阅读说明：本技术 用于在具有旋转叶片与气体注入的固定空腔室中涂覆粒子的反应器 (Reactor for coating particles in a fixed-cavity chamber with rotating blades and gas injection ) 是由 乔纳森·弗兰克尔 科林·C·内科克 普拉文·K·纳万克尔 夸克·特伦 戈文德拉·德赛 塞卡 于 2020-04-22 设计创作，主要内容包括：一种涂覆粒子的反应器,包括：用于保持待涂覆粒子的床的固定的真空腔室,固定的真空腔室具有形成半圆柱体的下部和上部；位于腔室的上部中的真空端口；叶片组件；用于使叶片组件的驱动轴旋转的电机；用于输送第一流体的化学物质输送系统；以及第一气体注入组件,第一气体注入组件用于从化学物质输送系统接收第一流体,并且具有孔,孔被配置为将第一反应物或前驱物气体注入腔室的下部,并使得第一反应物或前驱物气体实质上与半圆柱体的弯曲内表面相切地流动。(A particle-coated reactor comprising: a fixed vacuum chamber for holding a bed of particles to be coated, the fixed vacuum chamber having a lower portion and an upper portion forming a semi-cylinder; a vacuum port located in an upper portion of the chamber; a blade assembly; a motor for rotating the drive shaft of the blade assembly; a chemical delivery system for delivering a first fluid; and a first gas injection assembly for receiving a first fluid from the chemical delivery system and having an orifice configured to inject a first reactant or precursor gas into a lower portion of the chamber and to flow the first reactant or precursor gas substantially tangential to the curved inner surface of the semi-cylinder.)

1. A particle-coated reactor comprising:

a fixed vacuum chamber for holding a bed of particles to be coated, the chamber having a lower portion and an upper portion, the lower portion forming a half cylinder;

a vacuum port located in the upper portion of the chamber;

a blade assembly comprising

A rotatable drive shaft extending through the chamber along an axial axis of the semi-cylinder,

a plurality of blades extending radially from the drive shaft such that rotation of the drive shaft by the motor causes the plurality of blades to revolve around the drive shaft; and

a motor for rotating the drive shaft; and

a chemical delivery system for delivering a first fluid;

a first gas injection assembly receiving the first fluid from the chemical delivery system and having an orifice configured to inject a first reactant or precursor gas into the lower portion of the chamber such that the first reactant or precursor gas flow is injected into the chamber substantially tangential to the curved inner surface of the semi-cylinder.

2. The reactor of claim 1, wherein the first gas injection assembly is configured to inject the first reactant or precursor gas in a direction perpendicular to the axial axis.

3. The reactor of claim 1, wherein the first gas injection assembly comprises a first plurality of holes extending in a first row parallel to the axial axis, and wherein the first gas injection assembly is configured to inject the first reactant or precursor gas via the first plurality of holes.

4. The reactor of claim 3, wherein the first plurality of apertures are located in a lower quarter of the lower portion of the chamber.

5. The reactor of claim 3, wherein the chemical delivery system is configured to deliver a second fluid, and the reactor further comprises a second gas injection assembly that receives the second fluid from the chemical delivery system and has an aperture configured to inject a second reactant or precursor gas into the lower portion of the chamber and such that the second reactant or precursor gas flows substantially tangential to the curved inner surface of the semi-cylinder.

6. The reactor of claim 5, wherein the second gas injection assembly comprises a second plurality of holes extending in a second column parallel to the axial axis, and wherein the second gas injection assembly is configured to inject the second reactant or precursor gas via the second plurality of holes.

7. The reactor of claim 3, wherein the first gas injection assembly comprises a manifold and a plurality of conduits extending from the manifold to the first plurality of nozzles, and the reactor comprises a restriction between the manifold and the plurality of conduits.

8. A particle-coated reactor comprising:

a fixed vacuum chamber for holding a bed of particles to be coated, the chamber having a lower portion and an upper portion, the lower portion forming a half cylinder;

a vacuum port located in the upper portion of the chamber;

a blade assembly comprising

A rotatable drive shaft extending through the chamber along an axial axis of the semi-cylinder,

a plurality of blades extending radially from the drive shaft such that rotation of the drive shaft by the motor causes the plurality of blades to revolve around the drive shaft; and

a motor for rotating the drive shaft; and

a chemical delivery system for delivering a plurality of fluids including at least a first liquid;

a first gas injection assembly that receives the first liquid from the chemical delivery system, the first gas injection assembly comprising a vaporizer to convert the first liquid to a first reactant or precursor gas, a manifold to receive the first reactant or precursor gas from the vaporizer, and a plurality of conduits leading from the manifold to a plurality of holes in the lower portion of the chamber.

9. The reactor of claim 8 wherein the evaporator, manifold and channels are formed as one piece.

10. The reactor of claim 8 comprising a channel connecting the chemical delivery system to deliver inert gas from the chemical delivery system to the manifold.

11. The reactor of claim 9, wherein the evaporator comprises a cavity, a heater for heating a wall of the cavity, and a nozzle for atomizing the first liquid as it enters the cavity.

12. A method of coating particles comprising the steps of:

dispensing particles into a vacuum chamber to fill at least a lower portion of the chamber forming a half cylinder;

evacuating the chamber via a vacuum port in an upper portion of the chamber;

rotating the blade assembly such that the plurality of blades revolve around the drive shaft; and

injecting a first reactant or precursor gas into the lower portion of the chamber as the blade assembly rotates such that the first reactant or precursor gas flows substantially tangential to the curved inner surface of the semi-cylinders.

13. A method of coating particles comprising the steps of:

dispensing particles into a vacuum chamber to fill at least a lower portion of the chamber forming a half cylinder;

evacuating the chamber via a vacuum port in an upper portion of the chamber;

rotating the blade assembly such that the plurality of blades revolve around the drive shaft;

flowing reactants or precursors from the chemical delivery system to the vaporizer;

converting the first liquid into a first reactant or precursor gas in the vaporizer; and

passing the gas from the vaporizer to a plurality of apertures in the lower portion of the chamber via a manifold and a plurality of channels.

14. A method of coating particles comprising:

distributing particles into a vacuum chamber to form a bed of particles in at least a lower portion of the chamber forming a semi-cylinder;

evacuating the chamber via a vacuum port in an upper portion of the chamber;

rotating a blade assembly such that a plurality of blades revolve around a drive shaft to agitate the particles in the particle bed;

injecting reactant or precursor gases into the lower portion of the chamber via a plurality of conduits to coat the particles as the blade assembly rotates; and

injecting the reactant or precursor gas, or purge gas, through the plurality of channels at a sufficiently high velocity such that the reactant or precursor gas or purge gas deagglomerates the particles in the particle bed.

15. The method of claim 14, comprising the steps of: the reactant or precursor gas is injected at a sufficiently high velocity such that the reactant or precursor gas deagglomerates the particles.

16. The method of claim 14, comprising the steps of: the purge gas is injected at a sufficiently high velocity such that the purge gas depolymerizes the particles.

17. The method of claim 14, comprising the steps of: the purge gas is injected at a greater velocity than the reactant or precursor gases.

18. A particle-coated reactor comprising:

a fixed vacuum chamber for holding a bed of particles to be coated;

a blade assembly comprising a rotatable drive shaft and one or more blades in the vacuum chamber, the blades connected to the drive shaft such that rotation of the drive shaft by a motor agitates the particles in the particle bed;

a chemical delivery system comprising a gas injection assembly for delivering reactants or precursor gases and a purge gas to the lower portion of the chamber;

at least one flow regulator for controlling the flow rates of the reactant or precursor gas and the purge gas;

a controller configured to

Causing the chemical delivery system to inject the reactant or precursor gas into the lower portion of the chamber to coat the plasma as the blade assembly rotates; and

causing the chemical delivery system and the at least one flow regulator to inject the reactant or precursor gas or the purge gas into the chamber at a sufficiently high velocity such that the reactant or precursor or purge gas deagglomerates particles in the particle bed.

19. The reactor of claim 18, wherein the controller is configured to cause the at least one regulator to flow the reactant or precursor gas into the chamber at a sufficiently high velocity such that the reactant or precursor gas deagglomerates particles.

