Method and system for spray drying temperature-sensitive products

Abstract

Systems and methods for vacuum spray drying are provided. In one embodiment, the method for spray drying includes estimating an outlet temperature to achieve a minimum drying rate at atmospheric pressure based on a selected liquid feed and a selected liquid-to-gas ratio, calculating a predicted dryer pressure at which the minimum drying rate can be reached at a reduced outlet temperature, and spray drying the selected liquid feed at the selected liquid-to-gas ratio, the predicted dryer pressure, and the reduced outlet temperature. The reduced outlet temperature is less than the maximum temperature, and the predicted dryer pressure comprises an approximation of droplet solidification.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 385,928, entitled "METHODS AND SYSTEMS FOR SPRAY DRYING TEMPERATURE SENSITIVE PRODUCTS," filed December 2, 2022. The entire contents of the above-identified application are incorporated herein by reference for all purposes.

[0002] This specification relates generally to spray drying of temperature sensitive products under vacuum conditions. [Background technology]

[0003] Spray drying is a commonly used technique in pharmaceutical manufacturing. It involves introducing microdroplets of a suspension or solution into a drying chamber and allowing them to interact with a hot gas stream. Energy from the hot gas vaporizes the liquid phase of the suspension or solution, leaving behind solid particles. While spray drying is often performed at atmospheric pressure, some situations require vacuum spray drying (VSD), in which the pressure in the drying chamber is maintained below atmospheric pressure. For example, the product being dried may be heat-sensitive. Reducing the pressure in the drying chamber increases the mass flux from the gas-liquid interface at a constant temperature. Compared to atmospheric drying processes, the drying temperature in VSD processes can be lowered while achieving the same drying rate. As another example, the liquid phase may contain a high-boiling point solvent, such as dimethyl sulfoxide (DMSO), in which case reduced pressure may be required to efficiently remove the liquid phase. However, under vacuum conditions, the efficiency of heat transfer from the heated gas to the droplets decreases, which can reduce the drying rate and maximum throughput when using VSD.

[0004] Other attempts to address low throughput include modifying VSD systems to enhance heat transfer. An example of this approach is shown in U.S. Patent No. 8,966,783, where high throughput is achieved by providing a superheated fluid in immediate contact with droplets of suspension / solution introduced into a vacuum environment. Summary of the Invention [Problem to be solved by the invention]

[0005] However, the inventors of the present application have recognized several potential challenges with such systems. As one example, even the low boiling points achieved by such systems may be too hot for some temperature-sensitive pharmaceutical products. If reducing the drying chamber pressure is the only mechanism used to reduce the temperature to which the product is exposed, the size of the vacuum pump required for the throughput used in manufacturing may become impractically large. [Means for solving the problem]

[0006] In one example, the above problem can be at least partially addressed by a spray drying method that includes estimating an outlet temperature to achieve a minimum drying rate at atmospheric pressure based on a selected liquid feed and liquid-to-gas ratio; calculating a predicted dryer pressure at which the minimum drying rate can be reached at a reduced outlet temperature, where the reduced outlet temperature is less than the maximum temperature and the predicted dryer pressure includes an approximation of droplet solidification; and spray drying the selected liquid feed at the selected liquid-to-gas ratio, predicted dryer pressure, and reduced outlet temperature. In this manner, the product can be dried at a temperature where product degradation does not occur. Furthermore, process conditions at which the drying rate can be sufficient when using conventionally sized spray drying equipment can be identified. Furthermore, if the drying rate is determined to be insufficient, modifications to conventional spray drying systems, including extending the spray dryer, can be used. Furthermore, in examples where vacuum conditions are required within the spray drying system, an improved cyclone design can be used to reduce the chamber pressure achieved for a given vacuum pump power.

[0007] It should be understood that the foregoing summary is provided to introduce a selection of concepts in a simplified form that are further described in the detailed description. It is not intended to identify key or essential features of the claimed subject matter, the scope of which is defined uniquely by the claims that follow the detailed description. Moreover, the claimed subject matter is not limited to implementations that solve any disadvantages noted above or in any part of this disclosure. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 shows a block diagram of the workflow for spray drying compounds under reduced pressure. [Figure 2] FIG. 1 shows an illustration of droplets over time in a spray drying process. [Figure 3] 1 is a graph showing relative drying rate as a function of drying chamber outlet temperature calculated for a range of drying chamber pressures. [Figure 4A]1 shows a flow chart of an example method for determining the drying chamber outlet temperature and drying chamber pressure. [Figure 4B] 4B shows a continuation of the flowchart of the method shown in FIG. 4A. [Figure 5] An example of a co-current vacuum spray drying system is shown. [Figure 6] An example of a countercurrent vacuum spray drying system is shown. [Figure 7] 1 is a graph showing pressure drop as a function of gas flow rate for a 2-inch diameter cyclone. [Figure 8] 1 is a graph showing pressure drop as a function of gas flow rate for a 3-inch diameter cyclone. DETAILED DESCRIPTION OF THE INVENTION

[0009] The following description relates to systems and methods for spray drying temperature-sensitive products. In one example, a vacuum spray drying (VSD) system, such as the system shown schematically in FIG. 1, can be used to spray dry temperature-sensitive products. Reducing the pressure in the drying chamber of the VSD can potentially achieve acceptable drying rates at lower temperatures. A desired chamber pressure and spray dryer configuration that allows drying below a selected maximum temperature can be selected based on a droplet liquid evaporation model, as shown in FIG. 2. Using a set of reference conditions (e.g., chamber pressure, outlet temperature, and liquid-to-gas ratio), a graph of relative drying rate as a function of outlet temperature for a range of chamber pressures can be plotted, as shown in FIG. 3. As an example, the chamber pressure corresponding to a desired minimum relative drying rate (e.g., 1) and a desired outlet temperature can be calculated according to the method shown as a flowchart in FIGS. 4A and 4B. In some examples, the desired minimum rate may depend on the VSD configuration, including the drying chamber height, the liquid and gas feed configuration, and the cyclone size. An example of a VSD with co-current liquid and gas feed configuration is shown in Figure 5, and an example of a VSD with counter-current liquid and gas feed configuration is shown in Figure 6. Cyclone size can affect the minimum pressure of a VSD system because the pressure drop across the cyclone increases as the cyclone dimensions decrease. Increasing the cyclone size can decrease the minimum VSD pressure, while decreasing the cyclone size can increase the minimum VSD pressure. As an example, pressure drop as a function of gas flow rate is shown in Figures 7 and 8 for a 2-inch diameter cyclone and a 3-inch diameter cyclone, respectively.

[0010] Referring now to FIG. 1 , a schematic diagram of a vacuum spray drying (VSD) system 100 is shown. The VSD system 100 may include a drying chamber 106. The drying chamber 106 may be configured to receive a heated gas 102 and a liquid feed 104. In some examples, the drying chamber 106 may be a jacketed drying chamber including a jacket layer 107 fluidly coupled to a temperature-controlled chamber 109. By setting the temperature of the temperature-controlled chamber 109, a user can actively control the temperature of the drying chamber 106. Under vacuum conditions, the heated gas 102 may be flowed at a lower mass flow rate compared to conventional (e.g., atmospheric) spray drying. A lower mass flow rate may increase the impact of heat exchange with the environment on the operating temperature (e.g., outlet temperature) of the drying chamber 106. The jacket layer 107 and temperature-controlled chamber 109 insulate the drying chamber from heat exchange with the environment, potentially increasing the accuracy of controlling the operating temperature of the drying chamber 106. Additionally, the jacket layer 107 and temperature controlled chamber 109 may allow for spray drying at temperatures below ambient room temperature.

