阅读说明：本技术 用于在具有旋转桨的固定的腔室中涂覆颗粒的反应器 (Reactor for coating particles in a stationary chamber with rotating paddles ) 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：一种用于涂覆颗粒的反应器包括：固定的真空腔室,所述固定的真空腔室用于容纳待涂布的颗粒床；在腔室的上部中的真空端口；化学输送系统,所述化学输送系统经配置以将反应物气体或前驱物气体注入腔室的下部；桨叶组件；和马达,所述马达用于旋转所述桨叶组件的驱动轴。腔室的所述下部形成半圆柱体。所述桨叶组件包括：可旋转的驱动轴,所述可旋转的驱动轴沿着所述半圆柱体的轴线延伸穿过所述腔室；和多个桨叶,所述多个桨叶从所述驱动轴径向地延伸,以使得由所述马达旋转所述驱动轴的旋转使所述多个桨叶围绕所述驱动轴运行。(A reactor for coating particles comprising: a fixed vacuum chamber for containing a bed of particles to be coated; a vacuum port in an upper portion of the chamber; a chemical delivery system configured to inject a reactant gas or a precursor gas into a lower portion of a chamber; a blade assembly; and a motor for rotating a drive shaft of the paddle assembly. The lower portion of the chamber forms a semi-cylinder. The blade assembly includes: a rotatable drive shaft extending through the chamber along the axis of the semi-cylinder; and a plurality of paddles extending radially from the drive shaft such that rotation of the drive shaft by the motor causes the plurality of paddles to orbit about the drive shaft.)

1. A reactor for coating particles, comprising:

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

a vacuum port in the upper portion of the chamber;

a chemical delivery system configured to inject a reactant gas or a precursor gas into the lower portion of the chamber;

a paddle assembly, the paddle assembly comprising:

a rotatable drive shaft extending through the chamber along the axis of the semi-cylinder,

a plurality of paddles extending radially from the drive shaft such that rotation of the drive shaft by the motor causes the plurality of paddles to orbit about the drive shaft; and

a motor for rotating the drive shaft.

2. The reactor of claim 1, the outer edge of the paddle being separated from the inner surface of the lower portion of the chamber wall by a gap.

3. The reactor of claim 1, wherein the plurality of paddles comprises: a first plurality of outer blades located a first radial distance from the drive shaft and a first plurality of inner blades located a second radial distance from the drive shaft, wherein the second radial distance is less than the first radial distance.

4. The reactor of claim 3, wherein said first plurality of outer paddles is oriented at a first tilt angle and said first plurality of inner paddles is oriented at a second tilt angle, said second tilt angle being opposite in sign to said first tilt angle.

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

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

7. The reactor of claim 6, wherein the plurality of paddles comprises: 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, wherein the fourth radial distance is less than the third radial distance, wherein the second plurality of outer paddles are oriented at a third tilt angle to drive particles in the second direction and the second plurality of inner paddles are oriented at a fourth tilt angle to drive particles in the first direction.

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

9. The reactor of claim 7, wherein the first plurality of outer paddles and the first plurality of inner paddles are disposed on a first side of a separation plane passing through the chamber perpendicular to the axis, and the second plurality of outer paddles and the second plurality of inner paddles are disposed on an opposite second side of the separation plane.

10. A reactor as claimed in claim 9, comprising a port for delivering particles to or receiving particles from the chamber, the port being provided at the partition plane.

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

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 travel about the drive shaft; and

injecting a reactant gas or a precursor gas into the lower portion of the chamber as the paddle assembly rotates.

13. The method of claim 12, comprising the steps of: the particles are coated by atomic layer deposition or molecular layer deposition.

14. The method of claim 12, wherein the particles comprise a core comprising a drug.

15. A reactor for coating particles, comprising:

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

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

a chemical delivery system configured to inject a reactant gas or a precursor gas into the lower portion of the chamber;

a paddle assembly, the paddle assembly comprising:

a rotatable drive shaft extending through the chamber along the axis of the semi-cylinder,

a plurality of paddles extending radially from the drive shaft such that rotation of the drive shaft by the motor causes the plurality of paddles to orbit about the drive shaft, the plurality of paddles comprising a plurality of groups of paddles, wherein each group of paddles is disposed in a common plane perpendicular to the drive shaft, and wherein each group of paddles comprises: an outer blade located at a first radial distance from the drive shaft and an inner blade located at a second radial distance from the drive shaft, wherein the second radial distance is less than the first radial distance; and

a motor for rotating the drive shaft.

Technical Field

The present disclosure relates to coating particles (e.g., particles comprising an active pharmaceutical ingredient) with thin organic and inorganic films.