20. The reactor of claim 18, wherein the controller is configured to cause the at least one regulator to flow the purge gas into the chamber at a sufficiently high velocity such that the purge gas deagglomerates particles.

Technical Field

The present disclosure relates to coated particles, such as particles comprising an active pharmaceutical ingredient, having organic and inorganic thin films.

Background

The pharmaceutical industry is very interested in developing improved formulations of Active Pharmaceutical Ingredients (API). The formulation may affect the stability and bioavailability, among other characteristics, of the API. The formulation may also affect various aspects of the manufacture of the Drug (DP), such as the simplicity and safety of the manufacturing process.

Many techniques have been developed for encapsulating or coating APIs. Some prior techniques for API coating include spray coating, plasma polymerization, hot wire Chemical Vapor Deposition (CVD), and rotating reactors. Spray coating is an industrially scalable technique that has been widely adopted by the pharmaceutical industry. However, the non-uniformity of the coating (both intra-particle and inter-particle non-uniformity) prevents the use of these techniques to improve the delivery characteristics or stability of the Active Pharmaceutical Ingredient (API). Particle agglomeration during spray coating also poses significant challenges. At the same time, techniques such as plasma polymerization are difficult to scale, are only applicable to certain precursor chemistries, and may lead to degradation of sensitive APIs. The existing hot-wire CVD process using a hot-wire radical source inside the reaction vessel is poorly scalable and is not suitable for a heat-sensitive API. Rotary reactors include Atomic Layer Deposition (ALD) and induced cvd (icvd) reactors. However, ALD reactors are suitable for inorganic coatings, not for organic polymer coatings, and existing iCVD designs do not adequately protect against API degradation and cannot be produced on a large scale. Other techniques include polymer screen coating, pan coating (pan coating), atomized coating, and fluidized bed reactor coating.

Disclosure of Invention

In one aspect, a reactor for coating particles comprises: a fixed vacuum chamber for holding a bed of particles to be coated, the fixed vacuum chamber having a lower portion and an upper portion forming a semi-cylinder; a vacuum port located in an upper portion of the chamber; a blade assembly; a motor for rotating the drive shaft of the blade assembly; a chemical delivery system for delivering a first fluid; and a first gas injection assembly for receiving a first fluid from the chemical delivery system, and having an orifice configured to inject a first reactant or precursor gas into a lower portion of the chamber and to cause the first reactant or precursor gas to flow substantially tangential to the curved inner surface of the semi-cylinder. The blade assembly includes: a rotatable drive shaft extending through the chamber along an axial axis of the semi-cylinder; and radially extending the plurality of blades from the drive shaft such that rotation of the drive shaft by the motor causes the plurality of blades to revolve around the drive shaft.

In another aspect, a method of coating particles comprises: dispensing particles into the vacuum chamber to fill at least a lower portion of the chamber forming the semi-cylinder; evacuating the chamber via a vacuum port in an upper portion of the chamber; rotating the blade assembly such that the plurality of blades revolve around the drive shaft; and injecting a reactant or precursor gas into the lower portion of the chamber as the blade assembly rotates such that the first reactant or precursor gas flows substantially tangential to the curved inner surface of the semi-cylindrical body.

Particular embodiments may include one or more of the following features.

The first gas injection assembly may be configured to inject reactant or precursor gases in a direction perpendicular to the axial axis. The first gas injection assembly may include a first plurality of apertures extending in a first row parallel to the axial axis, and wherein the first gas injection assembly may be configured to inject a reactant or precursor gas through the first plurality of apertures. The first plurality of apertures may be located in a lower quarter of the lower portion of the chamber. The first plurality of apertures may be located in a lower quarter of the lower portion of the chamber.

The chemical delivery system may be configured to deliver a second fluid, and the second gas injection assembly may receive the second fluid from the chemical delivery system, and the second gas injection assembly has an aperture configured to inject a second reactant or precursor gas into the lower portion of the chamber such that the second reactant or precursor gas flows substantially tangential to the curved inner surface of the semi-cylinder. The second gas injection assembly may include a second plurality of holes extending in a second row parallel to the axial axis, and the second gas injection assembly may be configured to inject the reactant or precursor gas through the second plurality of holes.

The first gas injection assembly may include a manifold and a plurality of conduits extending from the manifold to the first plurality of nozzles. Each duct opens onto the ceiling of the corresponding hole. A restriction may be formed between the manifold and the plurality of tubes.

In another aspect, a reactor for coating particles includes: a fixed vacuum chamber for holding a bed of particles to be coated, the fixed vacuum chamber having a lower portion and an upper portion forming a semi-cylinder; a vacuum port located in an upper portion of the chamber; a blade assembly; a motor for rotating the driving shaft; and a chemical delivery system for delivering a plurality of fluids including at least a first liquid; and a first gas injection assembly receiving a first liquid from the chemical delivery system. The first gas injection assembly includes a vaporizer for converting a first liquid into a first reactant or precursor gas, a manifold for receiving the first reactant or precursor gas from the vaporizer, and a plurality of conduits leading from the manifold to a plurality of holes in a lower portion of the chamber. The blade assembly includes: a rotatable drive shaft extending through the chamber along an axial axis of the semi-cylinder; and a plurality of blades extending radially from the drive shaft such that rotation of the drive shaft by the motor causes the plurality of blades to revolve around the drive shaft.

In another aspect, a method of coating particles comprises: dispensing particles into the vacuum chamber to fill at least a lower portion of the chamber forming the semi-cylinder; evacuating the chamber via a vacuum port in an upper portion of the chamber; rotating the blade assembly such that the plurality of blades revolve around the drive shaft; flowing reactants or precursors from the chemical delivery system to the vaporizer; converting the first liquid into a first reactant or precursor gas in a vaporizer; and passing gas from the evaporator to a plurality of holes located in a lower portion of the chamber via the manifold and the plurality of channels.

Particular embodiments may include one or more of the following features.

The evaporator may be positioned proximate to the manifold. The evaporator, manifold and channels may be formed as one piece.

The channel may be configured to deliver an inert gas from the chemical delivery system to the manifold. The channels may be directly fluidly connected to the manifold. The channel may be directly fluidly connected to the inlet carrying the first liquid. The vaporizer may include a cavity, a heater for heating a wall of the cavity, and a nozzle for atomizing the first liquid as it enters the cavity. The channel may be directly fluidly connected to the cavity.

In another aspect, a method of coating particles comprises: distributing the particles into a vacuum chamber to form a bed of particles in at least a lower portion of the chamber forming the semi-cylinders; evacuating the chamber via a vacuum port in an upper portion of the chamber; rotating the blade assembly such that the plurality of blades revolve around the drive shaft to agitate particles in the particle bed; injecting reactant or precursor gases through a plurality of conduits into a lower portion of the chamber to coat the particles as the blade assembly rotates; and injecting a reactant or precursor gas or purge gas through the plurality of channels at a sufficiently high velocity such that the reactant or precursor gas or purge gas deagglomerates the particles in the particle bed.

Particular embodiments may include one or more of the following features.

The reactant or precursor gas may be injected at a sufficiently high velocity (e.g., at a velocity of less than 10m/s) to deagglomerate the particles. Purge gas may be injected at a sufficiently high velocity to de-agglomerate the particles. The purge gas may be injected at a greater velocity than the reactant or precursor gases, for example at a velocity of 30-200 m/s. The gas may be injected at a velocity low enough to avoid rat-holes (rat-holes), to avoid powder blowing out of the powder bed, and to avoid blasting the abrasive particles. The particles may be re-agglomerated prior to removal from the chamber. There may be multiple cycles of depolymerization and deposition.

The particles may have an active pharmaceutical ingredient and may have an average particle size of 1-30 μm.

