Reactor for coating particles in a stationary chamber with a rotating paddle

Abstract

To provide a reactor for bringing a layer uniform in particles or between particles and capable of encapsulating or coating a drug substance (API) and providing characteristics consistent by a drug preparation, and a method for coating the particles.SOLUTION: An reactor for coating particles includes: a fixed vacuum chamber for holding the bed of the particles to be coated; a vacuum port in the upper part of the chamber; a chemical delivery system formed so as to eject reaction gas or precursor gas to the lower part of the chamber; a paddle assembly; and a motor for rotating the drive shaft of the paddle assembly. The lower part of the chamber is semi-cylindrical, and the paddle assembly includes; a drive shaft extended through the chamber in the semi-cylindrical axial direction; and a plurality of paddles extended in the radial direction from the drive shaft so as to rotate the drive shaft by the motor to rotate the plurality of paddles around the drive shaft.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present disclosure relates to coating particles, such as particles containing active pharmaceutical ingredients, with organic and inorganic thin films. [Background technology]

[0002] Developing improved formulations of active pharmaceutical ingredients (APIs) is important 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.

[0003] Many techniques have been developed for encapsulating or coating APIs. Some existing techniques for coating APIs include spray coating, plasma polymerization, hot-wire chemical vapor deposition (CVD), and rotary reactors. Spray coating is an industrially scalable technique that has been widely adopted in the pharmaceutical industry. However, nonuniform coatings (both within particles and from particle to particle) hinder 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. Meanwhile, techniques such as plasma polymerization are difficult to scale, are applicable only to specific precursor chemistries, and can lead to degradation of sensitive APIs. Existing hot-wire CVD processes, which utilize a hot-wire radical source inside the reactor, are not very scalable and are not suitable for heat-sensitive APIs. Rotary reactors include atomic layer deposition (ALD) and initiation CVD (iCVD) reactors. However, ALD reactors are suitable for inorganic coatings, not organic polymer coatings. Furthermore, existing iCVD designs cannot adequately prevent API degradation and are not amenable to mass production. Other techniques include polymer mesh coating, pan coating, aerosolized coating, and fluidized bed reactor coating. Summary of the Invention

[0004] In one aspect, a reactor for coating particles includes a stationary vacuum chamber for holding a bed of particles to be coated, a vacuum port in an upper portion of the chamber, a chemical delivery system configured to inject a reactant or precursor gas into a lower portion of the chamber, a paddle assembly, and a motor for rotating a drive shaft of the paddle assembly. The lower portion of the chamber forms a semi-cylinder. The paddle assembly includes a rotatable drive shaft extending through the chamber along the axial axis of the semi-cylinder and a plurality of paddles extending radially from the drive shaft such that rotation of the drive shaft by the motor orbits the plurality of paddles around the drive shaft.

[0005] Implementations may include one or more of the following features.

[0006] The paddles can be configured to sweep along the entire length of the chamber. The outer ends of the paddles can be separated from the inner surface of the lower portion of the chamber wall by a gap. The gap can be 1-3 mm.

[0007] The plurality of paddles may include a first plurality of outer paddles at a first radial distance from the drive shaft and a first plurality of inner paddles at a second radial distance from the drive shaft. The second radial distance may be shorter than the first radial distance. The first plurality of outer paddles may be oriented at a first oblique angle to drive particles in a first direction along the axial axis, and the first plurality of inner paddles may be oriented at a second oblique angle to drive particles in a second direction along the axial axis opposite the first direction. The second oblique angle may be equal in magnitude to the first oblique angle and opposite in sign to the first oblique angle.

[0008] The plurality of paddles may include a second plurality of outer paddles at a third radial distance from the drive shaft and a second plurality of inner paddles at a fourth radial distance from the drive shaft. The fourth radial distance may be less than the third radial distance. The third radial distance may be equal to the first radial distance, and the fourth radial distance may be equal to the second radial distance.

[0009] The second plurality of outer paddles may be oriented at a third oblique angle to drive the particles in the second direction, and the second plurality of inner paddles may be oriented at a fourth oblique angle to drive the particles in the first direction. The third oblique angle may be equal to the second oblique angle, and the fourth oblique angle may be equal to the first oblique angle.

[0010] The first plurality of outer paddles and the first plurality of inner paddles may be positioned on a first side of a dividing surface through the chamber perpendicular to the axial axis, and the second plurality of outer paddles and the second plurality of inner paddles may be positioned on an opposing second side of the dividing surface. Ports for delivering particles to or receiving particles from the chamber may be positioned in the dividing surface. The first plurality of outer paddles and the second plurality of outer paddles may be oriented to drive particles toward the ports, and the first plurality of inner paddles and the second plurality of inner paddles may be oriented to drive particles away from the ports.

[0011] The plurality of paddles may include paddles evenly spaced along the drive shaft. The plurality of paddles may include multiple groups of paddles, each group of paddles positioned in a common plane perpendicular to the drive shaft.

[0012] In another aspect, a method of coating particles includes dispensing particles into a vacuum chamber to fill at least a lower portion of the chamber forming a half cylinder, evacuating the chamber through a vacuum port in an upper portion of the chamber, rotating a paddle assembly such that a plurality of paddles orbit a drive shaft, and injecting a reactant or precursor gas into the lower portion of the chamber as the paddle assembly rotates.

[0013] Implementations may include one or more of the following features.

[0014] The particles may be coated by atomic layer deposition or molecular layer deposition. The particles may have a core containing the drug.

[0015] Implementations may include one or more of the following anticipated advantages, but are not limited to: Particles, e.g., API particles, can be coated within a mass production process, thereby providing lower manufacturing costs and a lower priced drug product; Particles can be coated with a thin layer, thereby providing a drug product with an advantageous volume fraction of the API; Furthermore, the process can result in a uniform API encapsulation layer within and between particles, providing more consistent properties to the drug formulation.

[0016] 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; however, 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.

[0017] Other features and advantages of the invention will be apparent from the following detailed description, the drawings, and the claims. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 is a schematic front view of a reactor for ALD and / or CVD coating of particles, e.g., drugs, including a stationary drum. [Figure 2] 2 is a schematic side view of the reactor of FIG. 1. FIG. 2 can be taken along line 2-2 of FIG. [Figure 3A] FIG. 2 is a schematic side view of a paddle assembly. [Figure 3B] 3B is a front view of the paddle assembly of FIG. 3A. FIG. 3B can be taken along line 3B-3B of FIG. 3A. [Figure 3C] FIG. 10 is a schematic side view of another implementation of a paddle assembly. [Figure 3D] 3D is a front view of the paddle assembly of FIG. 3C, which can be taken along line 3D-3D in FIG. [Figure 4] FIG. 2 is a schematic perspective view of a paddle. [Figure 5] FIG. 1 is a schematic side view of a group of paddles from a paddle assembly. [Figure 6A] FIG. 10 is a schematic side view of another implementation of a group of paddles from a paddle assembly. [Figure 6B] FIG. 10 is a schematic side view of yet another implementation of a group of paddles from a paddle assembly. [Figure 7] 7 is a schematic side view of a paddle from the group of paddles of Figures 5 or 6. Figure 7 can be taken along line 7-7 of Figure 4. [Figure 8] 8 is a schematic side view of a gas injection port, which can be taken along line 8-8 of FIG. [Figure 9] FIG. 9 is a schematic top view of the gas injection port of FIG. 8. [Figure 10] FIG. 1 is a schematic perspective view, partially in section, showing gas injection ports. DETAILED DESCRIPTION OF THE INVENTION

[0019] Like reference numbers and designations in the various drawings indicate like elements.