Background

The development of improved formulations (formulations) of Active Pharmaceutical Ingredients (APIs) is of great interest to the pharmaceutical industry. The formulation may affect the stability and bioavailability of the API, as well as other characteristics. The formulation may also affect various aspects of Drug Product (DP) manufacturing (e.g., ease and safety of manufacturing processes).

A number of 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 rotating reactors. Spray coating is an industrially scalable technique that has been widely adopted by the pharmaceutical industry. However, coating non-uniformity (both within the particles and from particle to particle) prevents the use of these techniques to improve the delivery profile or stability of the Active Pharmaceutical Ingredient (API). Particle agglomeration during spraying also causes significant problems. At the same time, techniques such as plasma polymerization are difficult to scale, are only applicable to certain precursor chemicals (chemistries), and can lead to degradation of sensitive APIs. Existing hot filament CVD processes that utilize a hot filament free radical source inside the reaction vessel are not scalable and are not suitable for use with thermally sensitive APIs. The rotary reactor comprises: atomic Layer Deposition (ALD) and induced cvd (icvd) reactors. However, ALD reactors are suitable for inorganic coatings and not for organic polymer coatings, and existing iCVD designs do not adequately protect APIs from degradation and cannot be scaled up for high volume manufacturing. Other techniques include: polymer mesh coating, pan coating, spray coating, and fluidized bed reactor coating.

Disclosure of Invention

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

Embodiments may include: one or more of the features described below.

The plurality of paddles may be configured to sweep along the entire length of the chamber (sweep). The outer edge of the paddle may be separated from the inner surface of the lower portion of the chamber wall by a gap. The gap may be 1-3 mm.

The plurality of paddles may include: a first plurality of outer blades located at a first radial distance from the drive shaft and a first plurality of inner blades located at a second radial distance from the drive shaft. The second radial distance may be less than the first radial distance. The first plurality of outer blades may be oriented at a first angle of inclination to drive particles in a first direction along the axis, and the first plurality of inner blades may be oriented at a second angle of inclination to drive particles in a second direction along the axis opposite the first direction. The second tilt angle may be equal in magnitude and opposite in sign to the first tilt angle.

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

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

The first plurality of outer paddles and the first plurality of inner paddles may be disposed on a first side of a separation plane passing through the chamber perpendicular to the axis, and the second plurality of outer paddles and the second plurality of inner paddles may be disposed on an opposite second side of the separation plane. Ports for delivering particles to or receiving particles from the chamber may be provided at the partition plane. The first and second pluralities of outer paddles may be oriented to drive particles toward the port, and the first and second pluralities of inner paddles may be oriented to drive particles away from the port.

The plurality of paddles may include: paddles are evenly spaced along the drive shaft. The plurality of paddles may include: a plurality of sets of blades, and the blades of each set may be arranged in a common plane perpendicular to the drive shaft.

In another aspect, a method of coating particles comprises the steps of: dispensing particles into a vacuum chamber to fill 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 paddle assembly such that a plurality of paddles orbit about a drive shaft, and injecting a reactant or precursor gas into the lower portion of the chamber as the paddle assembly rotates.

Embodiments may include: one or more of the following features.

The particles may be coated by atomic layer deposition or molecular layer deposition. The particles may have a core comprising a drug (drug).

Embodiments may include (but are not limited to): one or more of the following possible advantages. Particles (e.g., API particles) may be coated in a high volume manufacturing process, thereby providing lower manufacturing costs and reduced drug prices. The particles may be coated with a thin layer, thereby providing a pharmaceutical product with an API having a favorable volume fraction. In addition, the process may produce layers of encapsulated API that are uniform within and from particle to particle, thereby providing more consistent characteristics for pharmaceutical formulations.

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. These 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 (which includes a fixed drum (drum)) for ALD and/or CVD coating of particles (e.g., drugs).

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 a 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 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 top view of the gas injection port of fig. 8.

Fig. 10 is a schematic perspective view showing a partial section of a gas injection port.

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

Detailed Description

There are various methods for encapsulating API particles. In many cases, these methods produce relatively thick coatings. While these coatings may impart desirable properties, the high ratio of coating to API may make it difficult to produce a pharmaceutical product having a volume fraction of API as high as desired. Furthermore, the coating encapsulating the API may be non-uniform, making it difficult to provide a formulation with consistent properties. Furthermore, coating techniques that can provide satisfactory consistency are not scalable to industrial manufacturing.

One solution to these problems is to use a stationary "drum" in which the particles are agitated by rotating paddles and the process gas is injected into the drum through the side wall of the drum. This forces the process gas to permeate the particle bed, which improves the uniformity of the coating on the particles.