In another aspect, a reactor for coating particles includes: a fixed vacuum chamber for holding a bed of particles to be coated; a blade assembly comprising a rotatable drive shaft and one or more blades in the vacuum chamber, the blades connected to the drive shaft such that rotation of the drive shaft by the motor agitates particles in the particle bed; a chemical delivery system including a gas injection assembly for delivering a precursor or reactive gas and a purge gas to a lower portion of the chamber; at least one flow regulator for controlling the flow rates of the precursor or reactant gas and the purge gas; a controller configured to cause the chemical delivery system to inject a reactant or precursor gas into a lower portion of the chamber to coat the particles as the blade assembly rotates; and configured to cause the chemical delivery system and the at least one flow regulator to inject a reactant or precursor gas or purge gas into the chamber at a sufficiently high velocity such that the reactant or precursor or purge gas deagglomerates particles in the particle bed.

Particular embodiments may include one or more of the following.

The controller may be configured to cause the at least one regulator to flow the reactant or precursor gas into the chamber at a sufficiently high velocity (e.g., a velocity of less than 10m/s) such that the reactant or precursor gas deagglomerates the particles. The controller may be configured to cause the at least one regulator to flow purge gas into the chamber at a sufficiently high rate such that the purge gas deagglomerates the particles. The controller is configured to cause the at least one regulator to flow the purge gas into the chamber at a greater velocity (e.g., a velocity of 30-200 m/s) than the reactant or precursor gas.

Implementations may include, but are not limited to, one or more of the following possible advantages. Particles, such as API particles, can be coated in a high volume production process, thereby reducing production costs and reducing drug prices. The particles may be coated in a thin layer to provide a favorable volume fraction of API for the pharmaceutical product. In addition, this treatment may result in the (multiple) layers encapsulating the API being uniform within the particle and between individual particles, thereby providing more consistent characteristics for the pharmaceutical formulation.

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

Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims.

Drawings

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 (drum).

Fig. 2 is a schematic side view of the reactor of fig. 1. Fig. 2 may be taken along line 2-2 in fig. 1.

FIG. 3A is a schematic side view of a blade assembly.

FIG. 3B is a front side view of the blade assembly of FIG. 3A. Fig. 3B may be taken along line 3B-3B in fig. 3A.

FIG. 3C is a schematic side view of another embodiment of a blade assembly.

FIG. 3D is a front side view of the blade assembly of FIG. 3C. Fig. 3D may be taken along line 3D-3D in fig. 3C.

Fig. 4 is a schematic perspective view of a blade.

FIG. 5 is a schematic side view of a set of blades from the blade assembly.

FIG. 6A is a schematic side view of another embodiment of a set of blades from the blade assembly.

FIG. 6B is a schematic side view of yet another embodiment of a set of blades from the blade assembly.

Fig. 7 is a schematic side view of a blade from the set of blades in fig. 5 or 6. Fig. 7 may be taken along line 7-7 in fig. 4.

Fig. 8 is a schematic side view of a gas injection port. Fig. 8 may be taken along line 8-8 in fig. 1.

Fig. 9 is a schematic plan view of the gas injection port of fig. 8.

Fig. 10 is a schematic, partially cut-away perspective view illustrating a gas injection assembly.

Like reference symbols in the various drawings indicate like elements.

Detailed Description

There are a variety of ways to encapsulate API particles. In many cases, these methods produce coatings that are relatively thick. While such coatings may impart desirable properties, the high ratio of coating to API may make it difficult to manufacture a pharmaceutical product in which the volume fraction of API is as high as desired. In addition, the coating encapsulating the API may be uneven, making it difficult to provide a formulation with consistent properties. Furthermore, coating techniques that provide satisfactory consistency cannot be used in industrial manufacturing.

One approach to solving these problems is to use a stationary "drum" in which the particles are agitated by rotating blades and then process gas is injected into the drum via the drum sidewalls. This action may force the process gas to permeate through the particle bed, which may improve the uniformity of the coating throughout the particle

Another problem is that particles tend to collect in the reaction chamber. As a result, the process gas may not coat the areas contacted by the particles, resulting in non-uniformity of the coating. Although stirring the particle bed with blades may prevent some agglomeration, the particles still tend to form micro-agglomerates, e.g., agglomerates up to 10 times the primary particle size. In some techniques, the powder is removed from the reactor for depolymerization. However, removing the powder can significantly affect yield and may provide an opportunity for contamination or spillage.

One way in which this problem can be solved is to flow a process and/or purge gas through the bed of particles at a rate sufficient to de-agglomerate the particles.

The average particle size (D50) of the particles treated using the apparatus and methods discussed below may be in the range of 1-30 μm, such as 1-10 μm, although nanoscale particles are also possible. The particles may include both an API and an excipient, or the particles may consist of an API.

Medicine

The term "drug" in the broad sense includes all small molecule (e.g., non-biological) APIs. The drug may be selected from the group consisting of: analgesics, anesthetics, anti-inflammatory agents, anthelmintics, antiarrhythmics, anti-asthmatics, antibiotics, anti-cancer agents, anticoagulants, antidepressants, anti-diabetic agents. Drugs, antiepileptics, antihistamines, antitussives, antihypertensives, antimuscarinics, antimycobacterial agents, antineoplastics, antioxidants, antipyretics, immunosuppressants, immunostimulants, antithyroids, antivirals, anxiolytic sedatives, hypnotics, antipsychotics, astringents, bacteriostats, beta-adrenoceptor blockers, blood products, blood substitutes, bronchodilators, buffers, cardiac inotropic agents, chemotherapeutic agents, contrast agents, corticosteroids, antitussives, expectorants, mucolytics, diuretics, dopaminergic agents, anti-Parkinson's disease agents, free radical scavengers, growth factors, hemostatic tics, immunological agents, lipid modulators, muscle relaxants, sympathomimetics, parathyroid calcitonin, bisphosphonates, prostaglandins, radiopharmaceuticals, hormones, steroids, neurones, neuroleptics, anticonvulsants, anti-inflammatory agents, anti-anxiety agents, anti-hypnotics, anti-anxiety agents, anti-inflammatory agents, anti-anxiety agents, anti-inflammatory agents, sex hormones, anti-allergic agents, appetite stimulants, anorectic agents, steroids, sympathomimetics, thyroid agents, vaccines, vasodilators, and xanthines.

Exemplary types of small molecule drugs include, but are not limited to, acetaminophen, clarithromycin, azithromycin, ibuprofen, fluticasone propionate, salmeterol, pazopanib hydrochloride, pabociclib, and amoxicillin clavulanate potassium.

Pharmaceutically acceptable excipients, diluents and carriers

Pharmaceutically acceptable excipients include, but are not limited to:

(1) surfactants and polymers comprising: polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium lauryl sulfate, polyvinyl alcohol, crospovidone, polyvinylpyrrolidone-polyvinylacrylate copolymers, cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, carbomers and their polymers, emulsifiers, gums, starches, organic acids and their salts, vinylpyrrolidone and vinyl acetate;

(2) binders, such as cellulose, crosslinked polyvinylpyrrolidone, microcrystalline cellulose;

(3) fillers such as lactose monohydrate, lactose anhydrous, microcrystalline cellulose and various starches;

(4) lubricants, for example, agents which affect the flow properties of the powder to be compressed, include colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, colloidal silica, and the like.

(5) A sweetener, such as any natural or artificial sweetener, including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame potassium;

(6) a flavoring agent;

(7) preservatives, for example potassium sorbate, methyl paraben, propyl paraben, benzoic acid and its salts, other esters of parahydroxybenzoic acid (for example butyl paraben), alcohols (for example ethyl or benzyl alcohol), phenolic chemicals (for example phenol) or quaternary compounds (for example benzalkonium chloride);

(8) a buffering agent;

(9) diluents, such as pharmaceutically acceptable inert fillers, e.g. microcrystalline cellulose, lactose, dibasic calcium phosphate, sugars and/or mixtures of any of the foregoing;

(10) wetting agents, such as corn starch, potato starch, corn starch and modified starches and mixtures thereof;

(11) a disintegrant; such as croscarmellose sodium, crospovidone, sodium starch glycolate; and

(12) effervescent agents, for example effervescent couples (e.g. effervescent couples), such as organic acids (e.g. citric, tartaric, malic, fumaric, adipic, succinic and alginic acids and anhydrides and acid salts) or carbonates (e.g. sodium, potassium, magnesium, sodium, L-lysine and arginine carbonates) or bicarbonates (e.g. sodium or potassium bicarbonate)

Metal oxide material

In a broad sense, the term "metal oxide material" includes all materials formed from the reaction of an element considered to be a metal with an oxy-oxidant. 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 as well as oxides of other materials (e.g., silicon dioxide).

