Low-temperature atomic-scale surface coating method for improving electron beam damage resistance of heat-sensitive powder

Abstract

The invention discloses a low-temperature atomic-scale surface coating method for improving electron beam damage resistance of heat-sensitive powder, which is based on a fluidized bed atomic layer deposition technology, and comprises the following steps: under the conditions of normal pressure and low temperature of 30-60 DEG C, taking a silane precursor, trimethylaluminum and an oxidizing agent as reaction sources; and growing a compact oxide film (SiO2 / Al2O3 / TiO2) of 1-10 nm on the surface of the heat-sensitive powder in situ. According to the continuous defect-free nano film formed by the method, the electron beam irradiation resistance of the heat-sensitive powder can be remarkably improved, and the heat stability (the thermal decomposition temperature is increased by more than or equal to 30 DEG C) and the SEM imaging quality (the surface charge accumulation is reduced by more than 80%) are synchronously improved. According to the method, the technical bottleneck of a traditional high-temperature coating process is broken through, the microscopic observation problem caused by heat sensitivity and insulativity of the heat-sensitive powder is solved, and a high-reliability solution is provided for drug carrier preparation optimization and nanoscale microscopic analysis.

Description

Technical Field

[0001] The present invention belongs to the cross - field of electron microscopy analysis and pharmaceutical preparation technology, and specifically relates to a surface treatment method based on atomic layer deposition (ALD) technology. By in - situ growing a nanoscale dense oxide film at low temperature, the anti - electron - beam irradiation ability, thermal stability and microscopic imaging quality of heat - sensitive powders are significantly improved. Background Art

[0002] Heat - sensitive powders are usually used as excipients and drug carriers widely used in pharmaceutical preparations, and their physical and chemical properties directly affect the processing stability of the preparations and the drug release performance. However, heat - sensitive powders (such as hydroxyl - containing α - lactose, drug carriers, etc.) face many key challenges in electron microscopy observations (SEM / TEM) and pharmaceutical applications.

[0003] First of all, due to the presence of active groups such as hydroxyl groups in the molecular chain, heat - sensitive powders are prone to bond breakage and free - radical reactions under the irradiation of high - energy electron beams (200 keV) in TEM, resulting in morphological distortion (structural collapse occurs within 30 seconds of irradiation).

[0004] Secondly, the surface charge effect: the insulating properties of powder particles cause rapid accumulation of surface charges during SEM observation (charge density > 10^3e / μm 2 ) at an accelerating voltage of 10 kV, leading to blurred imaging and deteriorated resolution (contrast reduction > 50%), which severely restricts the accurate analysis of their microscopic morphology and drug - loading behavior.

[0005] In the prior art, in order to improve the thermal stability or imaging performance of heat - sensitive powders, methods such as physical coating (such as polymer coating) or chemical vapor deposition (CVD) are often used for surface modification. However, the physical coating method has problems such as poor film uniformity and easy peeling, while the CVD process needs to be carried out at high temperature (> 300°C), which is extremely likely to cause thermal decomposition failure of heat - sensitive powders (low thermal decomposition temperature (T d = 150 - 200°C). And other traditional modification technologies also have obvious limitations: for example, existing solution coating and CVD methods are difficult to achieve sub - nanoscale uniform coating (coverage rate < 85%), and high temperature / chemical erosion is likely to damage the surface active sites of powder particles, and the residual solvent affects electron microscopy observation; the plasma spraying method requires high temperature (> 400°C) to cause thermal decomposition of the substrate, and the coating is uneven (local porosity > 15%); the ion beam sputtering method has high equipment costs and insufficient film adhesion (scratch critical load < 1 mN).

[0006] To address the above problems, the present invention proposes an atomic-level surface engineering strategy based on low-temperature ALD. By precisely controlling the crystal structure and interfacial bonding force of oxide films (SiO2 / Al2O3 / TiO2), full-surface passivation of thermosensitive powders is achieved at 30 - 60 °C, breaking through the bottlenecks in their microscopic observation and pharmaceutical applications. Summary of the Invention

[0007] In view of the defects of thermosensitive powders as drug carriers, such as poor thermal stability (low decomposition temperature), susceptibility to electron beam irradiation damage during electron microscopy (SEM / TEM) observation, and poor imaging quality caused by surface charge accumulation, the present invention proposes a surface modification method based on atomic-level film coating technology. The aim is to coat nanoscale dense (SiO2 / Al2O3 / TiO2) films on the surface of thermosensitive powders through a low-temperature atomic-level film coating process, synchronously solving the following technical problems:

[0008] 1. Improve the electron beam irradiation resistance of thermosensitive powders to avoid structural collapse or morphological distortion during TEM / SEM observation;

[0009] 2. Improve the insulation of thermosensitive powders, reduce surface charge accumulation during SEM imaging, and improve image resolution;

[0010] 3. Enhance the thermal stability of thermosensitive powders, inhibit moisture absorption caking and high-temperature decomposition behavior, and extend the drug storage life;

[0011] 4. Break through the application bottleneck of traditional atomic-level film coating processes on thermosensitive organic powders and achieve low-temperature and high-efficiency coating.

