Flush Nozzle Assembly

Abstract

The nozzle assembly includes a nozzle, a manifold, and a wand body. The nozzle, manifold, and wand body can be coupled together to provide a robust spray drying system that can withstand high temperatures and / or high pressures of the feedstock. In some embodiments, an internal shoulder portion of the manifold can engage sides of the nozzle collar to limit distal movement of the nozzle relative to the manifold.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of prior U.S. Provisional Patent Application No. 62 / 933,156, filed November 8, 2019, which is incorporated by reference in its entirety.

[0002] The systems and methods disclosed herein are directed to spray drying systems and methods. [Background technology]

[0003] Spray drying systems can be used to produce powders from feed stocks for a variety of applications, from milk powder to bulk drugs and pharmaceuticals. Spray drying at elevated temperatures may be desirable to provide improved spray formulations, such as increased product throughput by promoting improved uniformity, more uniform particle size, and / or drug solubility. However, high temperatures and / or pressures of the feed stock can pose significant design challenges, and therefore improved spray drying systems capable of operating at elevated temperatures are desirable. Summary of the Invention

[0004] Various embodiments of a spray drying system, including a nozzle assembly, are disclosed herein.

[0005] In one embodiment, a nozzle assembly is provided that includes a nozzle, a manifold, and a wand body. The nozzle may have a nozzle distal end, a nozzle proximal end, a nozzle collar located between the nozzle distal end and the nozzle proximal end, a first central passageway, a nozzle distal portion extending from a first side of the nozzle collar to the nozzle distal end, and a nozzle proximal portion extending from a second side of the nozzle collar to the nozzle proximal end. The manifold has a manifold distal end, a manifold proximal end, a second central passageway in which the nozzle is received, at least one manifold sweep gas passageway, and an internal shoulder portion that engages with the first side of the nozzle collar to limit distal movement of the nozzle relative to the manifold. The wand body has a wand body distal end, a wand body proximal end, an inner tube having a groove in an enlarged portion of the inner tube at the wand body distal end, and at least one wand body sweep gas passageway. A sealing member (e.g., an O-ring) may be positioned in a groove in the inner tube, and at least a portion of the nozzle proximal portion may extend into the inner tube of the wand body, the sealing member forming a radial seal between an outer surface of the nozzle proximal portion and the inner tube of the wand body. In some embodiments, the nozzle proximal end may be chamfered.

[0006] In other embodiments, a gland end may be provided having a proximal portion that extends into the enlarged portion of the inner tube and a distal portion that engages the second side of the nozzle collar to limit proximal movement of the nozzle relative to the wand body. A biasing member (e.g., a spring washer) may be positioned between the distal portion of the gland end and the second side of the nozzle collar to bias the first side of the nozzle collar against the interior shoulder portion of the manifold.

[0007] In some embodiments, an air cap may be provided having a proximal opening, a distal opening, and an air cap passageway that tapers from the proximal opening to the distal opening. A distal nozzle portion may extend through the air cap passageway, and the distal opening of the air cap may be flush with the nozzle distal end. In other embodiments, the distal nozzle portion may be recessed relative to the distal opening of the air cap, or in yet other embodiments, the distal nozzle portion may extend beyond the distal opening of the air cap.

[0008] In yet another embodiment, the nozzle assembly may include a swirl insert positioned between the manifold and the air cap. The swirl insert may include a nozzle passage through which the nozzle extends and one or more additional passages for receiving a sweep gas. The one or more additional passages may be formed at an angle to the nozzle passage.

[0009] In some embodiments, the air cap may be sized to receive the swirl insert within the proximal opening. An air cap nut may be provided that extends over the air cap to secure the air cap to the distal end of the manifold. The manifold may include a manifold collar, the manifold proximal end may extend into the wand body such that the manifold proximal end surrounds a portion of the inner tube of the wand body, the proximal side of the manifold collar engaging a distal surface of the wand body. The sealing member may be received in a groove adjacent the proximal side of the manifold collar.

[0010] In some embodiments, a centering disk may be provided having a central opening and one or more slots radially outward of the central opening. The centering disk may be secured to the inner tube with the inner tube positioned in the central opening. The second central passage may be defined by an inner surface of the manifold extending from an inner shoulder portion of the manifold to an air channel connection within the manifold, the length of the inner surface of the manifold being at least 20%, 30%, or 40% of the length of the portion of the nozzle extending from the nozzle collar to the air shroud. The air channel connection may comprise a cylindrical groove cutout.

[0011] In another embodiment, the nozzle assembly includes a nozzle, a wand body, a sealing member (e.g., an O-ring), and a gland end. The nozzle may have a nozzle distal end, a nozzle proximal end, a nozzle collar located between the distal end and the proximal end, a first central passageway, a nozzle distal portion extending from a first side of the nozzle collar to the nozzle distal end, and a nozzle proximal portion extending from a second side of the nozzle collar to the nozzle proximal end. The wand body may have a wand body distal end, a wand body proximal end, an inner tube having a groove in an enlarged portion of the inner tube at the wand body distal end, and at least one wand body sweep gas passageway. A sealing member may be positioned in the groove of the inner tube, and at least a portion of the nozzle proximal portion extends through the sealing member into the inner tube of the wand body. The gland end may have a proximal portion that extends within the enlarged portion of the inner tube and a distal portion that engages the second side of the nozzle collar to limit proximal movement of the nozzle relative to the wand body.

[0012] In some embodiments, the nozzle proximal end may be chamfered. A biasing member may be positioned between the distal portion of the gland end and the second side of the nozzle collar to bias the first side of the nozzle collar away from the wand body.

[0013] In other embodiments, a manifold may also be provided having a manifold distal end, a manifold proximal end, a second central passage in which the nozzle is received, at least one manifold sweep gas passage, and an internal shoulder portion that engages a first side of the nozzle collar to limit distal movement of the nozzle relative to the manifold. An air cap, swirl insert, and air cap nut may also be provided having a proximal opening, a distal opening, and an air cap passage that tapers from the proximal opening to the distal opening.