Atomic Layer Deposition (ALD)

Atomic layer deposition is a thin film deposition technique in which sequential addition of self-limiting monolayers of elements or compounds allows the thickness and uniformity of film deposition to be controlled at the atomic or molecular monolayer level. Self-limited refers to the formation of only one atomic layer at a time and requires subsequent processing steps to regenerate the surface and allow further deposition.

Molecular Layer Deposition (MLD)

Molecular layer deposition is similar to atomic layer deposition, but uses organic precursors and forms organic thin films. In a typical MLD process, two homobifunctional precursors are used. A first precursor is introduced into the chamber. Molecules of the first precursor react with reactive groups on the substrate surface via corresponding linkage chemistry to add a molecular layer of the first precursor with new reactive sites on the substrate surface. After purging, a second precursor is introduced, and molecules of the second precursor react with new reaction sites provided by the first precursor to produce a molecular layer of the first precursor coupled to the second precursor. Followed by another purge cycle.

Reactor system

Fig. 1-2 illustrate a reactor system 100 for coating particles with a thin film coating. The reactor system 100 may be coated using ALD and/or MLD coating conditions. The reactor system 100 allows deposition processes (ALD or MLD) to be performed at higher process temperatures (above 50 ℃, e.g., 50-100 ℃) or lower process temperatures (e.g., below 50 ℃, e.g., at 35 ℃ or below 35 ℃). For example, the reactor system 100 can form a thin film oxide on particles by ALD primarily at temperatures in the range of 22-35 deg.C (e.g., 25-35 deg.C, 25-30 deg.C, or 30-35 deg.C). Generally, the particles may be held or maintained at this temperature. This may be achieved by maintaining or maintaining the reaction gases and/or the inner surfaces of the reaction chamber at this temperature.

The reactor system 100 includes a fixed vacuum chamber 110, the fixed vacuum chamber 110 surrounding a blade assembly 150.

The vacuum chamber 110 is surrounded by chamber walls 112. The lower portion 110a of the chamber 110 forms a semi-cylinder having a semi-circular cross-section (as viewed along the central axis of the semi-cylinder). The cross-section of the upper portion 110b (again viewed along the central axis of the semi-cylinder) is uniform along the length of the chamber 110 (the length along the central axis of the semi-cylinder). This can help ensure a uniform flow of gas along the length of the chamber. If the gas flow is sufficiently uniform, the cross-section may be non-uniform, for example, narrowing toward the top when viewed horizontally (but perpendicular to the central axis of the semi-cylinder) to reduce the volume of the chamber 110.

The cross-section of the upper portion 110b may be additionally selected to save space in a manufacturing facility while still enclosing the blade assembly 150. For example, the upper portion 110b of the chamber 110 may be a rectangular solid (see fig. 6A), a semi-cylinder with a semi-circular cross-section, or other suitable shape that does not impede rotation of the blade assembly 150. In some embodiments, the upper portion 110b of the chamber has a lower section 110c, the lower section 110c being adjacent to the lower portion 110a and having vertical sidewalls, e.g., a rectangular solid volume. The upper section 110c, which extends 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 the semi-cylinder).

In some embodiments, for example as shown in fig. 6B (but may be combined with other blade assemblies), 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, may provide space for the vacuum port 132 and/or the powder delivery port 116. This configuration may avoid powder build-up at portions along the sidewall 12 that are inaccessible to the vanes 154 (e.g., caused by the vane assembly throwing powder).

The chamber walls 110 may be a material inert to the deposition process (e.g., stainless steel) and/or the inner surfaces of the chamber walls 110 may be coated with a material inert to the deposition process. In some embodiments, a viewing port 114 of transparent material (e.g., quartz) may be formed through the chamber wall 112 to allow an operator to view the interior of the chamber 110.

In operation, the chamber 110 is partially filled with particles, e.g., particles comprising an API, that provide the particle bed 10. To obtain a higher throughput, the particle bed 10 fills at least the lower portion 110a of the chamber, e.g., the top surface 12 of the particle bed 10 is at the lower portion 110a or above the lower portion 110a (indicated as a). On the other hand, the top surface 12 of the particle bed 10 should be below the top of the vane assembly 150 (indicated by B) to avoid undesirable mixing of the particle bed. The chamber walls 112 may include one or more sealable ports 116 to allow particles to be placed into the chamber 110 or removed from the chamber 110.

The chamber 110 is coupled to a vacuum source 130. A port 132 through the chamber wall 112 to connect the vacuum source 130 to the chamber may be located in the upper portion 110b of the chamber 110. Specifically, the port 132 may be located above the desired location of the top surface 12 of the particle bed, for example, above the top of the vane assembly 150 (indicated at B), such as in the chamber ceiling.

The vacuum source 130 can be an industrial vacuum pump sufficient to establish a pressure of less than 1Torr (e.g., 1to 100mTorr, such as 50 mTorr). The vacuum source 130 allows the chamber 110 to be maintained at a desired pressure and allows for the removal of reaction byproducts and unreacted process gases.

The port 132 may be covered by a filter 134 to prevent particles thrown into the airflow by the vane assembly from escaping the reaction chamber 110. Additionally, the system may include a filter cleaner to remove particles from the filter 134. As one example, the filter cleaner may be a mechanical rapper that impacts the filter; this will shake off particles on the filter. As another example, the gas source 136 (which may be provided by the gas source 142e) may periodically provide pulses of inert gas (e.g., nitrogen) to the gas line 138 between the port 132 and the vacuum source 130. The pulse of gas returns to the chamber 110 via the filter 134 and may blow particles out of the filter 134. Isolation valves 139a, 139b may be used to ensure that only one of gas source 136 or vacuum source 130 is fluidly connected to line 138 at a time.

The chamber 110 is also coupled to a chemical delivery system 140. The chemical delivery system 140 includes a plurality of fluid sources 142, the plurality of fluid sources 142 coupled to respective delivery tubes 143, controllable valves 144, and fluid supply lines 146. The chemical delivery system 140 delivers the fluid to one or more gas injection assemblies 190, and the gas injection assemblies 190 inject the fluid in vapor form into the chamber 110. Chemical delivery system 140 may include a combination of flow restrictors, gas flow controllers, pressure sensors, and ultrasonic flow meters to provide controllable flow rates of the various gases into chamber 110. The chemical delivery system 140 may also include one or more temperature control components, such as heat exchangers, resistive heaters, and the like, to heat or cool the various gases before they flow into the chamber 110.

The chemical delivery system 140 may include five fluid sources142a, 142b, 142c, 142d, 142 e. Two of the fluid sources, such as fluid sources 142a, 142b, may provide two chemically different precursors or reactants for a deposition process for forming an oxide layer on the particles. For example, the first fluid source 142a may provide Trimethylaluminum (TMA) or titanium tetrachloride (TiCl)₄) And fluid gas source 142b may provide water. Two other of the fluid sources, such as fluid sources 142c, 142d, may provide two chemically different precursors or reactants for the deposition process to form a polymer material on the oxide layer. For example, third fluid source 142c can provide adipoyl chloride, and fourth fluid source 142d can provide ethylene diamine. One of the fluid sources, such as the fifth fluid source 142e, may provide an inert gas, such as argon or N₂To purge between cycles or half cycles in the deposition process.

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, and the use of more gas sources may enable the formation of even more various stack structures.

For one or more fluid sources, the chemical delivery system 140 delivers precursors or reactants in liquid form to the gas injection assembly 190. The gas injection assembly 190 includes a vaporizer 148 for converting liquid to vapor just prior to the precursors or reactants entering the injection manifold 194. This reduces the upstream pressure loss so that more pressure loss occurs across the particle bed 10. The more pressure loss that occurs across the particle bed 10, the lower the injection orifices that can be placed and the greater the likelihood of reaction occurring when all of the precursor is passed over the particle bed at a given flow rate. The evaporator 149 can be proximate to the reactor sidewall, e.g., fixed to the reactor wall side 112 or housed within the reactor wall side 112.