[0011] The liquid supply 104 may be a suspension or solution containing a liquid phase and a product either suspended or dissolved in the liquid phase. The VSD system 100 may be configured to dry products that are sensitive to high temperatures. As an example, the product may be an active pharmaceutical ingredient (API) in a pharmaceutical formulation. The pharmaceutical formulation may include an API and other excipients. As an example, the API may be a protein with pharmacological activity (e.g., an antibody, enzyme, bacteriophage, cytokine, hormone, etc.). In some examples, the product may be a model compound used as a surrogate for the API. This model compound may be useful for testing drying methods before drying more expensive APIs. Model compounds may include bovine serum albumin (BSA), model antibodies, and lysozyme, among others. Certain secondary, tertiary, and quaternary structures may be required for a protein to have pharmacological activity. High temperatures can damage protein structure, rendering them inactive. As another example, the API may include nucleic acids such as DNA or RNA. Types of RNA include, but are not limited to, messenger RNA (mRNA), transfer RNA (tRNA), and / or small interfering RNA (siRNA). High temperatures can increase the rate of hydrolysis, thereby degrading nucleic acids. As a further example, the API can be self-assembled nanoparticles encapsulating a pharmaceutical compound. The self-assembled nanoparticles can be formed from biologically compatible molecules suitable for pharmaceutical formulation. For example, the self-assembled nanoparticles can be formed from lipids, block copolymers, amphiphilic polymers (e.g., hypromellose acetate succinate), etc. In some examples, the self-assembled nanoparticles may not be APIs but may be carriers of APIs. For example, the self-assembled nanoparticles can form hollow shells encapsulating the API. For example, lipid nanoparticles encapsulating RNA fragments can be spray-dried. The structure of the self-assembled nanoparticles can be altered by high heat, potentially exposing and degrading the encapsulated pharmaceutical compound during drying. As an additional example, the product can be an amorphous solid dispersion of a small molecule API. As an example, a small molecule can be between 100 Da and 2,000 Da.Exposure to high temperatures can cause crystallization of the API, reducing its efficacy.

[0012] The liquid phase may be water or a highly volatile organic solvent (e.g., acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, etc., or some combination thereof) having a boiling point of 100°C or less at standard pressure. As an example, the liquid phase may be 100% water. Alternatively, the liquid phase may be 50% to 100% water by weight and 50% or less organic solvent by weight. As a further example, the liquid phase may comprise 5% to 100% low-volatility organic solvent. The low-volatility organic solvent may be an organic solvent having a boiling point above 150°C at standard pressure (e.g., 1 atm), such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or N,N-dimethylacetamide (DMAC). The remainder of the liquid phase may be composed of a miscible cosolvent, which may be water or a highly volatile organic solvent.

[0013] The heating gas 102 may be, for example, air or nitrogen. Nitrogen may be used as the heating gas 102 if the product is susceptible to oxidation or if the liquid phase is flammable. The heating gas 102 and liquid feed 104 may be introduced into the drying chamber 106. The liquid feed 104 may enter the drying chamber 106 through an atomizer 105. The atomizer 105 may be configured to disperse the liquid feed 104 into small droplets, thereby maximizing the amount of liquid surface area exposed to the heating gas 102. As an example, the atomizer 105 may be configured for two-fluid atomization. Other atomizer configurations, including, but not limited to, pressure atomization and rotary atomization, are also contemplated within the scope of the present disclosure. The liquid feed 104 and heating gas 102 may enter the drying chamber 106 in a variety of configurations. In one embodiment, the heating gas 102 and liquid feed 104 may both enter the drying chamber 106 at the top in a co-flow configuration. Further details regarding VSD systems in a co-current configuration are provided below with reference to Figure 5. In an alternative embodiment, the liquid feed 104 may enter the drying chamber 106 at the top, while the heated gas 102 may enter the drying chamber 106 at the bottom in a counter-current configuration. Further details regarding VSD systems in a counter-current configuration are provided below with reference to Figure 6.

[0014] The operating parameters of the VSD system 100 can be selected so that interaction of the heated gas 102 and the liquid feed 104 with the atomized droplets evaporates the liquid phase by the time the atomized droplets exit the drying chamber 106. The operating parameters can include the pressure within the drying chamber 106, the temperature at the outlet of the drying chamber 106, the temperature at the inlet of the drying chamber 106, and the ratio of the liquid feed 104 to the heated gas 102. In an example where the VSD system 100 is configured for cocurrent spray drying, adjusting the outlet temperature of the drying chamber 106 can have a greater impact on the quality of the dried product than adjusting the inlet temperature of the drying chamber 106. In an example where the VSD system 100 is configured for countercurrent spray drying, adjusting the inlet temperature of the drying chamber 106 can have a greater impact on the quality of the dried product than adjusting the outlet temperature of the drying chamber 106. As further described below with respect to FIGS. 2 and 3, the effect of the operating parameters on the drying rate can be predicted by a model. In this manner, operating parameters can be selected that result in a desired drying rate at a temperature that does not degrade the product. Additionally or alternatively, the model may be used to determine whether changes to the size of the drying chamber 106 are required to obtain a dried product under achievable operating parameters.

[0015] The product may exit the drying chamber 106 and enter the cyclone 108. The cyclone 108 may be configured to separate product particles 110 from the heated gas by vortex separation. The product particles 110 may be collected from an outlet of the cyclone 108. A vacuum 112 may be fluidly connected to the drying chamber 106 through the cyclone 108. In this manner, the vacuum 112 may evacuate the drying chamber 106, thereby reducing the operating pressure within the drying chamber 106. The size of the cyclone 108, which is disposed between the vacuum 112 and the drying chamber 106, may be selected based on the desired operating pressure of the VSD 100. In one example, a larger cyclone 108 may reduce the pressure drop between the inlet of the cyclone 108 and the outlet of the cyclone 108, which may reduce the load on the vacuum 112. The size of the cyclone 108 is described further below.

[0016] Other improvements to VSD systems, such as the VSD100, involve enhancing the transfer of heat from the heated gas to the liquid feed under vacuum conditions to increase throughput. However, in such systems, some products may be exposed to temperatures high enough to degrade the product. Instead, operating conditions and VSD system design may be selected so that the product can be dried at an acceptable rate at temperatures below the boiling point of the liquid phase of the liquid feed. Operating conditions may include drying chamber pressure, outlet temperature, and the ratio of drying gas to liquid feed. VSD system design may include cocurrent or countercurrent flow configuration, drying chamber size, and cyclone size.