[0020] Various methods exist for encapsulating API particles. These methods often result in relatively thick coatings. While such coatings can impart desirable properties, the high coating-to-API ratio can make it difficult to create a drug product with the necessary high volume fraction of API. Furthermore, the coating encapsulating the API can be non-uniform, making it difficult to provide a formulation with consistent properties. Furthermore, coating techniques capable of providing satisfactory consistency have not been scalable for industrial production.

[0021] One approach that may address these problems is to use a stationary "drum" in which the particles are agitated by rotating paddles, and process gas is injected into the drum through the drum sidewall, which allows the process gas to penetrate the particle bed and improves coating uniformity across the particles.

[0022] drugs The term "drug" in its broadest sense includes all small molecule (e.g., non-biologic) APIs. Drugs include analgesics, anesthetics, anti-inflammatory agents, anthelmintics, antiarrhythmic agents, antiasthmatic agents, antibiotics, anticancer agents, anticoagulants, antidepressants, antidiabetics, antiepileptics, antihistamines, antitussives, antihypertensives, antimuscarinics, antimycobacterial agents, antineoplastic agents, antioxidants, antipyretics, immunosuppressants, immunostimulants, antithyroid agents, antivirals, anxiolytics, sedatives, hypnotics, neuroleptics, astringents, bacteriostatics, beta-adrenergic receptor blocking agents, blood products, blood substitutes, bronchodilators, buffers, cardiac inotropes, chemotherapeutics, synthetic drugs, and the like. The agent may be selected from the group consisting of contrast media, corticosteroids, cough suppressants, expectorants, mucolytics, diuretics, dopaminergic agents, antiparkinsonian agents, free radical scavengers, growth factors, hemostatic agents, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, bisphosphonates, prostaglandins, radiopharmaceuticals, hormones, sex hormones, antiallergic agents, appetite stimulants, anorexics, steroids, sympathomimetics, thyroid agents, vaccines, vasodilators, and xanthines.

[0023] Exemplary types of small molecule drugs include, but are not limited to, acetaminophen, clarithromycin, azithromycin, ibuprofen, fluticasone propionate, salmeterol, pazopanib HCl, palbociclib, and amoxicillin clavulanate potassium.

[0024] Pharmaceutically acceptable excipients, diluents, and carriers Pharmaceutically acceptable excipients include, but are not limited to: (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, carboxymethylethyl 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, microcrystalline cellulose, etc.; (3) fillers, such as lactose monohydrate, anhydrous lactose, 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, silica gel, etc.; (5) Sweeteners, e.g., any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K; (6) flavoring agents; (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 compounds such as phenol, or quaternary compounds such as benzalkonium chloride; (8) Buffer; (9) Diluents, such as pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, sugars, and / or mixtures of any of the foregoing; (10) Wetting agents, such as corn starch, potato starch, maize starch, modified starch, and mixtures thereof; (11) Disintegrants, such as croscarmellose sodium, crospovidone, sodium starch glycolate, and the like; and (12) Effervescent agents, for example, 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 carbonate, and arginine carbonate), or bicarbonates (e.g., sodium bicarbonate or potassium bicarbonate).

[0025] Metal Oxide Materials In its broadest sense, the term "metal oxide material" 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. The term "oxide material" includes metal oxide materials and oxides of other materials, such as silicon dioxide.

[0026] Atomic Layer Deposition (ALD) Atomic layer deposition is a thin film deposition technique in which the sequential addition of self-limiting monolayers of elements or compounds allows the deposition of films with thicknesses and uniformities controlled down to the atomic or molecular monolayer level. Self-limiting means that only a single atomic layer is formed at a time, and subsequent process steps are required to regenerate the surface to allow further deposition.

[0027] 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. The first precursor is introduced into the chamber. Molecules of the first precursor react with reactive groups on the substrate surface via corresponding bonding chemistry, depositing a molecular layer of the first precursor on the substrate surface with new reactive sites. After purging, the second precursor is introduced, and the molecules of the second precursor react with the new reactive sites provided by the first precursor, creating a molecular layer of the first precursor bound to the second precursor. This is followed by another purge cycle.

[0028] Reactor System 1-2 illustrate 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 processing temperatures (above 50°C, e.g., 50-100°C) or lower processing temperatures, e.g., below 50°C, e.g., 35°C or lower. For example, the reactor system 100 can form a thin film oxide on particles primarily by ALD at a temperature of 22-35°C, e.g., 25-35°C, 25-30°C, or 30-35°C. Generally, the particles can remain or be maintained at such temperatures. This can be achieved by allowing the reactant gases and / or the interior surfaces of the reactor chamber to remain or be maintained at such temperatures.

[0029] The reactor system 100 includes a stationary vacuum chamber 110 that surrounds a paddle assembly 150 .

[0030] The vacuum chamber 110 is surrounded by a chamber wall 112. The lower portion 110b of the chamber 110 forms a semi-cylinder with a semicircular cross-section (when viewed along the central axis of the semi-cylinder). The cross-section of the upper portion 110b (again, when viewed along the central axis of the semi-cylinder) can be uniform along the length of the chamber 110 (the length is along the central axis of the semi-cylinder). This helps ensure uniform gas flow along the length of the chamber. If the gas flow is sufficiently uniform, the cross-section can be non-uniform, for example, narrowing toward the top when viewed horizontally but perpendicular to the central axis of the semi-cylinder.

[0031] The cross section of the upper portion 110b can be selected to conserve space in a manufacturing facility while still enclosing the paddle assembly 150. For example, the upper portion 110b of the chamber 110 can be a rectangular parallelepiped (see FIG. 6A), a semi-cylinder with a semicircular cross-section, or any other suitable shape that does not obstruct the rotation of the paddle assembly 150. In some implementations, the upper portion 110b of the chamber is adjacent to the lower portion 110a and has a lower section 110c with vertical sidewalls, e.g., a rectangular parallelepiped volume. The upper section 110c, which extends between the lower section 110c and the ceiling 112a of the chamber 110, can have a cross-section that is triangular or trapezoidal (again, when viewed along the central axis of the semi-cylinder).

