Flash nozzle assembly

A nozzle assembly includes a nozzle, a manifold, and wand body. The nozzle, manifold, and wand body can be coupled together to provide a robust spray drying system that can withstand elevated temperature and/or pressure feed stock. In some embodiments, an internal shoulder portion of the manifold can engage with a side of a nozzle collar to restrict distal movement of the nozzle relative to the manifold.

FIELD

The systems and methods disclosed herein are directed to spray drying systems and methods.

BACKGROUND

Spray drying systems can be used to produce powders from feed stocks for applications that vary from powdered milk to bulk chemicals and pharmaceuticals. Spray drying at elevated temperatures can be desirable to provided improved spray formulations, such as improved homogeneity, more uniform particle size, and/or increasing the product throughput by enhancing the solubility of the drug. However, the elevated temperatures and/or pressures of the feed stock can introduce significant design challenges and, as such, improvements in spray drying systems that are capable of operating at elevated temperatures are desirable.

SUMMARY

Various embodiments of spray drying systems, including nozzle assemblies are disclosed herein.

In one embodiment, a nozzle assembly is provided that comprises a nozzle, a manifold, and wand body. The nozzle can have a nozzle distal end, a nozzle proximal end, a nozzle collar located between the nozzle distal end and the nozzle proximal end, 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 through 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 restrict 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 with 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) can be positioned in the groove of the inner tube and at least a portion of the nozzle proximal portion can extend into the inner tube of the wand body with 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 can be chamfered.

In other embodiments, a gland end can be provided with a proximal portion that extends into the enlarged portion of the inner tube and a distal portion that engages with the second side of the nozzle collar to restrict proximal movement of the nozzle relative to the wand body. A biasing member (e.g., a spring washer) can 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 internal shoulder portion of the manifold.

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

In yet other embodiments, the nozzle assembly can include a swirl insert positioned between the manifold and air cap. The swirl insert can include a nozzle passageway through which the nozzle extends and one or more additional passageways for receiving a sweep gas. The one or more additional passageways can be formed at an angle relative to the nozzle passageway.

In some embodiments, the air cap can be sized to be receive the swirl insert within the proximal opening. An air cap nut can be provided to extend over the air cap to secure the air cap to the distal end of the manifold. The manifold can include a manifold collar, and the manifold proximal end can extend into the wand body so that the manifold proximal end surrounds a portion of the inner tube of the wand body and a proximal side of the manifold collar engages with a distal surface of the wand body. A sealing member can be received in a groove adjacent the proximal side of the manifold collar.

In some embodiments, a centering disk with a central opening and one or more slots radially outward of the central opening can be provided. The centering disk can be secured to the inner tube with the inner tube positioned in the central opening. The second central passageway can be defined by an interior surface of the manifold that extends from the internal should portion of the manifold to an air-channel connection 254 within the manifold, the length of the interior surface of the manifold being at least 20%, 30%, or 40% of a length of the portion of the nozzle that extends from the nozzle collar to the air shroud. The air-channel connection can comprise a cylindrical groove cutout.

In another embodiment, a nozzle assembly comprises a nozzle, a wand body, a sealing member (e.g., an O-ring), and a gland end. The nozzle can have a nozzle distal end, a nozzle proximal end, a nozzle collar located between the distal end and the proximal end, 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 can have a wand body distal end, a wand body proximal end, an inner tube with 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. The sealing member can be positioned in the groove of the inner tube and at least a portion of the nozzle proximal portion extending through the sealing member into the inner tube of the wand body. The gland end can have a proximal portion that extends into the enlarged portion of the inner tube and a distal portion that engages with the second side of the nozzle collar to restrict proximal movement of the nozzle relative to the wand body.

In some embodiments, nozzle proximal end can be chamfered. A biasing member can 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.