[0017] A model of droplet drying within a drying chamber (such as drying chamber 106 of FIG. 1 ) may be shown by diagram 200 in FIG. 2 . Droplet 202 may include liquid feed droplet 204. Liquid feed droplet 204 may be surrounded by heated gas 206. Heat transfer between heated gas 206 and liquid feed droplet 204 may occur at interface 208. In one example, first droplet 202 may be the droplet at the top of the drying chamber at the beginning of the drying process. Arrow 214 may indicate the passage of drying time and the passage of droplet 202 through the drying chamber. After a certain amount of drying time, interface 208 may recede and liquid feed droplet 204 may become smaller. The rate at which interface 208 recede may be referred to as the interfacial velocity and may be proportional to the drying rate. The interfacial velocity is given by Equation 1 below:

number

[0018] The surface temperature of the liquid feed droplet may depend on the physical properties of the liquid phase and the operating parameters of the VSD system. The surface temperature of the liquid feed droplet may be calculated from a mass and energy balance at the interface 208, leading to Equation 2 below:

number

[0019] Equations 1 and 2 may assume that the liquid phase of the liquid feed droplet 204 and the composition of the heated gas 206 are in equilibrium at the interface 208. Furthermore, Equations 1 and 2 assume that the liquid feed droplet is in a pure liquid phase (e.g., no product suspended / dissolved in the liquid phase). If product is present within the liquid feed droplet 204, a shell 212 of product may form on the surface of the liquid feed droplet 204 as the interface 208 recedes. Therefore, Equations 1 and 2 may not be able to predict a priori the drying rate when the liquid feed contains product. However, the outlet temperature (T out ) and the pressure in the drying chamber (e.g., dryer chamber) (P dryer The relative effect on drying rate of adjusting the liquid-to-gas ratio (T) may be the same whether the liquid phase contains product or not. Thus, the operating parameters at reference conditions, including a given liquid-to-gas ratio, that result in the lowest drying rate can be empirically determined and a model including Equations 1 and 2 can be used to calculate T. out YaP dryer A range of tuning conditions can be calculated, including: By calculating parameters for relative velocity change as described above, the model can include an approximation of droplet solidification. In other words, the model accounts for liquid evaporation from the droplet as an approximation of the droplet's drying kinetics. By capturing the droplet's drying kinetics, further approximations for droplet solidification can be made.

[0020] An example of a graph 300 showing relative drying rate as a function of outlet temperature at different pressures is shown in FIG. 3. Graph 300 may correspond to a liquid-gas mass ratio of 0.016, a liquid feed of water, and a desired product concentration. Reference spray drying parameters may be selected that result in a marginally acceptable liquid feed drying rate and liquid-gas mass ratio. For example, at an ambient pressure of 0.9 bar and an outlet temperature of 35° C., a liquid-gas ratio of 0.016 may result in a marginally acceptable drying rate. In one embodiment, the reference spray drying parameters may be selected based on experiments conducted with a short spray dryer. In an alternative embodiment, the reference spray drying parameters may be selected based on prior knowledge of the spray drying process. A marginally acceptable drying rate is the minimum drying rate (R min ), below which the product may not exit the drying chamber as dry particles but may instead adhere to the walls of the drying chamber (e.g., drying chamber 106 in FIG. 1). min may be the rate at which the yield of particles exiting the drying chamber during steady-state continuous operation is equal to or greater than a minimum yield. The minimum yield may depend on the identity and amount of the product. In one embodiment, R min In an alternative embodiment, the yield at R min The yield at may be greater than 70%. A marginally acceptable drying rate may be set at 1.0 on the relative drying rate scale shown on the y-axis of graph 300 and corresponding to line 302.

[0021] Using equations 1 and 2, T at different drying chamber pressures out The relative drying rate as a function of T can be calculated. Plot 304 corresponds to an ambient pressure of 0.9 bar, plot 306 corresponds to a pressure of 0.5 bar, plot 308 corresponds to a pressure of 0.1 bar, and plot 310 corresponds to a pressure of 0.05 bar. As shown in graph 300, as the pressure in the drying chamber decreases, a relative drying rate of 1.0 increases with the decrease in pressure at a lower T. out It may be possible to reach 。 For example, plot 308 shows the Tout shows that a relative drying rate of 1.0 may be achieved at 11°C. The minimum pressure in the dryer chamber may be limited by the size of the pump available. For example, a commercial-scale VSD system may achieve a practical minimum pressure of 0.05 bar in the drying chamber. Thus, T out is the upper temperature threshold of the product (T max ) P dryer can be selected.

[0022] Additionally, a vertical spray dryer or countercurrent spray drying configuration may be used to increase the residence time of the particles in the drying chamber. In this manner, a decrease in the relative drying rate (e.g., less than 1.0) may be marginally acceptable. As an example, the height of the drying chamber may be twice as high as that of a rectangular dryer. As an example, for the same L / G ratio, a relative drying rate of 0.4 (shown by line 312 in graph 300) may be determined to be the minimum drying rate for a vertical spray dryer or a countercurrent spray dryer. If the marginally acceptable relative drying rate is reduced to 0.4, as shown in plot 304, then T out The temperature may be reduced from 35°C to 25°C. However, reconfiguring a spray drying system by increasing the drying chamber height or spray drying in a countercurrent configuration may be practically limited when moving to a commercial-scale VSD system. For this reason, lowering the drying chamber pressure may be preferable to increasing the drying chamber height. In this manner, graph 300 may be used to determine the desired T of the water-liquid phase with a liquid-gas mass ratio of 0.016. out Based on this, the drying chamber pressure and drying chamber height can be selected.

[0023] 5, a schematic diagram of a VSD system 500 in a co-current configuration is shown. The VSD system 500 can include a liquid feed 502 and a heating gas 504. The liquid feed 502 can include a product and a liquid phase and can be similar to the liquid feed 104 in FIG. 1. The heating gas 504 can be nitrogen gas and can be similar to the heating gas 102 in FIG. 1. Gas can be removed from the VSD system 500 by a vacuum pump 524. In one example, P dryer can be controlled by the feed rate of the heated gas 504 into the drying chamber 506. The liquid feed 502 may be atomized using a liquid atomizer or introduced from the top of the drying chamber 506 (e.g., relative to the axis of gravity). Various methods of atomization are contemplated within the scope of the present disclosure and may include conventional pressure atomization, two-fluid atomization, and rotary atomization, as well as other non-conventional atomization methods. The heated gas 504 may also be introduced from the top of the drying chamber 506. The heated gas 504 and the liquid feed 502 may travel in the same direction downward through the drying chamber 506. In this manner, the temperature to which the product is exposed may be minimized. However, the heated gas 504 may drive the product particles toward the bottom of the drying chamber, thus reducing the residence time of the product within the drying chamber 506, thereby reducing R minを T required to achieve out and P dryer In some examples, the VSD system 500 may be configured to include an elongated drying chamber 506 to increase the residence time of the product within the drying chamber 506.