[0032] 6B (although other paddle assemblies may be combined), the curved portion of the chamber wall is along the lower section 110c of the upper chamber 110b. The upper section 110d, which extends between the lower section 110c and the ceiling 112a of the chamber 110, can provide space for the vacuum port 132 and / or the powder delivery port 116. This configuration can avoid powder buildup, for example, caused by the paddle assembly delivering powder, along portions of the side wall 12 that are out of reach of the paddle 154.

[0033] The chamber walls 110 can be made of a material that is inert to the deposition process, such as stainless steel, and / or the interior surfaces of the chamber walls 110 can be coated with a material that is inert to the deposition process. In some implementations, a viewing port 114 of a transparent material, such as quartz, is formed through the chamber walls 112 to allow an operator to view the interior of the chamber 110.

[0034] During operation, the chamber 110 is partially filled with particles, e.g., API-containing particles, thereby providing the particle bed 10. For good throughput, the particle bed 10 fills at least the lower portion 110a of the chamber. For example, the upper surface 12 of the particle bed 10 is at or above the lower portion 110 (designated A). Meanwhile, the upper surface 12 of the particle bed 10 should be below the top of the paddle assembly 150 (designated B) to avoid insufficient mixing of the particle bed. The chamber wall 112 can include one or more sealable ports 116 to allow particles to be placed into and removed from the chamber 110.

[0035] The chamber 110 is coupled to a vacuum source 130. A port 132 that connects to the vacuum source 130 through the chamber wall 112 may be located in the top 110b of the chamber 110. In particular, the port 132 may be located above the expected location of the upper surface 12 of the particle bed, for example, above the top (designated B) of the paddle assembly 150 (e.g., in the chamber ceiling).

[0036] The vacuum source 130 may be an industrial vacuum pump sufficient to establish a pressure of less than 1 Torr, for example, 1 to 100 mTorr, e.g., 50 mTorr. The vacuum source 130 ensures that the chamber 110 is maintained at a desired pressure and that reaction by-products and unreacted process gases are removed.

[0037] Port 132 can be covered by filter 134 to prevent particles delivered into the gas stream by the paddle assembly from escaping reactor chamber 110. Additionally, the system can include a filter cleaner for cleaning particles from filter 134. As one example, the filter cleaner can be a mechanical knocker for striking the filter, thereby shaking particles off the filter. As another example, gas source 136 (which can be provided by gas source 142e) can periodically provide pulses of an inert gas, such as nitrogen, into gas line 138 between port 132 and vacuum source 130. The pulses of gas can pass through filter 134 and back toward chamber 110, blowing particles off filter 134. Isolation valves 139a, 139b can be used to ensure that only one of gas source 136 or vacuum source 130 is fluidly connected to line 138 at a time.

[0038] The chamber 110 is also coupled to a chemical delivery system 140. The chemical delivery system 140 includes multiple fluid sources 142, controllable valves 144, and fluid supply lines 146 connected by individual delivery tubes 143. The chemical delivery system 140 delivers fluids to one or more gas injection assemblies 190, which inject the fluids in vapor form into the chamber 110. The chemical delivery system 140 may include a combination of restrictors, gas flow controllers, pressure transducers, and ultrasonic flow meters to provide controllable flow rates of various gases into the chamber 110. The chemical delivery system 140 may also include one or more temperature control components, such as heat exchangers, resistance heaters, etc., to heat or cool the various gases before they flow into the chamber 110.

[0039] The chemical delivery system 140 may include five fluid sources 142a, 142b, 142c, 142d, and 142e. Two of the fluid sources, e.g., fluid sources 142a and 142b, may provide two chemically distinct precursors or reactants for a deposition process to form an oxide layer on the particles. For example, the first fluid source 142a may provide trimethylaluminum (TMA) or titanium tetrachloride (TiCl4), while the fluid gas source 142b may provide water. Two of the fluid sources, e.g., fluid sources 142c and 142d, may provide two chemically distinct precursors or reactants for a deposition process to form a polymer material on the oxide layer. For example, the third fluid source 142c may provide adipoyl chloride, and the fourth gas source 142d may provide ethylenediamine. One of the fluid sources, for example the fifth fluid source 142e, may provide an inert gas, such as argon or N2, for purging between cycles or half cycles during the deposition process.

[0040] Although FIG. 1 illustrates five fluid sources, the use of fewer gas sources may still be compatible with the deposition of oxide or polymer layers, while the use of more gas sources may enable the formation of a wider variety of layered structures.

[0041] For one or more of the fluid sources, chemical delivery system 140 delivers precursors or reactants in liquid form to gas injection assembly 190. Gas injection assembly 190 includes a vaporizer 148 for converting the liquid to a vapor just before the precursor or reactant enters injection manifold 194. This reduces upstream pressure loss, allowing more pressure loss to occur across particle bed 10. The more pressure loss that occurs across particle bed 10, the lower the injection apertures can be located, increasing the likelihood that all precursors will react as they pass through the particle bed at a given flow rate. Vaporizer 149 can be directly adjacent to the reactor sidewall. For example, it can be affixed to or housed within reactor sidewall 112.

[0042] 1, there is a manifold 194 for each precursor or reactant fluid, and each manifold 194 may be separately fluidly connected to chamber 110. Thus, the precursors or reactants cannot mix until they actually enter chamber 110. Alternatively, gas lines from fluid sources 142 may be joined, for example by valves, as a combined fluid supply line. Gas injection assembly 190 is described further below.

[0043] As described above, the paddle assembly 150 is positioned within the chamber 110 to agitate particles in the particle bed. The paddle assembly 150 includes a rotatable drive shaft 152 and a plurality of paddles 154. The paddles 154 are connected to the drive shaft 152 by struts 156 extending outward from the drive shaft 152 such that rotation of the drive shaft 152 about the axis of rotation 153 carries the paddles 154 in a circular path (see arrow C) about the axis of rotation 153. The struts 156 may extend perpendicular to the drive shaft 152. The drive shaft 152 and the axis of rotation 153 may extend along the boundary between the upper and lower portions 110b and 1110a of the chamber 110.

[0044] The drive shaft 152 is driven by a motor 160 located outside the chamber 110. For example, the drive shaft 152 can extend through the chamber wall 112, with one end coupled to the motor 160. A bearing vacuum seal 162 can be used to seal the chamber 110 from the external environment. The other end of the drive shaft can be supported by a bearing inside the chamber 110; for example, the end of the drive shaft 152 can fit into a recess in the inner surface of the chamber wall 112. Alternatively, the drive shaft 152 can simply be held in a cantilever configuration, with the end of the drive shaft unsupported. This can be advantageous for disassembly and cleaning. The motor 160 can rotate the drive shaft 152 and paddle assembly 150 at speeds of 0.1 to 60 rpm.

