Reactor for coating particles in a fixed chamber with rotating paddles

Abstract

The present invention provides a coating apparatus and method that can appropriately prevent the degradation of active pharmaceutical ingredients (APIs) and is suitable for mass production. [Solution] The reactor for coating particles includes a fixed vacuum chamber for holding a bed of particles to be coated, a vacuum port in the upper part of the chamber, a chemical delivery system configured to inject a 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 forms a semicylinder. The paddle assembly includes a rotatable drive shaft extending through the chamber along the axial axis of the semicylinder, and a plurality of paddles extending radially from the drive shaft such that rotation of the drive shaft by the motor causes the paddles to orbit the paddles around the drive shaft.

Description

Technical Field

[0001] The present disclosure relates to coating particles, such as particles containing an active pharmaceutical ingredient (API), with organic and inorganic thin films.

Background Art

[0002] Developing improved formulations of active pharmaceutical ingredients (APIs) is important for 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, non-uniform coatings (both within particles and from particle to particle) impede the use of these techniques to improve the delivery profile or stability of active pharmaceutical ingredients (APIs). Particle aggregation during spray coating also presents an important challenge. On the other hand, techniques such as plasma polymerization are difficult to scale and are applicable only to specific precursor chemistries, which can lead to degradation of sensitive APIs. Existing hot wire CVD processes that utilize a hot wire radical source inside a reaction vessel are not very scalable and are not suitable for heat-sensitive APIs. Rotary reactors include atomic layer deposition (ALD) and initiated CVD (iCVD) reactors. However, ALD reactors are suitable for inorganic coatings and not for organic polymer coatings. Also, existing iCVD designs cannot adequately prevent degradation of APIs and cannot handle large-scale production. Other techniques include polymer mesh coating, pan coating, aerosolized coating, and fluid bed reactor coating.

Summary of the Invention

[0004] In one embodiment, a reactor for coating particles includes a fixed vacuum chamber for holding a bed of particles to be coated, a vacuum port in the upper part of the chamber, a chemical delivery system configured to inject a 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 forms a semicylinder. The paddle assembly includes a rotatable drive shaft extending through the chamber along the axial axis of the semicylinder, and a plurality of paddles extending radially from the drive shaft such that rotation of the drive shaft by the motor causes the paddles to orbit the drive shaft.

[0005] The embodiment may include one or more of the following features:

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

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

[0008] The multiple paddles may include a second set of multiple outer paddles at a third radial distance from the drive shaft, and a second set of multiple inner paddles at a fourth radial distance from the drive shaft. The fourth radial distance may be shorter 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 set of outer paddles may be oriented at a third angle to drive the particles in a second direction, and the second set of inner paddles may be oriented at a fourth angle to drive the particles in a first direction. The third angle may be equal to the second angle, and the fourth angle may be equal to the first angle.

[0010] The first plurality of outer paddles and the first plurality of inner paddles may be positioned on a first side surface of a dividing plane passing through a chamber perpendicular to an axial axis, and the second plurality of outer paddles and the second plurality of inner paddles may be positioned on a second opposing side surface of the dividing plane. Ports for delivering particles to or receiving particles from the chamber may be positioned on the dividing plane. 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] Multiple paddles may include paddles uniformly spaced along the drive shaft. Multiple paddles may also include groups of paddles, each group of paddles may be positioned in a common plane perpendicular to the drive shaft.

[0012] In another embodiment, a method for coating particles includes dispensing particles into a vacuum chamber to fill at least the lower part of the chamber to form a semi-cylindrical chamber; evacuating the chamber through a vacuum port in the upper part of the chamber; rotating a paddle assembly so that a plurality of paddles orbit a drive shaft; and injecting a reaction gas or precursor gas into the lower part of the chamber as the paddle assembly rotates.

[0013] The embodiment 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 a drug.

[0015] The implementation may include, but is not limited to, one or more of the following anticipated advantages: Particles, such as API particles, can be coated within a mass production process, thereby providing lower manufacturing costs and lower-priced drug products. Particles can be coated in a thin layer, thus providing a drug product with a favorable volume fraction of API. Furthermore, the process can result in a layer that encapsulates a uniform API within and between particles, providing more consistent properties for the drug formulation.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention pertains. While methods and materials for use in the present invention are described herein, other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative and not intended to be limiting.

[0017] Other features and advantages of the present invention will become apparent from the embodiments, drawings, and claims for carrying out the invention described below. [Brief explanation of the drawing]

[0018] [Figure 1] Schematic front view of a reactor for ALD and / or CVD coating of particles, such as drugs, including a fixed drum. [Figure 2] Schematic side view of the reactor of FIG. 1. FIG. 2 can be taken along line 2-2 of FIG. 1. [Figure 3A] Schematic side view of a paddle assembly. [Figure 3B] Front view of the paddle assembly of FIG. 3A. FIG. 3B can be taken along line 3B-3B of FIG. 3A. [Figure 3C] Schematic side view of another implementation form of the paddle assembly. [Figure 3D] Front view of the paddle assembly of FIG. 3C. FIG. 3D can be taken along line 3D-3D of FIG. 3C. [Figure 4] Schematic perspective view of a paddle. [Figure 5] Schematic side view of a group of paddles from a paddle assembly. [Figure 6A] Schematic side view of another implementation form of a group of paddles from a paddle assembly. [Figure 6B] Schematic side view of yet another implementation form of a group of paddles from a paddle assembly. [Figure 7] Schematic side view of a paddle from a group of paddles of FIG. 5 or 6. FIG. 7 can be taken along line 7-7 of FIG. 4. [Figure 8] Schematic side view of a gas injection port. FIG. 8 can be taken along line 8-8 of FIG. 1. [Figure 9] Schematic top view of the gas injection port of FIG. 8. [Figure 10] Schematic perspective view of a partial cross-section showing the gas injection port.

