Large-Scale Synthesis of Pharmaceuticals and Biologicals Using Thin Film Freezing

Abstract

The present invention encompasses a method for the large scale (preferably under cGMP or cGLP) preparation of micron or submicron sized particles containing pharmaceutical or bioactive agents. The system and method includes a cryogenic cooling system that includes a novel shroud that enhances the cooling effect, thereby reducing product loss and increasing product yield.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 319,482, filed March 14, 2022, the entirety of which is incorporated herein by reference.

[0002] The present invention encompasses a method for preparing micron or submicron sized particles containing active pharmaceutical ingredients and drug products on a large scale (preferably under cGMP conditions). The system and method includes a cryogenic cooling system including a shroud and cold nitrogen gas return plenum that locally enhances the cooling effect, thereby reducing product loss and increasing product yield. [Background technology]

[0003] Without limiting the scope of the invention, this background is described in connection with systems and methods for large-scale production of stable submicron-sized particles of an active pharmaceutical agent.

[0004] The ability to generate stable submicron-sized and micron-sized particles with high surface area creates opportunities including, but not limited to, oral, injectable, and pulmonary delivery applications. Stable submicron particles also have many inherent advantages for pulmonary delivery. Although particles need to have an aerodynamic diameter between about 1 to about 3 μm for efficient deep lung delivery, submicron particles can form porous nanoaggregated microparticles that can be effectively delivered to the lungs. Highly porous aerosolized particles have advantages over dense micron-sized powders, such as more rapid dissolution in the lungs leading to increased long-term responses.

[0005] The present invention relates to a thin film freezing (TFF) system and process for producing stable submicron particles. Droplets of aqueous and / or organic solutions and / or slurries containing an active agent, optionally with one or more excipients, are dropped onto a rotating stainless steel drum. The drum is hollow and filled with cryogenic temperatures. Upon impact, the droplets spread into a thin film and freeze in less than a second. The frozen film is continuously removed from the drum by a scraper blade attached to the rotating drum surface and collected in a container, where it is subsequently freeze-dried.

[0006] Process-scale (e.g., large-scale) cryogenic synthesis under current good manufacturing practice (cGMP) creates challenges with respect to scaling up the cGMP process, as well as steps for quality control and consistency of the final formulation. During larger-scale cryogenic synthesis in a cGMP environment, a temperature of -50 o It is important to maintain a stable sub-zero roller surface temperature, below 200 °C, while at the same time preventing melting from occurring during ice collection, which could damage the desired final dry powder structure achieved after freeze drying.

[0007] The inventors have surprisingly discovered that the inclusion of a shroud covering all or at least a portion of the system allows for localized and controlled cooling of both the freezing drum and the ambient gas temperature within the shroud where the pharmaceutical ice accumulates. Additionally, the inventors have further discovered that the inclusion of a gas plenum allows for efficient use and control of the flow of cryogenic gas across the frozen accumulated formulation, further ensuring product quality and ice stability (e.g., no product meltback). Summary of the Invention

[0008] The present invention encompasses systems and methods for large-scale (e.g., commercial quality) thin film freezing processes for the manufacture of active agents or compositions containing active agents with increased yields, reduced contamination, and improved safety. Large-scale methods (e.g., cGMP or cGLP quality standards) provide an efficient and robust process for freezing commercial quantities of active agents and then lyophilizing or sublimating them to form dry powder formulations in the form of stable micron and submicron sized particles.

[0009] In general, the present invention encompasses a system for thin film freezing of an active pharmaceutical ingredient including a freeze roller drum assembly comprising (1) a freeze cylinder assembly, (2) a scraper assembly, (3) a frame assembly, (4) a motor assembly, and (5) a manifold assembly, wherein the freeze cylinder assembly is maintained at a stable sub-zero temperature to freeze the formulation.

[0010] In certain embodiments, the system further comprises a shroud that optionally covers the entire system assembly or at least a portion of each of the assemblies (1)-(5). The inventors have surprisingly discovered that the shroud (i) enables the localized cold liquid N2 environment to maintain a stable sub-zero temperature and low humidity environment, (ii) enables safer operation of the cryogenic freezing equipment, (iii) improves the quality of the final product by reducing the occurrence of ice melt back, and (iii) reduces inadvertent contamination with bioburden (e.g., bacteria) or airborne particles, including viable and non-viable particulates.

[0011] In certain embodiments, the freezing cylinder assembly is maintained at a stable sub-freezing temperature using a cryogenic source.

[0012] In certain embodiments, the cryogenic source is a cryogenic solid, a cryogenic gas, a cryogenic liquid, or a heat transfer fluid capable of reaching cryogenic temperatures.

[0013] In certain embodiments, the system further comprises at least one gas plenum that allows the cryogenic liquid, cryogenic gas, or heat transfer fluid to be recirculated throughout the system.

[0014] In certain embodiments, the system further includes a filter or filtration system that filters the cryogenic source entering the shroud to remove bioburden and / or particulate matter, including viable and non-viable particulates, from entering the system.

[0015] In certain embodiments, the cryogenic solid, cryogenic gas, cryogenic liquid, or heat transfer fluid is at a temperature below -50 o Less than C, preferably -70 o Less than C, preferably -100 o C. In certain embodiments, a cryogenic source contacts the freezing cylinder assembly to maintain a stable sub-freezing temperature. In certain embodiments, a cryogenic liquid contacts the freezing cylinder assembly to maintain a stable sub-freezing temperature. In certain embodiments, the system further includes a heat exchanger to maintain a stable sub-freezing temperature.

[0016] In certain embodiments, the cryogenic liquid is an inert liquid or gas, hi certain embodiments, the inert liquid or gas is liquid nitrogen or liquid argon.

[0017] In certain embodiments, the cryogenic solid is dry ice.

[0018] In certain embodiments, the active agent includes a small molecule active agent or a bioactive agent.

[0019] In certain embodiments, the system is contained within an enclosure.

[0020] In another embodiment, the invention encompasses a system for large scale thin film freezing of formulations, including a freezing roller drum assembly comprising (1) a freezing cylinder assembly, (2) a scraper assembly, (3) a frame assembly, (4) a motor assembly, (5) a manifold assembly, and (6) a shroud covering at least a portion of each of assemblies (1)-(5), wherein the freezing cylinder assembly is maintained at a stable sub-zero temperature to freeze an active agent.

[0021] In certain embodiments, the freezing cylinder assembly is maintained at a stable sub-freezing temperature using a cryogenic source.

[0022] In certain embodiments, the system further comprises at least one gas plenum that allows the cryogenic source to recirculate through the system.

[0023] In certain embodiments, the system further includes a filter or filtration system that filters the cryogenic source entering the shroud to remove bioburden and / or particulate matter, including viable and non-viable particulates, from entering the system.

[0024] In certain embodiments, the cryogenic source is a cryogenic solid, a cryogenic gas, a cryogenic liquid, or a heat transfer fluid capable of reaching cryogenic temperatures.

[0025] In certain embodiments, a cryogenic source contacts the freezing cylinder assembly to maintain a stable sub-zero temperature. In certain embodiments, the cryogenic solid, cryogenic gas, cryogenic liquid, or heat transfer fluid is at a temperature below -50°C. o Less than C, preferably -70 o Less than C, preferably -100 oC Temperatures below 1000° C. can be reached.

[0026] In certain embodiments, a cryogenic liquid contacts the freezing cylinder assembly to maintain a stable sub-freezing temperature. In certain embodiments, the cryogenic liquid is an inert liquefied gas. In certain embodiments, the inert liquefied gas is liquid nitrogen or liquid argon.

[0027] In certain embodiments, the cryogenic solid is dry ice.

[0028] In certain embodiments, the active agent includes a small molecule active agent or a bioactive agent. In certain embodiments, the active agent is dissolved in an aqueous or organic solvent or a pharma- ceutically acceptable carrier.

[0029] In certain embodiments, the system is contained within an enclosure.

[0030] In another embodiment, the invention encompasses a method for large scale thin film freezing of an active agent comprising (a) utilizing the system disclosed herein, the method comprising (i) cooling a solid surface of a freezing cylinder assembly to below −70° C., (ii) dissolving or dispersing an active agent in a solution, and (iii) contacting the solution with the cold solid surface of the freezing cylinder assembly to freeze the solution.

[0031] In certain embodiments, the cold surface is cooled using a cryogenic source.

[0032] In certain embodiments, the cryogenic source is a cryogenic solid, a cryogenic gas, a cryogenic liquid, or a heat transfer fluid capable of reaching cryogenic temperatures.

[0033] In certain embodiments, the system further comprises a shroud covering at least a portion of each of the assemblies (1)-(5).

[0034] In a particular embodiment, the freezing cylinder assembly uses a cryogenic source to produce a stable sub-zero temperature, preferably -50 o Maintained below C.

[0035] In certain embodiments, the system further comprises at least one gas plenum that allows a cryogenic liquid, a cryogenic gas, or a heat transfer fluid to be circulated within the system.

[0036] In certain embodiments, the system further includes a filter or filtration system that filters the cryogenic source entering the shroud to remove bioburden and / or particulate matter, including viable and non-viable particulates, from entering the system.

[0037] In certain embodiments, the cryogenic solid, cryogenic gas, cryogenic liquid, or heat transfer fluid is at a temperature below -50 o Less than C, preferably -70 o Less than C, preferably -100 o Temperatures below C can be reached.

[0038] In certain embodiments, a cryogenic source contacts the freezing cylinder assembly to maintain a stable sub-zero temperature.

[0039] In certain embodiments, the cryogenic liquid contacts the freezing cylinder assembly to maintain a stable sub-freezing temperature, hi certain embodiments, the system further includes a heat exchanger for maintaining a stable sub-freezing temperature.

[0040] In certain embodiments, the cryogenic liquid is an inert liquefied gas, hi certain embodiments, the inert liquefied gas is liquid nitrogen or liquid argon.

[0041] In certain embodiments, the cryogenic solid is dry ice.