[0014] In yet another embodiment, a spray drying system may be provided that includes a drying chamber, a nozzle assembly as described above and positioned within the drying chamber, and an air-liquid manifold coupled to the nozzle assembly.

[0015] The foregoing and other objects, features and advantages of the present invention will become more apparent from the following detailed description which proceeds with reference to the accompanying drawings. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 is a schematic diagram of a spray drying apparatus and system. [Diagram 2] 1 illustrates a schematic diagram of a portion of an exemplary flush nozzle assembly. [Diagram 3] FIG. 2 illustrates an exemplary flush nozzle assembly. [Figure 4A] 1 illustrates an exemplary air shroud for a flush nozzle assembly. [Figure 4B] 1 illustrates an exemplary air shroud for a flush nozzle assembly. [Figure 5A] 1 illustrates an exemplary swirl insert for a flush nozzle assembly. [Figure 5B] 1 illustrates an exemplary swirl insert for a flush nozzle assembly. [Figure 5C] 1 illustrates an exemplary swirl insert for a flush nozzle assembly. [Figure 6A] 1 illustrates an exemplary gland end of a flush nozzle assembly. [Figure 6B] 1 illustrates an exemplary gland end of a flush nozzle assembly. [Figure 7A] 1 illustrates an exemplary centering disk for a flush nozzle assembly. [Figure 7B] 1 illustrates an exemplary centering disk for a flush nozzle assembly. [Figure 8] FIG. 4 illustrates an exploded view of the nozzle assembly shown in FIG. 3. [Figure 9] 1 illustrates an exemplary top connection of a nozzle assembly to an air-liquid manifold. [Figure 10] 10 illustrates an exploded view of the exemplary top connection shown in FIG. 9. [Figure 11] FIG. 1 illustrates another exemplary flush nozzle assembly. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] General Considerations As used in this application, the singular forms "a," "an," and "the" include the plural unless the context clearly indicates otherwise. Additionally, the term "includes" means "comprise." Additionally, as used herein, the term "and / or" means any one item or combination of items in a phrase. Additionally, the term "exemplary" means serving as a non-limiting example, instance, or illustration. As used herein, the terms "eg" and "for example" introduce a list of one or more non-limiting embodiments, examples, instances, and / or illustrations.

[0018] Unless otherwise indicated, all numbers expressing amounts of ingredients, molecular weights, percentages, temperatures, times, and the like, as used in the specification or claims should be understood as being modified by the term "about". Thus, unless otherwise indicated, numerical parameters implicitly or explicitly stated are approximations that may depend on the desired properties sought and / or the limits of detection under standard testing conditions / methods. When directly and explicitly distinguishing the embodiments from the prior art discussed, the numbers of the embodiments are not approximations unless the word "about" is stated.

[0019] Although some operations of the disclosed methods are described in a particular order for convenient presentation, it should be understood that such description encompasses rearrangements unless a particular ordering is required by specific language described below. For example, operations described sequentially may in some cases be rearranged or performed simultaneously. Furthermore, for simplicity, the accompanying drawings may not show the various ways in which the disclosed items and methods can be used in conjunction with other items and methods. In addition, the description may use terms such as "providing," "producing," "determining," and "selecting" to describe the disclosed methods. These terms are detailed descriptions of actual operations that are performed. The actual operations that correspond to these terms will vary depending on the particular implementation and will be readily discernible by one of ordinary skill in the art having the benefit of this disclosure.

[0020] The systems and methods described herein, and their individual components, should not be construed in any manner as being limited to the particular uses or systems described herein. Instead, the present disclosure is directed to all novel and non-obvious features and aspects of the various disclosed embodiments, both alone and in various combinations and subcombinations with each other. For example, any feature or aspect of the disclosed embodiments may be used in various combinations and subcombinations with each other, as would be recognized by a person skilled in the relevant art in light of the information disclosed herein. In addition, the disclosed systems, methods, and components thereof are not limited to any particular aspect or feature, or combination thereof, and the disclosed and methods do not require that any one or more particular advantages exist or problems be solved.

[0021] Spray drying system and method As used herein, the term "spray drying" refers to a process in which a liquid mixture is broken down into small droplets (e.g., atomized) and the solvent is rapidly removed (e.g., dried) from the mixture in a vessel (e.g., drying chamber) in which a strong driving force exists for evaporation of the solvent from the droplets. The strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of the solvent in the spray drying apparatus well below the vapor pressure of the solvent at the temperature of the dried droplets. This may be accomplished, for example, by mixing the droplets with a warm drying gas, by maintaining the pressure in the spray drying apparatus at a partial vacuum (e.g., 0.01 atm to 0.50 atm), or both.

[0022] Referring to the drawings, FIG. 1 shows an apparatus 100 suitable for carrying out embodiments of the disclosed process. In the following discussion, the spray-drying apparatus is described as being cylindrical. However, the dryer can take any other cross-sectional shape suitable for spray drying of the spray solution, including square, rectangular, and octagonal, among others. Also, the spray-drying apparatus is depicted as having one nozzle. However, multiple nozzles can be included in the spray-drying apparatus to achieve a higher throughput of the spray solution.

[0023] The apparatus 100 includes a feed suspension tank 102, a heat exchanger 104, a drying chamber 106, a nozzle 108, and a particle collection means 110. In one embodiment, at least one solute is combined with a solvent in the feed suspension tank 102 to form a feed suspension. The feed suspension is at a temperature T1 below the ambient pressure boiling point of the solvent. The temperature T1 is also lower than the temperature TS at which the solute solubility is equal to the solute concentration in the solvent. If the solute comprises multiple solutes, the temperature T1 is lower than the temperature at which the solubility of at least one solute is equal to the concentration of that solute in the solvent. At least a portion of the solute, i.e., the undissolved solute, is suspended in the solvent. If desired, one or more mixing means can be provided to keep the feed suspension homogeneous during processing. If the solvent is flammable, oxygen can be excluded from the process. For example, inert gases such as nitrogen, helium, argon, and the like can be used to fill voids in the feed suspension tank for safety reasons.

