further increase the temperature of the gas, that the first and further temperature increases each proceed at a specified increment and duration, and that flow of the gas is adjusted to enhance drying efficiency without causing material degradation, meltback, or both. Independent claim 15 has been further amended to specify a vapor meter, corresponding increment and duration limitations, and a gas-flow adjustment limitation reciting the gas supply system and the temperature control unit. Independent claim 27 has been further amended to specify that the means for controlling the temperature is configured to adjust flow of the gas to enhance drying efficiency without causing material degradation, meltback, or both.

3. Basis in the Application as FiledThe amendments introduce no subject matter that extends beyond the disclosure in the international application as filed. The added features correspond to the subject matter of dependent claims 5, 6, 7, 13, 18, 20, 23, and 31 as originally filed, and are further supported by the description as filed at paragraphs [0008], [0011], [0052], [0081], [0082], [0083], [0095], and [0170].

4. Impact on the Description and DrawingsThe amendments do not affect the description or the drawings of the international application.

5. ReservationThe Applicant reserves the right to submit further amendments under Article 34 and to respond in writing to the Written Opinion of the International Searching Authority in due course, and does not acquiesce to any conclusion set forth in the Written Opinion by the filing of these amendments.

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