[0024] In some examples, drying chamber 506 may be a jacketed drying chamber including a jacket 507 fluidly coupled to a temperature-controlled chamber 509. Jacket 507 and temperature-controlled chamber 509 may be similar to jacket 107 and temperature-controlled chamber 109 of FIG. 1. A fluid whose temperature is controlled by the temperature-controlled chamber may be circulated through jacket 507 to actively control the temperature of drying chamber 506. In this manner, the effect of environmental temperature on the temperature of drying chamber 506 may be minimized.

[0025] The output of the drying chamber 506 may be fed to the inlet of a cyclone 512. The cyclone 512 may be configured to separate the desired product particles from the exhaust gases and fine dust (e.g., particle diameter less than 5 μm). A product isolation valve 508 may be disposed between the outlet of the lower part of the cyclone 512 and a removable product collection chamber 510. When the product isolation valve 508 is in the open position, the desired product particles may flow into the removable product collection chamber 510, and both the cyclone 512 and the removable product collection chamber 510 may be under vacuum. When the product isolation valve 508 is in the closed position, the removable product collection chamber 510 may be vented to atmospheric pressure and emptied while the cyclone 512 is under vacuum. In this manner, product may be collected without shutting down or de-vacuuming the remaining components of the VSD system 500.

[0026] The fine dust and exhaust gas exit through the top of cyclone 512 and pass through filter 514. Filter 514 may be configured to collect the fine dust while allowing the exhaust gas to pass through. VSD system 500 may optionally include a liquid collection system located within box 515 of FIG. 5. The liquid collection system may include a heat exchanger 516 fluidly coupled to a cooler 518. Heat exchanger 516 may receive the hot exhaust gas from filter 514 and pass the hot exhaust gas over components cooled by cooler 518. Liquid from the hot exhaust gas may condense on cooler components as the hot exhaust gas cools, and the condensed liquid may accumulate at the bottom of heat exchanger 516. The cooled exhaust then enters vacuum pump 524. Cooling the exhaust gas densifies the exhaust gas before it enters vacuum pump 524, making it more efficient and improving the P minmay decrease. Increasing the efficiency of the vacuum pump in this manner may become more important as the size of the VSD system increases (e.g., larger spray dryers and larger vacuum pumps). Additionally, moisture in the exhaust gas may condense as it cools in heat exchanger 516, and liquid effluent 522 may be pumped from the bottom of heat exchanger 516 by liquid pump 520. If vacuum pump 524 cannot tolerate the presence of moisture, it may be desirable to remove liquid effluent 522 from the exhaust gas before it reaches vacuum pump 524.

[0027] The exhaust gas may be drawn by a vacuum pump 524 and discharged from the vacuum pump 524 as exhaust 526. The exhaust 526 may contain both moisture from the liquid phase and the heated gas 504. The vacuum pump 524 may include a gas ballast 525. The gas ballast 525 may purge the moisture that enters the vacuum pump 524 with the exhaust gas with the exhaust 526. If the VSD system 500 does not include a liquid collection system 515, the gas ballast 525 may be opened more frequently.

[0028] 6, a schematic diagram of a VSD system 600 in a counterflow configuration is shown. VSD system 600 may include similar components to VSD system 500, such as cyclone 512 and vacuum pump 524. Similar components are numbered the same as in FIG. 5 and will not be described again.

[0029] The liquid feed 502 may be atomized by a liquid atomizer and introduced into the drying chamber 506 through the top, where it may travel downward through the drying chamber 506 by the action of gravity. Here, we consider both conventional and non-conventional configurations for liquid atomization (e.g., two-fluid atomization, pressure atomization, rotary atomization, etc.). The heated gas 504 may be introduced into the drying chamber through the side of the lower portion of the drying chamber 506 (against gravity) and directed upward toward the top of the drying chamber 506. In this way, the atomized droplets may move away from the top of the drying chamber 506 before interacting with the heated gas 504. Upon interacting with the upwardly moving heated gas 504, the path of the atomized droplets may be directed back toward the top of the drying chamber 506. In this way, the residence time of the atomized droplets within the drying chamber 506 may be increased. The increased residence time allows for a selected T out and P dryer For this purpose, a shorter drying chamber may be selected.

[0030] VSD system 600 may include a chamber particle isolation valve 602 and a chamber product collection chamber 604. The chamber particle isolation valve 602 and the chamber product collection chamber 604 may be located at the lowest point of drying chamber 506 relative to gravity and may be used similarly to product isolation valve 508 and removable product collection chamber 510. Larger particle products that may fall out of the upward flow of heated gas 504 may be collected from the bottom of drying chamber 506 through an open chamber particle isolation valve 602, and the chamber product collection chamber 604 may be fluidly isolated from VSD system 600 when chamber particle isolation valve 602 is in a closed position. Smaller product particles may be discharged from the top of drying chamber 506 and directed to cyclone 512. Components located downstream of drying chamber 506 may be configured similarly to VSD system 500.

[0031] In some embodiments, the chamber particle isolation valve 602 and the chamber product collection chamber 604 may be omitted, and the heated gas 504 may enter the drying chamber 506 from a lower position in the drying chamber 506 relative to gravity. In such an example, the particles are collected in a removable product collection chamber 510. In this manner, the overall number of parts in the VSD system 600 may be reduced, thereby reducing the complexity and cost of the system.

[0032] A cyclone, such as cyclone 512 in FIGS. 5 and 6 and cyclone 108 in FIG. 1, may be selected for use in a VSD system, such as VSD system 100, VSD system 500, and / or VSD system 600. In addition to considering how well the cyclone can separate particulate products from the exhaust gas, the cyclone may be fluidly coupled to both the drying chamber and a vacuum. Therefore, the pressure drop between the cyclone outlet and the cyclone inlet can affect the pressure in the drying chamber. For a comparable mass flow rate, a cyclone in a spray drying system operating at atmospheric pressure may have a lower relative pressure drop than a cyclone in a VSD system. In other words, the pressure drop experienced by a cyclone in a VSD system may be a larger percentage of the overall system pressure than in a spray drying system operating at atmospheric pressure. Therefore, the size of the cyclone in a VSD system may be larger than that of a comparable spray drying system operating at atmospheric pressure. As an example, increasing the size of the cyclone may include increasing the maximum diameter of the cyclone, and the sizes of the additional cyclone components (e.g., height, inlet diameter, and outlet diameter) may be increased in size proportionally to the increased maximum diameter. Table 1 below provides an example of the effect of cyclone pressure drop on other spray dryer system properties, assuming negligible pressure drop across the filter. [Table 1] Table 1: Exemplary drying chamber pressures for different cyclone pressure drops and different vacuum pump pressures

[0033] Comparing Example A and Example B, for equivalent drying chamber pressures, increasing the cyclone pressure drop from 10 mbar to 50 mbar can require a vacuum pump pressure reduction from 90 mbar to 50 mbar (a reduction of approximately 40%). Reducing the vacuum pressure can require a larger capacity vacuum pump. Furthermore, comparing Examples C and D, the cyclone pressure drop also increases from 10 mbar to 50 mbar. However, in the case of Examples C and D, the spray drying pressure is maintained at 1000 mbar. At higher drying chamber pressures, the required pressure change in vacuum between Example C and Example D can be relatively small (e.g., a reduction of approximately 4%). This relationship is a result of the ideal gas law, which states that volumetric flow rate is inversely proportional to the absolute pressure of the system.