As shown in fig. 1, there may be a manifold 194 for each precursor or reactant fluid, and each manifold 194 may be individually fluidly connected to chamber 110. Thus, the precursors or reactants are not mixed until actually within the chamber 110. Alternatively, the gas line from the fluid source 142 may be joined as a combined fluid supply line, for example, by a valve. The gas injection assembly 190 will be discussed further below.

As described above, a blade assembly 150 is located in the chamber 110 to agitate the particles in the particle bed. Blade assembly 150 includes a rotatable drive shaft 152 and a plurality of blades 154. The vanes 154 are connected to the drive shaft 152 by struts 156 that extend outwardly from the drive shaft 152 such that rotation of the drive shaft 152 about the axis of rotation 153 carries the vanes 154 in a circular path about the axis of rotation 153 (see arrow C). The strut 156 may extend perpendicular to the drive shaft 152. The driving shaft 152 and the rotation shaft 153 may extend along a boundary between the upper portion 110b and the lower portion 110a of the chamber 110.

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

At least some of the vanes 154 are held in a position by struts 156 such that the outer edges of the vanes 154 nearly contact the inner surface 114 of the chamber wall 112 as the drive shaft 152 rotates. However, the outer edges of the vanes 154 remain separated from the inner surface by a small gap G1, for example 1-4 mm. The gap G1 may be as small as possible within manufacturing tolerances so that the blades 154 do not scrape against the outer wall 112.

The axis of rotation 153 of the drive shaft 152 may be parallel, e.g., collinear, with the central axis of the cylinder defining the lower portion 110 a. In this case, as the drive shaft 152 rotates, the outer edges of the vanes 154 may sweep the inner surface of the lower portion 110a, e.g., the entire inner surface of the half cylinder.

Vanes 154 may be spaced along drive shaft 152 to ensure that the vanes that nearly contact inner surface 114 provide coverage along substantially the entire length of reactor chamber 110. In particular, blades 154 are spaced apart and have a width W (along the axis of rotation) such that blade assembly 150s sweeps through a volume without gaps. In particular, the width W may be greater than the pitch of the blades along the drive shaft 152. The vanes at different axial positions along the length of the drive shaft may be angularly offset. For example, as shown in fig. 3A and 3B, the vanes 154 may be arranged in a helical pattern around the drive shaft 152. However, many other configurations are possible for the angular offset, such as alternating sides of the drive shaft.

In some embodiments, some of the vanes 154 are radially closer to the drive shaft 152 than other vanes 154. The vanes 154b closer to the drive shaft may be referred to as "inner vanes" and the vanes 154a farther from the drive shaft may be referred to as "outer vanes". The inner and outer blades 154a, 154b may not radially overlap, or may partially radially overlap. For example, the inner and outer blades may overlap up to 20% of the radial span S of the outer blade (e.g., G ≧ 0.8S).

The outer blades 154a may be spaced apart and have a width (along the axis of rotation) such that there are no gaps in the volume swept by the outer blades 154 a. In particular, the width of the outer blades 154a may be greater than the pitch of the outer blades 154a along the drive shaft 152. Adjacent outer blades 154a along the length of the drive shaft may be angularly offset. Similarly, the inner blades 154b may also be spaced apart and have a width (along the axis of rotation) such that there are no gaps in the volume swept by the inner blades 154 b. In particular, the width of the inner blade 154b may be greater than the pitch of the inner blade 154b along the drive shaft 152. Adjacent inner lobes 154b along the length of the drive shaft may be angularly offset. For example, as shown in fig. 3C and 3D, the inner lobes 154b may be arranged in a first helical pattern about the drive shaft 152 and the outer inner lobes 154a may be arranged in a second helical pattern about the drive shaft 152. The helices of the inner blade 154a and the outer blade 154b are shown as being 180 ° out of phase, but this is not required. Furthermore, many other configurations are possible for the angular offset between adjacent blades, for example, the blades may be placed on alternating sides of the drive shaft.

Referring to fig. 4, each vane 154 may be a generally planar body having a major surface 170 to urge particles in the particle bed and a thinner edge 172 to contact the inner surface of the lower portion 110a of the chamber 110. As shown in fig. 4, the blades 154 may be flared. Alternatively, as shown in fig. 1 and 2, the vanes may be generally rectangular, such as rectangular with rounded edges. The surface 170 of the blade 154 may be flat or the surface 170 may be concave, such as a scoop. Additionally, in some embodiments, the vanes 154 are plow-shaped, e.g., convex or sharply convex with respect to the direction of movement of the vanes. .

Referring to fig. 1, in some embodiments, the blades are clustered in groups in a common plane perpendicular to the axis of rotation 153. The vanes in a set may be spaced at substantially equal angular intervals about the drive shaft 152. A group may comprise four blades, but two, three, or five, or more blades may also be used.

For example, referring to fig. 1 and 5, the blade assembly 150 includes a group 180 of four blades 180a, 180b, 180c, 180d, the four blades 180a, 180b, 180c, 180d being spaced at a 90 degree angle and equidistant from the drive shaft 152 and the rotational axis 153. The blades 180a-180d may be positioned to nearly contact the semi-cylindrical inner surface of the lower portion 110a of the chamber 110 a.

As shown in fig. 1 and 2, blade assembly 150 may include multiple sets of blades located at different positions along drive shaft 132. For example, the leaf assemblies may include groups 180, 182, 184, 186, 188. In the case of three or more sets, the sets of blades may be spaced at substantially equal intervals along the drive shaft 152. Each group may have the same number of blades, for example four blades. The blades in adjacent groups may be angularly offset about the axis of rotation, for example by half the angle between the blades in a group. For example, if a group has four blades spaced 90 ° apart about the axis of rotation, adjacent groups of blades may be offset by 45 °.

In some embodiments, such as shown in FIG. 1, the blades in a group may be located at substantially equal distances from the axis of rotation 153, e.g., the struts 156 may have the same length. .

However, in some embodiments, some blades in a group are positioned radially closer to the drive shaft 152 than other blades in the group. For example, the blade assembly 150 shown in fig. 6A includes a set of four blades 180a ', 180b', 180c ', 180d' spaced at 90 degree angles. Two blades, such as two opposing blades 180a 'and 180c', are located a first distance from the drive shaft 152. The two vanes may be positioned to nearly contact the semi-cylindrical inner surface 112 of the lower portion 110 a. Two other of the blades, such as two opposing blades 180b 'and 180d', are a second, shorter distance from the drive shaft 152.

As another example, the blade assembly shown in FIG. 6B includes a set of eight blades 180a-180h spaced at 45 degree angles. The four outer blades 154a (e.g., blades 180a-180d) are located a first distance from the drive shaft 152. The four vanes 154a may be positioned to nearly contact the semi-cylindrical inner surface 112 of the lower portion 110 a. The four inner vanes 154b (e.g., vanes 180e-180h) are located a second, shorter distance from the drive shaft 152. The outer blades 154a and the inner blades 154b are placed in an alternating arrangement around the drive shaft 152.

In some embodiments, some of the blade sets have blades that are radially closer to the drive shaft 152 than other blade sets. For example, the blade assembly 150 includes a group 182 having four inner blades 182a, 182b, 182c, 182d, the four inner blades 182a, 182b, 182c, 182d being spaced at 90 degree angles and equidistant from the drive shaft 152 and the rotational axis 153. The outer edges of the lobes 182a-182d are spaced apart from the semi-cylindrical inner surface of the lower portion 110a of the chamber 110a by a gap G. The inner lobes 182a-182d are radially inward compared to the outer lobes 180a-180 d.

Referring back to fig. 1, 5, and 7, each blade 154 may be positioned and oriented such that an axis N perpendicular to a plane 170 of the blade 154 is perpendicular to a radius R from the rotational axis 153 to the blade 154. However, in some embodiments, one or more of the blades 154 may be angled such that the orbital rotation of the blades 154 about the axis of rotation 153 tends to force particles radially toward or away from the axis of rotation 153.