[0024] Typically, the temperature and flow rate of the drying gas are selected so that the droplets of the sprayed solution, which are essentially solid and form a fine powder, are sufficiently dry by the time they reach the walls of the apparatus so that they do not adhere to the walls of the apparatus. The actual length of time to achieve this level of drying depends on the size of the droplets and the conditions under which the process is operated. The droplet size can range from 1 μm to 500 μm in diameter, with the size depending on the desired particle size of the spray-dried powder. Due to the large surface-to-volume ratio of the droplets and the large driving force for the evaporation of the solvent, the actual drying time is no more than a few seconds, often less than 0.1 seconds. The solidification time should be less than 100 seconds, often less than a few seconds.

[0025] For convenience, the feed suspension can be maintained at about ambient temperature, however, this is not a limitation of the disclosed process. In general, the temperature T1 of the feed suspension can range from 0° C. to 50° C. or higher. Temperatures below 0° C. can also be utilized, particularly where there are stability concerns for the solute.

[0026] The feed suspension in the feed suspension tank 102 is delivered to a pump 112 which directs the feed suspension to a heat exchanger 104. The heat exchanger may have a feed suspension inlet 114, a spray solution outlet 116, and a heating fluid inlet and outlet (not shown). The feed suspension enters the heat exchanger 104 via the feed suspension inlet 114 at a temperature T1 and exits as a spray solution via the spray solution outlet 116 at a temperature T2, which is greater than the feed suspension temperature T1.

[0027] In one embodiment, T1 is equal to or greater than TS, which is the temperature at which the solute solubility is equal to the solute concentration in the solvent at equilibrium. Those skilled in the art will appreciate that several factors affect the dissolution of the solute in the solvent, including solute particle size, flow conditions of the suspension, and the residence time of the solute particles in the solvent at TS. In the following discussion, TS is the temperature at which the solute concentration in the solvent is equal to the solubility of the solute in the solvent at temperature TS at equilibrium (i.e., when the solute concentration has no net change over time). In one embodiment, when T1 is equal to or greater than TS, the solute is essentially completely dissolved in the solvent at equilibrium and the spray solution is not a suspension at T1. "Essentially completely dissolved" means that less than 5% by weight of the solute remains undissolved. When the solute includes an active agent and an excipient, T1 is selected such that the active agent is essentially completely dissolved in the solvent at T1, while the excipient may be dissolved, dispersed, or highly swollen in the solvent so that the excipient acts as if it were dissolved. In these embodiments, the feed suspension tank 102 can be considered a spray solution tank, and the feed suspension inlet 114 can be considered a spray solution inlet.

[0028] To prevent unwanted evaporation / boiling of the solvent in the spray solution, the pump 112 may be configured to increase the pressure of the spray solution such that the pressure of the spray solution at the spray solution outlet 116 is greater than the vapor pressure of the solvent at temperature T2. In one embodiment, the pump 24 increases the pressure of the spray solution to a pressure in the range of 2 atm to 400 atm. In another embodiment, the pressure of the spray solution when it leaves the heat exchanger 30 is greater than 10 atm. The temperature of the spray solution when it enters the nozzle 108 may be approximately the same as T2. Preferably, it is within temperature T2 of 30°C.

[0029] In one embodiment, the spray solution temperature T2 is greater than the ambient pressure boiling point of the solvent. In one embodiment, T2 is less than TS and the spray solution is a suspension at T2.

[0030] In another embodiment, the spray solution exiting the heat exchanger may be at any temperature T2 greater than T1, as long as T2 is greater than or equal to TS. In one embodiment, when T2 is greater than or equal to TS, the solute is essentially completely dissolved in the solvent and the spray solution is not a suspension at T2. If the process is aimed at forming a solid amorphous dispersion of the active agent and excipients, T2 is greater than or equal to the temperature at which the active agent solubility at equilibrium is equal to the active agent concentration in the solvent (i.e., TS). In such an embodiment, T2 is preferably at least 10°C greater than TS. The temperature T2 may be at least 10°C greater than T1, at least 20°C greater than T1, at least 30°C greater than T1, at least 40°C greater than T1, or even at least 50°C greater than T1. In one embodiment, the temperature T2 is at least 50°C. In another embodiment, the temperature T2 is at least 70°C. In another embodiment, the temperature T2 is at least 80°C. In another embodiment, the temperature T2 is at least 90°C. In another embodiment, T2 is at least 100° C. In yet another embodiment, T2 is at least 120° C.

[0031] The heat exchanger 114 may be any design where heat is transferred to the feed suspension resulting in an increase in temperature. In one embodiment, the heat exchanger 114 is an indirect heat exchanger, where a heating fluid contacts the feed suspension through a heat transfer surface. Exemplary indirect heat exchangers include tube-in-tube and tube-in-shell devices, both of which are well known in the art. The heat exchanger 114 may also be a direct heat exchanger, where a heating fluid, such as steam, is injected directly into the feed suspension resulting in an increase in the temperature of the feed suspension. In yet another embodiment, the feed suspension flows over a hot surface, such as a resistive heating element, resulting in an increase in the temperature of the feed suspension. Other heating sources, such as microwave and ultrasonic devices, capable of increasing the temperature of the feed suspension may also be used.

[0032] The residence time of the feed suspension in the heat exchanger 114 may be minimized to limit the time the suspension / solution is exposed to high temperatures. The residence time of the suspension / solution in the heat exchanger may be less than 30 minutes, less than 20 minutes, less than 10 minutes, less than 5 minutes, or less than 1 minute.