[0045] At least some of the paddles 154 are held by posts 156 in a position where the outer ends of the paddles 154 nearly contact the inner surface 114 of the chamber wall 112 as the drive shaft 152 rotates. However, the outer ends of the paddles 154 remain separated from the inner surface by a small gap G1, for example, 1 to 4 mm. The gap G1 can be made as small as possible within manufacturing tolerances so that the paddles 154 do not rub against the outer wall 112.

[0046] The rotation axis 153 of the drive shaft 152 may be parallel to, e.g., collinear with, the central axis of the cylinder defining the lower portion 110a, in which case rotation of the drive shaft 152 may cause the outer end of the paddle 154 to sweep across, e.g., the entire, semi-cylindrical inner surface of the lower portion 110a.

[0047] The paddles 154 may be spaced along the drive shaft 152 to ensure that the paddles that are in substantial contact with the interior surface 114 provide coverage along substantially the entire length of the reactor chamber 110. In particular, the paddles 154 may be spaced and have a width W (along the axis of rotation) such that there are no gaps within the space swept by the paddle assembly 150. In particular, the width W may be greater than the pitch of the paddles along the drive shaft 152. Paddles at different axial positions along the length of the drive shaft may be angularly offset. For example, as shown in FIGS. 3A and 3B , the paddles 154 may be arranged in a helical pattern around the drive shaft 152. However, many other configurations for angular offset are possible, such as, for example, on alternating sides of the drive shaft.

[0048] In some implementations, some of the paddles 154 are positioned radially closer to the drive shaft 152 than other paddles 154. The paddles 154b closer to the drive shaft are referred to as the "inner paddles," and the paddles 154a farther from the drive shaft are referred to as the "outer paddles." The inner and outer paddles 154a, 154b may not overlap radially, or may only partially overlap radially. For example, the inner and outer paddles may overlap by up to 20% of the radial span S of the outer paddles (e.g., G≧0.8*S).

[0049] The paddles 154a may be spaced apart and have a width (along the axis of rotation) such that there are no gaps in the space swept by the outer paddles 154a. In particular, the width W of the outer paddles 154a may be greater than the pitch of the outer paddles 154a along the drive shaft 152. Adjacent outer paddles 154a along the length of the drive shaft may be angularly offset. Similarly, the inner paddles 154b may be spaced apart and have a width (along the axis of rotation) such that there are no gaps in the space swept by the inner paddles 154b. In particular, the width W of the inner paddles 154b may be greater than the pitch of the inner paddles 154b along the drive shaft 152. Adjacent inner paddles 154b along the length of the drive shaft may be angularly offset. For example, as shown in FIGS. 3C and 3D , the inner paddles 154b may be arranged in a first spiral around the drive shaft 152, and the outer inner paddles 154a may be arranged in a second spiral around the drive shaft 152. Although the helices of the inner and outer paddles 154a, 154b are shown as being 180° out of phase, this is not required. Furthermore, many other configurations for the angular offset between adjacent paddles are possible. For example, the paddles could be positioned on alternating sides of the drive shaft.

[0050] 4, each paddle 154 can be a generally planar body having a major surface 170 for pushing particles within the particle bed and a thinner edge 172 that will contact the inner surface of the lower portion 110a of the chamber 110. As shown in FIG. 4, the paddles 154 can be flared in a fan shape. Or, as shown in FIGS. 1 and 2, the paddles can be generally rectangular, e.g., rectangular with rounded edges. The surface 170 of the paddles 154 can be flat, or the surface 170 can be concave, e.g., spoon-shaped. Additionally, in some implementations, the paddles 154 are plow-shaped, such as convex or sharply convex relative to the direction of motion of the paddle.

[0051] 1, in some implementations, the paddles are clustered into groups positioned in a common plane perpendicular to the axis of rotation 153. The paddles within a group may be spaced at substantially equal angular intervals around the drive shaft 152. A group may include four paddles, although two, three, five or more paddles may be used.

[0052] 1 and 5, paddle assembly 150 includes a group of four paddles 180a, 180b, 180c, 180d that are equidistant and spaced at 90 degrees from drive shaft 152 and axis of rotation 153. Paddles 180a-180d can be positioned to generally contact the inner surface of the semi-cylindrical lower portion 110a of chamber 110a.

[0053] 1 and 2, paddle assembly 150 may include multiple groups of paddles positioned at different locations along drive shaft 132. For example, paddle assembly 150 may include groups 180, 182, 184, 186, and 188. If there are three or more groups, the groups of paddles may be substantially equally spaced along drive shaft 152. Each group may have the same number of paddles, for example, four paddles. Paddles in adjacent groups may be angularly offset about the axis of rotation, for example, by half the angle between paddles in the group. For example, if a group has four paddles spaced 90° apart about the axis of rotation, paddles in adjacent groups may be offset by 45°.

[0054] 1, the paddles of a group may be positioned substantially equidistant from the axis of rotation 153. For example, the posts 156 may have the same length.

[0055] However, in some implementations, some of the paddles in a group are positioned radially closer to the drive shaft 152 than other paddles in the group. For example, the paddle assembly 150 shown in FIG. 6A includes a group of four paddles 180a', 180b', 180c', 180d' spaced 90° apart. Two of the paddles, e.g., two opposing paddles 180a' and 180c', are positioned a first distance from the drive shaft 152. These two paddles may be positioned so as to nearly contact the semi-cylindrical inner surface 112 of the lower portion 110a. Another two of the paddles, e.g., two opposing paddles 180b' and 180d', are positioned a second distance from the drive shaft 152.

[0056] As another example, the paddle assembly shown in FIG. 6B includes a group of eight paddles 180a-180h spaced 45° apart. Four outer paddles 154a, e.g., paddles 180a-180d, are located a first distance from the drive shaft 152. These four outer paddles 154a may be positioned so as to nearly contact the semi-cylindrical inner surface 112 of the lower portion 110a. Four inner paddles 154b, e.g., paddles 180e-180h, are located a second, shorter distance from the drive shaft 152. The outer paddles 154a and inner paddles 154b are arranged in an alternating pattern around the drive shaft 152.

[0057] In some implementations, some of the groups of paddles have paddles positioned radially closer to the drive shaft 152 than other groups of paddles. For example, the paddle assembly 150 includes a group 182 of four inner paddles 182a, 182b, 182c, 182d that are equidistant and spaced 90 degrees from the drive shaft 152 and rotational axis 153. The outer ends of the paddles 182a-182d are spaced from the semi-cylindrical inner surface of the lower portion 110a of the chamber 110a by a gap G. The inner paddles 182a-182d are radially inward compared to the outer paddles 180a-180d.