Medicine

The term "drug" includes in its broadest sense: 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, anticancer agents, anticoagulants, antidepressants, antidiabetics, antiepileptics, antihistamines, antitussives, antihypertensives, antimuscarinics, antimycobacterial agents, antineoplastics, antioxidants, antipyretics, immunosuppressive agents, immunostimulants, antithyroids, antivirals, anxiolytic sedatives, hypnotics, neuroleptics, astringents, bacteriostats, beta-adrenergic receptor blockers, blood products, blood substitutes, bronchodilators, buffers, cardiac contractiles, chemotherapeutic agents, imaging agents, corticosteroids, antitussives, expectorants, mucolytics, diuretics, dopaminergic agents, antiparkinsonian agents, free radical scavengers, growth factors, hemostats, immunological agents, lipid regulators, anti-cancer agents, anti, Muscle relaxants, parasympathetic agents, parathyroid calcitonin, bisphosphonates, prostaglandins, radiopharmaceuticals, hormones, sex hormones, antiallergic agents, appetite stimulants, anorexia agents, steroids, sympathomimetics, thyroid agents, vaccines, vasodilators, and xanthines.

Exemplary types of small molecule drugs include (but are not limited to): p-acetamidophenol, clarithromycin, azithromycin, ibuprofen, fluticasone propionate, salmeterol, pazopanib hydrochloride, palbocillin, 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 (e.g., cellulose, cross-linked polyvinylpyrrolidone, microcrystalline cellulose);

(3) fillers (e.g., lactose monohydrate, anhydrous lactose, microcrystalline cellulose, and various starches);

(4) lubricants (e.g., agents acting on the flowability of the powder to be compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, colloidal silica);

(5) a sweetener (e.g., any natural or artificial sweetener including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame potassium);

(6) a flavoring agent;

(7) preservatives (e.g., potassium sorbate, methyl hydroxybenzoate, propyl hydroxybenzoate, benzoic acid and salts thereof, other esters of parahydroxybenzoic acid (e.g., butyl paraben), alcohols (e.g., ethanol or benzyl alcohol), phenolic chemicals (e.g., phenol), or quaternary ammonium compounds (e.g., benzalkonium chloride));

(8) a sustained release agent;

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

(10) wetting agents (e.g., cereal starch, potato starch, corn starch, and modified starches, and mixtures thereof);

(11) a disintegrant; for example, croscarmellose sodium, crospovidone, sodium starch glycolate; and

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

Metal oxide material

The term "metal oxide material" includes in its broadest sense: all materials formed by the reaction of elements considered as metals with oxy-oxidants. 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, such as 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 deposition of films with thickness and uniformity controlled to the atomic or molecular monolayer level. Self-limiting means that only a single atomic layer is formed at a time and subsequent process steps are required to regenerate the surface 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. During a typical MLD process, two homogeneous bifunctional precursors (homo-bifunctional 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 the corresponding linking chemistry, adding a molecular layer of the first precursor on the substrate surface with new reactive sites. After purging, a second precursor is introduced and molecules of the second precursor react with new reaction sites provided by the first precursor, thereby creating a molecular layer of the first precursor linked to the second precursor. After which another purge cycle is performed.

Reactor system

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

The reactor system 100 includes: a fixed vacuum chamber 110 enclosing the paddle assembly 150.

The vacuum chamber 110 is enclosed by chamber walls 112. The lower portion 110a of the chamber 110 is formed as 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, as viewed along the central axis of the semi-cylinder) may be uniform along the length of the chamber 110 (the length being along the central axis of the semi-cylinder). This may help to ensure uniform airflow along the length of the chamber. If the gas flow is sufficiently uniform, the cross-section may be non-uniform (e.g., 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 parallelepiped (see fig. 6A), a semi-cylinder having 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 (lower section)110c adjacent to the lower portion 110a and having vertical sidewalls (e.g., a rectangular parallelepiped volume). The upper section 110c extending between the lower section 110c of the chamber 110 and the ceiling 112a may have a triangular or trapezoidal cross-section (again, as viewed along the central axis of the semi-cylinder).

In some embodiments, for example, as shown in fig. 6B (but which may be combined with other blade assemblies), the curved portion of the chamber wall follows the lower section 110c of the upper chamber 110B. An upper section 110d extending between the lower section 110c and the top plate 112a of the chamber 110 may provide a volume for the vacuum port 132 and/or the powder delivery port 116. This configuration may avoid powder build-up along a portion of the sidewall 12 that is inaccessible to the paddle 154 (e.g., due to the paddle assembly throwing powder).

The chamber walls 110 may be a material that is 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 that is inert to the deposition process. In some embodiments, a viewing port 114 composed of a 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, chamber 110 is partially filled with particles (e.g., particles containing an API) that provide a bed 10 of particles. 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 at a)). On the other hand, the top surface 12 of the particle bed 10 should be below the top of the paddle assembly 150 (indicated at B) to avoid poor mixing of the particle bed. The chamber walls 112 may include one or more sealing ports 116 to allow particles to be placed into the chamber 110 and 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 a desired location of the top surface 12 of the particle bed (e.g., above the top of the paddle assembly 150 (indicated at B) (e.g., in the chamber ceiling)).