Additionally, each blade 154 may be angled at an oblique angle relative to a plane perpendicular to the axis of rotation 153. In particular, each blade 154 may be angled such that the orbital motion of the blade 154 about the axis of rotation 153 tends to force particles in a direction parallel to the axis of rotation 153. For example, as shown in fig. 5 and 7, blade 180a is oriented such that a normal N to a plane 170 of blade 154 is at an oblique angle α with respect to rotational axis 153, when viewed along a radius between blade 180a and rotational axis 153 (e.g., parallel to strut 156). In this configuration, the blades will have an instantaneous motion vector C as they revolve around the axis of rotation 153. The angle of inclination a of the blade 180a will drive the powder in a direction D perpendicular to C. The inclination angle α may be between 15 ° and 75 °, for example between 30 ° and 60 °, for example about 45 °.

The inner blades in one set may be oriented to have a common pitch angle α and the outer blades in one set may be oriented to have a common pitch angle α'. In some embodiments, all of the inner blades along drive shaft 152 are oriented at a common pitch angle α, and all of the outer blades along drive shaft 152 are oriented at a common pitch angle α'.

The angles α 'and α' are not equal. In particular, the angles α 'and α' may have opposite signs. In some embodiments, angle α' is equal in magnitude but opposite in sign to angle α, e.g., the outer blade has a pitch angle of + α and the outer blade has a pitch angle of- α.

In some embodiments, the outer blades 154 are angled such that the orbital motion of the blade tips forces the particles in a first direction parallel to the axis of rotation 153, while the inner blades 154 are angled such that the motion of the inner blades 154 forces the particles in an anti-parallel direction (i.e., a second direction opposite the first direction). For example, referring to fig. 6 and 7, the outer blades 180a 'and 180c' in the group 180 may force the particles in the direction D, while the inner blades 180b 'and 180D' in the group may force the particles in the opposite direction to D.

Referring to fig. 2, in some embodiments, port 116a is located somewhere along the length of chamber 110, such as near the center of the length of chamber 110. Port 116a may be used to transport and/or remove particles from reactor 100. In such embodiments, the outer blade may be oriented to push particles toward port 116a, while the inner blade may be oriented to push particles away from port 116 a.

For example, the outer leaves of groups 180 and 182 may push particles to the left toward port 116a, and the inner leaves of groups 180 and 182 may push particles to the right away from port 116. Conversely, the outer lobes of groups 184, 186, and 188 may push particles to the right toward port 116a, while the inner lobes of groups 184, 186, and 188 may push particles to the left away from port 116 a. A blade oriented to urge particles in a first direction (e.g., to the left) may be oriented with a tilt angle + α, while a blade oriented to urge particles in an opposite second direction (e.g., to the right) may be oriented with a tilt angle- α.

The blades in different groups (e.g. adjacent groups) may have different pitch angles if the blades in each group are at the same radial distance from the drive shaft. For example, a particle may be urged in a direction D with reference to the blades 180a-180D in the first set 180, while a particle may be urged in a direction opposite to D by the blades 182a-182D in the second set 180.

Referring to fig. 1 and 8, the chemical delivery system 140 is coupled to the chamber 110 through a gas injection assembly 190. The gas injection assembly includes a plurality of holes 192 extending through the chamber wall 112. The apertures 192 may be arranged in rows, for example, parallel to the rotational axis 153 of the drive shaft 152. Although fig. 8 illustrates a single row of holes 192, the system may have multiple rows of holes. In particular, there may be different rows of holes for different reactants or precursors. Additionally, there may be multiple rows of holes for a given reactant and/or precursor.

The holes 192 are located below the desired location of the particle bed top surface 12. In particular, the holes 192 through the chamber wall 112 may be located in the lower portion 110b of the chamber 110. For example, the apertures 192 may extend through a curved semi-circular portion of the sidewall 112. The aperture 192 may be located in a lower half of the chamber wall 112 of the lower portion 110b, for example a lower third, for example a lower fourth, for example a lower fifth, of the chamber wall 112 of the lower portion 110b (as measured via the vertical direction). The diameter of the holes may be 0.5mm to 3 mm. While fig. 1 shows the aperture 192 as extending horizontally through the chamber wall, this is not required, as explained further below.

Referring to fig. 1 and 9, the gas injection assembly 190 includes a manifold 194, the manifold 194 having a plurality of conduits 196 leading from the manifold 194 to the apertures 192. The manifold 194 and conduit 196 may be formed as a passage through a solid body 196 that provides a portion of the chamber wall 112. The evaporator 148 may be positioned immediately upstream of the manifold 194.

Inert carrier gas (e.g. N)₂) May flow from a fluid source (e.g., fluid source 142e) into manifold 194 via one or more passages 198. In operation, carrier gas may be continuously flowed into manifold 194, i.e., whether precursor gas or reactor gas is being flowed into manifold 194. As one example, a carrier gas may be injected into fluid line 146 via passage 198a before the liquid reaches the vaporizer. As another example, the carrier gas may be injected directly into the vaporizer 148 via the channel 198 b. As another example, the carrier gas may be injected directly into the manifold 194 via the channel 198 c.

When a precursor or reactor gas is not injected into chamber 110 through manifold 194, the carrier gas flow may prevent another precursor or reactor gas being injected from another manifold from flowing back into apertures 192. The carrier gas flow may also prevent particles in the particle bed 10 from contaminating the pores 192, e.g., plugging the pores. Additionally, the carrier gas may provide a purge gas for purge operations when no precursors or reactor gases are injected into the chamber 110.

When the precursor gas is also flowing, the flow of the carrier gas to the vaporizer 149 may improve the vaporization of the precursor or reactant liquid. Without being bound by any particular theory, the carrier gas flow may help shear the liquid during atomization, which may result in smaller droplet sizes that may evaporate more quickly. When the precursor gases are also flowing, the carrier gas inflow manifold 148 may help draw the precursor gases out of the vaporizer.

Gas from chemical delivery system 130 flows from the orifices into chamber 110 in the direction indicated by the arrows. Assuming that the chamber 110 is partially filled with particles, gas is injected near the bottom of the particle bed 10. Thus, the chemicals in the gas must "bubble" through the body of the particle bed 10 to escape and be drawn out by the vacuum port 132. This may help ensure that the particles are uniformly exposed to the gas.

The direction of rotation of blade assembly 150 (indicated by arrow C) may be such that the blades sweep through apertures 192() in a direction having the same component (i.e., no anti-parallel component) as the direction of airflow (as indicated by arrow E). This may prevent particles from being forced back against the airflow and blocking the aperture 192.

Referring to fig. 10, the gas injection assembly 190 may be configured to inject gas into the chamber 110 in the following directions: the direction of the airflow is substantially parallel to the instantaneous direction of movement of the blade 154 as it passes through the aperture 192. In other words, the direction of the gas flow as injected may be substantially tangential to the curved inner surface 114 of the cylindrical bottom portion 110a of the chamber 110. Additionally, the gas injection assembly 190 may be positioned and oriented such that the gas flow is toward the bottom of the chamber 110 (rather than toward the surface of the power bed).

Each conduit 196 may include a first conduit portion 196a extending at a shallow angle toward the inner surface 114. The first conduit portion 196a opens into the chamber 110 at the aperture 192. As shown in fig. 10, the hole 192 may be a fan-shaped recess having a sharp dent, and then its depth is gradually reduced in the rotation direction (indicated by arrow C) of the blade 154. The first conduit portion 196a may lead to the top plate 192a of the aperture 192 formed by the sharp indentation. This configuration may reduce the likelihood of particles entering the conduit 196. Additionally, the first conduit portion 196a may be wider than the intended diameter of the particle. This may reduce the risk of particles blocking the first conduit portion 196 a.

The conduit 196 also includes a second conduit portion 196b that extends between the manifold 194 and the first conduit portion 196 a. The second conduit portion 196b is narrower than the first conduit portion 196 a. This narrower conduit portion 196b controls the flow and flow distribution out of the manifold 194.