In other embodiments, a manifold also be provided with a manifold distal end, a manifold proximal end, a second central passageway through 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 restrict distal movement of the nozzle relative to the manifold. An air cap, a swirl insert, and an air cap nut can also be provided. having a proximal opening, a distal opening, and an air-cap passageway that tapers from the proximal opening to the distal opening;

In yet another embodiment, a spray drying system can 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.

DETAILED DESCRIPTION

General Considerations

As used in this application the singular forms “a,” “an,” and “the” include the plural forms unless the context clearly dictates otherwise. Additionally, the term “includes” means “comprises.” Furthermore, as used herein, the term “and/or” means any one item or combination of items in the phrase. In addition, the term “exemplary” means serving as a non-limiting example, instance, or illustration. As used herein, the terms “e.g.,” and “for example,” introduce a list of one or more non-limiting embodiments, examples, instances, and/or illustrations.

The systems and methods described herein, and individual components thereof, should not be construed as being limited to the particular uses or systems described herein in any way. Instead, this disclosure is directed toward all novel and non-obvious features and aspects of the various disclosed embodiments, alone and in various combinations and subcombinations with one another. For example, any features or aspects of the disclosed embodiments can be used in various combinations and subcombinations with one another, as will be recognized by an ordinarily skilled artisan in the relevant field(s) in view of the information disclosed herein. In addition, the disclosed systems, methods, and components thereof are not limited to any specific aspect or feature or combinations thereof, nor do the disclosed things and methods require that any one or more specific advantages be present or problems be solved.

Spray Drying Systems and Methods

As used herein, the term “spray drying” refers to processes involving breaking up liquid mixtures into small droplets (e.g., atomization) and rapidly removing solvent from the mixture (e.g., drying) in a container (e.g., a drying chamber) where there is a strong driving force for evaporation of solvent from the droplets. The strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of solvent in the spray-drying apparatus well below the vapor pressure of the solvent at the temperature of the drying droplets. This can be accomplished, for example, by mixing the liquid droplets with a warm drying gas, maintaining the pressure in the spray-drying apparatus at a partial vacuum (e.g., 0.01 atm to 0.50 atm), or both.

Turning to the drawings,FIG.1illustrates an apparatus100suitable for performing embodiments of the disclosed processes. In the following discussion, the spray-drying apparatus is described as being cylindrical. However, the dryer may take any other cross-sectional shape suitable for spray drying a spray solution, including square, rectangular, and octagonal, among others. The spray-drying apparatus is also depicted as having one nozzle. However, multiple nozzles can be included in the spray-drying apparatus to achieve higher throughput of the spray solution.

The apparatus100includes a feed suspension tank102, a heat exchanger104, a drying chamber106, a nozzle108, and a particle-collection means110. In one embodiment, at least one solute is combined with a solvent in the feed suspension tank102to form a feed suspension. The feed suspension is at a temperature T1, which is below the ambient-pressure boiling point of the solvent. Temperature T1is also below TS, the temperature at which the solute solubility equals the solute concentration in the solvent. When the solute comprises more than one solute, temperature T1is below the temperature at which at least one solute's solubility equals that solute's concentration in the solvent. At least a portion of the solute is suspended, that is not dissolved, in the solvent. If desired, one or more mixing means can be provided to keep the feed suspension homogeneous while processing. If the solvent is flammable, oxygen can be excluded from the process. For example, an inert gas, such as nitrogen, helium, argon, and the like, can be used to fill the void space in the feed suspension tank for safety reasons.

Generally, the temperature and flow rate of the drying gas is chosen so that the droplets of spray solution are dry enough by the time they reach the wall of the apparatus that they are essentially solid, form a fine powder, and do not stick to the apparatus wall. The actual length of time to achieve this level of dryness depends on the size of the droplets and the conditions at which the process is operated. Droplet sizes may range from 1 μm to 500 μm in diameter, the size being dependent on the desired particle size of the spray dried powder. The large surface-to-volume ratio of the droplets and the large driving force for evaporation of solvent lead to actual drying times of a few seconds or less, and often less than 0.1 second. Solidification times should be less than 100 seconds, and often less than a few seconds.

