Rotating reactor for uniform particle coating with thin films.

Abstract

A method for coating particles with thin organic and inorganic films is provided. [Solution] A method for coating particles, comprising: distributing particles within a rotary vacuum chamber; rotating the rotary vacuum chamber in a first direction along an axial axis of the rotary vacuum chamber; evacuating the rotary vacuum chamber through a vacuum port within the rotary vacuum chamber; rotating a paddle assembly in a second direction so that a plurality of paddles orbit a drive shaft; and injecting a process gas onto the particles through a plurality of gas outlets located on the plurality of paddles, wherein as the plurality of paddles orbit, at least one gas outlet of the plurality of gas outlets is located within a particle bed formed by the particles and permeates the process gas through the particles held within the rotary vacuum chamber.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 683,763, filed June 12, 2018, the disclosure of which is incorporated by reference.

[0002] The present disclosure relates to coating particles, for example particles containing active pharmaceutical ingredients, with thin organic and inorganic films. [Background technology]

[0003] Developing improved formulations of active pharmaceutical ingredients (APIs) is of great interest to the pharmaceutical industry. Formulations can affect the stability and bioavailability of APIs, as well as other properties. Formulations can also affect various aspects of drug product (DP) manufacturing, such as the ease and safety of the manufacturing process.

[0004] Numerous techniques have been developed to encapsulate or coat APIs. Some existing techniques for coating APIs include spray coating, plasma polymerization, hot-wire chemical vapor deposition (CVD), and rotating reactors. Spray coating is an industrially scalable technique that has been widely adopted in the pharmaceutical industry. However, coating non-uniformity (both within a particle and from particle to particle) prevents the use of these techniques to improve the delivery profile or stability of active pharmaceutical ingredients (APIs). Particle agglomeration during spray coating also poses significant challenges. On the other hand, techniques such as plasma polymerization are difficult to scale, are applicable only to certain precursor chemistries, and may result in degradation of sensitive APIs. Hot-wire systems have been developed that utilize a cold substrate as a condensation medium for gases and radicals. Rotating reactors include atomic layer deposition (ALD) and initiated CVD (iCVD) reactors. However, ALD reactors are suitable for inorganic coatings but not for organic polymer coatings, and existing iCVD designs do not adequately prevent API degradation and are not scalable for mass production. Other techniques include polymer mesh coating, pan coating, aerosolized coating, and fluidized bed reactor coating. Summary of the Invention

[0005] In general, one innovative aspect of the subject matter described herein may be embodied in a reactor for coating particles including one or more motors; a rotary vacuum chamber configured to hold a plurality of particles to be coated, a cylindrical portion of the rotary vacuum chamber having an inner diameter, the rotary vacuum chamber coupled to the one or more motors to rotate the rotary vacuum chamber in a first direction about an axial axis of the cylindrical portion of the rotary vacuum chamber; a vacuum port for evacuating gas from the rotary vacuum chamber; a paddle assembly including a rotatable drive shaft extending through the rotary vacuum chamber along the axial axis of the rotary vacuum chamber and at least one paddle extending radially from the drive shaft, the rotatable drive shaft coupled to the one or more motors such that rotation of the drive shaft by the one or more motors causes the at least one paddle to orbit about the drive shaft in a second direction; and a chemical supply system configured to inject a process gas at the particles, the at least one paddle including a gas outlet of the chemical supply system for injecting the process gas at the particles.

[0006] Implementations may include one or more of the following features: In some implementations, the rotation in the first direction is the same rotational sense as the rotation in the second direction, e.g., clockwise or counterclockwise.

[0007] In some embodiments, the gas outlet of the chemical delivery system is located on the rear edge of at least one paddle.

[0008] In some embodiments, the vacuum port is aligned with the axial axis of the rotating vacuum chamber.

[0009] In some embodiments, the at least one paddle is one of a plurality of paddles configured to sweep along an entire length of the rotary vacuum chamber along an axial axis of the rotary vacuum chamber. The at least one paddle may further include an antistatic brush located between outer edges of the paddle and in contact with a surface of the inner diameter of the rotary vacuum chamber.

[0010] In some embodiments, the reactor further comprises a port for supplying particles to or receiving particles from the rotating vacuum chamber.

[0011] In some embodiments, the axial axis of the rotating vacuum chamber is oriented horizontally with respect to gravity.

[0012] In general, another aspect of the subject matter described herein includes one or more motors; a rotary vacuum chamber configured to hold a plurality of particles to be coated, a cylindrical portion of the rotary vacuum chamber having an inner diameter, the rotary vacuum chamber coupled to the one or more motors; a controller configured to cause the one or more motors to rotate the rotary vacuum chamber in a first direction about an axial axis of the cylindrical portion of the rotary vacuum chamber at a rotational speed sufficient to centrifuge the plurality of particles against the inner diameter of the rotary vacuum chamber; a vacuum port for evacuating gas from the rotary vacuum chamber; and a controller configured to rotate the rotary vacuum chamber along the axial axis of the cylindrical portion of the rotary vacuum chamber at a rotational speed sufficient to centrifuge the plurality of particles against the inner diameter of the rotary vacuum chamber. The present invention can be implemented in a reactor for coating particles, the reactor comprising: a paddle assembly including a rotatable drive shaft extending through the member and at least one paddle extending radially from the drive shaft, the rotatable drive shaft being coupled to the one or more motors such that rotation of the drive shaft by the one or more motors causes the at least one paddle to orbit about the drive shaft in a second direction; and a chemical supply system configured to inject a process gas at the particles, the at least one paddle including a gas outlet of the chemical supply system for injecting the process gas at the particles.

[0013] In some embodiments, the controller is configured to cause the one or more motors to rotate the rotary vacuum chamber about the axial axis at a rotational speed greater than 15 RPM. The rotational speed of the drive shaft relative to the rotary vacuum chamber about the axial axis can be at least 4 rpm.

[0014] In some embodiments, the reactor further includes a base for supporting the reactor on a mounting surface, the rotating vacuum chamber being secured to the base with an axial axis perpendicular to the mounting surface.

[0015] In some embodiments, the rotation in the first direction is an opposite rotational sense to the rotation in the second direction.

[0016] In some embodiments, at least one paddle includes a rake-shaped feature including multiple teeth such that the teeth of the paddle contact the particles when the chemical supply system is injecting process gases into the particles. The gas outlet of the chemical supply system can be located at the rear edge of at least one of the multiple teeth of the rake-shaped feature of the paddle. The outer edge of the paddle can be separated from the surface of the inner diameter of the rotary vacuum chamber by a gap, for example a gap of 1-3 mm.

[0017] In some embodiments, at least one paddle includes a T-shaped feature that includes a segment parallel to a surface of the inner diameter of the rotating vacuum chamber.

[0018] In general, another aspect of the subject matter described herein can be practiced in a method that includes dispensing particles into a rotary vacuum chamber; rotating the rotary vacuum chamber in a first direction along an axial axis of the rotary vacuum chamber such that the particles form a toroid on an inner wall of the rotary vacuum chamber; evacuating the chamber through a vacuum port in the rotary vacuum chamber aligned on the axial axis of the rotary vacuum chamber; rotating a paddle assembly in a second direction such that a plurality of paddles orbit a drive shaft; and injecting a process gas into the particles through a plurality of gas outlets located on the plurality of paddles.

[0019] In some embodiments, the methods include coating the particles by atomic layer deposition or molecular layer deposition.

[0020] In general, another aspect of the subject matter described herein includes one or more motors; a rotary vacuum chamber configured to hold a plurality of particles to be coated, a cylindrical portion of the rotary vacuum chamber having an inner diameter and coupled to the one or more motors; a controller configured to cause the one or more motors to rotate the rotary vacuum chamber in a first direction about an axial axis of the cylindrical portion of the rotary vacuum chamber at a rotational speed such that the particles undergo tumbling agitation; a vacuum port for evacuating gas from the rotary vacuum chamber; and a controller configured to rotate the rotary vacuum chamber along the axial axis of the rotary vacuum chamber. The present invention can be implemented in a reactor including a paddle assembly including a rotatable drive shaft extending through the particle and at least one paddle extending radially from the drive shaft, the rotatable drive shaft being coupled to the one or more motors such that rotation of the drive shaft by the one or more motors causes the at least one paddle to orbit about the drive shaft in a second direction, and a chemical supply system configured to inject a process gas at the particles, the at least one paddle including a gas outlet of the chemical supply system for injecting the process gas at the particles.

[0021] In some embodiments, the controller is configured to cause the one or more motors to rotate the rotary vacuum chamber about the axial axis at a rotational speed of less than 6 rpm.

[0022] The rotational speed of the drive shaft relative to the rotating vacuum chamber about the axial axis can be selected such that the relative motion of the paddle 158 within the powder does not cause crushing and / or damage to the powder during the rotational motion of the rotating vacuum chamber and the paddle assembly.

[0023] In some embodiments, the reactor further comprises a stationary vacuum chamber, where the rotating vacuum chamber is disposed within the stationary vacuum chamber.

[0024] In some embodiments, the reactor further comprises a vacuum pump coupled to the stationary vacuum chamber and coupled to the vacuum port to evacuate gas from the rotary vacuum chamber. The chemical delivery system and the one or more motors can be coupled to the stationary vacuum chamber.