The vacuum source 130 can be an industrial vacuum pump sufficient to generate a pressure of less than 1Torr, such as 1to 100mTorr (e.g., 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 gas stream by the paddle assembly from escaping the reactor chamber 110. In addition, the system may include a filter cleaner to remove particles from the filter 134. As one example, the filter cleaner may be a mechanical impactor for impacting the filter; this can cause the particles to shake away from the filter. As another example, the gas source 136 (which may be provided by the gas source 142e) may periodically provide a pulse of inert gas (e.g., nitrogen) to the gas line 138 between the port 132 and the vacuum source 130. The pulse of gas travels back through the filter 134 toward the chamber 110 and may blow particles out of the filter 134. Isolation valves 139a, 139b may be used to ensure that only one of the gas source 136 or vacuum source 130 is fluidly coupled 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 coupled by 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 that 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 a controllable flow rate of the various gases into chamber 110. The chemical delivery system 140 may also include one or more temperature control components (e.g., heat exchangers, resistance heaters, etc.) to heat or cool the various gases prior to flowing into the chamber 110.

Chemical delivery system 140 may include: 5 fluid sources 142a, 142b, 142c, 142d, 142 e. Two of the fluid sources (e.g., fluid sources 142a, 142b) may provide two chemically different precursors or reactants for a deposition process that forms an oxide layer on the particles. For example,the first fluid source 142a may provide Trimethylaluminum (TMA), or titanium tetrachloride (TiCl4), while the fluid gas source 142b may provide water. Two other of the fluid sources (e.g., fluid sources 142c, 142d) may provide two chemically different precursors or reactants for a deposition process that forms a polymer material on an oxide layer. For example, the third fluid source 142c can provide adipoyl chloride and the fourth fluid source 142d can provide ethylene diamine. One of the fluid sources (e.g., the fifth fluid source 142e) may provide an inert gas (e.g., argon or N)₂) For purging between cycles or half-cycles in the deposition process.

Although fig. 1 illustrates 5 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 an even greater variety of laminate structures.

For one or more of the fluid sources, the chemical delivery system 140 delivers the precursor or reactant in liquid form to the gas injection assembly 190. The gas injection assembly 190 includes a vaporizer 148 to convert liquid to vapor immediately before precursors or reactants enter the injection manifold 194. This reduces the upstream pressure loss so that more pressure loss occurs throughout 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 that all of the precursors will react when they pass through the particle bed at a given flow rate. Evaporator 149 can be proximate to a reactor sidewall (e.g., fixed to reactor wall side 112 or housed within reactor wall side 112).

As shown in fig. 1, there may be one manifold 194 for each precursor or reactant fluid, and each manifold 194 may be separately fluidly connected to chamber 110. Thus, the precursors or reactants do not mix until actually within the chamber 110. Alternatively, gas lines from the fluid source 142 may be joined as a combined fluid supply line (e.g., by a valve). The gas injection assembly 190 will be discussed further hereinafter.

As previously described, a paddle assembly 150 is disposed in the chamber 110 to agitate the particles in the particle bed. The paddle assembly 150 includes: a rotatable drive shaft 152 and a plurality of paddles 154. The blades 154 are connected to the drive shaft 152 by struts (strut)156 extending outwardly from the drive shaft 152 such that rotation of the drive shaft 152 about the axis of rotation 153 carries the blades 154 along a circular path (see arrow C) about the axis of rotation 153. 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.

Drive shaft 152 is driven by a motor 160 located outside of chamber 110. For example, the drive shaft 152 may extend through the chamber wall 112 with one end coupled to the motor 160. A bearing vacuum seal 162 may be used to seal the chamber 110 from the external environment. The other end of the drive shaft may be supported by a bearing within the chamber 110 (e.g., the end of the drive shaft 152 may fit into a groove 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 the paddle assembly 150 at a speed of 0.1to 60 rpm.

At least some of the paddles 154 are held in a position by the struts 156 such that the outer edges of the paddles 154 nearly contact the inner surface 114 of the chamber wall 112 as the drive shaft 152 rotates. However, the outer edge of the paddle 154 is maintained separated from the inner surface by a small gap G1 (e.g., 1to 4 mm). Gap G1 may be as small as possible within manufacturing tolerances so that blades 154 do not scrape against 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, rotation of the drive shaft 152 may cause the outer edges of the paddles 154 to sweep across the inner surface of the semi-cylinder of the lower portion 110a (e.g., across the entire inner surface of the semi-cylinder).