Mode for Carrying Out the Invention

[0019] Similar reference numerals and names in the various drawings indicate similar elements.

[0020] There are various methods for encapsulating API particles. In many cases, these methods result in relatively thick coatings. Such coatings can provide desirable properties, but if the ratio of the coating to the API is high, it can be difficult to create a drug product with a high enough volume fraction of the API. Further, the coating encapsulating the API can be non-uniform, making it difficult to provide a formulation with consistent properties. Additionally, coating techniques that could provide satisfactory consistency were not scalable to industrial production.

[0021] A technique that can address these problems is to use a stationary “drum” in which the particles are agitated by rotating a paddle, and a processing gas is injected into the drum through the drum sidewall. This allows the process gas to penetrate the particle bed, improving the uniformity of the coating across the particles.

[0022] Drug The term “drug” in its broadest sense includes all small molecules (e.g., non-biological) APIs. Drugs can be selected from the group consisting of analgesics, anesthetics, anti-inflammatory agents, anthelmintics, antiarrhythmics, anti-asthma agents, antibiotics, anti-cancer agents, anticoagulants, antidepressants, anti-diabetic drugs, anti-epileptic drugs, anti-histamines, antitussives, antihypertensive drugs, anti-muscarinic drugs, anti-mycobacterial drugs, anti-tumor drugs, antioxidants, antipyretics, immunosuppressive agents, immunostimulants, anti-thyroid drugs, anti-viral drugs, anxiolytics, hypnotics, neuroleptics, astringents, bacteriostatics, beta-adrenergic receptor blockers, blood products, blood substitutes, bronchodilators, buffers, cardiotonic agents, chemotherapeutic agents, contrast agents, corticosteroids, cough suppressants, expectorants, mucolytics, diuretics, dopaminergic agents, anti-Parkinson's drugs, free radical scavengers, growth factors, hemostatic agents, immunizing agents, lipid regulators, muscle relaxants, parasympathomimetics, parathyroid calcitonin, bisphosphonates, prostaglandins, radiopharmaceuticals, hormones, sex hormones, anti-allergy agents, appetite stimulants, anorectics, steroids, sympathomimetics, thyroid agents, vaccines, vasodilators, and xanthines.

[0023] Examples 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 additives, diluents, and carriers Pharmaceutically acceptable additives include, but are not limited to, the following: (1) Surfactants and polymers including the following: polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium lauryl sulfate, polyvinyl alcohol, crospovidone, polyvinylpyrrolidone-polyvinyl acrylate copolymer, cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose phthalate, polyacrylate and polymethacrylate, urea, sugars, polyols, carbomers and their polymers, emulsifiers, sugar gums, starch, 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 colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel, and other agents that affect the fluidity of the powder being compressed; (5) Sweeteners, such as any natural or artificial sweeteners including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame potassium; (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, phenol 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 above; (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, etc.; and (12) Effervescent couples such as foaming agents, for example, organic acids (e.g., citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid, as well as anhydrides and 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 that enables the deposition of films with uniformly controlled thickness and uniformity at the atomic or molecular level through the sequential addition of self-controlled monolayers of elements or compounds. Self-controlled means that only a single atomic layer is formed at a time, and subsequent process steps are required to regenerate the surface and allow for further deposition.

[0027] Molecular layer deposition (MLD) Molecular layer deposition (MLD) is similar to atomic layer deposition (MLD) but uses organic precursors to form organic thin films. In a typical MLD process, two homobifunctional precursors are used. The first precursor is introduced into the chamber. The molecules of the first precursor react with reactive groups on the substrate surface via corresponding bonding chemistry to add a molecular layer of the first precursor to the substrate surface, which has new reaction sites. After purging, the second precursor is introduced, and the molecules of the second precursor react with new reaction sites provided by the first precursor, which generate a molecular layer of the first precursor bonded to the second precursor. This is followed by another purging cycle.

[0028] Reactor system Figure 1-2 illustrates a reactor system 100 for coating particles with a thin film coating. The reactor system 100 can carry out coating using ALD and / or MLD coating conditions. The reactor system 100 ensures that the deposition process (ALD or MLD) is carried out at a higher processing temperature (above 50°C, e.g., 50-100°C) or a lower processing temperature, 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 mainly by ALD at temperatures of 22-35°C, e.g., 25-35°C, 25-30°C, or 30-35°C. Generally, particles can remain or be maintained at such temperatures. This can be achieved by leaving or maintaining the reaction gas and / or the internal surface of the reactor chamber at such temperatures.

[0029] The reactor system 100 includes a fixed vacuum chamber 110 surrounding the paddle assembly 150.

[0030] The vacuum chamber 110 is surrounded by chamber walls 112. The lower part 110 of the chamber 110 forms a semicylinder with a semicircular cross-section (when viewed along the central axis of the semicylinder). The cross-section of the upper part 110b (again, when viewed along the central axis of the semicylinder) can be uniform along the length of the chamber 110 (the length is along the central axis of the semicylinder). This helps ensure a 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 towards the top when viewed horizontally but perpendicular to the central axis of the semicylinder.

[0031] The cross section of the upper part 110b can be selected to enclose the paddle assembly 150 while saving space within the manufacturing facility. For example, the upper part 110b of the chamber 110 may be a rectangular parallelepiped (see Figure 6A), a semi-cylindrical shape 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 part 110b of the chamber is adjacent to the lower part 110a and has a lower section 110c, e.g., a rectangular parallelepiped volume, with vertical side walls. The upper section 110c extending between the lower section 110c and the ceiling 112a of the chamber 110 may have a triangular or trapezoidal cross-section (again, viewed along the central axis of a semi-cylindrical shape).

[0032] In some implementations, as shown in Figure 6B for example (although it can be combined with other paddle assemblies), the curved portion of the chamber wall follows the lower section 110c of the upper chamber 110b. The upper section 110d, extending between the lower section 110c and the ceiling 112a of the chamber 110, may provide space for the vacuum port 132 and / or powder delivery port 116. This configuration can avoid powder accumulation along the portion of the side wall 12 that the paddle 154 cannot reach, for example, caused by the paddle assembly delivering the powder.

[0033] The chamber wall 110 may be made of a material inert to the deposition process, such as stainless steel. And / or, the inner surface of the chamber wall 110 may be coated with a material inert to the deposition process. In some implementations, a viewing port 114 made of a transparent material, such as quartz, is formed through the chamber wall 112 to allow the operator to view the inside of the chamber 110.

[0034] During operation, the chamber 110 is partially filled with particles, such as API-containing particles, thereby providing a particle bed 10. For good throughput, the particle bed 10 fills at least the lower part 110a of the chamber. For example, the upper surface 12 of the particle bed 10 is at or above the lower part 110 (indicated as A). On the other hand, the upper surface 12 of the particle bed 10 must be below the upper part (indicated as B) of the paddle assembly 150 to avoid insufficient mixing of the particle bed. The chamber wall 112 may include one or more sealable ports 116 to allow particles to be placed into and removed from the chamber 110.

[0035] Chamber 110 is connected to a vacuum source 130. A port 132 connecting to the vacuum source 130 through the chamber wall 112 may be located in the upper part 110b of chamber 110. In particular, port 132 may be located above the predicted position of the upper surface 12 of the particle bed, for example, above the upper part (indicated as 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, from 1 to 100 mTorr, for example, 50 mTorr. The vacuum source 130 ensures that the chamber 110 is maintained at the desired pressure and that reaction byproducts and unreacted process gases are removed.

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

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

[0039] The chemical substance delivery system 140 may include five fluid sources 142a, 142b, 142c, 142d, and 142e. Two of the fluid sources, for example, fluid sources 142a and 142b, may provide two chemically different precursors or reactants for a deposition process to form an oxide layer on 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 other fluid sources, for example, fluid sources 142c and 142d, may provide two chemically different 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, a 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] Figure 1 illustrates five fluid sources, but the use of fewer gas sources can still be compatible with the deposition of oxide or polymer layers, while the use of more gas sources can enable the formation of an even wider variety of layered structures.

[0041] With respect to one or more of the fluid sources, the chemical delivery system 140 delivers a precursor or reactant in liquid form to the gas injection assembly 190. The gas injection assembly 190 includes a vaporizer 148 for converting the liquid into vapor just before the precursor or reactant enters the injection manifold 194. This reduces the upstream pressure loss and allows for more pressure loss to occur throughout the particle bed 10. The greater the pressure loss that occurs throughout the particle bed 10, the lower the injection opening can be positioned, and the greater the likelihood that all of the precursor will react as it passes through the particle bed at a given flow rate. The vaporizer 149 may be directly adjacent to the reactor sidewall. For example, it may be fixed to the reactor wall side 112 or housed inside it.

[0042] As shown in Figure 1, there are separate manifolds 194 for each precursor or reaction fluid, and each manifold 194 can be separately fluidically connected to the chamber 110. Thus, the precursors or reactants cannot be mixed until they actually enter the chamber 110. Alternatively, the gas line from the fluid source 142 can be joined as a combined fluid supply line, for example by a valve. The gas injection assembly 190 will be 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 number of paddles 154. The paddles 154 are connected to the drive shaft 152 by support struts 156 extending outward from the drive shaft 152, such that the rotation of the drive shaft 152 around the rotation axis 153 carries the paddles 154 in a circular path around the rotation axis 153 (see arrow C). The support struts 156 may extend perpendicular to the drive shaft 152. The drive shaft 152 and the rotation axis 153 may extend along the boundary between the upper 110b and lower 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 connected 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 on the inner surface of the chamber wall 112. Alternatively, the drive shaft 152 can be easily held in a cantilever configuration with the end of the drive shaft unsupported. This may be advantageous for disassembly and cleaning. The motor 160 can rotate the drive shaft 152 and the paddle assembly 150 at speeds from 0.1 to 60 rpm.