[0042] In certain embodiments, the composition or active agent includes a small molecule active agent or a bioactive agent.

[0043] In certain embodiments, the system is contained within an enclosure.

[0044] In a separate step, the solvent can be removed, for example by sublimation or freeze-drying.

[0045] In certain embodiments, the resulting particles have a volume average particle size of less than 0.05 microns to 25 microns.

[0046] In certain embodiments, the resulting particles have a diameter of at least 2 m 2 / g, at least 4m 2 / g, at least 6m 2 / g, at least 8m 2 / g, or at least 10m 2 / g surface area.

[0047] In certain embodiments, the resulting particles exhibit in vitro dissolution rates that are at least 1.5 times better, 2 times better, 2.5 times better, 3 times better, 3.5 times better, 4 times better, 4.5 times better, or 5 times better than that of the unprocessed active agent or formulation.

[0048] In certain embodiments, the cooling surface is cooled using a cryogenic solid, a cryogenic gas, a cryogenic liquid, or a heat transfer fluid capable of reaching cryogenic temperatures.

[0049] In certain embodiments, the aqueous or organic solvents include, but are not limited to, water, alcohols, ethers, halocarbons, hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, esters, acetates, organic acids, amines, ketones, sulfones, nitriles, carbonates, and combinations thereof.

[0050] In certain embodiments, the particles have a volume average particle size of from about 0.05 microns to about 150 microns after they are dispersed in water.

[0051] In certain embodiments, the solution further comprises at least a stabilizer.

[0052] In certain embodiments, the stabilizer is selected from the group consisting of phospholipids, surfactants, polymeric surfactants, vesicles, polymers selected from copolymers, homopolymers and block polymers, dispersing aids, and combinations thereof.

[0053] In certain embodiments, the solution is removed using lyophilization, sublimation, or evaporation.

[0054] In certain embodiments, the present invention relates to the use of a closed system in which the active agent is dissolved and / or dispersed in one or more solvents, and the active ingredient is dispersed in a volume of about 50, 100, 150, 200, 250, 200, 400, or 500 cm -1 The method includes spraying or dripping droplets of a solvent containing a dissolved and / or dispersed biological agent or pharmaceutical agent such that the droplets are exposed to an air-liquid interface of less than about 100 μm in area / volume, e.g., to increase stability, and contacting the droplets with a frozen surface having a temperature difference of at least 30° C. between the droplets and the surface, the surface being less than about 500 μm in thickness and having a surface area to volume ratio of about 25 to about 500 cm. -1 The mixture is frozen into a thin film.

[0055] In certain embodiments, the large-scale systems and methods for thin film freezing improve the physicochemical properties of active agents, thereby enhancing bioavailability, for example, by generating amorphous nanostructured aggregates with significantly enhanced surface area, higher dissolution rates, and supersaturation, by rapidly inducing nucleation followed by arrest of particle growth via polymer stabilization and particle growth arrest by solvent solidification.

[0056] In certain embodiments, large-scale systems and methods for cryogenically cooling active agents provide improved macroscopic performance in vitro and in vivo.

[0057] In another embodiment, the invention encompasses a large-scale cryogenic system for thin film freezing of an active agent using a freeze roller drum assembly (see Figures 1 and 2) optionally contained within an enclosure, the freeze roller drum assembly including a shroud that covers part or all of the freeze roller drum assembly system. The inclusion of the shroud system surprisingly and unexpectedly improves purity, yield, and safety due to a much cooler and drier (i.e., arid) processing environment than exists as well as the containment of oxygen-displacing gas. In various embodiments, the shroud slows the freezing rate of the process and prevents ice from accumulating on the drum from moisture present in standard cGMP air. Additionally, the shroud avoids reversal of melting after freezing by ensuring a stable sub-freezing temperature locally near the freeze roller assembly and ice collector.

[0058] In certain embodiments, the present invention encompasses systems and methods for large-scale thin film freezing manufacturing of dry powder formulations of an active agent, the system including a shroud.

[0059] In various embodiments, the present systems and methods, including the shroud, provide the following surprising and unexpected results. a. The shroud maintains the internal environment such that as the liquid nitrogen evaporates, it dries out the internal atmosphere within the closed system, preventing ice formation on the rollers. b. The shroud allows the local cold liquid and evolved gaseous N2 environment to maintain a stable sub-freezing ambient air temperature to prevent re-melting of the ice product which would destroy the final powder nanostructure properties. c. The shroud also improves robustness in the operating environment and reduces off-gassing N2 This allows for the safe collection and disposal of d. The shroud reduces particle loss in the final dry powder formulation, prevents inadvertent inhalation by workers, and avoids inadvertent contamination with airborne particles.

[0060] In various embodiments, the shroud is constructed from, for example, aluminum, polymer, plastic, or stainless steel, or combinations thereof.

[0061] In certain embodiments, the cryogenic system includes a freezing zone adjacent to and including the freezing cylinder assembly. In certain embodiments, the cryogenic system is preferably cooled using liquid nitrogen or another suitable cryogen (e.g., liquid argon and conventional refrigerants). In certain embodiments, the cryogenic system is preferably cooled using refrigerants including chlorofluorocarbons, hydrochlorofluorocarbons, and hydrofluorocarbons. In certain embodiments, the system also includes a collection tray that contains or is cooled by ice chips, preferably dry ice (i.e., frozen CO2), or other suitable cryogenic material. In certain embodiments, the dry ice chips do not contact the thin film frozen collection product. In certain embodiments, the cryogenic system is cooled to a temperature of about ±10°C. o In another embodiment, the cryogenic system maintains a steady state temperature within about ±2 o C. In certain embodiments, the shroud includes double pane windows in the space between the windows to increase insulation and constant temperature of the system.

[0062] In certain embodiments, the system is contained within an enclosure. In other embodiments, the enclosure includes at least one conveyor for moving the product through the system. The film freezing system and shroud system also optionally include at least one sensor disposed on the shroud and configured to detect, for example, temperature, pressure, and / or amount of product on the freezing cylinder assembly or collection assembly.

[0063] In certain embodiments, a conveyor included in the enclosure is configured to move the system linearly in response to detection by the at least one sensor. The enclosure may further include at least one track, and the at least one linear conveyor is enclosed within the at least one track, for example, to enable transport of produced products within the enclosure.

[0064] In certain embodiments, the freeze roller drum assembly includes a constant injection of liquid cooling liquid into the freeze zone of the system. In certain embodiments, the liquid cooling liquid is liquid argon or liquid nitrogen. In certain embodiments, the liquid cooling liquid is liquid nitrogen.

[0065] In certain embodiments, the liquid nitrogen can be under pressure or vacuum to eliminate flow obstructions due to volume expansion.

[0066] In a particular embodiment, the shroud assembly of the frozen roller drum assembly system is adapted to hold the liquid nitrogen at -90 o The shroud assembly allows for the separation of the inlet (e.g., coolant supply inlet) tubes so that the liquid reaches the freezing roller drum assembly and collection tray at temperatures below 100° C. In certain embodiments, the shroud assembly also prevents or minimizes the liquid flow from forming bubbles so as not to create a vapor lock condition that limits cooling power. In certain embodiments, the system operates near the critical point of the liquid-vapor system, resulting in a denser vapor phase than would be the case if it were operating near atmospheric pressure. This results in much less volumetric expansion of the liquid into the vapor phase, making the resulting vapor phase a much more effective coolant.

[0067] In certain embodiments, the cryogenic thin film freezing method includes an initial chill to cool the system including the collection assembly and the freezing cylinder assembly and associated components of the system that are cooled from room temperature to a target cooling temperature using liquid nitrogen as the system operates. The collection assembly contained within the system is cooled with dry ice chips and then the entire system is further cooled using liquid nitrogen.

[0068] The embodiments implemented in the present invention will be described in detail below with reference to the accompanying drawings. In the description and drawings, the same or equivalent components, parts, and processes are designated by the same reference numerals, and redundant descriptions are appropriately omitted. The scale and shape of each part shown in the figures are set for convenience to facilitate the description, and should not be construed as limiting unless otherwise specified. The embodiments are examples and do not limit the scope of the present invention. All features and combinations described in the embodiments are not necessarily essential to the present invention. [Brief description of the drawings]

[0069] [Figure 1] 1 shows the freeze roller assembly with the shroud and manifold removed. [Diagram 2] 1 shows a freeze roller assembly with a shroud covering the roller assembly and a manifold added above the shroud. [Diagram 3] FIG. 2 is an exterior side view showing the motor assembly that rotates the drum and the manifold assembly located above the shroud. [Figure 4] FIG. 2 shows an exterior rear view of the freeze roller assembly within the shroud with the manifold located above the shroud. [Diagram 5] A side view of the freeze roller assembly shroud is shown showing the liquid nitrogen inlet and exhaust ports, as well as the product inlet to the manifold above the shroud. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] For a more complete understanding of the features and advantages of the present invention, reference should be made to the detailed description of the invention taken in conjunction with the examples and claims.

[0071] Although the making and use of various embodiments of the invention are described in detail below, it should be understood that the invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not limit the scope of the invention.

[0072] To facilitate the understanding of the present invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by one of ordinary skill in the art relevant to the present invention.

[0073] Terms such as "a," "an," and "the" are not intended to refer only to a singular entity, but include the general class of which a specific example may be used for illustration. Although the terms used herein are used to describe particular embodiments of the invention, their usage is not intended to limit the invention, except as noted in the claims.

[0074] As used herein, the terms "a," "an," or "a(n)" are indefinite articles and when used herein in reference to a substituent or a "group of substituents" mean at least one.

[0075] As used herein, the term "about" when referring to a value includes ±10% of the stated value. For example, about 50% includes the range of 45% to 55%, and about 20 molar equivalents includes the range of 18 to 22 molar equivalents. Thus, when referring to ranges, "about" refers to ±10% of the stated value at each end of each stated range. For example, a ratio of about 1 to about 3 (weight / weight) includes the range of 0.9 to 3.3.