The paddles 154 may be spaced along the drive shaft 152 to ensure that the paddles that nearly contact the inner surface 114 provide coverage along substantially the entire length of the reactor chamber 110. Specifically, the blades 154 are spaced apart and have a width W (along the axis of rotation) such that there is no gap in the volume swept by the blade assembly 150. Specifically, the width W may be greater than the pitch of the blades along the drive shaft 152. The blades at different radial positions along the length of the drive shaft may be angularly offset. For example, as shown in fig. 3A and 3B, the blades 154 may be arranged in a helical pattern around the drive shaft 152. However, many other configurations are possible for the angular offset (e.g., alternating sides of the drive shaft).

In some embodiments, some of the blades 154 are disposed radially closer to the drive shaft 152 (than other blades 154). The blade 154b closer to the drive shaft may be referred to as an "inner blade", and the blade 154a further from the drive shaft may be referred to as an "outer blade". The inner and outer blades 154b, 154a may not radially overlap, or may partially radially overlap. For example, the inner and outer blades may overlap by at most 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 is no gap in the volume swept by the outer blades 154 a. Specifically, 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. Specifically, the width of the inner blades 154b may be greater than the pitch of the inner blades 154b along the drive shaft 152. Adjacent inner blades 154b along the length of the drive shaft may be angularly offset. For example, as shown in fig. 3C and 3D, the inner blades 154b may be arranged in a first helical pattern around the drive shaft 152 and the outer inner blades 154a may be arranged in a second helical pattern around the drive shaft 152. The helices of the inner and outer blades 154b, 154a are shown as being 180 ° out of phase, but this is not required. Further, many other configurations are possible for the angular offset between adjacent blades (e.g., blades may be placed on alternating sides of the drive shaft).

Referring to fig. 4, each paddle 154 may be a generally flat body having a major surface 170 for pushing particles in the particle bed, and a thinner edge 172 that will contact the inner surface of the lower portion 110a of the chamber 110. As shown in fig. 4, the blades 154 may be flared. Alternatively, as shown in fig. 1 and 2, the blade may be substantially rectangular (e.g., rectangular with rounded edges). The surface 170 of the paddle 154 may be flat, or the surface 170 may be concave (e.g., scoop-shaped). Further, in some embodiments, the blade 154 is plow-shaped (e.g., convex or sharply convex with respect to the direction of motion of the blade).

Returning to fig. 1, in some embodiments, the blades are grouped in groups disposed in a common plane perpendicular to the axis of rotation 153. The blades in a group may be spaced at substantially equal angular intervals about the drive shaft 152. A group may include: 4 paddles (although 2, 3, or 5 or more paddles may be used).

For example, referring to fig. 1 and 5, blade assembly 150 includes: a group 180 of 4 paddles 180a, 180b, 180c, 180d that are angularly spaced by 90 degrees and are equidistant from the drive shaft 152 and the rotational shaft 153. Paddles 180a-180d may be positioned to nearly contact the semi-cylindrical inner surface of lower portion 110a of chamber 110 a.

As shown in fig. 1 and 2, blade assembly 150 may include: a plurality of sets of blades disposed at different locations along the drive shaft 132. For example, the blade assembly may include: groups 180, 182, 184, 186, 188. In the case of three or more groups, the groups of blades may be spaced at substantially equal intervals along the drive shaft 152. Each group may have the same number of paddles (e.g., 4 paddles). The blades in adjacent groups may be angularly offset about the axis of rotation (e.g., offset by half the angle between the blades within a group). For example, if a group has 4 blades spaced 90 ° apart around the axis of rotation, the blades of adjacent groups may be offset by 45 °.

In some embodiments, for example, as shown in fig. 1, the blades in a group may be located at substantially the same distance from the axis of rotation 153 (e.g., the struts 156 may have the same length).

However, in some embodiments, some of the blades in a group are disposed radially closer to the drive shaft 152 (than other blades in the group). For example, blade assembly 150 shown in FIG. 6A includes: a set of 4 paddles 180a ', 180 b', 180c ', 180 d' spaced at 90 degrees. Two of the blades (e.g., two opposing blades 180a 'and 180 c') are located a first distance from the drive shaft 152. The two paddles may be positioned to nearly contact the semi-cylindrical inner surface 112 of the lower portion 110 a. Two other of the blades (e.g., two opposing blades 180b 'and 180 d') are located at a second, shorter distance from the drive shaft 152.

As another example, the blade assembly shown in fig. 6B includes: a group of 8 paddles 180a-180h spaced at an angle of 45 degrees. The 4 outer blades 154a (e.g., blades 180a-180d) are located at a first distance from the drive shaft 152. The 4 outer blades 154a may be disposed to nearly contact the semi-cylindrical inner surface 112 of the lower portion 110 a. The 4 inner blades 154b (e.g., blades 180e-180h) are located at a second, shorter distance from the drive shaft 152. The outer blades 154a and the inner blades 154b are placed around the drive shaft 152 in an alternating arrangement.