[0034] As another example, the mass flow rate of the drying gas (e.g., heating gas 504) can be adjusted to a desired drying rate (e.g., R min While the cyclone's performance, including collection efficiency and pressure drop, may be based on volumetric flow rate, VSD systems require cyclone size adjustments to balance collection efficiency and pressure drop. Reducing the drying chamber pressure for a constant mass flow rate can result in different volumetric flow rates, and vice versa.

[0035] Next, Figures 7 and 8 further illustrate the effect of drying chamber pressure and cyclone size on pressure drop across the cyclone. Figure 7 includes a graph 700 of pressure drop as a function of gas flow rate for a 2-inch diameter cyclone, and Figure 8 includes a graph 800 of pressure drop as a function of gas flow rate for a 3-inch diameter cyclone. Plot 702 in Figure 7 corresponds to a chamber pressure of 183 mbar, plot 704 corresponds to a chamber pressure of 263 mbar, plot 706 corresponds to a chamber pressure of 359 mbar, and plot 708 corresponds to a chamber pressure of 900 mbar. For a given gas flow rate, a comparison of plots 702, 704, 706, and 708 shows that the pressure drop across the cyclone increases as the chamber pressure decreases.

[0036] A similar trend of increasing pressure drop with decreasing chamber pressure is also seen in graph 800 of Figure 8. Graph 800 includes plot 802 corresponding to a chamber pressure of 184 mbar, plot 804 corresponding to a chamber pressure of 252 mbar, and plot 804 corresponding to a chamber pressure of 338 mbar. Furthermore, comparing the plots of graph 800 and graph 700, for approximately the same gas flow rate and comparable chamber pressures (e.g., plots 702 and 802), the pressure drop for a 2-inch cyclone shown in graph 700 is greater than the corresponding pressure drop shown in graph 800.

[0037] Increasing the cyclone size may reduce the effective pressure of the vacuum pump, but smaller cyclones may be able to collect the dried product more efficiently than larger cyclones. Selecting a cyclone for a VSD system may involve balancing the required cyclone collection efficiency with reducing the pressure drop across the cyclone. Methods for selecting cyclones for a VSD system are discussed further below with respect to Figures 4A and 4B.

[0038] VSD system drying chamber pressure (P dryerA flowchart of an example of a method 400 for selecting the flow rate and drying chamber height is shown in FIGS. 4A and 4B. The VSD system can be similar to the VSD system 100 shown in FIG. 1. Furthermore, the VSD system can be configured as a co-current system, such as the VSD system 500 of FIG. 5, or as a counter-current system, such as the VSD system 600 of FIG. 6. Furthermore, the method 400 can include parameter estimation based on experiments using a reference spray dryer. In one example, the reference spray dryer can be a short bench-scale spray dryer operating in a co-current configuration at atmospheric pressure. Furthermore, parameters can be estimated based on an extended spray drying system. The extended spray drying system can be configured to increase the residence time of particles in the drying chamber. For example, the extended spray drying system can be configured as a counter-current spray dryer, and the drying chamber height can be increased. The extended spray dryer can be operated at atmospheric pressure.

[0039] The VSD system may be used to spray dry temperature sensitive products suspended or dissolved in a liquid phase, as described above with respect to the products in the liquid feed 104 of Figure 1. The product is spray dried at a maximum temperature (T max ) can be characterized by T max may depend on the product being spray dried. In some instances, T max can be lower than the boiling point of the liquid phase. max may be 5° C. below the boiling point of the liquid phase. In some instances, the liquid phase comprises a mixture of solvents, each solvent in the mixture having a different boiling point, and T max may be below the boiling point of the majority of the liquid phase (e.g., below 5°C), where majority of the liquid phase refers to 50% or more by volume of the liquid phase. In some examples, the product may be an API, and T max may be the decomposition temperature of the API. Above the decomposition temperature, the API may decompose and lose its effectiveness as an active ingredient in a pharmaceutical formulation. The method 400 may determine the minimum rate (R min ) or higher. dryer , Tout The minimum velocity may allow the user to select the desired flow rate (flow rate, drying chamber height, co-current or counter-current configuration, liquid phase, and liquid-gas ratio). The minimum velocity may be below the velocity at which the product may adhere to the walls of the drying chamber instead of exiting the drying chamber as particles, resulting in a minimum yield of product, as discussed above with respect to FIG.

[0040] At 402, method 400 includes selecting a desired liquid-to-gas mass ratio and liquid feed. The liquid-to-gas mass ratio (L / G mass ratio) can be controlled by selecting the liquid feed rate and the heated gas feed rate. The liquid feed can be similar to liquid feed 104 in FIG. 1 and can include a liquid phase and a product at a desired concentration. The desired concentration can be selected based on the physical properties of the product in the liquid phase (e.g., solubility, viscosity, and / or stability in the liquid phase) and the required throughput of the method. As an example, the concentration of the product in the liquid phase can be 0.1 to 30% by weight. The liquid phase can be selected based on the solubility characteristics and compatibility of the product. For example, nucleic acid-containing products can be compatible with most aqueous liquid phases, and amorphous solid dispersions can be compatible with most organic liquid phases.

[0041] At 404, method 400 calculates the R for a selected L / G mass ratio at atmospheric pressure for a reference spray dryer configuration. min The criterion T required to bring out In one example, T out and R min can be determined experimentally (e.g., empirically) by using a reference spray drying system to spray dry with the liquid feed and L / G ratio selected in 402. In one example, the reference spray drying system can be a short spray dryer configured as a co-current spray dryer used in a laboratory environment.

[0042] At 406, the method 400 max The following T out With R min This involves calculating the predicted dryer pressure to achieve T maxmay be less than 35°C, less than 25°C, less than 15°C, or less than 6°C. As a further example, when the liquid phase comprises a low-volatility organic solvent, T max may be less than 80° C., less than 70° C., or less than 60° C. Furthermore, in instances where the liquid phase is a blend of different solvents, T max may be below the boiling point of the liquid phase or below the boiling point of the majority of the liquid phase. dryer may be 0.05 bar below ambient pressure. dryer may be less than or equal to 0.8 bar, or P dryer may be 0.5 bar or less. dryer P may be in the range of 0.2 bar to 0.6 bar, or in the range of 0.05 bar to 0.6 bar, or in the range of 0.01 bar to 0.8 bar, or in the range of 0.01 bar below ambient pressure up to 0.05 bar. dryer and T out can be calculated using Equations 1 and 2, as described above with respect to FIG. min T may be proportional to the target interfacial velocity for the liquid feed and L / G mass ratio selected in 402. out and P dryer R by adjusting min The relative change in can be predicted using Equations 1 and 2 without requiring prediction of absolute drying rates.

[0043] At 408, the method 400 includes selecting the smallest available cyclone. Selecting the smallest cyclone may include selecting, from among the available cyclones, the cyclone with the highest cyclone collection efficiency for the dry powder. Cyclone collection efficiency may refer to the ratio of the mass of dry particles recovered from the cyclone to the total mass of dry particles exiting the drying chamber. Increasing the cyclone collection efficiency may also increase the overall yield of the dried product. As an example, the smallest available cyclone may have a diameter of 0.5 inches.