For convenience, the feed suspension can be maintained at near-ambient temperatures; however, this is not a limitation of the disclosed processes. Generally, the temperature of the feed suspension, T1, can range from 0° C. to 50° C. or even higher. Temperatures of less than 0° C. may also be utilized, especially when there are stability concerns about the solute.

The feed suspension in the feed suspension tank102is delivered to a pump112, which directs the feed suspension to the heat exchanger104. The heat exchanger can have a feed suspension inlet114, a spray solution outlet116, a heating fluid inlet and outlet (not shown). The feed suspension enters the heat exchanger104through the feed suspension inlet114at temperature T1, and exits as the spray solution through the spray solution outlet116at temperature T2, which is greater than the feed suspension temperature T1.

In one embodiment, T1is greater than or equal to TS, the temperature at which the solute solubility equals the solute concentration in the solvent at equilibrium. One of ordinary skill will understand that several factors affect dissolution of a solute in a solvent, including the solute particle size, the 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 when at equilibrium (i.e., when the solute concentration has no net change over time). In one embodiment, when T1is greater than or equal to TS, the solute, at equilibrium, is essentially completely dissolved in the solvent and the spray solution is not a suspension at T1. By “essentially completely dissolved” is meant that less than 5 wt % of the solute remains undissolved. If the solute comprises an active agent and an excipient, T1is 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 such that it acts as if it were dissolved. In these embodiments, feed suspension tank102can be considered to a spray solution tank, and feed suspension inlet114can be considered to be a spray solution inlet.

To prevent unwanted vaporization/boiling of the solvent in the spray solution, pump112can be configured to increase the pressure of the spray solution such that the pressure of the spray solution at spray solution outlet116is greater than the vapor pressure of the solvent at temperature T2. In one embodiment, the pump24increases the pressure of the spray solution to a pressure ranging from 2 atm to 400 atm. In another embodiment, the pressure of the spray solution as it exits the heat exchanger30is greater than 10 atm. The temperature of the spray solution when it enters the nozzle108can be generally the same as T2. Preferably, it is within 30° C. of temperature T2.

In one embodiment, the spray solution temperature T2is greater than the ambient-pressure boiling point of the solvent. In one embodiment, T2is less than TS, and the spray solution is a suspension at T2.

In another embodiment, the spray solution exiting the heat exchanger may be at any temperature, T2, which is greater than T1, as long as T2is greater than or equal to TS. In one embodiment, when T2is 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. When it is the object of the process to form a solid amorphous dispersion of an active agent and an excipient, T2is greater than or equal to the temperature at which the active agent solubility at equilibrium equals the active agent concentration in the solvent (that is, TS). In such an embodiment, T2preferably is at least 10° C. greater than TS. Temperature T2may be at least 10° C. greater than T1, at least 20° C. greater than T1, at least 30° C. greater than Tl, at least 40° C. greater than T1, or even at least 50° C. greater than T1. In one embodiment, temperature T2is at least 50° C. In another embodiment, temperature T2is at least 70° C. In another embodiment, temperature T2is at least 80° C. In another embodiment, temperature T2is at least 90° C. In another embodiment, T2is at least 100° C. In still another embodiment, T2is at least 120° C.

The heat exchanger114may be of any design wherein heat is transferred to the feed suspension resulting in an increase in temperature. In one embodiment, the heat exchanger114is an indirect heat exchanger, wherein a heating fluid is in contact with the feed suspension through a heat-transfer surface. Exemplary indirect heat exchangers include tube-in-tube devices and tube-in-shell devices, both well-known in the art. The heat exchanger114may also be a direct heat exchanger, in which 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 resistance heating element, resulting in an increase in temperature of the feed suspension. Other heating sources may also be used, such as microwaves and ultrasonic devices that can increase the temperature of the feed suspension.