In some embodiments, some of the groups of blades have blades disposed radially closer to the drive shaft 152 (as compared to other groups of blades). For example, blade assembly 150 includes: a set 182 of 4 inner paddles 182a, 182b, 182c, 182d that are angularly spaced at 90 degrees and equidistant from the drive shaft 152 and the rotational shaft 153. The outer edges of paddles 182a-182d are spaced apart from the semi-cylindrical inner surface of lower portion 110a of chamber 110a by a gap G. The inner blades 182a-182d are radially inward compared to the outer blades 180a-180 d.

Referring 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 paddles 154 may be angled such that the travel of the paddles 154 about the axis of rotation 153 tends to force the particles radially toward or away from the axis of rotation 153.

Further, each paddle 154 may be at an oblique angle relative to a plane perpendicular to the axis of rotation 153. Specifically, each paddle 154 may be angled such that the travel of the paddles 154 about the axis of rotation 153 tends to propel particles in a direction parallel to the axis of rotation 153. For example, as shown in fig. 5 and 7, blade 180a is oriented: an axis N perpendicular to plane 170 of blade 154 is at an oblique angle α relative 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, as the blade travels around the axis of rotation 153, it will have an instantaneous motion vector C. The tilt angle a of paddle 180a will drive the powder in a direction D perpendicular to C. The tilt angle alpha may be between 15-75 deg. (e.g., between 30-60 deg. (e.g., about 45 deg.)).

The inner blades in a group may be oriented with a common pitch angle α, and the outer blades in a group may be oriented with a common pitch angle α'. In some embodiments, all of the inner blades along the drive shaft 152 are oriented to have a common pitch angle α, and all of the outer blades along the drive shaft 152 are oriented to have 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 to angle α, but opposite in sign to angle α (e.g., the pitch angle of the outer blade is + α, and the pitch angle of the outer blade is- α).

In some embodiments, the outer paddles 154 are angled such that the end of the paddle's travel drives the particles in a first direction parallel to the axis of rotation 153, while the inner paddles 154 are angled such that the travel of the inner paddles 154 tends to drive 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 paddles 180a 'and 180 c' in the set 180 may drive particles in the direction D, while the inner paddles 180b 'and 180D' in the set may drive 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 (e.g., near the center). The port 116a may be used to convey and/or withdraw particles from the reactor 100. In this embodiment, the outer paddle may be oriented to push particles toward port 116a and the inner paddle may be oriented to push particles away from port 116 a.

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

The blades in different groups (e.g. (adjacent groups)) may have different inclination angles if the blades in each group have the same radial distance from the drive shaft. For example, reference to paddles 180a-180D in the first set 180 may drive particles in direction D, while paddles 182a-182D in the second set 180 may drive particles in a direction opposite to D.

Referring to fig. 1 and 8, the chemical delivery system 140 is coupled to the chamber 110 by 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 a row (e.g., parallel to the rotational axis 153 of the drive shaft 152). Although fig. 8 illustrates a single column of apertures 192, the system may have multiple columns of apertures. In particular, there may be different columns of holes for different reactants or precursors. Furthermore, there may be multiple columns of holes for a given reactant and/or precursor.

The holes 192 are located below the desired location of the top surface 12 of the particle bed. Specifically, 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 disposed in a lower half (e.g., a lower third, e.g., a lower quarter, e.g., a lower fifth, as measured in a vertical direction) of the chamber wall 112 of the lower portion 110 b. The holes may have a diameter of 0.5 to 3 mm. Although fig. 1 illustrates: the holes 192 are illustrated as extending horizontally through the chamber wall, but this is not required (as further explained below).

Referring to fig. 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 bore 192. The manifold 194 and the channel 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 disposed directly upstream of the manifold 194.

Inert carrier gas (e.g. N)₂) May flow from one of the fluid sources (e.g., fluid source 142e) through one or more passages 198 into manifold 194. In operation, carrier gas may flow continuously into manifold 194 (i.e., whether or not precursor or reactor gas is flowing 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 no precursor or reactor gas is injected into chamber 110 via manifold 194, the flow of carrier gas may prevent backflow into holes 192 of another precursor or reactor gas injected from another manifold. The flow of carrier gas may also prevent fouling (e.g., clogging of the pores) of the pores 192 by the particles in the particle bed 10. In addition, a carrier gas may provide a purge gas for a purge operation when no precursors or reactor gases are injected into the chamber 110.

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

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

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

Referring to fig. 10, the gas injection assembly 190 may be configured to inject gas into the chamber 110 in a gas flow direction substantially parallel to the instantaneous direction of motion of the blades 154 as they pass through the apertures 192. In other words, the direction of the airflow may be substantially tangential to the curved inner surface 114 of the cylindrical bottom 110a of the chamber 110.

Each channel 196 may include: a first channel portion 196a that extends at a shallow angle toward the inner surface 114. The first channel portion 196a is open to the chamber 110 at the aperture 192. As shown in fig. 10, the holes 192 may be fan-shaped (grooved) grooves with sharp indentations, the depth of which then gradually decreases in the direction of rotation of the blades 154 (indicated by arrow C). The first channel portion 196a may be open toward the top plate 192a of the hole 192 formed by the sharp indentation. This configuration may reduce the likelihood of particles entering the channel 196. Further, the first channel portion 196a may be wider than the intended diameter of the particle. This may reduce the risk of particles clogging the first channel portion 196 a.

The trench 196 also includes: a second channel portion 196b extending between the manifold 194 and the first channel portion 196 a. The second channel portion 196b is narrower than the first channel portion 196 a. The narrower channel portions 196b control the flow rate and flow distribution out of the manifold 194.

The evaporator 148 may include: an internal cavity 148a, the internal cavity 148a being surrounded by walls that are 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 by a nozzle 147. As the liquid passes through the nozzle 147, it is atomized. The combination of elevated temperature, rapid pressure change, and high surface area of the aerosol facilitates rapid vaporization of large quantities of reactants or precursors. The cavity 149a of the evaporator 148 can extend along a substantial portion (e.g., at least half) of the length of the chamber 110. Liquid reactant or precursor may be injected at one point of the cavity through nozzle 147, and the holes 148c for reactant or precursor vapor to enter manifold 194 may be located at the opposite end (along the length of chamber 110) of the cavity chamber.

As described above, the evaporator 148 may be integrated into the body providing the manifold. For example, the evaporator 148, the manifold 194, and the channel 196 may all be portions of a single 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 a coolant flowing in cooling channels in the chamber walls, or other components in the sidewall 112 or on the sidewall 112.

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

Generally, the controller 105 is configured to operate the reactor system 100 according to a "recipe". The recipe specifies for each controllable element an operation value as a function of time. For example, the recipe may specify the time the vacuum source 130 is operating, the time and flow rate of each gas source 142a-142e, the rotation rate of the drive shaft 152 set by the motor 160, and so forth. The controller 105 may receive the recipe as computer-readable data (e.g., it is stored on a non-transitory computer readable medium).

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

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

Operation of

Initially, particles are loaded into a chamber 110 in the reactor system 100. The particles may have a solid core (e.g., one of the drugs discussed above) that includes the drug. The solid core may optionally include: and (3) an excipient. 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 for the coating into chamber 110. The gas precursors alternately permeate 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-scale control of the deposition. Further, the ALD and/or MLD reaction may be performed under low temperature conditions (e.g., below 50 ℃ (e.g., below 35 ℃)).

Suitable reactants for use in ALD processes include: any one or combination of monomer vapor, metal organics, metal halides, oxidants (e.g., ozone or water vapor, and polymeric 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. For the MLD process, as an example, the fluid source 142c can provide adipoyl chloride and the fourth fluid 142d can provide ethylene diamine in a vapor or gaseous state.

In operation, as the paddle 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 paddle assembly 150 agitates the particles to keep them separated, ensuring that a large surface area of the particles remains exposed. This allows for a rapid, uniform reaction between the particle surface and the process gas.

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

As described above, the coating process may be performed at low processing temperatures (e.g., below 50 ℃ (e.g., at or below 35 ℃). Arrowed, the particles can be maintained or maintained at these temperatures during all steps (i) - (ix) as described previously. Generally, during steps (i) - (ix), the temperature of the interior of the reactor chamber does not exceed 35 ℃. This may be accomplished by injecting the first reactant gas, the second reactant gas, and the inert gas into the chamber at these temperatures during separate cycles. Further, if desired, the physical components of the chamber may be maintained or maintained at these 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 (e.g., using the process described previously). In some embodiments, the controller may alternate between depositing an oxide layer and depositing a polymer layer on the drug-containing particles by the reactor system 100, thereby forming a multilayer structure having alternating layers of composition.

Continuous flow operation

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

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

i) gas distribution system 140 is operated to flow a first reactant gas (e.g., TMA) from source 142a into chamber 110 until particle bed 10 is filled with the first reactant gas. For example, the first reactant gas may flow at a specified flow rate and flow for a specified time interval (or until the 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 reactant gas is mixed with an inert gas as the first reactant gas flows into the chamber. The specified pressure or partial pressure can be 0.1Torr to half the saturation pressure of the reactant gas.

ii) the flow of the first reactant gas is stopped and the vacuum source 140 evacuates (e.g., reduces to a pressure below 1Torr (e.g., to 1to 100mTorr (e.g., 50mTorr)) the chamber 110.