[0044] At 410, the method 400 determines the selected L / G mass ratio, P dryerand T out , the increase in system pressure due to the pressure drop in the selected cyclone (ΔP cyclone ) ΔP cyclone The cyclone is located at the entrance of the cyclone (P in ) and exit (P out ) pressure difference (P in -P out ) Since the pressure decreases in the direction of flow through the cyclone, ΔP cyclone is a positive value. cyclone can be calculated based on the physical dimensions of the cyclone and the characteristics of the heated gas feed. Additionally or alternatively, ΔP in a selected cyclone cyclone may be determined based on dynamic simulations or empirically by measuring the pressure in the system immediately upstream and downstream of the cyclone.

[0045] At 414, the method 400 determines the P dryer P min and ΔP cyclone This includes determining whether or not P is greater than or equal to the sum of P min P may be the minimum drying chamber pressure that can be realistically achieved in a commercially sized drying chamber. min HA P vac It may depend on P vac may be the lowest pressure in a drying chamber fluidly coupled to the vacuum pump without any intervening components causing an additional pressure drop. The size and / or power of a vacuum pump (e.g., vacuum pump 524) included in the VSD system may be such that P vac As an example, P vac In another example, P vac may be 0.01 bar. vac may be in the range of 0.01 bar to 0.05 bar, or P vac may be equal to or greater than 0.01 bar. vac is the pressure drop across the cyclone (ΔP cycloneAdditionally or alternatively, the inclusion of a heat exchanger located downstream of the cyclone and upstream of the vacuum pump can increase the P min As mentioned above, the heat exchanger may densify the gas exhaust before it reaches the vacuum pump, thereby increasing the efficiency of the vacuum pump. min may be in the range of 0.05 bar to 0.6 bar. min may be in the range of 0.01 bar to 0.8 bar.

[0046] P dryer P min and ΔP cyclone If ΔP is less than the sum of ΔP, then the method 400 proceeds to 416, which includes determining whether a larger cyclone is available. The larger cyclone may have a larger maximum diameter, and the pressure drop across the larger cyclone may be less than the pressure drop across the smaller cyclone. Furthermore, ΔP cyclone may decrease in size as the size of the cyclone increases, with a corresponding decrease in pressure drop across the cyclone. If a larger cyclone is available, method 400 proceeds to 412 and includes selecting the next smallest available cyclone, which may be larger than the currently selected cyclone. Method 400 then returns to 410 and selects the L / G mass ratio, P dryer , and T out , ΔP for the next smallest available cyclone cyclone This includes determining:

[0047] If a larger cyclone is not available, method 400 proceeds to 426 to determine whether the spray dryer can be expanded. If the spray dryer cannot be expanded, method 400 returns to 402 and a new L / G mass ratio and / or liquid feed is selected. If the spray dryer can be expanded, method 400 proceeds to 428 and determines whether the relative drying rate of the expanded spray dryer is reduced (reduced R minThe extended spray dryer may be a spray dryer configured to increase the residence time of the product within the drying chamber. As an example, the extended spray dryer may include a drying chamber that is taller than the reference spray dryer. Additionally, the drying chamber of the extended spray dryer may include a drying chamber that is taller than the reference spray dryer. min The expanded spray dryer may be configured as a countercurrent spray dryer. min To determine the reduced R for selected liquid feeds and L / G ratios, a laboratory scaled spray dryer was used. min This may include experimentally determining

[0048] At 430, the method 400 max Less than T out Reduced minimum drying speed (e.g., reduced R min ) to achieve the extended P dryer This involves calculating the extended P dryer can be calculated using equations 1 and 2 above. As the residence time of the particles in the drying chamber increases from the base spray dryer to the extended spray dryer, the reduced R min is R min is smaller (e.g., slower) than the extended P dryer HA P dryer At 432, the method 400 calculates the expanded P dryer P min +ΔP cyclone Determine whether it is greater than or equal to the extended P dryer P min +ΔP cyclone If so, the method 400 proceeds to 434, where the determined T out and reduced R min The extended P dryerSpray drying is performed using a spray dryer and using an extended spray dryer configuration (e.g., a countercurrent configuration and / or an elevated drying chamber height). In some examples, spray drying the liquid feed further includes controlling the jacket temperature of a jacketed drying chamber. As an example, the jacket may be similar to jacket 107 of FIG. 1, and the jacket temperature may be controlled by setting the temperature of a temperature-controlled vessel (e.g., temperature-controlled vessel 109 of FIG. 1) fluidly coupled to the jacket. In this manner, during spray drying of the liquid feed, T out The processing temperature, such as the jacket temperature, can be controlled with greater precision than if the jacket temperature were not controlled. In some examples, the product may be a pharmaceutical product, and the spray-dried pharmaceutical product may be included in a pharmaceutical formulation.

[0049] In 432, the expanded P dryer P min +ΔP cyclone If it is determined to be less than 、 The method 400 continues at 402 where a different liquid feed and / or L / G ratio is selected. As an example, the fraction of low volatility organic solvent in the liquid phase can be reduced. Alternatively, the L / G ratio can be reduced.

[0050] Now, going back to 414, the method 400 dryer P min +ΔP cyclone If so, the method 400 proceeds to 418 and calculates the determined L / G mass ratio, P dryer , and T out Cyclone collection efficiency (CE) cyclone In some instances, CE cyclone can be determined experimentally using a model system. For example, the yield of a test spray in which the liquid feed contains excipients and no API is calculated by CE, assuming all losses are due to the cyclone. cyclone Additionally or alternatively, CE cyclonemay be calculated based on the physical properties of the cyclone and the expected median spray dried particle size. The method 400 then proceeds to 422, where CE cyclone is the minimum acceptable collection efficiency (CE min ) or greater. In some examples, min In a further example, CE min The method 400 may be cyclone CE min If so, the method 400 proceeds to 434 and performs a spray drying process using a spray drying system configured as a reference spray drying system including the selected cyclone, at the selected L / G ratio and at least R min T out and P dryer The method 400 includes performing spray drying of the selected liquid feed with CE cyclone CE min If it is determined that it is not, the method 400 proceeds to 424 and includes selecting a smaller cyclone, if available. The smallest cyclone may have the greatest collection efficiency. Selecting a smaller cyclone increases the pressure drop across the cyclone, reducing ΔP cyclone This may increase the magnitude of P dryer is no longer P min +ΔP cyclone If the determined T is not greater than 420, the method 400 may proceed to 426 and include determining whether the spray dryer can be expanded. After the determination in step 426, the method 400 may proceed as described above. The method 400 may then proceed to 426 using the selected spray dryer and cyclone to determine whether the determined T is greater than 420. out and P dryer After spray drying the product in step 434, the process ends.