[0033] The spray solution at the spray solution outlet 116 is directed to the drying chamber 106 where it enters a nozzle 108 for atomizing the spray solution into droplets 118. The temperature of the spray solution as it enters the nozzle 108 is an atomization temperature designated as T3. In one embodiment, T3 is equal to or less than T2. ​​When it is desired to keep the solute essentially completely dissolved in the spray solution (i.e., T2 is greater than TS), it is often desirable for T3 to be at or near T2. However, there may be advantages to T3 being significantly lower than T2. ​​For example, solute degradation may be reduced or atomization in a particular nozzle may be more effective when T3 is significantly lower than T2. ​​In some cases, it is rather desirable for T3 to be low enough so that the solute is essentially not completely dissolved in the solvent. In such cases, the solution may be below the point where the solute is essentially completely dissolved for a short enough time that all the solute remains dissolved until the solution is atomized. Alternatively, the solution may be below the point where the solutes are essentially completely dissolved for long enough that one or more of the solutes may precipitate or crystallize out of solution. In one embodiment, the temperature T3 is less than 5° C. lower than T2. ​​In another embodiment, the temperature T3 is less than 20° C. lower than T2. ​​In another embodiment, the temperature T3 is less than 50° C. lower than T2. ​​In yet another embodiment, both temperatures T2 and T3 are higher than TS. In one embodiment, the temperatures T2 and T3 are at least 5° C. higher than TS. In another embodiment, the temperatures T2 and T3 are at least 20° C. higher than TS. In yet another embodiment, the temperatures T2 and T3 are at least 50° C. higher than TS.

[0034] In one embodiment, the apparatus 100 may be configured to minimize the time that the spray solution is at a temperature above T3. This may be accomplished by locating the spray solution outlet 116 as close to the nozzle 108 as possible. Alternatively, the size of the tubing or fluid connection between the spray solution outlet 116 and the nozzle 108 may be small to minimize the volume of the spray solution and reduce the time that the spray solution is at a temperature above T3. The time that the spray solution is at a temperature above T3 may be less than 30 minutes, less than 20 minutes, less than 10 minutes, less than 5 minutes, or even less than 1 minute.

[0035] A heated drying gas 120 may be delivered to the drying chamber along with the droplets 118. The drying gas may be virtually any gas, however, to minimize the risk of fire or explosion due to ignition of flammable vapors and to minimize undesirable oxidation of the solute, an inert gas such as nitrogen, nitrogen-enriched air, helium, or argon is utilized. The temperature of the heated drying gas at the inlet of the drying chamber may be between 20°C and 300°C.

[0036] In the drying chamber 106, at least a portion of the solvent is removed from the droplets to form a plurality of particles that include the solute. Generally, it is desired that the droplets are sufficiently dry before contacting the drying chamber surfaces so as not to stick to or coat the chamber surfaces.

[0037] The particles, along with the evaporated solvent and drying gas, exit the drying chamber at outlet 122 and are directed to a particle collection means 110. Suitable particle collection means include cyclones, filters, electrostatic particle collectors, etc. In the particle collection means 110, the evaporated solvent / drying gas 124 is separated from the plurality of particles 126 allowing for collection of the particles.

[0038] Exemplary Nozzle System and Method of Using Same - Patent application FIG. 2 shows a schematic diagram of an exemplary flush nozzle assembly 108. The flush nozzle assembly 108, a central passage 128, and an outer passage 130. The central passage 128 is in fluid communication with the incoming spray solution 132, and the outer passage 130 is in fluid communication with a sweep gas 134. The sweep gas may be any suitable gas, such as, for example, nitrogen, nitrogen-enriched air, helium, or argon. In some embodiments, the sweep gas 134 is the same as the drying gas 120. In other embodiments, the sweep gas may have a different composition than the drying gas. The temperature and flow rate of the sweep gas may depend at least in part on the desired operating variables, such as, for example, T3, spray solution flow rate, etc.

[0039] The flush nozzle 108 has an inlet end represented by A and an outlet end represented by B. The spray solution 132 from the heat exchanger (shown in FIG. 1) can enter the central passage 128 at A, and the sweep gas 134 can enter the outer passage 130 at A. As the spray solution 132 travels through the central passage 128 from inlet A to outlet B, the pressure in the central passage can decrease due to a pressure drop. Those skilled in the art will appreciate that the amount of pressure drop in the flush nozzle is a function of several factors, including the length of the central passage, the diameter of the central passage, the flow rate of the spray solution, and the viscosity of the spray solution. The pressure of the spray solution when it exits the flush nozzle as droplets (at outlet B) is the pressure in the spray drying chamber. Between inlet A and outlet B, the pressure of the spray solution can decrease to a value less than the vapor pressure of the solvent in the spray solution, resulting in the formation of vapor bubbles of the solvent (e.g., by boiling and / or flash evaporation). As the atomized solution 132 exits the central passageway 128 at outlet B, it is a fluid 136 that includes droplets of the atomized solution and vapor phase solvent.

[0040] The sweep gas 134 exiting through the outer passage outlet 138 is in fluid communication with the fluid 136 exiting through the central passage 128. The sweep gas 134 reduces the likelihood of solid material forming at the outlet of the central or outer passages. Additionally, the flow rate of the sweep gas can be used as a source to control secondary atomization of the exiting water droplets.

[0041] 3 shows a flush nozzle assembly 200. The flush nozzle assembly 200 includes an air shroud 202 and a swirl insert 204 that are secured to the end of a manifold 206 using a shroud nut 208. A nozzle 210 is positioned within the manifold 206. The nozzle 210 has a first end 212 that extends through the air shroud 202 and a second end 214 that extends into an inner tube within a wand body 216, the first end 212 and second end 214 being separated by a nozzle collar 218.

[0042] Figures 4A and 4B show an example air shroud 202, and Figures 5A, 5B, and 5C show an example swirl insert 204. As shown in Figure 3, the swirl insert 204 may be at least partially received within an interior area of ​​the air shroud. Figures 4A and 4B show a recessed area 205 at a first end 207 of the air shroud that may be sized to receive the swirl insert 204.

[0043] As shown in Figures 5A, 5B, and 5C, the swirl insert 204 can include a central opening through which the nozzle 210 can extend and one or more openings 209 circumferentially surrounding the opening through which the sweep gas can pass. As shown in Figures 5B and 5C, each of the openings 209 can extend at an angle from a first end to a second end of the swirl insert 204 to provide a rotational component to the sweep gas as it passes from the first end to the second end of the swirl insert 204. In some embodiments, instead of a separate component, the swirl insert can be integrated with the air shroud.