[0045] At least some of the paddles 154 are held by the support 156 in a position where the outer ends of the paddles 154 are in near contact with 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 the manufacturing tolerance so that the paddles 154 do not rub against the outer wall 112.

[0046] The axis of rotation 153 of the drive shaft 152 may be parallel to, for example, collinear with, the central axis of the cylinder that defines the lower part 110a. In this case, the rotation of the drive shaft 152 allows the outer end of the paddle 154 to sweep across the inner surface of the semi-cylinder of the lower part 110a, for example, across the entire inner surface of the semi-cylinder.

[0047] The paddles 154 can be spaced along the drive shaft 152 to ensure that the paddles, which are in substantially contact with the internal surface 114, provide covering along substantially the entire length of the reactor chamber 110. In particular, the paddles 154 can be spaced and have a width W (along the axis of rotation) such that there are no gaps in the space swept by the paddle assembly 150. In particular, the width W can 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 can be angularly offset. For example, as shown in Figures 3A and 3B, the paddles 154 can be arranged in a spiral pattern around the drive shaft 152. However, many other configurations are possible for angular offset, such as 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 the other paddles 154. Paddles 154b closer to the drive shaft are called "inner paddles," and paddles 154a further from the drive shaft are called "outer paddles." The inner and outer paddles 154a and 154b may not overlap radially, or they may partially overlap radially. For example, the inner and outer paddles may overlap for up to 20% of the radial span S of the outer paddle (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 is no gap in the space swept by the outer paddles 154a. In particular, the width W of the outer paddles 154a can 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 can be angularly offset. Similarly, the inner paddles 154b may be spaced apart and have a width (along the axis of rotation) such that there is no gap in the space swept by the inner paddles 154b. In particular, the width of the inner paddles 154b can 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 can be angularly offset. For example, as shown in Figures 3C and 3D, the inner paddles 154b may be arranged in a first helix around the drive shaft 152, and the outer inner paddles 154a may be arranged in a second helix around the drive shaft 152. The spirals of the inner and outer paddles 154a and 154b are shown to be 180° out of phase, but this is not necessary. Furthermore, many other configurations of angular offset between adjacent paddles are possible. For example, the paddles may be arranged on alternating sides of the drive shaft.

[0050] Referring to Figure 4, each paddle 154 may have a generally flat body with a main surface 170 for pushing particles in the particle bed, and a thinner edge 172 that will contact the inner surface of the lower part 110a of the chamber 110. As shown in Figure 4, the paddle 154 may be fan-shaped and flared. Alternatively, as shown in Figures 1 and 2, the paddle may be generally rectangular, for example, a rectangle with rounded edges. The surface 170 of the paddle 154 may be flat, or the surface 170 may be concave, for example, spoon-shaped. Furthermore, in some implementations, the paddle 154 may be plow-shaped, such as convex or sharply convex, with respect to the direction of paddle motion.

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

[0052] For example, referring to Figures 1 and 5, the paddle assembly 150 includes a group of four paddles 180a, 180b, 180c, and 180d that are equidistant from the drive shaft 152 and the rotation axis 153, spaced at 90-degree angles. The paddles 180a-180d can be positioned to be in substantially contact with the semi-cylindrical inner surface of the lower part 110a of the chamber 110a.

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

[0054] In some implementations, as shown in Figure 1, for example, the group's paddles may be positioned substantially equidistant from the rotation axis 153. For example, the support columns 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 the other paddles in the group. For example, the paddle assembly 150 shown in Figure 6A includes a group of four paddles 180a', 180b', 180c', and 180d' spaced 90° apart. Two of the paddles, for example, two opposing paddles 180a' and 180c', are positioned at a first distance from the drive shaft 152. These two paddles may be positioned so as to be in near contact with the inner surface 112 of the semi-cylindrical lower part 110a. The other two of the paddles, for example, two opposing paddles 180b' and 180d', are positioned at a second distance from the drive shaft 152.

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

[0057] In some implementations, some groups of paddles have paddles positioned radially closer to the drive shaft 152 than paddles in other groups. For example, paddle assembly 150 includes a group 182 of four inner paddles 182a, 182b, 182c, and 182d that are equidistant and spaced 90 degrees apart from the drive shaft 152 and the rotation axis 153. The outer ends of paddles 182a-182d are spaced apart from the semi-cylindrical inner surface of the lower part 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] Returning to Figures 1, 5, and 7, each paddle 154 can be positioned and oriented such that the axis N perpendicular to the plane 170 of the paddle 154 is perpendicular to the radius R through which the paddle 154 passes from the axis of rotation 153. However, in some implementations, one or more paddles 154 can be angled such that the trajectory of the paddle 154 around the axis of rotation 153 tends to force the particles radially toward or away from the axis of rotation 153.