[0051] An example of spray drying trehalose as an aqueous test solution containing trehalose as a model test compound at a concentration of 14 wt % using a VSD (such as VSD100 in FIG. 1) and a conventional spray dryer (CSD) configured for different spray drying conditions at atmospheric pressure is shown below in Table 1. The batch size and atomization method for the VSD and conventional spray dryer were kept substantially the same. [Table 2] Table 1: Comparison of trehalose spray drying with a vacuum spray dryer and a conventional spray dryer Both VSD and CSD systems operate at a T below the boiling point of water at a specified chamber pressure. out The trehalose test solution was spray dried at 100°C. dryer is the desired T out To achieve the minimum drying rate at the desired P dryer For the same outlet temperature, the VSD was able to achieve comparable yields at a 5-fold higher L / G ratio (e.g., 5-fold higher throughput) than the CSD. Furthermore, as shown in Table 1, to achieve comparable yields to the VSD at comparable L / G ratios, T in and T out The temperature is raised to 41°C and 32°C, respectively. max In the example, in and T out In instances with lower L / G ratios (e.g., CS-1 and CS-2), yields may be comparable to VSD, as increased gas flow rates may be required to dry the same liquid feed faster. dryer Spray drying using a VSD may allow for high yield spray drying while avoiding other less desirable methods of increasing gas flow rate, such as lowering L / G or extending the spray dryer height or contact time.

[0052] As another example shown in Table 2 below, a 14% trehalose solution was diluted with different P dryer The mixture may be spray-dried at room temperature. [Table 3] Table 2: Different P dryer Comparison of VSDs in Wet yield % is P dryer may vary based on uncontrollable system variability rather than as a function of R min Based on the above modeling, P dryer When calculating, the maximum P dryer can be selected. dryer is calculated P dryer Amounts less than this may not have any positive or negative effect on yield. dryer By calculating , the user may be able to select an economical vacuum system that is suitable for the intended purpose and is not over-powered for little, if any, added benefit.

[0053] As a further example, trehalose is spray dried from aqueous solutions at two different concentrations with different VSD configurations, some of which include cyclones of different diameters, as shown in Table 3 below. [Table 4] Table 3: Comparison of spray drying with different solutions using different cyclones As shown in Table 3, the diameter of the cyclone can be reduced to achieve acceptable P dryer If P is achieved, a smaller cyclone diameter can improve yield due to the higher cyclone collection efficiency of the smaller cyclone. Comparing VSD-1 and VSD-2, a smaller cyclone diameter can improve yield. dryerIn some instances, such as comparing a VSD-3 to a VSD-4, the vacuum system may be adjusted to compensate for the larger pressure drop in the smaller cyclone. In such instances, P dryer is the target P based on the calculations of Equations 1 and 2, as described above with respect to method 400. dryer , the yield increase from the smaller cyclone may be greater than the yield increase from the smaller cyclone if the vacuum system cannot be adjusted.

[0054] Additionally, a 14% trehalose liquid feed may be spray dried in a countercurrent configuration (eg, VSD600 in Figure 6) as shown in Table 4 below. [Table 5] Table 4: Spray drying results in countercurrent configuration As mentioned above, T in When spray drying in a countercurrent configuration, the yield and properties of the resulting particles are affected by T out As shown in Table 4, in Examples 1 and 2, T in In this way, the T while maintaining a wet yield of over 50% is increased. in Increasing τ may allow for higher throughput.

[0055] The technical effect of method 400 is dryer and T out Select T max Lower T out The spray dryer configuration and operating parameters can be selected to provide acceptable drying rates, including approximation of droplet solidification, without thermal damage to the product. In this way, the time and labor required to spray dry a temperature-sensitive product can be reduced. Furthermore, the need for a vertical drying chamber in a countercurrent configuration can be determined. Furthermore, increasing the size of the cyclone can reduce the P of the VSD. minIn this way, the need for a vertical drying chamber or counter-current configuration may be avoided.

[0056] The present disclosure also provides support for a spray drying method, including: estimating an outlet temperature for achieving a minimum drying rate at atmospheric pressure based on a selected liquid feed and a selected liquid-to-gas ratio; calculating a predicted dryer pressure at which the minimum drying rate can be reached at a reduced outlet temperature, where the reduced outlet temperature is less than the maximum temperature and the predicted dryer pressure includes an approximation of droplet solidification; and spray drying the selected liquid feed at the selected liquid-to-gas ratio, predicted dryer pressure, and reduced outlet temperature. In a first embodiment of the method, the selected liquid feed comprises a liquid phase and a product. In a second embodiment of the method, optionally, the method includes the first embodiment, but the maximum temperature depends on the product contained in the liquid phase. In a third embodiment of the method, optionally, the method includes one or both of the first and second embodiments, but the reduced outlet temperature is less than the boiling point of the liquid phase at the predicted dryer pressure. In a fourth embodiment of the method, optionally, the method includes one or more or each of the first through third embodiments, but the product is an active pharmaceutical ingredient. A fifth embodiment of the method optionally includes one or more or each of the first through fourth embodiments, except that estimating the reduced outlet temperature includes experiments using a reference spray drying system. A sixth embodiment of the method optionally includes one or more or each of the first through fifth embodiments, except that the predicted dryer pressure is within a range of 0.01 bar to a maximum of 0.05 bar below ambient pressure. A seventh embodiment of the method optionally includes one or more or each of the first through sixth embodiments, except that spray drying the selected liquid feed further includes controlling the jacket temperature of a jacketed drying chamber. An eighth embodiment of the method optionally includes one or more or each of the first through seventh embodiments, except that the minimum pressure in the dryer chamber is reduced by a heat exchanger located downstream of the cyclone and upstream of the vacuum pump, or by increasing the size of the cyclone.A ninth embodiment of the method optionally includes one or more or each of the first through eighth embodiments, except that the selected liquid feed comprises water and the maximum temperature is less than 35° C., less than 25° C., 15° C., or less than 6° C., or the selected liquid feed comprises a low-volatility organic solvent and the maximum temperature is less than 80° C., less than 70° C., or less than 60° C. A tenth embodiment of the method optionally includes one or more or each of the first through ninth embodiments, except that the spray drying at the minimum drying rate comprises spray drying in a spray drying system configured as a reference spray drying system, and the spray drying at the reduced minimum drying rate comprises spray drying in a spray drying system configured as an extended spray drying system.

[0057] The present disclosure also provides support for a vacuum spray drying system including a liquid feed and a gas feed fluidly coupled to a drying chamber, a cyclone fluidly coupled to the drying chamber and configured to receive a dried product, and a vacuum pump coupled to the drying chamber via the cyclone, wherein the height of the drying chamber, the size of the cyclone, and the output of the vacuum pump are determined by a model relating a minimum drying rate at reference conditions to a minimum rate at adjusted conditions. In a first embodiment of the system, the adjusted conditions include a dryer pressure below atmospheric pressure and an outlet temperature below the boiling point of the majority of the liquid feed at the drying chamber pressure. In a second embodiment of the system, optionally including the first embodiment, the liquid feed and the gas feed are coupled to the drying chamber in a co-current or counter-current configuration. In a third embodiment of the system, optionally including one or both of the first and second embodiments, the minimum drying rate is a rate corresponding to a yield in steady-state continuous operation of greater than 50%.