[0012] To solve the existing technical problems, the present invention proposes a surface treatment method for thermosensitive powders. The core lies in forming a continuous, dense, and thickness-controllable SiO2 film on the surface of thermosensitive powders through a low-temperature atomic-level film coating process combined with pretreatment and post-treatment strategies. The specific operation steps are as follows:

[0013] 1. Pretreatment steps

[0014] (1) Vacuum dehydration: Place α-lactose monohydrate or anhydrous β-lactose (particle size 1 - 100 μm) in a vacuum drying oven and dehydrate it at 50 - 60 °C for 1 - 3 hours to remove surface adsorbed water and part of the crystal water, avoiding interference from water molecules in the subsequent atomic-level film coating process reaction;

[0015] (2) Plasma activation: Use oxygen plasma to perform surface treatment on the dehydrated α-lactose monohydrate or anhydrous β-lactose (particle size 1 - 100 μm) (power 50 - 200 W, treatment time 1 - 10 minutes). Enhance surface activity and improve precursor adsorption efficiency by etching and introducing oxygen-containing functional groups.

[0016] 2. Atomic Layer Deposition (ALD) Coating Process

[0017] (1) Reaction Conditions:

[0018] Deposition temperature: 30 - 60 °C (preferably 40 - 50 °C), and the pressure in the reaction chamber is at atmospheric pressure (no vacuum environment is required);

[0019] Precursor combination: Silane-based precursors (such as SiCl4) and oxidants (water vapor or ozone) are alternately introduced, supplemented with an inert carrier gas (such as nitrogen or argon);

[0020] Pulse parameters: The pulse time ratio of the silane precursor to water vapor is 1:2 to 1:3, the single-cycle purge time is 15 - 60 seconds, and the total number of cycles is 5 - 40 times.

[0021] (2) Fluidized Bed Reactor Design:

[0022] The combination of atomic layer deposition (ALD) and a fluidized bed reactor realizes uniform coating of a large amount of powder or granular materials by introducing the ALD's layer-by-layer thin film deposition technology into the dynamic particle handling environment of the fluidized bed. The fluidized bed suspends and fully mixes the particles through gas or liquid, providing an ideal reaction environment for uniform contact and efficient mass transfer for ALD; while ALD forms a conformal thin film on the particle surface with atomic-level precision through a self-limiting cycle (adsorption, purge, reaction, re-purge) of alternately introducing precursors and co-reactants. The combination technology mainly realizes batch processing by optimizing the gas distributor design of the fluidized bed (such as a concave sieve plate) and integrating the powder atomic layer deposition (PALD) process, solves the limitations of traditional ALD equipment in processing powders with a high specific surface area, and optimizes the reaction conditions with the help of on-line monitoring technology.

[0023] 3. Post-treatment Process

[0024] (1) Annealing treatment: Gradient annealing (30 - 60 °C, 10 - 30 minutes) is carried out on the coated particles in an inert gas atmosphere to eliminate the internal stress in the thin film and enhance the binding force between SiO2 and the lactose surface;

[0025] (2) Dispersion and Observation: The annealed particles are ultrasonically dispersed in absolute ethanol for 10 minutes and transferred to a TEM carbon support film (diameter 3.05 mm) for electron microscope observation to verify the thin film quality and anti-irradiation performance.

[0026] 4. Thin Film Properties and Effects

[0027] (1) Thin film structure: By controlling the number of cycles (5 - 40 times) of the atomic-level thin film coating process, a continuous and defect-free SiO2 thin film with a thickness of 1 - 10 nm (preferably 2 - 5 nm) and a surface roughness of <1 nm is obtained;

[0028] (2) Electron beam damage resistance: The tolerance time of the coated thermosensitive powder under 200 keV TEM electron beam irradiation is increased to more than 5 times that of the untreated sample, and the morphology remains intact;

[0029] (3) SEM imaging optimization: At an acceleration voltage of 5 - 20 kV, the surface charge accumulation is reduced by more than 80%, and the image resolution is significantly improved;

[0030] (4) Thermal stability improvement: The thermal decomposition temperature is increased by ≥30 °C, and after storing for 30 days in an environment with a humidity of ≥75%, the integrity retention rate of the thin film is >90%, and there is no moisture absorption and caking phenomenon for the thermosensitive powder.

[0031] The beneficial effects of the present invention are as follows:

[0032] 1. Low-temperature compatibility: The atomic-level thin film coating process at 30 - 60 °C avoids the thermal decomposition of thermosensitive powder and retains its crystal structure and drug loading performance;

[0033] 2. Process efficiency: The design of the atmospheric pressure fluidized bed reactor enables continuous production, and the single-cycle time is ≤2 minutes, which is suitable for large-scale applications;

[0034] 3. Film controllability: The film thickness and density are precisely controlled through parameters such as pulse time ratio and number of cycles;

[0035] 4. Multifunctional modification: A single step simultaneously improves the radiation resistance, thermal stability, and imaging performance of thermosensitive powder, reducing the cost of drug formulation development. Description of the Drawings

[0036] Figure 1 It is a comparison diagram of SEM / TEM of lactose particles before and after low-temperature ALD coating passivation treatment;

[0037] (a) SEM image of lactose particles without low-temperature ALD coating passivation treatment;

[0038] (b) SEM image of lactose particles after SiO2 coating passivation treatment;

[0039] (c) Structure of untreated lactose particles after TEM irradiation;

[0040] (d) Morphology of coated lactose particles after TEM irradiation;

[0041] (e) Mapping graphic morphology of coated lactose particles after TEM irradiation.

[0042] Figure 2 It is a curve showing the relationship between the thickness of the SiO2 thin film and the number of atomic-level thin film coating cycles;

[0043] Figure 3 It is a comparative chart of thermogravimetric analysis (TGA);

[0044] Figure 4 It is the humidity test result of the film integrity. Specific Embodiments

[0045] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments, but the protection scope of the present invention is not limited. Unless otherwise specified, the experimental methods used in the present invention are all conventional methods, and the experimental equipment, materials, reagents, etc. used can be obtained from commercial channels.

[0046] Example 1: α-Lactose Monohydrate Surface Coating of ML001

[0047] Step 1: Pretreatment

[0048] Raw materials: α-lactose monohydrate ML001 (particle size 10 - 50 μm); Vacuum dehydration: Place the lactose particles in a vacuum drying oven and dehydrate at 60°C for 3 hours to remove surface adsorbed water and part of the crystal water; Plasma activation: Treat with oxygen plasma (power 150 W, treatment time 5 minutes) to enhance surface activity.

[0049] Step 2: Atomic-Level Coating of SiO2 Thin Film

[0050] Reactor: Atmospheric pressure fluidized bed atomic-level thin film coating reactor, with nitrogen as the fluidizing gas; Precursors: SiCl4 (pulse time 30 seconds) and H2O (pulse time 180 seconds), pulse time ratio 1:2; Purge time: 180 seconds (nitrogen purge); Number of cycles: 20 times; Deposition temperature: 50°C. Step 3: Post-treatment Annealing: In a nitrogen atmosphere, heat to 50°C at a rate of 5°C / min and hold for 20 minutes; Dispersion Observation: Ultrasonically disperse the particles in absolute ethanol for 10 minutes, drop them onto a TEM carbon support film (diameter 3.05 mm), and dry for TEM testing.

[0051] Effect Verification:

[0052] Thin film thickness: 3 nm (measured by ellipsometer), surface roughness 0.8 nm (AFM analysis). TEM test: Under a 200 keV electron beam, the tolerance time reaches 6 times that of the untreated sample (30 minutes vs. 5 minutes), Figure 1 c shows the structural collapse of the untreated lactose particles after TEM irradiation, Figure 1 d shows the complete morphology of the coated lactose particles after TEM irradiation, Figure 1e shows the complete morphology of the coated lactose particles after TEM irradiation mapping. SEM imaging: At an acceleration voltage of 15 kV, the image resolution is improved, and the surface charge accumulation is reduced by 85%. Figure 1 a is the SEM image of lactose particles without low-temperature ALD coating passivation treatment, showing blurred imaging caused by surface charge accumulation. Figure 1 b is the SEM image of lactose particles after SiO2 coating passivation treatment, showing a clear surface morphology. Thermal stability: TGA shows that the decomposition temperature is increased from 25 °C to 300 °C at a rate of 5 °C / min. The mass loss curves of untreated lactose particles and SiO2-coated lactose at a heating rate of 25 °C / min show that the thermal decomposition temperature of the coated sample is increased by ≥30 °C. By comparing the TGA curves, the enhanced effect of the SiO2 film on the thermal stability of lactose particles can be intuitively reflected: decomposition temperature delay: the decomposition start temperature of the coated lactose particles is increased from 150 °C to above 200 °C; mass loss inhibition: the mass retention rate in the range of 200 - 250 °C is increased by more than 40%; hygroscopicity improvement: the mass loss in the low-temperature section (0 - 60 °C) is reduced, indicating that the film blocks the adsorption of water molecules. ( Figure 3 ) Humidity test: After storing at 75% humidity for 30 days, the film integrity is maintained at 93%, and the particles do not agglomerate. Figure 4 )

[0053] Example 2: Anhydrous β-lactose Coating on the surface of 206

[0054] Step 1: Pretreatment

[0055] Raw materials: Anhydrous β-lactose 206 (particle size 50 - 100 μm); Vacuum dehydration: Dehydration at 60 °C for 3 hours; Plasma activation: Oxygen plasma treatment (power 150 W, treatment time 5 minutes).

[0056] Step 2: Atomic-level coating of SiO2 film

[0057] Precursors: SiCl4 (pulse time 30 s) and H2O (pulse time 180 s), pulse time ratio 1:3; Purge time: 300 s; Number of cycles: 20 times; Deposition temperature: 60 °C.

[0058] Step 3: Post-treatment

[0059] Annealing: Gradient annealing in an argon atmosphere (holding at 50 °C for 10 minutes → holding at 60 °C for 20 minutes); Dispersion observation: The same as in Example 1.

[0060] Effect verification:

[0061] Film thickness: 5 nm, surface roughness 0.5 nm; TEM tolerance time: increased to 7 times that of the untreated sample; thermal decomposition temperature: increased from 195 °C to 230 °C; humidity test: film integrity maintained at 96%, and good particle fluidity.

[0062] Example 3: Verification of Low-temperature Rapid Coating

[0063] Step 1: Pretreatment

[0064] Raw materials: α-lactose monohydrate (particle size 1 - 10 μm); vacuum dehydration: dehydrated at 50 °C for 1 hour; plasma activation: power 50 W, treatment time 10 minutes.

[0065] Step 2: Atomic-level coating of SiO2 film

[0066] Precursors: SiCl4 (pulse time 30 s) and H2O (pulse time 180 s); purge time: 300 s; number of cycles: 5 times; deposition temperature: 40 °C.

[0067] Effect verification:

[0068] Film thickness: 1 nm, surface roughness 0.9 nm; TEM tolerance time: increased to 3 times that of the untreated sample; thermal decomposition temperature: the thermal decomposition temperature of SiO2-coated lactose increased by ≥ 30 °C, and the mass loss rate in the range of 200 - 250 °C decreased by more than 40%.

[0069] The film thickness (1 - 10 nm) corresponding to different numbers of cycles (5 - 40 times) was measured by an ellipsometer to verify the thickness controllability ( Figure 2 )

[0070] Industrial application example:

[0071] The SiO2-coated lactose obtained in Example 1 was used as an excipient for ibuprofen sustained-release tablets and compared with untreated heat-sensitive powders; drug release curve: the release rate fluctuation of the formulation coated with heat-sensitive powders decreased by 15% in a pH 6.8 medium, showing more stable controlled-release performance; accelerated stability test (40 °C / 75% RH, 3 months): the formulation coated with heat-sensitive powders did not absorb moisture and caking, and the drug content retention rate was 98.5% (92.3% for the untreated group).

[0072] The above is only a specific embodiment of the present invention with relatively good creativity, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and should be covered by the protection scope of the present invention.

Claims

1. A surface treatment method for enhancing the electron beam damage resistance of thermosensitive powders, characterized in that It includes the following steps: Under the condition of 30 - 60 °C, using a silane-based precursor and an oxidant as reaction sources, a highly conformal and uniform atomic-level dense oxide film is deposited on the surface of the thermosensitive powder; by controlling the number of film deposition cycles, the thickness of the SiO2 film reaches 1 - 10 nm, and then annealing treatment and dispersion observation are carried out; the silane-based precursor is silicon tetrachloride; the oxidant includes any one of water vapor or ozone; the thermosensitive powder includes any one of α-lactose monohydrate or anhydrous β-lactose.

2. The method according to claim 1, wherein The pulse time ratio of the silane-based precursor to water vapor is 1:2 to 1:3, the purge time for a single cycle is 15 - 60 seconds, and the total number of cycles is 5 - 40 times.

3. The method according to claim 1, wherein, The thermosensitive powder also includes a pretreatment step, specifically including: placing the thermosensitive powder in a vacuum drying oven at 50 - 60 °C for dehydration for 1 - 3 hours, and then performing oxygen plasma treatment to enhance the surface adsorption activity.

4. The method according to claim 1, wherein The temperature of the annealing treatment is 30 - 60 °C, and the time is 10 - 30 minutes.

5. The method according to claim 1, characterized in that The dispersion observation specifically includes: dispersing the sample in absolute ethanol, ultrasonicating for 10 min, suspending the particles in ethanol, transferring them to a regular TEM ordinary carbon support film, and putting them into an electron microscope for observation.

6. A heat-sensitive powder with electron beam irradiation resistance, characterized in that, Prepared by using the method according to any one of claims 1 - 5.

7. Use of the thermosensitive powder with electron beam irradiation resistance according to claim 6 in the preparation of a drug carrier preparation.

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