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

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

[0061] Angles α' and α' are not equal. In particular, angles α' and α' can have opposite signs. In some implementations, angle α' is the same magnitude as angle α but has the opposite sign; for example, the oblique angle is +α for the outer paddle and -α for the outer paddle.

[0062] In some implementations, the outer paddles 154 are angled such that the orbit of the paddles terminates to force particles in a first direction parallel to the axis of rotation 153, while the inner paddles 154 are angled such that the orbit of the inner paddles 154 tends to force particles in an antiparallel direction, i.e., a second direction opposite to the first direction. For example, referring 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 the group can force particles in the opposite direction to D.

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

[0064] For example, the outer paddles of groups 180 and 182 can push particles to the left toward port 116a, and the inner paddles of groups 180 and 182 can push particles to the right toward port 116a. Conversely, the outer paddles of groups 184, 186, and 188 can push particles to the right toward port 116a, and the inner paddles of groups 184, 186, and 188 can push particles to the left toward port 116a. Paddles oriented to push particles in a first direction, for example to the left, may be oriented at an angle of +α, while paddles oriented to push particles in the opposite second direction, for example to the right, may be oriented at an angle of -α.

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

[0066] Referring to Figures 1 and 8, the chemical delivery system 140 is connected to the chamber 110 by a gas injection assembly 190. The gas injection assembly includes a plurality of openings 192 extending through the chamber wall 112. The openings 192 may, for example, be arranged parallel to the axis of rotation 153 of the drive shaft 152. Although Figure 8 illustrates a single row of openings 192, the system may have multiple rows of openings. In particular, different rows of openings may exist for different reactants or precursors. Furthermore, multiple rows of openings may exist for a given reactant and / or precursor.

[0067] The opening 192 is located below the predicted position of the upper surface 12 of the particle bed. In particular, the opening 192 passing through the chamber wall 112 may be located in the lower part 110b of the chamber 110. For example, the opening 192 may extend through a curved semicircular portion of the side wall 112. The opening 192 may be located in the lower half of the chamber wall 112 in the lower part 110b, for example, the lower third, for example, the lower quarter, for example, the lower fifth (when measured vertically). The opening may have a diameter of 0.5 to 3 mm. Figure 1 illustrates the opening 192 extending horizontally through the chamber wall, but this is not necessary, as will be further explained below.

[0068] Referring to Figures 1 and 9, the gas injection assembly 190 includes a manifold 194 having a plurality of channels 196 leading from the manifold 194 to the opening 192. The manifold 194 and channels 196 may be formed as passages through a solid body 196 that provides part of the chamber wall 112. The vaporizer 148 may be positioned just upstream of the manifold 194.

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

[0070] When no precursor or reactor gas is being injected into the chamber 110 through manifold 194, the carrier gas flow can prevent backflow of another precursor or reactor gas being injected from another manifold into opening 192. The carrier gas flow can also prevent fouling of opening 192 by particles in the particle bed 10, for example, blockage of the opening. Furthermore, the carrier gas can provide a purge gas for purging operations when no precursor or reactor gas is being injected into the chamber 110.

[0071] The flow of carrier gas to vaporizer 149 when a precursor gas is also flowing can improve the vaporization of the precursor or reaction liquid. Without being limited by any specific theory, the flow of carrier gas can help shear the liquid during aerosolization, which may lead to smaller droplet sizes, thereby allowing for rapid vaporization. The flow of carrier gas to manifold 194 when a precursor gas is also flowing can help discharge the precursor gas from the vaporizer.

[0072] The gas from the chemical delivery system 130 flows out through the opening (indicated by arrow E) and enters the chamber 110. Assuming the chamber 110 is partially filled with particles, the gas is injected near the bottom of the particle bed 10. Therefore, the chemicals of the gas need to "bubble" through the body of the particle bed 10 so that they leak out and are discharged through the vacuum port 132. This can help ensure that the particles are uniformly exposed to the gas.

[0073] The rotational direction of the paddle assembly 150 (indicated by arrow C) may be such that the paddle sweeps across the opening 192 in a direction that has a component in the same direction as the gas flow (indicated by arrow E) (i.e., does not have an antiparallel component). This prevents particles from being pushed back against the gas flow and blocking the opening 192.

[0074] Referring to Figure 10, the gas injection assembly 190 may be configured to inject gas into the chamber 110 in a direction of gas flow that is substantially parallel to the instantaneous direction of motion of the paddle 154 as it passes over the opening 192. In other words, the direction of gas flow may be substantially in contact with the curved inner surface 114 of the cylindrical bottom 110a of the 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 opening 192. As shown in Figure 10, the opening 192 may be a scalloped recess having a sharp indentation followed by a depth that gradually decreases along the rotational direction of the paddle 154 (indicated by arrow C). The first channel portion 196a may open into the ceiling 192a of the opening 192 formed by the sharp indentation. This configuration can reduce the possibility of particles entering the channel 196. Furthermore, the first channel portion 196 may be wider than the expected diameter of the particles. This can reduce the risk of particles clogging the first channel portion 196a.

[0076] Channel 196 also includes a second channel portion 196b extending 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 the flow distribution exiting the manifold 194.