[0044] 3, the second end 214 of the nozzle 210 receives a biasing member 220 (e.g., a spring washer) and a gland end 222. A heat and solvent resistant sealing member 224 (e.g., a Kalrez® O-ring) may be positioned over the nozzle 210 and received within a gland in an inner tube 226 of the wand body 216. The second end 214 of the nozzle 210 may be chamfered to facilitate placement of the O-ring over the nozzle 210, thereby reducing the risk of O-ring damage and simplifying assembly.

[0045] As shown in FIG. 3, rather than abutting the end of the nozzle, the O-ring 224 surrounds at least a portion of the nozzle to provide a radial seal with the nozzle. This arrangement provides an improved seal while reducing potential compression and rotation of the O-ring, reducing potential damage to the O-ring. In addition, the nozzle collar 218 abuts directly against the manifold wall on one side and is biased downwardly by a spring washer 220 on the other side. This arrangement can reduce variation in the vertical alignment of the nozzle with the tip of the air shroud 202.

[0046] The nozzle 210 may have a distal portion extending from one side of the nozzle collar 218 to a first end (i.e., the distal end or outlet end) and a proximal portion extending from the other side of the nozzle collar 218 to a second end (i.e., the proximal end or inlet end).

[0047] The portion of the nozzle 210 that contacts the manifold is shown in Figure 3 as length L1. Preferably, this length is at least 20% of the length of the portion of the nozzle 210 that extends from the nozzle collar 218 to the air shroud 202. In other embodiments, L1 may be at least 30% or at least 40% of length L2. In some embodiments, length L1 is between 20% and 80% or between 30% and 70% of length L2.

[0048] Another sealing member 228 (e.g., a silicone O-ring) may be disposed over the manifold threads 230 or extensions adjacent the manifold collar 232. The manifold 206 may be received within the wand body 216, such as by engaging an opposing threaded portion, as shown in FIG. 3. In some embodiments, the adjacent surfaces may be sized to contact to limit the amount of pressure applied to the sealing member 228. For example, in some embodiments, the opposing faces of the manifold collar 232 and the wand body 216 may contact one another (e.g., by having a face on the manifold collar "bottom out" on the wand body face) to limit further relative motion. The seal formed by the sealing member 228 may limit air from escaping between the two portions and provide consistent concentric alignment of the manifold within the wand body.

[0049] The use of the gland end 222 facilitates easier insertion of the heat and solvent resistant O-ring 224. To ensure that the O-ring 224 remains in the desired position, the spring washer 220 tensions the gland end 222 to maintain the position of both the gland end 222 and the nozzle 210. Additionally, the L-shape of the gland end 222 allows a portion of the gland end 222 to extend into the gland and completely encase the O-ring 224 within the gland, limiting movement of the O-ring 224 out of the gland and adversely affecting the radial seal. FIGS. 6A and 6B show an exemplary gland end 222 in greater detail, including a concentric extension 223 extending from the body 225 to provide the L-shape in the cross-sectional view shown in FIG. 3.

[0050] 3, the fit and design of the connection between the gland end 222 and the inner tube 226 within the wand body 216 provides a robust and highly repeatable connection for sealing and nozzle alignment, advantageously eliminating operator variability and improving ease of assembly. Additionally, the thickness of the gland end in conjunction with the spring washer ensures that there are no gaps and that the nozzle, O-ring, and gland end remain in the desired position.

[0051] 3, the boss seal fitting 236 may be coupled (e.g., by welding) to the inner tube 226 and connect the inner tube 226 to the wand 216 with a threaded fitting. In some embodiments, the centering disk 238 may also be secured (e.g., by welding) to the inner tube 226 to provide improved concentric alignment. FIGS. 7A and 7B show an exemplary centering disk 238 in more detail. The cylindrical centering disk 238 includes a central opening 239 for receiving the inner tube 226 and one or more slots 241 extending from the central opening 239 for the passage of the sweep gas.

[0052] In some embodiments, the boss seal connections on both sides of the wand may be the same, making the inner tube 226 and manifold 206 connections independent of the wand orientation.

[0053] FIG. 8 shows an exploded view of the nozzle assembly shown in FIG. 3. As can be seen from FIG. 8, an exemplary assembly method can include the following steps: The swirl insert 204 may be positioned into the air shroud 202, and the air shroud 202 may be pressed into the manifold 206. The shroud nut 208 may be tightened (e.g., hand tightened). An O-ring 228 (e.g., a silicone AS568-908 O-ring) may be turned onto the manifold threads. The spring washer 220 and gland end 222 may be placed onto the short end of the nozzle 210 with the flat side of the gland end 222 facing the spring washer 220. The nozzle 210 may then be positioned into the manifold 206 and slowly pressed until it stops, ensuring that the nozzle tip is positioned as desired, for example, flush with the tip of the air shroud 202. As used herein, the term "flush" refers to two surfaces that are completely or substantially level with each other.

[0054] An O-ring (e.g., Kalrez AS568-006) may be pressed into the groove (gland) of the inner tube of the wand body, and pressure may be applied as necessary to seat it properly. The O-rings should be evenly distributed in the groove (gland) and not angled or protruding. A lubricant such as ethanol may be used to facilitate the O-rings sliding into the gland. Finally, the manifold / nozzle assembly may be threaded into the wand body 216 until it bottoms out. In this orientation, the flat metal surface under the O-rings of the manifold is preferably in contact with the metal surface of the wand body.