[0058] 1, 5, and 7, each paddle 154 may be positioned and oriented such that an axis N normal to the plane 170 of the paddle 154 is normal to a radius R passing from the axis of rotation 153 to the paddle 154. However, in some implementations, one or more paddles 154 may be angled such that the orbit of the paddle 154 around the axis of rotation 153 tends to force particles radially toward or away from the axis of rotation 153.

[0059] Additionally, each paddle 154 may be at an oblique angle relative to a plane perpendicular to the rotation axis 153. In particular, each paddle 154 may be angled such that the orbit of the paddle 154 around the rotation axis 153 tends to force particles in a direction parallel to the rotation axis 153. For example, as shown in FIGS. 5 and 7 , paddle 180 a is oriented such that an axis N perpendicular to the plane 170 of the paddle 154 is at an oblique angle α relative to the rotation axis 153 when viewed along a radius between the paddle 180 a and the rotation axis (e.g., parallel to the support posts 156). In this configuration, as the paddle orbits around the rotation axis 153, the paddle has an instantaneous motion vector C. The oblique angle α of the paddle 180 a may be between 15° and 75°, e.g., between 30° and 60°, e.g., approximately 45°.

[0060] The inner paddles of a group can be oriented at a common oblique angle α, and the outer paddles of a group can be oriented at a common oblique angle α'. In some implementations, all of the inner paddles along drive shaft 152 are oriented at a common oblique angle α, and all of the outer paddles along drive shaft 152 are oriented at a common oblique angle α'.

[0061] Angles α' and α' are not equal. In particular, angles α' and α' may have opposite signs. In some implementations, angle α' has the same magnitude but opposite sign as angle α, e.g., the oblique angle is +α on the outer paddle and −α on the outer paddle.

[0062] In some implementations, the outer paddles 154 are angled such that the revolutions of the paddles terminate to force particles in a first direction parallel to the axis of rotation 153, while the inner paddles 154 are angled such that the revolutions of the inner paddles 154 tend to force particles in an anti-parallel direction, i.e., a second direction opposite to the first direction. For example, with reference to Figures 6 and 7, the outer paddles 180a' and 180c' of group 180 can force particles in direction D, while the inner paddles 180b' and 180d' of group 180 can force particles in a direction opposite D.

[0063] 2, in some implementations, port 116a is located somewhere along the length of chamber 110, for example near its center. Port 116a can be used to deliver and / or collect particles to and / or from reactor 100. In such implementations, the outer paddle can be oriented to push particles toward port 116a, and the inner paddle can be oriented to push particles out of port 116a.

[0064] For example, the outer paddles of groups 180 and 182 can push particles leftward toward port 116a, while the inner paddles of groups 180 and 182 can push particles rightward out of port 116a. Conversely, the outer paddles of groups 184, 186, and 188 can push particles rightward toward port 116a, while the inner paddles of groups 184, 186, and 188 can push particles leftward out of port 116a. Paddles oriented to push particles in a first direction, e.g., leftward, can be oriented at an oblique angle +α, while paddles oriented to push particles in an opposite second direction, e.g., rightward, can be oriented at an oblique angle −α.

[0065] If the paddles in each group have the same radial distance from the drive shaft, the paddles in different groups, e.g., adjacent groups, may have different oblique angles. For example, referring to paddles 180a-180d in first group 180, they may urge particles in direction D, while paddles 182a-182d in second group 180 may urge particles in a direction opposite to D.

[0066] 1 and 8, chemical delivery system 140 is coupled to chamber 110 by gas injection assembly 190. Gas injection assembly 190 includes a plurality of apertures 192 extending through chamber wall 112. Apertures 192 may, in one example, be arranged parallel to, for example, the rotational axis 153 of drive shaft 152. While FIG. 8 illustrates a single row of apertures 192, the system may have multiple rows of apertures. In particular, there may be different rows of apertures for different reactants or precursors. Furthermore, there may be multiple rows of apertures for a given reactant and / or precursor.

[0067] The aperture 192 is located below the expected location of the particle bed upper surface 12. In particular, the aperture 192 through the chamber wall 112 may be located in the lower portion 110b of the chamber 110. For example, the aperture 192 may extend through a curved semicircular portion of the side wall 112. The aperture 192 may be positioned in the lower half, e.g., the lower third, e.g., the lower quarter, e.g., the lower fifth (as measured vertically), of the chamber wall 112 of the lower portion 110b. The aperture may have a diameter of 0.5 to 3 mm. While FIG. 1 illustrates the aperture 192 extending horizontally through the chamber wall, this is not necessary, as will be explained further below.

[0068] 1 and 9, gas injection assembly 190 includes a manifold 194 having a plurality of channels 196 leading from manifold 194 to apertures 192. Manifold 194 and channels 196 may be formed as passages through a solid body 196 that provides a portion of chamber wall 112. Vaporizer 148 may be positioned immediately upstream of manifold 194.

[0069] An inert carrier gas, such as N2, can flow from one of the fluid sources, such as fluid source 142e, through one or more passages 198 to manifold 194. During operation, the carrier gas can flow continuously to manifold 194, i.e., regardless of whether precursor or reactor gas is flowing to manifold 194. As one example, the carrier gas can be injected into fluid line 146 through passage 198a before the liquid reaches the vaporizer. As another example, the carrier gas can be injected directly into vaporizer 148 through passage 198b. As another example, the carrier gas can be injected directly into manifold 194 through passage 198c.

[0070] When a precursor or reactor gas is not being injected into the chamber 110 through the manifold 194, the flow of carrier gas can prevent backflow of another precursor or reactor gas being injected from another manifold into the apertures 192. The flow of carrier gas can also prevent fouling, e.g., blockage, of the apertures 192 by particles in the particle bed 10. Additionally, the carrier gas can provide a purge gas for a purge operation when a precursor or reactor gas is not being injected into the chamber 110.

[0071] The flow of carrier gas into the vaporizer 149 when precursor gas is also flowing can improve the vaporization of the precursor or reactant liquid. Without being limited by any particular theory, the flow of carrier gas can help shear the liquid during aerosolization, which can lead to smaller droplet sizes, which can then vaporize more quickly. The flow of carrier gas into the manifold 194 when precursor gas is also flowing can help evacuate the precursor gas from the vaporizer.

[0072] Gas from chemical delivery system 130 flows out of the aperture in the direction (indicated by arrow E) and into chamber 110. Assuming chamber 110 is partially filled with particles, the gas is injected near the bottom of particle bed 10. Thus, the gas chemical must "bubble" through the body of particle bed 10 to escape and be exhausted by vacuum port 132. This can help ensure that the particles are uniformly exposed to the gas.

[0073] The direction of rotation of the paddle assembly 150 (indicated by arrow C) may be such that the paddle sweeps across the aperture 192 in a direction that has a component in the same direction as the gas flow (indicated by arrow E) (i.e., has no anti-parallel component). This may prevent particles from being pushed back against the gas flow and blocking the aperture 192.

[0074] 10 , gas injection assembly 190 can be configured to inject gas into chamber 110 with the direction of gas flow substantially parallel to the instantaneous direction of motion of paddle 154 as it passes over aperture 192. In other words, the direction of gas flow can be substantially tangent to curved inner surface 114 of cylindrical bottom 110 a of chamber 110.

[0075] Each channel 196 may include a first channel portion 196a extending at a shallow angle toward the inner surface 114. This first channel portion 196a opens the chamber 110 at an aperture 192. As shown in FIG. 10 , the aperture 192 may be a scalloped recess having a sharp indentation followed by a depth that gradually decreases along the direction of rotation of the paddle 154 (indicated by arrow C). The first channel portion 196a may open to a ceiling 192a of the aperture 192 formed by the sharp indentation. This configuration may reduce the likelihood of particles entering the channel 196. Additionally, the first channel portion 196 may be wider than the expected diameter of the particle. This may reduce the risk of the particle clogging the first channel portion 196a.

[0076] The channel 196 also includes a second channel portion 196b that extends between the manifold 194 and the first channel portion. The second channel portion 196b may be narrower than the first channel portion 196a. This narrower channel portion 196b controls the flow rate and flow distribution out of the manifold 194.

[0077] The vaporizer 148 may include a walled interior cavity 148a heated by a heater 148b, such as a resistive heater, a thermoelectric heater, or a heat lamp. The fluid supply passage 146 is connected to the cavity 148a by a nozzle 147. The liquid is aerosolized as it passes through the nozzle 147. The combination of the high temperature, rapid pressure change, and high surface area of ​​the aerosol allows for rapid vaporization of large volumes of reactant or precursor. The cavity 149a of the vaporizer 148 may extend along a substantial portion, e.g., at least half, of the length of the chamber 110. The liquid reactant or precursor may be injected through the nozzle 147 in one of the cavities, and apertures 148c for the reactant or precursor vapor to enter the manifold 194 may be located at opposite ends of the cavity chamber (along the length of the chamber 110).

[0078] As noted above, the vaporizer 148 may be integrated into the body that provides the manifold. For example, the vaporizer 148, manifold 194, and channels 196 may all be part of a single, unitary body.

[0079] In some implementations, one or more temperature control components are integrated into the chamber walls 112 to allow for control of the temperature of the chamber 110, such as resistive heaters, thermoelectric coolers, heat exchangers, or coolants flowing through cooling channels in the chamber walls or other components in or on the side walls 112.

[0080] The reactor system 10 also includes a controller 105 coupled to various controllable components, such as a vacuum source 130, a chemical delivery system 140, a motor 160, a temperature control system, etc., for controlling the operation of the reactor system 100. The controller 105 may also be coupled to various sensors, such as pressure sensors, flow meters, etc., to provide closed-loop control of the pressure of the gas in the chamber 110.

[0081] Generally, the controller 105 is configured to operate the reactor system 100 according to a "recipe." The recipe specifies the operating values ​​of each controllable element as a function of time. For example, the recipe may specify the time for which the vacuum source 130 is activated, the time and flow rate of each gas source 142a-142e, the rotational speed of the drive shaft 152 set by the motor 160, etc. The controller 105 may receive the recipe as computer-readable data (stored on a non-transitory computer-movable medium).

[0082] The controller 105 and other computing device portions of the systems described herein may 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, such as a non-transitory machine-readable storage medium. Such computer programs (also known as programs, software, software applications, or code) may be written in any form of programming language, including compiled or interpreted languages, and may 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 implementations, the controller 105 is a general-purpose programmable computer. In some implementations, the controller may be implemented using special-purpose logic circuitry, such as an FPGA (field-programmable gate array) or an ASIC (application-specific integrated circuit).

[0083] When one or more computer systems are configured to perform particular operations or functions, it means that the systems have installed thereon software, firmware, hardware, or a combination thereof that causes the systems to perform the operations or functions during operation. When one or more computer programs are configured to perform particular operations or functions, it means that one or more programs contain instructions that, when executed by a data processing device, cause the device to perform the operations or functions.

[0084] operation Initially, particles are loaded into chamber 110 of reactor system 100. The particles may have a solid core containing a drug, such as one of the drugs described above. The solid core may also optionally contain an additive. Once the access port is sealed, controller 105 operates reactor system 100 according to a recipe to form a thin oxide layer and / or a thin polymer layer on the particles.

[0085] During operation, reactor system 100 performs ALD and / or MLD thin film coating processes by introducing gaseous precursors of the coating into chamber 110. The gaseous precursors are alternately spiked into reactor chamber 110. This allows the deposition process to be a solvent-free process. The half-reactions of the deposition process are self-limiting, which can provide deposition control at the angstrom or nanometer level. Furthermore, the ALD and / or MLD reactions can be performed at low temperature conditions, such as below 50° C., e.g., below 35° C.

[0086] Suitable reactants for ALD processes include any one or combination of the following: monomer vapors, organometallics, metal halides, oxides such as ozone or water vapor, and polymer or nanoparticle aerosols (dry or wet). For example, first fluid source 142a may provide gaseous trimethylaluminum (TMA) or titanium tetrachloride (TiCl4), while second gas source 142b may provide water. For MLD, by way of example, fluid source 142c may provide adipoyl chloride, and fourth fluid 142d may provide vapor or gaseous ethylenediamine.

[0087] During operation, as the paddle assembly 150 rotates, one type of gas flows from the chemical delivery system 140 to the particle bed 10 in the lower portion 110a of the chamber 110. The rotation of the paddle assembly 150 agitates the particles, separating them 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.

[0088] For both ALD and MLD processes, two reactant gases are alternately supplied to the chamber 110, and each reactant gas supply step is followed by a purge cycle in which an inert gas is supplied to the chamber 110 to push out the reactant gas and by-products used in the previous step.

[0089] As noted above, the coating process can be carried out at low processing temperatures, e.g., below 50°C, e.g., 35°C or lower. In particular, the particles can remain or be maintained at such temperatures during all of steps (i)-(ix) above. Generally, 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 each cycle. Furthermore, physical components of the chamber can remain or be maintained at such temperatures, as needed, e.g., using a cooling system, e.g., a thermoelectric cooler.

[0090] In some implementations, the controller can cause the reactor system 100 to first deposit an oxide layer on the drug-containing particles and then deposit a polymer layer over the particulate oxide layer using the process described above. In some implementations, the controller can cause the reactor system 100 to alternate between depositing an oxide layer and a polymer layer on the drug-containing particles to form a multilayer structure having layers of alternating composition.

[0091] Continuous flow behavior For an ALD process, the controller 105 can operate the reactor system 100 as follows.

[0092] In the first reaction half-cycle, motor 160 rotates paddle wheel 150 to agitate the particles while: i) The gas distribution system 140 is operated to flow a first reactant gas, e.g., TMA, from a source 142a into the chamber 110 until the particle bed 10 is saturated with the first reactant gas. For example, the first reactant gas can flow at a specified flow rate for a specified period of time or until a sensor measures a specified first pressure or partial pressure of the first reactant gas in the upper portion 110b of the chamber. In some implementations, the first reactant gas is mixed with an inert gas as it flows into the chamber. The specified pressure or partial 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 the vacuum source 140 evacuates the chamber 110, for example to a pressure less than 1 Torr, for example 1 to 100 mTorr, for example 50 mTorr.

[0093] These steps (i)-(ii) may be repeated a number of times as determined by the strategy, for example, from 2 to 10 times.

[0094] Next, in the first purge cycle, the motor 160 rotates the paddle wheel 150 to agitate the particles while: iii) The gas distribution system 140 is operated to flow only an inert gas, e.g., N2, from source 142e into the chamber 110. The inert gas can flow at a specified flow rate for a specified period of time or until a sensor measures a second specified pressure of the inert gas in the upper portion 110b of the chamber. The second specified pressure can be between 1 and 100 Torr. iv) A vacuum pump 140 evacuates the chamber 110, for example to a pressure less than 1 Torr, for example 1 to 500 mTorr, for example 50 mTorr.

[0095] These steps (iii)-(iv) may be repeated a number of times determined by the strategy, for example 6 to 20 times.

[0096] In the second reaction half-cycle, motor 160 rotates paddle assembly 150 to agitate the particles while: v) The gas distribution system 30 is operated to flow a second reactant gas, e.g., HO, from the source 142b into the chamber 110 until the particle bed 10 is saturated with the second reactant gas. Again, the second reactant gas can flow at a specified flow rate for a specified period of time or until a sensor measures a specified third pressure or partial pressure of the second reactant gas in the upper portion 110b of the chamber. In some implementations, the second reactant gas is mixed with an inert gas as it flows into the chamber. The third pressure can be from 0.1 Torr to half the saturation pressure of the second reactant gas. vi) A vacuum pump 140 evacuates the chamber 110, for example to a pressure below 1 Torr, for example 1 to 500 mTorr, for example 50 mTorr.

[0097] These steps (v)-(vi) can be repeated as many times as determined by the strategy, for example, from 2 to 10 times.

[0098] A second purge cycle is then performed, which may be identical to the first purge cycle, including steps (vii) and (vii), or may involve a different number of repetitions of steps (iii)-(iv), or may be performed at a different pressure.

[0099] The cycle of the first reaction half cycle, first purge cycle, second reaction half cycle, and second purge cycle can be repeated a number of times set by the strategy, for example, from 1 to 10 times.

[0100] Although the operation is described above for an ALD process, the operation is similar for MLD. In particular, in steps (i) and (v), the reactive gas is replaced with a process gas and pressure appropriate for the deposition of the polymer layer. For example, step (i) can use vapor or gaseous adipoyl chloride, and step (v) can use vaporous ethylenediamine.

[0101] Additionally, although operation is described above for an ALD or MLD process, the system can be used for a chemical vapor deposition (CVD) process, in which case both reactants are flowed simultaneously into chamber 110 to react inside the chamber, e.g., during step (i), and the second reaction half-cycle can be omitted.

[0102] Pulsed flow operation In another implementation, one or more of the gases (e.g., reactive gases and / or inert gases) may be supplied in pulses, where the chamber 110 is filled with gas to a specified pressure, a delay time is allowed to elapse, and the chamber is evacuated by the vacuum source 140 before the next pulse begins.

[0103] In particular, for an ALD process, the controller 105 can operate the reactor system 100 as follows.

[0104] In the first reaction half-cycle, motor 160 rotates paddle wheel 150 to agitate the particles while: i) The gas delivery system 140 is operated to flow a first reactant gas, e.g., TMA, from a source 142a into the chamber 110 until a first specified pressure is achieved in the upper portion 110b of the chamber. The specified 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, allowing a specified delay time to elapse, e.g., as measured by a timer in the controller, to allow the first reactant to flow through the particle bed 10 in the chamber 110 and react with the surfaces of the particles. iii) A vacuum pump 140 evacuates the chamber 110, for example to a pressure less than 1 Torr, for example 1 to 100 mTorr, for example 50 mTorr.

[0105] These steps (i)-(iii) may be repeated a number of times as determined by the strategy, for example, from 2 to 10 times.

[0106] Next, in the first purge cycle, the motor 160 rotates the paddle wheel 150 to agitate the particles while: iv) The gas delivery system 140 is operated to flow an inert gas, such as N, from the source 142e into the chamber 110 until a second specified pressure is achieved, which may be between 1 and 100 Torr. v) The flow of inert gas is stopped and a specified delay time, measured, for example, by a timer in the controller, is allowed to elapse, allowing the inert gas to diffuse through the particles in particle bed 10 and replace the reactant gas and vaporous by-products. vi) A vacuum pump 140 evacuates the chamber 110, for example to a pressure below 1 Torr, for example 1 to 500 mTorr, for example 50 mTorr.

[0107] These steps (iv)-(vi) can be repeated a number of times determined by the strategy, for example 6 to 20 times.

[0108] In the second reaction half-cycle, motor 160 rotates paddle assembly 150 to agitate the particles while: Vii) The gas delivery system 30 is operated to flow a second reactant gas, e.g., H, from the source 142b into the chamber 110 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 to allow a specified delay time to elapse, as measured, for example, by a timer in the controller, thereby allowing the second reactant gas to flow through the particle bed 10 and react with the surfaces of the particles inside the drum chamber 110. ix) A vacuum pump 140 evacuates the chamber 110, for example to a pressure less than 1 Torr, for example 1 to 500 mTorr, for example 50 mTorr.

[0109] These steps (vii)-(ix) may be repeated as many times as determined by the strategy, for example from 2 to 10 times.

[0110] A second purge cycle is then performed, which may be identical to the first purge cycle or may involve a different number of repetitions of steps (iv)-(vi) and may involve different delay times and / or pressures.

[0111] The cycle of the first reaction half cycle, first purge cycle, second reaction half cycle, and second purge cycle can be repeated a number of times set by the strategy, for example, from 1 to 10 times.

[0112] Additionally, one or more of the gases (e.g., reactive gases and / or inert gases) may be supplied in pulses, where the chamber 110 is filled with gas to a specified pressure, a delay time is allowed to elapse, and the chamber is evacuated by the vacuum source 140 before the next pulse begins.

[0113] Although the operation is described above for an ALD process, the operation is similar for MLD. In particular, in steps (i) and (vii), the reactive gas is replaced with a process gas and pressure appropriate 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.