[0058] The present disclosure also provides a method for supporting a spray-dried pharmaceutical formulation by selecting a liquid-to-gas mass ratio and a liquid feed, the selected liquid feed including an active pharmaceutical ingredient and a liquid phase; estimating an outlet temperature to achieve a minimum drying rate at atmospheric pressure based on the selected liquid feed and the selected liquid-to-gas mass ratio; and calculating a predicted dryer pressure at which the minimum drying rate can be reached at a reduced outlet temperature, the reduced outlet temperature being below the decomposition temperature of the active pharmaceutical ingredient and the predicted dryer pressure including an approximation of droplet solidification. In a first embodiment of the system, the active pharmaceutical ingredient is a protein, nucleic acid, self-assembled nanoparticle, or small molecule. A second embodiment of the system optionally includes the first embodiment, but the reduced outlet temperature is below the boiling point of the majority of the liquid phase at the predicted dryer pressure. A third embodiment of the system optionally includes one or both of the first and second embodiments, but wherein the reduced outlet temperature spray drying includes spray drying at less than 35° C., less than 25° C., or less than 15° C. when the liquid phase is predominantly aqueous. A fourth embodiment of the system optionally includes one or more or each of the first through third embodiments, but wherein the reduced outlet temperature spray drying includes spray drying at less than 80° C., less than 70° C., or less than 60° C. when the liquid phase is predominantly a low-volatility organic solvent.

[0059] In an alternative embodiment, the present disclosure provides support for a spray drying method including: calculating a predicted dryer pressure at which a minimum drying rate for a selected liquid feed and liquid-to-gas ratio can be achieved at an outlet temperature, where the outlet temperature is less than the maximum temperature; comparing the predicted dryer pressure to a minimum pressure in the dryer chamber, where the minimum pressure in the dryer chamber is determined by the size of the vacuum pump and the size of the cyclone; and estimating a reduced minimum drying rate if the predicted dryer pressure is less than the minimum pressure in the dryer chamber, where the reduced minimum drying rate is reduced by extending the residence time of the product in the drying chamber; and spray drying the selected liquid feed at the minimum drying rate or the reduced minimum drying rate with the selected liquid-to-gas ratio, predicted dryer pressure, and outlet temperature. In a first embodiment of the method, spray drying the selected liquid feed further includes controlling the jacket temperature of the jacketed drying chamber. A second embodiment of the method optionally includes the first embodiment, but the minimum pressure in the dryer chamber is 0.01 bar or greater. A third embodiment of the method optionally includes one or both of the first and second embodiments, but extending the product residence time includes selecting an increased drying chamber height or spray drying in a countercurrent configuration. A fourth embodiment of the method optionally includes one or more or each of the first through third embodiments, but the minimum pressure in the dryer chamber is reduced by a heat exchanger or by increasing the size of the cyclone. A fifth embodiment of the method optionally includes one or more or each of the first through fourth embodiments, but the selected liquid feed comprises water and the maximum temperature is less than 35°C, less than 25°C, 15°C, or less than 6°C. A sixth embodiment of the method optionally includes one or more or each of the first through fifth embodiments, but the selected liquid feed comprises a low-volatility organic solvent and the maximum temperature is less than 80°C, less than 70°C, or less than 60°C.A seventh embodiment of the method optionally includes one or more or each of the first through sixth embodiments, except that spray drying at a minimum drying rate includes spray drying in a spray drying system configured as a reference spray drying system, and spray drying at a reduced minimum drying rate includes spray drying in a spray drying system configured as an extended spray drying system.

[0060] The following claims particularly point out certain combinations and subcombinations that are deemed novel and unobvious. These claims may refer to "an" element or "first" element, or equivalents thereof. Such claims should be understood to include the incorporation of one or more such elements, and do not require or exclude two or more such elements. Other combinations and subcombinations of the disclosed features, functions, elements, and / or properties may be claimed through amendment of the claims or through the presentation of new claims in this or a related application. Such claims, whether broader, narrower, equal, or different in scope from the original claims, are also deemed to be encompassed within the subject matter of this disclosure.

Claims

1. A spray drying method comprising: estimating an outlet temperature to achieve a minimum drying rate at atmospheric pressure based on a selected liquid feed and a selected liquid-to-gas ratio; calculating a predicted dryer pressure at which the minimum drying rate can be reached at a reduced outlet temperature, the reduced outlet temperature being less than a maximum temperature, and the predicted dryer pressure comprising an approximation of droplet solidification; spray drying the selected liquid feed at the selected liquid-to-gas ratio, the predicted dryer pressure, and the reduced outlet temperature; A method comprising:

2. The method of claim 1 , wherein the selected liquid feed comprises a liquid phase and a product.

3. 3. The method of claim 2, wherein the maximum temperature depends on the product contained in the liquid phase.

4. The method of claim 2 , wherein the reduced outlet temperature is below the boiling point of the liquid phase at the predicted dryer pressure.

5. 3. The method of claim 2, wherein the product is an active pharmaceutical ingredient, and the active pharmaceutical ingredient is a protein, a nucleic acid, a self-assembled nanoparticle, or a small molecule.

6. The method of claim 1 , wherein estimating the reduced outlet temperature comprises experimentation with a reference spray drying system.

7. The method of claim 1 , wherein the predicted dryer pressure is in the range of 0.01 bar to a maximum of 0.05 bar below ambient pressure.

8. The method of claim 1 , wherein spray drying the selected liquid feed further comprises controlling the jacket temperature of a jacketed drying chamber.

9. 10. The method of claim 1, wherein the minimum pressure in the dryer chamber is reduced by a heat exchanger located downstream of the cyclone and upstream of the vacuum pump, or by increasing the size of the cyclone.

10. 10. The method of claim 1, wherein the selected liquid feed comprises water and the maximum temperature is less than 35°C, less than 25°C, 15°C, or less than 6°C, or wherein the selected liquid feed comprises a low-volatility organic solvent and the maximum temperature is less than 80°C, less than 70°C, or less than 60°C.

11. 2. The method of claim 1, wherein spray drying at the minimum drying rate comprises spray drying in a spray drying system configured as a reference spray drying system, and wherein spray drying at the reduced minimum drying rate comprises spray drying in a spray drying system configured as an extended spray drying system.

12. A vacuum spray drying system a liquid supply and a gas supply fluidly coupled to the drying chamber; a cyclone fluidly coupled to the pre-drying chamber and configured to receive the dried product; a vacuum pump coupled to the drying chamber via the cyclone; the height of the drying chamber, the size of the cyclone, and the output of the vacuum pump are determined by a model relating a minimum drying rate at a reference condition to a minimum drying rate at an adjusted condition; Vacuum spray drying system.

13. 13. The vacuum spray drying system of claim 12, wherein the regulated conditions include a dryer pressure below atmospheric pressure and an outlet temperature below the boiling point of the majority of the liquid feed at the drying chamber pressure.

14. 13. The vacuum spray drying system of claim 12, wherein the liquid and gas feeds are coupled to the drying chamber in a co-current or counter-current configuration.

15. 13. The vacuum spray drying system of claim 12, wherein the minimum drying rate is a rate corresponding to a yield of greater than 50% in steady-state continuous operation.

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