[0055] FIG. 9 shows an exemplary top connection of the nozzle assembly 200 to the air-liquid manifold 240, and FIG. 10 shows an exploded view of this section of the nozzle assembly. Another O-ring 242 (e.g., silicone AS568-908) is positioned over the threads of the boss seal fitting 236 and in the groove 244. The boss seal fitting 236 may be inserted into the wand 216 until it bottoms out. The flat metal surface on the O-ring on the threaded inner tube preferably contacts the metal surface of the wand. Another O-ring 246 (e.g., silicone AS568-113 O-ring) may be positioned in a groove inside the nozzle wand adapter 248. The nozzle wand adapter 248 may then be threaded onto the end portion 250 of the threaded inner tube.

[0056] A gasket 252 (eg, a Teflon® gasket) may be placed onto the nozzle wand adapter 248 and the air-liquid manifold 240 may be threaded onto the nozzle wand adapter 248 .

[0057] When assembled, high temperature and pressure fluid can flow through the inner passage of the inner tube 226 and into the capillary nozzle 210. Upon exiting the nozzle 210, the fluid rapidly expands and undergoes a phase change (i.e., the fluid "flashes" to atomize as discussed herein). Simultaneously, a sheath gas (e.g., nitrogen or other suitable gas) flows through the outer passage between the inner tube 226 and the wand 216, into the manifold 206, through the swirl insert 204, and exits the air shroud 202 near the tip of the nozzle 210 to provide improved atomization and prevent material buildup at the tip of the nozzle 210.

[0058] The different structures disclosed herein may vary in their dimensions. For example, the wand body disclosed herein may vary in length from 10 inches to 35 inches, or from 10 inches to 30 inches, or from 10 inches to 20 inches, or from 20 inches to 30 inches, depending on the particular application. The length and diameter of the nozzle may also vary. For example, the total length of the nozzle may vary from 3.5 cm to 11 cm, or from 5 cm to 9 cm, or from 5.5 to 7 cm. In some embodiments, the inner diameter of the nozzle may vary from 100 μm to 1000 μm, or from 150 μm to 900 μm, or from 150 μm to 200 μm, or from 350 μm to 850 μm, depending on the particular application. The inner diameter of the nozzle may vary along its length. For example, in some embodiments, a larger inner diameter portion may be at the proximal end and a smaller inner diameter portion may extend to the distal end. In embodiments where the inner diameter goes down to a smaller inner diameter, the smaller inner diameter section can have a length from 3 cm up to 11 cm. Of course, a smaller nozzle length may require modifications to other parts of the system. For example, as one of ordinary skill in the art reading this disclosure will understand, the length of the manifold 206 may be shortened to accommodate a shorter nozzle.

[0059] As discussed above, the distal nozzle portion may extend through the air cap passageway and the distal opening of the air cap may be flush with the nozzle distal end, or in other embodiments, the distal nozzle portion may extend beyond the distal opening of the air cap. Figure 11 shows the flush nozzle assembly 200 shown in Figure 3. However, instead of being flush with the distal opening of the air cap, the nozzle distal end extends outwardly from the distal opening of the air cap.

[0060] The amount that the nozzle extends outward from the distal opening can vary. In some embodiments, the amount that the nozzle distal end extends outward from the distal opening varies from 0 (e.g., a flush) to 3 mm, or in other embodiments, from 0 (e.g., a flush) to 2 mm, or in still other embodiments, from 0 (e.g., a flush) to 1 mm. In another embodiment, the nozzle distal end extends outward from the distal opening 0.5 mm to 1.5 mm.

[0061] Exemplary Spray Formulations and Feed Suspensions The systems and methods described herein may be used with a variety of feed stocks. In one embodiment, the feed stock is a feed suspension comprising an active agent, a matrix material, and a solvent, where at least a portion of the active agent, a portion of the matrix material, or a portion of both the active agent and the matrix material are suspended or not dissolved in the solvent. In some embodiments, the solvent may be an organic solvent. In one embodiment, the feed suspension consists essentially of the active agent, the matrix material, and the solvent. In yet another embodiment, the feed suspension consists of the active agent, the matrix material, and the solvent. In yet another embodiment, the feed suspension consists of particles of the active agent suspended in a solution of the matrix material dissolved in the solvent. It will be appreciated that in such a feed suspension, a portion of the active agent and the matrix material may dissolve up to their solubility limits at the temperature of the feed suspension.

[0062] As used herein, the term "active agent" refers to a drug, medicament, pharmaceutical, therapeutic, dietary supplement, nutrient, or other compound. An active agent may be a "small molecule" generally having a molecular weight of 2000 Daltons or less. An active agent may also be a "bioactive." Bioactive agents include proteins, antibodies, antibody fragments, peptides, oligonucleotides, vaccines, and various derivatives of such materials. In one embodiment, the active agent is a small molecule. In another embodiment, the active agent is a bioactive. In yet another embodiment, the active agent is a mixture of a small molecule and a bioactive. In yet another embodiment, the compositions made by certain disclosed processes include two or more active agents.

[0063] As used herein, the term "solvent" refers to water or other compounds, such as organic compounds, that can be used to dissolve or suspend solutes. Suitable solvents can include water; alcohols, such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones, such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters, such as ethyl acetate and propyl acetate; and various other solvents, such as tetrahydrofuran, acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane. Generally, low volatility solvents, such as dimethylacetamide or dimethylsulfoxide, can also be used in combination with volatile solvents. Mixtures of solvents, such as 50% methanol and 50% acetone, can also be used, as well as mixtures with water.

[0064] As used herein, the term "organic solvent" refers to a solvent that is an organic compound. In one embodiment, the solvent is volatile and has an ambient pressure boiling point of 150°C or less. In another embodiment, the solvent has an ambient pressure boiling point of 100°C or less. Suitable solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate and propyl acetate; and various other solvents such as tetrahydrofuran, acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane. In combination with generally volatile solvents, low volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used. Mixtures of solvents such as 50% methanol and 50% acetone can also be used, as well as mixtures with water. In one embodiment, the organic solvent contains less than 50% water by weight. In another embodiment, the organic solvent contains less than 25% water by weight. In yet another embodiment, the organic solvent contains less than 10% water by weight. In yet another embodiment, the organic solvent contains less than 5% water by weight. In another embodiment, the organic solvent is essentially free of water.