[0077] The vaporizer 148 may include an internal cavity 148a surrounded by walls heated by a heater 148b, such as a resistance heater, thermoelectric heater, or heating lamp. This 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 the rapid vaporization of a large amount of reactant or precursor. The cavity 149a of the vaporizer 148 may extend along a substantial portion, for example, 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 openings 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 described above, the vaporizer 148 may be integrated into a body that provides the manifold. For example, the vaporizer 148, manifold 194, and channel 196 may all be part of a single, integrated body.

[0079] In some implementations, one or more temperature control components are integrated into the chamber wall 112 to enable temperature control of the chamber 110. For example, a resistance heater, thermoelectric cooler, heat exchanger, or cooling channels in the chamber wall, or a coolant flowing through other components in or on the side wall 112.

[0080] The reactor system 10 also includes a controller 105 connected 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 connected to various sensors, such as a pressure sensor, a flow meter, etc., to provide closed-loop control of the gas pressure in the chamber 110.

[0081] Generally, the controller 105 is configured to operate the reactor system 100 according to a “policy.” The policy specifies the operating values ​​of each controllable element over time. For example, the policy may specify the operating time of the vacuum source 130, the time and flow rate of each gas source 142a-142e, the rotational speed of the drive shaft 152 set by the motor 160, and so on. The controller 105 can receive the policy as computer-readable data (stored in a non-transient computer-operated medium).

[0082] The controller 105 and other computer components of the system described herein may be implemented in digital electronic circuits, or in computer software, firmware, or hardware. For example, the controller may include a processor that executes computer programs stored in computer program products such as non-transient machine-readable storage media. Such computer programs (also known as programs, software, software applications, or code) can be written in any form of programming language, including compiled or interpreted languages, and can be deployed in any form, including as standalone programs or as modules, components, subroutines, or other units 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 circuits, such as FPGAs (Field-Programmable Gate Arrays) or ASICs (Application-Specific Integrated Circuits).

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

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

[0085] During operation, the reactor system 100 carries out the ALD and / or MLD thin film coating process by introducing a gaseous precursor of the coating into the chamber 110. The gaseous precursor is alternately spiked into the reactor chamber 110. This allows the deposition process to be a solvent-free process. The half-reactions of the deposition process are self-controlled, which can provide deposition control at the angstrom or nanometer level. Furthermore, the ALD and / or MLD reactions can be carried out under low temperature conditions, such as below 50°C, for example, below 35°C.

[0086] Suitable reactants for the ALD method include any or a combination of the following: monomer vapors, organometallic compounds, metal halides, oxides 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), while the second gas source 142b may provide water. With respect to MLD, for example, the fluid source 142c may provide adipoyl chloride, and the fourth fluid 142d may provide vapor or gaseous ethylenediamine.

[0087] During operation, as the paddle assembly 150 rotates, a type of gas flows from the chemical delivery system 140 to the particle bed 10 in the lower part 110a of the chamber 110. The rotation of the paddle assembly 150 agitates and separates the particles, ensuring that a large surface area of ​​the particles remains exposed. This allows for a high-speed, uniform interaction between the particle surface and the processing gas.

[0088] In both the ALD and MLD processes, two reaction gases are alternately supplied to the chamber 110, and a purge cycle follows each step in supplying the reaction gases. During the purge cycle, an inert gas is supplied to the chamber 110, pushing out the reaction gases and by-products used in the previous step.

[0089] As described above, the coating process can be carried out at a low processing temperature, for example, below 50°C, for example, below 35°C. In particular, the particles may remain at or be maintained at such a temperature throughout all of steps (i)-(ix) above. Generally, the temperature inside the reactor chamber will not exceed 35°C during steps (i)-(ix). This can be achieved by ensuring that the first reaction gas, the second reaction gas, and the inert gas are injected into the chamber at such temperatures during each cycle. Furthermore, the physical components of the chamber may remain at or be maintained at such a temperature, for example, by using a cooling system, for example, a thermoelectric cooler, if necessary.

[0090] In some implementations, the controller can use the above process to first deposit an oxide layer on the drug-containing particles, and then deposit a polymer layer on top of the particulate oxide layer in the reactor system 100. In some implementations, the controller can alternately deposit oxide layers and polymer layers on the drug-containing particles in the reactor system 100 to form a multilayer structure having layers of alternating compositions.

[0091] Continuous flow of motion With respect to the ALD process, the controller 105 can operate the reactor system 100 as follows.

[0092] During the first half-cycle of the reaction, the motor 160 rotates the paddle wheel 150 to agitate the particles: i) The gas distribution system 140 is operated to flow a first reaction gas, e.g., TMA, from the source 142a to the chamber 110 until the particle bed 10 is saturated with the first reaction gas. For example, the first reaction gas may 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 reaction gas at the top 110b of the chamber. In some implementations, the first reaction gas is mixed with an inert gas once it flows into the chamber. The specified pressure or partial pressure can range from 0.1 Torr to half the saturation pressure of the reaction gas. ii) The flow of the first reaction gas is stopped, and the vacuum source 140 evacuates the chamber 110 to a pressure, for example, less than 1 Torr, for example from 1 to 100 mTorr, for example from 50 mTorr.