[0025] In some embodiments, the rotating vacuum chamber further comprises a surface of the inner diameter of the rotating vacuum chamber having a horizontal baffle or an angled baffle.

[0026] In general, another aspect of the subject matter described herein can be practiced in a method that includes dispensing particles into a rotary vacuum chamber; rotating the rotary vacuum chamber in a first direction along an axial axis of the rotary vacuum chamber such that the particles fill a lower portion of the rotary vacuum chamber as the rotary vacuum chamber rotates in the first direction; evacuating the chamber through a vacuum port in the rotary vacuum chamber aligned on the axial axis of the rotary vacuum chamber; rotating a paddle assembly in a second direction such that a plurality of paddles orbit a drive shaft; and injecting a process gas into the particles through a plurality of gas outlets located on the plurality of paddles.

[0027] In some embodiments, the methods include coating the particles by atomic layer deposition or molecular layer deposition.

[0028] In some embodiments, the particles comprise a core that contains the drug.

[0029] In some embodiments, the rotating vacuum chamber is configured to perform initiated chemical vapor deposition.

[0030] In some embodiments, the method further comprises depositing an organic or inorganic coating on the particles. The organic or inorganic coating can be an inorganic metal oxide. The organic or inorganic coating can be an organic polymer.

[0031] Embodiments may include, but are not limited to, one or more of the following possible advantages: Particles (e.g., API particles) can be coated in a bulk production process, thereby providing lower manufacturing costs and reduced drug price. Particles can be coated with a thin layer(s), thus providing a drug product with an advantageous volume fraction of the API. Furthermore, this process can result in a layer(s) encapsulating the API that is uniform within and between particles, providing more consistent properties to the drug formulation.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0033] Other features and advantages of the invention will become apparent from the following detailed description and drawings, and from the claims. [Brief description of the drawings]

[0034] [Figure 1] FIG. 1 is a schematic front view of an exemplary reactor for ALD and / or CVD coating of particles (e.g., drugs) that includes a rotating vacuum chamber. [Diagram 2] FIG 2 is a schematic side view of the reactor of FIG 1. FIG 2 can be taken along line QQ of FIG 1. [Figure 3A] FIG. 1 is a schematic side view of another exemplary reactor for ALD and / or CVD coating of particles (e.g., drugs) that includes a vertically oriented rotating vacuum chamber. [Figure 3B] FIG. 1 is a schematic side view of another exemplary reactor for ALD and / or CVD coating of particles (e.g., drugs) that includes a vertically oriented rotating vacuum chamber. [Figure 4] FIG. 1 is a schematic front view of another exemplary reactor for ALD and / or CVD coating of particles (e.g., drugs) that includes a rotating vacuum chamber. [Diagram 5] Fig. 5 is a schematic side view of the reactor of Fig. 4. Fig. 5 can be taken along line QQ of Fig. 4. [Figure 6] 3A-C are schematic diagrams of various views of a scoop-shaped paddle, and FIG. 3D are schematic diagrams of various views of a T-shaped paddle with and without an antistatic brush component. [Figure 7] 1A and 1B are schematic side views of the reactor system of FIGS. 1-5 having a T-shaped paddle. [Figure 8] FIG. 1 is a flow diagram of an exemplary process for utilizing a reactor system to coat particles. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Like reference numbers and designations in the various drawings indicate like elements.

[0036] There are various methods for encapsulating API particles. In many cases, these methods result in a relatively thick coating. Although such coatings can impart desirable properties, the high ratio of coating to API can make it difficult to create a drug product with a desired high volume fraction of API. Furthermore, the coating that encapsulates the API can be non-uniform, making it difficult to provide a formulation with consistent properties. Furthermore, coating techniques that can provide a satisfactory consistency have not been scalable for industrial manufacturing.

[0037] One approach that may address these issues is to use a rotating "drum" where the particles are centrifuged against the inner wall of the rotating drum through rotational motion of the drum in a first direction, and a paddle rotating in a second direction (e.g., the same or opposite direction as the first direction) agitates the particle bed. Process gas can be injected into the particle bed through a gas outlet located on the paddle. This allows the process gas to permeate through the particle bed and improve the uniformity of the coating across the particles.

[0038] Another approach that may address these issues is to use a rotating vacuum chamber "drum" where the particles are agitated by both the rotation of the rotating vacuum chamber and the paddles of a paddle assembly rotating relative to the rotating vacuum chamber, and process gas is injected into the particles through gas outlets located on the paddles, allowing the process gas to permeate through the particles and improve the uniformity of the coating across the particles.

[0039] Drugs The term "drug" in its broadest sense includes all small molecule (e.g., non-biological) APIs. Drugs include analgesics, anesthetics, anti-inflammatory drugs, anthelmintics, antiarrhythmic drugs, antiasthmatic drugs, antibiotics, anticancer drugs, anticoagulants, antidepressants, antidiabetic drugs, antiepileptic drugs, antihistamines, antitussives, antihypertensive drugs, antimuscarinic drugs, antibiotics, antineoplastic drugs, antioxidants, antipyretics, immunosuppressants, immunostimulants, antithyroid drugs, antivirals, anxiolytics, sedatives, hypnotics, neuroleptics, astringents, bacteriostatic drugs, beta-adrenergic receptor blocking drugs, blood products, blood substitutes, bronchodilators, buffers, cardiac inotropes, chemotherapy drugs, contrast media, adrenal corticosteroids, and the like. The therapeutic agent may be selected from the group consisting of steroids, antitussives, expectorants, mucolytics, diuretics, dopamine agonists, antiparkinsonian drugs, free radical scavengers, growth factors, hemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, bisphosphonates, prostaglandins, radiopharmaceuticals, hormones, sex hormones, antiallergic drugs, appetite stimulants, anorexics, steroids, sympathomimetics, thyroid agents, vaccines, vasodilators, and xanthines.

[0040] Exemplary classes of small molecule drugs include, but are not limited to, acetaminophen, clarithromycin, azithromycin, ibuprofen, fluticasone propionate, salmeterol, pazopanib HCl, palbociclib, and amoxicillin clavulanate potassium.

[0041] Pharmaceutically acceptable excipients, diluents, and carriers Pharmaceutically acceptable excipients include, but are not limited to, the following: (1) Surfactants and polymers including polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium lauryl sulfate, polyvinyl alcohol, crospovidone, polyvinylpyrrolidone-polyvinyl acrylate copolymers, cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, carbomers and their polymers, emulsifiers, sugar gums, starches, organic acids and their salts, vinylpyrrolidone and vinyl acetate; (2) Binders such as cellulose, cross-linked polyvinylpyrrolidone, and microcrystalline cellulose; (3) fillers such as lactose monohydrate, lactose anhydrous, microcrystalline cellulose, and various starches; (4) Lubricants such as agents that affect the flowability of the powder being compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel; (5) Sweeteners, such as any natural or artificial sweetener, including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K; (6)Fragrance, (7) Preservatives such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic chemicals such as phenol, or quaternary compounds such as benzalkonium chloride; (8) Buffer, (9) Diluents, such as pharma- ceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, calcium hydrogen phosphate, sugars, and / or mixtures of any of the foregoing; (10) Wetting agents, such as corn starch, potato starch, maize starch, and modified starches, and mixtures thereof; (11) Disintegrants such as croscarmellose sodium, crospovidone, and sodium starch glycolate; (12) Effervescent agents such as effervescent couples such as organic acids (e.g., citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid and anhydrides and acid salts), or carbonates (e.g., sodium carbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L-lysine, and arginine carbonate) or bicarbonates (e.g., sodium bicarbonate or potassium bicarbonate).

[0042] Metal Oxide Materials The term "metal oxide material" in its broadest sense includes all materials formed from the reaction of elements considered to be metals with oxygen-based oxidizing agents. Exemplary metal oxide materials include, but are not limited to, aluminum oxide, titanium dioxide, iron oxide, gallium oxide, magnesium oxide, zinc oxide, niobium oxide, hafnium oxide, tantalum oxide, lanthanum oxide, and zirconium dioxide. Exemplary oxidizing agents include, but are not limited to, water, ozone, and inorganic peroxides.

[0043] Atomic Layer Deposition (ALD) Atomic layer deposition is a thin film deposition technique in which the successive addition of self-limiting monolayers of elements or compounds allows the deposition of films with thickness and uniformity controlled to the level of atomic or molecular monolayers. Self-limiting means that only a single atomic layer is formed at a time, and a subsequent process step is required to regenerate the surface and allow further deposition.

[0044] Molecular layer deposition (MLD) Molecular layer deposition is similar to atomic layer deposition, but uses organic precursors to form organic thin films. During a typical MLD process, two homobifunctional precursors are used. A first precursor is introduced into the chamber. Molecules of the first precursor react with reactive groups on the substrate surface via corresponding linking chemistry, adding a molecular layer of the first precursor on the substrate surface with new reactive sites. After purging, a second precursor is introduced and the molecules of the second precursor react with the new reactive sites provided by the first precursor to generate a molecular layer of the first precursor linked to the second precursor. This is followed by another purge cycle.