The residence time of the feed suspension in the heat exchanger114can be minimized so as to limit the time the suspension/solution is exposed to elevated 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.

The spray solution at the spray solution outlet116is directed to a drying chamber106, where it enters a nozzle108for atomizing the spray solution into droplets118. The temperature of the spray solution when it enters the nozzle108is the spray temperature, designated as T3. In one embodiment, T3is less than or equal to T2. When it is desired to keep the solute essentially completely dissolved in the spray solution (i.e., T2is greater than TS), it is often desirable for T3to be at or near T2. However, there are sometimes advantages to having T3significantly less than T2. For example, degradation of the solute may be reduced or atomization in certain nozzles may be more effective when T3is significantly less than T2. In some cases, it is even desirable for T3to be sufficiently low that the solute is not essentially completely dissolved in the solvent. In such cases, the solution may be below the point at which the solutes are essentially completely dissolved for a sufficiently short time such that all the solutes remain dissolved until the solution is atomized. Alternatively, the solution may be below the point at which the solutes are essentially completely dissolved for a sufficiently long time that one or more of the solutes may precipitate or crystallize from solution. In one embodiment, temperature T3is less than 5° C. less than T2. In another embodiment, temperature T3is less than 20° C. less than T2. In another embodiment, temperature T3is less than 50° C. less than T2. In still another embodiment, both temperatures T2and T3are greater than TS. In one embodiment, temperatures T2and T3are at least 5° C. greater than TS. In another embodiment, temperatures T2and T3are at least 20° C. greater than TS. In yet another embodiment, temperatures T2and T3are at least 50° C. greater than TS.

In one embodiment, the apparatus100can be configured such that the time the spray solution is at a temperature greater than T3is minimized. This may be accomplished by locating the spray solution outlet116as close as possible to the nozzle108. Alternatively, the size of the tubing or fluid connections between the spray solution outlet116and the nozzle108may be small, minimizing the volume of spray solution and reducing the time the spray solution is at a temperature greater than T3. The time the spray solution is at a temperature greater than T3may be less than 30 minutes, less than 20 minutes, less than 10 minutes, less than 5 minutes, or even less than 1 minute.

A heated drying gas120can be delivered into the drying chamber with the droplets118. The drying gas may be virtually any gas, but to minimize the risk of fire or explosions 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 can be between from 20° to 300° C.

In the drying chamber106, at least a portion of the solvent is removed from the droplets to form a plurality of particles comprising the solute. Generally, it is desired that the droplets are sufficiently dry by the time they come in contact with the drying chamber surface that they do not stick or coat the chamber surfaces.

The particles, along with the evaporated solvent and drying gas, exit the drying chamber at outlet122, and are directed to a particle-collection means110. Suitable particle-collection means include cyclones, filters, electrostatic particle collectors, and the like. In the particle-collection means110, the evaporated solvent/drying gas124is separated from a plurality of particles126, allowing for collection of the particles.

Exemplary Nozzle Systems and Methods of Using the Same

FIG.2shows a schematic illustration of an exemplary flash nozzle assembly108. Flash nozzle assembly108a central passageway128and an outer passageway130. Central passageway128is in fluid communication with an inflowing spray solution132and outer passageway130is in fluid communication with a sweep gas134. The sweep gas may be any suitable gas, such as, for example, nitrogen, nitrogen-enriched air, helium, or argon. In some embodiments, the sweep gas134is the same as the drying gas120. In other embodiments, the sweep gas can have a different composition than the drying gas. The temperature and flow rate of the sweep gas can depend, at least in part, on the desired operating variables, e.g., T3, spray solution flow rate, etc.