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

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

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

[0096] During the second half-cycle of the reaction, the motor 160 rotates the paddle assembly 150 to agitate the particles: v) The gas distribution system 30 is operated to flow a second reaction gas, such as H2O, from the source 142b into the chamber 110 until the particle bed 10 is saturated with the second reaction gas. The second reaction gas may then 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 reaction gas at the top 110b of the chamber. In some implementations, the second reaction gas is mixed with an inert gas once it flows into the chamber. The third pressure can range from 0.1 Torr to half the saturation pressure of the second reaction gas. vi) The vacuum pump 140 evacuates the chamber 110 to a pressure, for example, less than 1 Torr, for example from 1 to 500 mTorr, for example 50 mTorr.

[0097] These steps (v)-(vi) may be repeated a number of times set by the policy, for example, from 2 to 10 times.

[0098] Next, a second purge cycle is performed. This second purge cycle, having steps (vii) and (vii), may be identical to the first purge cycle, or it may have a different number of repetitions of steps (iii)-(iv), or a different specified pressure.

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

[0100] The procedure is described above for the ALD process, but the procedure is similar for MLD. In particular, in steps (i) and (v), the reaction gas is replaced with an appropriate treatment gas and pressure for the deposition of the polymer layer. For example, step (i) can use vaporized or gaseous adipoyl chloride, and step (v) can use vaporized ethylenediamine.

[0101] Furthermore, although the operation is described above for ALD or MLD processes, the system can be used for chemical vapor deposition (CVD) processes. In this case, both reactants are simultaneously introduced into chamber 110 so that they react inside the chamber, for example during step (i). The second half-cycle of reaction can be omitted.

[0102] Pulsed flow operation In another implementation, one or more gases (e.g., a reaction gas and / or an inert gas) may be supplied in pulses. Here, 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, with respect to the ALD process, the controller 105 can operate the reactor system 100 as follows:

[0104] During the first half-cycle of the reaction, the motor 160 rotates the paddle wheel 150 to agitate the particles: i) The gas distribution system 140 is operated to flow a first reaction gas, such as TMA, from the source 142a to the chamber 110 until a first specified pressure is achieved at the top 110b of the chamber. The specified pressure can range from 0.1 Torr to half the saturation pressure of the reaction gas. ii) The flow of the first reaction gas is stopped, allowing a specified delay time, for example, measured by a timer in the controller, to elapse. This allows the first reactant to flow through the particle bed 10 in the chamber 110 and react with the surface of the particles. iii) The vacuum pump 140 evacuates the chamber 110 to a pressure, for example, less than 1 Torr, for example from 1 to 100 mTorr, for example from 50 mTorr.

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

[0106] Next, in the first purge cycle, while the motor 160 rotates the paddle wheel 150 to agitate the particles: iv) The gas distribution system 140 is operated to flow an inert gas, such as N2, from the source 142e to the chamber 110 until a second specified pressure is achieved. The second specified pressure may be between 1 and 100 Torr. v) The flow of the inert gas is stopped, allowing a specified delay time, for example, measured by a timer in the controller, to elapse. This allows the inert gas to diffuse through the particles in the particle bed 10, replacing the reaction gas and vaporized by-products. vi) The vacuum pump 140 evacuates the chamber 110 to a pressure, for example, less than 1 Torr, for example from 1 to 500 mTorr, for example 50 mTorr.

[0107] These steps (iv)-(vi) may be repeated a number of times set by the policy, for example, from 6 to 20 times.

[0108] During the second half-cycle of the reaction, the motor 160 rotates the paddle assembly 150 to agitate the particles: Vii) The gas distribution system 30 is operated to flow a second reaction gas, for example H2, from source 142b to chamber 110 until a third specified pressure is achieved. The third pressure can range from 0.1 Torr to half the saturation pressure of the reaction gas. viii) The flow of the second reaction gas is stopped, allowing a specified delay time, for example, measured by a timer in the controller, to elapse. This allows the second reaction gas to flow through the particle bed 10 and react with the surface of the particles inside the drum chamber 110. ix) The vacuum pump 140 evacuates the chamber 110 to a pressure, for example, less than 1 Torr, for example from 1 to 500 mTorr, for example 50 mTorr.

[0109] These steps (vii)-(ix) may be repeated a number of times set by the policy, for example, from 2 to 10 times.

[0110] Next, a second purge cycle is performed. This second purge cycle may be identical to the first purge cycle, or it may differ in the number of repetitions of steps (iv)-(vi), as well as the delay time and / or pressure.

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

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

[0113] The procedure is described above for the ALD process, but the procedure is similar for MLD. In particular, in steps (i) and (vii), the reaction gas is replaced with an appropriate treatment gas and pressure for the deposition of the polymer layer. For example, step (i) can use vaporized or gaseous adipoyl chloride, and step (vii) can use vaporized ethylenediamine.

[0114] Furthermore, although the operation is described above for ALD or MLD processes, the system can be used for chemical vapor deposition (CVD) processes. In this case, both reactants are simultaneously introduced into chamber 110 so that they react inside the chamber, for example during step (i). The second half-cycle of reaction can be omitted.

[0115] conclusion This disclosure provides apparatus and methods 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 their total thickness is controlled from several nanometers to several micrometers. The articles to be coated may consist of API alone or a combination of API and one or more additives. The coating processes described herein can provide APIs with a higher glass transition temperature compared to uncoated APIs, a lower crystallization rate of amorphous APIs compared to uncoated APIs, and lower surface mobility of API molecules within the particles compared to uncoated APIs. Importantly, the dissolution of the particles can be altered. Because the coatings are relatively thin, drug products with high drug loading can be achieved. Furthermore, since multiple coatings can be applied to the same reactor, it is advantageous in terms of cost and ease of manufacture.

[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 should be understood that reactor systems may be held vertically or in any other orientation during transport, assembly, etc.

[0117] Several embodiments of the present invention have been described. Nevertheless, it will be understood that various modifications can be made without departing from the essence and scope of the present invention.

Claims

1. A reactor for coating particles, A fixed vacuum chamber for holding a bed of particles to be coated, comprising a chamber having a lower and upper part that form a semi-cylindrical shape, The vacuum port in the upper part of the chamber, A chemical delivery system configured to inject a reaction gas or precursor gas into the lower part of the chamber, Paddle assembly, A rotatable drive shaft extending through the chamber along the axial axis of the semi-cylindrical, The rotation of the drive shaft by the motor causes the drive shaft to orbit the plurality of paddles around the drive shaft, with a plurality of paddles extending radially from the drive shaft, A paddle assembly including, A motor for rotating the drive shaft, A reactor, including

2. The reactor according to claim 1, wherein the outer end of the paddle is separated from the lower inner surface of the chamber wall by a gap.

3. The reactor according to claim 1, wherein the plurality of paddles 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 being smaller than the first radial distance.

4. The reactor according to claim 3, wherein the first plurality of outer paddles are oriented at a first angle, and the first plurality of inner paddles are oriented at a second angle, the same angle as the first angle.

5. The reactor according to claim 4, wherein the second angle is equal in magnitude to the first angle.

6. The reactor according to claim 3, wherein when the first plurality of paddles and the second plurality of paddles orbit the drive shaft in the same direction, the first plurality of outer paddles are oriented at a first angle to drive particles in a first direction along the axial axis, and the first plurality of inner paddles are oriented at a second angle to drive particles in a second direction along the axial axis opposite to the first direction.

7. The reactor according to claim 6, wherein the plurality of paddles 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 being smaller than the third radial distance, the second plurality of outer paddles being oriented at a third angle to drive particles in a second direction, and the second plurality of inner paddles being oriented at a fourth angle to drive particles in a first direction.

8. The reactor according to claim 7, wherein the third radial distance is equal to the first radial distance, the fourth radial distance is equal to the second radial distance, the third angle is equal in magnitude to the first angle and in the opposite direction, and the fourth angle is equal in magnitude to the second angle and in the opposite direction.

9. The reactor according to claim 7, wherein the first plurality of outer paddles and the first plurality of inner paddles are positioned on a first side surface of a dividing surface passing through the chamber perpendicular to the axial axis, and the second plurality of outer paddles and the second plurality of inner paddles are positioned on a second side surface of the dividing surface.

10. The reactor according to claim 9, comprising a port for delivering particles to or receiving particles from the chamber, the port being positioned on the dividing surface.

11. The reactor according to claim 10, wherein the first plurality of outer paddles and the second plurality of outer paddles are oriented to drive particles toward the port, and the first plurality of inner paddles and the second plurality of inner paddles are oriented to drive particles away from the port.

12. A method for coating particles, Dispense particles into a vacuum chamber to fill at least the lower part of the chamber, which forms a semi-cylindrical shape. The chamber is evacuated through a vacuum port in the upper part of the chamber, Rotating the paddle assembly so that multiple paddles orbit the drive shaft, As the paddle assembly rotates, the reaction gas or precursor gas is injected into the lower part of the chamber. Methods that include...

13. The method according to claim 12, comprising coating the particles by atomic layer deposition or molecular layer deposition.

14. The method according to claim 12, wherein the particles include a core containing a drug.

15. A reactor for coating particles, A fixed vacuum chamber for holding a bed of particles to be coated, comprising a chamber having a lower and upper part that form a semi-cylindrical shape, The vacuum port in the upper part of the chamber, A chemical delivery system configured to inject a reaction gas or precursor gas into the lower part of the chamber, Paddle assembly, A rotatable drive shaft extending through the chamber along the axial axis of the semi-cylindrical, A plurality of paddles extending radially from the drive shaft such that the rotation of the drive shaft by the motor causes the paddles to orbit the plurality of paddles around the drive shaft, wherein the plurality of paddles includes a group of paddles, each group of paddles positioned on a common plane perpendicular to the drive shaft, and each group of paddles includes an outer paddle at a first radial distance from the drive shaft and an inner paddle at a second radial distance from the drive shaft, the second radial distance being smaller than the first radial distance, A paddle assembly including, A motor for rotating the drive shaft, A reactor, including

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