The evaporator 148 can include an internal cavity 148a, the internal cavity 148a being surrounded by walls heated by a heater 148b (e.g., a resistive heater, a thermoelectric heater, a heat lamp, etc.). The fluid supply channel 146 is coupled to the cavity 148a through a nozzle 147. The liquid is atomized as it passes through the nozzle 147. The combination of elevated temperature, rapid pressure change, and high aerosol surface area allows for rapid vaporization of large quantities of reactants or precursors. The cavity 149a of the evaporator 148 can extend along a substantial portion of the length of the chamber 110, e.g., at least half of the length of the chamber 110. Liquid reactants or precursors may be injected through nozzles 147 at one point of the chamber, and orifices 148c that admit reactant or precursor vapors into manifold 194 may be located at opposite ends of the chamber (along the length of chamber 110).

As described above, the evaporator 148 may be integrated into the body providing the manifold. For example, the evaporator 148, manifold 194, and conduit 196 may all be part of a single unitary body.

In some embodiments, one or more temperature control components are integrated into the chamber walls 112 to allow control of the temperature of the chamber 110. Such as a resistive heater, a thermoelectric cooler, a heat exchanger or coolant flowing in a cooling conduit in a chamber wall, or other components in the sidewall 112 or on the sidewall 112.

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

Generally, the controller 105 is configured to operate the reactor system 100 according to a "recipe". The recipe assigns an operating value to each controllable element as a function of time. For example, the recipe may specify the time the vacuum source 130 is on, 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 the like. The controller 105 may receive the recipe as computer readable data (e.g., stored on a non-transitory computer readable medium).

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

For a system of one or more computers to be configured to perform a particular operation or action, it is meant that the system has installed thereon software, firmware, hardware, or a combination thereof that in operation causes the system to perform the operation or action. For one or more computer programs that are to be configured to perform particular operations or actions, it is meant that the one or more programs include instructions that, when executed by a data processing apparatus, cause the apparatus to perform the operations or actions.

Operation of

Initially, particles are loaded into the chamber 110 in the reactor system 100. The particles may have a solid core comprising a drug, for example one of the drugs mentioned above. The solid core may also optionally include excipients. Once any access ports are sealed, the controller 105 operates the reactor system 100 according to the recipe to form a thin film oxide layer and/or a thin polymer layer on the particles.

In operation, reactor system 100 performs ALD and/or MLD thin film coating processes by introducing gaseous precursors of the coating into chamber 110. Gaseous precursors are alternately incorporated into reactor chamber 110. This allows the deposition process to be a solvent-free process. The half-reaction of the deposition process is self-limiting, which can provide angstrom or nanometer deposition control. In addition, the ALD and/or MLD reaction may be performed under low temperature conditions, such as below 50 ℃, such as below 35 ℃.

Suitable reactants for use in ALD processes include any one or combination of the following: monomer vapors, metal organics, metal halides, oxidants (e.g., ozone or water vapor), and polymer or nanoparticle aerosols (dry or wet). For example, the first fluid source 142a may provide Trimethylaluminum (TMA) or titanium tetrachloride (TiCl4), while the second gas source 142b may provide water. For the MLD process, for example, the fluid source 142c can provide adipoyl chloride, and the fourth fluid 142d can provide gaseous or gaseous ethylenediamine.

In operation, as the blade assembly 150 rotates, one of the gases flows from the chemical delivery system 140 into the particle bed 10 in the lower portion 110a of the chamber 110. The rotation of the blade assembly 150 agitates the particles to keep them separated, thereby ensuring that a large surface area of the particles remains exposed. This allows the particle surface to interact rapidly and uniformly with the process gas.

For both ALD processing and MLD processing, two reactant gases are alternately supplied to the chamber 110, each step of supplying a reactant gas being followed by a purge cycle in which an inert gas is supplied to the chamber 110 to exhaust the by-product and reactant gases used in the previous step.

As mentioned above, the coating treatment may be carried out at a low treatment temperature, for example below 50 ℃, for example below or equal to 35 ℃. In particular, the particles may be held or maintained at this temperature during all steps (i) - (ix) above. Typically, during steps (i) - (ix), the temperature inside the reactor chamber does not exceed 35 ℃. This may be accomplished by injecting the first reactive gas, the second reactive gas, and the inert gas into the chamber at the temperature in the respective circulating species. Additionally, if desired, physical components of the chamber may be maintained or maintained at such temperatures, for example, using a cooling system (e.g., a thermoelectric cooler).

In some embodiments, the controller may cause the reactor system 100to first deposit an oxide layer on the drug-containing particles, and then deposit a polymer layer over the oxide layer on the particles, for example using the process described above. In some embodiments, the controller may alternate the reactor system 100 between depositing an oxide layer and depositing a polymer layer on the drug-containing particles, thereby forming a multilayer structure having layers of alternating composition.

Continuous flow operation

For ALD processing, the controller 105 may operate the reactor system 100 as follows.

In the first reactant half cycle, when the motor 160 rotates the paddle wheel 150 to agitate the particles:

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 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 reactant gas in the upper portion 110b of the chamber. In some embodiments, the first reactive gas mixes with the inert gas as it flows into the chamber. The specified pressure or partial pressure may be 0.1Torr to half the saturation pressure of the reaction 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 below 1Torr, for example, to 1to 100mTorr, for example, 50 mTorr.

These steps (i) - (ii) may be repeated a number of times set by the recipe, for example, two to ten times.

Next, in the first cleaning cycle, as the motor 160 rotates the paddle wheel 150 to agitate the particles:

iii) operating the gas distribution system 140 to only let inert gas (e.g., N)₂) From source 142e into chamber 110. The inert gas may be flowed for a specified period of time at a specified flow rate or until the sensor measures a specified second pressure of the inert gas in the upper chamber portion 110 b. The second specified pressure may be 1to 100 Torr.

iv) the vacuum pump 140 evacuates the chamber 110, for example, to a pressure below 1Torr, for example, to 1to 500mTorr, for example, 50 mTorr.

These steps (iii) - (iv) may be repeated a number of times set by the recipe, for example six to twenty times.

In the second reactant half cycle, as the motor 160 rotates the paddle wheel 150 to agitate the particles:

v) operating the gas distribution system 30 to supply a second reactant gas (e.g., H)₂O) from source 142b into chamber 110 until particle bed 10 is saturated with the second reactant gas. Likewise, the second reactant gas may flow at a specified flow rate for a specified period of time or until a specified third pressure or partial pressure of the second reactant gas in the upper portion 110b of the chamber is measured by the sensor. In some embodiments, the second reactive gas mixes with the inert gas as it flows into the chamber. The third pressure can be 0.1Torr to half the saturation pressure of the second reactant gas.

vi) the vacuum pump 140 evacuates the chamber 110, for example, to a pressure below 1Torr, for example, to 1to 500mTorr, for example, 50 mTorr.

These steps (v) - (vi) may be repeated a number of times set by the recipe, for example, two to ten times.

Next, a second purge cycle is performed. The second purification cycle with steps (vii) and (vii) may be the same as the first purification cycle, or may have a different number of repetitions and/or a different specified pressure than steps (iii) - (iv).

The cycle of the first reactant half cycle, the first purge cycle, the second reactant half cycle, and the second purge cycle may be repeated a number of times set by the recipe, for example, one to ten times.

Operation is discussed above in terms of ALD processing, but MLD operation is similar thereto. In particular, in steps (i) and (v), the reactive gas is replaced with a suitable process gas and pressure to deposit the polymer layer. For example, step (i) may use adipoyl chloride in a vapor or gaseous state, while step (v) may use ethylenediamine in a vapor state.

Further, although operations using ALD or MLD processes are discussed above, the system may be used for Chemical Vapor Deposition (CVD) processes. In this case, for example during step (i), two reactants are simultaneously flowed into the chamber 110 to react inside the chamber. The second reactant half cycle may be omitted.

Pulse stream operation

In another embodiment, one or more gases (e.g., reactant gases and/or inert gases) may be supplied in pulses, wherein chamber 110 is filled with gas to a specified pressure, allowed to elapse of a delay time, and then evacuated by vacuum source 140 before the next pulse begins.