The flash nozzle108a has an inlet end, represented by A, and an outlet end, represented by B. The spray solution132from the heat exchanger (shown inFIG.1) can enter central passageway128at A and the sweep gas134can enter outer passageway130at A. As the spray solution132travels through the central passageway128from inlet A to outlet B, the pressure within central passageway can decrease due to a pressure drop. One of ordinary skill will understand that the amount of pressure drop in the flash nozzle will be a function several factors, including the length of the central passageway, the diameter of the central passageway, the flow rate of the spray solution, and the viscosity of the spray solution. The pressure of the spray solution when it exits the flash nozzle as droplets (at outlet B) will be the pressure in the spray drying chamber. Between inlet A and outlet B, the pressure of the spray solution can decrease to a value that is less than the vapor pressure of the solvent in the spray solution, leading to the formation of vapor bubbles of the solvent (e.g., by boiling and/or flash evaporation). By the time the spray solution132exits outlet B of the central passageway128, it is a fluid136comprising droplets of spray solution and vapor-phase solvent.

The sweep gas134exiting through the outer passageway outlet138is in fluid communication with the fluid136exiting through the central passageway128. The sweep gas134decreases the likelihood that solid material will form at the exit of the central or outer passageways. Additionally, the flowrate of the sweep gas can be used as a source for controlling secondary atomization of the exiting drops.

FIG.3illustrates a flash nozzle assembly200. Flash nozzle assembly200includes an air shroud202and a swirl insert204that are secured onto an end of a manifold206using a shroud nut208. A nozzle210is positioned within the manifold206. The nozzle210has a first end212that extends through the air shroud202and a second end214that extends into an inner tube in a wand body216, with the first end212and second end214being separated by a nozzle collar218.

As shown inFIGS.5A,5B, and5C, the swirl insert204can comprise a central opening through which the nozzle210can extend and one or more one or more openings209that circumferentially surround the opening through which the sweep gas can pass. As shown inFIGS.5B and5C, each of the openings209can extend at an angle from a first end to a second end of the swirl insert204to provide a rotational component to the sweep gas as it passes from the first end to the second end of the swirl insert204. In some embodiments, instead of a separate component, the swirl insert can be integrated with the air shroud.

Referring again toFIG.3, the second end214of nozzle210receives a biasing member220(e.g., a spring washer) and a gland end222. A temperature- and solvent-resistant sealing member224(e.g., a Kalrez® O-ring) can be positioned over the nozzle210and received in a gland of an inner tube226of the wand body216. The second end214of the nozzle210can be chamfered to reduce the risk of O-ring damage and simplify assembly by making it easier to position the O-ring over the nozzle210.

As shown inFIG.3, rather than abutting the end of the nozzle, O-ring224surrounds at least a portion of the nozzle to provide a radial seal with the nozzle. This arrangement reduces potential compression and rotation of the O-ring, reducing potential damage to the O-ring while providing an improved seal. In addition, nozzle collar218directly abuts a wall of the manifold on one side and is biased downwardly on the other side by the spring washer220. This arrangement can reduce variability in vertical alignment of the nozzle with the tip of the air shroud202.

The nozzle210can have a distal portion that extends from one side of the nozzle collar218to a first end (i.e., a distal or exit end) and a proximal portion that extends from the other side of the nozzle collar218towards a second end (i.e., a proximal or entrance end).

The portion of the nozzle210that is contact with the manifold is illustrated as length L1inFIG.3. Preferably, this length is at least 20% of the length of the portion of the nozzle210that extends from nozzle collar218to the air shroud202. In other embodiments, L1can be at least 30% or at least 40% of the length L2. In some embodiments, the length L1is between 20% and 80% or between 30% and 70% of the length L2.

Another sealing member228(e.g., a silicone O-ring) can be placed over a manifold thread230, or extending portion, adjacent a manifold collar232. The manifold206can be received into the wand body216as shown inFIG.3, such as by engaging opposing threaded portions. In some embodiments, adjacent surfaces can be sized to come into contact to restrict an amount of pressure applied on the sealing member228. For example, in some embodiments, opposing faces of the manifold collar232and wand body216can come into contact with each other to restrict further relative movement (e.g., by causing the face on the manifold collar to “bottom out” on the wand body face). The seal formed by the sealing member228can restrict air from escaping between the two parts and provide a consistent concentric alignment of the manifold within the wand body.

The use of gland end222facilitates easier insertion of the temperature- and solvent-resistant O-ring224. To ensure the O-ring224remains in the desired position, spring washer220puts tension on gland end222to maintain the position of both gland end222and nozzle210. In addition, the L-shape of the gland end222allows a portion of the gland end222to extend into the gland, fully encasing the O-ring224in the gland and restricting movement of the O-ring224out of the gland and negatively impacting the radial seal.FIGS.6A and6Bshow an exemplary gland end222in more detail, including a concentric extending portion223which extends from the main body225to provide the L-shape in the cross-sectional view shown inFIG.3.

The fit and design of the connection between the gland end222and inner tube226in the wand body216, as shown inFIG.3, provide a robust and highly-repeatable connection for seal and nozzle alignment, which advantageously removes operator variability and improves the ease of assembly. In addition, the thickness of the gland end, in conjunction with the spring washer ensures there are no gaps and the nozzle, O-ring, and gland end remain in their desired positions.

Referring again toFIG.3, a boss seal fitting236can be coupled to the inner tube226(e.g., by welding) to connect the inner tube226to the wand216with the threaded fitting. In some embodiments, a centering disk238can also be secured to the inner tube226(e.g., by welding) to provide improved concentric alignment.FIGS.7A and7Bshow an exemplary centering disk238in more detail. The cylindrical centering disk238comprises a central opening239to receive the inner tube226and one or more slots241extending from the central opening239for the sweep gas to pass through.

In some embodiments, the boss seal connection on either side of the wand can be the same, making the connection of the inner tube226and manifold206is independent of wand orientation.

FIG.8illustrates an exploded view of the nozzle assembly shown inFIG.3. As can be seen fromFIG.8, an exemplary assembly method can include the following steps. The swirl insert204can be positioned in the air shroud202, and air shroud202can be pressed into the manifold206. The shroud nut208can be tightened (e.g., hand-tightened). O-ring228(e.g., a silicone AS568-908 O-ring) can be rolled over the manifold threads. The spring washer220and the gland end222can be placed over the short end of the nozzle210with the flat side of the gland end222facing the spring washer220. The nozzle210can then be positioned it into the manifold206, pressing gently until it stops, which ensures that the nozzle tip is positioned as desired, e.g., flush with the tip of the air shroud202. As used herein, the term “flush” refers to two surfaces that are completely or substantially level with one another.

An O-ring (e.g., Kalrez AS568-006) can be pressed into the groove (gland) in the inner tube of the wand body, and pressure applied as needed to seat properly. The O-ring is desirably evenly distributed in the groove (gland) and isn't angled or protruding. To help the O-ring slide into the gland easier, a lubricant, such as ethanol, can be used. Finally, the manifold/nozzle assembly can be threaded into the wand body216until it bottoms out. In this orientation, the flat metal surface below the O-ring of the manifold preferably contacts the metal surface of the wand body.

FIG.9illustrates an exemplary top connection of the nozzle assembly200to an air-liquid manifold240, andFIG.10illustrates an exploded view of this section of the nozzle assembly. Another O-ring242(e.g., a silicone AS568-908) is positioned over threads of the boss seal fitting236and into the groove244. The boss seal fitting236can be threated into the wand216until it bottoms out. The flat metal surface above the O-ring on the threaded inner tube preferably contacts the metal surface of the wand. Another O-ring246(e.g., a silicone AS568-113 O-ring) can be positioned in a groove inside a nozzle wand adapter248. The nozzle wand adapter248can then be threaded onto an end portion250of the threaded inner tube.

A gasket252(e.g., a Teflon® gasket) can be placed onto the nozzle wand adapter248, and the air-liquid manifold240can be threaded onto the nozzle wand adapter248.

Once assembled, fluid at high temperature and pressure can flow through the inner passageway of the inner tube226and into the capillary nozzle210. Upon exiting the nozzle210, the fluid rapidly expands and undergoes a phase change (i.e., the fluid “flash” atomizes as discussed herein). Concurrently, a sheath gas (e.g., nitrogen or other suitable gas) flows through the outer passageway between the inner tube226and wand216, into the manifold206, through the swirl insert204, and exits the air shroud202in the vicinity of the tip of the nozzle210to provide improved atomization and prevent buildup of material at the tip of the nozzle210.

The different structures disclosed herein can vary in their dimensions. For example, the wand body disclosed herein can 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 nozzle length and diameters can also vary. For example, the nozzle overall length can 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 nozzle inner diameter can 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 nozzle inner diameter may vary along its length. For example, in some embodiments, a larger inner diameter portion can be at a proximal end and a smaller inner diameter portion can extend to the distal end. For embodiments in which the inner diameter steps down to a smaller inner diameter, the smaller inner diameter portion can have a length of 3 cm up to 11 cm. Smaller nozzle lengths may, of course, require modifications to other portions of the system. For example, as one of ordinary skill in the art reading this disclosure would understand, a length of the manifold206can be reduced to accommodate a shorter nozzle.

As discussed above, the distal nozzle portion can extend through the air-cap passageway and the distal opening of the air cap can be flush with the nozzle distal end or, in other embodiments, the distal nozzle portion can extend beyond the distal opening of the air cap.FIG.11illustrates the flash nozzle assembly200shown inFIG.3. However, instead of being flush with the distal opening of the air cap, the nozzle distal end extends outward from the distal opening of the air cap.

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., flush) to 3 mm, or in other embodiments, from 0 (e.g., flush) to 2 mm, or in yet other embodiments from 0 (e.g., flush) to 1 mm. In another embodiment, the nozzle distal end extends outward from the distal opening by 0.5 mm to 1.5 mm.

Exemplary Spray Formulations and Feed Suspensions

The systems and methods described herein can be used with a variety of feed stocks. In one embodiment, the feed stock is a feed suspension that comprises an active agent, a matrix material, and a solvent, wherein at least a portion of the active agent, a portion of the matrix material, or a portion of both active agent and matrix material are suspended or not dissolved in the solvent. In some embodiments, the solvent can be an organic solvent. In one embodiment, the feed suspension consists essentially of an active agent, a matrix material, and a solvent. In still another embodiment, the feed suspension consists of an active agent, a matrix material, and a solvent. In yet another embodiment, the feed suspension consists of particles of active agent suspended in a solution of matrix material dissolved in the solvent. It will be recognized that in such feed suspensions, a portion of the active agent and the matrix material may dissolve up to their solubility limits at the temperature of the feed suspension.

As used herein, the term “active agent” refers to a drug, medicament, pharmaceutical, therapeutic agent, nutraceutical, nutrient, or other compound. The active agent may be a “small molecule,” generally having a molecular weight of 2000 Daltons or less. The active agent may also be a “biological active.” Biological actives include proteins, antibodies, antibody fragments, peptides, oligoneucleotides, 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 biological active. In still another embodiment, the active agent is a mixture of a small molecule and a biological active. In yet another embodiment, the compositions made by certain of the disclosed processes comprise two or more active agents.

As used herein, the term “solvent” refers to water or other compounds, such as an organic compound, that can be used to dissolve or suspend the solute. 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. Lower volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used, generally in combination with a volatile solvent. Mixtures of solvents, such as 50% methanol and 50% acetone, can also be used, as can mixtures with water.

As used herein, the term “organic solvent” means a solvent that is an organic compound. In one embodiment, the solvent is volatile, having 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. Lower volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used, generally in combination with a volatile solvent. Mixtures of solvents, such as 50% methanol and 50% acetone, can also be used, as can mixtures with water. In one embodiment, the organic solvent contains less than 50 wt % water. In another embodiment, the organic solvent contains less than 25 wt % water. In still another embodiment, the organic solvent contains less than 10 wt % water. In yet another embodiment, the organic solvent contains less than 5 wt % water. In another embodiment, the organic solvent contains essentially no water.

In some embodiments, the feed suspension can further include an excipient. As used herein, the term “excipient” means a substance that may be beneficial to include in a composition with an active agent. The term “excipient” includes inert substances as well as functional excipients that may result in beneficial properties of the composition. Exemplary excipients include but are not limited to polymers, sugars, salts, buffers, fats, fillers, disintegrating agents, binders, surfactants, high surface area substrates, flavorants, carriers, matrix materials, and so forth.

Exemplary Products

The systems and methods described herein can be used to form a variety of spray-dried products.

For example, the particles may 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 of greater than 10 μm. In still another embodiment, the particles have an average diameter of greater than 20 μm. In still another embodiment, the particles have an average diameter of 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 still another embodiment, the particles have a mass median aerodynamic diameter ranging from 1 μm to 5 μm.

In one embodiment, the plurality of particles produced by the processes and in the apparatuses disclosed herein are inhalable particles that can be inhaled by a subject (e.g., human or animal) As used herein, the term “inhalation” refers to delivery to a subject through the mouth or nose. In one embodiment, the spray-dried particles are delivered to the “upper airways.” The term “upper airways” refers to delivery to 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 airways.” The term “lower airways” refers to delivery to the trachea, bronchi, bronchioles, alveolar ducts, alveolar sacs, and alveoli.

In one embodiment, the particles have a mass median aerodynamic diameter (MMAD) of about 5 to 100 μm. In another embodiment, the particles have a MMAD of about 10 to 70 μm. Mass median aerodynamic diameter (MMAD) is the median aerodynamic diameter based on particle mass. In a sample of particles, 50% of the particles by weight will have an aerodynamic diameter greater than the MMAD, and 50% of the particles by weight will have an aerodynamic diameter smaller 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 can have an MMAD of less than about 20 μm, or even less than about 10 μm. In another embodiment, the particles have a MMAD ranging from 0.5 μm to 10 μm. In still another embodiment, the particles have a MMAD ranging from 1 μm to 5 μm.

In one embodiment, the particles are intended for inhalation and have a MMAD of 0.5 to 100 μm. In another embodiment, the particles are intended for inhalation and have a MMAD of 0.5 to 70 μm.

In one embodiment, the particles are intended for delivery to the upper airways, and have a MMAD of greater than 10 μm. In another embodiment, the particles are intended for delivery to the upper airways and have a MMAD of 10 to 100 μm, and wherein 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 airways and have a MMAD of 10 to 70 μm, and 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 lower airways, and have a MMAD of less than 10 μm. In one embodiment, the particles are intended for delivery to the lower airways, and have a MMAD of 0.5 to 10 μm, and the weight fraction of particles having an aerodynamic diameter of greater than 10 μm is less than 0.1. In another embodiment, the particles are intended for delivery to the lower airways, and have a MMAD of 0.5 to 7 μm, and the weight fraction of particles having an aerodynamic diameter of greater than 7 μm is less than 0.1.

In one embodiment, the concentration of solvent remaining in the particles when they are collected (that is, the concentration of residual solvent) is less than 10 wt % based on the total weight of the particles. In another embodiment, the concentration of residual solvent in the particles when they are collected is less than 5 wt %. In yet another embodiment, the concentration of residual solvent in the particles is less than 3 wt %. In another embodiment, a drying process subsequent to the spray-drying process may 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, incorporated herein by reference.

The nozzle assemblies and systems disclosed herein can provide improvements in assembling and operating spray drying system by providing nozzle assemblies that are easier and more consistent to manufacture, improved concentric alignment of nozzles, including reducing eccentric and vertical alignment of the tip of a nozzle within an air shroud, and increased robustness that can better withstand the elevated temperatures and/or pressures of a spray solution.