[0076] As used herein, the terms "active pharmaceutical ingredient", "active agent", and "drug formulation" are used interchangeably and refer to a substance that may be used in a finished pharmaceutical product (FPP) with the intention of imparting pharmacological activity or having a direct effect on the diagnosis, cure, mitigation, treatment or prevention of disease, or having a direct effect on the restoration, correction, or alteration of physiological function in humans. An "active pharmaceutical ingredient", "active agent", and "drug formulation" may be a small molecule (e.g., a cannabinoid, an antibiotic, or an antifungal agent) or a biologic (e.g., a protein, an antibody, or an mRNA) and may be used alone in the methods of the compositions of the invention or may be included in an aqueous or organic solvent or a pharma- ceutically acceptable carrier. Illustrative, non-limiting examples of "active pharmaceutical ingredients," "active agents," and "formulations" that may be used in embodiments of the present invention include nucleic acids, RNA (including siRNA, mRNA, microRNA, ncRNA), DNA (including pDNA), DNase, peptides, proteins, fAbs, mAbs, phages, adeno-associated viruses, virus-like particles, bacteria, viral fragments, activated viruses, lentiviruses, recombinant vesicular stomatitis viruses, alpha-1-antitrypsin, interleukins, protease inhibitors, interleukin receptors, monoclonal antibodies, muramyl dipeptides, catalase, phosphatases, kinases, receptor antagonists, receptor agonists, dismutases, calcitonin, hormones, interferons, insulin, growth factors, erythropoietin, heparin, and the like. , vasopressin, peptides, albuterol sulfate, terbutaline sulfate, insulin, glucagon-like peptides, C-peptide, erythropoietin, calcitonin, human growth hormone, luteinizing hormone, prolactin, sugars, lipids, amino acids, fatty acids, phenolic compounds, alkaloids, adrenocorticotropic hormone, leuprolide, interferon alpha-2b, interferon beta-1a, sargramotim, aldesleukin, interferon alpha-2a, interferon alpha, n3α-peptide, or proteinase inhibitors, etidronic acid, nafarelin, chorionic gonadotropin, prostaglandin E2, epoprostenol, acarbose, metformin, or desmopressin, cyclodextrin, cannabinoids, plant extracts, antibiotics,Gene therapy agents, catalysts, adsorbents, pigments, coatings, personal care products, abrasives, particles for sensors, metals, alloys, ceramics, membrane materials, nutritional substances, anti-cancer drugs and antibiotics, analgesics, anti-convulsants; anti-diabetic agents, anti-fungal agents, anti-tumor agents, anti-Parkinson's agents, anti-rheumatic agents, appetite suppressants, biological response modifiers, cardiovascular agents, central nervous system stimulants, contraceptives, diagnostic agents, dopamine receptor agonists, orthostatic function Functional impairment agents, fertility agents, gastrointestinal agents, hormones, immunomodulators, antihypercalcemic agents, mast cell stabilizers, muscle relaxants, nutritional supplements, eye drops, osteoporosis agents, psychotherapeutic agents, parasympathomimetics, parasympatholytic agents, respiratory agents, sedatives, skin and mucous membrane agents, smoking cessation agents, steroids, sympatholytic agents, urinary tract agents, uterine relaxants, vaginal agents, vasodilators, antihypertensive agents, hyperthyroid agents, antihyperthyroid agents, antiasthmatic agents, dizziness agents, cardiovascular system Drugs, respiratory drugs, sympathetic nervous system drugs, cholinomimetics, adrenergic or adrenergic uronic acid blockers, antidepressants, antihypertensives, anti-inflammatory drugs, antianxiety drugs, immunosuppressants, antimigraine drugs, sedatives / hypnotics, antianginal drugs, antipsychotics, antimanic drugs, antiarrhythmic drugs, antiarthritic drugs, anti-analgesics, anticoagulants, thrombolytic drugs, antifibrinolytic drugs, hemolytic drugs, antiplatelet drugs, anticonvulsants, antihistamines / antipruritic drugs, carbamazepines ... Examples of active agents include, but are not limited to, agents useful for calcium regulation, antivirals, anti-infectives, bronchodilators, hormones, hypoglycemic agents, hypolipidemic agents, proteins, nucleic acids, agents useful for erythropoiesis stimulation, agents useful for anti-ulcer / anti-reflux, anti-nausea / anti-emetics, oil-soluble vitamins, mitotane, visazine, halonitro acid ureas, anthracyclines, voriconazole, tacrolimus, remdesivir, or ellipticine. It will be understood that this list is not exhaustive and is for illustrative purposes only. It will further be understood that a compound may be included in more than one class of active agents, e.g., peptides and proteins.

[0077] As used herein, the term "administering" means administering a composition of the present invention to a subject.

[0078] "Bioavailability" as used herein is a term that refers to the degree to which a drug becomes available to target tissues after being administered to the body. Low bioavailability is a significant problem encountered in the development of pharmaceutical compositions, especially those that contain active ingredients that are poorly soluble in water. In certain embodiments, the active agent may be water-soluble, poorly water-soluble, highly non-soluble, or insoluble. Those skilled in the art will recognize that various methodologies may be used to increase the solubility of the active agent (e.g., using different solvents, excipients, carriers, glycosylation, lipidation, degradation, combination with one or more salts, and addition of various salts).

[0079] The term "carrier" as used herein refers to any liquid in which an active agent or composition can be included in the process of the present invention.For example, an active agent or composition can be dissolved or dispersed in a liquid carrier, but it is not necessary for the active agent or composition to be dissolved in the carrier.

[0080] The term "composition" as used herein is intended to encompass a product comprising one or more active pharmaceutical ingredients or agents, or formulations described herein, and optionally one or more pharma- ceutically acceptable excipients, carriers, or diluents, resulting from the combination of particular ingredients, such as particular ingredients in particular amounts, as described herein, in particular amounts, etc., defined throughout the originally filed disclosure.

[0081] As used herein, the term "cryogenic" refers to a system or process that is maintained at a constant temperature for a period of time (e.g., 1, 5, 15, 30, 60 minutes, or 1, 2, 3, 4, 5, 6 hours), e.g., at least -50 o C means that the temperature is maintained at a cryogenic temperature below -50 °C. o C temperature or lower and maintains this temperature.

[0082] The term "fine fraction" as used herein is defined to mean that portion of the delivered material (i.e., the formulation containing respirable aggregates and particles (either droplets, or dry powder)) that is actually delivered to the lungs. The fine fraction will depend on the performance of the particles and respirable aggregates as well as the performance of the delivery device. This fine fraction will generally include respirable aggregates having a mass median aerodynamic diameter of about 1 to about 5 μm. This is the desired size, such as droplets delivered in a nebulizer or pressurized metered dose inhaler (pMDI), or droplets or powder containing aggregates and particles delivered in a dry powder inhaler (DPI).

[0083] As used herein, the term "heat exchanger" refers to a system or component of a system used to transfer heat from one medium to another. These media may be gases, liquids, or a combination of both. Heat exchangers of the present invention may optionally include a compressor / condenser, piping, and a circulating fluid or gas.

[0084] The term "inert" as used herein refers to a substance that does not cause a chemical reaction or change when in contact with another substance. For example, an inert gas or inert liquefied gas, when in contact with an active agent or active pharmaceutical ingredient of the present invention, does not cause a chemical reaction between the inert gas or inert liquefied gas and the active agent or active pharmaceutical ingredient.

[0085] The term "large scale" as used herein refers to the thin film freezing methods described herein that use amounts of active agent ranging from about 0.1 kg to about 25 kg. In certain embodiments, "large scale" refers to about 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25 kg or more of active agent.

[0086] The term "maintained" as used herein means to maintain approximately the same state for a period of time (e.g., about 1, 5, 15, 30, 60 minutes, or 1, 2, 3, 4, 5, 6 hours, etc.).o Maintaining at a temperature below about -50°C means maintaining the temperature below about -50°C for a period of time (including, but not limited to, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes, or 1, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours, or any time interval therebetween). o This means that the temperature is kept below C.

[0087] As used herein, the term "particle" is used to describe particles that include an active agent, which are described in more detail below. The particles form individual units within the respirable aggregate, such that the respirable aggregate contains one or more particles that include an active agent dispersed throughout the respirable aggregate.

[0088] As used herein, the term "respirable aggregate" is used to describe an aggregate of one or more particles, the aggregate being approximately 1 m2 / More preferably, the surface area of ​​the respirable aggregate is greater than about 5 m2 / g, and even more preferably, greater than about 10m2 / g, and even more preferably about 20m2 / g. The inhalable aggregates may also include smaller engineered active agent particles, each active agent particle having a particle size of less than about 1 μm. The inhalable aggregates may be, for example, a dry powder, or a dry powder dispersed in a liquid to form one or more liquid droplets. The inhalable aggregates of the present invention are also readily wettable, as demonstrated by contact angle measurements of disks formed by pressing the inhalable aggregates into tablet form. Such contact angle measurements are less than about 50 degrees, preferably less than 40 degrees, more preferably less than about 30 degrees, and even more preferably less than 20 degrees. Furthermore, the inhalable aggregates of the present invention, when dry, have a porosity of at least about 10%, more preferably at least 25%, even more preferably at least about 40%, even more preferably at least 60%, and up to about 80%. The inhalable aggregates of the present invention exhibit a density of about 0.1 g / mL to about 5 g / mL.

[0089] The term "therapeutically effective amount" or "effective amount" as used herein refers to an amount of an active pharmaceutical ingredient, active agent, or formulation useful for treating or ameliorating a specified disease or condition, or exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount" or "effective amount" further includes within its meaning a non-toxic but sufficient amount of the particular agent referred to to produce the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on factors such as the subject's general health and the patient's age. The actual amount will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0090] The terms "treat," "treating," or "treatment," as used herein, refer to any indication of successful treatment or amelioration of an injury, disease, or condition, including any objective or subjective parameter, such as relief, remission, attenuation of symptoms or making the injury, disease, or condition more tolerable to the patient, slowing the rate of degeneration or decline, an end point of decline without degeneration, improvement in the patient's physical or mental health, etc. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical exam, a neuropsychiatric exam, and / or a psychiatric evaluation.

[0091] The term "viable and non-viable particulates" refers to biological particulates (eg, bacteria, sometimes referred to as bioburden) and non-biological particulates (eg, dust or other non-living matter that may be airborne).

[0092] The abbreviation "(w / w)" refers to the phrase "weight percent concentration", i.e., the percentage of a particular substance in a mixture as measured by the weight or mass or weight amount of a component of a composition disclosed herein compared to the total weight of the composition. Thus, the amount is less than a unit and represents the weight percent amount of the component relative to the total weight of the composition. For example, a 2% (w / w) solution means that 2 grams of solute are dissolved in 100 grams of solution.

[0093] Overview of the embodiment The present invention encompasses systems and methods for large-scale (e.g., commercial cGMP quality) thin film freezing processes of active pharmaceutical ingredients, active agents, and formulations with increased yields, reduced contamination, and improved safety. The large-scale (e.g., cGMP quality) methods provide an efficient and robust process for freezing commercial-scale quantities of dry powder formulations that can produce stable sub-micron sized particles (e.g., mm or nm sized particles). The systems and methods can be optionally implemented in a closed enclosure system that houses a freezing roller drum assembly for preparation of thin film freezing of active agents that ultimately results in micron-sized and sub-micron sized particles. The enclosure can include multiple inlet and exhaust ports, including one or more compressed or blown liquid nitrogen gas inlets, which can be controlled by one or more regulating valves to maintain a steady state internal temperature and pressure. Each of the inlet and outlet ports allows the flow of cryogenic gas or liquid to pass through an optional high-flow filter to remove particulate matter. The gas can then be optionally directed through a dehumidifier to produce a stable dry atmosphere. The gas can then be directed through a first flow valve proximal to the freeze roller drum assembly (see FIG. 1) that controls the amount and rate of liquid nitrogen into the freeze assembly. After leaving the enclosure assembly, the gas flow flows to the ambient atmosphere or through a control valve to a vacuum fan, with the amount and rate of exhaust flow controlled by a post freeze assembly valve. A vacuum hose can serve as a connection between the freeze assembly and the vacuum flow valve.

[0094] The freeze roller drum assembly (101) is shown in Figure 1. The manifold assembly includes a product inlet (204, Figure 2) that branches into one or more droplet orifices (206). This droplet stream is then directed to the freezing section of the freeze roller drum assembly (105), which includes a solid, cryogenically cooled surface where the droplets are frozen on contact.

[0095] Each of the components located proximal to or distal to the frozen roller drum assembly (101) are optional. For example, the frozen assembly (101) can be attached directly to a liquid nitrogen source without the use of high flow filters, dehumidifiers, or control valves, and without any components other than the frozen roller drum assembly (101). Alternatively, the assembly can be contained within an enclosure, optionally including flow filters, dehumidifiers, or control valves, which can be added to the enclosure in any combination with the frozen roller drum assembly.

[0096] One advantage of the enclosure of the present invention is that most embodiments are relatively inexpensive to assemble. The tubing, piping, and / or hoses used to construct each section may be made from many different materials, including metal, plastic, glass, rubber, and other similar substances sufficient to contain liquids and gases at low temperatures.

[0097] In certain embodiments, a pressure gradient of gas is applied across the enclosure, with a higher gas pressure at the proximal end of the enclosure and a lower gas pressure at the distal end of the enclosure, with ambient air pressure typically between the pressure gradient values. Preferably, the cooling gas used in this system is liquid nitrogen. Gas may flow into the freezing roller drum assembly through a pressurized gas hose that is coupled to the assembly by a hose coupling. Coupling the hose to the assembly may be accomplished by a variety of methods, including simply sliding the hose over the assembly to allow friction to keep the hose in place, placing a simple clamp over the hose to further secure it in place, or adding a sticky substance between the hose and the assembly. In general, any means of keeping the hose in place to avoid gas leakage between the hose and the assembly is sufficient for coupling the hose. In one embodiment of the present invention, the pressurized gas hose is saturated water vapor.

[0098] In some embodiments, the thin film freezing systems and methods are not contained in an enclosure. In general, the freeze roller drum assembly includes: (1) a freeze cylinder assembly (105), (2) a scraper assembly (109), (3) a frame assembly (103), (4) a motor assembly (107), (5) a manifold assembly (206), and (6) a shroud (202) that covers all or a portion of assemblies 1-5.

[0099] The freezing cylinder assembly is first frozen at approximately -50 °C, for example using liquid nitrogen. o In various embodiments, the temperature is brought to a temperature of less than about 0 o Less than C, typically about -50 o Below C, about -70 o Below C, about -90 o Below C, about -110 o Less than C or about -130 o Less than C.

[0100] When the freezing cylinder assembly (105) containing the cryogenic cylinder (106) is cooled to a desired temperature, droplets of the solvent containing the activator are slowly dripped from the manifold through the product inlet (204) and through a series of outlet orifices (206) on the cryogenic surface (106) of the freezing cylinder assembly (105), e.g., a frozen metal surface. Other cryogenic surfaces may include metal, ceramic, polymer, or plastic surfaces, or combinations thereof. The temperature of the cryogenic surface of the freezer cylinder assembly is maintained at a constant temperature using liquid nitrogen, liquid argon, other liquefied or slush cryogenic gas, or other suitable heat transfer fluid. The sample droplets containing the activator are flash frozen upon contact with the cryogenic surface (106) of the freezing roller drum assembly (105) and then collected in the form of frozen flakes or droplets from the surface using a scraper assembly (109).

[0101] Freezing Roller Drum Assembly Section Embodiments of the individual sections of the freeze roller drum assembly (101) are described in more detail in the following paragraphs. In general, the freeze roller drum assembly includes (1) a freeze cylinder assembly (105) including a cryogenic surface (106), (2) a scraper assembly (109), (3) a frame assembly (103), (4) a motor assembly (107), (5) a manifold assembly (206), and (6) a shroud (202) that covers all or a portion of assemblies 1-5. In certain embodiments, the freeze roller drum assembly is disposed within an enclosure system, for example. In other embodiments, the freeze roller drum assembly is a stand-alone system that is not within an enclosure system.

[0102] Freezing Roller Drum Assembly An embodiment of a freezing roller drum assembly (101) is shown in FIG. 1. The freezing roller drum assembly (101) includes a freezing cylinder assembly (105), which includes a cryogenic cylinder (106), a scraper assembly (109), a frame assembly (103), an enclosure assembly (202) (see FIG. 2), and a motor assembly (107). In various embodiments, an activator is dripped onto the freezing cylinder assembly (105), particularly the cryogenic cylinder (106), which rapidly freezes the activator. The scraper (109) then removes the activator from the freezing cylinder assembly, where it is collected in a collection tray or other suitable container. The collection container maintains the cold temperature at a constant temperature, preferably using dry ice or another cooling method.

[0103] In certain embodiments, the freezing roller drum assembly includes a shroud (202) that maintains the internal atmosphere and the freezing cylinder assembly (105) at a constant temperature. The shroud assembly is shown in FIG. 2. The shroud assembly is designed to maintain a constant temperature by flowing liquid nitrogen gas from the inlet in the direction of the freezing cylinder assembly until the gas exits the exhaust port of the shroud. The inventors have surprisingly discovered that the inclusion of a shroud system allows for localized and controlled cooling of both the freezing drum and the ambient gas temperature within the shroud where the pharmaceutical ice accumulates. Additionally, the inventors have further discovered that the inclusion of a gas plenum allows for efficient use and control of the flow of cold nitrogen gas across the frozen accumulated formulation, further ensuring product quality and ice stability (e.g., no product meltback).

[0104] Droplet freezing section - Freezing cylinder assembly In one embodiment, droplets of a solvent containing an active agent enter the freeze roller assembly through a product inlet tube in the manifold assembly (206).

[0105] An embodiment of the freezing cylinder assembly (105, without shroud) is shown in FIG. 1. The primary function of this section is to provide a surface area for droplets of active agent to instantly freeze onto the cryogenic freezing cylinder (106). The shroud on the assembly (see FIG. 2) serves the purpose of maintaining a constant temperature with the secondary function of controlling the flow and subsequent direction of liquid nitrogen in and around the freezing cylinder assembly (101). In a specific embodiment, the temperature is maintained using a freezing cryogenic gas (e.g., liquid nitrogen or argon). The solvent containing the active agent enters the top of the manifold assembly through a product inlet (204), the solvent is dripped through one or more outlet orifices (206) connected to the product inlet, and the droplets instantly freeze onto the cryogenic surface of the freezing cylinder assembly (105).

[0106] The freezing cylinder assembly (105) is shown in Figure 1. In this particular embodiment, a freezing cryogenic gas (e.g., liquid nitrogen) flows within a central cylinder of the freezing cylinder assembly (105) to maintain a low temperature of the cylinder (106). The liquid droplets enter a product inlet (204), then flow through a manifold assembly (206) through multiple product outlet orifices, and then impact the cryogenic cylinder (106) of the freezing cylinder assembly (105), resulting in very rapid freezing of the liquid droplets.

[0107] Sample particles frozen using this method are then collected using a scraper assembly (109), which allows for collection of the products during the freezing process. In certain embodiments, the primary use of the system is to rapidly freeze small droplets of fluids using a very cold target.

[0108] According to one embodiment, the freeze roller drum assembly (105) achieves thin film freezing of the active agent. In a particular embodiment, the freeze roller drum assembly is configured to cool the system to a target temperature using a circulating cooling gas, often liquid nitrogen or liquid argon, for example, although other gases appropriate for the cooling temperature may be utilized.

[0109] In certain embodiments, the freeze roller drum assembly includes a shroud assembly that maintains a more constant internal temperature, protects against contamination and biofouling, and / or particulate matter, including viable and non-viable particulates, and increases overall yield. The process includes first cooling the system to a desired temperature. The active agent (e.g., small molecule or biological agent) is first dissolved or dispersed in one or more solvents, followed by spraying or dripping droplets of the solvent containing the dissolved or dispersed active agent to disperse the active agent over a range of 50, 100, 150, 200, 250, 300, 400, or even 500 cm. -1The droplets are exposed to an air-liquid interface of less than about 100° C. per surface area / volume and contacted with a frozen surface of the freezing cylinder assembly having a temperature difference between the droplets and the freezing cylinder assembly surface of at least about 30° C. In certain embodiments, the temperature difference between the droplets and the freezing cylinder assembly surface is at least about 10° C. o C, 20 o C, 30oC, 40oC o C, or 50 o It's C.

[0110] In certain embodiments, the cryogenic surface freezes the droplets to a thickness of less than 500 μm and a surface area to volume ratio of 25 to 500 cm -1 In certain embodiments, the surface freezes the droplets into a film less than 500 μm, less than 400 μm, less than 300 μm, less than 200 μm, less than 100 μm, less than 50 μm, less than 25 μm, less than 10 μm, or less than 1 μm thick.

[0111] In certain embodiments, the surface is adapted to freeze droplets to provide a surface area to volume ratio of about 25 to 500 cm -1 , about 50~400cm -1 , about 75~300cm -1 , or about 100-200cm -1 In a particular embodiment, the surface is formed by freezing droplets to a thickness of about 500 cm. -1 , about 450cm -1 , about 400cm -1 , about 350cm- 1 , about 300cm -1 Less than 250cm -1 , about 200cm -1 , about 150cm -1 , about 100cm -1 , or about 50 cm -1 Make the film thinner.

[0112] In one embodiment, the method further comprises removing the solvent from the frozen material to form particles. In one embodiment, the droplets freeze in about 10, 20, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 500, 1,000, and 2,000 milliseconds upon contact with the surface. In another embodiment, the droplets freeze in about 50 and 150 milliseconds upon contact with the surface. In another embodiment, the droplets have a diameter between 1 and 500 mm at room temperature. In another embodiment, the droplets form a thin film on the surface with a thickness of 10 to 500 μm.

[0113] In another embodiment, the droplets are from about 50 to about 250 o C / sec, about 100 to about 200 o C / sec, about 150 to about 175 o C / sec, about 160~170 o C / sec.

[0114] In another embodiment, the particles after solvent removal are about 10 mm 2 / gr, 15, 25, 50, 75, 100, 125, 150, or approx. 200m 2 / gr surface area.

[0115] In one embodiment, the droplets include an active agent, such as a small molecule active agent or a biological agent, and the particles have less than 50% of the active agent on the particle surface. The active agent particles have less than about 25%, 15%, 10%, or 5% of the active agent on the surface. In another embodiment, the particles are submicron in diameter and may include particle fibers less than 1 micron in diameter.

[0116] In one embodiment, the surface is cooled by a cryogenic solid, cryogenic gas, cryogenic liquid, or heat transfer fluid capable of reaching cryogenic temperatures or temperatures below the freezing point of the solvent. In another aspect, the solvent further comprises one or more excipients selected from sugars, phospholipids, surfactants, polymeric surfactants, vesicles, polymers including copolymers and homopolymers and biopolymers, dispersion aids, and serum albumin.

[0117] In various embodiments, the percentage of active agent in the pharma- ceutically acceptable excipient is about 0.1% to about 100%. In various embodiments, the percentage of active agent in the pharma- ceutically acceptable excipient is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9 or about 100%.

[0118] In certain embodiments, the freezing cylinder assembly is mounted, for example, in a system In addition to cooling the freezing cylinder assembly, the collection assembly is also cooled, for example, using dry ice, liquid nitrogen, or other suitable means.

[0119] In certain embodiments, the target cooling temperature is a desired cryogenic temperature selected from a range of temperatures from a predetermined lower limit temperature to a predetermined upper limit temperature. The lower limit temperature is, for example, the lowest temperature to which cooling can be achieved by the cryogenic cooling system, for example, -170 o The upper temperature limit may be, for example, a desired cryogenic temperature determined according to the material used, but may be, for example, below the liquid nitrogen temperature, or about -50°C. o C, about -60 o C, about -70 o C, about -80 o C, about -90 o C, about -100 o C, about -110 o C, about -120 o C, about -130 o C, about -140 o C, about -150 o C, -160 oC, or about -170 o C is the cryogenic temperature.

[0120] In various embodiments, the cryogenic system includes a freeze roller drum assembly, which further includes a shroud system that maintains a constant temperature, dries the local ambient environment, and reduces bioburden and particulate matter, including viable and non-viable particulates, increasing the yield of the active agent.

[0121] In certain embodiments, the cryogenic cooling system optionally includes a cryocooler that continuously cools the cooling gas of the cryogenic cooling system. In other embodiments, the cryogenic cooling system optionally includes a gas supply line and / or a gas return line that includes one or more flexible or rigid pipes.

[0122] In a particular embodiment, a gas flow path is provided around or within a freeze roller drum assembly that is cooled by flowing a cooling gas through it. The cold gas flow path includes an inlet and an outlet. A gas supply line is connected to the inlet of the gas flow path, and a gas return line is connected to the outlet of the cold gas flow path. Thus, the cold gas flows from the gas supply line through the inlet into a gas pipe and from the gas pipe through the outlet into the gas return line.

[0123] In certain embodiments, the freezing roller drum assembly includes a product inlet (204) that allows the product to enter multiple product inlet tubes (206), and then multiple droplets are provided onto the freezing cylinder assembly to dissolve or disperse the active agent in a solvent that contacts the freezing cylinder assembly (105) (e.g., by dripping or spraying) and freezes on the cryogenic cylinder (106) surface. The frozen product is then scraped (109) from the freezing cylinder assembly and deposited in a collection tray (111) that is at a constant or steady temperature.

[0124] In certain embodiments, neither the gas supply line nor the gas withdrawal line is in physical contact with the active agent being cooled: the gas supply line extends from an inlet in a direction toward the pharmaceutical or biological agent being cooled, and the gas withdrawal line extends from an outlet in a direction away from the active agent being cooled.

[0125] In certain embodiments, the system of the present invention may also optionally include a heat exchanger configured to allow cooling gases flowing through the gas supply line and the gas return line to exchange heat with each other between the gas supply line and the gas return line, the heat exchanger helping to improve the cooling efficiency of the cryogenic cooling system.

[0126] In certain embodiments, the cryogenic system may operate at ambient positive or negative atmospheric pressure.

[0127] In certain embodiments, the cryogenic system includes one or more sensors, such as a temperature sensor. The temperature sensor may be located anywhere within the cooling gas flow path, including the gas flow path. Additionally, multiple temperature sensors may be located at different locations within or around the cooling gas flow path.

[0128] In certain embodiments, the cryogenic cooling system includes a controller for controlling the cryogenic cooling system. The controller includes a gas flow control unit. The gas flow control unit includes a timer and an initial cooling setting. The controller is located in the ambient environment. The controller may be installed in a gas circulation source, for example, a compressor.

[0129] In a specific embodiment, the control device of the cryogenic cooling system is realized as a hardware configuration by elements and circuits including a computer CPU and memory, and as a software configuration by a computer program or the like.

[0130] In certain exemplary embodiments, when an enclosure is used, initial cooling of the enclosure system is a control process of the cryogenic cooling system that rapidly cools both the enclosure and the freezing roller assembly (101) from room temperature to the target cooling temperature, and is performed when the cryogenic cooling system is activated. The initial cooling cools the enclosure and the freezing cylinder assembly from room temperature to the target cooling temperature. After completion of the initial cooling, the cryogenic system transitions to steady-state cooling to maintain the enclosure and the freezing cylinder assembly at the target cooling temperature. In certain embodiments, the temperature reduction rate in the initial cooling is faster than the temperature reduction rate in the steady-state cooling.

[0131] The controller is configured to initiate initial cooling of the enclosure and the freezing cylinder assembly in synchronization with operation of the cryogenic cooling system, for example, the controller initiates initial cooling of the refrigerated freezing cylinder assembly simultaneously with operation of the cryogenic cooling system or a predetermined delay time from when the cryogenic cooling system is activated.

[0132] Typically, the operation of the cryogenic cooling system means the operation of the gas circulation source. Thus, the control device may be configured to start the initial cooling of the cooling target in synchronization with the operation of the gas circulation source. Alternatively, the control device may be configured to start the initial cooling in synchronization with the operation of the gas circulation source.

[0133] In a particular embodiment, the cryogenic cooling system includes a main switch. The main switch includes an operating tool, such as a manually operable operating button or switch, configured to output a system activation command signal to the controller when operated. When a technician operates the main switch, the cryogenic system is activated and begins to operate. The main switch can function not only as an activation switch for the cryogenic cooling system, but also as a stop switch for the cryogenic cooling system.

[0134] The main switch may be installed in the control device or its casing, or, if the upper control device is provided separately from the control device, the upper control device may be configured to output a system start command signal to the control device.

[0135] The controller is configured to initiate initial cooling according to the received system startup command signal. The controller is configured to control the gas circulation source to perform initial cooling of the cooling object. During initial cooling, the controller controls the gas circulation source to cause cooling gas to flow through the cooling gas flow passage according to a predetermined flow rate pattern. The controller may control the gas circulation source to perform steady-state cooling of the cooling object after the initial cooling or at another suitable time.

[0136] The gas or gas-liquid mixture flow control unit is configured to determine a target cooling gas flow rate based on an initial cooling setting and an elapsed time from the start of the initial cooling. The gas flow control unit is configured to control the gas circulation source such that cooling gas flows through the cooling gas flow path at the determined target cooling gas flow rate. The gas flow control unit is configured to generate a gas circulation source control signal and output the gas circulation source control signal to the gas circulation source such that cooling gas is delivered to the cooling gas flow path by the gas circulation source at the target cooling gas flow rate.