[0114] Additionally, although operation is described above for an ALD or MLD process, the system can be used for a chemical vapor deposition (CVD) process, in which case both reactants are flowed simultaneously into chamber 110 to react inside the chamber, e.g., during step (i), and the second reaction half-cycle can be omitted.

[0115] conclusion The present disclosure provides an apparatus and method for preparing pharmaceutical compositions comprising API-containing particles encapsulated by one or more oxide layers and / or one or more polymer layers. The coating layers are conformal and have a controlled total thickness ranging from a few nanometers to several micrometers. The coated article can consist of the API alone or in combination with one or more additives. The coating process described herein can provide APIs with higher glass transition temperatures compared to uncoated APIs, lower crystallization rates for amorphous forms of the API compared to uncoated APIs, and reduced surface mobility of API molecules within the particles compared to uncoated APIs. Importantly, particle dissolution can be modified. Because the coatings are relatively thin, drug products with high drug loadings can be achieved. Finally, multiple coatings can be applied in the same reactor, providing benefits in terms of cost and ease of manufacturing.

[0116] The term relative positioning is used to refer to the relative positioning of parts within a system or the orientation of parts during operation. It is understood that the reactor system may be held in a vertical or some other orientation during transport, assembly, etc.

[0117] Although several embodiments of the present invention have been described, it will nevertheless be understood that various modifications can be made without departing from the spirit and scope of the invention.

Claims

1. 1. A reactor for coating particles, comprising: a stationary vacuum chamber for holding a bed of particles to be coated, the chamber having a lower portion and an upper portion forming a semi-cylinder; a vacuum port in the upper portion of the chamber; a chemical delivery system configured to inject a reactant or precursor gas into the lower portion of the chamber; 1. A paddle assembly comprising: a rotatable drive shaft extending through the chamber along the axial axis of the semi-cylinder; a plurality of paddles extending radially from the drive shaft such that rotation of the drive shaft causes the plurality of paddles to orbit around the drive shaft; a motor for rotating the drive shaft; a paddle assembly including: Including, the reactant gas or the precursor gas is injected into the lower part of the stationary vacuum chamber along a gas flow direction through a plurality of apertures; the drive shaft is oriented and rotated by the motor that causes the plurality of paddles to orbit around the drive shaft such that the plurality of paddles cross the plurality of apertures along a sweep direction; the plurality of apertures extend through a chamber wall of the lower part of the stationary vacuum chamber such that the gas flow direction is parallel to a component of the sweep direction, and the sweep direction does not include any component anti-parallel to the gas flow direction.

2. 10. The reactor of claim 1, wherein a paddle of the plurality of paddles includes a planar body including a major surface configured to push particles in the bed of particles as the motor causes the plurality of paddles to orbit around the drive shaft, and a thinner edge configured to contact an inner surface of the lower portion of the chamber.

3. The reactor of claim 2 wherein said planar body of said paddle comprises a sector shape.

4. 3. The reactor of claim 2 wherein said planar body surface of said paddle is flat.

5. 10. The reactor of claim 1, wherein the chemical delivery system is configured to inject the reactant gas or the precursor gas through a bed of particles held in the lower portion of the stationary vacuum chamber as the paddle assembly rotates.

6. 2. The reactor of claim 1, wherein the rotation of the drive shaft by the motor, which causes the plurality of paddles to orbit around the drive shaft, is substantially parallel to the flow of the reactant gas or the precursor gas injected into the stationary vacuum chamber.

7. 10. The reactor of claim 1 wherein said plurality of paddles are configured to sweep along the entire length of said chamber.

8. 10. The reactor of claim 1 wherein an outer end of said paddle is separated from an inner surface of said lower portion of said chamber wall by a gap.

9. the plurality of paddles includes a first plurality of outer paddles and a first plurality of inner paddles; 10. The reactor of claim 1, wherein said first plurality of outer paddles are oriented at a first oblique angle and said first plurality of inner paddles are oriented at a second oblique angle opposite in sign to said first oblique angle.

10. 10. The reactor of claim 9 wherein said second oblique angle is equal in magnitude to said first oblique angle.

11. 2. The reactor of claim 1, wherein said plurality of paddles comprises a first plurality of outer paddles at a first radial distance from said drive shaft and a first plurality of inner paddles at a second radial distance from said drive shaft, wherein when the first and second plurality of paddles orbit in the same direction around said drive shaft, said first plurality of outer paddles are oriented at a first oblique angle to drive particles in a first direction along said axial axis and said first plurality of inner paddles are oriented at a second oblique angle to drive particles in a second direction opposite said first direction along said axial axis.

12. 12. The reactor of claim 11, wherein said plurality of paddles comprises a second plurality of outer paddles at a third radial distance from said drive shaft and a second plurality of inner paddles at a fourth radial distance from said drive shaft, said fourth radial distance being less than said third radial distance, said second plurality of outer paddles being oriented at a third oblique angle to drive particles in said second direction, and said second plurality of inner paddles being oriented at a fourth oblique angle to drive particles in said first direction.

13. 13. The reactor of claim 12, wherein said third radial distance is equal to said first radial distance, said fourth radial distance is equal to said second radial distance, said third oblique angle is equal in magnitude and opposite in direction to said first oblique angle, and said fourth oblique angle is equal in magnitude and opposite in direction to said second oblique angle.

14. 14. The reactor of claim 13 wherein said third bevel angle is equal to said second bevel angle and said fourth bevel angle is equal to said first bevel angle.

15. 15. The reactor of claim 14, wherein said first plurality of outer paddles and said first plurality of inner paddles are positioned on a first side of a dividing plane through said chamber perpendicular to said axial axis, and said second plurality of outer paddles and said second plurality of inner paddles are positioned on a second side of said dividing plane opposite said first side.

16. 1. A method of coating particles, comprising: dispensing particles into a vacuum chamber to fill at least a lower portion of said chamber forming a half cylinder; evacuating the chamber through a vacuum port in a top portion of the chamber; rotating a paddle assembly with a motor so that the plurality of paddles orbit the drive shaft; injecting a reactant or precursor gas into the lower portion of the chamber as the paddle assembly rotates; Including, the reactant gas or the precursor gas is injected into the lower part of the chamber along a gas flow direction through a plurality of apertures; the drive shaft is oriented and the motor rotates the drive shaft to cause the paddles to orbit around the drive shaft such that the paddles cross the apertures along a sweep direction; the apertures extend through a chamber wall of the lower part of the chamber such that the gas flow direction is parallel to a component of the sweep direction, and the sweep direction does not include any component anti-parallel to the gas flow direction; method.

17. 17. The method of claim 16, comprising coating the particles by atomic layer deposition or molecular layer deposition.

18. 18. The method of claim 17, wherein the particles comprise a core containing a drug.

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