[0045] Reactor System FIG. 1-2 shows a reactor system 100 for coating particles with a thin film coating. The reactor system 100 can perform coatings using ALD and / or MLD coating conditions. The reactor system 100 allows the deposition process (ALD or MLD) to be performed at higher (greater than 50° C., e.g., 50-100° C.) or lower processing temperatures, e.g., below 50° C., e.g., 35° C. or less. For example, the reactor system 100 can form thin film metal oxides on particles primarily by ALD at temperatures of 22-35° C., e.g., 25-35° C., 25-30° C., or 30-35° C. In general, the particles can remain or be maintained at such temperatures. Thereby, the reactant gases and / or the interior surfaces of the reactor chamber can remain or be maintained at such temperatures. For example, heating can be achieved by heater cartridges embedded in the chamber body, water channels in the chamber body using a heat exchanger, or a heater jacket on the chamber body.

[0046] The reactor system 100 includes a stationary vacuum chamber 110 that surrounds a rotating vacuum chamber 112. The stationary vacuum chamber 110 is surrounded by an outer chamber wall 114. The rotating vacuum chamber 112 is surrounded by an inner chamber wall 116. The chamber walls 114 and 116 can be of a material that is inert to the deposition process (e.g., stainless steel) and / or the interior surfaces of the chamber walls 114 and 116 can be coated with a material that is inert to the deposition process.

[0047] The cross-section of the rotary vacuum chamber 112 (e.g., as viewed along the central axis of the cylinder) may be uniform along the length of the chamber 112 (the length is along the central axis of the cylinder), which may help ensure uniform gas flow along the length of the chamber.

[0048] The stationary vacuum chamber 110 may include one or more vacuum ports 118 for evacuating gases (e.g., process gases) from the stationary vacuum chamber 110 and the rotary vacuum chamber 112. The stationary vacuum chamber includes a gas inlet port 120 coupled to a chemical supply system 122 located outside the stationary vacuum chamber 110. The gas inlet port 120 further couples process gases from the gas inlet port 120 located in the stationary vacuum chamber through a gas supply manifold 124 to a gas inlet port 126 located on a central axis 165 of the rotary vacuum chamber 112. Although the gas supply manifold 124 is depicted generally in FIG. 1 as entering the chamber along the periphery of the cylindrical chamber, in the embodiment described with reference to FIGS. 1 and 2, the gas supply manifold is collinear with the central axis of the chamber 112 through a passage in the drive shaft 156 (e.g., as shown in FIG. 2).

[0049] The system 100 includes one or more motors 130a, 130b external to the stationary vacuum chamber 110 configured to provide torque that translates into rotational motion of one or more components of the system 100. The motors 130a, 130b can be, for example, a drum motor 130a and a paddle motor 130b. The motors 130a and 130b can be, for example, brushless direct current (DC) motors. In some implementations, the motors 130a and 130b incorporate gear reduction, for example, at a ratio of 20:1.

[0050] Drum motor 130a is coupled to rotary vacuum chamber 112 and configured to provide torque that is converted into rotational motion of rotary vacuum chamber 112 during operation of system 100. Paddle motor 130b is coupled to paddle assembly 132 and configured to provide torque that is converted into rotational motion of the paddle assembly during operation of system 100. Although described with reference to Figures 1 and 2 as drum motor 130a and paddle motor 130b, fewer or more motors could be configured to provide torque that is converted into rotational motion of one or more components of system 100.

[0051] The system 100 includes a vacuum source 134 (e.g., one or more vacuum pumps) coupled to the vacuum port 118 via a gas exhaust manifold 136. In some embodiments, a gas source 139 is coupled to the gas exhaust manifold 136 (e.g., a purge gas for diluting process gases exhausted from the system 100). The gas exhaust manifold 136 is configured to establish a vacuum in the stationary vacuum chamber 110 and the rotary vacuum chamber 112. The vacuum source 134 can be an industrial vacuum pump sufficient to establish a pressure of less than 1 Torr (e.g., 1-100 mTorr, e.g., 50 mTorr). The vacuum source 134 allows the chambers 110, 112 to be maintained at a desired pressure and allows reaction by-products and unreacted process gases to be removed.

[0052] The chemical supply system 122 includes a number of fluid sources 138 connected by respective supply tubes 140, controllable valves 142, and fluid supply lines 144. The chemical supply system 122 supplies fluids to a gas supply manifold 124, which injects the fluids in vapor form into the rotating vacuum chamber 112 via a gas inlet port 126. The gas inlet port 126 is further connected to a paddle manifold 164, which is connected to one or more gas outlets 166 (shown in FIG. 2 ) located on at least one paddle 158 of the paddle assembly 132. The chemical supply system 122 may include a combination of restrictors, gas flow controllers, pressure transducers, and thermal mass flow controllers / meters to provide controllable flow rates of various gases into the rotating vacuum chamber 112. The chemical supply system 122 may also include one or more temperature control components (e.g., heat exchangers, resistive heaters, etc.) to heat or cool the various gases before flowing into the chamber 112.

[0053] The chemical supply system 122 may include five fluid sources 138a, 138b, 138c, 138d, 138e. Two of the fluid sources (e.g., fluid sources 138a, 138b) may provide two chemically different precursors or reactants to a deposition process for forming a metal oxide layer on the particles. For example, the first fluid source 138a may provide trimethylaluminum (TMA) or titanium tetrachloride (TiCl4), while the fluid gas source 138b may provide water. The other two fluid sources (e.g., fluid sources 138c, 138d) may provide two chemically different precursors or reactants to a deposition process for forming a polymeric material on the metal oxide layer. For example, the third fluid source 138c may provide adipoyl chloride, and the fourth gas source 138d may provide ethylenediamine. One of the fluid sources (eg, the fifth fluid source 138e) can provide an inert gas (eg, argon or N2) for purging between cycles or half-cycles of the deposition process.

[0054] Although FIG. 1 shows five fluid sources, the use of fewer gas sources could still accommodate the deposition of metal oxide or polymer layers, while the use of more gas sources could enable the formation of a wider range of layered structures.

[0055] For one or more of the fluid sources, the chemical supply system 122 supplies the precursor or reactant in liquid form to the gas supply manifold 124. The chemical supply system 122 may include a vaporizer 146 to convert the liquid to a vapor just before the precursor or reactant enters the gas inlet 120. This reduces the pressure loss upstream, and more pressure loss may occur across the particles 148 in the chamber 112. The more pressure loss occurs across the particles 148, the lower the injection aperture can be placed, and the more likely all of the precursor will react as it traverses the particle bed at a given flow rate. The vaporizer 146 may be directly adjacent to the outer wall of the stationary vacuum chamber 110, for example, fixed to or housed adjacent the gas inlet port 120.

[0056] 1, the gas supply manifold 124 can be utilized to supply multiple precursor or reactant fluid sources 138. A manifold 151 is fluidly coupled to the gas inlet port 120.

[0057] The rotary vacuum chamber 112 is encapsulated within and supported by the stationary vacuum chamber 110. The rotary vacuum chamber 112 includes an inner surface 150 along the inner diameter of the chamber wall 116. In some embodiments, as depicted in Figures 1 and 2, the rotary vacuum chamber includes a cylindrical portion, with the axis of rotation aligned on the central axis of the cylinder. The rotary vacuum chamber 112 is coupled to a vacuum-tight rotary union, which is coupled to the stationary vacuum chamber 110 by threads inside the rotary vacuum chamber 112 via a rotary motion feedthrough 129, as depicted in Figure 2.

[0058] 2, the rotary vacuum chamber 112 is coupled to one or more motors (e.g., drum motor 130a), where the drum motor 130a is operable to generate torque that can be converted into rotational motion of the rotary vacuum chamber in a first direction 152 (e.g., clockwise about an axial axis QQ). The coupling between the rotary vacuum chamber 112 and the one or more motors can be through a rotary motion vacuum feedthrough 128, as depicted in FIG. 2. One or more mechanical couplings 154 can be utilized between the drum motor 130a and the rotary vacuum chamber 112 to convert the torque output from the motor 130a into rotational motion of the rotary vacuum chamber 112 in the first direction 152. In some implementations, the mechanical couplings 154 can be a belt and pulley system, where the belt can be flexible to accommodate some misalignment and runout of the drum motor 130a and the rotary vacuum chamber 112. The motion of the rotary vacuum chamber 112 can be clockwise (CW), counterclockwise (CCW), or alternating CW and CCW. In some embodiments, the port 113 of the rotary vacuum chamber is coupled by a key block to a rotary motion feedthrough 129 for transferring torque between the drum motor 130a and the rotary vacuum chamber 112.

[0059] The paddle assembly 132 includes a drive shaft 156 and one or more paddles 158 coupled to the drive shaft 156. The drive shaft 156 is oriented along an axial axis QQ of the rotary vacuum chamber 112. The paddles 158 are affixed to the drive shaft 156 along its length. The paddles are positioned such that an outer surface 115 of the paddle 158 is spaced a threshold distance (e.g., gap 117) from an inner surface 150 of the rotary vacuum chamber 112. More details about the paddles 158 are provided below.

[0060] The paddle assembly 132 is coupled to one or more motors (e.g., paddle motor 130b) outside the vacuum chamber 110 via a rotary vacuum feedthrough 128 (e.g., including a vacuum compatible bearing). The paddle motor 130b is configured to apply torque to the drive shaft 156 such that the drive shaft 156 rotates in a second direction 160 about the axis of the central axis 118 aligned with the axis QQ of the drive shaft 156. One or more mechanical linkages 162 may be utilized between the paddle motor 130b and the drive shaft 156 to convert the torque output from the motor 130b into rotational motion of the paddle assembly 132 in the second direction 160 (e.g., counterclockwise relative to the axial axis QQ). In some implementations, the mechanical linkages 162 may be a belt and pulley system, where the belt may be compliant to allow for some misalignment and runout of the paddle motor 130b and the drive shaft 156 of the paddle assembly 132. The motion of the drive shaft 156 can be clockwise (CW) or counterclockwise (CCW).

[0061] In some implementations, the rotary motion vacuum feedthrough 128 is a bearing vacuum seal that can be used to seal the stationary vacuum chamber 110 from the outside environment. The drive shaft 156 can then pass through a portion of the stationary vacuum chamber 110 and a port 113 in the rotary vacuum chamber 112 so as to rotate freely relative to the rotary vacuum chamber 112. A lip seal can be positioned between the port 113 and the rotary motion feedthrough 129 to prevent powder in the rotary vacuum chamber 112 from passing down the drive shaft 156 to the bearing of the rotary motion feedthrough 129.

[0062] In some implementations, the first direction 152 and the second direction 160 are opposite directions, e.g., clockwise and counterclockwise. The first direction 152 and the second direction 160 may instead be the same direction, e.g., both clockwise or both counterclockwise.

[0063] The paddle assembly 132 further includes a paddle manifold 164 coupled to the gas inlet port 126. The paddle manifold 164 couples the inlet port 126 to one or more gas outlets 166 located on at least one paddle 158 of the paddle assembly 132. This allows process gas (e.g., reactant or precursor gas) to flow from the chemical delivery system 122 and be injected into the rotating vacuum chamber 112 via the outlets on the paddle 158. In some embodiments, each of the multiple paddles 158a, 158b, 158c of the paddle assembly 132 includes multiple gas outlets 166 coupled to the paddle manifold 164 such that process gas is injected into the rotating vacuum chamber via the multiple gas outlets 166.

[0064] The multiple paddles 158 of the paddle assembly 132 may be distributed (e.g., evenly spaced) along the axial axis of the drive shaft 156 to ensure uniform distribution of process gas injected into the rotary vacuum chamber 112 via gas outlets 166 located on each of the multiple paddles 158.

[0065] 2, the paddles 158 of the paddle assembly 132 are oriented on the drive shaft 156 such that the alignment of the paddles results in little or no lateral gap in the interaction between the paddles 158 and the particles 148. In some embodiments, as shown in FIG. 2, only a portion 159 of the paddles 158 of the paddle assembly 132 contacts the particles 148 during operation of the system 100.

[0066] In some embodiments, due to the rotation of the paddle assembly 132 in the second direction 160, process gas is injected into the rotary vacuum chamber 112 from gas outlets located on the paddle 158 in a direction 168 opposite the instantaneous movement of the paddle 158. In other words, a plurality of gas outlets 166 are located on the rear edge of the paddle 158 such that process gas is injected into the rotary vacuum chamber 112 from the gas outlets 166 in a direction opposite the rotational movement of the paddle 158. In one example, the paddle assembly 132 is rotating in a clockwise direction and process gas is injected into the rotary vacuum chamber 112 in a counterclockwise direction. Further details of the gas outlet configuration are discussed below.

[0067] An inert carrier gas (e.g., N2) may flow into the paddle manifold 164 from one of the fluid sources (e.g., fluid source 138e). During operation, the carrier gas may flow continuously into the paddle manifold 164 (i.e., whether or not a precursor or reactor gas is flowing into the paddle manifold 164). When a precursor or reactor gas is not being injected into the chamber 112 through the manifold 164, the flow of the carrier gas may prevent backflow of another precursor or reactor gas being injected from another manifold into the gas outlet 166. The flow of the carrier gas may also prevent contamination of the gas outlet 166 by particles 148, e.g., blockage of the apertures. Additionally, the carrier gas may provide a purge gas for a purge operation when a precursor or reactor gas is not being injected into the chamber 112.

[0068] A flow of carrier gas into the vaporizer 146 when precursor gas is also flowing can also improve the vaporization of the precursor or reactant liquid. Without being limited by any particular theory, the carrier gas flow can help shear the liquid during aerosolization, which can result in smaller droplet sizes and more rapid vaporization. A flow of carrier gas into the paddle manifold 164 when precursor gas is also flowing can help draw the precursor gas out of the vaporizer 146.

[0069] In some embodiments, one or more temperature control components are integrated into the inner chamber wall 116 to allow for control of the temperature of the rotating vacuum chamber 112, such as resistive heaters, thermoelectric coolers, heat exchangers, or coolants flowing through cooling channels in the chamber wall, or other components in or on the side wall 116.

[0070] The system 100 further includes a controller 170 operable to control operation of at least the chemical delivery system 122 and the one or more motors 130a, 130b. The controller 170 may be configured to operate the paddle motor 130b to generate rotational movement of the paddle assembly 132 in the second direction 160 at a rotational speed of up to 200 revolutions per minute (rpm). The controller 170 may further be configured to operate the drum motor 130a to generate rotational movement of the rotary vacuum chamber 112 in the first direction 152 at a rotational speed of up to 200 rpm (e.g., in the range of 1-60 (rpm)). In some implementations, the controller 170 is configured to operate the drum motor 130a to generate a rotational speed of the rotary vacuum chamber 112 that exceeds a threshold rotational speed (e.g., greater than 15 rpm). 1 and 2, the rotational speed is high enough that the particles 148 are centrifugally forced against the inner surface 150 of the rotary vacuum chamber 112 (which may be referred to as a "high speed" rotational motion). This may result in a toroidal bed of particles 148 on the inner surface 150. The amount of compression of the bed of particles formed by the high speed rotational motion of the rotary vacuum chamber 112 may depend, for example, on the rotational speed of the rotary vacuum chamber 112. The controller 170 may also be coupled to various sensors (e.g., pressure sensors, flow meters, etc.) to provide closed loop control of the chamber rotational speed and the pressure of the gas within the chamber 110.

[0071] In some embodiments, the rotational speed of the drum motor 130a can be selected based on the desired force experienced by particles 148 present within the rotating vacuum chamber 112 during operation of the reactor, as described by equation (1). TIFF0007644061000001.tif8170 where F is the acceleration of the rotating vacuum chamber 112 (e.g., revolutions per minute squared (rpm 2 ) multiplied by the radius r of the rotating vacuum chamber 112. When a threshold amount of force is exceeded, the particle 148 is forced centrifugally against the inner surface 150 of the rotating vacuum chamber 112. The amount of force F depends in part on the radius of the rotating vacuum chamber 112, which may be in the range of, for example, 100-300 mm. In one example, the radius of the rotating vacuum chamber 112 is 215 mm.

[0072] In general, the controller 170 is configured to operate the reactor system 100 according to a "recipe." The recipe specifies operating values ​​for each controllable element as a function of time. For example, the recipe may specify the time that the vacuum source 132 operates, the time and flow rate of each gas source 138a-138e, the rotational speed of the rotating vacuum chamber 114 and the drive shaft 156 as set by the motors 130a, 130b, etc. The controller 170 may receive the recipe as computer-readable data (e.g., stored in a non-transitory computer-readable medium).

[0073] The system 100 further includes a first loading port 172 located on the stationary vacuum chamber 110 and a second loading port 174 located on the rotating vacuum chamber 112, which can be aligned to allow access to the interior of the rotating vacuum chamber 112 for transporting particles 148 to be processed. The first loading port 172 and the second loading port 174 can be sealed during operation of the reactor system 100 such that the ports maintain a vacuum established within the respective vacuum chambers. Methods for operation of the reactor system 100 are described in further detail below.

[0074] The system 100 further includes a particle filter 176 that allows gas to be exhausted from the rotary vacuum chamber 112 via a vacuum port 118 located in the stationary vacuum chamber 110. In some embodiments, as depicted in FIG. 2, the vacuum port 118 for the system 100 is aligned with the drive shaft 156 along the QQ axis. In addition, the system 100 may include a filter cleaner to remove particles from the filter 176. As one example, the filter cleaner may be a mechanical knocker to knock the filter, which shakes off the particles from the filter. As another example, the gas source 139 may periodically supply a pulse of an inert gas (e.g., nitrogen) to the exhaust manifold 136 between the vacuum port 118 and the vacuum source 134. The pulse of gas may pass back through the filter 176 toward the chamber 112, blowing the particles off the filter 176. Isolation valves 139a, 139b may be used to ensure that only one of the gas source 138 or vacuum source 134 is fluidly connected to the exhaust manifold 136 at a time.

[0075] The reactor system 100 can include a base 173 for supporting the reactor 100 on a mounting surface 171. In some embodiments, the reactor system 100 is secured to the base 173 such that the axial axis 165 is perpendicular to the mounting surface 171. As a result, assuming a horizontal mounting surface 171, the drive shaft and the axial axis 165 are oriented parallel to gravity, i.e., vertically. Figure 3A is a schematic side view of another exemplary reactor for ALD and / or CVD coating of particles (e.g., drugs) including a vertically oriented rotating vacuum chamber 100'.

[0076] 1 and 2, the reactor system 100 is fixed to a base 173 such that the axial axis 165 and the drive shaft 156 are perpendicular to a mounting surface 171. As a result, assuming a horizontal mounting surface, the axis of rotation of the rotating vacuum chamber 114 is perpendicular to gravity.

[0077] 3A, the vertical drive shaft 157 is coupled to the vertically oriented rotary vacuum chamber 135 at a bottom surface 174 of the rotary vacuum chamber 135. In some embodiments, the vertical drive shaft 157 can instead be coupled to the vertically oriented rotary vacuum chamber 135 at a surface 175 of the rotary vacuum chamber 135.

[0078] During operation of the reactor system 100′ depicted in FIG 3A, the controller 170 is configured to operate the drum motor 130a to generate a rotational speed of the vertically oriented rotary vacuum chamber 135 that is high enough to centrifugally force the particles 148 against the inner surface 150 of the vertically oriented rotary vacuum chamber 135. This can result in a toroidal bed of the particles 148 on the inner surface 150.

[0079] In some embodiments, a vacuum port 119 for evacuating gases from the chamber 113 is located on a side of the stationary vacuum chamber 110. The vacuum port 119 may be oriented opposite the rotary vacuum feedthrough 128 that connects the drive shaft 157 into the chamber 113.

[0080] FIG. 3B is a schematic side view of another exemplary reactor for ALD and / or CVD coating of particles (e.g., drugs) that includes a vertically oriented rotating vacuum chamber 100″. As depicted in FIG. 3B , a vertical drive shaft 157 is coupled to the vertically oriented rotating vacuum chamber 135 at a bottom surface 174 of the rotating vacuum chamber 135. In some embodiments, the vertical drive shaft 157 can instead be coupled to the vertically oriented rotating vacuum chamber 135 at a surface 175 of the rotating vacuum chamber 135.

[0081] Additionally, the reactor 100″ includes an inner wall 149 (e.g., defining an inner periphery) within the rotary vacuum chamber 135 that separates a first region 151 of the rotary vacuum chamber configured to receive the particles 148 from a second region 153 not configured to receive the particles 148. The paddle 158 of the paddle assembly 133 is coupled to the drive shaft 157 such that the paddle 158 and at least one gas outlet 166 located on the paddle 158 are located partially within the first region 151. During operation of the reactor system 100′ depicted in FIG. 3B , the controller 170 is configured to operate the drum motor 130a to generate a rotational speed of the vertically oriented rotary vacuum chamber 135 such that the particles within the chamber 135 do not form a toroid with respect to the inner surface 150 of the rotary vacuum chamber 135.

[0082] 4-5 show another exemplary reactor system 100''' for coating particles with a thin film coating. The reactor system 100''' is capable of performing coatings using ALD and / or MLD coating conditions.

[0083] In some implementations, the rotational speed of the rotary vacuum chamber 112 is below a threshold rotational speed (e.g., below 15 rpm), and the particles 148 within the rotary vacuum chamber undergo tumbling agitation while the rotary vacuum chamber 112 is in rotational motion. For example, the chamber 112 may rotate at 6-15 rpm. At a sufficiently low rotational speed, the particles within the chamber 112 do not form a toroid with respect to the inner surface 150 of the rotary vacuum chamber 112. The controller 182 is configured to operate the drum motor 130a to generate a rotational speed of the rotary vacuum chamber 112 in the first direction 152 that is below the threshold rotational speed.

[0084] During operation of the reactor system 100''', the particles transported to the rotary vacuum chamber 112 form a particle bed 178 located below a lower portion 180 inside the rotary vacuum chamber 112 against gravity. As the rotary vacuum chamber 112 rotates about an axial axis defined by QQ, the particles in the particle bed 178 undergo tumbling agitation. Some of the particles may briefly rise due to the rotation, but fall back into the powder bed due to gravity. Thus, most or all of the particles remain in the lower portion 180 of the rotary vacuum chamber 112.

[0085] In some implementations, the rotary vacuum chamber 112 rotates at a rotational speed below a threshold rotational speed (e.g., a speed of 6-15 RPM). The controller 170 can be configured to operate the drum motor 130a to generate rotational motion in alternating directions (e.g., alternating between clockwise and counterclockwise) within the rotary vacuum chamber 112. This can aid in agitation of the particles to improve coating uniformity. The speed of the alternating direction, e.g., the amount of time the chamber 112 rotates in a first direction versus a second direction, can be selected based on the particular recipe and / or particles 178 being coated by the reactor system 100''.

[0086] 4 and 5, one or more paddles 158 of the paddle assembly 132 do not contact the particle bed 178 at a given time during a rotation of the paddle assembly about an axial axis defined by QQ. For example, paddle 158a contacts the particle bed 178, and paddles 158b and 158c do not contact the particle bed 178 at any given moment of rotation of the paddle assembly 132.

[0087] 4, the rotating vacuum chamber 112 rotates in a first direction 152 and the paddle assembly 132 rotates in a second, opposite direction 160. The centers of rotation of the rotating vacuum chamber 112 and the paddle assembly 132 are on the same axial axis that is aligned with the center of the cylindrical portion of the rotating vacuum chamber 112.

[0088] In some embodiments, the rotary vacuum chamber 112 includes a baffle on the inner surface 150 of the chamber 112, and the baffle can be oriented to move particles from the particle bed 178 from a first side of the rotary vacuum chamber 112 to a second side of the rotary vacuum chamber 112 as the rotary vacuum chamber 112 rotates about an axial axis at a rotational speed in a first direction 152.

[0089] As described above with reference to Figures 1 and 2, the paddles 158 of the paddle assembly 132 can have various configurations. Here, three variations on the paddle design of the paddle assembly are described. However, alternative embodiments with similar functions can be envisioned. In general, the shape and orientation of the paddles 158 of the paddle assembly 132 are selected such that the paddles 158 of the paddle assembly 132 provide mechanical agitation of the particles 148 (and / or particle bed 178) present in the rotating vacuum chamber 112 during operation of the reactor system (e.g., reactor system 100, 100', 100'''). The paddles 158 further include one or more gas outlets 166 located on the paddles 158 for injecting process gas from the chemical distribution system 122 into the rotating vacuum chamber 112 during operation of the reactor system 100, 100', 100'''. The paddles 158 are secured onto and oriented along a drive shaft (e.g., drive shaft 156) to provide substantially uniform coverage of mechanical agitation and process gas injection along the length of the cylindrical portion of the rotary vacuum chamber 112 during operation of the reactor system 100, 100', 100''' (e.g., during rotational movement of the paddle assembly 132 in the second direction 160).

[0090] As depicted in FIGS. 1-5, the paddle 158 of the paddle assembly 132 can be a scoop-shaped paddle. FIGS. 6A-6C are schematic diagrams of various views of a scoop-shaped paddle 600. As depicted in FIG. 6A, the scoop-shaped paddle 600 includes a base shaft 602 that is coupled to a drive shaft of the paddle assembly (e.g., drive shaft 156 of the paddle assembly 132). The paddle further includes a crossbar 604 that is coupled to the base shaft 602 of the paddle 600 and a number of tines 606 that are each coupled to the crossbar 604 and extend away from a base 608 of the paddle 600. The number of tines 606 can have a length in the range of 50-100 mm (e.g., 78 mm). The contour of the tines 606 can be selected such that the tines 606 move gently through the powder as the paddle assembly rotates. In one example, the tines 606 are teardrop-shaped.

[0091] In some embodiments, the dimensions of paddle 600 (e.g., length of base shaft 603 and length 605 of teeth 606) may be selected such that when paddle 600 is secured to a drive shaft of a paddle assembly (e.g., drive shaft 156 of paddle assembly 132), the distance (e.g., gap 117) between outer surfaces 607 (e.g., outer surfaces 115) of teeth 606 of paddle 600 is less than a threshold distance (e.g., 1-3 mm) from an inner surface of a rotating vacuum chamber (e.g., rotating vacuum chamber 112).

[0092] The base shaft 602, cross bar 604, and tines 606 each have internal piping and / or passages 610 that are connected to a paddle manifold (e.g., paddle manifold 164). Process gases may flow 612 through the base shaft 602, into the cross bar 604, and into the tines 606 via the internal piping and / or passages 610. FIG. 6B shows a “top down” view C illustrating an example location of the internal piping and / or passages 610 within the tines 606 of the paddle 600.

[0093] 6C, the process gas is then injected into the rotary vacuum chamber (e.g., rotary vacuum chamber 112) through multiple gas outlets 614 (e.g., gas outlets 166) located on the paddle 600, such as one or more gas outlets 614 located on each tooth 606. The gas outlets 614 can have a diameter in the range of 0.5-3 mm (e.g., 1 mm diameter) and the spacing between adjacent gas outlets 614 can be in the range of 5-15 mm (e.g., 8 mm spacing). The number of gas outlets 614 per tooth 606 can be in the range of 5-20 gas outlets 614 (e.g., 7 gas outlets 614 per tooth 606). The gas outlets 614 can be positioned on the tooth 606 along a line that bisects the width of the tooth 606.

[0094] In some implementations, the gas outlets 614 are located on the teeth 606 of the paddle 600. For example, each tooth 606 can have a single gas outlet 614. The gas outlets 614 are located on a surface, indicated by B, of each tooth 606 that corresponds to the trailing edge of the paddle 600 when the paddle 600 rotates about the second direction (e.g., the second direction 160) within the rotary vacuum chamber 112. Although shown in FIG. 6C as the gas outlets 614 aligned along axis DD with evenly distributed spacing 616 between each gas outlet 614, the gas outlets can be offset relative to one another and / or have variable spacing.

[0095] In some implementations, the paddles of the paddle assembly (e.g., paddle assembly 132) are T-shaped. Figures 6D-6G are schematic diagrams of various views of a T-shaped paddle 650 with and without an antistatic brush component 664. As depicted in Figure 6D, the T-shaped paddle 650 includes a base shaft 652 and a crossbar 654, where the base shaft 652 is coupled to a drive shaft of the paddle assembly (e.g., drive shaft 156 of paddle assembly 132) and the crossbar 654 is located at an end 656 of the base shaft 652 opposite the face where the base shaft 652 is coupled to the drive shaft.

[0096] In some embodiments, the dimensions of paddle 650 (e.g., length 651 of base shaft 652 and width 653 of crossbar 654) can be selected such that when paddle 650 is secured to a drive shaft of a paddle assembly (e.g., drive shaft 156 of paddle assembly 132), the distance (e.g., gap 117) between surfaces 655 (e.g., surfaces 115) of crossbar 654 is less than a threshold distance (e.g., 1-3 mm) from an inner surface of a rotary vacuum chamber (e.g., rotary vacuum chamber 112).

[0097] The base shaft 652 and crossbar 654 each have internal piping and / or passages 610 that are coupled to a paddle manifold (e.g., paddle manifold 164). Process gases may flow 630 through the base shaft 652 and into the crossbar 654 via the internal piping and / or passages 610. Figure 6E shows a "top-down" view C illustrating an example location of the internal piping and / or passages 610 within the crossbar 654 of the paddle 650.

[0098] 6F, the process gas is then injected into the rotary vacuum chamber (e.g., rotary vacuum chamber 112) via multiple gas outlets 658 (e.g., gas outlets 166) located on the paddle 650, such as one or more gas outlets 658 located on the crossbar 54. The gas outlets 658 can have a diameter in the range of 0.5 mm-3 mm (e.g., 1 mm diameter) and the spacing between the gas outlets 658 can be in the range of 5-15 mm (e.g., 10 mm between each gas outlet 658). The number of gas outlets 658 located on each paddle 650 can be in the range of 5-20 gas outlets 658 (e.g., 8 gas outlets). In some embodiments, the plurality of gas outlets 658 are located on a crossbar 654 of the paddle 650, the plurality of gas outlets 658 being located on a surface, indicated by E, of the crossbar 654 that corresponds to the trailing edge of the paddle 650 when the paddle 650 is rotating about the second direction (e.g., the second direction 160) within the rotary vacuum chamber 112. Further details of the paddle assembly, including the T-shaped paddle 650, are discussed below with reference to Figures 7A and 7B.

[0099] 6F is shown as a plurality of gas outlets 654 aligned along axis GG with evenly distributed spacing 660 between each gas outlet 658, the plurality of gas outlets may be offset relative to one another and / or have variable spacing. The plurality of gas outlets 658 may be distributed in multiple rows and / or multiple patterns on the surface of the crossbar's trailing edge surface, indicated by E, on the trailing edge of the paddle 650, where the configuration of the plurality of gas outlets 658 may be selected to optimize a substantially even distribution of process gas injected by the paddle assembly into the rotary vacuum chamber (e.g., the rotary vacuum chamber 112 by the paddle assembly 132).

[0100] In some implementations, the T-shaped paddle 650 further includes an antistatic brush component 662 located on the outer surface 655 of the crossbar 654, as shown in FIG. 6G. The antistatic brush component 662 can be constructed of a semi-flexible material (e.g., high temperature inert rubber / plastic, thin aluminum fins, etc.). The material of the antistatic brush 662 can be selected to contact the inner surface of the rotating vacuum chamber to sweep particles (e.g., particles 148 and / or particle bed 178) from the inner surface of the rotating vacuum chamber during the rotational movement of the paddle assembly. The material of the antistatic brush component 662 can further be selected to avoid damage to the inner surface of the rotating vacuum chamber (e.g., avoid scratching or denting the surface) due to contact between the antistatic brush component 662 and the inner surface of the rotating vacuum chamber 112.

[0101] When the paddle 650 is fixed and oriented on the drive shaft of a paddle assembly in the rotary vacuum chamber (e.g., the drive shaft 156 of the paddle assembly 132 in the rotary vacuum chamber 112), the anti-static brush component 662 is located between the end faces 655 of the T-shaped paddle 650 and contacts the inner surface of the rotary vacuum chamber (e.g., the inner surface 150 of the rotary vacuum chamber 112).

[0102] In some embodiments, the antistatic brush component 662 includes a plurality of fins 664, and the density and / or spacing of the fins 664 of the antistatic brush component 662 can be selected to ensure coverage of the entire length of the inner surface of the rotating vacuum chamber throughout a complete rotation (e.g., 360 degrees) of the paddle assembly relative to the rotating vacuum chamber.

[0103] In some embodiments, the reactor systems 100, 100', and 100''' described with reference to Figures 1-5 can include a T-shaped paddle 650. Figures 7A and 7B are schematic side views of the reactor system of Figures 1-5 with a T-shaped paddle (e.g., T-shaped paddle 650). The gap 117 between the surface 115 of the crossbar 654 of the T-shaped paddle 650 and the inner surface 150 of the rotating vacuum chamber 112 can be less than a threshold distance (e.g., less than 3 mm).

[0104] In some embodiments, the spacing 702 of the T-shaped paddles 650 of the paddle assembly 132 along the axial axis QQ may be selected such that during rotational motion of the paddle assembly 132, there is substantially uniform mechanical agitation and process gas injection across the multiple paddles 650 along the length of the cylindrical portion of the rotary vacuum chamber 112. In some embodiments, the spacing 702 may be zero or less than zero (e.g., the T-shaped paddles 650 may overlap).

[0105] In some implementations, as described with reference to Figure 7B, the T-shaped paddle 650 can include an antistatic brush component 662. Figure 7B is a schematic side view of the reactor system of Figures 1-5 with a T-shaped paddle including an antistatic brush component. The antistatic brush component 662 located on the T-shaped paddle 650 of the paddle assembly 132 is in contact with the inner surface 150 of the rotating vacuum chamber 112.

[0106] Reactor system operation 8 is a flow diagram of an exemplary process utilizing a reactor system to coat particles. In a first step, particles are dispensed (802) into a rotating vacuum chamber. As described with reference to FIGS. 1-7, a reactor system (e.g., reactor systems 100, 100', and 100''') includes an outer stationary vacuum chamber 110 and an inner rotating vacuum chamber 112, where loading ports (e.g., loading ports 172, 174) on each of the stationary and rotating vacuum chambers can be aligned to allow transfer / unloading of particles to be coated into the reactor system.

[0107] The particles (e.g., particle 148) can have a solid core that includes a drug (e.g., one of the drugs described above). The solid core can also optionally include an excipient. Once any loading ports (e.g., loading ports 172, 174) are sealed, a controller (e.g., controller 170) operates a reactor system (e.g., reactor system 100, 100', 100''') according to a recipe to form a thin metal oxide layer and / or a thin polymer layer on the particles.

[0108] The rotary vacuum chamber is rotated along a first direction along an axial axis of the rotary vacuum chamber such that the particles form a toroid on the inner wall of the rotary vacuum chamber (804). In some implementations, a controller (e.g., controller 170) is configured to operate a drum motor (e.g., drum motor 130a) to generate rotational motion within the rotary vacuum chamber (e.g., rotary vacuum chamber 112) at a rotational speed greater than a threshold rotational speed such that the particles form a toroid on the inner wall 150 of the rotary vacuum chamber 112. The threshold rotational speed can be, for example, a rotational speed of 10 RPM, 12 RPM, 15 RPM, etc.

[0109] In some implementations, the controller is configured to operate the drum motor to generate rotational movement of the rotary vacuum chamber at a rotational speed of the rotary vacuum chamber that is less than a threshold rotational speed. For a rotational speed that is less than the threshold rotational speed, the rotary vacuum chamber is rotated (805) in a first direction along an axial axis of the rotary vacuum chamber such that particles fill a lower portion of the rotary vacuum chamber when the rotary vacuum chamber is rotating in the first direction. The rotational speed that is less than the threshold rotational speed can be in the range of 6-15 RPM, for example. In one example, the rotary vacuum chamber 112 rotates in the first direction 152 and the lower portion 180 of the rotary vacuum chamber 112 is filled with the particle bed 178 such that particles in the particle bed 178 undergo tumbling agitation.

[0110] The rotary vacuum chamber is evacuated (806) through a vacuum port in the rotary vacuum chamber aligned on the axial axis of the rotary vacuum chamber. In some embodiments, the vacuum source 134 evacuates the rotary vacuum chamber 112 through the stationary vacuum chamber 110 (e.g., via filter 176) and through the exhaust manifold 134. A low pressure environment can be established within the rotary vacuum chamber 112, for example, at a pressure less than 1 Torr, for example, 1-500 mTorr, for example, down to 50 mTorr.

[0111] The paddle assembly is rotated (808) in a second direction such that the multiple paddles orbit the drive shaft. In some implementations, the controller 170 is configured to operate the paddle motor 130b to generate rotational movement of the paddle assembly 132 in the second direction 160 at a second rotational speed. The second rotational direction of the paddle assembly 132 may be the same direction as or opposite to the first rotational direction of the rotary vacuum chamber 112. The controller 170 may be configured to operate the paddle motor 130a to generate rotational movement of the paddle assembly 132 at a rotational speed of up to 200 rpm.

[0112] Process gas is injected into the particles through multiple gas outlets located on the multiple paddles (810). In some embodiments, the reactor system performs ALD and / or MLD thin film coating processes by introducing gas precursors of the coating into the rotating vacuum chamber 112. The gas precursors are alternatively spiked into the rotating vacuum chamber 112. This allows the deposition process to be a solvent-free process. The half-reactions of the deposition process are self-limiting, providing angstrom or nanometer level deposition control. Additionally, ALD and / or MLD can be performed at low temperature conditions (e.g., below 50° C., e.g., below 35° C.). The flow rate of the process gas can be selected based on the type of process gas being injected. For example, the flow rate of HO process gas can be 1-2 standard liters per minute (slm) of vaporized precursor for 10 kg of powder. In another example, the flow rate of HO process gas could be in the range of 0.5-1 slm for low surface area powders. In another example, TMA or TiCl4 can have a volumetric flow rate of less than 1 slm, for example. In another example, the carrier gas flow rate can be in the range of, for example, 1-3 slm for 10-15 kg of powder.

[0113] Suitable reactants for ALD processes include any or a combination of monomer vapors, metal organics, metal halides, oxidizers such as ozone or water vapor, and polymer or nanoparticle aerosols (dry or wet). For example, the first fluid source 142a may provide gaseous trimethylaluminum (TMA) or titanium tetrachloride (TiCl4), and the second gas source 138b may provide water. For MLD processes, by way of example, the liquid source 142c may provide adipoyl chloride, and the fourth liquid 142d may provide vaporizable or gaseous ethylenediamine.

[0114] In some embodiments, one of the process gases flows from the chemical delivery system 122 through a gas outlet 166 located on the paddle 158 of the paddle assembly 132 to the particles 148 as the paddle assembly 132 rotates. The rotation of the paddle assembly 132 agitates the particles, keeping them separated and ensuring that a large surface area of ​​the particles remains exposed, allowing for rapid and uniform interaction of the particle surfaces with the process gas.

[0115] For both the ALD and MLD processes, two reactant gases are alternately supplied to the rotating vacuum chamber 112, and each step of supplying a reactant gas is followed by a purge cycle in which an inert gas is supplied to the chamber 112 to push out the reactant gas and by-products used in the previous step.

[0116] In some embodiments, the reactor system is operated in a continuous flow mode of operation, e.g., for an ALD process. During an ALD process, the controller 170 can operate the reactor system (e.g., reactor system 100, 100', 100''') as follows: In a first reactant half-cycle, the drum motor 130a rotates the rotary vacuum chamber 112 and the paddle motor 130b rotates the paddle assembly 132 to agitate the particles 148. i) The chemical delivery system 122 is operated to flow a first reactant gas (e.g., TMA) from a gas source 138a through a gas outlet 166 located on the paddle 158 into the rotating vacuum chamber 112 until the particles 148 (e.g., particle bed 178) are saturated with the first reactant gas. For example, the first reactant gas may flow at a particular flow rate and for a particular time, or until a sensor measures a particular first pressure or partial pressure of the first reactant gas in the chamber 112. In some embodiments, the first reactant gas is mixed with an inert gas as it flows into the chamber. The particular pressure or partial pressure may be from 0.1 Torr to half the saturation pressure of the reactant gas. ii) The flow of the first reactant gas is stopped and the vacuum source 134 evacuates the chamber 112 to a pressure, for example, less than 1 Torr, for example, 1-100 mTorr, for example, 50 mTorr.

[0117] These steps (i)-(ii) can be repeated a number of times set by the strategy, for example 2-10 times.

[0118] Next, in a first purge cycle, drum motor 130a rotates rotary vacuum chamber 112 and paddle motor 130b rotates paddle assembly 132 to agitate particles 148. iii) The chemical delivery system 122 is operated to flow only an inert gas (e.g., N2) from the gas source 138e into the chamber 112 via the gas outlet 166 located on the paddle 158 of the paddle assembly 132. The inert gas may flow at a particular flow rate and for a particular time or until a sensor measures a particular second pressure of the inert gas in the chamber 112. The second particular pressure may be 1-100 Torr. iv) The vacuum source 134 evacuates the chamber 112 to a pressure, for example less than 1 Torr, for example 1-500 mTorr, for example 50 mTorr.

[0119] These steps (iii)-(iv) can be repeated a number of times as determined by the strategy, for example 6-20 times.

[0120] In the second reactant half-cycle, drum motor 130 a rotates rotary vacuum chamber 112 and paddle motor 130 b rotates paddle assembly 132 to agitate particles 148 . v) The chemical delivery system 122 is operated to flow a second reactant gas (e.g., HO) from the gas source 138b through the gas outlet 166 located on the paddle 158 of the paddle assembly 132 into the chamber 112 until the particles 148 are saturated with the second reactant gas. Again, the second reactant gas may flow at a particular flow rate, for a particular time, or until a sensor measures a particular third pressure or partial pressure of the second reactant gas in the chamber 112. In some embodiments, the second reactant gas is mixed with an inert gas as it flows into the chamber. The third pressure may be 0.1 Torr to half the saturation pressure of the second reactant gas. vi) A vacuum source 134 evacuates the chamber 112, for example to a pressure less than 1 Torr, for example 1-500 mTorr, for example 50 mTorr.

[0121] These steps (v)-(vi) can be repeated as many times as determined by the strategy, for example 2-10 times.

[0122] A second purge cycle is then performed, which may involve steps (vii) and (vii) and may be identical to the first purge cycle or may have a different number of repetitions of steps (iii)-(iv) and / or a different specific pressure.

[0123] The cycle of a first reactant half cycle, a first purge cycle, a second reactant half cycle, and a second purge cycle can be repeated a number of times set by the recipe, for example, 1-10 times.

[0124] Although the operation is described above using an ALD process, the operation is similar for MLD. In particular, in steps (i) and (v), the reactant gas is replaced with an appropriate process gas and pressure for the deposition of the polymer layer. For example, step (i) can use vapor or gaseous adipoyl chloride and step (v) can use vapor ethylenediamine.

[0125] Additionally, although operation is described above using an ALD or MLD process, the system could be used for a chemical vapor deposition (CVD) process, in which case both reactants would be flowed simultaneously into chamber 110 to react within the chamber, e.g., during step (i), and the second reactant half-cycle could be omitted.

[0126] In some embodiments, the reactor system (e.g., reactor system 100, 100', 100''') operates in a pulsed flow operating mode, where one or more of the gases (e.g., reactive gases and / or inert gases) can be supplied in a pulse in which the chamber 112 is filled with gas to a particular pressure, a delay time is allowed to elapse, and the chamber is evacuated by the vacuum source 134 before the next pulse begins.

[0127] In particular, for an ALD process, the controller 170 can operate the reactor system 100 as follows.

[0128] In the first reactant half-cycle, drum motor 130 a rotates rotary vacuum chamber 112 and paddle motor 130 b rotates paddle assembly 132 to agitate particles 148 . i) The chemical delivery system 122 is operated to flow a first reactant gas (e.g., TMA) from the gas source 138a into the chamber 112 through the gas outlet 166 located on the paddle 158 of the paddle assembly 132 until a first particular pressure is achieved in the chamber 112. The particular pressure can be from 0.1 Torr to half the saturation pressure of the reactant gas. ii) The flow of the first reactant gas is stopped and a certain delay time is allowed to elapse, for example as measured by a timer in the controller, to allow the first reactant to flow past the particles 148 in the rotating vacuum chamber 112 and react with the surfaces of the particles. iii) The vacuum source 134 evacuates the chamber 112 to a pressure, for example less than 1 Torr, for example 1-100 mTorr, for example 50 mTorr.

[0129] These steps (i)-(iii) can be repeated a number of times as determined by the strategy, for example 2-10 times.

[0130] Next, in a first purge cycle, drum motor 130a rotates rotary vacuum chamber 112 and paddle motor 130b rotates paddle assembly 132 to agitate particles 148. iv) The chemical delivery system 122 is operated to flow an inert gas (e.g., N2) from the gas source 138e into the chamber 112 through the gas outlet 166 located on the paddle 158 of the paddle assembly 132 until a second specified pressure is achieved. The second specified pressure can be 1-100 Torr. v) The flow of inert gas is stopped and a certain delay time is allowed to elapse, for example as measured by a timer in the controller, to allow the inert gas to diffuse through the particles in the particle bed 10 and displace the reactant gas and any vaporous by-products. vi) A vacuum source 132 evacuates the chamber 112, for example to a pressure less than 1 Torr, for example 1-500 mTorr, for example 50 mTorr.

[0131] These steps (iv)-(vi) can be repeated a number of times as determined by the strategy, for example 6-20 times.

[0132] In the second reactant half-cycle, drum motor 130 a rotates rotary vacuum chamber 112 and paddle motor 130 b rotates paddle assembly 132 to agitate particles 148 . vii) The chemical delivery system 122 is operated to flow a second reactant gas (e.g., HO) from the gas source 138b into the chamber 112 through a gas outlet 166 located on the paddle 158 of the paddle assembly 132 until a third specified pressure is achieved. The third pressure can be from 0.1 Torr to half the saturation pressure of the reactant gas. viii) The flow of the second reactant gas is stopped and a certain delay time is allowed to elapse, for example as measured by a timer in the controller, to allow the second reactant gas to flow through the particles 148 and react with the surfaces of the particles in the rotating vacuum chamber 112. ix) A vacuum source 134 evacuates the chamber 112, for example to a pressure less than 1 Torr, for example 1-500 mTorr, for example 50 mTorr.

[0133] These steps (vii)-(ix) can be repeated as many times as determined by the strategy, for example 2-10 times.

[0134] A second purge cycle is then performed which may be identical to the first purge cycle or may have a different number of repetitions of steps (iv)-(vi) and / or a different delay time and / or a different pressure.

[0135] The cycle of a first reactant half cycle, a first purge cycle, a second reactant half cycle, and a second purge cycle can be repeated a number of times set by the recipe, for example, 1-10 times.

[0136] Additionally, one or more of the gases (e.g., reactive gases and / or inert gases) may be supplied in a pulse in which the rotating vacuum chamber 112 is filled with gas to a particular pressure, a delay time is allowed to elapse, and the chamber is evacuated by the vacuum source 134 before the next pulse begins.

[0137] The operation is described above using an ALD process, but is similar for MLD. In particular, in steps (i) and (vii), the reactant gas is replaced with an appropriate process gas and pressure for the deposition of the polymer layer. For example, step (i) can use vapor or gaseous adipoyl chloride, and step (vii) can use vaporous ethylenediamine.

[0138] Additionally, although operation is described above using an ALD or MLD process, the system could be used for a chemical vapor deposition (CVD) process, in which case both reactants would be flowed simultaneously into chamber 110 to react within the chamber, e.g., during step (i), and the second reactant half-cycle could be omitted.

[0139] As mentioned above, the coating process can be carried out at low temperatures, e.g., below 50°C, e.g., below 35°C. In particular, the particles 148 can remain or be maintained at such temperatures during all of steps (i)-(ix) above. In general, the temperature inside the reactor chamber does not exceed 35°C during steps (i)-(ix). This can be achieved by having the first reactant gas, the second reactant gas, and the inert gas injected into the chamber at such temperatures during their respective cycles. In addition, the physical components of the chamber can remain or be maintained at such temperatures, e.g., using a cooling system (e.g., a thermoelectric cooler) as needed.

[0140] In some embodiments, the controller can cause the reactor system 100 to first deposit a metal oxide layer on the drug-containing particles and then deposit a polymer layer on the metal oxide layer on the particles, for example using the process described above. In some embodiments, the controller can cause the reactor system 100 to alternate between depositing a metal oxide layer and depositing a polymer layer on the drug-containing particles to form a multi-layer structure having layers of alternating composition.

[0141] The controller 170 and other computing device parts of the systems described herein can be implemented in digital electronic circuitry, or in computer software, firmware, or hardware. For example, the controller may include a processor that executes a computer program stored in a computer program product (e.g., a non-transitory machine-readable storage medium). Such computer programs (also known as programs, software, software applications, or code) can be written in any type of programming language, including compiled or interpreted languages, and can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. In some embodiments, the controller 105 is a general-purpose programmable computer. In some embodiments, the controller can be implemented using special purpose logic circuitry, such as an FPGA (field programmable gate array) or an ASIC (application-specific integrated circuit).

[0142] A computer system or systems configured to perform a particular operation or action means that the system has installed thereon software, firmware, hardware, or a combination thereof that causes the system to perform the operation or action during operation. A computer program or programs configured to perform a particular operation or action means that the program or programs contain instructions that, when executed by a data processing device, cause the device to perform the operation or action. The present disclosure provides an apparatus and method for preparing a pharmaceutical composition comprising an API-containing particle encapsulated by one or more layers of metal oxide and / or one or more layers of polymer. The coating layer is conformal and of controlled thickness ranging from a few nanometers to a few micrometers overall. The coated article may consist of only the API or a combination of the API and one or more excipients. The coating process described herein can provide an API with an increased glass transition temperature of the API compared to an uncoated API, a reduced crystallization rate of the amorphous form of the API compared to an uncoated API, and a reduced surface mobility of the API molecules in the particle compared to an uncoated API. Importantly, the dissolution of the particle can be altered. Because the coating is relatively thin, pharmaceutical products with high drug loading can be achieved. Finally, multiple coatings can be applied in the same reactor, providing advantages in terms of cost and ease of manufacturing.

[0143] It should be understood that the term relative positioning is used to refer to the relative positioning of components within a system or the orientation of components during operation, and that the reactor system may be maintained in a vertical orientation or some other orientation during transportation, assembly, etc. A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention.

Claims

1. 1. A method for coating a plurality of particles, comprising: distributing the plurality of particles within a rotating vacuum chamber; rotating a cylindrical portion of the rotary vacuum chamber in a first direction along an axial axis of the rotary vacuum chamber at a rotational speed less than a threshold rotational speed such that a portion of the plurality of particles distributed within the rotary vacuum chamber provides a particle bed remaining in a lower portion of the rotary vacuum chamber; evacuating the rotary vacuum chamber through a vacuum port in the rotary vacuum chamber; rotating the paddle assembly in a second direction such that the plurality of paddles orbit the drive shaft; injecting a process gas into a particle bed formed by the plurality of particles through a plurality of gas outlets located on the plurality of paddles; as the paddles rotate, a portion of each paddle having at least one gas outlet formed therein sequentially penetrates into the particle bed, causing the process gas to permeate directly into the particle bed through gaps between the particles held in the rotating vacuum chamber.

2. Rotating the rotary vacuum chamber in the first direction along the axial axis of the rotary vacuum chamber, The method of claim 1 , comprising rotating the cylindrical portion of the rotary vacuum chamber at a rotational speed such that the plurality of particles undergo tumbling agitation.

3. The method of claim 2, wherein the rotational speed is approximately 6-15 RPM.

4. 1. A method for coating a plurality of particles, comprising: distributing the plurality of particles within a rotating vacuum chamber; rotating the cylindrical portion of the rotary vacuum chamber in a first direction along an axial axis of the rotary vacuum chamber at a rotational speed greater than a threshold rotational speed such that the plurality of particles form a toroidal shaped particle bed on an inner wall of the rotary vacuum chamber; evacuating the rotary vacuum chamber through a vacuum port in the rotary vacuum chamber; rotating the paddle assembly in a second direction such that the plurality of paddles orbit the drive shaft; injecting a process gas into a particle bed formed by the plurality of particles through a plurality of gas outlets located on the plurality of paddles; and as the plurality of paddles orbit, at least one gas outlet of the plurality of gas outlets is located within the particle bed and causes the process gas to permeate into the particle bed through gaps between the plurality of particles held in the rotating vacuum chamber.

5. The method of claim 4, wherein the rotational speed is greater than 15 RPM.

6. The method of claim 5, wherein the rotational speed of the drive shaft relative to the rotating vacuum chamber about the axial axis is at least 4 RPM.

7. 7. The method of claim 1, wherein injecting the process gas into the particle bed through the plurality of gas outlets further comprises supplying the process gas through a chemical supply passage located in the paddle assembly.

8. The method of claim 7 , wherein the chemical supply passage supplies the process gas through a base shaft and plate portion of one or more of the plurality of paddles.

9. The method of claim 1 , wherein the vacuum ports are aligned on the axial axis of the rotating vacuum chamber.

10. 10. The method of claim 1, comprising coating the plurality of particles by atomic layer deposition or molecular layer deposition.

11. The method of claim 1 , comprising coating the plurality of particles by chemical vapor deposition.

12. 12. The method of claim 1, wherein the plurality of particles comprises an active pharmaceutical ingredient.

13. The method of claim 10 , wherein the plurality of particles comprises a core containing a drug.

14. 14. The method of claim 1, further comprising depositing an organic or inorganic coating on the plurality of particles.

15. The method of claim 14 , wherein the organic or inorganic coating comprises an inorganic metal oxide.

16. The method of claim 14 , wherein the organic or inorganic coating comprises an organic polymer.

17. 17. The method of claim 1, wherein the first direction is opposite to the second direction.

18. A method according to any one of claims 1 to 17, wherein the rotating vacuum chamber is evacuated through a particle filter provided in the rotating vacuum chamber and through the vacuum port.

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