[0137] In certain embodiments, the timer is configured to measure the elapsed time. The timer is configured to measure the elapsed time according to a system start command signal. The timer is capable of calculating the elapsed time from the start of the initial cooling.

[0138] The initial cooling setting predetermines a target cooling gas flow rate for each time from the start to the completion of the initial cooling according to a predetermined flow rate pattern. The initial cooling setting may have a function, a look-up table, a map, or another format that represents a correspondence between elapsed time and the target cooling gas flow rate.

[0139] The target cooling gas flow rate is set, for example, so that the cryogenic cooling system provides sufficient cooling capacity to cool the object to be cooled to the target temperature. The target cooling gas flow rate can be appropriately set for each cooling temperature based on the designer's empirical knowledge or the designer's experiments and simulations.

[0140] It is convenient to express the flow rate of cooling gas as a mass flow rate. As is well known, the mass flow rate is constant at each location in the cooling gas flow path, so the flow rate of cooling gas delivered from the gas circulation source is equal to the flow rate of cooling gas flowing through the freeze cylinder assembly gas flow path. However, where applicable, the flow pattern may also be described as a volumetric flow rate or other flow rate versus time.

[0141] In certain embodiments, the fixed flow rate may refer to a cooling gas flow rate for maximizing the cooling capacity of the cryogenic cooling system at a target cooling temperature and optimal flow rate for steady-state cooling. The cooling temperature for steady-state operation typically coincides with the target cooling temperature for initial cooling.

[0142] In certain embodiments, the cryogenic system includes a liquid nitrogen source (not shown), optionally a cryogenic heat exchanger, and an exhaust or vent line. Cryogenic liquid nitrogen is supplied to the cryogenic system to maintain a constant temperature within the enclosure system. After transferring most of its refrigeration capacity to the freezing cylinder assembly, the remaining nitrogen gas is exhausted via the vent line. In some applications, it may be possible to utilize the exhausted nitrogen gas in other cooling applications or recycle the gas.

[0143] In a particular embodiment, a shrouded freezer roller drum assembly (see FIG. 1) includes multiple circulation loops that include exit orifices (206) from a product inlet (204) that are fed through a shroud cover (202) from a manifold assembly.

[0144] During this freezing step, the cryogenic cooling system continuously maintains the temperature of the cryogenic cylinder at a predetermined temperature to ensure that the product is completely frozen. The exact temperature set point during this freezing step may vary depending on the active agent being frozen and the solvent system utilized.

[0145] How to use The present invention includes compositions and methods for preparing micron- or submicron-sized particles by dissolving or dispersing an active agent and one or more excipients in one or more solvents. The methods also provide methods for preparing micron- or submicron-sized particles in which the active agent is dispersed within a range of about 50, 100, 150, 200, 250, 300, 400, or even 500 cm. -1 and contacting or dispersing the droplets on a frozen surface having a temperature difference of at least 30°C between the droplets and the surface, the surface freezing, contacting or dispersing the droplets into a thin film and surface area less than 500 μm thick, the surface area to volume ratio being about 25 to about 500 cm. -1 The range is.

[0146] In one embodiment, the method further comprises removing the solvent from the frozen material to form particles. In one embodiment, the droplets freeze upon contact with the surface in about 50, 75, 100, 125, 150, 175, 200, 250, 500, 1,000, and 2,000 milliseconds. In another aspect, the droplets freeze upon contact with the surface in about 50 and 150 milliseconds. In another aspect, the droplets have a diameter of 2-5 mm at room temperature. In another aspect, the droplets form a thin film on the surface with a thickness of 50-500 μm. In another aspect, the cooling rate of the droplets is 50-250 μm. o In another embodiment, the particles after solvent removal are 10, 15, 25, 50, 75, 100, 125, 150, or 200 mm 2 / gr surface area.

[0147] Another embodiment of the invention includes a method for preparing micron- or submicron-sized solvent particles, the method comprising spraying or dripping droplets of an active agent and optionally one or more excipients into an aqueous or organic solvent(s), the droplets being dispersed in a solution having a volume of less than 50 cm. -1 The method also includes contacting the droplet with a frozen surface having a temperature difference of at least 30°C between the droplet and the surface, and the droplet is exposed to a liquid-air interface having a thickness of less than 500 μm and a surface area to volume ratio of 25 to 500 cm. -1 The method may further include removing the solvent from the frozen material to form particles.

[0148] In one embodiment, the invention includes a formulation comprising particles prepared using a cryogenic freezing system that includes spraying or dripping droplets of an active agent and one or more excipients into a solvent(s), resulting in micron or submicron sized solvent particles (e.g., active agent). -1 The method also includes contacting the droplet with a frozen surface having a temperature difference of at least 30°C between the droplet and the surface, and the droplet has a thickness of less than 500 μm and a surface area to volume ratio of 25 to 500 cm. -1 The liquid freezes into a thin film.

[0149] Yet another embodiment includes compositions and methods for preparing micron or submicron sized particles by preparing an emulsion containing a water soluble active agent in solution. -1 The method includes spraying or dripping droplets of the solution such that they are exposed to an air-liquid interface of less than an area / volume, and contacting the droplets with a freezing surface having a temperature difference of at least 30oC between the droplets and the surface, where the surface freezes the droplets into a thin film less than 500μm thick and with a surface area to volume ratio of 25-500cm-1.

[0150] Yet another embodiment includes a system for preparing solvent nanoparticles and solvent microparticles, comprising a solvent source comprised of one or more solvents. Also included is a vessel for storing a cryogenic liquid selected from the group consisting of carbon dioxide, nitrogen, ethane, propane, helium, argon, or isopentane, and an insulated nozzle having an end and a tip, the end of the nozzle being connected to the solvent source and the tip being positioned above and below the level of the cryogenic liquid. In one aspect, the solution source further comprises water, at least one organic solvent, or a combination thereof. In one aspect, the organic solvent is selected from the group consisting of ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, tert-butyl alcohol, dimethyl sulfoxide, N,N-dimethylformamide, diethyl ether, methylene chloride, ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, toluene, hexane, heptane, pentane, and combinations thereof.

[0151] In another embodiment, the method of spray freezing includes spraying a solvent containing an active agent through an insulated nozzle, where the spray rapidly produces frozen solvent particles having a size range of 1 nm to 10 microns. In one aspect, the solvent particles produced have a particle size of less than 10 microns. In another aspect, the solvent particles are produced in a size range of less than 50 nm. 2 / g or greater surface area. In one embodiment, the cryogenic material is a liquid, gas, solid, or surface. In another embodiment, the one or more solvents include a first solvent that is less volatile than a second solvent, and the more volatile solvent is removed but not the second solvent. In yet another embodiment, the one or more solvents include a first solvent that is less volatile than a second solvent, and the more volatile solvent is removed by evaporation, sublimation, freeze drying, vacuum, heat, or chemically.

[0152] Yet another embodiment of the present invention includes a single step, single vial method for preparing micron or submicron sized particles by lowering the temperature of the vial, wherein the vial has a temperature difference of at least 30°C between the solvent and the vial. -1The method includes spraying or dripping droplets of an active agent and one or more excipients dissolved or dispersed in a solvent(s) directly onto the vial such that the droplets are exposed to an air-liquid interface of less than 500 μm in thickness and 25-500 cm in surface area to volume. -1 The droplets may freeze in about 50, 75, 100, 125, 150, 175, 200, 250, 500, 1,000, and 2,000 milliseconds upon contact with the surface, and may even freeze in about 50, 150-500 milliseconds upon contact with the surface. In one embodiment, the droplets have a diameter between 0.1-5 mm at room temperature, or even between 2-4 mm at room temperature. In another embodiment, the droplets form a thin film on the surface that is 50-500 μm thick. In one specific embodiment, the droplets form a thin film that is between about 50 and about 250 μm thick. o The vial has a cooling rate of 10 ...

[0153] The ability to generate stable submicron- and micron-sized protein particles with high surface area would create new possibilities for oral, depot, pulmonary, injectable, and transdermal delivery applications. In pulmonary delivery, high surface area porous particles with aerodynamic diameters of about 1 to about 3 μm can be deposited more efficiently in the deep lung compared to dense particles with similar aerodynamic diameters. In depot delivery, submicron active agent particles of about 300 to about 500 nm have been uniformly encapsulated in microparticles with diameters of about 10 to about 50 μm, achieving high loadings.

[0154] Compositions of the Invention Pharmaceutically acceptable carriers can be used with any active agent, and can include any solvent. The use of such media and agents for pharmaceutical active substances is well known in the art. Auxiliary active ingredients can also be incorporated into the composition.

[0155] In certain embodiments, the pharmaceutical composition may contain, for example, at least about 0.1% of the active agent. In other embodiments, the active agent may comprise from about 0.1% to about 99.9% of the total weight of the composition, depending on the product. In various embodiments, the percentage (w / w) of the active agent in the composition is about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9%.

[0156] In other non-limiting examples, the dosage can also be about 1 microgram / kg / body weight, about 5 micrograms / kg / body weight, about 10 micrograms / kg / body weight, about 50 micrograms / kg / body weight, 100 micrograms / kg / body weight, about 200 micrograms / kg / body weight, about 350 micrograms / kg / body weight, about 500 micrograms / kg / body weight, about 1 milligram / kg / body weight, about 5 milligrams / kg / body weight, about 10 milligrams / kg / body weight, about 50 milligrams / kg / body weight, about 100 milligrams / kg / body weight, about 200 milligrams / kg / body weight, about 350 milligrams / kg / body weight, about 500 milligrams / kg / body weight, about 1000 mg / kg / body weight or more per administration, and can include any range derivable therein. Non-limiting examples of ranges derivable from the numbers recited herein include ranges of about 5 mg / kg / body weight to about 100 mg / kg / body weight, about 5 μg / kg / body weight to about 500 mg / kg / body weight, etc.

[0157] The active agent may be used in a variety of application methods, including oral delivery as tablets, capsules or suspensions. This includes pulmonary and nasal delivery, topical delivery as emulsions, ointments, or creams, and parenteral delivery as suspensions, solutions, microemulsions, or depots. The resulting powder may be redispersed at a convenient time in saline, buffered saline, water, buffered aqueous media, amino acid solutions, vitamin solutions, carbohydrate solutions, and the like, as well as combinations of any two or more thereof, to obtain a suspension that can be administered to a mammal.

[0158] The solvent may be an aqueous solvent such as water, one or more organic solvents, or a combination thereof. When used, the organic solvent may be water-miscible or water-immiscible. Suitable organic solvents include, but are not limited to, ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, tert-butyl alcohol, dimethyl sulfoxide, N,N-dimethylformamide, diethyl ether, methylene chloride, ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, toluene, hexane, heptane, pentane, and combinations thereof.

[0159] Excipients and adjuvants may be used in the present invention, but may have some activity in their own right, for example, antioxidants are generally defined in this application as compounds that improve the efficiency and / or effectiveness of an active agent. It is also possible to have multiple active agents in a given solution, such that the particles formed contain multiple active agents.

[0160] As mentioned, excipients and auxiliary agents may be used to enhance the efficacy and efficiency of the active agent. Non-limiting examples of auxiliary agents that may be included in the solution containing the active agent that is dropped or dispersed according to the present invention include, but are not limited to, cryoprotectants, lyoprotectants, surfactants, bulking agents, stabilizers, polymers, protease inhibitors, antioxidants, and absorption enhancers. Excipients may be selected to modify the intended function of the active agent by improving flux or bioavailability, or to control or delay the release of the active agent. Specific non-limiting examples include sucrose, trehalose, Span 80, Tween 80, Brij 35, Brij 98, Pluronic, Sucroester 7, Sucroester 11, Sucroester 15, Sodium Lauryl Sulfate, Oleic Acid, Laureth-9, Laureth-8, Lauric Acid, Vitamin E TPGS, Gelucire 50 / 13, Gelucire 53 / 10, Labrafil, Dipalmitoylphosphatidylcholine, Glycolic Acid and its Salts, Deoxycholic Acid and its Salts, Sodium Fusidate, Cyclodextrin, Polyethylene Glycol, Labrasol, Polyvinyl Alcohol, Polyvinylpyrrolidone, and Tyloxapol. The process of the present invention can be used to modify the morphology of active agents, resulting in highly porous microparticles and nanoparticles.

[0161] In certain embodiments, the present invention demonstrates a novel method for producing stable submicron particles. The thin film freezing method involves droplets typically falling from a given height and impacting, spreading, and freezing on a cooled solid substrate. In various embodiments, the droplets fall from a given height and are cooled to approximately -50°C.o C, -70 o C, -90 o C, -110 o C, -130 o C, or about -150 o C. Typically, the size of the fully frozen droplets is about 10 mm in diameter and about 200 μm in height. In various embodiments, the rotating surface of the cryogenic cylinder (106) rotates at a speed of about 3 revolutions per minute (rpm), 5 rpm, 6 rpm, 7 rpm, 8 rpm, 9 rpm, 10 rpm, 11 rpm, 12 rpm, 13 rpm, 14 rpm, 15 rpm, 16 rpm, 17 rpm, 18 rpm, 19 rpm, 20 rpm, 25 rpm, or 30 rpm.

[0162] As will be apparent to those skilled in the art, the droplets can be delivered to the cold or frozen surface in a variety of ways and configurations. For example, to provide high throughput capabilities, the droplets can be delivered parallel, continuous, central, intermediate, or peripherally onto a platen, platter, plate, roller, or conveyor surface. The frozen or frozen surface can be a roller, belt, solid surface, circular, cylindrical, conical, elliptical, etc. that freezes the droplets. In a continuous process, a belt, platen, plate, or roller can be particularly useful. In operation, the frozen droplets can form beads, strings, films, or lines of frozen substrate and activator that are removed from the surface using a scraper, wire, ultrasonic, or other mechanical separator prior to the freeze-drying process. Once material is removed from the surface of the belt, platen, roller, or plate, the surface is free to accept additional material in a continuous process.

[0163] After the frozen particles are scraped from the cryogenic cylinder and collected, the solvent can be removed by sublimation to provide the final particles.

[0164] Delivery of the final particles can be accomplished by any suitable delivery means. For example, for inhalation delivery, this can include a nebulizer, dry powder inhaler, or metered dose inhaler. The most suitable delivery means will depend on the active agent to be delivered, the desired effective amount of that active agent, and the unique characteristics of a given patient. EXAMPLES

[0165] Example 1

[0166] Exemplary embodiments of the thin film freezing (TFF) method

[0167] An aqueous solution of the active agent is passed at a flow rate of 4 mL / min through a 17-gauge (1.1 mm ID, 1.5 mm OD) stainless steel needle producing droplets of 3.6 mm diameter, or a 3.9 mm ID, 6.4 mm OD stainless steel tube producing droplets of 5.6 mm diameter. The droplets are dropped from a height of 10 cm above a rotating stainless steel drum that is 17 cm long and 12 cm in diameter. The stainless steel drum is hollow and has walls 0.7 cm thick. It is filled with dry ice or liquid nitrogen to maintain the drum surface temperature at approximately -90 °C, respectively. o C or -110 o The drum is maintained at 25° C. Before each run, the surface temperature of the drum is checked using a DiGi-Sense® Type K thermometer with a surface probe thermocouple attachment at a 45° angle (Eutech Instruments). The drum rotates at approximately 12-20 rpm and is powered by a Heidolph RZR2041 mechanical overhead stirrer (ESSLAB) connected to a gear reducer. Upon impact, the droplets transform into a thin film and freeze. The frozen thin film is removed from the drum by a stainless steel blade mounted along the rotating drum surface. The frozen thin film is then placed 5 cm into a 400 mL Pyrex® beaker filled with liquid nitrogen.

[0168] Drying and Shelving

[0169] The frozen slurry is dried using a Virtis Advantage freeze dryer (The Virtis Company, Inc.). The 400 mL beaker containing the frozen slurry is covered with a single layer of Kimwipes. Primary drying was performed at -40oC for 36 hours at 300 mTorr, and secondary drying was performed at 25oC for 24 hours at 100 mTorr. A linear ramp was used with a shelf temperature from -40oC to +25oC at 100 mTorr for 12 hours.

[0170] Transfer and storage of dry powders After the freeze-drying cycle was completed, the freeze-dryer was purged with nitrogen when the vacuum was released to reduce the time the powder was exposed to water vapor in the ambient air before transfer. The samples were then quickly transferred to a dry box maintained at 14% RH, and the powder was transferred to 20 mL scintillation vials. Each vial was then covered with a 24 mm Teflon® faced silicone septum (Wheaton) and held in place by an open-top screw-cap lid. The vials were purged with dry nitrogen for 2 minutes through a needle piercing the septum and an additional needle for gas evacuation.

[0171] surface area measurement

[0172] The surface area of ​​the dry powder is measured with a Quantachrome Nova 2000 (Quantachrome) BET instrument. The dry powder is transferred to a glass BET sample cell in a dry box. The sample is then degassed under vacuum for a minimum of 12 hours. Particle size analysis.

[0173] Example 2

[0174] Formulation of API

[0175] 500 g of Active Pharmaceutical Ingredient A is dissolved in 6.84 kg of acetonitrile in a 10 L stainless steel vessel under vortex mixing. 30 g of Excipient B is dissolved in 8.8 kg of water for injection in a second 10 L stainless steel vessel under vortex mixing. The contents of SS Vessel #1 and SS Vessel #2 are then transferred to a 20 L SS nitrogen blanketed and ground vessel and mixed uniformly using an integrated overhead vessel mixer.

[0176] Continuous thin film freezing

[0177] This API / excipient mixture, dissolved in a water-acetonitrile solvent mixture, is then pumped at a flow rate of 50 ml / min through the tubing orifices of a manifold with an internal diameter of 0.838 mm, which produces a continuous stream of discrete droplets (3-5 mm in diameter) each. The tubing manifold is positioned directly above the rotating freezing cylinder assembly, with a distance of 8 cm between the cylinder surface and the outlet of the manifold orifice.

[0178] These droplets continuously drop and rapidly freeze upon contact with the cryogenically cooled surface of the rotating freezing cylinder assembly. The cylinder rotates at 20 RPM, causing the frozen droplets to be continuously removed by a stationary scraper blade assembly and dropped onto a cooled collection tray. This also ensures that a continuously regenerated fresh freezing surface is available for the droplets of continuously produced formulations.

[0179] The surface of the freezer cylinder assembly is maintained at -130°C ± 20°C during the entire production run by controlling the supply of cryogenic liquid to the drum using a direct contact thermocouple probe based on real-time surface temperature readings using a DiGi-Sense® Type K thermometer.

[0180] Freeze drying

[0181] Once the entire batch is frozen and collected in trays, the trays are then loaded into a 15-tray Virtis Ultra freeze dryer that is pre-chilled to a shelf temperature of -60oC. Once all trays are loaded, the freeze dryer is pumped down to 100mTorr and held for 300 minutes. Primary drying then occurs at -40oC for 1200 minutes and secondary drying at 25oC for 2400 minutes. After drying is complete, the TFF processed bulk API and excipient powders are transferred from the trays to the appropriate secondary bulk containers for further processing and final packaging.

[0182] surface area measurement

[0183] The surface area of ​​the dry powder is measured with a Quantachrome Nova 2000 (Quantachrome) BET instrument. The dry powder is transferred to a glass BET sample cell in a dry box. The sample is then degassed under vacuum for a minimum of 12 hours before analysis.

[0184] Particle size analysis

[0185] Size distribution of dry powders is measured by multi-angle laser light scattering using a Malvern Mastersizer-S (Malvern Instruments). A mass of 30-100 mg of powder is suspended in 10 mL of acetonitrile, and the suspension is then sonicated for 1 min on ice using a Branson Sonifier 450 (Branson Ultrasonics) equipped with a 102 converter and tip operating in pulsed mode at 35 W. Typical light blocking values ​​ranged from 11% to 13%. An aliquot of the sonicated suspension was then dispensed into a 500 mL acetonitrile bath for analysis.

[0186] Example 3

[0187] Formulation of API

[0188] 6.0 kg of acetonitrile and 6.0 kg of tert-butanol are first mixed homogeneously in a 20L SS nitrogen blanketed and grounded vessel using an integrated overhead mixer. Next, 20 g of active pharmaceutical ingredient C is dissolved in this acetonitrile / tert-butanol solvent system under vortex mixing conditions. Finally, 750 grams of excipient D, which is insoluble in acetonitrile / tert-butanol, is then slowly added to the same 20L vessel under slight vortex conditions to produce a well-mixed slurry. A slight vortex is maintained throughout the TFF processing of this material to ensure that a homogenous slurry exists while minimizing attrition of the slurry particles over time.

[0189] Continuous thin film freezing

[0190] This API / excipient slurry dispersed in acetonitrile / tert-butanol solvent is then pumped at a flow rate of 50 ml / min through the tubing orifices of a manifold with an internal diameter of 0.838 mm, each producing a continuous stream of discrete droplets (3-5 mm in diameter). The tubing manifold is positioned directly above the rotating freezing cylinder assembly, with a distance of 8 cm between the cylinder surface and the outlet of the manifold orifice.

[0191] These droplets continuously drop and rapidly freeze upon contact with the cryogenically cooled surface of the rotating freezing cylinder assembly. The cylinder rotates at 20 RPM, causing the frozen droplets to be continuously removed by a stationary scraper blade assembly and dropped onto a cooled collection tray. This also ensures that a continuously regenerated fresh freezing surface is available for the droplets of continuously produced formulations.

[0192] The surface of the freezer cylinder assembly is maintained at -130°C ± 20°C during the entire production run by controlling the supply of cryogenic liquid to the drum using a direct contact thermocouple probe based on real-time surface temperature readings using a DiGi-Sense® Type K thermometer.

[0193] Freeze drying

[0194] Once the entire batch is frozen and collected in trays, the trays are then loaded into a 15-tray Virtis Ultra freeze dryer that is pre-chilled to a shelf temperature of -60oC. Once all trays are loaded, the freeze dryer is pumped down to 100mTorr and held for 300 minutes. Primary drying then occurs at -40oC for 1200 minutes and secondary drying at 25oC for 2400 minutes. After drying is complete, the TFF processed bulk API and excipient powders are transferred from the trays to the appropriate secondary bulk containers for further processing and final packaging.

[0195] surface area measurement

[0196] The surface area of ​​the dry powder is measured with a Quantachrome Nova 2000 (Quantachrome) BET instrument. The dry powder is transferred to a glass BET sample cell in a dry box. The sample is then degassed under vacuum for a minimum of 12 hours before analysis.

[0197] Particle size analysis

[0198] Size distribution of dry powders is measured by multi-angle laser light scattering using a Malvern Mastersizer-S (Malvern Instruments). A mass of 30-100 mg of powder is suspended in 10 mL of acetonitrile, and the suspension is then sonicated for 1 min on ice using a Branson Sonifier 450 (Branson Ultrasonics) equipped with a 102 converter and tip operating in pulsed mode at 35 W. Typical light blocking values ​​ranged from 11% to 13%. An aliquot of the sonicated suspension was then dispensed into a 500 mL acetonitrile bath for analysis.

[0199] Although the invention has been specifically described with respect to the separation and capture of carbon dioxide, it should be understood that the invention may readily be used to separate other gases.

[0200] Although prior art and literature may be referenced in this specification, it will be understood that such reference does not constitute an acknowledgement that these are part of the general knowledge in the art in Australia or anywhere else.

[0201] Numerous variations and modifications, in addition to those already described, will suggest themselves to those skilled in the relevant art without departing from the basic inventive concept. All such variations and modifications are to be considered within the scope of the present invention, the nature of which is to be determined from the foregoing description.

Claims

1. 1. A system for thin film freezing of an active agent or composition, comprising: (i) a freeze roller drum assembly comprising: (1) a freezing cylinder assembly; (2) a scraper assembly; and (3) a frame assembly; and (4) a motor assembly; and (5) a manifold assembly; The freezing cylinder assembly is o The system includes the freeze roller drum assembly, the freeze roller drum assembly being maintained at a temperature below 100°C.

2. The system of claim 1 , further comprising a shroud covering at least a portion of each of the assemblies (1)-(5).

3. The system of claim 2 , wherein at least a portion of the shroud is a double window shroud.

4. The system of claim 1 , further comprising at least one gas plenum that allows a cryogenic liquid, a cryogenic gas, or a heat transfer fluid to circulate within the system.

5. The cryogenic source may be a cryogenic solid, a cryogenic gas, a cryogenic liquid, or a cryogenic o 13. The system of claim 1, wherein the heat transfer fluid is capable of maintaining a temperature below 13.degree.

6. The system of claim 4 , further comprising a filter or filtration system that filters the cryogenic source entering the shroud to reduce or eliminate viable and non-viable particulates entering the system.

7. The cryogenic solid, the cryogenic gas, the cryogenic liquid, or the heat transfer fluid is at a temperature of -50 o 13. The system of claim 1, capable of maintaining a temperature below 13.degree.

8. Cryogenic gas contacts the freezing cylinder assembly to o 13. The system of claim 1, wherein the system maintains a temperature below 13.degree.

9. Cryogenic liquid contacts the freeze cylinder assembly to a temperature of -50 o 13. The system of claim 1, wherein the system maintains a temperature below 13.degree.

10. Temperature -50 o 10. The system of claim 1 further comprising a heat exchanger for maintaining a temperature below C.

11. The system of claim 4 , wherein the cryogenic liquid is an inert liquefied gas.

12. 12. The system of claim 11, wherein the inert liquefied gas is liquefied helium, liquefied nitrogen, or liquefied argon, or a combination thereof.

13. The system of claim 5 , wherein the cryogenic source is dry ice.

14. The system of claim 1 , wherein the active agent or composition comprises a small molecule active agent or a bioactive agent.

15. 1. A system for thin film freezing of an active agent or composition, comprising: (i) a freeze roller drum assembly comprising: (1) a freezing cylinder assembly; (2) a scraper assembly; and (3) a frame assembly; and (4) a motor assembly; and (5) a manifold assembly; (6) a shroud covering at least a portion of each of the assemblies (1)-(5); The freezing cylinder assembly is o said system including said freezing roller drum assembly being maintained at a temperature below 100°C.

16. The system of claim 15 , wherein at least a portion of the shroud is a double window shroud.

17. The freezing cylinder assembly is cooled to -50 °C using a cryogenic source. o 16. The system of claim 15, wherein the temperature is maintained at less than C.

18. 20. The system of claim 17, further comprising at least one gas plenum that allows a cryogenic source to circulate within the system.

19. 20. The system of claim 17, wherein the cryogenic source is a cryogenic solid, a cryogenic gas, a cryogenic liquid, or a heat transfer fluid capable of maintaining a cryogenic temperature.

20. A cryogenic source contacts the freezing cylinder assembly and maintains a temperature of -50 o 20. The system of claim 19, wherein the system maintains a temperature below C.

21. Cryogenic liquid contacts the freeze cylinder assembly to a temperature of -50 o 16. The system of claim 15, wherein the system maintains a temperature below C.

22. 22. The system of claim 21, wherein the cryogenic liquid is an inert liquefied gas.

23. 23. The system of claim 22, wherein the inert liquefied gas is liquefied helium, liquefied nitrogen, or liquefied argon.

24. 20. The system of claim 19, wherein the cryogenic source is dry ice.

25. 1. A method for thin film freezing of an active agent or composition, comprising: (a) utilizing the system of claim 1 or claim 15, the method comprising: (i) cooling the surface of the freezing cylinder assembly to a temperature below −50° C.; (ii) dissolving or dispersing an active agent or composition in a liquid carrier to form an intermediate liquid mixture; (iii) contacting the intermediate liquid mixture containing the active agent or composition with the freezing cylinder assembly to freeze the intermediate mixture.

26. 26. The method of claim 25, wherein the surface of the freezing cylinder is cooled using a cryogenic source.

27. The cryogenic source may be a cryogenic solid, a cryogenic gas, a cryogenic liquid, or a cryogenic o 27. The method of claim 26, wherein the heat transfer fluid is capable of maintaining a temperature below C.

28. 26. The method of claim 25, wherein the system further comprises at least one gas plenum for circulating a cryogenic liquid, a cryogenic gas, or a heat transfer fluid within the system.

29. 30. The method of claim 28, wherein the system further comprises a filter or filtration system that filters the cryogenic source entering the shroud to reduce or remove viable and non-viable particulates from entering the system.

30. The cryogenic solid, the cryogenic gas, the cryogenic liquid, or the heat transfer fluid is at a temperature of -50 o 30. The method of claim 28, wherein the temperature can be maintained below C.

31. 31. The method of claim 30, wherein a cryogenic liquid contacts the freeze cylinder assembly.

32. 32. The method of claim 31 , wherein the cryogenic liquid is an inert liquefied gas.

33. 33. The method of claim 32, wherein the inert liquefied gas is liquefied helium, liquefied nitrogen, or liquefied argon.

34. 31. The method of claim 30, wherein the cryogenic solid is dry ice.

35. 26. The method of claim 25, wherein the liquid carrier is water, an alcohol, an ether, a halocarbon, a hydrocarbon, a halogenated hydrocarbon, an aromatic hydrocarbon, an ester, an acetate, an organic acid, an amine, a ketone, a sulfone, a nitrile, a carbonate, or a combination thereof.

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