[0065] In some embodiments, the feed suspension may further comprise an excipient. As used herein, the term "excipient" refers to a substance that may be beneficial to include in a composition that includes an active agent. The term "excipient" includes inactive substances as well as functional excipients that may provide beneficial properties to the composition. Exemplary excipients include, but are not limited to, polymers, sugars, salts, buffers, fats, fillers, disintegrants, binders, surfactants, high surface area substrates, flavors, carriers, matrix materials, and the like.

[0066] Exemplary Products The systems and methods described herein can be used to form a variety of spray-dried products.

[0067] For example, the particles can be of any desired size. In one embodiment, the particles have an average diameter ranging from 0.5 μm to 500 μm. In another embodiment, the particles have a diameter ranging from 0.5 μm to 100 μm. In another embodiment, the particles have an average diameter greater than 10 μm. In yet another embodiment, the particles have an average diameter greater than 20 μm. In yet another embodiment, the particles have an average diameter greater than 30 μm. In yet another embodiment, the particles have a mass median aerodynamic diameter ranging from 0.5 μm to 10 μm. In yet another embodiment, the particles have a mass median aerodynamic diameter ranging from 1 μm to 5 μm.

[0068] In one embodiment, the particles produced by the processes and apparatus disclosed herein are respirable particles that can be inhaled by a subject (e.g., a human or animal). As used herein, the term "inhalation" refers to delivery to a subject via the mouth or nose. In one embodiment, the spray-dried particles are delivered to the "upper respiratory tract." The term "upper respiratory tract" refers to delivery to the nasal, oral, pharyngeal, and laryngeal passages, including the nose, mouth, nasopharynx, oropharynx, and larynx. In another embodiment, the spray-dried particles are delivered to the "lower respiratory tract." The term "lower respiratory tract" refers to delivery to the trachea, bronchi, bronchioles, alveolar ducts, alveolar sacs, and alveoli.

[0069] In one embodiment, the particles have a mass median aerodynamic diameter (MMAD) of about 5-100 μm. In another embodiment, the particles have a MMAD of about 10-70 μm. The mass median aerodynamic diameter (MMAD) is the median aerodynamic diameter based on the mass of the particles. In a sample of particles, 50% of the particles by weight have an aerodynamic diameter greater than the MMAD and 50% of the particles by weight have an aerodynamic diameter less than the MMAD. In yet another embodiment, the particles have an average diameter of 50 μm, or even 40 μm, or 30 μm. In other embodiments, the particles may have an MMAD less than about 20 μm, or even less than about 10 μm. In another embodiment, the particles have an MMAD in the range of 0.5 μm to 10 μm. In yet another embodiment, the particles have an MMAD in the range of 1 μm to 5 μm.

[0070] In one embodiment, the particles are intended for inhalation and have an MMAD of 0.5 to 100 μm, hi another embodiment, the particles are intended for inhalation and have an MMAD of 0.5 to 70 μm.

[0071] In one embodiment, the particles are intended for delivery to the upper respiratory tract and have an MMAD of greater than 10 μm. In another embodiment, the particles are intended for delivery to the upper respiratory tract and have an MMAD of 10-100 μm, where the weight fraction of particles having an aerodynamic diameter of less than 10 μm is less than 0.1. In another embodiment, the particles are intended for delivery to the upper respiratory tract and have an MMAD of 10-70 μm, where the weight fraction of particles having an aerodynamic diameter of less than 10 μm is less than 0.1.

[0072] In another embodiment, the particles are intended for delivery to the lower respiratory tract and have an MMAD of less than 10 μm. In one embodiment, the particles are intended for delivery to the lower respiratory tract and have an MMAD of 0.5-10 μm, with the weight fraction of particles having an aerodynamic diameter greater than 10 μm being less than 0.1. In another embodiment, the particles are intended for delivery to the lower respiratory tract and have an MMAD of 0.5-7 μm, with the weight fraction of particles having an aerodynamic diameter greater than 7 μm being less than 0.1.

[0073] In one embodiment, the concentration of solvent remaining in the particles when the particles are collected (i.e., the concentration of residual solvent) is less than 10% by weight based on the total weight of the particles. In another embodiment, the concentration of residual solvent when the particles are collected is less than 5% by weight. In yet another embodiment, the concentration of residual solvent in the particles is less than 3% by weight. In another embodiment, a drying process following the spray drying process can be used to remove residual solvent from the particles. Exemplary processes include tray drying, fluid bed drying, vacuum drying, and the drying processes described in WO2006 / 079921 and WO2008 / 012617, which are incorporated herein by reference.

[0074] The nozzle assemblies and systems disclosed herein can provide improvements in the assembly and operation of spray drying systems by providing nozzle assemblies that are easier to manufacture and more consistent, improved concentric alignment of the nozzle, including reducing eccentricity and vertical alignment of the nozzle tip within the air shroud, and increased robustness that can better withstand high temperatures and / or pressures of the spray solution.

[0075] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are merely preferred examples of the invention and should not be considered as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of those claims.

Claims

1. 1. A nozzle assembly comprising: a nozzle having a nozzle distal end, a nozzle proximal end, a nozzle collar located between the nozzle distal end and the nozzle proximal end, a first central passageway, a nozzle distal portion extending from a first side of the nozzle collar to the nozzle distal end, and a nozzle proximal portion extending from a second side of the nozzle collar to the nozzle proximal end; a manifold having a manifold distal end, a manifold proximal end, a second central passage in which the nozzle is received, at least one manifold sweep gas passage, and an internal shoulder portion that engages the first side of the nozzle collar to limit distal movement of the nozzle relative to the manifold; a wand body having a wand body distal end, a wand body proximal end, an inner tube having a groove in an enlarged portion of the inner tube at the wand body distal end, and at least one wand body sweep gas passage; a first sealing member positioned within the groove of the inner tube; and Equipped with A nozzle assembly, wherein at least a portion of the nozzle proximal portion extends within the inner tube of the wand body, and the first sealing member forms a radial seal between an outer surface of the nozzle proximal portion and the inner tube of the wand body.

2. 10. The nozzle assembly of claim 1, further comprising a gland end having a proximal portion extending within the enlarged portion of the inner tube and a distal portion engaging the second side of the nozzle collar to limit proximal movement of the nozzle relative to the wand body.

3. 3. The nozzle assembly of claim 2, further comprising a biasing member positioned between the distal portion of the gland end and the second side of the nozzle collar, the biasing member biasing the first side of the nozzle collar against the interior shoulder portion of the manifold.

4. a proximal opening, a distal opening, and a taper from the proximal opening to the distal opening; an air cap having an air cap passage; Further equipped with A nozzle assembly according to any preceding claim, wherein the nozzle distal portion extends through the air cap passageway, the distal opening of the air cap being flush with the nozzle distal end.

5. an air cap having a proximal opening, a distal opening, and an air cap passageway that tapers from the proximal opening to the distal opening; Further equipped with A nozzle assembly as claimed in any preceding claim, wherein the nozzle distal portion extends through the air cap passage and the nozzle distal end extends outwardly from the distal opening of the air cap.

6. a swirl insert positioned between the manifold and the air cap, the swirl insert including a nozzle passage through which the nozzle extends and one or more additional passages for receiving a sweep gas; Including, A nozzle assembly as claimed in claim 4 or 5, wherein the one or more additional passages are formed at an angle to the nozzle passage.

7. The nozzle assembly of claim 6 , wherein the air cap is sized to receive the swirl insert within the proximal opening.

8. A nozzle assembly as claimed in any one of claims 5 to 7, further comprising an air cap nut extending over the air cap to secure the air cap to a distal end of the manifold.

9. A nozzle assembly according to any one of claims 4 to 8, wherein the manifold further comprises a manifold collar, the manifold proximal end extending into the wand body such that the manifold proximal end surrounds a portion of the inner tube of the wand body, and a proximal side of the manifold collar engaging a distal surface of the wand body.

10. The nozzle assembly of claim 9 , further comprising a second sealing member received in a groove adjacent the proximal side of the manifold collar.

11. 11. A nozzle assembly as claimed in any one of claims 4 to 10, further comprising a centering disk having a central opening and one or more slots radially outward of said central opening, said centering disk being secured to said inner tube with said inner tube positioned in said central opening.

12. 12. A nozzle assembly as claimed in any one of claims 5 to 11, wherein the second central passage is defined by an inner surface of the manifold extending from the interior shoulder portion of the manifold to an air channel connection within the manifold, the length of the inner surface of the manifold being at least 20%, 30%, or 40% of the length of the portion of the nozzle extending from the nozzle collar to the air cap.

13. The nozzle assembly of claim 12 , wherein the air channel connection comprises a cylindrical groove cutout.

14. The nozzle according to any one of claims 1 to 13, wherein the nozzle proximal end is chamfered. Zuru assembly.

15. A nozzle assembly according to any preceding claim, wherein the first sealing member is an O-ring.

16. The nozzle assembly of claim 10 , wherein the second sealing member is an O-ring.

17. The nozzle assembly of claim 3 , wherein the biasing member is a spring washer.

18. 1. A nozzle assembly comprising: a nozzle having a nozzle distal end, a nozzle proximal end, a nozzle collar located between the nozzle distal end and the nozzle proximal end, a first central passageway, a nozzle distal portion extending from a first side of the nozzle collar to the nozzle distal end, and a nozzle proximal portion extending from a second side of the nozzle collar to the nozzle proximal end; a wand body having a wand body distal end, a wand body proximal end, an inner tube having a groove in an enlarged portion of the inner tube at the wand body distal end, and at least one wand body sweep gas passage; a sealing member positioned within the groove of the inner tube, at least a portion of the nozzle proximal portion extending through the sealing member into the inner tube of the wand body; a gland end having a proximal portion extending into the enlarged portion of the inner tube and a distal portion engaging the second side of the nozzle collar to limit proximal movement of the nozzle relative to the wand body; A nozzle assembly comprising:

19. The nozzle assembly of claim 18 , wherein the nozzle proximal end is chamfered.

20. 20. A nozzle assembly as claimed in claim 18 or 19, further comprising a biasing member positioned between the distal portion of the gland end and the second side of the nozzle collar, the biasing member biasing the first side of the nozzle collar away from the wand body.

21. 21. The nozzle assembly of any one of claims 18-20, further comprising a manifold having a manifold distal end, a manifold proximal end, a second central passage in which the nozzle is received, at least one manifold sweep gas passage, and an internal shoulder portion that engages the first side of the nozzle collar to limit distal movement of the nozzle relative to the manifold.

22. an air cap having a proximal opening, a distal opening, and an air cap passageway that tapers from the proximal opening to the distal opening; a swirl insert received within an air cap, the swirl insert comprising a nozzle passage through which the nozzle extends and one or more additional angled passages; an air cap nut extending over the air cap to secure the air cap to the manifold distal end; 22. The nozzle assembly of claim 21 further comprising:

23. The nozzle distal portion extends through the air cap passage and in front of the air cap.

23. The nozzle assembly of claim 22, wherein the distal opening is flush with the nozzle distal end.

24. The nozzle assembly of claim 22 , wherein the nozzle distal portion extends through the air cap passageway and the nozzle distal end extends outwardly from the distal opening of the air cap.

25. 1. A spray drying system comprising: A drying chamber; A nozzle assembly according to any one of claims 1 to 24; an air-liquid manifold coupled to the nozzle assembly; Equipped with The nozzle assembly is positioned within the drying chamber.

26. 1. A spray drying system comprising: forming a plurality of droplets by atomizing a spray solution using a nozzle assembly according to any one of claims 1 to 24; delivering the plurality of droplets into a drying chamber; delivering a drying gas into the drying chamber to at least partially dry the plurality of droplets to form a plurality of particles; directing the plurality of particles out of the drying chamber; A spray drying system comprising:

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