These steps (i) - (ii) may be repeated as many times as set by the recipe (e.g., two to ten times).

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

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

iv) the vacuum pump 140 evacuates (e.g., reduces to a pressure below 1Torr (e.g., to 1to 500mTorr (e.g., 50mTorr)) the chamber 110.

These steps (iii) to (iv) may be repeated as many times as set by the recipe (e.g., six to twenty times).

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

v) the gas distribution system 30 is operated such that the second reactant gas (e.g., H)₂O) from source 142b into chamber 110 until particle bed 10 is filled with the second reactant gas. Again, the second reactant gas may flow at a specified flow rate and for a specified time interval (or until the sensor measures a specified third pressure or partial pressure of the second reactant gas in the upper portion 110b of the chamber). In some embodiments, the second reactant gas is mixed with an inert gas as the second reactant gas 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 (e.g., to a pressure below 1Torr, e.g., to 1to 500mTorr (e.g., 50 mTorr)).

These steps (v) - (vi) may be repeated as many times as set by the recipe (e.g., 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 cycles of the first reactant half cycle, the first purge cycle, the second reactant half cycle, and the second purge cycle may be repeated as many times as set by the recipe (e.g., once to ten times).

Operation is discussed in the foregoing using an ALD process, but is similar to MLD. In particular, in steps (i) and (v), the reactant gas is replaced by an appropriate process gas and pressure for deposition of the polymer layer. For example, step (i) may use vaporous or gaseous adipoyl chloride, and step (v) may use vaporous ethylenediamine.

Further, although operation is discussed in the foregoing with an ALD or MLD process, the system may be used with a Chemical Vapor Deposition (CVD) process. In this case, both reactants flow into the chamber 110 simultaneously to perform the reaction within the chamber (e.g., during step (i)). The second reactant half cycle may be omitted.

Pulsed flow operation

In another embodiment, one or more gases (e.g., reactant gases and/or inert gases) may be supplied in pulses, wherein 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.

Specifically, for an ALD process, the controller 105 may operate the reactor system 100 as described below.

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

i) the gas distribution system 140 is operated such that a first reactant gas (e.g., TMA) flows from the source 142a into the chamber 110 until a first specified pressure is reached in the upper portion 110b of the chamber. The specified pressure can be 0.1Torr to half the saturation pressure of the reactant gas.

ii) stopping the flow of the first reactant gas and allowing a specified delay time to elapse (e.g., as 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 surface of the particles.

iii) the vacuum pump 140 evacuates (e.g., reduces to a pressure below 1Torr (e.g., to 1to 100mTorr (e.g., 50 mTorr)).

These steps (i) - (iii) may be repeated as many times as set by the recipe (e.g., two to ten times).

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

iv) the gas distribution system 140 is operated such that only inert gas (e.g., N)₂) From source 142e into chamber 110 until a second specified 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 (e.g., as 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 reactant gases and any vaporous by-products.

vi) the vacuum source 140 evacuates the chamber 110 (e.g., to a pressure below 1Torr, e.g., to 1to 500mTorr (e.g., 50 mTorr)).

These steps (iv) - (vi) may be repeated as many times as set by the recipe (e.g., six to twenty times).

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

vii) gas distribution system 30 is operated such that a second reactant gas (e.g., H2O) flows from source 142b into chamber 110 until a third specified pressure is reached. The third pressure can be 0.1Torr to half the saturation pressure of the reactant gas.

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

ix) the vacuum source 140 evacuates the chamber 110 (e.g., to a pressure below 1Torr, e.g., to 1to 500mTorr (e.g., 50 mTorr)).

These steps (vii) - (ix) may be repeated as many times as set by the recipe (e.g., two to ten times).

Next, a second purge cycle is performed. The 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 cycles of the first reactant half cycle, the first purge cycle, the second reactant half cycle, and the second purge cycle may be repeated as many times as set by the recipe (e.g., once to ten times).

In addition, one or more gases (e.g., reactant gases and/or inert gases) may be supplied in pulses, wherein 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.

Operation is discussed in the foregoing using an ALD process, but is similar to MLD. In particular, in steps (i) and (vii), the reactant gases are replaced with appropriate process gases and pressures for deposition of the polymer layer. For example, step (i) may use either vaporous or gaseous adipoyl chloride, and step (vii) may use vaporous ethylenediamine.

Further, although operation is discussed in the foregoing with an ALD or MLD process, the system may be used with a Chemical Vapor Deposition (CVD) process. In this case, both reactants flow into the chamber 110 simultaneously to perform the reaction within the chamber (e.g., during step (i)). The second reactant half cycle may be omitted.

Conclusion

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

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

Some 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.