In particular, for ALD processes, the controller 105 may operate the reactor system 100 as follows.

In the first reactant half cycle, when the motor 160 rotates the paddle wheel 150 to agitate the particles:

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 a first specified pressure is reached in the upper portion 110b of the chamber. The specified pressure may be 0.1Torr to half the saturation pressure of the reaction gas.

ii) stopping the flow of the first reactant gas and allowing a specified delay time to elapse, such as a delay time measured by a timer in the controller. This allows the first reactant to flow through the particle bed 10 in the chamber 110 and react with the particle surface.

iv) the vacuum pump 140 evacuates the chamber 110, for example to a pressure below 1Torr, for example to 1to 500m Torr, for example 50m Torr.

These steps (i) - (iii) may be repeated a number of times set by the recipe, for example two to ten times.

Next, in the first cleaning cycle, as the motor 160 rotates the paddle wheel 150 to agitate the particles:

iv) operating the gas distribution system 140 to inject an inert gas (e.g., N)₂) From source 142e into chamber 110 until a second designated pressure is reached. The second specified pressure may be 1to 100 Torr.

v) stopping the flow of inert gas and allowing a specified delay time to elapse, such as the delay time measured by a timer in the controller. This allows the inert gas to diffuse through the particles in the particle bed 10 to displace the reaction gas and any vaporous by-products.

vi) the vacuum pump 140 evacuates the chamber 110, for example, to a pressure below 1Torr, for example, to 1to 500mTorr, for example, 50 mTorr.

These steps (iv) - (vi) may be repeated a number of times set by the recipe, for example, six to twenty times.

In the second reactant half cycle, as the motor 160 rotates the paddle wheel 150 to agitate the particles:

vii) operating gas distribution system 30 to inject a second reactant gas (e.g., H)₂O) from source 142b into chamber 110 until a third designated pressure is reached. The third pressure may be 0.1Torr to half the saturation pressure of the reaction gas.

viii) stopping the flow of the second reactant gas and allowing a specified delay time, such as a delay time measured by a timer in the controller, to elapse. This allows the second reactant gas to flow through the particle bed 10 and react with the particle surfaces within the drum chamber 110.

ix) vacuum pump 140 evacuates chamber 110, for example to a pressure below 1Torr, for example to 1to 500mTorr, for example 50 mTorr.

These steps (vii) - (ix) may be repeated a number of times set by the recipe, for example, two to ten times.

Next, a second purge cycle is performed. This second purge cycle may be the same as the first purge cycle, or may have a different number of repetitions and/or a different delay time and/or a different pressure than steps (iv) - (vi).

The cycle of the first reactant half cycle, the first purge cycle, the second reactant half cycle, and the second purge cycle may be repeated a number of times set by the recipe, for example, one to ten times.

Further, one or more gases (e.g., reactant gases and/or inert gases) may be supplied in pulses, wherein chamber 110 is filled with the gas to a specified pressure, allowing a delay time to elapse, and then the chamber is evacuated by vacuum source 140 before the next pulse begins.

Operation is discussed above in terms of ALD processing, but MLD operation is similar thereto. In particular, in steps (i) and (vii), the reaction gases are replaced with suitable process gases and pressures to deposit the polymer layer. For example, step (i) may use adipoyl chloride in a vapor or gaseous state, while step (vii) may use ethylenediamine in a vapor state.

Also, while the above discusses operation using ALD or MLD processing, the system may be used for Chemical Vapor Deposition (CVD) processing. In this case, for example during step (i), two reactants are simultaneously flowed into the chamber 110 to react inside the chamber. The second reactant half cycle may be omitted.

Depolymerization with gas streams

As mentioned above, even if the particles are agitated by the blades, the particles may still form micro-agglomerates, e.g., agglomerates formed from several particles or agglomerates of agglomerates up to 10 times the primary particle size.

However, one or more gases (e.g., reactive gases and/or inert gases) may be injected in a manner that causes depolymerization of the particles in the particle bed in chamber 110. Such methods enable such depolymerization to occur in situ, for example, in a purge step between reactant gas exposures, thereby increasing throughput and increasing yield by eliminating vacuum breaks and atmospheric exposures that can occur during ex situ processing of depolymerization.

A related problem is the overall management of gas-particle interactions. In delivering the reactant gases to the chamber for deposition, it is desirable that the reactant gases be moved slowly to provide the process gases with as long a residence time in the powder as possible, while still preventing backflow of particles into the manifold fast enough. If the velocity of the reactant gas is too high, the reactant gas will have no time or exposure for the reaction to proceed and a rat hole (rat hole) will be created.

The depolymerization may be carried out via a reactive gas, a purge gas, or both. Assuming that a purge gas (i.e., an inert gas) is used for depolymerization, the gas must be fast enough to carry out depolymerization, but not so fast that "rat holes" are formed in the powder bed. The vane rotation speed can be used in combination with higher purge gas speeds to reduce the formation of rat holes during jet depolymerization. Furthermore, the gas flow must be slow enough to retain the powder in the powder bed, rather than "blow" the powder bed and into the exhaust system. Assuming that a reactive gas is used for depolymerization, it will be subject to the constraints of the inert gas and other constraints of the deposition described above.

The particular flow and pressure ranges will depend on the particle size and composition, the degree of agitation of the blades.

In the step of performing the treatment with the reactive gas, the chamber may be maintained at a pressure of 1to 100Torr, for example, 20to 50Torr, and the flow rate of the reactive gas (or a mixture of the reactive gas and the inert gas) may be lower than 10m/s, for example, 1to 10 m/s. In some embodiments, these velocities, for example less than 10m/s, may be sufficient to provide depolymerization by the reactive gas (or a mixture of reactive and inert gases) during the deposition step.

In some embodiments, during the inert gas purge step, the purge gas flows into the process chamber at the same velocity (e.g., 1-10m/s) as the gas flow in the deposition step. In some embodiments, the purge gas flows into the processing chamber at a higher velocity than during the deposition step, but still less than 10 m/s. In some embodiments, the flow rate may be increased to 30-200m/s, for example 50-100 m/s. Such velocities are sufficient to break up the micro-agglomerates, but not the primary particles. The velocity may be maintained within the supersonic velocity range of the jet mill, for example less than 340 m/s. In some embodiments, the velocity of the purge gas is increased (e.g., to above 30 m/s) during a portion of the purge step, but is maintained at a lower velocity (e.g., less than 10m/s) or the same velocity as during the deposition step during the remainder of the purge step.

The chamber pressure may be set during the purge step to a pressure lower than the pressure maintained during the deposition step, such as less than 20Torr, such as 1-20 Torr.

In some embodiments, the disaggregation is temporary, e.g., the particles may reaggregate prior to subsequent deposition. However, the entire particle should still be coated during multiple deposition cycles by breaking up the micro-agglomerates, thereby forming new contact points during the re-aggregation process. In some embodiments, the deagglomeration is continued for a time sufficient for a simultaneous or subsequent deposition step to effectively coat the entire particle, but the particles re-aggregate as they are removed from the chamber.

Conclusion

The present disclosure provides apparatus and methods for preparing pharmaceutical compositions comprising particles comprising an API comprising particles encapsulated by one or more layers of an oxide and/or one or more layers of a polymer. The coating is conformal and has a controlled total thickness from a few nanometers to a few micrometers. The article to be coated may consist of the API alone or in combination with one or more excipients. The coating methods described herein can provide an API with an API having an increased glass transition temperature relative to the uncoated API, a reduced crystallization rate of the API relative to the amorphous form of the uncoated API, and a reduced surface mobility of API molecules in the particles relative to the uncoated API. Importantly, particle dissolution can be altered. Because the coating is relatively thin, a drug with a high drug loading can be obtained. Finally, since multiple coatings can be applied in the same reactor, there are advantages in terms of both cost and ease of manufacture.

The term relative positioning is used to refer to the relative positioning of components within the system or the orientation of the components during operation. It should be understood that the reactor system may be maintained in a vertical orientation or other orientation during shipping, assembly, etc.

A number of specific embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention.