Drug coating state online monitoring method and device

Abstract

The invention discloses a drug coating state online monitoring method and device, and the method comprises the steps: employing an optical fiber femtosecond laser as a light source core, and transmitting femtosecond laser for detection; a terahertz time-domain spectrometer is adopted as a detection instrument, and a terahertz probe of the spectrometer is fixed to the outer side of a mesh of a to-be-detected sample coating pan; the time delay of the probe light emitted by the fiber femtosecond laser is adjusted by controlling the fiber time delay line, and the signal emission and reception of the terahertz probe are synchronously controlled; the terahertz probe transmits a signal to a to-be-detected sample and converts a received terahertz return signal into an electric signal, and the electric signal is amplified by the lock-in amplifier and then transmitted to the terminal equipment; and the terminal equipment generates terahertz time-domain spectroscopic data according to the received signal, and calculates the coating thickness of the to-be-detected sample. The method and the device can solve the problems that the measurement result is lagged and the coating thickness distribution state and the uniformity cannot be detected in real time in the prior art.

Description

Technical Field

[0001] This invention relates to the field of drug preparation technology, and in particular to a method and apparatus for online monitoring of drug coating status. Background Technology

[0002] Drug coating refers to the precise application of polymer materials to the outer surface of solid dosage forms (such as tablets and pills) according to specific process specifications. After drying, this forms one or more functional protective layers that adhere tightly to the dosage form surface. This protective layer has multiple key functions: it can effectively mask unpleasant odors or irritating tastes inherent in the drug, improving patient medication adherence; it can achieve physical isolation of drug components, preventing unnecessary chemical reactions between the drug and the external environment or other components; and by controlling the composition and structure of the coating material, it can achieve controlled or sustained-release functions. In the quality control system of drug coating, coating thickness is one of the core indicators. If the coating layer thickness does not meet the design standards, an effective sustained-release barrier may not be formed, making it difficult to meet the expected drug release curve and protection requirements. It may also lead to unnecessary consumption of coating material, increasing production costs. Meanwhile, coating uniformity is also a key dimension of quality control. Insufficient coating uniformity may lead to a series of quality problems: local coating that is too thin may cause the drug to be released prematurely in the body, resulting in a "dose dumping" phenomenon and causing toxic side effects; if the local thickness of the gastric-soluble coating is insufficient, it may cause a decrease in gastric resistance and make it unable to maintain a stable form in the stomach; in terms of appearance, uneven coating may cause defects such as spots and bumps on the surface of the dosage form, affecting product recognition and patient trust; and local coating defects may also damage the stability of the drug, leading to an accelerated degradation rate of the active ingredient and shortening the product's shelf life.

[0003] In existing technologies, the detection of drug coating thickness largely relies on offline weighing, microscopic imaging, Raman spectroscopy, or near-infrared spectroscopy. Offline weighing calculates thickness by measuring the mass difference before and after coating and combining this with the density of the coating material; however, its accuracy is easily affected by factors such as the surface roughness of the dosage form and the uniformity of the coating material. Microscopic imaging requires slicing the sample and obtaining local thickness data through microscopic imaging, which is cumbersome and destructive. Raman spectroscopy is a qualitative and quantitative analysis method based on the inelastic scattering effect of molecules on incident light. It is non-destructive and rapid, and unaffected by the presence of water molecules. However, real-time online monitoring of the coating thickness or weight gain of drug formulations remains challenging when the coating layer does not contain Raman-active substances but the core contains strongly Raman-active substances. Near-infrared spectroscopy is a method for identifying and quantifying molecular structures based on the absorption characteristics of the detected molecules to electromagnetic radiation with wavelengths of 700–2500 nm. It mainly reflects the combination or overtone absorption of hydrogen-containing groups. However, due to the complexity of the coating system, real-time detection using Raman or near-infrared spectroscopy requires the establishment of a chemometric model. Since the spectrum contains not only information on coating thickness or weight gain but also background noise and other irrelevant information, it is difficult to properly process or transform the spectrum. Selecting suitable wavelength bands is a research challenge for improving the predictive power and robustness of the calibration model. Summary of the Invention

[0004] The purpose of this invention is to provide a method and apparatus for online monitoring of drug coating status. This method and apparatus can solve the problems of lagging measurement results in the prior art, which cannot detect the coating thickness distribution and uniformity in real time, and also solve the pain points of traditional technology relying on calibration models and being prone to failure.

[0005] The objective of this invention is achieved through the following technical solution: A method for online monitoring of drug coating status, the method comprising: Step 1: Use a fiber femtosecond laser as the core light source to emit femtosecond laser for detection. The output end of the fiber femtosecond laser is connected to the terahertz probe of the terahertz time-domain spectrometer through a fiber time delay line. Step 2: Use a terahertz time-domain spectrometer as the detection instrument, and fix the terahertz probe of the spectrometer to the outside of the coating pan mesh of the sample to be tested. Step 3: Adjust the time delay of the probe light emitted by the fiber femtosecond laser by controlling the fiber time delay line, and synchronously control the signal transmission and reception of the terahertz probe. Step 4: The terahertz probe transmits a signal to the sample under test and converts the received terahertz return signal into an electrical signal, which is then amplified by a lock-in amplifier and transmitted to the terminal device. Step 5: The terminal device generates terahertz time-domain spectral data based on the received signal and calculates the coating thickness of the sample to be tested.

[0006] An online monitoring device for drug coating status, the device comprising: The fiber femtosecond laser emits femtosecond laser light for detection. The output of the fiber femtosecond laser is connected to the terahertz probe of the terahertz time-domain spectrometer via a fiber optic time delay line. As a detection instrument, the terahertz time-domain spectrometer has its terahertz probe fixed to the outside of the coating pan mesh of the sample to be tested. The terahertz probe transmits a signal to the sample to be tested and converts the received terahertz return signal into an electrical signal, which is then amplified by a lock-in amplifier and transmitted to the terminal equipment. Fiber optic time delay line is used to adjust the time delay of the probe light emitted by the fiber femtosecond laser and to synchronously control the signal transmission and reception of the terahertz probe. The terminal device is used to generate terahertz time-domain spectral data based on the signal transmitted by the terahertz probe and to calculate the coating thickness of the sample to be tested.

[0007] As can be seen from the technical solutions provided by the present invention, the above-mentioned methods and devices can solve the problems of lagging measurement results in the prior art, which cannot detect the coating thickness distribution and uniformity in real time, and solve the pain points of traditional technologies that rely on calibration models and are prone to failure. Attached Figure Description

[0008] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the following description of the embodiments will be briefly introduced. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0009] Figure 1 This is a schematic flowchart of the online monitoring method for drug coating status provided in an embodiment of the present invention; Figure 2 This is a schematic diagram of the structure of the device described in an embodiment of the present invention; Figure 3 This is a schematic diagram of the coating thickness measurement results in Embodiment 1 of the present invention; Figure 4 This is a schematic diagram of the coating thickness measurement results in Embodiment 2 of the present invention. Detailed Implementation

[0010] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments, and do not constitute a limitation of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0011] like Figure 1 The diagram shown is a schematic flowchart of an online drug coating status monitoring method provided in an embodiment of the present invention. The method includes: Step 1: Use a fiber femtosecond laser as the core light source to emit femtosecond laser for detection. The output end of the fiber femtosecond laser is connected to the terahertz probe of the terahertz time-domain spectrometer through a fiber time delay line. In this step, the fiber femtosecond laser has a laser wavelength of 1569±20 nm, an output power of 80-120 mW, a pulse width of <100 fs, a repetition frequency of 80±10 MHz, a polarization extinction ratio of ≥20 dB, and an output power fluctuation of ≤1%.

[0012] Step 2: Use a terahertz time-domain spectrometer as the detection instrument, and fix the terahertz probe of the spectrometer to the outside of the coating pan mesh of the sample to be tested. In this step, the terahertz probe of the terahertz time-domain spectrometer can measure a spectral range of 0.1-4THz, a peak dynamic range ≥80 dB, an input optical power ≤30 mW, a minimum detection thickness ≤30 μm, a maximum detection thickness ≥15 mm, a thickness detection error ≤2 μm, and a lateral resolution ≤0.3 mm.

[0013] In practice, the distance between the terahertz probe and the coating pan of the sample to be tested is less than 5 mm.

[0014] Step 3: Adjust the time delay of the probe light emitted by the fiber femtosecond laser by controlling the fiber time delay line, and synchronously control the signal transmission and reception of the terahertz probe. Step 4: The terahertz probe transmits a signal to the sample under test and converts the received terahertz return signal into an electrical signal, which is then amplified by a lock-in amplifier and transmitted to the terminal device. Step 5: The terminal device generates terahertz time-domain spectral data based on the received signal and calculates the coating thickness of the sample to be tested.

[0015] In this step, the unique penetrating power of terahertz waves is utilized in conjunction with the principle of reflection-based time-of-flight imaging. Based on the time delay of the reflection signals from different interfaces within the sample, longitudinal high-resolution tomography of the sample is achieved. The formula for calculating the coating thickness of the sample to be tested is: ; The speed of light; The coating thickness of the sample to be tested; Delay for terahertz signals; denoted as the refractive index of the sample to be tested.

[0016] The terminal device used can be any device that includes an algorithm processing module, such as a computer.

[0017] In practice, the sample to be tested must have a flat and stable surface during measurement, with the ambient temperature maintained between 15-30 ℃ and the ambient humidity maintained between 20-80%. Samples monitored by a terahertz time-domain spectrometer should have a response at the 0.1-4 THz spectral position.

[0018] In addition, in specific implementation, the detection instrument has a horizontal transmission dynamic range ≥80 dB when measuring in transmission mode, an incident / reflection angle of 30-180° when measuring in reflection mode, a maximum scanning range of 150 mm*150 mm in two-dimensional plane in reflection imaging mode, and an imaging resolution of 0.3 mm.

[0019] Based on the aforementioned method, embodiments of the present invention also provide an online monitoring device for drug coating status, such as... Figure 2 The diagram shown is a structural schematic of the device according to an embodiment of the present invention. The device includes: The fiber femtosecond laser emits femtosecond laser light for detection. The output of the fiber femtosecond laser is connected to the terahertz probe of the terahertz time-domain spectrometer via a fiber optic time delay line. As a detection instrument, the terahertz time-domain spectrometer has its terahertz probe fixed to the outside of the coating pan mesh of the sample to be tested. The terahertz probe transmits a signal to the sample to be tested and converts the received terahertz return signal into an electrical signal, which is then amplified by a lock-in amplifier and transmitted to the terminal equipment. Fiber optic time delay line is used to adjust the time delay of the probe light emitted by the fiber femtosecond laser and to synchronously control the signal transmission and reception of the terahertz probe. The terminal device is used to generate terahertz time-domain spectral data based on the signal transmitted by the terahertz probe and to calculate the coating thickness of the sample to be tested.

[0020] The specific implementation process of each component in the above device is described in the method embodiment.

[0021] It is worth noting that the contents not described in detail in the embodiments of the present invention belong to the prior art known to those skilled in the art.

[0022] To facilitate verification of the technical effects of the solution provided by this invention, specific examples are given below: Example 1: Jianwei Xiaoshi tablets were used as the monitoring sample. The terahertz probe was fixed on the outside of the mesh of the coating machine for the monitoring sample. The probe distance was <5 mm. The diameter of the perforation of the coating pan was 1.3 m and the opening rate was 51%. The terahertz time-domain spectrometer had a recording rate of 120 Hz. The fiber femtosecond laser emitted a laser wavelength of 1560 nm, a laser power of 100 mW, and a laser pulse width of 80 fs.

[0023] like Figure 3 The diagram shown is a schematic representation of the coating thickness measurement results in Embodiment 1 of the present invention. Figure 3 It can be seen that the digestive tablets respond to terahertz waves of different frequencies.

[0024] Example 2: Herba Sarcandrae tablets were used as the monitoring sample. The terahertz probe was fixed on the outside of the coating machine mesh with a probe distance of <5 mm. The diameter of the coating pan perforation was 1.3 m with an opening rate of 51%. The terahertz time-domain spectrometer had a recording rate of 120 Hz. The fiber femtosecond laser emitted a laser wavelength of 1560 nm with a laser power of 100 mW and a laser pulse width of 80 fs.

[0025] like Figure 4 The diagram shown is a schematic representation of the coating thickness measurement results in Embodiment 2 of the present invention. Figure 4 It can be seen that the herb *Sarcandra glabra* tablets respond to different terahertz waves.

[0026] In practice, the distribution of coating thickness can also be output in the form of a chart.

[0027] In summary, the monitoring method described in this embodiment of the invention has the advantages of short detection time and online monitoring capability; at the same time, it has little temperature influence, maintaining an ambient temperature of 15-30 ℃; it is easy to operate, and the calculation of sample thickness does not rely on a chemometric calibration model, which can make up for the shortcomings of existing spectrometers on the market that cannot measure some samples.

[0028] Furthermore, those skilled in the art will understand that all or part of the steps in the methods of the above embodiments can be implemented by a program instructing related hardware, and the corresponding program can be stored in a computer-readable storage medium, such as a read-only memory, a disk, or an optical disk.

[0029] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims. The information disclosed in the background section is intended only to enhance the understanding of the overall background technology of the present invention and should not be construed as an admission or implication in any way that such information constitutes prior art known to those skilled in the art.

Claims

1. A method for online monitoring of drug coating status, characterized in that, The method includes: Step 1: Use a fiber femtosecond laser as the core light source to emit femtosecond laser for detection. The output end of the fiber femtosecond laser is connected to the terahertz probe of the terahertz time-domain spectrometer through a fiber time delay line. Step 2: Use a terahertz time-domain spectrometer as the detection instrument, and fix the terahertz probe of the spectrometer to the outside of the coating pan mesh of the sample to be tested. Step 3: Adjust the time delay of the probe light emitted by the fiber femtosecond laser by controlling the fiber time delay line, and synchronously control the signal transmission and reception of the terahertz probe. Step 4: The terahertz probe transmits a signal to the sample under test and converts the received terahertz return signal into an electrical signal, which is then amplified by a lock-in amplifier and transmitted to the terminal device. Step 5: The terminal device generates terahertz time-domain spectral data based on the received signal and calculates the coating thickness of the sample to be tested.

2. The method for online monitoring of drug coating status according to claim 1, characterized in that, In step 5, specifically, longitudinal high-resolution tomography of the sample is achieved based on the time delay of the reflection signals of the terahertz signal at different interfaces within the sample, wherein: The formula for calculating the coating thickness of the sample to be tested is: ； The speed of light; The coating thickness of the sample to be tested; Delay for terahertz signals; denoted as the refractive index of the sample to be tested.

3. The method for online monitoring of drug coating status according to claim 1, characterized in that, In step 1, the fiber femtosecond laser has a laser wavelength of 1569±20 nm, an output power of 80-120 mW, a pulse width of <100 fs, a repetition frequency of 80±10 MHz, a polarization extinction ratio of ≥20 dB, and an output power fluctuation of ≤1%.

4. The method for online monitoring of drug coating status according to claim 1, characterized in that, In step 2, the terahertz probe of the terahertz time-domain spectrometer can measure a spectral range of 0.1-4 THz, a peak dynamic range ≥80 dB, an input optical power ≤30 mW, a minimum detection thickness ≤30 μm, a maximum detection thickness ≥15 mm, a thickness detection error ≤2 μm, and a lateral resolution ≤0.3 mm.

5. The method for online monitoring of drug coating status according to claim 1, characterized in that, In step 2, the distance between the terahertz probe and the coating pan of the sample to be tested is <5 mm.

6. The method for online monitoring of drug coating status according to claim 1, characterized in that, The sample to be tested must have a flat and stable surface during measurement, with the ambient temperature maintained between 15-30 ℃ and the ambient humidity maintained between 20-80%. Samples monitored by a terahertz time-domain spectrometer should have a response at the 0.1-4 THz spectral position.

7. An online monitoring device for drug coating status, characterized in that, The device includes: The fiber femtosecond laser emits femtosecond laser light for detection. The output of the fiber femtosecond laser is connected to the terahertz probe of the terahertz time-domain spectrometer via a fiber optic time delay line. As a detection instrument, the terahertz time-domain spectrometer has its terahertz probe fixed to the outside of the coating pan mesh of the sample to be tested. The terahertz probe transmits a signal to the sample to be tested and converts the received terahertz return signal into an electrical signal, which is then amplified by a lock-in amplifier and transmitted to the terminal equipment. Fiber optic time delay line is used to adjust the time delay of the probe light emitted by the fiber femtosecond laser and to synchronously control the signal transmission and reception of the terahertz probe. The terminal device is used to generate terahertz time-domain spectral data based on the signal transmitted by the terahertz probe and to calculate the coating thickness of the sample to be tested.

Images